Pharmaceutical composition and its preparation method and applicationTechnical field
The present invention relates to technical field of medicine, particularly relate to a kind of pharmaceutical composition and its preparation method and application.
Background technology
Pulmonary tuberculosis is a kind of disease affecting people's health in tuberculosis, along with the appearance of the anti-tuberculosis drugs such as streptomycin and isoniazid, makes pulmonary tuberculosis become a kind of treatable disease.But due to the deficiency of relevant knowledge and the lack of standardization for the treatment of, make Mycobacterium tuberculosis drug-resistant more and more serious.
Pulmonary tuberculosis is the disease that a kind of infectiousness caused by tubercule bacillus is stronger.Three kinds that determine in World Health Organization (WHO) need in the disease of priority control, and pulmonary tuberculosis is only second to acquired immune deficiency syndrome (AIDS).China is the serious country of Pulmonary Tuberculosis, and in addition along with the drug resistance of tubercule bacillus, the drug resistance patient of China is also in continuous increase.Therefore the medicine, the particularly medicine of tuberculosis drug resistance of exploitation treating pulmonery tuberculosis disease are very necessary.
Although the effect of the anti-mycobacterium tuberculosis of cycloserine is more weak than streptomycin, it not easily produces drug resistance.So cycloserine is mainly used in the pulmonary tuberculosis that treatment drug resistance tubercule bacillus causes.
Cycloserine, except the infection being used for the treatment of tubercule bacillus and causing, can also be used for the treatment of other some diseases.US Patent No. 2014018349, World Intellectual Property Organization WIPO patent WO2008118785, European patent EP 2338482 and European patent EP 0378134 all disclose the treatment that cycloserine can be used for psychosis, depression or Alzheimer.US Patent No. 2014213621 discloses the treatment that cycloserine can be used for chronic pain.
All there is the granted listing of the product of cycloserine in the U.S., Europe, Japan and China, be used for the treatment of the pulmonary tuberculosis that tubercule bacillus causes.
The preparation mainly rapid release class preparation of the existing cycloserine emerged, its compositions particle diameter is very little, D90granularity is less than 64 μm, the stability of preparation is poor, in acceleration environment (temperature 40 DEG C, humidity 75%) lower seal stores 40 days, the percentage composition of preparation labelled amount drops to 43.3% from 99.1%, accelerating 40 days degradation amounts is 56.3%, and acceleration environment lower seal stores 180 days, and principal agent is almost all degraded.Store 180 days at normal temperature condition (temperature 25 DEG C, humidity 60%) lower seal, the percentage composition of preparation labelled amount drops to 86.4% from 99.1%, and normal temperature condition 180 days degradation amounts are 12.8%.Because preparation is more unstable, the safety of therapeutic effect and use therefore can be affected.
Russ P RU2248205 discloses and in cycloserine, adds some filleies and be filled in capsule, and improve the mobility of capsule 's content and the stability of preparation, the filler wherein added is Calcium Phosphate, Dibasic Dihydrate, micropowder silica gel and calcium stearate mainly.This capsule adds Calcium Phosphate, Dibasic Dihydrate to improve the mobility of capsule 's content, but due to the frictional force comparatively easy abrasion machine of die of Calcium Phosphate, Dibasic Dihydrate, even causes the problem that powder variable color is fast for a long time.This patent does not have concrete detection numerical value to show the situation of its stability, according to the preparation that this patent prescription is obtained, its stability is still poor, in acceleration environment (temperature 40 DEG C, humidity 75%) lower seal stores 180 days, the percentage composition of preparation labelled amount drops to 65.4% from 99.3%, and accelerating 180 days degradation amounts is 34.1%.Store 180 days at normal temperature condition (temperature 25 DEG C, humidity 60%) condition lower seal, the percentage composition of preparation labelled amount drops to 94.8% from 99.3%, and normal temperature condition 180 days degradation amounts are 4.5%.This prescription finds the problem that there is content variable color in stability test in addition, reason may bring content into the metal particle in die wear, and then make effective ingredient accelerated degradation relevant, this patent does not solve the bad problem of this type of variety stability, does not find that there is the patent of open raising cycloserine preparation stability yet.
Therefore, need in the market to develop a kind of stability better cycloserine preparation to meet clinical demand.
Summary of the invention
Based on this, the object of this invention is to provide a kind of pharmaceutical composition of cycloserine of good stability.
Concrete technical scheme is as follows:
A kind of pharmaceutical composition, this pharmaceutical composition comprises cycloserine and adjuvant, the D of described pharmaceutical composition90particle diameter is 75 ~ 380 μm, and the consumption of described adjuvant accounts for 9 ~ 45% of pharmaceutical composition gross mass.
Wherein in some embodiments, described adjuvant comprises Pulvis Talci, and binding agent and/or compressibility adjuvant.
Wherein in some embodiments, described talcous consumption accounts for 9 ~ 45% of pharmaceutical composition total amount, and the consumption of described binding agent accounts for 0 ~ 6% of pharmaceutical composition gross mass, and the consumption of described compressibility adjuvant accounts for 0 ~ 16% of pharmaceutical composition gross mass.
Wherein in some embodiments, described adjuvant comprises Pulvis Talci and binding agent, and described talcous consumption accounts for 23 ~ 38% of pharmaceutical composition gross mass, and the consumption of described binding agent accounts for 0.05 ~ 2% of pharmaceutical composition gross mass.
Wherein in some embodiments, described adjuvant comprises Pulvis Talci and compressibility adjuvant, and described talcous consumption accounts for 23 ~ 38% of pharmaceutical composition gross mass, and the consumption of described compressibility adjuvant accounts for 8 ~ 14% of pharmaceutical composition gross mass.
Wherein in some embodiments, described binding agent is selected from one or more in polyvinylpyrrolidone, hypromellose, hyprolose, ethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, hyetellose, dextrin; Described compressibility adjuvant is selected from one or more in lactose, starch, calcium hydrogen phosphate, microcrystalline Cellulose, mannitol, dextrin.
Wherein in some embodiments, the dosage form of this pharmaceutical composition is capsule, and the Capsules of described capsule is gelatin hollow capsule or hypromellose Capsules, the loss on drying <15.0% of described Capsules.
Another object of the present invention is to provide the preparation method of aforementioned pharmaceutical compositions.
Concrete technical scheme is as follows:
The preparation method of aforementioned pharmaceutical compositions, comprises the steps:
By D90particle diameter is that the cycloserine of 75 ~ 380 μm is mixed homogeneously by described mass percent with adjuvant, obtains described pharmaceutical composition;
Or mixed by described mass percent with adjuvant by cycloserine, then carry out wet granulation, dry granulation or fluidized bed granulation, dry, sieve granulate, obtains described pharmaceutical composition;
Or adjuvant is carried out wet granulation, dry granulation or fluidized bed granulation, and dry, sieve granulate, obtains D90particle diameter is the granules of accessories of 75 ~ 380 μm, then with D90particle diameter is that the cycloserine of 75 ~ 380 μm mixes by described mass percent, obtains described pharmaceutical composition.
Wherein in some embodiments, the loss on drying of described pharmaceutical composition is between 0.2 ~ 2%, D90particle diameter is between 120 ~ 380 μm.
Another object of the present invention is to provide the application of aforementioned pharmaceutical compositions.
Concrete technical scheme is as follows:
The application of aforementioned pharmaceutical compositions in the phthisical medicine that causes of preparation treatment tubercule bacillus.
Aforementioned pharmaceutical compositions is applied in the medicine of preparation treatment psychosis, depression, Alzheimer or chronic pain.
Principle of the present invention and advantage as follows:
The present invention is directed to the deficiencies in the prior art, a kind of pharmaceutical composition of cycloserine is provided, specifically a kind of rapid release class capsule containing cycloserine.
Current cycloserine preparation mainly capsule, but the less stable of its preparation, in normal temperature condition (temperature 25 DEG C, humidity 60%) and acceleration environment (40 DEG C, humidity 75%) under the degraded of preparation principal agent all very fast, affect the curative effect of preparation and the safety of use.
The present invention not only increases by the particle diameter (and then improve pharmaceutical composition particle diameter) that improves adjuvant and the amount of loss on drying that controls pharmaceutical composition the speed that preparation discharges, and drastically increases the stability of preparation.
The D of pharmaceutical composition of the present invention90particle diameter is between 75 ~ 380 μm, and loss on drying is between 0.2 ~ 2%.
Cycloserine by adding adjuvant in cycloserine, or is combined the mode of granulation, by the D of pharmaceutical composition by pharmaceutical composition of the present invention with adjuvant90size controlling, at 75 ~ 380 μm, not only makes capsule 's content have good mobility and lubricity, also improves the rate of release of preparation and the stability of preparation.Adjuvant in prescription mainly Pulvis Talci, and binding agent and/or compressibility adjuvant.
The dosage form of pharmaceutical composition of the present invention is capsule, and the Capsules of described capsule is gelatin hollow capsule or hypromellose Capsules, the loss on drying <15.0% of described Capsules.
The stability of pharmaceutical composition of the present invention compared with prior art has larger lifting, optimum example is in normal temperature condition (temperature 25 DEG C, humidity 60%) lower seal stores 180 days, the degradation amount <0.5% of the percentage composition of preparation labelled amount, acceleration environment (40 DEG C, humidity 75%) lower seal stores 180 days, the degradation amount <4.0% of the percentage composition of preparation labelled amount.
Detailed description of the invention
By the following examples the present invention is further elaborated.
Comparative example 1
Cycloserine accounts for total amount 90.9%, cycloserine content 99.713%, Pulvis Talci 325 order (particle diameter 44 μm).
Prescription:
Preparation method:
200 mesh sieves crossed by the cycloserine getting recipe quantity, and Pulvis Talci that is rear and recipe quantity mixes, and fills No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.769%, and in water, disintegration time is 5 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 1.
Comparative example 2
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, Pulvis Talci 325 order.
Prescription:
Preparation method:
200 mesh sieves crossed by the cycloserine getting recipe quantity, and Pulvis Talci that is rear and recipe quantity mixes, and fills No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.521%, and in water, disintegration time is 5 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 1.
Comparative example 3
Cycloserine accounts for total amount 55.6%, cycloserine content 99.713%, Pulvis Talci 325 order.
Prescription:
Preparation method:
200 mesh sieves crossed by the cycloserine getting recipe quantity, and Pulvis Talci that is rear and recipe quantity mixes, and fills No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.672%, and in water, disintegration time is 5 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 1.
Comparative example 4
Cycloserine accounts for total amount 64.1%, cycloserine content 99.668%, Pulvis Talci 325 order.
Prescription:
Preparation method:
200 mesh sieves crossed by the cycloserine getting recipe quantity, and Pulvis Talci that is rear and recipe quantity mixes, and fills No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.530%, and in water, disintegration time is 5 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 1.
Table 1
Embodiment 5
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, Pulvis Talci 200 order (particle diameter 75 μm).
Prescription:
Preparation method:
200 mesh sieves crossed by the cycloserine getting recipe quantity, and Pulvis Talci that is rear and recipe quantity mixes, and fills No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.496%, and in water, disintegration time is 5 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 2.
Embodiment 6
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, Pulvis Talci 200 order.
Prescription:
Preparation method:
100 mesh sieves crossed by the cycloserine getting recipe quantity, and Pulvis Talci that is rear and recipe quantity mixes, and fills No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.583%, and in water, disintegration time is 5 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 2.
Embodiment 7
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, Pulvis Talci 100 order (particle diameter 150 μm).
Prescription:
Preparation method:
100 mesh sieves crossed by the cycloserine getting recipe quantity, and Pulvis Talci that is rear and recipe quantity mixes, and fills No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.578%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 2.
Embodiment 8
Cycloserine accounts for total amount 64.1%, cycloserine content 99.619%, Pulvis Talci 100 order.
Prescription:
Preparation method:
100 mesh sieves crossed by the cycloserine getting recipe quantity, and Pulvis Talci that is rear and recipe quantity mixes, and fills No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.544%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 2.
Table 2
Embodiment 9
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 100 order of wet granulation, and solvent is water, and binding agent accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The Pulvis Talci of recipe quantity and PVP K30 are mixed, add appropriate water soft material, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, crosses 100 mesh sieve granulate, obtains the granules of accessories after granulation by dried granule.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 1.201%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 10
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and adjuvant 60 order (particle diameter 250 μm) of wet granulation, solvent is water, and binding agent accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The Pulvis Talci of recipe quantity and PVP K30 are mixed, add appropriate water soft material, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, crosses 60 mesh sieve granulate, obtains the granules of accessories after granulation by dried granule.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 1.015%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 11
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 order of wet granulation, and solvent is water, and binding agent accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The Pulvis Talci of recipe quantity and PVP K30 are mixed, add appropriate water soft material, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, crosses 60 mesh sieve granulate, obtains the granules of accessories after granulation by dried granule.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 2.183%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 12
Cycloserine accounts for total amount 90.9%, cycloserine content 99.713%, and adjuvant 40 order (particle diameter 380 μm) of wet granulation, solvent is water, and binding agent accounts for total amount 0.25%, and binding agent is PVP K30.
Prescription:
Preparation method:
The Pulvis Talci of recipe quantity and PVP K30 are mixed, add appropriate water soft material, rear mistake 20 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, crosses 40 mesh sieve granulate, obtains the granules of accessories after granulation by dried granule.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.627%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 13
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 order of wet granulation, and solvent is ethanol, and binding agent accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The Pulvis Talci of recipe quantity and PVP K30 are mixed, add appropriate ethanol soft material, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, crosses 60 mesh sieve granulate, obtains the granules of accessories after granulation by dried granule.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.756%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 14
Cycloserine accounts for total amount 55.6%, cycloserine content 99.713%, adjuvant 60 order of wet granulation, and solvent is ethanol, and binding agent accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The Pulvis Talci of recipe quantity and PVP K30 are mixed, add appropriate ethanol soft material, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, crosses 60 mesh sieve granulate, obtains the granules of accessories after granulation by dried granule.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.701%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 15
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 ~ 80 order of fluidized bed granulation, and solvent is ethanol, and binding agent accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to PVP K30 alcoholic solution, the Pulvis Talci of recipe quantity is placed in fluid bed spray and adds PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, the cycloserine of recipe quantity is crossed after 100 mesh sieves with granulate after auxiliary materials and mixing, then fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.723%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 16
Cycloserine accounts for total amount 64.1%, cycloserine content 99.474%, adjuvant 60 order of wet granulation, and solvent is ethanol, and binding agent accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to PVP K30 alcoholic solution, add the Pulvis Talci soft material of recipe quantity again, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, dried granule is crossed 60 mesh sieve granulate, obtain the granules of accessories after granulation.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.635%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 17
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 order of wet granulation, and solvent is ethanol, and binding agent accounts for total amount 0.1%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to PVP K30 alcoholic solution, add the Pulvis Talci soft material of recipe quantity again, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, dried granule is crossed 60 mesh sieve granulate, obtain the granules of accessories after granulation.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.697%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 18
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 order of wet granulation, and solvent is ethanol, and binding agent accounts for total amount 3%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to PVP K30 alcoholic solution, add the Pulvis Talci soft material of recipe quantity again, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, dried granule is crossed 60 mesh sieve granulate, obtain the granules of accessories after granulation.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.640%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 19
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 40 order of wet granulation, and solvent is ethanol, and binding agent accounts for total amount 6%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to PVP K30 alcoholic solution, add the Pulvis Talci soft material of recipe quantity again, rear mistake 20 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, dried granule is crossed 40 orders (particle diameter 380 μm) sieve, obtain the granules of accessories after granulation.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.814%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 20
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 order of wet granulation, and solvent is water, and binding agent accounts for total amount 1.0%, and binding agent is hypromellose E5.
Prescription:
Preparation method:
The Pulvis Talci of recipe quantity and hypromellose E5 are mixed, add appropriate water soft material, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, crosses 60 mesh sieve granulate, obtains the granules of accessories after granulation by dried granule.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.558%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Embodiment 21
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 order of wet granulation, and solvent is water, and binding agent accounts for total amount 1.0%, and binding agent is hyprolose MF.
Prescription:
Preparation method:
The Pulvis Talci of recipe quantity and hyprolose MF are mixed, add appropriate water soft material, rear mistake 40 mesh sieve wet granular, dry 2h at being placed in 60 DEG C, crosses 60 mesh sieve granulate, obtains the granules of accessories after granulation by dried granule.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.679%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 3.
Table 3
Embodiment 22
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 order of dry granulation, and compressibility supplementary product consumption accounts for total amount 10%, and compressibility adjuvant is Lactis Anhydrous.
Prescription:
Preparation method:
By dry granulation after the Pulvis Talci of recipe quantity and Lactis Anhydrous mixing, make 60 object granules of accessories.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 1.215%, and in water, disintegration time is 5 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 4.
Embodiment 23
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 order of dry granulation, and compressibility supplementary product consumption accounts for total amount 16%, and compressibility adjuvant is Lactis Anhydrous.
Prescription:
Preparation method:
By dry granulation after the Pulvis Talci of recipe quantity and Lactis Anhydrous mixing, make 60 object granules of accessories.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 1.153%, and in water, disintegration time is 5 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 4.
Embodiment 24
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, adjuvant 60 order of dry granulation, and compressibility supplementary product consumption accounts for total amount 10%, and compressibility adjuvant is starch.
Prescription:
Preparation method:
By dry granulation after the Pulvis Talci of recipe quantity and starch mixing, make 60 object granules of accessories.The cycloserine of recipe quantity is crossed 100 mesh sieves, then with granulate after auxiliary materials and mixing, fill No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 1.589%, and in water, disintegration time is 5 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 4.
Table 4
Embodiment 25
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is dry granulation 60 order together with adjuvant, and compressibility supplementary product consumption accounts for total amount 0%.
Prescription:
Preparation method:
The cycloserine of recipe quantity is crossed 100 mesh sieves, then dry granulation after mixing with Pulvis Talci, make 60 object granules, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.637%, and in water, disintegration time is 14 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all less than 70%.
Stability data is in table 5.
Embodiment 26
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is dry granulation 60 order together with adjuvant, and compressibility supplementary product consumption accounts for total amount 10%, and compressibility adjuvant is Lactis Anhydrous.
Prescription:
Preparation method:
The cycloserine of recipe quantity is crossed 100 mesh sieves, then dry granulation after mixing with Pulvis Talci and Lactis Anhydrous, make 60 object granules, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.985%, and in water, disintegration time is 9 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 85%.
Stability data is in table 5.
Embodiment 27
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is dry granulation 60 order together with adjuvant, and compressibility supplementary product consumption accounts for total amount 10%, and compressibility adjuvant is starch.
Prescription:
Preparation method:
The cycloserine of recipe quantity is crossed 100 mesh sieves, then dry granulation after mixing with Pulvis Talci and starch, make 60 object granules, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 1.122%, and in water, disintegration time is 12 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all less than 85%.
Stability data is in table 5.
Table 5
Embodiment 28
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is wet granulation 60 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 0%.
Prescription:
Preparation method:
The cycloserine of recipe quantity is crossed 100 mesh sieves, appropriate ethanol soft material is added after mixing with Pulvis Talci again, cross 40 mesh sieve wet granulars, dry 2h at being placed in 60 DEG C, dried granule is crossed 60 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.667%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 6.
Embodiment 29
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is wet granulation 60 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, add the PVP K30 alcoholic solution configured again, stir evenly soft material processed, after 40 mesh sieve wet granulars, dry 2h at being placed in 60 DEG C, again the granule of drying is crossed 60 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.784%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 6.
Table 6
Embodiment 30 (preferred embodiment)
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.532%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 7.
Embodiment 31
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 6.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.661%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 7.
Embodiment 32
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is water, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the aqueous solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 aqueous solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.620%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 7.
Embodiment 33
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, solvent is ethanol, binder dosage accounts for total amount 3.0%, and binding agent is PVP K30, and the loss on drying of gelatin hollow capsule is 13.6%.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.568%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 7.
Embodiment 34
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, solvent is ethanol, binder dosage accounts for total amount 3.0%, and binding agent is PVP K30, and the loss on drying of gelatin hollow capsule is 16.8%.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.699%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 7.
Embodiment 35 (preferred embodiment)
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, solvent is ethanol, binder dosage accounts for total amount 3.0%, and binding agent is PVP K30, and the loss on drying of hypromellose Capsules is 2.2%.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 hypromellose Capsules by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.762%, and in water, disintegration time is 8 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 85%.
Stability data is in table 7.
Table 7
Embodiment 36
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.676%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 8.
Embodiment 37
Cycloserine accounts for total amount 64.1%, cycloserine content 99.668%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.804%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 8.
Embodiment 38
Cycloserine accounts for total amount 64.1%, cycloserine content 99.619%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.758%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 8.
Embodiment 39
Cycloserine accounts for total amount 64.1%, cycloserine content 99.474%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.692%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 8.
Table 8
Embodiment 40
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.637%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 9.
Embodiment 41
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.741%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 9.
Embodiment 42
Cycloserine accounts for total amount 64.1%, cycloserine content 99.713%, and cycloserine is fluidized bed granulation 60 ~ 80 order together with adjuvant, and solvent is ethanol, and binder dosage accounts for total amount 1.0%, and binding agent is PVP K30.
Prescription:
Preparation method:
The PVP K30 of recipe quantity is configured to the alcoholic solution of PVP K30, the cycloserine of recipe quantity is crossed 100 mesh sieves, mix with Pulvis Talci again, be placed in fluid bed spray and add PVP K30 alcoholic solution wet granular, and drying is carried out under fluidized state, cross 60 orders to 80 mesh sieve granulate, then the granule after granulating is filled No. 1 gelatin hollow capsule by every capsules containing the specification of cycloserine 250mg.
Capsule prepared by said method, its loss on drying is 0.608%, and in water, disintegration time is 4 minutes, and the dissolution of 15 minutes in pH1.2, pH4.0, pH6.8 and water is all greater than 90%.
Stability data is in table 9.
Table 9
The pharmaceutical composition that the embodiment of the present invention prepares can be applicable to prepare in the phthisical medicine that causes for the treatment of tubercule bacillus.Can also be applied in the medicine of preparation treatment psychosis, depression, Alzheimer or chronic pain and apply.
Each technical characteristic of the above embodiment can combine arbitrarily, for making description succinct, the all possible combination of each technical characteristic in above-described embodiment is not all described, but, as long as the combination of these technical characteristics does not exist contradiction, be all considered to be the scope that this description is recorded.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be construed as limiting the scope of the patent.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.