CN110917162A - Ambrisentan oral pharmaceutical composition and preparation method thereof - Google Patents

Abstract

The invention provides an ambrisentan oral pharmaceutical composition and a preparation method thereof, and the prepared ambrisentan tablet has smooth and clean surface, good content uniformity, high dissolution rate and small dissolution difference among batches under the condition of avoiding using lactose. The preparation process is simple, the reproducibility is good, and the quality and the medication safety of the preparation can be remarkably improved.

Description

Ambrisentan oral pharmaceutical composition and preparation method thereof

Technical Field

The invention belongs to the field of medicinal preparations, and particularly relates to an ambrisentan oral preparation and a preparation method thereof.

Background

Pulmonary Arterial Hypertension (PAH) is a specific type of PH and is a serious, progressive and life-threatening disease of the pulmonary vasculature characterized by extreme vasoconstriction and abnormal proliferation of smooth muscle cells in the pulmonary artery wall. Severe constriction of blood vessels in the lungs results in very high pulmonary artery pressures. These high pressures make it difficult for the heart to pump blood through the lungs for oxygenation. Patients with PAH suffer from extreme shortness of breath as the heart strives to pump against these high pressures. Patients with PAH typically develop a significant increase in Pulmonary Vascular Resistance (PVR) and a sustained rise in Pulmonary Arterial Pressure (PAP), which ultimately leads to right ventricular failure and death. Pulmonary hypertension drugs are mainly classified into phosphodiesterase-5 (PDE-5) inhibitors, prostacyclins, and endothelin receptor antagonists according to their mechanisms of action. Wherein, the endothelin receptor antagonist can be completely combined with endothelin receptor, thereby achieving the purpose of delaying disease deterioration, therefore, the research on the pulmonary hypertension drug in recent years tends to be Endothelin Receptor Antagonist (ERA).

Ambrisentan was first an endothelin receptor antagonist developed by BASF Pharma. The drug was approved by FDA at 6/15 of 2007 and CFDA at 19/10 of 2010 and was orally administered for the treatment of pulmonary hypertension. The chemical name of ambrisentan is (+) - (2S) -2- [ (4, 6-dimethyl pyrimidine-2-yl) oxy]-3-methoxy-3, 3-diphenylpropanoic acid of formula C₂₂H₂₂N₂O₄The molecular weight is 378.42, and the structure is shown in formula (I).

In the current prescription on the market, the filler of ambrisentan contains lactose, and the content of lactose is very high, which is not beneficial to the application of lactose intolerant patients, so that the development of an ambrisentan pharmaceutical composition which does not contain lactose and can meet the requirements of preparation is necessary.

Disclosure of Invention

The invention aims to provide the lactose-free ambrisentan pharmaceutical composition, and the tablet has good hardness and high content uniformity and can meet the preparation requirements.

Specifically, the invention is realized by the following technical scheme:

the invention provides an ambrisentan oral pharmaceutical composition, which comprises an ambrisentan solid, a filler and a lubricant.

Preferably, the ambrisentan solid comprises ambrisentan, mannitol, croscarmellose sodium or hydroxypropylmethyl cellulose, optionally comprising castor oil.

Preferably, the weight percentages of the components of the anlison solid are as follows:

further preferably, the weight percentages of the components are as follows:

preferably, the weight ratio of the hydroxypropyl methylcellulose to the castor oil is 5: 1-1: 1, preferably 3: 1-2: 1.

Preferably, the lubricant is selected from stearic acid, magnesium stearate, aerosil, talc and polyethylene glycol.

Preferably, the weight percentages of the components are as follows:

65-80% of ambrisentan solid

15 to 30 percent of filling agent

0.5 to 5 percent of lubricant.

Further preferably, the weight percentages of the components are as follows:

70-80% of ambrisentan solid

19 to 28 percent of filling agent

0.5 to 2.5 percent of lubricant.

In addition, the invention also provides a preparation method of the ambrisentan oral pharmaceutical composition, which comprises the following preparation processes:

1) weighing hydroxypropyl cellulose and/or castor oil according to a proportion, and preparing into an aqueous solution or an ethanol aqueous solution;

2) adding prescribed amounts of ambrisentan, mannitol and croscarmellose sodium into the solution, and performing wet granulation;

3) uniformly mixing the particles obtained in the step 2) with a filler and a lubricant;

4) pressing the obtained granules into plain tablets by adopting a stamping die;

5) optionally, the tablet core of the plain tablet obtained above is sprayed with a film coating solution to obtain a film coated tablet.

Preferably, the preparation method comprises the following preparation processes:

1) weighing hydroxypropyl cellulose and castor oil according to a proportion, and preparing into an aqueous solution or an ethanol aqueous solution;

2) adding prescribed amounts of ambrisentan, mannitol and croscarmellose sodium into the solution, and performing wet granulation;

3) uniformly mixing the granules obtained in the step 2) with the pre-crosslinked starch and magnesium stearate;

4) pressing the obtained granules into plain tablets by adopting a stamping die;

5) optionally, the tablet core of the plain tablet obtained above is sprayed with a film coating solution to obtain a film coated tablet.

Preferably, the ethanol aqueous solution is 50-90% ethanol aqueous solution.

The ambrisentan tablet prepared by the invention has the advantages of simple production process and good reproducibility, the obtained ambrisentan tablet has high dissolution rate, small dissolution difference among batches can be realized without controlling process parameters such as particle size and the like, and the ambrisentan tablet is particularly suitable for people who are intolerant to lactose and has wide market prospect.

Detailed Description

To further illustrate the present invention, the present invention will be specifically described with reference to specific examples, but the scope of the present invention is not limited to the specific examples.

Example 1

Dissolving hydroxypropyl methylcellulose and castor oil in 50g of purified water to obtain a solution, and adding the prepared solution into an auxiliary material consisting of ambrisentan, mannitol and croscarmellose sodium for wet granulation. After drying, granulating by using a 60-mesh sieve, adding magnesium stearate and pre-crosslinked starch, mixing, and pressing the obtained granules into plain tablets with the hardness of 5-7 kg.

Example 2

Dissolving hydroxypropyl methylcellulose and castor oil in 50g of purified water to obtain a solution, and adding the prepared solution into an auxiliary material consisting of ambrisentan, mannitol and croscarmellose sodium for wet granulation. After drying, granulating by using a 60-mesh sieve, adding magnesium stearate and pre-crosslinked starch, mixing, and pressing the obtained granules into plain tablets with the hardness of 5-7 kg.

Example 3

Dissolving hydroxypropyl methylcellulose and castor oil in 50g of purified water to obtain a solution, and adding the prepared solution into an auxiliary material consisting of ambrisentan, mannitol and croscarmellose sodium for wet granulation. After drying, granulating by using a 60-mesh sieve, adding magnesium stearate and pre-crosslinked starch, mixing, and pressing the obtained granules into plain tablets with the hardness of 5-7 kg.

Example 4

Dissolving hydroxypropyl methylcellulose and castor oil in 50g of purified water to obtain a solution, and adding the prepared solution into an auxiliary material consisting of ambrisentan, mannitol and croscarmellose sodium for wet granulation. After drying, granulating by using a 60-mesh sieve, adding magnesium stearate and pre-crosslinked starch, mixing, and pressing the obtained granules into plain tablets with the hardness of 5-7 kg.

Example 5

Dissolving hydroxypropyl methylcellulose and castor oil in 50g of purified water to obtain a solution, and adding the prepared solution into an auxiliary material consisting of ambrisentan, mannitol and croscarmellose sodium for wet granulation. After drying, granulating by using a 60-mesh sieve, adding magnesium stearate and pre-crosslinked starch, mixing, and pressing the obtained granules into plain tablets with the hardness of 5-7 kg.

Example 6

Dissolving hydroxypropyl methylcellulose and castor oil in 50g of purified water to obtain a solution, and adding the prepared solution into an auxiliary material consisting of ambrisentan, mannitol and croscarmellose sodium for wet granulation. After drying, granulating by using a 60-mesh sieve, adding magnesium stearate and microcrystalline cellulose, mixing, and pressing the obtained granules into plain tablets with the hardness of 5-7 kg.

Test example 1 friability measurement

The friability of the tablets was measured by the method (100 rounds) under the item "0923 tablet friability test method" of the general rules of the four parts of the chinese pharmacopoeia 2015 edition without fracture, cracking and crushed tablets. For tablets that require coating, it is essential that the core have a good friability index, since such tablets need to undergo subsequent coating, which, if the friability properties are poor, can result in tablet wear during the coating process.

Sample (I)	Degree of friability	Sample (I)	Degree of friability
				Example 1	0.09％	Example 4	0.08％
Example 2	0.12％	Example 5	0.13％
				Example 3	0.08％	Example 6	0.05％

Test example 2 content uniformity examination

The content uniformity is detected by referring to a method for checking the content uniformity of 0941 in general rules of 'Chinese pharmacopoeia' of 2015 edition.

Sample (I)	A+2.2S	Sample (I)	A+2.2S
				Example 1	2.4	Example 4	2.6
Example 2	2.1	Example 5	2.6
				Example 3	2.8	Example 6	2.8

Test example 3 drug dissolution examination

Dissolution medium: 0.1mol/L hydrochloric acid and pH6.8 phosphate buffer solution, 900 ml;

the dissolution method comprises the following steps: paddle method, 50 rpm;

temperature of the medium: 37.0 +/-0.5 ℃;

sampling: sampling 5ml after 5min, 10min, 15min, 30min and 45min respectively, filtering by a mixed cellulose membrane, and simultaneously supplementing isothermal same medium;

sample preparation: in the ambrisentan tablets provided in example 1 and example 5, 30 tablets were randomly sampled from each batch, and the dissolution of each batch in different dissolution media was examined.

The samples prepared in examples 2-5 have the same effect as example 1, and as can be seen from the dissolution data of the self-made samples, the ambrisentan preparation prepared by the invention can realize good dissolution without processes such as particle size control and the like, and has small batch-to-batch difference and consistent dissolution.

Claims (10)

1. An ambrisentan oral pharmaceutical composition is characterized by comprising an ambrisentan solid, a filler and a lubricant.

2. An ambrisentan oral pharmaceutical composition according to claim 1, characterized in that the ambrisentan solid comprises ambrisentan, mannitol, croscarmellose sodium or hydroxypropylmethyl cellulose, optionally comprising castor oil.

3. The ambrisentan oral pharmaceutical composition according to claim 2, wherein the weight percentages of the components of the ambrisentan solid are as follows:

preferably, the weight percentages of the components are as follows:

4. an ambrisentan oral pharmaceutical composition according to claim 2, characterized in that the weight ratio of hydroxypropyl methylcellulose to castor oil is 5: 1-1: 1, preferably 3: 1-2: 1.

5. An ambrisentan oral pharmaceutical composition according to claim 1, characterised in that the filler is selected from microcrystalline cellulose, pregelatinized starch, dextrin and sorbitol.

6. An ambrisentan oral pharmaceutical composition according to claim 1, characterized in that said lubricant is selected from stearic acid, magnesium stearate, aerosil, talc and polyethylene glycol.

7. The ambrisentan oral pharmaceutical composition according to claim 1, characterized in that the weight percentages of the components are as follows:

65-80% of ambrisentan solid

15 to 30 percent of filling agent

0.5 to 5 percent of lubricant.

8. The preparation method of the ambrisentan oral pharmaceutical composition comprises the following preparation processes:

1) weighing hydroxypropyl cellulose and/or castor oil according to a proportion, and preparing into an aqueous solution or an ethanol aqueous solution;

2) adding prescribed amounts of ambrisentan, mannitol and croscarmellose sodium into the solution, and performing wet granulation;

3) uniformly mixing the particles obtained in the step 2) with a filler and a lubricant;

4) pressing the obtained granules into plain tablets by adopting a stamping die;

5) optionally, the tablet core of the plain tablet obtained above is sprayed with a film coating solution to obtain a film coated tablet.

9. The process for preparing an ambrisentan oral pharmaceutical composition according to claim 8, comprising the following steps:

1) weighing hydroxypropyl cellulose and castor oil according to a proportion, and preparing into an aqueous solution or an ethanol aqueous solution;

2) adding prescribed amounts of ambrisentan, mannitol and croscarmellose sodium into the solution, and performing wet granulation;

3) uniformly mixing the granules obtained in the step 2) with the pre-crosslinked starch and magnesium stearate;

4) pressing the obtained granules into plain tablets by adopting a stamping die;

5) optionally, the tablet core of the plain tablet obtained above is sprayed with a film coating solution to obtain a film coated tablet.

10. The process for preparing an ambrisentan oral pharmaceutical composition according to claim 8, wherein the aqueous ethanol solution is 50-90% aqueous ethanol solution.