TW448056B - Pharmaceutical controlled release tables containing a carrier made of cross-linked amylose and hydroxypropylmethylcellulose - Google Patents

Abstract

Disclosed is a pharmaceutical controlled release tablet containing an active ingredient in combination with a carrier made of cross-linked amylose in which hydroxymethylpropylcellulose (HPMC) with a viscosity higher than or equal to 4000 cps is added as an adjuvant. The addition of HPMC to the tablet permits to control the effect of enzymes, and more particular alpha-amylase present in the intestinal medium, on the cross-linked amylose used as a carrier, and thus to reduce the dependence of the kinetics of release upon the concentration of enzymes present in the medium.

Description

^ 4a 〇5 ^ B7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of Invention (/) Field of the Invention The present invention relates to the Canadian Patent Case No. 2, which was published in April, 1994. The invention described and claimed in No. 41,774 is published in U.S. Patent No. 5,456,921, which is published in the year; the two related improvements belong to the applicant of this claim. Correctly, the present invention relates to a controlled-release forbidden tablet, which contains a carrier-bound active ingredient made of multi-crosslinked starch, and two hydroxyl groups having a viscosity higher than or equal to 4,000 cps. Propyl methyl cellulose (HPMC), as a kind of adjuvant, was added to Cai Jian. The present invention is also related to the use of the ingot form described above, which has a viscosity equal to or higher than 4,000 cps and is used as a kind of adjuvant, so that it can control enzymes, especially in the The effect of starch in the intestinal medium on multi-forked starch can reduce the dependence of the kinetics of active ingredient release on the enzyme concentration in the medium. A brief description of the prior art is mentioned in the Canadian Patent No. 2,00,774 and the U.S. Patent No. 5,456,921 mentioned above, which describe the oral compressed anti-drill dose of one or more active ingredients at a certain time with a control The efficacy of delivering or releasing the above-mentioned doses at a rate. Such described tablets contain up to 60% by weight of one or more active ingredients that may be natural. Such a bond also contains at least a weight percent of a vehicle or carrier composed of starch cross-linked with a suitable multi-crosslinking agent, and each gram of starch is cross-linked with 0.1 to 10 grams of multi-crosslinking agent. The preferred amount is 1 gram of powder per gram of powder, which is cross-linked with 6 grams of multi-crosslinking agent. Using gas methyl ά Order Λ 4 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 4

f Diyun ^ It is stated that (2) a polycross obtained by using a milk dioxin or 2,3-dibromopropanol as a polycrosslinking agent, is known as Con tram id in the following. Better 'but not necessary; so' because most foods, including the U.S. Food and Drug Administration shoulder, and the 'era control organization' have approved years of starch cross-linking with these two agents

The main advantage of Coirtramid is that it maintains a fixed release rate (zero order kinetics). 'Unlike most carriers currently used in compressed tablets, < Controlled release, in most carriers, the active ingredient is controlled by Diffusion and release, which follow the Fickian release kinetics (the cumulative release fraction is proportional to the square root of time) ◊ From a practical point of view, in aqueous media, Contramid will form: a kind of porous water condensate, which can be used as an activity The carrier of the ingredients' can also provide controlled release of the latter after oral administration. In the intestinal medium, this hydrogel is very sensitive to the effects of digestive enzymes that will attack the chain of powder and degrade the forbidden tablets, which will ensure its decomposition in the digestive tract. In this regard, ^ starch_enzyme I is particularly effective in accelerating the release of active ingredients from medicinal tablets' and it is used as a kind of adjuvant in the formulation of banned tablets constituting AD ^^ February 3, 1994 The main content of the published International Patent Application No. WO 94 / 〇2121, which belongs to the applicant of this claim. The tablets manufactured in this method are effective in most patients and can provide appropriate controlled release effects. Based on the fact that the activity of enzymes varies considerably from individual to individual, and that it changes as a function of food consumption, etc., there is a degree of difference between patients and patients. Since con_ tramid is sensitive to falling starch, this variability applies to the Chinese National Standard (CNS) A4 specification (210X2.97 mm) for at least one paper it standard. (Read the precautions on the back before filling in this Page) Ding 44δ 05s V. Description of the invention (3)

These jobs are sold in the _ printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, so the adjuvant is added to search for the unique properties of Tramid. For those who make full use of the subject level, the invention is based on the invention of ~ shan ^ found that a very special inventor accidentally discovered its Cowid in order to make a wide and often special number The enzyme that is added to the medium ^ 到 is enough to resist the release of the marriage product due to any significant ^ tW decomposition in the intestinal rate ii. The ban on t 3 is currently used in pharmaceuticals In the field of Africa! The famous hydrogel wins, that is, propyl methylcellulose (Na >. However, 丨 suitable for banning only when its viscosity is equal to or higher than 4,000 centipoise (cps), And the adjuvant is effective when the amount added to the medicine is between 1% and 3G% of the total weight of the suspected drug. When the amount is less than 1%, the amount of HpMC added to the tablet is not enough. What you want to achieve. Above 30%, HpM The amount of C is too high, which will affect the carrier, which is no longer mainly made of Conramid, and therefore will result in the release of FUkian kinetics. According to the present invention, 'it has been found to have a value equal to or 疋 南 于 4 When HPMC with a viscosity of 0 〇〇cps is added to Contramid, it can give some unique and unexpected properties that cannot be inferred from the data currently known on the product. , And there is a low dependence on the release kinetics of enzymes in the medium. This finding is quite surprising, because the addition of other species is used in 1 Please read the note of ΐτ and then order the page @ 瓦 ^ 隼 () (210X297 公 — 陆 Τ 4448．05 $ 13. δ Α7 Β7 V. Description of the invention (+) Polymers in the pharmaceutical field as substitutes for HPMC ', such as ethyl cellulose, f-based Cellulose, hydroxypropyl cellulose (HPC), or Carbomer, etc. [A similar test only yields negative results, which will be shown below. Therefore, the first object of the present invention is to provide a certain amount containing at least one active ingredient Oral Controlled release drug bond: This drug bond contains up to 60% by weight of the active ingredient. It is mixed and compressed with at least a weight percentage of a carrier containing a cross-linked polyether crosslinking agent: powder, and each 1CG Grams of starch are crosslinked with 0.1 to 10 grams of a multi-crosslinking agent. According to the present invention, the carrier actually: comprises: from 30% to 90% of multi-crosslinked starch; and from 10% to 30 % Hydroxypropylmethylcellulose '(HPMC) having a viscosity equal to or higher than cps.} The above percentages are weight percentages based on the total weight of the tablets. Example 0 (The second object of the present invention is to provide a Method capable of controlling the influence of enzymes on carriers in patients; oral controlled release forbidden tablets' This tablet contains at least one active ingredient of up to 60 25% by weight, and at least 40% by weight of the carrier, the carrier Contains starch cross-linked with poly-cross-linking agents, and each 1 C0 grams of starch is cross-linked with 0.1 to 10 grams of poly-cross-linking agents. The method comprises the step of adding hydroxypropyl methylcellulose (HPMC) having a viscosity equal to or higher than 4⑽0 CPS to a carrier as an adjuvant. The tablets thus obtained have excellent resistance to enzyme mediators. And only very low dependence on the concentration of enzymes in the medium. They are using 6 paper sizes that are in accordance with Chinese National Standard (CNS) A4 specifications (2 〖0X297mm） (Please read the precautions on the back before filling out this page) -a-Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 48 Q 5 6

Fifth, the invention, jr, also has good mechanical resistance, which is an advantage from a commercial point of view. A study of the following non-limiting statement, including the results of some tests made by the inventor ', will give a clearer understanding of the invention and its many advantages. Main Description of the Invention As previously described, the present invention relates to the preparation of an orally compressed forbidden tablet containing one or more active ingredients so that a controlled release of the active ingredients can be obtained in a given time. Such compressed tablets contain up to 60% by weight of one or more active ingredients, mixed and compressed with a carrier of at least% by weight, which is a starch crosslinked and crosslinked with a suitable poly-crosslinking agent. The manufactured and per gram grams of starch is crosslinked with G. 1 to 10 grams of polycrosslinker. With regard to control knowledge, it is meant to release j for a period of time at a similar fixed (linear) rate, which can be as long as M hours or beyond. ί Member of the Ministry of Economic Affairs and Intellectual Property Bureau X. Consumer News Agency printed The active ingredient used in Cai ingots can be in any form that can be taken orally. A non-limiting list of examples includes sedatives, antacids, anti-inflammatory agents, vasodilators, stimulants, anti-hindered amines, vasoconstrictor nerve swords, anti-blood coagulants, anti-arrhythmias Agents, blood medicaments, hypoglycemic agents, diuretics, anti-asthmatic contraceptives, anti-asthma, jh vomiting agents, antispasmodics and so on. It exists in __ form. The preferred size is between 25 and 7 μm. The active ingredient is preferably in the form of a powder and mixed with a carrier manufactured by Contmu 2IGX297. 5. The invention (heart) manufacturing carrier, and then the mixture obtained by this method is compressed to obtain the desired medicine. ingot. The compression operation is preferably performed at a pressure of 0.1 S metric ton per square centimeter. (Please read the precautions on the reverse side before filling out this page) The essence of the present invention is that the carrier capable of preparing the multi-linked cross-linked powder of compressed medicine spin actually contains from 30% to 90% of contramid and ^ From ⑽ to 而 you have hydroxypropyl methylcellulose | (HPMC) with a viscosity equal to or higher than 4,000 cps. The percentage is based on the weight percentage of the total weight of the tablets. The HPMC coupling used is defined by the No. 2208 and No. 2910 (USP standard, XXjjj level) in the 23rd edition of US Pharmacopedia. Selected by HPMC. The viscosity of this standard is based on an aqueous solution of rhenium at a temperature of 2 01〇 ± 0 · 1. (Measured at 0 o'clock. HPMC 2208 has a methoxy content from 19% to 24% and a p-propoxy content from p 4% to 12%. For example, it has 100, 4000, 15000, | The product of 100,000 cps viscosity printed by the Ministry of Intellectual Property Bureau's Consumer Cooperative is sold by THE DOW CHEMICAL CO. Under the trademarks of j Methocel K > 100, 4M, 15M and 100M. FfPMC 2910 is available from 28? ≪ to 3. % Methoxy content and hydroxypropoxy content from 7% to 12%. For example, this product with a viscosity of 4OQ and 100,000 cps is manufactured by THE DOW CHEMI CAL CO. Methocel E-4M and 1 0 0M's trademark | Sale. The carrier of the multi-crosslinking powder may also contain one or more other ingredients currently used in the preparation of compressed tablets, including:

— Fillers such as lactose or recommended sugar, the amount of which does not exceed 40% by weight; I 8 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Print "ΊΉ 月" Α7 丨 B7. V. Description of the invention (7) —Slip aids such as silicon dioxide, whose amount does not exceed 10% by weight; — Adhesives, whose amount does not exceed 10¾ by weight 1—Lubricants and anti-adhesives, such as magnesium stearate, in amounts not exceeding 5% by weight; and—disintegrants, in amounts not exceeding 5% by weight. Compressed tablets may be shaped tablets or Form of dry coating (dual core): In the first case, the HPMC used is preferably selected from HPMC 2208 and 2910 with a viscosity higher than 4000 cps. It is best to select HPMC with a viscosity of 100,000 cps 2208. In the second case, that is, forbidden ingots for dry noodles, the best HPMC used is also selected from HPMC 22 (T8 and 2910, their viscosity may not only be higher, but also equal to 4000 cps. These dry packs The compressed medicine key contains an internal core, including a quantitative amount of active ingredients, and an external surface layer, containing another active ingredient of the same amount or other kind, mixed and compressed with a carrier containing multi-crosslinked starch. And HPMC. The core may also include a carrier containing multi-crosslinked starch and HPMC. Dry noodles are particularly useful because their surface layer provides higher elasticity in release kinetics, which at the beginning May be slow, and may be fast at the end, or the other way round, and the decoration of a highly active ingredient, especially when the above ingredients are highly soluble in leech. In most cases In such cases, such tablets can ensure a two-step release kinetics. As previously noted, when a person wants a controlled release of an active ingredient — ^ 1.1 nn In ^^^ 1 1 'In V «., Vs I- -i (Please read the notes on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

A7 B7 5. Invention description (accounting) will use Qing c ’as some other such as ㈣-based cellulose ⑽ c) to ^. The polymer sold under the trademark "House" is manufactured as _. In this connection, 'DL Ming with a non-limiting example' can be reversed and published in 1962, Patent No. 3 06. No. 143 and Western Iteration publishes Canadian Patent No. ^ in 985. U.S. Patent No. 3,065, teaches that HPMC can be used for the preparation of controlled-release compressed tablets, as long as it is used in an amount greater than M% by weight. The patent case also induces that HpMC will form a viscous barrier layer, which is made of gelatin that expands under the reaction of water. Its gradual erosion in the gastrointestinal tract improves the desired controlled release. (See the decomposition time in the glass tester in Example 2). The patent mentions the slow decomposition and release of active ingredients of compressed tablets over a period of more than 4 hours. This is different from the characteristics that the compressed tablets of the present invention do not easily expand in an enzyme medium and do not decompose in a glass test tube for a period of more than 20 hours. In addition ,: In the example of the ® shrinking tablet of the present invention, the release time is much longer than that of US Patent No. 3 J65,143. The Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs printed Canadian Patent Nos. 1,88, and ei4, demonstrating that HPMC can be used with a small amount of excipients' to prepare a dust shrinkage bond containing 70.95% active ingredients' and A slow release was obtained in a glass test tube. This system, as mentioned in U.S. Patent No. 3,065,143, will form a soft / sticky gelatinous barrier layer, which will be based on Fickian kinetics (the cumulative release fraction is the square root of time Proportional) releases the active ingredient by diffusion. The patent case does not mention the use of HPMC to give the product made from multi-crosslinked starch. The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 4q q

A7 B7 Five L. The forbidden ingot of the invention description (points) can resist g. The reaction of the enzyme starch in the intestinal fluid, please read the back I. Matters and then %% of the compressed tablets described in Sigma Plus Patent No. 1188,614 on this page Conversely, it contains multiple crosslinks according to the present invention Starch and compressed tablets can maintain their original shape when placed in an aqueous medium, and at least # 24 ″ (the time required to release the active ingredient). There is no mucus production, and it is released at a fixed rate (zero-order kinetics) and continues for a longer period of time than in the case of the example of Canadian Patent No. 88,6 ". The same technology. In order to prove the correctness of the foregoing claims and information, the present inventors have done many experiments. Manufacture of compression lock keys · Use the technology described in detail in Canadian Patent No. 2,041,774 'to formulate including Experiments with Contramid tablets with or without HPMC as a carrier and dry coated compressed tablets. Other gelling polymers were also tested for comparison. Ministry of Economic Affairs Bureau of Intellectual Property The industrial and commercial cooperatives print all compressed tablets in the form of compressed tablets that weigh 500 rags and contain 50 mg of aspirin (ASA) 'as an example of an active ingredient. The concentration is 0 to 30% by weight of HPMC and 60% to 60% by weight of Coruraroid are used in combination with 0.25% magnesium stearate as an anti-adhesive agent. The compression key has a diameter of 12.7mm and is on both sides &Amp; from In the form of a flat cylinder. According to the procedure described in Canadian Patent No. 2,04,774, the 'Contramid used to prepare the compressed medicine key is 100 grams per 100 grams; the standard size of the paper is applicable to the country of China Standard (CNS) A4 specification (210X297 mm) 4 〇s June ΐ: τ ^ A7 ι B7 gas, f clear description ((〇) powder uses 3-5 grams of gas and methyl methyl oxygen as a multi-crosslinking agent A dry-coated compressed tablet made from Tritium has a core containing 128 mg of hydrogenated pseudoephedrine as an example of an active ingredient, and the hydrochloride pseudoephedrine and Umg are used as carriers. Contramid mixing. A HPMC containing 72 ^ of hydrogenated pseudoephedrine, 406 [^ (: 〇11) ^ 31 ^ (1 and 12 0: ^ (20%) HPMC 2 2 0 S / 1 G The surface wrapper of 〇〇〇00 is the predatory heart. According to the procedure detailed in Canadian Patent No. 2,040,774, 3.5 grams per 100 grams of starch is used as a multi-crosslinking Chloromethyl-oxytriamidine to prepare Co nt ram id used to make compressed ingots ° Many HPMC are obtained in different viscosities Their names have been abbreviated in the following cases:. HPMC 2208 100 cps = HPMC 2208/100 HPMC 2208 4000 cps = HPMC 2208/4000 HPMC 2208 100000 cps = HPMC 2208/100000 HPMC 2910 4000 cps = HPMC 2910/4000 on glass The analysis in the test tube under the stirring of 37¾ determines the solubility of the active ingredients in the compressed forbidden tablets formulated as described above. All experiments were repeated at least twice, and the dissolution conditions were as follows: Device: USP Dissolution Device Type 3; Stirring: Stirring 1G times per minute; Dissolution environment: 2 hours in an acidic environment (PH 1.2); (Please read the Please fill in this page for further information) Packing--Order printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives. This paper is printed in accordance with Chinese National Standards (CNS) A4 specifications (21〇'297297) A7 B7 5. Description of the invention (〖 |) For 2 hours in acid-blocking buffer (PH 7.0) with or without enzyme (although the concentration of bacterial starch is between 0 and 732 Iu / ml); and in phosphate buffer (PH 7 · 0) 10 hours; a brief description of the diagrams In the attached diagrams, the results obtained from these experiments are illustrated, where: Figure 1 is a curve showing 50 mg ASA, Contramide and different concentrations of The dissolution profile of HPMC 2 0 0/1 000 5,000 g Kelvin, the phosphate buffer solution contains 18 IU / ml enzyme. Figure 2 is a curve illustrating the dissolution profile of a 500 mg compressed tablet containing 50 mg ASA, Con tr amid, and 20% HPMC 2208/10000, in which the phosphate buffer solution contains different concentrations Enzymes. Figure 3 is a curve showing the dissolution profile of a 500 mg compressed tablet containing 50 mg ASA and Contraraid, but not HPMC, in which the phosphate buffer contains enzymes at different concentrations. Figure 4 is a curve illustrating the dissolution profile of a 500 mg compressed tablet containing 50 mg ASA, Contramid, and 20% HPMC 2208/100. The scale acid buffer contains enzymes of different concentrations. . Figure 5 is a curve showing the dissolution profile of a 500 mg compressed tablet containing 50 mg of ASA, Conramid and 20% gelling polymer, in which the scale acid buffer contains 18 IU / ml Enzymes. This paper size applies Chinese National Standards (CNS) M specifications (210X297 mm) {Please read the notes on the back before filling this page) Order · Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 0 5 $ A7 B7 V. Invention Explanation (丨 >) Figure 6 is a curve illustrating the dissolution profile of compressed tablets containing the hydrogenated pseudoephedrine Con-tramid and 2G% HPMC, in which the phosphate buffer contains 18 IU / ral. Enzymes. Compressed tablets in tablet form (a) Effect of HPMC concentration In the 1δ I.U./rai enzyme medium, the concentration of HPMC directly affects the enzyme resistance and active ingredient release curve of compressed tablets. However, in a low-concentration (< 10%) environment, the compressed ingot will have an irregular and unmanufacturable release effect. Above 10%, the curve will be linear. The release time is significantly extended by 20% to 30%. This proves that as the concentration of HPMC increases, the characteristics of the compressed tablets in the form of tablets + change dramatically. Under the minimum 10% of HPMC, compressed ingots have better enzyme resistance, which can form a more linear and more reproducible release curve. At 20% or more HPMC, compressed tablets have very good enzyme resistance. (b) Protection on enzyme media Figures 1 and 2 show that HPMC 2208/100 00 will directly affect the enzyme resistance of compressed ingots. When 20% of HPMC 2208/100000 is added to the Con-tramid carrier The effect of the enzyme concentration on the curve is very limited, even in the case of complete enzyme deficiency, a lower release rate can be noticed. Even at low concentrations, compressed tablets that do not contain HPMC 22O8 / 10GOOO are very sensitive to enzymes. However, in non-enzymatic media, its release is almost the same as that of HPMC 2208/10 0000 with an ink shrinkage bond. Release the same. This observation proves that HPMC's controlled release characteristics of Con tr amid itself are not 14 (please read the notes on the back before filling this page) (CNS) A4 specification (21〇 ×: 297 mm) 448〇5 &; '· ^:' A7 '— B7 .___ V. Description of the invention u》) · ·---2 direct effects' and S has an effect on the sensitivity of compression to enzymes. For comparison, the rogue 2208 / 1Q0 was tested in a similar situation. The figure shows that the enzyme effect is very significant when compared with 11 ((:) with a viscosity of 10000 (). Therefore, it can be assumed that the molecular weight of j is a major factor in resisting enzyme degradation. (C) Many Effect of the compound form \ > Experiments performed with several polymers capable of forming a hydrogel in an aqueous medium have revealed the unique characteristics of HPMC 2200S / 10000. Figure 5. Can not be similar to other test substances including liver 肊 with a viscosity of 40OG cps, all result in the rapid release of active ingredients. Therefore, we can see that HPMC with high viscosity can get the best protection effect. The results of the dry coated compressed tablets in the following analysis are obtained from the compressed noodles of the dried noodles. Figure 6 shows that when the dried noodles contain HPMC 22〇8 / 1 () 〇 () () Hour 'It has good properties of the enzyme-resistant medium. Figure 7 further shows that when the low viscosity fjpMC of 4,000 Cps is used, the protection effect of ύ is very significant. It is obvious that' Situations outside the scope of the invention as defined in the attached patent application park 'It can still be modified as described above. J __ ~ _ This paper size is suitable for financial and family relations (CNS) from the threat (21Qx 297 male (谙 Please read the precautions on the back before filling out this page) r, tT. Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs

Claims (1)

^ 4 ~ fTn ^ ------- Ί y. Eight V .: < 乂 广 Γ- 修 土 ^ 7 " ..... 衣 η + · η 曰 · **** 丨 丨 Α8 BS C8 D8 6. Apply for a patent. A pharmaceutical composition containing at least one oral controlled-release medicinal tablet with a certain amount of active ingredient. The medicinal composition of the tablet contains a maximum of 60/0 weight percent of the active ingredient. The active ingredient is mixed with at least 40% by weight of the carrier and compressed 'the carrier contains starch crosslinked with a polycrosslinker, and each 100 grams of starch is crosslinked with 0-1 to 10 grams The agent parent link is characterized in that the above carrier actually contains: from 30% to 90% of the above-mentioned multi-crosslinked starch; and from 10% to 30% of hydroxypropyl having a viscosity equal to or higher than 4,000 cps HPMC, the above percentage is a weight percentage based on the total weight of the pharmaceutical composition of the tablet. 2. The pharmaceutical composition of the medicinal substance according to item 1 of the patent application scope, wherein the carrier is at least Also contains acceptable fillers, slip agents, adhesives, lubricating anti-adhesives and dispersants 3. The pharmaceutical composition of a tablet as described in item 2 of the scope of patent application, wherein the active ingredient and the carrier containing multiple cross-linking agents are both in powder form, and they will be mixed and tested to The pharmaceutical composition required for the preparation of the system; and the multi-crosslinked starch contained in the above carrier are prepared per 100 grams of the powder and 1 to 6 grams of the multi-crosslinking agent .; Standard ^ .. .;- tPlease read the notes on the back and fill in ^. This page} Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ~ J ~~ .. 2 44δ〇5 6, Α8 Β8 C8 D8 π, patent scope 4. If applied The pharmaceutical composition of the medicinal tablet according to item 2 of the patent scope, wherein the medicinal composition of the aforementioned medicinal tablet is in the form of a tablet, and the HPMC contained in the carrier has a viscosity higher than 4000 cps. 5. The pharmaceutical composition of the tablet according to item 4 of the patent application park, wherein the HPMC contained in the carrier is in the form of HPMC 2208. 6. The pharmaceutical composition of the medicinal tablet as described in item 5 of the scope of patent application, wherein the HPMC contained in the carrier application is in the form of HPMC 2208 and has a degree of 1000 cps. 7. The pharmaceutical composition of a tablet according to item 6 of the scope of patent application, comprising 20% by weight of HPMC 2208 having a viscosity of looooo cps. 8_ The pharmaceutical composition of the medicinal tablet according to item 7 of the scope of patent application, which contains 10% by weight of the above active ingredients, wherein the multi-crosslinked starch contained in the above carrier is 100 grams per 100 grams. The starch is prepared with 3,5 g of chlorofluorenyl-trioxane which is used as the above-mentioned multi-crosslinking agent. 9. The pharmaceutical composition of the medicinal bond as described in item 4 of the scope of patent application, wherein the HPMC contained in the carrier is in the form of HPMC 2910. 10. The pharmaceutical composition of the medicinal tablet according to item 2 of the scope of the patent application, wherein the medicinal composition of the aforementioned medicinal tablet is in a dry coating form. This paper was printed from sijia 21 & 297 / > ^ 7 (please read the precautions on the back before filling in this page) " · Order 'Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 〇5 © Α8 Β8 C8 D8 A. Scope of patent application 〆.Ί .---- Ί ,,-t-- Jf * ^ 1 (Please read the notes on the back before filling this page} U · If the scope of patent application is the first; 10 The pharmaceutical composition of the medicine tablet includes a core, which contains a certain amount of the above-mentioned active ingredients, and an external surface layer, which contains another amount of the same active ingredient or other kinds of active ingredients, which is the same as the above-mentioned The carrier is mixed and compressed, and the carrier contains the above-mentioned multi-crosslinked starch and HPMC. 12. The pharmaceutical composition of the medicinal tablet according to item 11 of the patent application scope, wherein the core also includes a multi-cross-linked starch powder 13. The pharmaceutical composition of the tablet as described in item 12 of the scope of the patent application, the HPMC contained in the carrier is one of the forms of HPMC 2208 and HPMC 2910. The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Printing 14. A method for controlling the effect of enzymes on the carrier of a pharmaceutical composition for oral controlled release tablets in patients. The above pharmaceutical composition of tablets contains at least one active ingredient of up to 60% by weight, and at least one 40% by weight of the carrier 'The carrier contains starch cross-linked with the poly-crosslinking agent, and each 100 grams of starch is cross-linked with 0.1 to 10 grams of the poly-cross-linking agent' The above method includes A step of adding hydroxypropylmethylcellulose (HPMC) 10-30% by weight having a viscosity equal to or higher than 4000 cps as a adjuvant to the above carrier. The method described above, wherein the paper size of the above-mentioned medicine bond is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ^ 48 〇5 A8 B8 C8 D8 VI. Patent application scope The pharmaceutical composition is formed of tablets 'And the HPMC added to the carrier has a viscosity higher than 4000 cps. (Please read the precautions on the back before filling this page) 16. The method described in item 15 of the scope of patent application, which is added to the carrier HPMC is in the form of HPMC 2208. 17. The method according to item 16 of the patent application, wherein the HPMC 2208 added to the carrier has a viscosity of 100,000 cps. 18. The method according to item 17 of the patent application, wherein The carrier is added with 20% by weight of ρρM (:: 2208) with a viscosity of 100,000 cps. The above percentage is based on the total weight of the pharmaceutical composition of the tablet. 19. The method according to item 15 of the scope of patent application, wherein the HPMC added to the carrier is in the form of HPMC 2910. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20. The method as described in item 14 of the scope of patent application, wherein the above-mentioned pharmaceutical composition of the medicine bond is in the form of a dry coating, and includes a core including The above active ingredient, and an external surface layer, contain another amount of the same active ingredient or other active ingredients, mixed with the above-mentioned carrier, and the carrier contains the above-mentioned multi-crosslinked starch, which Linked starch has been added to HPMC. 21. The method according to item 20 of the scope of patent application, wherein the HPMC added to the carrier is one of the forms of HPMC 2208 and HPMC 2910. The paper size is universal T country standard (CNS) A4 specification (210X297 mm) Application date g / oj Case number (0 ^^ 88 category (the above are filled out by the Bureau) A4 ^ IC4 448056 Description of invention patent The book contains a medical incontinence composition of a controlled-release medicated tablet containing a carrier composed of poly-crosslinked starch hydrocarbylpropyl cellulose (Revised Patent Specification No. 86104588) DING English PHARMACEUTICAL CONTROLLED RELEASE TABLE ^ CONTAINING A CARRIER MADE OF CROSS-LINKED Name Nationality AMYLOSE AND YDROXYPROPYLMETHYLCBLLULOSE 1. Zhou Nad. Frances Kousi 2. Jacques Weilfried_Inventor Canada Residence 'Residence 1. Canada H7L 4X7 Lafort (Quebec) Mouth No. 358 2 Canada J4K3E8 Raffel (Quebec) Houbin No. 358 Order the name of the experimental pharmaceutical company (name) Ministry of Economic Affairs tlN-t is a field M industry consumer cooperative printed applicant nationality Canadian residence, residence (office) Representative name Canada J7E 1M5 Saint Titlissey (Quebec) McDonald's No. 140 East Bolanville, James dagger paper The scale is applicable to the Chinese National Standard (0 Yang) 8 4 specifications (210 father 297 mm) ^ 4a 〇5 ^ 吆 7 B7 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (/) Field of the invention The present invention is And the US Patent No. 5,456,921 published and claimed in the Canadian Patent Case No. 2,040,774, which was published in April 1994, and was published in April 1994; Both cases belong to the applicant of this claim. Correctly, the present invention relates to a controlled release forbidden tablet, which contains a carrier-bound active ingredient made of multi-crosslinked starch. Or hydroxypropyl methylcellulose (HPMC) with a viscosity of 4,000 cps, as a kind of adjuvant, is added to Cai Jian. The present invention is also related to the Cai Ding form described above, which has an equal or Viscosity higher than 4000cps and its use as a kind of adjuvant, which enables it to control enzymes, especially the effect of starch continued on multi-chain starch in the intestinal medium, so it can Reduce active ingredient release The dependence of the kinetics of the enzyme on the medium. A brief description of the prior art is mentioned above in Canadian Patent No. 2,00,774 and U.S. Patent No. 5,456,921, both of which describe the oral administration of one or more active ingredients Compressed forbidden doses deliver or release the efficacy of these doses at a controlled rate over a period of time. Such described tablets contain up to 60% by weight of one or more active ingredients that may be natural. Such a bond also contains at least a weight percent of a vehicle or carrier composed of starch cross-linked with a suitable multi-crosslinking agent, and each gram of starch is cross-linked with 0.1 to 10 grams of multi-crosslinking agent. The preferred amount is 1 gram of powder per gram of powder, which is cross-linked with 6 grams of multi-crosslinking agent. Using gas methyl ά Order Λ 4 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 4 f Diyun ^ It is stated that (2) a polycross obtained by using a milk dioxin or 2,3-dibromopropanol as a polycrosslinking agent, is known as Con tram id in the following. The best 'but not necessary; so' because most foods including the U.S. Food and Drug Administration shoulder and the 'era control organization' has approved years ago the starch cross-linked with these two agents. The main advantage of Coirtramid is that it maintains A fixed release rate (zero-order kinetics) 'is different from most of the carriers currently used in compressed tablets. ≪ Controlled release. In most carriers, the active ingredient is released by diffusion, which conforms to Fickian. Release kinetics (accumulated release fraction is proportional to the square root of time) ◊ From a practical point of view, in aqueous media, Contramid will form: a kind of porous hydrogel that can be used as a carrier of an active ingredient and can be Provide controlled release of the latter after oral administration. In the intestinal medium, this hydrogel is very sensitive to the effects of digestive enzymes that will attack the chain of powder and degrade the forbidden tablets, which will ensure its decomposition in the digestive tract. In this regard, ^ starch_enzyme I is particularly effective in accelerating the release of active ingredients from medicinal tablets' and it is used as a kind of adjuvant in the formulation of banned tablets constituting AD ^^ February 3, 1994 The main content of the published International Patent Application No. WO 94 / 〇2121, which belongs to the applicant of this claim. The tablets manufactured in this method are effective in most patients and can provide appropriate controlled release effects. Based on the fact that the activity of enzymes varies considerably from individual to individual, and that it changes as a function of food consumption, etc., there is a degree of difference between patients and patients. Since con_ tramid is sensitive to falling starch, this variability applies to the Chinese National Standard (CNS) A4 specification (210X2.97 mm) for at least one paper it standard. (Read the precautions on the back before filling in this Page) Ding 44δ 05s V. Description of the invention (3) These jobs are sold in the _ printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, so the adjuvant is added to search for the unique properties of Tramid. For those who make full use of the subject level, the invention is based on the invention of ~ shan ^ found that a very special inventor accidentally discovered its Cowid in order to make a wide and often special number The enzyme that is added to the medium ^ 到 is enough to resist the release of the marriage product due to any significant ^ tW decomposition in the intestinal rate ii. The ban on t 3 is currently used in pharmaceuticals In the field of Africa! The famous hydrogel wins, that is, propyl methylcellulose (Na >. However, 丨 suitable for banning only when its viscosity is equal to or higher than 4,000 centipoise (cps), And the adjuvant is effective when the amount added to the medicine is between 1% and 3G% of the total weight of the suspected drug. When the amount is less than 1%, the amount of HpMC added to the tablet is not enough. What you want to achieve. Above 30%, H The amount of pMC is too high, which will affect the carrier, which is no longer mainly made of Conramid, and therefore will result in the release of FUkian kinetics. According to the present invention, 'it has been found to have equal to or 疋 南 于 4 When HPMC with a viscosity of 0 〇〇cps is added to Contramid, it can give some unique and unexpected properties that cannot be inferred from the data currently known on the product. , And there is a low dependence on the release kinetics of enzymes in the medium. This finding is quite surprising, because the addition of other species is used in 1 Please read the note of ΐτ and then order the page @ 瓦 ^ 隼 () (210X297 公 — 陆 Τ 4448．05 $ 13. δ Α7 Β7 V. Description of the invention (+) Polymers in the pharmaceutical field as substitutes for HPMC ', such as ethyl cellulose, f-based Cellulose, hydroxypropyl cellulose (HPC), or Carbomer, etc. [Negative results are obtained only after conducting similar tests, which will be shown below. Therefore, the first object of the present invention is to provide a certain number of active ingredients containing at least one active ingredient. Amount of oral controlled release drug bond: This drug bond contains up to 60% by weight of the active ingredient, mixed with at least a weight% of a carrier, and the carrier contains a cross-linked polyether crosslinking agent: powder And each 1 CG gram of starch is cross-linked with 0.1 to 10 grams of multi-crosslinking agent. According to the present invention, the carrier actually: contains: from 30% to 90% of multi-crosslinked starch; and from 10 % To 30% of hydroxypropyl methylcellulose '(HPMC) having a viscosity equal to or higher than cps.} The above percentages are weight percentages based on the total weight of the tablets. Example 0 (second of the present invention The purpose is to provide a method that can control the effect of enzymes on the carrier in patients; oral controlled release forbidden tablets. The tablet contains at least one active ingredient of up to 60% by weight, and at least 40% by weight of the active ingredient. A carrier comprising a starch crosslinked with a polycrosslinking agent, and each 1C0 g of starch is crosslinked with 0.1 to 10 grams of a polycrosslinking agent. The method comprises the step of adding hydroxypropyl methylcellulose (HPMC) having a viscosity equal to or higher than 4⑽0 CPS to a carrier as an adjuvant. The tablets thus obtained have excellent resistance to enzyme mediators. And only very low dependence on the concentration of enzymes in the medium. They are using 6 paper sizes that are in accordance with Chinese National Standard (CNS) A4 specifications (2 〖0X297mm） (Please read the precautions on the back before filling out this page) -a-Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 48 Q 5 6 Fifth, the invention, jr, also has good mechanical resistance, which is an advantage from a commercial point of view. A study of the following non-limiting statement, including the results of some tests made by the inventor ', will give a clearer understanding of the invention and its many advantages. Main Description of the Invention As previously described, the present invention relates to the preparation of an orally compressed forbidden tablet containing one or more active ingredients so that a controlled release of the active ingredients can be obtained in a given time. Such compressed tablets contain up to 60% by weight of one or more active ingredients, mixed and compressed with a carrier of at least% by weight, which is a starch crosslinked and crosslinked with a suitable poly-crosslinking agent. The manufactured and per gram grams of starch is crosslinked with G. 1 to 10 grams of polycrosslinker. With regard to control knowledge, it is meant to release j for a period of time at a similar fixed (linear) rate, which can be as long as M hours or beyond. ί Member of the Ministry of Economic Affairs and Intellectual Property Bureau X. Consumer News Agency printed The active ingredient used in Cai ingots can be in any form that can be taken orally. A non-limiting list of examples includes sedatives, antacids, anti-inflammatory agents, vasodilators, stimulants, anti-hindered amines, vasoconstrictor nerve swords, anti-blood coagulants, anti-arrhythmias Agents, blood medicaments, hypoglycemic agents, diuretics, anti-asthmatic contraceptives, anti-asthma, jh vomiting agents, antispasmodics and so on. It exists in __ form. The preferred size is between 25 and 7 μm. The active ingredient is preferably in the form of a powder and mixed with a carrier manufactured by Contmu 2IGX297. 5. The invention (heart) manufacturing carrier, and then the mixture obtained by this method is compressed to obtain the desired medicine. ingot. The compression operation is preferably performed at a pressure of 0.1 S metric ton per square centimeter. (Please read the precautions on the reverse side before filling out this page) The essence of the present invention is that the carrier capable of preparing the multi-linked cross-linked powder of compressed medicine spin actually contains from 30% to 90% of contramid and ^ From ⑽ to 而 you have hydroxypropyl methylcellulose | (HPMC) with a viscosity equal to or higher than 4,000 cps. The percentage is based on the weight percentage of the total weight of the tablets. The HPMC coupling used is defined by the No. 2208 and No. 2910 (USP standard, XXjjj level) in the 23rd edition of US Pharmacopedia. Selected by HPMC. The viscosity of this standard is based on an aqueous solution of rhenium at a temperature of 2 01〇 ± 0 · 1. (Measured at 0 o'clock. HPMC 2208 has a methoxy content from 19% to 24% and a p-propoxy content from p 4% to 12%. For example, it has 100, 4000, 15000, | The product of 100,000 cps viscosity printed by the Ministry of Intellectual Property Bureau's Consumer Cooperative is sold by THE DOW CHEMICAL CO. Under the trademarks of j Methocel K > 100, 4M, 15M and 100M. FfPMC 2910 is available from 28? ≪ to 3. % Methoxy content and hydroxypropoxy content from 7% to 12%. For example, this product with a viscosity of 4OQ and 100,000 cps is manufactured by THE DOW CHEMI CAL CO. Methocel E-4M and 1 0 0M's trademark | Sale. The carrier of the multi-crosslinking powder may also contain one or more other ingredients currently used in the preparation of compressed tablets, including:-fillers such as lactose or sucrose Material, the amount of which does not exceed 40% by weight; I 8 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ΊΉ 'Month' Α7 丨 B7. V. Description of the invention (7) —Slip aids such as silicon dioxide , Whose amount does not exceed 10% by weight;-adhesives, whose amount does not exceed 10¾% by weight 1-lubricants and anti-adhesives such as magnesium stearate, whose amount does not exceed 5% by weight; and -Disintegrating agent, the amount of which does not exceed 5% by weight. Compressed tablets may be in the form of tablets or dry coating (dual core). In the first case, the HPMC used is preferably self-owned Choose from HPMC 2208 and 2910 with viscosity higher than 4000 cps. It is best to choose HPMC 2208 with viscosity of 100,000 cps. In the second case, it is the forbidden bar of dry noodles, and the best HPMC used is also from HPMC Choose between 22 (T8 and 2910), their viscosity may not only be higher, but also equal to 4000 cps. These dry-coated compressed drug keys contain an internal core, including a quantitative amount of active ingredients, and a The outer surface layer, containing another active ingredient of the same or another amount, is mixed and compressed with a carrier containing multi-crosslinked starch and HPMC. The core may also include a carrier containing multi-crosslinked starch and HPMC Dry noodle tablets are particularly useful because their surface layer provides higher elasticity in release kinetics, which may be slow at the beginning and (may be fast at the end, or vice versa) And a highly active ingredient, especially when the above ingredients are highly soluble in leech. In most cases, such tablets ensure a two-step release kinetics. As previously pointed out, when one wants controlled release of an active ingredient— ^ 1.1 nn In ^^^ 1 1 'In V «., Vs I-i (Please read the notes on the back before filling this page) This paper Applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 5. Invention description (accounting) will use Qing c ’as some other such as ㈣-based cellulose ⑽ c) to ^. The polymer sold under the trademark "House" is manufactured as _. In this connection, 'DL Ming with a non-limiting example' can be reversed and published in 1962, Patent No. 3 06. No. 143 and Western Iteration publishes Canadian Patent No. ^ in 985. U.S. Patent No. 3,065, teaches that HPMC can be used for the preparation of controlled-release compressed tablets, as long as it is used in an amount greater than M% by weight. The patent case also induces that HpMC will form a viscous barrier layer, which is made of gelatin that expands under the reaction of water. Its gradual erosion in the gastrointestinal tract improves the desired controlled release. (See the decomposition time in the glass tester in Example 2). The patent mentions the slow decomposition and release of active ingredients of compressed tablets over a period of more than 4 hours. This is different from the characteristics that the compressed tablets of the present invention do not easily expand in an enzyme medium and do not decompose in a glass test tube for a period of more than 20 hours. In addition ,: In the example of the ® shrinking tablet of the present invention, the release time is much longer than that of US Patent No. 3 J65,143. The Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs printed Canadian Patent Nos. 1,88, and ei4, demonstrating that HPMC can be used with a small amount of excipients' to prepare a dust shrinkage bond containing 70.95% active ingredients' and A slow release was obtained in a glass test tube. This system, as mentioned in U.S. Patent No. 3,065,143, will form a soft / sticky gelatinous barrier layer, which will be based on Fickian kinetics (the cumulative release fraction is the square root of time Proportional) releases the active ingredient by diffusion. The patent case does not mention the use of HPMC to give the product made from multi-crosslinked starch. The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 4q q A7 B7 Five L. The forbidden ingot of the invention description (points) can resist g. The reaction of the enzyme starch in the intestinal fluid, please read the back I. Matters and then %% of the compressed tablets described in Sigma Plus Patent No. 1188,614 on this page Conversely, it contains multiple crosslinks according to the present invention Starch and compressed tablets can maintain their original shape when placed in an aqueous medium, and at least # 24 ″ (the time required to release the active ingredient). There is no mucus production, and it is released at a fixed rate (zero-order kinetics) and continues for a longer period of time than in the case of the example of Canadian Patent No. 88,6 ". The same technology. In order to prove the correctness of the foregoing claims and information, the present inventors have done many experiments. Manufacture of compression lock keys · Use the technology described in detail in Canadian Patent No. 2,041,774 'to formulate including Experiments with Contramid tablets with or without HPMC as a carrier and dry coated compressed tablets. Other gelling polymers were also tested for comparison. Ministry of Economic Affairs Bureau of Intellectual Property The industrial and commercial cooperatives print all compressed tablets in the form of compressed tablets that weigh 500 rags and contain 50 mg of aspirin (ASA) 'as an example of an active ingredient. The concentration is 0 to 30% by weight of HPMC and 60% to 60% by weight of Coruraroid are used in combination with 0.25% magnesium stearate as an anti-adhesive agent. The compression key has a diameter of 12.7mm and is on both sides Yes & a mp; in the form of a flat cylinder. According to the procedure described in Canadian Patent No. 2,04,774, the 'Contramid used to prepare the compressed drug bond is 100 grams per 100 grams; Applicable to China National Standard (CNS) A4 specification (210X297 mm) 4 〇s June: τ ^ Α7 ι B7 gas, f clear instructions ((〇) powder using 3_ 5 grams and as a cross-linking agent A dry-coated compressed tablet made of oxytrioxane has a core containing 128 mg of hydrogenated pseudoephedrine as an example of an active ingredient, and the hydrochloride pseudoephedrine and Umg are treated as Contramid mixture used as a carrier. One HPMC containing 72 ^ hydrogenated pseudoephedrine, 406 [^ (: 〇11) ^ 31 ^ (1 and 12 0: ^ (20%) HPMC 2 2 0 S / 1 G 〇OO00 surface wraps the predatory heart. According to the procedure detailed in Canadian Patent No. 2,040,774, 3.5 grams per 100 grams of starch is used as a kind Multi-crosslinking agent chloromethyl-oxytriamidine to prepare Co nt ram id ° used for making compressed ingots ° Obtained in different viscosities Many HPMCs have their names abbreviated in the following cases:. HPMC 2208 100 cps = HPMC 2208/100 HPMC 2208 4000 cps = HPMC 2208/4000 HPMC 2208 100000 cps = HPMC 2208/100000 HPMC 2910 4000 cps = HPMC 2910 / 4000 Analysis in a glass test tube under 37¾ agitation determines the solubility of the active ingredient in the compressed forbidden tablet formulated as described above. All experiments were repeated at least twice, and the dissolution conditions were as follows: Device: USP Dissolution Device Type 3; Stirring: Stirring 1G times per minute; Dissolution environment: 2 hours in an acidic environment (PH 1.2); (Please read the Please fill in this page for further information) Packing--Order printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives. This paper is printed in accordance with Chinese National Standards (CNS) A4 specifications (21〇'297297) A7 B7 5. Description of the invention (〖 |) For 2 hours in acid-blocking buffer (PH 7.0) with or without enzyme (although the concentration of bacterial starch is between 0 and 732 Iu / ml); and in phosphate buffer (PH 7 · 0) 10 hours; a brief description of the diagrams In the attached diagrams, the results obtained from these experiments are illustrated, where: Figure 1 is a curve showing 50 mg ASA, Contramide and different concentrations of The dissolution profile of HPMC 2 0 0/1 000 5,000 g Kelvin, the phosphate buffer solution contains 18 IU / ml enzyme. Figure 2 is a curve illustrating the dissolution profile of a 500 mg compressed tablet containing 50 mg ASA, Con tr amid, and 20% HPMC 2208/10000, in which the phosphate buffer solution contains different concentrations Enzymes. Figure 3 is a curve showing the dissolution profile of a 500 mg compressed tablet containing 50 mg ASA and Contraraid, but not HPMC, in which the phosphate buffer contains enzymes at different concentrations. Figure 4 is a curve illustrating the dissolution profile of a 500 mg compressed tablet containing 50 mg ASA, Contramid, and 20% HPMC 2208/100. The scale acid buffer contains enzymes of different concentrations. . Figure 5 is a curve showing the dissolution profile of a 500 mg compressed tablet containing 50 mg of ASA, Conramid and 20% gelling polymer, in which the scale acid buffer contains 18 IU / ml Enzymes. This paper size applies Chinese National Standards (CNS) M specifications (210X297 mm) {Please read the notes on the back before filling this page) Order · Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 0 5 $ A7 B7 V. Invention Explanation (丨 >) Figure 6 is a curve illustrating the dissolution profile of compressed tablets containing the hydrogenated pseudoephedrine Con-tramid and 2G% HPMC, in which the phosphate buffer contains 18 IU / ral. Enzymes. Compressed tablets in tablet form (a) Effect of HPMC concentration In the 1δ I.U./rai enzyme medium, the concentration of HPMC directly affects the enzyme resistance and active ingredient release curve of compressed tablets. However, in a low-concentration (< 10%) environment, the compressed ingot will have an irregular and unmanufacturable release effect. Above 10%, the curve will be linear. The release time is significantly extended by 20% to 30%. This proves that as the concentration of HPMC increases, the characteristics of the compressed tablets in the form of tablets + change dramatically. Under the minimum 10% of HPMC, compressed ingots have better enzyme resistance, which can form a more linear and more reproducible release curve. At 20% or more HPMC, compressed tablets have very good enzyme resistance. (b) Protection on enzyme media Figures 1 and 2 show that HPMC 2208/100 00 will directly affect the enzyme resistance of compressed ingots. When 20% of HPMC 2208/100000 is added to the Con-tramid carrier The effect of the enzyme concentration on the curve is very limited, even in the case of complete enzyme deficiency, a lower release rate can be noticed. Even at low concentrations, compressed tablets that do not contain HPMC 22O8 / 10GOOO are very sensitive to enzymes. However, in non-enzymatic media, its release is almost the same as that of HPMC 2208/10 0000 with an ink shrinkage bond. Release the same. This observation proves that HPMC's controlled release characteristics of Con tr amid itself are not 14 (please read the notes on the back before filling this page) (CNS) A4 specification (21〇 ×: 297mm) 448 OFo A5 B5 —, Chinese abstract (Invention u: Control containing a carrier composed of poly-crosslinked powder and light propyl methyl vicin Pharmaceutical composition with drug release bond Disclosed herein is a controlled-release drug compared to a pharmaceutical composition, which contains an active ingredient combined with a carrier made of multi-linked crosslinked powder, 〇0 0 cps viscosity of propyl methyl cellulose (HPMC), as a kind of banned, added to the forbidden tablets. HPMC added to osmium tablets can control enzymes, especially in intestinal media Heart starch, which affects the carrier made of multi-crosslinked starch. Therefore, it can reduce the dependence of the kinetics of the active ingredient release on the concentration of the enzyme present in the medium. 'Abstract of the Invention (Invention 0: PHARMACEUTICALCONTROLLED RELEASE TABLE 歹 CONTAINING A CARRIER MADE OF CROSS-LINKED AMYLOSE AND YDROXYPROPYLMETHYLCELLULOSE \ --- r -------.-- ^) — ^! (Please read the precautions on the back before filling in this page 櫊) Printed by the Consumers Cooperative of the Central Elevator Bureau of the Ministry of Economic Affairs Disclosed is a pharmaceutical controlled release tablet containing an active ingredient in combination with a carrier made of cross-linked amylose in which hydroxymethylpropylcellufose (HPMC) with a viscosity higher than or equal to 4000 cps is added as an adjuvant. The addition of HPMC to the tablet permits to control the effect of enzymes, and more particular alpha-amylase present in the intestinal medium, on the cross-linked amylose used as a carrier, and thus to reduce the dependence of the kinetics of release upon the concentration 〇.f enzymes present in the medium. * The standard for killing paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) ^ 4 ~ fTn ^ ------ -Ί y. Eight V .: < 乂 广 Γ- 修 土 ^ 7 " ..… 衣 η + · η said. **** 丨 丨. A8 BS C8 D8 6. Patent application. A pharmaceutical composition containing at least one oral controlled release medicinal tablet with a certain amount of active ingredients. The medicinal composition of this tablet contains at most 60/0% by weight of the active ingredient, the active ingredient is mixed with at least 40% by weight of the carrier and compressed 'the carrier contains starch crosslinked with a multi-crosslinking agent, and each 100 grams of Starch is parentally linked to a multi-crosslinking agent of 0 to 10 grams, which is characterized in that the above carrier actually contains: from 30% to 90% of the above-mentioned multi-crosslinking starch; and from 10% to 30% having an amount equal to or greater than It is hydroxypropyl fluorenyl cellulose (HPMC0) with a viscosity higher than 4,000 cps. The above percentage is a weight percentage based on the total weight of the pharmaceutical composition of the tablet. 2. The medicinal composition as described in item 1 of the scope of patent application, wherein the carrier also contains at least one of an acceptable filler, a slipping agent, an adhesive, a lubricating anti-adhesive, and a dispersant Ingredients. 3. The pharmaceutical composition of the medicinal tablets according to item 2 of the scope of the patent application, wherein the active ingredient and the carrier containing multiple cross-linking agents are both in powder form, and they will be mixed and tested to produce the required The tested pharmaceutical composition; and the multi-crosslinked starch contained in the carrier are prepared from 100 g of powder and 1 to 6 g of multi-crosslinking agent. ; Standard ^ ...;- tPlease read the notes on the back and fill in ^. This page} Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ~ J ~~ .. 2