CN113876719A - Oseltamivir dry syrup and preparation method thereof - Google Patents

Oseltamivir dry syrup and preparation method thereof Download PDF

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Publication number
CN113876719A
CN113876719A CN202111289203.3A CN202111289203A CN113876719A CN 113876719 A CN113876719 A CN 113876719A CN 202111289203 A CN202111289203 A CN 202111289203A CN 113876719 A CN113876719 A CN 113876719A
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oseltamivir
dry syrup
weight percent
preparation
syrup according
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Inventor
魏涛
姜海涛
杨蕾
徐岩
杨景杰
关晓丽
梁佳辉
郑倩
葛京城
李宏亮
李玉娟
陈丹
杨槐
张玉华
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HARBIN PHARMACEUTICAL GROUP TECHNOLOGY CENTER
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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
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/1611—Inorganic compounds
    • 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
    • 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
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

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  • Life Sciences & Earth Sciences (AREA)
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  • Inorganic Chemistry (AREA)
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  • Communicable Diseases (AREA)
  • Oncology (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses oseltamivir dry syrup and a preparation method thereof, relates to the field of medicine preparation, and aims to provide oseltamivir dry syrup and a preparation method thereof. The oseltamivir dry syrup preparation of the invention consists of 4.0 weight percent of oseltamivir, 89.0 to 93.0 weight percent of filling agent, 0.5 to 2.0 weight percent of preservative, 0.5 to 2.0 weight percent of antioxidant, 0.5 to 2.0 weight percent of glidant and 0.5 to 2.0 weight percent of sweetening agent. The granules prepared by the formula and the method have good uniformity and stability, low related substances, high dissolution rate and high bioavailability, and the preparation process is convenient and easy, has low cost, does not need any special equipment and is suitable for industrial production. The invention is applied to the field of medicine preparation.

Description

Oseltamivir dry syrup and preparation method thereof
Technical Field
The invention relates to the field of medicine preparation, in particular to oseltamivir dry syrup and a preparation method thereof.
Background
Oseltamivir phosphate, (3R,4R,5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester phosphate CAS No.204255-11-8, molecular formula C16H28N2O4.H3PO4Molecular weight 410.40. Neuraminidase (NA) inhibitor antiviral drug, which is a class of anti-influenza virus drugThe oseltamivir phosphate serving as a novel neuraminidase inhibitor has the advantages of being effective to A, B type influenza viruses, difficult to resist drugs, good in patient tolerance, high in safety and the like, and is clinically used for preventing and treating influenza.
Chinese patent application No. 201510049631.7 discloses oseltamivir dry syrup and a preparation method thereof. The granule adopts sucrose and sodium cyclamate as adjuvants to improve taste, and has low dissolution rate, which is below 95% in water as buffer solution for 30 min.
Application No. CN200610066995 discloses oseltamivir phosphate granules and a preparation method thereof, wherein sucrose is used as a diluent, and CN104940125A discloses a diluent used in an oseltamivir phosphate solid preparation is maltose syrup. CN112587484A discloses oseltamivir phosphate dry syrup and a preparation method thereof, wherein the adopted diluent is povidone, saccharin sodium and mesochain glycerate. No consideration is given to whether the stability impurity is lower than the original impurity.
Disclosure of Invention
The invention aims to provide oseltamivir dry syrup and a preparation method thereof, the oseltamivir dry syrup has good taste, rapid granule disintegration, high dissolution rate, high bioavailability and convenient clinical administration, and the preparation method has simple process and controllable quality and is suitable for industrial production.
The oseltamivir dry syrup consists of 4.0 wt% of oseltamivir phosphate, 89.0-93.0 wt% of a filling agent, 0.5-2.0 wt% of a preservative, 0.5-2.0 wt% of an antioxidant, 0.5-2.0 wt% of a glidant and 0.5-2.0 wt% of a sweetening agent.
Further, the adhesive is 50% ethanol solution by volume.
Further, the antioxidant is polyvinyl alcohol.
Further, the glidant is silicon dioxide.
Further, the preservative is sodium benzoate.
Further, the sweetener is aspartame.
Further, the filling agent is sorbitol.
Further, oseltamivir dry syrup contains 0.9 g of oseltamivir per unit dose.
The preparation method of the oseltamivir dry syrup is carried out according to the following contents:
weighing 0.5-2.0 wt% of antioxidant, dissolving in water, heating to dissolve, spraying and granulating 4.0 wt% of oseltamivir phosphate by using a fluidized bed, uniformly mixing the oseltamivir phosphate, the filling agent, the preservative, the glidant and the sweetening agent according to an equivalent progressive method, adding the adhesive into a wet granulator to prepare a soft material, extruding and rolling the soft material by using a 0.6 screen to granulate, drying the wet granules in a boiling dryer, measuring the content and the moisture of the main drug of the granules, determining the loading amount, and packaging the granules with 30 g per unit dose.
Furthermore, the material temperature of the boiling dryer reaches 30-40 ℃, and the drying moisture is controlled to be below 1%.
Furthermore, 40-50 wt% of the material is added with adhesive to make soft material.
The invention provides oseltamivir phosphate dry syrup which comprises oseltamivir phosphate, polyvinyl alcohol, sodium benzoate, sorbitol, aspartame and silicon dioxide. In order to solve the problem that impurities are higher due to Maillard reaction between free amino of oseltamivir phosphate and reducing sugar, on one hand, raw material medicines are protected, polyvinyl alcohol is dissolved, oseltamivir phosphate is subjected to spray granulation, and the contact chance with sorbitol is reduced. Sorbitol, on the other hand, with low reducing sugars, was chosen as filler. In the preparation process, in order to ensure the uniform content of the raw materials in the granules, the raw and auxiliary materials are uniformly mixed, and the glidant silicon dioxide is added, so that the problem of nonuniform mixing of the raw and auxiliary materials is solved. In addition, the granule needs good particle shape, and the addition of ethanol as a binder can prepare the good particle shape without affecting the dissolution rate. The formula is added with a proper amount of sweetener, preferably aspartame safe to human bodies, and the proper amount of sweetener can improve the compliance of patients in taking.
The research of the invention develops oseltamivir dry syrup with a plurality of advantages: for example, the particles are added into water, can be rapidly disintegrated, are suitable for being taken with water and are convenient for patients to take. The granule content is uniform, and the dosage can be conveniently selected according to the age and weight of patients.
The granules of the invention (especially using the preferred formulation) are prepared with the following advantages:
(1) the granule has uniform appearance, good fluidity, accurate loading, uniform content and high dissolution rate;
(2) the dry syrup has low impurity and good stability;
(3) the dissolution rate of the dry syrup in a buffer solution with pH1.2 is more than 95% within 10 min;
(4) the dry syrup is convenient to take, and the administration dosage of the children patients is easy to determine;
(5) the production process is simple and easy to implement, and the cost is low.
Detailed Description
It will be understood by those of ordinary skill in the art that the foregoing embodiments are specific examples for carrying out the invention, and that various changes in form and details may be made therein without departing from the spirit and scope of the invention in practice.
To make the objects, aspects and advantages of the embodiments of the present invention more apparent, the following detailed description clearly illustrates the spirit of the disclosure, and any person skilled in the art, after understanding the embodiments of the disclosure, may make changes and modifications to the technology taught by the disclosure without departing from the spirit and scope of the disclosure.
The exemplary embodiments of the present invention and the description thereof are provided to explain the present invention and not to limit the present invention.
Prescription components Example 1 Example 2 Example 3
Oseltamivir phosphate 20 20 20
Sorbitol 470 / /
Erythritol and its preparation method / 470 /
Mannitol / / 470
Polyvinyl alcohol 5 5 5
Silicon dioxide 2.5 2.5 2.5
Sodium benzoate 0.5 0.5 0.5
Aspartame 2 2 2
Ethanol 125 125 125
The preparation method comprises the following steps:
firstly, granulating: adding polyvinyl alcohol into water, heating and stirring, completely melting, and performing spray granulation by a fluidized bed.
II, sieving: weighing the components according to the prescription, premixing the silicon dioxide, the aspartame, the sodium benzoate and the sorbitol, and sieving the premixed silicon dioxide, the aspartame, the sodium benzoate and the coated oseltamivir phosphate together by a 60-mesh sieve for later use.
Thirdly, mixing: the sieved material was placed in a three-dimensional motion mixer and mixed for 10 minutes.
Fourthly, preparation of adhesive (50% ethanol): weighing the formula amount of ethanol: purified water 1: 1, preparing the adhesive for later use.
Fifthly, mixing and granulating: putting the mixed material into a wet mixing granulator, and adding 40-50 wt% of ethanol based on the weight of the material into an adhesive to prepare a soft material, wherein the specific conditions are as follows: stirring parameters 500rpm, shearing 1000rpm granulation time 3 min. The prepared soft material is placed in an extrusion rounding machine with a 0.6 screen.
Sixthly, drying: drying the granules by using a fluidized bed, wherein the drying temperature is 30-40 ℃, and the drying moisture is controlled to be below 0.5%.
Seventhly, subpackaging: calculated according to the content of 30mg/g product, each package should contain 0.9 g of oseltamivir phosphate, and the loading amount is about 30 g.
The product prepared by the above-mentioned process was subjected to dissolution measurement, and the results are shown in table 2, and the formulation of example 1 was close to the dissolution behavior of the original reference preparation (oseltamivir phosphate dry syrup 3%, manufactured by seiko corporation, china and foreign pharmaceuticals, lot No. 21030101).
Figure BDA0003334006370000041
Example 1 oseltamivir phosphate dry syrup test results are as follows:
Figure BDA0003334006370000042
cumulative dissolution rate test results
In order to examine the performance of the reference preparation more intuitively, the product prepared according to the process is placed in a stability box, the stability box is placed under the conditions of high temperature of 60 ℃ and high humidity of 90% for 10 days, and the difference of the prescription of the sample under different conditions is evaluated, and the result is shown in table 3. The sorbitol is selected to obviously improve the stability of the preparation, and the preparation of the invention has similar dissolution behavior compared with the original preparation, has less total impurities compared with the original preparation and is more beneficial to storage in the environment.
Table 4 stability test results of oseltamivir phosphate dry syrups of example 1, example 2 and example 3
Figure BDA0003334006370000051

Claims (10)

1. Oseltamivir dry syrup is characterized by consisting of 4.0 weight percent of oseltamivir phosphate, 89.0 to 93.0 weight percent of filling agent, 0.5 to 2.0 weight percent of preservative, 0.5 to 2.0 weight percent of antioxidant, 0.5 to 2.0 weight percent of glidant and 0.5 to 2.0 weight percent of sweetening agent.
2. The oseltamivir dry syrup according to claim 1, wherein the binder is 50% by volume of ethanol solution.
3. The oseltamivir dry syrup according to claim 1, wherein the antioxidant is polyvinyl alcohol.
4. The oseltamivir dry syrup according to claim 1, wherein the glidant is silicon dioxide.
5. The oseltamivir dry syrup according to claim 1, wherein the preservative is sodium benzoate.
6. The oseltamivir dry syrup according to claim 1, wherein the sweetener is aspartame.
7. The oseltamivir dry syrup according to claim 1, wherein the filler is sorbitol.
8. The oseltamivir dry syrup according to claim 1, wherein 0.9 g of oseltamivir is contained in the oseltamivir dry syrup per unit dose.
9. The process for preparing oseltamivir dry syrup according to claim 1, which is carried out as follows:
weighing 0.5-2.0 wt% of antioxidant, dissolving in water, heating to dissolve, spraying and granulating 4.0 wt% of oseltamivir phosphate by using a fluidized bed, uniformly mixing the oseltamivir phosphate, the filling agent, the preservative, the glidant and the sweetening agent according to an equivalent progressive method, adding the adhesive into a wet granulator to prepare a soft material, extruding and rolling the soft material by using a 0.6 screen to granulate, drying the wet granules in a boiling dryer, measuring the content and the moisture of the main drug of the granules, determining the loading amount, and packaging the granules with 30 g per unit dose.
10. The process for preparing oseltamivir dry syrup according to claim 9, wherein the temperature of the material in the boiling dryer is 30-40 ℃, and the drying moisture is controlled below 1%.
CN202111289203.3A 2021-11-02 2021-11-02 Oseltamivir dry syrup and preparation method thereof Withdrawn CN113876719A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104940125A (en) * 2014-03-28 2015-09-30 广东东阳光药业有限公司 Solid preparation of oseltamivir phosphate
WO2020180093A2 (en) * 2019-03-05 2020-09-10 주식회사 코아팜바이오 Oseltamivir-containing pharmaceutical composition
CN112121027A (en) * 2020-08-25 2020-12-25 北京民康百草医药科技有限公司 Medicinal composition of oseltamivir phosphate coated granules, application and preparation method
CN112587484A (en) * 2020-12-21 2021-04-02 长江润发(苏州)医药科技有限公司 Oseltamivir phosphate dry syrup and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104940125A (en) * 2014-03-28 2015-09-30 广东东阳光药业有限公司 Solid preparation of oseltamivir phosphate
WO2020180093A2 (en) * 2019-03-05 2020-09-10 주식회사 코아팜바이오 Oseltamivir-containing pharmaceutical composition
CN112121027A (en) * 2020-08-25 2020-12-25 北京民康百草医药科技有限公司 Medicinal composition of oseltamivir phosphate coated granules, application and preparation method
CN112587484A (en) * 2020-12-21 2021-04-02 长江润发(苏州)医药科技有限公司 Oseltamivir phosphate dry syrup and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
潘卫三: "《工业药剂学》", 31 December 2019 *

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