Swellable oral pharmaceutical composition

Abstract

A swellable oral composition is described that forms a semi-solid product when water is added prior to administration. The composition is particularly suitable for administration to subjects who may have difficulty or be reluctant to swallow solid oral compositions such as tablets and capsules.

Description

[Technical Field]

[0001] Field

[0001] The present disclosure relates to swellable oral compositions that form semi-solid products upon addition of water prior to administration, which are particularly suitable for administration to subjects who may have difficulty or be reluctant to swallow solid oral compositions such as tablets and capsules. [Background technology]

[0002] background

[0002] Tablets and capsules are the most widely used dosage forms for oral drug administration. However, these dosage forms have several disadvantages. For example, it is estimated that 50% of the population has trouble swallowing tablets. Many elderly people find it particularly difficult to swallow tablets or capsules, and pediatric medication is compromised when subjects are unable or unwilling to swallow tablets or capsules. This can reduce compliance with treatment regimens and adversely affect the efficacy of administered medications. Furthermore, many therapeutic agents have a bitter taste and cannot be sprinkled on foods such as applesauce, a commonly used method of administering medication to children.

[0003]

[0003] The present disclosure solves these and other problems associated with solid oral dosage forms by providing a solid pharmaceutical product that is easily and quickly converted to a semi-solid form immediately prior to administration after the addition of a small amount of water. For individuals who are unable or unwilling to ingest solid oral dosage forms, the semi-solid product is more palatable, thus improving compliance and ensuring that the appropriate dosing regimen is administered to treat or cure the disease.

[0004]

[0004] U.S. Patent Nos. 8,383,154 and 8,383,155 describe the application of Parvulet® technology to produce swellable oral compositions that form semi-solid products when water is added. However, this technology has several limitations. This technology is particularly suitable for powder compositions. For some drugs, Parvulet® technology may need to be modified to adequately control the drug's dissolution and release rate. Summary of the Invention [Problem to be solved by the invention]

[0005] overview

[0005] A primary objective of the present disclosure is to provide novel drug dosage forms with enhanced patient acceptance. The novel solid pharmaceutical products of the present disclosure facilitate a convenient method of orally administering drugs, giving patients expanded options for adhering to treatment regimens in situations where bitter taste or difficulty in swallowing impairs compliance with the administration of traditional oral dosage forms such as tablets or capsules. The novel pharmaceutical products described herein also include controlled-release products that can effectively control the dissolution rate and release characteristics of the drug. [Means for solving the problem]

[0006]

[0006] Therefore, the present disclosure provides a solid pharmaceutical product for oral administration, comprising a drug-containing component and a swellable component. After the addition of a small amount of water, the product is completely converted into a semi-solid form, such as a semi-solid gel. The semi-solid form can be formed without applying shear or other mixing forces, and is easier to swallow than conventional dosage forms such as tablets or capsules.

[0007]

[0007] The present disclosure also provides a combination of drug-containing and swellable components that allows for the preparation of a robust tablet with properties that facilitate its complete conversion to a semi-solid form (e.g., a gel) within minutes by the addition of a small amount of water. The conversion can be achieved without stirring, shaking, heating, or any other method of mixing or applying shear force. One particular advantage of the tablets described herein is that their preparation can be easily scaled up for commercial manufacture. [Brief explanation of the drawings]

[0008] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0008] Photographs of the product of Example 1 before and after the addition of water are shown. [Figure 2]

[0009] The dissolution of the product of Example 1 is shown compared to the dissolution of the drug microsphere component alone. [Figure 3]

[0010] 1 shows a photograph of the product of Example 2 after the addition of water. [Figure 4]

[0011] The dissolution of the product of Example 2 is shown compared to the dissolution of the drug microsphere component alone. [Figure 5]

[0012] 1 shows the release profile of the product of Example 3 in pH 5.8 phosphate buffer. [Figure 6]

[0013] 1 shows the release profile of the product of Example 4 in pH 5.8 phosphate buffer. DETAILED DESCRIPTION OF THE INVENTION

[0009] Detailed Description

[0014] The present disclosure provides a solid pharmaceutical product comprising a drug-containing component and a swellable component. The disclosure also provides methods for manufacturing the product, converting the product into a semi-solid form (e.g., a gel), and administering the semi-solid form to a patient. The product can conveniently be presented as a powder or granules packaged, for example, in a sachet, for use, or can be a robust tablet with properties that allow for rapid and complete conversion to a semi-solid product after the addition of a small amount of water.

[0010] definition

[0015] As used herein, the terms "drug," "active agent," or "active pharmaceutical agent" include pharmaceutically acceptable and therapeutically effective agents and any pharmaceutically acceptable salts, racemates, and enantiomers thereof. It may be selected from several pharmaceutical categories, such as, for example, antibacterial agents, analgesics, antidiabetic agents, anti-inflammatory agents, neuroleptics, antipsychotics, carbonic anhydrase inhibitors, antiallergic agents, antiasthmatic agents, antihistamines, proton pump inhibitors, steroids, corticosteroids, anticonvulsants, antiepileptics, bronchodilators, hypnotics, expectorants, mucolytics, anticancer agents, cardiovascular hypolipidemic agents, gingipain inhibitors, antibiotics, antivirals, vitamins, minerals, peptides, enzymes, proteins, oligonucleotides, biologics, and probiotics. The drug may be lipophilic or hydrophilic. It may be a Class II drug, which includes drugs that are prone to abuse (i.e., known to have properties that may lead to addiction).

[0011] As used herein, the term "controlled release" includes the terms extended release, modified release, delayed release, sustained release or immediate release.

[0012]

[0016] As used herein, the singular forms "a," "an," and "the" include plural references unless the content clearly dictates otherwise. Thus, for example, "a water-soluble polymer" includes a mixture of one or more water-soluble polymers.

[0013]

[0017] The term "about" when used herein to refer to a quantity includes "exactly." For example, "about 60 seconds" includes exactly 60 seconds and values ​​close to 60 seconds (e.g., 50 seconds, 55 seconds, 59 seconds, 61 seconds, 65 seconds, 70 seconds, etc.). In some instances, in the context of the present disclosure, the term "about" refers to an approximate quantity that differs from adjacent values. For example, in the disclosure of "about 65, about 70, about 75," "about 70" refers to an amount as low as a value greater than 65.5 or less than 74.5. When the term "about" is used in connection with a range of values, it refers to both the minimum and maximum values ​​of that range (e.g., "about 1 to 50 μm" means "about 1 μm to about 50 μm").

[0014]

[0018] Unless otherwise indicated, all percentages and ratios are calculated by weight based on the total weight of the ingredient, or the total weight of the composition, or the total weight of the dosage form.

[0015]

[0019] Throughout this specification, all expressions such as percentages and ratios are by weight unless otherwise stated.

[0016]

[0020] The term "drug-containing component" includes a plurality of drug microparticles or drug minitablets.

[0017]

[0021] "Drug microparticles" are drug-containing solids having particle diameter sizes in the micrometer range and may include, for example, microspheres, microcapsules, beads, granules, pellets, or microtablets. A plurality of drug microparticles may conveniently be present in powder form.

[0018]

[0022] "Mini tablets", "mini tabs" or "MMTS" TM " (Multi Minitablet System) is a tablet having a diameter of about 1 mm to about 2 mm. Minitablets may contain one or more drugs and excipients.

[0019]

[0023] "Effective amount" or "therapeutically effective amount," as used herein, means the amount of a drug that would be administered one or more times daily to a patient with a disorder to produce the desired therapeutic effect.

[0020] Purpose of this disclosure

[0024] A primary object of the present disclosure is a solid pharmaceutical product comprising a drug-containing component and a swellable component, which is completely converted to a semi-solid form within about 2 minutes after addition of water without the application of shear or other mixing forces.

[0021]

[0025] A second object of the present disclosure is a tablet comprising a drug-containing component and a swellable component, which is completely converted to a semi-solid form within about 2 minutes after addition of water without the application of shear or other mixing forces.

[0022] Drug-containing ingredients

[0026] The drug-containing component of the present disclosure may comprise a plurality of drug microparticles that can control the release of the drug from the pharmaceutical composition. Alternatively, the drug-containing component of the present disclosure may comprise a plurality of drug mini-tablets, which may or may not be coated.

[0023]

[0027] In one embodiment of the present disclosure, the microparticles are microspheres. In certain embodiments, the microspheres are composed of one or more waxes, lipids, cellulose, and other excipients such as controlled release agents, and have a drug content ranging from about 1% w / w to about 90% w / w.

[0024]

[0028] The microspheres, in one embodiment, may provide an extended release of the drug. Such "extended-release microspheres" may also be combined with a free or "immediate" fraction of the drug so that the patient benefits from a rapid initial dose combined with an extended (e.g., "all-day") administration. The immediate fraction of the drug is a drug component that immediately releases the drug, with greater than about 85% of the drug released within 30 minutes of administration.

[0025]

[0029] In one embodiment of the present disclosure, the microparticles are microcapsules comprising a core / shell structure, where the core portion comprises the drug and excipients, and the shell portion encapsulating the core comprises a hydrophobic matrix and a pH-responsive material.

[0026]

[0030] Controlled-release microparticles can be manufactured according to a variety of methods, including, but not limited to, melt spray congealing, prilling, spray chilling, spray drying, spinning disk, hot melt extrusion, melt granulation, fluidized bed coating, Wurster coating, pan coating, extrusion-spheronization, emulsion, or coacervation.

[0027]

[0031] In one aspect, the microparticles are produced by a melt-spray-condensation process that utilizes an accelerating co-flowing gas stream in combination with piezoelectric vibration.

[0028]

[0032] The microparticles of the present disclosure can also be prepared using Optimμm® technology.

[0029]

[0033] Examples of the preparation of microcapsules are described in U.S. Pat. No. 10,426,734, U.S. Patent Application Publication No. 20160354317, and U.S. Patent Application Publication No. 2019035655.

[0030]

[0034] In one embodiment, the microparticles, including the microcapsules of the present disclosure, have an average particle size (diameter) of about 90 μm to about 1000 μm (as measured, for example, by a Malvern particle size analyzer), have a generally spherical shape, and a narrow particle size distribution.

[0031]

[0035] In one embodiment, the drug microparticles are microspheres and nanospheres having an average particle size (diameter) of about 50 μm to about 100 μm. Ninety percent of these particles have a diameter that is within 2% of the average particle diameter. Preparation of these particles is carried out using Optimμm® technology, as described in U.S. Patent Nos. 6,669,961, 7,368,130, 8,409,621, and 7,309,500.

[0032]

[0036] In one embodiment of the present disclosure, the microparticles have an average particle size (diameter) of about 50 μm to about 300 μm.

[0033]

[0037] In certain embodiments, the microparticles have an average particle size (diameter) of about 50 μm to about 300 μm and comprise a hydrophobic matrix material. The microparticles may also contain other excipients, such as stabilizers and / or release-modifying agents. Such microparticles and their preparation are described in U.S. Patent No. 10,398,649. These particles are particularly suitable for use with hydrophilic drugs.

[0034]

[0038] In one particular embodiment, the microparticles have an average particle size of 200 μm or less (e.g., about 150 μm to about 200 μm). Such particles may advantageously have a polymeric coating. For example, the microparticles may have an average particle size of about 150 μm to about 200 μm and a polymeric coating of about 10% to about 20% w / w.

[0035]

[0039] In one specific embodiment of the present disclosure, the microparticles are microcapsules with an average particle size of 200 μm or less. Such particles can advantageously have a coating, for example, an ethyl cellulose coating. Such microcapsules can be prepared by standard methods, namely, coacervation. In one example, microcapsules with an average particle size of 200 μm or less and an ethyl cellulose coating are prepared by coacervation with ethyl cellulose in cyclohexane.

[0036]

[0040] In one embodiment of the present disclosure, the microparticles are minitablets. Minitablets have an average diameter of about 2 mm or less, for example, about 1 mm to about 2 mm, particularly about 2 mm. Minitablets can be produced in a conventional tablet press equipped with multiple tooling. The production of minitablets is similar to the production of standard tablets, but the small dies require excellent powder flow, precise control of process parameters, and special care during the assembly of the tablet press to avoid tooling damage. Minitablets may be coated or uncoated. Minitablets (or Minitabs®) can be prepared using the same excipients as those described below for regular-sized tablets.

[0037]

[0041] In some embodiments, the drug is present in an amount ranging from about 30% to about 60% by weight of the total mass of the microparticle, e.g., about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% by weight (including each value and subrange therebetween).

[0038]

[0042] In one particular embodiment, the drug is lipophilic and the drug loading is at most 50%.

[0039] Swelling ingredients

[0043] The swellable components of the present disclosure provide flowability and palatability to pharmaceutical compositions at ambient temperatures when mixed with water. The swellable components can be conveniently prepared as described in U.S. Patent Nos. 8,383,154 and 8,383,155.

[0040]

[0044] In one aspect of the present disclosure, the swellable component comprises one or more swellable hydrophilic polymers.

[0041]

[0045] In another aspect of the present disclosure, the swellable component comprises one or more swellable hydrophilic polymers and one or more hydrophilic agents, which may be added to the swellable component to improve the swelling properties of the swellable hydrophilic polymers and ultimately the solid pharmaceutical product.

[0042]

[0046] In one embodiment of the above aspect, the one or more swellable hydrophilic polymers comprise from about 20% to about 80% by weight of the total swellable components.

[0043]

[0047] The hydrophilic polymers herein can form highly viscous materials or gels upon the addition of water. These are preferably hydrocolloids such as gellan gum, agar, alginate, carrageenan, locust bean gum, cellulose derivatives, and starch derivatives. In one embodiment, the swellable hydrophilic polymer is gellan gum. In a particular embodiment, the swellable hydrophilic polymer is high-acyl gellan gum, or gellan gum acylated to a degree of up to four for every two repeats of glucose-rhamnose-glucuronic acid units in the polymer.

[0044]

[0048] The hydrophilic agent may conveniently be selected from the group consisting of electrolytes, organic acids and osmotic agents, and mixtures thereof.

[0045]

[0049] One class of suitable osmotic agents includes osmopolymers such as hydrophilic vinyl and acrylic polymers, polysaccharides, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), PVA / PVP copolymers, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), carboxymethyl cellulose (CMC), carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, and sodium starch glycolate. Another class of suitable osmotic agents includes water-soluble organic acids, salts and sugars; osmotically effective solutes (osmogens) such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol, raffinose, sucrose, glucose, fructose, lactose, inulin, instant sugar, citric acid, succinic acid and tartaric acid.

[0046]

[0050] In one aspect of the present disclosure, the swelling component comprises gellan gum (e.g., high acyl gellan gum) and one or more hydrophilic agents.

[0047]

[0051] In one aspect of the present disclosure, the swellable component comprises one or more swellable hydrophilic polymers and a hydrophilic agent that is an osmogen.

[0048]

[0052] In one aspect of the present disclosure, the swelling component includes gellan gum (e.g., high acyl gellan gum) and a hydrophilic agent that is an osmogen.

[0049]

[0053] In one embodiment of the above aspect, the osmogen is a natural sugar or sugar substitute.

[0050]

[0054] In certain embodiments of the above aspects, the osmogen is selected from mannitol and lactose.

[0051]

[0055] In more particular embodiments, the swelling component comprises gellan gum (e.g., high acyl gellan gum), a hydrophilic agent selected from lactose and mannitol, and a compression aid. In preferred embodiments, the swelling component comprises gellan gum (e.g., high acyl gellan gum), lactose, and silicified microcrystalline cellulose.

[0052]

[0056] Examples of hydrophilic electrolytes include ionizable substances such as monovalent, divalent, or polyvalent ionizable salts. The salts may be selected from inorganic salts including, for example, sulfates, chlorides, borates, bromides, etc. of various alkali metals and / or alkaline earth metals, as well as ionizable alkaline earth organic salts such as citrates, acetates, lactates, calcium sulfate, or sodium chloride. Examples of hydrophilic organic acids include benzoic acid, succinic acid, citric acid, and adipic acid.

[0053]

[0057] In certain embodiments, the swelling component comprises gellan gum (e.g., high acyl gellan gum), lactose, calcium citrate, and silicified microcrystalline cellulose. In another particular embodiment, the swelling component comprises gellan gum (e.g., high acyl gellan gum), mannitol, calcium citrate, and silicified microcrystalline cellulose.

[0054]

[0058] Conveniently, the swelling component can be in powder or granular form before mixing with the drug-containing component. However, if the drug-containing component includes multiple minitablets, the swelling component can also be presented as multiple minitablets before dry-blending with the drug-containing component minitablets. The swelling component minitablets will conveniently have approximately the same dimensions as the drug-containing component minitablets and are prepared in a similar manner. Thus, the swelling component minitablets have an average diameter of about 2 mm or less, e.g., about 1 mm to about 2 mm, particularly about 2 mm. These minitablets can be produced in a conventional tablet press equipped with multiple tools and may be coated or uncoated. The swelling component minitablets (or minitabs) can be prepared using the same excipients as those described below for regular-sized tablets.

[0055]

[0059] In certain embodiments, the swellable component mini-tablets comprise gellan gum (e.g., high acyl gellan gum), a hydrophilic agent selected from lactose and mannitol, and a compression aid such as silicified microcrystalline cellulose. In a preferred embodiment, the swellable component mini-tablets comprise gellan gum (e.g., high acyl gellan gum), lactose, and silicified microcrystalline cellulose.

[0056] solid pharmaceutical products

[0060] The solid pharmaceutical product of the present disclosure comprises a drug-containing component and a swellable component, and the product is completely converted to a semi-solid form within about 2 minutes after addition of water without the application of shear or other mixing forces.

[0057]

[0061] The drug-containing component may comprise a plurality of microparticles or minitablets as described above. The drug microparticles may conveniently be present in the final product at a concentration of about 1% to about 80% w / w. Similarly, the drug minitablets may conveniently be present in the final product at a concentration of about 1% to about 80% w / w.

[0058]

[0062] The type of microparticle and its components dictate the drug release kinetics and other patient-centric benefits (e.g., taste masking). Microparticles can be designed to release the drug at a slow or fast rate, thus allowing patients to benefit from the therapeutic effects without ingesting unpleasant-tasting or large pills.

[0059]

[0063] The solid pharmaceutical product swells and forms a semi-solid mass / gel within about 2 minutes after addition of a predetermined amount of water without the application of shear or other mixing forces to encourage the formation of a homogeneous semi-solid mass / gel.

[0060]

[0064] In one embodiment of the present disclosure, the solid pharmaceutical product is prepared as a loose powder by dry blending the drug-containing component and the swellable component. The powder can be conveniently packaged in the form of a sachet prior to use. For oral administration, the sachet is opened and the powder contents are poured into a dispensing device such as a spoon. After adding a predetermined small amount of water to the powder, sufficient to form a semi-solid mass / gel without any powder product remaining, the patient can swallow the mass / gel. The mass / gel should have a smooth consistency that allows the subject to swallow the product without discomfort. In certain embodiments, the semi-solid mass / gel is formed within about 60 seconds, particularly within about 45 seconds, and preferably within about 30 seconds, of adding the predetermined small amount of water to the solid pharmaceutical product in powder form.

[0061]

[0065] In one embodiment of the present disclosure, the solid pharmaceutical product is prepared as a tablet by first forming a dry mixture of the drug-containing component and the swellable component, and then compressing the resulting mixture to form a tablet using conventional tableting methods. In certain embodiments, the tablet so formed exhibits a tablet friability of 1% or less, e.g., about 0.5% or less. In further embodiments, the tablet is completely converted to a semi-solid form (e.g., a gel) within about 2 minutes, preferably about 90 seconds, after adding a small amount of water. In certain embodiments, the tablet is completely converted to a semi-solid form (e.g., a gel) within about 45 seconds after adding a small amount of water.

[0062]

[0066] Applicant has discovered that incorporating a compression aid into a solid pharmaceutical product prior to tabletting is advantageous for producing tablets having the following combination of characteristics: (1) a tablet friability of 1% or less (e.g., 0.5% or less), (2) a tablet hardness value (N) such that the tablet is sufficiently robust for large-scale manufacturing and packaging, and (3) the tablet is completely converted to a semi-solid form (e.g., a gel) within about 2 minutes after the addition of a small amount of water.

[0063]

[0067] Moreover, surprisingly, the inclusion of a compression aid in combination with a specific osmogen in the swelling component results in improved tablet characteristics (1), (2) and (3).

[0064]

[0068] Examples of suitable compression aids include microcrystalline cellulose, such as silicified microcrystalline cellulose (eg SMCC90 Prosolv).

[0065]

[0069] Osmogens of particular interest for use in the tablet products herein include sugars such as mannitol (eg, Mannogem 2028 or Partek M200) and lactose (eg, Capsulac 60 or Lactose mono).

[0066] In certain embodiments, the present disclosure provides a tablet comprising a drug-containing component and a swellable component, the tablet comprising gellan gum, a compression aid (e.g., silicified microcrystalline cellulose), and an osmogen selected from mannitol (e.g., Mannogem 2028 or Partek M200) and lactose (e.g., Capsulac 60 or Lactose mono). In even more specific embodiments, the present disclosure provides a tablet comprising a drug-containing component and a swellable component, the tablet comprising gellan gum, lactose (e.g., Capsulac 60 or Lactose mono) as an osmogen, and silicified microcrystalline cellulose as a compression aid. In preferred embodiments, the tablet is completely converted to a semi-solid form within about 2 minutes, e.g., 45 seconds, after addition of water without the application of shear or other mixing forces.

[0067]

[0070] In certain embodiments, drugs that may be included in the solid pharmaceutical products of the present disclosure include ibuprofen, cetirizine, and acetaminophen (APAP).

[0068]

[0071] In certain embodiments, the ibuprofen microparticles may be combined with the swellable component in a concentration of 20-65% or 50-65% w / w in the final product, and in a preferred embodiment, it amounts to 62% w / w.

[0069]

[0072] In certain embodiments, the cetirizine microparticles can be combined with the swelling component in the final product at a concentration of 10-50% w / w, and in a preferred embodiment, it amounts to 30% w / w.

[0070]

[0073] In certain embodiments, acetaminophen (APAP) microparticles can be combined / blended with the swellable component at a concentration of 10-50% w / w in the final product, in preferred embodiments, 24% w / w, or 30% w / w, or 36% w / w.

[0071]

[0074] In one particular embodiment, the solid pharmaceutical product comprises cetirizine microparticles in an amount of about 30% w / w based on the total weight of the composition, exhibiting a D[4,3] size distribution of about 250 μm, and further comprises a swellable component comprising gellan gum (high acyl) in an amount of about 28% w / w in the swellable component, the swellable component further comprising calcium citrate in combination with mannitol.

[0072]

[0075] In one particular embodiment, the solid pharmaceutical product comprises acetaminophen microparticles in an amount of 24%, or 30%, or 36% w / w based on the total weight of the composition, and further comprises a swellable component comprising gellan gum (high acyl) in an amount of about 15-30%, preferably 20% or 25% w / w based on the total weight of the product.

[0073]

[0076] In one embodiment of the present disclosure, a solid pharmaceutical product comprises acetaminophen microparticles in an amount of about 24% w / w based on the total weight of the product, and further comprises a swelling component comprising gellan gum (high acyl) in an amount of about 20% w / w based on the total weight of the product, the swelling component further comprising lactose.

[0074]

[0077] In one particular embodiment of the present disclosure, a solid pharmaceutical product comprises ibuprofen microparticles in an amount of about 62% w / w based on the total weight of said product, having a D[4,3] size distribution of about 250 μm, and further comprising a swellable component comprising gellan gum (high acyl) in an amount of about 52% w / w of the swellable component, wherein the swellable component further comprises calcium citrate.

[0075] Embodiment

[0078] Embodiment 1: A controlled release pharmaceutical composition comprising a drug microparticle component and a swellable component.

[0076]

[0079] Embodiment 2: The composition of embodiment 1, wherein the drug microparticles are incorporated into a swellable component comprising at least one swellable hydrophilic polymer.

[0077]

[0080] Embodiment 3: The composition of embodiment 1 or embodiment 2, wherein the swellable component further comprises a hydrophilic agent.

[0078]

[0081] Embodiment 4: The composition of any of the preceding embodiments, wherein the swellable hydrophilic polymer is high acyl gellan gum.

[0079]

[0082] Embodiment 5: The composition of any of the preceding embodiments, wherein the drug microparticles are present in a concentration of 1% to 80% w / w of the total weight of the composition.

[0080]

[0083] Embodiment 6: The composition of any of the preceding embodiments, wherein the drug microparticles are present in an amount of about 1-80% w / w of the total weight of the composition, and the hydrophilic polymer is present in an amount of about 20-80% w / w of the swellable component.

[0081]

[0084] Embodiment 7: The composition of any of the preceding embodiments, wherein the drug microparticles are microspheres having an average diameter of 50 to 100 μm as measured by Malvern, and 90 percent of these particles have a diameter that is within 2% of the average diameter of the particles.

[0082]

[0085] Embodiment 8: The composition of any one of embodiments 1 to 6, wherein the drug microparticles have particles with a particle diameter of about 50 to about 300 μm, and comprise a hydrophobic matrix material, a stabilizer, and a release-modifying agent.

[0083]

[0086] Embodiment 9: The composition of any one of embodiments 1 to 6, wherein the drug microparticles are microcapsules comprising a core-shell structure, the core portion comprising the drug and excipients, and the shell portion encapsulating the core comprising a hydrophobic matrix.

[0084]

[0087] Embodiment 10: The composition of any one of the preceding embodiments, wherein the composition is in the form of a tablet, powder, capsule, or sachet.

[0085]

[0088] Embodiment 11: The composition of any one of the preceding embodiments, wherein the drug is ibuprofen, the drug microparticles are present in an amount of 50-65% w / w of the composition and have a D[4,3] size distribution of about 250 μm, and gellan gum (HA) is in an amount of about 20-80% w / w of the swelling component, and the swelling component comprises calcium citrate.

[0086]

[0089] Embodiment 12: The composition of any one of embodiments 1-10, wherein the drug is cetirizine, the drug microparticles are present in an amount of 10-50% w / w of the composition and have a D[4,3] size distribution of about 250 μm, and gellan gum (HA) is in an amount of about 20-80% w / w of the swelling component, and the swelling component comprises calcium citrate and mannitol.

[0087]

[0090] Embodiment 13: The composition of any one of embodiments 1-6 or 10, wherein the drug microparticles have a particle size of less than 200 μm.

[0088]

[0091] Embodiment 14: The composition of one of embodiments 1-6 or 10, wherein the drug microparticles have a particle size of less than 200 μm and are ethylcellulose coacervated microcapsules.

[0089]

[0092] Embodiment 15: The composition of embodiment 14, wherein the drug is acetaminophen (APAP), the drug microparticles are present in an amount of about 10-50% of the composition, the gellan gum (HA) is in an amount of about 15-30% w / w of the composition, and the swelling component comprises lactose.

[0090]

[0093] Embodiment 16: A method of administering to a patient the controlled release pharmaceutical composition of any one of the preceding embodiments after addition of an aqueous medium without the application of shear forces.

[0091]

[0094] The following examples illustrate solid pharmaceutical products of the present disclosure. [Example]

[0092] Example Example 1. Preparation of extended release ibuprofen sachets

[0095] To prepare the drug component (microspheres), a molten solution consisting of 64% carnauba wax, 25% ibuprofen, 10% stearic acid, and 1% ethyl cellulose was mixed under stirring at 100°C. The molten solution was then processed by a melt-spray congealing process utilizing an accelerated coflowing gas stream combined with piezoelectric vibration. The resulting cooled powder exhibited a size distribution of D[4,3] approximately 250 μm.

[0093]

[0096] To make the swelling component, 38.9% SMCC Prosolv®, 52.1% gellan gum (HA), 7.9% calcium citrate and 1.1% D&C Red #7 were high shear granulated.

[0094]

[0097] To make the pharmaceutical composition, the microsphere component was dry blended with the swellable component such that the microspheres constituted 62% of the dosage form weight (equivalent to a 200 mg ibuprofen dose).

[0095]

[0098] For the swelling test of the compositions, 10 mL of tap water was added to the dry pharmaceutical powder placed on a spoon to form a palatable matrix with an applesauce-like consistency for 18 seconds (n=10). Photographs of the product before and after the addition of water are shown in Figure 1.

[0096]

[0099] For dissolution testing, the pharmaceutical compositions were dissolution tested (n=6) in 900 mL of pH 7.2 sodium phosphate buffer at 50 rpm using a USP Type II apparatus and compared to the dissolution of the microsphere component alone (see Figure 2).

[0097] Example 2. Preparation of immediate release cetirizine tablets

[0100] To prepare the drug component (microspheres), a molten solution consisting of 45% carnauba wax, 45% glyceryl monostearate, 5% Eudragit® E-PO, and 5% cetirizine was prepared under stirring at 100°C. The molten solution was then processed by a melt-spray-congealing process utilizing an accelerated coflowing gas stream combined with piezoelectric vibration. The resulting cooled powder exhibited a size distribution of D[4,3] approximately 250 μm.

[0098]

[0101] To make the swellable component, 57.6% SMCC Prosolv®, 28.8% gellan gum (HA), 7.2% mannitol, 4.3% calcium citrate, 0.6% D&C Red #7, and 1.0% magnesium stearate were high shear granulated.

[0099]

[0102] To make the pharmaceutical composition, the microsphere component was then dry blended with the swellable component such that the microspheres constituted 30% of the dosage form weight (equivalent to a 10 mg cetirizine dose).

[0100]

[0103] Finally, to make tablets, the powder blend was compressed into tablets at 350 psi using 15 mm FFRE tooling.

[0101]

[0104] For dosage form swelling testing, 7 mL of tap water was added to the dry tablets on a spoon for 43 seconds to form a palatable matrix with a "soft serve" appearance (n=10). A photograph of the product after water addition is shown in Figure 3.

[0102]

[0105] For dissolution testing, tablets were dissolution tested (n=6) in 900 mL of 0.1 N HCl at 50 rpm using USP Type II apparatus and compared to the dissolution of the microsphere component alone (see Figure 4).

[0103] Example 3. Berry Flavored Acetaminophen 160 mg Tablets

[0106] Preparation of drug component: Acetaminophen (APAP) microcapsules were prepared by a coacervation process using ethyl cellulose in cyclohexane.

[0104]

[0107] Preblend Preparation: Calcium citrate tetrahydrate, citric acid, malic acid, color, flavor, and sucralose were added to a 2 L blender and blended for 10 minutes at 20 rpm. The blend was then discharged and passed through a Comil 045R screen at 1850 rpm.

[0105]

[0108] Blend Preparation: APAP microcapsules (coacervated Microcaps®), preblend, SMCC, lactose, and gellan gum were added to a 15 L blender and blended for 20 minutes at 20 rpm. Magnesium stearate was added and the mixture was blended for 5 minutes at 20 rpm.

[0106]

[0109] Tableting: The blend was tableted to a total tablet weight of 709 mg and a diameter of 13 mm. The friability was 0.3% and the hardness was 35 N.

[0107] [Table 1]

[0108] [Table 2]

[0109]

[0110] The release profile of berry flavored APAP 160 mg tablets was obtained in pH 5.8 phosphate buffer at 50 rpm. USP Spec: NLT 80% @ 30 min (see Figure 5).

[0110]

[0111] Stability Data: Berry flavor APAP 160 mg tablets were subjected to stability testing under long-term conditions (25°C, 60% humidity) and accelerated conditions (40°C, 75% humidity) in bottles without desiccant. The results are presented in Table 3.

[0111] [Table 3]

[0112] Stability Data: Berry flavor APAP 160 mg tablets were subjected to stability testing under long-term conditions (25°C, 60% humidity) and accelerated conditions (40°C, 75% humidity) in bottles containing desiccant. The results are presented in Table 4.

[0113] [Table 4]

[0114] Example 4. Cherry Flavored Acetaminophen 160 mg Tablets Preparation of Drug Ingredients: Acetaminophen (APAP) microcapsules were prepared by a coacervation process using ethyl cellulose in cyclohexane.

[0115] Preblend Preparation: Calcium citrate tetrahydrate, citric acid, color, flavor, and sucralose were added to a 3 L blender and blended for 10 minutes at 20 rpm. The blend was then discharged and passed through a comil 045R screen at 1850 rpm.

[0116] Blend Preparation: APAP microcapsules (coacervated Microcaps®), preblend, SMCC, lactose, and gellan gum were added to a 15 L blender and blended for 20 minutes at 20 rpm. Magnesium stearate was then added and the mixture was blended for 5 minutes at 20 rpm.

[0117] Tableting: The blend was tableted to a total tablet weight of 709 mg and a diameter of 13 mm. The friability was 0.3% and the hardness was 34 N.

[0118] [Table 5]

[0119] [Table 6]

[0120]

[0117] The release profile of cherry flavored APAP 160 mg tablets was obtained in pH 5.8 phosphate buffer at 50 rpm. USP Spec: NLT 80% @ 30 min (see Figure 6).

[0121] Stability Data: Cherry flavored APAP 160 mg tablets were subjected to stability testing under long-term conditions (25°C, 60% humidity) and accelerated conditions (40°C, 75% humidity) in bottles without desiccant. The results are presented in Table 7.

[0122] [Table 7]

[0123] Stability Data: Cherry flavored APAP 160 mg tablets were subjected to stability testing under long-term conditions (25°C, 60% humidity) and accelerated conditions (40°C, 75% humidity) in bottles containing desiccant. The results are presented in Table 8.

[0124] [Table 8]

[0125] Example 5. Swelling test on 160 mg acetaminophen tablets Preparation of Drug Ingredients: Acetaminophen (APAP) microcapsules were prepared by a coacervation process using ethyl cellulose in cyclohexane.

[0126] Preblend Preparation: Calcium citrate tetrahydrate, citric acid, color, and sucralose were added to a 2 L blender and blended for 10 minutes at 20 rpm. The blend was then discharged and passed through a comil 045R screen at 1850 rpm.

[0127] Blend Preparation: APAP microcapsules (coacervated Microcaps®), preblend, SMCC, lactose, and gellan gum were added to a 15 L blender and blended for 20 minutes at 20 rpm. Magnesium stearate was added and the mixture was blended for 5 minutes at 20 rpm.

[0128] Tableting: The blend was tableted to a total tablet weight of 473 mg and diameter of 12 mm.

[0129] [Table 9]

[0130] Swelling was performed using a reconstitution volume of 4 ml of water. The swelling times for compositions containing 2% salt varied from 180 seconds to 28 seconds depending on the type of water used for swelling (hard water, type water, purified water). When formulations incorporated up to 3% w / w salt, the swelling times varied on average from 37 seconds to 33 seconds, regardless of the water type. These formulations swelled completely, even to the innermost core, and did not have a gummy inner center.

[0131] Example 6. Swelling test on 160 mg acetaminophen tablets Preparation of Drug Ingredients: Acetaminophen (APAP) microcapsules were prepared by a coacervation process using ethyl cellulose in cyclohexane.

[0132] Preblend Preparation: Calcium citrate tetrahydrate, citric acid, color, flavor, and sucralose were added to a 2 L blender and blended for 10 minutes at 20 rpm. The blend was then discharged and passed through a comil 045R screen at 1850 rpm.

[0133] Blend Preparation: APAP microcapsules (coacervated Microcaps®), preblend, SMCC, lactose, and gellan gum were added to a 15 L blender and blended for 20 minutes at 20 rpm. Magnesium stearate was added and the mixture was blended for 5 minutes at 20 rpm.

[0134] Tableting: The blend was tableted to a total tablet weight of 567 mg and diameter of 12 mm.

[0135] [Table 10]

[0136] Swelling was performed using a reconstituted volume of 4 ml of water. The formulation containing 2% flavor had a swelling time of 33 seconds in purified water and 32 seconds in tap water. However, it contained an unswollen inner core. The formulation containing 2% sieved flavor (the de-lumping / sieving process promotes dispersion of the flavor within the blend matrix) had a swelling time of 31 seconds in purified water and 30 seconds in tap water. It did not contain an unswollen core.

[0137] Example 7. Swelling test on 160 mg acetaminophen tablets Preparation of Drug Ingredient: Acetaminophen microcapsules were prepared by a coacervation process using ethyl cellulose in cyclohexane.

[0138] Preblend Preparation: Calcium citrate tetrahydrate, citric acid, color, and sucralose were added to a 2 L blender and blended for 10 minutes at 20 rpm. The blend was then discharged and passed through a comil 045R screen at 1850 rpm.

[0139] Blend Preparation: APAP microcapsules (coacervated Microcaps®), preblend, SMCC, lactose, and gellan gum were added to a 15 L blender and blended for 20 minutes at 20 rpm. Magnesium stearate was added and the mixture was blended for 5 minutes at 20 rpm.

[0140] Tableting: The blend was tableted as pink round lozenge shaped tablets.

[0141] [Table 11]

[0142]

[0134] Swelling was performed using a reconstitution volume of 4 ml of water. Tablets containing mannitol had a total tablet weight of 565 mg and tablets containing lactose had a total tablet weight of 709 mg.

[0143] Mannitol tablets: Increasing hardness (from 14N to 25N) to improve friability (from more than 2.0% to 1.0%) increased the swelling time, and unswollen cores were observed in swollen tablets. Swelling was 37 seconds for tablets with low hardness (14N) and high friability (more than 2%), and more than 120 seconds for tablets with high hardness (25N) and low friability (1.0%).

[0144] Lactose tablets: High hardness (35 N) was achieved with less compression force. The lactose-containing tablets had a friability of 3% and swelled adequately in both purified water (51 seconds) and tap water (67 seconds). They lacked a gummy inner center (unswollen core).

[0145] Example 8. Uncoated placebo minitabs + minitabs of swellable ingredient Step 1: Preparation of uncoated placebo minitabs (2.0 mm) Lactose monohydrate (69.5 parts) and silicified microcrystalline cellulose (SMCC 90) (29.5 parts) were placed in an L-IBC blender and blended for 15 minutes at 10 rpm. Sodium stearyl fumarate (1 part) was sieved through a 35 mesh screen and then added to the blender (containing lactose and SMCC) and further blended for 5 minutes to produce a homogenous blend for compression (batch size: 1 kg). A rotary tablet press Manesty Betapress equipped with a mini-tablet tool set (16, each 2 mm in diameter) configured for a target mini-tablet weight of 5.5 mg was set with the following compression parameters: fill depth setting: 2 mm; compression force setting: ≤1.3 kN (main compression: approx. 2.5 mm); pre-compression setting: 0.12 kN (pre-compression: approx. 8 mm); force feeder speed setting: 0, turret rpm: 35; average weight of tested mini-tabs: 7.1 mg / mini-tab and hardness 14 N.

[0146] Step 2: Preparation of swellable component in minitab (2.0 mm) form Gellan gum (Kelcogel CG-HA) (20.0 parts), silicified microcrystalline cellulose (SMCC 90) (15.0 parts), mannitol granules (59.8 parts), citric acid (1.2 parts), and calcium citrate tetrahydrate (3.0 parts) were placed in an L-IBC blender and blended for 15 minutes at 10 rpm. Magnesium stearate NF (1.0 part) was added to the blender (containing gellan gum, SMCC 90, mannitol granules, citric acid, and calcium citrate tetrahydrate) and blended for an additional 5 minutes to produce a homogenous blend for compression (batch size: 1 kg). A rotary tablet press, Manesty Betapress, equipped with a mini-tablet tool set (16, each 2 mm in diameter) configured for a target weight of 10.0 mg mini-tablets was set with the following compression parameters: fill depth: set value: 2 mm; compression force: 1.3 kN or less (main compression: approximately 2.5 mm); pre-compression: 0.12 kN (pre-compression: approximately 8 mm); force feeder speed: 0; turret rpm: 35.

[0147] Step 3: Combining the products of steps 1 and 2 An uncoated placebo mini-tab prepared in Step 1 was added to a spoon. A mini-tab of the swelling ingredient prepared in Step 2 was then added to the same spoon. Water was added to the spoon, causing the ingredients to swell. The resulting homogenous gel-like preparation formed within minutes.

[0148] Example 9. Coated Placebo Minitabs + Swellable Component Minitabs Step 1: Preparation of coated placebo minitabs (2.2 mm) Minitabs were prepared as described in Step 1 of Example 8. These minitab cores (1,818.2 g) were coated with a stabilizing coating comprising OPADRY II white coating (363.6 g) dissolved / dispersed in 2,060.4 g of USP water in a Glatt GPCG-3 equipped with a 6-inch Wurster insert, a peristaltic pump for a spray rate of 6 mL / min to 12 mL / min and a 0.8 mm nozzle tip size, an air distribution plate "D" and a 100 mesh product support screen, and a dedicated filter bag at the following parameters: inlet temperature setpoint - 61°C; process air rate - 70 cfm; atomizing air - 1.0 bar; target product temperature: 43-47°C. The coated minitabs were then compressed as described in Step 1 of Example 8.

[0149] Step 2: Combining the product of Step 1 above and the product of Step 2 of Example 8 A coated placebo mini-tab prepared in Step 1 was added to a spoon. A mini-tab of the swellable ingredient prepared in Step 2 of Example 8 was then added to the same spoon. Water was added to the spoon, causing the ingredients to swell. The resulting homogenous gel-like preparation formed within minutes.

[0150] Example 10. Swellable placebo tablets containing xylitol The xylitol was passed through a Comill 032R (0.032 inch) screen at 1850 rpm. The color, flavor, and sucralose were combined with 100 g of ground xylitol and then mixed for 2 minutes more. The combined color, flavor, sucralose, and xylitol were passed through a Comill. Kelcogel, the ground combined color, flavor, sucralose, and xylitol, and an additional 100 g of ground xylitol were added to the jar in that order and then blended for 30 minutes at 15 rpm. 300 g of this blend was removed. Sodium stearyl fumarate was added to the blend and mixed for 10 minutes at 15 rpm. The blend was tableted using 14 mm circular dimple tooling to a tablet weight of 600 mg. US Pharmaceutical Convention <1216> The friability of the tablets was measured according to FDA guidance and found to be greater than 1%, which is unacceptable for tablets according to FDA guidance. It is also known that friability values ​​greater than 1% are not considered adequate robustness for packaging and shipping. The tablets exhibited a swelling time of 65-75 seconds.

[0151] [Table 12]

[0152] Example 11. Swellable placebo tablets containing xylitol and 5, 10, 20, 30 and 40% w / w silicified microcrystalline cellulose (SMCC) Prosolv SMCC 90 was incorporated into the xylitol blend described in Example 10 at 5, 10, 20, 30, and 40% w / w, and the blends were tableted at a target weight of 600 mg using a Carver press at 300 psi force with 14 mm circular dimple shaped tooling. Tablet hardness was observed to increase from 13 N to 24 N as the percentage of SMCC in the formulation increased and the corresponding % xylitol decreased. Swelling time decreased from 63 seconds for the 5% SMCC formulation to 33 seconds for the 40% SMCC formulation.

[0153] [Table 13]

[0154] Example 12. Swellable placebo tablets containing xylitol and silicified microcrystalline cellulose (SMCC) without flavors or colorants SMCC, xylitol, Kelcogel, and sucralose were blended for at least 5 minutes. Sodium stearyl fumarate was added to the bottle and blended for at least 2 minutes. Tablets were prepared using a Carver press and 14 mm diamond tooling at 600 PSI. The tablets produced had a hardness of 35-45 N. Tablet friability was approximately 0.7%-0.9%.

[0155] [Table 14]

[0156] Example 13. Swellable placebo tablets containing xylitol and silicified microcrystalline cellulose (SMCC) The xylitol was passed through a Comill 032R (0.032 inch) round screen. The color, flavor, and sucralose were combined with 100 g of ground xylitol and then mixed for 2 minutes or more. The combined color, flavor, sucralose, and xylitol were passed through a Comill. Approximately half of the SMCC, half of the xylitol, gellan gum, ground color, flavor, sucralose, and the remaining half of the SMCC and xylitol were added to the jar in that order and then blended for 30 minutes at 15 rpm. Sodium stearyl fumarate was added to the jar and blended for 15 minutes at 15 rpm. The blend was tableted using a Fetti 52i tablet press with four tooling stations and 14 mm round diamond tooling at a target weight of 600 mg using the following compression parameters: 2.32 (main compression), pre-compression setting of approximately 0.64 kN; force feeder speed setting of 40, and turret rpm of 5. The prepared tablets had a hardness of 28-48 N. The friability of the tablets was about 0.6%-0.9%.

[0157] [Table 15]

[0158] Example 14. Swellable placebo tablets containing silicified microcrystalline cellulose (SMCC) and either mannitol (Samples A and B) or lactose (Samples C and D) instead of xylitol In this preparation, the xylitol present in the previous examples was replaced with another ingredient, namely, mannitol (Mannogem 2080 and Partek M200) or lactose (Capsulac 60 and lactose monohydrate), and the blend was tableted. The formulations containing xylitol exhibited higher than desired tablet friability, even with the presence of the compression aid SMCC. Mannitol and lactose were evaluated here as alternative hydrophilic agents to xylitol. These agents were found to improve the robustness of the formulation. The produced tablets were tested for swelling time and tablet hardness.

[0159] All ingredients except for the sodium stearyl fumarate and half of the SMCC were combined and then mixed for at least 2 minutes. The combined color, flavor, sucralose, half of the SMCC, and either mannitol or lactose were passed through a Comill. Approximately half of the SMCC and the sodium stearyl fumarate were added to the jar and blended for 2 minutes at 15 rpm. The blend was compressed to 300 psi using a Carver press with 14 mm round diamond tooling.

[0160] [Table 16]

[0161] [Table 17]

[0162] [Table 18]

[0163] [Table 19]

[0164] Four tablets (Tablets A to D, including Samples A to D) containing the compositions described in Tables 15 to 18, prepared according to Example 14, were tested for water swelling and tablet hardness. One tablet was placed in a weighing boat, 5 ml of tap water was added, and a timer was started to measure the time (seconds) required for the tablet to completely absorb the water. This test was repeated six times. Table 20 lists the water swelling results and tablet hardness.

[0165] [Table 20]

[0166] Example 15. Swellable placebo tablets containing silicified microcrystalline cellulose (SMCC) and lactose instead of xylitol 100g of SMCC was added to the color, flavor, and sucralose and mixed for at least 2 minutes before passing through a 100-mesh screen. Capsulac 60 (alpha lactose monohydrate with a particle size distribution of 10% NMT <100μm, 40-70% NMT <250μm, 90% NMT <400μm, and 97% NMT <630μm), Kelcogel, citric acid, the blended SMCC, color, flavor, and sucralose, and 100g of SMCC were added to a jar in this order and blended for 30 minutes at 15 rpm. Sodium stearyl fumarate was added to the jar and blended for 15 minutes at 15 rpm. The blends were tableted at a target weight of 600 mg using a Fetti 52i tablet press with four tooling stations and 14 mm round diamond tooling, using the following compression parameters: main compression setting of approximately 2.3 mm (approximately 14 kN), pre-compression setting of approximately 4.3 mm (approximately 0.7 kN), force feeder speed setting of 40 rpm, and turret setting of 5 rpm. The tablets prepared have hardness values ​​of 34 to 53 N and thicknesses of approximately 3.6 mm. Tablet friability is 0.2% to 0.5%.

[0167] [Table 21]

Claims

1. A tablet for administration as a semi-solid product, comprising a drug-containing component and a swellable component comprising microcrystalline cellulose, an osmogen, and electrolytes, wherein the tablet is completely converted to a semi-solid form within 2 minutes of adding water without the application of shear or other mixing forces.

2. 2. The tablet of claim 1, wherein the tablet has a friability of 1% or less.

3. 3. The tablet of claim 2, which is completely converted to a semi-solid form within 90 seconds of adding water.

4. 4. The tablet of claim 2 or 3, which is completely converted to a semi-solid form within 45 seconds after the addition of water.

5. The tablet of any one of claims 1 to 4, wherein the drug-containing component comprises a plurality of drug microparticles selected from drug microspheres and drug microcapsules.

6. A tablet described in any one of claims 1 to 5, wherein the swellable component further comprises at least one water-swellable hydrophilic polymer.

7. 7. The tablet of claim 6, wherein the water-swellable hydrophilic polymer comprises gellan gum.

8. 7. The tablet of claim 6, wherein the water-swellable hydrophilic polymer comprises high acyl gellan gum.

9. 2. The tablet of claim 1, wherein the osmogen is selected from the group consisting of magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol, raffinose, sucrose, glucose, fructose, lactose, inulin, instant sugar, citric acid, succinic acid, tartaric acid, and mixtures thereof.

10. 2. The tablet of claim 1, wherein the osmogen is selected from lactose and mannitol.

11. 11. The tablet of claim 10, wherein the osmogen is alpha lactose monohydrate.

12. The tablet of claim 1, wherein the electrolyte comprises an ionizable salt.

13. 13. The tablet of claim 12, wherein the electrolyte is calcium citrate.

14. A tablet as described in claim 1, further containing an organic acid.

15. 15. The tablet of claim 14, wherein the organic acid is citric acid.

16. The tablet described in claim 1, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

17. 2. The tablet of claim 1, wherein the swellable components comprise gellan gum, the osmogen, and silicified microcrystalline cellulose.

18. 10. The tablet of claim 1, which is completely converted to a semi-solid form within 90 seconds of adding water.

19. 10. The tablet of claim 1, which is completely converted to a semi-solid form within 45 seconds after the addition of water.

20. A tablet described in any one of claims 1 to 18, having an average diameter of 1 mm to 2 mm.

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