WO2007008045A1

WO2007008045A1 - Pharmaceutical compositions containing clopidogrel bisulfate

Info

Publication number: WO2007008045A1
Application number: PCT/KR2006/002779
Authority: WO
Inventors: Jeong Ku; Dong-Kwon Lim; Eun-Young Yang; Tae-Kun An; Eun-Kyung Jeon; Kwang-Do Choi; Yong-Sik Youn; Tae-Hyoung Kim; Hea-Ran Suh; Chang-Ju Kim
Original assignee: Cj Cheiljedang Corp.
Priority date: 2005-07-14
Filing date: 2006-07-14
Publication date: 2007-01-18
Also published as: JP2009501214A; KR20070009851A; US20090042930A1; GB0801341D0; GB2442664A; DE112006001853T5

Abstract

Provided is a pharmaceutical composition including clopidogrel bisulfate and a pregelatinized starch. The pharmaceutical composition in which the stability of clopido grel bisulfate is significantly enhanced can be obtained by mixing clopidogrel bisulfate w ith the pregelatinized starch.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING CLOPIDOGREL BISULFATE

TECHNICAL FIELD The present invention relates to pharmaceutical compositions containing clopido grel bisulfate, and in particular, to a pharmaceutical composition containing clopidogrel bisulfate to improve the stability of clopidogrel.

BACKGROUND ART

Clopidogrel is a dextro-rotatory enantiomer of methyl alpha-5-(4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate, which is disclosed in US 4,847, 265. A ccording to US 4,847,265, clopidogrel is useful as a medicine for prophylaxis and the tr eatment of thromboembolism, such as thrombosis, or myocardial infarction, by acting a s a platelet aggregation inhibitor.

EP 281459 discloses clopidogrel bisulfate prepared to improve stability and solu bility of clopidogrel. However, EP 281459 does not disclose the polymorphism of poly morphic crystalline forms of clopidogrel bisulfate.

However, it was discovered in US 6,429,210 that clopidogrel bisulfate can exist i n different polymorphic crystalline forms which differ from each other in terms of stability , physical properties, spectral characteristics and the process by which the different poly morphic crystalline forms are prepared. In US 6,429,210, the clopidogrel bisulfate disc losed in EP 281459 is named Crystalline Form I and a novel polymorph sulfate disclose d in US 6,429,210 is named Crystalline Form II. In addition, a method of preparing the novel polymorph sulfate is disclosed in US 6,429,210. According to US 6,429,210, th e powder of Crystalline Form Il is more compact and much less electrostatic than Cryst alline Form I and may hence have better formulation processibility. In particular, clopid ogrel bisulfate in its polymorphic Crystalline Form Il is thermodynamically more stable th an Crystalline Form I. Since such thermodynamic stability results in a delay of decomp osition of medicines over time, Plavix®, which is a commercially available clopidogrel bi sulfate, contains Crystalline Form Il according to US 6,429,210 as an active ingredient.

However, in the method of preparing Crystalline Form Il disclosed in US 6,429,2 10, the mother liquors from which Crystalline Form I are obtained yield Crystalline Form i Il after a 3 to 6 months period. With respect to the method of preparing Crystalline F orm Il disclosed in US 6,429,210, Crystalline Form Il of clopidogrel bisulfate requires su bstantially more time and efforts than Crystalline Form I. Despite such problems of req uiring more time and effects, Crystalline Form Il is still commercially used due to high st ability in medicine over time resulting from its thermodynamic stability. In the present a pplication, "stability" refers to a tendency that a relative amount of impurities and/or dec omposed products that can be generated during formulation and/or storage is minimize d.

However, if the use of Crystalline Form I of clopidogrel bisulfate guarantees stabi lity equal to or higher than when Crystalline Form Il is used, there is no reason to use C rystalline Form Il of clopidogrel bisulfate for which a manufacturing period is 3 or more months longer than Crystalline Form I. Accordingly, in this case, the use of Crystalline Form I of the clopidogrel bisulfate may be advantageous in terms of time and effort.

DESCRIPTION OF THE DRAWING

FIG. 1 is a graph illustrating the results of the dissolution test on tablets prepar ed according to Examples 1 and 2 and Comparative Examples 1 through 4, according t o an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL PROBLEM

The inventors of the present application studied clopidogrel-containing pharmace utical compositions in which clopidogrel bisulfate has a high stability and completed the invention disclosed in the present application. Accordingly, the present invention provides clopidogrel-containing pharmaceutic al compositions capable of improving the stability of clopidogrel bisulfate.

TECHNICAL SOLUTION

According to an aspect of the present invention, there is provided a pharmaceuti cal composition comprising clopidogrel bisulfate and pregelatinized starch. In the pharmaceutical composition, the amount of clopidogrel bisulfate can be in the range of 30-40 parts by weight, and the amount of the pregelatinized starch can be i n the range of 10-70 parts. In addition, the clopidogrel bisulfate-containing pharmaceu tical composition may further comprise an additive which is conventionally used in the t echnical field of pharmaceutics. In the clopidogrel bisulfate-containing pharmaceutical composition, the clopido grel bisulfate can be Crystalline Form I or Crystalline Form II. When the clopidogrel bi sulfate is Crystalline Form I, stability equal to or higher than when commercially availabl e Crystalline Form Il is used can be obtained. When the clopidogrel bisulfate is Crysta Nine Form II, a higher stability can be obtained than when commercially available Crysta Nine Form Il is used.

The gelatinized starch of the pharmaceutical composition can be any pregelati nized starch. For example, the pregelatinized starch can be selected from the group c onsisting of pregelatinized corn starch, prepotato starch, pregelatinized wheat starch, a nd a mixture thereof.

The pharmaceutical composition can be formulated in a solid-phase preparatio n having various shapes. For example, the pharmaceutical composition can be formul ated in a various solid-phase pharmaceutical preparation in the form of, particularly, gra nules, tablets, or capsules. Hereinafter, the present invention will be described in detail.

Inventors of the present application conducted research to improve the stabilit y of clopidogrel bisulfate and discovered that when clopidogrel bisulfate is formulated b y mixing clopidogrel bisulfate with pregelatinized starch, the stability of clopidogrel bisulf ate substantially increases. Accordingly, the present invention provides a pharmaceuti cal composition comprising clopidogrel bisulfate and pregelatinized starch capable of im proving the stability of clopidogrel bisulfate.

In the pharmaceutical composition, the amount of clopidogrel bisulfate may be in the range of 30-40 parts by weight and the amount of the pregelatinized starch may b e in the range of 10-70 parts by weight. When the amount of clopidogrel bisulfate and pregelatinized starch are within these ranges, the clopidogrel bisulfate can be effectivel y stable. However, the amounts of clopidogrel bisulfate and the pregelatinized starch are not limited thereto. When the amount of pregelatinized starch is greater than 10 p arts by weight, the stability of the clopidogrel bisulfate can substantially increase. Ho wever, the preferred amount of the pregelatinized starch is in the range of 15-20 parts b y weight.

The pregelatinized starch can improve the stability of the clopidogrel bisulfate, w hich is contained in the pharmaceutical composition and can control the speed of releas e of the medicine. The pregelatinized starch has a molecular formula of (C6HioO₅)_n and the molecul ar weight of the pregelatinized starch is in the range of 300-1000. The pregelatinized s tarch has higher flowability and compressibility than a starch so that it has been used a s a binder in a dry tableting process. In some cases, the pregelatinized starch can be used together with a diluent and a lubricant. The lubricant can be magnesium stearate but according to the amount thereof, the hardness or ejection can deteriorate. Accor dingly, in general, a stearic acid or sodium stearyl fumarate is used as the lubricant. T he pregelatinized starch can also be used during a process of manufacturing wet granul es, and has a moisture content of 18-23%. The pregelatinized starch has hygroscopici ty and is stored in a tightly closed container in a dark, cold chamber. Starch 1500 havi ng a low moisture content contains moisture of 7% or less and generally used to formul ate into a capsule.

It has been reported that when the pregelatinized starch, such as Starch 1500, is alone used with aspirins that can be affected by moisture, or when the pregelatinize d starch and microcrystalline cellulose (MCC), such as Avicel, is used with aspirins, the stability of aspirins can increase. This is because pregelatinized starch inherently is in dined to retain 10-15% of moisture therein so that the starch can remove all the moistur e of a preparation and protect the primary components from moisture itself and/or a sub stance affected by moisture (The Effect of STARCH 1500 On The Stability of Aspirin Pe Nets Stored Under Accelerated Conditions Charles R et al, Colorcon, West Point, PA, USA AAPS, October, 2001 ).

As such, the inventors of the present application added the pregelatinized star ch to clopidogrel bisulfate and observed an increase in the stability of the clopidogrel b isulfate. As described above, although the pregelatinized starch is known to improve the stability of a medicine that is sensitive to moisture, clopidogrel bisulfate is not a su bstance that is sensitive to moisture and there were no attempts to improve the stabilit y of Crystalline Form I of clopidogrel bisulfate by adding the pregelatinized starch to cl opidogrel bisulfate despite a need to improve the stability of Crystalline Form I of clopi dogrel bisulfate. However, the inventors of the present application discovered that wh en the pregelatinized starch is added to clopidogrel bisulfate during a process of formu lating clopidogrel bisulfate, Crystalline Form I of clopidogrel bisulfate has a stability eq ual to or greater than Crystalline Form Il of clopidogrel bisulfate, and the stability of Cry stalline Form Il substantially increases. The pregelatinized starch used in the embodiment of the present invention can be any pregelatinized starch. For example, the pregelatinized starch can be selected from the group consisting of pregelatinized corn starch, such as Starch 1500, pregelatin ized potato starch, pregelatinized wheat starch, and a mixture thereof. Particularly, the pregelatinized starch may be Starch 1500 which is a pregelatinized corn starch having a low moisture content.

The composition including clopidogrel bisulfate and pregelatinized starch accor ding to an embodiment of the present invention can be formulated into a solid preparati on. According to the kind of the dosage form which is formulated, various additives th at are commonly used in the field of pharmaceutics may be further added to the compo sition comprising clopidogrel bisulfate and pregelatinized starch.

An additive, which is to be further added to the composition, may be different a ccording to the dosage form which is formulated. For example, the composition may f urther include a conventional additive selected from the group consisting of a diluent, a I ubricant, a disintegrant, a binder, etc.

The diluent can be selected from the group consisting of a microcrystalline cell ulose (MCC), such as Avicel; dextrose; starch; sucrose; lactose; sorbitol; mannitol; calci urn phosphate, such as bicalcium, tricalcium; and a mixture thereof. However, the dilu ent is not limited thereto. When the diluent is the MCC, the amount of MCC may be in the range of 10-90 wt%, preferably 20-40 wt%, based on the total weight of the unit dos age formulation.

The lubricant can be selected from the group consisting of light anhydrous silic ic acid; metallic stearate, such as magnesium stearate; talc; staric acid; sodium stearyl f umarate; hydrogenanated vegetable oil; wax having a high melting point; and a mixture thereof, but the lubricant is not limited thereto. The amount of lubricant may be in the r ange of 0.2-2 wt%, but preferably about 0.75 wt%, based on the total weight of the unit dosage formulation.

The disintegrant can be starch glycolic sodium, such as Primojel; starch; algini c acid or a sodium salt thereof; talc; corn starch; or a mixture thereof. The binder can be polyvinylpyrrolidone, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxy methylcellulose, hydroxypro pylcellulose, copovidone, or a mixture thereof. A solvent used to prepare the tablets c an be water, ethanol, or lower alcohols, such as isopropanol. The composition according to an embodiment of the present invention may furt her include, in addition to the additives described above, other additives commonly use d in the field of pharmaceutics depending on the dosage form which is formulated. For example, other additives may include an azotropic mixture, an absorbing agent, a colo ring agent, a flavoring agent, or a sweetening agent.

The composition according to an embodiment of the present invention is prefer ably formulated into tablets. A method of formulating the composition into tablets can be a wet granulation method, a dry granulation method, or a direct compression method . The amount of clopidogrel bisulfate, which is an active component, is 75 mg per unit which is in the range of 30-40 wt% based on the total weight of the conventional tablets, and the degree of mixing does not need to be considered when the composition is mix ed.

Accordingly, the pharmaceutical composition according to an embodiment of t he present invention can be prepared by simply mixing an active component, Starch 15 00, and Avicel PH 102, and then additionally mixing the mixture with a lubricant, such as assodium stearyl fumarate. The prepared pharmaceutical composition is then formul ated into a tablet.

The tablet formed using the pharmaceutical composition may be covered by a film coating layer. The film coating layer can be formed of any polymer that can form a film coating layer. The amount of polymer used may be as low as possible in order to control the size of the tablet and to effectively prepare the tablet. The amount of poly mer may be in the range of about 1-10 wt%, preferably about 3-5 wt%, based on the tot al amount of the formulation.

The coating can be performed according to a conventional coating method. I n particular, the coating may be performed using aqueous coating by a pan coating met hod used to coat tablets. For example, in aqueous coating by a general pan coating m ethod, commercially available opadry AMB (Aqueous Moisture Barrier), which is a coati ng agent including 45.52% of PVA (polyvinyl alcohol) and can be obtained from Colorco n Co., is suspended in water in order to prepare a coating solution, and then a pan coat er, such as a Hi-coater, is filled with the coating solution. Then, the coating is perform ed at a influx temperature of 50 to 80 ^°C and an discharged air temperature of about 30 - 45 ⁰C . The coated product is dried using a conventional method, such as a drying m ethod using dry air for 30 minutes, in order to form a film coating layer. The pharmaceutical composition according to an embodiment of the present in vention may further include, in addition to the additives used for the formulation, a stabil izer known in the art to hinder the decomposition of an active component, as required. The stabilizer can be an antioxidant, such as ascorbyl palmitate, ascorbyl stearate; an aqueous chelating agent, such as sodium ethylenediaminetetracetic acid (EDTA), sodiu m ascorbate; or the like.

ADVANTAGEOUS EFFECTS

As described above, according to the present invention, a clopidogrel bisulfate -pharmaceutical composition in which the stability of clopidogrel bisulfate is significantly enhanced can be obtained by mixing clopidogrel bisulfate with a pregelatinized starch.

BEST MODE

The present invention will be described in further detail with reference to the folio wing examples. These examples are for illustrative purposes only and are not intend ed to limit the scope of the present invention. <Example>

Examples 1 and 2, and Comparative Examples 1 through 4 (1 ) Preparation of Tablets Tablets were prepared using active components and additives in composition r atios according to Examples 1 and 2 and Comparative Examples 1 through 4 illustrated in Table 1 , respectively. In each of Examples land 2 and Comparative Examples 1 t hrough 3, all the components, but except of sodium stearyl fumarate, were mixed in a c omposition ratio illustrated in Table 1 using a mixer, and then sodium stearyl fumarate was added thereto and completely mixed. The mixture was compressed using a rotary press (Korsch PH 106) in order to be formulated into 100,000 white tablets. The weig ht of a unit tablet was 248 mg. Table 1

In Comparative Example 4, an active component, mannitol, avicel, PEG, and L -HPC were mixed in a composition ratio illustrated in Table 1 , and then granulated usin g hydrogenated caster oil. Then, the resultant granules were collected through an 18 mesh sieve, and then dried using an air flow dryer at a temperature in a range of 40 to 45⁰C . The dried product was uniformly arranged through a 20 mesh sieve and then co mpressed using a rotary press (Korsch PH 106) in order to produce 100,000 white table ts. The weight of a unit tablet was 248 mg. The pellet prepared according to Compar ative Example 4 is the same as a commercially available Plavix formulated using Crysta Nine Form Il of clopidogrel bisulfate , except that Crystalline Form I was used instead of Crystalline Form Il of clopidogrel bisulfate.

(2) Preparation and coating of coating suspension

Each of the prepared tablets were loaded to a coating pan (Hi-coater) and the discharge air temperature was maintained at a temperature in the range of about 30 to 40 °C . 12 g of opadry AMB (obtained from Colorcon Co.) coating agent was suspende d in 48 g of water in order to prepare a coating solution. The coating solution was spra yed onto the dry tablets using a spray operating by air pressure, and then dried with air for about 10 minutes. The amount of the obtained coated layer was 4.83% of each pel let. The average weight of each pellet was in the range of 256 - 264 mg.

Experimental Example 1 : Dissolution Test

Comparative Dissolution Tests on tablets prepared according to Examples 1 a nd 2 and Comparative Examples 1 through 4 and a Plavix, which is commercially availa ble from Sanofi-synthelabo Co., were carried out.

Dissolution Tests were carried out according to Dissolution Test Article 2 of Ge neral Test of Korea Pharmacopoeia. The conditions of a buffer solution are 37 ^°C , 50 r pm, and a pH of 2.0. The samples were collected 15, 30, and 60 minutes after the dis solution tests were initiated. The analysis of the samples was carried out by chromato graphy under the conditions as shown in Table 2.

Table 2

The results obtained from the dissolution tests are shown in Table 3 and FIG.

1.

Table 3

As shown in Table 3 and FIG. 1 , it was discovered that 30 minutes after the di ssolution initiation, about 80 % or more of the active ingredients contained in the tablets prepared according to Examples 1 and 2 and Comparative Examples 1 through 4 were released.

Experimental Test 2: Stability Test

The tablets prepared according to Examples 1 and 2 and Comparative Exampl es 1 through 4 and Plavix (obtained from Sanofi-Synthelabo Co.) were stored at 60°C(r elative humidity of 80%) for 4 weeks and the contents (%) of the active ingredients cont ained in the respective tablets were measured.

In the respective cases, 20 tablets were crushed into powder and then mixed. Then, 260.0 mg of the powder mixture was suspended in 50 ml_ of methanol. The su spension was exposed to ultrasonic waves for 5 minutes and stirred using a magnetic st irrer for 30 minutes, and then methanol was added thereto until the amount of the result ant solution was 100.0 ml_. The obtained solution was left to sit for 10 minutes. Meth anol was added to 5.0 ml_ of the left to sit solution until the total amount of the solution was 50.0 ml_. The resultant solution was filtered through a 0.45 μm micropore membr ane. At this point, 5 ml_ of the initially filtered solution was left unused. The content a nalysis was performed under chromatography conditions as shown in Table 2.

The results are shown in Table 4.

Table 4

According to the results shown in Table 4, the tablets comprising pregelatinize d starch prepared according to Examples 1 and 2 have a higher stability than Plavix an d the tablets prepared according to Comparative Examples 1 through 4.

Claims

1. A pharmaceutical composition comprising clopidogrel bisulfate and pregelatin ized starch.

2. The pharmaceutical composition of claim 1 , wherein the amount of clopidogre

I bisulfate is in the range of 30-40 parts by weight and the amount of the pregelatinized starch is in the range of 10-70 parts by weight.

3. The pharmaceutical composition of claim 1 , wherein the clopidogrel bisulfate i s Crystalline Form I or Crystalline Form II.

4. The pharmaceutical composition of claim 1 , wherein the pregelatinized starch is selected from the group consisting of pregelatinized corn starch, pregelatinized potat o starch, pregelatinized wheat starch, and a mixture thereof.

5. A tablet formed of the pharmaceutical composition of any one of claims 1 thro ugh 4.