TW200946127A - Pharmaceutical compositions to treat Hyperlipidemia or Hypercholesteremia - Google Patents

Abstract

The present invention relates to a pharmaceutical compositions containing low dosage of fenofibratem, which is made by granulating fenofibrate and mixing with the other constituents which can increase the biological utilization. The biological utilization of the pharmaceutical compositions of the present invention is about equal to that of the high-dosage formulation of the original manufacturer, but the tablet dosage and volume are reduced for oral administration easily. Furthermore, since it's not necessary to granulate fenofibrate with the surface-active agent and any other compositions together for achieving the same biological utilization, the expensive and time-consuming processes can be eliminated, and the cost can be reduced to feedback to the requiring patients.

Description

200946127 IX. Description of the invention: [Technical field to which the invention pertains] ^The invention relates to a pharmaceutical composition for treating hyperlipemia and hypercholesterolemia, and more particularly to a low dose of fenofibrate (fenofibrate) pharmaceutical composition. [Prior Art] 化学 The chemical name of the compound fenofibrate is 2-[4-(4-chlorobenzylidene)phenoxy]_2-methyl-propionic acid" thioglycolate. It is a kind of fiber ester drug, and fenofibrate is a derivative of flbric acid. Its mechanism for regulating blood lipids is to activate the peroxisome proliferator-activated receptor α, which can be used to treat adult endogeneity. Hyperlipidemia, hypercholesterolemia - A daily dose of 300 to 400 mg of fenofibrate can reduce cholesterol blood by 20 to 25% and reduce triglycerideemia by 4〇~5〇%. The main metabolite of Norbert in plasma is fennobarelide, and the plasma elimination half-life of noberatic acid is about 2 hours. The average sputum can reach the maximum plasma concentration of plasma at 5 hours. The daily plasma drug concentration of 15 μg/ml was given at a dose of 15 μg/ml. This concentration exhibited a steady state throughout the treatment period. The solubility of fenofibrate in water was extremely poor. That is, it is a poorly water-soluble drug, so solve this problem. The problem seems to be important for the curative effect. In the Taiwan Patent Publication No. 200731964, it is pointed out that the pheno-barrel is poorly dissolved in water, but when it is in the state of eating, it is therapeutically treated. Acceptable levels of absorption are greater, but when administered in a "fasting state", the degree of absorption is less. In particular, when taken with food in the form of lozenge type 200946127, the absorption of the orally administered lozenge increased by about 35%, and special formulations have been used to improve fenofibrate, especially with regard to the use of micronization. Biocompatibility of Fino Burrett. Co-micronization of fenofibrate with a surfactant is disclosed, for example, in U.S. Patent Nos. 4,895,726 and 5,880,148. U.S. Patent Nos. 6,074,670 and 6,277,405 disclose the application of micronized fenofibrate to a water-soluble carrier together with an optional surfactant. U.S. Patent No. 6,814,977 discloses the dissolution of fenorelbide in a medium chain fatty acid glyceride. U.S. Patent No. 6,719,999 discloses the dissolution of fenorelbide in glycerol, propylene glycol or dimethyl isosorbide, and the dissolution of fenofibrate in diethylene glycol by U.S. Patent No. 5,827,536. 'Making fenofibrate micronized' in monoethyl ether. U.S. Publication No. 20040087656 discloses Philipburet having a particle size of less than 2000 nm with improved bioavailability. U.S. Publication No. 20030224059 (also Japanese Patent Publication No. 200731964) discloses that microparticles of active pharmaceutical ingredients are deuterated by sublimation micropowder, and polyethylene glycol, polyethylene-propylene glycol, disintegrating agent, organic acid are added. The main purpose of the above patents is to increase the bioavailability of Fenobrecht. W098/31361 discloses a process for improving the bioavailability of fennobrid by combining a water-dispersible inert carrier with micronized fenofibrate, a hydrophilic polymer and optionally a surfactant . The hydrophilic polymer is polyvinylpyrrolidone in an amount of at least 20% by weight based on the total weight of the composition. However, this patent has the disadvantage of requiring a large amount of pvp and other excipients. US Patent Publication No. 20040142903 (Taiwan Patent No.: 200946127 200509988) 'Disclose the use of pharmaceutical combination Fino Burrit 5~35% weight ί J (four) 4~3G% weight ratio, - metal metal and 7 or test ' Eleven-based sulphate ~1 〇% by weight, an inorganic carrier which is insoluble in water and wettable, can form a pheno-Brit dispersion and a medically inert carrier or dilution 5~ A dry weight of 3 〇% by weight, and a therapeutic carrier or diluent, is wet-formed into wet granules at 50 C to 1 Torr. The wet granules are dried to obtain dry granules, and the granules are ground to a particle size of about i mm or less, and finally a pharmaceutically acceptable inert carrier or diluent is added to obtain a final mixture. However, the addition of sodium dodecyl sulfate and dokana salt significantly increased the dissolution rate of fenofibrate, and the effect of these surfactants increased with the increase of its addition #' but not linearly; The main purpose of adding cyclodextrin is to overcome the low solubility of fenofibrate in water towels, and thus the comparison of the composition of the invention and the amount of active metabolite blood of TRICOR shows that the invention and the composition of the prior art The bioavailability is almost the same as that of the original manufacturer, and the advantage of this patent is that Fenobrecht does not need to be co-micronized with the surfactant, and the bioavailability is substantially the same as the original*, but in the embodiment, the composition contains 22% by weight. | (4) Braid's such low drug content will cause the formulation to be too bulky, making it difficult for the patient to take it orally, or splitting into two pieces. SUMMARY OF THE INVENTION In view of the deficiencies of the prior art, the object of the present invention is to develop -

The weight is small, the dosage of fenofibrate is small, but still can achieve good therapeutic effect, the pharmaceutical composition' and the simple process for preparing the pharmaceutical composition. The test reduces the cost through the reduction of raw materials and the reduction of the process. J 200946127 can still balance the treatment effect.

For the purpose of Da Shi, the pharmaceutical composition for treating hyperlipemia or hypercholesterolemia of the present invention comprises: micronized fenofibrate 1 〇〇 weight; fraction; unmicronized cellulose丨 to 5 parts by weight (relative to 1 part by weight of fenofibrate); 0.5 to 60 parts by weight of the alkali metal or alkaline earth metal non-micronized sulphate (relative to 1 〇〇 weight) Parts of fenofibrate; and unmicronized pharmaceutically acceptable disintegrating or dilute or lubricant or mixtures thereof from 20 to 600 parts by weight (relative to 1 part by weight of fenofibrate); The total weight of the pharmaceutical composition is more than milligrams and not more than 300 milligrams; and the aforementioned fenofibrate weight is less than 180 milligrams but not less than 160 milligrams. - The present invention also comprises a method of preparing the above pharmaceutical composition, the method comprising the steps of: (a) adjusting the particle size of the Fenobrecht raw material to about 3 μm or less, and (b) preparing the step (a) The fenofibrate microparticles are granulated with cellulose, a diluent, an alkali metal or alkaline earth metal lauryl sulfate, and pure water to prepare wet granules; (c) at 50 ° C to 1 Torr. (: drying at the temperature of step (b) wet granules to form dry granules; (sentence step (c) dry granules for granulating to reduce the particle size of dry granules; and (e) adding pharmaceutically acceptable disintegrating lubricant Or a mixture thereof to prepare a product. The pharmaceutical composition of the present invention has a total weight of 3 mg in a preferred dosage form and a weight of 16 〇 mg of fenofibrate contained therein, and the & The pharmaceutical composition is a tablet, a capsule or a powder form. The pharmaceutical composition comprising fenofibrate of the present invention can improve the utilization of the organism when orally administered to a patient in need of treatment for reducing gold fat ^ The amount of the excipient' is therefore small in size, which makes the patient easy to take orally, and can save manufacturing costs and reduce the selling price. Meanwhile, the invention contains the pharmaceutical composition of Finobrecht, which will only be Fino Burberry. Special micro-chemical and 8 200946127 力力进Micronized Finobrecht's bioavailability of other ingredients to 1 degree' material requires the granulation of Fenobrecht and any of its composition, so that the process can be simplified, Therefore, it is possible to save time and improve efficiency. Embodiments The pharmaceutical composition for treating hyperlipemia or hypercholesterolemia according to the present invention comprises: micronized fenofibrate 1 part by weight; unmicronized cellulose 丨 to 50 parts by weight (relative to 1 part by weight of fenofibrate); non-micronized metal or soil test metal 12 sulfosyl sulfate 〇. 5 to 60 parts by weight (relative to 1 〇〇 weight菲诺伯瑞特). and non-micronized pharmaceutical acceptable diluent 20 to 6 parts by weight (phase 10G fenofibine); and non-micronized pharmaceutical acceptable pen powder or The lubricant or a mixture thereof is up to 2 g parts by weight of fenofibrate. The total weight of the aforementioned pharmaceutical composition is more than 250 mg and not more than milligrams; and the aforementioned phenanthrene is 180 mg but not less than 160 mg.里 - The particle size of the pharmaceutical composition towel of the present invention is less than about 30 micrometers, more preferably about 1 to 25 micrometers, and the composition of the pharmaceutical composition is four millimeters. Jober's body has a Fino 300 mg. The total weight of the medical composition is The invention refers to the state of cellulose, such as sodium, methyl cellulose, ethyl cellulose, and propyl fiber; 9 200946127 ϋΐ ί ί ί ί ί ί ί ί ί ί 2009 2009 2009 2009 2009 2009 2009 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物The base fiber is particularly suitable for the cellulose state of the present invention as: the sulfur is higher than the metal or the soil test metal twelve-heart n-parameter collapse--the powder is the control drug in the technical field. The substance, the detachment and the absorption of the substance, in principle, can not be used in the present invention. The specific embodiment includes, but does not affect the stone a: carboxymethylcellulose calcium, carboxy Methylcellulose sodium, gelatinous di-diethylpolymethylcellulose sodium, cross-linked slow-methylcellulose cross-linking heart ethylene metric tons, melon turn, (four) Meiming, A, ^ ^ , Suprakin potassium , powdered cellulose, pregelatinized starch: 2, sodium, transbasic starch, sodium, or mixed carboxymethyl cellulose sodium is preferred. The diluent referred to by the parent is to provide the fluidity, lubricity, and compressibility of the prepared medical doctor, and the release property of the drug can be made with the aforementioned agent. Examples of diluents suitable for use in the present invention include, but are not limited to, microcrystalline cellulose, microfiber starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, Portuguese, dextrin, dextrose, Hydrated dicalcium phosphate, tri-phosphate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, poly-acid ester, potassium carbonate, powdered cellulose, sodium carbonate, sorbose: or a mixture thereof, Among them, lactose is preferred. / The lubricant referred to in the present invention functions to orally adhere the drug to the mucosa of the digestive tract wall, and is suitable for the state of the lubricant of the present invention & package 200946127, but not limited to calcium stearate, glyceryl Palmitic acid stearate, magnesium oxide, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium alginate, sodium lauryl sulfate, sodium stearyl sulfate, stearic acid, talc, stearic acid Sour acid and magnesium stearate, sodium stearyl sulphate, argonized vegetable oil, hydrogenated castor oil, light mineral oil or mixtures thereof, of which magnesium stearate is preferred. The invention also includes a method of preparing the above pharmaceutical composition, the steps of which can be detailed as follows: First, step (a) is to round up the particle size of the Fen Noribet raw material to about 30 microns or less; and then proceed to step (b) Preparing wet granules by mixing granules of Nobelite microparticles with cellulose, diluent, alkali metal or alkaline earth metal lauryl sulfate and pure water; then at 1 〇〇C Drying at the temperature to make the wet granules of the step (8); then performing the step (d) to dry the granules into the granules of the step (4) ==== adding the medicine to be able to be connected to the * In the sample, the preparation of the pharmaceutical heart of the present invention, the gelatin i drug ^ ^ step W, the product of the step (4) is compressed into a tablet salt, disintegrating # 卜 稀 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 And ^疋义义 and the same pattern as above. The particle size is 30 micrometers, and the Bradbury mechanical micronized particles are divided into the embodiment, the Finobrew: about 1 〇 to 25 μm, and the 0.1 to 10 μm. The particle size of the % mechanical micronized particles is more suitable for the pharmaceutical capsule or powder form of the present invention. The sorrow of the substance is oral lozenge, glue 200946127 In the best mode of implementation, the pharmaceutical group of the present invention has a basis weight of 300 mg, and the weight of pheno-Brit is included.

❹ In order to more specifically present the technical features of the present invention, the following, each aspect and composition examples will illustrate how to specifically achieve the present invention by means of a redistribution between various components, especially all of the groups are used as micropowder. The fenofibrate microparticles are 100 parts by weight by weight; at the same time, it should be noted that all of the following pharmaceuticals of the present invention are used. The embodiments and the components of the examples are only fenofibrate microparticles.微粒 Micronized, the other components are not micronized. In one or more solid oral administrations of the present invention comprising a pharmaceutical composition, it is a micronized fluorarubicin microparticle 1 0.5 to 60 parts by weight of sodium lauryl sulfate salt, about 2 〇 to 6 〇. 〇Lactose, about 1~50 parts by weight of decyl cellulose, mix the above four ingredients in a high shear mixer to form a powder mixture, and then add water 诸如 (such as ethanol, decyl alcohol or isopropanol) to the powder. Solvent to form a wet particulate mixture' and drying at 50 ° C to 1 Torr (TC to obtain dry particles, which are sieved to remove large particles. About 重量 by weight of crosslinked carboxymethyl fibers The sodium sulphate is added to the pulverized granules together with 1 to 20 parts by weight of magnesium stearate, followed by uniform mixing, and then the granules are swelled to form a troche. Another pharmaceutical composition of the present invention includes a pharmaceutical composition. In a solid oral dosage form, it comprises about 100 parts by weight of micronized fenofibrate microparticles, about 20 to 600 parts by weight of lactose, and about 刈 刈 by weight of thiol cellulose, at high shear. The above three components are mixed in the stomach of the mixer to form a powder mixture. 0.5 to 60 parts by weight of sodium lauryl sulfate is added to water or an alcohol (such as ethanol, & propanol or isopropanol) to dissolve and dissolve uniformly, and then added to the powder, which already contains ten 12 200946127. A solvent of sodium is prepared to form a wet granule mixture, and dried at a temperature of 100 ° C to obtain dry granules which are sieved to remove large granules. About 1 to 20 parts by weight of cross-linked carboxy fluorenyl group The granules are added to the granulated magnesium granules by adding the granules of the granules of the granules to the granules of the granules of the granules of the granules. The solid oral dosage form comprising the pharmaceutical composition comprises about 1 part by weight of micronized fenofibrate microparticles, about fj00 parts by weight of lactose, and about 1 to 59 parts by weight of decyl cellulose. In the high-knife combination, the above three components are mixed to form a powder mixture. The sodium sulfonate sodium sulfate is added to water or an alcohol (such as ethanol, η-energy) to dissolve the homogeneous suspension. And then sprayed into the powder as a suspension type to prepare Wet the mixture of particles and dry it at 5 〇t to remove H to obtain dry granules, which are sieved with a sieve to about 1 to 2 g parts by weight of hetero-methylcellulose and mixed in the left. In the present invention, it is a combination of the above two types of ingredients: about 2 to 50 parts by weight of the lactose, about 1 to 50 parts by weight of the pull-up. ❹/基素, in high shear mixing to micronized fenofibrate, and then the suspension is sprayed through the net to remove large particles. The granules will be dried and sieved. 20 parts by weight of stearic acid = part of the cross-linked carboxymethyl fiber particles are mixed and hooked, and then ground after grinding; after sieving the under-slurry particles can be compressed to obtain ingot 13 200946127

In another solid oral dosage form comprising a pharmaceutical composition of the present invention, it comprises 1 part by weight of micronized fenofibrate microparticles, about 0.5 to 60 parts by weight of sodium lauryl sulfate, About 2 to 6 parts by weight of lactose, about 1 to 5 parts by weight of methylcellulose, about 1 to 20 parts by weight of croscarmrone, sodium cellulose, about 1 to 2 parts by weight of stearic acid Magnesium is prepared by mixing the above six components in a high shear mixer to form a powder mixture. The mixture is placed in a dry granulator for dry granulation to form irregular granules which are then compressed into ingots. Buying another solid oral mash containing a pharmaceutical composition in July, which will contain 100 parts by weight of micronized fenofibrate microparticles 2. 5 to 60 parts of sodium lauryl sulfate, about 2 〇~6〇〇 parts by weight, ',, about 1~50, heavy-weight methylcellulose, mixed in a high-cut mixer; The mixture is placed in a dry granulator to dry w particles to form irregular granules. 2 parts by weight of cross-linked dimethylcellulose nano, magnesium sulphate and irregular granular material are mixed. The substance is compressed into ingots. 1 Correction of 9 samples of the mixture in the solids σ dosage form of the s pharmaceutical composition, about 1 to 50 parts by weight of methylcellulose J 2 lactose, cellulose-based sodium, and (4) The weight of the ^ ^ ^ 乂 几 several complexes filled into ". (4) Preparing the inoculum, and then mixing the mixture of 12 ===== 200946127 from the solution by spray drying, wet granules, dry granules, powder ί, to form a tablet or capsule, the tablet or capsule It can dissolve the Fenovo sulphate in the solution, so it has different bioavailability for oral patients' and saves costs. Example 1. The ratio of phenanthrene bristles 160mg bond or heterocyst component is not due to the 韭 韭 枸 I I 60 I60mg ingot or capsule composition group first group second group third group fourth group Fino Burret 160 160 160 160 lactose 95 90 85 80 sodium lauryl sulfate 20 20 20 20 decyl cellulose 5 10 15 20 croscarmellose sodium 12 12 12 12 magnesium stearate 8 8 8 8 pure water or alcohol Class two··———— • Total rain (mg) 300 300 300 "300 ~ Imperial method (1) ❿ A fine-fibrillated fenofibrate, lactose, + dialkyl in a still-cut mixer Sodium sulphate, methyl cellulose, mixed ingredients in a high-cut mixer to form a powder mixture. The powder mixture is added to the pure ^ will be in the 5 wet = bed dry method (2) 15 200946127 in high cut Mixing φ-based fiber sin, in the ancient form of micronized fenofibrate, lactose, methanoate / ten-year-old three components - powder ❹ Ο the wet granule sodium solvent is prepared into a wet granule mixture. Dry welding at 50 ° C. Cellulose steel and hard fat in spleen bed dryer or box tray dryer ^Grain sieved 'and added cross-linking a few in the rotating system _ on the _ intogot ^ ° uniform. New will be the final mixture of the base fiber ^ micronized phenanthrene, lactose, sodium formate added water or alcohol = (b) = base Fiber surplus. Will be granulated (4), and add people to cross-link and slow the uniformity of the nails, and finally the final = four, although the ϊί dibasic sulfate Naga water scales are mixed and dissolved to form a special powder, then = Prepare the preparation into a "granular blending = bed (four) or box tray dryer will be in === Han most =; = cellulose nano and stearic acid money into. All hooks, after the final, the final exhibit is compressed on the rotary inspection machine into a suspect 16 200946127

Preparation method (5) Micronized fenofibrate, sodium dodecyl sulfate, lactose, methyl cellulose, cross-linked carboxylic acid methyl cellulose sodium and magnesium stearate in a high shear mixing device The above six components are mixed to form a powder mixture to prepare. The mixed powder is then placed in a dry granulator for dry granulation to form a particulate material which is compressed into ingots. ’

Method for making sputum (6) Micronized fenofibrate, lactose, methyl cellulose, mixed with the above three components in a high-cut mixer to form a powder mixture, and then the mixed powder is placed in a dry granulator. Dry granulation to form a granule, then add cross-linked carboxylic acid thiol cellulose sodium di- chelate for mixing, and mix the good particles f for ^ = 制备 Preparation method (7) Micronized Finobo Reiter, sodium dodecyl sulfate, lactose, calcium crosslinked acid methylcellulose steel, magnesium stearate, mixed in the high shear mixer to form a powder mixture to make the mixture Into a capsule. Example 2. Bioavailability analysis The difference in bioavailability between the pharmaceutical composition of the present invention and the original TRIC® R® composition was investigated. This experiment has 40 subjects' after a one-month treatment blank period and 17 200946127 drink control and two-month medication. Oral Fino's sputum two hours after breakfast, let the test ^1^(0 . 0.5 . Γ, ί. 1 5 J>7 2 Ϊ =, hour, 5 hours, 6 hours, 7 hours, 8 hours , ί i 3 hours 24 hours, 36 hours, 叮丄 2 hours, small %, 48 hours, hours, 6 hours hours ^ Fruit column ^^ # plasma samples for pharmacokinetic analysis.

InC max tricor®

InAUC〇_t InAUC 〆0—〇〇8.499 2.140 5.334 5.361 ❹ The composition of the present invention 8.045 ~ : ~'- ----____I_I_ ' See the composition of the present invention and the original development product TRK:, the music dynamics There is no significant difference in the data gap between the parameters c_, inc legs, inAuc (1), and “00. Therefore, it is evaluated that the two have bioequivalence. 2.085 Time (minutes) 1 10 ΤΊ 60 80 100 120 180 TRICOR® (including 160 mg 菲诺伯瑞特) 18.5 53.99 85.61 100.1 101.7 101.8 101.9 102.0 101.9 101.9 102.0 102.1 102.1 Composition of the invention (containing 160 mg of fenofibrate) 29.57 63.79 84.59 91.74 95.26 97.03 98.75 99.26 99.54 99.80 --- a 99.81 99.86 99.86 As can be seen from the above table, the original factory contains 160 mg of fenofibrate tablets (total weight)

The elution rate of 1S 200946127 700~800 mg), and the 16-inch tablet (the total weight of lion mg) of the present invention are not only in the bioavailability, but also in the dissolution rate, but the total weight is reduced. View above. These values in the field show that the present invention does reduce the weight of the tablet in only the buzzer (four) machine and is therefore easy to swallow. No work wind knife Ο 160, Kefei, Bury, the time of the purchase of tablets, the month of January, February, the content of 104.8 104.5 104.2

After 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, the stability test's results showed that after the preservation, the non-Nobelit was almost completely dissolved, so The formulation of the pharmaceutical composition of the present invention has the property of stabilizing fenofibrate. In summary, the pharmaceutical composition of the present invention is substantially the same in bioavailability as the composition of the original high-dose dosage form, but is substantially the same as the original high-dose dosage form. The tablet volume is easy to orally. And because the present invention does not require the simultaneous micronization of Fenobrecht with surfactants and any other combination, it is desirable to achieve the same bioavailability effect - thus eliminating expensive and time consuming processes and reducing cost feedback. Patients with needs. All the features disclosed in this specification may be combined with other methods, and each of the features disclosed in this specification may be selectively 19 19146127

The same, equal or similar purpose features are substituted, and therefore, all of the features disclosed in this specification are only one example of equal or similar features, except for the particularly salient features. While the invention has been described above in terms of the preferred embodiments thereof, it is not intended to limit the invention, and various modifications and changes can be made without departing from the spirit and scope of the invention. 20

Claims (1)

200946127 X. Patent application scope: 1. A pharmaceutical for treating hyperlipemia or hypercholesterolemia, which includes: '' σ micronized fenofibrate 100 parts by weight; unmicronized cellulose 1 to 50 parts by weight (relative to 1 part by weight of Finobrecht); ❷ 0.5 to 60 parts by weight of the alkali metal or alkaline earth metal lauryl sulfate without micronization (relative to 1 part by weight of fenofibrate); pharmaceutically acceptable diluent without micronization 20 to 60 〇 heavy* injury (relative to 100 parts by weight of Philipbrit); and mixed-person medicine acceptable disintegrating agent or lubricant Weiqi G for _ part by weight of Philipbrick); 300 mg; 250 mg U at 160 mg. The weight of the Bertrand is less than 180 mg, not lower than the former compound, of which 5. If you apply for a special brake, you will be 1 G micron. The above-mentioned fiber material light medical composition, which = 6 · if the application of the base cellulose or a mixture thereof, the cellulose is methyl cellulose. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition according to claim 1, wherein the 200946127 metal or soil test metal tungstosulfate is a twelfth base. The pharmaceutical composition, wherein: sodium, gum bear: strontium is alginic acid, calcium carboxymethylcellulose, carboxymethyl cellulose, bismuth oxide, croscarmellose sodium, crosslinked carboxymethyl纤雄, 铒^ 聚乙烯, guar gum, guar gum, aluminum citrate, methyl fiber Desalination in::, acesulfame, potassium blakelin, powdered cellulose, pregelatinization, strontium, sodium 1 sodium, sodium starch glycolate, starch or a mixture thereof. -·, +, and mountain apply for the pharmaceutical composition described in item 8 of the patent scope, wherein the 刖 朋 朋 朋 散 散! The pharmaceutical composition according to claim 1, wherein the bismuth is microcrystalline cellulose, fine cellulose, lactose, starch, ^> coagulated starch, calcium carbonate, calcium sulfate, sugar, and glucose. Agent, dextrin, dextrose, dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate, potassium carbonate, powdered fiber , sodium chloride, sorbitol, talc or a mixture thereof. The pharmaceutical composition according to claim 10, wherein the diluent is lactose. 12. The pharmaceutical composition according to claim 1, wherein the lubricant is calcium stearate, glyceryl palmitate stearate, magnesium oxide, prosham (p〇l〇xamer), Polyethylene glycol, polyvinyl alcohol, sodium, sodium lauryl sulfate, sodium sulphate, stearic acid, slipperygic acid and magnesium stearate, sodium succinate, hydrogenation Plant & stone, rouge castor oil, light mineral oil or a mixture thereof. Ice, gasification 13. The pharmaceutical agent described in claim 12 is the magnesium stearate. σ % 'where 22 200946127 of Fang Baoshen ^ special township (4) 1 according to the pharmaceutical composition; (4) the particle size of the Finoburet raw material is adjusted to about 3G micron to prepare the wet ten-salt sulfate Pure water is used to form granules to form 1G (the temperature of rc is the temperature of the filament (b) wet particle size; /) (4) (4) dry listening and riding to reduce dry particles to produce | Adding medicines can accept disintegrating agents, lubricants or mixtures thereof. The method described in item M of the package can be used as a pill. Step (f) compressing the product of the step (4) into a tablet, a capsule, or a method according to the item 14, wherein the above-mentioned propyl propyl ketone cellulose, methyl cellulose, ethyl cellulose, 171 Cellulose, hydroxypropylcellulose or a mixture thereof. The vitamin system is the method described in claim 16, wherein the fiber, the present methyl cellulose. The method of claim 14, wherein the base 19 is a dodecyl sulfate which is sodium dodecyl sulfate. The powder system is the method described in the 14th item of the patent range, wherein the aforementioned collapse state of dioxin, algae 1, methyl cellulose, sodium carboxymethyl cellulose, calcium sulphate, cross-linking, eve, and Sodium carboxymethyl cellulose, croscarmellose cellulose fluorovinyl pyrrolidone, guar gum, aluminum citrate, methyl cellulose, 23 v 200946127 = prime; Laclin potassium, powdered oryzanol, Pregelatinized starch, sodium sulphate per starch, sodium starch, or a mixture thereof. 20. The powder according to claim 19 of the patent application is a cross-body. ~ 中别说朋2/. As claimed in the scope of claim 14, the release agent J is microcrystalline cellulose, fine cellulose, lactose: ❹ = two ίί: acid chloride dance, phosphate three mother, Gaoling = Town 22. For example, the 21st release agent of the patent scope is lactose. Item "万忐" which describes the method described in item 14 of the patent scope, i = T fat is called glyceryl palmitic acid hard brain, magnesium oxide ί rosam (p〇l〇xamer ), polyethylene glycol, = 2 = sodium sulphate, stearic acid, talc, zinc stearate: 24 · as claimed in the scope of g 23 slipper is magnesium stearate. The total weight of the 々 丹 Y 引 引 人 人 人 人 人 人 人 Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ 300 300 300 300 300 300 300 300 300 26· If the scope of application is 箆25 is & is a spinning agent, capsule or powder type. (4) Pharmaceutical composition, its system 200946127 VII. Designation of representative representatives: (1) The representative representative of the case is: ( ). (2) A brief description of the component symbols of this representative figure: None 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: