CN110960498A - Preparation method of heat-unstable pharmaceutical composition - Google Patents
Preparation method of heat-unstable pharmaceutical composition Download PDFInfo
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- CN110960498A CN110960498A CN201911352828.2A CN201911352828A CN110960498A CN 110960498 A CN110960498 A CN 110960498A CN 201911352828 A CN201911352828 A CN 201911352828A CN 110960498 A CN110960498 A CN 110960498A
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- 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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- 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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention relates to a heat-unstable pharmaceutical composition and a preparation method thereof, wherein a method of adding a coolant of dry ice in a mixing and granulating process to sublimate and absorb heat to cool a material or cooling the material by using a refrigeratable mixing barrel is adopted, the temperature of the mixed material is kept between-10 ℃ and-5 ℃, and the temperature of the material is kept between-5 ℃ and 0 ℃ in the granulating process, so that the product is ensured to be produced in a low-temperature state; meanwhile, in the tabletting process, a die sleeve is added into the tabletting machine, and the cooling and demoulding of the tabletting are ensured by adopting a method of injecting a lubricant into cooled compressed air; the product prepared by the method can effectively prolong the effective period of the product; the invention discloses a preparation method of a heat-labile pharmaceutical composition.
Description
Technical Field
The invention relates to a preparation method of a heat-unstable medicine composition in the field of medicinal preparations.
Background
The production and preparation processes commonly used in the pharmaceutical industry at present comprise wet granulation and dry granulation.
The wet granulation is generally carried out by water or ethanol, the temperature of the water granulation is generally about 60 ℃ in the material drying process, and the temperature of the drying process is required to be about 50 ℃ even if the ethanol granulation is adopted.
Although the dry granulation process has a water cooling process to cool the pressing wheel of the dry press, the material still generates heat in the extrusion forming process, and the temperature can reach about 40 ℃.
Similarly, the material generates heat in the tabletting process, so that the tablet generates heat (the temperature of the tablet is about 50 ℃), and the heat is accumulated after the heated tablet is placed in a closed plastic barrel, so that the temperature of the material is increased.
The traditional process has the influence on the stability of the heat-unstable medicine due to the generation of heat, so that the effective period of the product is short.
Taking β -lactam drugs as an example, β -lactam ring is the structural active center of the antibiotics, which is active and the most unstable part in the molecular structure, chev phile, leigang, leishaohua, etc. reported in the research on the stability of β -lactam antibiotics to heat (vol. 48, No. 4 of the proceedings of the western medical college 2008), β -proportion of the ring-opening product of the lactam antibiotics is relatively increased with the increase of temperature, so that β -lactam antibiotics are relatively stable in aqueous alkali at low temperature.
Patent No. CN101780085 describes a cefprozil pharmaceutical composition, which is produced by adopting a traditional dry granulation process; the patent No. CN102526059 discloses a cefprozil pharmaceutical composition which is produced by adopting a traditional wet granulation process.
At present, β -lactam drugs on the market at home, such as cefprozil tablets, cefprozil dry suspensions, cefdinir capsules and amoxicillin potassium clavulanate granules, have the effective period of 18 months or 24 months, and the effective period of foreign products can reach 48 months.
According to the inquiry, the process adopted by the existing patent is basically the traditional process, and the validity period is short, so that the existing process needs to be improved, the validity period of the product is prolonged, and the waste of social resources is avoided.
Disclosure of Invention
The invention provides a preparation method of a heat-unstable medicine composition aiming at the technical defects of the traditional process.
The technical scheme of the invention is as follows:
a method for preparing a heat-labile pharmaceutical composition is provided.
The technical scheme of the invention is as follows:
a process for preparing the thermally unstable medicine composition used for treating the diseases caused by high temp is disclosed, which is prepared from thermally unstable medicine, filler, disintegrant, adhesive, lubricant, coolant and suspending aid through proportional mixing, and preparing tablet, dry suspension, particles and capsule.
Specifically, the cefprozil tablets of the invention are calculated according to the mass of each 1000 cefprozil tablets: 250g of cefprozil, 20-40 g of disintegrating agent, 10-20 g of adhesive, 1-2 g of lubricant, 400g of filler and a proper amount of dry ice.
The cefprozil dry suspension is prepared from the following raw materials (by mass) in 1000 tablets: 125g of cefprozil, 45-75 g of disintegrating agent, 20-30 g of adhesive, 3-6 g of lubricant, 15-30 g of suspending agent, 1500g of filler and a proper amount of dry ice.
The cefdinir capsule of the invention comprises the following components by mass per 1000 granules: 100g of cefdinir, 10-20 g of disintegrating agent, 5-10 g of adhesive, 0.5-1 g of lubricant, 200g of filler and a proper amount of dry ice.
The amoxicillin potassium clavulanate granules are calculated by the mass of each 1000 packages: 200g of amoxicillin, 28.5g of clavulanate potassium, 45-75 g of disintegrating agent, 20-30 g of adhesive, 3-6 g of lubricant, 1500g of filler and a proper amount of dry ice.
Further, the filler is at least one of lactose, microcrystalline cellulose and sucrose.
Further, the disintegrating agent is at least one of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium and sodium carboxymethyl starch.
Further, the binder is at least one of povidone K30 and hypromellose E5.
Further, the lubricant is at least one of magnesium stearate, talcum powder and silicon dioxide.
Further, the coolant is dry ice.
Further, the suspending agent is sodium carboxymethylcellulose.
A preparation method of the pharmaceutical composition of the invention comprises the following steps:
step 1, controlling the particle size of raw and auxiliary materials to be less than 60 meshes, and micronizing the lubricant (d (0.9) is less than or equal to 10 mu m).
And 2, mixing and granulating, namely uniformly mixing the raw and auxiliary materials (the tablet lubricant is added in the tabletting process, and the dry suspension, the granules and the capsules are mixed with the raw and auxiliary materials), adding dry ice or mixing by adopting a refrigeratable mixing barrel to cool the materials to-10 to-5 ℃, keeping the materials at-5 to 0 ℃ in the granulating process, and directly filling the granules after granulating or subpackaging the granules with the capsules, the granules and the dry suspension to obtain the product.
And step 3, tabletting: and for tablets, tabletting the granules prepared in the step 2, adding a die sleeve into the tabletting machine, and injecting a lubricant by adopting cooled compressed air to ensure cooling and demoulding of the tabletting.
The invention has the characteristics that:
the preparation method of the invention is characterized in that: adding a coolant dry ice into a product or mixing the materials by adopting a refrigerable mixing barrel to cool the materials to minus 10 ℃ to minus 5 ℃, keeping the materials between minus 5 ℃ and 0 ℃ in the process of tabletting, adding a die sleeve into a tabletting machine in the process of tabletting, and injecting a lubricant by using cooled compressed air to ensure cooling and demoulding of the tabletting.
According to the method, the low temperature of the materials in the whole production process is ensured, the stability of the medicine is ensured, the product quality can be well protected, the product stability in five years is compared, and the result shows that each quality index of the product in 5 years has no obvious difference from the data in 0.
Detailed Description
The following description is presented to facilitate an understanding of the invention and to enable any person skilled in the art to make or use the invention without limiting it.
Example 1.
Cefprozil 250g
Lactose 119g
Low-substituted hydroxypropylcellulose 20g
Povidone K3010 g
Magnesium stearate 1g
Dry ice q.s.
Making into 1000 tablets
The preparation method of the cefprozil tablet comprises the following steps: the particle size of the raw and auxiliary materials is controlled to be less than 60 meshes except for the lubricant, the raw and auxiliary materials are weighed for standby use, after the raw and auxiliary materials are uniformly mixed, dry ice is added or a refrigeratable mixing barrel is adopted to cool the mixed material to-10 to-5 ℃, then granulation is carried out, the temperature of the material is kept between-5 and 0 ℃ in the process, the granulated material is tabletted, in the process of tabletting, a die sleeve is added into a tabletting machine, the cooled compressed air is injected into the lubricant (micronized, d (0.9) is less than or equal to 10 mu m), the accuracy of cooling and demoulding of tabletting is guaranteed, and the product is prepared after tabletting.
The long-term stability tests (test conditions: 25 + -2 ℃, RH60 + -5%) are carried out on the above examples, the key quality indexes (content, related substances, dissolution rate) are detected according to the second part of the Chinese pharmacopoeia 2015 edition, and the long-term stability test results of the examples are as follows:
the test result shows that: by adopting the preparation method, the product can be stable in quality within 5 years.
Example 2.
Cefprozil 250g
Microcrystalline cellulose 88g
Crosslinked Povidone 40g
Hydroxypropyl methylcellulose E520 g
Talcum powder 2g
Dry ice q.s.
Making into 1000 tablets
The preparation method of the cefprozil tablet comprises the following steps: the particle size of the raw and auxiliary materials is controlled to be less than 60 meshes except for the lubricant, the raw and auxiliary materials are weighed for standby use, after the raw and auxiliary materials are uniformly mixed, dry ice is added or a refrigeratable mixing barrel is adopted to cool the mixed material to-10 to-5 ℃, then granulation is carried out, the temperature of the material is kept between-5 and 0 ℃ in the process, the granulated material is tabletted, in the process of tabletting, a die sleeve is added into a tabletting machine, the cooled compressed air is injected into the lubricant (micronized, d (0.9) is less than or equal to 10 mu m), the accuracy of cooling and demoulding of tabletting is guaranteed, and the product is prepared after tabletting.
The long-term stability tests (test conditions: 25 + -2 ℃, RH60 + -5%) are carried out on the above examples, the key quality indexes (content, related substances, dissolution rate) are detected according to the second part of the Chinese pharmacopoeia 2015 edition, and the long-term stability test results of the examples are as follows:
the test result shows that: by adopting the preparation method, the product can be stable in quality within 5 years.
Example 3.
Cefprozil 250g
Lactose 103g
Low-substituted hydroxypropylcellulose 15g
Cross-linked Povidone 15g
Povidone K3015.5g
Silica 1.5g
Dry ice q.s.
Making into 1000 tablets
The preparation method of the cefprozil tablet comprises the following steps: the particle size of the raw and auxiliary materials is controlled to be less than 60 meshes except for the lubricant, the raw and auxiliary materials are weighed for standby use, after the raw and auxiliary materials are uniformly mixed, dry ice is added or a refrigeratable mixing barrel is adopted to cool the mixed material to-10 to-5 ℃, then granulation is carried out, the temperature of the material is kept between-5 and 0 ℃ in the process, the granulated material is tabletted, in the process of tabletting, a die sleeve is added into a tabletting machine, the cooled compressed air is injected into the lubricant (micronized, d (0.9) is less than or equal to 10 mu m), the accuracy of cooling and demoulding of tabletting is guaranteed, and the product is prepared after tabletting.
The long-term stability tests (test conditions: 25 + -2 ℃, RH60 + -5%) are carried out on the above examples, the key quality indexes (content, related substances, dissolution rate) are detected according to the second part of the Chinese pharmacopoeia 2015 edition, and the long-term stability test results of the examples are as follows:
the test result shows that: by adopting the preparation method, the product can be stable in quality within 5 years.
Example 4.
Cefprozil 125g
1292g of cane sugar
Sodium carboxymethylcellulose 15g
Low-substituted hydroxypropylcellulose 45g
Povidone K3020 g
Silica 3g
Dry ice q.s.
Making into 1000 bags
The preparation method of the cefprozil dry suspension comprises the following steps: the particle size of the raw and auxiliary materials is controlled to be less than 60 meshes, the lubricant is micronized (d (0.9) is less than or equal to 10 mu m), the raw and auxiliary materials are weighed for later use, after the raw and auxiliary materials are uniformly mixed, dry ice is added or a refrigeratable mixing barrel is adopted to cool the mixed material to-10 ℃ to-5 ℃, then granulation is carried out, the temperature of the material is kept between-5 ℃ and 0 ℃ in the process, and the granulated material is granulated and subpackaged to obtain the product.
The long-term stability tests (test conditions: 25 + -2 ℃, RH60 + -5%) are carried out on the above examples, the key quality indexes (content, related substances, dissolution rate) are detected according to the second part of the Chinese pharmacopoeia 2015 edition, and the long-term stability test results of the examples are as follows:
the test result shows that: by adopting the preparation method, the product can be stable in quality within 5 years.
Example 5.
Cefprozil 125g
Sucrose 1234g
Sodium carboxymethylcellulose 30g
Croscarmellose sodium 75g
Hydroxypropyl methylcellulose E530 g
Magnesium stearate 6g
Dry ice q.s.
Making into 1000 bags
The preparation method of the cefprozil dry suspension comprises the following steps: the particle size of the raw and auxiliary materials is controlled to be less than 60 meshes, the lubricant is micronized (d (0.9) is less than or equal to 10 mu m), the raw and auxiliary materials are weighed for later use, after the raw and auxiliary materials are uniformly mixed, dry ice is added or a refrigeratable mixing barrel is adopted to cool the mixed material to-10 ℃ to-5 ℃, then granulation is carried out, the temperature of the material is kept between-5 ℃ and 0 ℃ in the process, and the granulated material is granulated and subpackaged to obtain the product.
The long-term stability tests (test conditions: 25 + -2 ℃, RH60 + -5%) are carried out on the above examples, the key quality indexes (content, related substances, dissolution rate) are detected according to the second part of the Chinese pharmacopoeia 2015 edition, and the long-term stability test results of the examples are as follows:
the test result shows that: by adopting the preparation method, the product can be stable in quality within 5 years.
Example 6.
Cefdinir 100g
Lactose 84.5g
Croscarmellose sodium 10g
Povidone K305 g
Magnesium stearate 0.5g
Dry ice q.s.
Making into 1000 granules
The preparation method of the cefdinir capsule comprises the following steps: the particle size of the raw and auxiliary materials is controlled to be less than 60 meshes, the lubricant is micronized (d (0.9) is less than or equal to 10 mu m), the raw and auxiliary materials are weighed for later use, after the raw and auxiliary materials are uniformly mixed, dry ice is added or a refrigerable mixing barrel is adopted to cool the mixed material to-10 ℃ to-5 ℃, then granulation is carried out, the temperature of the material is kept between-5 ℃ and 0 ℃ in the process, the granulated material is directly filled into capsules, and the product is prepared after the filling is finished.
The long-term stability tests (test conditions: 25 + -2 ℃, RH60 + -5%) are carried out on the above examples, the key quality indexes (content, related substances, dissolution rate) are detected according to the second part of the Chinese pharmacopoeia 2015 edition, and the long-term stability test results of the examples are as follows:
the test result shows that: by adopting the preparation method, the product can be stable in quality within 5 years.
Example 7.
Cefdinir 100g
Microcrystalline cellulose 69g
Sodium carboxymethyl starch 20g
Hypromellose E510 g
Silica 1g
Dry ice q.s.
Making into 1000 granules
The preparation method of the cefdinir capsule comprises the following steps: the particle size of the raw and auxiliary materials is controlled to be less than 60 meshes, the lubricant is micronized (d (0.9) is less than or equal to 10 mu m), the raw and auxiliary materials are weighed for later use, after the raw and auxiliary materials are uniformly mixed, dry ice is added or a refrigerable mixing barrel is adopted to cool the mixed material to-10 ℃ to-5 ℃, then granulation is carried out, the temperature of the material is kept between-5 ℃ and 0 ℃ in the process, the granulated material is directly filled into capsules, and the product is prepared after the filling is finished.
The long-term stability tests (test conditions: 25 + -2 ℃, RH60 + -5%) are carried out on the above examples, the key quality indexes (content, related substances, dissolution rate) are detected according to the second part of the Chinese pharmacopoeia 2015 edition, and the long-term stability test results of the examples are as follows:
the test result shows that: by adopting the preparation method, the product can be stable in quality within 5 years.
Example 8.
Cefdinir 100g
Microcrystalline cellulose 76g
6g croscarmellose sodium
Sodium carboxymethyl starch 10g
Hydroxypropyl methylcellulose E57.5g
Talcum powder 0.5g
Dry ice q.s.
Making into 1000 granules
The preparation method of the cefdinir capsule comprises the following steps: the particle size of the raw and auxiliary materials is controlled to be less than 60 meshes, the lubricant is micronized (d (0.9) is less than or equal to 10 mu m), the raw and auxiliary materials are weighed for later use, after the raw and auxiliary materials are uniformly mixed, dry ice is added or a refrigerable mixing barrel is adopted to cool the mixed material to-10 ℃ to-5 ℃, then granulation is carried out, the temperature of the material is kept between-5 ℃ and 0 ℃ in the process, the granulated material is directly filled into capsules, and the product is prepared after the filling is finished.
The long-term stability tests (test conditions: 25 + -2 ℃, RH60 + -5%) are carried out on the above examples, the key quality indexes (content, related substances, dissolution rate) are detected according to the second part of the Chinese pharmacopoeia 2015 edition, and the long-term stability test results of the examples are as follows:
the test result shows that: by adopting the preparation method, the product can be stable in quality within 5 years.
Example 9:
amoxicillin 200g
Potassium clavulanate 28.5g
1181.5g of cane sugar
Croscarmellose sodium 60g
Hydroxypropyl methylcellulose E525 g
Magnesium stearate 5g
Dry ice q.s.
Making into 1000 bags
The preparation method of the amoxicillin potassium clavulanate granules comprises the following steps: the particle size of the raw and auxiliary materials is controlled to be less than 60 meshes, the lubricant is micronized (d (0.9) is less than or equal to 10 mu m), the raw and auxiliary materials are weighed for later use, after the raw and auxiliary materials are uniformly mixed, dry ice is added or a refrigeratable mixing barrel is adopted to cool the mixed material to-10 ℃ to-5 ℃, then granulation is carried out, the temperature of the material is kept between-5 ℃ and 0 ℃ in the process, and the granulated material is granulated and subpackaged to obtain the product.
The long-term stability tests (test conditions: 25 + -2 ℃, RH60 + -5%) are carried out on the above examples, the key quality indexes (content, related substances, dissolution rate) are detected according to the second part of the Chinese pharmacopoeia 2015 edition, and the long-term stability test results of the examples are as follows:
the test result shows that: by adopting the preparation method, the product can be stable in quality within 5 years.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (5)
1. A heat-labile pharmaceutical composition characterized by: the composition consists of a heat-labile medicament, a filling agent, a disintegrating agent, a bonding agent, a lubricating agent, a coolant, namely dry ice (removed in the process), and a suspending agent (used for dry suspension), and is prepared into tablets, granules, dry suspension and capsules according to requirements.
2. The pharmaceutical composition of claim 1, wherein the heat labile drug is selected from the group consisting of, but not limited to, β -lactam drugs, the disintegrant is low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, the filler is lactose, microcrystalline cellulose, sucrose, the binder is povidone K30, hypromellose E5, the lubricant is talc, magnesium stearate, silicon dioxide, the cooling agent is dry ice, and the suspending agent is sodium carboxymethyl cellulose.
3. The pharmaceutical composition according to claim 1, characterized by comprising the following parts by weight:
100-250 parts of heat-labile medicine
10-75 parts by weight of disintegrating agent
5-30 parts by weight of adhesive
0.5 to 6 parts by weight of a lubricant
0-30 parts of suspending agent
Adding 200-1500 parts by weight of filler
And a proper amount of dry ice.
4. The process for preparing the pharmaceutical composition according to claim 1, wherein the capsule, dry suspension or granule is characterized in that it comprises the following steps:
step 1, ensuring that the particle size of raw and auxiliary materials is controlled to be less than 60 meshes, micronizing a lubricant (d (0.9) is less than or equal to 10 mu m), and weighing for later use;
and 2, mixing and granulating, namely uniformly mixing all the raw and auxiliary materials, adding a proper amount of dry ice for mixing or adopting a refrigeratable mixing barrel to cool the materials to the temperature of minus 10 ℃ to minus 5 ℃, keeping the temperature of the materials between minus 5 ℃ and 0 ℃ in the granulating process, and directly filling capsules or dry suspensions or granules into granulated granules to obtain the product.
5. Process for the preparation of a pharmaceutical composition according to claim 1, characterized in that it comprises the following steps:
step 1, ensuring that the particle size of raw and auxiliary materials is controlled to be less than 60 meshes, micronizing a lubricant (d (0.9) is less than or equal to 10 mu m), and weighing for later use;
step 2, mixing and granulating, namely uniformly mixing the raw materials except the lubricant, adding a proper amount of dry ice for mixing or adopting a mixing barrel capable of refrigerating to cool the materials to-10 ℃ to-5 ℃, and keeping the materials at-5 ℃ to 0 ℃ in the granulating process;
and step 3, tabletting: and (3) for tablets, tabletting the granules prepared in the step (2), adding a die sleeve into the tablet machine, and injecting a lubricant by adopting cooled compressed air to ensure cooling and demoulding of tabletting so as to prepare the product.
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| CN102836129A (en) * | 2011-06-22 | 2012-12-26 | 南京亿华药业有限公司 | Cefprozil dry suspension and preparation method thereof |
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