CN106619523B - (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
- CN106619523B CN106619523B CN201510704917.4A CN201510704917A CN106619523B CN 106619523 B CN106619523 B CN 106619523B CN 201510704917 A CN201510704917 A CN 201510704917A CN 106619523 B CN106619523 B CN 106619523B
- Authority
- CN
- China
- Prior art keywords
- parts
- oxo
- hydroxy
- particles
- putting
- 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
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
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: about 1 part of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide, about 0.8-1.2 parts of mannitol, about 0.6-1.2 parts of microcrystalline cellulose, about 0.9-1.3 parts of sodium carboxymethylcellulose, about 1.0-1.5 parts of lactose, about 0.05-0.09 part of magnesium stearate, about 0.6-1.1 part of polyethylene glycol 4000, about 0.6-1.0 part of hydroxypropyl methylcellulose, about 0.3-0.8 part of low-substituted hydroxypropyl cellulose, about 0.06-0.1 part of polysorbate 80 and about 6-10 parts of ethanol solution with the volume fraction of 50% -70%; the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles prepared according to the invention have the advantages of high dissolving speed, no more than 30 seconds of total dissolving time of the particles, good stability in the storage process, difficult moisture absorption and agglomeration of products, long shelf life of the products up to 36 months, simple and feasible preparation process and worth of market popularization.
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 ═ 1.00in water), and has a solubility superior to that of the 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 poor stability in the storage process, strong hygroscopicity of the particles, easy adhesion and connection, short shelf life, low 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 with high dissolution speed and good 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, and sodium carboxymethylcellulose; 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 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 (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles are not easy to absorb moisture and adhere to bonding blocks, the product stability is good, the shelf life is long, and the particle 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, 0.8-1.2 parts of mannitol, 0.6-1.2 parts of microcrystalline cellulose, 0.9-1.3 parts of sodium carboxymethylcellulose, 1.0-1.5 parts of lactose, 0.05-0.09 part of magnesium stearate, 40000.6-1.1 parts of polyethylene glycol, 0.6-1.0 part of hydroxypropyl methylcellulose, 0.3-0.8 part of low-substituted hydroxypropyl cellulose, 800.06-0.1 part of polysorbate, and 6-10 parts of 50-70% volume fraction ethanol solution; putting (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose and polysorbate 80 into a universal pulverizer, pulverizing, sieving with 100 mesh sieve, putting into a wet granulator, adding an adhesive, starting the granulator (a 24-mesh nylon sieve is arranged), 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 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; 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, 0.9-1.1 part of mannitol, 0.8-1.0 part of microcrystalline cellulose, 1.0-1.2 parts of sodium carboxymethylcellulose, 1.0-1.3 parts of lactose, 0.06-0.08 part of magnesium stearate, 0-1.0 part of polyethylene glycol 40000.7, 0.7-0.9 part of hydroxypropyl methylcellulose, 0.5-0.8 part of low-substituted hydroxypropyl cellulose, 800.07-0.09 part of polysorbate, and 8-10 parts of ethanol solution with the volume fraction of 50% -70%; putting (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose and polysorbate 80 into a universal pulverizer, pulverizing, sieving with 100 mesh sieve, putting into a wet granulator, adding an adhesive, starting the granulator (a 24-mesh nylon sieve is arranged), 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 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; 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. 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;
2. and (3) granulating: putting the mixed powder obtained after the pretreatment into a wet granulator, adding an adhesive, starting the granulator (a 24-mesh nylon sieve is arranged), and starting granulation;
3. 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);
4. 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 standby;
(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 24-mesh nylon 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 (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles prepared by the invention have the advantages of high dissolving speed, no more than 30 seconds of total dissolving time of the particles, good stability in the storage process, difficult moisture absorption and agglomeration of products, long shelf life of the products up to 36 months, simple and feasible preparation process and worth of 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:
| composition (I) | Dosage of |
| (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide | 1 part of |
| Mannitol | 0.9 portion |
| Microcrystalline cellulose | 0.8 portion of |
| Sodium carboxymethylcellulose | 1.0 part |
| Lactose | 1.0 part |
| Magnesium stearate | 0.06 part |
| Polyethylene glycol 4000 | 0.7 portion of |
| Hydroxypropyl methylcellulose | 0.7 portion of |
| Low-substituted hydroxypropyl cellulose | 0.5 portion |
| Polysorbate 80 | 0.07 part of |
| Ethanol solution with volume fraction of 50% | 8 portions of |
Making into 1000 bags
The preparation process comprises the following steps:
1. pretreatment of raw materials and auxiliary materials: taking (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted carboxymethyl cellulose and polysorbate 80 in a prescription amount, putting 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 an ethanol solution with the volume fraction of 50% according to the prescription amount, starting the granulator (a 24-mesh nylon sieve is installed), and starting granulation;
3. 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);
4. 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 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 24-mesh nylon sieve, and controlling the environmental temperature to be below 25 ℃ and the relative humidity to be below 50%;
6. total mixing: pulverizing magnesium stearate, sieving with a 100-mesh sieve, adding into the 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 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) | 23 seconds | 25 seconds | 22 seconds | 26 seconds | 22 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Dissolving time (min) | 23 seconds | 25 seconds | 22 seconds | 26 seconds | 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.
And (2) test II: 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: character, moisture, particle size, solubility, related substances, content, microbial limit accelerated test stability record:
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, 36 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 properties, moisture, granularity, dissolubility, related substances, content and microorganism limit after long-term test for 36 months, and all meet the relevant regulations of quality standard draft for production. The product has stable quality after long-term test for 36 months, so the product has a minimum effective period of 36 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:
| composition (I) | Dosage of |
| (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide | 1 part of |
| Mannitol | 1.1 parts of |
| Microcrystalline cellulose | 1.0 part |
| Sodium carboxymethylcellulose | 1.2 parts of |
| Lactose | 1.3 parts of |
| Magnesium stearate | 0.08 portion of |
| Polyethylene glycol 4000 | 1.0 part |
| Hydroxypropyl methylcellulose | 0.9 portion |
| Low-substituted hydroxypropyl cellulose | 0.8 portion of |
| Polysorbate 80 | 0.09 part |
| Ethanol solution with volume fraction of 70% | 10 portions of |
Making into 1000 bags
The preparation process comprises the following steps: prepared according to the preparation process of example 1. According to the test method of the example 1, the dissolution time measurement and the sample stability test are respectively carried out, 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 stability test result shows that the sample quality is stable in 6 months and the sample quality is stable in 36 months, so the product has at least 36 months of effective period.
Example 3
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules prepared by the following steps:
| composition (I) | Dosage of |
| (S) -4-hydroxy-2-oxo-1-Pyrrolidine acetamide | 1 part of |
| Mannitol | 1.0 part |
| Microcrystalline cellulose | 0.9 portion |
| Sodium carboxymethylcellulose | 1.1 parts of |
| Lactose | 1.2 parts of |
| Magnesium stearate | 0.07 part of |
| Polyethylene glycol 4000 | 0.8 portion of |
| Hydroxypropyl methylcellulose | 0.8 portion of |
| Low-substituted hydroxypropyl cellulose | 0.7 portion of |
| Polysorbate 80 | 0.08 portion of |
| Ethanol solution with volume fraction of 60 percent | 9 portions of |
Making into 1000 bags
The preparation process comprises the following steps: prepared according to the preparation process of example 1. According to the test method of the example 1, the dissolution time measurement and the sample stability test are respectively carried out, 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 stability test result shows that the sample quality is stable in 6 months and the sample quality is stable in 36 months, so the product has at least 36 months of effective period.
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:
| examples | 4 | 5 | 6 |
| (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide | 1 part of | 1 part of | 1 part of |
| Mannitol | 1.0 part | 1.1 parts of | 0.9 portion |
| Microcrystalline fibreVegetable extract | 1.0 part | 0.9 portion | 0.8 portion of |
| Sodium carboxymethylcellulose | 1.0 part | 1.1 parts of | 1.2 parts of |
| Lactose | 1.3 parts of | 1.2 parts of | 1.1 parts of |
| Magnesium stearate | 0.08 portion of | 0.08 portion of | 0.08 portion of |
| Polyethylene glycol 4000 | 0.8 portion of | 0.9 portion | 0.9 portion |
| Hydroxypropyl methylcellulose | 0.7 portion of | 0.8 portion of | 0.9 portion |
| Low-substituted hydroxypropyl cellulose | 0.8 portion of | 0.7 portion of | 0.8 portion of |
| Polysorbate 80 | 0.08 portion of | 0.09 part | 0.07 part of |
| Volume fraction of 60% ethanol | 9 portions of | 8 portions of | 8 portions of |
The preparation process comprises the following steps: prepared according to the preparation process of example 1. The dissolution time and the sample stability tests of the examples 4, 5 and 6 are respectively carried out according to the test method of the example 1, the dissolution time of the samples prepared by the examples 4, 5 and 6 is determined to be fast, the dissolution time of a plurality of samples is less than 30 seconds, the stability test results of the samples prepared by the examples 4, 5 and 6 indicate that the quality of the samples is stable in 6 months and the quality is stable in 36 months, so the validity period of the samples prepared by the examples 4, 5 and 6 is at least 36 months.
Claims (3)
1. 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, 0.8-1.2 parts of mannitol, 0.6-1.2 parts of microcrystalline cellulose, 0.9-1.3 parts of sodium carboxymethylcellulose, 1.0-1.5 parts of lactose, 0.05-0.09 part of magnesium stearate, 40000.6-1.1 parts of polyethylene glycol, 0.6-1.0 part of hydroxypropyl methylcellulose, 0.3-0.8 part of low-substituted hydroxypropyl cellulose, 800.06-0.1 part of polysorbate, and 6-10 parts of 50-70% volume fraction ethanol solution; putting (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose and polysorbate 80 into a universal pulverizer, pulverizing, sieving with a 100-mesh sieve, putting into a wet granulator, adding 50-70% ethanol solution by volume fraction, starting the granulator provided with 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 in terms of 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.
2. The (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules of claim 1, prepared from the following raw and auxiliary materials in weight ratio: 1 part of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide, 0.9-1.1 part of mannitol, 0.8-1.0 part of microcrystalline cellulose, 1.0-1.2 parts of sodium carboxymethylcellulose, 1.0-1.3 parts of lactose, 0.06-0.08 part of magnesium stearate, 0-1.0 part of polyethylene glycol 40000.7, 0.7-0.9 part of hydroxypropyl methylcellulose, 0.5-0.8 part of low-substituted hydroxypropyl cellulose, 800.07-0.09 part of polysorbate, and 8-10 parts of ethanol solution with volume fraction of 50% -70%.
3. A process for the preparation of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide granules according to claim 1 or 2, which is characterized by the following steps:
A. pretreatment of raw materials and auxiliary materials: taking (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose and polysorbate 80 in a prescription amount, putting the mixture into a universal pulverizer, pulverizing and sieving with a 100-mesh sieve for later use;
B. and (3) granulating: putting the mixed powder obtained after the pretreatment into a wet granulator, adding 50-70% of ethanol solution by volume fraction, starting the granulator provided with a 24-mesh nylon sieve, and starting granulation;
C. 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 in terms of mass percentage;
D. coating:
d (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;
d (2) 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. 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%;
F. total mixing: pulverizing magnesium stearate, sieving with a 100-mesh sieve, adding into the granules, and mixing for 10-20 min by using a three-dimensional motion mixer;
G. 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510704917.4A CN106619523B (en) | 2015-10-27 | 2015-10-27 | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510704917.4A CN106619523B (en) | 2015-10-27 | 2015-10-27 | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106619523A CN106619523A (en) | 2017-05-10 |
| CN106619523B true CN106619523B (en) | 2020-08-28 |
Family
ID=58815660
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510704917.4A Active CN106619523B (en) | 2015-10-27 | 2015-10-27 | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106619523B (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 |
| 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 |
| CN103735545A (en) * | 2011-11-23 | 2014-04-23 | 重庆润泽医药有限公司 | Applications of levorotary oxiracetam and oxiracetam in preparing drugs for preventing or treating coma |
-
2015
- 2015-10-27 CN CN201510704917.4A patent/CN106619523B/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 |
| CN103735545A (en) * | 2011-11-23 | 2014-04-23 | 重庆润泽医药有限公司 | Applications of levorotary oxiracetam and oxiracetam in preparing drugs for preventing or treating coma |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106619523A (en) | 2017-05-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103610680A (en) | Cefuroxime axetil composition and preparation method thereof | |
| CN104586854A (en) | Cefuroxime axetil pharmaceutical composition and preparation method thereof | |
| CN102202691B (en) | Lactose and cellulose-based tableting aid | |
| CN106619523B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof | |
| CN104447795A (en) | Cefadroxil compound and pharmaceutical composition comprising same | |
| CN109718215A (en) | A kind of Ezetimibe piece | |
| CN107510681B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide particles and preparation method thereof | |
| CN102525997A (en) | Moisture-proof coating citicoline sodium capsule and preparation method thereof | |
| CN104173307A (en) | Preparation method of ezetimibe tablet | |
| CN107510664B (en) | Levo-oxiracetam particle and preparation method thereof | |
| CN113440487A (en) | Caragana tablets and preparation method thereof | |
| CN106890155B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide effervescent tablet and preparation method thereof | |
| CN102311452A (en) | Cefixime crystal, preparation method thereof and tablet composition containing same | |
| 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 | |
| CN103315972A (en) | Moxifloxacin hydrochloride tablets and preparation method thereof | |
| CN106606485A (en) | Good taste levo S-oxiracetam particle and preparation method thereof | |
| CN107510672A (en) | Good oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of a kind of stability and preparation method thereof | |
| CN106619526A (en) | Good-stability (S)-4-hydroxy-2 oxo-1-pyrrolidine acetamide granule and preparation method thereof | |
| CN106511310B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide sustained-release capsule with good stability 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 | |
| CN106890153B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide effervescent tablet with good stability 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 | |
| CN106890151B (en) | Stable levorotatory oxiracetam effervescent tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| 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 |