CN116211810A - Preparation method of oseltamium phosphate Wei Ganhun suspension - Google Patents
Preparation method of oseltamium phosphate Wei Ganhun suspension Download PDFInfo
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- CN116211810A CN116211810A CN202310274628.XA CN202310274628A CN116211810A CN 116211810 A CN116211810 A CN 116211810A CN 202310274628 A CN202310274628 A CN 202310274628A CN 116211810 A CN116211810 A CN 116211810A
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- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 55
- 239000010452 phosphate Substances 0.000 title claims abstract description 55
- 239000000725 suspension Substances 0.000 title claims abstract description 55
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000002245 particle Substances 0.000 claims abstract description 57
- 239000000463 material Substances 0.000 claims abstract description 46
- 239000000203 mixture Substances 0.000 claims abstract description 44
- 238000002156 mixing Methods 0.000 claims abstract description 42
- 239000003814 drug Substances 0.000 claims abstract description 30
- 239000008187 granular material Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000004806 packaging method and process Methods 0.000 claims abstract description 9
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 138
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 claims description 85
- 229960002194 oseltamivir phosphate Drugs 0.000 claims description 82
- 239000004408 titanium dioxide Substances 0.000 claims description 69
- 229960005196 titanium dioxide Drugs 0.000 claims description 69
- 229920001285 xanthan gum Polymers 0.000 claims description 61
- 239000000230 xanthan gum Substances 0.000 claims description 56
- 229940082509 xanthan gum Drugs 0.000 claims description 56
- 235000010493 xanthan gum Nutrition 0.000 claims description 56
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- 239000000600 sorbitol Substances 0.000 claims description 31
- 238000007873 sieving Methods 0.000 claims description 30
- 229940079593 drug Drugs 0.000 claims description 27
- 239000004376 Sucralose Substances 0.000 claims description 20
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 20
- 235000010234 sodium benzoate Nutrition 0.000 claims description 20
- 239000004299 sodium benzoate Substances 0.000 claims description 20
- 235000019408 sucralose Nutrition 0.000 claims description 20
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 19
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 16
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- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 8
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- 239000004480 active ingredient Substances 0.000 claims description 4
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- HWPKGOGLCKPRLZ-UHFFFAOYSA-M monosodium citrate Chemical compound [Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O HWPKGOGLCKPRLZ-UHFFFAOYSA-M 0.000 claims description 4
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 235000013923 monosodium glutamate Nutrition 0.000 description 4
- 239000004223 monosodium glutamate Substances 0.000 description 4
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229940061367 tamiflu Drugs 0.000 description 4
- 241000234295 Musa Species 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
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- 238000000227 grinding Methods 0.000 description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
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- 235000010215 titanium dioxide Nutrition 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010069767 H1N1 influenza Diseases 0.000 description 1
- 241000712431 Influenza A virus Species 0.000 description 1
- 241000713196 Influenza B virus Species 0.000 description 1
- 208000002979 Influenza in Birds Diseases 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
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- 206010064097 avian influenza Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 201000010740 swine influenza Diseases 0.000 description 1
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- 241000712461 unidentified influenza virus Species 0.000 description 1
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- 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
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- 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
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- A—HUMAN NECESSITIES
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- 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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Abstract
The invention discloses a preparation method of an oseltamium phosphate Wei Ganhun suspension, which relates to the technical field of pharmaceutical chemistry, and comprises the steps of preprocessing raw materials and auxiliary materials, preparing medicine-containing particles, preparing auxiliary material particles, and total mixing and packaging, so that the oseltamium phosphate Wei Ganhun suspension is obtained, one auxiliary material which is not easy to react with oseltamium phosphate and a preparation process are used in the mixture, under the premise that the strict requirements on the reducing sugar levels of various sugar alcohols are not required, the oseltamium phosphate Wei Ganhun suspension can be stabilized, meanwhile, the preparation process is easier to granulate, the total impurity increase amount of the prepared oseltamium phosphate Wei Ganhun suspension in the long-term storage process is less, the stability is high, and the problem of the stability of the oseltamium phosphate Wei Ganhun suspension is solved, and meanwhile, the preparation method of the oseltamium phosphate Wei Ganhun suspension which is economical, simple and suitable for industrial production is provided.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of an oseltamium phosphate Wei Ganhun suspension.
Background
Oseltamivir phosphate is the most commonly used drug for treating avian influenza, H1N1 influenza A virus and influenza B virus, and is one of the most effective drugs, so that the occurrence of influenza complications can be greatly reduced. The mechanism of action is that oseltamivir phosphate is orally taken, substances similar to virus neuraminidase are produced by metabolism in human bodies, the substances are competitively involved in the process of virus propagation, and the release of viruses from infected cells is interfered, so that the propagation of influenza viruses is reduced;
the prior oseltamivir phosphate preparation is mainly a capsule, and the capsule is mainly used for adult patients, on one hand, because the dosage is too large, the capsule is not easy to accurately administer for children patients, the medication safety cannot be ensured, and on the other hand, the capsule is not easy to swallow, and has poor compliance for the old, children and severe patients, so in recent years, syrup suitable for children patients is developed for facilitating the children patients to take, but because oseltamivir phosphate has a certain bitter taste, other auxiliary materials capable of inhibiting or improving the taste of oseltamivir phosphate in solution are required to be added for covering the bitter taste of oseltamivir phosphate, the syrup is inconvenient to carry, the influence of the corrective on related substances of products is extremely large, the quality is not easy to control, and the dry suspension prepared into liquid preparations before the temporary use is more suitable for the old, children and the people unsuitable for swallowing;
the primary amino group in the oseltamivir phosphate bulk drug structure can react with reducing sugar in a Maillard reaction, the appearance is yellow, impurities are generated, and the stability of oseltamivir phosphate particles adopting sorbitol as a filling agent in the prior art is still poor, so that the oseltamivir phosphate Wei Ganhun suspension adopting sorbitol as the filling agent and having good stability is sought, and the preparation method thereof is a technical problem to be solved in the present day;
for example, chinese patent publication No. CN101389323a discloses a pharmaceutical composition containing oseltamivir phosphate, which comprises an excipient selected from 1 or more kinds of sugars and sugar alcohols having an equilibrium moisture content of 1 wt% or less at 25 ℃ and a relative humidity of 70%, wherein the contents of glucose and mannose contained as impurities in the sugars and sugar alcohols are 0.01 wt% or less with respect to the sugar or sugar alcohol, respectively, and oseltamivir phosphate;
for example, chinese patent publication No. CN104138355a discloses a method for preparing an oseltamium phosphate Wei Ganhun suspension, and also discloses a technical scheme of using a combination of sorbitol and sugar alcohol as a filler (see example 8 of the disclosure), wherein the maximum unknown single impurity of the particles obtained in example 8 is 0.18% at 0 day, the total impurities are 0.32%, the maximum unknown single impurity after 30 days of acceleration is 0.19%, and the total impurities are 0.38%;
the invention provides a preparation method of an oseltamium phosphate Wei Ganhun suspension for solving the problem.
Disclosure of Invention
The invention aims to provide a preparation method of an oseltamium phosphate Wei Ganhun suspension, which is used for solving the technical problems in the background art: the primary amino group in the oseltamivir phosphate bulk drug structure can react with reducing sugar in Maillard reaction, the appearance is yellow, impurities are generated, and the stability of oseltamivir phosphate particles adopting sorbitol as a filling agent in the prior art is still poor, so that the oseltamivir phosphate Wei Ganhun suspension adopting sorbitol as the filling agent and having good stability is sought, and the preparation method of the oseltamivir phosphate suspension is a technical problem to be solved urgently at present.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the preparation method of the oseltamium phosphate Wei Ganhun suspension is characterized by comprising the following steps of: the preparation method of the oseltamium phosphate Wei Ganhun suspension comprises the following steps:
step one: pretreating raw and auxiliary materials, and weighing the raw and auxiliary materials of the following components in parts by weight: 17-23 parts of oseltamivir phosphate, 420-480 parts of sorbitol, 2-4 parts of xanthan gum, 20-30 parts of anhydrous monosodium citrate, 1-2 parts of sodium benzoate, 1-2 parts of titanium dioxide and 0.1-1 part of sucralose;
step two: preparing drug-containing particles, mixing 17-23 parts of oseltamivir phosphate with 1-2 parts of titanium dioxide, then mixing with 2-4 parts of xanthan gum to ensure that the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum meets the mixing strategy, pouring the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum into a wet granulator, adding 80-150 parts of sorbitol and 10-20 parts of wetting agent for stirring, cutting and granulating, sieving the wet particles with a 20-30 mesh sieve, drying at 50-65 ℃, and sieving the dry particles with a 20-30 mesh sieve to obtain the drug-containing particles;
step three: preparing auxiliary material particles, namely pouring 300-320 parts of sorbitol, 20-30 parts of anhydrous sodium citrate, 1-2 parts of sodium benzoate and 0.1-1 part of sucralose into a wet granulator, adding 25-35 parts of wetting agent for stirring, cutting and granulating, sieving the wet granules with a 20-30 mesh sieve for finishing, drying at 50-65 ℃, and sieving the dry granules with a 20-30 mesh sieve for finishing to obtain the auxiliary material particles;
step four: mixing, namely weighing 3-4 parts of fruit essence, and mixing with the drug-containing particles and the auxiliary material particles;
step five: packaging to obtain the oseltamium phosphate Wei Ganhun suspension.
The mixing strategy is: step 201: determination of oseltamium phosphate Wei Zhiliang m for mixing, respectively 1 Mass m of titanium dioxide 2 Mass m of xanthan gum 3 And the total mass M of the mixture, the content proportion of oseltamivir phosphate in the mixture is as follows
The titanium dioxide content in the mixture is +.>
The content ratio of xanthan gum in the mixture is +.>
Step 202: phosphorus is added intoThe mixture of oseltamivir acid, titanium dioxide and xanthan gum is uniformly divided into n equal parts, and the content ratio x of oseltamivir phosphate, titanium dioxide and xanthan gum in each equal part is measured n 、y n And z n The method comprises the steps of carrying out a first treatment on the surface of the Step 203: calculating the variance of the content ratio of oseltamivir phosphate
Variance of the content ratio of titanium dioxide>
Variance of the content ratio of xanthan gum->
Step 204: when->
And->
When the content of the active ingredients is less than 0.001, oseltamivir phosphate, titanium dioxide and xanthan gum are fully mixed.
In the first step, oseltamivir phosphate is screened by a 18-40-mesh screen, sorbitol is screened by an 80-mesh screen, anhydrous citric acid monosodium is screened by a 30-80-mesh screen, sodium benzoate is screened by a 30-80-mesh screen, titanium dioxide is screened by a 30-80-mesh screen, and sucralose is screened by a 30-80-mesh screen.
In the fourth step, the fruit essence is mixed essence of banana, strawberry and honey peach powder.
In the second step, the wetting agent used is 30-60% ethanol water solution.
In step two, the wet granulation is granulated with a 24 mesh screen.
In step three, the drying temperature was 65 ℃.
In step five, the weight of each bag was 13g.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention provides an auxiliary material which is not easy to react with oseltamivir phosphate and a preparation process thereof, and under the premise of not needing to make strict requirements on the reducing sugar levels of various sugar alcohols, the oseltamivir phosphate Wei Ganhun suspension can be stabilized, and meanwhile, granulation is easier during preparation.
2. The increase trend of the impurities of the sample prepared by the method is smaller than that of the impurities in the prior grinding product Tamiflu, and the total impurities of the prepared oseltamium phosphate Wei Ganhun suspension are less in increase and high in stability in the long-term storage process.
3. The invention provides a mixing strategy, which can effectively detect whether oseltamivir phosphate, titanium dioxide and xanthan gum are fully mixed, and prevent the condition that the stability of the medicine is affected by uneven material distribution.
4. The invention solves the problem of the stability of the oseltamium phosphate Wei Ganhun suspension, and simultaneously provides an economic, simple and convenient preparation method of the oseltamium phosphate Wei Ganhun suspension suitable for industrial production.
Drawings
Fig. 1 is a flow chart of a preparation method of the oseltamium phosphate Wei Ganhun suspension.
Fig. 2 is a flow chart of a mixing strategy of a preparation method of the oseltamium phosphate Wei Ganhun suspension.
Detailed Description
The following examples of the present invention are presented in order to illustrate and describe the invention in more detail and not to limit the invention to the form disclosed, and many modifications and variations will be apparent to those skilled in the art.
Example 1
The invention provides an auxiliary material which is not easy to react with oseltamivir phosphate and a preparation process thereof, under the premise of not providing strict requirements for reducing sugar levels of various added sugar alcohols, the oseltamivir phosphate Wei Ganhun suspension is stable, meanwhile, the preparation is easier to granulate, the increasing trend of prepared sample impurities is smaller than that of impurities in the prior grinding product Tamiflu, the total impurity increasing amount of the prepared oseltamivir phosphate Wei Ganhun suspension in the long-term storage process is small, the stability is high, and the preparation method of the oseltamivir phosphate Wei Ganhun suspension is characterized by comprising the following steps of: the preparation method of the oseltamium phosphate Wei Ganhun suspension comprises the following steps:
step one: pretreating raw and auxiliary materials, and weighing the raw and auxiliary materials of the following components in parts by weight: 17-23 parts of oseltamivir phosphate, 420-480 parts of sorbitol, 2-4 parts of xanthan gum, 20-30 parts of anhydrous monosodium citrate, 1-2 parts of sodium benzoate, 1-2 parts of titanium dioxide and 0.1-1 part of sucralose;
step two: preparing drug-containing particles, mixing 17-23 parts of oseltamivir phosphate with 1-2 parts of titanium dioxide, then mixing with 2-4 parts of xanthan gum to ensure that the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum meets the mixing strategy, pouring the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum into a wet granulator, adding 80-150 parts of sorbitol and 10-20 parts of wetting agent for stirring, cutting and granulating, sieving the wet particles with a 20-30 mesh sieve, drying at 50-65 ℃, and sieving the dry particles with a 20-30 mesh sieve to obtain the drug-containing particles;
step three: preparing auxiliary material particles, namely pouring 300-320 parts of sorbitol, 20-30 parts of anhydrous sodium citrate, 1-2 parts of sodium benzoate and 0.1-1 part of sucralose into a wet granulator, adding 25-35 parts of wetting agent for stirring, cutting and granulating, sieving the wet granules with a 20-30 mesh sieve for finishing, drying at 50-65 ℃, and sieving the dry granules with a 20-30 mesh sieve for finishing to obtain the auxiliary material particles;
step four: mixing, namely weighing 3-4 parts of fruit essence, and mixing with the drug-containing particles and the auxiliary material particles;
step five: packaging to obtain the oseltamium phosphate Wei Ganhun suspension.
In example 1, the mixing strategy is: step 201: determination of oseltamium phosphate Wei Zhiliang m for mixing, respectively 1 Mass m of titanium dioxide 2 Xanthan gumQuantity m 3 And the total mass M of the mixture, the content proportion of oseltamivir phosphate in the mixture is as follows
The titanium dioxide content in the mixture is +.>
The content ratio of xanthan gum in the mixture is +.>
Step 202: the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum is uniformly divided into n equal parts, and the content ratio x of oseltamivir phosphate, titanium dioxide and xanthan gum in each equal part is measured n 、y n And z n The method comprises the steps of carrying out a first treatment on the surface of the Step 203: calculating the variance of the content ratio of oseltamivir phosphate>
Variance of the content ratio of titanium dioxide>
Variance of the content ratio of xanthan gum->
Step 204: when->
And->
When the content of the active ingredients is less than 0.001, oseltamivir phosphate, titanium dioxide and xanthan gum are fully mixed.
In the first step, oseltamivir phosphate is screened by a 18-40-mesh screen, sorbitol is screened by an 80-mesh screen, anhydrous citric acid monosodium is screened by a 30-80-mesh screen, sodium benzoate is screened by a 30-80-mesh screen, titanium dioxide is screened by a 30-80-mesh screen, and sucralose is screened by a 30-80-mesh screen.
In the fourth step, the fruit essence is mixed essence of banana, strawberry and honey peach powder.
In the second step, the wetting agent used is 30-60% ethanol water solution.
In step two, the wet granulation is granulated with a 24 mesh screen.
In step three, the drying temperature was 65 ℃.
In step five, the weight of each bag was 13g.
In example 1, comparative examples 1 to 4 were set to prepare oseltamium phosphate Wei Ganhun suspensions, and comparative examples 1 to 4 were different from examples in the mixing order and the combination order of the materials in 2 kinds of granules at the time of granulation, except for the above differences, and the other conditions were the same.
Comparative example 1
The preparation method of the oseltamium phosphate Wei Ganhun suspension comprises the following steps:
step one: raw and auxiliary materials are pretreated, and the raw and auxiliary materials of the following components in parts by weight are weighed: 17-23 parts of oseltamivir phosphate is sieved by a sieve with 18-40 meshes, 420-480 parts of sorbitol is sieved by a sieve with 30-80 meshes, 20-30 parts of anhydrous citric acid monosodium glutamate is sieved by a sieve with 30-80 meshes, 1-2 parts of sodium benzoate is sieved by a sieve with 30-80 meshes, 1-2 parts of titanium dioxide is sieved by a sieve with 30-80 meshes, and 0.1-1 part of sucralose is sieved by a sieve with 30-80 meshes;
step two: preparing drug-containing granules, namely pouring oseltamivir phosphate, sorbitol, anhydrous sodium citrate, sodium benzoate, sucralose, titanium dioxide and 2-4 parts of xanthan gum into a wet granulator, adding 40-60 parts of wetting agent for stirring, cutting and granulating, sieving the wet granules with a 20-30 mesh sieve, drying at 50-65 ℃, and sieving the dry granules with 20-30 mesh sieve to obtain dry granules;
step three: mixing, namely weighing 3-4 parts of fruit essence and mixing with the dry particles to obtain total mixed particles;
step four: packaging, wherein the weight of each bag is 13g, to obtain the oseltamium phosphate Wei Ganhun suspension.
Comparative example 2
The preparation method of the oseltamium phosphate Wei Ganhun suspension comprises the following steps:
step one: raw and auxiliary materials are pretreated, and the raw and auxiliary materials of the following components in parts by weight are weighed: 17-23 parts of oseltamivir phosphate is sieved by a sieve with 18-40 meshes, 420-480 parts of sorbitol is sieved by a sieve with 30-80 meshes, 20-30 parts of anhydrous citric acid monosodium glutamate is sieved by a sieve with 30-80 meshes, 1-2 parts of sodium benzoate is sieved by a sieve with 30-80 meshes, 1-2 parts of titanium dioxide is sieved by a sieve with 30-80 meshes, and 0.1-1 part of sucralose is sieved by a sieve with 30-80 meshes;
step two: preparing drug-containing granules, pouring oseltamivir phosphate, anhydrous sodium citrate and 2-4 parts of xanthan gum into a wet granulator, adding 80-150 parts of sorbitol, adding 10-20 parts of wetting agent, stirring, cutting and granulating, sieving the wet granules with a 20-30 mesh sieve, and drying at 50-65 ℃, and sieving the dry granules with 20-30 mesh sieve to obtain the drug-containing granules;
step three: preparing auxiliary material particles, pouring 300-320 parts of sorbitol, titanium dioxide, sodium benzoate and sucralose into a wet granulator, adding 25-35 parts of wetting agent, stirring, cutting and granulating, sieving the wet particles with a 20-30 mesh sieve, drying at 50-65 ℃, and sieving the dry particles with 20-30 mesh sieve to obtain auxiliary material particles;
step four: mixing, namely weighing 3-4 parts of fruit essence, and mixing with the drug-containing particles and the auxiliary material particles;
step five: packaging, wherein the weight of each bag is 13g, to obtain the oseltamium phosphate Wei Ganhun suspension.
Comparative example 3
The preparation method of the oseltamium phosphate Wei Ganhun suspension comprises the following steps:
step one: raw and auxiliary materials are pretreated, and the raw and auxiliary materials of the following components in parts by weight are weighed: 17-23 parts of oseltamivir phosphate is sieved by a sieve with 18-40 meshes, 420-480 parts of sorbitol is sieved by a sieve with 30-80 meshes, 20-30 parts of anhydrous citric acid monosodium glutamate is sieved by a sieve with 30-80 meshes, 1-2 parts of sodium benzoate is sieved by a sieve with 30-80 meshes, 1-2 parts of titanium dioxide is sieved by a sieve with 30-80 meshes, and 0.1-1 part of sucralose is sieved by a sieve with 30-80 meshes;
step two: preparing drug-containing granules, pouring oseltamivir phosphate and 80-150 parts of sorbitol into a wet granulator, adding 10-20 parts of xanthan gum solution as an adhesive, stirring, cutting and granulating, sieving the wet granules with a 20-30 mesh sieve, granulating, drying at 50-65 ℃, and sieving the dry granules with a 20-30 mesh sieve to obtain the drug-containing granules;
step three: preparing auxiliary material particles, namely pouring 300-320 parts of sorbitol, titanium dioxide, anhydrous sodium citrate, sodium benzoate and sucralose into a wet granulator, adding 25-35 parts of wetting agent, stirring, cutting and granulating, sieving the wet particles with a 20-30 mesh sieve, granulating, drying at 50-65 ℃, and sieving the dry particles with a 20-30 mesh sieve to obtain auxiliary material particles;
step four: mixing, namely weighing 3-4 parts of fruit essence, and mixing with the drug-containing particles and the auxiliary material particles;
step five: packaging, wherein the weight of each bag is 13g, to obtain the oseltamium phosphate Wei Ganhun suspension.
Comparative example 4
The preparation method of the oseltamium phosphate Wei Ganhun suspension comprises the following steps:
step one: raw and auxiliary materials are pretreated, and the raw and auxiliary materials of the following components in parts by weight are weighed: 17-23 parts of oseltamivir phosphate is sieved by a sieve with 18-40 meshes, 420-480 parts of sorbitol is sieved by a sieve with 30-80 meshes, 20-30 parts of anhydrous citric acid monosodium glutamate is sieved by a sieve with 30-80 meshes, 1-2 parts of sodium benzoate is sieved by a sieve with 30-80 meshes, 1-2 parts of titanium dioxide is sieved by a sieve with 30-80 meshes, and 0.1-1 part of sucralose is sieved by a sieve with 30-80 meshes;
step two: preparing drug-containing granules, namely pouring oseltamivir phosphate, titanium dioxide, anhydrous sodium citrate, sodium benzoate, sucralose and 2-4 parts of xanthan gum into a wet granulator, adding 10-20 parts of wetting agent for stirring, cutting and granulating, sieving the wet granules with a 20-30 mesh sieve, and drying at 50-65 ℃, and sieving the dry granules with 20-30 mesh sieve to obtain the drug-containing granules;
step three: preparing auxiliary material particles, pouring sorbitol into a wet granulator, adding 25-35 parts of wetting agent, stirring, cutting and granulating, sieving the wet particles with a 20-30 mesh sieve, granulating, drying at 50-65 ℃, and sieving the dry particles with 20-30 mesh sieve to obtain auxiliary material particles;
step four: mixing, namely weighing 3-4 parts of fruit essence, and mixing with the drug-containing particles and the auxiliary material particles;
step five: packaging, wherein the weight of each bag is 13g, to obtain the oseltamium phosphate Wei Ganhun suspension.
The samples prepared in example 1, the samples prepared in each comparative example and the samples prepared by the original grinding "Tamiflu" were subjected to stability study under the conditions of temperature 40+ -2deg.C and humidity 75+ -5%, and key impurity changes were examined, and the experimental results are shown in Table 1 below:
TABLE 1 stability acceleration test (40 ℃,75% RH) impurity detection results
As can be seen from table 1, the samples prepared in example 1 and the samples prepared in each comparative example prepared by the method of the present invention had an increase in impurities less than that of Tamiflu and the samples of example 1 had a trend of increase in impurities less than those of the samples of comparative examples 1 to 4 over time, and it was found that the examples made it possible to stabilize the oseltamium phosphate Wei Ganhun suspension and to make it easier to granulate the preparation without requiring severe demands on the levels of reducing sugar with various added sugar alcohols.
Example 2
The invention provides a mixing strategy, which can effectively detect whether oseltamivir phosphate, titanium dioxide and xanthan gum are fully mixed, and prevent the situation that the stability of the medicine is affected by uneven material distribution, and the specific scheme is that as shown in fig. 1 and 2, a preparation method of oseltamivir phosphate Wei Ganhun suspension is characterized in that: the preparation method of the oseltamium phosphate Wei Ganhun suspension comprises the following steps:
step one: pretreating raw and auxiliary materials, and weighing the raw and auxiliary materials of the following components in parts by weight: 17-23 parts of oseltamivir phosphate, 420-480 parts of sorbitol, 2-4 parts of xanthan gum, 20-30 parts of anhydrous monosodium citrate, 1-2 parts of sodium benzoate, 1-2 parts of titanium dioxide and 0.1-1 part of sucralose;
step two: preparing drug-containing particles, mixing 17-23 parts of oseltamivir phosphate with 1-2 parts of titanium dioxide, then mixing with 2-4 parts of xanthan gum to ensure that the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum meets the mixing strategy, pouring the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum into a wet granulator, adding 80-150 parts of sorbitol and 10-20 parts of wetting agent for stirring, cutting and granulating, sieving the wet particles with a 20-30 mesh sieve, drying at 50-65 ℃, and sieving the dry particles with a 20-30 mesh sieve to obtain the drug-containing particles;
step three: preparing auxiliary material particles, namely pouring 300-320 parts of sorbitol, 20-30 parts of anhydrous sodium citrate, 1-2 parts of sodium benzoate and 0.1-1 part of sucralose into a wet granulator, adding 25-35 parts of wetting agent for stirring, cutting and granulating, sieving the wet granules with a 20-30 mesh sieve for finishing, drying at 50-65 ℃, and sieving the dry granules with a 20-30 mesh sieve for finishing to obtain the auxiliary material particles;
step four: mixing, namely weighing 3-4 parts of fruit essence, and mixing with the drug-containing particles and the auxiliary material particles;
step five: packaging to obtain the oseltamium phosphate Wei Ganhun suspension.
In example 2, the mixing strategy is: step 201: determination of oseltamium phosphate Wei Zhiliang m for mixing, respectively 1 Mass m of titanium dioxide 2 Mass m of xanthan gum 3 And the total mass M of the mixture, the content proportion of oseltamivir phosphate in the mixture is as follows
The titanium dioxide content in the mixture is +.>
The content ratio of xanthan gum in the mixture is +.>
Step 202: the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum is uniformly divided into n equal parts, and the content ratio x of oseltamivir phosphate, titanium dioxide and xanthan gum in each equal part is measured n 、y n And z n The method comprises the steps of carrying out a first treatment on the surface of the Step 203: calculating the variance of the content ratio of oseltamivir phosphate>
Variance of the content ratio of titanium dioxide>
Variance of the content ratio of xanthan gum->
Step 204: when->
And->
When the content of the active ingredients is less than 0.001, oseltamivir phosphate, titanium dioxide and xanthan gum are fully mixed.
In the first step, oseltamivir phosphate is screened by a 18-40-mesh screen, sorbitol is screened by an 80-mesh screen, anhydrous citric acid monosodium is screened by a 30-80-mesh screen, sodium benzoate is screened by a 30-80-mesh screen, titanium dioxide is screened by a 30-80-mesh screen, and sucralose is screened by a 30-80-mesh screen.
In the fourth step, the fruit essence is mixed essence of banana, strawberry and honey peach powder.
In the second step, the wetting agent used is 30-60% ethanol water solution.
In step two, the wet granulation is granulated with a 24 mesh screen.
In step three, the drying temperature was 65 ℃.
In step five, the weight of each bag was 13g.
In example 2, it was determined that oseltamivir phosphate Wei Zhiliang was 20 parts by weight, titanium dioxide was 2 parts by weight, xanthan gum was 3 parts by weight, and the total mass of the mixture was 25 parts by weight, then oseltamivir phosphate was 0.80% in the mixture, titanium dioxide was 0.08% in the mixture, and xanthan gum was 0.12% in the mixture; the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum is uniformly divided into 10 equal parts, and the content ratio of oseltamivir phosphate in each equal part of the mixture is measured to be 0.76, 0.79, 0.81, 0.80, 0.78 and 0.77 respectivelyThe titanium dioxide content ratio is respectively 0.08, 0.07, 0.09, 0.10, 0.07, 0.09, 0.06, 0.08 and 0.09, and the xanthan gum content ratio in each equal part of the mixture is respectively 0.16, 0.13, 0.12, 0.11, 0.12, 0.14, 0.10, 0.14 and 0.14; calculating the variance of the content ratio of oseltamivir phosphate
0.00037, variance of the titanium dioxide content ratio->
0.00013, variance of the content ratio of xanthan gum>
0.00038%>
And->
All are smaller than 0.001, which indicates that oseltamivir phosphate, titanium dioxide and xanthan gum are fully mixed.
Comparative example 5
In this comparative example 5, oseltamium phosphate Wei Ganhun suspension was prepared in the same manner as in example 2, and the difference between comparative example 5 and example 2 was whether oseltamium phosphate, titanium dioxide and xanthan gum were sufficiently mixed or not, except for the above differences.
In comparative example 5, it was determined that oseltamivir phosphate Wei Zhiliang was 20 parts by weight, titanium dioxide was 2 parts by weight, xanthan gum was 3 parts by weight, and the total mass of the mixture was 25 parts by weight, then oseltamivir phosphate was 0.80% in the mixture, titanium dioxide was 0.08% in the mixture, and xanthan gum was 0.12% in the mixture; the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum is uniformly divided into 10 equal parts, and the content ratio of oseltamivir phosphate in each equal part of the mixture is measured to be 0.75, 0.76, 0.82 and 0.85 respectively,0.78, 0.76, 0.83, 0.81, 0.77, 0.78, the titanium dioxide content of each equal part of the mixture is respectively 0.09, 0.07, 0.08, 0.05, 0.12, 0.06, 0.08, 0.10, 0.09, 0.08, and the xanthan gum content of each equal part of the mixture is respectively 0.16, 0.17, 0.10, 0.18, 0.09, 0.13, 0.14; calculating the variance of the content ratio of oseltamivir phosphate
0.00113, variance of the titanium dioxide content ratio->
0.00036, variance of the content ratio of xanthan gum>
0.00112, wherein the variance of the content ratio of titanium dioxide is>
Less than 0.001, wherein the variance of the content ratio of oseltamivir phosphate is +.>
And the variance of the content ratio of xanthan gum +.>
Greater than 0.001 indicates that oseltamivir phosphate, titanium dioxide, and xanthan gum are not adequately mixed.
The samples prepared in example 2 and comparative example 5 above were subjected to stability studies at a temperature of 40.+ -. 2 ℃ and a humidity of 75.+ -. 5%, and key impurity changes were examined, and the experimental results are shown in Table 2 below:
TABLE 2 influence of uniformity of mixing on stability test (40 ℃ C., 75% RH) impurity detection results
| Impurity/embodiment | Example 2 | Comparative example 5 |
| RRT＝0.18 | 0.094 | 0.128 |
| RRT＝0.55 | 0.088 | 0.166 |
| RRT＝0.66 | Not detected | 0.192 |
| RRT＝0.71 | 0.085 | Not detected |
| RRT＝0.80 | 0.063 | 0.074 |
| RRT＝1.14 | 0.248 | Not detected |
| RRT＝1.26 | Not detected | 0.258 |
| RRT＝1.38 | Not detected | 0.049 |
| RRT＝1.67 | 0.163 | 0.167 |
| Total impurities | 0.741 | 1.034 |
As can be seen from table 2, the increase in the impurity of example 2 of the sample prepared by the method of the present invention was smaller than that of comparative example 5 over time, and it was found that the oseltamivir phosphate, titanium dioxide and xanthan gum were sufficiently mixed to make the oseltamium phosphate Wei Ganhun suspension more stable.
It is evident that the embodiments described are only some, but not all, embodiments of the present invention, and that all other embodiments, both to the person skilled in the art and to the relevant art(s), based on the embodiments of the present invention without creative effort, shall fall within the scope of protection of the present invention, as structures, devices and methods of operation not specifically described and illustrated herein are all carried out according to the conventional means of the art, unless specifically described and defined.
Claims (8)
1. The preparation method of the oseltamium phosphate Wei Ganhun suspension is characterized by comprising the following steps of: the preparation method of the oseltamium phosphate Wei Ganhun suspension comprises the following steps:
step one: pretreating raw and auxiliary materials, and weighing the raw and auxiliary materials of the following components in parts by weight: 17-23 parts of oseltamivir phosphate, 420-480 parts of sorbitol, 2-4 parts of xanthan gum, 20-30 parts of anhydrous monosodium citrate, 1-2 parts of sodium benzoate, 1-2 parts of titanium dioxide and 0.1-1 part of sucralose;
step two: preparing drug-containing particles, mixing 17-23 parts of oseltamivir phosphate with 1-2 parts of titanium dioxide, then mixing with 2-4 parts of xanthan gum to ensure that the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum meets the mixing strategy, pouring the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum into a wet granulator, adding 80-150 parts of sorbitol and 10-20 parts of wetting agent for stirring, cutting and granulating, sieving the wet particles with a 20-30 mesh sieve, drying at 50-65 ℃, and sieving the dry particles with a 20-30 mesh sieve to obtain the drug-containing particles;
step three: preparing auxiliary material particles, namely pouring 300-320 parts of sorbitol, 20-30 parts of anhydrous sodium citrate, 1-2 parts of sodium benzoate and 0.1-1 part of sucralose into a wet granulator, adding 25-35 parts of wetting agent for stirring, cutting and granulating, sieving the wet granules with a 20-30 mesh sieve for finishing, drying at 50-65 ℃, and sieving the dry granules with a 20-30 mesh sieve for finishing to obtain the auxiliary material particles;
step four: mixing, namely weighing 3-4 parts of fruit essence, and mixing with the drug-containing particles and the auxiliary material particles;
step five: packaging to obtain the oseltamium phosphate Wei Ganhun suspension.
2. The method for preparing the oseltamium phosphate Wei Ganhun suspension according to claim 1, which is characterized in that: the mixing strategy is: step 201: determination of oseltamium phosphate Wei Zhiliang m for mixing, respectively 1 Mass m of titanium dioxide 2 Mass m of xanthan gum 3 And the total mass M of the mixture, the content proportion of oseltamivir phosphate in the mixture is as follows
The titanium dioxide content in the mixture is +.>
The content ratio of xanthan gum in the mixture is +.>
Step 202: the mixture of oseltamivir phosphate, titanium dioxide and xanthan gum is uniformly divided into n equal parts, and the content ratio x of oseltamivir phosphate, titanium dioxide and xanthan gum in each equal part is measured n 、y n And z n The method comprises the steps of carrying out a first treatment on the surface of the Step 203: calculating the variance of the content ratio of oseltamivir phosphate>
Variance of the content ratio of titanium dioxide>
Variance of the content ratio of xanthan gum->
Step 204: when->
And->
When the content of the active ingredients is less than 0.001, oseltamivir phosphate, titanium dioxide and xanthan gum are fully mixed.
3. The method for preparing the oseltamium phosphate Wei Ganhun suspension according to claim 2, which is characterized in that: in the first step, oseltamivir phosphate is screened by a 18-40-mesh screen, sorbitol is screened by an 80-mesh screen, anhydrous citric acid monosodium is screened by a 30-80-mesh screen, sodium benzoate is screened by a 30-80-mesh screen, titanium dioxide is screened by a 30-80-mesh screen, and sucralose is screened by a 30-80-mesh screen.
4. The method for preparing the oseltamium phosphate Wei Ganhun suspension according to claim 3, wherein the method comprises the following steps: in the fourth step, the fruit essence is mixed essence of banana, strawberry and honey peach powder.
5. The method for preparing the oseltamium phosphate Wei Ganhun suspension according to claim 4, which is characterized in that: in the second step, the wetting agent used is 30-60% ethanol water solution.
6. The method for preparing the oseltamium phosphate Wei Ganhun suspension according to claim 5, wherein the method comprises the following steps: in step two, the wet granulation is granulated with a 24 mesh screen.
7. The method for preparing the oseltamium phosphate Wei Ganhun suspension according to claim 6, wherein the method comprises the following steps: in step three, the drying temperature was 65 ℃.
8. The method for preparing the oseltamium phosphate Wei Ganhun suspension according to claim 7, wherein the method comprises the following steps: in step five, the weight of each bag was 13g.
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