CN116115581A

CN116115581A - Ketorolac tromethamine biphasic controlled release tablet and preparation method thereof

Info

Publication number: CN116115581A
Application number: CN202310278516.1A
Authority: CN
Inventors: 刘辉; 曾媛; 张莹; 石林; 胡华; 姚晨; 马毅慧; 谢向阳; 张国伟; 王淞; 田巍; 熊菁; 许宁宁; 李牧恒; 李玉靓
Original assignee: General Hospital of Central Theater Command of PLA
Current assignee: General Hospital of Central Theater Command of PLA
Priority date: 2023-03-21
Filing date: 2023-03-21
Publication date: 2023-05-16

Abstract

The invention belongs to the technical field of preparation of pharmaceutical preparations, and particularly relates to ketorolac tromethamine biphasic controlled release tablets and a preparation method thereof. The ketorolac tromethamine biphasic controlled release tablet comprises a controlled release layer and a quick release layer, wherein the controlled release layer comprises a double-layer tablet core containing a drug-containing layer and a semipermeable coating film arranged outside the double-layer tablet core, the semipermeable coating film is used for penetrating water molecules, one side of the semipermeable coating film, which faces the drug-containing layer, is provided with a drug release hole, and the double-layer tablet core enables the ketorolac tromethamine of the drug-containing layer to be released after absorbing the water molecules penetrated by the semipermeable coating film; the quick-release layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable quick-release layer auxiliary materials. The invention has both quick release effect and zero-order release characteristic controlled release effect, realizes quick and long-acting effects of the medicine, can continuously and stably release the medicine within 24 hours, is beneficial to controlling the long-term stability of the blood concentration in the body during the medicine taking period of a patient, reduces the medicine taking frequency to be once daily, and provides an analgesic medicine preparation with higher safety and more stable and long-acting analgesic effect for clinic.

Description

Ketorolac tromethamine biphasic controlled release tablet and preparation method thereof

Technical Field

The invention relates to the technical field of preparation of pharmaceutical preparations, in particular to ketorolac tromethamine biphasic controlled release tablets and a preparation method thereof.

Background

The subjective feeling of severe pain to patients is intolerable, and serious patients can cause physiological dysfunction phenomena such as strong body stress response, high oxygen consumption, high metabolism, immunity decline and the like, so that the treatment effect of the patients is affected, and the clinical common postoperative pain management is also more and more important.

Ketorolac tromethamine was first developed by the united kingdom Syntex company, and was approved for market in the united states in 1993, is a non-steroidal drug with potent analgesic activity, and is a non-selective Cyclooxygenase (COX) inhibitor that converts to ketorolac in humans to exert therapeutic effects, which inhibits Prostaglandin (PG) synthesis by blocking the cyclooxygenase or collagen-induced platelet aggregation of arachidonic acid to achieve analgesic, anti-inflammatory and antipyretic effects. Ketorolac tromethamine is used for short-term treatment of acute severe pain requiring opioid level analgesic, especially for relieving moderate severe pain, and is clinically used for postoperative pain relief and relieving symptoms such as acute renal colic, biliary colic, wound pain, cancer middle and late pain, toothache, trigeminal neuralgia, etc. Compared with the traditional narcotic analgesic, ketorolac tromethamine does not directly act on opioid receptors, has no addiction, has an analgesic effect which is stronger than that of aspirin, indomethacin and naproxen, has an anti-inflammatory effect which is equivalent to or better than that of indomethacin, naproxen and phenylbutazone, and has no obvious interference on respiratory and circulatory systems.

The ketorolac tromethamine commonly used dosage forms which are marketed in succession at home and abroad comprise capsules, injection, eye drops and the like, and the dosage forms in the research stage comprise skeleton type sustained release tablets, oral sustained release microcapsules, sustained release implants, nasal sprays, gastric floating tablets, osmotic pump tablets and the like. The marketed preparation has the problems of short plasma half-life (generally 4-6 hours) of ketorolac tromethamine, short duration of drug effect, 3-4 times daily administration of clinical common dosage forms and the like, so that the fluctuation of blood concentration is large, the peak-valley fluctuation phenomenon of blood concentration is caused, and the effectiveness and compliance of drug treatment are reduced. The slow release dosage form in the research stage has long-acting analgesic effect, but can not release the active ingredients of the medicine rapidly, can not realize the effect of rapid analgesic effect at the same time, and is unfavorable for the treatment of patients with acute and severe pain. Therefore, the development of a novel ketorolac tromethamine preparation which can be stably released and can be rapidly dissolved is of great significance.

Disclosure of Invention

Aiming at the problems of short duration of drug effect, need of repeated administration or slow drug release and incapability of rapidly releasing the active ingredients of the drugs in the prior art, the invention provides a ketorolac tromethamine biphasic controlled release tablet and a preparation method of the ketorolac tromethamine biphasic controlled release tablet.

In order to achieve the above purpose, the present invention is specifically realized by the following technical scheme:

the invention provides a ketorolac tromethamine biphasic controlled release tablet, which comprises a controlled release layer and a quick release layer from inside to outside, wherein the controlled release layer comprises a bilayer tablet core containing a medicine containing layer and a semipermeable coating film arranged outside the bilayer tablet core, the semipermeable coating film is used for penetrating water molecules, one side of the semipermeable coating film, which faces the medicine containing layer, is provided with a medicine release hole, and the bilayer tablet core enables ketorolac tromethamine of the medicine containing layer to release medicine Kong Shichu after absorbing the water molecules penetrated by the semipermeable coating film; the quick-release layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable quick-release layer auxiliary materials, wherein the quick-release layer auxiliary materials comprise one or more of a filler, a disintegrating agent and a lubricant.

The term "therapeutically effective amount" refers to any amount of a compound, agent, formulation, or composition sufficient to achieve its intended purpose, e.g., a desired biological or medical response in a cell, tissue, or subject, e.g., in certain embodiments of the invention, the intended purpose may be: sufficient to prevent the development of or to some extent reduce the symptoms of pain, inflammation and/or fever being treated. The therapeutically effective amount will vary depending on the activity of the active ingredient, the pain, inflammation and/or fever disorder and the severity thereof, the age, weight and health of the individual to whom it is administered, and the like. Treatment and like terms encompass any therapy for humans or animals other than humans, which may be directed to an existing condition, or may be prophylactic (prophylactic treatment), which includes curative, palliative or prophylactic effects. Treatment may also include curing, alleviating or preventing symptoms associated with the disease rather than contributing to the underlying cause of the disease.

The term "pharmaceutically acceptable" refers to components that do not interfere with the efficacy of the biological activity of the active ingredient ketorolac tromethamine and that are not significantly toxic to the body at the concentrations at which they are administered, including any one or more of solvents, dispersants, diluents, fillers, wetting agents, binders, disintegrants, lubricants, preservatives, suspending agents, emulsifiers, excipients, flavoring agents, osmotic pressure regulators, colorants, and the like. The use of the above components for pharmaceutically active substances is well known in the art.

After the double-layer tablet core is pressed, insoluble polymer materials such as cellulose acetate and the like are used for coating the double-layer tablet core to form a semi-permeable rigid outer film, one or more drug release holes with proper pore diameters are arranged on the rigid outer film, and finally, a quick release layer which contains effective active drugs and can be quickly released is prepared on the outermost side to form the ketorolac tromethamine double-phase controlled release tablet which is orderly sequenced into the double-layer tablet core, the semi-permeable coating film and the quick release layer from inside to outside, wherein the double-layer tablet core and the semi-permeable coating film form a controlled release layer, and the controlled release effect of the quick release layer and the controlled release effect of the zero-order drug release characteristics of the controlled release layer are achieved. When the biphasic controlled release tablet enters a body, the quick release layer is quickly disintegrated when meeting water, so that the quick release of ketorolac tromethamine is realized, the effective blood concentration is quickly reached, then water molecules penetrate from the semipermeable coating film, the bilayer tablet core slowly absorbs water and expands to generate very high osmotic pressure, the ketorolac tromethamine in the biphasic controlled release tablet is pushed to be released from the drug release holes of the semipermeable coating film at a constant speed and quantitatively, thereby achieving good controlled release effect, being beneficial to controlling the long-term stability of the blood concentration in the body during the taking period of a patient, reducing the taking times, improving the drug treatment effect and the compliance of the patient, reducing adverse reactions of the drug and reducing toxic and side effects.

Optionally, the double-layer tablet core is formed by pressing a medicine-containing layer and a boosting layer, and for better controlled release of medicine, the weight ratio of the medicine-containing layer to the boosting layer is 1.5-4:1.

optionally, the drug-containing layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable drug-containing layer auxiliary materials, wherein the drug-containing layer auxiliary materials comprise a suspending agent, an osmotic pressure promoter, a lubricant, an adhesive and a colorant, and the weight percentages of the components are as follows: 18-35% of ketorolac tromethamine, 40-70% of suspending agent, 4-37% of osmotic pressure promoter, 0.3-4% of lubricant, 1-4% of adhesive and 0-0.09% of colorant; preferably, the weight percentages of the components are as follows: 22-30% of ketorolac tromethamine, 50-70% of suspending agent, 4-20% of osmotic pressure promoter, 0.4-2% of lubricant, 1-3% of adhesive and 0-0.07% of colorant. Further, it is also possible to include a wetting agent which is added or reduced according to the specific temperature and humidity conditions of the production environment, for example, when the humidity is high, and when the humidity is dry, the amount of the wetting agent can be appropriately increased, and the content is not limited. Wherein:

the suspending agent is selected from one or more of polyoxyethylene, acacia, hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, povidone, copovidone, carbomer, pectin, gelatin, agar, colloidal magnesium silicate, polyethylene glycol, glycerol, alginic acid and alginic acid derivatives with molecular weight of 100000-900000; the alginic acid and alginic acid derivative are at least one selected from alginic acid, sodium alginate, ammonium alginate, calcium alginate, magnesium alginate, potassium alginate and propylene glycol alginate.

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

The lubricant is one or more selected from magnesium stearate, calcium stearate, stearic acid, micro silica gel, talcum powder, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate and sodium laurylsulfate. The binder is one or more selected from starch slurry, povidone, copovidone, methylcellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose and gelatin.

The wetting agent is selected from water, ethanol or a mixed solution of water and ethanol.

The colorant is selected from one or more of iron oxide red, iron oxide yellow, iron oxide brown, iron oxide violet and iron oxide black.

Optionally, the boosting layer comprises a propellant, an osmotic pressure accelerator, a retarder, a lubricant, an adhesive and a colorant, wherein the weight percentages of the components are as follows: 25-75% of propellant, 12-50% of osmotic pressure promoter, 2.5-25% of retarder, 0.3-4% of lubricant, 4-9% of adhesive and 0-0.6% of colorant; preferably, the weight percentages of the components are as follows: 30-70% of propellant, 15-45% of osmotic pressure promoter, 3-20% of retarder, 0.4-2% of lubricant, 6-8% of adhesive and 0.4-0.6% of colorant. Further, it is also possible to include a wetting agent which is added or reduced according to the specific temperature and humidity conditions of the production environment, for example, when the humidity is high, and when the humidity is dry, the amount of the wetting agent can be appropriately increased, and the content is not limited. Wherein:

the propellant is selected from one or more of polyoxyethylene with molecular weight of 4000000-8000000, povidone with molecular weight of 10000-360000, carbopol with molecular weight of 450000-4000000, polyacrylic acid with molecular weight of 80000-200000, polyhydroxy methyl acrylic acid alkyl ester with molecular weight of 30000-5000000, polyethylene glycol with polymerization degree of 200-30000 crosslinked with glyoxal, formaldehyde or glutaraldehyde, sodium carboxymethyl starch, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, carbomer, low substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, copolyvidone, methyl cellulose, crosslinked agar, mixture of carboxymethyl cellulose and alginic acid derivative; the alginic acid and alginic acid derivative are at least one selected from alginic acid, sodium alginate, ammonium alginate, calcium alginate, magnesium alginate, potassium alginate and propylene glycol alginate.

The retarder is selected from one or more of carbomer, hypromellose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, povidone, resin, starch and stearic acid.

The optional ranges of the osmotic pressure enhancer, the lubricant, the binder, the wetting agent, and the colorant are the same as the medicated layer. It should be noted that the foregoing components of the drug-containing layer and the boost layer may be the same or different, e.g., in some embodiments, the osmotic pressure promoters of the drug-containing layer and the boost layer are both selected from sodium chloride, in other embodiments, the osmotic pressure promoter of the drug-containing layer is selected from sodium chloride, and the osmotic pressure promoter of the boost layer is selected from mannitol.

When the biphasic controlled release tablet is in a liquid environment, water molecules enter a bilayer tablet core through a pore-forming agent of the semipermeable tablet and/or a polymer pore channel formed by a film forming material in the semipermeable tablet, after the bilayer tablet core is wetted by liquid, the polymer materials such as a propellant in a boosting layer absorb water and expand outwards, so that the internal osmotic pressure is increased, and meanwhile, under the action of an osmotic pressure promoter, the internal osmotic pressure is increased to enable ketorolac tromethamine to be released from a drug release hole of the semipermeable tablet. The mass of the semipermeable coating film is 3-20% of the total weight of the double-layer tablet core, and is preferably 10-14%.

Optionally, the semipermeable coating comprises a film forming material, a plasticizer and a porogen. The weight of each component is as follows: 4mg-65mg of film forming material, 0 mg-2.5 mg of plasticizer and 0.15 mg-2.5 mg of pore-forming agent. Preferably, the weight of each component is as follows: 15mg-24mg of film forming material, 0-1.5mg of plasticizer and 0.5-0.7mg of pore-forming agent. Wherein:

the film forming material is selected from one or more of cellulose acetate, ethyl cellulose, cellulose triacetate, methyl acetate cellulose, ethyl acetate cellulose, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate carbonate, cellulose acetate chloroacetate, cellulose acetate oxalate, cellulose acetate sulfonate, cellulose acetate propionate, cellulose acetate diacetate, cellulose acetate octoate, cellulose acetate laurate, cellulose acetate tosylate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate butyrate, cellulose propionate, cellulose tripentact, cellulose tripalmitate, cellulose disuccinate, cellulose dipalmitate, acrylic resin, polyoxyethylene, polyvinyl chloride, polyethylene, polyvinyl alcohol, polycarbonate, polylactic acid derivatives, polyurethane and ethylene-vinyl acetate copolymer.

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, triacetin, castor oil, polyethylene glycol with molecular weight of 100-10000 and propylene glycol. Preferably one or more of diethyl phthalate and polyethylene glycol having a molecular weight of 400-8000.

The pore-forming agent is selected from one or more of polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, eudragit RL/RS, povidone, copovidone, sorbitol, mannitol, lactose, sucrose, propylene glycol, glycerol and water-soluble inorganic salt with molecular weight of 100-10000. The aforementioned compounds dissolve upon contact with water molecules to leave pores through which water molecules pass.

And dissolving the film forming material, the plasticizer and the pore-forming agent by using a solvent, uniformly stirring to obtain coating liquid, and coating the double-layer tablet core by using the coating liquid. The solvent used to dissolve the semipermeable membrane material is selected from the group consisting of acetone, methylene chloride, a methylene chloride/isopropyl alcohol mixed solvent (95:5), methyl acetate, and an acetone/water mixed solvent (95:5).

The medicine release holes of the semipermeable coating are laser holes or mechanical holes, the medicine release holes are one or more, the inner diameter is 0.2mm-1.2mm, and the preferable inner diameter is 0.7mm-0.9mm.

Optionally, the quick-release layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable quick-release layer auxiliary materials, wherein the quick-release layer auxiliary materials comprise one or more of a filler, a disintegrating agent and a lubricant, and the mass percentages of the components are as follows: 1 to 3.5 percent of ketorolac tromethamine, 85 to 95 percent of filler, 3 to 12 percent of disintegrating agent and 0.4 to 1.6 percent of lubricant. Wherein:

the filler is selected from one or more of microcrystalline cellulose, mannitol, sorbitol, lactose, starch, pregelatinized starch, dextrin, sucrose, calcium hydrogen phosphate, calcium phosphate and calcium sulfate.

The disintegrating agent is one or more selected from crosslinked sodium carboxymethyl cellulose, crosslinked povidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, alginic acid, sodium alginate and sodium carboxymethyl starch.

The lubricant is one or more selected from magnesium stearate, calcium stearate, stearic acid, micro silica gel, talcum powder, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate and sodium laurylsulfate. It should be noted that the lubricant of the immediate release layer and the lubricant of the drug-containing layer and the lubricant of the boosting layer may be the same kind or different kinds, for example, in some embodiments, the lubricant of the immediate release layer, the lubricant of the drug-containing layer, and the lubricant of the boosting layer are all selected from magnesium stearate, in other embodiments, the lubricant of the immediate release layer is selected from hydrogenated vegetable oil, the lubricant of the drug-containing layer is selected from magnesium stearate, and the lubricant of the boosting layer is selected from talc.

In addition, based on the same inventive concept, the invention also provides a preparation method of the ketorolac tromethamine biphasic controlled release tablet, which comprises the following steps:

s1, preparing a double-layer sheet core: the medicine-containing layer particles and the boosting layer particles are mixed according to the weight ratio of 1.5-4:1 pressing into a double-layer sheet core;

s2, coating a semipermeable coating film: respectively dissolving a film forming material, a plasticizer and a pore-forming agent in a solvent, uniformly stirring to obtain a coating solution, coating the double-layer tablet core by using the coating solution, increasing the weight of the coating to 3-20% of the total weight of the double-layer tablet core, and drying to obtain the double-layer tablet core coated with the semipermeable coating film;

s3, punching a medicine release hole: punching a hole on one side of the semipermeable coating film facing the drug-containing layer to form a drug release hole for releasing the drug in the double-layer tablet core, thereby obtaining a controlled release layer;

s4, preparing a quick release layer: uniformly mixing the components of the quick release layer to obtain a mixture, spreading half of the mixture in a die of a tablet press, placing the controlled release layer in the middle of the step S3, covering the other half of the mixture, and performing compression coating to obtain the ketorolac tromethamine biphasic controlled release tablet.

Specifically, the method of compression coating adopts one of a wet granulation post-compression coating method, a powder direct compression coating method and a film coating method.

The preparation method of the ketorolac tromethamine biphasic controlled release tablet has the same advantages as those of the ketorolac tromethamine biphasic controlled release tablet in the prior art, and the preparation method is described above and is not repeated here.

The invention has the advantages and positive effects that:

the invention uses insoluble polymer materials such as cellulose acetate and the like to coat the double-layer tablet core to form a semipermeable coating film, a plurality of drug release holes with proper pore diameters are arranged on the semipermeable coating film, and the outermost side is provided with a quick release layer containing effective active drugs and capable of being rapidly released, so as to form a controlled release layer formed by the double-layer tablet core and the semipermeable coating film and a ketorolac tromethamine biphasic controlled release tablet of the quick release layer, when the ketorolac tromethamine biphasic controlled release tablet enters a body, the quick release layer rapidly disintegrates when meeting water, the rapid release of ketorolac tromethamine is realized, the effective blood concentration is rapidly reached, then water molecules penetrate from the semipermeable coating film, the double-layer tablet core slowly absorbs water and expands to generate high osmotic pressure, and the ketorolac tromethamine in the semipermeable tablet is pushed to be released from the drug release holes of the semipermeable coating film at a constant speed and quantitatively, so that a good controlled release effect is achieved. The invention has both the quick release effect of the quick release layer and the controlled release effect of the zero-order drug release characteristic of the controlled release layer, realizes the quick-acting and long-acting effects of the drug, can continuously and stably release the drug within 24 hours, is beneficial to controlling the long-term stability of the blood concentration in the body of a patient during the period of taking the drug, reduces the taking frequency to be once per day, and provides a drug preparation with higher safety and more stable and long-acting analgesic effect for clinic.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for the description of the embodiments will be briefly described below, and it is apparent that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.

FIG. 1 is a graph showing the drug release profile of a dual-phase controlled release tablet of ketorolac tromethamine according to example 1 of the present invention;

FIG. 2 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 2 of the present invention;

FIG. 3 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 3 of the present invention;

FIG. 4 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 4 of the present invention;

FIG. 5 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 5 of the present invention;

FIG. 6 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 6 of the present invention;

FIG. 7 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 7 of the present invention;

FIG. 8 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 8 of the present invention;

FIG. 9 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 9 of the present invention;

FIG. 10 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 10 of the present invention;

FIG. 11 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 11 of the present invention;

FIG. 12 is a graph showing the drug release profile of the ketorolac tromethamine biphasic controlled release tablet of example 12 of the present invention;

FIG. 13 is a graph showing the mean blood concentration versus time for the ketorolac tromethamine biphasic controlled release tablet of example 13 of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the accompanying drawings and specific embodiments. The specific embodiments described herein are to be considered in an illustrative sense only and are not intended to limit the invention.

Various modifications to the precise description of the invention will be readily apparent to those skilled in the art from the information contained herein without departing from the spirit or scope of the appended claims. It is to be understood that the scope of the invention is not limited to the defined processes, properties or components, as these embodiments, as well as other descriptions, are merely illustrative of specific aspects of the invention. Indeed, various modifications of the embodiments of the invention which are obvious to those skilled in the art or related fields are intended to be within the scope of the following claims.

For a better understanding of the present invention, and not to limit its scope, all numbers expressing quantities, percentages, and other values used in the present invention are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated otherwise, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. Each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. In addition, the terms "comprising," "including," "containing," "having," and the like are intended to be non-limiting, as other steps and other ingredients may be added that do not affect the result.

The experimental methods, which do not address specific conditions in the following examples, are generally in accordance with the conditions recommended by the manufacturer.

Examples 1 to 12

The ketorolac tromethamine biphasic controlled release tablet of examples 1-12 comprises a controlled release layer and a quick release layer from inside to outside, wherein the controlled release layer comprises a double-layer tablet core formed by pressing a drug-containing layer and a boosting layer and a semipermeable coating film arranged outside the double-layer tablet core, and the controlled release layer and the quick release layer both comprise a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable auxiliary materials. Specifically, the prescription composition of each example is shown in tables 1-4.

TABLE 1 immediate release layer formulations of examples 1-12 (for every 1000 tablets)

TABLE 2 prescription of drug-containing layers of examples 1-12 (for every 1000 tablets)

TABLE 3 boosting layer prescriptions for examples 1-12 (for every 1000 tablets)

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TABLE 4 semipermeable coating formulations of examples 1-12 (per 1000mL dose)

The preparation method of the ketorolac tromethamine biphasic controlled release tablet taking example 1 as an example comprises the following steps:

s1, preparing a double-layer sheet core: weighing the prescription amount of medicine and other medicine-containing layer components passing through an 80-mesh sieve, mixing according to an equal progressive method, preparing a soft material by using an adhesive, passing through a 20-mesh sieve to obtain wet particles, drying the wet particles at 40 ℃ for 4-8h, finishing the particles by using an 18-mesh sieve, and uniformly mixing the dry particles with the prescription amount of lubricant to obtain medicine-containing layer particles; weighing the components of the boosting layer with the prescription amount passing through a 80-mesh sieve, and preparing boosting layer particles according to a preparation method of the drug-containing layer particles; pressing the drug-containing layer particles and the boosting layer particles into a double-layer tablet core, wherein the tablet diameter is 5mm-10mm;

s2, coating a semipermeable coating film: dissolving a plasticizer and a pore-forming agent in a solvent, slowly adding a film-forming material, stirring uniformly to obtain a coating solution, coating the double-layer tablet core with the coating solution until the coating weight is increased to 3-20% of the total weight of the double-layer tablet core, and drying in an oven for 12-24 hours to obtain the double-layer tablet core coated with the semipermeable coating film, wherein the coating weight increase is specifically shown in Table 5;

table 5 coating weight gain (per tablet) for examples 1-12

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S3, punching a medicine release hole: one or more 0.2mm-1.2mm drug release holes on the semipermeable coating film to obtain a controlled release layer;

s4, preparing a quick release layer: mixing the components of the quick release layer uniformly, granulating by a wet method or directly mixing the materials for later use to obtain a mixture, spreading half of the mixture in a die of a tablet press, placing the controlled release layer in the middle in the step S3, covering the other half of the mixture, and performing compression coating to obtain the ketorolac tromethamine biphasic controlled release tablet.

The preparation methods of examples 2-12 are the same as in example 1 except that the components are different, and are not repeated here.

The drug release profile in the ketorolac tromethamine biphasic controlled release tablets of examples 1-12 was determined by High Performance Liquid Chromatography (HPLC). Chromatographic conditions: a DIKMAC18 column (250 mm. Times.4.6 mm,5 μm); mobile phase: methanol to water to glacial acetic acid (65:34:1), detection wavelength: 322nm, liquid phase flow rate: 0.9mL min ^-1 Column temperature: 40 ℃, sample injection amount: 20. Mu.L. Taking the sample, taking 4mL of release solution according to a release degree measuring method (43 rd edition United states pharmacopoeia), taking 600mL of release medium, regulating the rotation speed of a dissolution instrument to be 50r/min, taking the sampling time after standard operation, and taking the 4mL of release solution, and filtering the solution by a 0.45 mu m filter head to be used as a sample solution.

The release curves for examples 1-12 are shown in FIGS. 1-12, respectively.

As can be seen from figures 1-12, the ketorolac tromethamine biphasic controlled release tablet of the invention has both quick release effect and zero-order release characteristic controlled release effect, and can initially release the drug, rapidly reach effective blood concentration, and release the drug to completion at a basically constant rate according to zero order at 24 h. The long-acting reagent for continuous drug release for 24 hours can be taken once a day, and the frequency of taking the medicine is greatly reduced.

Example 13

Beagle canine pharmacokinetic studies and bioavailability studies were performed with the ketorolac tromethamine biphasic controlled release tablet prepared in example 1. Experimental animals: beagle, clean grade, about 10.0±2.0kg,6, male and female halves.

Dosing regimen: the test formulation and the reference formulation were subjected to a two-cycle crossover single administration experiment, with a 7d wash period between the two cycles. The reference formulation (ketorolac tromethamine capsule, available from Shandong New age pharmaceutical Co., ltd., lot number 242201001) was administered 1 time, 1 time 3.5 granules; the test formulation (i.e., ketorolac tromethamine biphasic controlled release tablet of the present invention) was administered 1 time, 1 time and 1 tablet. After a 7d wash period, administration was cross-administered.

Blood collection time point: blood samples were collected from the test formulations before oral administration (0 h), 7.5min, 15min, 30min, 45min, 1.0h, 1.5h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h, 10.0h, 12.0h, 16.0h, 18.0h, and 24.0h, respectively. The reference preparations were collected before oral administration (0 min), 7.5min, 15min, 30min, 45min, 1.0h, 1.5h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h, 12.0h, 24.0h, respectively. According to the set blood sampling time point, the vein of the forelimb is sampled by about 1mL, and a whole blood sample is placed under normal temperature, centrifuged within 2 hours after collection, 1700g and centrifuged at 4 ℃ for 10min. And (3) temporarily storing the centrifuged plasma in-20 ℃ for 2 hours, and completely transferring to-80 ℃ for preservation after the plasma sample is collected.

The concentration of the analyte in the plasma after oral administration of ketorolac tromethamine formulation to beagle dogs was determined by HPLC method. The mean plasma concentration versus time curve was plotted for each animal tested and the results are shown in figure 13 and the specific pharmacokinetic parameters are shown in table 5.

TABLE 5 essential pharmacokinetic parameters of test formulations and reference formulations

Note that: c (C) _max Maximum blood concentration, T _max The peak time of the blood concentration is shown, the AUC is the area under the curve of the drug, and the MRT is the average residence time of the drug in the body.

As can be seen from fig. 13, the average blood concentration of the reference preparation reached a peak at about 2.0h after administration, and then slowly decreased to 8h, i.e., decreased to less than 10% of the peak concentration; the tested preparation can reach the same blood concentration as the reference preparation in 0.5h, and the average blood concentration reaches a peak value about 8.0h after taking the preparation, so that the stable blood concentration is obviously obtained, and the high level is maintained in 1-16h, thereby achieving the purpose of test design.

From the data in Table 5, the relative bioavailability of the test formulation was 94.8%, and the test formulation was bioequivalent to the reference formulation by analysis of variance and double single sided t-test and 90% confidence interval analysis. Cmax and Tmax of the tested preparation and the reference preparation are subjected to multi-factor variance analysis, and the results show that: the Tmax of the tested preparation is obviously prolonged (P is less than 0.01) compared with that of the reference preparation, and the Cmax of the tested preparation is obviously reduced (P is less than 0.01) compared with that of the reference preparation, so that the tested preparation has good quick release and controlled release effects.

The remaining examples can also be concluded to be the same or similar to the previous experimental results. The remaining experimental data are not presented here again.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.

Claims

1. The ketorolac tromethamine biphasic controlled release tablet is characterized by comprising a controlled release layer and a quick release layer from inside to outside, wherein the controlled release layer comprises a bilayer tablet core containing a drug-containing layer and a semipermeable coating film arranged outside the bilayer tablet core, the semipermeable coating film is used for penetrating water molecules, one side of the semipermeable coating film, which faces the drug-containing layer, is provided with a drug release hole, and the bilayer tablet core enables ketorolac tromethamine of the drug-containing layer to release Kong Shichu from the semipermeable coating film after absorbing the water molecules penetrated by the semipermeable coating film;

the quick-release layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable quick-release layer auxiliary materials, wherein the quick-release layer auxiliary materials comprise a filler, a disintegrating agent and a lubricant, and the mass percentages of the components are as follows: 1 to 3.5 percent of ketorolac tromethamine, 85 to 95 percent of filler, 3 to 12 percent of disintegrating agent and 0.4 to 1.6 percent of lubricant.

2. The ketorolac tromethamine biphasic controlled release tablet according to claim 1 wherein the filler in the immediate release layer is selected from one or more of microcrystalline cellulose, mannitol, sorbitol, lactose, starch, pregelatinized starch, dextrin, sucrose, dibasic calcium phosphate, tribasic calcium phosphate and tribasic calcium sulfate;

the disintegrating agent in the quick-release layer is selected from one or more of croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, alginic acid, sodium alginate and carboxymethyl starch sodium;

the lubricant in the quick release layer is one or more selected from magnesium stearate, calcium stearate, stearic acid, micro silica gel, talcum powder, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate and sodium lauryl sulfate.

3. The ketorolac tromethamine biphasic controlled release tablet according to claim 1 or 2, wherein the bilayer tablet core is formed by pressing a drug-containing layer and a boosting layer, and the weight ratio of the drug-containing layer to the boosting layer is 1.5-4:1.

4. the ketorolac tromethamine biphasic controlled release tablet of claim 3, wherein the drug-containing layer comprises a therapeutically effective amount of ketorolac tromethamine and pharmaceutically acceptable drug-containing layer excipients, the drug-containing layer excipients comprise a suspending agent, an osmotic pressure accelerator, a lubricant, a binder and a colorant, and the weight percentages of the components are: 18-35% of ketorolac tromethamine, 40-70% of suspending agent, 4-37% of osmotic pressure promoter, 0.3-4% of lubricant, 1-4% of adhesive and 0-0.09% of colorant;

the boosting layer comprises a propellant, an osmotic pressure accelerator, a retarder, a lubricant, an adhesive, a wetting agent and a colorant, wherein the weight percentages of the components are as follows: 25-75% of propellant, 12-50% of osmotic pressure promoter, 2.5-25% of retarder, 0.3-4% of lubricant, 4-9% of adhesive and 0-0.6% of colorant.

5. The ketorolac tromethamine biphasic controlled release tablet according to claim 4 wherein the suspending agent in the drug-containing layer is selected from one or more of polyoxyethylene, acacia, hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, ethylcellulose, hydroxyethyl cellulose, povidone, copovidone, carbomer, pectin, gelatin, agar, colloidal magnesium silicate, polyethylene glycol, glycerol and alginic acid derivatives having a molecular weight of 100000-900000; the alginic acid and alginic acid derivative are selected from one or more of alginic acid, sodium alginate, ammonium alginate, calcium alginate, magnesium alginate, potassium alginate and propylene glycol alginate.

6. The ketorolac tromethamine biphasic controlled release tablet according to claim 4 wherein the propellant in the boost layer is selected from one or more of polyoxyethylene with molecular weight 4000000-8000000, povidone with molecular weight 10000-360000, carbopol with molecular weight 450000-4000000, polyacrylic acid with molecular weight 80000-200000, polyhydroxymethacrylate alkyl ester with molecular weight 30000-5000000, polyethylene glycol with polymerization degree of 200-30000 cross-linked with glyoxal, formaldehyde or glutaraldehyde, sodium carboxymethyl starch, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, carbomer, low substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, copovidone, methyl cellulose, cross-linked agar, mixtures of carboxymethyl cellulose and alginic acid derivatives; the alginic acid and alginic acid derivative are selected from one or more of alginic acid, sodium alginate, ammonium alginate, calcium alginate, magnesium alginate, potassium alginate and propylene glycol alginate;

the retarder in the boosting layer is one or more selected from carbomer, hypromellose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, povidone, resin, starch and stearic acid.

7. The ketorolac tromethamine biphasic controlled release tablet of claim 4 wherein the osmotic pressure promoter in the drug-containing layer and the boost layer is independently selected from one or more of sodium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, sodium bicarbonate, lactose, glucose, sucrose, fructose, mannitol, sorbitol, xylitol, erythrose, aqueous sodium phosphate, sodium hydrogen phosphate, sodium carboxymethyl cellulose;

the lubricant in the medicine-containing layer and the boosting layer is independently selected from one or more of magnesium stearate, calcium stearate, stearic acid, micro silica gel, talcum powder, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate and sodium lauryl sulfate;

the binder in the drug-containing layer and the boosting layer is independently selected from one or more of starch slurry, povidone, copovidone, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose and gelatin;

the wetting agent in the drug-containing layer and the boosting layer is independently selected from water, ethanol or a mixed solution of water and ethanol;

the colorant in the drug-containing layer and the boosting layer is independently selected from one or more of iron oxide red, iron oxide yellow, iron oxide brown, iron oxide violet and iron oxide black.

8. The ketorolac tromethamine biphasic controlled release tablet according to claim 1 or 2, wherein the semipermeable coating film comprises a film forming material, a plasticizer and a pore-forming agent, and the components are as follows by weight: 4mg-65mg of film forming material, 0 mg-2.5 mg of plasticizer and 0.15 mg-2.5 mg of pore-foaming agent.

9. The ketorolac tromethamine biphasic controlled release tablet according to claim 8, wherein the film forming material is selected from one or more of cellulose acetate, ethylcellulose, cellulose triacetate, methyl acetate cellulose acetate, ethyl acetate cellulose acetate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate carbonate, cellulose acetate chloroacetate, cellulose acetate oxalate, cellulose acetate sulfonate, cellulose acetate propionate, cellulose acetate diacetate, cellulose acetate octoate, cellulose acetate laurate, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate butyrate, cellulose propionate, cellulose tripentaginate, cellulose triacontanoate, cellulose tripalmitate, cellulose disuccinate, cellulose dipalmitate, acrylic resin, polyoxyethylene, polyvinyl chloride, polyethylene, polyvinyl alcohol, polycarbonate, polylactic acid derivatives, polyurethane and ethylene-vinyl acetate copolymers;

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, triacetin, castor oil, polyethylene glycol with molecular weight of 100-10000 and propylene glycol;

the pore-forming agent is selected from one or more of polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, eudragit RL/RS, povidone, copovidone, sorbitol, mannitol, lactose, sucrose, propylene glycol, glycerol and water-soluble inorganic salt with molecular weight of 100-10000.

10. A method for preparing a ketorolac tromethamine biphasic controlled release tablet, which is characterized by being used for preparing the ketorolac tromethamine biphasic controlled release tablet according to any one of claims 1-9, and comprising the following steps: