CN107157943B

CN107157943B - Topiroxostat preparation and preparation method thereof

Info

Publication number: CN107157943B
Application number: CN201710351488.6A
Authority: CN
Inventors: 王明刚; 陈阳生; 臧云龙; 刘晓霞; 孙桂玉
Original assignee: CP Pharmaceutical Qingdao Co Ltd
Current assignee: CP Pharmaceutical Qingdao Co Ltd
Priority date: 2017-05-18
Filing date: 2017-05-18
Publication date: 2021-02-19
Anticipated expiration: 2037-05-18
Also published as: CN107157943A

Abstract

The invention discloses a topiroxostat preparation and a preparation method thereof. The dripping pill has the advantages of good roundness, rapid medicine dissolution, high bioavailability, simple production process, stable quality of the obtained product and suitability for large-scale production.

Description

Topiroxostat preparation and preparation method thereof

Technical Field

The invention relates to a western medicine preparation technology, in particular to a topiroxostat dripping pill and a preparation method thereof, belonging to the technical field of medicines.

Background

Hyperuricemia means that the serum uric acid level exceeds 7.0mg/dL, is the main cause of urate deposition (gouty arthritis, kidney injury, etc.), and is manifested by the fact that the serum uric acid concentration exceeds the solubility in body fluids. Gout is characterized in that sodium urate in a supersaturated state is separated out in a micro-crystal mode along with the rise of blood uric acid level, and is deposited on tissues or organs such as joints, synovium, tendons, kidneys and connective tissues to form gout stones, acute and chronic inflammation and tissue injury are caused, and multiple system damages such as arthritis, urinary calculi and kidney diseases appear. In China, about 1.2 hundred million patients with gout and hyperuricemia exist, and high-incidence age men and postmenopausal women are the middle-aged and the elderly, but the patients tend to be younger in recent years. The existing uric acid reducing medicines have the defects of different degrees and need to be improved.

Topiroxostat is a selective Xanthine Oxidase (XOR) inhibitor with no purine structure. Has obvious inhibiting effect on the XOR of the oxidized form and the reduced form, so the effect of reducing the uric acid is stronger and more durable, and the topiroxostat can be used for treating gout and hyperuricemia. Compared with allopurinol, the method has two obvious advantages: 1. allopurinol only has an inhibiting effect on reduced XOR, and topiroxostat has a remarkable inhibiting effect on oxidized XOR and reduced XOR, so that the effect of reducing uric acid is more powerful and lasting; 2. since allopurinol is a purine analog, which inevitably causes other enzyme activities involved in purine and pyridine metabolism, it is necessary to repeatedly administer large doses to maintain a high drug level in allopurinol therapy, which also causes serious and even fatal adverse reactions due to drug accumulation, while topiroxostat is a non-purine XOR inhibitor, and thus has better safety.

The dropping pill has simple using equipment and easily controlled process conditions; the preparation has stable quality and accurate measurement; the matrix has large liquid medicine containing amount, and can solidify the liquid medicine; the dripping pill prepared by solid dispersion technology has the advantages of rapid absorption and high bioavailability. The inclusion compound has the following advantages: covering up bad odor, reducing drug irritation, increasing drug dissolution rate and bioavailability, and improving drug stability.

Disclosure of Invention

In order to solve the defects of poor stability and low bioavailability of the existing Topiroxostat preparation and research and develop a dropping pill with stable quality, the invention provides the Topiroxostat dropping pill by screening auxiliary materials and optimizing the process through a large number of tests. Topiroxostat is prepared into inclusion compound, then the inclusion compound is prepared into dropping pills, and the inclusion and dropping pill technologies are combined into a whole, so that the advantages of the inclusion compound and the dropping pills are achieved. The dripping pill has stable quality and high bioavailability.

In order to achieve the purpose, the invention adopts the technical scheme that:

the Topiroxostat dripping pill comprises Topiroxostat, an inclusion material, a matrix, a stabilizer and a condensate, and is characterized in that the Topiroxostat dripping pill comprises the following components in percentage by weight:

topiroxostat 5-15%

10 to 20 percent of inclusion material

70 to 80 percent of matrix

1 percent of stabilizer

Proper amount of condensate

Preferably, the content of each component is as follows according to weight percentage:

topiroxostat 10%

The inclusion material is 15 percent

75 percent of matrix

1 percent of stabilizer

Proper amount of condensate

Wherein the inclusion material is beta-cyclodextrin; the matrix is one or more of polyethylene glycol 6000, poloxamer or stearic acid; the stabilizer is sodium dihydrogen phosphate and disodium hydrogen phosphate; the condensate is liquid paraffin.

Wherein, the matrix is preferably polyethylene glycol 6000 or poloxamer; preferably, the weight ratio of the polyethylene glycol 6000 to the poloxamer is 1: 1.

the Topiroxostat dripping pill can be prepared by the following method:

(1) dissolving topiroxostat and the coating material in proportion by using 80% ethanol as a medium, filtering the obtained solution through a microporous filter membrane until the solution is clear, separating the topiroxostat inclusion compound from the mixture, and crushing the topiroxostat inclusion compound and sieving the crushed topiroxostat inclusion compound through a 100-mesh and 200-mesh sieve;

(2) grinding and uniformly mixing the matrix and the stabilizer, heating and melting the mixture in water, and uniformly mixing the mixture;

(3) adding the topiroxostat inclusion compound prepared in the step (1) into the melt prepared in the step (2), uniformly mixing, pouring into an inclined liquid tank, and keeping the temperature at 65-75 ℃ for 10 minutes;

(4) dripping the medicinal liquid into 0-20 deg.C condensate to form dripping pill, adsorbing the condensate, and drying the dripping pill.

The topiroxostat dropping pill provided by the invention has the following beneficial effects:

(1) the quality is stable, the dissolution rate and bioavailability of the medicine are increased, and the stability of the medicine is improved;

(2) the selected auxiliary materials are common, the production process is simple, the obtained product has good roundness and stable quality, and the method is suitable for large-scale production.

Detailed Description

The following further describes the embodiments of the present invention with reference to examples, but these examples are only illustrative and do not limit the scope of the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.

A preparation method of topiroxostat dripping pills comprises the following steps:

EXAMPLE 1 preparation of Topiroxostat dropping pill

According to the raw and auxiliary materials in the following formula, the Topiroxostat dropping pill is prepared according to the preparation method. Where "/" indicates unused.

Test example 1 measurement of the smoothness and roundness rates and the dissolution and dispersion time limits of Topiroxostat pills obtained in examples 1 to 6

The smooth rounding rate and the dissolution time limit of the prepared dropping pill are detected according to the method specified in 0108 of the general rule of the four departments of the version in 2015 from the Chinese pharmacopoeia, and the measurement results are shown in table 1.

TABLE 1 Topiroxostat dropping pill examination table obtained in examples 1 to 6

As can be seen from Table 1, the Topiroxostat dripping pill of example 4 has better smoothness, roundness rate and dissolution time limit, which shows that the Topiroxostat dripping pill prepared by using polyethylene glycol 6000 and poloxamer as the coated substrate has excellent effect.

EXAMPLE 7-11 preparation of Topiroxostat dropping pill

According to the raw and auxiliary materials in the following formula, the Topiroxostat dropping pill is prepared according to the preparation method.

Test example 2 measurement of the rounding rate and the dissolution time period of Topiroxostat pills obtained in examples 7 to 11

The measurement method was the same as in test example 1, and the measurement results are shown in Table 2.

TABLE 2 Topiroxostat dropping pill examination table obtained in examples 7 to 11

As can be seen from table 2, the topiroxostat dripping pill in example 9 has better smoothness, roundness rate and dissolution time limit, which indicates that when the weight ratio of the polyethylene glycol 6000 as the matrix to the poloxamer is 1:1, the prepared topiroxostat dripping pill has more excellent effect compared with the dripping pills with other than the specific ratio.

Claims

1. The Topiroxostat dripping pill consists of a Topiroxostat clathrate, a matrix and a stabilizer, wherein the clathrate comprises Topiroxostat and an inclusion material, and is characterized in that the Topiroxostat dripping pill comprises the following components in parts by weight:

100 portions of topiroxostat

150 parts of inclusion material

750 portions of matrix

Stabilizer 1 part

The inclusion material is beta-cyclodextrin; the matrix is polyethylene glycol 6000 and poloxamer, and the weight ratio is 1: 1; the stabilizer is sodium dihydrogen phosphate and disodium hydrogen phosphate.