CN107510664B - Levo-oxiracetam particle and preparation method thereof - Google Patents
Levo-oxiracetam particle and preparation method thereof Download PDFInfo
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- CN107510664B CN107510664B CN201610424868.3A CN201610424868A CN107510664B CN 107510664 B CN107510664 B CN 107510664B CN 201610424868 A CN201610424868 A CN 201610424868A CN 107510664 B CN107510664 B CN 107510664B
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- oxiracetam
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- 229960001227 oxiracetam Drugs 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title abstract description 37
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 17
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 13
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 12
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 12
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- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 claims abstract description 10
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 5
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- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 18
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- YIKYNHJUKRTCJL-UHFFFAOYSA-N Ethyl maltol Chemical compound CCC=1OC=CC(=O)C=1O YIKYNHJUKRTCJL-UHFFFAOYSA-N 0.000 description 1
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
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- 238000007917 intracranial administration Methods 0.000 description 1
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- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
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- 239000002664 nootropic agent Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 238000005070 sampling Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
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- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The levo-oxiracetam particle is characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.5-1.0 part of L-cysteine, 0.7-1.3 parts of mannitol, 0.5-1.2 parts of microcrystalline cellulose, 1.0-1.5 parts of sodium carboxymethylcellulose, 1.1-1.5 parts of lactose, 0.12-0.16 part of talcum powder, 40000.6-1.2 parts of polyethylene glycol, 0.7-1.3 parts of hydroxypropyl methylcellulose and 8-15 parts of starch slurry with the mass volume fraction of 6-8%; the addition of impurities in the preparation process of the prepared levo-oxiracetam particles is small, the addition is only 0.03%, the powder layer amount of the product is small, the particle size is uniform, the fluidity is good, the repose angle is less than 37 degrees, the loading difference is less than 5%, the stability in the storage process is good, the product is not easy to absorb moisture and agglomerate, and the shelf life of the product is as long as 24 months.
Description
Technical Field
The invention mainly relates to the technical field of pharmacy, and in particular relates to a levo-oxiracetam particle and a preparation method thereof.
Background
Oxiracetam (oxiracetam, CAS No.: 62613-82-5) has the chemical name of 4-hydroxy-2-oxo-1-pyrrolidine acetamide, is an anti-hypoxia nootropic drug (the compound is disclosed in US4118396) which is synthesized for the first time in 1974 by ISFS. P.A. company of Italy, is a cyclic GABOB derivative, can promote the synthesis of phosphorylcholine and phosphorylethanolamine, promote brain metabolism, penetrate blood brain barrier, has stimulation effect on specific central nervous pathways, can improve intelligence and memory, has better curative effect on cerebrovascular diseases, brain trauma, brain tumor, intracranial infection, brain degeneration diseases and the like, and has extremely low toxicity, no mutagenic effect, carcinogenic effect and reproductive toxicity. The chemical structure and preparation of oxiracetam is disclosed in US4118396 by Giorgio et al, and the pharmaceutical efficacy of oxiracetam in the S configuration (levo) is shown in the clinical results in WO9306826A by Chiodini et al, which is stronger than that in the R configuration (dextro), with oxiracetam and levooxiracetam structures shown below.
The existing oxiracetam particles mainly have the technical problems of large impurity increase, more particle powder layers, difficult control of particle size, poor stability in the storage process, strong hygroscopicity of the particles, easy adhesion of connecting blocks, short shelf life and the like in the preparation process.
Disclosure of Invention
The invention aims to provide the levorotatory oxiracetam particles with controllable particle size and good stability.
The invention also aims to provide a preparation method of the levo-oxiracetam particles.
The aim of the invention is realized by the following technical measures:
the levo-oxiracetam granules with good stability are characterized by being prepared by taking levo-oxiracetam as a raw material and adding a certain amount of filler, flavoring agent, adhesive, lubricant and coating material; wherein the filler is one or more of starch, lactose, dextrin, sugar powder, calcium sulfate, sucrose, mannitol, microcrystalline cellulose, glucose, sodium carboxymethylcellulose, and L-cysteine; the flavoring agent is one or more of sucrose, maltose, ethyl maltol, sucralose, stevioside, sorbitol, mannitol, glucose and aspartame; the adhesive is one or more of water, ethanol, sucrose, starch slurry, dextrin, carboxymethyl cellulose and polyvinylpyrrolidone; the lubricant is one or more of talcum powder, magnesium stearate, polyethylene glycol, stearic acid, calcium stearate, sodium lauryl sulfate, superfine silica powder, magnesium oxide and paraffin; the coating material is one or more of polyethylene glycol 4000, polyethylene glycol 6000, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene acetaldehyde diethylamine ethyl ester, and hydroxypropyl methylcellulose phthalate.
The inventor discovers that the addition of impurities is small in the preparation process of the levo-oxiracetam particles, the product is not easy to absorb moisture, is not easy to adhere to a connecting block, has uniform particle size, small loading difference, good product stability and long shelf life by matching the specific auxiliary material type with the specific formula dosage proportioning relation and matching with a special preparation method; the levo-oxiracetam particle is characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.5-1.0 part of L-cysteine, 0.7-1.3 parts of mannitol, 0.5-1.2 parts of microcrystalline cellulose, 1.0-1.5 parts of sodium carboxymethylcellulose, 1.1-1.5 parts of lactose, 0.12-0.16 part of talcum powder, 40000.6-1.2 parts of polyethylene glycol, 0.7-1.3 parts of hydroxypropyl methylcellulose and 8-15 parts of starch slurry with the mass volume fraction of 6-8%; taking the formula amount of levo-oxiracetam, L-cysteine, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose and lactose, placing the mixture into a universal pulverizer, pulverizing the mixture, sieving the mixture by a 100-mesh sieve, placing the mixture into a wet granulator, adding starch slurry with the mass fraction of 6-8%, starting the granulator (installing a 18-mesh nylon sieve), and starting granulation; putting the wet particles into a fluidized bed, setting the temperature of the hotbed to be 50-70 ℃, and starting drying for 50-55 minutes; taking polyethylene glycol 4000 and hydroxypropyl methylcellulose in the formula amount, and adding water to prepare coating liquid with the mass volume fraction of 8-10% for later use; putting the dry particles into a fluidized bed, and introducing hot air to enable the dry particles to be in suspension fluidization, wherein the bed temperature is 40-50 ℃; atomizing the coating solution through a nozzle of the fluidized bed, continuously adding the coating solution into the fluidized bed, setting the spraying speed to be 50-60 rpm, setting the atomizing pressure to be 0.8-1.0 bar, continuously feeding air for drying, continuously heating for 10-15 minutes after the solution is sprayed, stopping heating, cooling and discharging; placing the coated granules in a crushing and granulating machine, and sieving and granulating by using a 20-mesh sieve; and (3) crushing the talcum powder according to the prescription amount, sieving the crushed talcum powder by a 100-mesh sieve, adding the crushed talcum powder into the granules, and mixing the granules for 10-20 min by a three-dimensional motion mixer to obtain the talcum powder.
In order to further improve the stability of the levorotatory oxiracetam particles and prolong the shelf life, the levorotatory oxiracetam particles are characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.7-0.9 part of L-cysteine, 0.9-1.2 parts of mannitol, 0.7-1.0 part of microcrystalline cellulose, 1.1-1.3 parts of sodium carboxymethylcellulose, 1.2-1.4 parts of lactose, 0.13-0.15 part of talcum powder, 40000.7-1.1 parts of polyethylene glycol, 0.8-1.2 parts of hydroxypropyl methylcellulose and 10-13 parts of starch slurry with the mass volume fraction of 6-8%; taking the formula amount of levo-oxiracetam, L-cysteine, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose and lactose, placing the mixture into a universal pulverizer, pulverizing the mixture, sieving the mixture by a 100-mesh sieve, placing the mixture into a wet granulator, adding starch slurry with the mass fraction of 6-8%, starting the granulator (installing a 18-mesh nylon sieve), and starting granulation; putting the wet particles into a fluidized bed, setting the temperature of the hotbed to be 50-70 ℃, and starting drying for 50-55 minutes; taking polyethylene glycol 4000 and hydroxypropyl methylcellulose in the formula amount, and adding water to prepare coating liquid with the mass volume fraction of 8-10% for later use; putting the dry particles into a fluidized bed, and introducing hot air to enable the dry particles to be in suspension fluidization, wherein the bed temperature is 40-50 ℃; atomizing the coating solution through a nozzle of the fluidized bed, continuously adding the coating solution into the fluidized bed, setting the spraying speed to be 50-60 rpm, setting the atomizing pressure to be 0.8-1.0 bar, continuously feeding air for drying, continuously heating for 10-15 minutes after the solution is sprayed, stopping heating, cooling and discharging; placing the coated granules in a crushing and granulating machine, and sieving and granulating by using a 20-mesh sieve; and (3) crushing the talcum powder according to the prescription amount, sieving the crushed talcum powder by a 100-mesh sieve, adding the crushed talcum powder into the granules, and mixing the granules for 10-20 min by a three-dimensional motion mixer to obtain the talcum powder.
A preparation method of levo-oxiracetam particles is characterized by comprising the following steps:
1. pretreatment of raw materials and auxiliary materials: taking the formula amount of the levo-oxiracetam, the filler and the flavoring agent, placing the mixture into a universal pulverizer, pulverizing the mixture, and sieving the pulverized mixture with a 100-mesh sieve for later use;
2. and (3) granulating: putting the mixed powder obtained after the pretreatment into a wet granulator, adding an adhesive, starting the granulator (a nylon sieve with 18 meshes is installed), and starting granulation;
3. and (3) drying: putting the wet particles into a fluidized bed, setting the temperature of the hotbed to be 50-70 ℃, and starting drying; observing the boiling condition and the blowing condition of the particles at any time, preventing the particles from sticking to the bottom of a pot to cause coking or gelatinization, and ensuring that the moisture of the particles is less than or equal to 3 percent, wherein the drying time is 50-55 minutes;
4. coating:
(1) preparation of coating liquid: taking the coating material according to the prescription amount, and adding water to prepare a solution with the mass volume fraction of 8-10% for later use;
(2) and (3) coating process: putting the dry particles into a fluidized bed, and introducing hot air to enable the dry particles to be in suspension fluidization, wherein the bed temperature is 40-50 ℃; atomizing the coating solution through a nozzle of the fluidized bed, continuously adding the coating solution into the fluidized bed, setting the spraying speed to be 50-60 rpm, setting the atomizing pressure to be 0.8-1.0 bar, continuously feeding air for drying, continuously heating for 10-15 minutes after the solution is sprayed, stopping heating, cooling and discharging to obtain coating particles;
5. finishing and screening: placing the coated granules in a crushing and granulating machine, sieving and granulating by using a 20-mesh sieve, and controlling the environmental temperature to be below 25 ℃ and the relative humidity to be below 50%;
6. total mixing: crushing the lubricant, sieving the crushed lubricant with a 100-mesh sieve, adding the crushed lubricant into the granules, and mixing the mixture for 10 to 20 minutes by using a three-dimensional motion mixer;
7. inner packaging: packaging with a particle packaging machine, setting the packaging specification to be 1 g/bag, and controlling the environmental temperature to be below 25 ℃ and the relative humidity to be below 50% to obtain the product.
The invention has the following beneficial effects:
the addition amount of impurities in the preparation process of the levorotatory oxiracetam particles is small, the addition amount is only 0.03%, the powder layer amount of the product is small, the particle size of the particles is uniform, the fluidity is good, the repose angle is less than 37 degrees, the loading difference is less than 5%, the stability in the storage process is good, the product is not easy to absorb moisture and agglomerate, the shelf life of the product is as long as 24 months, the preparation process is simple and feasible, and the levorotatory oxiracetam particle is worthy of market.
Detailed Description
The present invention is described in detail below by way of examples, it being necessary to note that the following examples are provided only for illustrating the present invention and are not to be construed as limiting the scope of the present invention, and modifications or substitutions of the method, steps or conditions of the present invention may be made without departing from the spirit and spirit of the present invention.
Example 1
The levo-oxiracetam particle is prepared by the following steps:
the preparation process comprises the following steps:
1. pretreatment of raw materials and auxiliary materials: taking the prescribed amount of levo-oxiracetam, L-cysteine, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose and lactose, placing the mixture into a universal pulverizer, pulverizing and sieving with a 100-mesh sieve for later use;
2. and (3) granulating: placing the mixed powder obtained after the pretreatment in a wet granulator, adding starch slurry with the mass fraction of 6%, starting the granulator (a nylon sieve with 18 meshes is installed), and starting granulation;
3. and (3) drying: putting the wet particles into a fluidized bed, setting the temperature of the hotbed to be 50-70 ℃, and starting drying; observing the boiling condition and the blowing condition of the particles at any time, preventing the particles from sticking to the bottom of a pot to cause coking or gelatinization, and ensuring that the moisture of the particles is less than or equal to 3 percent, wherein the drying time is 50-55 minutes;
4. coating:
(1) preparation of coating liquid: taking polyethylene glycol 4000 and hydroxypropyl methylcellulose in the formula amount, and adding water to prepare a solution with the mass volume fraction of 8-10% for later use;
(2) and (3) coating process: putting the dry particles into a fluidized bed, and introducing hot air to enable the dry particles to be in suspension fluidization, wherein the bed temperature is 40-50 ℃; atomizing the coating solution through a nozzle of the fluidized bed, continuously adding the coating solution into the fluidized bed, setting the spraying speed to be 50-60 rpm, setting the atomizing pressure to be 0.8-1.0 bar, continuously feeding air for drying, continuously heating for 10-15 minutes after the solution is sprayed, stopping heating, cooling and discharging to obtain coating particles;
5. finishing and screening: placing the coated granules in a crushing and granulating machine, sieving and granulating by using a 20-mesh sieve, and controlling the environmental temperature to be below 25 ℃ and the relative humidity to be below 50%;
6. total mixing: pulverizing talcum powder, sieving with a 100-mesh sieve, adding the sieved granules, and mixing for 10-20 min by using a three-dimensional motion mixer;
7. inner packaging: packaging with a particle packaging machine, setting the packaging specification to be 1 g/bag, and controlling the environmental temperature to be below 25 ℃ and the relative humidity to be below 50% to obtain the product.
Test one: determination of angle of repose of particles
1. Test materials: example 1 sample after total mixing during preparation
2. The test method comprises the following steps: example 1 after the total mixing was completed, the angle of repose was measured by sampling at each of the upper, middle, lower, left and right points of the three-dimensional motion mixer, and the fluidity was evaluated;
3. and (3) test results:
4. and (4) test conclusion: as can be seen from the test results in the table above, the angle of repose is less than 36 degrees in five measurements, indicating good particle flowability.
And (2) test II: difference in charge
1. Test materials: 10 bags of the granules prepared in example 1 were taken, and the difference in the amount of the granules was checked according to the item of the second appendix of the edition of Chinese pharmacopoeia (2010).
2. The determination method comprises the following steps: taking 10 bags of the test article, respectively weighing the weight of the content in each bag, and comparing the weight of each bag with the marked content.
3. And (3) test results: the results of the charge difference check are shown in the following table:
4. and (4) test conclusion: as can be seen from the test results in the table above, the difference of the loading of the product is less than +/-4%, which proves that the difference of the loading is stable and small.
Experiment three: the influence of the formula of the levorotatory oxiracetam particles on the increase of impurities in the preparation process
1. Experimental materials:
left-handed oxiracetam particle samples: prepared as in example 1.
Levo-oxiracetam control sample: the samples prepared in the absence of L-cysteine based on the formulation of example 1 were prepared according to the same procedure as in example 1.
2. The experimental method comprises the following steps: in the preparation process of embodiment 1, the related substances of the levo-oxiracetam bulk drug and the levo-oxiracetam particle finished product are respectively measured, and the impurity increase condition of the levo-oxiracetam particle in the preparation process is observed. Meanwhile, the prescription of the example 1 lacking L-cysteine is taken as a reference prescription, the preparation method of the example 1 is adopted, the related substances of the levorotatory oxiracetam bulk drug and the levorotatory oxiracetam particle finished product are respectively measured, and the impurity increase condition of the levorotatory oxiracetam particle in the preparation process is observed.
3. The results of the experiment are shown in the following table:
4. and (4) experimental conclusion: the formula of example 1, in combination with a specific preparation method, increases the related substances by only 0.03%, which is significantly better than the control sample.
And (4) testing: stability experiment of levo-oxiracetam particles
Experimental materials:
levo-oxiracetam particles: prepared for example 1.
The accelerated test method comprises the following steps: the levo-oxiracetam particles prepared in example 1 are packaged on the market, put in an acceleration experiment box, sampled for a certain time and inspected on an investigation project.
Accelerated test temperature: 40 +/-2 DEG C
Accelerated test humidity: RH 75% +/-5%
Investigation time: 0. months 1, 2, 3 and 6
And (4) investigation indexes are as follows: property, water content, particle size, solubility, related substances, content, and microbial limit
Recording the stability of the accelerated test:
the results of accelerated experiments show that: the quality of each detection index of the sample in the accelerated 6 months is equivalent to that of the sample in the 0 month, which shows that the product has stable quality and better stability in the accelerated experiment for 6 months.
The long-term experimental method comprises the following steps: the levo-oxiracetam particles prepared in example 1 are packaged on the market, placed in a long-term sample box, sampled for a certain time and inspected on an investigation project.
Long-term experimental temperature: 25 +/-2 DEG C
Humidity of long-term experiment: RH 60% +/-10%
Investigation time: 0. 3, 6, 9, 12, 18, 24 months
And (4) investigation indexes are as follows: property, water content, particle size, solubility, related substances, content, and microbial limit
Long-term test stability recording:
long-term tests show that: the product has no significant change in character, moisture, granularity, dissolubility, related substances, content and microorganism limit after long-term test for 24 months, and all meet the relevant regulations of quality standard draft for production. The product has stable quality for 24 months in long-term test, so the product has a minimum effective period of 24 months, and the long-term test is still in the process of continuous investigation.
Example 2
The levo-oxiracetam particle is prepared by the following steps:
the preparation process comprises the following steps: prepared according to the preparation process of example 1. The test method of the embodiment 1 is used for testing, the testing result of the Huizhijiao test shows that the product has good particle fluidity, the Huizhijiao is lower than 37 degrees, the loading difference test shows that the loading difference of the product is less than 5 percent, the loading of the product is stable and controllable, the stability test result shows that the quality of the sample is stable for 6 months, the quality is stable for 24 months, the effective period of the product is at least 24 months, the effect test result of the product prescription on the impurity increase in the preparation process shows that the impurity increase in the preparation process of the product is small, and related substances in the preparation process are only increased by 0.02 percent.
Example 3
The levo-oxiracetam particle is prepared by the following steps:
the preparation process comprises the following steps: prepared according to the preparation process of example 1. The test method of the embodiment 1 is used for testing, the testing result of the Huizhijiao test shows that the product has good particle fluidity, the Huizhijiao is lower than 35 degrees, the loading difference test shows that the loading difference of the product is less than 4 percent, the loading of the product is stable and controllable, the stability test result shows that the quality of the sample is stable for 6 months, the quality is stable for 24 months, the effective period of the product is at least 24 months, the effect test result of the product prescription on the impurity increase in the preparation process shows that the impurity increase in the preparation process of the product is small, and related substances in the preparation process are only increased by 0.03 percent.
Examples 4 to 6: the levo-oxiracetam particle is prepared from the following raw and auxiliary materials in parts by weight, and the preparation method is the same as that in example 1:
| examples | 4 | 5 | 6 |
| Levo-oxiracetam | 1 part of | 1 part of | 1 part of |
| L-cysteine | 0.9 portion | 0.8 portion of | 0.7 portion of |
| Mannitol | 1.0 part | 1.1 parts of | 1.0 part |
| Microcrystalline cellulose | 0.9 portion | 0.8 portion of | 0.9 portion |
| Sodium carboxymethylcellulose | 1.1 parts of | 1.2 parts of | 1.3 parts of |
| Lactose | 1.4 parts of | 1.3 parts of | 1.2 parts of |
| Talcum powder | 0.13 part | 0.14 part | 0.15 part |
| Polyethylene glycol 4000 | 1.0 part | 0.9 portion | 0.8 portion of |
| Hydroxypropyl methylcellulose | 0.9 portion | 1.0 part | 1.1 parts of |
| Starch slurry with mass fraction of 7% | 11 portions of | 12 portions of | 12 portions of |
The preparation process comprises the following steps: prepared according to the preparation process of example 1. The samples prepared in the examples 4, 5 and 6 are tested according to the test method of the example 1, the results of the testing of the repose angle of the products prepared in the examples 4, 5 and 6 show that the flowability of the particles of the product is good, the repose angle is respectively lower than 37 degrees, 36 degrees and 36 degrees, the difference of the loading of the products prepared in the examples 4, 5 and 6 is less than 5 percent, the loading of the product is stable and controllable, the results of the stability tests of the examples 4, 5 and 6 show that the quality of the sample is stable in 6 months and the quality of the sample is stable in 24 months for a long time, so the effective period of the product is at least 24 months, the influence test results of the formulas of the products prepared in the examples 4, 5 and 6 on the increase of impurities in the preparation process show that the increase of the impurities in the preparation process is small, and the related substances of the samples prepared in the examples 4, 5 and 6.
Claims (3)
1. The levo-oxiracetam particle is characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.5-1.0 part of L-cysteine, 0.7-1.3 parts of mannitol, 0.5-1.2 parts of microcrystalline cellulose, 1.0-1.5 parts of sodium carboxymethylcellulose, 1.1-1.5 parts of lactose, 0.12-0.16 part of talcum powder, 40000.6-1.2 parts of polyethylene glycol, 0.7-1.3 parts of hydroxypropyl methylcellulose and 8-15 parts of starch slurry with the mass volume fraction of 6-8%; taking the formula amount of levo-oxiracetam, L-cysteine, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose and lactose, placing the mixture into a universal pulverizer, pulverizing the mixture, sieving the pulverized mixture with a 100-mesh sieve, placing the pulverized mixture into a wet granulator, adding starch slurry with the mass fraction of 6-8%, starting the granulator provided with an 18-mesh nylon sieve, and starting granulation; putting the wet particles into a fluidized bed, setting the temperature of the hotbed to be 50-70 ℃, and starting drying for 50-55 minutes; taking polyethylene glycol 4000 and hydroxypropyl methylcellulose in a prescription amount, and adding water to prepare coating liquid with the mass volume fraction of 8-10% for later use; putting the dry particles into a fluidized bed, and introducing hot air to enable the dry particles to be in suspension fluidization, wherein the bed temperature is 40-50 ℃; atomizing the coating solution through a nozzle of the fluidized bed, continuously adding the coating solution into the fluidized bed, setting the spraying speed to be 50-60 rpm, setting the atomizing pressure to be 0.8-1.0 bar, continuously feeding air for drying, continuously heating for 10-15 minutes after the solution is sprayed, stopping heating, cooling and discharging; placing the coated granules in a crushing and granulating machine, and sieving and granulating by using a 20-mesh sieve; and (3) crushing the talcum powder according to the formula amount, sieving the crushed talcum powder with a 100-mesh sieve, adding the crushed talcum powder into the whole granules, and mixing the granules for 10-20 min by using a three-dimensional motion mixer.
2. The levo-oxiracetam particle as claimed in claim 1, which is prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.7-0.9 part of L-cysteine, 0.9-1.2 parts of mannitol, 0.7-1.0 part of microcrystalline cellulose, 1.1-1.3 parts of sodium carboxymethylcellulose, 1.2-1.4 parts of lactose, 0.13-0.15 part of talcum powder, 78-1.1 parts of polyethylene glycol 40000.7, 0.8-1.2 parts of hydroxypropyl methylcellulose and 10-13 parts of starch slurry with the mass volume fraction of 6-8%.
3. The process for preparing levo-oxiracetam particles according to claim 1 or 2, characterized in that it is prepared by the following steps:
a, pretreatment of raw and auxiliary materials: taking the prescribed amount of levo-oxiracetam, L-cysteine, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose and lactose, placing the mixture into a universal pulverizer, pulverizing and sieving with a 100-mesh sieve for later use;
b, granulating: putting the mixed powder obtained after the pretreatment into a wet granulator, adding an adhesive, starting the granulator provided with a nylon sieve of 18 meshes, and starting granulation;
c, drying: putting the wet particles into a fluidized bed, setting the temperature of the hotbed to be 50-70 ℃, and starting drying; observing the boiling condition and the blowing condition of the particles at any time, preventing the particles from sticking to the bottom of a pot to cause coking or gelatinization, and ensuring that the moisture of the particles is less than or equal to 3 percent, wherein the drying time is 50-55 minutes;
d, coating:
d, configuring coating liquid: taking polyethylene glycol 4000 and hydroxypropyl methylcellulose in a prescription amount, and adding water to prepare coating liquid with the mass volume fraction of 8-10% for later use;
and D, a coating process: putting the dry particles into a fluidized bed, and introducing hot air to enable the dry particles to be in suspension fluidization, wherein the bed temperature is 40-50 ℃; atomizing the coating solution through a nozzle of the fluidized bed, continuously adding the coating solution into the fluidized bed, setting the spraying speed to be 50-60 rpm, setting the atomizing pressure to be 0.8-1.0 bar, continuously feeding air for drying, continuously heating for 10-15 minutes after the solution is sprayed, stopping heating, cooling and discharging to obtain coating particles;
e, granule finishing and screening, namely putting the coated granules into a crushing and granule finishing machine, sieving and finishing the granules by using a 20-mesh sieve, and controlling the environmental temperature to be below 25 ℃ and the relative humidity to be below 50%;
f, total mixing: crushing talcum powder, sieving with a 100-mesh sieve, adding the crushed talcum powder into the granules, and mixing for 10-20 min by using a three-dimensional motion mixer;
g, inner package: packaging with a particle packaging machine, setting the packaging specification to be 1 g/bag, and controlling the environmental temperature to be below 25 ℃ and the relative humidity to be below 50% to obtain the product.
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| CN101766595A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Solid preparation with levo-oxiracetam as active component |
| CN103599083A (en) * | 2013-12-06 | 2014-02-26 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam slow-release tablet and preparation method thereof |
| CN104739796A (en) * | 2013-12-27 | 2015-07-01 | 重庆东泽医药科技发展有限公司 | An oxiracetam tablet and a preparing method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766595A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Solid preparation with levo-oxiracetam as active component |
| CN103599083A (en) * | 2013-12-06 | 2014-02-26 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam slow-release tablet and preparation method thereof |
| CN104739796A (en) * | 2013-12-27 | 2015-07-01 | 重庆东泽医药科技发展有限公司 | An oxiracetam tablet and a preparing method thereof |
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