Methods for preparing compositions of cyclooxygenase-2 (COX-2) inhibitors

Abstract

The present disclosure relates to a method for making a composition of a cyclooxygenase-2 (COX-2) inhibitor that includes a water-soluble excipient, HPMC, an organic acid, and one or more other ingredients. The composition may be in the form of a pellet, tablet, capsule, or granule in which the API is highly soluble or capable of rapid disintegration in aqueous media. In some embodiments, the composition further includes a carbonate salt to form a weak effervescent disintegration formulation.

Description

[Technical field]

[0001] The present invention relates broadly to pharmaceutical formulations and compositions, their methods of manufacture and use, and more specifically to the preparation of pharmaceutical formulations and compositions comprising an active ingredient and an organic acid having improved solubility.

[0002] CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to Australian Provisional Application No. 2022900898, which is incorporated herein by reference in its entirety. [Background technology]

[0003] To be absorbed, a drug must be present in the form of a solution at the site of absorption. Various techniques are used to improve the solubility of drugs, including physical and chemical drug modification, particle size reduction, crystal engineering, salt formation, solid dispersions, and use of surfactants. Oral bioavailability depends on multiple factors, including aqueous solubility, drug permeability, dissolution rate, first-pass metabolism, and pre-metabolism. The most common cause of poor oral bioavailability is attributed to poor solubility and permeability. The term "soluble" is sometimes used for materials that form colloidal suspensions of very fine solid particles in liquids.

[0004] It is estimated that roughly 50% of people have difficulty swallowing tablets and capsules, which has a significant impact on adherence to medication. In other cases, many patients do not have water or alternative fluids on hand when taking tablets or capsules. Orally disintegrating tablets (ODTs) and dispersible tablets allow patients to place the tablet on or under the tongue, facilitating the administration of medication without the need for drinking water or other fluids.

[0005] Poorly water-soluble drugs require high doses to reach therapeutic plasma concentrations after oral administration.

[0006] These poorly water soluble drugs result in slow drug absorption, leading to inadequate and variable bioavailability and gastrointestinal mucosal toxicity.For orally administered drugs, solubility is the most important rate-limiting parameter for achieving desired blood concentrations.

[0007] Drug solubility is often related to the size of the drug particle: as the particles get smaller, the surface area to volume ratio increases. Larger surface area increases interactions with the solvent, increasing solubility.

[0008] Celecoxib (CEL) and imrecoxib are selective cyclooxygenase-2 (COX-2) inhibitors therapeutically indicated for the treatment of rheumatoid arthritis, osteoarthritis, acute pain, and inflammation. Celecoxib is a white or nearly white, crystalline or amorphous powder, hydrophilic (log P of 3.0) and practically insoluble in water. However, its low solubility and dissolution rate hinder its absorption in the intestine, resulting in the need to administer large amounts of celecoxib, but its low bioavailability leaves a lot of unabsorbed celecoxib in the gastrointestinal tract, causing many gastrointestinal side effects such as gastric ulcers, gastric erosion, bleeding, or gastric perforation.

[0009] The strength of celecoxib available on the market is 200 mg per capsule, with twice-daily dosing as needed. If celecoxib were in tablet form, it would have a lower drug release or dissolution rate than capsules and would not be able to maintain adequate blood levels. Therefore, celecoxib in the traditional market is a capsule, but the production rate of capsules is slower than tablets, and the production cost of capsules is higher than tablets. Currently, there are no celecoxib tablets on the market.

[0010] Imurecoxib is similar to celecoxib (CEL) and is a selective cyclooxygenase-2 (COX-2) inhibitor indicated for the treatment of rheumatoid arthritis, osteoarthritis, acute pain, and inflammation. Imurecoxib is a white or almost white, crystalline or amorphous powder that is hydrophilic and practically insoluble in water. Imurecoxib may cause side effects similar to those of celecoxib.

[0011] Calcium carbonate is another poorly soluble drug. It appears as a white, odorless powder or colorless crystals. Calcium carbonate has very low solubility in pure water (15 mg / L at 25°C). Calcium carbonate is a calcium supplement for the prevention and treatment of osteoporosis. On the market, for example, there are tablets of USP 1250 mg. Such tablets are used to treat calcium deficiency. The recommended dose for adults is 0.5-4 g per day, taken in divided doses three times a day.

[0012] In the body, calcium is a mineral that makes up bones, dissolves in the blood, and regulates bodily functions. The normal range of blood calcium levels is 8.5 to 10.3 mg / dL. In a person weighing 70 kg, the blood volume is approximately 5-6 liters. The total amount of calcium ions in the blood is less than 630 mg. For 4 g of calcium carbonate, the amount of calcium ions is 1600 mg. Apparently, 90% of ingested calcium carbonate is wasted and excreted through the large intestine, which may cause constipation.

[0013] Providing new formulations of water-insoluble APIs with new high solubility may reduce the dosage of water-insoluble drugs and their side effects. There is an unmet need for high dissolution rates for celecoxib, imrecokib, and calcium carbonate.

[0014] For poorly water-soluble APIs or large-volume drugs, such as 1500 mg calcium carbonate tablets or 400 mg celecoxib tablets, the amount of alimentary fluid required for drug disintegration is so large that the disintegration time is excessively long and the absorption window in alimentary systems is narrow. It is desirable to speed up drug disintegration by adding an extender to the formulation to significantly reduce the drug disintegration time to about 1 to 3 minutes and to increase the particle and powder surface area to increase interaction with water and increase drug dissolution and absorption. Orally disintegrating and dispersible tablets allow the patient to place the tablet on or under the tongue and administer the drug without needing to drink water or other liquids to aid swallowing.

[0015] The term "orally dispersible tablets" is the term used by the European Pharmacopoeia to refer to tablets that disperse quickly in the mouth before being swallowed. The term "orally disintegrating tablets" or ODTs is the term used by the European Pharmacopoeia and the United States Pharmacopoeia (USP) to refer to tablets that disintegrate in the mouth within one minute. The testing equipment for the disintegration time of these two types of tablets is the same.

[0016] OODTs are formulated with the goal of improving the disintegration of the formulation and facilitating the administration of the drug via the oral cavity. To achieve a rapid disintegration rate, a suitable tablet formulation should provide high porosity, low density, and low hardness. This type of dosage form is often chosen by patients who have difficulty swallowing and is also suitable for geriatric and pediatric patients, or patients who have difficulty swallowing or are bedridden and do not have easy access to water or other liquids.

[0017] Dosage forms that disintegrate in the presence of trace amounts of water may have one or more advantages, such as stability, accurate dosing, ease of manufacture, small package size, and easy handling by the patient. Orally disintegrating dosage forms, including those with weak effervescent orally disintegrating tablet formulations, may also be beneficial in minimizing or preventing the risk of obstruction of the digestive tract, and may be particularly beneficial for patients who do not have easy access to water or other liquids, and may be easier to administer to pediatric patients, elderly patients, patients with mental or cognitive disorders, and psychiatric patients. Other advantages of orally disintegrating dosage forms include reducing or preventing the risk of choking due to a tablet getting stuck in the airway, and may also reduce or prevent the risk of choking if a tablet gets stuck in the esophagus. For example, if an orally disintegrating tablet or ODT gets stuck in a patient's airway or esophagus, an advantage of the tablet according to the present invention is that it will partially disintegrate within one or even three minutes, allowing the patient to restore breathing. Fast dissolution and fast absorption of the drug may provide a rapid onset of action.

[0018] Dispersible tablets typically disintegrate in water within about three minutes and are commonly administered in two ways: (1) by dispersing the dosage form in an aqueous solution (such as water, juice, etc.) and then taking the resulting suspension or solution by mouth, or (2) by placing the dispersible dosage form in the mouth without the need for drinking water or other liquids.

[0019] Dispersible tablets can be manufactured by well-known techniques such as compressing particles containing large amounts of physically disintegrating expanders such as cross-linked povidone or cross-linked sodium carboxymethylcellulose. Typically, the amount of expander can be 50% or more of the total tablet weight.

[0020] Various processes can be adopted to produce ODTs using lyophilization, molding, cotton candy process, spray drying, mass extrusion, compaction, and other well-known techniques. The disadvantage of the lyophilization process is that it requires expensive equipment and is complicated compared to normal manufacturing processes. A further disadvantage is that ODTs prepared by the lyophilization process also require special packaging materials.

[0021] Orally disintegrating or dispersible tablets are particularly needed for larger tablets, for example to aid administration and prevent or reduce the risk of choking. There is also a demand for ODTs that disintegrate with very little water and disintegrate quickly in the mouth for administering drugs to paediatric and elderly patients.

[0022] Other advantages offered by orally disintegrating tablets are that the ability to take the medication without water may eliminate or reduce issues with adherence to medication. Also, the bioavailability of drugs delivered as orally disintegrating tablets or ODTs may be higher than alternative dosage forms, potentially reducing side effects due to first-pass metabolism.

[0023] Rapidly disintegrating tablets, or also known as fast-disintegrating preparations, offer advantages over alternative forms such as effervescent tablets, suspensions, chewing gums and chewable tablets in order to improve patient compliance.

[0024] Orally disintegrating tablets are particularly useful in one or more of several typical scenarios: 1. Emergency medications that are absorbed through the oral mucosa, such as nitroglycerin and nifedipine. 2. Medications for patients with swallowing disorders (e.g., esophageal cancer patients). 3. Antinausea drugs, such as ondansetron, ramosetron, granisetron, and metoclopramide. 4. Patients with cognitive impairment or non-compliance with medications, such as antidepressants and antipsychotics. 5. Medication for children, elderly, and bedridden patients who do not have easy access to water or other fluids. 6. Emergencies such as stroke, angina, and myocardial infarction.

[0025] A challenge in developing a rapidly disintegrating tablet is the requirement for good physical and disintegration properties. Currently, disintegration tests for orally disintegrating tablets are not specified in the United States Pharmacopeia (USP) and European Pharmacopeia, and test results for dispersible tablets only approximate the actual disintegration time of the ODT in the oral cavity.

[0026] The manufacturing methods for rapidly disintegrating tablets include freeze-drying, spray-drying, wet granulation, dry granulation, direct compression, etc. Each of these common processes has processing disadvantages. For example, although ODTs made by freeze-drying comply with the Chinese Pharmacopoeia (CP), the freeze-drying equipment is expensive, and the manufacturing process is time-consuming and complicated. ODTs produced by freeze-drying have unacceptable fragility (more than 1%) and low tablet weight. In addition, a particular disadvantage is that freeze-drying cannot produce ODTs with more than 50 mg of active ingredient (API). .

[0027] The evaluation method for orally disintegrating tablets is specified in the Chinese Pharmacopoeia (CP), which limits the vertical movement of the stainless steel tube containing the ODT to within 10 mm ± 1 mm. Many orally disintegrating tablets on the US market do not comply with the Chinese Pharmacopoeia, except for ODTs manufactured by freeze-drying.

[0028] Examples of ODTs manufactured using conventional excipients include APIs selected from acetaminophen, rofecoxib, tramadol, diphenhydramine, domperidone, zolmitriptan, cetirizine, zolpidem tartrate, ibuprofen, etc. Examples of ODTs manufactured by freeze-drying methods known in the art include APIs selected from ondansetron, ramosetron, granisetron, loratadine, piroxicam, benzoic acid, famotidine, olanzapine, risperidone, tiposarine, selegiline, clonazepam, and loperamide hydrochloride.

[0029] A typical composition of a lyophilized ODT includes the API, matrix, and other excipients. After lyophilization, the preparation has a certain shape and strength. The key step to make the lyophilized tablet loose and porous as required for an ODT is the quick freezing. To distribute the API evenly within the suspension before lyophilization, long chain polymeric substances such as polypeptides (with gelatin or dehydrated gelatin), polysaccharides (dextran, mannitol, starch, etc.), gums (with gum arabic, xanthan gum), fibrinogen, alginic acid, PVP, polyvinyl alcohol, etc. may be added. Other excipients may be added depending on the specific composition desired. Wetting agents (ethanol), pigments (iron oxide), preservatives, antioxidants, flavors, etc. may also be included.

[0030] The principle of ODT production by freeze-drying is to make API into a suspension, then freeze it rapidly to a solid, and then remove water by sublimation under vacuum from the frozen state. Therefore, the API must be insoluble in water. Therefore, this method is not suitable for water-soluble APIs, and after water sublimation, the solution becomes amorphous powder and cannot form tablets. From the results, freeze-dried products are generally loose and porous, and can quickly absorb water and collapse.

[0031] The US Food and Drug Administration (FDA) has also found that the disintegration times of these products range from a few seconds to over a minute, but most have a disintegration time of around 30 seconds or less. This means that different manufacturing techniques, different sizes and weights of tablets, different volumes of disintegration fluid, and different disintegration mechanisms will result in different disintegration times. Other parameters that need to be considered in developing an appropriate ODT and manufacturing method include tablet size, tablet weight, API solubility, and the impact of these factors on the development objectives of such products. Furthermore, the preferred tablet weight recommended by the FDA is 500 mg or less.

[0032] There remains a demand for ODTs that can be produced on an industrial scale in a simple manner using common excipients at low cost, preferably in accordance with the Chinese Pharmacopoeia (CP).

[0033] For water-soluble APIs, the faster the disintegration in the stomach, the better the absorption by the patient. However, this has not been found to be the case for water-insoluble APIs such as celecoxib, imrecoxib, and calcium carbonate. Therefore, new formulations with higher dissolution or dissociation are needed to reduce alluratory side effects for the market.

[0034] Celecoxib is a weakly acidic compound and does not dissociate easily in gastric juice, so the HCl in gastric juice inhibits the dissociation of weak acids in water by the common ion effect, which reduces the absorption of celecoxib.

[0035] For celecoxib capsules on the market, the time to reach Cmax is 3 hours, but the Cmax is very low at about 700 ng / mL. For a 60 kg woman with a blood volume of 5000 mL, the total amount of celecoxib in the blood at Cmax is only 3.5 mg, which is only 1.75% of the ingested drug (200 mg capsule). Most of the ingested celecoxib is not absorbed and acts as a toxicant in the intestine, which may cause side effects.

[0036] There are no micronized celecoxib tablets or capsules on the market. There are no products with a higher dissolution rate than celecoxib from other manufacturers. The new compositions are expected to have a higher solubility of celecoxib, and therefore the new compositions may have less API per dose. The new compositions will be as follows: celecoxib 160 mg per composition, celecoxib 150 mg per composition, celecoxib 140 mg per composition, celecoxib 130 mg per composition, and each of these compositions has bioequivalence to the original manufacturer's 200 mg celecoxib capsules, and the intestinal side effects of the present invention are much lower compared to the original manufacturer's 200 mg celecoxib capsules, while the effects remain almost the same. The formulation form of the composition may be in the form of particles, tablets, or capsules. . Summary of the Invention [Means for solving the problem]

[0037] The present invention relates broadly to pharmaceutical formulations and methods of use. More specifically, the present invention relates to pharmaceutical formulations comprising an active ingredient and an organic acid having improved solubility properties.

[0038] An embodiment of the present invention relates to a method of manufacturing a composition of COX-2 (cyclooxygenase-2) inhibitors, including celecoxib and imrecoxib, comprising a water-soluble excipient consisting of HPMC (hydroxypropyl methylcellulose) and an organic acid. In some circumstances, the composition further comprises a carbonate salt to form a weakly effervescent disintegration formulation.

[0039] The selective cyclooxygenase-2 (COX-2) inhibitor composition includes celecoxib or imrecoxib, an organic acid selected from the group consisting of ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, or mixtures thereof. The composition may further include a lubricant of cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, and magnesium stearate, and mixtures thereof. The composition may be in the form of a tablet, granule, capsule, dispersible tablet, or orally disintegrating tablet.

[0040] Another selective cyclooxygenase-2 (COX-2) inhibitor composition includes celecoxib, hydroxypropyl methylcellulose (HPMC E5), and pellets made from sugar or mannitol. This formulation may be in the form of a capsule or pellets.

[0041] Another selective cyclooxygenase-2 (COX-2) inhibitor formulation contains imrecoxib, HPMC E5, and pellets made from sugar or mannitol. This formulation may be in the form of a capsule or a bag of pellets.

[0042] Another composition includes celecoxib, an organic acid selected from malic acid, maleic acid, succinic acid, ascorbic acid, tartaric acid, citric acid, or mixtures thereof, and calcium carbonate. The composition further includes cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, and magnesium stearate, or mixtures thereof. The composition may be in the form of a tablet, granule, capsule, dispersible tablet, or orally disintegrating tablet. The composition increases the solubility of both calcium ions and celecoxib in water. The combination of calcium carbonate, celecoxib, and the organic acid reduces the amount of calcium carbonate required.

[0043] Another composition of the invention includes imrecoxib and an organic acid selected from malic acid, maleic acid, succinic acid, ascorbic acid, tartaric acid, citric acid, or mixtures thereof, and further includes cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, or mixtures thereof. The composition may be in tablet, granule, or capsule form.

[0044] Another composition of the present invention includes imrecoxib, calcium carbonate, an organic acid selected from malic acid, maleic acid, succinic acid, ascorbic acid, tartaric acid, citric acid, or mixtures thereof, and further includes cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, or mixtures thereof. The composition may be in tablet, granule, or capsule form.

[0045] Another composition of the present invention includes calcium carbonate and an organic acid selected from malic acid, maleic acid, succinic acid, ascorbic acid, tartaric acid, citric acid, or mixtures thereof, and further includes cross-linked povidone, microcrystalline cellulose, magnesium stearate, and mixtures thereof. The composition may be in the form of a tablet, granule, capsule, orally disintegrating, mildly effervescent tablet, or dispersible tablet. t.

[0046] The dissociation rate of commercially available calcium carbonate preparations is 100% in 200 mL of gastric acid, but only about 1.3% in 900 mL of neutral pure water. In general, human males do not have excess gastric juice in their stomachs, so the digestion of calcium carbonate in men is very limited.

[0047] The dissociation rate of calcium ions in calcium carbonate tablets ranges from 45% to 75% when a small amount of weak acid is included, the pH of the solution after dissolution is 4.9 or more in 200 mL of neutral pure water, and the molar ratio of calcium carbonate to the two acids is in the range of 0.35:1 to 1:1. The dissociation rate of calcium ions ranges from 24% to 75% when the molar ratio of calcium carbonate to the two acids is in the range of 0.15:1 to 1:1. The weak acid is selected from ascorbic acid, malic acid, maleic acid, ascorbic acid, and tartaric acid, and the amount of weak acid is limited to a range such that the pH of the final dissociation solution is 4.9 or more.

[0048] Other demands require calcium carbonate ODTs, dispersible tablets, or tablets with an amount of organic acid to form a highly dissociated composition with a pH of 4.9 or higher after dissociation in neutral pure water. Thus, the calcium carbonate dose may be less than 150 mg, less than 100 mg, less than 75 mg, or less than 40 mg, but the calcium ions absorbed are much higher than in a typical 1500 mg tablet.

[0049] The dissociation of calcium ions in commercially available calcium carbonate tablets was only 1.4% in 900 mL of neutral pure water. We know that the concentration of calcium ions in human blood is about 9.2 mg / dL or 92 mg per liter. A 70 kg human has about 5.5 liters of blood, and the total amount of calcium ions in the blood is about 500 mg.

[0050] In an adult human, the body stores 1-2 kilograms of calcium ions (average is 1100 g), 99% of which is in the bones, which act as large storage containers. Only 1% is in the plasma and about 0.1% in the extracellular fluid.

[0051] The dosage of calcium carbonate tablets available on the market is 1500 mg. If calcium is absorbed 100%, the amount of ions absorbed is 1200 mg, which is twice the total amount of calcium ions in the blood of the human body. Obviously, more than 90% of calcium is not absorbed and remains in the large intestine, causing constipation. The invention of calcium carbonate tablets with high dissociation composition is needed. This special composition has a dissociation rate of 24% to 75%, depending on the relative amount of acid to the amount of calcium carbonate contained, which allows the intake of calcium carbonate to be reduced to 75 mg per day, but still provides sufficient calcium to the human body without causing the side effects of large amounts of calcium carbonate such as constipation, burping, and difficulty in swallowing. The gentle high dissociation of the calcium carbonate tablets of the invention may prevent the occurrence of a burning sensation in the mouth when the formulation is in the form of an orally disintegrating tablet.

[0052] The selective cyclooxygenase-2 (COX-2) inhibitor composition comprises celecoxib, imrecoxib, an organic acid selected from the group consisting of ascorbic acid, malic acid, maleic acid, ascorbic acid, tartaric acid, and citric acid, and hydroxypropylmethylcellulose (HPMC E5). The composition further comprises cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and mixtures thereof. The composition may be in the form of tablets, granules, or capsules.

[0053] Another composition of selective cyclooxygenase-2 (COX-2) inhibitors includes pellets made of celecoxib, HPMC E5 (hydroxypropyl methylcellulose), and sugar or mannitol. This composition is produced by dissolving 1 part of celecoxib and 1 to 2 parts of HPMC E5 in 10-15 parts of 95% ethanol. The alcohol solution containing celecoxib and HPMC E5 in ethanol is spread on a fluidized bed containing 1 to 2 parts of sugar pellets. After the sugar pellets are covered with multiple coating layers of celecoxib and HPMC E5 in ethanol, the pellets become larger and larger. The strength of celecoxib per capsule is 65 mg to 160 mg, and the dissolution rate of celecoxib is more than 60% in a dissolution test at 50 RPM after 180 minutes in an environment containing 2.5 g of sodium dodecyl sulfate in 1000 mL of neutral pure water.

[0054] Another composition of selective cyclooxygenase-2 (COX-2) inhibitor contains pellets made of imrecoxib, HPMC E5 (hydroxypropylmethylcellulose) and sugar or mannitol. This composition is manufactured by dissolving 1 part of imrecoxib and 1 to 2 parts of HPMC E5 in 10-15 parts of 95% ethanol. The ethanol solution of imrecoxib and HPMC E5 is spread on a fluidized bed containing 1 to 2 parts of sugar pellets. The sugar pellets become larger and larger after multiple coating layers with the imrecoxib and HPMC E5 ethanol solution. The strength of imrecoxib per capsule is 40 mg to 80 mg and has a dissolution rate of imrecoxib of 60% or more after 180 minutes at 50 RPM in an environment containing 2.5 g of sodium dodecyl sulfate in 1000 mL of neutral pure water.

[0055] In one aspect of the invention, the weak effervescent disintegration formulation comprises a weak acid-base pair. The weak acid is selected from monosodium salts of binary acids, monopotassium salts of binary acids, monosodium salts of ternary acids, monopotassium salts of ternary acids, ascorbic acid, a small amount of a binary acid, and the weak base is selected from calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate. And the API, the composition disintegrates in neutral pure water and has a pH of 4.9 or greater.

[0056] In examples, weak effervescent disintegration formulations may be in the form of immediate release tablets, orally disintegrating tablets, dispersible tablets, sublingual tablets, or granules. The weight of the tablet determines the disintegration time and therefore whether it is an ODT or dispersible tablet.

[0057] In an embodiment, the weak acid may be selected from ascorbic acid, monosodium malic acid, monosodium maleic acid, monosodium succinic acid, monosodium adipic acid, monosodium oxalic acid, monosodium citric acid, monosodium tartaric acid, monosodium fumaric acid, monopotassium malic acid, monopotassium maleic acid, monopotassium succinic acid, monopotassium adipic acid, monopotassium oxalic acid, monopotassium citric acid, monopotassium tartaric acid, monopotassium fumaric acid, small amounts of binary acids and mixtures thereof.

[0058] In an embodiment, a weak effervescent disintegration formulation may contain only one weak acid.

[0059] In an embodiment, the binary acid may be selected from tartaric acid, malic acid, maleic acid, adipic acid, fumaric acid, succinic acid, and ascorbic acid.

[0060] In an embodiment, the weak acid is a binary acid selected from maleic acid, maleic acid, succinic acid, adipic acid, fumaric acid, and tartaric acid, and the weak base is calcium carbonate, and the molar ratio of binary acid to calcium carbonate may be less than 1. And the dissolution of calcium ions is in the range of 10% to 75% under agitation of 75 RPM in 900 mL of neutral pure water during 30 minutes measurement.

[0061] In the examples, the weak acid is ascorbic acid and the weak base is calcium carbonate alone, the weight ratio of ascorbic acid to calcium carbonate ranges from 1.0:1.0 to 4.0:1.0, and the dissolution of calcium ions ranges from 10% to 65% under agitation of 75 RPM in 900 mL of neutral pure water during a 30 minute measurement.

[0062] In an embodiment, the weak effervescent disintegration formulation may further include one or more excipients selected from a filler, a swelling agent, and a lubricant. The swelling agent may be selected from cross-linked povidone and cross-linked sodium carboxymethyl cellulose. The lubricant may be selected from magnesium stearate, PEG 6000, colloidal silicate, and mixtures thereof. In example embodiments, the API may be selected from vitamins, minerals, food nutrients, triptan drugs, 5-HT3 antagonist anti-nausea drugs, dihydropyridine calcium channel antagonists, antihistamines, sartans, alpha-glucosidase inhibitors, antifibrinoline drugs, serotonin reuptake inhibitors, atypical antidepressants, selective COX-2 inhibitors, NSAIDs, hormonal contraceptives, and antiepileptic drugs.

[0063] In a preferred embodiment, the weak base is calcium carbonate.

[0064] In an embodiment, a weak effervescent disintegration formulation may consist of ascorbic acid, malic acid, and calcium carbonate.

[0065] Other compositions include calcium carbonate, glucosamine hydrochloride, cross-linked povidone, cross-linked soda carboxymethyl cellulose, microcrystalline cellulose, magnesium stearate, and mixtures thereof, and the compositions have calcium ion solubility of 37% to 55% and a final pH of disintegration in the range of 6.6 to 7.0.

[0066] The weakly effervescent disintegrating formulation consists of sodium bicarbonate, glucosamine sulfate, cross-linked povidone, magnesium stearate, and PVPK30; the formulation is in the form of granules or dispersible tablets and has a pH range of 6.5 to 7.5 in 200 mL of neutral water.

[0067] Another example of a weakly effervescent disintegrating formulation contains 500 mg of glucosamine hydrochloride, 200 mg of sodium bicarbonate, 200 mg of cross-linked povidone, and magnesium stearate in the form of granules or dispersible tablets with a pH in the range of 6.5 to 7.5 in 200 mL of neutral water.

[0068] The composition of celecoxib includes celecoxib and one or more organic acids selected from ascorbic acid, malic acid, maleic acid, meleic acid, succinic acid, citric acid, cross-linked soda carboxymethyl cellulose, cross-linked povidone, microcrystalline cellulose, magnesium stearate, and mixtures thereof, and the formulation is in the form of granules, capsules, tablets, or dispersible tablets.

[0069] Another composition of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib includes pellets made of celecoxib, HPMC E5, and sugar or mannitol. This composition is created by dissolving 1 part celecoxib and 1 to 2 parts HPMC E5 in 10-15 parts absolute ethanol. The alcoholic solution of celecoxib and HPMC E5 is sprayed into a fluidized bed containing 1 to 2 parts sugar pellets. The coating of the pellets increases the diameter of the pellets until they reach the appropriate size. The solubility of the 160 mg celecoxib pellets of the invention is in 1000 mL of sodium phosphate buffer 0.25% sodium dodecyl sulfate at pH 7 dissolves more than 60% of the celecoxib at 50 RPM for 180 minutes after dissolution testing; this formulation is in the form of capsules or pellets.

[0070] Another composition of selective cyclooxygenase-2 (COX-2) inhibitors includes pellets made of imrecoxib, HPMC E5, and sugar or mannitol. This composition is created by dissolving 1 part imrecoxib and 1 to 2 parts HPMC E5 in 10-15 parts absolute ethanol. The alcohol solution of imrecoxib and HPMC E5 is sprayed into a fluidized bed containing 1 to 2 parts sugar pellets. The solubility of the 80 mg imrecoxib pellets of the invention is such that in 1000 mL of sodium phosphate buffer, pH 7, 0.25% sodium dodecyl sulfate, more than 60% of the imrecoxib dissolves at 50 RPM for 180 minutes after dissolution testing; this formulation is in the form of capsules or pellets.

[0071] Another composition of imrecoxib includes one or more organic acids selected from ascorbic acid, malic acid, maleic acid, meleic acid, succinic acid, citric acid, cross-linked soda carboxymethyl cellulose, cross-linked povidone, microcrystalline cellulose, magnesium stearate, and mixtures thereof, and the formulation is in the form of granules, capsules, tablets, or dispersible tablets.

[0072] Another composition of the invention comprises celecoxib, ascorbic acid, cross-linked povidone, cross-linked soda carboxymethyl cellulose, microcrystalline cellulose, magnesium stearate, and mixtures thereof, the formulation being in the form of granules, capsules, tablets, or dispersible tablets, and the ratio of ascorbic acid to celecoxib is 1:1 to 6:1 by weight.

[0073] Another composition of the invention comprises celecoxib, malic acid, cross-linked povidone, cross-linked soda carboxymethyl cellulose, microcrystalline cellulose, magnesium stearate, and mixtures thereof, the formulation being in the form of granules, capsules, tablets, or dispersible tablets, and the ratio of malic acid to celecoxib is 1:1 to 6:1 by weight.

[0074] Another composition of the invention comprises celecoxib, meleic acid, cross-linked povidone, cross-linked soda carboxymethyl cellulose, microcrystalline cellulose, magnesium stearate, and mixtures thereof, the formulation being in the form of granules, capsules, tablets, or dispersible tablets, and the ratio of meleic acid to celecoxib is 1:1 to 6:1 by weight.

[0075] Another composition of the invention comprises celecoxib, succinic acid, cross-linked povidone, cross-linked soda carboxymethyl cellulose, magnesium stearate, and mixtures thereof, the formulation being in the form of granules, capsules, tablets, or dispersible tablets, and the ratio of succinic acid to celecoxib is 1:1 to 6:1 by weight.

[0076] Another composition of the invention comprises celecoxib, citrus acid, cross-linked povidone, cross-linked soda carboxymethyl cellulose, magnesium stearate, and mixtures thereof, the formulation being in the form of granules, capsules, tablets, or dispersible tablets, and the ratio of citrus acid to celecoxib is 1:1 to 6:1 by weight.

[0077] Another composition of the invention comprises celecoxib, citric acid, cross-linked povidone, cross-linked soda carboxymethyl cellulose, magnesium stearate, and mixtures thereof, the formulation being in the form of granules, capsules, tablets, or dispersible tablets, and the ratio of citric acid to celecoxib is 1:1 to 6:1 by weight.

[0078] The composition of the inventive 160 mg celecoxib tablet has a solubility of approximately 125 mg celecoxib in 1000 mL of pH 7 sodium phosphate buffer solution containing 0.25% sodium lauryl sulfate at 120 minutes after dissolution testing at a stirring speed of 50 RPM. This is approximately the same as the dissolution of a 200 mg strength CELEBREX (celecoxib) capsule in the same isolation environment and conditions. In other words, one inventive 160 mg celecoxib tablet is equivalent to a drug substance producer's 200 mg CELEBREX capsule in vitro.

[0079] The celecoxib or imrecoxib compositions of the invention are prepared from an alcoholic solution as follows: 1. Place 1 part celecoxib powder into a tank containing 12-20 parts ethanol or benzyl alcohol. 2. Dissolve in a tank containing alcohol and celecoxib, containing 1 to 6 parts of an organic acid selected from marinic acid, ascorbic acid, meleic acid, succinic acid, tartaric acid, citric acid or a mixture thereof. 3. In the fluid bed, about 1 part of cross-linked carboxymethyl soda cellulose (croscarmellose sodium), 1 part of cross-linked povidone, 0.1 part of sodium lauryl sulfate, and some excipients such as microcrystalline cellulose are placed, and then an alcoholic solution of celecoxib and an organic acid is sprayed onto the fluid bed. Then, an aqueous solution of povidone, which acts as a binder, is sprayed onto the fluid bed. The resulting granules are mixed with magnesium stearate and then compressed into tablets or filled into capsules or granule bags.

[0080] The ratio of organic acid to COX-2 inhibitors, including celecoxib or imrecoxib, is 1:1 to 6:1 by weight. In one formulation, the ratio of organic acid to celecoxib or imrecoxib is 1:1 by weight. In another formulation, the ratio of organic acid to celecoxib or imrecoxib is 2:1 by weight. In another formulation, the ratio of organic acid to celecoxib or imrecoxib is 3:1 by weight. In another formulation, the ratio of organic acid to celecoxib or imrecoxib is 4:1 by weight. In another formulation, the ratio of organic acid to celecoxib or imrecoxib is 5:1 by weight. In another formulation, the ratio of organic acid to celecoxib or imrecoxib is 6:1 by weight. The organic acid is selected from ascorbic acid, malic acid, maleic acid, succinic acid, oenothermic acid, citric acid, or mixtures thereof.

[0081] After the inventive celecoxib composition is dissolved in an aqueous solution, the solubility of the celecoxib tablet is much higher than that of commercially available celecoxib capsules of the same strength, which results in increased absorption in alimentary systems and reduced side effects compared to commercially available celecoxib capsules of the same strength.

[0082] Celecoxib can be used to relieve joint pain. Many cases of joint pain in patients are due to calcium deficiency. A combination formulation of celecoxib and calcium carbonate may reduce the amount of celecoxib needed to relieve joint pain, but the amount of calcium carbonate ingested is very high and the dissociation of calcium carbonate in neutral pure water is low, about 1.4%.

[0083] A composition containing celecoxib, calcium carbonate, and one organic acid has a better therapeutic effect than a combination of celecoxib and calcium carbonate. This is because the organic acid breaks down calcium carbonate in water into CO2 and calcium ions, which are easier to absorb than using calcium carbonate tablets alone. The organic acid is selected from ascorbic acid, malic acid, maleic acid, succinic acid, oenothermic acid, citric acid, or a mixture thereof.

[0084] In an embodiment of a composition comprising celecoxib, calcium carbonate, and an organic acid, the acidity of the composition may increase the dissociation and absorption of celecoxib. This may decrease the amount of celecoxib that needs to be taken to relieve joint pain and may reduce alimentary side effects compared to commercially available celecoxib capsules. After the inventive composition comprising celecoxib, calcium carbonate, and an organic acid dissolves in an alimentary system, the acidity reacts with the calcium carbonate to release calcium ions, facilitating tablet disintegration. This results in high dissociation of calcium ions and rapid disintegration of the formulation, allowing such a composition to: 1. It reduces the amount of celecoxib you need to take to relieve joint pain and reduces the alimentary side effects of celecoxib. 2. Reduce the amount of calcium carbonate that needs to be taken to treat calcium deficiency, and supplementation of calcium ions to treat calcium deficiency further reduces the amount of celecoxib needed to treat joint pain and further reduces the side effects of celecoxib. 3, The high dissolution of calcium carbonate and celecoxib reduces both the strength of celecoxib and calcium carbonate needed to treat joint pain.

[0085] The celecoxib-containing compositions of the invention include 65-200 mg of celecoxib, 65-960 mg of an organic acid selected from ascorbic acid, malic acid, maleic acid, succinic acid, oenothermic acid, citric acid or mixtures thereof, 50-160 mg of crospovidone, 50-160 mg of cross-linked carboxymethylcellulose, povidone or polyvinylpyrrolidone (PVP), and a small amount of magnesium stearate, such compositions being provided in the form of granules, capsules, tablets, or dispersible tablets.

[0086] The celecoxib-containing composition of the invention comprises 65-200 mg of celecoxib, 65-960 mg of ascorbic acid, 50-160 mg of crospovidone, 50-160 mg of cross-linked carboxymethylcellulose, a small amount of magnesium stearate and PVPK 30. This allows the composition to be provided in the form of granules, capsules, tablets, or dispersible tablets.

[0087] The celecoxib-containing composition of the invention comprises 65-200 mg of celecoxib, 65-960 mg of malic acid, 50-160 mg of crospovidone, 50-160 mg of cross-linked carboxymethylcellulose, a small amount of magnesium stearate and PVPK 30. This allows the composition to be provided in the form of granules, capsules, tablets, or dispersible tablets.

[0088] The celecoxib-containing composition of the invention contains 65-200 mg of celecoxib, 65-960 mg of maleic acid, 50-160 mg of crospovidone, 50-160 mg of cross-linked carboxymethylcellulose, a small amount of magnesium stearate and PVPK 30. This allows the composition to be provided in the form of granules, capsules, tablets, or dispersible tablets.

[0089] The celecoxib-containing composition of the invention comprises 65-200 mg of celecoxib, 65-960 mg of succinic acid, 50-160 mg of crospovidone, 50-160 mg of cross-linked carboxymethylcellulose, a small amount of magnesium stearate and PVPK 30. This allows the composition to be provided in the form of granules, capsules, tablets, or dispersible tablets.

[0090] The celecoxib-containing composition of the invention comprises 65-200 mg of celecoxib, 65-960 mg of citric acid, 50-160 mg of crospovidone, 50-160 mg of cross-linked carboxymethylcellulose, a small amount of magnesium stearate and PVPK 30. This allows the composition to be provided in the form of granules, capsules, tablets, or dispersible tablets.

[0091] The calcium carbonate-containing composition of the invention includes calcium carbonate and an organic acid, where the calcium carbonate dissociates from carbon dioxide to produce carbon dioxide and calcium ions in a molar ratio of from 0.15:1 to 1:1.

[0092] The calcium carbonate-containing composition of the invention includes both calcium carbonate and an organic acid, has a molar ratio of calcium carbonate dissociating from carbon dioxide of between 0.15:1 and 1:1, has a calcium ion dissolution rate of between about 20% and 75% 30 minutes after the start of the test as measured in 900 mL of neutral pure water at a stirring speed of 75 RPM, and disintegrates to a pH of greater than 4.9 in 900 mL of neutral pure water, and is provided in the form of a tablet, capsule, granule, orally disintegrating tablet, or dispersible tablet.

[0093] The inventive composition has a molar ratio such that calcium carbonate dissociates from 25 mg to 250 mg (0.25-2.5 mmol) of calcium carbonate and 0.0375 mmol to 2.5 mmol of carbon dioxide, the dissolution rate of calcium ions is approximately 20% to 75% 30 minutes after the start of the test as measured in 900 mL of neutral pure water at a stirring speed of 75 RPM, the composition disintegrates to a pH greater than 4.9 in neutral pure water, and is provided in the form of a tablet, capsule, granule, orally disintegrating tablet, or dispersible tablet.

[0094] In one embodiment, the weak effervescent disintegration formulation of the composition of the invention comprises calcium carbonate, a weak acid selected from malic acid, ascorbic acid, succinic acid, maleic acid, succinic acid, adipic acid, fumaric acid, oenothermic acid, or tartaric acid, which dissociates calcium carbonate from a small amount of carbon dioxide, an excipient selected from cross-linked povidone and cross-linked carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and mixtures thereof, the formulation being provided in the form of an orally disintegrating tablet or a dispersible tablet with a disintegration time according to the USP, and having a calcium dissolution rate of 20% or more in 900 mL of neutral pure water measured at a stirring speed of 75 RPM after 30 minutes from the start of the test, and further the composition has a pH of 4.9 or more and a calcium ion dissolution rate of 20% to 75% in 900 mL of neutral pure water.

[0095] In one embodiment, the weak effervescent disintegration formulation may include calcium carbonate as the only weak base and ascorbic acid as the weak acid. The weight ratio of ascorbic acid to calcium carbonate may be from 1.0:1.0 to 3.0:1.0. The formulation may further include one or more excipients selected from cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and mixtures thereof. The formulation may have a calcium dissolution rate of about 20% to 65% in 900 mL of neutral purified water stirred at 75 RPM after 30 minutes.

[0096] Weakly effervescent disintegration formulations may have a pH greater than 4.9 after disintegration in 900 mL of neutral pure water and a dissolution rate of about 20% to 75% where calcium carbonate dissociates from carbon dioxide selected from malic acid, maleic acid, succinic acid, and maleic acid.

[0097] Another embodiment of the inventive composition includes calcium carbonate and malic acid, wherein the molar ratio of malic acid to calcium carbonate is between 0.15:1 and 1:1, the dissolution rate of calcium ions is between about 20% and 75% 30 minutes after the start of the test as measured in 900 mL of neutral pure water at a stirring speed of 75 RPM, and the composition disintegrates to a pH greater than 4.9 in neutral pure water, and is provided in the form of a tablet, capsule, granule, orally disintegrating tablet, or dispersible tablet.

[0098] Another embodiment of the inventive composition includes calcium carbonate and maleic acid, wherein the molar ratio of maleic acid to calcium carbonate is from 0.15:1 to 1:1, the dissolution rate of calcium ions is about 20% to 75% 30 minutes after the start of the test as measured in 900 mL of neutral pure water at a stirring speed of 75 RPM, and the composition disintegrates to a pH of greater than 4.9 in neutral pure water, and is provided in the form of a tablet, capsule, granule, orally disintegrating tablet, or dispersible tablet.

[0099] Another embodiment of the inventive composition includes calcium carbonate and succinic acid, wherein the molar ratio of succinic acid to calcium carbonate is from 0.15:1 molar to 1:1 molar, the dissolution rate of calcium ions is about 20% to 75% 30 minutes after the start of the test as measured in 900 mL of neutral pure water at a stirring speed of 75 RPM, and the composition disintegrates to a pH of greater than 4.9 in neutral pure water, and is provided in the form of a tablet, capsule, granule, orally disintegrating tablet, or dispersible tablet.

[0100] Another embodiment of the inventive composition includes calcium carbonate and tartaric acid, the molar ratio of tartaric acid to calcium carbonate being between 0.15:1 molar and 1:1 molar, the dissolution rate of calcium ions is between about 20% and 75% 30 minutes after the start of the test as measured in 900 mL of neutral pure water at a stirring speed of 75 RPM, the composition disintegrates to a pH of greater than 4.9 in neutral pure water, and is provided in the form of a tablet, capsule, granule, orally disintegrating tablet, or dispersible tablet.

[0101] Another embodiment of the inventive composition includes calcium carbonate and citric acid, the molar ratio of citric acid to calcium carbonate is between 0.25:1 and 0.8:1, the dissolution rate of calcium ions is about 45% to 75% 30 minutes after the start of the test as measured in 900 mL of neutral pure water at a stirring speed of 75 RPM, and the composition disintegrates to a pH of greater than 4.9 in neutral pure water, and is provided in the form of a tablet, capsule, granule, orally disintegrating tablet, or dispersible tablet.

[0102] Another embodiment of the inventive composition includes 25 mg to 250 mg of calcium carbonate and 25 mg to 750 mg of ascorbic acid, the dissolution rate of calcium ions is about 20% to 65% 30 minutes after the start of the test as measured in 900 mL of neutral pure water at a stirring speed of 75 RPM, the composition disintegrates to a pH of greater than 4.9 in neutral pure water, and is provided in the form of a tablet, capsule, granule, orally disintegrating tablet, or dispersible tablet.

[0103] Another embodiment of the composition of the invention includes celecoxib, malic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of malic acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet, capsule, or particulate form. Another embodiment of the inventive composition includes celecoxib, malic acid, calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of malic acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet or granule form.

[0104] Another embodiment of the inventive composition includes celecoxib, succinic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of succinic acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet, capsule, or particulate form.

[0105] Another embodiment of the inventive composition includes celecoxib, succinic acid, calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of succinic acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in the form of tablets, granules, or capsules.

[0106] Another embodiment of the inventive composition includes celecoxib, succinic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of succinic acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet, capsule, or particulate form.

[0107] Another embodiment of the composition of the invention includes celecoxib, succinic acid, calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of succinic acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet or granule form.

[0108] Another embodiment of the inventive composition includes celecoxib, ascorbic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of ascorbic acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet, capsule, or particulate form.

[0109] Another embodiment of the inventive composition includes celecoxib, ascorbic acid, calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of ascorbic acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet or granule form.

[0110] Another embodiment of the inventive composition includes celecoxib, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of tartaric acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet, capsule, or particulate form.

[0111] In another embodiment of the invention, the composition includes celecoxib, tartaric acid, calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, and the weight ratio of tartaric acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in capsule, tablet, or particulate form.

[0112] Another embodiment of the invention is a composition comprising celecoxib, citric acid, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, wherein the weight ratio of citric acid to celecoxib may be 1:1 to 6:1. Such a composition may be provided in tablet, capsule, or particulate form.

[0113] In another embodiment of the invention, the composition includes celecoxib, citric acid, calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, and the weight ratio of citric acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet or granule form.

[0114] In another embodiment of the invention, the composition includes imrecoxib, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, and the weight ratio of tartaric acid to imrecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet, capsule, or particulate form.

[0115] In another embodiment of the invention, the composition includes imrecoxib, maleic acid, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, and the weight ratio of maleic acid to imrecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet, capsule, or particulate form.

[0116] In another embodiment of the invention, the composition includes celecoxib, tartaric acid, calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, and the weight ratio of tartaric acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in capsule, tablet, or particulate form.

[0117] Another embodiment of the invention is a composition comprising celecoxib, citric acid, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, wherein the weight ratio of citric acid to celecoxib may be 1:1 to 6:1. Such a composition may be provided in tablet, capsule, or particulate form.

[0118] In another embodiment of the invention, the composition includes celecoxib, citric acid, calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, and the weight ratio of citric acid to celecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet or granule form.

[0119] Another embodiment of the invention includes imrecoxib, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate, and the weight ratio of tartaric acid to imrecoxib may be 1:1 to 6:1. Such compositions may be provided in tablet, capsule, or particulate form.

[0120] In an embodiment of the weak effervescent disintegration formulation of the present invention, the weak base is calcium carbonate and the weight of calcium carbonate per each tablet can be less than 150 mg. The binary acid can be selected from tartaric acid, malic acid, maleic acid, adipic acid, fumaric acid, and succinic acid, and the ratio of binary acid to calcium carbonate can be in the range of molar ratio of 0.35:1.0 to 1.0:1.0.

[0121] In advantageous embodiments, the weak effervescent disintegration formulations of the present invention may have a calcium ion solubility in 900 mL of neutral pure water when stirred at 75 RPM for 30 minutes within the range of about 10% to 75%. In alternative embodiments, the weak effervescent disintegration formulations may have a calcium ion solubility in 900 mL of neutral pure water within the range of about 10% to 70%, or about 10% to 65%, or about 10% to 60%, or about 15% to 75%, or about 15% to 70%, or about 15% to 65%, or about 15% to 60%, or about 20% to 75%, or about 20% to 70%, or about 20% to 65%, or about 20% to 60%, or about 30% to 65%, or about 40% to 60%.

[0122] In the calcium carbonate embodiments of the present invention, the weight of calcium carbonate per tablet may be 120 mg or less, 100 mg or less, 90 mg or less, 75 mg or less, 60 mg or less, and 40 mg or less. The weak acid may be selected from ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, and succinic acid. The amount of acid in the composition is limited by the final pH of disintegration of calcium carbonate, which may be greater than 4.9 after disintegration in 900 mL of neutral pure water and the solubility of calcium ions in 900 mL of neutral pure water may be within the range of about 20% to 75%. The dosage of calcium carbonate of the present invention is 120 mg, 100 mg, 90 mg, 75 mg, 60 mg, 40 mg for adults and 60 mg, 40 mg, or 20 mg for children, and the composition is provided in the form of particles, capsules, tablets, orally disintegrating tablets, or dispersible tablets.

[0123] According to an embodiment, the weak effervescent disintegration formulation includes calcium carbonate, ascorbic acid, and an API selected from dietary nutrients (vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin D or D3, vitamin E, vitamin K, niacinic acid, folic acid, pantothenic acid, choline, biotin, glucosamine salts, and mixtures thereof). The formulation is provided in the form of a dispersible tablet having a calcium solubility in 900 mL of neutral purified water within the range of 20% to 65% when agitated at 75 RPM and measured after 30 minutes.

[0124] In a preferred embodiment, calcium carbonate may be the only source of calcium in the tablet.

[0125] In preferred embodiments, the amount of calcium carbonate contained per tablet is less than 75 mg, or less than 50 mg, or less than 25 mg per day. In some embodiments, the dissolution rate of calcium per tablet ranges from 20% to 76% when the pH of the solution resulting from disintegration is 5 or greater. In some embodiments, the weak effervescent disintegration formulation is selected from ascorbic acid, calcium carbonate, vitamin D3, and a glucosamine salt selected from glucosamine HCl and glucosamine sulfate, and further includes one or more excipients selected from cross-linked povidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate, in the form of a dispersible tablet with a pH after disintegration in neutral pure water of greater than 4.9, a calcium solubility in neutral pure water of greater than 10%, preferably greater than 20%, and in the range of 20% to 80%, measured in 900 mL of neutral pure water at a stirring speed of 75 RPM, and measured after 30 minutes.

[0126] In one embodiment, the weak effervescent disintegration formulation is selected from calcium carbonate, ascorbic acid, and dietary nutrients selected from vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin D3, vitamin E, vitamin K, niacinic acid, folic acid, pantothenic acid, choline, biotin, iron, copper, zinc, magnesium, potassium, chloride, iodide, manganese, salts thereof, and mixtures thereof. The formulation further comprises one or more excipients selected from cross-linked povidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate, and is in the form of an orally disintegrating or dispersible tablet having a pH greater than 4.9 after disintegration in neutral pure water and a solubility of calcium greater than 10% in neutral pure water.

[0127] In one embodiment, the weak effervescent disintegration formulation comprises an API that is an α-glucosidase inhibitor selected from miglibose (miglitol), acarbose, and voglibose, calcium carbonate, a binary acid selected from citric acid or phosphoric acid, maleic acid, adipic acid, fumaric acid, tartaric acid, succinic acid, and ascorbic acid, and the formulation may further comprise one or more excipients selected from cross-linked povidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate.

[0128] In one embodiment, the weak effervescent disintegration formulation is selected from acarbose, calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, and magnesium stearate, and the formulation has a pH of greater than 4.9 after disintegration in 900 mL of neutral purified water.

[0129] Another composition of the invention includes acarbose, calcium carbonate, citric acid, cross-linked povidone, microcrystalline cellulose, magnesium stearate, wherein the formulation has a pH of greater than 4.9 after disintegration in 900 mL of neutral water, and wherein the formulation is in the form of an orally disintegrating tablet.

[0130] Another composition of the invention includes acarbose, calcium carbonate, an acid selected from citric acid, malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, and mixtures thereof, the formulation further includes one or more excipients selected from cross-linked povidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate, the formulation has a pH greater than 4.9 after disintegration in 900 mL of neutral water, and the formulation is in the form of an orally disintegrating tablet.

[0131] Another composition of the invention includes miglitol, calcium carbonate, an organic acid selected from citric acid, malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, cross-linked povidone, microcrystalline cellulose, and magnesium stearate, the formulation having a pH greater than 4.9 after disintegration in 900 mL of neutral water, and the formulation is in the form of an orally disintegrating tablet.

[0132] In one embodiment, the weak effervescent disintegration formulation comprises calcium carbonate, an acid selected from malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, succinic acid, ascorbic acid, and mixtures thereof, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and a hormonal contraceptive selected from desogestrel, norgestrel, levonorgestrel, megestrol, noresterone, norgestimate, noresterone oxime, ethinyl estradiol, dsetinyl estradiol, quinestrol, gestosterone, megestrol acetate, progesterone, and mifepristone, the formulation having a pH greater than 4.9 after disintegration in neutral pure water and in the form of an orally disintegrating or dispersible tablet.

[0133] In one embodiment, the weak effervescent disintegration formulation includes calcium carbonate, malonic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and levonorgestrel, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and is in the form of an orally disintegrating tablet.

[0134] In one embodiment, the weak effervescent disintegration formulation includes calcium carbonate, malonic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and mifepristone, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and is in the form of an orally disintegrating or dispersible tablet.

[0135] In one embodiment, the weak effervescent disintegration formulation includes calcium carbonate, malonic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and quinestrol, and the formulation is in the form of an orally disintegrating tablet having a pH of greater than 4.9 after disintegration in neutral purified water.

[0136] The composition of the invention includes progesterone, calcium carbonate, an acid selected from malic acid, maleic acid, ascorbic acid, citric acid, and cross-linked povidone, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and is in the form of an orally disintegrating or dispersible tablet.

[0137] In one embodiment, the weak effervescent disintegration formulation includes calcium carbonate, malonic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and progesterone, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and is in the form of an orally disintegrating or dispersible tablet.

[0138] The composition of the invention includes megestrol acetate, calcium carbonate, an acid selected from malic acid, maleic acid, malic acid, citric acid, and mixtures thereof, and cross-linked povidone, the formulation having a pH greater than 4.9 after disintegration in neutral purified water and in the form of an orally disintegrating or dispersible tablet.

[0139] In one embodiment, the weak effervescent disintegration formulation includes calcium carbonate, malonic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and megestrol acetate, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and is in the form of an orally disintegrating or dispersible tablet.

[0140] In one embodiment, the weak effervescent disintegration formulation comprises a weak base selected from sodium bicarbonate and potassium bicarbonate, sodium monohydrogen tartrate, sodium monohydrogen maleate, sodium monohydrogen tartrate, sodium monohydrogen succinate, sodium monohydrogen adipate, tartrate monohydrogen oxalate, tartrate monohydrogen citrate, potassium monohydrogen tartrate, potassium monohydrogen maleate, tartrate monohydrogen potassium succinate, tartrate monohydrogen potassium adipate. the formulation has a pH greater than 4.9 after disintegration in neutral purified water and is in the form of an orally disintegrating tablet.

[0141] In one embodiment, the weak effervescent disintegration formulation includes sodium bicarbonate, sodium monohydrogen tartrate, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and amlodipine, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and is in the form of an orally disintegrating tablet.

[0142] In one embodiment, the weak effervescent disintegration formulation includes sodium bicarbonate, sodium monohydrogen tartrate, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and nitrendipine, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and is in the form of an orally disintegrating tablet.

[0143] In one embodiment, the weak effervescent disintegration formulation includes sodium bicarbonate, sodium monohydrogen tartrate, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and nimodipine, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and is in the form of an orally disintegrating tablet.

[0144] In one embodiment, the weak effervescent disintegration formulation includes sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and nifedipine, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and is in the form of an orally disintegrating tablet.

[0145] In one embodiment, the weak effervescent disintegration formulation may be selected from the group consisting of sodium bicarbonate, potassium bicarbonate, monosodium monotartrate, monosodium monotartrate maleic acid monosodium monotartrate succinic acid monosodium monotartrate adipic acid monosodium monotartrate oxalate, monosodium monotartrate citric acid monosodium monotartrate tartrate, potassium bicarbonate, monopotassium monotartrate, monopotassium monotartrate maleic acid monopotassium monotartrate succinic acid monopotassium monotartrate adipic acid The formulation includes a weak acid selected from monopotassium tartrate oxalate, monopotassium tartrate citrate monopotassium tartrate tartrate, and mixtures thereof, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and a sartan API selected from losartan, candesartan, valsartan, telmisartan, fimasartan, irbesartan, and salts thereof, the formulation having a pH greater than 4.9 after disintegration in neutral purified water and in the form of an orally disintegrating or dispersible tablet.

[0146] In one embodiment, the weak effervescent disintegration formulation includes sodium bicarbonate, monosodium tartrate, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and valsartan, and the formulation has a pH of greater than 4.9 following disintegration in neutral purified water.

[0147] The compositions of the present invention include sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, and losartan potassium, and the formulation has a pH of greater than 4.9 after disintegration in neutral purified water and is in the form of an orally disintegrating or dispersible tablet.

[0148] Another composition of the present invention includes sodium bicarbonate, monosodium tartrate, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, magnesium stearate, and irbesartan, wherein the formulation has a pH of greater than 4.9 after disintegration in neutral purified water and is in the form of an orally disintegrating tablet.

[0149] Another composition of the invention includes an acid selected from calcium carbonate, tartaric acid, maleic acid, succinic acid, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, magnesium stearate, and irbesartan, and the formulation is in the form of an orally disintegrating tablet having a pH greater than 4.9 after disintegration in neutral pure water and a pH greater than 4.9 after disintegration in neutral pure water.

[0150] In one embodiment, the weak effervescent disintegration formulation includes sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and candesartan, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and in the form of an orally disintegrating tablet.

[0151] In one embodiment, the weak effervescent disintegration formulation includes sodium bicarbonate, monosodium tartrate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and telmisartan, the formulation having a pH greater than 4.9 after disintegration in neutral purified water and in the form of an orally disintegrating tablet.

[0152] In one embodiment, the weak effervescent disintegration formulation includes calcium carbonate, an acid selected from tartaric acid, maleic acid, adipic acid, fumaric acid, tartaric acid, and ascorbic acid, a selective COX-2 inhibitor selected from celecoxib and imrecoxib, the formulation having a pH greater than 4.9 after disintegration in neutral purified water, and in the form of an orally disintegrating or dispersible tablet.

[0153] Another aspect of the invention includes a formulation in the form of a tablet, granule, or capsule comprising a selective COX-2 inhibitor selected from celecoxib or imrecoxib, one of the acids selected from the group consisting of malic acid, maleic acid, succinic acid, tartaric acid, ascorbic acid, and citric acid, and a weight ratio of the acid to celecoxib or imrecoxib of 1:1 to 6:1, and the dissolution rate of celecoxib or imrecoxib is 60% or more in 120 minutes after a dissolution test in 1000 mL of a sodium phosphate buffer solution of pH 7, the pH of the dissolution solution being less than 3.5.

[0154] In one embodiment, the weak effervescent dissociation formulation comprises calcium carbonate, malic acid, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and celecoxib, and produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0155] In one embodiment, the weak effervescent dissociation formulation comprises calcium carbonate, malic acid, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and imrecoxib, and produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0156] In another configuration of celecoxib, each formulation contains 65 mg to 200 mg of celecoxib, organic acids consisting of ascorbic acid, malic acid, maleic acid, succinic acid, and citric acid, or mixtures thereof, 50 mg to 160 mg of cross-linked povidone, 50 mg to 160 mg of cross-linked sodium carboxymethyl cellulose, magnesium stearate, and a trace amount of PVPK30 in the form of granules, capsules, or tablets in which the dissolution rate of celecoxib is 60% or greater after 120 minutes in 1000 mL of a pH 7 sodium phosphate buffer solution containing 2.5 g of sodium dodecyl sulfate.

[0157] In another configuration of the celecoxib of the invention, each dose is in the form of granules or tablets containing 65 mg to 200 mg of celecoxib, acids consisting of ascorbic acid, malic acid, maleic acid, succinic acid, and citric acid, or mixtures thereof, and trace amounts of calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, magnesium stearate, and PVPK30, and in which the dissolution rate of celecoxib and calcium ions is 60% or more after 120 minutes in 1000 mL of a sodium phosphate buffer solution of pH 7 containing 2.5 g of sodium dodecyl sulfate.

[0158] In the imrecoxib invention, each dose contains 40 mg to 80 mg of imrecoxib, an acid selected from ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, and citric acid, or mixtures thereof, cross-linked povidone, and cross-linked sodium carboxymethyl cellulose. The formulation is in the form of a granule, capsule, or tablet.

[0159] In one embodiment, the low effervescent dissociation formulation comprises bicarbonate, a monosodium salt of a binary acid, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and etoricoxib, and produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0160] In one embodiment, the weak effervescent dissociation formulation comprises calcium carbonate, an acid selected from malic acid, maleic acid, adipic acid, fumaric acid, succinic acid, tartaric acid, succinic acid, ascorbic acid, citric acid, and mixtures thereof, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and a serotonin reuptake inhibitor selected from fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, and salts thereof, and produces a pH of 4.9 or higher after dissociation in neutral pure water.

[0161] In one embodiment, the low effervescent disintegration formulation comprises calcium carbonate, malonic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and fluoxetine hydrochloride in the form of an orally disintegrating tablet that produces a pH of 4.9 or greater after disintegration in neutral purified water.

[0162] In one embodiment, the weak effervescent disintegration formulation comprises calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and paroxetine hydrochloride in the form of an orally disintegrating tablet that produces a pH of 4.9 or greater upon disintegration in neutral purified water.

[0163] In one embodiment, the weak effervescent dissociation formulation comprises calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and fluvoxamine, and produces a pH of 4.9 or higher after dissociation in neutral pure water.

[0164] In one embodiment, the weak effervescent dissociation formulation comprises an acid selected from bicarbonate, potassium bicarbonate, monosodium malate, monosodium melate, monosodium succinate, monosodium adipate, monosodium oxalate, monosodium citrate, monosodium tartrate, monopotassium malate, monopotassium melate, monopotassium succinate, monopotassium adipate, monopotassium oxalate, monopotassium tartrate, and mixtures thereof, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and an antifibrinolytic agent selected from 6-aminocaproic acid, tranexamic acid, and hydroxybenzylamine, and produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0165] In one embodiment, the weak effervescent dissociation formulation comprises bicarbonate, monosodium tartrate, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and tranexamic acid, and produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0166] In one embodiment, the low effervescent dissociation formulation comprises bicarbonate, monosodium tartrate, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and 6-aminocaproic acid, and produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0167] In one embodiment, the low effervescent dissociation formulation comprises bicarbonate, monosodium tartrate, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and hydroxybenzylamine, and produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0168] Other compositions of the invention include an acid selected from tranexamic acid, sodium bicarbonate, potassium bicarbonate, monosodium malate, monosodium melate, monosodium succinate, monosodium citrate, monosodium tartrate, monopotassium malate, monopotassium melate, monopotassium succinate, monopotassium tartrate, cross-linked sodium carboxymethyl cellulose, and cross-linked povidone. The formulation is in the form of an orally disintegrating or dispersible tablet that produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0169] In one embodiment, the weak effervescent release formulation comprises calcium carbonate, an acid selected from malic acid, maleic acid, succinic acid, adipic acid, fumaric acid, succinic acid, ascorbic acid, and mixtures thereof, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and an antihistamine selected from cetirizine, levocetirizine, hydroxyzine, promethazine, fexofenadine, loratadine, terfenadine, desloratadine, chlorpheniramine, dexchlorpheniramine, clemastine, triprolidine, and diphenhydramine or a salt thereof. The formulation is in the form of an orally disintegrating tablet that produces a pH of 4.9 or greater after dissolution in neutral pure water.

[0170] In one embodiment, the weak effervescent disintegration formulation comprises calcium carbonate, malonic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and loratadine. The formulation is in the form of an orally disintegrating tablet that produces a pH of 4.9 or greater after disintegration in neutral pure water.

[0171] In one embodiment, the weak effervescent disintegration formulation comprises calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and clemastine. The formulation is in the form of an orally disintegrating tablet that produces a pH of 4.9 or higher after disintegration in neutral pure water.

[0172] In one embodiment, the weak effervescent disintegration formulation comprises calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and cetirizine. The formulation is in the form of an orally disintegrating tablet that produces a pH of 4.9 or greater after disintegration in neutral pure water.

[0173] In one embodiment, the weak effervescent disintegration formulation comprises calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and olanzapine. The formulation is in the form of an orally disintegrating tablet that produces a pH of 4.9 or greater after disintegration in neutral pure water.

[0174] In one embodiment, the weak effervescent dissociation formulation comprises calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and quetiapine. The formulation is in a form that produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0175] In one embodiment, the weak effervescent dissociation formulation comprises calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and paliperidone or a salt thereof. The formulation is in a form that produces a pH of 4.9 or higher after dissociation in neutral pure water.

[0176] In one embodiment, the weak effervescent release formulation comprises calcium carbonate, an acid selected from malic acid, maleic acid, succinic acid, adipic acid, fumaric acid, succinic acid, ascorbic acid, and mixtures thereof, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and a triptan drug selected from rizatriptan, sumatriptan, zolmitriptan, naratriptan, almotriptan, eletriptan, and frovatriptan. The formulation is in the form of an orally disintegrating or dispersible tablet that produces a pH of 4.9 or greater after dissolution in neutral pure water.

[0177] In one embodiment, the weak effervescent dissociation formulation comprises calcium carbonate, maleic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and rizatriptan. The formulation is in a form that produces a pH of 4.9 or higher after dissociation in neutral pure water.

[0178] In one embodiment, the weak effervescent dissociation formulation comprises calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and sumatriptan. The formulation is in a form that produces a pH of 4.9 or greater after dissociation in neutral pure water.

[0179] In one embodiment, the weak effervescent dissociation formulation comprises calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, menthol, aspartame, magnesium stearate, and zolmitriptan. The formulation is in a form that produces a pH of 4.9 or higher after dissociation in neutral pure water. In another configuration of the present invention, it comprises calcium carbonate, an acid selected from malic acid, maleic acid, succinic acid, tartaric acid, ascorbic acid, and citric acid, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and sildenafil citrate. The formulation is in the form of an orally disintegrating or dispersible tablet that produces a pH of 4.9 or higher after dissociation in neutral pure water.

[0180] Another aspect of the invention relates to a method for preparing a weak effervescent, fast disintegrating formulation comprising the steps of: mixing a weak acid (selected from monosodium malate, monosodium melate, monosodium succinate, monosodium adipate, monosodium oxalate, monosodium citrate, monosodium tartrate, monopotassium malate, monopotassium melate, monopotassium succinate, monopotassium adipate, monopotassium oxalate, monopotassium citrate, or monopotassium tartrate) with an acidic or neutral API, a filler, and optionally a swelling agent in a fluid bed or granulator to prepare an acidic granule; drying the acidic granule; mixing the dried acidic granule with a weak base (selected from sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, and calcium carbonate powder or granules), and optionally a filler, a lubricant, a sweetener, and a mint; compressing the mixture to form a weak effervescent, fast disintegrating formulation, the formulation having a pH of 4.9 or greater after dissociation in neutral purified water, preferably 200 mL of neutral purified water.

[0181] The method of preparation of the composition of celecoxib is as follows: 1. Mix 1 part of celecoxib with 1-6 parts of an organic acid selected from ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, and citric acid, or a mixture thereof, and an alcohol selected from ethanol or benzyl alcohol until completely dissolved. 2. Place one part of the cross-linked povidone and one part of the cross-linked sodium carboxymethylcellulose into a fluid bed or granulator. 3. An alcohol solution containing celecoxib and an organic acid is sprayed onto the fluidized bed. 4. A small amount of 8% PVPK30 in water is sprayed onto the fluidized bed and dried until the particle size is about 24 mesh. The particles produced are dried by hot air, mixed with magnesium stearate, and compressed into tablets or filled into capsules or sachets.

[0182] According to another aspect of the present invention, there is provided a method for preparing a weak effervescent disintegration formulation comprising the steps of: mixing a weak base (selected from calcium carbonate, potassium carbonate, sodium carbonate) with a basic or neutral API, a filler, and optionally a leavening agent in a fluid bed or granulator to prepare granules of the weak base; drying the granules of the weak base; mixing the dried granules with a weak acid and optionally a filler, a lubricant, a sweetener, and a mint; compressing the mixture to form a weak effervescent disintegration formulation, which has a pH of 4.9 or greater after dissociation in neutral pure water.

[0183] The method for preparing the weak effervescent disintegration formulation is as follows: preparing an acid granule containing a weak acid (selected from monosodium malate, monosodium melate, monosodium succinate, monosodium adipate, monosodium oxalate, monosodium citrate, monosodium tartrate, monopotassium malate, monopotassium melate, monopotassium succinate, monopotassium adipate, monopotassium oxalate, monopotassium citrate, or monopotassium tartrate) by mixing in a fluid bed or granulator; drying the acid granule; preparing an acid granule containing a weak base (selected from sodium carbonate, potassium carbonate, lithium sodium carbonate, and calcium carbonate) with a basic or neutral API, a filler, and optionally a leavening agent in a fluid bed or granulator; drying the basic granule; mixing the dried acid granule and the weak base granule, optionally including a filler, a lubricant, a sweetener, and a mint; compressing the mixture to form a weak effervescent formulation, the formulation having a pH of 4.9 or greater after dissociation in neutral pure water.

[0184] The composition of the present invention comprises a water insoluble API (celecoxib, imrecoxib, calcium carbonate), an organic acid selected from ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, or a mixture thereof, cross-linked povidone, cross-linked sodium carboxymethylcellulose, magnesium stearate, or PEG 6000. The composition is in the form of granules, capsules, tablets, or dispersible tablets and has a high dissolution rate of the API contained in the composition in an aqueous medium.

[0185] The present invention broadly relates to convenient drug delivery systems and methods for their manufacture, preferably using simple and low-cost methods using common excipients. More specifically, the present invention relates to rapidly disintegrating dosage forms, such as weakly effervescent tablets or granules, orally disintegrating tablets (ODTs) and dispersible tablets, and methods for their manufacture and administration. The weakly effervescent formulations according to the present invention are suitable for buccal administration or administration of a wide range of pharmaceutical or dietary nutrients, such as APIs (vitamins, minerals, etc.).

[0186] Another composition of the present invention includes celecoxib, an organic acid selected from ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, or mixtures thereof, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate. The formulation has a high dissolution rate of celecoxib in aqueous media. The high solubility of celecoxib of the present invention is higher than that of commercially available celecoxib capsules, reducing the amount of celecoxib required to treat joint pain, thereby reducing the gastrointestinal side effects of celecoxib. The weight ratio of organic acid to celecoxib is within the range of 1:1 to 6:1, with a preferred range of 2:1 to 5:1.

[0187] Another composition of the present invention includes imrecoxib, an organic acid selected from ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, or mixtures thereof, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate. This formulation has a high dissolution rate of imrecoxib in aqueous media. The high dissolution rate of imrecoxib in the present invention reduces the amount of imrecoxib required to treat pain, thereby reducing the gastrointestinal side effects of imrecoxib.

[0188] The composition of the present invention includes celecoxib, calcium carbonate, and an organic acid selected from ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, etc., to increase calcium ion dissociation in the digestive system. Additionally, the present invention includes celecoxib or imrecoib, calcium carbonate, and an organic acid to increase calcium ion dissociation and dissolution of celecoxib or imrecoib in aqueous media or in the digestive system.

[0189] Another composition of the present invention contains ascorbic acid, calcium carbonate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate. The formulation is present in the form of granules, capsules, tablets, or orally disintegrating tablets and has a high dissolution rate of calcium ions in neutral pure water. The high dissolution rate of calcium ions in the present invention reduces the amount of calcium carbonate required to treat joint pain or hypocalcemia and reduces the digestive side effects of calcium carbonate, such as constipation, compared to commercially available calcium carbonate tablets. The weight ratio of ascorbic acid to calcium carbonate is in the range of 1:1 to 3:1. After the formulation is dissociated in 200 mL of neutral pure water, the pH range of the suspension formed is 4.9 or higher. The dissolution of calcium ions is about 20-65% in 900 mL of neutral pure water under agitation of 75 RPM in 30 minutes.

[0190] An embodiment of the present invention relates to a weak effervescent formulation comprising a carbonate salt and a weak organic acid. In a preferred embodiment, the weak effervescent formulation comprises a carbonate salt, a weak organic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, or PEG 6000. After the carbonate salt weak effervescent dissociation formulation dissociates in neutral pure water, the pH of the suspension formed is 4.9 or greater, and therefore the formulation can exist in the form of an orally disintegrating tablet (ODT) or a disintegrating tablet.

[0191] The composition of the present invention includes an organic acid selected from ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, etc., calcium carbonate, cross-linked povidone, and magnesium stearate. The formulation is in the form of granules, capsules, tablets, orally disintegrating tablets, or disintegrating tablets, and has a high dissociation rate of calcium ions in a neutral aqueous medium. The high dissociation rate of calcium ions of the present invention reduces the amount of calcium carbonate required to treat hypocalcemia and reduces the digestive side effects of calcium carbonate, such as constipation, compared to commercially available calcium carbonate tablets. The molar ratio of binary acid to calcium carbonate is in the range of 0.15:1 to 1:1. After the formulation is dissociated in 900 mL of neutral pure water, the pH of the suspension formed is 4.9 or higher. The solubility of calcium ions of the calcium carbonate of the present invention is about 20-75% in 900 mL of neutral pure water under agitation of 75 RPM for 30 minutes.

[0192] The composition of the present invention contains calcium carbonate, malonic acid, cross-linked povidone, and magnesium stearate or PEG 6000. The formulation exists in the form of granules, capsules, tablets, or orally disintegrating tablets, and the solubility of calcium ions in neutral pure water is approximately 20-75% in 900 mL of neutral pure water under agitation of 75 RPM for 30 minutes, and the pH of the suspension formed is 4.9 or higher.

[0193] Another composition of the invention includes calcium carbonate, maleic acid, cross-linked povidone, and magnesium stearate. The formulation is in the form of granules, capsules, tablets, or orally disintegrating tablets, and has a calcium ion solubility in neutral pure water of about 20-75% in 900 mL of neutral pure water under stirring at 75 RPM for 30 minutes, and the pH of the suspension formed is 4.9 or greater.

[0194] Another composition of the invention includes calcium carbonate, succinic acid, cross-linked povidone, and magnesium stearate. The formulation is in the form of granules, capsules, tablets, orally disintegrating tablets, or disintegrating tablets, and has a calcium ion solubility in neutral pure water of about 20-75% in 900 mL of neutral pure water under agitation of 75 RPM for 30 minutes, and the pH of the suspension formed is 4.9 or greater.

[0195] Another composition of the invention includes calcium carbonate, tartaric acid, cross-linked povidone, and magnesium stearate. The formulation is in the form of granules, capsules, tablets, orally disintegrating tablets, or disintegrating tablets, and has a calcium ion solubility in neutral pure water of about 20-75% in 900 mL of neutral pure water under agitation at 75 RPM for 30 minutes, and a suspension formed with a pH of 4.9 or greater. Another composition of the invention includes calcium carbonate, citric acid, cross-linked povidone, and magnesium stearate or PEG 6000. The formulation exists in the form of granules, capsules, tablets, orally disintegrating tablets, or disintegrating tablets, and the solubility of calcium ions in neutral pure water is about 20-75% in 900 mL of neutral pure water under stirring at 75 RPM for 30 minutes, and the pH of the suspension formed is 4.9 or greater.

[0196] Another composition of the invention includes calcium carbonate, ascorbic acid, cross-linked povidone, and magnesium stearate or PEG 6000. The formulation exists in the form of granules, capsules, tablets, orally disintegrating tablets, or disintegrating tablets, and the solubility of calcium ions in neutral pure water is approximately 20-65% in 900 mL of neutral pure water under agitation of 75 RPM for 30 minutes, and the pH of the suspension formed is 4.9 or greater.

[0197] Another composition of the invention includes calcium carbonate, glucosamine sulfate, cross-linked povidone, and magnesium stearate. The formulation exists in granule or tablet form, and the solubility of calcium ions in neutral pure water is approximately 35-55% in 900 mL of neutral pure water under agitation at 75 RPM for 30 minutes, and the pH of the suspension formed ranges from 6.5 to 7.5.

[0198] Another composition of the invention includes 25 mg to 150 mg of calcium carbonate, 250 mg to 1500 mg of glucosamine hydrochloride, cross-linked povidone, and magnesium stearate. The formulation is in the form of granules, capsules, or tablets and has a calcium ion dissolution of about 35-55% in 30 minutes in 900 mL of neutral purified water as measured at a stirring speed of 75 RPM, and the pH of the suspension formed ranges from 6.5 to 7.5.

[0199] Another weak effervescent release formulation of the present invention comprises sodium bicarbonate, glucosamine sulfate, cross-linked povidone, and magnesium stearate, the formulation being in the form of granules, capsules, or dispersible tablets and having a pH in the range of 6.5 to 7.5 in 200 mL of neutral water.

[0200] Another weak effervescent release formulation of the present invention comprises 1 part glucosamine hydrochloride, 0.1 to 1 part sodium bicarbonate, 0.2 to 0.4 parts cross-linked povidone, and magnesium stearate, which formulation is in the form of granules or dispersible tablets and has a pH in the range of 6.5 to 7.5 in 200 mL of neutral water.

[0201] According to the present invention, the orally disintegrating or dispersible tablets of the present invention do not irritate the oral cavity by having a pH of 4.9 or higher after dissolution, for example, a pH range of 4.9 to 7.5, or a pH range of 4.9 to 7.0, or a pH range of 5 to 7.

[0202] Another embodiment of the present invention relates to a weak effervescent formulation of calcium carbonate and an organic acid. In a preferred embodiment, the weak effervescent formulation comprises calcium carbonate, a weak organic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, and magnesium stearate or PEG 6000.

[0203] The weak organic acid may be a monocarboxylic acid or a dicarboxylic acid (hereinafter also referred to as dicarboxylic acid). In a preferred embodiment, the organic acid is a dicarboxylic acid. In a preferred embodiment, the organic acid is selected from malic acid, melic acid, succinic acid, adipic acid, fumaric acid, tartaric acid, ascorbic acid, and citric acid. In a particularly preferred embodiment, the organic acid is malic acid.

[0204] By adjusting the relative amounts of calcium carbonate and organic acids, the final pH of the solution after dissociation can be adjusted to pH 5 to 7 to prevent oral irritation and the dissociation of calcium ions can be controlled to 20 to 75%. High dissociation of calcium ions allows for good calcium absorption and reduces the strength and dose per day taken to maintain normal blood calcium levels.

[0205] Weak effervescent formulations according to the present invention include a pair of weak effervescent chemicals and an API. The pair of effervescent chemicals constitutes a weak acid / base pair. The acid / base pair is specified or constrained such that when the formulation is added to water, the resulting solution has a pH of 4.9 or greater. In one embodiment, the weak effervescent chemical pair is a calcium carbonate and a diacid pair. In another embodiment, the weak effervescent chemical pair is sodium or potassium bicarbonate and a monosodium salt of a diacid (such as malate or malic acid). These formulations may also include APIs, including pharmaceutical drugs or food nutrients such as vitamins and minerals.

[0206] The formulations according to the invention may contain a wide range of APIs from different drug classes, such as hemostatic agents, antihypertensive agents, antiemetic agents, sartans, hypoglycemic agents, antiallergic agents, erectile dysfunction drugs, contraceptives, antidepressants, and COX-2 inhibitors.

[0207] According to an embodiment of the present invention, the dissociation time of calcium carbonate is typically less than 3 minutes in a small volume of neutral (optimally pure) water, for example, about 100-300 mL volume, particularly about 200 mL volume. Due to the favorable dissociation time, such formulations have an advantageous effect of preventing or reducing the risk of choking even for large tablets. After the weakly effervescent dissociation formulation is dissociated in neutral pure water (for example, about 200 mL of neutral pure water), the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation can be in the form of an orally disintegrating or dispersible tablet.

[0208] One embodiment of the present invention relates to a weak effervescent formulation comprising malic acid and calcium carbonate. In a preferred embodiment, the weak effervescent formulation comprises calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. The molar ratio of malic acid to calcium carbonate is in the range of 0.15:1.0 or 0.35:1.0 to 1.0:1.0 in a preferred embodiment. After dissociation in neutral pure water, for example in a volume of about 100-300 mL, particularly in a volume of about 200 mL, the pH range of the suspension or solution formed is 4.9 or higher, preferably 5 to 7. Thus, the formulation can be in the form of an orally disintegrating or dispersible tablet. The dissolution rate of calcium carbonate in the weak effervescent formulation may be 20% or higher and less than 75% after 30 minutes in a volume of 900 mL in neutral pure water when stirred at a speed of about 75 RPM.

[0209] The amount of calcium carbonate in a weak effervescent formulation, for example a weak effervescent tablet formulation, is less than 150 mg. In a preferred embodiment, the amount of calcium carbonate in a weak effervescent tablet formulation for adults ranges from about 40 mg to about 125 mg per tablet, for example about 75 mg of calcium carbonate. Such weak effervescent tablet formulations typically have a calcium ion dissolution in the range of 20% to 75%. The preferred daily intake of calcium carbonate for adults is typically in the range of 40 mg to 80 mg. The daily intake of calcium carbonate for children is typically in the range of 20 mg to 75 mg.

[0210] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate and tartaric acid. In a preferred embodiment, the weak effervescent formulation comprises calcium carbonate, tartaric acid, cross-linked povidone, cross-linked soda carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. The molar ratio of tartaric acid to calcium carbonate is in the range of 0.35:1.0 to 1.0:1.0 in a preferred embodiment. After the weak effervescent formulation dissociates in neutral pure water, the pH range of the suspension or solution formed ranges from 5 to 7. Thus, the formulation can be in the form of a capsule, granule, orally disintegrating tablet, or dispersible tablet. The dissolution rate of calcium carbonate in the weak effervescent formulation may range from 20% or more to 75% after 30 minutes in a volume of 900 mL in neutral pure water when stirred at a speed of about 75 RPM. The amount of calcium carbonate contained in each tablet of the weak effervescent tablet may be less than 150 mg. A preferred amount of weak effervescent tablets for adults may contain, for example, about 50 mg to about 125 mg of calcium carbonate per tablet. Such weak effervescent tablet formulations typically have calcium ion dissolution in the range of 20% to 75%. A preferred daily intake of calcium carbonate for adults is typically in the range of 50 mg to 125 mg. A preferred intake of calcium carbonate for children is typically in the range of 20 mg to 100 mg.

[0211] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate and succinic acid. In a preferred embodiment, the weak effervescent formulation comprises calcium carbonate, succinic acid, cross-linked povidone, cross-linked soda carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. The molar ratio of succinic acid to calcium carbonate is in the range of 0.35:1.0 to 1.0:1.0 in a preferred embodiment. After the weak effervescent formulation dissociates in neutral pure water, for example in a volume of about 100-300 mL, particularly in a volume of about 200 mL, the pH of the suspension or solution formed may be 4.9 or higher. Thus, the formulation may be in the form of particles, capsules, tablets, orally disintegrating tablets, or dispersible tablets. The dissolution rate of calcium carbonate in the weak effervescent formulation may be 20% or higher after 30 minutes in neutral pure water, for example in a volume of 900 mL, when stirred at a speed of about 75 RPM. In a preferred embodiment, the amount of calcium carbonate contained in each tablet may be less than 150 mg. A preferred amount of weak effervescent tablets for adults may contain, for example, about 50 mg to about 125 mg of calcium carbonate per tablet. Such weak effervescent tablet formulations typically have calcium ion dissolution in the range of 20% to 75%. A preferred daily intake of calcium carbonate for adults is typically in the range of 50 mg to 125 mg. A preferred intake of calcium carbonate for children is typically in the range of 20 mg to 100 mg.

[0212] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate and adipic acid. In a preferred embodiment, the weak effervescent formulation may comprise calcium carbonate, adipic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. The molar ratio of adipic acid to calcium carbonate is preferably in the range of 0.35:1.0 to 1.0:1.0. After the weak effervescent tablet formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation may be in the form of an orally disintegrating or dispersible tablet. The solubility of calcium in the weak effervescent formulation may be 20% or higher in 30 minutes when stirred at 75 RPM in 900 mL of neutral pure water. In a preferred embodiment, the amount of calcium carbonate contained in each tablet may be less than 150 mg. A preferred amount of weak effervescent tablets for adults may contain, for example, about 50 mg to about 125 mg of calcium carbonate per tablet. Such weak effervescent tablet formulations typically have calcium ion dissolution in the range of 20% to 75%. A preferred daily intake of calcium carbonate for adults is typically in the range of 50 mg to 125 mg. A preferred intake of calcium carbonate for children is typically in the range of 20 mg to 100 mg.

[0213] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate and fumaric acid. In a preferred embodiment, the weak effervescent formulation may comprise calcium carbonate, fumaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. The molar ratio of fumaric acid to calcium carbonate is preferably in the range of 0.35:1.0 to 1.0:1.0. After the weak effervescent tablet formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation may be in the form of an orally disintegrating or dispersible tablet. The solubility of calcium in the weak effervescent formulation may be 20% or higher in 30 minutes when stirred at 75 RPM in 900 mL of neutral pure water. In a preferred embodiment, the amount of calcium carbonate contained in each tablet may be less than 150 mg. A preferred amount of weak effervescent tablets for adults may, for example, comprise about 50 mg to about 125 mg of calcium carbonate per tablet. The recommended daily intake of calcium carbonate for adults is usually in the range of 50 mg to 125 mg. The recommended daily intake of calcium carbonate for children is usually in the range of 20 mg to 100 mg.

[0214] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate and ascorbic acid. In a preferred embodiment, the weak effervescent formulation may comprise calcium carbonate, ascorbic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. The ratio of calcium carbonate to ascorbic acid is preferably in the range of about 1.0:1.0 to about 1.0:3.0 by weight. After the weak effervescent tablet formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed is greater than 4.9 and less than 7, so that the formulation may be in the form of a capsule, tablet, orally disintegrating tablet, dispersible tablet, or granule. The solubility of calcium in the weak effervescent formulation is greater than 20% in 30 minutes and may range from 20-65% when stirred at 75 RPM in 900 mL of neutral pure water.

[0215] According to a preferred embodiment, the amount of calcium carbonate contained in each tablet is in the range of 20 mg to 125 mg, preferably in the range of 20 mg to 100 mg, more preferably in the range of 20 mg to 75 mg, the solubility of calcium ions is in the range of 20% to 75%, and the pH of the final solution or suspension resulting from dissolution of the calcium carbonate tablet, dispersible tablet, or ODT is in the range of pH 5 to 7 in 200 mL of neutral pure water.

[0216] The vitamins and minerals are food supplements including dietary supplement substances such as vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin A, vitamin D, vitamin E, vitamin K, folic acid, niacinic acid, pantothenic acid, choline, biotin, calcium carbonate, ferrous sulfate, copper sulfate, zinc sulfate, sodium chloride, magnesium sulfate, potassium chloride, etc. In an embodiment, the present invention allows such food supplements to be formulated as weakly effervescent disintegrating preparations, such as orally disintegrating or dispersible tablets or granules, comprising the food supplement, a pair consisting of a weak acid and a carbonate, and one or more excipients selected from fillers, diluents, lubricants, and leavening agents. After the weakly effervescent disintegrating preparation of the food supplement is disintegrated in neutral pure water, the pH of the suspension or solution formed may be 4.9 or higher.

[0217] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, ascorbic acid, and a glucosamine salt (selected from glucosamine chloride and glucosamine sulfate). In a preferred embodiment, the weak effervescent formulation may comprise calcium carbonate, ascorbic acid, a glucosamine salt (selected from glucosamine chloride and glucosamine sulfate), cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. The weight ratio of calcium carbonate to ascorbic acid is preferably in the range of 1:1 to 1:3. After the weak effervescent tablet formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed is 4.9 or higher, so that the formulation may be in the form of a tablet or dispersible tablet. The solubility of calcium in the weak effervescent formulation is 20% or higher and may range from 20% to 80% when measured in 900 mL of neutral pure water under agitation at 75 RPM for 30 minutes.

[0218] Another embodiment relates to a formulation comprising calcium carbonate, ascorbic acid, and a glucosamine salt (selected from glucosamine chloride and glucosamine sulfate). In a preferred embodiment, the amount of calcium carbonate in each tablet is in the range of 15 mg to 75 mg, the amount of ascorbic acid in each tablet is in the range of 15 mg to 225 mg, the amount of glucosamine salt is in the range of 300 mg to 750 mg for glucosamine chloride or in the range of 386 mg to 965 mg for glucosamine sulfate, and the solubility of calcium ions is in the range of 20% to 75% or 20% to 80%.

[0219] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, ascorbic acid, and a glucosamine salt (selected from glucosamine chloride and glucosamine sulfate). In a preferred embodiment, the weak effervescent formulation may comprise calcium carbonate, ascorbic acid, glucosamine hydrochloride, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. The weight ratio of calcium carbonate to ascorbic acid is preferably in the range of 1:1 to 1:3. After the weak effervescent formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed is in the range of 4.9 to 7.0, so that the formulation may be in the form of a dispersible tablet or tablet. Also, the solubility of calcium in the weak effervescent formulation is greater than 20% and may range from 20% to 80% when measured in 900 mL of neutral pure water under agitation at 75 RPM for 30 minutes.

[0220] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, ascorbic acid, and glucosamine sulfate. In a preferred embodiment, the weak effervescent formulation may comprise calcium carbonate, ascorbic acid, glucosamine sulfate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. The weight ratio of calcium carbonate to ascorbic acid is preferably in the range of 1:1 to 1:3. After the weak effervescent disintegration formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed is 4.9 or higher, the solubility of calcium ions may be in the range of 40% to 80% when measured in 900 mL of neutral pure water under stirring at 75 RPM for 30 minutes, and the formulation may be in the form of granules, tablets, or dispersible tablets.

[0221] Another embodiment of the present invention relates to a weak effervescent disintegration formulation comprising calcium carbonate, ascorbic acid, glucosamine salt, and vitamin D3. In a preferred embodiment, the weak effervescent disintegration formulation may comprise calcium carbonate, ascorbic acid, glucosamine salt, vitamin D3, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After the weak effervescent disintegration formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed may be 4.9 or more, the solubility of calcium ions may be 20% or more when measured in 900 mL of neutral pure water under stirring at 75 RPM for 30 minutes, and the formulation may be in the form of a dispersible tablet.

[0222] Another embodiment of the present invention relates to a weak effervescent disintegration formulation comprising calcium carbonate, ascorbic acid, glucosamine sulfate, vitamin D3, and chondroitin sulfate. In a preferred embodiment, the weak effervescent disintegration formulation may comprise calcium carbonate, ascorbic acid, glucosamine sulfate, vitamin D3, chondroitin sulfate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After the weak effervescent disintegration formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed may be 4.9 or more, the solubility of calcium ions may be 20% or more when measured in 900 mL of neutral pure water under stirring at 75 RPM for 30 minutes, and the formulation may be in the form of a dispersible tablet.

[0223] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, ascorbic acid, and one or more vitamins selected from vitamin A, vitamin E, vitamin D3, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, and folic acid. In a preferred embodiment, the weak effervescent formulation may comprise calcium carbonate, ascorbic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and one or more vitamins selected from vitamin A, vitamin E, vitamin D3, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, and folic acid. After the weak effervescent disintegrating formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed may be 4.9 or more, the solubility of calcium ions may be 20% or more when measured in 900 mL of neutral pure water under stirring at 75 RPM for 30 minutes, and the formulation may be in the form of a dispersible tablet.

[0224] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, ascorbic acid, and one or more dietary supplements selected from vitamin A, vitamin D3, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, folic acid, nicotinic acid, pantothenic acid, choline, biotin, iron, copper, zinc, potassium, chloride, magnesium, sodium, and salts thereof, and mixtures thereof. In a preferred embodiment, the weak effervescent formulation may comprise calcium carbonate, ascorbic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and one or more dietary supplements selected from vitamin A, vitamin D3, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, folic acid, nicotinic acid, pantothenic acid, choline, biotin, iron, copper, zinc, potassium, chloride, magnesium, sodium, and salts thereof, and mixtures thereof. After the weakly effervescent disintegrating formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed may be 4.9 or greater, the solubility of calcium ions may be 20% or greater when measured in 900 mL of neutral pure water under stirring at 75 RPM for 30 minutes, and the formulation may be in the form of a dispersible tablet.

[0225] The mild effervescent tablet formulation according to the present invention is suitable for formulation with a wide range of APIs.

[0226] Another embodiment of the present invention relates to a weak effervescent formulation comprising a bicarbonate (e.g., sodium bicarbonate or potassium bicarbonate), a weak organic acid, and an API selected from hemostatic agents, antihypertensive agents, 5-HT3 antagonist antiemetics, sartans, hypoglycemic agents, antiallergic agents, contraceptives, antidepressants, NSAIDs, COX-2 inhibitors, and antiepileptics. In a preferred embodiment, the weak effervescent formulation may comprise a bicarbonate (e.g., sodium bicarbonate or potassium bicarbonate), a weak organic acid, hemostatic agents, antihypertensive agents, 5-HT3 antagonist antiemetics, sartans, hypoglycemic agents, antiallergic agents, contraceptives, antidepressants, NSAIDs, COX-2 inhibitors, and antiepileptics, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000.

[0227] In a preferred embodiment, the low effervescent formulation may comprise bicarbonate (e.g., sodium bicarbonate or potassium bicarbonate), a weak organic acid, an API selected from hemostatic agents, antihypertensive agents, 5-HT3 antagonists antiemetics, sartans, antidiabetics, antiallergic agents, contraceptives, antidepressants, NSAIDs, COX-2 inhibitors, and antiepileptics, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000.

[0228] In another preferred embodiment, the weak effervescent formulation may include a carbonate (e.g., calcium carbonate) and a weak organic acid such as malic acid, maleic acid, succinic acid, adipic acid, fumaric acid, tartaric acid, ascorbic acid, etc., an API, and one or more excipients such as fillers, diluents, lubricants, and bulking agents.

[0229] In another preferred embodiment, the weak effervescent formulation may include a carbonate, such as sodium bicarbonate, a weak acid, such as sodium bitartrate or sodium malate, an API, and one or more excipients, such as fillers, diluents, lubricants, and bulking agents.

[0230] Advantageously, after a weakly effervescent disintegrating formulation is disintegrated in neutral pure water (e.g., about 200 mL of neutral pure water), the pH of the suspension or solution formed is 4.9 or higher, and the formulation may be in the form of an ODT or dispersible tablet. The weight of the tablet determines the disintegration time and therefore whether it is an ODT or dispersible tablet. Disintegration time determines the classification of the formulation. Dispersible tablets usually disintegrate in water within 3 minutes and are commonly administered in two ways: (1) by dispersing the dosage form in a glass containing water, juice, or other aqueous solution or liquid and then taking the resulting suspension or solution by mouth, or (2) by placing the dispersible dosage form in the mouth and taking it without the need to drink water or other liquid. Disintegration time: <1 min = ODT Less than 3 minutes, more than 1 minute = dispersible tablets

[0231] The disintegration time depends on the swelling forces within the tablet. This force can be a physical force resulting from the absorption of water, for example, from cross-linked povidone or cross-linked sodium carboxymethylcellulose. In other embodiments, this force can be due to a chemical reaction that causes an explosion within the tablet due to CO2 generation. However, this chemical reaction must not be too violent or it will burn the tongue. The invention is therefore based on a weakly effervescent disintegrating tablet, characterized in that the pH of the solution or suspension after disintegration or dissolution is 4.9 or higher. A pH of 4.9 or higher has the property of limiting the severity of the acid salt reaction. The higher the pH, for example in the range of pH 6.0 to pH 7, the weakly effervescent CO2 generation reaction that occurs is mitigated. The low effervescent formulations of the present invention can be used in combination with a wide range of APIs, including vitamins, minerals, dietary nutrients, triptans, dihydropyridine calcium channel blockers, antihistamines, 5-HT3 antagonist antiemetics, sartans, alpha-glucosidase inhibitors, antifibrinoline drugs, non-classical antidepressants, selective COX-2 inhibitors, NSAIDs, hormonal contraceptives, and antiepileptic drugs.

[0232] In some embodiments, some formulations may have a low amount of API per tablet (e.g., less than 25 mg of API per tablet), and therefore the final tablet weight may be less than 150 mg. In some embodiments, such formulations may be prepared as dispersible tablets that disintegrate in water within about 3 minutes. In other embodiments, such formulations may be advantageously prepared as ODTs that disintegrate in water in about 1 minute. In preferred embodiments, the amount of API may be less than 20 mg, less than 15 mg, less than 10 mg, less than 5 mg, or less than 3 mg per tablet. In other embodiments, the amount of API may be less than 12 mg per tablet.

[0233] In some embodiments, some formulations may have a moderate amount of API per tablet, e.g., about 25-50 mg, or about 50-100 mg, or about 100-150 mg per tablet. In other embodiments, some formulations may have a high dose of API, e.g., about 150-200 mg API per tablet. Such formulations may be difficult to make into ODTs, since the total tablet weight including the oxide would be 500 mg or more. In some embodiments, tablets with moderate amounts of API (e.g., 50 mg to 100 mg API) can be made into ODTs or dispersible tablets, while tablets with high amounts of API (e.g., 100 mg to 200 mg API) can be made into dispersible tablets, because disintegration requires additional time.

[0234] In a preferred embodiment, the ODT or dispersible tablet is in a suitably stable form. In certain embodiments, the ODT or dispersible tablet is shelf stable for at least 2 months, or at least 4 months, or at least 6 months, or at least 10 months, or at least 12 months, or at least 18 months, or at least 24 months.

[0235] The low effervescent formulations of the present invention may be used in combination with a broad range of APIs including triptans, dihydropyridine calcium channel blockers, antihistamines, sartans, 5-HT3 antagonist antiemetics, alpha-glucosidase inhibitors, antifibrinoline drugs, non-classical antidepressants, selective COX-2 inhibitors, NSAIDs, hormonal contraceptives, and antiepileptic drugs.

[0236] In a preferred embodiment, the stability of a formulation of a basic API containing a weak base can be improved by using bicarbonate as the weak base.

[0237] Triptan drugs include rizatriptan, sumatriptan, zolmitriptan, naratriptan, almotriptan, eletriptan, and frovatriptan, which are called acute drugs and are designed to treat migraine attacks or cluster headaches after the migraine attack or cluster headache attack has begun. Acute drugs help relieve symptoms such as migraine pain, nausea, and sensitivity to light and sound. The rapid dissolution of such drugs is highly advantageous in weak effervescent formulations, such as orally disintegrating or orally disintegrating tablets. In accordance with the present invention, triptan drugs such as rizatriptan, sumatriptan, zolmitriptan, naratriptan, almotriptan, eletriptan, and frovatriptan can be formed into a pair of weakly acidic disintegrating formulations (e.g., tablets or granules) consisting of a weak acid and a carbonate salt, and can include a pair of other excipients such as a filler, diluent, lubricant, and swelling agent. After a weakly foaming disintegration formulation disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher.

[0238] Another embodiment of the present invention relates to a weak foaming formulation comprising calcium carbonate, an acid selected from malic acid, malic acid, adipic acid, fumaric acid, tartaric acid, and ascorbic acid, a leavening agent, a diluent, a filler, a lubricant, and a triptan drug selected from rizatriptan, sumatriptan, zolmitriptan, naratriptan, almotriptan, eletriptan, and frovatriptan, etc. After the triptan disintegrating formulation disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher. Thus, the formulation is in the form of an ODT.

[0239] Another embodiment of the present invention relates to a weak foaming formulation comprising calcium carbonate (e.g., 10 mg), malic acid (e.g., 10 mg), rizatriptan (e.g., 5 mg), cross-linked povidone, microcrystalline cellulose, magnesium stearate, and PEG 6000. After this weak foaming disintegration formulation disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, this formulation is in the form of an orally disintegrating tablet.

[0240] Another embodiment of the present invention relates to a weak foaming formulation comprising calcium carbonate (e.g., 10 mg), malic acid (e.g., 10 mg), sumatriptan (e.g., 25 mg to 100 mg), cross-linked povidone, cross-linked soda carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After this weak foaming disintegrating formulation disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, this formulation is in the form of an orally disintegrating tablet.

[0241] Another embodiment of the present invention relates to a weak foaming formulation comprising calcium carbonate (e.g., 10 mg), malic acid (e.g., 10 mg), zolmitriptan (e.g., 2.5 mg to 5 mg), cross-linked povidone, microcrystalline cellulose, magnesium stearate, and PEG 6000. After this weak foaming disintegrating formulation disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, this formulation is in the form of an orally disintegrating tablet.

[0242] Another embodiment of the present invention relates to a weak foaming formulation comprising calcium carbonate (e.g., 10 mg), malic acid (e.g., 10 mg), naratriptan (e.g., 2.5 mg or 5 mg), cross-linked povidone, microcrystalline cellulose, magnesium stearate, and PEG 6000. After this weak foaming disintegrating formulation disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus, this formulation is in the form of an orally disintegrating tablet.

[0243] Another embodiment of the present invention relates to a weak foaming formulation comprising calcium carbonate (e.g., 10 mg), malic acid (e.g., 10 mg), almotriptan (e.g., 6.25 mg to 12.5 mg), cross-linked povidone, microcrystalline cellulose, magnesium stearate, and PEG 6000. After this weak foaming disintegrating formulation disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, this formulation is in the form of an orally disintegrating tablet.

[0244] Another embodiment of the present invention relates to a weak foaming formulation comprising calcium carbonate (e.g., 10 mg), malic acid (e.g., 15 mg), eletriptan (e.g., 40 mg), cross-linked povidone, cross-linked soda carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After this weak foaming disintegrating formulation disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, this formulation is in the form of an orally disintegrating tablet.

[0245] Another embodiment of the present invention relates to a weak foaming formulation comprising calcium carbonate (e.g., 10 mg), malic acid (e.g., 14 mg), frovatriptan (e.g., 2.5 mg), cross-linked povidone, microcrystalline cellulose, magnesium stearate, and PEG 6000. After this weak foaming disintegration formulation disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, this formulation is in the form of an orally disintegrating tablet.

[0246] Another embodiment of the present invention relates to a weak foaming formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and tramadol hydrochloride. After the weak foaming formulation of tramadol hydrochloride disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus, the formulation is in the form of an orally disintegrating tablet.

[0247] Another composition of the present invention includes calcium carbonate, malic acid, cross-linked povidone, magnesium stearate, and tramadol hydrochloride. After the tramadol hydrochloride composition disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and therefore, the composition is in the form of an orally disintegrating tablet.

[0248] Another composition of the present invention includes calcium carbonate, malic acid, cross-linked povidone, magnesium stearate, and sildenafil citrate. After the sildenafil citrate composition disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the composition is in the form of an orally disintegrating tablet.

[0249] Another formulation of the present invention includes calcium carbonate, malic acid, cross-linked povidone, microcrystalline cellulose, magnesium stearate, and sildenafil citrate. After the sildenafil citrate formulation disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an orally disintegrating tablet. 5-HT3 (5-hydroxytryptamine-3

[0250] Antiemetics of 5-HT3 (5-hydroxytryptamine-3) receptor antagonists include ondansetron, dolasetron, granisetron, palonosetron, ramosetron, etc. These drugs are used to reduce or prevent emesis induced by chemotherapy and radiotherapy, especially for cancer. 5-HT3 antagonists such as ondansetron HCl, dolasetron HCl, granisetron HCl, palonosetron HCl, and ramosetron HCl are soluble in water and therefore cannot be made into ODT by freeze-drying. According to the present invention, water-soluble salts of 5-HT3 antagonists such as ondansetron HCl, dolasetron HCl, granisetron HCl, palonosetron HCl, and ramosetron HCl may be made into weakly effervescent disintegrable preparations, i.e., orally disintegrating tablets or orally disintegrating tablets or granules, containing or essentially consisting of a pair of a weak acid and a carbonate. After such a disintegrable preparation is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher. .

[0251] Another configuration of the present invention includes calcium carbonate (e.g., 10 mg), malic acid (e.g., 14 mg), a 5-HT3 (5-hydroxytryptamine-3) receptor antagonist or a salt thereof selected from ondansetron HCl, dolasetron HCl, granisetron HCl, palonosetron HCl, and ramosetron HCl, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. Such a disintegrating formulation is in the form of an orally disintegrating tablet, since the pH of the suspension or solution formed after disintegration in neutral pure water, e.g., 200 mL of neutral pure water, is 4.9 or higher.

[0252] Another embodiment of the present invention relates to a weakly effervescent disintegrable formulation comprising calcium carbonate, an acid selected from malic acid, maleic acid, citric acid, tartaric acid, and ascorbic acid, a leavening agent, a diluent, a filler, a lubricant, and an antiemetic agent selected from a 5-HT3 antagonist, or a salt thereof, such that after disintegration of the 5-HT3 antagonist disintegrable formulation in neutral pure water, the pH of the suspension formed is 4.9 or more, so that the formulation is in the form of an orally disintegrating tablet.

[0253] Another formulation of the present invention includes calcium carbonate, malic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and ondansetron HCl. The ondansetron HCl components disintegrate in neutral pure water, resulting in a suspension having a pH of 4.9 or greater, such that the formulation is in the form of an orally disintegrating tablet.

[0254] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, malonic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and granisetron hydrochloride. After the weak effervescent formulation of granisetron hydrochloride is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, the formulation is in the form of an ODT.

[0255] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, malonic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and ramosetron hydrochloride. After the weak effervescent formulation of ramosetron hydrochloride is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, the formulation is in the form of an ODT.

[0256] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, malonic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and palonosetron. After the weak effervescent formulation of palonosetron is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, the formulation is in the form of an ODT.

[0257] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, malonic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and dolasetron hydrochloride. After the weak effervescent formulation of dolasetron hydrochloride is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, the formulation is in the form of an ODT. Calcium channel blockers

[0258] Calcium channel antagonists such as amlodipine, L-amlodipine, felodipine, nitrendipine, nimodipine, benidipine, nifedipine, etc. have a sustained antihypertensive effect and patients can take them once a day or twice a day. However, if a patient experiences a sudden rise in blood pressure, it is preferable to take a rapid antihypertensive drug. In accordance with the present invention, calcium channel antagonists such as amlodipine, L-amlodipine, felodipine, nitrendipine, benidipine, nimodipine, nifedipine, etc. can be processed into weakly effervescent disintegrable preparations, such as orally disintegrating tablets or particles, containing a weak acid and a carbonate. These preparations may contain one or more excipients, such as a filler, a diluent, a lubricant, and a swelling agent. After the weakly effervescent disintegrable preparation disintegrates in neutral (pure) water, the pH of the suspension or solution formed is 4.9 or higher. .

[0259] In another embodiment, the invention comprises a weak effervescent formulation comprising a carbonate, a weak acid, a calcium channel antagonist selected from amlodipine, L-amlodipine, felodipine, nitrendipine, benidipine, nifedipine, lacidipine, nimodipine, lecardipine, manidipine, nicardipine, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After the weak effervescent disintegrable formulation is disintegrated in neutral purified water (e.g., 200 mL of neutral purified water), the pH of the suspension or solution formed is 4.9 or higher, and the formulation is in the form of an orally dispersible tablet.

[0260] Other embodiments of the present invention include weak effervescent formulations containing sodium bicarbonate, potassium bicarbonate, monosodium tartrate, monosodium acetate, monosodium citrate, monosodium tartrate, monopotassium acetate, monopotassium citrate, dihydrogen pyridine derivative calcium channel antagonists such as nifedipine, felodipine, amlodipine, revamlodipine, benidipine, nitrendipine, nimodipine, lacidipine. After the weak effervescent disintegrable formulation is disintegrated with neutral pure water, the pH of the suspension or solution formed is between 4.9 and 7.5, and the formulation is in the form of an ODT.

[0261] Another embodiment of the invention includes a weak effervescent formulation comprising sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, nifedipine. After the weak effervescent nifedipine formulation disintegrates in neutral water, the pH of the suspension or solution formed is 4.9 or greater, and the formulation is in the form of an ODT.

[0262] Another formulation of the present invention includes sodium bicarbonate, monosodium tartrate, monosodium malate, monosodium maleate, monosodium succinate, monosodium citrate, cross-linked povidone, magnesium stearate, and nifedipine. After the composition of nifedipine disintegrates in neutral water, the pH of the suspension formed is 4.9 or higher, and thus, this formulation is in the form of an ODT.

[0263] Related to another embodiment of the present invention is a weak effervescent formulation comprising sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and felodipine. After the weak effervescent formulation of felodipine is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an ODT.

[0264] Related to another embodiment of the present invention is a weak effervescent formulation comprising sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and amlodipine. After the weak effervescent formulation of amlodipine is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or greater, and thus, the formulation is in the form of an ODT.

[0265] Related to another embodiment of the present invention is a weak effervescent formulation comprising sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and revamlodipine. After the weak effervescent formulation of revamlodipine is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus, the formulation is in the form of an ODT.

[0266] Related to another embodiment of the present invention is a weak effervescent formulation comprising sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and lacidipine. After the weak effervescent formulation of lacidipine is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an ODT.

[0267] Related to another embodiment of the present invention is a weak effervescent formulation comprising sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and benidipine. After the weak effervescent formulation of benidipine is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an ODT.

[0268] Related to another embodiment of the present invention is a weak effervescent formulation comprising sodium bicarbonate, monosodium tartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and nitrendipine. After the nitrendipine invention disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or greater, and thus, the formulation is in the form of an ODT.

[0269] Related to another embodiment of the present invention is a weakly effervescent formulation comprising sodium bicarbonate (e.g., 10 mg), sodium bicarbonate tartrate (e.g., 13 mg), nimodipine (e.g., 10 mg), cross-linked povidone, microcrystalline cellulose, magnesium stearate, and PEG 6000. After the weakly effervescent disintegrable formulation is disintegrated in 200 mL of neutral purified water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an orally dispersible tablet.

[0270] Another formulation of the present invention includes sodium bicarbonate, monosodium tartrate, monosodium malate, monosodium maleate, monosodium succinate, monosodium citrate, nimodipine, cross-linked povidone, and magnesium stearate. After this composition is disintegrated in 200 mL of neutral purified water, the pH of the suspension formed is 4.9 or higher, and thus, this formulation is in the form of an orally dispersible tablet. Antihistamines

[0271] Antihistamines are a class of APIs that inhibit histamine release from histamine-1 receptors and are primarily used to treat allergies or cold and flu symptoms. However, some first generation antihistamines may also be used to treat other conditions. Antihistamines are very helpful in relieving symptoms of allergic reactions, such as swelling and inflammation. In accordance with the present invention, antihistamines such as levocetirizine, hydroxyzine, cetirizine, promethazine, fexofenadine, loratadine, terfenadine, desloratadine, chlorpheniramine, dexchlorpheniramine, clemastine, triprolidine, and diphenhydramine can be processed into weakly effervescent disintegrable preparations, e.g., orally disintegrating tablets or particles, consisting of a weak acid and a carbonate and containing one or more excipients selected from a filler, a diluent, a lubricant, and a swelling agent. After these weakly effervescent disintegrable preparations are disintegrated in neutral (pure) water, the pH of the suspension or solution formed is 4.9 or higher.

[0272] Related to another embodiment of the present invention is a weakly effervescent formulation comprising carbonate, a weak acid, levocetirizine, hydroxyzine, cetirizine, promethazine, fexofenadine, diphenhydramine, loratadine, terfenadine, desloratadine, chlorpheniramine, dexchlorpheniramine, clemastine, triprolidine, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After the weakly effervescent disintegrable formulation is disintegrated in 200 mL of neutral pure water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an orally dispersible tablet.

[0273] Another formulation of the present invention includes calcium carbonate, an organic acid selected from malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, and mixtures thereof, cross-linked povidone, and fexofenadine. After the composition of the present invention is disintegrated in 200 mL of neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT.

[0274] Other embodiments of the invention include calcium carbonate, malic acid, and an antihistamine such as cetirizine, levocetirizine, hydroxyzine, promethazine, fexofenadine, loratadine, terfenadine, desloratadine, chlorpheniramine, dexchlorpheniramine, clemastine, triprolidine, and diphenhydramine. After the weakly effervescent disintegrable formulation of this antihistamine is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or greater, and thus the formulation is in the form of an ODT.

[0275] Another composition of the present invention includes calcium carbonate, malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, cetirizine, levocetirizine, hydroxyzine, promethazine, fexofenadine, loratadine, terfenadine, desloratadine, chlorpheniramine, dexchlorpheniramine, clemastine, triprolidine, diphenhydramine, cross-linked povidone, and magnesium stearate. After the composition of the present invention is disintegrated in 200 mL of neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus, the formulation is in the form of an ODT.

[0276] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and cetirizine. After the weak effervescent disintegrable formulation of cetirizine disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT.

[0277] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and levocetirizine. After the weak effervescent disintegrable formulation of levocetirizine disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT.

[0278] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and loratadine. After the weak effervescent disintegrable formulation of loratadine disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or greater, and thus the formulation is in the form of an ODT.

[0279] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and desloratadine. After the weak effervescent disintegrable formulation of desloratadine disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or greater, and thus the formulation is in the form of an ODT.

[0280] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and fexofenadine. After the weak effervescent disintegrable formulation of fexofenadine disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT.

[0281] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and terfenadine. After the weak effervescent disintegrable formulation of terfenadine disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet).

[0282] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and chlorpheniramine. After the weak effervescent disintegrable formulation of chlorpheniramine disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet).

[0283] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and clemastine. After the weak effervescent disintegrable formulation of clemastine disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet).

[0284] Another composition of the present invention includes calcium carbonate, fexofenadine, cross-linked povidone, and an organic acid selected from malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, citric acid, and magnesium stearate. After the composition of fexofenadine disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus, the composition is an ODT (orally disintegrating tablet). Alpha-glucosidase inhibitors

[0285] Alpha-glucosidase inhibitors such as acarbose (Acarbose) act by competitive and reversible inhibition of intestinal enzymes. They slow down carbohydrate digestion and glucose absorption. This results in a smaller and slower rise in blood glucose levels after a meal that lasts effectively all day. In accordance with the present invention, acarbose (Acarbose) and the like can be formulated into a weakly effervescent disintegrating preparation, e.g., an orally disintegrating tablet or granule, consisting of a pair of a weak acid and carbonic acid and containing one or more excipients selected from a filler, a diluent, a lubricant, and a swelling agent. After the weakly effervescent disintegrating preparation of an alpha-glucosidase inhibitor disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher.

[0286] Related to other embodiments of the present invention is a weakly effervescent formulation comprising calcium carbonate, a binary acid selected from malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, and mixtures thereof; a bulking agent, a diluent, a filler, a lubricant, and an alpha-glucosidase inhibitor selected from acarbose. After the weakly effervescent disintegrable formulation of alpha-glucosidase disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or greater, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or granules.

[0287] Related to another embodiment of the present invention is a weak effervescent formulation comprising a carbonate, a weak acid, an alpha-glucosidase inhibitor selected from acarbose, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After the weak effervescent disintegrable formulation of the alpha-glucosidase inhibitor disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an orally disintegrating tablet.

[0288] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and acarbose. After the weak effervescent disintegrable formulation of acarbose disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet).

[0289] Another embodiment of the weak effervescent formulation includes sodium bicarbonate, monohydrated sodium citrate, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and voglibose. After the weak effervescent formulation of voglibose is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet).

[0290] Related to another embodiment of the present invention is a weak effervescent formulation comprising sodium bicarbonate, monohydrated sodium citrate, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and miglibose. After the weak effervescent formulation of miglitol (miglibose) is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or granules.

[0291] Another embodiment of the composition of the present invention includes calcium carbonate, an organic acid selected from malic acid, maleic acid, oenothermic acid, ascorbic acid, and citric acid, cross-linked povidone, microcrystalline cellulose, magnesium stearate, and miglitol. After the composition of miglitol disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the composition is in the form of an ODT (orally disintegrating tablet).

[0292] Another composition of the present invention includes calcium carbonate, acarbose, an organic acid selected from malic acid, maleic acid, oenothermic acid, ascorbic acid, and citric acid, cross-linked povidone, microcrystalline cellulose, and magnesium stearate. After the acarbose composition disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the composition is in the form of an ODT (orally disintegrating tablet).

[0293] Another composition of the present invention includes calcium carbonate, citric acid, acarbose, cross-linked povidone, microcrystalline cellulose, and magnesium stearate. After the acarbose composition disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the composition is in the form of an ODT (orally disintegrating tablet). Angiotensin II receptor blockers (sartans)

[0294] Sartans are angiotensin II receptor antagonists, which bind to the angiotensin II receptor type 1 (AT1) and inhibit the arterial constricting and sodium-retentive effects of the renin-angiotensin system. Their main applications are in the treatment of hypertension, diabetic nephropathy, and congestive heart failure. According to the present invention, sartans, such as losartan, candesartan, telmisartan, valsartan, fimasartan, and irbesartan, are made into a weakly effervescent disintegrable formulation (e.g., orally disintegrating tablet or granule) consisting of a pair of a weak acid and a carbonic acid, and containing one or more excipients selected from a filler, a diluent, a lubricant, and a swelling agent. After the weakly effervescent disintegrable formulation of sartans is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or dispersible tablet.

[0295] Another embodiment of the present invention relates to a weak effervescent formulation comprising sodium bicarbonate, potassium bicarbonate, malic acid monohydrate, maleic acid monohydrate, succinic acid monohydrate, adipic acid monohydrate, citric acid, ascorbic acid, weineric acid, potassium maleate monohydrate, sodium maleate monohydrate, potassium succinate monohydrate, sodium succinate monohydrate, potassium gallate monohydrate, sodium gallate monohydrate, potassium oxalate monohydrate, sodium oxalate monohydrate, and an angiotensin II receptor antagonist (sartan) selected from losartan, candesartan, telmisartan, valsartan, olmesartan, fimasartan, irbesartan or a salt thereof. After the weak effervescent disintegrable formulation of sartan disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or dispersible tablet.

[0296] In another embodiment, the present invention comprises a weak effervescent formulation comprising a carbonate, a weak acid (optimally not a binary acid), an angiotensin II receptor antagonist (Sartan) selected from losartan, candesartan, telmisartan, valsartan, olmesartan, fimasartan, irbesartan, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After the Sartan weak effervescent disintegrable formulation disintegrates in 200 mL of neutral purified water, the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet).

[0297] Related to another embodiment of the present invention is a weakly effervescent formulation comprising sodium bicarbonate, tartaric acid monohydrate, a filler, a diluent, a lubricant, a swelling agent, and an effective therapeutic dose of losartan. After the weakly effervescent disintegrable formulation of losartan disintegrates in 200 mL of neutral purified water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an ODT (orally disintegrating tablet).

[0298] Related to another embodiment of the present invention is a weakly effervescent formulation comprising sodium bicarbonate, tartaric acid monohydrate, a filler, a diluent, a lubricant, a swelling agent, and an effective therapeutic dose of candesartan, wherein after the weakly effervescent disintegrable formulation of candesartan disintegrates in 200 mL of neutral purified water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an ODT (orally disintegrating tablet).

[0299] Related to another embodiment of the present invention is a weakly effervescent formulation comprising sodium bicarbonate, tartaric acid monohydrate, a filler, a diluent, a lubricant, a swelling agent, and an effective therapeutic dose of telmisartan, wherein after the weakly effervescent disintegrable formulation of telmisartan is disintegrated in 200 mL of neutral purified water, the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or dispersible tablet.

[0300] Related to another embodiment of the present invention is a weakly effervescent formulation comprising sodium bicarbonate, tartaric acid monohydrate, a filler, a diluent, a lubricant, a swelling agent, and an effective therapeutic dose of valsartan. After the weakly effervescent disintegrable formulation of valsartan disintegrates in 200 mL of neutral purified water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or dispersible tablet.

[0301] Related to another embodiment of the present invention is a weakly effervescent formulation comprising sodium bicarbonate, tartaric acid monohydrate, a filler, a diluent, a lubricant, a swelling agent, and an effective therapeutic dose of fimasartan, wherein after the weakly effervescent disintegrable formulation of fimasartan is disintegrated in 200 mL of neutral purified water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or dispersible tablet.

[0302] Related to another embodiment of the present invention is a weakly effervescent formulation comprising sodium bicarbonate, tartrate monohydrate, a filler, a diluent, a lubricant, a swelling agent, and an effective therapeutic dose of irbesartan, wherein after the weakly effervescent disintegrable formulation of irbesartan disintegrates in 200 mL of neutral purified water, the pH of the suspension or solution formed is 4.9 or greater, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or dispersible tablet.

[0303] Related to another embodiment of the present invention is a weak effervescent formulation comprising sodium bicarbonate, tartrate monohydrate, microcrystalline cellulose, cross-linked soda carmellose, magnesium stearate, PEG 6000, and olmesartan. After the weak effervescent disintegrable formulation of olmesartan disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet).

[0304] Related to another embodiment of the present invention is a formulation comprising sodium bicarbonate, tartrate monohydrate, cross-linked soda carmellose, magnesium stearate, and irbesartan. After the formulation of irbesartan disintegrates in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or dispersible tablet.

[0305] Another aspect of the present invention is a formulation comprising sodium bicarbonate, mono-sodium tartrate, mono-sodium malate, mono-sodium maleate, mono-sodium succinate, mono-potassium tartrate, mono-potassium maleate, mono-potassium succinate, mono-potassium tartrate, cross-linked soda carmellose, magnesium stearate, and irbesartan. After the formulation of irbesartan disintegrates in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is in the form of an ODT (orally disintegrating tablet) or dispersible tablet. Antifibrinolytic drugs

[0306] Antifibrinolytic drugs consist of 6-aminocaproic acid, p-hydroxybenzylamine, and tranexamic acid. Such drugs inhibit the activation of fibrinogen, preventing it from being activated to the fibrinolysin enzyme, and prolong the period of dissolution of blood clots. 6-aminocaproic acid, tranexamic acid, and p-hydroxybenzylamine will be made into a weakly effervescent disintegrating preparation, for example in the form of an orally disintegrating or dispersible tablet, consisting of a weak acid and a carbonate, a filler, a diluent, a lubricant, and a swelling agent. After the weakly effervescent disintegrating preparation of antifibrinolytic drugs disintegrates in neutral water, the pH of the suspension formed is 4.9 or higher, and this preparation can be prepared in the form of an ODT or dispersible tablet.

[0307] In an embodiment, the present invention includes a weak effervescent formulation comprising a carbonate, a weak acid, an antifibrinolytic therapy selected from 6-aminocaproic acid, tranexamic acid, p-hydroxybenzylamine, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After the weak effervescent disintegrable formulation of the antifibrinolytic therapy is disintegrated in neutral pure water, the pH of the suspension or solution formed is 4.9 or higher, and thus the formulation is prepared in the form of a dispersible tablet.

[0308] Related to another embodiment of the present invention is a weakly effervescent formulation consisting of an acid selected from sodium bicarbonate, potassium bicarbonate, monoxide salts (monoxide malic acid, monoxide maleic acid, monoxide succinic acid, monoxide adipic acid, monoxide oxalate, monoxide citric acid, monoxide tartaric acid, potassium monoxide malic acid, potassium monoxide maleic acid, potassium monoxide succinic acid, potassium monoxide adipic acid, potassium monoxide oxalate, potassium monoxide tartaric acid, and mixtures thereof); an antifibrinolytic therapeutic agent selected from 6-aminocaproic acid, tranexamic acid, and p-hydroxybenzylamine. After the weakly effervescent disintegrable formulation of antifibrinolytic therapeutic agent is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation can be prepared in the form of an ODT or dispersible tablet.

[0309] In an embodiment of the present invention, the weak effervescent formulation is selected from sodium bicarbonate, maleic monoxide, cross-linked soda carmellose, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and 6-aminocaproic acid. After the weak effervescent disintegrable formulation of 6-aminocaproic acid is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, and therefore the formulation is prepared in the form of an ODT or dispersible tablet.

[0310] Related to another embodiment of the present invention is a weak effervescent formulation selected from sodium bicarbonate, maleic monoxide, cross-linked soda carmellose, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and tranexamic acid. After the weak effervescent disintegrable formulation of tranexamic acid is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, and therefore the formulation is prepared in the form of an ODT or dispersible tablet.

[0311] Related to another embodiment of the present invention is a weak effervescent formulation selected from sodium bicarbonate, tartrate monooxide, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and p-hydroxybenzylamine. After the weak effervescent disintegrable formulation of p-hydroxybenzylamine is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, and thus the formulation is prepared in the form of an ODT or dispersible tablet.

[0312] Related to another embodiment of the present invention is a composition consisting of tranexamic acid, sodium bicarbonate, potassium bicarbonate, monoxide malic acid, monoxide maleic acid, monoxide succinic acid, monoxide succinic acid, monoxide citric acid, monoxide tartaric acid, potassium monoxide malic acid, potassium monoxide maleic acid, potassium monoxide succinic acid, potassium monoxide succinic acid, potassium monoxide citric acid, potassium monoxide tartrate, cross-linked soda carmellose, and magnesium stearate. After the tranexamic acid composition is disintegrated with neutral pure water, the pH of the suspension formed is 4.9 or higher, and therefore the formulation is prepared in the form of an ODT or dispersible tablet. Serotonin reuptake inhibitors

[0313] Serotonin reuptake inhibitors are a type of antidepressant that act by inhibiting the reuptake of serotonin. The class of serotonin reuptake inhibitors includes fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram. These drugs can be formulated into weakly effervescent disintegrating preparations, e.g., orally disintegrating or orally disintegrating tablets, consisting of a pair consisting of a weak acid and a carbonate, and one or more excipients selected from fillers, diluents, lubricants, and bulking agents. Serotonin reuptake inhibitor preparations disintegrate in neutral water such that the pH of the resulting suspension or solution is greater than 4.9.

[0314] Another embodiment of the present invention comprises calcium carbonate, malic acid, an acid selected from fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, or an acid selected from ascorbic acid, and a selective serotonin reuptake inhibitor. The weakly effervescent disintegration formulation of the selective serotonin reuptake inhibitor disintegrates in neutral pure water, and the pH of the resulting suspension is greater than 4.9. Therefore, the formulation can be prepared in the form of an ODT or dispersible tablet.

[0315] In another embodiment, the invention relates to a weakly effervescent formulation comprising calcium carbonate, malic acid, a serotonin reuptake inhibitor selected from fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram or a salt thereof, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After disintegration in 200 mL of neutral purified water, the resulting suspension or solution has a pH greater than 4.9. Thus, the formulation can be prepared in the form of an orally disintegrating tablet.

[0316] Another embodiment of the present invention relates to a weak effervescent formulation consisting of calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and fluoxetine. The weak effervescent formulation of fluoxetine disintegrates in neutral pure water, and the resulting suspension has a pH greater than 4.9. Therefore, the formulation can be prepared in the form of an ODT.

[0317] Another embodiment of the present invention relates to a weakly effervescent formulation consisting of calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and paroxetine. After disintegration in neutral pure water, the resulting suspension has a pH greater than 4.9. Therefore, the formulation can be prepared in the form of an ODT.

[0318] Another embodiment of the present invention relates to a weak effervescent formulation consisting of calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and sertraline. The weak effervescent formulation of sertraline, after disintegration in neutral pure water, has a pH of the resulting suspension greater than 4.9. Therefore, the formulation can be prepared in the form of an ODT or dispersible tablet.

[0319] Another embodiment of the present invention relates to a weak effervescent formulation consisting of calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and fluvoxamine. The weak effervescent formulation of fluvoxamine, after disintegration in neutral pure water, has a pH of the resulting suspension greater than 4.9. Therefore, the formulation can be prepared in the form of an ODT or dispersible tablet.

[0320] Another embodiment of the present invention relates to a weak effervescent formulation consisting of calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and citalopram. The weak effervescent formulation of citalopram, after disintegration in neutral pure water, has a pH of the resulting suspension greater than 4.9. Therefore, the formulation can be prepared in the form of an ODT or dispersible tablet.

[0321] Another embodiment of the present invention relates to a weak effervescent formulation consisting of calcium carbonate, malic acid, cross-linked povidone, cross-linked soda carmellose, microcrystalline cellulose, magnesium stearate, PEG 6000, and escitalopram. The weak effervescent formulation of escitalopram, after disintegration in neutral pure water, has a pH of the resulting suspension greater than 4.9. Therefore, the formulation can be prepared in the form of an ODT. Atypical antidepressants

[0322] The atypical antidepressants, including aripiprazole, olanzapine, quetiapine, ziprazidone, clozapine, and paliperidone, can be processed into weakly effervescent disintegrable preparations, such as orally disintegrating tablets or granules, which consist of a weak acid and a carbonate salt and contain one or more excipients selected from a filler, a diluent, a lubricant, and a swelling agent. After the atypical antidepressant preparation is disintegrated in neutral pure water, the pH of the resulting suspension or solution is greater than 4.9.

[0323] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, an acid selected from malic acid, citric acid, and ascorbic acid, and an atypical antidepressant selected from aripiprazole, olanzapine, quetiapine, ziprazidone, clozapine, and paliperidone, wherein after the formulation of the atypical antidepressant is disintegrated in neutral pure water, the resulting suspension or solution has a pH of 4.9 or greater.

[0324] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and aripiprazole. After the aripiprazole formulation is disintegrated in neutral pure water, the pH of the resulting suspension or solution is 4.9 or greater.

[0325] Another embodiment of the invention relates to a weak effervescent formulation comprising calcium carbonate, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and olanzapine. After the olanzapine formulation is disintegrated in neutral pure water, the pH of the resulting suspension or solution is 4.9 or greater.

[0326] Another embodiment of the invention relates to a weak effervescent formulation comprising calcium carbonate, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and clozapine. After the clozapine formulation is disintegrated in neutral pure water, the pH of the resulting suspension or solution is 4.9 or greater.

[0327] Another embodiment of the invention relates to a weak effervescent formulation comprising calcium carbonate, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and quetiapine. After the formulation of quetiapine is disintegrated in neutral pure water, the pH of the resulting suspension or solution is 4.9 or greater.

[0328] Another embodiment of the invention relates to a weak effervescent formulation comprising calcium carbonate, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and ziprazidone hydrochloride. After the ziprazidone formulation is disintegrated in neutral pure water, the pH of the resulting suspension or solution is 4.9 or greater.

[0329] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and paliperidone. After the paliperidone formulation is disintegrated in neutral pure water, the resulting suspension has a pH of 4.9 or greater.

[0330] Another embodiment of the invention relates to a weakly effervescent formulation comprising calcium carbonate, tartaric acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and nicorandil. After the nicorandil formulation is disintegrated in neutral pure water, the pH of the resulting suspension is 4.9 or greater. Nonsteroidal anti-inflammatory drugs

[0331] Nonsteroidal anti-inflammatory drugs are used to treat osteoarthritis, rheumatoid arthritis, acute pain, menstrual cramps, and period symptoms.

[0332] Another embodiment of the present invention relates to a weakly effervescent formulation comprising calcium carbonate, an acid selected from malic acid, tartaric acid, succinic acid, and ascorbic acid, a leavening agent, a diluent, a filler, a lubricant, and a nonsteroidal anti-inflammatory drug selected from diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, oxaprozin, and piroxicam. After the weakly effervescent disintegration formulation of the nonsteroidal anti-inflammatory drug disintegrates in neutral pure water, the pH of the suspension formed is greater than 4.9, and thus the formulation is prepared in the form of an ODT or dispersible tablet.

[0333] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and ibuprofen. After the weak effervescent formulation of ibuprofen disintegrates in neutral water, the pH of the suspension formed is greater than 4.9, and thus the formulation is prepared in the form of an ODT or dispersible tablet.

[0334] Another embodiment of the invention relates to a composition comprising ibuprofen, calcium carbonate, malic acid, succinic acid, ascorbic acid, cross-linked povidone, microcrystalline cellulose, and magnesium stearate. After the ibuprofen composition disintegrates in neutral water, the pH of the suspension formed is greater than 4.9, and thus the formulation is prepared in the form of an ODT or dispersible tablet.

[0335] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and piroxicam. After the weak effervescent formulation of piroxicam is disintegrated in neutral pure water, the pH of the suspension formed is greater than 4.9, and thus the formulation is prepared in the form of an ODT.

[0336] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, malic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and Oxaprozin. After the weak effervescent formulation of Oxaprozin is disintegrated in neutral water, the pH of the suspension formed is greater than 4.9, and thus the formulation is prepared in the form of an ODT.

[0337] Another embodiment of the present invention relates to a weak effervescent formulation comprising baking soda, sodium bitartrate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and sodium valproate. After the weak effervescent formulation is disintegrated in neutral purified water, the pH of the suspension formed is greater than 4.9, and thus the formulation is prepared in the form of an ODT or dispersible tablet.

[0338] Another embodiment of the present invention relates to a weak effervescent formulation comprising baking soda, sodium bitartrate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and phenytoin sodium. After the weak effervescent formulation is disintegrated in neutral purified water, the pH of the suspension formed is greater than 4.9, and thus the formulation is prepared in the form of an ODT or dispersible tablet.

[0339] Another embodiment of the composition of the present invention includes phenytoin sodium, baking soda, potassium bicarbonate, sodium bitartrate, maleic bitartrate, fumaric bitartrate, citric bitartrate, tartrate, tartrate, tartrate, citric bitartrate, tartrate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and magnesium stearate. After the composition of phenytoin sodium is disintegrated in neutral pure water, the pH of the suspension formed is greater than 4.9, and thus the formulation is prepared in the form of an ODT or dispersible tablet. Selective COX-2 inhibitors

[0340] The celecoxib composition includes 65 mg to 200 mg of celecoxib, 65 mg to 800 mg of povidone, 65 mg to 160 mg of cross-linked sodium carboxymethylcellulose, magnesium stearate, and a trace amount of PVPK30, and the composition is in the form of granules, capsules, and tablets and has a dissolution rate of 60% or more of celecoxib at 120 minutes after testing in 1000 mL of pH 7 sodium phosphate buffer containing 2.5 g of sodium dodecyl sulfate at 50 RPM.

[0341] Another composition of celecoxib includes 65 mg to 200 mg of celecoxib, 65 mg to 800 mg of povidone, 65 mg to 160 mg of cross-linked sodium carboxymethylcellulose, magnesium stearate, and a trace amount of PVPK30, said composition being in the form of granules or tablets, and having a dissolution rate of 60% or more of celecoxib in 1000 mL of pH 7 sodium phosphate buffer containing 2.5 g of sodium dodecyl sulfate and a dissolution rate of 85% or more of calcium ions in 900 mL of neutral water at 120 minutes after testing. Another composition of imrecoxib contains 40 mg to 100 mg of imrecoxib, 40 mg to 480 mg of povidone tetraacetate, and 40 mg to 480 mg of povidone tetraacetate, the composition being in the form of granules, capsules, or tablets.

[0342] Another composition of imrecoxib contains 40 mg to 100 mg of imrecoxib, 40 mg to 480 mg of povidone tetrahydrate, and 30 mg to 60 mg of calcium carbonate, said composition being in the form of granules, tablets, or capsules.

[0343] Another composition of the invention is 65 mg to 160 mg of celecoxib in the form of a granule, capsule, or tablet having a dissolution rate of 60% or more of celecoxib after a 120 minute dissolution test in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate, and 65 mg to 160 mg of celecoxib in the form of a granule, capsule, or tablet having a dissolution rate of 60% or more of celecoxib after a 120 minute dissolution test in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate.

[0344] Another composition of the invention is 65 mg to 160 mg of celecoxib in the form of a granule, capsule, or tablet having a dissolution rate of 60% or more of celecoxib after a 120 minute dissolution test in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate, and 65 mg to 160 mg of celecoxib in the form of a granule, capsule, or tablet having a dissolution rate of 60% or more of celecoxib after a 120 minute dissolution test in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate.

[0345] Another composition of the invention is in the form of granules, capsules, or tablets having a dissolution rate of 60% or more of celecoxib after a dissolution test of 65 mg to 160 mg of celecoxib in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate for 120 minutes, and a dissolution rate of 60% or more of celecoxib after a dissolution test of 65 mg to 160 mg of celecoxib in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate for 120 minutes. Other compositions of the invention include 65 mg to 160 mg of celecoxib in the form of a granule, capsule, or tablet having a dissolution rate of 60% or more of the celecoxib in a dissolution test after 120 minutes in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate, and 65 mg to 160 mg of celecoxib in the form of a granule, capsule, or tablet having a dissolution rate of 60% or more of the celecoxib in a dissolution test after 120 minutes in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate.

[0346] Other compositions of the invention include 65 mg to 160 mg of celecoxib in the form of a granule, capsule, or tablet having a dissolution rate of 60% or more of the celecoxib in a dissolution test in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate after 120 minutes, and 65 mg to 160 mg of celecoxib in the form of a granule, capsule, or tablet having a dissolution rate of 60% or more of the celecoxib in a dissolution test in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate after 120 minutes.

[0347] Other compositions of the invention include 65 mg to 160 mg of celecoxib in the form of granules, capsules, or tablets having a dissolution rate of 60% or more of celecoxib in a dissolution test after 120 minutes in 1000 mL of sodium phosphate buffer / 0.25% sodium dodecyl sulfate, and in the form of tablets, granules, or capsules containing celecoxib, calcium carbonate, phosphate, cross-linked povidone, cross-linked carboxymethylcellulose, microcrystalline cellulose, and magnesium stearate.

[0348] Other compositions of the invention include celecoxib, calcium carbonate, malonic acid phosphate, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, microcrystalline cellulose, and magnesium stearate, in the form of a tablet, granules, or capsule.

[0349] Other compositions of the invention include celecoxib, calcium carbonate, maleic acid, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, microcrystalline cellulose, and magnesium stearate in the form of a tablet, granule, or capsule.

[0350] Other compositions of the invention include celecoxib, calcium carbonate, tartaric acid, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, microcrystalline cellulose, and magnesium stearate in the form of a tablet, granule, or capsule.

[0351] Other compositions of the invention include celecoxib, calcium carbonate, citric acid, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, microcrystalline cellulose, and magnesium stearate in the form of a tablet, granule, or capsule.

[0352] Other compositions of the invention include celecoxib, calcium carbonate, succinic acid, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, microcrystalline cellulose, and magnesium stearate in the form of a tablet, granule, or capsule.

[0353] Other compositions of the invention include celecoxib, calcium carbonate, ascorbic acid, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, microcrystalline cellulose, and magnesium stearate in the form of granules, capsules, or tablets.

[0354] Selective COX-2 inhibitors, such as celecoxib, etoricoxib, and imrecoxib, are used to treat osteoarthritis, rheumatoid arthritis, and acute pain. Selective COX-2 inhibitors are formulated to be weakly effervescent disintegrating preparations, i.e., disintegrating tablets or orally disintegrating tablets, containing, for example, a pair consisting of a weak acid and a carbonate salt and one or more excipients selected from fillers, diluents, lubricants, and bulking agents. After a weakly effervescent disintegrating preparation of a selective COX-2 inhibitor disintegrates in neutral pure water, the pH of the suspension formed is greater than 4.9.

[0355] In another embodiment of the present invention, the present invention relates to a weak effervescent formulation comprising a selective COX-2 inhibitor selected from celecoxib, etoricoxib, and imrecoxib, which comprises calcium carbonate, malonic acid phosphate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000, such that after disintegration in neutral pure water, the pH of the suspension formed is greater than 4.9.

[0356] In another embodiment of the present invention, the present invention relates to a weak effervescent formulation comprising a selective COX-2 inhibitor selected from celecoxib and imrecoxib, comprising calcium carbonate, tartaric acid, maleic acid, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000 such that after disintegration in neutral pure water, the pH of the suspension formed is greater than 4.9.

[0357] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malonic acid phosphate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and celecoxib, where the pH of the suspension formed after disintegration of the weak effervescent formulation of celecoxib in neutral pure water is greater than 4.9, and thus the formulation is in the form of an ODT or orally disintegrating tablet.

[0358] Related to another embodiment of the present invention is a weak effervescent formulation comprising sodium bicarbonate, monohydrogen tartrate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and etoricoxib, where the pH of the suspension formed after the weak effervescent formulation of etoricoxib is disintegrated in neutral pure water is greater than 4.9, and thus the formulation is in the form of an ODT or orally disintegrating tablet.

[0359] Related to another embodiment of the present invention is a weak effervescent formulation comprising calcium carbonate, malonic acid phosphate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and imrecoxib, where the pH of the suspension formed after the weak effervescent formulation of imrecoxib is disintegrated in neutral pure water is greater than 4.9, and thus the formulation is in the form of an ODT or orally disintegrating tablet. Hormonal contraceptives

[0360] Hormonal contraceptives, such as desogestrel, norgestrel, levonorgestrel, megestrol, norethisterone, norgestimate, norethisterone oxime, ethinyl estradiol, quinestrol, decetinyl estradiol, megestrol acetate, and progesterone, are formulated into weakly effervescent disintegrating preparations, such as disintegrating tablets or orally disintegrating tablets, containing a pair of a weak acid and a carbonate and one or more excipients selected from fillers, diluents, lubricants, and swelling agents. After a weakly effervescent disintegrating preparation of a hormonal contraceptive disintegrates in neutral water, the pH of the suspension or solution formed is greater than 4.9.

[0361] Other embodiments of the present invention include sodium bicarbonate, potassium bicarbonate, monosodium hydrogen tartrate, monosodium hydrogen tartrate maleate, monosodium hydrogen tartrate succinate, monosodium hydrogen tartrate adipate, monosodium hydrogen tartrate oxalate, monosodium hydrogen tartrate citrate, monosodium hydrogen tartrate tartrate, monopotassium hydrogen tartrate maleate, monopotassium hydrogen tartrate maleate, monopotassium hydrogen tartrate succinate, monopotassium hydrogen tartrate ... The present invention relates to a weakly effervescent preparation comprising monopotassium enoate, monopotassium tartrate, ascorbic acid, a bulking agent, a diluent, a filler, a lubricant, and a hormonal contraceptive selected from desagestrel, norgestrel, levonorgestrel, megestrol, noresterone, norgestimate, noresterone oxime, ethinyl estradiol, quinistrol, desginyl estradiol, megestrol acetate, progesterone, or a combination thereof. After the weakly effervescent disintegration preparation of the hormonal contraceptive disintegrates in neutral pure water, the pH of the suspension or solution formed is greater than 4.9, and thus the preparation is in the form of an ODT.

[0362] Another embodiment of the present invention relates to a weak effervescent formulation comprising calcium carbonate, tartaric acid, desogestrel, norgestrel, levonorgestrel, megestrol, noresterone, norgestimate, noresterone oxime, ethinyl estradiol, quinistrol, destinyl estradiol, megestrol acetate, and progesterone, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, and PEG 6000. After the weak effervescent disintegration formulation of the hormonal contraceptive disintegrates in neutral pure water, the pH of the suspension or solution formed is greater than 4.9, so that the formulation is in the form of an orally dispersible tablet.

[0363] Another embodiment of the present invention relates to a weak effervescent formulation comprising sodium bicarbonate, monotartrate bitartrate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and desogestrel. A weak effervescent formulation of desogestrel is formed after disintegration in neutral pure water.

[0364] Another embodiment of the present invention relates to a weak effervescent formulation comprising sodium bicarbonate, monotartrate bitartrate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and norgestrel. After the weak effervescent formulation of norgestrel is disintegrated in neutral pure water, the pH of the suspension formed is greater than 4.9, and thus the formulation is in the form of an ODT.

[0365] Another embodiment of the present invention relates to a weak effervescent formulation comprising sodium bicarbonate, monotartrate bitartrate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and levonorgestrel. After the weak effervescent formulation of levonorgestrel is disintegrated in neutral pure water, the pH of the suspension formed is greater than 4.9, and thus the formulation is in the form of an ODT.

[0366] Another embodiment of the present invention relates to a weak effervescent formulation comprising sodium bicarbonate, monotartrate bitartrate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and norestinone. After the weak effervescent formulation of norestinone is disintegrated in neutral pure water, the pH of the suspension formed is greater than 4.9, and thus the formulation is in the form of an ODT.

[0367] Another embodiment of the present invention relates to a weak effervescent formulation comprising sodium bicarbonate, monotartrate bitartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and megestrol. After the weak effervescent formulation of megestrol is disintegrated in neutral pure water, the pH of the suspension formed is greater than 4.9, and thus the formulation is in the form of an ODT.

[0368] Another embodiment of the present invention relates to a weak effervescent formulation comprising sodium bicarbonate, monotartrate bitartrate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium stearate, PEG 6000, and ethinyl estradiol. After the ethinyl estradiol weak effervescent formulation is disintegrated in neutral pure water, the pH of the suspension formed is greater than 4.9, and thus the formulation is in the form of an ODT.

[0369] Another embodiment of the present invention relates to a weak effervescent formulation comprising sodium bicarbonate, monotartrate bitartrate, cross-linked povidone, microcrystalline cellulose, magnesium stearate, PEG 6000, and progesterone. After the weak effervescent formulation of progesterone is disintegrated in neutral pure water, the pH of the suspension formed is greater than 4.9, and thus the formulation is in the form of an ODT. Anticonvulsants

[0370] In other embodiments, the API may be an antiepileptic drug, including carbamazepine, primidone, topiramate, phenytoin sodium, phenylbarbital, sodium valproate, ethosuximide, lamotrigine, or gabapentin.

[0371] In another embodiment of the present invention, the composition comprises an antiepileptic drug consisting of calcium carbonate, an organic acid selected from the group consisting of malic acid, maleic acid, succinic acid, tartaric acid, citric acid, and ascorbic acid, and an epilepsy drug consisting of phenylbarbital, carbamazepine, topiramate, ethosuximide, gabapentin, phenytoin sodium, and sodium valproate. The composition further comprises cross-linked povidone, microcrystalline cellulose, and magnesium stearate. After the composition of the present invention is disintegrated in neutral pure water, the pH of the suspension formed is greater than 4.9, so that the composition is in the form of an ODT or dispersible tablet.

[0372] In another aspect of the present invention, the composition comprises phenobarbital, calcium carbonate, cross-linked povidone, microcrystalline cellulose, and an acid selected from malic acid, citric acid, ascorbic acid, etc. After the composition of phenobarbital is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, so that the composition is in the form of an ODT or dispersible tablet.

[0373] In another aspect of the present invention, the composition is comprised of phenobarbital, calcium carbonate, malic acid, cross-linked povidone, and magnesium stearate. After the composition of phenobarbital is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, so that the composition is in the form of an ODT or dispersible tablet.

[0374] Another aspect of the present invention is a combination of carbamazepine, calcium carbonate, and an acid selected from malic acid, citric acid, ascorbic acid, etc. After the carbamazepine composition is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, so that the composition is in the form of an ODT or dispersible tablet.

[0375] In another aspect of the present invention, the composition comprises calcium carbonate, malic acid, citric acid, ascorbic acid, ethosuximide, cross-linked povidone, and magnesium stearate. After the composition of ethosuximide is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or higher, so that the composition is in the form of an ODT or dispersible tablet.

[0376] Another configuration of the invention comprises a combination of calcium carbonate, malic acid, citric acid, ascorbic acid, topiramate, cross-linked povidone, and magnesium stearate. After the composition of topiramate is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or greater.

[0377] In another aspect of the present invention, the composition comprises calcium carbonate, malic acid, citric acid, ascorbic acid, gabapentin, cross-linked povidone, and magnesium stearate. After the composition of gabapentin is disintegrated in neutral pure water, the pH of the suspension formed is 4.9 or more, so that the composition is in the form of an ODT or dispersible tablet.

[0378] Another aspect of the present invention is a combination of calcium carbonate, an acid selected from malic acid, tartaric acid, succinic acid, ascorbic acid, and citric acid, cross-linked povidone, and sildenafil, which is in the form of an ODT since it disintegrates in 200 mL of neutral water and has a pH of 4.9 or higher.

[0379] In another aspect, the present invention relates to a method for orally administering a drug without or with little water or other beverages. In certain preferred embodiments, the method comprises administering an orally disintegrating or dispersible tablet. In certain preferred embodiments, the method comprises administering a stable form of an orally disintegrating or dispersible tablet. The drug may be administered in the form of a weak effervescent tablet according to the present invention, which comprises an orally disintegrating or dispersible tablet.

[0380] In one or more embodiments, the mild effervescent tablets according to the present invention may include APIs, vitamins, minerals, dietary nutrients, weak acid and weak base pairs, physical disintegration aids, bulking agents, binders, fillers, sweeteners, and lubricants.

[0381] In one or more embodiments, the weak base may be a carbonate, such as sodium bicarbonate, calcium carbonate, potassium bicarbonate, lithium bicarbonate, magnesium carbonate, and the like.

[0382] In accordance with an embodiment of the present invention, the weak acid / weak base pair generates sufficient gas to disintegrate the tablet in an aqueous medium. The disintegration time is affected by the force generated by the gas and the size of the tablet. In various embodiments, the disintegration time can be within about 1 minute, or within about 1.5 minutes, or within about 2 minutes, or within about 2.5 minutes, or within about 3 minutes. After the weak effervescent disintegration tablet of the present invention disintegrates in neutral pure water, the pH of the suspension or solution is 4.9 or higher, and preferably within the range of pH 5 to 7.

[0383] In certain embodiments of the invention, when the pharmaceutical excipient comprises bicarbonate, the organic acid is a weak acid selected from monosodium malate, monosodium maleate, monosodium succinate, monosodium adipic acid, monosodium fumaric acid, monosodium oxalate, monosodium citric acid, monosodium tartaric acid, monopotassium malate, monopotassium maleate, monopotassium succinate, monopotassium adipic acid, monopotassium oxalate, monopotassium citric acid, monopotassium tartaric acid, or ascorbic acid. In preferred embodiments, the other excipients may be selected from cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, aspartame, sucralose, menthol, magnesium stearate, PEG 6000, and colloidal silica, or combinations thereof.

[0384] In a particular embodiment of the invention, when the pharmaceutical excipient comprises calcium carbonate, the organic acid is selected from monomalic acid, monomaleic acid, monosuccinic acid, monoadipic acid, ascorbic acid, fumaric acid, and tartaric acid, and the molar ratio of the two acids to calcium carbonate may be in the range of 0.35:1.0 to 1.25:1.0 or 0.15:1.0 to 1.0:1.0.

[0385] In certain embodiments of the invention, when the pharmaceutical excipient comprises calcium carbonate, the organic acid may be a trace amount of ascorbic acid, with the molar ratio of ascorbic acid to calcium carbonate being within the range of 0.5:1.0, 1.0:1.0 to 1.75:1.0 or 1.50:1.0.

[0386] In preferred embodiments, the other excipients may be selected from cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, aspartame, peppermint, colloidal silica, magnesium stearate, and PEG 6000, or combinations thereof. Yet another aspect of the present invention relates to a method for producing a weakly foaming pharmaceutical composition, the method comprising making acidic particles, preferably weakly acidic particles, and alkaline particles or powder. In a preferred embodiment, the weak acid granules may be made by mixing a weak acid selected from monosodium malate, monosodium maleate, monosodium succinate, monosodium adipic acid, monosodium fumarate, monosodium oxalate, monosodium citric acid, monosodium tartaric acid, monopotassium malate, monopotassium maleate, monopotassium succinate, monopotassium adipic acid, monopotassium oxalate, monopotassium citric acid, monopotassium tartaric acid, and ascorbic acid with an acid API, acid vitamins, minerals, cross-linked povidone, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, and aspartame. This mixture is then blended into an acid granule or formed into an acid granule in a fluid bed or wet granulator, for example, through sparging with a PVPK30 solution.

[0387] In a preferred embodiment, alkaline granules are made by mixing a carbonate, such as calcium, magnesium, potassium, sodium, lithium carbonate, or a bicarbonate, such as sodium, potassium, lithium, with an alkaline API, aspartame, peppermint, or a combination thereof. The acidic and alkaline granules are then mixed with one or more other excipients, such as colloidal silica, magnesium stearate, and PEG 6000, and compressed into an ODT or dispersible tablet.

[0388] Yet another aspect of the present invention relates to a method for preparing a highly soluble composition comprising celecoxib, the method comprising the steps of: 1. Mix 1 part celecoxib with 1-6 parts organic acid selected from ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, and citric acid or mixtures thereof, and an alcohol selected from ethanol and benzyl alcohol, and mix until the celecoxib and organic acid are completely dissolved. 2. Place one part cross-linked povidone, one part cross-linked sodium carboxymethylcellulose, and a small amount of sodium dodecyl sulfate (SDS) into a fluid bed or granulator. 3. The alcoholic solution from step 1, containing celecoxib and an organic acid, is sprayed into a fluidized bed or granulator. 4. A small amount of aqueous 8% PVPK30 is sprayed into the fluid bed and dried until the granule size is about 24 mesh. The resulting granules are then mixed with magnesium stearate and compressed into tablets or filled into capsules or granule bags.

[0389] DEFINITIONS In order to more fully understand the invention described herein, the following definitions are provided for the purposes of this disclosure:

[0390] The term "comprises" is an inclusive term that is to be interpreted as including the term that follows it and not excluding other unrecited elements.

[0391] The term "consisting essentially of" means that the list of elements may include additional ingredients or excipients, which do not contribute substantially to the operation of the invention.

[0392] The term "comprise" is an exclusive term and means only that it consists of. The term "therapeutically effective amount" or "effective amount" means the amount sufficient to produce the desired therapeutic effect when administered to an animal for treating a disease, disorder, or condition (e.g., an amount that affects treatment for the disease).

[0393] The term "consisting of" is an exclusive term and simply means consisting of... The term "therapeutically effective amount" or "effective amount" refers to an amount that, when administered to an animal, is effective enough to treat a disease, disorder, or condition (e.g., an amount that affects the treatment of the disease).

[0394] The terms "composition" and "formulation" are synonymous and are used interchangeably herein.

[0395] 0.25% Sodium Dodecyl Sulfate / pH 7 Sodium Phosphate Buffer Solution 1000 mL refers to 1000 mL of pH 7 Sodium Phosphate Buffer Solution containing 2.5 grams of Sodium Dodecyl Sulfate.

[0396] The terms "dissolution" and "dissociation" are synonymous and are used interchangeably here.

[0397] The term "PVP" refers to polyvinylpyrrolidone.

[0398] The term "RPM" refers to revolutions per minute.

[0399] Pellets = spheros, small spheres. [Brief description of the drawings]

[0400] [Figure 1] Figure 1 is a graph showing celecoxib plasma concentrations following administration of a 150 mg celecoxib formulation to a male beagle dog (subject A1) as compared to a 200 mg CELEBREX capsule manufactured by Pfizer, as described in Example 16. [Diagram 2] Figure 2 is a graph showing celecoxib plasma concentrations following administration of a 150 mg celecoxib formulation to a male beagle dog (subject A2) as compared to a 200 mg CELEBREX capsule manufactured by Pfizer, as described in Example 16. [Diagram 3] Figure 3 is a graph showing celecoxib plasma concentrations following administration of a 150 mg celecoxib formulation to a female beagle dog (subject B1) as compared to a 200 mg CELEBREX capsule manufactured by Pfizer, as described in Example 16. [Figure 4]Figure 4 is a graph showing celecoxib plasma concentrations following administration of a 150 mg celecoxib formulation to a female beagle dog (subject B2) as compared to a 200 mg CELEBREX capsule manufactured by Pfizer, as described in Example 16. [Diagram 5] Figure 5 is a graph showing the mean celecoxib plasma concentrations following administration of a 150 mg celecoxib formulation to four beagle dogs (subjects A1, A2, B1, and B2) as compared to a 200 mg CELEBREX capsule manufactured by Pfizer, as described in Example 16. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0401] The invention will be described with reference to various specific and preferred embodiments and techniques, however, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

[0402] Tablet composition The composition containing the highly soluble cyclooxygenase-2 (COX-2) inhibitor of the present invention includes celecoxib or imrecoxib and an organic acid. The organic acid is selected from malic acid, ascorbic acid, maleic acid, succinic acid, tartaric acid and citric acid. The amount of the organic acid is much greater than the amount of celecoxib or imrecoxib, and the ratio between them is about 1:1 to 6:1. The higher the amount of the organic acid, the higher the solubility of celecoxib or imrecoxib. The composition of the present invention may be in the form of a granule, tablet, or capsule. The composition further includes a small amount of cross-linked povidone, cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone such as PVPK30, magnesium stearate, or a combination thereof. The celecoxib in the composition provides a higher solubility of celecoxib in aqueous media or in the digestive system compared to commercially available celecoxib capsules, and increased absorption when ingested by humans.

[0403] Compositions with organic acids may contain calcium carbonate as a disintegrant or chemical leavening agent. Such compositions may be called weak effervescent disintegration formulations. Weak effervescent disintegration formulations, on the other hand, may contain a pair of base and acid along with other APIs. The addition of calcium carbonate to the composition speeds up tablet disintegration. Compositions of celecoxib with organic acids and calcium carbonate increase the solubility of both celecoxib and calcium ions. The low foaming formulations of the present invention can be prepared by a variety of methods known in the art.

[0404] Examples of pharma- ceutically acceptable gas-producing carbonates include calcium carbonate, magnesium carbonate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, lithium carbonate, and lithium bicarbonate.

[0405] Examples of weak acids include maleic acid monohydrate, maleic acid monohydrate, succinic acid monohydrate, adipic acid monohydrate, fumaric acid monohydrate, oxyacetic acid monohydrate, citric acid monohydrate, tartaric acid monohydrate, potassium maleate monohydrate, potassium maleate monohydrate, potassium succinate monohydrate, potassium adipic acid monohydrate, potassium oxyacetate monohydrate, potassium citrate monohydrate, potassium tartrate monohydrate, etc. Also included are ascorbic acid, malic acid, maleic acid, succinic acid, tartaric acid, and citric acid.

[0406] Compositions of calcium carbonate and organic acids may be characterized as weakly effervescent disintegrating formulations, where the organic acid breaks down calcium carbonate, increasing the dissociation of calcium ions and increasing absorption in the almentary system. The organic acid breaks down calcium carbonate into calcium ions, which combine with the acid to form water-soluble calcium salts, such as calcium malate, calcium malate, and the water-soluble calcium salts of binary acids, such as carbon dioxide. These formulations may be called weakly effervescent disintegrating formulations if they contain CO2 as a chemical leavening or disintegrating agent, the amount of organic acid is moderate, and the final pH of the disintegrating solution is greater than 4.9 in 200 mL of neutral water.

[0407] In other embodiments involving calcium and magnesium carbonates, the weak acids may be malic, maleic, succinic, adipic, fumaric, and tartaric acids. These acids are preferably used in small amounts with molar ratios of binary acid to calcium carbonate ranging from 0.35:1.0 to 1.0:1.0.

[0408] In certain embodiments, the monosodium salt of the binary acid may not be strong enough to react with calcium carbonate, and it is preferable to use a relatively moderate amount of binary acid to induce the reaction of calcium carbonate. The pH of the final reaction solution will limit how fast or violent the reaction is. The mole ratio of binary acid to calcium carbonate ranges from 0.35:1.0 to 1.0:1.0. In a preferred embodiment, the mole ratio is 0.35:1.0 to 1.0:1.0. (This mole ratio range is calculated based on 1 mmole of ascorbic acid = 176 mg and 1 mmole of calcium carbonate = 100 mg.)

[0409] The pH of the final reaction solution limits how fast or violent the reaction will be. If the pH of the final reaction solution is greater than 4.9, the amount of acid added is adequate.

[0410] Examples of bulking agents or physical disintegration aids include cross-linked povidone, cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, low-substituted cellulose, sodium carboxymethyl starch, and hydroxypropyl starch.

[0411] Examples of fillers, lubricants, and sweeteners include microcrystalline cellulose, aspartame, peppermint, colloidal silica, magnesium stearate, PEG 6000, etc., or combinations thereof.

[0412] In certain preferred embodiments, the formulations of the invention include calcium carbonate and ascorbic acid, dibasic acids, and other common auxiliary agents. Ideally, this will promote the gas-producing reaction and the production of carbon dioxygen, but prevent a burning sensation in the mouth. After the weakly effervescent fast disintegrating tablet is disintegrated in neutral water (preferably neutral pure water), the pH of the suspension or mixture formed is greater than 4.9. Maintaining a pH above 4.9 controls the rate of the reaction and prevents a burning sensation in the mouth.

[0413] In another preferred embodiment, the weakly effervescent, fast disintegrating formulation comprises hydrogen carbonate and a weak acid selected from monosodium malate, monosodium malate, monosodium succinate, monosodium adipate, monosodium fumarate, monosodium oxylate, monosodium citrate, monosodium tartrate. The advantage of using a weak acid is that it prevents the development of a burning sensation in the mouth. After disintegration of the weakly effervescent tablet in neutral water, the pH of the suspension formed is above 4.9 and the formulation takes the form of an ODT or dispersible tablet.

[0414] Advantageously, weakly effervescent tablet formulations in the form of ODT or dispersible tablets can be administered without water into the patient's mouth. Ideally, weakly effervescent tablet formulations will partially or completely disintegrate within about 3 minutes, or within about 2.5 minutes, or within about 2 minutes, or within about 1.5 minutes, or within about 1 minute. The time taken for dissolution may depend on the size of the tablet.

[0415] One advantage of the preferred embodiment of the present invention is that the tablet partially disintegrates within 1 minute or completely disintegrates within 1 minute, thereby preventing or reducing the occurrence of the side effect of aspiration even when the tablet weighs more than 1 gram or more than 2 grams.

[0416] Calcium is a mineral that makes up bones and is also a salt that dissolves in the blood and regulates bodily functions. The normal range of blood calcium levels for most people is 8.6 to 10.3 mg / dL. The human body has about 3000 mL to 4500 mL of blood, and therefore the maximum amount of blood calcium the body can have is 450 mg. Many calcium carbonate tablets on the market have a strength of 1500 mg, which is equivalent to about 600 mg of calcium ions. If 600 mg of calcium ions are absorbed into the body, it can lead to hypercalcemia, constipation, kidney stones, and the death of the patient. Importantly, the absorption rate of calcium in calcium carbonate tablets on the market is low, and most calcium carbonate either precipitates on the surface of the colon mucosa, causing constipation, or passes through the digestive system. .

[0417] A calcium carbonate tablet available on the market may have a dissolution rate of 100% in 900 mL of pH 1.2 HCl solution, but only 3.2% in 20 mL of pH 1.2 solution. Most people do not have more than 20 mL of stomach acid on an empty stomach. As a result, the calcium ions in a regular calcium carbonate tablet do not dissolve completely in the stomach, and calcium absorption is low. Manufacturers of products on the market may increase the dosage of calcium carbonate in each tablet. However, as mentioned above, high doses of calcium carbonate can cause adverse effects such as hypercalcemia and constipation.

[0418] One product currently on the market is a calcium carbonate / vitamin C effervescent tablet known as CalVive C effervescent tablet. CalVive C tablets are formulated for once-daily administration and contain 950 mg of vitamin C and 247 mg of calcium ions. The tablet weighs approximately 7.01 grams and is 3.3 centimeters in diameter. The disintegration time of CalVive C tablets is 130 seconds in 900 mL of pure water at pH 7, and the pH of the solution after disintegration is 4.48. The dissolution rate of calcium carbonate / vitamin C effervescent tablets is 97% in 900 mL of pure water at pH 7. Other ingredients of the tablet include citric acid, vitamin C, baking soda, calcium lactate gluconate, and calcium carbonate. The tablet is formulated to be dissolved in 200 mL of water and consumed. The primary effervescent agents are citric acid and sodium carbonate. Additionally, the tablet contains a high amount of calcium obtained from water-soluble calcium lactate gluconate.

[0419] In contrast, in an advantageous embodiment of the present invention, the calcium comes only from calcium carbonate, which functions as the API and gas generating effervescent agent. The calcium malate formed is water soluble, unlike calcium citrate, which is slightly soluble in water. The present invention does not contain citric acid, as it is a ternary acid and a strong acid. Unlike calcium tablets available on the market, the calcium carbonate weak effervescent tablets according to the present invention may be ODT or dispersible tablets. In a preferred embodiment, the calcium tablets according to the present invention may partially disintegrate within about 1 minute or completely disintegrate within about 3 minutes.

[0420] In one embodiment, the weak effervescent tablet according to the invention contains 75 mg of calcium carbonate (corresponding to 30 mg of calcium ions) and the dissolution rate of the tablet in 900 mL of neutral pure water is 65-75%. Advantageously, such a tablet may release about 20 mg of calcium ions in the digestive system. In contrast, a regular calcium carbonate tablet may contain 1000 mg of calcium carbonate (corresponding to 400 mg of calcium ions). In 900 mL of neutral (pH 7) water, the dissolution rate of calcium in a regular tablet is less than 1.5%, which means that only 6 mg of calcium ions are absorbed in the digestive system. The remaining calcium carbonate in a regular tablet is expelled from the alternary system and may cause constipation. Moreover, if 1500 mg of calcium carbonate is ingested per day and the dissolution rate of the ingested calcium carbonate is 50%, then 300 mg of calcium ions are dissolved or absorbed, which may cause hypercalcemia in the patient.

[0421] The calcium carbonate and vitamin C (ascorbic acid) in the weak effervescent tablet according to the present invention may be an ODT or dispersible tablet. In a preferred embodiment, the weak effervescent tablet may partially disintegrate within about 1 minute or completely disintegrate within about 3 minutes and has a dissolution rate of 20% or more but less than 75% in 900 mL of pure water at pH 7.

[0422] In a preferred embodiment, the present invention relates to a weakly effervescent disintegrating formulation containing less than 75 mg of calcium carbonate per tablet per day, with a dissolution rate of calcium ions ranging from 20 to 75%.

[0423] In another aspect, the present invention relates to a method of treating hypocalcemia or calcium deficiency in a subject, comprising administering to the subject a weakly effervescent disintegrating formulation having a dissolution rate in the range of 20 to 75% containing less than 75 mg of calcium carbonate per dosage form per day.

[0424] In one embodiment, the dosage form may be an orally disintegrating tablet, a dispersible tablet, a sublingual tablet, a tablet, a capsule, or a granule. EXAMPLES

[0425] Common methods for tablet production The following embodiments describe high solubility compositions containing celecoxib, imrecoxib, or calcium carbonate and methods of making low effervescent formulations according to the present invention.

[0426] Embodiment 1 The preparation of the celecoxib composition is as follows: A. Dissolve 1 part celecoxib and 1-6 parts of an organic acid selected from meleic acid, malic acid, tartaric acid, succinic acid, citric acid, and ascorbic acid in 10-20 parts of a liquid alcohol selected from the group consisting of ethanol and benzyl alcohol. B. Granulation: 1 part cross-linked povidone, 1 part cross-linked sodium carboxymethyl cellulose, and 0.1 part sodium dodecyl are added to a fluid bed. C. The ethanol solution containing celecoxib and organic acid from process 1 is sprayed into the fluid bed. Then the powder is granulated with 8% PVPK30 in the fluid bed and dried until the moisture is less than 4%. All the granulation process can also be done in the granulator with other methods. The above granules and magnesium stearate are mixed and then compressed into tablets. D. The dissolution rate of celecoxib in the above composition is greater than or equal to 60% in 1000 mL of sodium phosphate buffer at pH 7 containing 2.5 grams of SDS, the pH being within the range of 2.7 to 3.2. E. C granules may be mixed with calcium carbonate granules and then compressed into tablets or filled into capsules containing celecoxib, the organic acid, and calcium carbonate.

[0427] EMBODIMENT 2 Calcium carbonate and vitamin C mild effervescent tablets are manufactured using two granulation processes: 1st Granulation: Calcium carbonate is mixed with cross-linked povidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and sprayed with 8% PVPK30 in a wet granulator or fluid bed, and the wet granules are dried in an oven or fluid bed to a moisture content of less than 4%. Second granulation: Ascorbic acid is mixed with cross-linked povidone, microcrystalline cellulose, aspartame and sprayed with 8% PVPK30 in a wet granulator or fluid bed, and the wet granules are dried in an oven or fluid bed to a moisture content of less than 4%. . The two kinds of granules prepared above are sprayed with magnesium stearate and peppermint ethanol solution, then compressed into tablets. After the weak effervescent tablets disintegrate in neutral water, the pH of the suspension formed is 6.32, which is above 4.9, so the formulation is dispersible tablets or ODT, which is preferred, especially when the tablet size is small. Below is Table 1 showing the results in 900 mL of pure water at pH 7 for comparison of tablets produced according to embodiment 2 and embodiment 3 with CaCO3 / Vitamin D3 tablets from other manufacturers. [Table 1]

[0428] EMBODIMENT 3 Calcium carbonate weak effervescent tablets may be manufactured using two granulation processes: Granulation 1: Calcium carbonate is mixed with cross-linked povidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and sprayed with 8% PVPK30 in a fluidized bed, then the granules are dried until the moisture content is less than 4%. Granulation 2: One organic acid selected from malic acid, meleic acid, succinic acid, adipic acid, citric acid, fumaric acid, and tartaric acid is mixed with crospovidone, microcrystalline cellulose, and aspartame, and sprayed with 8% PVPK30 in a fluidized bed, and then the granules are dried until the moisture content is less than 4%. The above prepared two kinds of granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the weak effervescent tablet prepared according to the present invention disintegrates in neutral water, the pH of the suspension formed is 5.99, which is above 4.9, so the formulation takes the form of a dispersible tablet. From the above table, the weak effervescent tablet prepared according to the present invention results in faster dissolution compared to ordinary calcium carbonate tablets. Adding a small amount of binary acid to calcium carbonate tablets can significantly increase the dissolution of calcium ions in the stomach. The experiments of embodiment 2 and embodiment 3 show that the addition of ascorbic acid can shorten the disintegration time, and the addition of ascorbic acid in the formulation can increase the dissolution of calcium ions in neutral pure water. The experiments show that the composition of calcium carbonate and ascorbic acid according to the present invention has a higher dissolution rate than ordinary calcium carbonate tablets. The complex of calcium carbonate and ascorbic acid has a shorter disintegration time than ordinary calcium carbonate.

[0429] EMBODIMENT 4 Mild effervescent tablets containing calcium carbonate, vitamin C and glucosamine salts are manufactured using two granulation processes: Granulation 1: Calcium carbonate is mixed with cross-linked povidone, microcrystalline cellulose and sprayed with 8% PVPK30 in a fluid bed, then the granules are dried until the moisture content is less than 4%. Granulation 2: Ascorbic acid is mixed with glucosamine salt HCl, cross-linked povidone, microcrystalline cellulose, aspartame and sprayed with 8% PVPK30 in a fluidized bed, then the granules are dried until the moisture content is less than 4%. The two types of granules prepared above and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the weak effervescent tablets prepared according to the present invention disintegrate in neutral water, the pH of the suspension formed is not less than 4.9, so the formulation takes the form of a dispersible tablet. Dissolution testing at 30 minutes for a tablet composition containing 25 mg calcium carbonate, 50 mg vitamin C, 500 mg glucosamine HCl in 900 mL neutral purified water at a Stirling speed of 75 RPM as shown in Table 2. [Table 2]

[0430] EMBODIMENT 5 Mild effervescent tablets containing calcium carbonate and vitamins (vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin A, vitamin D, folic acid, vitamin E, vitamin K, niacinic acid, folic acid, pantothenic acid, choline, biotin) are manufactured using two granulation processes: Granulation 1: Calcium carbonate is mixed with Crospovidone, Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B12, Folic Acid, Niacinic Acid, Pantothenic Acid, Choline, Biotin, Vitamin A Powder, Vitamin D Powder, Microcrystalline Cellulose, and sprayed with 8% PVPK30 in wet granulator, then the wet granules are dried in oven until the moisture content is less than 4%. Granulation 2: Ascorbic acid is mixed with crospovidone, microcrystalline cellulose, and aspartame and sprayed with 8% PVPK30 in a fluidized bed. Then vitamin E and vitamin K in ethanol are sprayed into the fluidized bed. The above prepared two granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the weak effervescent tablet prepared according to the present invention disintegrates in neutral water, the pH of the suspension formed is not less than 4.9, so the formulation takes the form of a dispersible tablet.

[0431] EMBODIMENT 6 Mild effervescent calcium carbonate tablets containing Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B12, Vitamin C, Vitamin A, Vitamin D, Vitamin E, Vitamin K, Niacinic Acid, Folic Acid, Pantothenic Acid, Choline, Biotin, Calcium Carbonate, Ferrous Sulfate, Copper Sulfate, Zinc Sulfate, Magnesium Sulfate, Potassium Chloride, Sodium Chloride are manufactured using two granulation processes: Granulation 1: Calcium carbonate is mixed with Crospovidone, Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B12, Vitamin A, Vitamin D, Folic Acid, Niacinic Acid, Pantothenic Acid, Choline, Biotin, Ferrous Sulfate, Copper Sulfate, Zinc Sulfate, Magnesium Sulfate, Potassium Chloride, Sodium Chloride, Microcrystalline Cellulose, and sprayed with 8% PVPK30 in wet Granulator, then the wet granules are dried in oven until the moisture content is less than 4%. Granulation 2: Ascorbic acid is mixed with crospovidone, microcrystalline cellulose, and aspartame and sprayed with 8% PVPK30 in a fluidized bed. Then vitamin E and vitamin K in ethanol are sprayed into the fluidized bed. The above prepared two kinds of granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the weak effervescent tablet prepared according to the present invention disintegrates in neutral water, the pH of the suspension formed is not less than 4.9, so the formulation takes the form of a dispersible tablet.

[0432] EMBODIMENT 7 Weakly effervescent disintegrating tablets of antiepileptic drugs (phenytoin sodium, phenobarbital, sodium valproate, ethosuximide (pKa 10.73), lamotrigine (pKa 15), gabapentin (pKa 4.63)) can be manufactured using two granulation processes: First granulation: Sodium or potassium bicarbonate is mixed with one of phenytoin sodium, phenobarbital, sodium valproate, ethosuximide, lamotrigine, gabapentin, 5% cross-linked povidone by tablet weight, 5% cross-linked soda carboxymethyl cellulose by tablet weight, 5% microcrystalline cellulose by tablet weight, sprayed with 8% PVPK30 in a fluid bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. Second granulation: One weak acid selected from the group of monosodium phosphate malate, monosodium phosphate malate, monosodium phosphate succinate, monosodium phosphate adipate, monosodium phosphate oxalate, monosodium citrate, monosodium tartrate, ascorbic acid, monopotassium malate, monopotassium malate, monopotassium succinate, monopotassium adipate, monopotassium oxalate, monopotassium citrate, monopotassium tartrate is mixed with about 5% cross-linked povidone by weight of the tablet, about 5% cross-linked carboxymethyl soda cellulose by weight of the tablet, about 5% microcrystalline cellulose by weight of the tablet, aspartame, sprayed with 8% PVPK30 in a fluidized bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. The above two granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the resulting weak effervescent tablets are disintegrated in neutral water, the pH of the suspension formed is above 4.9, so the formulation takes the form of ODT or dispersible tablets.

[0433] EMBODIMENT 8 Weakly effervescent disintegrating tablets using sartan APIs (losartan, candesartan, valsartan, telmisartan, fimasartan, irbesartan, etc.) can be manufactured using two granulation processes: First granulation: Sodium or potassium bicarbonate is mixed with cross-linked povidone at about 5% of tablet weight, cross-linked soda carboxymethyl cellulose at about 5% of tablet weight, microcrystalline cellulose at about 5% of tablet weight, aspartame and one sartan selected from losartan, candesartan, valsartan, telmisartan, fimasartan, irbesartan, sprayed with 8% PVPK30 in a fluidized bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. Second granulation: One of the weak acids selected from monosodium phosphate malate, monosodium phosphate malate, monosodium phosphate succinate, monosodium phosphate adipate, monosodium phosphate oxalate, monosodium citrate, monosodium tartrate, ascorbic acid, monopotassium malate, monopotassium malate, monopotassium succinate, monopotassium adipate, monopotassium oxalate, monopotassium citrate, monopotassium tartrate or mixtures thereof is mixed with about 5% of the tablet weight of cross-linked povidone, about 5% of the tablet weight of cross-linked carboxymethyl soda cellulose, about 5% of the tablet weight of microcrystalline cellulose, aspartame, sprayed with 8% PVPK30 in a fluid bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. The above two granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the inventive weak effervescent tablet disintegrates in neutral water, the pH of the formed suspension is above 4.9, so the formulation takes the form of ODT or dispersible tablet.

[0434] EMBODIMENT 9 Weakly effervescent disintegrating tablets with selective COX-2 inhibitors (e.g. celecoxib, etoricoxib, imrecoxib) can be manufactured using two granulation processes: First granulation: Calcium carbonate is mixed with cross-linked povidone at approximately 5% of the tablet weight, cross-linked soda carboxymethyl cellulose at approximately 5% of the tablet weight, microcrystalline cellulose at approximately 5% of the tablet weight, aspartame and sprayed with 8% PVPK30 in a fluid bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. Second granulation: Celecoxib or imrecoxib COX-2 inhibitor and one acid selected from monosodium phosphate malate, monosodium phosphate malate, monosodium phosphate adipate, monosodium phosphate fumarate, monosodium phosphate tartrate, monosodium phosphate succinate and ascorbic acid are mixed with about 5% cross-linked povidone by tablet weight, about 5% cross-linked carboxymethyl soda cellulose by tablet weight, about 5% microcrystalline cellulose by tablet weight and aspartame, sprayed with 8% PVPK30 in a fluid bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. The above two granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the inventive weak effervescent tablet disintegrates in neutral water, the pH of the suspension formed is 4.9 or higher, so the formulation takes the form of ODT or dispersible tablet.

[0435] EMBODIMENT 10 Weakly effervescent disintegrating tablets with alpha-glucosidase inhibitors (e.g., miglitol (miglibose), acarbose, voglibose) can be manufactured using two granulation processes: First granulation: Calcium carbonate is mixed with cross-linked povidone at about 5-10% of the tablet weight, cross-linked carboxymethyl soda cellulose at about 5-10% of the tablet weight, microcrystalline cellulose at about 5% of the tablet weight, one alpha-glucosidase inhibitor selected from miglitol (miglibose), acarbose, voglibose, aspartame, sprayed with 8% PVPK30 in a fluidized bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. Second granulation: One weak acid selected from malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, succinic acid, ascorbic acid, citric acid and mixtures thereof is mixed with about 5-10% of the tablet weight of cross-linked povidone, about 5-10% of the tablet weight of cross-linked soda carboxymethyl cellulose, about 5% of the tablet weight of microcrystalline cellulose and aspartame, sprayed with 8% PVPK30 in a fluidized bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. The above two granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the inventive weak effervescent tablet disintegrates in neutral water, the pH of the formed suspension is above 4.9, so the formulation takes the form of ODT.

[0436] EMBODIMENT 11 Weakly effervescent disintegrating tablets with antihistamines (e.g. levocetirizine, cetirizine, hydroxyzine, promethazine, fexofenadine, loratadine, desloratadine, diphenhydramine, terfenadine, chlorpheniramine, dexchlorpheniramine, clemastine, triprolidine, etc.) can be manufactured using two granulation processes: First granulation: An antihistamine selected from cetirizine, levocetirizine, terfenadine, hydroxyzine, promethazine, fexofenadine, loratadine, desloratadine, diphenhydramine, chlorpheniramine, clemastine, dexchlorpheniramine, triprolidine, and calcium carbonate is mixed with about 5-20% of the tablet weight of cross-linked povidone, about 5-20% of the tablet weight of cross-linked carboxymethyl soda cellulose, and about 5% of the tablet weight of microcrystalline cellulose, sprayed with 8% PVPK30 in a fluid bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. Second granulation: One weak acid selected from malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, succinic acid, ascorbic acid is mixed with about 5-20% of the tablet weight of cross-linked povidone, about 5-20% of the tablet weight of cross-linked soda carboxymethyl cellulose, about 5% of the tablet weight of microcrystalline cellulose, sprayed with 8% PVPK30 in a fluidized bed, granulation continues until the granule size exceeds 40 mesh, then dried until the moisture content is less than 4%. The above two granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the inventive weak effervescent tablet disintegrates in neutral water, the pH of the formed suspension is above 4.9, so the formulation takes the form of ODT.

[0437] EMBODIMENT 12 Weakly effervescent disintegrating tablets with serotonin reuptake inhibitors (e.g. fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) can be manufactured using two granulation processes: First granulation: Calcium carbonate is mixed with about 5-15% of the tablet weight of cross-linked povidone, about 5-15% of the tablet weight of cross-linked soda carboxymethyl cellulose, about 5% of the tablet weight of microcrystalline cellulose, sprayed with 8% PVPK30 in a fluid bed, granulation continues until the granule size is larger than 40 mesh, then dried until the moisture content is less than 4%. Second granulation: One acid selected from malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, succinic acid, ascorbic acid is mixed with about 5-15% of the tablet weight of cross-linked povidone, about 5-15% of the tablet weight of cross-linked soda carboxymethyl cellulose, about 5% of the tablet weight of microcrystalline cellulose, and one serotonin reuptake inhibitor selected from fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram or a salt thereof, sprayed with 8% PVPK30 in a fluidized bed, and the granules are then dried until the moisture content is less than 4%. The above two granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the inventive weak effervescent tablet disintegrates in neutral water, the pH of the formed suspension is above 4.9, so the formulation takes the form of ODT.

[0438] EMBODIMENT 13 Weakly effervescent disintegrating tablets using non-classical antidepressants such as aripiprazole, olanzapine, quetiapine, ziprazidone, clozapine, and paliperidone are manufactured using a two-stage granulation process. First granulation: Calcium carbonate is mixed with about 5-20% of the tablet weight of cross-linked povidone, about 5-20% of the tablet weight of cross-linked soda carboxymethyl cellulose, and about 5% of the tablet weight of microcrystalline cellulose, sprayed with 8% PVPK30 in a fluid bed, granulation continues until the granule size is greater than 40 mesh, then dried until the moisture content is less than 4%. Second granulation: One weak acid selected from malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, succinic acid and ascorbic acid is mixed with about 5-20% of the tablet weight of cross-linked povidone, about 5-20% of the tablet weight of cross-linked soda carboxymethyl cellulose, about 5% of the tablet weight of microcrystalline cellulose and one non-classical antidepressant selected from aripiprazole, olanzapine, quetiapine, ziprazidone, clozapine or paliperidone, sprayed with 8% PVPK30 in a fluid bed, the granules are then dried until the moisture content is less than 4%. The above two granules and magnesium stearate are mixed, then sprayed with peppermint ethanol solution, and then compressed into tablets. After the inventive weak effervescent tablet disintegrates in neutral water, the pH of the formed suspension is above 4.9, so the formulation takes the form of ODT.

[0439] EMBODIMENT 14 Among antifibrinolytic drugs, weakly effervescent disintegrating tablets such as 6-aminocaproic acid (EACA), tranexamic acid, and p-hydroxybenzylamine are manufactured using two granulation processes: First granulation: Sodium bicarbonate or potassium bicarbonate is mixed with cross-linked povidone at about 5% of the tablet weight, cross-linked sodium carboxymethyl cellulose at about 5% of the tablet weight, microcrystalline cellulose at about 5% of the tablet weight, and one of the antifibrinolytic therapeutic agents selected from 6-aminocaproic acid, tranexamic acid, and p-hydroxybenzylamine, sprayed with 8% PVPK30 in a fluidized bed, and continued granulation until the particle size is greater than 40 mesh, then dried until the moisture content is less than 4%. Second granulation: An acid selected from monosodium malate, monosodium melate, monosodium succinate, monosodium adipate, monosodium oxalate, monosodium citrate, ascorbic acid, monosodium tartrate, monopotassium malate, monopotassium melate, monopotassium succinate, monopotassium adipate, monopotassium oxalate, monopotassium citrate, and monopotassium tartrate is mixed with about 5% of cross-linked povidone, about 5% of cross-linked sodium carboxymethyl cellulose, about 5% of microcrystalline cellulose, and aspartame, sprayed with 8% PVPK30 in a fluidized bed, and continued granulation until the particle size is greater than 40 mesh, then dried until the moisture content is less than 4%. Both types of granules above are mixed with magnesium stearate, then sprayed with mint ethanol solution and compressed into tablets. After the weak effervescent tablets disintegrate in neutral water, the pH of the suspension formed is above 4.9 and the composition takes the form of an ODT or dispersible tablet.

[0440] EMBODIMENT 15 Weakly effervescent disintegrating tablets of dihydropyridine-type calcium channel blockers (such as nifedipine, felodipine, amlodipine, levamlodipine, benidipine, nitrendipine, nimodipine, lacidipine, etc.) are manufactured using two granulation processes: First granulation: Sodium or potassium bicarbonate is mixed with about 5% to 20% of the tablet weight of cross-linked povidone, about 5% to 20% of the tablet weight of cross-linked sodium carboxymethyl cellulose, about 5% of the tablet weight of microcrystalline cellulose, any dihydropyridine calcium channel blocker selected from nifedipine, felodipine, amlodipine, levamlodipine, benidipine, nitrendipine, nimodipine, lacidipine, and aspartame, sprayed with 8% PVPK30 in a fluidized bed, continued granulation until the particle size is greater than 40 mesh, then dried until the moisture content is less than 4%. Second granulation: A weak acid selected from monosodium malate, monosodium melate, monosodium succinate, monosodium adipate, monosodium oxalate, monosodium citrate, monosodium tartrate, monopotassium malate, monopotassium melate, monopotassium succinate, monopotassium adipate, monopotassium oxalate, monopotassium citrate, and monopotassium tartrate is mixed with about 5% to 20% of the tablet weight of cross-linked povidone, about 5% to 20% of the tablet weight of cross-linked sodium carboxymethyl cellulose, about 5% of the tablet weight of microcrystalline cellulose, and aspartame, sprayed with 8% PVPK30 in a fluidized bed, and continued granulation until the particle size is larger than 40 mesh, and then dried until the moisture content is less than 4%. Both types of granules above are mixed with magnesium stearate, then sprayed with mint ethanol solution and compressed into tablets. After disintegration of the weak effervescent tablets in neutral water, the pH of the suspension formed is above 4.9 and the composition takes the form of an ODT.

[0441] Working Example Below are some examples of cyclooxygenase-2 (COX-2) inhibitor compositions and methods for making weakly effervescent disintegrating tablets, which are not intended to limit the invention in any way but are illustrative of the various formulations described herein.

[0442] Example 1: A comparison of the composition of celecoxib tablets containing maleic acid and CELEBREX 200 mg capsules (manufacturer of origin) is shown in Table 3. [Table 3] Celecoxib was dissolved in ethanol and mixed with lactose and SDS, the mixture was dried in an oven, then crushed into a fine powder and granulated in a wet granulator with the other formulation ingredients listed in the table above. The tablets produced were subjected to dissolution testing and the results were inferior to CELEBREX.

[0443] Example 2: A comparison of the composition of celecoxib tablets containing maleic acid and CELEBREX 200 mg capsules (manufacturer of origin) is shown in Table 4. [Table 4] Celecoxib and malic acid were dissolved in ethanol, the mixture was heated in an oven, and then placed in a granulator with the other formulation ingredients listed above and PVPK30. After passing through a mesh, the resulting granules were heated in an oven until the moisture content was less than 4%. The resulting granules were mixed with magnesium stearate and compressed into tablets. It was found that the dissolution rate of celecoxib in the composition was determined by the amount of organic acid.

[0444] Example 3: Composition of Celecoxib Tablets Containing Maleic Acid Celecoxib and maleic acid: 2250 g cross-linked sodium carboxymethylcellulose and 2250 g cross-linked povidone were mixed in a fluid bed. 2400 g celecoxib and 4800 g maleic acid were dissolved in 10 liters of ethanol and sprayed into the fluid bed, the mixture was dried and a small amount of povidone K30 aqueous solution (300 g) was sprayed into the fluid bed to form granules. Overall Mixing: The granules were mixed with magnesium stearate (9 g) and then compressed into tablets.

[0445] Test results: Hardness / Pressure: 2.7-4.6 kg, Tablet Weight: 820 mg The solubility of celecoxib was 122 mg or 76.25% per 1000 mL in 0.25% sodium dodecanoate in pH 7 sodium phosphate buffer at 50 RPM, 120 minutes after dissolution test. The entire granulation process can also be carried out in a granolator. A table of other compositions of celecoxib in different proportions of acids selected from maleic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, citric acid, and cross-linked sodium carboxymethylcellulose, cross-linked povidone is shown in Table 5. [Table 5]

[0446] The dissolution of CELEBREX 200 mg celecoxib capsules is 124 mg or 62% in 1000 mL in 0.25% sodium dodecanoate / pH 7 sodium phosphate buffer at 50 RPM in 120 minutes after dissolution testing. The invention formulations of 150-160 mg tablets had similar dissolution amounts of 124-127 mg, but the dissolution rates varied from 76% to 84.6%. In formulations 1 to 3, the higher the amount of malic acid, the higher the dissolution of celecoxib. In formulation 5, the dissolution of celecoxib is lower than formulation 1. This is because the bulking agent formulation is only cross-linked povidone. Both cross-linked povidone and cross-linked sodium carboxymethylcellulose seem to be better than a single formulation. The ratio of organic acid to celecoxib is 2:1 to 5:1, and the dissolution of celecoxib is proportional to the amount of organic acid in the composition.

[0447] Example 4: Calcium carbonate weakly effervescent disintegrating tablets [Table 6]

[0448] There were two granulation processes in the production. Granulation 1: 7 kg calcium carbonate, 1.4 kg microcrystalline cellulose, and 0.934 kg cross-linked povidone were placed in a fluidized bed. Then, 8% PVP K30 was sprayed into the fluidized bed. Spraying was stopped when the particle size reached 30 mesh, and heating was stopped when the moisture content was less than 4%. Granulation 2: 4.67 kg malic acid, 46.7 g aspartame, and 1.4 kg microcrystalline cellulose were placed in a fluidized bed. Then, 8% PVP K30 was sprayed into the fluidized bed. Spraying was stopped when the particle size reached 30 mesh, and heating was stopped when the moisture content was less than 4%. Granules 1 and 2 were each mixed with 0.164 kg of magnesium stearate, sprayed with the peppermint / ethanol solution, and then compressed into tablets. The disintegration time was 130-155 seconds and the calcium ion content of each tablet was 61 mg. The degree of grinding was 0.4%. After the weak effervescent tablets disintegrated in neutral water, the pH of the suspension formed was 5.91, indicating that the composition is a dispersible tablet. After dissolution test in neutral pure water at 37°C and 75 RPM after 30 minutes, as shown in Table 7 with different molar ratios of malic acid and calcium carbonate.

[0449] .In Table 7 showing different molar ratios of malic acid and calcium carbonate (100mg CaCO3) in neutral pure water at 37°C after 30 minutes of dissolution test, 900 mL at 75 RPM. [Table 7]

[0450] This example shows that the more acid added, the greater the dissociation of calcium ions and the less calcium carbonate that needs to be administered to the patient.

[0451] Example 5: Comparison of calcium carbonate tablets with calcium carbonate / vitamin C and CaCO3 / vitamin D3 [Table 8] As shown in Table 8, this example shows that the addition of a small amount of leavening agent decreases the disintegration time. This example also shows that adding an acid to the composition increases the dissolution of calcium ions in pH 7 pure water. This example also shows that malic acid is stronger than ascorbic acid.

[0452] Example 6: Low-effervescent calcium carbonate and vitamin C disintegrating tablets [Table 9] Granulation: Place 7 kg of calcium carbonate, 1.4 kg of microcrystalline cellulose, and 1.75 kg of cross-linked povidone in a fluidized bed. Then spray 8% PVPK30 into the fluidized bed. Stop spraying when the particles are 40 mesh or larger, and stop heating when the moisture content is less than 4%. Granulation 2: Place 12.25 kg of ascorbic acid, 80 g of aspartame, and 2.1 kg of microcrystalline cellulose in a fluidized bed. Then spray 8% PVPK30 into the fluidized bed. Stop spraying when the moisture content is less than 4%. Granulation and Granulation 2 are mixed with 0.266 kg of magnesium stearate and peppermint / ethanol solution, respectively, and then compressed into tablets. The disintegration time is 75-90 seconds. Each tablet contains 40.6 mg of calcium ion. The powder density is 0.31%. After disintegration of the weak effervescent tablets in neutral water, the pH of the suspension formed is 6.32, and this composition is a dispersible tablet.

[0453] Example 7: Mildly effervescent disintegrating tablets of calcium carbonate, vitamin C, and glucosamine HCl [Table 10] Granulation 1: Place 7.5 kg of glucosamine HCl, 2.5 kg of ascorbic acid, 1.0 kg of microcrystalline cellulose, and 0.8 kg of cross-linked povidone in a fluidized bed. Then spray 8% PVPK30 into the fluidized bed. Stop spraying when the particle size reaches 30 mesh and stop heating when the moisture content is less than 4%. Granulation 2: Place 1.5 kg of calcium carbonate, 0.2 kg of microcrystalline cellulose, 0.2 kg of cross-linked povidone, and 40 g of aspartame in a wet granulator. Then spray the granulator with 8% PVPK30. The wet granules pass through a 30 mesh size and are heated in a 65°C oven for 6-8 hours until the moisture content is less than 4%. Granulation 1 and granulation 2 are mixed with 0.14 kg of magnesium stearate and peppermint / ethanol solution respectively and then compressed into tablets with disintegration time of 90-120 seconds. The powder density is 0.31%. After disintegration of the weak effervescent tablets in neutral water, the pH of the suspension formed is 6.32, and this composition is a dispersible tablet.

[0454] Example 8: Vitamin C weakly effervescent disintegrating tablet C Granulation 1: 0.7 kg baking soda, 0.7 kg cross-linked povidone, and 0.2 kg microcrystalline cellulose were placed in a wet granulator. Then, 0.6 g of lemon yellow powder containing 8% PVPK30 was sprayed. The wet granules were passed through a 30 mesh sieve and heated in a 65°C oven for 6-8 hours until the moisture content was less than 4%. Granulation 2: Place 4 kg of ascorbic acid, 0.4 kg of microcrystalline cellulose, and 0.4 kg of cross-linked povidone, 40 g of aspartame in a fluidized bed. Then spray 8% PVPK30 into the fluidized bed. Stop spraying when the particle size reaches 30 mesh and stop heating when the moisture content is less than 4%. Granulation 1 and granulation 2 are mixed with 0.07 kg of magnesium stearate and peppermint / ethanol solution respectively and then compressed into tablets. The disintegration time is 45-55 seconds. The fineness is 0.41%. After disintegration of the weak effervescent tablet in neutral pure water, the pH of the suspension formed is 6.02, and this composition is an orally dispersible tablet (ODT).

[0455] Example 9: Mildly effervescent multivitamin tablets [Table 11] Granulation 1: Place 7.5 kg of calcium carbonate, 1.5 kg of cross-linked povidone, and 1.0 kg of microcrystalline cellulose in a fluidized bed. Then spray with 8% PVPK30 containing 2 g of lemon yellow powder. Stop spraying when the particle size reaches 30 mesh and heat until the moisture content is less than 4%. Granulation 2: 7.5 kg of ascorbic acid, 1.0 kg of microcrystalline cellulose, and 1.0 kg of cross-linked povidone, 49 g of aspartame are placed in a fluidized bed. Then, 800 mL of a solution containing 50 g of folic acid, 25 g of vitamin B1, 25 g of vitamin B2, 25 g of vitamin B6, and 0.25 g of vitamin B12 are sprayed. Then, 1000 mL of 95% ethanol containing vitamin A (8 g), vitamin E (250 g), vitamin K (0.75 g), and vitamin D3 (0.5 g) is sprayed into the fluidized bed containing ascorbic acid. Then, 8% PVPK30 is sprayed into the fluidized bed. Spraying is stopped when the size of the particles reaches 30 mesh, and heating is stopped until the moisture content is less than 4%. Ranulation 1 and granulation 2 are each mixed with 0.16 kg of magnesium stearate and peppermint / ethanol solution and then compressed into tablets. The disintegration time is about 91-100 seconds. The fineness is 0.41%. After the weak effervescent tablet disintegrates in neutral water, the pH of the suspension formed is 6.0, and this composition is a dispersible tablet.

[0456] Example 10: Nifedipine (10 mg x 12000 tablets) weakly effervescent disintegrating tablets 1. Dissolve nifedipine (200 g) in 4000 g of 96% ethanol. Add aspartame (64 g) and cross-linked povidone (1200 g) to the above solution and stir evenly. The mixture is dried in an oven until the alcohol is almost evaporated. Then the dried powder is passed through an 80 mesh sieve to get nifedipine mixture (1336 g). 2. Add menthol (21.6 g) to 26 g of 96% ethanol. 3. The nifedipine mixture from step 1 (878.4 g) and sodium bitartrate (180 g) are placed in a wet granulator and mixed evenly, then an aqueous solution of cross-linked povidone K30 (559 g) is added. The contents in the machine are stirred and passed through a 30 mesh sieve. The resulting granules are dried for about 4 hours until the moisture content is 3.24%, after which a menthol ethanol solution (47.6 g) is sprayed onto the granules, which are then heated for about 1-2 hours. 4. Total blend: Particles (1008 g), baking soda (77.95 g), and magnesium stearate (10 g) are blended and then compressed into tablets.

[0457] Test results: Hardness / Pressure: 1.0-1.5kg Tablet weight: 107 mg Disintegration time: CHP 39-46 s; USP 20-36 s Brittleness: 0.21% After the weak effervescent tablet disintegrates in neutral water, the pH of the suspension formed is 7.45 and this composition is an ODT. Example 11: Weakly effervescent disintegrating tablets of celecoxib (200 mg) 1. Dissolve Povidone K30 (32 g) in purified water (600 g) and stir evenly. 2. Add menthol (50 g) to 96% ethanol (65 g) and mix well. 3. Celecoxib (800 g), aspartame (70 g), microcrystalline cellulose (100 g) and sodium monohydrogen chloride (310 g) were added to the wet granulator and mixed evenly, then povidone K30 aqueous solution (300 g) was added to the granulator and the material was mixed for 100 seconds. The material was passed through a 30 mesh sieve and dried to a moisture content of 3.4%. Menthol ethanol solution (115 g) was then sprayed onto the particles, which were then passed through a 30 mesh sieve. 4. Comprehensive blend: Particles (1200 g), baking soda (170 g), cross-linked monosodium carboxymethylcellulose (75 g), silicon dioxide (14 g), and magnesium stearate (14 g) are mixed together and then compressed into tablets.

[0458] Test results: Hardness / Pressure: 2.7-4.6kg Tablet weight: 360 mg Disintegration time: CHP 48-55 s; USP 26-35 s Brittleness: 0.72% After a weakly effervescent tablet of celecoxib disintegrates in neutral water, the pH of the suspension formed is 6.06, and this composition is an ODT.

[0459] Example 12: Weakly effervescent disintegrating tablets of irbesartan (150 mg) 1. Dissolve Povidone K30 (24 g) in purified water (456 g) while stirring evenly. 2. Add menthol (40 g) to 96% ethanol (48 g) and mix well. 3. Irbesartan (600 g), aspartame (52 g), microcrystalline cellulose (120 g), and sodium monohydrogen chloride (308 g) were placed in a wet granulator and mixed evenly, then povidone K30 aqueous solution (300 g) was added to the granulator and the material was stirred for 100 seconds. The material was sieved through a 30 mesh sieve and dried until the moisture content was 3.6%. Then, menthol ethanol solution (88 g) was sprayed onto the particles, and the particles were passed through a 30 mesh sieve. 4. Comprehensive blend: Particles (1058 g), baking soda (170 g), cross-linked monosodium carboxymethylcellulose (61.8 g), silicon dioxide (12.8 g), and magnesium stearate (12.8 g) are mixed and then compressed into tablets.

[0460] Test results: Hardness / Pressure: 2.5-3.6kg Tablet weight: 360 mg Disintegration time: CHP 53-60 s; USP 32-43 s Brittleness: 0.52% After a weakly effervescent tablet of irbesartan disintegrates in neutral water, the pH of the suspension formed is 5.9 and this composition is an ODT.

[0461] Example 13: Effect of different ascorbic acid ratios on calcium dissolution in 900 mL of pH 7 pure water Calcium carbonate (25 mg) / ascorbic acid (25 mg) tablets [Table 12]

[0462] Calcium carbonate (25 mg) / ascorbic acid (50 mg) tablets [Table 13]

[0463] Calcium carbonate (25 mg) / ascorbic acid (50 mg) tablets [Table 14]

[0464] Calcium Carbonate (25 mg) / Ascorbic Acid (75 mg) Tablet + Ascorbic Acid (25 mg) in a Container [Table 15] As can be seen from the above example, calcium dissolution increases proportionately with the addition of ascorbic acid, but when the ratio of ascorbic acid to calcium carbonate exceeds 3:1, calcium dissolution does not increase further. Therefore, the preferred ratio of ascorbic acid to calcium carbonate in the composition is 1:1 to 3:1, with 3:1 being especially preferred.

[0465] Example 14: Effect of different molar ratios of citric acid and calcium carbonate on the dissolution of calcium ions after 30 min in 900 mL of pure neutral water after stirring at 37 °C Calcium carbonate (100 mg) / citric acid (192 mg) tablets (1:1) Calcium carbonate (100 mg) / citric acid (172.8 mg) tablet (1:0.9) Calcium carbonate (100 mg) / citric acid (154 mg) tablets (1:0.8) Calcium carbonate (100 mg) / citric acid (134 mg) tablet (1:0.7) Calcium carbonate (100 mg) / citric acid (115 mg) tablets (1:0.6) [Table 16]

[0466] Citric acid is a ternary acid and therefore more powerful than binary acids. For an orally disintegrating tablet to be safe, the molar ratio of citric acid to calcium carbonate should be less than 0.8:1. Example 15: Composition of 135 mg celecoxib pellets and 135 mg HPMC E5 2700 g of celecoxib and 2700 g of HPMC E5 were dissolved in 25.6 liters of 95% ethanol and sprayed into a fluid bed containing 2800 g of sugar pellets with a size of 0.5-0.7 mm. Blending: The pellets were mixed with magnesium stearate and then packed into capsules.

[0467] Test results: The dissolution rate of celecoxib was 112 mg or 83% in 1000 mL of neutral purified water containing 2.5 g of sodium dodecyl sulfate after a 180-minute dissolution test at 50 RPM.

[0468] Example 16: Bioavailability Study of 150 mg Celecoxib Tablets vs. CELEBREX 200 mg Capsules in Beagle Dogs A bioavailability study of celecoxib in dogs was conducted in four healthy beagle dogs (body weight: A1 (13.6 kg), B1 (10.8 kg); female dog body weight: A2 (10.7 kg), B2 (16.0 kg)).

[0469] 150 mg celecoxib tablets, US NANO batch number: S220519, were studied in four beagle dogs against 200 mg CELEBREX capsules (batch number: DN4886) manufactured by Pfizer Pharmaceuticals LLC (Manufacturer: Pfizer Pharmaceuticals LLC; Address: Road 689, Km. 1.9, Vega Baja, Puerto Rico 00693; China Subpackaging Factory: Pfizer Pharmaceutical Co., LTD; Address: No. 22 Daqing Road, Dalian Economic and Technological Development Zone). [Table 17] Two beagles were administered one CELEBREX capsule (200 mg) each on October 12, 2021, and two beagles were administered one CELEBREX capsule (200 mg) each on October 19, 2021. Serial blood samples (approximately 4 mL) were collected from each animal at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after dosing by drawing blood from an armpit vein using heparin as an anticoagulant. After centrifugation of the samples, plasma was extracted via acetonitrile precipitation and centrifugation. Plasma concentrations of celecoxib were measured by UPLC-MS using a standard plasma curve method. On May 25, 2022, four beagle dogs were each administered one 150 mg tablet of celecoxib invented by NANO, USA. Serial blood samples (approximately 4 mL) were collected from each animal by drawing blood from an armpit vein using heparin as an anticoagulant before dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. After centrifugation of the samples, plasma was extracted via acetonitrile precipitation and centrifugation. Plasma concentrations of celecoxib were measured by UPLC-MS using a standard plasma curve method. The washout period between two drug administrations in dogs is more than 6 months. The supernatant was directly injected into UHPLC-MS for analysis, and the obtained data were used to calculate the pharmacokinetic parameters shown in Table 18, and the mean plasma concentration-time test results are listed in Figures 1 to 5. [Table 18] In the foregoing specification, the invention has been described with reference to certain specific embodiments and examples thereof. However, it will be apparent that various modifications and changes may be made thereto without departing from the broad spirit and scope of the broad invention. It is further contemplated that such compositions may be utilized in additional locations not specifically mentioned herein. Such obvious modifications are deemed to fall within the scope of the appended claims. This specification is to be considered in an illustrative and not restrictive sense.

[0470] Mode of the invention 1. A method for preparing a composition comprising a cyclooxygenase-2 (COX-2) inhibitor selected from celecoxib and imrecoxib; One or more water-soluble excipients selected from HPMC (hydroxypropyl methylcellulose); and an organic acid selected from malic acid, maleic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, or mixtures thereof; a method comprising dissolving a COX-2 inhibitor and a water-soluble excipient in alcohol and mixing with a swelling agent and a filler; The composition is in the form of pellets, capsules, granules, or tablets. 2. The method of Form 1, wherein the COX-2 inhibitor is celecoxib, and the composition further comprises cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate. 3. The method of Form 1, wherein the COX-2 inhibitor is celecoxib, and the composition further comprises cross-linked povidone and cross-linked sodium carboxymethyl cellulose, and wherein the composition has a dissolution rate of 60% or more of the celecoxib in 1000 mL of pH 7 sodium phosphate buffer containing 0.25% sodium dodecyl sulfate when stirred at 50 RPM for 120 minutes. 4. The method of any of Forms 1 to 3, wherein the amount of organic acid is 1 to 6 times the weight of celecoxib in the composition. 5. The method of any of Forms 1 to 4, wherein the COX-2 inhibitor is celecoxib and the organic acid is malic acid. 6. The method of any of Forms 1 to 4, wherein the COX-2 inhibitor is celecoxib and the organic acid is tartaric acid. 7. The method of any of Forms 1 to 4, wherein the COX-2 inhibitor is celecoxib and the organic acid is maleic acid. 8. The method of any of Forms 1 to 4, wherein the COX-2 inhibitor is celecoxib and the organic acid is succinic acid. 9. In any one of the methods of forms 1 to 4, the COX-2 inhibitor is celecoxib and the organic acid is citric acid. 10. The method of any one of forms 1 to 4, wherein the COX-2 inhibitor is celecoxib and the organic acid is ascorbic acid. 11. The method of Form 1, wherein the COX-2 inhibitor is imrecoxib, and the composition further comprises cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, and wherein the composition has a dissolution rate of 60% or more of imrecoxib in 1000 mL of pH 7 sodium phosphate buffer containing 0.25% sodium dodecyl sulfate when stirred at 50 RPM for 120 minutes. 12. The method of Form 1, wherein the COX-2 inhibitor is celecoxib and the organic acid is from the group selected from maleic acid, succinic acid, citric acid, malic acid, citric acid, and ascorbic acid; the composition further comprises cross-linked povidone, cross-linked sodium carboxymethyl cellulose, calcium carbonate, and magnesium stearate, and wherein the composition has a dissolution rate of 60% or more of celecoxib in 1000 mL of pH 7 sodium phosphate buffer containing 0.25% sodium 12-carbon fatty acid when stirred at 50 RPM for 120 minutes. 13. The method of Form 1, wherein the COX-2 inhibitor is imrecoxib, calcium carbonate, the organic acid is from the group selected from maleic acid, succinic acid, citric acid, malic acid, citric acid, and ascorbic acid; and the composition further comprises cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate. 14. The method of Form 1, wherein the composition comprises granules consisting of celecoxib, hydroxypropyl methylcellulose, and sugar or mannitol, and the composition has the form of a granule or a capsule. 15. A method of Form 1, wherein the composition comprises granules consisting of celecoxib, 1 to 2 parts of hydroxypropyl methylcellulose, and 1 to 2 parts of sugar or mannitol, the composition is in the form of a granule or capsule, and the composition has a dissolution rate of 60% or more of celecoxib in 1000 mL of neutral pure water containing 2.5 g of sodium dodecyl sulfate fatty acid when stirred at 50 RPM for 180 minutes. 16. The method of Form 1, wherein the composition comprises granules consisting of imrecoxib, hydroxypropyl methylcellulose, and sugar or mannitol, and the composition has the form of a granule or a capsule. 17. A method of Form 1, wherein the composition comprises granules consisting of 1 part imrecoxib, 1 to 2 parts hydroxypropyl methylcellulose, and 1 to 2 parts sugar or mannitol, the composition is in the form of a granule or capsule, and the composition has a dissolution rate of 60% or more of imrecoxib in 1000 mL of neutral pure water containing 2.5 g of sodium 12-carbon fatty acid when stirred at 50 RPM for 180 minutes. 18. A weak effervescent disintegration formulation containing a weak acid-base pair, wherein the weak acid is selected from monosodium salts of binary acids, monopotassium salts of binary acids, monosodium salts of ternary acids, ascorbic acid, binary acids, or mixtures thereof, the weak base is selected from calcium carbonate, baking soda, potassium citrate, and lithium baking soda, and the API is selected from calcium carbonate, glucosamine, acarbose, miglitol, dihydropyridine calcium channel blockers, nimodipine, triptans, antihistamines, sartans, 5-HT3 antagonists, antifibrinoline agents, nonclassical antidepressants, NSAIDs, hormonal contraceptives, and antiepileptics, and the pH of the formulation when disintegrated in neutral pure water is greater than 4.9. 19. A weak effervescent disintegration formulation of Form 18, comprising calcium carbonate, ascorbic acid, cross-linked povidone, and magnesium stearate, wherein the ratio of weight of ascorbic acid to weight of calcium carbonate is within the range of 1:1 to 3:1, and the composition has a pH greater than 4.9 when disintegrated in 200 mL of neutral pure water, and the dissolution rate of calcium ions is within the range of 20% to 65% when the formulation is stirred at 75 RPM in 900 mL of neutral water and measured after 30 minutes. 20. A weak effervescent disintegration formulation of Form 18, comprising calcium carbonate, an organic acid selected from oenothermic acid, malic acid, succinic acid, and ascorbic acid, wherein the molar ratio of acid to calcium carbonate is within the range of 0.15:1.0 to 1.0:1.0, and wherein the composition has a pH greater than 4.9 when disintegrated in 200 mL of neutral pure water, and wherein the dissolution rate of calcium ions is within the range of 20% to 75% when the formulation is stirred at 75 RPM in 900 mL of neutral pure water and measured after 30 minutes. 21. A weak effervescent disintegration formulation of Form 18, containing calcium carbonate, citric acid, cross-linked povidone, and magnesium stearate, having a molar ratio of citric acid to calcium carbonate less than 0.8:1, a pH greater than 4.9 when the formulation disintegrates in 200 mL of neutral water, and a dissolution rate of calcium ions within the range of 20% to 75% when the formulation is stirred at 75 RPM in 900 mL of neutral pure water and measured after 30 minutes. 22. A weak effervescent disintegration formulation of Form 18, comprising calcium carbonate, maleic acid, cross-linked povidone, and magnesium stearate, wherein the molar ratio of maleic acid to calcium carbonate is within the range of 0.15:1 to 1:1, and the formulation is in the form of granules, capsules, tablets, orally disintegrating tablets, or dispersible tablets, the pH of the formulation is greater than 4.9 when disintegrated in 200 mL of neutral pure water, and the dissolution rate of calcium ions is within the range of 20% to 75% when the formulation is stirred at 75 RPM in 900 mL of neutral pure water and measured after 30 minutes. 23. A weak effervescent disintegration formulation of Form 18, comprising calcium carbonate, malic acid, cross-linked povidone, and magnesium stearate, wherein the molar ratio of malic acid to calcium carbonate is within the range of 0.15:1 to 1:1, and the formulation is in the form of granules, capsules, tablets, orally disintegrating tablets, or dispersible tablets, the pH of the formulation is greater than 4.9 when disintegrated in 200 mL of neutral pure water, and the dissolution rate of calcium ions is within the range of 20% to 75% when the formulation is stirred at 75 RPM in 900 mL of neutral pure water and measured after 30 minutes. 24. A weak effervescent disintegration formulation of Form 18, comprising calcium carbonate, tartaric acid, cross-linked povidone, and magnesium stearate, wherein the molar ratio of tartaric acid to calcium carbonate is within the range of 0.15:1 to 1:1, and the formulation is in the form of granules, capsules, tablets, dispersible tablets, or orally disintegrating tablets, the pH of the formulation is greater than 4.9 when disintegrated in 200 mL of neutral pure water, and the dissolution rate of calcium ions is within the range of 20% to 75% when the formulation is stirred at 75 RPM in 900 mL of neutral pure water and measured after 30 minutes. 25. A weak effervescent disintegration formulation of Form 18, comprising calcium carbonate, succinic acid, cross-linked povidone, and magnesium stearate, wherein the molar ratio of succinic acid to calcium carbonate is within the range of 0.15:1 to 1:1, and the pH exceeds 4.9 when the formulation is disintegrated in 200 mL of neutral pure water, and the dissolution rate of calcium ions is within the range of 20% to 75% when the formulation is stirred at 75 RPM in 900 mL of neutral pure water and measured after 30 minutes. 26. A weak effervescent disintegration formulation of Form 18, comprising calcium carbonate, glucosamine hydrochloride or its salts, cross-linked povidone, and magnesium stearate, wherein the formulation is in the form of granules or tablets, and wherein, when the formulation is stirred at 75 RPM in 900 mL of neutral pure water and measured after 30 minutes, the dissolution rate of calcium ions is within the range of approximately 35% to 55%, and the pH of the suspension formed is within the range of 6.5 to 7.5. 27. A weak effervescent disintegration preparation of Form 18, containing sodium bicarbonate, glucosamine hydrochloride or its salts, cross-linked povidone, and magnesium stearate, the preparation being in the form of granules, capsules, or dispersible tablets, and having a pH within the range of 6.5 to 7.5 after the preparation is disintegrated in 200 mL of neutral pure water. 28. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, glucosamine sulfate, cross-linked povidone, and magnesium stearate, the formulation being in the form of granules, capsules, or dispersible tablets, and having a pH within the range of 6.5 to 7.5 after the formulation is disintegrated in 200 mL of neutral purified water. 29. A weak effervescent disintegration formulation of Form 18, comprising acarbose, calcium carbonate, an acid selected from malic acid, maleic acid, tartaric acid, ascorbic acid, or citric acid, and cross-linked povidone, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 30. A weak effervescent disintegration formulation of Form 18, comprising miglitol, calcium carbonate, an acid selected from malic acid, maleic acid, tartaric acid, ascorbic acid, or citric acid, and cross-linked povidone, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 31. A weak effervescent disintegration formulation of Form 18, comprising megestrol, calcium carbonate, an acid selected from malic acid, maleic acid, tartaric acid, ascorbic acid, or citric acid, and cross-linked povidone, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 32. A weak effervescent disintegration formulation of Form 18, comprising progesterone, calcium carbonate, an acid selected from malic acid, maleic acid, tartaric acid, ascorbic acid, or citric acid, and cross-linked povidone, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 33. A weak effervescent disintegrating formulation of Form 18, comprising a weak base selected from sodium bicarbonate and potassium bicarbonate, an acid selected from sodium tartrate, sodium maleate, sodium succinate, sodium citrate, and sodium tartrate, cross-linked povidone, and nifedipine, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 34. A weak effervescent disintegrating formulation of Form 18, comprising a weak base selected from sodium bicarbonate and potassium bicarbonate, an acid selected from sodium tartrate, sodium maleate, sodium succinate, sodium citrate, and sodium tartrate, cross-linked povidone, and nimodipine, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 35. A weak effervescent disintegration formulation of Form 18, comprising a weak base selected from sodium bicarbonate and potassium bicarbonate, an acid selected from sodium tartrate, sodium maleate, sodium succinate, sodium citrate, and sodium tartrate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and a sartan API selected from losartan, candesartan, valsartan, telmisartan, fimasartan, irbesartan or a salt thereof, wherein the formulation is in the form of an orally disintegrating or dispersible tablet, and wherein the formulation has a pH greater than 4.9 after disintegration in 200 mL of neutral purified water. 36. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked sodium carboxymethyl cellulose, and valsartan, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 37. A weak effervescent disintegration formulation of Form 18, comprising sodium bicarbonate, sodium tartrate, cross-linked sodium carboxymethyl cellulose, and irbesartan, the formulation being in the form of an orally disintegrating tablet, and having a pH greater than 4.9 after disintegration in 200 mL of neutral purified water. 38. A weak effervescent disintegration formulation of Form 18 containing a weak base selected from bicarbonate, monosodium tartrate, monosodium maleate, monosodium succinate, monosodium citrate, monosodium tartrate, monopotassium tartrate, monopotassium maleate, monopotassium succinate, and monopotassium citrate, cross-linked povidone, and an antifibrinolytic agent selected from 6-aminocaproic acid or transaminic acid, and having a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral purified water. 39. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, monosodium tartrate, cross-linked sodium carboxymethyl cellulose, and transaminic acid, the formulation being in the form of a dispersible tablet, and having a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral purified water. 40. A weak effervescent disintegration formulation of Form 18, comprising sodium bicarbonate, sodium tartrate, cross-linked povidone, and a serotonin reuptake inhibitor selected from fluoxetine, paroxetine, sertraline, fluvoxamine or a salt thereof, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 41. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked sodium carboxymethyl cellulose, and sertraline, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 42. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked sodium carboxymethyl cellulose, and fluvoxamine, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 43. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked povidone, and fexofenadine, the formulation being in the form of an orally disintegrating tablet, and having a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral purified water. 44. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked povidone, and an atypical antidepressant selected from quetiapine or ziprasidone, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 45. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked povidone, and quetiapine, the formulation being in the form of an orally disintegrating tablet, and having a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral purified water. 46. ​​A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked povidone, and ziprasidone, the formulation being in the form of an orally disintegrating tablet, and having a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral purified water. 47. A weak effervescent disintegration formulation of Form 18, comprising sodium bicarbonate, sodium tartrate, cross-linked povidone, and a triptan drug selected from sumatriptan or eletriptan, wherein the formulation is in the form of an orally disintegrating tablet, and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 48. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked povidone, and sumatriptan, the formulation being in the form of an orally disintegrating tablet, and having a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral purified water. 49. A weak effervescent disintegration formulation of Form 18, comprising ibuprofen, sodium bicarbonate, sodium tartrate, cross-linked povidone, and an organic acid selected from maleic acid, tartaric acid, succinic acid, maleic acid, ascorbic acid, and citric acid, wherein the formulation is in the form of an ODT (oral disintegrating tablet), and wherein the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral pure water. 50. A weak effervescent disintegration formulation of Form 18, comprising sodium bicarbonate, sodium tartrate, cross-linked povidone, and an organic acid containing an antiepileptic drug selected from phenobarbital, carbamazepine, topiramate, ethosuximide, gabapentin, and phenytoin, and an ascorbic acid selected from citric acid, wherein the formulation is in the form of an orally disintegrating or dispersible tablet, and the pH of the formulation is greater than 4.9 after disintegration in 200 mL of neutral purified water. 51. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked povidone, and an organic acid containing phenobarbital, the formulation being in the form of an ODT, and the pH of the formulation being greater than 4.9 after disintegration in 200 mL of neutral pure water. 52. A weak effervescent disintegration formulation of Form 18, containing sodium bicarbonate, sodium tartrate, cross-linked povidone, phenytoin sodium, and an organic acid selected from monosodium malate, monosodium melate, monosodium succinate, monosodium citrate, and monosodium tartrate, is in the form of an ODT and has a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral purified water. 53. A weak effervescent disintegration formulation of Form 18, comprising sodium bicarbonate, sodium tartrate, cross-linked povidone, and an organic acid selected from maleic acid, tartaric acid, succinic acid, maleic acid, ascorbic acid, and citric acid, produces a suspension and is in the form of an ODT. 54. A weak effervescent disintegration formulation of Form 18, comprising sildenafil, sodium bicarbonate, an organic acid selected from maleic acid, tartaric acid, succinic acid, maleic acid, ascorbic acid, and citric acid, cross-linked povidone, the formulation being in the form of an ODT (oral disintegrating tablet), and having a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral pure water. 55. A weak effervescent disintegration formulation of Form 18, comprising sodium bicarbonate, an organic acid selected from maleic acid, succinic acid, ascorbic acid, and citric acid, and the 5-HT3 (5-hydroxytryptamine-3) receptor antagonists ondansetron HCl, dolasetron HCl, granisetron HCl, palonosetron HCl, and ramosetron HCl, or salts thereof, in the form of an ODT (oral disintegration tablet), and having a pH greater than 4.9 after disintegration in 200 mL of neutral pure water. 56. A weak effervescent disintegration formulation of Form 18, containing ondansetron HCl, sodium bicarbonate, maleic acid, and cross-linked povidone, is in the form of an ODT (oral disintegrating tablet) and has a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral pure water. 57. A weak effervescent disintegration formulation of Form 18, containing granisetron HCl, sodium bicarbonate, maleic acid, and cross-linked povidone, is in the form of an ODT (oral disintegrating tablet) and has a pH greater than 4.9 after the formulation disintegrates in 200 mL of neutral pure water. 58. A method for manufacturing a pellet composition of celecoxib as defined in Form 1 includes the steps of: a) Dissolve 1 part celecoxib and 1-2 parts HPMC E5 in 10-15 parts liquid alcohol selected from ethanol or benzyl alcohol. b) 1 to 2 parts of sugar pellets are placed in a fluidized bed. c) The alcoholic solution containing celecoxib and HPMC E5 obtained in step a) is sprayed into the fluidized bed. d) Mixing the pellets obtained in step c) with magnesium stearate. e) The pellets obtained in step d) are filled into capsules or granule containers, preferably bags. The composition has a dissolution rate of 60% or more of celecoxib in 1000 mL of 0.25% sodium dodecyl sulfate / pH 7 sodium phosphate buffer solution under stirring conditions of 50 RPM for 180 minutes, and the composition is in the form of pellets. 59. A method for preparing a composition of celecoxib as defined in Form 1, comprising the steps of: a) Dissolve 1 part celecoxib and 1-6 parts organic acid in 10-20 parts liquid alcohol, where the organic acid is selected from maleic acid, malic acid, tartaric acid, succinic acid, citric acid, and ascorbic acid, and the alcohol is selected from ethanol or benzyl alcohol. b) Granulation: Place in a fluidized bed 1 part cross-linked povidone, 1 part cross-linked sodium carboxymethyl cellulose, and a small amount of sodium dodecyl sulfate (approximately 20 mg per tablet). c) The ethanolic solution containing celecoxib and an organic acid obtained in step a) is sprayed into the fluidized bed. d) The powder obtained in step c) is granulated by spraying 8% aqueous PVPK30 into a fluidized bed. e) drying the granules obtained in step d) until the moisture content is less than 4%; f) The granules obtained in step e) are mixed with magnesium stearate. g) The granules obtained in step f) are compressed into tablets or preferably filled into capsules or granule containers, bags. This composition has a dissolution rate of 60% or more of celecoxib in 1000 mL of 0.25% sodium dodecyl sulfate / pH 7 sodium phosphate buffer when stirred at 50 RPM for 120 minutes. 60. A method of treating hypocalcemia or calcium deficiency in a subject includes administering to the subject one of the following: a therapeutically effective amount of any of the formulations of Forms 18 to 26; or A weakly effervescent disintegrating formulation comprising calcium carbonate and an organic acid selected from malic acid, tartaric acid, succinic acid, maleic acid, ascorbic acid and citric acid, wherein the daily dose of calcium carbonate is less than 80 mg, the pH of the formulation after disintegration in 200 mL of neutral pure water is 4.9 or higher, the solubility range of calcium ions in 900 mL of neutral pure water is 20% to 75%, and the formulation is in the form of a tablet, capsule, or granule. . 61. A method for the treatment or prevention of a disease or condition comprising administering to a subject a composition as defined in any of Forms 1 to 17 or a formulation as defined in any of Forms 18 to 57. Particularly preferably, the disease or condition is hypocalcemia or calcium deficiency. 62. Use of a method for the manufacture of a medicament using a composition as defined in any of Forms 1 to 17 or a formulation as defined in any of Forms 18 to 57, in particular for treating or preventing hypocalcemia or calcium deficiency. 63. The composition as defined in Forms 1 to 17 or the formulation as defined in Forms 18 to 57 is for use in treating or preventing a disease or condition, particularly hypocalcemia or calcium deficiency, in a subject. 64. Weakly effervescent disintegration preparations containing an active pharmaceutical ingredient, one or more excipients, and a weak acid-base pair, The formulation is in the form of granules, pellets, capsules, tablets, orally disintegrating tablets, or dispersible tablets. The weak acid is an organic acid selected from a monosodium salt of a binary acid, a monopotassium salt of a binary acid, a monosodium salt of a ternary acid, a monopotassium salt of a ternary acid, ascorbic acid, a binary acid, or a mixture thereof; The weak base is selected from calcium carbonate, baking soda, potassium carbonate or lithium carbonate. The active ingredient (API) is selected from cyclooxygenase-2 (COX-2) inhibitors, calcium carbonate, glucosamine, acarbose, miglitol, dihydropyridine calcium channel blockers, nimodipine, triptans, antihistamines, sartans, 5-HT3 antagonist antiemetics, antifibrinoline preparations, nonclassical antidepressants, NSAIDs, hormonal contraceptives, and antiepileptic drugs, salts thereof, or mixtures thereof; and The one or more excipients are selected from hydroxypropyl methylcellulose (HPMC), cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, or mixtures thereof. 65. In the preparation of form 64, the organic acid is selected from malic acid, maleic acid, succinic acid, tartaric acid, citric acid, ascorbic acid and its salts, monosodium malate, monosodium melate, monosodium succinate, monosodium citrate, monosodium tartaric acid, monopotassium malate, monopotassium melate, monopotassium succinate, monopotassium citrate, monopotassium tartaric acid, or mixtures thereof. 66. A formulation in form 64 or 65 containing cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, where the API is a cyclooxygenase-2 (COX-2) inhibitor selected from celecoxib and imrecoxib. 67. A formulation of Form 64, wherein the COX-2 inhibitor is celecoxib. 68. A formulation of Form 64, wherein the COX-2 inhibitor is imrecoxib. 69. A formulation of form 65, wherein the amount of organic acid is 1 to 6 times the weight of celecoxib in the composition. 70. Form 67 or Form 68 formulations, where the formulation has a dissolution rate of 60% or more of the COX-2 inhibitor in 0.25% sodium dodecyl sulfate / pH 7 sodium phosphate buffer at 50 RPM at 120 minutes after dissociation testing. 71. A dosage form of Form 67 or Form 68, wherein the dosage form is in the form of a pellet or capsule, the dosage form further comprises sugar or mannitol, the dosage form comprises one part of a COX-2 inhibitor, one to two parts of hydrophilic methylcellulose, and one to two parts of pellets comprised of sugar or mannitol, and the dosage form has a dissolution rate of 60% or more of the COX-2 inhibitor in neutral purified water containing 2.5 g of sodium dodecyl sulfate at 50 RPM at 180 minutes after dissociation testing. 72. A formulation of T form 65 in which the API is calcium carbonate. 73. A formulation of Form 72, containing cross-linked povidone and magnesium stearate, wherein the organic acid is ascorbic acid, the ratio of the weight of ascorbic acid to the weight of calcium carbonate is in the range of 1:1 to 3:1, and the formulation has a dissolution rate of calcium ions in 900 mL of neutral water in the range of 20% to 65% when measured at a stirring speed of 75 RPM for 30 minutes. 74. A dosage form of Form 72, comprising cross-linked povidone and magnesium stearate, wherein the organic acid is selected from tartaric acid, malic acid, maleic acid, and succinic acid, and wherein the molar ratio of the organic acid to calcium carbonate is in the range of 0.15:1.0 to 1.0:1.0, and wherein the dosage form, upon disintegration in 200 mL of neutral pure water, has a pH greater than 4.9 and a dissolution rate of calcium ions in 900 mL of neutral pure water in the range of 20% to 75% when measured at a stirring speed of 75 RPM. 75. A dosage form of Form 72, containing cross-linked povidone and magnesium stearate, the organic acid is citric acid, the molar ratio of citric acid to calcium carbonate is less than 0.8:1, and the dosage form, upon disintegration in 200 mL of neutral water, has a pH greater than 4.9 and a dissolution rate of calcium ions in 900 mL of neutral pure water in the range of 20% to 75% when measured at a stirring speed of 75 RPM. 76. A dosage form of 72, comprising cross-linked povidone and magnesium stearate, wherein the formulation further comprises glucosamine or a salt thereof, wherein the formulation has a calcium ion solubility in 900 mL of neutral purified water in the range of about 35% to 55% when measured at a stirring speed of 75 RPM, and the pH of the suspension formed is in the range of 6.5 to 7.5. 77. A dosage form of Form 72, comprising cross-linked povidone, the organic acid selected from malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, and citric acid, and further comprising an API selected from acarbose, miglitol, megestrol, or progesterone, wherein the dosage form has a pH greater than 4.9 upon disintegration in 200 mL of neutral purified water, and wherein the dosage form is in the form of an orally disintegrating tablet. 78. A dosage form 64 comprising an API selected from sodium bicarbonate, glucosamine hydrochloride and glucosamine sulfate, or salts thereof, cross-linked povidone, and magnesium stearate, wherein the dosage...

Claims

**Claim 1**: A composition of a cyclooxygenase-2 (COX-2) inhibitor, wherein the COX-2 inhibitor is selected from the group consisting of celecoxib and imrecoxib, the composition comprises a water-soluble excipient selected from the group consisting of HPMC (hydroxypropyl methylcellulose) and an organic acid selected from the group consisting of malic acid, maleic acid, succinic acid, tartaric acid, citric acid, and ascorbic acid, the composition dissolves the COX-2 inhibitor and the water-soluble excipient in alcohol and then mixes it with a swelling agent and a filler, and the composition is produced in the form of pellets, capsules, granules, or tablets. **Claim 2** The composition of the COX-2 inhibitor according to claim 1, comprising an organic acid selected from the group consisting of celecoxib, tartaric acid, maleic acid, succinic acid, malic acid, citric acid, and ascorbic acid, and further comprising cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, so that the composition is in the form of granules, capsules, or tablets; and / or comprising an organic acid selected from the group consisting of celecoxib, tartaric acid, maleic acid, succinic acid, malic acid, citric acid, and ascorbic acid, and further comprising cross-linked povidone and cross-linked sodium carboxymethyl cellulose, the composition is in the form of granules, capsules, or tablets, and has a dissolution rate of more than 60% of celecoxib in 1000 mL of 0.25% sodium dodecyl sulfate / pH 7 sodium phosphate buffer at 50 RPM 120 minutes after the dissolution test; and / or comprising an organic acid selected from the group consisting of celecoxib, tartaric acid, maleic acid, succinic acid, malic acid, citric acid, and ascorbic acid, the amount of the organic acid being 1 to 6 times the weight of celecoxib in the composition, and further comprising cross-linked povidone and cross-linked sodium carboxymethyl cellulose, so that the composition is in the form of granules, tablets, or capsules, and has a dissolution rate of more than 60% of celecoxib in 1000 mL of 0.25% sodium dodecyl sulfate / pH 7 sodium phosphate buffer at 50 RPM 120 minutes after the dissolution test; and / or It contains celecoxib and malic acid, and further contains cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, whereby the composition is in the form of granules, capsules, or tablets; and / or It contains celecoxib and tartaric acid, and further contains cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, whereby the composition is in the form of granules, capsules, or tablets; and / or It contains celecoxib and maleic acid, and further contains cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, whereby the composition is in the form of granules, capsules, or tablets; and / or It contains celecoxib and succinic acid, and further contains cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, whereby the composition is in the form of granules, capsules, or tablets; and / or It contains celecoxib and citric acid, and further contains cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, whereby the composition is in the form of granules, capsules, or tablets; and / or It contains celecoxib and ascorbic acid, and further contains cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, whereby the composition is in the form of granules, capsules, or tablets; and / or It contains imrecoxib and an organic acid or a mixture thereof selected from the group consisting of maleic acid, succinic acid, tartaric acid, malic acid, citric acid, and ascorbic acid, and further contains cross-linked sodium carboxymethyl cellulose, cross-linked povidone, and magnesium stearate, whereby the composition is in the form of granules, capsules, or tablets, and has a dissolution rate of more than 60% of imrecoxib in 1000 mL of 0.25% sodium dodecyl sulfate / pH 7 sodium phosphate buffer at 50 RPM at 120 minutes after the dissolution test; and / or comprising an organic acid selected from the group consisting of celecoxib, maleic acid, succinic acid, tartaric acid, malic acid, citric acid, and ascorbic acid, and further comprising crospovidone, cross-linked sodium carboxymethyl cellulose, calcium carbonate, and magnesium stearate, wherein the composition is in the form of granules, tablets, or capsules, and has a dissolution rate of celecoxib of 60% or more in 1000 mL of 0.25% sodium dodecyl sulfate / pH 7 sodium phosphate buffer at 50 RPM after 120 minutes of dissolution testing; and / or comprising an organic acid selected from the group consisting of imrecoxib, calcium carbonate, maleic acid, succinic acid, tartaric acid, malic acid, citric acid, and ascorbic acid, and further comprising crospovidone, cross-linked sodium carboxymethyl cellulose, and magnesium stearate, wherein the composition is in the form of granules, tablets, or capsules; and / or comprising pellets consisting of celecoxib, hydroxypropyl methylcellulose, and sugar or mannitol, wherein the composition is in the form of pellets or capsules; and / or comprising 1 part of celecoxib, 1 to 2 parts of hydroxypropyl methylcellulose, and 1 to 2 parts of pellets consisting of sugar or mannitol, wherein the composition is in the form of pellets or capsules, and has a dissolution rate of celecoxib of 60% or more in 1000 mL of neutral pure water and contains 2.5 g of sodium dodecyl sulfate at 50 RPM after 180 minutes of testing; and / or comprising pellets consisting of imrecoxib, hydroxypropyl methylcellulose, and sugar or mannitol, wherein the composition is in the form of pellets or capsules; and / or comprising 1 part of imrecoxib, 1 to 2 parts of hydroxypropyl methylcellulose, and 1 to 2 parts of pellets consisting of sugar or mannitol, wherein the composition is in the form of pellets or capsules, and has a dissolution rate of imrecoxib of 60% or more in 1000 mL of neutral pure water and contains 2.5 g of sodium dodecyl sulfate at 50 RPM after 180 minutes of testing, A composition, characterized by the above.

3. A weakly foaming disintegrating formulation containing a weak acid-base pair, wherein the weak acid is selected from the monosodium salt of a dibasic acid, the monopotassium salt of a dibasic acid, the monosodium salt of a tribasic acid, ascorbic acid, a dibasic acid, and mixtures thereof, the weak base is selected from calcium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, and the formulation contains an API selected from calcium carbonate, glucosamine, acarbose, miglitol, a dihydropyridine calcium antagonist, nimodipine, a triptan, an antihistamine, a sartan, an antiemetic of a 5-HT3 antagonist, an antifibrinolin drug, a non-classical antidepressant, an NSAID, a hormonal contraceptive, and an antiepileptic drug, and the formulation decomposes in neutral pure water with a pH exceeding 4.

9.

4. The weakly foaming disintegrating formulation according to claim 3, containing calcium carbonate, ascorbic acid, cross-linked povidone, magnesium stearate, wherein the ratio of the weight of ascorbic acid to the weight of calcium carbonate is in the range of 1:1 to 3:1, the formulation is in the form of a capsule, tablet, orally disintegrating tablet, or dispersible tablet, disintegrates in 200 mL of neutral pure water, has a pH exceeding 4.9, and the dissolution rate of calcium ions in 900 mL of neutral water with stirring at 75 RPM at 30 minutes is in the range of 20% to 65%; and / or containing calcium carbonate, tartaric acid, malic acid, maleic acid, and the molar ratio of these acids is in the range of 0.15:1.0 to 1.0:1.0, the formulation is in the form of granules, capsules, tablets, or dispersible tablets, disintegrates in 200 mL of neutral pure water, has a pH exceeding 4.9, and the dissolution rate of calcium ions in 900 mL of neutral water with stirring at 75 RPM at 30 minutes is in the range of 20% to 75%; and / or containing calcium carbonate, citric acid, cross-linked povidone, magnesium stearate, wherein the molar ratio of citric acid to calcium carbonate is less than 0.8:1, the formulation is in the form of granules, capsules, tablets, or dispersible tablets, disintegrates in 200 mL of neutral water, has a pH exceeding 4.9, and the dissolution rate of calcium ions in 900 mL of neutral water with stirring at 75 RPM at 30 minutes is in the range of 20% to 75%; and / or It contains calcium carbonate, maleic acid, cross-linked povidone, and magnesium stearate, the molar ratio of maleic acid to calcium carbonate ranges from 0.15:1 to 1:1, the preparation is in the form of granules, capsules, tablets, orally disintegrating tablets, or dispersible tablets, disintegrates in 200 mL of neutral pure water, the pH exceeds 4.9, and the dissolution rate of calcium ions in 900 mL of neutral water ranges from 20% to 75% when stirred at 75 RPM at 30 minutes; and / or It contains calcium carbonate, malic acid, cross-linked povidone, and magnesium stearate, the molar ratio of malic acid to calcium carbonate ranges from 0.15:1 to 1:1, the preparation is in the form of granules, capsules, tablets, orally disintegrating tablets, or dispersible tablets, disintegrates in 200 mL of neutral pure water, the pH exceeds 4.9, and the dissolution rate of calcium ions in 900 mL of neutral water ranges from 20% to 75% when stirred at 75 RPM at 30 minutes; and / or It contains calcium carbonate, tartaric acid, cross-linked povidone, and magnesium stearate, the molar ratio of tartaric acid to calcium carbonate ranges from 0.15:1 to 1:1, the preparation is in the form of granules, capsules, tablets, dispersible tablets, or orally disintegrating tablets, disintegrates in 200 mL of neutral pure water, the pH exceeds 4.9, and the dissolution rate of calcium ions in 900 mL of neutral water ranges from 20% to 75% when stirred at 75 RPM at 30 minutes; and / or It contains calcium carbonate, succinic acid, cross-linked povidone, and magnesium stearate, the molar ratio of succinic acid to calcium carbonate ranges from 0.15:1 to 1:1, the preparation disintegrates in 200 mL of neutral pure water, the pH exceeds 4.9, and the dissolution rate of calcium ions in 900 mL of neutral water ranges from 20% to 75% when stirred at 75 RPM at 30 minutes; and / or It contains calcium carbonate, glucosamine hydrochloride, cross-linked povidone, and magnesium stearate, the preparation is in the form of granules or tablets, the dissolution rate of calcium ions in 900 mL of neutral pure water ranges from about 35% to 55%, and the pH ranges from 6.5 to 7.5; and / or It contains sodium bicarbonate, glucosamine hydrochloride or its salts, cross-linked povidone, and magnesium stearate. The preparation is in the form of granules, capsules, or dispersible tablets, and the pH after disintegration in 200 mL of neutral pure water is in the range of 6.5 to 7.5; and / or It contains sodium bicarbonate, glucosamine sulfate, cross-linked povidone, and magnesium stearate. The preparation is in the form of granules, capsules, or dispersible tablets, and the pH in 200 mL of neutral pure water is in the range of 6.5 to 7.5; and / or It contains acarbose, calcium carbonate, an acid selected from the group consisting of malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, and citric acid, and cross-linked povidone. The preparation is in the form of an orally disintegrating tablet, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or. It contains miglitol, calcium carbonate, an acid selected from the group consisting of malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, and citric acid, and cross-linked povidone. The preparation is in the form of an orally disintegrating tablet, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or It contains megestrol, calcium carbonate, an acid selected from the group consisting of malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, and citric acid, and cross-linked povidone. The preparation is in the form of an orally disintegrating tablet, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or. It contains progesterone, calcium carbonate, an acid selected from the group consisting of malic acid, maleic acid, tartaric acid, succinic acid, ascorbic acid, and citric acid, and cross-linked povidone. The preparation is in the form of an orally disintegrating tablet, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or It contains a weak base selected from the group consisting of sodium bicarbonate and potassium bicarbonate, an acid selected from the group consisting of sodium malate, sodium maleate, sodium succinate, sodium citrate, and sodium tartrate, cross-linked povidone, and nifedipine. The preparation is in the form of an orally disintegrating tablet, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or A weak base selected from the group consisting of sodium bicarbonate and potassium bicarbonate, an acid selected from the group consisting of sodium hydrogen malate, sodium hydrogen maleate, sodium hydrogen succinate, sodium hydrogen citrate, and sodium hydrogen tartrate, crospovidone, and nimodipine, wherein the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or A weak base selected from the group consisting of sodium bicarbonate and potassium bicarbonate, an acid selected from the group consisting of sodium hydrogen malate, sodium hydrogen maleate, sodium hydrogen succinate, sodium hydrogen citrate, and sodium hydrogen tartrate, crospovidone, croscarmellose sodium, and a sartan API selected from the group consisting of losartan, candesartan, valsartan, telmisartan, fimasartan, irbesartan, and salts thereof, wherein the preparation is in the form of an orally disintegrating tablet or a dispersible tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or Containing sodium bicarbonate, sodium hydrogen tartrate, croscarmellose sodium, and valsartan, wherein the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or Containing sodium bicarbonate, sodium hydrogen tartrate, croscarmellose sodium, and irbesartan, wherein the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or A bicarbonate, an acid selected from the group consisting of sodium hydrogen malate, sodium hydrogen maleate, sodium hydrogen succinate, sodium hydrogen citrate, and sodium hydrogen tartrate, crospovidone, and an antifibrinolytic agent selected from the group consisting of 6-aminocaproic acid and tranexamic acid, wherein the preparation has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or Containing sodium bicarbonate, sodium hydrogen tartrate, croscarmellose sodium, and tranexamic acid, wherein the preparation is in the form of a dispersible tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or An organic acid selected from the group consisting of calcium carbonate, malic acid, maleic acid, succinic acid, tartaric acid, citric acid and ascorbic acid, cross-linked povidone, and a serotonin reuptake inhibitor selected from fluoxetine, paroxetine, sertraline, fluvoxamine and salts thereof, wherein the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or Containing calcium carbonate, malic acid, cross-linked sodium carboxymethyl cellulose, and sertraline, the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or Containing calcium carbonate, malic acid, cross-linked sodium carboxymethyl cellulose, and fluvoxamine, the preparation is an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or An organic acid selected from the group consisting of calcium carbonate, malic acid, maleic acid, succinic acid, tartaric acid, ascorbic acid and citric acid, cross-linked povidone and fexofenadine, wherein the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or An organic acid selected from the group consisting of calcium carbonate, malic acid, maleic acid, succinic acid, tartaric acid, ascorbic acid and citric acid, cross-linked povidone and an atypical antidepressant selected from quetiapine and diprasidone, wherein the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or Containing calcium carbonate, malic acid, cross-linked povidone and quetiapine, the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or Containing calcium carbonate, malic acid, cross-linked povidone and diprasidone, the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or An acid selected from the group consisting of calcium carbonate, malic acid, maleic acid, succinic acid, tartaric acid, ascorbic acid and citric acid, cross-linked povidone, and a triptan drug selected from sumatriptan and eletriptan, wherein the preparation is in the form of an orally disintegrating tablet and has a pH exceeding 4.9 after disintegration in 200 mL of neutral pure water; and / or Containing calcium carbonate, malic acid, cross-linked povidone and sumatriptan, the preparation is in the form of an orally disintegrating tablet, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or Containing an organic acid selected from the group consisting of ibuprofen, calcium carbonate, malic acid, tartaric acid, succinic acid, maleic acid, ascorbic acid and citric acid and cross-linked povidone, the preparation is in the form of an ODT, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or Containing an organic acid selected from the group consisting of calcium carbonate, malic acid, malic acid, succinic acid, tartaric acid, citric acid and ascorbic acid, and an antiepileptic drug selected from phenobarbital, carbamazepine, topiramate, ethosuximide, gabapentin, and phenytoin, the preparation is in the form of an orally disintegrating tablet or a dispersible tablet, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or Containing calcium carbonate, malic acid, phenobarbital, cross-linked povidone, the preparation is in the form of an ODT, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or Containing a base selected from the group consisting of sodium bicarbonate and potassium bicarbonate, sodium phenytoin, cross-linked povidone, sodium malate, sodium maleate, sodium succinate, sodium citrate, sodium tartrate, potassium malate, potassium maleate, potassium succinate, potassium citrate, potassium tartrate, an acid selected from the group consisting of cross-linked povidone, the preparation is in the form of an ODT, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or Containing an acid selected from the group consisting of calcium carbonate, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, and ascorbic acid, topiramate, cross-linked povidone, and magnesium stearate, the preparation disintegrates in 200 mL of neutral pure water, and the pH of the formed suspension exceeds 4.9; and / or Containing sildenafil, calcium carbonate, malic acid, tartaric acid, succinic acid, maleic acid, ascorbic acid, an acid selected from the group consisting of citric acid and cross-linked povidone, the preparation is in the form of an ODT, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or An acid selected from the group consisting of calcium carbonate, malic acid, tartaric acid, succinic acid, citric acid, ascorbic acid, a 5-HT3 (5-hydroxytryptamine-3) receptor antagonist selected from the group consisting of ondansetron HCl, dolasetron HCl, granisetron HCl, palonosetron HCl, ramosetron HCl or salts thereof, crosslinked povidone, the preparation is in the form of ODT, and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or Containing ondansetron HCl, calcium carbonate, malic acid, and crosslinked povidone, the preparation is in the form of an orally disintegrating tablet (ODT), and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9; and / or Containing granisetron HCl, calcium carbonate, malic acid, and crosslinked povidone, the preparation is in the form of an orally disintegrating tablet (ODT), and the pH after disintegration in 200 mL of neutral pure water exceeds 4.9, A preparation, characterized by the above.

5. A method for producing a pellet composition of a cyclooxygenase-2 (COX-2) inhibitor of celecoxib, comprising the following steps: a) Dissolving 1 part of celecoxib and 1-2 parts of HPMC E5 in 10-15 parts of a liquid alcohol selected from the group consisting of ethanol and benzyl alcohol; b) Putting 1-2 parts of sugar pellets into a fluidized bed, spraying the ethanol solution into the fluidized bed, mixing the produced pellets with magnesium stearate, and filling it into capsules or granule bags, whereby a dissolution rate of more than 60% of celecoxib can be obtained under the condition of 50 RPM at 180 minutes after the dissolution test A method, characterized in that the composition is in the form of pellets.

6. A method for producing a composition of a cyclooxygenase-2 (COX-2) inhibitor of celecoxib, comprising the following steps: a) Dissolving 1 part of celecoxib and 1-6 parts of an organic acid selected from the group consisting of maleic acid, malic acid, tartaric acid, succinic acid, citric acid and ascorbic acid in 10-20 parts of a liquid alcohol selected from the group consisting of ethanol and benzyl alcohol; b) Putting 1 part of crosslinked povidone, 1 part of crosslinked carboxymethylcellulose, and a small amount of sodium dodecyl sulfate (about 20 mg / tablet) into a fluidized bed, and spraying the ethanol solution into the fluidized bed; c) granulating the powder with 8% aqueous PVPK30 in a fluidized bed and drying until the moisture content is less than 4%; d) mixing the obtained granules with magnesium stearate and filling it into tablets or capsules or granule bags, whereby a dissolution rate of celecoxib of 60% or more is obtained under the condition of 50 RPM at 120 minutes after the dissolution test characterized by including the steps. **Claim 7**: A composition comprising one or more cyclooxygenase-2 (COX-2) inhibitors and one or more water-soluble excipients. **Claim 8**: A weakly foaming disintegrating preparation comprising a weak acid-base pair and one or more active pharmaceutical ingredients (APIs). **Claim 9**: Use of an organic acid and calcium carbonate in the manufacture of a preparation, composition or medicament for the treatment of hypocalcemia or calcium deficiency in a subject, wherein the organic acid is selected from the group consisting of malic acid, tartaric acid, succinic acid, maleic acid, ascorbic acid and citric acid, the daily dose of calcium carbonate is less than 80 mg, the pH of the preparation after disintegration in 200 mL of neutral pure water exceeds 4.9, the dissolution range of calcium ions in 900 mL of neutral pure water is from 20% to 75%, and the preparation is in the form of tablets, capsules or granules. **Claim 10**: Use of the composition according to claim 1, 2 or 7, or the weakly foaming disintegrating preparation according to claim 3, 4 or 8, in the manufacture of a medicament for the treatment of hypocalcemia or calcium deficiency in a subject. **Claim 11**: A method for manufacturing the composition according to claim 1, 2 or 7, comprising dissolving a COX-2 inhibitor and a water-soluble excipient in alcohol, mixing with a swelling agent and a filling agent, and forming the composition into pellets, capsules, granules or tablets. **Claim 12**: A pellet composition of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, comprising the following steps: a) dissolving 1 part of celecoxib and 1 to 2 parts of HPMC E5 in 10 to 15 parts of a liquid alcohol selected from the group consisting of ethanol and benzyl alcohol; and b) placing 1 to 2 parts of sugar pellets in a fluidized bed and spraying the ethanol solution containing celecoxib and HPMC E5 onto the fluidized bed; mixing the produced pellets with magnesium stearate, then filling into capsules or granule bags, and having an elution rate of celecoxib in 1000 mL of 0.25% sodium dodecyl sulfate / pH 7 sodium phosphate buffer at 50 RPM exceeding 60% after 180 minutes in an elution test, and the composition being in the form of pellets. **Claim 13**: Any of the invention, its embodiments or applicable claim categories, e.g., a product, method or use included in the subject matter first described, disclosed or explained in this patent application; and / or The use of one or more cyclooxygenase-2 (COX-2) inhibitors in the manufacture of a medicament, composition, combination or product for preventing, improving or treating a disorder, disease or health condition; and / or The use of a weak acid-base pair and one or more active pharmaceutical ingredients (APIs) in the manufacture of a medicament, composition, combination or product for preventing, improving or treating a disorder, disease or health condition; and / or The use of calcium carbonate and an organic acid in the manufacture of a medicament, composition, combination or product for preventing, improving or treating a disorder, disease or health condition; and / or The use of a weak foaming disintegrating formulation as defined herein in the manufacture of a medicament, composition, combination or product for preventing, improving or treating a disorder, disease or health condition; and / or The use of one or more cyclooxygenase-2 (COX-2) inhibitors, or a weak acid-base pair with one or more active pharmaceutical ingredients (APIs), or a weak foaming disintegrating formulation as defined herein, and one or more additional agents in the manufacture of a single or separate medicament, single or separate composition, single or separate combination, or single or separate product for preventing, improving or treating a disorder, disease or health condition; and / or Use of one or more cyclooxygenase-2 (COX-2) inhibitors, or a weak acid-base pair with one or more active pharmaceutical ingredients (APIs), or a weak foaming disintegration formulation as defined herein, in combination with one or more additional agents, in the manufacture of a medicament, composition, combination or product for preventing, improving or treating a disorder, disease or health condition.

Images