CN103705927A - Prasugrel composition and use thereof - Google Patents

Abstract

The invention relates to a prasugrel composition and a use thereof. The prasugrel composition contains prasugrel, an inorganic acid and pharmaceutically acceptable accessory materials. The prasugrel composition is characterized in that the unit dosage of the prasugrel composition and its preparation have pH values less than or equal to 5.0. A solid preparation prepared from the prasugrel composition has a low pH value, large solubility, good stability and a low production cost. The prasugrel composition can effectively solve the problems of poor dissolution and poor absorption of prasugrel without use of processing of prasugrel into a prasugrel medical salt or use of a surfactant for solubilization in the preparation and without use of the high-amount solid organic acid and thus the prasugrel composition has a practical value for prasugrel exploitation and application.

Description

A kind of prasugrel compositions and application thereof

Technical field

The present invention relates to medicine and preparation field thereof, be specifically related to a kind of prasugrel compositions and application thereof.

Background technology

Prasugrel (Prasugrel), is for No. CAS 150322-43-3, molecular formula C20H207N03S, molecular weight 373.44, chemical name is 2-[2-(acetoxyl group)-6, and 7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also]-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone.By Japan the first-tri-, be total to novel thiophene the pyridines antiplatelet drug of (Daiichi Sankyo) drugmaker and Li Lai (Eli Lilly) company's joint development, it is oral effectively.Prasugrel is water insoluble, is soluble in ethyl acetate, is slightly soluble in ether, current its hydrochlorate of clinical use.Hydrochloric acid prasugrel sheet (Prasugrel, commodity are called Efient) in February, 2009 23Huo European Union approval listing, for pre-Radix Stephaniae Tetrandrae, accept emergency treatment and will postpone atherothrombosis (atherothrombosis) event of the Acute Coronary Syndrome Patients of percutaneous arteria coronaria intervention art, and get permission U.S.'s listing on July 10th, 2009, for reducing the thrombosis risk in percutaneous coronary intervention (pci).The same with clopidogrel, prasugrel is also the prodrug of a non-activity, need to active metabolite, could irreversibly suppress the P2Y12 adenosine diphosphate (ADP) receptor in platelet through cytochrome P 450 Enzyme metabolic conversion.Prasugrel has higher prodrug to active metabolite conversion ratio and higher bioavailability, its onset is faster and can reduce the Different therapeutical effect between individuality, can reduce to a greater degree main ischemic cardiovascular events incidence, thereby the curative effect of prasugrel is better than clopidogrel, have broad application prospects.The structural formula of hydrochloric acid prasugrel is shown in figure (1).

At present, at hydrochloric acid prasugrel sheet European, U.S.'s listing, its specification is 5mg, 10mg, and initial dose is 60mg, and maintenance dose is 10mg.From the dissolubility of prasugrel and hydrochloric acid prasugrel, the fat-soluble hydrochloric acid prasugrel that is better than of prasugrel, its dissolubility in pH1-7 is all poor than hydrochloric acid prasugrel, at pH1-4 slightly soluble, atomic molten in pH5, insoluble in pH6-7.According to the disclosed former equipment registration data of grinding of FDA, oral after, prasugrel is hydrolyzed to the thiolactone (R-95913) of non-activity at the rapid ester of the intestines and stomach, and then under the effect of P450 enzyme system, generates absorbed into serum after active metabolite (R-138727).For the normal patient of gastric acid secretion, while taking separately hydrochloric acid prasugrel or prasugrel, both bioavailability are close; When share proton pump inhibitor (PPT) or bisfentidine or other factors and cause gastric pH to raise, the bioavailability of prasugrel is starkly lower than hydrochloric acid prasugrel.Compare with prasugrel, hydrochloric acid prasugrel has higher bioavailability under higher gastric pH, on the one hand this to be greater than prasugrel relevant with the dissolubility of hydrochloric acid prasugrel, the salt acid molecule that may also contain with hydrochloric acid prasugrel on the other hand can reduce gastric pH and to promote that ester is hydrolyzed relevant.Therefore,, if improve the bioavailability of prasugrel, except improving by suitable mode the dissolution of prasugrel under different pH, it is also necessary reducing gastric pH.Er Yuanyan company has applied for the Patents (US20080166893) of prasugrel hydrochloride having, and the further research and development of prasugrel can only look for another way.

Human normal gastric juice amount is 10-100ml, average 50ml, and its pH is 0.9-1.8, and the many factors such as food, medicine, disease all can cause that gastric pH raises, and wherein pH3.5-7.0 is low acid, and pH7.0 is anacidity.Consider that gastric pH is often among dynamic change, prasugrel is not suitable for as medicinal forms.Chinese patent (CN2010158669.5) report, first adopt cyclodextrin and derivant thereof that prasugrel is made to clathrate, or adopt hydrophilic material (polyvidone class, poly-second-glycols, cellulose family etc.) that prasugrel is made to solid dispersion, then make preparation with surfactant (sodium lauryl sulphate, Tweens, span, poloxamer etc.) and other pharmaceutic adjuvants, its dissolution is close with hydrochloric acid prasugrel or higher, the method complex process, cost are higher, also use the surfactant of high level, thereby may have safety issue.Chinese patent (CN201110059625.1) report, first by prasugrel micronization (particle diameter at 90% cumulative volume place is below 75 μ m), make preparation with pharmaceutic adjuvant again, it has good dissolution, under multiple pH condition, all there is good dissolution characteristic, the method is carried out micronization processes to prasugrel, needs specific equipment, and has compared with high material loss and increase production cost.Also have Chinese patent (CN200810146101.4) that prasugrel is made to sulfate, Chinese patent (CN201010197041.6) is made hydrobromate etc. by prasugrel, owing to having ester bond in prasugrel molecule, in the preparation process of salify, decompose on the one hand, prasugrel pharmaceutical salts less stable in preservation process (there are some researches show on the other hand, hydrochloric acid prasugrel can generate less desirable catabolite and be subject to hydrolysis impact, prasugrel stability is better than hydrochloric acid prasugrel), these all have adverse effect for drug quality.

Chinese patent (CN201110200680.8) report, is added in acidic excipient after prasugrel is dissolved in to solvent, mixs homogeneously after dry with filler, disintegrating agent, binding agent, lubricant etc. again, granulates, then makes various dosage forms.The method is added to solid organic acid (citric acid after prasugrel is dissolved in to solvent (acetone or aqueous acetone solution), maleic acid, fumaric acid, tartaric acid, Aspartic Acid, the mixture of one or more in glutamic acid), dry through air blast or boiling or spraying, may there is organic solvent residual in this process, heat drying also may affect the content of principal agent, especially the method needs the solid organic acid (if the consumption of citric acid in 5mg dosage specification is up to 20-500mg) of higher dosage, patient for medication patient especially long-term prescription has potential side effect, for example citric acid to human body without direct harm, but it can promote excretion and the deposition of calcium in body, the long-term edible product containing citric acid can cause hypocalcemia, and can increase the probability of suffering from duodenal carcinoma, the existing nervous system of watch for children is unstable, easily excited, autonomic nervous dysfunction, adult is tetany, muscle spasm, paraesthesia, pruritus and symptom of digestive tract etc.

Summary of the invention

The object of this invention is to provide a kind of prasugrel compositions.

Prasugrel compositions of the present invention, is characterized in that containing prasugrel, mineral acid and pharmaceutically acceptable adjuvant.

Prasugrel compositions of the present invention, is characterized in that mineral acid is hydrochloric acid, phosphoric acid, sulfur aqueous acid, alcoholic solution or ethanol-water solution.

Prasugrel compositions of the present invention, is characterized in that the pH value of units dosage composition is less than or equal to 5.0.

Prasugrel compositions of the present invention, is characterized in that pharmaceutically acceptable adjuvant includes but not limited to filler, disintegrating agent, binding agent, lubricant, correctives, fluidizer, antiseptic, coating materials.Described pharmaceutically acceptable adjuvant is extensive use in medicament technical field, those skilled in the art can be suitable select, as filler comprises starch, dextrin, sucrose, lactose, pregelatinized Starch, mannitol, sorbitol, microcrystalline Cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate etc.; Disintegrating agent comprises starch, microcrystalline Cellulose, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Binding agent comprises starch slurry, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvidone etc.; Lubricant comprises magnesium stearate, calcium stearate, stearic acid, micropowder silica gel, Pulvis Talci, castor oil hydrogenated, stearoyl-fumarate calcium etc.; Correctives comprises sucrose, glucose, saccharin sodium, stevioside, aspartame, Fructus Citri tangerinae essence, strawberry essence etc.; Fluidizer comprises micropowder silica gel, Pulvis Talci etc.; Antiseptic comprises sodium benzoate, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sorbic acid, potassium sorbate etc.

The present invention also aims to the application of described prasugrel compositions in useful in preparing drug formulations, wherein said pharmaceutical preparation is the pharmaceutically acceptable dosage forms such as tablet, capsule, it is characterized in that the pH of each unit dose formulations is less than or equal to 5.0.

Prasugrel compositions of the present invention or preparation are used for the treatment of the cardiovascular and cerebrovascular diseases such as heart failure, apoplexy, unstable angina pectoris, especially for the postoperative anticoagulant therapy of vascular repair.

Beneficial effect of the present invention:

The inventor studies by experiment, in advance mineral acid is mixed with partial supplementary material (filler, disintegrating agent etc.), is dried, then mix homogeneously with prasugrel, partial supplementary material (disintegrating agent, lubricant etc.), makes needed dosage form.The method organic solvent-free is residual, and principal agent (prasugrel) also has good stability without undergoing heat drying process, and the mineral acid that especially the method is used is safer to human body, and example hydrochloric acid itself is exactly the composition of gastric acid.Technique of the present invention is simple, cost is lower, and the preparation of making can effectively improve the stripping problem of prasugrel, can reduce gastric pH again and promotes to absorb, and principal agent steady quality, Product Safety are good simultaneously, and this Application and Development for prasugrel has practical value.

The evaluation methodology that the present invention adopts is as follows:

1.pH pH-value determination pH

Get the compositions containing unit dose prasugrel, or 1, or 1 capsules content, add the evenly rear pH of mensuration of 50ml aqueous dispersion.

2. dissolution determination

Get 1, preparation or 1, using pH1.0 hydrochloric acid solution, pH4-6 buffer salt solution, pH6.8 buffer salt solution as dissolution medium, according to 2010 editions two appendix XC first methods of Chinese Pharmacopoeia or the second method, test, adopt HPLC to measure.

3. sample size is measured

Chromatographic condition: C18 chromatographic column; Mobile phase is acetonitrile-water (65: 35); Flow velocity is 1.0ml/min; Detection wavelength is 212nm.

It is appropriate that precision takes prasugrel reference substance, adds mobile phase and make the solution that concentration is about 0.1mg/ml, in contrast product solution; Precision takes sample appropriate (being equivalent to prasugrel 5mg), adds mobile phase and makes the solution that concentration is about 0.1mg/ml, as sample solution.Two kinds of solution difference injection liquid chromatographies, record chromatogram.By external standard method, with calculated by peak area, obtain.

4. sample stability research

Sample airtight package, is placed in 40 ℃ ± 2 ℃, the climatic chamber of RH75% ± 5%, in sampling in 0 month, 6 months, adopts said method to measure dissolution and content.

Accompanying drawing explanation

Fig. 1 is the structural formula of hydrochloric acid prasugrel.

The specific embodiment

Following examples are intended to the present invention further to explain, and relevant technologies condition etc. does not limit excursion of the present invention.

Embodiment 1: prasugrel compositions A

Take mannitol 85g, microcrystalline Cellulose (PH102) 40g, cross-linking sodium carboxymethyl cellulose 5g, hyprolose 5g, mixing is sieved, add dilute hydrochloric acid (concentrated hydrochloric acid: water, 1: 3v/v) 90g, mixes 40 ℃ of dry 1h, add prasugrel 10g, Glyceryl Behenate 3g mix homogeneously, get 160mg, add 50ml aqueous dispersion even, recording pH is 4.12.

Embodiment 2: prasugrel compositions B

Take mannitol 85g, microcrystalline Cellulose (PH102) 40g, cross-linking sodium carboxymethyl cellulose 5g, hyprolose 5g, mixing is sieved, add dilute hydrochloric acid (concentrated hydrochloric acid: ethanol, 1: 3v/v) 120g, mixes 40 ℃ of dry 1h, add prasugrel 5g, Glyceryl Behenate 3g mix homogeneously, get 170mg, add 50ml aqueous dispersion even, recording pH is 3.10.

Embodiment 3: prasugrel compositions C

Take calcium hydrogen phosphate 90g, microcrystalline Cellulose (PH102) 45g, cross-linking sodium carboxymethyl cellulose 5g, hyprolose 5g, mixing is sieved, add dilute hydrochloric acid (concentrated hydrochloric acid: water, 1: 3v/v) 120g, mixes 40 ℃ of dry 1h, add prasugrel 5, Glyceryl Behenate 3g mix homogeneously, get 180mg, add 50ml aqueous dispersion even, recording pH is 3.26.

Embodiment 4: prasugrel compositions D

Take calcium hydrogen phosphate 90g, microcrystalline Cellulose (PH102) 45g, cross-linking sodium carboxymethyl cellulose 5g, hyprolose 5g, mixing is sieved, add phosphoric acid,diluted (phosphoric acid: water, 1: 3v/v) 120g, mixes 40 ℃ of dry 1h, add prasugrel 5g, Glyceryl Behenate 3g mix homogeneously, get 180mg, add 50ml aqueous dispersion even, recording pH is 3.20.

Embodiment 5: prasugrel compositions E

Take calcium hydrogen phosphate 90g, microcrystalline Cellulose (PH102) 45g, cross-linking sodium carboxymethyl cellulose 5g, hyprolose 5g, mixing is sieved, add phosphoric acid,diluted (phosphoric acid: 75% ethanol, 1: 3v/v) 120g, mixes 40 ℃ of dry 1h, add prasugrel 10g, Glyceryl Behenate 3g mix homogeneously, get 180mg, add 50ml aqueous dispersion even, recording pH is 3.25.

Embodiment 6: prasugrel composition F

Take calcium hydrogen phosphate 90g, microcrystalline Cellulose (PH102) 45g, cross-linking sodium carboxymethyl cellulose 5g, hyprolose 5g, mixing is sieved, add dilute sulfuric acid (sulphuric acid: water, 1: 5v/v) 120g, mixes 40 ℃ of dry 1h, add prasugrel 10g, Glyceryl Behenate 3g mix homogeneously, get 180mg, add 50ml aqueous dispersion even, recording pH is 3.16.

Embodiment 7: prasugrel sheet

Get prasugrel compositions A, be pressed into 1000.Get 6, add respectively 50ml aqueous dispersion even, recording average pH is 4.16.

Get prasugrel compositions B, be pressed into 1000.Get 6, add respectively 50ml aqueous dispersion even, recording average pH is 3.20.

Get prasugrel compositions C, be pressed into 1000.Get 6, add respectively 50ml aqueous dispersion even, recording average pH is 3.31.

Embodiment 8: prasugrel capsule

Get prasugrel compositions D, fill obtains 1000.Get 6 intragranulars tolerant, add respectively 50ml aqueous dispersion even, recording average pH is 3.32.

Get prasugrel compositions E, fill obtains 1000.Get 6 intragranulars tolerant, add respectively 50ml aqueous dispersion even, recording average pH is 3.28.

Embodiment 9: dissolution determination

Get the capsule that tablet that embodiment 6 makes and embodiment 7 make, according to dissolution method (2010 editions two appendix XC the second methods of Chinese Pharmacopoeia and first method), test, take respectively pH1.0 hydrochloric acid solution, pH5.0 buffer salt solution, pH6.8 buffer salt solution is medium, rotating speed is per minute 50 to turn, operation in accordance with the law, sampling and measuring in the time of 45 minutes, the results are shown in Table 1.

Table 1 dissolution determination result

Preparation title	pH1.0	pH5.0	pH6.8
				Tablet A	99.2％	75.8％	58.4％
Tablet B	99.4％	82.5％	63.7％
				Tablet C	100.3％	87.1％	71.6％

[0050]?

Capsule D	98.6％	73.6％	57.2％
				Capsule E	99.7％	83.2％	64.1％
Efient-5mg	98.6％	76.4％	54.2％
				Efient-10mg	98.2％	68.5％	55.8％

Embodiment 10: stability study

Sample adopts two aluminum airtight packages, is placed in 40 ℃ ± 2 ℃, the climatic chamber of RH75% ± 5%, in sampling in 0 month, 6 months, measures dissolution (take pH1.0 hydrochloric acid solution as medium) and content.The results are shown in Table 2.

Table 2 results of stability

Claims (7)

1. a prasugrel compositions, is characterized in that containing prasugrel, mineral acid and pharmaceutically acceptable adjuvant.

2. by prasugrel compositions claimed in claim 1, it is characterized in that mineral acid is hydrochloric acid, phosphoric acid, sulfur aqueous acid, alcoholic solution or ethanol-water solution.

3. by prasugrel compositions claimed in claim 1, it is characterized in that the pH value of units dosage composition is less than or equal to 5.0.

4. by prasugrel compositions claimed in claim 1, it is characterized in that pharmaceutically acceptable adjuvant includes but not limited to filler, disintegrating agent, binding agent, lubricant, correctives, fluidizer, antiseptic, coating materials.

5. the application of the prasugrel compositions of claim 1 in useful in preparing drug formulations, wherein said pharmaceutical preparation is the pharmaceutically acceptable dosage forms such as tablet, capsule, it is characterized in that the pH of each unit dose formulations is less than or equal to 5.0.

6. described in claim 1 or 5, prasugrel compositions or preparation are used for the treatment of the cardiovascular and cerebrovascular diseases such as heart failure, apoplexy, unstable angina pectoris.

7. described in claim 1 or 5, prasugrel compositions or preparation are used for the postoperative anticoagulant therapy of vascular repair.

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