WO2017107242A1 - Pharmaceutical composition, preparation method and application thereof - Google Patents

Pharmaceutical composition, preparation method and application thereof Download PDF

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Publication number
WO2017107242A1
WO2017107242A1 PCT/CN2015/100130 CN2015100130W WO2017107242A1 WO 2017107242 A1 WO2017107242 A1 WO 2017107242A1 CN 2015100130 W CN2015100130 W CN 2015100130W WO 2017107242 A1 WO2017107242 A1 WO 2017107242A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
cycloserine
capsule
amount
mesh
Prior art date
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PCT/CN2015/100130
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French (fr)
Chinese (zh)
Inventor
陈日星
陈建豪
罗盛莲
范红银
陈万英
郝小妹
Original Assignee
广州瑞尔医药科技有限公司
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Publication of WO2017107242A1 publication Critical patent/WO2017107242A1/en

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition and a preparation method and application thereof.
  • Tuberculosis is a disease affecting people's health in tuberculosis. With the emergence of anti-tuberculosis drugs such as streptomycin and isoniazid, tuberculosis has become a treatable disease. However, due to the lack of relevant knowledge and the irregular treatment, the drug resistance of Mycobacterium tuberculosis has become more and more serious.
  • Tuberculosis is a highly contagious disease caused by Mycobacterium tuberculosis. Among the three diseases that need to be controlled by the World Health Organization, tuberculosis is second only to AIDS. China is a country with a serious tuberculosis epidemic. In addition, with the resistance of tuberculosis, China's drug-resistant patients are also increasing. Therefore, the development of anti-tuberculosis drugs, especially anti-tuberculosis drugs are very necessary.
  • cycloserine is mainly used to treat tuberculosis caused by drug-resistant tuberculosis.
  • cycloserine can also be used to treat other diseases.
  • the use of cycloserine for the treatment of psychosis, depression or Alzheimer's disease is disclosed in US Patent No. US2014018349, World Intellectual Property Patent WO2008118785, European Patent No. EP 2 338 482, and European Patent No. EP 0 378 134.
  • U.S. Patent No. 2014,213,621 discloses the use of cycloserine for the treatment of chronic pain.
  • the preparation of the existing cycloserine is mainly an immediate release preparation, the composition has a small particle size, the D 90 particle size is less than 64 ⁇ m, the stability of the preparation is relatively poor, and the seal is sealed under accelerated conditions (temperature 40 ° C, humidity 75%). After 40 days of storage, the percentage of the labeled amount of the preparation was reduced from 99.1% to 43.3%, the degradation amount was accelerated to 56.3% for 40 days, and the sealed storage was accelerated for 180 days under accelerated conditions, and the main drug was almost completely degraded.
  • the percentage of the labeled amount of the preparation was reduced from 99.1% to 86.4%, and the degradation amount at room temperature for 180 days was 12.8%. Because the preparation is relatively unstable, it will affect the therapeutic effect and the safety of use.
  • Russian patent RU 2248205 discloses the addition of some fillers to cycloserine and filling in capsules to improve the fluidity of the contents of the capsules and the stability of the preparation, wherein the fillers added are mainly calcium phosphate dihydrate, silica gel and stearic acid. calcium.
  • the capsule increases the calcium phosphate dihydrate to increase the fluidity of the capsule contents, but since the frictional force of the calcium phosphate dihydrate is large, it is easy to wear the machine, and even causes a problem that the powder discolors quickly for a long time.
  • the patent does not have a specific test value to show its stability.
  • the preparation prepared according to the patent prescription is still inferior in stability, and is sealed and stored for 180 days under accelerated conditions (temperature 40 ° C, humidity 75%).
  • the percentage of the amount decreased from 99.3% to 65.4%, and the accelerated amount of degradation in 180 days was 34.1%.
  • Under normal temperature conditions temperature 25 ° C, humidity 60%
  • the storage was sealed for 180 days, the percentage of the labeled amount of the preparation was reduced from 99.3% to 94.8%, and the degradation amount at room temperature for 180 days was 4.5%.
  • the prescription found that there is a problem of discoloration of the content in the stability test, which may be related to the fact that the metal particles in the wear of the mold are brought into the content, thereby accelerating the degradation of the active ingredient, and the patent does not solve the problem that the stability of the variety is not good.
  • the problem has not been found to have a patent that publicly increases the stability of the cycloserine formulation.
  • a pharmaceutical composition comprising cycloserine and an adjuvant, said pharmaceutical composition having a D 90 particle size of from 75 to 380 ⁇ m, said adjuvant being used in an amount of from 9 to 45% by weight based on the total mass of the pharmaceutical composition.
  • the excipient comprises talc, and a binder and/or compressible excipient.
  • the talc is used in an amount of 9 to 45% by weight based on the total amount of the pharmaceutical composition
  • the binder is used in an amount of 0 to 6% based on the total mass of the pharmaceutical composition.
  • the amount used is from 0 to 16% of the total mass of the pharmaceutical composition.
  • the excipient comprises talc and a binder, the talc being used in an amount of from 23 to 38% by weight based on the total mass of the pharmaceutical composition, and the amount of the binder being based on the total mass of the pharmaceutical composition. 0.05 to 2%.
  • the excipient comprises talc and a compressible adjuvant
  • the talc is used in an amount of 23 to 38% by weight of the total mass of the pharmaceutical composition
  • the compressive auxiliary is used in a total amount of the pharmaceutical composition. 8 to 14% of the mass.
  • the binder is selected from the group consisting of polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, ethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose
  • the compressible auxiliary material is one or more selected from the group consisting of lactose, starch, calcium hydrogen phosphate, microcrystalline cellulose, mannitol, and dextrin.
  • the pharmaceutical composition is in the form of a capsule, and the hollow capsule of the capsule is a gelatin hollow capsule or a hypromellose hollow capsule, and the hollow capsule has a loss on drying of ⁇ 15.0%.
  • Another object of the present invention is to provide a process for the preparation of the above pharmaceutical composition.
  • the preparation method of the above pharmaceutical composition comprises the following steps:
  • the cycloserine having a D 90 particle size of 75-380 ⁇ m and the auxiliary material are uniformly mixed according to the mass percentage, thereby obtaining the pharmaceutical composition;
  • the cycloserine and the auxiliary material are mixed according to the mass percentage, and then subjected to wet granulation, dry granulation or fluidized bed granulation, dried, and sieved to obtain the pharmaceutical composition;
  • the cycloserine is mixed in the above percentage by mass to obtain the pharmaceutical composition.
  • the pharmaceutical composition has a loss on drying of from 0.2 to 2% and a D 90 particle size of from 120 to 380 ⁇ m.
  • Another object of the invention is to provide the use of the above pharmaceutical compositions.
  • the above pharmaceutical composition is used in the preparation of a medicament for treating psychosis, depression, Alzheimer's disease or chronic pain.
  • the present invention is directed to the deficiencies of the prior art, and provides a pharmaceutical composition of cycloserine, in particular, an immediate release capsule containing cycloserine.
  • the current cycloserine preparation is mainly a capsule, but the stability of the preparation is poor.
  • the degradation of the main drug in the preparation under normal temperature conditions (temperature 25 ° C, humidity 60%) and accelerated conditions (40 ° C, humidity 75%) Fast, affecting the efficacy of the preparation and the safety of use.
  • the present invention not only increases the rate of release of the formulation by increasing the particle size of the excipient (and thereby increasing the particle size of the pharmaceutical composition) and controlling the amount of dry weight loss of the pharmaceutical composition, but also greatly enhances the stability of the formulation.
  • the pharmaceutical composition of the present invention has a D 90 particle size of from 75 to 380 ⁇ m and a loss on drying of from 0.2 to 2%.
  • the pharmaceutical composition of the present invention can control the D 90 particle diameter of the pharmaceutical composition to 75-380 ⁇ m by adding an auxiliary material to the cycloserine or combining the cycloserine with the auxiliary material, thereby not only making the capsule content have good fluidity. As well as lubricity, it also increases the release rate of the formulation and the stability of the formulation.
  • the excipients in the prescription are mainly talc, as well as binders and/or compressible excipients.
  • the pharmaceutical composition of the present invention is in the form of a capsule, and the hollow capsule of the capsule is a gelatin hollow capsule or a hypromellose hollow capsule, and the hollow capsule has a loss on drying of ⁇ 15.0%.
  • the stability of the pharmaceutical composition of the present invention is greatly improved compared with the prior art, and the optimal example is at normal temperature (temperature 25 ° C, Humidity 60%) sealed for 180 days, the amount of degradation of the indicated amount of the formulation is ⁇ 0.5%, sealed for 180 days under accelerated conditions (40 ° C, humidity 75%), and the amount of degradation of the indicated amount of the formulation ⁇ 4.0%.
  • the cyclic serine accounted for 90.9% of the total, the cycloserine content was 99.713%, and the talc powder was 325 mesh (particle size 44 ⁇ m).
  • the capsule prepared by the above method had a loss on drying of 0.769%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the talc powder was 325 mesh.
  • the capsule prepared by the above method had a loss on drying of 0.521%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 55.6% of the total, the cycloserine content was 99.713%, and the talc powder was 325 mesh.
  • the capsule prepared by the above method had a loss on drying of 0.672%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.668%, and the talc powder was 325 mesh.
  • the capsule prepared by the above method had a loss on drying of 0.530%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the talc powder was 200 mesh (particle size 75 ⁇ m).
  • the capsule prepared by the above method had a loss on drying of 0.496%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the talc powder was 200 mesh.
  • the capsule prepared by the above method had a loss on drying of 0.583%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cycloserine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the talc powder was 100 mesh (particle size 150 ⁇ m).
  • the capsule prepared by the above method had a loss on drying of 0.578%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • Cycloserine accounted for 64.1% of the total, the content of cycloserine was 99.619%, and the talc powder was 100 mesh.
  • the capsule prepared by the above method had a loss on drying of 0.544%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation excipient 100 mesh, the solvent was water, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
  • the capsule prepared by the above method had a loss on drying of 1.201%, a disintegration time of 4 minutes in water, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation excipient 60 mesh (particle size 250 ⁇ m), the solvent was water, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
  • the capsule prepared by the above method had a loss on drying of 1.015%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounts for 64.1% of the total, the cycloserine content is 99.713%, the wet granulation auxiliary material is 60 mesh, the solvent is water, the binder accounts for 1.0% of the total, and the binder is polyvinylpyrrolidone K30.
  • the capsule prepared by the above method had a loss on drying of 2.183%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 90.9% of the total, the cycloserine content was 99.713%, the wet granulation adjuvant 40 mesh (particle size 380 ⁇ m), the solvent was water, the binder accounted for 0.25% of the total, and the binder was polyvinylpyrrolidone K30.
  • the capsule prepared by the above method had a loss on drying of 0.627%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was ethanol, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
  • the capsule prepared by the above method had a loss on drying of 0.756%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 55.6% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was ethanol, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
  • the capsule prepared by the above method had a loss on drying of 0.701%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the fluidized bed granulation auxiliary material was 60-80 mesh, the solvent was ethanol, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as a polyvinylpyrrolidone K30 ethanol solution, and the prescribed amount of talc powder is placed in a fluidized bed and sprayed with polyvinylpyrrolidone K30 ethanol solution to prepare wet particles, and dried in a fluidized state. After 60-mesh to 80-mesh sieve, the prescribed amount of cycloserine was sieved through 100 mesh and mixed with the granulated excipients, and then the No. 1 gelatin hollow capsule was filled according to the specification of 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.723%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.474%, the wet granulation adjuvant was 60 mesh, the solvent was ethanol, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured into a polyvinylpyrrolidone K30 ethanol solution, and a prescribed amount of talc powder is added to the soft material, and the wet granules are sieved through 40 mesh, and dried at 60 ° C for 2 hours to dry the granules. After 60 mesh sieves, the granules after granulation were obtained.
  • the prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.635%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was ethanol, the binder accounted for 0.1% of the total amount, and the binder was polyvinylpyrrolidone K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured into a polyvinylpyrrolidone K30 ethanol solution, and a prescribed amount of talc powder is added to the soft material, and the wet granules are sieved through 40 mesh, and dried at 60 ° C for 2 hours to dry the granules. After 60 mesh sieves, the granules after granulation were obtained.
  • the prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.697%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was ethanol, the binder accounted for 3% of the total, and the binder was polyvinylpyrrolidone K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured into a polyvinylpyrrolidone K30 ethanol solution, and a prescribed amount of talc powder is added to the soft material, and the wet granules are sieved through 40 mesh, and dried at 60 ° C for 2 hours to dry the granules. After 60 mesh sieves, the granules after granulation were obtained.
  • the prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.640%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation adjuvant 40 mesh, the solvent was ethanol, the binder accounted for 6% of the total, and the binder was polyvinylpyrrolidone K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured into a polyvinylpyrrolidone K30 ethanol solution, and a prescribed amount of talc powder is added to the soft material, and the wet granules are sieved through a 20 mesh sieve, and dried at 60 ° C for 2 hours to dry the granules. After 40 mesh (particle size 380 ⁇ m) sieve, the granules after the granulation were obtained.
  • the prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.814%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounts for 64.1% of the total, the cycloserine content is 99.713%, the wet granulation auxiliary material is 60 mesh, the solvent is water, the binder accounts for 1.0% of the total, and the binder is hypromellose E5.
  • the capsule prepared by the above method had a loss on drying of 0.558%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was water, the binder accounted for 1.0% of the total, and the binder was hydroxypropylcellulose MF.
  • the capsule prepared by the above method had a loss on drying of 0.679%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the dry granulation auxiliary material was 60 mesh, the compressible auxiliary material accounted for 10% of the total amount, and the compressible auxiliary material was anhydrous lactose.
  • talc powder and anhydrous lactose were mixed and then dry granulated to prepare 60-mesh auxiliary granules.
  • the prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 1.215%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the dry granulation auxiliary material was 60 mesh, the compressible auxiliary material accounted for 16% of the total amount, and the compressible auxiliary material was anhydrous lactose.
  • talc powder and anhydrous lactose were mixed and then dry granulated to prepare 60-mesh auxiliary granules.
  • the prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 1.153%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the dry granulation auxiliary material was 60 mesh, the compressible auxiliary material accounted for 10% of the total, and the compressible auxiliary material was starch.
  • talc powder and starch were mixed and then dry granulated to prepare 60-mesh auxiliary granules.
  • the prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 1.589%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • Cycloserine accounted for 64.1% of the total, and the content of cycloserine was 99.713%.
  • the cyclic serine was co-granulated with the auxiliary materials by 60 mesh, and the amount of compressible auxiliary materials accounted for 0% of the total.
  • the prescribed amount of cycloserine is passed through a 100 mesh sieve, mixed with talc powder, and then dry granulated to prepare 60-mesh granules, and then the granulated granules are filled with gelatin hollow capsules of No. 1 gelatin capsules per capsule containing 250 mg of cycloserine. .
  • the capsule prepared by the above method had a loss on drying of 0.637%, a disintegration time in water of 14 minutes, and a dissolution rate of less than 70% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the cycloserine and the auxiliary materials together dried granulation 60 mesh, the compressive auxiliary materials accounted for 10% of the total, and the compressible auxiliary material was anhydrous lactose.
  • cycloserine was passed through a 100 mesh sieve, mixed with talc powder and anhydrous lactose, and then granulated by dry granulation to prepare granules of 60 mesh, and the granulated granules were filled in a capsule containing 250 mg of cycloserine per capsule. No. gelatin hollow capsule.
  • the capsule prepared by the above method had a loss on drying of 0.985%, a disintegration time in water of 9 minutes, and a dissolution rate of more than 85% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the cycloserine and the auxiliary materials together dried granulation 60 mesh, the compressive auxiliary materials accounted for 10% of the total, and the compressible auxiliary material was starch.
  • cycloserine is passed through a 100 mesh sieve, mixed with talc powder and starch, and then dry granulated to prepare 60-mesh granules, and then the granulated granules are filled with gelatin No. 1 in a capsule containing 250 mg of cycloserine per capsule. Hollow capsules.
  • the capsule prepared by the above method had a loss on drying of 1.122%, a disintegration time in water of 12 minutes, and a dissolution rate of less than 85% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the cycloserine was wet-granulated with the excipients by 60 mesh.
  • the solvent was ethanol, and the binder amounted to 0% of the total amount.
  • the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and then an appropriate amount of soft material made of ethanol is added, and the wet granules are sieved through 40 mesh, dried at 60 ° C for 2 hours, and the dried granules are passed through 60 mesh.
  • the granules were sieved, and the granulated granules were filled with No. 1 gelatin hollow capsules according to the specification of 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.667%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • the cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the cycloserine was wet granulated with the excipients by 60 mesh, the solvent was ethanol, the binder amounted to 1.0% of the total amount, and the binder was polyvinylpyrrolidone K30.
  • the prescribed amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and then the prepared polyvinylpyrrolidone K30 ethanol solution is added and stirred.
  • the soft material is made, and the wet granules are sieved through 40 mesh, dried at 60 ° C for 2 h, and then the dried granules are sieved through 60 mesh, and the granulated granules are in the form of 250 mg of cycloserine per capsule. Fill the No. 1 gelatin hollow capsule.
  • the capsule prepared by the above method had a loss on drying of 0.784%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
  • the prescribed amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is prepared. After passing through a 100 mesh sieve, it is mixed with talc powder, and placed in a fluidized bed, sprayed with polyvinylpyrrolidone K30 ethanol solution to make wet granules, and dried in a fluidized state. After 60 mesh to 80 mesh sieve granules, The granulated granules were filled with No. 1 gelatin hollow capsules in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.532%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content accounted for 6.0% of total, and binder was polyvinylpyrrolidone. K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.661%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was water, binder was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
  • the prescribed amount of polyvinylpyrrolidone K30 is placed in an aqueous solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to be sprayed with polyvinylpyrrolidone K30 aqueous solution to be wet.
  • the granules are dried in a fluidized state, and the granules are sieved through 60 mesh to 80 mesh, and the pellets after granulation are filled with gelatin hollow capsule No. 1 in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method has a loss on drying of 0.620%, a disintegration time in water of 4 minutes, and a pH of 1.2, pH 4.0, The dissolution rate at pH 6.8 and 15 minutes in water was greater than 90%.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder was 3.0% of total, and binder was polyvinylpyrrolidone. K30, gelatin hollow capsules have a loss on drying of 13.6%.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.568%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder was 3.0% of total, and binder was polyvinylpyrrolidone. K30, gelatin hollow capsules have a loss on drying of 16.8%.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.699%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder was 3.0% of total, and binder was polyvinylpyrrolidone. K30, hypromellose hollow capsules had a loss on drying of 2.2%.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. Wet the granules and dry them in a fluidized state. After granulating through 60 mesh to 80 mesh, the granulated granules are filled with No. 1 hypromellose hollow capsules according to the specification of 250 mg of cycloserine per capsule. .
  • the capsule prepared by the above method had a loss on drying of 0.762%, a disintegration time in water of 8 minutes, and a dissolution rate of more than 85% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.676%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.668%, cycloserine was mixed with excipients to form granules of 60-80 mesh, solvent was ethanol, binder was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.804%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • Cycloserine accounted for 64.1% of the total, and the content of cycloserine was 99.619%.
  • the cycloserine was mixed with the excipients to make 60-80 mesh fluidized bed.
  • the solvent was ethanol, the binder was 1.0% of the total amount, and the binder was polyvinylpyrrolidone. K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.758%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • Cycloserine accounted for 64.1% of the total, and the content of cycloserine was 99.474%.
  • the cycloserine was mixed with the auxiliary material in the fluidized bed to make 60-80 mesh, the solvent was ethanol, the binder content was 1.0%, and the binder was polyvinylpyrrolidone. K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.692%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.637%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.741%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
  • the prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution.
  • the granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
  • the capsule prepared by the above method had a loss on drying of 0.608%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
  • the pharmaceutical composition prepared by the embodiment of the invention can be applied to the preparation of a medicament for treating tuberculosis caused by Mycobacterium tuberculosis. It can also be applied to the preparation of a medicament for treating psychosis, depression, Alzheimer's disease or chronic pain.

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Abstract

The present invention relates to a pharmaceutical composition and a preparation method and an application thereof. The pharmaceutical composition consists of cycloserine and an adjuvant, wherein the D90 particle diameter of the pharmaceutical composition is 75-380 μm and the amount of the adjuvant accounts for 9-45% of the pharmaceutical composition. The pharmaceutical composition of the present invention has largely improved stability.

Description

药物组合物及其制备方法和应用Pharmaceutical composition and preparation method and application thereof 技术领域Technical field
本发明涉及药物制剂技术领域，特别是涉及一种药物组合物及其制备方法和应用。The invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition and a preparation method and application thereof.
背景技术Background technique
肺结核是结核病中一种影响人民身体健康的疾病，随着链霉素和异烟肼等抗结核病药物的出现，使肺结核病成为一种可以治疗的疾病。但是由于相关知识的不足和治疗的不规范，使得结核杆菌耐药越来越严重。Tuberculosis is a disease affecting people's health in tuberculosis. With the emergence of anti-tuberculosis drugs such as streptomycin and isoniazid, tuberculosis has become a treatable disease. However, due to the lack of relevant knowledge and the irregular treatment, the drug resistance of Mycobacterium tuberculosis has become more and more serious.
肺结核是一种由结核杆菌引起的传染性较强的疾病。在世界卫生组织确定的三种需要重点控制的疾病中，肺结核仅次于艾滋病。中国是肺结核流行严重的国家，此外随着结核杆菌的耐药，中国的耐药病人也在不断增加。故开发抗肺结核病的药物，特别是抗结核耐药的药物是十分必要的。Tuberculosis is a highly contagious disease caused by Mycobacterium tuberculosis. Among the three diseases that need to be controlled by the World Health Organization, tuberculosis is second only to AIDS. China is a country with a serious tuberculosis epidemic. In addition, with the resistance of tuberculosis, China's drug-resistant patients are also increasing. Therefore, the development of anti-tuberculosis drugs, especially anti-tuberculosis drugs are very necessary.
虽然环丝氨酸的抗结核杆菌的作用比链霉素的弱，但其不易产生耐药。所以环丝氨酸主要用于治疗耐药结核杆菌引起的肺结核。Although the anti-tuberculosis strain of cycloserine is weaker than streptomycin, it is less susceptible to drug resistance. Therefore, cycloserine is mainly used to treat tuberculosis caused by drug-resistant tuberculosis.
环丝氨酸除了用于治疗结核杆菌引起的感染外，还可以用于治疗其它的一些疾病。美国专利US2014018349，世界知识产权专利WO2008118785，欧洲专利EP2338482以及欧洲专利EP0378134均公开了环丝氨酸可用于精神病、抑郁症或阿尔茨海默病的治疗。美国专利US2014213621公开了环丝氨酸可用于慢性疼痛的治疗。In addition to the infections caused by Mycobacterium tuberculosis, cycloserine can also be used to treat other diseases. The use of cycloserine for the treatment of psychosis, depression or Alzheimer's disease is disclosed in US Patent No. US2014018349, World Intellectual Property Patent WO2008118785, European Patent No. EP 2 338 482, and European Patent No. EP 0 378 134. U.S. Patent No. 2014,213,621 discloses the use of cycloserine for the treatment of chronic pain.
在美国、欧洲、日本以及中国均有环丝氨酸的产品获批上市，用于治疗结核杆菌引起的肺结核。Products with cycloserine in the United States, Europe, Japan, and China have been approved for the treatment of tuberculosis caused by Mycobacterium tuberculosis.
现有面世的环丝氨酸的制剂主要是速释类制剂，其组合物粒径很小，D90粒度小于64μm，制剂的稳定性比较差，在加速条件(温度40℃，湿度75％)下密封存储40天，制剂标示量的百分含量从99.1％降到43.3％，加速40天降解量为56.3％，加速条件下密封存储180天，主药几乎已全部降解。在常温条件(温度25℃，湿度60％)下密封存储180天，制剂标示量的百分含量从99.1％降到86.4％，常温条件180天降解量为12.8％。由于制剂比较不稳定，因此会影响治疗效果以及使用的安全性。The preparation of the existing cycloserine is mainly an immediate release preparation, the composition has a small particle size, the D 90 particle size is less than 64 μm, the stability of the preparation is relatively poor, and the seal is sealed under accelerated conditions (temperature 40 ° C, humidity 75%). After 40 days of storage, the percentage of the labeled amount of the preparation was reduced from 99.1% to 43.3%, the degradation amount was accelerated to 56.3% for 40 days, and the sealed storage was accelerated for 180 days under accelerated conditions, and the main drug was almost completely degraded. After being sealed and stored for 180 days under normal temperature conditions (temperature 25 ° C, humidity 60%), the percentage of the labeled amount of the preparation was reduced from 99.1% to 86.4%, and the degradation amount at room temperature for 180 days was 12.8%. Because the preparation is relatively unstable, it will affect the therapeutic effect and the safety of use.
俄罗斯专利RU2248205公开了在环丝氨酸中加入一些填充剂并填充于胶囊，来改善胶囊内容物的流动性和制剂的稳定性，其中加入的填充剂主要是二水合磷酸钙、微粉硅胶和硬脂酸钙。该胶囊剂增加了二水合磷酸钙来提高胶囊内容物的流动性，但由于二水合磷酸钙的摩擦力较大故容易磨损机器，长时间甚至导致粉末变色快的问题。该专利没有具体的检测数值显示其稳定性的状况，按照该专利处方制得的制剂，其稳定性仍然较差，在加速条件(温度40℃，湿度75％)下密封存储180天，制剂标示量的百分含量从99.3％降到65.4％，加速180天降解量为34.1％。在常温条件(温度25℃，湿度60％)条件下密封存储180天，制剂标示量的百分含量从99.3％降到94.8％，常温条件180天降解量为4.5％。另外该处方在稳定性试验中发现存在内容物变色的问题，原因可能与模具磨损中的金属微粒带入内容物，进而使有效成分加速降解有关，该专利并没有解决此类品种稳定性不好的问题，也没有发现有公开提高环丝氨酸制剂稳定性的专利。Russian patent RU 2248205 discloses the addition of some fillers to cycloserine and filling in capsules to improve the fluidity of the contents of the capsules and the stability of the preparation, wherein the fillers added are mainly calcium phosphate dihydrate, silica gel and stearic acid. calcium. The capsule increases the calcium phosphate dihydrate to increase the fluidity of the capsule contents, but since the frictional force of the calcium phosphate dihydrate is large, it is easy to wear the machine, and even causes a problem that the powder discolors quickly for a long time. The patent does not have a specific test value to show its stability. The preparation prepared according to the patent prescription is still inferior in stability, and is sealed and stored for 180 days under accelerated conditions (temperature 40 ° C, humidity 75%). The percentage of the amount decreased from 99.3% to 65.4%, and the accelerated amount of degradation in 180 days was 34.1%. Under normal temperature conditions (temperature 25 ° C, humidity 60%), the storage was sealed for 180 days, the percentage of the labeled amount of the preparation was reduced from 99.3% to 94.8%, and the degradation amount at room temperature for 180 days was 4.5%. In addition, the prescription found that there is a problem of discoloration of the content in the stability test, which may be related to the fact that the metal particles in the wear of the mold are brought into the content, thereby accelerating the degradation of the active ingredient, and the patent does not solve the problem that the stability of the variety is not good. The problem has not been found to have a patent that publicly increases the stability of the cycloserine formulation.
因此，目前市场上需要开发一种稳定性更好的环丝氨酸制剂以满足临床的需求。Therefore, there is a need in the market to develop a more stable cycloserine formulation to meet clinical needs.
发明内容Summary of the invention
基于此，本发明的目的是提供一种稳定性好的环丝氨酸的药物组合物。Based on this, it is an object of the present invention to provide a pharmaceutical composition of a stable cycloserine.
具体的技术方案如下：The specific technical solutions are as follows:
一种药物组合物，该药物组合物包括环丝氨酸和辅料，所述的药物组合物的D90粒径为75～ 380μm，所述辅料的用量占药物组合物总质量的9～45％。A pharmaceutical composition comprising cycloserine and an adjuvant, said pharmaceutical composition having a D 90 particle size of from 75 to 380 μm, said adjuvant being used in an amount of from 9 to 45% by weight based on the total mass of the pharmaceutical composition.
在其中一些实施例中，所述辅料包括滑石粉，以及粘合剂和/或可压性辅料。In some of these embodiments, the excipient comprises talc, and a binder and/or compressible excipient.
在其中一些实施例中，所述滑石粉的用量占药物组合物总量的9～45％，所述粘合剂的用量占药物组合物总质量的0～6％，所述可压性辅料的用量占药物组合物总质量的0～16％。In some embodiments, the talc is used in an amount of 9 to 45% by weight based on the total amount of the pharmaceutical composition, and the binder is used in an amount of 0 to 6% based on the total mass of the pharmaceutical composition. The amount used is from 0 to 16% of the total mass of the pharmaceutical composition.
在其中一些实施例中，所述辅料包括滑石粉和粘合剂，所述滑石粉的用量占药物组合物总质量的23～38％，所述粘合剂的用量占药物组合物总质量的0.05～2％。In some of the embodiments, the excipient comprises talc and a binder, the talc being used in an amount of from 23 to 38% by weight based on the total mass of the pharmaceutical composition, and the amount of the binder being based on the total mass of the pharmaceutical composition. 0.05 to 2%.
在其中一些实施例中，所述辅料包括滑石粉和可压性辅料，所述滑石粉的用量占药物组合物总质量的23～38％，所述可压性辅料的用量占药物组合物总质量的8～14％。In some embodiments, the excipient comprises talc and a compressible adjuvant, the talc is used in an amount of 23 to 38% by weight of the total mass of the pharmaceutical composition, and the compressive auxiliary is used in a total amount of the pharmaceutical composition. 8 to 14% of the mass.
在其中一些实施例中，所述粘合剂选自聚乙烯吡咯烷酮、羟丙甲纤维素、羟丙纤维素、乙基纤维素、甲基纤维素、羧甲基纤维素钠、羟乙纤维素、糊精中一种或几种；所述可压性辅料选自乳糖、淀粉、磷酸氢钙、微晶纤维素、甘露醇、糊精中一种或几种。In some of these embodiments, the binder is selected from the group consisting of polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, ethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose One or several kinds of dextrin; the compressible auxiliary material is one or more selected from the group consisting of lactose, starch, calcium hydrogen phosphate, microcrystalline cellulose, mannitol, and dextrin.
在其中一些实施例中，该药物组合物的剂型为胶囊剂，所述胶囊剂的空心胶囊为明胶空心胶囊或羟丙甲纤维素空心胶囊，所述空心胶囊的干燥失重<15.0％。In some of these embodiments, the pharmaceutical composition is in the form of a capsule, and the hollow capsule of the capsule is a gelatin hollow capsule or a hypromellose hollow capsule, and the hollow capsule has a loss on drying of <15.0%.
本发明的另一目的是提供上述药物组合物的制备方法。Another object of the present invention is to provide a process for the preparation of the above pharmaceutical composition.
具体的技术方案如下：The specific technical solutions are as follows:
上述药物组合物的制备方法，包括如下步骤：The preparation method of the above pharmaceutical composition comprises the following steps:
将D90粒径为75～380μm的环丝氨酸与辅料按所述质量百分比混合均匀，即得所述药物组合物；The cycloserine having a D 90 particle size of 75-380 μm and the auxiliary material are uniformly mixed according to the mass percentage, thereby obtaining the pharmaceutical composition;
或，将环丝氨酸与辅料按所述质量百分比混合，然后进行湿法制粒、干法制粒或流化床制粒，干燥，过筛整粒，即得所述药物组合物；Or, the cycloserine and the auxiliary material are mixed according to the mass percentage, and then subjected to wet granulation, dry granulation or fluidized bed granulation, dried, and sieved to obtain the pharmaceutical composition;
或，将辅料进行湿法制粒、干法制粒或流化床制粒，干燥，过筛整粒，得D90粒径为75～380μm的辅料颗粒，再与D90粒径为75～380μm的环丝氨酸按所述质量百分比进行混合，即得所述药物组合物。Or the auxiliary wet granulation, dry granulation or fluidized bed granulation, dried and sieved and sieved to give the particle D 90 particle size of 75 ~ 380μm excipients, and then the D 90 particle size of 75 ~ 380μm is The cycloserine is mixed in the above percentage by mass to obtain the pharmaceutical composition.
在其中一些实施例中，所述药物组合物的干燥失重介于0.2～2％，D90粒径介于120～380μm。In some of these embodiments, the pharmaceutical composition has a loss on drying of from 0.2 to 2% and a D 90 particle size of from 120 to 380 μm.
本发明的另一目的是提供上述药物组合物的应用。Another object of the invention is to provide the use of the above pharmaceutical compositions.
具体的技术方案如下：The specific technical solutions are as follows:
上述药物组合物在制备治疗结核杆菌引起的肺结核的药物中的应用。The use of the above pharmaceutical composition for the preparation of a medicament for treating tuberculosis caused by Mycobacterium tuberculosis.
上述药物组合物在制备治疗精神病、抑郁症、阿尔茨海默病或慢性疼痛的药物中应用。The above pharmaceutical composition is used in the preparation of a medicament for treating psychosis, depression, Alzheimer's disease or chronic pain.
本发明的原理及优点如下：The principles and advantages of the present invention are as follows:
本发明针对现有技术的不足，提供一种环丝氨酸的药物组合物，具体而言是一种含环丝氨酸的速释类胶囊剂。The present invention is directed to the deficiencies of the prior art, and provides a pharmaceutical composition of cycloserine, in particular, an immediate release capsule containing cycloserine.
目前的环丝氨酸制剂主要是胶囊剂，但其制剂的稳定性较差，在常温条件(温度25℃，湿度60％)和加速条件(40℃，湿度75％)下制剂主药的降解都较快，影响制剂的疗效和使用的安全性。The current cycloserine preparation is mainly a capsule, but the stability of the preparation is poor. The degradation of the main drug in the preparation under normal temperature conditions (temperature 25 ° C, humidity 60%) and accelerated conditions (40 ° C, humidity 75%) Fast, affecting the efficacy of the preparation and the safety of use.
本发明通过提高辅料的粒径(进而提高药物组合物的粒径)和控制药物组合物的干燥失重的量不仅提高了制剂释放的速度，而且极大地提高了制剂的稳定性。The present invention not only increases the rate of release of the formulation by increasing the particle size of the excipient (and thereby increasing the particle size of the pharmaceutical composition) and controlling the amount of dry weight loss of the pharmaceutical composition, but also greatly enhances the stability of the formulation.
本发明的药物组合物的D90粒径介于75～380μm，干燥失重介于0.2～2％。The pharmaceutical composition of the present invention has a D 90 particle size of from 75 to 380 μm and a loss on drying of from 0.2 to 2%.
本发明的药物组合物通过在环丝氨酸中加入辅料，或将环丝氨酸与辅料联合制粒的方式，将药物组合物的D90粒径控制在75～380μm，不仅使胶囊内容物具有良好的流动性以及润滑性，也提高了制剂的释放速度和制剂的稳定性。处方中的辅料主要是滑石粉，以及粘合剂和/或可压性辅料。The pharmaceutical composition of the present invention can control the D 90 particle diameter of the pharmaceutical composition to 75-380 μm by adding an auxiliary material to the cycloserine or combining the cycloserine with the auxiliary material, thereby not only making the capsule content have good fluidity. As well as lubricity, it also increases the release rate of the formulation and the stability of the formulation. The excipients in the prescription are mainly talc, as well as binders and/or compressible excipients.
本发明的药物组合物的剂型为胶囊剂，所述胶囊剂的空心胶囊为明胶空心胶囊或羟丙甲纤维素空心胶囊，所述空心胶囊的干燥失重<15.0％。The pharmaceutical composition of the present invention is in the form of a capsule, and the hollow capsule of the capsule is a gelatin hollow capsule or a hypromellose hollow capsule, and the hollow capsule has a loss on drying of <15.0%.
本发明的药物组合物的稳定性与现有技术相比有较大的提升，最优例在常温条件(温度25℃， 湿度60％)下密封存储180天，制剂标示量的百分含量的降解量<0.5％，加速条件(40℃，湿度75％)下密封存储180天，制剂标示量的百分含量的降解量<4.0％。The stability of the pharmaceutical composition of the present invention is greatly improved compared with the prior art, and the optimal example is at normal temperature (temperature 25 ° C, Humidity 60%) sealed for 180 days, the amount of degradation of the indicated amount of the formulation is <0.5%, sealed for 180 days under accelerated conditions (40 ° C, humidity 75%), and the amount of degradation of the indicated amount of the formulation <4.0%.
具体实施方式detailed description
以下通过实施例对本发明做进一步阐述。The invention is further illustrated by the following examples.
对比例1Comparative example 1
环丝氨酸占总量90.9％，环丝氨酸含量99.713％，滑石粉325目(粒径44μm)。The cyclic serine accounted for 90.9% of the total, the cycloserine content was 99.713%, and the talc powder was 325 mesh (particle size 44 μm).
处方：prescription:
Figure PCTCN2015100130-appb-000001
Figure PCTCN2015100130-appb-000001
制备方法：Preparation:
取处方量的环丝氨酸过200目筛，后与处方量的滑石粉混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。Take a prescribed amount of cycloserine through a 200 mesh sieve, and then mix with the prescribed amount of talc powder, and fill the No. 1 gelatin hollow capsule according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.769％，在水中崩解时间为5分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.769%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表1。The stability data is shown in Table 1.
对比例2Comparative example 2
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，滑石粉325目。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the talc powder was 325 mesh.
处方：prescription:
Figure PCTCN2015100130-appb-000002
Figure PCTCN2015100130-appb-000002
制备方法：Preparation:
取处方量的环丝氨酸过200目筛，后与处方量的滑石粉混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。Take a prescribed amount of cycloserine through a 200 mesh sieve, and then mix with the prescribed amount of talc powder, and fill the No. 1 gelatin hollow capsule according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.521％，在水中崩解时间为5分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.521%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表1。The stability data is shown in Table 1.
对比例3Comparative example 3
环丝氨酸占总量55.6％，环丝氨酸含量99.713％，滑石粉325目。The cyclic serine accounted for 55.6% of the total, the cycloserine content was 99.713%, and the talc powder was 325 mesh.
处方：prescription:
Figure PCTCN2015100130-appb-000003
Figure PCTCN2015100130-appb-000003
制备方法：Preparation:
取处方量的环丝氨酸过200目筛，后与处方量的滑石粉混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。Take a prescribed amount of cycloserine through a 200 mesh sieve, and then mix with the prescribed amount of talc powder, and fill the No. 1 gelatin hollow capsule according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.672％，在水中崩解时间为5分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.672%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表1。The stability data is shown in Table 1.
对比例4Comparative example 4
环丝氨酸占总量64.1％，环丝氨酸含量99.668％，滑石粉325目。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.668%, and the talc powder was 325 mesh.
处方：prescription:
Figure PCTCN2015100130-appb-000004
Figure PCTCN2015100130-appb-000004
制备方法：Preparation:
取处方量的环丝氨酸过200目筛，后与处方量的滑石粉混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。Take a prescribed amount of cycloserine through a 200 mesh sieve, and then mix with the prescribed amount of talc powder, and fill the No. 1 gelatin hollow capsule according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.530％，在水中崩解时间为5分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.530%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表1。The stability data is shown in Table 1.
表1Table 1
Figure PCTCN2015100130-appb-000005
Figure PCTCN2015100130-appb-000005
实施例5Example 5
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，滑石粉200目(粒径75μm)。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the talc powder was 200 mesh (particle size 75 μm).
处方：prescription:
Figure PCTCN2015100130-appb-000006
Figure PCTCN2015100130-appb-000006
制备方法： Preparation:
取处方量的环丝氨酸过200目筛，后与处方量的滑石粉混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。Take a prescribed amount of cycloserine through a 200 mesh sieve, and then mix with the prescribed amount of talc powder, and fill the No. 1 gelatin hollow capsule according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.496％，在水中崩解时间为5分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.496%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表2。The stability data is shown in Table 2.
实施例6Example 6
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，滑石粉200目。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the talc powder was 200 mesh.
处方：prescription:
Figure PCTCN2015100130-appb-000007
Figure PCTCN2015100130-appb-000007
制备方法：Preparation:
取处方量的环丝氨酸过100目筛，后与处方量的滑石粉混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。Take a prescription amount of cycloserine through a 100 mesh sieve, and then mix it with the prescribed amount of talc powder, and fill the No. 1 gelatin hollow capsule according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.583％，在水中崩解时间为5分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.583%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表2。The stability data is shown in Table 2.
实施例7Example 7
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，滑石粉100目(粒径150μm)。The cycloserine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the talc powder was 100 mesh (particle size 150 μm).
处方：prescription:
Figure PCTCN2015100130-appb-000008
Figure PCTCN2015100130-appb-000008
制备方法：Preparation:
取处方量的环丝氨酸过100目筛，后与处方量的滑石粉混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。Take a prescription amount of cycloserine through a 100 mesh sieve, and then mix it with the prescribed amount of talc powder, and fill the No. 1 gelatin hollow capsule according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.578％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.578%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表2。The stability data is shown in Table 2.
实施例8Example 8
环丝氨酸占总量64.1％，环丝氨酸含量99.619％，滑石粉100目。Cycloserine accounted for 64.1% of the total, the content of cycloserine was 99.619%, and the talc powder was 100 mesh.
处方：prescription:
Figure PCTCN2015100130-appb-000009
Figure PCTCN2015100130-appb-000009
制备方法：Preparation:
取处方量的环丝氨酸过100目筛，后与处方量的滑石粉混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。Take a prescription amount of cycloserine through a 100 mesh sieve, and then mix it with the prescribed amount of talc powder, and fill the No. 1 gelatin hollow capsule according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.544％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.544%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表2。The stability data is shown in Table 2.
表2Table 2
Figure PCTCN2015100130-appb-000010
Figure PCTCN2015100130-appb-000010
实施例9Example 9
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，湿法制粒的辅料100目，溶剂为水，粘合剂占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation excipient 100 mesh, the solvent was water, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000011
Figure PCTCN2015100130-appb-000011
制备方法：Preparation:
将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀，加入适量的水制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过100目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。Mix the prescribed amount of talc powder with polyvinylpyrrolidone K30, add appropriate amount of water soft material, then sieve the wet granules through 40 mesh, dry at 60 ° C for 2 h, and dry the granules through 100 mesh sieve. , the granules after the granulation. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为1.201％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 1.201%, a disintegration time of 4 minutes in water, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例10Example 10
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，湿法制粒的辅料60目(粒径250μm)，溶剂为水，粘合剂占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation excipient 60 mesh (particle size 250 μm), the solvent was water, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
处方： Prescription:
Figure PCTCN2015100130-appb-000012
Figure PCTCN2015100130-appb-000012
制备方法：Preparation:
将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀，加入适量的水制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。Mix the prescribed amount of talc powder with polyvinylpyrrolidone K30, add appropriate amount of water soft material, then sieve the wet granules through 40 mesh, dry at 60 ° C for 2 h, and dry the granules through 60 mesh sieve. , the granules after the granulation. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为1.015％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 1.015%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例11Example 11
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，湿法制粒的辅料60目，溶剂为水，粘合剂占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounts for 64.1% of the total, the cycloserine content is 99.713%, the wet granulation auxiliary material is 60 mesh, the solvent is water, the binder accounts for 1.0% of the total, and the binder is polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000013
Figure PCTCN2015100130-appb-000013
制备方法：Preparation:
将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀，加入适量的水制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。Mix the prescribed amount of talc powder with polyvinylpyrrolidone K30, add appropriate amount of water soft material, then sieve the wet granules through 40 mesh, dry at 60 ° C for 2 h, and dry the granules through 60 mesh sieve. , the granules after the granulation. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为2.183％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 2.183%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例12Example 12
环丝氨酸占总量90.9％，环丝氨酸含量99.713％，湿法制粒的辅料40目(粒径380μm)，溶剂为水，粘合剂占总量0.25％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 90.9% of the total, the cycloserine content was 99.713%, the wet granulation adjuvant 40 mesh (particle size 380 μm), the solvent was water, the binder accounted for 0.25% of the total, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000014
Figure PCTCN2015100130-appb-000014
制备方法：Preparation:
将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀，加入适量的水制软材，后过20目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过40目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。Mix the prescribed amount of talc powder with polyvinylpyrrolidone K30, add appropriate amount of water soft material, then sieve the wet granules through 20 mesh, dry at 60 ° C for 2 h, and dry the granules through 40 mesh sieve. , the granules after the granulation. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.627％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.627%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例13Example 13
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，湿法制粒的辅料60目，溶剂为乙醇，粘合剂占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was ethanol, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000015
Figure PCTCN2015100130-appb-000015
制备方法：Preparation:
将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀，加入适量的乙醇制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。Mix the prescribed amount of talc powder with polyvinylpyrrolidone K30, add appropriate amount of soft material made of ethanol, then sieve the wet granules through 40 mesh, dry at 60 ° C for 2 h, and dry the granules through 60 mesh sieve. , the granules after the granulation. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.756％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.756%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例14Example 14
环丝氨酸占总量55.6％，环丝氨酸含量99.713％，湿法制粒的辅料60目，溶剂为乙醇，粘合剂占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 55.6% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was ethanol, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000016
Figure PCTCN2015100130-appb-000016
制备方法：Preparation:
将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀，加入适量的乙醇制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。Mix the prescribed amount of talc powder with polyvinylpyrrolidone K30, add appropriate amount of soft material made of ethanol, then sieve the wet granules through 40 mesh, dry at 60 ° C for 2 h, and dry the granules through 60 mesh sieve. , the granules after the granulation. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.701％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。 The capsule prepared by the above method had a loss on drying of 0.701%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例15Example 15
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，流化床制粒的辅料60～80目，溶剂为乙醇，粘合剂占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the fluidized bed granulation auxiliary material was 60-80 mesh, the solvent was ethanol, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000017
Figure PCTCN2015100130-appb-000017
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液，将处方量的滑石粉置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，将处方量的环丝氨酸过100目筛后与制粒后的辅料混匀，再按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as a polyvinylpyrrolidone K30 ethanol solution, and the prescribed amount of talc powder is placed in a fluidized bed and sprayed with polyvinylpyrrolidone K30 ethanol solution to prepare wet particles, and dried in a fluidized state. After 60-mesh to 80-mesh sieve, the prescribed amount of cycloserine was sieved through 100 mesh and mixed with the granulated excipients, and then the No. 1 gelatin hollow capsule was filled according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.723％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.723%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例16Example 16
环丝氨酸占总量64.1％，环丝氨酸含量99.474％，湿法制粒的辅料60目，溶剂为乙醇，粘合剂占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.474%, the wet granulation adjuvant was 60 mesh, the solvent was ethanol, the binder accounted for 1.0% of the total, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000018
Figure PCTCN2015100130-appb-000018
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液，再加入处方量的滑石粉制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured into a polyvinylpyrrolidone K30 ethanol solution, and a prescribed amount of talc powder is added to the soft material, and the wet granules are sieved through 40 mesh, and dried at 60 ° C for 2 hours to dry the granules. After 60 mesh sieves, the granules after granulation were obtained. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.635％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.635%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例17Example 17
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，湿法制粒的辅料60目，溶剂为乙醇，粘合剂占总量0.1％，粘合剂为聚乙烯吡咯烷酮K30。 The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was ethanol, the binder accounted for 0.1% of the total amount, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000019
Figure PCTCN2015100130-appb-000019
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液，再加入处方量的滑石粉制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured into a polyvinylpyrrolidone K30 ethanol solution, and a prescribed amount of talc powder is added to the soft material, and the wet granules are sieved through 40 mesh, and dried at 60 ° C for 2 hours to dry the granules. After 60 mesh sieves, the granules after granulation were obtained. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.697％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.697%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例18Example 18
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，湿法制粒的辅料60目，溶剂为乙醇，粘合剂占总量3％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was ethanol, the binder accounted for 3% of the total, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000020
Figure PCTCN2015100130-appb-000020
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液，再加入处方量的滑石粉制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured into a polyvinylpyrrolidone K30 ethanol solution, and a prescribed amount of talc powder is added to the soft material, and the wet granules are sieved through 40 mesh, and dried at 60 ° C for 2 hours to dry the granules. After 60 mesh sieves, the granules after granulation were obtained. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.640％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.640%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例19Example 19
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，湿法制粒的辅料40目，溶剂为乙醇，粘合剂占总量6％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation adjuvant 40 mesh, the solvent was ethanol, the binder accounted for 6% of the total, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000021
Figure PCTCN2015100130-appb-000021
Figure PCTCN2015100130-appb-000022
Figure PCTCN2015100130-appb-000022
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液，再加入处方量的滑石粉制软材，后过20目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过40目(粒径380μm)筛，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured into a polyvinylpyrrolidone K30 ethanol solution, and a prescribed amount of talc powder is added to the soft material, and the wet granules are sieved through a 20 mesh sieve, and dried at 60 ° C for 2 hours to dry the granules. After 40 mesh (particle size 380 μm) sieve, the granules after the granulation were obtained. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.814％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.814%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例20Example 20
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，湿法制粒的辅料60目，溶剂为水，粘合剂占总量1.0％，粘合剂为羟丙甲纤维素E5。The cyclic serine accounts for 64.1% of the total, the cycloserine content is 99.713%, the wet granulation auxiliary material is 60 mesh, the solvent is water, the binder accounts for 1.0% of the total, and the binder is hypromellose E5.
处方：prescription:
Figure PCTCN2015100130-appb-000023
Figure PCTCN2015100130-appb-000023
制备方法：Preparation:
将处方量的滑石粉与羟丙甲纤维素E5混匀，加入适量的水制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。Mix the prescribed amount of talc powder with hypromellose E5, add appropriate amount of water to make soft material, then sieve the wet granules through 40 mesh, dry at 60 ° C for 2 h, and pass the dried granules through a 60 mesh sieve. Whole grain, the granules after granulation are obtained. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.558％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.558%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
实施例21Example 21
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，湿法制粒的辅料60目，溶剂为水，粘合剂占总量1.0％，粘合剂为羟丙纤维素MF。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the wet granulation auxiliary material was 60 mesh, the solvent was water, the binder accounted for 1.0% of the total, and the binder was hydroxypropylcellulose MF.
处方：prescription:
Figure PCTCN2015100130-appb-000024
Figure PCTCN2015100130-appb-000024
制备方法：Preparation:
将处方量的滑石粉与羟丙纤维素MF混匀，加入适量的水制软材，后过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，得制粒后的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。Mix the prescribed amount of talc powder with hydroxypropyl cellulose MF, add appropriate amount of water soft material, then sieve the wet granules through 40 mesh, dry at 60 ° C for 2 h, and sieve the dried granules through 60 mesh. Granules, granules after granulation. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.679％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.679%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表3。The stability data is shown in Table 3.
表3table 3
Figure PCTCN2015100130-appb-000025
Figure PCTCN2015100130-appb-000025
实施例22Example 22
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，干法制粒的辅料60目，可压性辅料用量占总量10％，可压性辅料为无水乳糖。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the dry granulation auxiliary material was 60 mesh, the compressible auxiliary material accounted for 10% of the total amount, and the compressible auxiliary material was anhydrous lactose.
处方：prescription:
Figure PCTCN2015100130-appb-000026
Figure PCTCN2015100130-appb-000026
制备方法：Preparation:
将处方量的滑石粉和无水乳糖混匀后干法制粒，制60目的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of talc powder and anhydrous lactose were mixed and then dry granulated to prepare 60-mesh auxiliary granules. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为1.215％，在水中崩解时间为5分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 1.215%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表4。The stability data is shown in Table 4.
实施例23Example 23
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，干法制粒的辅料60目，可压性辅料用量占总量16％，可压性辅料为无水乳糖。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the dry granulation auxiliary material was 60 mesh, the compressible auxiliary material accounted for 16% of the total amount, and the compressible auxiliary material was anhydrous lactose.
处方：prescription:
Figure PCTCN2015100130-appb-000027
Figure PCTCN2015100130-appb-000027
制备方法：Preparation:
将处方量的滑石粉和无水乳糖混匀后干法制粒，制60目的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of talc powder and anhydrous lactose were mixed and then dry granulated to prepare 60-mesh auxiliary granules. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为1.153％，在水中崩解时间为5分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 1.153%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表4。The stability data is shown in Table 4.
实施例24Example 24
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，干法制粒的辅料60目，可压性辅料用量占总量10％，可压性辅料为淀粉。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the dry granulation auxiliary material was 60 mesh, the compressible auxiliary material accounted for 10% of the total, and the compressible auxiliary material was starch.
处方：prescription:
Figure PCTCN2015100130-appb-000028
Figure PCTCN2015100130-appb-000028
制备方法：Preparation:
将处方量的滑石粉和淀粉混匀后干法制粒，制60目的辅料颗粒。将处方量的环丝氨酸过100目筛，再与制粒后的辅料混匀，按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of talc powder and starch were mixed and then dry granulated to prepare 60-mesh auxiliary granules. The prescribed amount of cycloserine was passed through a 100 mesh sieve, and then mixed with the granulated auxiliary material, and the No. 1 gelatin hollow capsule was filled in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为1.589％，在水中崩解时间为5分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 1.589%, a disintegration time in water of 5 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表4。The stability data is shown in Table 4.
表4Table 4
Figure PCTCN2015100130-appb-000029
Figure PCTCN2015100130-appb-000029
Figure PCTCN2015100130-appb-000030
Figure PCTCN2015100130-appb-000030
实施例25Example 25
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起干法制粒60目，可压性辅料用量占总量0％。Cycloserine accounted for 64.1% of the total, and the content of cycloserine was 99.713%. The cyclic serine was co-granulated with the auxiliary materials by 60 mesh, and the amount of compressible auxiliary materials accounted for 0% of the total.
处方：prescription:
Figure PCTCN2015100130-appb-000031
Figure PCTCN2015100130-appb-000031
制备方法：Preparation:
将处方量的环丝氨酸过100目筛，再与滑石粉混匀后干法制粒，制60目的颗粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of cycloserine is passed through a 100 mesh sieve, mixed with talc powder, and then dry granulated to prepare 60-mesh granules, and then the granulated granules are filled with gelatin hollow capsules of No. 1 gelatin capsules per capsule containing 250 mg of cycloserine. .
上述方法制备的胶囊，其干燥失重为0.637％，在水中崩解时间为14分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均小于70％。The capsule prepared by the above method had a loss on drying of 0.637%, a disintegration time in water of 14 minutes, and a dissolution rate of less than 70% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表5。The stability data is shown in Table 5.
实施例26Example 26
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起干法制粒60目，可压性辅料用量占总量10％，可压性辅料为无水乳糖。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the cycloserine and the auxiliary materials together dried granulation 60 mesh, the compressive auxiliary materials accounted for 10% of the total, and the compressible auxiliary material was anhydrous lactose.
处方：prescription:
Figure PCTCN2015100130-appb-000032
Figure PCTCN2015100130-appb-000032
制备方法：Preparation:
将处方量的环丝氨酸过100目筛，再与滑石粉以及无水乳糖混匀后干法制粒，制60目的颗粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of cycloserine was passed through a 100 mesh sieve, mixed with talc powder and anhydrous lactose, and then granulated by dry granulation to prepare granules of 60 mesh, and the granulated granules were filled in a capsule containing 250 mg of cycloserine per capsule. No. gelatin hollow capsule.
上述方法制备的胶囊，其干燥失重为0.985％，在水中崩解时间为9分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于85％。The capsule prepared by the above method had a loss on drying of 0.985%, a disintegration time in water of 9 minutes, and a dissolution rate of more than 85% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表5。The stability data is shown in Table 5.
实施例27 Example 27
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起干法制粒60目，可压性辅料用量占总量10％，可压性辅料为淀粉。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the cycloserine and the auxiliary materials together dried granulation 60 mesh, the compressive auxiliary materials accounted for 10% of the total, and the compressible auxiliary material was starch.
处方：prescription:
Figure PCTCN2015100130-appb-000033
Figure PCTCN2015100130-appb-000033
制备方法：Preparation:
将处方量的环丝氨酸过100目筛，再与滑石粉以及淀粉混匀后干法制粒，制60目的颗粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of cycloserine is passed through a 100 mesh sieve, mixed with talc powder and starch, and then dry granulated to prepare 60-mesh granules, and then the granulated granules are filled with gelatin No. 1 in a capsule containing 250 mg of cycloserine per capsule. Hollow capsules.
上述方法制备的胶囊，其干燥失重为1.122％，在水中崩解时间为12分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均小于85％。The capsule prepared by the above method had a loss on drying of 1.122%, a disintegration time in water of 12 minutes, and a dissolution rate of less than 85% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表5。The stability data is shown in Table 5.
表5table 5
Figure PCTCN2015100130-appb-000034
Figure PCTCN2015100130-appb-000034
实施例28Example 28
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起湿法制粒60目，溶剂为乙醇，粘合剂用量占总量0％。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, and the cycloserine was wet-granulated with the excipients by 60 mesh. The solvent was ethanol, and the binder amounted to 0% of the total amount.
处方：prescription:
Figure PCTCN2015100130-appb-000035
Figure PCTCN2015100130-appb-000035
制备方法：Preparation:
将处方量的环丝氨酸过100目筛，再与滑石粉混匀后加入适量的乙醇制软材，过40目筛制湿颗粒，置于60℃下干燥2h，将干燥后的颗粒过60目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and then an appropriate amount of soft material made of ethanol is added, and the wet granules are sieved through 40 mesh, dried at 60 ° C for 2 hours, and the dried granules are passed through 60 mesh. The granules were sieved, and the granulated granules were filled with No. 1 gelatin hollow capsules according to the specification of 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.667％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。 The capsule prepared by the above method had a loss on drying of 0.667%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表6。The stability data is shown in Table 6.
实施例29Example 29
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起湿法制粒60目，溶剂为乙醇，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。The cyclic serine accounted for 64.1% of the total, the cycloserine content was 99.713%, the cycloserine was wet granulated with the excipients by 60 mesh, the solvent was ethanol, the binder amounted to 1.0% of the total amount, and the binder was polyvinylpyrrolidone K30.
处方：prescription:
Figure PCTCN2015100130-appb-000036
Figure PCTCN2015100130-appb-000036
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，再加入配置好的聚乙烯吡咯烷酮K30乙醇溶液，搅匀制软材，再过40目筛制湿颗粒，置于60℃下干燥2h，再将干燥的颗粒过60目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and then the prepared polyvinylpyrrolidone K30 ethanol solution is added and stirred. The soft material is made, and the wet granules are sieved through 40 mesh, dried at 60 ° C for 2 h, and then the dried granules are sieved through 60 mesh, and the granulated granules are in the form of 250 mg of cycloserine per capsule. Fill the No. 1 gelatin hollow capsule.
上述方法制备的胶囊，其干燥失重为0.784％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.784%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表6。The stability data is shown in Table 6.
表6Table 6
Figure PCTCN2015100130-appb-000037
Figure PCTCN2015100130-appb-000037
实施例30(优选实施例)Example 30 (Preferred Example)
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
处方：prescription:
Figure PCTCN2015100130-appb-000038
Figure PCTCN2015100130-appb-000038
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸 过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is prepared. After passing through a 100 mesh sieve, it is mixed with talc powder, and placed in a fluidized bed, sprayed with polyvinylpyrrolidone K30 ethanol solution to make wet granules, and dried in a fluidized state. After 60 mesh to 80 mesh sieve granules, The granulated granules were filled with No. 1 gelatin hollow capsules in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.532％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.532%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表7。The stability data is shown in Table 7.
实施例31Example 31
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量6.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content accounted for 6.0% of total, and binder was polyvinylpyrrolidone. K30.
处方：prescription:
Figure PCTCN2015100130-appb-000039
Figure PCTCN2015100130-appb-000039
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.661％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.661%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表7。The stability data is shown in Table 7.
实施例32Example 32
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为水，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was water, binder was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
处方：prescription:
Figure PCTCN2015100130-appb-000040
Figure PCTCN2015100130-appb-000040
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的水溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30水溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescribed amount of polyvinylpyrrolidone K30 is placed in an aqueous solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to be sprayed with polyvinylpyrrolidone K30 aqueous solution to be wet. The granules are dried in a fluidized state, and the granules are sieved through 60 mesh to 80 mesh, and the pellets after granulation are filled with gelatin hollow capsule No. 1 in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.620％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、 pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method has a loss on drying of 0.620%, a disintegration time in water of 4 minutes, and a pH of 1.2, pH 4.0, The dissolution rate at pH 6.8 and 15 minutes in water was greater than 90%.
稳定性数据见表7。The stability data is shown in Table 7.
实施例33Example 33
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量3.0％，粘合剂为聚乙烯吡咯烷酮K30，明胶空心胶囊的干燥失重为13.6％。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder was 3.0% of total, and binder was polyvinylpyrrolidone. K30, gelatin hollow capsules have a loss on drying of 13.6%.
处方：prescription:
Figure PCTCN2015100130-appb-000041
Figure PCTCN2015100130-appb-000041
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.568％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.568%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表7。The stability data is shown in Table 7.
实施例34Example 34
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量3.0％，粘合剂为聚乙烯吡咯烷酮K30，明胶空心胶囊的干燥失重为16.8％。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder was 3.0% of total, and binder was polyvinylpyrrolidone. K30, gelatin hollow capsules have a loss on drying of 16.8%.
处方：prescription:
Figure PCTCN2015100130-appb-000042
Figure PCTCN2015100130-appb-000042
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.699％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.699%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表7。 The stability data is shown in Table 7.
实施例35(优选实施例)Example 35 (Preferred Example)
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量3.0％，粘合剂为聚乙烯吡咯烷酮K30，羟丙甲纤维素空心胶囊的干燥失重为2.2％。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder was 3.0% of total, and binder was polyvinylpyrrolidone. K30, hypromellose hollow capsules had a loss on drying of 2.2%.
处方：prescription:
Figure PCTCN2015100130-appb-000043
Figure PCTCN2015100130-appb-000043
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号羟丙甲纤维素空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. Wet the granules and dry them in a fluidized state. After granulating through 60 mesh to 80 mesh, the granulated granules are filled with No. 1 hypromellose hollow capsules according to the specification of 250 mg of cycloserine per capsule. .
上述方法制备的胶囊，其干燥失重为0.762％，在水中崩解时间为8分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于85％。The capsule prepared by the above method had a loss on drying of 0.762%, a disintegration time in water of 8 minutes, and a dissolution rate of more than 85% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表7。The stability data is shown in Table 7.
表7Table 7
Figure PCTCN2015100130-appb-000044
Figure PCTCN2015100130-appb-000044
实施例36Example 36
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
处方：prescription:
Figure PCTCN2015100130-appb-000045
Figure PCTCN2015100130-appb-000045
Figure PCTCN2015100130-appb-000046
Figure PCTCN2015100130-appb-000046
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.676％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.676%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表8。The stability data is shown in Table 8.
实施例37Example 37
环丝氨酸占总量64.1％，环丝氨酸含量99.668％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of total, cycloserine content was 99.668%, cycloserine was mixed with excipients to form granules of 60-80 mesh, solvent was ethanol, binder was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
处方：prescription:
Figure PCTCN2015100130-appb-000047
Figure PCTCN2015100130-appb-000047
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.804％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.804%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表8。The stability data is shown in Table 8.
实施例38Example 38
环丝氨酸占总量64.1％，环丝氨酸含量99.619％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of the total, and the content of cycloserine was 99.619%. The cycloserine was mixed with the excipients to make 60-80 mesh fluidized bed. The solvent was ethanol, the binder was 1.0% of the total amount, and the binder was polyvinylpyrrolidone. K30.
处方：prescription:
Figure PCTCN2015100130-appb-000048
Figure PCTCN2015100130-appb-000048
制备方法： Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.758％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.758%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% at pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表8。The stability data is shown in Table 8.
实施例39Example 39
环丝氨酸占总量64.1％，环丝氨酸含量99.474％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of the total, and the content of cycloserine was 99.474%. The cycloserine was mixed with the auxiliary material in the fluidized bed to make 60-80 mesh, the solvent was ethanol, the binder content was 1.0%, and the binder was polyvinylpyrrolidone. K30.
处方：prescription:
Figure PCTCN2015100130-appb-000049
Figure PCTCN2015100130-appb-000049
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.692％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.692%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8 and water for 15 minutes.
稳定性数据见表8。The stability data is shown in Table 8.
表8Table 8
Figure PCTCN2015100130-appb-000050
Figure PCTCN2015100130-appb-000050
实施例40Example 40
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
处方： Prescription:
Figure PCTCN2015100130-appb-000051
Figure PCTCN2015100130-appb-000051
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.637％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.637%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表9。The stability data is shown in Table 9.
实施例41Example 41
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
处方：prescription:
Figure PCTCN2015100130-appb-000052
Figure PCTCN2015100130-appb-000052
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.741％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.741%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表9。The stability data is shown in Table 9.
实施例42Example 42
环丝氨酸占总量64.1％，环丝氨酸含量99.713％，环丝氨酸与辅料一起流化床制粒60～80目，溶剂为乙醇，粘合剂用量占总量1.0％，粘合剂为聚乙烯吡咯烷酮K30。Cycloserine accounted for 64.1% of total, cycloserine content was 99.713%, cycloserine was mixed with excipients for fluidized bed granulation of 60-80 mesh, solvent was ethanol, binder content was 1.0% of total, and binder was polyvinylpyrrolidone. K30.
处方：prescription:
Figure PCTCN2015100130-appb-000053
Figure PCTCN2015100130-appb-000053
Figure PCTCN2015100130-appb-000054
Figure PCTCN2015100130-appb-000054
制备方法：Preparation:
将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液，将处方量的环丝氨酸过100目筛，再与滑石粉混匀，置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒，并在流化状态下进行干燥，过60目到80目筛整粒，再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。The prescription amount of polyvinylpyrrolidone K30 is configured as an ethanol solution of polyvinylpyrrolidone K30, and the prescribed amount of cycloserine is passed through a 100 mesh sieve, and then mixed with talc powder, and placed in a fluidized bed to spray polyvinylpyrrolidone K30 ethanol solution. The granules were wetted and dried in a fluidized state, and the granules were sieved through a 60-mesh to 80-mesh sieve, and the granulated granules were filled with a No. 1 gelatin hollow capsule in a capsule containing 250 mg of cycloserine per capsule.
上述方法制备的胶囊，其干燥失重为0.608％，在水中崩解时间为4分钟，在pH 1.2、pH 4.0、pH 6.8以及水中的15分钟的溶出度均大于90％。The capsule prepared by the above method had a loss on drying of 0.608%, a disintegration time in water of 4 minutes, and a dissolution rate of more than 90% in pH 1.2, pH 4.0, pH 6.8, and water for 15 minutes.
稳定性数据见表9。The stability data is shown in Table 9.
表9Table 9
Figure PCTCN2015100130-appb-000055
Figure PCTCN2015100130-appb-000055
本发明实施例制备得到的药物组合物可应用于制备治疗结核杆菌引起的肺结核的药物中。还可以应用于制备治疗精神病、抑郁症、阿尔茨海默病或慢性疼痛的药物中应用。The pharmaceutical composition prepared by the embodiment of the invention can be applied to the preparation of a medicament for treating tuberculosis caused by Mycobacterium tuberculosis. It can also be applied to the preparation of a medicament for treating psychosis, depression, Alzheimer's disease or chronic pain.
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-described embodiments may be arbitrarily combined. For the sake of brevity of description, all possible combinations of the technical features in the above embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be considered as the scope of this manual.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。 The above-described embodiments are merely illustrative of several embodiments of the present invention, and the description thereof is more specific and detailed, but is not to be construed as limiting the scope of the invention. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

Claims (10)

  1. 一种药物组合物，其特征在于，该药物组合物包括环丝氨酸和辅料，所述的药物组合物的D90粒径为75～380μm，所述辅料的用量占药物组合物总质量的9～45％。A pharmaceutical composition comprising cycloserine and an auxiliary material, wherein the pharmaceutical composition has a D 90 particle size of 75 to 380 μm, and the auxiliary material is used in an amount of 9 to ～ of the total mass of the pharmaceutical composition. 45%.
  2. 根据权利要求1所述的药物组合物，其特征在于，所述辅料包括滑石粉，以及粘合剂和/或可压性辅料。The pharmaceutical composition according to claim 1, wherein the excipient comprises talc, and a binder and/or a compressible excipient.
  3. 根据权利要求2所述的药物组合物，其特征在于，所述滑石粉的用量占药物组合物总量的9～45％，所述粘合剂的用量占药物组合物总质量的0～6％，所述可压性辅料的用量占药物组合物总质量的0～16％。The pharmaceutical composition according to claim 2, wherein the talc is used in an amount of 9 to 45% by weight based on the total amount of the pharmaceutical composition, and the binder is used in an amount of 0 to 6 based on the total mass of the pharmaceutical composition. %, the compressible adjuvant is used in an amount of from 0 to 16% by weight based on the total mass of the pharmaceutical composition.
  4. 根据权利要求2或3所述的药物组合物，其特征在于，所述辅料包括滑石粉和粘合剂，所述滑石粉的用量占药物组合物总质量的23～38％，所述粘合剂的用量占药物组合物总质量的0.05～2％。The pharmaceutical composition according to claim 2 or 3, wherein the adjuvant comprises talc and a binder, and the talc is used in an amount of from 23 to 38% by weight based on the total mass of the pharmaceutical composition. The amount of the agent is from 0.05 to 2% by weight based on the total mass of the pharmaceutical composition.
  5. 根据权利要求2或3所述的药物组合物，其特征在于，所述辅料包括滑石粉和可压性辅料，所述滑石粉的用量占药物组合物总质量的23～38％，所述可压性辅料的用量占药物组合物总质量的8～14％。The pharmaceutical composition according to claim 2 or 3, wherein the auxiliary material comprises talc powder and a compressible auxiliary material, and the talc powder is used in an amount of 23 to 38% by mass of the total mass of the pharmaceutical composition. The amount of the pressure-sensitive auxiliary material is from 8 to 14% of the total mass of the pharmaceutical composition.
  6. 根据权利要求2或3所述的药物组合物，其特征在于，所述粘合剂选自聚乙烯吡咯烷酮、羟丙甲纤维素、羟丙纤维素、乙基纤维素、甲基纤维素、羧甲基纤维素钠、羟乙纤维素、糊精中一种或几种；所述可压性辅料选自乳糖、淀粉、磷酸氢钙、微晶纤维素、甘露醇、糊精中一种或几种。The pharmaceutical composition according to claim 2 or 3, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, ethylcellulose, methylcellulose, and carboxylate. One or more of methyl cellulose sodium, hydroxyethyl cellulose, dextrin; the compressible auxiliary material is selected from the group consisting of lactose, starch, calcium hydrogen phosphate, microcrystalline cellulose, mannitol, dextrin or Several.
  7. 根据权利要求2或3所述的药物组合物，其特征在于，该药物组合物的剂型为胶囊剂，所述胶囊剂的空心胶囊为明胶空心胶囊或羟丙甲纤维素空心胶囊，所述空心胶囊的干燥失重<15.0％。The pharmaceutical composition according to claim 2 or 3, wherein the pharmaceutical composition is in the form of a capsule, and the hollow capsule of the capsule is a gelatin hollow capsule or a hypromellose hollow capsule, the hollow The weight loss of the capsule was <15.0%.
  8. 权利要求1～7任一项所述的药物组合物的制备方法，其特征在于，包括如下步骤：The method for preparing a pharmaceutical composition according to any one of claims 1 to 7, which comprises the steps of:
    将D90粒径为75～380μm的环丝氨酸与辅料按所述质量百分比混合均匀，即得所述药物组合物；The cycloserine having a D 90 particle size of 75-380 μm and the auxiliary material are uniformly mixed according to the mass percentage, thereby obtaining the pharmaceutical composition;
    或，将环丝氨酸与辅料按所述质量百分比混合，然后进行湿法制粒、干法制粒或流化床制粒，干燥，过筛整粒，即得所述药物组合物；Or, the cycloserine and the auxiliary material are mixed according to the mass percentage, and then subjected to wet granulation, dry granulation or fluidized bed granulation, dried, and sieved to obtain the pharmaceutical composition;
    或，将辅料进行湿法制粒、干法制粒或流化床制粒，干燥，过筛整粒，得D90粒径为75～380μm的辅料颗粒，再与D90粒径为75～380μm的环丝氨酸按所述质量百分比进行混合，即得所述药物组合物。Or the auxiliary wet granulation, dry granulation or fluidized bed granulation, dried and sieved and sieved to give the particle D 90 particle size of 75 ~ 380μm excipients, and then the D 90 particle size of 75 ~ 380μm is The cycloserine is mixed in the above percentage by mass to obtain the pharmaceutical composition.
  9. 根据权利要求8所述的制备方法，其特征在于，所述药物组合物的干燥失重介于0.2～2％之间，D90粒径介于120～380μm。The preparation method according to claim 8, wherein the pharmaceutical composition has a loss on drying of between 0.2 and 2% and a D 90 particle size of from 120 to 380 μm.
  10. 权利要求1～7任一项所述的药物组合物在制备治疗结核杆菌引起的肺结核，精神病，抑郁症，阿尔茨海默病或慢性疼痛的药物中的应用。 Use of the pharmaceutical composition according to any one of claims 1 to 7 for the preparation of a medicament for treating tuberculosis, psychosis, depression, Alzheimer's disease or chronic pain caused by Mycobacterium tuberculosis.
PCT/CN2015/100130 2015-12-22 2015-12-31 Pharmaceutical composition, preparation method and application thereof WO2017107242A1 (en)

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