CN115089555B - Carbamazepine solid tablet and preparation method thereof - Google Patents

Carbamazepine solid tablet and preparation method thereof Download PDF

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Publication number
CN115089555B
CN115089555B CN202210877785.5A CN202210877785A CN115089555B CN 115089555 B CN115089555 B CN 115089555B CN 202210877785 A CN202210877785 A CN 202210877785A CN 115089555 B CN115089555 B CN 115089555B
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carbamazepine
tablet
hot melt
extrusion
weight
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CN115089555A (en
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陈晓冬
龚援
严勇朝
刘学军
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Shanghai Yaotan Pharmaceutical Research And Development Co ltd
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Shanghai Yaotan Pharmaceutical Research And Development Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Abstract

The invention provides a carbamazepine solid tablet and a preparation method thereof. The carbamazepine tablet provided by the invention comprises a carbamazepine solid dispersion, a diluent, a disintegrating agent and a lubricant, wherein the carbamazepine solid dispersion comprises carbamazepine and a carrier, and the carbamazepine solid dispersion is prepared by adopting a hot-melt extrusion technology; the carrier is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol 6000, polyvinyl alcohol, povidone K12, povidone K30, povidone K90, copovidone VA64 and Soluplus. The carbamazepine tablet provided by the invention has the advantages of low impurity content, high stability, high dissolution rate and the like.

Description

Carbamazepine solid tablet and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, in particular to the field of pharmaceutical preparations for treating epilepsy, and particularly relates to a carbamazepine solid tablet and a preparation method thereof.
Background
The carbamazepine tablet is mainly used for treating epilepsy, is also commonly used for treating peripheral neuralgia, manic depression, arrhythmia and other diseases, and is generally used as a first-choice medicament for treating epilepsy in clinic.
Carbamazepine tablets were developed by NOVARTIS corporation and approved by the FDA for the treatment of epilepsy in 19822, month 1, under the trade name TEGRETOL, and are oral tablets. The relative molecular weight is 236.27, the CAS registry number is 298-46-4, and the structure is shown in the following formula:
carbamazepine is a low-dissolution and high-permeability drug belonging to the BCS II class, has lower oral availability, and can ensure better bioavailability by clinically using large-dose administration, wherein the bioavailability of the BCS II class is usually limited by the dissolution rate, and if the dissolution rate is increased, the bioavailability is possibly improved greatly. Therefore, increasing the dissolution rate of BCS class ii drugs is critical to increasing their bioavailability.
In order to increase the dissolution rate of poorly water-soluble drugs, conventional methods include techniques of reducing particle size by micronization, preparing solid dispersions by spray drying, and nanocrystalline. However, these conventional methods have the disadvantages of complicated preparation process, many limiting conditions, difficult control of the process, difficult removal of impurities in the solvent residue, etc., so that the requirements of the techniques on equipment, process and personnel operation are very high.
The application of hot melt extrusion technology in the field of pharmaceutical preparations has attracted wide attention both at home and abroad in recent years. Hot melt extrusion offers a number of advantages, including: safety or environmental concerns may be reduced, energy in the solvent recovery step may be saved, and safety of personnel operations may be ensured. Furthermore, unlike conventional batch production systems, hot melt extrusion allows for continuous production. Therefore, how to increase the dissolution rate of carbamazepine by hot melt extrusion technology has become an important research topic in the industrial production of carbamazepine.
Disclosure of Invention
The invention aims to solve the technical problem of slower dissolution rate of carbamazepine in the prior art, and provides a carbamazepine tablet and a preparation method thereof. The carbamazepine tablet provided by the invention has the advantages of low impurity content, high stability, high dissolution rate and the like.
The invention provides a carbamazepine tablet which comprises a carbamazepine solid dispersion, a diluent, a disintegrating agent and a lubricant, wherein the carbamazepine solid dispersion comprises carbamazepine and a carrier,
the carbamazepine solid dispersion is prepared by adopting a hot melt extrusion technology;
the carrier is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol 6000, polyvinyl alcohol, povidone K12, povidone K30, povidone K90, copovidone VA64 and Soluplus.
Preferably, the carbamazepine solid dispersion further comprises a plasticizer.
Preferably, the carbamazepine solid dispersion consists of carbamazepine and a carrier.
Preferably, the carbamazepine solid dispersion consists of carbamazepine, a carrier and a plasticizer.
Preferably, the carbamazepine tablet consists of the following components: carbamazepine solid dispersion, diluent, disintegrant and lubricant.
Preferably, the carbamazepine tablet comprises, by weight, 1% -50% of carbamazepine, 10% -80% of a carrier, 0-40% of a plasticizer, 1% -60% of a diluent, 1% -10% of a disintegrant and 1% -5% of a lubricant.
Preferably, the weight percent of carbamazepine is 10% to 30%, most preferably 25%, the above percentages referring to the weight percent of the components in the carbamazepine tablet.
Preferably, the carrier is one or more of hydroxypropyl cellulose, polyethylene glycol 6000, polyvinyl alcohol, povidone K12, povidone K30, povidone K90 and Soluplus; more preferably povidone K30, soluplus, or a combination of povidone K30 and Soluplus.
Preferably, when the carrier is a combination of povidone K30 and Soluplus, the weight ratio of povidone K30 to Soluplus is 1:1 to 1:5, preferably 1:1.
Preferably, the carrier is present in an amount of 10% to 60% by weight, more preferably 25% to 50% by weight, most preferably 25% or 50% by weight, the above percentages referring to the weight of the components in the carbamazepine tablet.
Preferably, the plasticizer is one or more of sorbitol, xylitol and mannitol, preferably mannitol.
Preferably, the plasticizer is present in an amount of 1% to 20% by weight, more preferably 5% to 15% by weight, and most preferably 6.25%, 10% or 12.5% by weight, the above percentages referring to the weight of the components in the carbamazepine tablet.
Preferably, the diluent is one or more of microcrystalline cellulose, starch, dextrin, sucrose, lactose, mannitol and calcium hydrophosphate, and preferably microcrystalline cellulose and/or lactose.
Preferably, when the diluent is a combination of microcrystalline cellulose and lactose, the weight ratio of microcrystalline cellulose to lactose is from 1:1 to 5:1, preferably 2:1.
Preferably, the diluent is present in an amount of 1% to 50% by weight, more preferably 5% to 45% by weight, most preferably 6.25%, 8.75%, 12.5%, 18.75% or 43.75% by weight of the components in the carbamazepine tablet.
Preferably, the disintegrating agent is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium, preferably low-substituted hydroxypropyl cellulose and/or croscarmellose sodium, and most preferably low-substituted hydroxypropyl cellulose.
Preferably, the disintegrant is 3% to 5% by weight, more preferably 4% to 5% by weight, most preferably 4.375% by weight of the component in the carbamazepine tablet.
Preferably, the lubricant is one or more of magnesium stearate, stearic acid and sodium stearyl fumarate, preferably magnesium stearate.
Preferably, the weight percent of the lubricant is 1% to 3%, more preferably 1% to 2%, most preferably 1.875%, the above percentages referring to the weight percent of the components in the carbamazepine tablet.
Preferably, the carbamazepine tablet consists of the following components in weight percent, carbamazepine 25%, soluplus 25%, microcrystalline cellulose 43.75%, low substituted hydroxypropyl cellulose 4.375% and magnesium stearate 1.875%.
Preferably, the carbamazepine tablet consists of the following components in percentage by weight, 25% of carbamazepine, 30% of povidone K, 43.75% of microcrystalline cellulose, 4.375% of low-substituted hydroxypropyl cellulose and 1.875% of magnesium stearate.
Preferably, the carbamazepine tablet consists of the following components in percentage by weight, 25% of carbamazepine, 50% of Soluplus, 6.25% of mannitol, 12.5% of microcrystalline cellulose, 4.375% of low-substituted hydroxypropyl cellulose and 1.875% of magnesium stearate.
Preferably, the carbamazepine tablet consists of the following components in percentage by weight, 25% of carbamazepine, 25% of Soluplus, 30% of povidone K, 18.75% of microcrystalline cellulose, 4.375% of low-substituted hydroxypropyl cellulose and 1.875% of magnesium stearate.
Preferably, the carbamazepine tablet consists of the following components in weight percent, 25% carbamazepine, 50% Soluplus, 6.25% lactose, 12.5% microcrystalline cellulose, 4.375% low substituted hydroxypropyl cellulose and 1.875% magnesium stearate.
Preferably, the carbamazepine tablet consists of the following components in percentage by weight, 25% of carbamazepine, 25% of Soluplus, 30% of povidone K, 6.25% of mannitol, 12.5% of microcrystalline cellulose, 4.375% of low-substituted hydroxypropyl cellulose and 1.875% of magnesium stearate.
Preferably, the carbamazepine tablet consists of the following components in percentage by weight, 25% of carbamazepine, 25% of Soluplus, 30% of povidone K, 10% of mannitol, 8.75% of microcrystalline cellulose, 4.375% of low-substituted hydroxypropyl cellulose and 1.875% of magnesium stearate.
Preferably, the carbamazepine tablet consists of the following components in percentage by weight, 25% of carbamazepine, 25% of Soluplus, 30% of povidone K, 12.5% of mannitol, 6.25% of microcrystalline cellulose, 4.375% of low-substituted hydroxypropyl cellulose and 1.875% of magnesium stearate.
Preferably, the hot melt extrusion technique comprises the steps of,
(1) Mixing carbamazepine with a carrier to obtain a physical mixture before hot melt extrusion;
(2) The physical mixture before hot melt extrusion was extruded using a hot melt extruder to obtain carbamazepine solid dispersion.
Preferably, in the step (1), when the carbamazepine solid dispersion further comprises a plasticizer, the carbamazepine, carrier and plasticizer are mixed to obtain a physical mixture before hot melt extrusion.
Preferably, the step (1) is to crush carbamazepine and a carrier, then sieving the crushed carbamazepine and the carrier, and then mixing the crushed carbamazepine and the carrier.
Preferably, in the step (1), when the carbamazepine solid dispersion further comprises a plasticizer, the carbamazepine, the water-soluble carrier and the plasticizer are crushed and then screened and mixed.
Preferably, in the step (1), the screen is a 20-60 mesh screen, preferably a 20 mesh screen.
Preferably, in the step (1), the mixing is mixing by using a three-dimensional mixer.
Preferably, in the step (2), the hot melt extruder is a twin screw extruder.
Preferably, the hot-melt extrusion technique further comprises the step of presetting an extrusion temperature and an extrusion rotation speed of the hot-melt extruder.
Preferably, the extrusion setting temperature of the preset hot melt extruder is 110 ℃ to 180 ℃, preferably 140 ℃ to 180 ℃, and most preferably 170 ℃.
Preferably, the extrusion speed of the preset hot-melt extruder is 150r/min-300r/min, preferably 200r/min-250r/min, and most preferably 250r/min.
Preferably, the hot-melt extrusion technique further comprises the step of setting an extrusion temperature and an extrusion rotation speed at the time of hot-melt extrusion.
Preferably, the extrusion setting temperature at the time of hot melt extrusion is 110 ℃ to 180 ℃, preferably 140 ℃ to 180 ℃, most preferably 152 ℃, 155 ℃, 156 ℃, 158 ℃, 160 ℃, 162 ℃ or 168 ℃.
Preferably, the extrusion speed during hot melt extrusion is 150r/min-300r/min, preferably 200r/min-250r/min, and most preferably 223r/min, 225r/min, 227r/min, 230r/min, 236r/min, 240r/min or 245r/min.
Preferably, the step (2) is to extrude the physical mixture before hot-melt extrusion by using a hot-melt extruder, cool, crush and screen the physical mixture to obtain the carbamazepine solid dispersion.
Preferably, in the step (2), the screen is a 16-40 mesh screen, preferably a 20 mesh screen.
The invention provides a preparation method of carbamazepine tablets, which comprises the following steps,
(1) Mixing carbamazepine with a carrier to obtain a physical mixture before hot melt extrusion;
(2) Extruding the physical mixture before hot melt extrusion by using a hot melt extruder to obtain carbamazepine solid dispersion;
(3) Mixing the carbamazepine solid dispersion obtained in the step (4), a diluent, a disintegrating agent and a lubricant to obtain a mixture before tabletting;
(4) Tabletting the mixture before tabletting obtained in the step (3) to obtain carbamazepine tablets.
Preferably, the conditions and parameters of steps (1) and (2) are as described in any one of the present invention.
Preferably, in the step (3), the mixing is mixing by using a three-dimensional mixer.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
1. according to the carbamazepine tablet provided by the invention, a hot-melt extrusion technology is adopted, so that the carbamazepine is dispersed more uniformly in a carrier material, the dissolution rate of the carbamazepine tablet is obviously improved, and the drug effect is improved; the addition of the plasticizer also significantly improves the long-term stability of the carbamazepine tablet.
2. The preparation method of carbamazepine tablets provided by the invention has the advantages of simple process, reasonable formula, controllable process, no organic solvent residue, no introduction of other impurities in the whole process, and more importantly, the preparation method can be applied to actual mass continuous mass production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1: carbamazepine tablet prescription 1 (1000 tablets)
Uniformly mixing the carbamazepine and the Soluplus which are added with the materials to prepare a physical mixture before hot melting, setting the temperature of an extruder at 170 ℃, setting the rotating speed of a screw at 250r/min, uniformly adding the physical mixture before hot melting after the temperature rises to a set value and is stable, adjusting the hot melting extrusion temperature to 160 ℃ and the hot melting extrusion rotating speed to 236r/min, extruding all the materials according to the parameters, cooling, crushing and sieving by a 20-mesh sieve to obtain the carbamazepine solid dispersion.
Adding microcrystalline cellulose, low-substituted hydroxypropyl cellulose and the solid dispersion prepared by the method into a three-dimensional mixer, mixing at 10rpm for 15min, adding magnesium stearate, mixing at 10rpm for 5min to obtain a pre-tabletting material, and tabletting by a tabletting machine to obtain carbamazepine solid dispersion tablets.
Example 2: carbamazepine tablet prescription 2 (1000 tablets)
Uniformly mixing the carbamazepine and povidone K30 which are added with materials into a physical mixture before hot melting, setting the temperature of an extruder at 170 ℃, setting the rotating speed of a screw at 250r/min, uniformly adding the physical mixture before hot melting after the temperature rises to a set value and is stable, adjusting the hot melting extrusion temperature to 168 ℃ and the hot melting extrusion rotating speed to 245r/min, extruding all the materials according to the parameters, cooling, crushing and sieving with a 20-mesh sieve to obtain the carbamazepine solid dispersion.
Adding microcrystalline cellulose, low-substituted hydroxypropyl cellulose and the solid dispersion prepared by the method into a three-dimensional mixer, mixing at 10rpm for 15min, adding magnesium stearate, mixing at 10rpm for 5min to obtain a pre-tabletting material, and tabletting by a tabletting machine to obtain carbamazepine solid dispersion tablets.
Example 3: carbamazepine tablet formulation 3 (1000 tablets)
Uniformly mixing the carbamazepine, the Soluplus and the mannitol which are added with materials to prepare a physical mixture before hot melting, setting the temperature of an extruder at 170 ℃ and the rotating speed of a screw at 250r/min, uniformly adding the physical mixture before hot melting after the temperature rises to a set value and is stable, adjusting the hot melting extrusion temperature to 158 ℃ and the hot melting extrusion rotating speed to 230r/min, extruding all materials according to the parameters, cooling, crushing and sieving by a 20-mesh sieve to obtain the carbamazepine solid dispersion.
Adding microcrystalline cellulose, low-substituted hydroxypropyl cellulose and the solid dispersion prepared by the method into a three-dimensional mixer, mixing at 10rpm for 15min, adding magnesium stearate, mixing at 10rpm for 5min to obtain a pre-tabletting material, and tabletting by a tabletting machine to obtain carbamazepine solid dispersion tablets.
Example 4: carbamazepine tablet formulation 4 (1000 tablets)
Uniformly mixing the carbamazepine, the Soluplus and the povidone K30 which are added with materials into a physical mixture before hot melting, setting the temperature of an extruder at 170 ℃ and the rotating speed of a screw at 250r/min, after the temperature rises to a set value and is stable, uniformly adding the physical mixture before hot melting, adjusting the hot melting extrusion temperature at 162 ℃ and the rotating speed of the hot melting extrusion at 240r/min, extruding all materials according to the parameters, cooling, crushing and sieving with a 20-mesh sieve to obtain the carbamazepine solid dispersion.
Adding microcrystalline cellulose, low-substituted hydroxypropyl cellulose and the solid dispersion prepared by the method into a three-dimensional mixer, mixing at 10rpm for 15min, adding magnesium stearate, mixing at 10rpm for 5min to obtain a pre-tabletting material, and tabletting by a tabletting machine to obtain carbamazepine solid dispersion tablets.
Example 5: carbamazepine tablet formulation 5 (1000 tablets)
Uniformly mixing the internal materials carbamazepine and Soluplus to prepare a physical mixture before hot melting, setting the temperature of an extruder at 170 ℃, setting the rotating speed of a screw at 250r/min, uniformly adding the physical mixture before hot melting after the temperature rises to a set value and is stable, adjusting the hot melting extrusion temperature to 156 ℃ and the hot melting extrusion rotating speed to 227r/min, extruding all the materials according to the parameters, cooling, crushing and sieving by a 20-mesh sieve to obtain the carbamazepine solid dispersion.
Adding lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and the solid dispersion prepared by the method into a three-dimensional mixer, mixing for 15min at 10rpm, adding magnesium stearate, mixing for 5min at 10rpm to obtain a material before tabletting, and tabletting by a tabletting machine to obtain carbamazepine solid dispersion tablets.
Example 6: carbamazepine tablet prescription 6 (1000 tablets)
Uniformly mixing the internal materials carbamazepine, solplus, povidone K30 and mannitol to prepare a physical mixture before hot melting, setting the temperature of an extruder at 170 ℃, setting the rotating speed of a screw at 250r/min, after the temperature rises to a set value and is stable, uniformly adding the physical mixture before hot melting, adjusting the hot melting extrusion temperature to 162 ℃, and the hot melting extrusion rotating speed to 236r/min, extruding all the materials according to the parameters, cooling, crushing and sieving by a 20-mesh sieve to obtain the carbamazepine solid dispersion.
Adding microcrystalline cellulose, low-substituted hydroxypropyl cellulose and the solid dispersion prepared by the method into a three-dimensional mixer, mixing at 10rpm for 15min, adding magnesium stearate, mixing at 10rpm for 5min to obtain a pre-tabletting material, and tabletting by a tabletting machine to obtain carbamazepine solid dispersion tablets.
Example 7: carbamazepine tablet formulation 7 (1000 tablets)
Uniformly mixing the internal materials carbamazepine, solplus, povidone K30 and mannitol to prepare a physical mixture before hot melting, setting the temperature of an extruder at 170 ℃, setting the rotating speed of a screw at 250r/min, uniformly adding the physical mixture before hot melting after the temperature rises to a set value and is stable, adjusting the hot melting extrusion temperature to 155 ℃ and the hot melting extrusion rotating speed to 225r/min, extruding all the materials according to the parameters, cooling, crushing and sieving by a 20-mesh sieve to obtain the carbamazepine solid dispersion.
Adding microcrystalline cellulose, low-substituted hydroxypropyl cellulose and the solid dispersion prepared by the method into a three-dimensional mixer, mixing at 10rpm for 15min, adding magnesium stearate, mixing at 10rpm for 5min to obtain a pre-tabletting material, and tabletting by a tabletting machine to obtain carbamazepine solid dispersion tablets.
Example 8: carbamazepine tablet formulation 8 (1000 tablets)
Uniformly mixing the internal materials carbamazepine, solplus, povidone K30 and mannitol to prepare a physical mixture before hot melting, setting the temperature of an extruder at 170 ℃, setting the rotating speed of a screw at 250r/min, after the temperature rises to a set value and is stable, uniformly adding the physical mixture before hot melting, adjusting the hot melting extrusion temperature to 152 ℃, and the hot melting extrusion rotating speed to 223r/min, extruding all the materials according to the parameters, cooling, crushing and sieving by a 20-mesh sieve to obtain the carbamazepine solid dispersion.
Adding microcrystalline cellulose, low-substituted hydroxypropyl cellulose and the solid dispersion prepared by the method into a three-dimensional mixer, mixing at 10rpm for 15min, adding magnesium stearate, mixing at 10rpm for 5min to obtain a pre-tabletting material, and tabletting by a tabletting machine to obtain carbamazepine solid dispersion tablets.
Example 9: in vitro dissolution investigation of carbamazepine solid dispersion tablets
The conditions for in vitro dissolution investigation were as follows:
dissolution medium: ph=1.2 hydrochloric acid: taking 9ml of hydrochloric acid, adding 1000ml of water, and shaking uniformly.
Setting parameters of a dissolution instrument: temperature: 37 ℃, rotation speed: 75rpm, medium volume: 900ml, total time sampled: 120min, sampling time point: 5min, 10min, 15min, 30min, 45min, 60min, 90min, 120min.
Detecting a sample: carbamazepine tablets of examples 1-8.
Reference formulation: carbamazepine tablet (tegretol) -Novartis Pharmaceuticals UK Limited (northwest pharmaceutical, uk), lot number: FX000338.
Elution instrument brand model: brand model Agilent 708-DS
The results are shown in the following table 1,
table 1: examples 1 to 8pH1.2 cumulative dissolution of hydrochloric acid (in%)
From the cumulative dissolution tables of examples 1-8, it is evident that the formulations prepared by hot-melt extrusion process, after preparing the poorly soluble drug into solid dispersion using the highly water-soluble carrier material, were all > 85% at 30min time point, and were significantly improved compared with the reference formulation.
Example 10: stability test of carbamazepine solid dispersion tablet
1. Detection of related substances
Detecting a sample: carbamazepine tablets of examples 1-8.
A diluent: methanol: purified water = 50:50, v/v.
System applicability solution: about 25mg of carbamazepine is taken and placed in a 100ml measuring flask, and the diluent is added for dissolution and dilution to the scale, and shaking is carried out uniformly.
Sample solution preparation: respectively taking 20 carbamazepine tablets in examples 1-8, precisely weighing, grinding into powder, precisely weighing the proper amount (equivalent to 50mg of carbamazepine), placing into a 50ml measuring flask, adding 25ml of methanol to dissolve, diluting with water to a scale, shaking uniformly, filtering, discarding 5ml of primary filtrate, taking the subsequent filtrate as a sample solution 1-8, and preparing 2 parts in parallel.
Precisely transferring 1ml of the sample solution, placing in a 50ml measuring flask, adding diluent to a fixed volume to a scale, shaking uniformly, precisely measuring 5ml of the sample solution, placing in the 50ml measuring flask, adding diluent to a fixed volume to a scale, shaking uniformly, and taking the sample solution as a corresponding self-control solution.
The chromatographic conditions are as follows:
chromatographic column Liquid chromatographic column using cyanopropyl silane bonded silica gel as filler
Mobile phase Methanol: tetrahydrofuran: water (0.2% formic acid and 0.5% triethylamine), (12:3:85) v/v
Column temperature 35℃
Flow rate 1.0 mL/min
Detection wavelength 230nm
Elution mode Isocratic elution
Acquisition time 45.0 minutes
Sample injection volume 20μL
The test results are shown in Table 2.
2. Content detection
Control solution: about 50mg of carbamazepine reference substance is taken, precisely weighed, placed in a 50ml measuring flask, added with 25ml of methanol for dissolution, diluted with water to a scale, shaken well, precisely measured 5ml of carbamazepine reference substance placed in a 25ml measuring flask, diluted with a diluent to the scale, and shaken well.
Test solution: respectively taking 20 carbamazepine tablets in examples 1-8, precisely weighing, grinding into powder, precisely weighing 50mg, placing into a 50ml measuring flask, adding 25ml of methanol to dissolve, diluting with water to scale, shaking uniformly, filtering, precisely transferring 5ml of the continuous filtrate into a 25ml measuring flask, diluting with diluent to scale, shaking uniformly, taking as test sample solution 1-8, and preparing 2 parts in parallel.
The chromatographic conditions are the same as those of the detection of the relevant substances.
3. Cumulative dissolution detection:
dissolution medium: measuring 24mL of hydrochloric acid into 1L of deaerated purified water, and uniformly mixing.
Test solution: taking out 10ml of the solution, filtering, precisely measuring a proper amount of the subsequent filtrate, and quantitatively diluting with a dissolution medium to obtain a solution containing 6-15 mug per 1 ml.
Dissolution device Paddle method (second method of four general rules 0931 of Chinese pharmacopoeia 2020 edition)
Sample size 6*1 pieces
Rotational speed 50rpm
Dissolution medium Hydrochloric acid solution
Volume of solvent 900mL
Solvent temperature 37.0℃±0.5℃
Table 2: carbamazepine tablet stability data in examples 1-8
As can be seen from the data in the table, the content of carbamazepine tablets, the content of related substances and the cumulative dissolution change are small within 6 months, and the carbamazepine tablets have good stability; the effects of examples 3, 6, 7 and 8 show that the addition of plasticizer mannitol to carbamazepine tablets significantly reduces the impurities generated during storage, and that fewer impurities are generated during storage as the amount of mannitol increases.

Claims (15)

1. A carbamazepine tablet comprising a carbamazepine solid dispersion comprising carbamazepine and a carrier, a diluent, a disintegrant, and a lubricant, wherein the carbamazepine solid dispersion further comprises a plasticizer;
the carbamazepine solid dispersion is prepared by adopting a hot melt extrusion technology;
the carrier is one or more of hydroxypropyl cellulose, polyethylene glycol 6000, polyvinyl alcohol, povidone K12, povidone K30, povidone K90 and Soluplus;
the plasticizer is mannitol;
the carbamazepine tablet comprises, by weight, 10% -30% of carbamazepine, 10% -60% of a carrier, 5% -15% of a plasticizer, 1% -50% of a diluent, 3% -5% of a disintegrant and 1% -3% of a lubricant; the above percentages refer to the weight percentages of the components in the carbamazepine tablet.
2. The carbamazepine tablet according to claim 1, wherein,
(1) The diluent is one or more of microcrystalline cellulose, starch, dextrin, sucrose, lactose, mannitol and calcium hydrophosphate;
(2) The disintegrating agent is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium; and
(3) The lubricant is one or more of magnesium stearate, stearic acid and sodium stearyl fumarate.
3. Carbamazepine tablet according to claim 2, characterized in that it fulfils one or more of the following conditions:
(1) The weight percentage of carbamazepine is 25 percent, and the above percentages refer to the weight percentage of the components in the carbamazepine tablet;
(2) The carrier is povidone K30, soluplus or a combination of povidone K30 and Soluplus;
(3) The weight percentage of the carrier is 25% -50%, and the weight percentage of the components in the carbamazepine tablet;
(4) The weight percentage of the plasticizer is 6.25%, 10% or 12.5%, and the above percentages refer to the weight percentage of the components in the carbamazepine tablet;
(5) The diluent is microcrystalline cellulose and/or lactose;
(6) The weight percentage of the diluent is 5-45%, and the weight percentage of the components in the carbamazepine tablet;
(7) The disintegrating agent is low-substituted hydroxypropyl cellulose and/or croscarmellose sodium;
(8) The weight percentage of the disintegrating agent is 4% -5%, and the above percentage refers to the weight percentage of the components in the carbamazepine tablet;
(9) The lubricant is magnesium stearate; and
(10) The weight percentage of the lubricant is 1% -2%, and the weight percentage of the components in the carbamazepine tablet is defined as the weight percentage of the components.
4. Carbamazepine tablet according to claim 3, characterized in that it fulfils one or more of the following conditions:
(1) The weight percentage of the carrier is 25% or 50%, and the above percentage refers to the weight percentage of the components in the carbamazepine tablet;
(2) The weight percent of the diluent is 6.25%, 8.75%, 12.5%, 18.75% or 43.75%, which refers to the weight percent of the component in the carbamazepine tablet;
(3) The disintegrating agent is low-substituted hydroxypropyl cellulose;
(4) The weight percent of the disintegrating agent is 4.375%, and the above percentages refer to the weight percent of the components in the carbamazepine tablet; and
(5) The weight percent of the lubricant is 1.875%, the above percentages referring to the weight percent of the components in the carbamazepine tablet.
5. Carbamazepine tablet according to claim 3 or 4, characterized in that it fulfils one or more of the following conditions:
(1) When the carrier is the combination of povidone K30 and Soluplus, the weight ratio of povidone K30 to Soluplus is 1:1-1:5; and
(2) When the diluent is a combination of microcrystalline cellulose and lactose, the weight ratio of microcrystalline cellulose to lactose is 1:1-5:1.
6. Carbamazepine tablet according to claim 5, characterized in that it fulfils one or more of the following conditions:
(1) When the carrier is the combination of povidone K30 and Soluplus, the weight ratio of povidone K30 to Soluplus is 1:1; and
(2) When the diluent is a combination of microcrystalline cellulose and lactose, the weight ratio of microcrystalline cellulose to lactose is 2:1.
7. The carbamazepine tablet according to claim 1 wherein the carbamazepine solid dispersion is comprised of carbamazepine, a carrier and a plasticizer.
8. The carbamazepine tablet according to any one of claims 1-4, 6 or 7, wherein the carbamazepine tablet consists of: carbamazepine solid dispersion, diluent, disintegrant and lubricant.
9. The carbamazepine tablet according to claim 1, wherein the carbamazepine tablet is according to any of the following regimens:
scheme one: the carbamazepine tablet consists of the following components in percentage by weight;
scheme II: the carbamazepine tablet consists of the following components in percentage by weight, namely 25% of carbamazepine, 25% of Soluplus, 30% of povidone K, 6.25% of mannitol, 12.5% of microcrystalline cellulose, 4.375% of low-substituted hydroxypropyl cellulose and 1.875% of magnesium stearate;
scheme III: the carbamazepine tablet consists of the following components in percentage by weight, namely 25% of carbamazepine, 25% of Soluplus, 30% of povidone K, 10% of mannitol, 8.75% of microcrystalline cellulose, 4.375% of low-substituted hydroxypropyl cellulose and 1.875% of magnesium stearate;
scheme IV: the carbamazepine tablet consists of the following components in percentage by weight, namely 25% of carbamazepine, 25% of Soluplus, 30% of povidone K, 12.5% of mannitol, 6.25% of microcrystalline cellulose, 4.375% of low-substituted hydroxypropyl cellulose and 1.875% of magnesium stearate.
10. The carbamazepine tablet of claim 1 or 2, wherein the hot melt extrusion technique comprises the steps of,
(1) Mixing carbamazepine, a carrier and a plasticizer to obtain a physical mixture before hot melt extrusion;
(2) The physical mixture before hot melt extrusion was extruded using a hot melt extruder to obtain carbamazepine solid dispersion.
11. Carbamazepine tablet according to claim 10, characterized in that it fulfils one or more of the following conditions:
(1) In the step (1), carbamazepine, a carrier and a plasticizer are crushed and then screened, and then mixed;
(2) In the step (1), the mixing is performed by adopting a three-dimensional mixer;
(3) In the step (2), the hot melt extruder is a twin screw extruder;
(4) The hot-melt extrusion technology further comprises the following steps of presetting the extrusion temperature and the extrusion rotating speed of a hot-melt extruder;
(5) The hot-melt extrusion technology further comprises the following steps of setting extrusion temperature and extrusion rotating speed during hot-melt extrusion;
(6) And (2) extruding the physical mixture before hot melt extrusion by using a hot melt extruder, cooling, crushing and screening to obtain the carbamazepine solid dispersion.
12. Carbamazepine tablet according to claim 11, characterized in that it fulfils one or more of the following conditions:
(1) In the step (1), the screen mesh is a 20-60 mesh screen;
(2) The extrusion temperature of the preset hot melt extruder is 110-180 ℃;
(3) The extrusion rotating speed of the preset hot melt extruder is 150r/min-300r/min;
(4) The extrusion temperature during hot melt extrusion is 110-180 ℃;
(5) The extrusion rotating speed during hot melt extrusion is 150r/min-300r/min; and
(6) In the step (2), the screen mesh is a 16-40 mesh screen.
13. Carbamazepine tablet according to claim 12, characterized in that it fulfils one or more of the following conditions:
(1) In the step (1), the screen mesh is a 20-mesh screen;
(2) The extrusion temperature of the preset hot melt extruder is 140-180 ℃;
(3) The extrusion rotating speed of the preset hot melt extruder is 200r/min-250r/min;
(4) The extrusion temperature during hot melt extrusion is 140-180 ℃;
(5) The extrusion rotating speed during hot melt extrusion is 200r/min-250r/min; and
(6) In the step (2), the screen mesh is a 20-mesh screen.
14. Carbamazepine tablet according to claim 13, characterized in that it fulfils one or more of the following conditions:
(1) The extrusion temperature of the preset hot melt extruder is 170 ℃;
(2) The extrusion rotating speed of the preset hot melt extruder is 250r/min;
(3) The extrusion temperature in hot melt extrusion is 152 ℃, 155 ℃, 156 ℃, 158 ℃, 160 ℃, 162 ℃ or 168 ℃; and
(4) The extrusion rotating speed during hot melt extrusion is 223r/min, 225r/min, 227r/min, 230r/min, 236r/min, 240r/min or 245r/min.
15. The process for the preparation of carbamazepine tablets according to any one of claims 1 to 14, characterized in that it comprises the following steps,
(1) Mixing carbamazepine, a carrier and a plasticizer to obtain a physical mixture before hot melt extrusion;
(2) Extruding the physical mixture before hot melt extrusion by using a hot melt extruder to obtain carbamazepine solid dispersion;
(3) Mixing the carbamazepine solid dispersion obtained in the step (2), a diluent, a disintegrating agent and a lubricant to obtain a mixture before tabletting;
(4) Tabletting the mixture before tabletting obtained in the step (3) to obtain carbamazepine tablets;
wherein the conditions and parameters of steps (1) and (2) are as defined in any one of claims 11 to 14.
CN202210877785.5A 2022-07-25 2022-07-25 Carbamazepine solid tablet and preparation method thereof Active CN115089555B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107875126A (en) * 2017-11-10 2018-04-06 中国药科大学 A kind of carbamazepine solid dispersions and its preparation
CN109464398A (en) * 2018-11-30 2019-03-15 浙江工业大学 A kind of preparation method of the carbamazepine solid dispersions of high drug load

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Publication number Priority date Publication date Assignee Title
EP1942872A2 (en) * 2005-11-04 2008-07-16 Eastman Chemical Company Carboxyalkylcellulose esters for administration of poorly soluble pharmaceutically active agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107875126A (en) * 2017-11-10 2018-04-06 中国药科大学 A kind of carbamazepine solid dispersions and its preparation
CN109464398A (en) * 2018-11-30 2019-03-15 浙江工业大学 A kind of preparation method of the carbamazepine solid dispersions of high drug load

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