TWI419685B - Entacapone composition - Google Patents

Description

Anita composition

The present invention relates to an Entacapone composition comprising acetonide, PVP K30 and SDS. Further, the present invention relates to a process for the preparation of the aforementioned ampicone composition and use thereof.

(E)-2-Cyano-3-(3,4-dihydroxy-5-nitro-phenyl)-N,N-diethyl-2-propenylamine ((E) -2-cyano-3-(3,4-dihydroxy-5-nitro-phenyl)-N,N-diethyl-2-propenamide) is a drug currently known to be useful in the treatment of Parkinson's Disease.

Due to the low dissolution rate and low bioavailability of ampicone, the currently known ampoule compositions are mostly made into smaller particles by grinding or pulverization to increase their dissolution rate and bioactivity. availability. For example, US 2010/0104634 A1 is such that 90% of the Angkor particles have a particle size of less than 40 μm, while WO2009098661 A1 has a particle size of less than 30 μm by subjecting the particles of anaconone and sugar alcohol to a particle size process.

However, processes such as grinding or micronization tend to generate high heat, which deteriorates the drug. In addition, such processes have problems of low yield and high cost. Therefore, how to prepare an ampicone composition having a high elution rate or high bioavailability without a process such as grinding, pulverization or micronization is an extremely problem to be solved in the industry.

In order to solve the above problems, the inventors have developed an improved method capable of improving the elution rate of acetonide in the process of grinding, pulverizing or micronizing, and simplifying the process to increase the yield and reduce the production cost.

One object of the present invention is to provide an ampicone composition comprising acetonide or a pharmaceutically acceptable salt thereof, PVP K30, SDS, and at least one pharmaceutically acceptable excipient.

In order to achieve the above object, the present invention provides an ampicone composition comprising acetonide or a pharmaceutically acceptable salt thereof, PVP K30 and SDS; wherein the dose ratio of Angkorp: PVP K30:SDS is 1 : 0.05~0.6: 0.06~0.1, and its dissolution rate is greater than 88%.

In a preferred embodiment of the present invention, the dose ratio of Pantagon: PVP K30:SDS is 1:0.05 to 0.2:0.06; more preferably, the dose ratio is 1 :0.2:0.06.

In a preferred embodiment of the invention, the amphoteric composition has a dissolution rate of greater than 90%; more preferably, the dissolution rate is greater than 95%.

In a preferred embodiment of the present invention, the ampicone composition further comprises at least one excipient, and the excipient is selected from the group consisting of Microcrystalline Cellulose (MCC) and Mannitol (Mannitol). ), Cellulose, Hydroxypropyl Methylcellulose, Povidone, Crospovidone, Starch, Lactose, Carbohydrate, Croccarmellose Sodium ), or a combination thereof.

The present invention also provides a method for preparing an ampicone composition as described above, which comprises the following steps:

(a) Mixing Ankecapone or its pharmaceutically acceptable salt, PVP K30 and SDS, wherein the dose ratio of PVP K30:SDS is 1:0.05~0.6:0.06~0.1;

(b) passing the mixture obtained in the step (a) through a sieve, and the mesh of the sieve is below 180 μm, more preferably below 150 μm;

(c) granulating the mixture obtained in step (b);

(d) drying the granules obtained in step (c) until the moisture content is between 1% and 3%, resulting in an acetonide composition as described in claim 1 of the patent application; It can be a grinding, pulverizing or micronizing step having a particle size of less than 30 μm, or a mixture of pharmaceutically acceptable salts thereof, PVP K30 and SDS.

In a preferred embodiment of the present invention, the dosage ratio of the PVP K30:SDS in the step (a) of the foregoing method is 1:0.05~0.2:0.06; more preferably, the dose ratio is 1: 0.2: 0.06.

In a preferred embodiment of the invention, the granulation of step (c) of the foregoing process is wet granulation.

In a preferred embodiment of the invention, the foregoing method does not comprise a milling, comminuting or micronizing step of having a particle size of less than 40 μm of a mixture of ampicone or a pharmaceutically acceptable salt thereof, PVP K30 and SDS.

In a preferred embodiment of the present invention, the method step (a) further comprises at least one excipient, and the excipient is selected from the group consisting of microcrystalline cellulose, mannitol, cellulose, hydroxypropylmethyl Cellulose, povidone, crospovidone, starch, lactose, saccharide, croscarmellose sodium, or a combination thereof.

The present invention further provides a pharmaceutical composition comprising an ampicone composition as described above; preferably, a pharmaceutical composition for treating Parkinson's disease.

In a preferred embodiment of the invention, the aforementioned pharmaceutical composition further comprises Levodopa and Benserazide, or further comprises Levodopa and Carbidopa.

The present invention further provides a use of the ampicone composition as described above for the preparation of a pharmaceutical composition; preferably, for the preparation of a pharmaceutical composition for treating Parkinson's disease.

In a preferred embodiment of the invention, the pharmaceutical composition prepared by the foregoing uses further comprises levodopa and hydroxybenzidine, or further comprises levodopa and carbidopa.

It can be seen from the above that the ampicone composition provided by the present invention can increase the elution rate of the acetonide to more than 88% without the need of grinding, pulverization or micronization, compared with the conventional method. Not only the grinding-related steps are omitted, but the process is simplified, and there is no risk of deterioration of the safety due to the high heat caused by the grinding-related steps. It can also increase the yield and reduce the cost.

The following examples are merely illustrative of the preferred embodiments and are not intended to limit the scope of the invention. Appropriate changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention.

Example

First, according to the composition ratio of the following Table 1, the particles of the acetonide composition 1-6 were obtained.

MCC, SDS, PVP K30, mannitol and acetonide were sequentially mixed for 5 minutes, after which the mixture powder was passed through a 150 μm (100 mesh) sieve; the sieved powder was poured into a granulator. Spray deionized water for granulation. The resulting granules were dried in an oven at 50 ° C until the moisture content was between 1% and 3%, after which they were filled into capsules or tableted to give the acetonide composition 1-6.

The drug eliminator method for the acecoin is retrieved according to the Dissolution Methods Database provided on the FDA website (http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm) The dissolution test was carried out in which the dissolution was carried out using a USP standard paddle device at a speed of 50 rpm, and the solvent used was 900 mL of a pH 5.5 phosphate buffer solution for a test time of 120 minutes, followed by HPLC analysis. The dissolution rate is shown in Table 2 below.

It can be seen from the above that the elution rate of Ankekeone itself is about 81.15%. When the dose ratio of PVP K30:SDS is 1:0.05~0.6:0.06~0.1, the obtained Anitapeng composition The dissolution rate is greatly increased, up to 88%; when the dose ratio of PVP K30:SDS is 1:0.05~0.2:0.06, the dissolution rate of the obtained Anitapone composition can reach 90%. Above; and when the dose ratio of PVP K30:SDS is 1:0.2:0.06, the dissolution rate can reach over 95%.

Therefore, the use of the above ratio in the process of grinding, pulverization or micronization does not only have the advantages of high elution rate, simple process, etc., but also does not cause high heat due to grinding. The doubts that can be degraded.

Claims (18)

An Entacapone composition comprising acetonide or a pharmaceutically acceptable salt thereof, polyvinylpyrrolidone K30 (PVP K30) and sodium dodecyl sulfate (SDS); Anita Kepeng: PVP K30: SDS dose ratio is 1:0.05~0.6:0.06~0.1, and its dissolution rate is greater than 88%. As described in the scope of claim 1, the Antech composition, wherein the dose ratio of PVP K30:SDS is 1:0.05~0.2:0.06. As described in the scope of claim 2, the Ankekepeng composition, wherein the dose ratio of PVP K30:SDS is 1:0.2:0.06. The ampoule composition described in claim 1 of the patent application has a dissolution rate of more than 90%. The ampoule composition as described in claim 4 of the patent application has an elution rate of more than 95%. The ampoule composition according to claim 1, which further comprises at least one excipient, and the excipient is selected from the group consisting of microcrystalline cellulose, mannitol, cellulose, and hydroxypropyl group. Cellulose, povidone, crospovidone, starch, lactose, saccharide, croscarmellose sodium, or a combination thereof. A method for preparing an ampicone composition according to claim 1, which comprises the steps of: (a) treating orchardone or a pharmaceutically acceptable salt thereof, polyvinylpyrrolidone K30 (polyvinylpyrrolidone, PVP K30) And sodium dodecyl sulfate (SDS) mixed, wherein the dose ratio of Anitakepeng: PVP K30:SDS is 1:0.05~0.6:0.06~0.1; (b) passing the mixture obtained in the step (a) through a sieve, and the mesh of the sieve is below 180 μm; (c) granulating the mixture obtained in the step (b); (d) obtaining the obtained from the step (c) The granules are dried until the moisture content is between 1% and 3%, and the acetonide composition as described in claim 1 of the patent application is obtained; the above method does not include the acetonide or its pharmaceutically acceptable salt A grinding, pulverizing or micronizing step of a mixture of PVP K30 and SDS having a particle size of less than 30 μm. The method of claim 7, wherein the dose ratio of the step (a): PVP K30:SDS is 1:0.05~0.2:0.06. The method of claim 8, wherein the dose ratio of the step (a): PVP K30:SDS is 1:0.2:0.06. The method of claim 7, wherein the granulation of step (c) is wet granulation. The method of claim 7, which does not comprise a grinding, pulverizing or micronizing step of making a mixture of acetonide or a pharmaceutically acceptable salt thereof, a mixture of PVP K30 and SDS having a particle size of less than 40 μm. The method of claim 7, wherein the aforementioned step (a) further comprises at least one excipient, and the excipient is selected from the group consisting of microcrystalline cellulose, mannitol, cellulose, and hydroxypropyl group. Cellulose, povidone, crospovidone, starch, lactose, saccharide, croscarmellose sodium, or a combination thereof. A pharmaceutical composition comprising the acetonide composition as described in claim 1 of the patent application. The pharmaceutical composition according to claim 13, which is a pharmaceutical composition for treating Parkinson's disease. For example, the pharmaceutical composition described in claim 14 of the patent scope The step comprises Levodopa and Benserazide, or further comprising left dopa and Carbidopa. A use of the acetonide composition as described in claim 1 of the patent application for the preparation of a pharmaceutical composition. The use according to claim 16, wherein the pharmaceutical composition is a pharmaceutical composition for treating Parkinson's disease. The use of claim 16, wherein the pharmaceutical composition further comprises levodopa and hydroxybenzidine, or further comprises levodopa and carbidopa.