Ketorolac tromethamine biphasic controlled release tablets and preparation method thereof

Abstract

This invention belongs to the field of pharmaceutical preparation technology, and particularly relates to ketorolac tromethamine biphasic controlled-release tablets and their preparation method. The ketorolac tromethamine biphasic controlled-release tablets include a controlled-release layer and an immediate-release layer. The controlled-release layer includes a double-layer tablet core containing a drug-containing layer and a semi-permeable membrane disposed outside the double-layer tablet core. The semi-permeable membrane allows water molecules to pass through, and has release pores on its side facing the drug-containing layer. After the double-layer tablet core absorbs water molecules passing through the semi-permeable membrane, the ketorolac tromethamine containing the drug-containing layer is released. The immediate-release layer includes a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable immediate-release excipients. This invention combines the effects of immediate release and zero-order release with controlled release, achieving both rapid and long-lasting drug action. It can continuously and stably release the drug within 24 hours, which is beneficial for maintaining a stable blood drug concentration in patients during medication, reducing the frequency of dosing to once daily, and providing a safer, more stable, and longer-lasting analgesic drug formulation for clinical use.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a ketorolac tromethamine biphasic controlled-release tablet and its preparation method. Background Technology

[0002] Severe pain is unbearable for patients, and in severe cases, it can cause physiological dysfunctions such as excessive stress response, high oxygen consumption, high metabolism, and decreased immunity, thereby affecting the patient's treatment outcome. Postoperative pain management, a common clinical practice, is receiving increasing attention.

[0003] Ketoroxytromethorphan (KT), originally developed by Syntex in the UK and approved for marketing in the US in 1993, is a potent nonsteroidal anti-inflammatory drug (NSAID) and a non-selective cyclooxygenase (COX) inhibitor. It is converted into ketoroxylic acid in the body to exert its therapeutic effect. KT inhibits prostaglandin (PG) synthesis by blocking arachidonic acid cyclooxygenase or collagen-induced platelet aggregation, thus achieving analgesic, anti-inflammatory, and antipyretic effects. KT is used for short-term treatment of acute, severe pain requiring opioid-level analgesia, particularly for relieving moderate to severe pain. Clinically, it is mainly used for postoperative analgesia and to relieve symptoms of acute renal colic, biliary colic, traumatic pain, mid-to-late stage cancer pain, toothache, and trigeminal neuralgia. Compared with traditional narcotic analgesics, ketorolac tromethamine does not act directly on opioid receptors and is not addictive. Its analgesic effect is stronger than that of aspirin, indomethacin, and naproxen, and its anti-inflammatory effect is equivalent to or better than that of indomethacin, naproxen, and phenylbutazone. It also does not significantly interfere with the respiratory and circulatory systems.

[0004] Commonly available dosage forms of ketorolac tromethamine, both domestically and internationally, include capsules, injections, and eye drops. Formulations under investigation include matrix-type sustained-release tablets, oral sustained-release microcapsules, sustained-release implants, nasal sprays, gastric floating tablets, and osmotic pump tablets. Many of these marketed formulations suffer from problems such as a short plasma half-life (generally 4-6 hours) and a short duration of action, requiring 3-4 daily doses in common clinical formulations. This leads to significant fluctuations in blood drug concentrations and "peak-trough" fluctuations, reducing the effectiveness and compliance of treatment. While sustained-release formulations under investigation offer long-lasting analgesia, they cannot rapidly release the active ingredient, failing to achieve rapid analgesia simultaneously, which is detrimental to the treatment of acute and severe pain. Therefore, developing new ketorolac tromethamine formulations with stable release and rapid dissolution is of great significance. Summary of the Invention

[0005] To address the problems of short duration of drug efficacy, need for multiple administrations or slow drug release, and inability to rapidly release active drug components in existing technologies, this invention provides a ketorolac tromethamine biphasic controlled-release tablet and a method for preparing the ketorolac tromethamine biphasic controlled-release tablet.

[0006] To achieve the above objectives, the present invention is specifically implemented through the following technical solutions:

[0007] This invention provides a ketorolac tromethamine biphasic controlled-release tablet, comprising a controlled-release layer and an immediate-release layer from the inside out. The controlled-release layer includes a bilayer tablet core containing a drug-containing layer and a semi-permeable membrane disposed outside the bilayer tablet core. The semi-permeable membrane is permeable to water molecules and has a release pore on the side of the semi-permeable membrane facing the drug-containing layer. After the bilayer tablet core absorbs water molecules permeated through the semi-permeable membrane, the ketorolac tromethamine in the drug-containing layer is released from the release pore. The immediate-release layer includes a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable immediate-release layer excipients, which include one or more of fillers, disintegrants, and lubricants.

[0008] The term "therapeutic effective amount" refers to any amount of a compound, reagent, preparation, or composition sufficient to achieve its intended objective, such as a desired biological or medical response in cells, tissues, or a subject. For example, in some embodiments of the invention, the intended objective may be sufficient to prevent the development of treated pain, inflammation, and / or fever symptoms or to alleviate, to some extent, the treated pain, inflammation, and / or fever symptoms. Therapeutic effective amounts will vary depending on factors such as the activity of the active ingredient, the severity and nature of the pain, inflammation, and / or fever symptoms, and the age, weight, and health status of the individual administering the medication. The term "treatment" and similar terms cover any therapy applied to humans or animals other than humans. Treatment may be directed at an existing condition or may be preventative (preventative treatment), which includes curative, ablation, or preventative effects. Treatment may also include curative, ablation, or prevention of symptoms associated with a disease rather than acting on the underlying cause of the disease.

[0009] The term "pharmaceuticalally acceptable" refers to a component that does not interfere with the bioactivity of the active ingredient, ketorolac tromethamine, and is not significantly toxic to the body at the administered concentration. This includes any one or more combinations of solvents, dispersants, diluents, fillers, wetting agents, binders, disintegrants, lubricants, preservatives, suspending agents, emulsifiers, excipients, flavoring agents, osmotic pressure regulators, and colorants. The use of these components in pharmaceutically active substances is well known in the art.

[0010] This invention involves pressing a double-layer tablet core, then coating the core with an insoluble polymer such as cellulose acetate to form a semi-permeable rigid outer membrane. One or more drug release pores of suitable size are then formed on this rigid outer membrane. Finally, an immediate-release layer containing an effective active drug that can be rapidly released is prepared on the outermost layer, forming a ketorolac tromethamine biphasic controlled-release tablet arranged sequentially from the inside out as a double-layer tablet core, a semi-permeable coating membrane, and an immediate-release layer. The double-layer tablet core and the semi-permeable coating membrane constitute the controlled-release layer, combining the immediate-release effect of the immediate-release layer with the controlled-release effect of the zero-order release characteristic of the controlled-release layer. When the biphasic controlled-release tablet enters the body, the immediate-release layer rapidly disintegrates upon contact with water, achieving a rapid release of ketorolac tromethamine and quickly reaching an effective blood drug concentration. Then, water molecules permeate through the semi-permeable membrane, and the bilayer tablet core slowly absorbs water and swells, generating a high osmotic pressure. This propels the ketorolac tromethamine within the core to be released at a constant rate and in a quantitative manner through the drug release pores of the semi-permeable membrane, thereby achieving a good controlled-release effect. This helps to maintain a stable blood drug concentration in the patient's body over a long period of time, reducing the frequency of dosing, improving the therapeutic effect and patient compliance, and reducing adverse drug reactions and toxic side effects.

[0011] Optionally, the double-layer tablet core is formed by pressing a drug-containing layer and a booster layer together. In order to better control the release of the drug, the weight ratio of the drug-containing layer to the booster layer is 1.5-4:1.

[0012] Optionally, the drug-containing layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable drug-containing layer excipients, wherein the drug-containing layer excipients include a suspending agent, an osmotic pressure enhancer, a lubricant, a binder, and a colorant, with the following weight percentages: ketorolac tromethamine 18%-35%, suspending agent 40%-70%, osmotic pressure enhancer 4%-37%, lubricant 0.3%-4%, binder 1%-4%, and colorant 0%-0.09%; preferably, the following weight percentages are: ketorolac tromethamine 22%-30%, suspending agent 50%-70%, osmotic pressure enhancer 4%-20%, lubricant 0.4%-2%, binder 1%-3%, and colorant 0-0.07%. Further, it may include a wetting agent, the amount of which depends on the specific temperature and humidity conditions of the production environment. For example, when the humidity is high, it may not be added or the amount added may be reduced, while when the environment is dry, the amount may be appropriately increased. The content of this wetting agent is not limited here. Wherein:

[0013] The suspending agent is selected from one or more of the following: polyoxyethylene, gum arabic, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, povidone, copovidone, carbomer, pectin, gelatin, agar, colloidal magnesium silicate, polyethylene glycol, glycerol, and alginate and alginate derivatives, with a molecular weight of 100,000-900,000; the alginate and alginate derivatives are selected from at least one of the following: alginate, sodium alginate, ammonium alginate, calcium alginate, magnesium alginate, potassium alginate, and propylene glycol alginate.

[0014] The osmotic pressure enhancer is selected from one or more of sodium chloride, potassium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, sodium bicarbonate, lactose, glucose, sucrose, fructose, mannitol, sorbitol, xylitol, erythrose, hydrated sodium phosphate, sodium hydrogen phosphate, and sodium carboxymethyl cellulose; preferably selected from one or more of sodium chloride, potassium chloride, lactose, sucrose, mannitol, and sodium bicarbonate.

[0015] The lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium stearate fumarate, and sodium lauryl sulfate. The adhesive is selected from one or more of starch paste, povidone, copovidone, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, ethylcellulose, and gelatin.

[0016] The wetting agent is selected from water, ethanol, or a mixture of water and ethanol.

[0017] The colorant is selected from one or more of iron oxide red, iron oxide yellow, iron oxide brown, iron oxide purple, and iron oxide black.

[0018] Optionally, the booster layer includes a propellant, an osmotic pressure accelerator, a retarder, a lubricant, a binder, and a colorant, with the following weight percentages: propellant 25%-75%, osmotic pressure accelerator 12%-50%, retarder 2.5%-25%, lubricant 0.3%-4%, binder 4%-9%, and colorant 0%-0.6%; preferably, the following weight percentages are: propellant 30%-70%, osmotic pressure accelerator 15%-45%, retarder 3%-20%, lubricant 0.4%-2%, binder 6%-8%, and colorant 0.4%-0.6%. Further, it may include a wetting agent, the amount of which depends on the specific temperature and humidity conditions of the production environment. For example, when the humidity is high, it may be omitted or reduced, while in a dry environment, the amount may be appropriately increased. Its content is not limited here.

[0019] The propellant is selected from polyoxyethylene with a molecular weight of 4,000,000-8,000,000, polyvinyl chloride with a molecular weight of 10,000-360,000, polycarboxylate with a molecular weight of 450,000-4,000,000, polyacrylic acid with a molecular weight of 80,000-200,000, polyhydroxymethyl methacrylate with a molecular weight of 30,000-5,000,000, and poly(hydroxymethyl methacrylate) with a degree of polymerization of 200-30,000 crosslinked with glyoxal, formaldehyde, or glutaraldehyde. The mixture of ethylene glycol, sodium carboxymethyl starch, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, carbomer, low-substituted hydroxypropyl cellulose, croscarmellose sodium carboxymethyl cellulose, copovidone, methylcellulose, croscarmellose agar, and carboxymethyl cellulose, and one or more of alginate and alginate derivatives; wherein the alginate and alginate derivatives are selected from at least one of alginate, sodium alginate, ammonium alginate, calcium alginate, magnesium alginate, potassium alginate, and propylene glycol alginate.

[0020] The retardant is selected from one or more of carbomer, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, povidone, resin, starch, and stearic acid.

[0021] The range of optional components for the osmotic pressure enhancer, the lubricant, the adhesive, the wetting agent, and the colorant is the same as that for the drug-containing layer. It should be noted that the aforementioned components of the drug-containing layer and the booster layer can be of the same or different types. For example, in some embodiments, the osmotic pressure enhancer for both the drug-containing layer and the booster layer is selected from sodium chloride; in other embodiments, the osmotic pressure enhancer for the drug-containing layer is selected from sodium chloride, while the osmotic pressure enhancer for the booster layer is selected from mannitol.

[0022] The semi-permeable membrane is a water-permeable membrane. When the biphase controlled-release tablet of the present invention is in a liquid environment, water molecules enter the bilayer tablet core through the dissolution of the pore-forming agent in the semi-permeable membrane and / or the polymer channels formed by the film-forming material in the semi-permeable membrane. After the bilayer tablet core comes into contact with the liquid and becomes wetted, the propellant and other polymer materials in the booster layer absorb water and swell, accompanied by an outward expansion force, thereby increasing the internal osmotic pressure. At the same time, under the action of the osmotic pressure promoter, the internal osmotic pressure is increased to the point that ketorolac tromethamine is released from the drug release pores of the semi-permeable membrane. The mass of the semi-permeable membrane is 3%-20% of the total weight of the bilayer tablet core, preferably 10%-14%.

[0023] Optionally, the semi-permeable membrane comprises a film-forming material, a plasticizer, and a pore-forming agent. The weight percentages of each component are: film-forming material 4 mg-65 mg, plasticizer 0-2.5 mg, and pore-forming agent 0.15-2.5 mg. Preferably, the weight percentages of each component are: film-forming material 15 mg-24 mg, plasticizer 0-1.5 mg, and pore-forming agent 0.5-0.7 mg.

[0024] The film-forming material is selected from one or more of the following: cellulose acetate, ethyl cellulose, cellulose triacetate, cellulose methyl acetate, cellulose ethyl acetate, cellulose succinate, cellulose dimethylaminoacetate, cellulose ethyl acetate carbonate, cellulose chloroacetate, cellulose ethyl oxalate, cellulose methyl acetate sulfonate, cellulose butyl acetate sulfonate, cellulose propionate, cellulose diacetate, cellulose octanoate, cellulose laurate, cellulose p-toluenesulfonate, cellulose acetate butyrate, cellulose phthalate, cellulose acetate butyrate, cellulose propionate, cellulose trivalerate, cellulose tridodecanoate, cellulose tripalmitate, cellulose disuccinate, cellulose dipalmitate, acrylic resin, polyoxyethylene, polyvinyl chloride, polyethylene, polyvinyl alcohol, polycarbonate, polylactic acid derivatives, polyurethane, and ethylene-vinyl acetate copolymer.

[0025] The plasticizer is selected from one or more of dimethyl phthalate, diethyl phthalate, dioctyl phthalate, dimethoxyethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, glyceryl triacetate, castor oil, polyethylene glycol and propylene glycol with a molecular weight of 100-10000. Preferably, it is selected from one or more of diethyl phthalate and polyethylene glycol with a molecular weight of 400-8000.

[0026] The pore-forming agent is selected from one or more of the following: polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, Eudragit RL / RS, povidone, copovidone, sorbitol, mannitol, lactose, sucrose, propylene glycol, glycerol, and water-soluble inorganic salts, with a molecular weight of 100-10000. The aforementioned compounds dissolve upon contact with water molecules, leaving pores through which water molecules can pass.

[0027] The film-forming material, plasticizer, and pore-forming agent described above are dissolved in a solvent and stirred until homogeneous to obtain a coating solution. The coating solution is then used to coat the bilayer core. The solvent used to dissolve the semi-permeable coating material is selected from acetone, dichloromethane, a dichloromethane / isopropanol mixture (95:5), methyl acetate, or an acetone / water mixture (95:5).

[0028] The drug release pores of the semi-permeable membrane are formed by laser drilling or mechanical drilling. There is one or more drug release pores with an inner diameter of 0.2mm-1.2mm, preferably 0.7mm-0.9mm.

[0029] Optionally, the immediate-release layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable immediate-release layer excipients, wherein the immediate-release layer excipients comprise one or more of fillers, disintegrants, and lubricants, with the following mass percentages: ketorolac tromethamine 1%-3.5%, filler 85%-95%, disintegrant 3-12%, and lubricant 0.4%-1.6%.

[0030] The filler is selected from one or more of microcrystalline cellulose, mannitol, sorbitol, lactose, starch, pregelatinized starch, dextrin, sucrose, dicalcium phosphate, calcium phosphate, and calcium sulfate.

[0031] The disintegrant is selected from one or more of croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, alginate, sodium alginate, and sodium carboxymethyl starch.

[0032] The lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium stearate fumarate, and sodium lauryl sulfate. It should be noted that the lubricants for the immediate-release layer, the drug-containing layer, and the propulsion layer can be of the same or different types. For example, in some embodiments, the lubricants for the immediate-release layer, the drug-containing layer, and the propulsion layer are all selected from magnesium stearate; in other embodiments, the lubricant for the immediate-release layer is selected from hydrogenated vegetable oil, the lubricant for the drug-containing layer is selected from magnesium stearate, and the lubricant for the propulsion layer is selected from talc.

[0033] Furthermore, based on the same inventive concept, the present invention also provides a method for preparing the ketorolac tromethamine biphasic controlled-release tablets as described above, comprising the following steps:

[0034] S1. Preparation of double-layer tablet core: The drug-containing particles and the propulsion layer particles are pressed into a double-layer tablet core at a weight ratio of 1.5-4:1;

[0035] S2. Coating with a semi-permeable coating film: The film-forming material, plasticizer and pore-forming agent are dissolved in a solvent and stirred evenly to obtain a coating solution. The coating solution is then used to coat the bilayer core. The coating weight increases to 3%-20% of the total weight of the bilayer core. The bilayer core coated with a semi-permeable coating film is then dried to obtain the bilayer core.

[0036] S3. Drilling drug release holes: Drilling holes on the semi-permeable coating membrane on the side facing the drug-containing layer to form drug release holes for releasing the drug in the double-layer tablet core, thus obtaining a controlled-release layer;

[0037] S4. Preparation of immediate-release layer: After mixing the components of the immediate-release layer, a mixture is obtained. Half of the mixture is spread flat in the die of the tablet press. The controlled-release layer of step S3 is placed in the center. The other half of the mixture is covered on top and pressed to coat the mixture, thus obtaining ketorolac tromethamine biphasic controlled-release tablets.

[0038] Specifically, the pressing coating method adopts one of the following: wet granulation followed by pressing coating, powder direct pressing coating, or film coating.

[0039] The preparation method of the ketorolac tromethamine biphasic controlled-release tablet has the same advantages over the prior art as the ketorolac tromethamine biphasic controlled-release tablet described above, which has been mentioned before and will not be repeated here.

[0040] The advantages and positive effects of this invention are as follows:

[0041] This invention uses insoluble polymer materials such as cellulose acetate to coat a double-layer tablet core to form a semi-permeable membrane. This membrane has multiple drug release pores of suitable size. The outermost layer is an immediate-release layer containing the active drug that can be rapidly released. This forms a biphasic controlled-release tablet of ketorolac tromethamine, consisting of a double-layer tablet core, a semi-permeable membrane, and an immediate-release layer, arranged sequentially from the inside out. When the tablet enters the body, the immediate-release layer rapidly disintegrates upon contact with water, achieving rapid release of ketorolac tromethamine and quickly reaching an effective blood drug concentration. Then, water molecules permeate through the semi-permeable membrane, and the double-layer tablet core slowly absorbs water and swells, generating a high osmotic pressure. This propels the ketorolac tromethamine within it to be released at a constant rate and in a quantitative manner from the drug release pores of the semi-permeable membrane, thus achieving a good controlled-release effect. This invention combines the rapid-release effect of the immediate-release layer with the controlled-release effect of the zero-order release characteristic of the controlled-release layer, achieving both rapid and long-lasting drug action. It can continuously and stably release drugs within 24 hours, which is beneficial for controlling the long-term stability of blood drug concentration in patients during medication, reducing the frequency of medication to once a day, and providing a safer analgesic drug formulation with more stable and long-lasting analgesic effects for clinical use. Attached Figure Description

[0042] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0043] Figure 1 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 1 of the present invention is shown below.

[0044] Figure 2 This is the drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 2 of the present invention;

[0045] Figure 3 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 3 of the present invention is shown below.

[0046] Figure 4 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 4 of the present invention is shown below.

[0047] Figure 5 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 5 of the present invention is shown below.

[0048] Figure 6 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 6 of the present invention is shown below.

[0049] Figure 7 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 7 of the present invention is shown below.

[0050] Figure 8 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 8 of the present invention is shown below.

[0051] Figure 9 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 9 of the present invention is shown below.

[0052] Figure 10 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 10 of the present invention is shown below.

[0053] Figure 11 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 11 of the present invention is shown below.

[0054] Figure 12 The drug release curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 12 of the present invention is shown below.

[0055] Figure 13 This is the average blood concentration-time curve of the ketorolac tromethamine biphasic controlled-release tablets of Example 13 of the present invention. Detailed Implementation

[0056] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. The specific embodiments described herein are merely illustrative and are not intended to limit the invention.

[0057] Based on the information contained herein, various changes to the precise description of the invention can be readily made by those skilled in the art without departing from the spirit and scope of the appended claims. It should be understood that the scope of the invention is not limited to the defined processes, properties, or components, as these embodiments and other descriptions are merely illustrative of specific aspects of the invention. In fact, various modifications to embodiments of the invention that will be apparent to those skilled in the art or related fields are covered within the scope of the appended claims.

[0058] To better understand the invention and not to limit its scope, all figures indicating amounts, percentages, and other numerical values ​​used in this invention should, in all cases, be understood to be modified by the word "approximately." Therefore, unless specifically stated otherwise, the numerical parameters listed in the specification and appended claims are approximate values ​​and may vary depending on the desired properties being sought. Each numerical parameter should at least be considered as obtained based on reported significant figures and through conventional rounding methods. Furthermore, the terms "comprising," "including," "containing," "having," and similar words are non-limiting in meaning, allowing for the addition of other steps and components that do not affect the result.

[0059] Unless otherwise specified, the experimental methods described in the following examples are generally performed according to the conditions recommended by the manufacturer.

[0060] Examples 1-12

[0061] The ketorolac tromethamine biphasic controlled-release tablets of Examples 1-12 comprise, from the inside out, a controlled-release layer and an immediate-release layer. The controlled-release layer includes a bilayer tablet core formed by pressing together a drug-containing layer and a propulsion layer, and a semi-permeable coating membrane disposed outside the bilayer tablet core. Both the controlled-release layer and the immediate-release layer contain a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable excipients. Specifically, the formulation composition of each example is shown in Tables 1-4.

[0062] Table 1. Immediate-release layer formulations for Examples 1-12 (per 1000 tablets)

[0063]

[0064] Table 2. Drug-containing layer prescriptions for Examples 1-12 (per 1000 tablets)

[0065]

[0066] Table 3. Propellant layer formulations for Examples 1-12 (per 1000 tablets)

[0067]

[0068]

[0069] Table 4. Semi-permeable membrane formulations for Examples 1-12 (dosage per 1000 mL)

[0070]

[0071] Taking Example 1 as an example, the preparation method of ketorolac tromethamine biphasic controlled-release tablets includes the following steps:

[0072] S1. Preparation of double-layer tablet core: Weigh the prescribed amount of drug and other drug-containing layer components that have passed through an 80-mesh sieve, mix them by equal incremental addition, use a binder to make a soft material, pass it through a 20-mesh sieve to obtain wet granules, dry the wet granules at 40℃ for 4-8 hours, granulate them through an 18-mesh sieve, add the prescribed amount of lubricant to the dried granules and mix them evenly to obtain drug-containing layer granules; weigh the prescribed amount of each component of the propulsion layer that has passed through an 80-mesh sieve, and prepare propulsion layer granules according to the preparation method of drug-containing layer granules; press the drug-containing layer granules and propulsion layer granules into a double-layer tablet core with a tablet diameter of 5mm-10mm;

[0073] S2. Coating with a semi-permeable coating: Dissolve the plasticizer and pore-forming agent in a solvent, then slowly add the film-forming material and stir until uniform to obtain a coating solution. Then, use the coating solution to coat the double-layer film core. The coating weight gain is 3%-20% of the total weight of the double-layer film core. Place it in an oven and dry for 12-24 hours to obtain a double-layer film core coated with a semi-permeable coating. See Table 5 for the specific coating weight gain.

[0074] Table 5. Coating weight gain (per tablet) for Examples 1-12

[0075]

[0076]

[0077] S3. Create drug release pores: Create one or more 0.2mm-1.2mm drug release pores on the semi-permeable membrane to obtain a controlled-release layer;

[0078] S4. Preparation of immediate-release layer: After mixing the components of the immediate-release layer, wet granulation is performed or the materials are directly mixed for later use to obtain a mixture. Half of the mixture is spread flat in the die of the tablet press, the controlled-release layer of step S3 is placed in the center, the other half of the mixture is covered on top, and the coating is pressed to obtain ketorolac tromethamine biphasic controlled-release tablets.

[0079] The preparation methods of Examples 2-12 are the same as those of Example 1, except that the components are different, and will not be repeated here.

[0080] The drug release rate in the ketorolac tromethamine biphasic controlled-release tablets of Examples 1-12 was determined by high-performance liquid chromatography (HPLC). Chromatographic conditions: DIKMAC 18 column (250 mm × 4.6 mm, 5 μm); mobile phase: methanol:water:glacial acetic acid (65:34:1); detection wavelength: 322 nm; liquid flow rate: 0.9 mL / min. -1 Column temperature: 40℃, injection volume: 20μL. Take this product, and according to the release rate determination method (United States Pharmacopeia, 43rd edition), the release medium is 600mL of water, the dissolution apparatus speed is 50r / min, and after standard operation, wait for the sampling time, take 4mL of the release solution, filter it through a 0.45μm filter, and use it as the test solution.

[0081] The release curves of Examples 1-12 are shown below. Figure 1-12 .

[0082] Depend on Figure 1-12 It is known that the ketorolac tromethamine biphasic controlled-release tablets of the present invention combine the effects of immediate release and zero-order release, allowing for controlled-release effects. Drug release begins initially, rapidly reaching an effective blood concentration, and continues at a substantially constant rate of zero-order release until complete release over 24 hours. This long-acting drug with 24-hour continuous release allows for once-daily dosing, significantly reducing the frequency of administration.

[0083] Example 13

[0084] Pharmacokinetic and bioavailability studies were conducted on Beagle dogs using the ketorolac tromethamine biphasic controlled-release tablets prepared in Example 1. Experimental animals: Six clean-grade Beagles, approximately 10.0 ± 2.0 kg each, half male and half female.

[0085] Dosing regimen: A two-cycle crossover single-dose experiment was conducted with the test formulation and the reference formulation, with a 7-day washout period between the two cycles. The reference formulation (ketoroxyprogesterone acetate tromethamine capsules, purchased from Shandong New Era Pharmaceutical Co., Ltd., batch number: 242201001) was administered once, 3.5 capsules each time; the test formulation (i.e., the ketoroxyprogesterone acetate tromethamine biphasic controlled-release tablets of this invention) was administered once, 1 tablet each time. After the 7-day washout period, the crossover was performed.

[0086] Blood collection time points: For the test formulation, blood samples were collected before oral administration (0 h) and at 7.5 min, 15 min, 30 min, 45 min, 1.0 h, 1.5 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, 8.0 h, 10.0 h, 12.0 h, 16.0 h, 18.0 h, and 24.0 h after administration. For the reference formulation, blood samples were collected before oral administration (0 min) and at 7.5 min, 15 min, 30 min, 45 min, 1.0 h, 1.5 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, 8.0 h, 12.0 h, and 24.0 h after administration. Approximately 1 mL of blood was collected from the forelimb vein at the established time points. Whole blood samples were kept at room temperature and centrifuged within 2 h after collection at 1700 g and 4 °C for 10 min. After centrifugation, the plasma was temporarily stored at -20°C for 2 hours. After all plasma samples were collected, they were transferred to -80°C for storage.

[0087] The concentration of the analyte in plasma of beagle dogs after oral administration of ketorolac tromethamine was determined by HPLC. Mean plasma concentration-time curves were plotted for each test animal, and the results are shown below. Figure 13 The specific pharmacokinetic parameters are shown in Table 5.

[0088] Table 5. Main pharmacokinetic parameters of the test formulation and the reference formulation.

[0089]

[0090] Note: C max For maximum blood drug concentration, T max t is the time to peak plasma concentration, AUC is the area under the curve, and MRT is the mean residence time of the drug in the body.

[0091] from Figure 13 It can be seen that the average blood drug concentration of the reference formulation reached its peak at about 2.0 h after administration, and then slowly decreased, with the average blood drug concentration dropping to less than 10% of the peak concentration at 8 h. In contrast, the test formulation reached the same blood drug concentration as the reference formulation at 0.5 h, and the average blood drug concentration reached its peak at about 8.0 h after administration, exhibiting a clear steady-state blood drug concentration that remained at a high level from 1 to 16 h, thus achieving the purpose of the experimental design.

[0092] As shown in Table 5, the relative bioavailability of the test formulation was 94.8%. Analysis of variance, two-sided t-tests, and 90% confidence interval analysis confirmed that the test formulation was bioequivalent to the reference formulation. Multivariate analysis of variance for Cmax and Tmax of the test and reference formulations showed that the Tmax of the test formulation was significantly longer than that of the reference formulation (P < 0.01), and the Cmax of the test formulation was significantly lower than that of the reference formulation (P < 0.01), indicating that the test formulation had good immediate and controlled-release effects.

[0093] The other embodiments also yielded the same or similar experimental results as described above. Therefore, the remaining experimental data will not be repeated here.

[0094] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A ketorolac tromethamine biphasic controlled-release tablet, characterized in that, From the inside out, it includes a controlled-release layer and an immediate-release layer. The controlled-release layer includes a double-layer tablet core containing a drug-containing layer and a semi-permeable membrane disposed outside the double-layer tablet core. The semi-permeable membrane is used to allow water molecules to pass through, and a drug release pore is provided on the side of the semi-permeable membrane facing the drug-containing layer. After the double-layer tablet core absorbs the water molecules that pass through the semi-permeable membrane, the ketorolac tromethamine in the drug-containing layer is released from the drug release pore. The immediate-release layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable immediate-release layer excipients, the immediate-release layer excipients comprising fillers, disintegrants and lubricants, and each 1000 tablets of the immediate-release layer comprises the following components: 5 g of ketorolac tromethamine, 300 g of filler, 10 g of disintegrant, and 4.4 g of lubricant; The filler in the immediate-release layer is microcrystalline cellulose KG802; The disintegrant in the immediate-release layer is croscarmellose sodium cellulose; The lubricant in the quick-release layer is magnesium stearate; The double-layer tablet core is formed by pressing a drug-containing layer and a booster layer, wherein the weight ratio of the drug-containing layer to the booster layer is 1.5-4:1; The drug-containing layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable drug-containing layer excipients, including a suspending agent, an osmotic pressure enhancer, a lubricant, and a binder. Each 1000 tablets of the drug-containing layer comprises the following components: 30 g of ketorolac tromethamine, 62 g of suspending agent, 5 g of osmotic pressure enhancer, 0.5 g of lubricant, and 2.5 g of binder. The booster layer comprises a propellant, an osmotic pressure enhancer, a retarder, a lubricant, a binder, and a colorant. Each 1000 pieces of the booster layer comprise the following components: 35 g of propellant, 18 g of osmotic pressure enhancer, 6 g of retarder, 0.64 g of lubricant, 5 g of binder, and 0.3 g of colorant. The semi-permeable membrane comprises a film-forming material and a pore-forming agent, and each 1000 pieces of the semi-permeable membrane comprises the following components: 28.95 g of film-forming material and 1.1 g of pore-forming agent.

2. The ketorolac tromethamine biphasic controlled-release tablet according to claim 1, characterized in that, The suspending agent in the drug-containing layer is polyoxyethylene N10; The osmotic pressure enhancer in the drug-containing layer is sodium chloride; The lubricant in the drug-containing layer is magnesium stearate; The adhesive in the drug-containing layer is polyvinylpyrrolidone K30.

3. The ketorolac tromethamine biphasic controlled-release tablet according to claim 1, characterized in that, The propellant in the booster layer is polyoxyethylene WSR-303; The retardant in the booster layer is hydroxypropyl methylcellulose K4M; The osmotic pressure booster in the booster layer is sodium chloride; The lubricant in the booster layer is magnesium stearate; The adhesive in the booster layer is polyvinyl ketone K30; The colorant in the booster layer is iron oxide red.

4. The ketorolac tromethamine biphasic controlled-release tablet according to claim 1, characterized in that, The film-forming material in the semi-permeable membrane is cellulose acetate; The pore-forming agent is polyethylene glycol 4000.

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