WO2011032416A1

WO2011032416A1 - Pharmaceutical composition containing dopamine receptor agonist

Info

Publication number: WO2011032416A1
Application number: PCT/CN2010/074691
Authority: WO
Inventors: 鄢启平; 代勇; 李巧霞; 彭俊清; 胡功允
Original assignee: 浙江华海药业股份有限公司
Priority date: 2009-09-19
Filing date: 2010-06-29
Publication date: 2011-03-24
Also published as: CN102470123B; CN102470123A

Abstract

A pharmaceutical composition containing dopamine receptor agonist, in specific, a solid oral dosage form containing ropinirole or the pharmaceutically acceptable salts thereof, is disclosed. Said composition contains, in terms of the total weight of the dosage form, 0.1%-20.0% of ropinirole or its salts, 0.5%-20% calcium carboxymethylcellulose, 70.0%-98.0% fillers, 0.0%-5.0% binders, 0.0%-3.0% glidants and 0.1%-1.5% lubricants. The preparation method thereof is to mix ropinirole or its salts, calcium carboxymethylcellulose, fillers, binders, glidants and lubricants, then compress the raw materials mixture to tablets. Alternatively, the preparation method is to make granules by dry granulating or wet granulating followed by drying process, then to compress the result mixture to tablets after lubricant is added to. The present invention can significantly improve the stability and quality of the product, and the storage requirement thereof would be less strict.

Description

Pharmaceutical composition containing dopamine receptor agonist

The present application claims priority to Chinese Patent Application No. 200910178687.7, entitled "Pharmaceutical Composition Containing Dopamine Receptor Agonist", filed on September 19, 2009, the entire contents of In this application. Technical field

The present invention relates to an oral solid preparation composition of ropinirole or a pharmaceutically acceptable salt thereof and a process for the preparation thereof. Background technique

Ropinirole is a selective dopamine receptor agonist developed by SmithKline Beecham Corp of the United Kingdom for the treatment of Parkinson's disease. First listed in the UK in 1996 and subsequently listed in the US, Europe and other countries. In 2005, the US Food and Drug Administration (FDA) approved ropinirole for the treatment of moderate to severe restless leg syndrome (RLS). .

Currently marketed products, REQUIP®, manufactured by GlaxoSmithKline, are required to be stored at temperatures below 25 °C and are valid for 2 years. The storage conditions of the product depend on the sensitivity of the product to temperature and humidity. The validity period is also determined by the stability of the product under the corresponding conditions. It is found that the brand drug REQUIP® is extremely unstable under high temperature and high humidity conditions, indicating its temperature and The humidity is sensitive and the storage conditions are also higher. The present invention provides a composition having better stability, which is significantly less sensitive to temperature and humidity than branded drugs, and the storage conditions for the product can be significantly reduced. Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a solid oral preparation containing ropinirole or a salt thereof, and a preparation method, and the stability of the product prepared by using the prescription is remarkably improved.

The oral solid preparation of ropinirole hydrochloride is a fast-release product that is rapidly absorbed orally and peaks at 1-2 hours after oral administration. It is often necessary to add some excipients with rapid disintegration effect in the prescription to ensure rapid dissolution of the product. The study found that the brand drug REQUIP® grew rapidly under high temperature and high humidity conditions, indicating that it can not withstand the effects of high temperature and high humidity conditions, avoiding at 25 ° C or below. Light moisture storage is only valid for 2 years. There are strict requirements on the limits of individual impurities and total impurities in the quality control of preparation products. The content of impurities is one of the important indicators to measure the quality of preparation products. The invention uses carboxymethylcellulose calcium as a composition formed by an auxiliary material having a disintegrating effect, so that the stability of the product is remarkably improved, the growth of impurities is slow, and the influence degree of the product on high temperature and high humidity is remarkably lowered, so that the storage condition of the product is required. Lowering can reduce the storage cost of the product and extend the life of the product.

Specifically, the solid oral preparation of ropinirole or a salt thereof according to the present invention is composed of the following components by weight:

Ropinirole or a pharmaceutically acceptable salt thereof 0.1%-20.0%

Carboxymethylcellulose calcium 0.5%-10.0%

Filler 70.0%-98.0%

Adhesive 0.0%-5.0%

Glidant 0.0%-3.0%

Lubricant 0.1% - 1.5%

The sum of the weight percentages of the above components is 100%.

The form of the solid oral preparation ropinirole salt according to the present invention is preferably a hydrochloride salt which is in a prescribed weight ratio of 0.1% to 20.0%, and more preferably 0.1% to 10.0%.

According to the present invention, the amount of calcium carboxymethylcellulose is from 0.5% to 10.0% by weight of the sum of 4, particularly preferably from 2.0% to 5.0%.

The filler increases the dosage form weight in an oral preparation to a size acceptable for industrial production. The fillers selectable in the present invention include one or more of the following, but are not limited to: lactose (anhydrous and monohydrate), micro Crystalline cellulose, mannitol, maltodextrin, phosphoric acid 4 bow, starch, and the like. Preferably, the filler is microcrystalline cellulose and lactose, and the sum of the amounts thereof is from 70.0% to 98.0%, preferably from 80.0% to 98.0%, by weight of the total of the dosage forms. In wet granulation, the material is mainly granulated, thereby improving the fluidity of the material, facilitating tableting or dispensing; and improving the compressibility of the material in direct compression. The binder which can be selected in the present invention includes one or more of the following, but is not limited to: starch syrup, hydroxypropyl cellulose, hypromellose, povidone, ethyl cellulose, and the like. Preferably, the binder is hydroxypropyl cellulose, povidone, and more preferably The hydroxypropyl cellulose is selected, and when present, the binder comprises from 0.0% to 5.0% by weight of the total of the dosage form, particularly preferably from 2.0% to 3.0%.

The glidant is mainly used to improve the fluidity of the material in the preparation, especially in the direct compression of the mixed powder, which adheres to the surface of the mixed powder to reduce the friction between the materials and reduce the generation of static electricity. The glidants which can be selected in the present invention include one or more of the following, but are not limited to: colloidal silica, talc, magnesium silicate. Preferably, the glidant is colloidal silica, and when present, the amount of glidant is from 0.0% to 3.0%, preferably from 0.5% to 1.0%, by weight.

The lubricant acts as a lubricant for the tablet press during the formulation, reducing the force of the tablet during tableting, making the tablet easier to perform. Lubricants which may be selected for the present invention include one or more of the following, but are not limited to: magnesium stearate, stearic acid 4 bow, stearic acid, polyethylene glycol, glyceryl behenate, and the like. Preferably, the lubricant is magnesium stearate, and the lubricant is used in an amount of from 0.1% to 1.5% by weight, preferably from 0.5% to 1.0%, more preferably 0.5%.

The production process suitable for the present invention may be a powder mixing direct compression tablet or a mixed powder dry method. The granulation tablet may also be a wet granulation tablet, preferably a powder direct compression process.

In order to make the ropinirole hydrochloride and other materials in the composition evenly mixed and have good fluidity, the particle size of ropinirole hydrochloride should be controlled. Ropinirole hydrochloride The salt has a median particle diameter of at least 30 μm, preferably in the range of 50 to 100 μm.

The solid oral preparation according to the present invention is preferably a tablet, a granule, a capsule, and more preferably a tablet.

The direct compression tableting process of the powder is easy to enlarge, and the direct tableting process of the powder of the invention is:

(1) mixing or granulating ropinirole hydrochloride with calcium carboxymethylcellulose and a filler, a binder, a glidant;

(2), add lubricant to mix and compress.

The oral solid preparation of the present invention can be coated with a film by a coating process for the purpose of improving the appearance and improving the fluidity, making the product easy to distinguish and package.

When the solid preparation is coated, the film coating component may be a gastric-soluble acrylic resin, hypromellose, hydroxypropyl cellulose, povidone, polyvinyl alcohol, etc., preferably a keloid For the series of products, the coating weight gain is 2%-5%, preferably 2%-3%.

The prescription of the invention has good stability and the prescription process is simple. detailed description

The technical solution of the present invention will be further described below by way of specific embodiments, but the scope of protection of the present invention is not limited thereto: Embodiment 1

In order to more fully understand the present invention, some exemplary embodiments are given below as a reference, but the present invention is not limited to the following embodiments.

Prescription composition:

Production process steps:

(1) mixing ropinirole hydrochloride with microcrystalline cellulose or carboxymethyl cellulose calcium using a one-arm mixing hopper;

(2) adding lactose to the (1) mixture and mixing evenly;

(3), adding magnesium stearate, mixing;

(4), tableting, using a single punch tablet press, rotating speed 45rpm;

(5), coating, the coating powder is prepared into a concentration of 8% using a 70% ethanol solution, stirred for 30 minutes, coated with a high-efficiency coating machine, and the inlet air temperature is controlled from 45 ° C to 50 ° C, coating The weight gain is about 3%. Example 2

prescription

Ropinirole hydrochloride 5.7%

Direct lactose 59.8%

Microcrystalline cellulose 30.0%

Carboxymethylcellulose calcium 4.0%

Magnesium stearate 0.5%

03B64650 coated powder, weight gain of coating 3% or so

Production process steps:

(2) adding lactose to the (1) mixture and mixing evenly;

(3), adding magnesium stearate, mixing;

(4), tableting, using a single punch tablet press, rotating speed 45rpm;

(5), coating, the coating powder is prepared into a concentration of 8% using a 70% ethanol solution, stirred for 30 minutes, coated with a high-efficiency coating machine, and the inlet air temperature is controlled from 45 ° C to 50 ° C, coating The weight gain is about 3%. Example 3

Prescription composition:

Production process steps:

(1), mixing, ropinirole hydrochloride with microcrystalline cellulose, carboxymethylcellulose calcium, lactose Mix

(2), granulation, mixing powder using dry granulation mechanism;

(3), total mixing, adding magnesium stearate, mixing;

(4), tableting, using a single punch tablet press, rotating speed 45rpm;

(5), coating, the coating powder is prepared into a concentration of 8% using a 70% ethanol solution, stirred for 30 minutes, coated with a high-efficiency coating machine, and the inlet air temperature is controlled from 45 ° C to 50 ° C, coating The weight gain is about 3%. Example 4

Prescription composition

Production process steps:

(1) mixing, mixing ropinirole hydrochloride with microcrystalline cellulose, calcium carboxymethylcellulose, lactose, hydroxypropylcellulose;

(2) granulating, mixing the mixed powder with purified water using a wet granulation mechanism, and then drying it by using a fluidized bed;

(3), total mixing, adding magnesium stearate, mixing;

(4), tableting, using a single punch tablet press, rotating speed 45rpm;

(5), coating, the coating powder is prepared into a concentration of 8% using a 70% ethanol solution, stirred for 30 minutes, coated with a high-efficiency coating machine, and the inlet air temperature is controlled from 45 ° C to 50 ° C, coating The weight gain is about 3%. Example 5

Prescription composition:

Production process steps:

(1) mixing ropinirole hydrochloride with starch, carboxymethylcellulose calcium, colloidal silica using a one-arm mixing hopper;

(2) adding microcrystalline cellulose to the mixture (1) and mixing uniformly;

(3), adding magnesium stearate, mixing;

(4), tableting, using a single punch tablet press, rotating speed 45rpm;

(5), coating, the coating powder is prepared into a concentration of 8% using a 70% ethanol solution, stirred for 30 minutes, coated with a high-efficiency coating machine, and the inlet air temperature is controlled from 45 ° C to 50 ° C, coating The weight gain is about 3%. Example 6: Determination of the stability of the product of the present invention

The sample produced in each example and the brand name REQUIP® produced by GlaxoSmithKline

(Comparative) The effect of high temperature and high humidity conditions on the impurity change of the sample was investigated in a desiccator with a saturated open potassium nitrate solution at 60 ° C after opening the sheet and sealing with an aluminum bag. The impurities of the samples at different times under the conditions of initial and high temperature and high humidity were determined by high performance liquid chromatography, and the total impurities of each batch were compared. Stability measurement results:

(1) The product was placed in a desiccator with a saturated potassium nitrate solution at 60 ° C to investigate the effect of high temperature and high humidity conditions on the impurities of the sample. The sample impurity changes are as follows:

(2) The product is sealed in an aluminum bag and placed in a desiccant with a saturated potassium nitrate solution at 60 °C. The effect of high temperature and high humidity conditions on the impurities of the sample is investigated. The sample impurity changes are as follows:

Sample and sampling time Impurity A* Impurity B* Total impurities

Start -- 0.04 0.10 Example

Placed 5 days 0.03 0.06 0.16

1

Placed for 10 days 0.07 0.08 0.34 Start -- 0.02 0.02 Example

Placed for 5 days 0.02 0.03 0.14

2

Placed for 10 days 0.05 0.05 0.33

Starting 0.01 0.02 0.07 Example

Placed for 5 days 0.03 0.03 0.19

3

Placed 10 days 0.06 0.04 0.34

Starting 0.01 0.03 0.08 Example

Placed for 5 days 0.05 0.09 0.23

4

Place 10 days 0.09 0.13 0.46

Start -- 0.03 0.05 Example

Placed for 5 days 0.02 0.05 0.16

5

Placed for 10 days 0.05 0.09 0.32

Start -- 0.04 0.36 Reference placed 5 days 0.27 0.22 1.65

Placed for 10 days 0.64 0.54 3.97

* Imp-A: 4-[2-propylaminoethyl]-1,3-dihydro-2H-indol-2-one

* Imp-B: 4-[2-dipropylaminoethyl]-1Η-吲哚-2,3-one

The above data indicates that the composition has better stability than the branded product, and the sensitivity to high temperature and high humidity is remarkably lowered, which can lower the storage requirements of the product, achieve the reduced storage cost and extend the product expiration date.

Claims

Rights request

A solid oral preparation containing ropinirole or a pharmaceutically acceptable salt thereof, characterized in that it consists of the following weight percentage components:

Ropinirole or a pharmaceutically acceptable salt thereof 0.1%-20.0%

Carboxymethylcellulose calcium 0.5%-10.0%

Filler 70.0%-98.0%

Adhesive 0.0%-5.0%

Glidant 0.0%-3.0%

Lubricant 0.1% - 1.5%

The sum of the weight percentages of the above components is 100%.

The solid oral preparation according to claim 1, wherein the pharmaceutically acceptable salt is ropinirole hydrochloride.

The solid oral preparation according to claim 2, wherein the ropinirole hydrochloride has a median diameter of at least 30 μm, preferably in the range of 50 μm to ΙΟΟμηη.

The solid oral preparation according to claim 1, wherein the weight percentage of the ropinirole or a pharmaceutically acceptable salt thereof is 0.1% to 10.0% by weight of the sum.

The solid oral preparation according to claim 1, wherein the calcium carboxymethylcellulose is used in an amount of from 2.0% to 5.0% by weight.

The solid oral preparation according to claim 1, wherein the filler is selected from the group consisting of anhydrous lactose, lactose monohydrate, microcrystalline cellulose, mannitol, maltodextrin, and phosphoric acid 4 The amount of the mash, starch or the like is preferably from 80.0% to 98.0% by weight of the sum.

The solid oral preparation according to claim 1, wherein the binder is selected from the group consisting of starch, hydroxypropylcellulose, hypromellose, povidone, ethylcellulose; When present, it is preferably used in an amount of from 2.0% to 3.0% by weight of the sum.

The solid oral preparation according to claim 1, wherein the glidant is selected from the group consisting of colloidal silica, talc, magnesium silicate; and when used, the amount thereof is preferably a weight percentage And 0.5% - 1.0%.

The solid oral preparation according to claim 1, wherein the lubricant is selected from the group consisting of magnesium stearate, stearic acid 4 bow, stearic acid, and polyethylene glycol, and the amount thereof is preferably Weight The sum of the percentages is from 0.5% to 1.0%, more preferably 0.5%.

The solid oral preparation according to claim 1, wherein the solid oral preparation is a tablet, and the tablet is a plain tablet or a coated tablet, which is produced by the following steps:

(2) adding lubricant to mix and compress;

(3) If necessary, the tablets obtained in the step (2) are coated. .