TWI353836B - Process for producing pharmaceutical preparation c - Google Patents

Description

1353836 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 pirimidol and/or a salt thereof Crystal stabilization technology. [Prior Art] The chemical name of clopidogrel is (+)-(S)-ct-(2-phenylphenyl)-4,5,6,7-tetrahydrothiophene.

There have been many studies and reports that it has platelet inhibitory activity and is a platelet aggregation inhibitor that can prevent the formation of blood clots and reduce 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 pirimidol is administered in the form of its hydrogen sulphate, which has the experimental formula C16H16C1N02S. H2S04, which was first disclosed in EP 281459. This European patent describes the enantiomers of the tetrahydrothienopyridine derivatives and their pharmaceutically acceptable salts, which specifically discloses the gasipodil hydrogensulfate, the right-handed isomer of the hydrogen sulfate ( The dextrorotatory isomer has excellent platelet aggregation inhibitory activity, while its levorotatory isomer is less active and more responsive. However, Ε Ρ 2 814 5 9 does not mention that pirimidol has a variety of crystalline forms. 1353836

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 formulation of pirimidol hydrogen sulphate which evaluates the effect of the lubricant used in the pharmaceutical formulation on the storage stability of the resulting tablet. 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. The ingredients (such as microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and hydroxypropyl fluorenyl cellulose) are used as 1353836 pharmaceutical excipients to produce medicines with storage stability and maintaining a relatively active ingredient release rate. Lozenges. US 6914141 and WO 2007/049868 both describe the stability of a pharmaceutical product containing pirimidol hydrosulfate (in whatever crystalline form), but only to avoid the presence of the contained components in the storage process and in 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 gas pridori and/or a salt thereof, which comprises clopidogrel and/or a salt thereof and a lipophilic component, wherein the gas is pirated 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] 1353836 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 first 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, 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 lipophilic component is used in the first mixing step in an amount of from 1353,836, usually from 2% by weight to 10% by weight, preferably from 4% by weight to 8% by weight. 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. The glyceryl fatty acid ester, glycerylol dibehenate, polyethylene glycol, talc, and any combination thereof are preferably hydrogenated castor oil as a lipophilic component. Among the active ingredients used in the present invention, examples of the pharmaceutically acceptable salt of clopridol include, but are not limited to, hydrogen sulfate, hydrocyanate, hydrobromide and taurocholate. Among them, since pirimidol hydrosulfate has excellent platelet aggregation inhibitory activity, it 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. According to the disclosure of US Pat. No. 6,429,210, Form 1 shows an absorption band at 841 cm-1 in the infrared spectrum, and 1353836 crystal form 2 in this wave number. 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 pirimidol. According to the two published materials, the characteristic absorption wavelengths of the infrared spectrum of Form 1 and Form 2 of the gas-picuron hydrogen sulfate can be sorted out, as listed in the following table: Crystal 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. 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. The non-limiting 1353836. Powdered fiber--, kaolin, talc, polymethacrylate (such as Eudragit®), calcium carbonate, sulfuric acid dance, hydrogen sulphate dihydrate, acid-filled three-mother, magnesium citrate, oxidized town, gasification unloading And arbitrarily dissolving sodium, and any combination thereof; preferably microcrystalline cellulose, fine cellulose, deuterated cellulose, and any combination thereof; more preferably microcrystalline cellulose. As the name implies, hygroscopic agents are used to absorb the moisture around the storage environment and reduce the deterioration of the active component (4). Non-limiting examples of moisture absorbents suitable for use in the present invention include the following groups: lactose, dextrose, sucrose, house powder, dextrin, maltodextrin, glyceryl alcohol, sorbitol, xylitol, and Any combination of the foregoing; wherein, non-limiting examples of the powder are potato powder, m powder 'wheat (four), rice; temple powder, pregelatinized powder, and any combination of the former. In one embodiment of the method of the invention, the moisture absorbent is selected from the group consisting of mannitol, lactose, and combinations thereof. The use of a binder helps to bind the active ingredient to other excipient ingredients after compression to avoid breakage of the agent. Non-limiting examples of the binder suitable for use in the present invention include a m-based fi-based fiber, a poly-wife. Ketone m cellulose sodium, ethyl cellulose, methyl cellulose, ethyl cellulose, propyl cellulose (such as Klucel 8), methyl cellulose microcrystalline cellulose, dextrin, malt Dextrin powder (such as potato _, corn silk, wheat house powder, rice; palace powder, pre-gelatinized powder) 'Arabic gum, gelatin, alginic acid polyacrylic acid, sodium alginate, hydrogenated vegetable oil, Shi Xi Magnesium sulphate, polyaluminum, copolyvidone, polymethyl acrylate, and any combination of the foregoing. Preferably, transpropyl propylcellulose, polyethylene is used. More preferably as a binder from ketone, poly-dimensional, copolyvidone, polymethacrylic acid vinegar, or any combination of the foregoing, more preferably (tetra) propyl methyl 1353836. 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, sodium croscarmellose, carboxymethylcellulose, calcium carboxymethylcellulose, cross-linking Sodium methylcellulose, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, hydroxyl

Sodium starch-based sodium acetate (such as Explotab®), basal powder propionate S, sulphate powder, alginic acid, sodium alginate, glycolate, cross-linked polyvinylpyrrolidone (eg Kollidon® and Polyplasdone®), crospovidone, colloidal silica, guar gum, cation exchange resins, 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. (S)· 12 1353836 In one embodiment of the method of the present 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, based on the total weight of the active ingredient, preferably from 3% by weight to 20% by weight. 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 <S > 13 1353836 may additionally add a lubricant to the granules of the desired tablet 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, brown net stearic acid glycerin vinegar, hydrogenated vegetable oil, glycerin fatty acid S, glycerol Berylate, polyethylene glycol, talc, magnesium stearate, calcium stearate, zinc stearate, 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 decyl cellulose, decyl 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. (S > 14 1353836

Accordingly, the present invention further relates to a pharmaceutical preparation containing a gas-pipidine and/or a salt thereof, which comprises a gas-duratin and/or a salt thereof and a lipophilic component, wherein the gas is pirated and/or a salt thereof It 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 pirimidol hydrogensulfate and a lipophilic component hydrogenated castor oil, and the surface substance of the clopidogrel hydrogen sulfate The upper layer is coated with the hydrogenated castor oil. Furthermore, the pharmaceutical preparation of this embodiment further comprises a granulating excipient selected from the group consisting of microcrystalline cellulose, mannitol, lactose, hydroxypropyl cellulose, 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 1353836 make surgery into the metaly internal vessels; 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 ingot with a diameter of 8.6 mm was pressed by a rotary tableting machine. 16 1353836 Table 1 Ingredient (mg) Example 1 Example 2 Example 3 Example 4 Active ingredient gas pridore hydrogen sulfate (crystal form l) u 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 K306) --- — 0.5 0.5 Lipophilic component hydrogenated castor oil 7> 5 5 5 5 Cosolvent Polyethylene Glycol 60008> 5 5 5 5 Moisture Receptor Mannitol 15 ... 15 ... Lactose... 15 ... 15 Total Weight 240 240 240 240 * Shengda Synthetic Plant, 2> Mingtai, 3) San Fu, 4> Borculo Domo Ingredients, 5) Shih-Etsu, 6> BASF Aktiengesellschaft j 7) Vertellus Performance Materials Inc. 5 8) The Dow Chemival Company

Test Example 1: Dissolution test

The bare ingot obtained in the above Example 1 was commercially available with an equivalent amount of Pidoti Hydrogen Sulfate Lozenges (Plavix®, Sanofi-Aventis, Taiwan), and the dissolution tester (Sotax) conforming to the US Pharmacopoeia Specification No. 30 To do 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 a flow system. At 2, 4, 6, 8, 10, 15, 20, 25, 30, 40, and 50 minutes, take 6 samples of the eluate, and The absorption value at a wavelength of 240 nm was measured. 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 1353836

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 of the active ingredient. rate.

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 are based on the test method of the 30th edition of the US Pharmacopoeia. The main related substances and impurities are classified as hydrolysis byproducts (related substances A) and R-image isomers (related substances C). And 18 1353836 his single impurity, according to the recommendations of the 30th edition of the US Pharmacopoeia, related substances A, related substances C, other single impurities and total impurities should be less than 1.2%, 1.5%, 0.2%, 2.5%. The test results on the day of the formulation, 2 weeks and 2 months later are listed in Tables 4 to 7 below:

Table 4 Example 1 40 ° C 75% RH Related substances A (%) Related substances C (%) Other single maximum impurity (%) Total impurities (%) 0 days 0.09 0.76 0.04 0.89 2 weeks 0.16 0.77 0.04 1.00 February 0.64 0.75 0.05 1.47 Table 5 Example 2 40°C 75% RH Related substance A (%) Related substance C (%) Other single maximum impurity (%) Total impurity (%) 0 days 0.08 0.67 0.03 0.79 2 weeks 0.14 0.69 0.03 0.89 February 0.42 0.69 0.04 1.17 Table 6 Example 3 40. . 75% RH Related substance A (%) Related substance C (%) Other single maximum impurity (%) Total impurity (%) 0 days 0.09 0.73 0.04 0.87 2 weeks 0.16 0.77 0.04 0.99 February 0.83 0.88 0.06 1.78 (£ > 19 1353836 Table 7 Example 4 40 ° C 75% RH Related substances A (%) Related substances C (%) Other single maximum impurity (%) Total impurities (%) 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 It can be found from Table 4 to Table 7 that after two months, the content of impurities in the pharmaceutical preparation of the present invention still meets the recommendations of the 30th edition of the US Pharmacopoeia.

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 cnT1 to 400 cm·1 was scanned using a Fourier transform (FTIR) spectrometer with a scanning resolution of 4.0 cnT1 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 gastopuric hydrogensulfate is converted, and the result is as listed in Table 8: < S > 20 1353836 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)

1353836 Patent Application No. 097117807 Replaces the Patent Application Range (October 2010) X. Application Patent Range: Jin Hao. 3曰1 Revision (吏3本本公告1. A preparation of gas-containing piritop (( A method of ilopidogrel y and/or a salt thereof, comprising: performing a first mixing step of mixing a mixture of pidori and/or a salt thereof and a lipophilic component to provide a first mixture; and performing a first mixture; a second mixing step of mixing the first mixture with a granulating excipient granule; wherein the lipophilic component is selected from the group consisting of hydrogenated castor oil, stearic acid, glyceryl monostearate, palmityl a glyceryl stearate, a hydrogenated vegetable oil, a glycerin fatty acid ester, a glyceryl dibehenate, a polyethylene glycol, a talc, and any combination of the foregoing. 2. The method of claim 1, wherein the excipient The particle system comprises a component selected from the group consisting of a diluent, a moisture absorbent, a binder, a disintegrant, and any combination of the foregoing. 3. The method of claim 1, wherein the first The mixing step is a dry mixing operation. The method of claim 1, wherein the lipophilic component comprises hydrogenated castor oil. 5. The method of claim 1, wherein the first mixing step uses clopidogrel selected from the group consisting of Salt: a hydrogen sulphate, a hydrogen sulphate, a hydrobromide salt, a bovine cholate, and any combination of the foregoing. 6. The method of claim 5, wherein the clopidogrel is used in the first mixing step The method of claim 6, wherein the hydrogen sulphate is in the form of crystal form 1 or crystal form 2. 8. The method of claim 1 wherein the lipophilic component is in the first The mixing step is such that the amount is from 2% by weight to 8% by weight based on the total weight of clopidogrel and/or its salt. 9. The method of claim 8, wherein the amount of the lipophilic component is The method of claim 1, wherein the second mixing step further comprises mixing the first mixture with a helper before the second mixing step, based on the total weight of the chlorpheniramine and/or its salt. The method of claim 1 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 mannitol, sorbitol, xylitol 'lactose, dextrose, A method of claim 12, wherein the starch is selected from the group consisting of potato starch, corn starch, wheat starch, rice starch, and the like. The method of claim 12, wherein the moisture absorbent is selected from the group consisting of mannitol, lactose, and combinations thereof. The method 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 gas-duridine and/or its salt. 16. The method of claim 15, wherein the moisture absorbent is used in an amount of from 13% by weight to 2% by weight based on the total weight of the clopidogrel and/or its salt. A pharmaceutical preparation containing clopidogrel or a salt thereof, comprising 23 836 836 • I. Clopidogrel or a salt thereof and a lipophilic group selected from the following group • f ··Gasified lotus oil, stearic acid, glyceryl monostearate, glyceryl stearate, hydrogenated vegetable oil, glycerin fatty acid ester, glyceryl dibehenate, polyethylene glycol, talc' Any combination of the foregoing, wherein the pirimidol or a salt thereof is substantially coated with the lipophilic component; and is produced by the method of any one of claims 1 to 16. 18. The pharmaceutical preparation according to claim 5, wherein the lipophilic component is a hydrogenated secret oil. I. The pharmaceutical preparation according to claim 5, which comprises from 2% by weight to 1% by weight of the lipophilic component, based on the total weight of the gaspide and/or its salt. . The pharmaceutical preparation according to the item 19, which comprises 4% by weight to 8% by weight of the lipophilic component, based on the total weight of the gaspide and/or its salt. .Such as. A pharmaceutical preparation of 17 households is described in the following paragraphs, wherein the pirimidol salt is selected from the group consisting of hydrogen sulfate, hydrochloric acid hydrochloride, hydrogen desert acid salt, erocholic acid salt, and any combination of the foregoing. The pharmaceutical preparation according to claim 21, which comprises a gas salt of pirimidol sulfate. 3. The pharmaceutical preparation according to claim 22, wherein the nitrogen sulfate salt is in the form of a crystalline form or a crystalline form 2. 24. The pharmaceutical preparation according to claim 5, further comprising, xylitol, lactose, dextrose, Wei, dian powder source, dextrin, maltodextrin, and any combination of the foregoing. The pharmaceutical preparation according to claim 24, wherein the powder is selected from the group consisting of potato starch, corn _, wheat granules, lotus root starch, pregelatinized starch, 24 26.1353836 27. 28. 29. and Any combination of the foregoing. The pharmaceutical preparation according to claim 17, wherein the moisture absorbent is selected from the group consisting of mannitol, lactose, and combinations thereof. The pharmaceutical preparation according to claim 24, which comprises from 1% by weight to 25% by weight of the moisture absorbent, based on the total weight of the clopidogrel and/or its salt. Such as. The pharmaceutical preparation according to the above item 27, which comprises 13% by weight to 2% by weight of the moisture absorbent, based on the total weight of the gas piritop and/or a salt thereof. The pharmaceutical preparation according to claim 17, the soybean meal is of the formula. Eight lines are in the form of granules, capsules or ingots 25