CN104940125A - Solid preparation of oseltamivir phosphate - Google Patents

Abstract

The invention provides a solid preparation of oseltamivir phosphate; the solid preparation contains oseltamivir phosphate and a diluent with the effective treatment or prevention amount, wherein the diluent is maltitol; and the solid preparation further contains an adhesive and a selectable sweetening agent and/or edible essence. The solid preparation has the characteristics of being steady in quality, safe, effective, good in patient compliance and wide in drug application crowd. The invention further provides a preparation method of the solid preparation of oseltamivir phosphate. The preparation method is simple and feasible and is applied to industrial production.

Description

A kind of solid preparation of oseltamivir phosphate

technical field

The invention relates to the field of pharmaceutical preparations, in particular to a solid preparation of oseltamivir phosphate and a preparation method thereof.

Background technique

Oseltamivir (oseltamivir), the chemical name is (3R, 4R, 5S)-acetamide-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester, The structural formula is as follows:

Oseltamivir phosphate is a new type of neuraminidase (NA) inhibitor with high selectivity. It can be used for influenza virus infection, bronchitis, pneumonia, general pain and severe fever. Treatment and prevention, especially effective against influenza A and B viruses. Oseltamivir was launched in Switzerland in 1999. A large number of clinical practices have proved that it has the advantages of high efficiency, low drug resistance, good patient tolerance, and high safety. It is widely used in clinical practice to prevent and treat influenza.

At present, the formulations of oseltamivir phosphate listed in my country are mainly capsules, which are mainly used for adult patients. On the one hand, because the dose is too large, it is not easy to administer the medicine accurately to children, and the safety of the medicine cannot be guaranteed; For the convenience of children, a dry syrup suitable for children has also been developed, but because oseltamivir phosphate has a certain bitterness, in order to cover up its bitterness in the solution, it is necessary to add other excipients that can inhibit or improve its taste , the syrup is not only inconvenient to carry, but also difficult to control the quality.

Chinese patent CN 200610066995 discloses a granule of oseltamivir phosphate and a preparation method thereof. Sucrose is used as a diluent and a sweetener, and the prepared granule can be used for children. Among them, on the one hand, the compatibility between sucrose and API is poor, and impurities are likely to be produced during storage, which affects the quality stability of the product and the safety of medication; on the other hand, sucrose is a highly hygroscopic sugar. Especially when used in granules, which have a large surface area, it is easier to absorb moisture, which is not conducive to the storage of drugs; finally, sucrose has high calories and is not suitable for obese and diabetic patients.

Contents of the invention

Summary of the invention

The first aspect of the present invention provides a solid preparation of oseltamivir phosphate. The solid preparation provided has the characteristics of stable quality, safety and effectiveness, good patient compliance, and a wide range of drug users.

The second aspect of the present invention provides the preparation method of the oseltamivir phosphate solid preparation described in the first aspect, the process is simple and easy, and is suitable for industrial production.

Definition of Terms

The term "RT" stands for retention time, which refers to the time from the beginning of injection of the separated sample component to the maximum concentration of the component after the column.

The term "RRT" stands for relative retention time, which is the ratio of the corrected retention time of a component to that of the corresponding standard.

The term "comprising" or "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

In the foregoing context of this disclosure, whether or not the word "about" or "approximately" is used, all numbers disclosed herein are approximations. The value of each figure may have a difference of less than 10% or a reasonable difference considered by those skilled in the art, such as a difference of 1%, 2%, 3%, 4% or 5%.

Detailed description of the invention

The present invention is based on the deficiencies of the existing preparation research, and develops a solid preparation of oseltamivir phosphate through repeated research on the compatibility of API and different diluents. The solid preparation uses maltitol as a diluent. On the one hand, maltitol has good compatibility with the active ingredient in the stability test, and is not easy to absorb moisture. The quality remains stable for a long time under high humidity conditions, which improves the product quality and ensures the safety of the drug. Safety; on the other hand, maltitol is a polysaccharide alcohol with extremely low calories. Maltitol can hardly be decomposed by saliva, gastric juice, small intestinal membrane enzymes, etc. in the human body. Except for a part that can be used by intestinal bacteria, the rest have no It is digested and excreted, so it is suitable for obese and diabetic patients.

On the other hand, the present invention also studies the binder, and finds that the amount and concentration of the binder are the main factors affecting the particle yield of particles increasing above 60 mesh; by screening suitable binders, the granulation is smooth , to meet the production quality requirements.

In addition, the inventors have unexpectedly found that in the development of the present invention applied to the dosage form of taste-masking preparations, using sucralose as a sweetener can not only effectively mask the taste, but also be compatible with oseltamivir phosphate. Therefore, the present invention can be widely used in dosage forms requiring taste masking, especially in dosage forms for children.

In a first aspect, the present invention provides a solid preparation of oseltamivir phosphate, which comprises a pharmaceutical active ingredient oseltamivir phosphate and a diluent, wherein the diluent is maltitol.

The solid preparation, wherein the dosage ratio of oseltamivir phosphate and maltitol is 1:49-1:29.6.

The solid preparation also includes a binder, wherein the binder is selected from but not limited to polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, polyethylene glycol 6000, gum arabic, or a combination thereof . In some embodiments, the binder is polyvinylpyrrolidone.

In some embodiments, the binder is dissolved in a solvent to form a binder solution, and the solvent is selected from water or ethanol.

In some embodiments, the concentration of the binder solution is 1%-30% (w/w). In some embodiments, the concentration is 5%-15% (w/w).

The solid preparation may also optionally contain a sweetener and/or food flavor.

The sweetener is selected from but not limited to sucralose, aspartame, sodium saccharin, or combinations thereof.

The edible flavor is selected from but not limited to peach flavor, orange juice flavor, strawberry flavor, pineapple flavor, apple flavor, lychee flavor, mango flavor, lemon flavor, or a combination thereof.

The solid preparation comprises 0.2%-42.0% oseltamivir phosphate, 57%-98% maltitol and 0.1%-6.0% binder according to weight percentage. In some embodiments, 1.5%-5.0% oseltamivir phosphate, 94%-98% maltitol, 0.5%-3.0% binder are included.

In some embodiments, 0.01%-1.0% sweeteners, and/or food flavors are also included.

In some embodiments, a solid formulation of oseltamivir phosphate, comprising:

1) 0.2%-42.0% by weight of oseltamivir phosphate;

2) 57%-98% by weight of maltitol; and

3) 0.1-6.0% polyvinylpyrrolidone.

In some embodiments, a solid formulation of oseltamivir phosphate comprises:

1) 1.5%-5.0% by weight of oseltamivir phosphate;

2) 94%-98% by weight maltitol; and

3) 0.5%-3.0% polyvinylpyrrolidone.

In some embodiments, a solid formulation of oseltamivir phosphate, comprising:

1) 1.5%-5.0% by weight of oseltamivir phosphate,

2) 94%-98% by weight of maltitol,

3) 0.5%-3.0% polyvinylpyrrolidone,

4) 0.01-1.0% sucralose, and

5) 0.01-1.0% essence.

In some embodiments, the preparation form of the solid preparation of oseltamivir phosphate provided by the present invention is granule, chewable tablet or orally disintegrating tablet.

In some embodiments, each unit dose of oseltamivir phosphate granules contains 15 mg-150 mg of active ingredient calculated as oseltamivir; in some embodiments, each unit dose of oseltamivir phosphate granules contains Contains 15mg or 25mg of the active ingredient calculated as oseltamivir.

Another aspect of the present invention provides a preparation method of oseltamivir phosphate solid preparation, said method comprising mixing oseltamivir phosphate, diluent, binder and optional edible essence, and/or sweetener , sieving, adding binder solution to make soft material, sieving and drying, granulation and other steps.

In some embodiments, the solid preparation of oseltamivir phosphate can be prepared according to the following method:

1) Pass oseltamivir phosphate and maltitol through a 100-mesh sieve, and mix well;

2) adding the binder into the solvent to form a binder solution;

3) Add the binder solution to the mixed material in 1) to make a soft material, and use a 30-mesh screen to make wet granules;

4) Optionally add sweeteners and/or food flavors; dry the wet granules at a temperature of 60°C, and control the moisture content of the granules below 2%;

5) Sizing through a 20-mesh sieve, mixing the dry granules and passing through a 20-mesh sieve;

6) Divide the dry granules to make granules; or further compress to make tablets.

The oseltamivir phosphate solid preparation provided by the invention can be packaged into bottles or bags, or further compressed into tablets.

The oseltamivir phosphate solid preparation provided by the invention has uniform content and good storage stability, and is made into a unit package, which is convenient for storage and carrying; in addition, the low-calorie auxiliary material is suitable for taking by patients including obesity or diabetes, which expands the number of drug users Range, good taste and suitable preparation form are especially suitable for the preparation of children's medicine. The oseltamivir phosphate solid preparation provided by the invention has a simple preparation method, uses less auxiliary materials, reduces production costs, and is suitable for technological production.

Detailed ways

In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

All the reagents used in the present invention can be purchased from the market.

In the present invention, mg means milligram, g means gram, RT means retention time, and RRT means relative retention time.

Embodiment 1 Oseltamivir Phosphate and Diluent Compatibility Experiment

1) Compatibility test of API and sucrose, mannitol, fructose raw materials and excipients

Weigh an appropriate amount of raw materials and a mixture of raw and auxiliary materials into a vial, add an appropriate amount of purified water (w/w), seal it (simulating a high-temperature and high-humidity environment), and place it in an oven at 60°C. Take a sample on the 10th day to detect its related substances (Content data expressed in percentage, %).

Table 1. Compatibility results of API with sucrose, mannitol, and fructose at high temperature and high humidity for 10 days

Table 2. Compatibility results of API with water-soluble starch, maltodextrin, and maltitol at high temperature and high humidity for 10 days

Note: ND stands for "Not Detectable"

discuss:

The APIs in Table 1 and Table 2 are not the same batch of raw materials. Combining Table 1 and Table 2, by comparing with API and comparing the data of several groups after adding excipients, the total miscellaneous results show that maltitol has more impurities than other excipients. The lowest, can inhibit the production of related substances, and has the best compatibility with API. Although sucrose total miscellaneous 0.32 and maltitol 0.39 have a weak advantage, but because sucrose is easy to absorb moisture, in the test, the sucrose has a lumpy property after 10 days; and maltitol shows good compatibility and stability in terms of both properties and impurities .

Example 2 Oseltamivir Phosphate and Sweetener Compatibility Experiment

Refer to the second appendix XXIX of the Chinese Pharmacopoeia 2010 edition and the guidelines for the stability test of oseltamivir phosphate and pharmaceutical preparations to conduct accelerated tests on the above-mentioned prepared products to investigate the compatibility of API and sweeteners, and weigh appropriate amounts of raw materials and sweeteners Put an appropriate amount of the mixture in a vial, add an appropriate amount of purified water (w/w) and seal it (to simulate a high-temperature and high-humidity environment) and place it in an oven at 60°C. Take a sample on the 10th day to detect its related substances (the content data is represented by a percentage, % ), the relevant substances after the 0th day and the 10th day were sampled, and the results are shown in Table 3.

Table 3. Compatibility test results of oseltamivir phosphate and sweeteners

Remarks: ND means "Not Detectable", API is the same batch of API.

Discussion: The data showed that sucralose showed the least increase in total impurity content on days 0 and 10, showing good compatibility with the API.

Embodiment 3 binder concentration and the impact of content on particle size

The particle size distribution of the granules formulated with different binder concentrations was tested with a manual sieve, and the results are shown in Table 4.

Table 4. Effect of Different Binder Concentrations and Contents on Particle Size

discuss:

Prescription 1-Prescription 4, with the increase of PVP concentration, the yield of granules above 60 mesh can be increased, among which the granules above 60 mesh in prescription 4 reach 84%; prescription 5 uses water as the binder solvent, and no sticking to the screen occurs Phenomenon, and 84% of particles above 60 mesh; compared with prescription 5, prescription 6 adopts the same concentration of binder aqueous solution, but increases the amount of binder, and the particle size of particles above 60 mesh slightly increases, and there is no significant difference with prescription 5. The data in Table 3 shows that the granulation process of prescription 4-prescription 6 all meets the production requirements.

The prescription and preparation of embodiment 4 oseltamivir phosphate solid preparation

name Prescription amount (g) percentage(%) Oseltamivir Phosphate 19.71 1.87 Maltitol 973.3 92.5 PVPK30 59 5.6

Preparation Process:

Make PVPK30 into 15% ethanol solution, feed the raw and auxiliary materials according to 100% of the prescription amount, pass the raw and auxiliary materials through a 100-mesh sieve, add adhesive to make soft materials after mixing, and install 30-mesh sieve in YK-6 swinging granulator Dry the granules at a temperature below 60°C, control the water content of the granules to below 1.0%, sieve the granules through a 20-mesh sieve, mix the dry granules and pass through a 20-mesh sieve before submitting for inspection.

It is subpackaged into unit packs containing unit doses of oseltamivir to make granules; or further compressed into tablets.

The prescription and preparation of embodiment 5 oseltamivir phosphate solid preparation

name Prescription amount (g) percentage(%) Oseltamivir Phosphate 19.71 1.87 Maltitol 973.3 92.16 PVPK30 63 5.97

Preparation Process:

Make PVPK30 into a 10% aqueous solution, feed raw and auxiliary materials according to 100% of the prescription amount, pass the raw and auxiliary materials through a 100-mesh sieve, add binder to make soft materials after mixing, and install 30-mesh sieve in YK-6 swinging granulator to granulate , dry at below 60°C, control the water content of the granules below 1.0%, sieve the 20-mesh sieve, pass the dry granules through a 20-mesh sieve, and submit for inspection.

It is subpackaged into unit packs containing unit doses of oseltamivir to make granules; or further compressed into tablets.

The prescription and preparation of embodiment 6 oseltamivir phosphate solid preparation

name Prescription amount (g) percentage(%) Oseltamivir Phosphate 119 1.87 Maltitol 5840 92.15 PVPK30 378 5.97

Preparation Process:

Make PVPK30 into a 10% aqueous solution, weigh the raw and auxiliary materials according to the prescription, put them into the high-efficiency wet granulator, start the machine for pre-mixing for 7 minutes, add binder, granulate for 3 minutes, and discharge, YK-6 swinging granulator for 30 minutes Granulate with a mesh screen, dry at 55±10°C, and granulate with a 20-mesh screen. Measure the content and water content of the main drug in the granules, determine the filling volume, and divide the packaging.

Pack it into units containing a unit dose of oseltamivir, prepare it into granules, and pack it. Take 10 g of the above granule sample, heat 200 mg of water, stir for 5 minutes, observe the solubility of this product, and the result shows that it has completely melted. The soluble oseltamivir phosphate granules prepared above can be completely dispersed or dissolved in water, thereby ensuring the bioavailability of the granules and making it convenient for patients to take.

The oseltamivir phosphate granules prepared above can also be further compressed to form tablets.

The prescription and preparation of embodiment 7 oseltamivir phosphate solid preparation

name Prescription volume (g) percentage(%) Oseltamivir Phosphate 32.85 3.07 Maltitol 973.3 91.03 PVPK30 63 5.89

Preparation Process:

Make PVPK30 into a 10% aqueous solution, feed raw and auxiliary materials according to 100% of the prescription amount, pass the raw and auxiliary materials through a 100-mesh sieve, add binder to make soft materials after mixing, and granulate with a 30-mesh sieve in YK-6 swinging granulator , dry at below 60°C, control the water content of the granules below 1.0%, sieve the 20-mesh sieve, pass the dry granules through a 20-mesh sieve, and submit for inspection.

It is subpackaged into unit packs containing unit doses of oseltamivir to make granules; or further compressed into tablets.

The prescription and preparation of embodiment 8 oseltamivir phosphate solid preparation

name Prescription amount (g) percentage(%) Oseltamivir Phosphate 15.00 1.98 Maltitol 717.58 94.72 PVPK30 15.15 2.00

Sucralose 7.58 1.00 essence 0.23 0.03

Preparation Process:

Make PVPK30 into a 10% aqueous solution, feed raw and auxiliary materials according to 100% of the prescription amount, pass the raw and auxiliary materials through a 100-mesh sieve, add binder to make soft materials after mixing, and granulate with a 30-mesh sieve in YK-6 swinging granulator , dry at below 60°C, control the water content of the granules below 1.0%, sieve the 20-mesh sieve, pass the dry granules through a 20-mesh sieve, and submit for inspection.

It is subpackaged into unit packs containing unit doses of oseltamivir to make granules; or further compressed into tablets.

The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims (15)

1. a solid preparation for oseltamivir phosphate, it comprises active constituents of medicine oseltamivir phosphate and diluent, and wherein said diluent is maltose alcohol.

2. solid preparation according to claim 1, wherein the weight ratio of oseltamivir phosphate and maltose alcohol is 1:49 ~ 1:29.6.

3. solid preparation according to claim 1, also comprises binding agent, and described binding agent is polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, polyethylene glycol 6000, arabic gum or its combination.

4. solid preparation according to claim 3, also comprises sweeting agent and/or edible essence.

5. solid preparation according to claim 4, described sweeting agent is sucralose, aspartame, saccharin sodium or its combination.

6. solid preparation according to claim 4, described edible essence is peach flavor, essence for organi juice, strawberry essence, flavoring pineapple essence, apple essence, lychee flavor, Fructus Mangifera Indicae essence, Fructus Citri Limoniae essence or its combination.

7. solid preparation according to claim 1, calculates according to percetage by weight, comprises 0.20% ~ 42.00% oseltamivir phosphate, 57% ~ 98% maltose alcohol and 0.1 ~ 6.0% binding agent.

8. solid preparation according to claim 7, comprises:

1) oseltamivir phosphate of 0.20%-42.00% weight,

2) maltose alcohol of 57%-98% weight, and

3) 0.1-6.0% polyvinylpyrrolidone.

9. solid preparation according to claim 7, comprises:

1) oseltamivir phosphate of 1.5%-5.0% weight,

2) maltose alcohol of 94%-98% weight, and

3) 0.5%-3.0% polyvinylpyrrolidone.

10. solid preparation according to claim 7, also comprises 0.01-1.0% sweeting agent and/or 0.01-1.0% edible essence.

11. solid preparations according to claim 10, comprise:

1) oseltamivir phosphate of 1.5%-5.0% weight,

2) maltose alcohol of 94%-98% weight,

3) 0.5%-3.0% polyvinylpyrrolidone,

4) 0.01-1.0% sucralose, and

5) 0.01-1.0% essence.

12. according to the arbitrary described solid preparation of claim 1-11, and its dosage form is granule, chewable tablet or oral cavity disintegration tablet.

13. according to the arbitrary described solid preparation of claim 1-11, containing in the active component 15mg-150mg of Oseltamivir in the oseltamivir phosphate solid preparation of wherein per unit dosage.

14. solid preparations according to claim 13, containing in active component 15mg or 25mg of Oseltamivir in the oseltamivir phosphate solid preparation of wherein per unit dosage.

15. 1 kinds prepare as arbitrary in claim 1-14 as described in the method for solid preparation, comprise following steps:

1) oseltamivir phosphate, maltose alcohol are crossed 100 mesh sieves, abundant mix homogeneously;

2) binding agent is added in solvent, form binder solution;

3) binder solution being joined 1) in the material that mixes, soft material processed, with 30 eye mesh screen wet granulars;

4) optionally add sweeting agent and/or edible essence, mixing, granulate; Dry under wet granular being placed in temperature 60 C condition, control pellet moisture less than 2%;

5) 20 eye mesh screen granulate, cross 20 mesh sieves after always being mixed by dry granule;

6) by dry granule subpackage, granule is made; Or further tabletting, be prepared into tablet.