CN107510681B - (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof - Google Patents
(S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof Download PDFInfo
- Publication number
- CN107510681B CN107510681B CN201610428283.9A CN201610428283A CN107510681B CN 107510681 B CN107510681 B CN 107510681B CN 201610428283 A CN201610428283 A CN 201610428283A CN 107510681 B CN107510681 B CN 107510681B
- Authority
- CN
- China
- Prior art keywords
- parts
- oxo
- hydroxy
- honey
- particles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles are prepared from the following raw and auxiliary materials: 1 part of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide, 0.7-1.3 parts of L-cysteine, 1.0-1.5 parts of mannitol, 0.7-1.2 parts of microcrystalline cellulose, 0.9-1.5 parts of sodium carboxymethylcellulose, 0.7-1.3 parts of lactose, 0.13-0.18 part of magnesium stearate, 0.78-1.1 part of polyethylene glycol 40000.6, 0.9-1.7 parts of hydroxypropyl methylcellulose, 0.8-1.3 parts of low-substituted hydroxypropyl cellulose, 800.06-0.11 part of polysorbate, 0.5-1.2 parts of honey and 8-13 parts of ethanol solution with the volume fraction of 50-70%; the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles prepared by the invention have small impurity increment in the preparation process, only 0.03 percent of impurity increment, no adhesion of a screen mesh in the granulation process, easy granulation, high product dissolution speed, no more than 30 seconds of total dissolution time, good storage process stability, difficult moisture absorption and agglomeration of products and long shelf life of 24 months.
Description
Technical Field
The invention mainly relates to the technical field of pharmacy, and in particular relates to (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and a preparation method thereof.
Background
The chemical name of the levo-oxiracetam is as follows: the S- (-) -4-hydroxy-2-oxopyrrolidine-N-acetamide is white microcrystalline powder, has a melting point of 135-136 ℃, has an optical rotation of-36 degrees (C ═ 1.00inwater), and has a solubility superior to that of racemate. The chemical structural formula is shown as the following formula:
the drug is marketed in Italy in 1987 in the form of tablets, 800 mg; capsule, 800 mg; injection, 1g/5 ml. At present, only oxiracetam capsules and injection are sold on the market at home, and the main active ingredients are racemes. Lei et al, in patent publication No. CN 103735545A, mention (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide to have obvious effect of promoting wakefulness of coma caused by alcoholism, but dextro-oxiracetam has no effect basically, and the wakefulness promoting effect of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide is 2 times of that of racemic oxiracetam; the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide has obvious effect on promoting awakening of coma caused by trauma and anesthesia. Zhang Feng et al in the patent publication No. CN 103599101A disclose (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide has obvious improvement effect on learning, memory and cognition dysfunction of rats with traumatic brain injury caused by hydraulic pressure and free fall, and the drug effect is far higher than that of dextro oxiracetam. And 200mg/kg of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide is equivalent to 400mg/kg oxiracetam in effect. The results of the pharmacokinetic study showed that: (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide and dexoxiracetam showed no apparent chiral conversion in beagle dogs. There was no significant difference in the major pharmacokinetic parameters of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide in plasma after single i.v. administration of levorotatory and 2-fold doses of racemic oxiracetam to beagle dogs. The test results of safe pharmacology, acute toxicity, long-lasting toxicity and the like show that the toxicity of the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide and oxiracetam to the tested animals or cells is not obviously different under the same dosage level. The research results before clinical application show that (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide is the main active component of oxiracetam with drug effect in vivo, and the product can be used alone to reduce clinical application dosage and reduce potential toxic and side effects.
The existing (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles mainly have the technical problems of obvious impurity increase in the preparation process, easy adhesion of a screen mesh in the granulation process, difficult granulation, poor stability of the product in the storage process, strong hygroscopicity of the particles, easy adhesion of connected blocks, short shelf life, slow dissolution speed of the particles and the like.
Disclosure of Invention
The invention aims to provide (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles which are easy to prepare, high in dissolving speed and good in stability.
Another object of the present invention is to provide a method for preparing the above (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide particles.
The aim of the invention is realized by the following technical measures:
a (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide granule is prepared from (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide as raw material, and filler, correctant, binder, lubricant, disintegrant, 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, polyvinylpyrrolidone and honey; 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 disintegrating agent is one or more of low-substituted hydroxypropyl cellulose, polysorbate 80, sodium carboxymethyl starch and dry starch; 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 reasonable formula proportion of the inventor is matched with a specific preparation method, so that the impurity increment is small in the preparation process of the (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles, the granulation process is easy to granulate, a screen mesh cannot be adhered, the product is not easy to absorb moisture, an adhesive block is not easy to adhere, the stability is good, the shelf life is long, and the dissolving speed is high; the (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles are characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide, 0.7-1.3 parts of L-cysteine, 1.0-1.5 parts of mannitol, 0.7-1.2 parts of microcrystalline cellulose, 0.9-1.5 parts of sodium carboxymethylcellulose, 0.7-1.3 parts of lactose, 0.13-0.18 part of magnesium stearate, 0.78-1.1 part of polyethylene glycol 40000.6, 0.9-1.7 parts of hydroxypropyl methylcellulose, 0.8-1.3 parts of low-substituted hydroxypropyl cellulose, 800.06-0.11 part of polysorbate, 0.5-1.2 parts of honey and 8-13 parts of ethanol solution with the volume fraction of 50-70%; taking honey according to the prescription amount, placing the honey into an iron pan, adding purified water 2 times the weight of the honey, uniformly stirring, heating to 100-105 ℃, preserving heat for 20-25 minutes, taking out, filtering with a 80-mesh sieve, taking filtrate, cooling, adding ethanol according to the prescription amount, stirring and dissolving for later use; putting (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, L-cysteine, mannitol, microcrystalline cellulose, sodium carboxymethyl cellulose, lactose and low-substituted hydroxypropyl cellulose into a universal pulverizer, pulverizing, sieving with a 100-mesh sieve, putting into a wet granulator, adding the pre-treated honey ethanol solution and polysorbate 80, starting the granulator (installing a 24-mesh nylon sieve), and starting granulation; putting the wet granules into a blast drying oven, and setting the drying time at 50-60 ℃ to be 120-150 min to ensure that the water content of the granules is less than or equal to 3 percent (mass percentage); taking polyethylene glycol 4000 and hydroxypropyl methylcellulose in the formula amount, and adding water to prepare coating liquid with the mass fraction of 6-9% 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 ℃; and 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 the coating particles.
Furthermore, in order to further accelerate the dissolution speed of the (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles, improve the stability of the particles and prolong the shelf life; the (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles are characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide, 0.9-1.2 parts of L-cysteine, 1.2-1.4 parts of mannitol, 0.8-1.1 part of microcrystalline cellulose, 1.1-1.3 parts of sodium carboxymethylcellulose, 0.9-1.2 parts of lactose, 0.14-0.17 part of magnesium stearate, 0-1.0 part of polyethylene glycol 40000.8, 1.2-1.5 parts of hydroxypropyl methylcellulose, 0.9-1.2 parts of low-substituted hydroxypropyl cellulose, 800.07-0.09 part of polysorbate, 0.7-1.0 part of honey and 9-12 parts of ethanol solution with the volume fraction of 50-70%; taking honey according to the prescription amount, placing the honey into an iron pan, adding purified water 2 times the weight of the honey, uniformly stirring, heating to 100-105 ℃, preserving heat for 20-25 minutes, taking out, filtering with a 80-mesh sieve, taking filtrate, cooling, adding ethanol according to the prescription amount, stirring and dissolving for later use; putting (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, L-cysteine, mannitol, microcrystalline cellulose, sodium carboxymethyl cellulose, lactose and low-substituted hydroxypropyl cellulose into a universal pulverizer, pulverizing, sieving with a 100-mesh sieve, putting into a wet granulator, adding the pre-treated honey ethanol solution and polysorbate 80, starting the granulator (installing a 24-mesh nylon sieve), and starting granulation; putting the wet granules into a blast drying oven, and setting the drying time at 50-60 ℃ to be 120-150 min to ensure that the water content of the granules is less than or equal to 3 percent (mass percentage); taking polyethylene glycol 4000 and hydroxypropyl methylcellulose in the formula amount, and adding water to prepare coating liquid with the mass fraction of 6-9% 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 ℃; and 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 the coating particles.
A method for preparing (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide particles, comprising the steps of:
1. preparation of the adhesive: taking honey according to the prescription amount, placing the honey into an iron pan, adding purified water 2 times the weight of the honey, uniformly stirring, heating to 100-105 ℃, preserving heat for 20-25 minutes, taking out, filtering with a 80-mesh sieve, taking filtrate, cooling, adding ethanol according to the prescription amount, stirring and dissolving to obtain the honey-water-based composite material;
2. pretreatment of raw materials and auxiliary materials: taking (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, a filler, a flavoring agent and a disintegrating agent according to the prescription amount, putting the mixture into a universal pulverizer, and pulverizing and sieving the mixture by a 100-mesh sieve for later use;
3. and (3) granulating: putting the mixed powder obtained after the pretreatment into a wet granulator, adding an adhesive and polysorbate 80, starting the granulator (a 24-mesh nylon sieve is installed), and starting granulation;
4. and (3) drying: putting the wet granules into a blast drying oven, and setting the drying time at 50-60 ℃ to be 120-150 min to ensure that the water content of the granules is less than or equal to 3 percent (mass percentage);
5. coating:
(1) preparation of coating liquid: taking the coating material according to the prescription amount, and adding water to prepare coating liquid with the mass fraction of 6-9% 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;
6. finishing and screening: placing the coated granules in a crushing and granulating machine, sieving and granulating by using a 24-mesh nylon sieve, and controlling the environmental temperature to be below 25 ℃ and the relative humidity to be below 50%;
7. 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;
8. 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 (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles prepared by the invention have small impurity increment in the preparation process, only 0.03 percent of impurity increment, no adhesion of a screen mesh in the granulation process, easy granulation, high product dissolution speed, no more than 30 seconds of total dissolution time, good stability in the storage process, difficult moisture absorption and agglomeration of products, long shelf life of 24 months, simple and feasible preparation process and worthy market popularization.
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
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules prepared by the following steps:
the preparation process comprises the following steps:
1. preparation of the adhesive: taking honey according to the prescription amount, placing the honey into an iron pan, adding purified water 2 times the weight of the honey, uniformly stirring, heating to 100-105 ℃, preserving heat for 20-25 minutes, taking out, filtering with a 80-mesh sieve, taking filtrate, cooling, adding ethanol according to the prescription amount, stirring and dissolving to obtain the honey-water-based composite material;
2. pretreatment of raw materials and auxiliary materials: taking (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, L-cysteine, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose and low-substituted hydroxypropyl cellulose in a prescription amount, putting the mixture into a universal pulverizer, pulverizing and sieving with a 100-mesh sieve for later use;
3. and (3) granulating: putting the mixed powder obtained after the pretreatment into a wet granulator, adding an adhesive and polysorbate 80, starting the granulator (a 24-mesh nylon sieve is installed), and starting granulation;
4. and (3) drying: putting the wet granules into a blast drying oven, and setting the drying time at 50-60 ℃ to be 120-150 min to ensure that the water content of the granules is less than or equal to 3 percent (mass percentage);
5. coating:
(1) preparation of coating liquid: taking polyethylene glycol 4000 and hydroxypropyl methylcellulose in the formula amount, and adding water to prepare coating liquid with the mass fraction of 6-9% 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 bac, continuously feeding air for drying, continuously heating for 10-15 minutes after the solution is sprayed, stopping heating, cooling and discharging to obtain coated particles;
6. finishing and screening: placing the coated granules in a crushing and granulating machine, sieving and granulating by using a 24-mesh nylon sieve, and controlling the environmental temperature to be below 25 ℃ and the relative humidity to be below 50%;
7. 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;
8. 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.
In the granulation process, the observation shows that the granulation process of example 1 does not find the condition of sticking the screen, and the product is easy to granulate.
Test one: determination of dissolution time
1. Test materials: (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules, prepared in example 1;
2. the test method comprises the following steps: taking 10 bags of the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles prepared in example 1, placing the bags in a 100ml beaker, adding 50ml of purified water with the temperature of 25 ℃, standing, and observing the time required for complete dissolution;
3. the results of the tests are given in the following table:
| test number | 1# | 2# | 3# | 4# | 5# |
| Dissolving time (min) | 27 seconds | 23 seconds | 25 seconds | 26 seconds | 25 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Dissolving time (min) | 27 seconds | 23 seconds | 25 seconds | 21 second | 25 seconds |
4. And (4) test conclusion: as can be seen from the test results in the above table, the dissolution time of the granules measured many times is less than 30 seconds, which proves that the dissolution speed of the granules prepared according to the invention is high.
Experiment two: the invention relates to the influence of the formula of (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles on the increase of impurities in the preparation process
1. Experimental materials:
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide particle samples: prepared as in example 1.
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide particle control samples: 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 example 1, the related substances of the (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide bulk drug and the (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide granule finished product are measured respectively, and the increase of impurities in the (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide granules in the preparation process is observed. Meanwhile, the formula of example 1 lacking L-cysteine is taken as a reference formula, the preparation method of example 1 is adopted, related substances of the (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide bulk drug and the (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide particle finished product are respectively measured, and the impurity increase condition of the (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide particles 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 (3) test III: the invention relates to a (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particle stability experiment
Experimental materials:
(S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide particles: prepared for example 1.
The accelerated test method comprises the following steps: the (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules prepared in example 1 were packaged on the market, put in an accelerated laboratory box, sampled for a certain period of time, and examined for the items.
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 (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules prepared in example 1 were packaged on the market, placed in a long-term sample box, sampled for a certain period of time, and examined.
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
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules prepared by the following steps:
the preparation process comprises the following steps: prepared according to the preparation process of example 1. The phenomenon of screen adhesion is not found in the process of product granulation, and the product is easy to granulate. The test method of the embodiment 1 is used for testing, the dissolution time measurement shows that the product has high dissolution speed, the dissolution time of a plurality of samples is less than 30 seconds, the effect test result of the product prescription on the impurity increase in the preparation process shows that the impurity increase amount of the product in the preparation process is small, and related substances in the preparation process are only increased by 0.02 percent; the stability test result shows that the quality of the sample is stable for 6 months and the quality is stable for 24 months, so the validity period of the product is at least 24 months.
Example 3
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules prepared by the following steps:
the preparation process comprises the following steps: prepared according to the preparation process of example 1. The phenomenon of screen adhesion is not found in the process of product granulation, and the product is easy to granulate. The test method of the embodiment 1 is used for testing, the dissolution time measurement shows that the product has high dissolution speed, the dissolution time of a plurality of samples is less than 30 seconds, the test result of the influence of the product prescription on the impurity increase in the preparation process shows that the impurity increase amount of the product in the preparation process is small, and related substances in the preparation process are only increased by 0.03%; the stability test result shows that the quality of the sample is stable for 6 months and the quality is stable for 24 months, so the validity period of the product is at least 24 months.
Examples 4 to 6: the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles are prepared from the following raw and auxiliary materials in parts by weight, and the preparation method is the same as that of example 1:
the preparation process comprises the following steps: prepared according to the preparation process of example 1. No sticking of the screen mesh was observed in the pelletization of the products of examples 4, 5 and 6, and the products of examples 4, 5 and 6 were easily pelletized. The finished products prepared in the examples 4, 5 and 6 are tested according to the test method of the example 1, and the dissolution time measurement of the samples prepared in the examples 4, 5 and 6 shows that the product has high dissolution speed, the dissolution time of a plurality of samples is less than 30 seconds, the influence test result of the formulas of the products of the examples 4, 5 and 6 on the impurity increase in the preparation process shows that the impurity increase in the preparation process is small, and related substances in the preparation process are respectively increased by 0.02%, 0.03% and 0.03%; the stability test results of the samples prepared in examples 4, 5 and 6 show that the quality of the sample is stable for 6 months at an accelerated speed, and the quality is stable for 24 months for a long time, so that the samples prepared in examples 4, 5 and 6 have the effective period of at least 24 months.
Claims (2)
1. A preparation method of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles is characterized in that the particles are prepared from the following raw and auxiliary materials in parts by weight: 1 part of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide, 0.7-1.3 parts of L-cysteine, 1.0-1.5 parts of mannitol, 0.7-1.2 parts of microcrystalline cellulose, 0.9-1.5 parts of sodium carboxymethylcellulose, 0.7-1.3 parts of lactose, 0.13-0.18 part of magnesium stearate, 0.78-1.1 part of polyethylene glycol 40000.6, 0.9-1.7 parts of hydroxypropyl methylcellulose, 0.8-1.3 parts of low-substituted hydroxypropyl cellulose, 800.06-0.11 part of polysorbate, 0.5-1.2 parts of honey and 8-13 parts of ethanol solution with the volume fraction of 50-70%;
the preparation method comprises the following steps:
preparation of the adhesive: taking honey according to the prescription amount, placing the honey into an iron pan, adding purified water 2 times the weight of the honey, uniformly stirring, heating to 100-105 ℃, preserving heat for 20-25 minutes, taking out, filtering with a 80-mesh sieve, taking filtrate, cooling, adding ethanol solution according to the prescription amount, and stirring for dissolving to obtain the honey-water-based composite material;
b, pretreatment of raw and auxiliary materials: taking (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, L-cysteine, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose and low-substituted hydroxypropyl cellulose in a prescription amount, putting the mixture into a universal pulverizer, pulverizing and sieving with a 100-mesh sieve for later use;
c, granulating: placing the mixed powder obtained after the pretreatment into a wet granulator, adding the adhesive prepared in the step A and polysorbate 80, starting the granulator with a 24-mesh nylon sieve, and starting granulation;
and D, drying: putting the wet granules into a blast drying oven, and setting the drying time to be 120-150 min at the temperature of 50-60 ℃ to ensure that the water content of the granules is less than or equal to 3%; the percentage is the mass percentage content;
e, coating, namely E ⑴, namely preparing coating liquid, namely adding water into coating materials of polyethylene glycol 4000 and hydroxypropyl methylcellulose in a formula amount to prepare 6-9% of the coating liquid for later use, E ⑵, namely putting the dry particles into a fluidized bed, introducing hot air into the fluidized bed to enable the dry particles to be suspended and fluidized, keeping the bed temperature at 40-50 ℃, continuously adding the coating liquid into the fluidized bed through nozzle atomization of the fluidized bed, setting the spraying speed at 50-60 rpm and the atomization pressure at 0.8-1.0 bar, continuously introducing air for drying, continuously heating for 10-15 minutes after the solution is sprayed, stopping heating, cooling and discharging to obtain coated particles;
f, granule finishing and screening, namely placing the coated granules into a crushing and granule finishing machine, and screening and finishing the granules by using a 24-mesh nylon screen, wherein the environmental temperature is controlled to be below 25 ℃, and the relative humidity is controlled to be below 50%;
g, total mixing: crushing magnesium stearate, sieving with a 100-mesh sieve, adding into the granules after finishing, and mixing for 10-20 min by using a three-dimensional motion mixer;
h, 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.
2. The process for preparing (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules according to claim 1, wherein it is prepared from the following raw and auxiliary materials in weight ratio: 1 part of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide, 0.9-1.2 parts of L-cysteine, 1.2-1.4 parts of mannitol, 0.8-1.1 part of microcrystalline cellulose, 1.1-1.3 parts of sodium carboxymethylcellulose, 0.9-1.2 parts of lactose, 0.14-0.17 part of magnesium stearate, 0-1.0 part of polyethylene glycol 40000.8, 1.2-1.5 parts of hydroxypropyl methylcellulose, 0.9-1.2 parts of low-substituted hydroxypropyl cellulose, 800.07-0.09 part of polysorbate, 0.7-1.0 part of honey and 9-12 parts of ethanol solution with the volume fraction of 50-70%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610428283.9A CN107510681B (en) | 2016-06-15 | 2016-06-15 | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610428283.9A CN107510681B (en) | 2016-06-15 | 2016-06-15 | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107510681A CN107510681A (en) | 2017-12-26 |
| CN107510681B true CN107510681B (en) | 2020-07-03 |
Family
ID=60720087
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610428283.9A Active CN107510681B (en) | 2016-06-15 | 2016-06-15 | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107510681B (en) |
Citations (3)
| 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 |
| CN102579386A (en) * | 2012-03-19 | 2012-07-18 | 北京德众万全药物技术开发有限公司 | Stable oxiracetam preparation |
| WO2014087367A2 (en) * | 2012-12-09 | 2014-06-12 | Mahesh Kandula | Compositions and methods for the treatment of neurological diseases and its associated complications |
-
2016
- 2016-06-15 CN CN201610428283.9A patent/CN107510681B/en active Active
Patent Citations (3)
| 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 |
| CN102579386A (en) * | 2012-03-19 | 2012-07-18 | 北京德众万全药物技术开发有限公司 | Stable oxiracetam preparation |
| WO2014087367A2 (en) * | 2012-12-09 | 2014-06-12 | Mahesh Kandula | Compositions and methods for the treatment of neurological diseases and its associated complications |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107510681A (en) | 2017-12-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107510681B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof | |
| CN109718215A (en) | A kind of Ezetimibe piece | |
| CN104447795A (en) | Cefadroxil compound and pharmaceutical composition comprising same | |
| CN106619523B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof | |
| CN104173307A (en) | Preparation method of ezetimibe tablet | |
| CN107510664B (en) | Levo-oxiracetam particle and preparation method thereof | |
| CN107510685B (en) | (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles with uniform content and preparation method thereof | |
| CN107510657A (en) | Good levo-oxiracetam particle of a kind of content uniformity and preparation method thereof | |
| CN106890155B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide effervescent tablet and preparation method thereof | |
| CN107510679A (en) | A kind of content is uniform（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof | |
| WO2015000370A1 (en) | Pyrroloquinoline quinone lithium salt crystal and preparation method and application thereof | |
| CN107510672A (en) | Good oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of a kind of stability and preparation method thereof | |
| CN106606485A (en) | Good taste levo S-oxiracetam particle and preparation method thereof | |
| CN107510684A (en) | Good levo-oxiracetam particle of a kind of content uniformity and preparation method thereof | |
| CN106619526A (en) | Good-stability (S)-4-hydroxy-2 oxo-1-pyrrolidine acetamide granule and preparation method thereof | |
| CN107510676A (en) | A kind of content is uniform（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof | |
| CN107510682A (en) | It is a kind of（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof | |
| CN107510654A (en) | It is a kind of in good taste（S）Oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2 and preparation method thereof | |
| CN107510658A (en) | Oxo-1-pyrrolidine ethanamide particle of one kind (S) -4- hydroxyls -2 and preparation method thereof | |
| CN106943376B (en) | A kind of levo-oxiracetam particle and preparation method thereof | |
| CN106511310B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide sustained-release capsule with good stability and preparation method thereof | |
| CN107510674A (en) | A kind of levo-oxiracetam particle in good taste and preparation method thereof | |
| CN107510680A (en) | It is a kind of in good taste（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof | |
| CN107638414B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide sustained-release capsule and preparation method thereof | |
| CN107510665A (en) | Good levo-oxiracetam particle of a kind of content uniformity and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220714 Address after: 430000 No. 88, shendun fifth road, East Lake Development Zone, Wuhan, Hubei Province Patentee after: Wuhan Hengxinyuan Pharmaceutical Co.,Ltd. Address before: No. 9, Yubei District industry road, Chongqing, Chongqing Patentee before: CHONGQING RUNZE PHARMACEUTICAL Co.,Ltd. |