TW200946115A - Process for producing pharmaceutical preparation containg clopidogrel and/or its salt and pharmaceutical preparation produced thereby - Google Patents

Abstract

A process for producing a pharmaceutical preparation containing clopidogrel and/or its salt is provided. The process comprises conducting a first mixing step to mix clopidogrel and/or its salt with a hydrophobic component to provide a first mixture; and conducting a second mixing step to mix the first mixture with granulation excipient particles. Such a specific drug manufacturing technique can successfully prevent the clopidogrel and/or its salt contained in the resulted pharmaceutical preparation from contacting with the highly sensitive factors in environment, and thus enhances the storage stability of the preparation and stabilizes the crystal form of the clopidogrel and/or its salt.

Description

200946115 IX. Description of the Invention: [Technical Field] The present invention relates to a method for preparing a pharmaceutical preparation containing clopidogrel and/or a salt thereof, in particular, relating to clopidogrel and/or a salt thereof Crystal stabilization technology. [Prior Art] The chemical name of clopidogrel is (+)-(S)-a-(2-phenylphenyl)-4,5,6,7-tetrahydrothiophene.

There have been many studies and reports that clopidogrel has platelet inhibitory activity and is a platelet aggregation inhibitor that prevents thrombosis and reduces the chance of arterial occlusion. It is used to prevent vascular diseases such as atherosclerosis. The incidence of ischemic stroke, heart attack, or claudication. It is known that clopidogrel is administered in the form of its hydrogen sulphate having the experimental formula C16H16C1N02S. H2S04, which was first disclosed in EP 281459. This European patent teaches the enantiomers of tetrahydroheptime and butyl derivatives and their pharmaceutically acceptable salts, which specifically reveals the gastropinous hydrogensulfate, the right-handed homologue of the hydrogen sulfate The dextrorotatory isomer has excellent aggregation inhibition activity, while its levorotatory isomer is less active and less responsive. However, EP 281459 does not mention that clopidogrel hydrogen sulfate has a plurality of crystalline forms. 200946115

About a decade later, US 6429210 proposed a polymorphic form of pirimidol and its synthesis, and pointed out that the synthetic method disclosed in EP 281459 leads to the preparation of a gas-specific palladium hydrogensulfate. It is an irregular sheet, US 6429210, and the irregular crystalline form is defined as "Form 1". In addition, US 6429210 further finds another crystalline form of clopidogrel hydrogen sulfate, which is in the form of agglomerates, "crystal form 2", and it has been confirmed by tests that form 2 has better thermal stability than crystal form 1. With tightness. Currently, the commercially available product Plavix® is a tablet having the crystalline form 2 of pridolidine hydrogensulfate as an active ingredient, and each tablet contains about 98 g of the active ingredient. After understanding the properties of different crystal forms of clopidogrel hydrogen sulfate, relevant pharmaceutical researchers have further investigated the effects of the ingredients of pharmaceutical preparations on the stability of the drug. For example, U.S. Patent No. 6,914,141 discloses a lozenge formulation of clopidogrel hydrogen sulphate which evaluates the effect of the lubricant used in the pharmaceutical formulation on the storage stability of the lozenge produced. US 6914141 finds that when certain specific lubricants (such as stearic acid, zinc stearate, or stearin fumarate) are used, it replaces the hydrogenated castor oil or polyethylene used in the commercial product Plavix®. When the diol 6000 and the conventional pharmaceutical conventionally used magnesium stearate and calcium stearate, the tablet containing the gas-pitared hydrogen sulphate can be maintained at a relatively high quality, for example, when stored at 60 ° C for 2 In the week, the total decomposition product (impurity) is 1% to 1.3%. WO 2007/049868 further mentions how to reduce the content of impure substances in pharmaceutical preparations or pharmaceutical compositions containing gas-pipidine hydrogen sulfate (in whatever crystalline form), using starch and cellulose as a substrate. As a pharmaceutical excipient of 200946115, the ingredients (such as microcrystalline cellulose, low-substituted hydroxypropylcellulose, and hydroxypropylmethylcellulose) are used to prepare medicines with storage stability and maintaining a relatively active ingredient release rate. Lozenges. US 6914141 and WO 2007/049868 both describe the stability of pharmaceutical products containing clopidogrel hydrogen sulfate (in whatever crystalline form), but only to avoid the presence of the components contained in the storage process and the environment. The substance reacts to produce other substances (ie, impure substances), and the ink form stability of the gas-prepide hydrogen sulfate is not inked.

In order to improve the medicinal availability of the medically effective active ingredient clopidogrel and its salts, the inventors of the present invention have found that the use of specific formulation techniques and pharmaceutical compositions can effectively prevent high sensitivity factors (such as temperature and moisture). Contact with clopidogrel and/or its salt improves the storage stability of the pharmaceutical product while maintaining the release rate of the active ingredient contained therein, and can successfully prevent the crystal form conversion of the active ingredient. SUMMARY OF THE INVENTION An object of the present invention is to provide a method for preparing a pharmaceutical preparation containing a gas-pipidine and/or a salt thereof, comprising first performing a first mixing step to mix a mixture of pidori and/or a salt thereof An oleophilic component to provide a first mixture; followed by a second mixing step to mix the first mixture with an excipient granule. Another object of the present invention is to provide a pharmaceutical preparation containing a gas-picuridine and/or a salt thereof, which comprises a gaspidol and/or a salt thereof and a lipophilic component, wherein the clopidogrel and/or The salt is substantially coated with the lipophilic component. The basic spirit and other objects of the present invention, as well as the technical means and preferred embodiments of the present invention, can be readily understood by those of ordinary skill in the art. [Embodiment] 200946115 As used herein, unless otherwise specified, "active ingredient" means clopidogrel and/or a salt thereof.

In the preparation method of the present invention, a first mixing step is carried out, and the active ingredient is mixed with a lipophilic component to be blended to obtain a first mixture containing the active ingredient and the lipophilic component. In this case, since it is highly sensitive to environmental factors such as light, moisture, and temperature, it is susceptible to deterioration by environmental factors, and produces related impurities such as hydration products, which affect the quality of the drug. Thus, blending the active ingredient with a lipophilic ingredient to substantially cover the surface of the active ingredient will help to block contact of the highly sensitive environmental factor with the active ingredient. As used herein, "the lipophilic component substantially covers the surface of the active ingredient" means that a plurality of discrete fractions are present in the pharmaceutical preparation of the present invention, each of which is substantially composed of an active ingredient, and The surface of the small portion is substantially covered by the lipophilic component. In the first mixing step, a device having a mixing action such as a trough mixer, a small mixer, a high shear mixer, a spiral mixer, a belt mixer, a rolling mixer, a v-type mixer can be utilized. A suitable mixer such as a double-cone mixer is used to uniformly mix the active ingredient with the lipophilic component; preferably, it is dry-mixed without adding any moisture or solvent. Depending on the blending device used, different mixing times can be carried out so that the surface of the active ingredient is completely and appropriately coated with the lipophilic component as much as possible to achieve the desired barrier effect. For example, when blending is carried out using a double cone mixer at about 22 rpm, the first mixing step typically lasts at least 3 minutes. The amount of the lipophilic component in the first mixing step is generally from 2% by weight to 10% by weight, preferably from 4% by weight to 8% by weight, based on the total amount of the active ingredient 200946115. Here, if the amount of the lipophilic component is too low, the coating effect of the active ingredient may be poor, and the desired barrier effect may not be achieved; otherwise, the active ingredient may be excessively blocked, resulting in a dissolution rate of the preparation being too slow. . In order to enhance the blending result, the lipophilic component may be subjected to a pulverization treatment and/or a sieving treatment before the first mixing step to provide a lipophilic component having a suitable size, and then The active ingredients are mixed.

Any pharmaceutically acceptable lipophilic component can be employed in the methods of the invention. Here, pharmaceutically acceptable lubricants are generally lipophilic and can be used as a lipophilic component in the process of the present invention. For example, a lubricant selected from the group consisting of hydrogenated castor oil, stearic acid, glyceryl monostearate, palmitoyl stearate, hydrogenated vegetable oil, glycerin may be used in the present invention. A glyceryl fatty acid ester, a glycerylol dibehenate, a polyethylene glycol talc (talc), and any combination of the foregoing are preferably hydrogenated castor oil as a lipophilic component. Among the active ingredients used in the present invention, examples of pharmaceutically acceptable salts of clopridol include, but are not limited to, hydrogen sulfate, hydrochloride, hydrobromide, and taurocholate. Among them, clopidogrel hydrogen sulfate has an excellent platelet aggregation inhibitory activity and is particularly suitable for use in the method of the present invention. Here, the crystalline form of the active ingredient is not critical to the process of the present invention, exemplified by the gas-pipurious hydrogensulfate, which may comprise Form 1 and Form 2 in any crystalline form for use in the process of the invention. Regarding crystal form 1 and crystal form 2 of clopidogrel hydrogen sulfate, according to US Pat. No. 6,429,210, Form 1 shows an absorption band at 841 cm-1 in the infrared spectrum, and the crystal number 2 is in this wave number in 200946115. There is no obvious absorption underneath. In addition, the journal Acta Pharm. 54 (2004) 193-204 also reports on the analysis of the crystalline form of clopidogrel hydrogen sulfate. According to the two published materials, the characteristic absorption wavelengths of the infrared spectrum of Form 1 and Form 2 of clopidogrel hydrogen sulfate can be sorted out, as listed in the following table: Form 1 Crystal Form 2 1175 cm'1 1187 cm '1 841 cm'1 1155 cm'1 2987 cm'1 1029 cm·1

After obtaining the first mixture containing the active ingredient and the lipophilic component, followed by a second mixing step, the first mixture is mixed with an excipient granule to obtain a pharmaceutical preparation containing the active ingredient. As the first mixing step, the second mixing step may use, for example, a tank mixer, a small mixer, a high shear mixer, a spiral mixer, a belt mixer, a rolling mixer, a V-type mixer, a double cone mixer And various suitable devices having a blending action to mix the first mixture with the excipient particles. . As regards the excipient particles blended with the first mixture, the materials of preparation and methods of manufacture are well known to those skilled in the pharmaceutical arts. In the method of the present invention, the granulating excipients to be employed are preferably compatible with the active ingredients in addition to being pharmaceutically acceptable to maintain the stability of the resulting pharmaceutical preparation. Generally, granulating excipients typically include a diluent, a hygroscopic agent, a binder, a disintegrant, and any combination of the foregoing. Wherein, the diluent (dillient) is mainly used to dilute the active ingredient of the pharmaceutical preparation and is used to impart the desired shape to the medicament. Examples of non-limiting 200946115 properties include the following groups: microcrystalline cellulose, fine cellulose, powdered fiber. , kaolin, talc, polydecyl acrylate (eg Eudragit®) 'calcium carbonate, calcium sulphate, dibasic calcium phosphate dihydrate, tricalcium phosphate, magnesium carbonate, magnesium oxide, potassium chloride, sodium chloride, and the foregoing Any combination; preferably microcrystalline cellulose, fine cellulose, powdered cellulose, and any combination of the foregoing; more preferably microcrystalline cellulose.

As the name implies, hygroscopic agents are used to absorb moisture around the storage environment and reduce the deterioration of active ingredients by moisture. Non-limiting examples of moisture absorbents suitable for use in the present invention include the following groups: lactose, dextrose, sucrose, starch, dextrin, maltodextrin, mannitol, sorbitol, xylitol, and the foregoing. Any combination; wherein, non-limiting examples of starch are potato starch, corn starch, wheat starch, rice starch, pregelatinized starch, and any combination of the foregoing. In one embodiment of the method of the invention, the hygroscopic agent is selected from the group consisting of mannitol, lactose, and combinations thereof. The use of a binder helps to bond the active ingredient to other excipient ingredients after compression to avoid breakage of the agent. Non-limiting examples of binders suitable for use in the present invention include the following groups: hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, ethylcellulose, hydroxydecylcellulose, hydroxyethylcellulose , hydroxypropyl cellulose (eg K丨ucel®), methyl cellulose, microcrystalline cellulose, dextrin, maltodextrin, starch (eg potato starch, corn starch, wheat starch, rice starch, pre-gelatin) Condensed starch), gum arabic, gelatin, alginic acid, polyacrylic acid, sodium alginate, hydrogenated vegetable oil, magnesium oxalate, povidone, copolyvidone, polymethyl phthalate, and the foregoing Any combination. Preferably, hydroxypropionyl cellulose, polyethylene pyrrolidone, povidone, copolyvidone, polymethacrylate, or any combination of the foregoing is used as the binder, and more preferably hydroxypropyl Methyl 200946115 Cellulose, polyvinylpyrrolidone, or a combination thereof.

Further, the method of the present invention may optionally use a disintegrant as a granulating excipient to increase the dissolution rate of the preparation in the user. Non-limiting examples of disintegrants suitable for use in the present invention include the following groups: sodium carboxymethylcellulose, croscarmellose sodium, carboxymethylcellulose, calcium carboxymethylcellulose, cross-linking Methylcellulose sodium, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, glycolic acid; temple powder (such as Explotab®), warp base; temple powder propionic acid vinegar, methyl palace powder Sodium, alginic acid, sodium alginate, glycolate, cross-linked polyethylene, π ketone (such as Kollidon® and Polyplasdone®), crospovidone, colloidal dioxide, squash, melon Guar gum, cation exchange resin, and any combination of the foregoing. Depending on the experience of preparing the drug, relevant reference materials, and the use of the drug, pharmaceutical personnel can easily know the amount of each granulating agent. In the present invention, the total amount of the granulating excipient used is usually from about 35% by weight to about 65% by weight, preferably from 45% by weight to 55% by weight, based on the total weight of the obtained pharmaceutical preparation. Wherein, the diluent is used in an amount of about 15 to 25% by weight, the moisture absorbent is used in an amount of about 25% by weight to 35% by weight, and the binder is used in an amount of about 0.1% by weight based on the total weight of the pharmaceutical preparation prepared. Weight% to 0.5% by weight. The granule-forming excipients used are combined and passed through a conventional dry/wet granulation procedure to obtain excipient granules which will be mixed with the first mixture in a subsequent procedure. Taking the wet granulation method as an example, an appropriate amount of granulation and excipient is added in combination with an appropriate amount of water or solvent, and mixed by a mixing device such as a water refining machine to obtain a wet mass containing an excipient, and then The wet mass is sieved and dried to produce the excipient particles. 12 200946115 In one embodiment of the method of the invention, the second mixing step further comprises mixing a moisture absorbent. Herein, the first mixture and the excipient particles may be mixed first, and the moisture absorbent may be added, and the first mixture, the excipient particles and the moisture absorbent may be simultaneously added, and then stirred and blended. Adding a moisture absorbent in the second mixing step can further help absorb moisture which may exist in the preparation process, and also help to absorb external moisture to prevent the active ingredient from contacting with water and reacting to form a hydrated product. Such as impure substances, to maintain the quality of the drug.

The moisture absorbent suitable for the second mixing step may be selected from the above-mentioned ones for preparing the excipient particles, and the two may be the same or different, and are not particularly limited. In one embodiment of the invention, the same hygroscopic agent is selected for use in the excipient granulation step and the second mixing step. The amount of the moisture absorbent used in the second mixing step is generally from 10% by weight to 25% by weight, preferably from 13% by weight to 20% by weight, based on the total weight of the active ingredient. According to another embodiment of the method of the present invention, the first mixture is first mixed with a co-solvent prior to the second mixing step. The addition of this co-solvent improves the flowability of the uncompressed pharmaceutical ingredient and improves the operability of the pharmaceutical procedure. Here, as the co-solvent, for example, polyethylene glycol, sodium lauryl sulfate, polysorbate, or a combination thereof can be used, and polyethylene glycol is preferably used. After the mixing of the first mixture, the excipient granules and optionally the moisture absorbing agent is completed, the mixing procedure is completed to obtain a granule-shaped pharmaceutical preparation. Among them, in view of the manner of use of the drug or the convenience of packaging, the obtained granules can be further tableted to obtain a pharmaceutical preparation in the form of a tablet. Therefore, the method of the present invention may further comprise a tableting process after the second mixing step. For example, the tablet may be ingot by a single punching machine or a rotary tableting machine, and the obtained pellets may be made into a bare ingot. Furthermore, the needle 13 200946115, for the particles to be ingot, may be additionally added with a lubricant before the tableting, in order to prevent the obtained tablet from sticking to the tableting mold without being easily taken out. Non-limiting examples of suitable lubricants include the following groups: hydrogenated castor oil, stearic acid, glyceryl monostearate, palmitious stearic acid glycerin, hydrogenated vegetable oil, glycerin fatty acid I, glycerol Berylate, polyethylene glycol, talc, magnesium stearate, calcium stearate, stearic acid, mineral oil, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, Sodium stearyl fumarate, sodium acetate, and any combination of the foregoing.

In the technique for preparing a tablet, a coating step is usually performed on the obtained bare ingot, and the purpose thereof is mainly to protect the obtained preparation, increase the mouthfeel when the preparation is taken, and improve the appearance of the preparation, etc.; Examples include polyvinyl alcohol, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, povidone, and the like. Further, an additive such as a flavoring agent, a toner, or a coloring agent may be added in the second mixing step as needed to improve the mouthfeel and visual feeling when the obtained preparation is taken. By way of example, the additives include 474, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltitol, and tartaric acid. The method of the present invention may also fill the resulting pharmaceutical granules into a capsule after the second mixing step to provide a dosage form in the form of a capsule which improves the mouthfeel when the drug is administered. The pharmaceutical preparation obtained by the preparation method of the present invention can effectively prevent external environmental factors (such as moisture, temperature, etc.) from contacting the active ingredient, thereby increasing the storage stability of the pharmaceutical preparation; moreover, the medicine obtained by the method of the present invention The formulation, the crystalline form of the active ingredient contained therein is quite stable, especially the gas-puriral hydrogen sulfate, which can avoid conversion between the crystal forms for a long time, which can be further verified by the following examples. 14 200946115 Accordingly, the present invention is more directed to a pharmaceutical preparation containing a gaspiride and/or a salt thereof, which comprises clopidogrel and/or a salt thereof and a lipophilic component, wherein clopidogrel and/or The salt is substantially coated with the lipophilic component. The pharmaceutical preparations may be in any convenient form such as granules, capsules or lozenges. Herein, the components and the amounts thereof contained in the preparation of the pharmaceutical preparation of the present invention are as described above, and will not be described herein.

According to one embodiment of the pharmaceutical preparation of the present invention, which is obtained by the method of the present invention and comprises an active ingredient of clopidogrel hydrogensulfate and a lipophilic component hydrogenated castor oil, and the surface substance of the pirimidol hydrosulfate The upper layer is coated with the hydrogenated castor oil. Further, the pharmaceutical preparation of this embodiment further comprises a granulating excipient selected from the group consisting of microcrystalline cellulose, mannitol, lactose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and any combination of the foregoing, And a hygroscopic agent (ie, mannitol and/or lactose) added with a co-solvent polyethylene glycol and a second mixing step. As described above, since the pharmaceutical preparation of the present invention has a lipophilic layer coated on the active ingredient, more specifically, the living part of the pharmaceutical preparation of the present invention is covered by the lipophilic component, and the external component can be successfully blocked. Environmental factors are in contact with the active ingredient to avoid the formation of impurities. Furthermore, the use of a moisture absorbent component can also absorb external moisture and improve storage stability. Further, as described above, the pharmaceutical preparation of the present invention may optionally contain other additives such as a flavoring agent, a flavoring agent, and a coloring agent to improve the mouthfeel and visual sensation at the time of administration. The pharmaceutical preparation of the present invention is suitable for treating diseases such as cardiovascular and cerebrovascular disorders, such as thrombotic dysfunction associated with arteriosclerosis or diabetes, such as unstable stagnation, stroke, restenosis after angioplasty And endarterectomy or artificial 15 200946115 Compensatory surgery put into metallic internal blood vessels, etc.; also used to treat thrombosis, thrombosis, infarction, dementia caused by blood loss, peripheral arterial disease, blood dialysis, heart Anti-fibrillation and other related diseases. The present invention will be more specifically described by the following examples, which are intended to illustrate the invention and not to limit the scope of the invention.

Examples 1-4 The granulation excipients listed in Table 1 were subjected to a refining mechanism to obtain wet agglomerates, and the obtained wet agglomerates were sieved through a 24 mesh sieve and dried, and then passed through a mesh of 30 mesh to obtain The dosage granules are ready for use. The hydrogenated castor oil is pulverized and passed through a 200 mesh mesh with chlorphenidron hydrogen sulfate firstly mixed in a mixer, mixed for 5 minutes and then added with polyethylene glycol 6000 (which is first pulverized and then passed through 200 mesh and then used. Finally, the hygroscopic agent and the excipient particles were finally mixed for 10 minutes to complete the mixing procedure. Next, a circular bare key having a diameter of 8.6 mm was pressed by a rotary tableting machine. 16 200946115 Table 1 Ingredients (mg) Example 1 Example 2 Example 3 Example 4 Active ingredient gas pridore hydrogen sulfate (crystal form 1) υ 98 98 98 98 granulation excipient microcrystalline cellulose 2) 50 50 50 50 Mannitol 3> 66.5 ... 66.5 ... Lactose 4) 66.5 ... 66.5 Hydroxypropylmethylcellulose 5) 0.5 0.5 ... Polyvinylpyrrolidone Κ306) 0.5 0.5 Lipophilic component hydrogenated castor oil 7> 5 5 5 5 Cosolvent Polyethylene glycol 60008> 5 5 5 5 Moisture absorber mannitol 15 15 ... Lactose... 15 — 15 Total weight 240 240 240 240 1 ] Shengda synthetic waste, 2) Mingtai, 3) San Fu, 4> Borculo Domo Ingredients , 5) Shih-Etsu, 6 > BASF Aktiengesellschafl, 7) Vertellus Performance Materials Inc., 8) The Dow Chemival Company

Test Example 1: Dissolution test The bare ingot obtained in the above Example 1 was compared with a commercially available equivalent amount of clopidogrel hydrogen sulfate tablet (Plavix®, Taiwan Sanofi-Aventis), which was 30 in accordance with the United States Pharmacopoeia. The dissolution tester (Sotax) is used for the dissolution test. Take 1000 ml of pH 2.0 phosphate buffer solution (refer to the US Pharmacopoeia specification 30) as the dissolution test solution, pour into the dissolution test tank, and heat to 37±0.5 °C. . Then use a paddle to adjust the rotation speed at 50 rpm and adopt the flow system. Take 2 samples of the dissolution solution at 2, 4, 6, 8, 10, 15, 20, 25, 30, 40, 50 minutes and test. Its absorption at a wavelength of 240 nm, the results are shown in Table 2 and Table 3 below, and the average value of the dissolution rate versus time is plotted, as shown in Fig. 1. 17 200946115 Table 2 Table 3

Minute dissolution rate (%) of commercially available products SD 0 -0.1 0.03 2 2.86 2.07 4 13.29 3.7 6 23.97 5.17 8 34.9 6.32 10 44.56 7.29 15 64.42 8.62 20 79.13 8.65 25 88.77 7.51 30 94.27 5.85 35 96.55 4.42 40 97.63 3.46 45 98.27 2.79 50 98.62 2.48 Example 1 minute dissolution rate (%) SD 0 -0.01 0.03 2 0.96 0.43 4 8.38 1.91 6 20.07 3.07 8 31.6 2.94 10 42.47 3.92 15 63.71 6.41 20 81.15 6.03 25 94.48 5.12 30 99.46 3.41 35 101.83 2.21 40 102.43 2.01 45 102.75 1.81 50 102.99 1.73 It can be seen from the above Table 2 and Table 3 and Figure 1 that the pharmaceutical preparation prepared by the method of the present invention has a dissolution rate comparable to that of a commercially available product, exhibiting a comparable release rate of the active ingredient.

Test Example 2: Storage Stability The bare ingots obtained in the above Examples 1 to 4 were subjected to a stability accelerated test under the same conditions as those specified by the International Conference on Harmonization (ICH). The test was carried out at a temperature of 40 ° C and a humidity of 75% RH. The test analysis conditions were carried out according to the test method of the 30th edition of the United States Pharmacopoeia. The main related substances and impurities were classified as hydrolysis byproducts (related substances A) and R-image isomers (related substances C). And 200946115, he is a single impurity, according to the US Pharmacopoeia, the scope of the 3rd edition of the relevant substances A, related substances C, other single impurities and total impurities should be less than 12%, 丨5〇 / 〇, 0.2% &gt ; 2.5% 〇

The test results on the day of the formulation, 2 weeks and 2 months later are listed in Table 4 to Table 7 below: X 0 Example 403⁄4 I?%RH ----__ _〇天 Related substance A (%) Related substance C (%) Other single maximum impurity (%) Total impurities

table

Example 2 Related substance C (%) Other single maximum impurity (%) 0.03 0.03 0.04 Total impurity 0.79 0.89 1.17 Table 6 - Λ Related substance A (%) 'Related substance C (%) Other single maximum impurity (%) Total impurity d 0.09 -- 0.73 0.04 0.87 1 0.J6__ 0.77 0.04 0.99 ~~~ 3 0.83 ---- 0.88 0.06 1.78 200946115 Table 7 Example 4 40 ° C 75% RH Related substance A (%) Related substance C ( %) Other single maximum impurity (%) Total impurity (%) 0 days 0.10 0.70 0.03 0.84 2 weeks 0.14 0.74 0.04 0.95 February 0.68 0.79 0.04 1.54 Can be found from Table 4 to Table 7, after two months The content of the impurity in the pharmaceutical preparation of the present invention still meets the recommendation of the 30th edition of the US Pharmacopoeia, and does have

Its storage stability. Test Example 3: Crystal Stability

Taking the ingredients listed in Table 1, the preparation methods described in Examples 1, 2, 3 and 4 were repeated, and the tablets prepared after tableting were respectively ground to obtain 7.35 mg (about 3 mg of active ingredient) and 297. A milligram of potassium bromide was mixed, wherein the active ingredient was 1% by weight based on the total weight of the resulting mixture, and then a pressure of 10 kg/cm 2 was applied for 20 seconds to prepare a potassium bromide salt tablet sample. Further, a reference sample was prepared in the same manner but without the addition of clidophene hydrogen sulfate. The absorption of 4000 cm·1 to 400 cnT1 was scanned by a Fourier transform (FTIR) spectrometer with a scanning resolution of 4.0 cm·1 and a scanning interval of 2.0 cm·1. The detection of each sample was performed on the day of sample preparation and 32 cumulative scans after 2 months; the samples prepared from the components listed in Example 1 were more than 2 years later (actually 2 years and 4 months). Infrared scanning, as shown in Figure 2. According to the absorption wavelengths of the infrared spectra of the two crystal forms compared in the table of the specification, it is judged whether or not the crystal form of the clopidogrel hydrogen sulfate is converted, and the results are as listed in Table 8: 20 200946115 Table 8 Example 1 Example 2 Example 3 Example 4 0-day crystal form 1 crystal form 1 crystal form 1 crystal form 1 February crystal form 1 crystal form 1 crystal form 1 crystal form 1

As can be seen from Table 8, the crystal form of the clopidogrel hydrogen sulfate contained in each sample was maintained, and no crystal form conversion occurred. Fig. 2 further shows that the pharmaceutical preparation provided by the method of the present invention maintains the crystalline form of its active ingredient even after long-term storage. This shows that the effect of the crystalline form of the active ingredient in the obtained pharmaceutical preparation can be achieved by the method of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing the results of the dissolution test in the specification of the present invention; and Fig. 2 is a graph showing the infrared spectrum measured 2 years after the sample obtained in the formulation of Example 1 in Test Example 3. [Main component symbol description]

twenty one

Claims (1)

200946115 X. Patent application scope: 1. A method for preparing a pharmaceutical preparation containing clopidogrel and/or a salt thereof, comprising: 3. 4. 5. performing a first mixing step of mixing clopidogrel and/or its salt and a lipophilic component to provide a first mixture; and performing a second mixing step to mix the first mixture with a Granule-forming agent particles. The method of claim 1, wherein the excipient particles comprise a component selected from the group consisting of a diluent, a moisture absorbent, a binder, a disintegrant, and any combination of the foregoing. The method of claim 1, wherein the first mixing step is a dry mixing operation. The method of claim 1, wherein the lipophilic component is selected from the group consisting of hydrogenated castor oil, stearic acid, glyceryl monostearate, palmitic stearic acid glycerin, hydrogenated vegetable oil, glycerin fatty acid vinegar , glyceryl sorbic acid S, polyethylene glycol, talc, and any combination of the foregoing. The method of claim 4, wherein the lipophilic component comprises hydrogenated castor oil. 6. The method of claim 1, wherein the first mixing step employs a clopidogrel salt selected from the group consisting of hydrogen sulfate, hydrochloride, hydrobromide, and taurocholate. And any combination of the foregoing. 7. The method of claim 6 wherein the clopidogrel hydrogen sulphate is used in the first mixing step. 22 200946115 I The method of claim 7, wherein the hydrogen sulfate is in the form of Form 1 or Form 2. The method of the invention wherein the lipophilic component is used in the first mixing step f, and is 2 parts by weight based on the total weight of the clopidogrel and/or its salt. /〇 to 1〇, weight °/〇. The method of claim 9, wherein the secret ingredient is used in an amount of from 4% by weight to 8% by weight based on the total weight of the clopidogrel and/or its salt. η. The method of claimant, wherein prior to the second mixing step, further beta comprises mixing the first mixture with a co-solvent. The method of claim 11, wherein the co-solvent comprises polyethylene glycol. The method of claim i, wherein the second mixing step further comprises mixing a hygroscopic agent selected from the group consisting of H dance, sorbitol, xylitol, lactose, dextrose, The method of claim 13, wherein the starch is selected from the group consisting of: Ma Dian Dong Dian powder, Yu Qiu starch, and the like. Wheat (4), rice _, tumbling powder, and any combination of the preceding description. The method of claim 13, wherein the moisture absorbent is selected from the group consisting of glycochromeol, lactose, and combinations thereof. The method of claim 13, wherein the moisture absorbent is used in an amount of from 10% by weight to 25% by weight based on the total weight of the clopidogrel and/or its salt. The method of claim 16, wherein the moisture absorbent is used in an amount of from 13% by weight to 20% by weight based on the total weight of the gas and the salt thereof. I8·- a pharmaceutical preparation containing clopidogrel or a salt thereof, comprising 23 200946115 clopidogrel or a salt thereof and a lipophilic component, wherein the clopidogrel or a salt thereof is substantially The upper layer is coated with the lipophilic component. The pharmaceutical preparation according to claim 18, wherein the lipophilic component is selected from the group consisting of hydrogenated castor oil, stearic acid, glyceryl monostearate, palmitic stearic acid glycerin, hydrogenated vegetable oil, Glycerol fatty acid vinegar, glyceryl sorbic acid vinegar, polyethylene glycol, talc, and any combination of the foregoing. 20. The pharmaceutical preparation according to claim 19, wherein the lipophilic component is hydrogenated ramie oil. 21. The pharmaceutical preparation according to claim 18, which comprises from 2% by weight to 10% by weight of the lipophilic component, based on the total weight of the clopidogrel and/or its salt. 22. The pharmaceutical preparation according to claim 21, which comprises from 4% by weight to 8% by weight of the lipophilic component, based on the total weight of the gaspidol and/or its salt. 23. The pharmaceutical preparation of claim 18, wherein the clipridol salt is selected from the group consisting of hydrogen sulfate, hydrogenate, hydrobromide, bovine cholate, and any combination of the foregoing. 24. The pharmaceutical preparation of claim 23, which comprises pirimidol hydrogen sulphate. 25. The pharmaceutical preparation according to claim 24, wherein the hydrogen sulfate is in the form of Form 1 or Form 2. 26. The pharmaceutical preparation according to claim 18, further comprising a moisture absorbent selected from the group consisting of mannitol, sorbitol, xylitol, lactose, dextrose, sucrose, source of dinosaur, dextrin , maltodextrin, and any combination of the foregoing. 27. The pharmaceutical preparation of claim 26, wherein the starch is selected from the group consisting of potato starch, corn starch, wheat starch, rice starch, pregelatinized starch, 24 200946115, and any combination of the preceding. 28. The pharmaceutical preparation of claim a, wherein the hygroscopic group is selected from the group consisting of mannitol, lactose, and combinations thereof. The pharmaceutical composition according to claim 26, which comprises a 〇 weight y to a moisture absorbing agent, based on the total weight of clopidogrel and/or a salt thereof. 5% by weight. The pharmaceutical preparation according to claim 29, which comprises a sorbent of 13% by weight to θ, based on the total weight of the gaspide and/or its salt. 20重董% C 31. The pharmaceutical preparation according to claim 18, which is obtained by a method. The pharmaceutical preparation described in the Chinese Patent Application No. 32. 2 is in the form of a granule 'capsule or shape 0 25