TWI227144B - Sustained release matrix systems for highly soluble drugs - Google Patents

Abstract

Disclosed are sustained release oral solid dosage forms comprising a therapeutically effective amount of a medicament having a solubility of more than about 10 g/l; a pH modifying agent; and a sustained release matrix comprising a gelling agent, said gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, said dosage form providing a sustained release of said medicament after oral administration to human patients.

Description

1227144 Δ7 Α7 _ Β7 ___ V. Description of the invention () Background of the invention The advantages of controlled release products are already well known in the pharmaceutical field, and their advantages include: the ability to maintain blood in the blood for a relatively long time Drug levels, while increasing patient compliance by reducing the number of medications that must achieve the same effect. These advantages described above have been achieved by many different methods. For example, different hydrogel systems have been described for controlled release drugs. Some of them are synthetic, but most of them are semi-synthetic or natural. Source. Some include both synthetic and non-synthetic substances. But there are some hydrogel systems that require special production methods and special production equipment. Furthermore, there are some hydrogel systems that allow different drug release properties. Oral controlled release delivery systems must be carefully adjusted so that their release rate and release pattern can meet the physiological needs and periodical needs of the medication. For the most part, oral delivery systems have been classified based on the mechanism of release, such as zero, first, second, pseudo-first order, and the like, although there are many pharmaceutical compounds Drugs are released via other complex mechanisms. The first-level mechanism refers to the case where the reaction rate depends on the concentration of the reactant (and therefore the first power of the reactant). In this mechanism, the substance breaks down directly into one or more products. The secondary mechanism occurs when the experimentally determined rate of the reaction is directly proportional to the concentration of each of the two reactants or directly proportional to the second power of the concentration of one reactant. 3 This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before filling this page) ---- line one 1227144 A7 ____ B7__ 5. Description of the invention () Pseudo first order reactions (Pseudo first order reactions)-generally defined as manifesting as though it is controlled by the first-level mechanism and occurs when, for example, a reaction The amount of a substance is a second reaction when it is manipulated by being present in a large amount or remaining at a constant concentration compared to other substances. In this case, the reaction rate is determined by the substance being manipulated. The zero order mechanism refers to the case where the reaction rate is independent of the concentration of the reactant (and therefore depends on the zero power of the reactant), and its limiting factor is other than the concentration of the reactant (such as a drug). For example, the limiting factor in the zero-order mechanism can be the solubility of the reactive substance or the light intensity in a photochemical reaction. However, as mentioned earlier, many chemical reactions are not simple reactions of zero, first or second order, and the like, but instead consist of a combination of two or more reactions. In addition, other factors can affect the reaction rate, including temperature, PΗ, variability of food action, ionic and ionic strength dependence, viscosity dependence, corrosion / erosion variability, content consistency issues, flow grade Problems with weight consistency, problems with load capacity and mechanical strength, hydrolysis, photochemical decomposition, interactions between ingredients (such as the interaction of drugs and other ingredients in the formula, such as buffers, preservatives, and the like) Concentration of solvents with low dielectric constant (when reactions involve ions of opposite charge), etc. Although many controlled-release and sustained-release formulations are known, certain soluble to highly soluble drugs present difficulties in formulating when added to such formulations. Sustained drug with a continuous 4 paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----------- installation -------- order ---- ----- line (please read the precautions on the back before filling this page) 1227144 A7 ___ B7 ____ V. Description of the invention () The release formula is susceptible to "dose dumping" When the release of the active ingredient is delayed, but when the release starts, its rate is considerably higher. This increased release rate is related to changes in plasma, which may result in reduced therapeutic effects or increased toxicity, which are the same issues that must be addressed for sustained release formulations. In addition, it is often not easy to predict whether a particular sustained release formulation will provide the desired sustained release for a soluble to highly soluble drug. It has generally been found that considerable experimentation must be performed to obtain a sustained release formulation that provides the desired bioavailability of such drugs when ingested. To compensate for and provide a controlled release of a sustained to highly soluble drug as desired The unpredictability associated with formulations is sometimes considered to be necessary to provide a formulation with bi-modal or multi-Phasic kinetics. Bimodal or heterogeneous release characteristics can be: an initial high rate followed by a lower rate when the dosage form passes through the upper part of the small intestine where absorption is optimal, and finally when the dosage form enters the intestine the absorptivity is worse than before At the other end is another higher rate. Dual-mode release is considered beneficial for a number of reasons, including but not limited to, dual-mode release allows formulators to compensate for changes in the rate of drug absorption in the gastrointestinal tract by providing a rapid onset effect (when formulated When in the stomach) and to compensate for the relatively low absorption caused by providing a relatively fast release rate (for example when the formula is in the large intestine). So far, dual-mode release formulations have been provided in a number of different ways. 5 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------ ^ -------- ^ -------- -(Please read the notes on the back before filling this page) A7 1227144 ____B7__ V. Description of the Invention () For example, International Bulletin No. W0 / 8/7/00044 is a treatment that is considered to have dual-mode release characteristics formula. WO 8 7/0 0 0 4 4 describes a carrier base material for a therapeutically active drug in a solid-dose formulation, which is believed to produce a dual-mode release pattern, which is characterized by the rapidity of a drug The rate of initial release and then a substantially constant release over a period of time after which the release rate is higher than the previously observed constant rate. This carrier-based material is a bimodal hydroxypropyl methylcellulose ether having a methoxy content of 19 to 30%, a hydroxypropoxy content of 4 to 12%, and a range of 40 to 19,000 cps viscosity, average molecular weight from 20,000 to 1 40,000, and it confirms the dual mode version according to the analytical method described here. Bimodal hydroxypropyl methylcellulose contains 5 to 99% based on the total weight of the formulation, depending on the active ingredient and the desired drug release length. ACShan et al. "Gel-Matrix Systems Exhibiting Bimodal Controlled Release For Oral Drug Delivery", Jourrnal of Controlled Release, 9 (1989), 169-175 The page further reports that specific "kinds" of hydroxypropyl methylcellulose ethers were found to exhibit a dual-mode drug release pattern. However, in this study, a series of hydroxypropyl methylcellulose ether polymers were found to provide bimodal and nonbimodal release patterns from polymer-drug and matrix lozenges, and the results appear to be It depends on the polymer supplier (and therefore depends on, for example, the method of manufacture, ionic composition, variations in substituent distributions or molecules 6) This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) III 1 III AW · 1111111 ^ · 11111.11 (Please read the precautions on the back before filling out this page) A7 1227144 B7 V. Description of the invention () Depends on the distribution of the quantity). (Please read the precautions on the back before filling this page) P. Giunchedi et al. "Ketoprofen Pulsatile Absorption From‘ Multiple Unit ’Hydrophillic Matrices’ ’International

Journal of Pharmaceutics, 77 (1991), pp. 177-181 describes a prolonged release ketoprofen oral formulation containing a multiple unit formulation consisting of four hydrophilic mats of the same composition, each unit It contains 50 mg of the drug and is prepared with hydroxypropyl methylcellulose (Mathocel. RTM.) And placed in a gelatin capsule. Pulsatile plasma levels were obtained (two peaks at the second and eighth hours after dose administration), but in vitro tests resulted in a fairly constant drug release. U. Conte et al. "A New Ibuprofen Pulsed Release Oral Dosage Form", Drug Development And Industrial Pharmacy, 15 (14-16), pp. 2853-2596 ( 1989) reported that a pulsed release pattern was obtained from a three-layered lozenge, where two layers included a dose of a drug and the middle layer served as a control element to separate the drug layer. The control element is a mixture of water-swellable polymer (hydroxypropyl methylcellulose). An impermeable outer membrane is applied to the lozenge, and a super disintegrant (sodium starch gluconate and cross-linked polyvinyl pyrrolidone) is contained in the drug layer. K. A. Kahn et al. "Pharmaceutical retardation and in vivo performance of Brufen's retardation-a kind of Ibuprofen SR matrix sediment (Pharmaceutical 7 This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 Mm) 1227144 A7 _B7______ 5. Description of the invention ()

Aspects And In-Vivo Performance Of Brufen Retard-An Ibuprofen SR Matrix Tablet), 5 j Proced. Intern. Symp. Control. Rel. Bioact. Mater.? 19 (1991), Controlled Release Society, Inc. 0 mg of ibuprofen is formulated to be said to provide a dual-mode release profile. The release delaying agent used therein is xanthan gum, the ingredients are mixed to obtain an appropriate xanthan gum content, and then pressed into a tablet and coated with a film. The amount of xanthan gum included affects the rate of drug release. An increase in the particle size or film coating amount of the drug per lozenge does not significantly affect the rate of drug release. Although an increase in the particle size of xanthan gum causes a more significant burst effect, the application of a thin film coating overcomes this burst effect. The initial rapid release of the drug is assumed to be related to changes in gel layer formation, where larger particles gel more slowly and come off before a sticky matrix can be formed. In my U.S. Patent Nos. 4,9 94,276, 5,128,143, and 5,135,757 (which are incorporated herein by reference), a polydisperse heteropolydisperse has been reported (For example, a combination of a heteropolysaccharide such as xanthan gum and a polysaccharide gum such as locust bean gum that can be cross-linked with the heteropolysaccharide) can be processed into an oral solid dosage form by controlling the release of excipients, And lubricant powder, and then directly pressurized to obtain, by conventional wet granulation or a combination of the two. The drug is released from the formulation according to a zero-order or first-order mechanism. I own the US patent case Nos. 5,472,71 1 and 5,4 8 This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) ----------- installed- ------ Order ---------- line (please read the notes on the back before filling this page) A7 1227144 ____B7______ 5. Description of the invention () (Please read the notes on the back before filling (This page) No. 7, 8, 5 7 4 (herein incorporated by reference) reports a multi-phasic or bi-phasic control that can provide a therapeutically active drug in vitro The release formulation is achieved by adding an effective amount of a pharmaceutically acceptable surfactant and the above-mentioned excipients. One example of a highly soluble drug used in the present invention is diiltiazem, which is a derivative of benzothiazine with calcium antagonistic activity. Thiazone is widely used in Treatment of hypertension and angina. Therefore, great attention has been paid to the preparation of sustained release thiazepines which provide an acceptable release pattern. For example, U.S. Patent Nos. 4,894,240 and 5,36 4,620 (Goeghegan et al.) Describe a nine-dose formulation of azathione that is suitable for once-a-day administration. This formulation contains a thiazolone core and an organic Acid, which is surrounded by an insoluble multilayer film that releases azathione from nine doses at a rate that allows controlled absorption for 24 hours after application. Other techniques for the preparation of sustained-release azathione formulations have been described in the prior art. For example, U.S. Patent No. 5, 4 1 9, 9 1 7 (Chen et al.) Describes the use of a pharmaceutically effective dissociable compound to control the rate of release of azathione from a hydrogel Thing. Another example of a highly soluble drug for use in the present invention is oxybutynin. Oxybutyn is widely used to treat urinary diseases, such as overactive bladder. My U.S. patent case 5,399,359 reveals a sustained release formulation of oxybutynin, which contains a 9-paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1227144 δ7 Ά / ____ Β7 __ V. DESCRIPTION OF THE INVENTION () A pharmaceutically effective amount of oxybutynin dispersed in a sustained release matrix containing a gelling agent, an effective amount of a pharmaceutically acceptable water-soluble cationic cross-linking agent and an inert diluent The crosslinker can be crosslinked with the gelling agent when the formulation is exposed to an environmental liquid such as a gastrointestinal fluid. OBJECTS AND SUMMARY OF THE INVENTION An object of the present invention is to provide a sustained release formulation with bioavailability for soluble to highly soluble therapeutically active drugs. Another object of the present invention is to provide a multi-phase or bi-phase controlled release formulation for soluble to highly soluble drugs. Another object of the present invention is to provide a method for preparing a bioavailable sustained-release formulation for a soluble to highly soluble therapeutically active drug. Another object of the present invention is to provide a sustained-release oral solid dosage form which can be used to prepare a sustained-release oral solid dosage form of a soluble to highly soluble therapeutically active drug. Another object of the present invention is to provide a sustained release matrix suitable for providing a sustained release formulation when combined with a drug, which provides a therapeutically effective blood content of the drug for, for example, 12 or 24 hours. A further object of the present invention is to provide a sustained release matrix formulation of azathioneone which provides a plasma type similar to a commercially available sustained release formulation such as Cardizem CD. Another object of the present invention is to provide a sustained release matrix formulation of oxybutynin, which provides a plasma type similar to a commercially available sustained release formulation such as Ditropan XL. 10 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ----------- installation -------- order --------- -Line (Please read the notes on the back before filling this page) 1227144 A7 __B7 ___ V. Description of the invention () The above objectives and other objectives are achieved by the present invention, part of which is related to this amazing discovery, that is, adding a P Η modifiers in a dosage form containing a gelling agent will accelerate drug release from this dosage form and provide high bioavailability. In a specific embodiment, a sustained-release oral solid dosage form comprises a therapeutically effective amount of a drug having a solubility of more than about 10 grams per liter; a rhodamine modifier; and a sustained-release matrix comprising a gelling agent. The gelling agent includes a heteropolysaccharide gum and a homopolysaccharide gum that can be cross-linked with the heteropolysaccharide gum when exposed to an environmental liquid. Preferably, the dosage form provides a sustained release of the drug for at least about 12 hours, and preferably at least about 24 hours. In a specific embodiment, the dosage form further comprises a) a pharmaceutically acceptable surfactant, which can provide multi-phase release of the drug; b) an inert diluent selected from, for example, monosaccharide, disaccharide Sugars, polyols, or mixtures thereof; c) a hydrophobic substance that has slowed the water core effect of the gelling agent; and / or d) an effective amount of a pharmaceutically acceptable dissociable gel strength enhancer It is suitable for adjusting the release rate from the formed gel when the controlled release formulation is exposed to an environmental liquid. In a preferred embodiment, the formulation of the invention comprises a lozenge. In a preferred embodiment of the present invention, the ratio of the drug to the gelling agent is preferably between about 10: 1 to about X: 丄 〇, and more preferably between about 5: 1 to about 1: 5 and preferably between about 1.2 5 ·· 1 to about 2: 1. The present invention also relates to a method of providing a drug having high solubility in water. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). ---- Order ---------- line (please read the notes on the back before filling this page) A7 1227144 _B7 _ 5. Description of the invention () (Please read the notes on the back before filling in this Page) A method for a sustained release formulation comprising preparing a matrix comprising a gellant containing a heteropolysaccharide gum and a homopolysaccharide gum that can be crosslinked with the heteropolysaccharide gum when exposed to an environmental liquid; and a selective Dissociable gel strength enhancer, a selective inert pharmaceutical diluent; and a selective hydrophobic substance, followed by the addition of a soluble to highly soluble drug, a peptone modifier, and a selective pharmaceutical Acceptable surfactant. The resulting mixture is then tabletted to obtain a drug-to-gelling agent having a ratio between about 10: 1 to 1:10, more preferably between about 5: 1 to about 1: 5, and The product is preferably a ratio between about 1.2 5: 1 to about 2: 1 such that a gel matrix can be formed when the lozenge is exposed to an environmental liquid, and such that each of the lozenges contains A therapeutically effective amount of a drug. The resulting lozenges provide a therapeutically effective blood content of the drug of at least about 12 hours, and preferably about 24 hours. The invention further relates to a method for treating a patient by oral administration of an oral solid dosage form as described above. In a particularly preferred embodiment of the present invention, the matrix may be prepared from a pre-formed, sustained release excipient that contains, for example, about 10 to about 99% by weight of a gelling agent. , About 0 to about 20% by weight of a dissociable gel strength enhancer, about 1 to about 89% by weight of an inert pharmaceutical diluent, and about 1 to about 20% by weight of a hydrophobic substance. In another preferred embodiment, the mixture of the matrix and the inert pharmaceutical diluent is granulated before the drug is added, and it has a dispersion of a hydrophobic substance present in an amount sufficient to slow the hydration of the matrix without disrupting the hydration. 12 This paper size applies the Chinese National Standard (CNS) A4 specification (210 x 297 male H " 1227144 B7. V. Description of the invention) or solution. In another preferred embodiment, the first part of the drug is in The excipient is added during granulation, and the second part of the drug is added in an extragranularly manner or after the granulation step. This specific implementation of the granulation system provides the initial rapid release of the drug. In a specific embodiment, the drug is highly soluble, that is, it has a solubility of more than about 100 grams per liter. In other preferred embodiments, the drug contains a calcium channel blocker, preferably one Benzothiazine, most preferably thiazepine and its pharmaceutically acceptable salts. In other preferred embodiments, the drug contains an antispasmodic agent, preferably Austria Xibutin or a pharmaceutically acceptable salt thereof. The so-called `` sustained release '' 〃, for the purpose of the present invention, means that the therapeutically active substance is released from the formulation at a controlled rate, so that The effective drug content (but lower than the toxic content) of the drug in the blood can be maintained for an extended period of time, for example, at least about 12 hours or at least about 24 hours. The so-called `` bioavailabk '' ，, For the purposes of the present invention, it means that the therapeutically active drug is absorbed from a sustained release formulation and is available at a location in the body where drug action is needed. So-called soluble 〃, which means: treatment The active drug has a solubility in water of more than about 10 grams per liter (g / litre). The so-called `` highly soluble '' 〃, which means 13 paper standards are applicable to Chinese National Standard (CNS) A4 specifications ( 210 X 297 Public Love 1 '------------------- Order ---------- Line (Please read the precautions on the back before filling this page ) A7 1227144 ____B7 _ V. Invention () Means: The therapeutically active drug has a solubility in water of more than about 100 grams per liter (g / liter). The so-called "environmental fluid", which for the purpose of the present invention includes, for example, an aqueous solution, Or gastrointestinal fluid. For the purposes of the present invention, the term `` pH adjuster '' means any substance that reduces the dissociation of a drug so that it accelerates the release of the drug from the hydrogel matrix into the solution. The so-called \ 'C max The term 〃 means for the purposes of the present invention the maximum plasma concentration obtained by a drug after administration of a dosage form according to the invention. The term `` Tmax '' is used for the purpose of the present invention to mean the time elapsed from the time when a dosage form is administered until the drug reaches Cmax. The term `` W5G '' means for the purposes of the present invention the time measured by the width of the plasma concentration curve at a height of 50% of Cmax. For the purposes of the present invention, the dosage form may have dual-mode kinetics, and thus the attached dosage form may have multiple Cmaxs, Tmaxs, and W50. The following diagrams are illustrations of specific embodiments of the present invention and do not represent the scope of the present invention which is included in the scope of limited patent applications. Figure 1 is a graphical representation of the solubility (average percentage of dissolution over time) of Examples 1 and 2. Figure 2 is a graphical representation of the solubility (average percentage of dissolution over time) of Examples 3 and 4. Figure 3 is a graphical representation of the solubility (average percentage of dissolution over time) of Examples 5 and 6. 14 This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) -------------------- Order --------- (Please read the precautions on the back before filling this page) 1227144

V. Description of the invention (Figure 4 is a graph showing the solubility (average percentage of dissolution over time) of Examples 7 and 8. Figure 5 is a graph of solubility (average percentage of dissolution over time) of Examples 9 and 10 Figure 6 is a graphic representation of the solubility (average dissolution percentage over time) of Examples 11 and 12. Figure 17 is a graphic representation of the% release rate over time for Examples 11 and 12. Fig. 8 is a graph showing the solubility (average percentage of dissolution over time) of Examples 13 and 18. Fig. 9 is a graph of solubility (average percentage of dissolution over time) of Examples 19 and 20 in Examples. Fig. 10 is a graph showing the solubility (average dissolution percentage over time) of Examples 2 1 to 2 3. Fig. 1 is a graph of Example 24 and a reference standard (Cardizem CD2 40 mg). A graphical representation of the average plasma concentration of thiazepine over time. Figure 12 is a graphical representation of the average plasma concentration of azathione over time for Example 25 and a reference standard (Cardizem CD 240 mg). Figure 13 shows the solubility of Examples 2 6 and 27 (average percentage of dissolution over time). ). Figure 14 is a comparison diagram of the solubility of Example 3 7 (average dissolution percentage over time) and the solubility of a reference standard (DitropanXL). 15 This paper size applies the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) ------------ install -------- order ---------- line (please read the notes on the back before filling in (This page) 1227144 A7 ______B7____ 5. Description of the invention () Detailed description of the invention The sustained release matrix of the present invention may be a heterogeneous dispersive excipient (as previously reported in the unmanned U.S. Patent No. 4,9 9 4, 2 7 6 Nos. 5, 128, 143 and 5, 135, 757), which may include a gelling agent that exhibits multiplicative heteropolysaccharide gums and homopolysaccharide gums, such as a combination of two or more polysaccharide gums Higher viscosity and faster hydration than can be expected from these gums alone, the resulting gel will form faster and be harder. The term "heteropolysaccharide" used in the present invention Is defined as a water-soluble polysaccharide, which contains two or more saccharide units, and the heteropolysaccharide contains a branched or helical configuration It also has superior water-wicking properties and immense thickening properties. A particularly preferred heteropolysaccharide is xanthan gum, which is a high molecular weight (> 10 6) heteropolysaccharide. Other preferred heteropolysaccharides include derivatives of xanthan gum, such as dehydrogenated xanthan gum, carboxymethyl ether, and propylene glycol esters. The homopolysaccharide gums that can be crosslinked with heteropolysaccharides used in the present invention include: galactose Mannans (galactomannans), that is, polysaccharides composed purely of mannose and galactose. Galactomannans with a high proportion of unsubstituted mannose parts have been found to achieve more interactions with heteropolysaccharides. Compared to other galactomannans such as guar and hydroxypropyl guar, the locust bean gum system having a higher proportion of mannose to galactose is particularly preferred. When the ratio of the heteropolysaccharide gum to the homopolysaccharide material is about 1: 1: 1. At 5 o'clock, the controlled-release properties of the controlled-release formulation of the present invention may be the best, although at the 16 P-scale scale, using the Chinese National Standard \ cNS) A4 specification (210 X 297 mm) ^ 'I 丨 I-- ------ · 1111111 ^ 0 I I ------ I AW (Please read the notes on the back before filling out this page) 1227144 A7 ___B7 V. Description of the invention () Approximate weight of heterogeneous dispersing polysaccharides Heteropolysaccharide gums present in an amount of 10 to about 90% or more can provide an acceptable slow release product. Any combination of homopolysaccharide gums known to produce a multiplier effect when exposed to an aqueous solution can be used in accordance with the present invention. Such a multiplier effect of the sugar-gum combination of the present invention may also occur between two homopolysaccharides, or between two heteropolysaccharides. Other acceptable gelling agents that can be used in the present invention include those gelling agents that are known in the art. Examples include alginate, carrageenan, pectin, guar gum, modified starch, hydroxypropyl methylcellulose, methyl cellulose, and other fibrous substances such as sodium carboxymethyl cellulose and Hydroxypropyl cellulose. This list is not intended to be limiting. The inert diluent of the sustained release excipient preferably comprises a pharmaceutically acceptable saccharide, including: monosaccharide, disaccharide, or polyol, and / or a mixture of any of the foregoing. Examples of suitable inert pharmaceutical tinctures are: sucrose, dextrose, lactose, microcrystalline cellulose, guar gum, fructose, xylitol, sorbitol, starch, mixtures thereof, and the like. However, it is preferred to use soluble pharmaceutical tinctures, such as lactose, dextrose, sucrose, or mixtures thereof. Alternatively, the inert diluent or fluorene filling agent may include a diluent prepared by direct pressurization previously manufactured as described below. For example, the ingredients of the sustained release excipient can be dry mixed without using a wet granulation step. This step can be used, for example, when the active ingredient is directly added to the ingredients of the sustained release excipient. Grain will be completed in case. On the other hand, this step can also be used when no wet granulation step has been counted. If the mixture will be manufactured in a way that does not require a wet granulation step and the final mixture will be made into tablets, this paper size is applicable to China National Standard (CNS) A4 (210 X 297 public love) -------------------- Order --------- Line (Please read the precautions on the back before filling this page) 1227144 A7 ____B7_____ V. Invention Note () All or part of the inert diluent contains a pre-manufactured diluent, which is widely used in medical technology and can be obtained from many commercial sources. Directly pressurized excipients include Emococel® (microcrystalline cellulose, N. F ·), Emdex® (Dextrose, N · F. ), And Tab-Fine® (some directly pressed sugars, including sucrose, fructose, and dextrose), all of which are commercially available from Penwest Pharmaceuticals Co., Patterson, New York. Other diluents made by direct compression include those obtained from Sheffield Chemical, Union, N.  J.  07083 anhydrous lactose (lactose N · F ·, anhydrous direct tableting); Elcems® G-250 (powdered cellulose, N. F., obtained from Degussa, D-600 Frankfurt (Main) Germany) F. ); Fast-Flo Lactose® (lactose, N. lactose) from Foremost Whey Products, Banaboo, WI 53913 F., spray-dried); Maltrin® (aggregated maltodextrin) from Grain Processing Corp., Muscatine, IA 52761; from Roquet Corp., 645 5th Ave., New York, N.  10022 Neosorb 60⑧ (sorbitol, N · F ·, prepared by direct pressure): available from Ingredient Technology, Inc., Pennsauken, N.  J · 08110 of Nu-Tab® (can be obtained by pressing, N. F. ); Available from GAF Coi * p., New York, N.Y.  10020 Polyplasdone® (Crospovidone, N. F., cross-linked polyethylene bispyridone): available from Generichem Corp., Little Falls, N.J.  07424 Primojel® (Sodium Starch Gluconate, N · F ·, Xiangyl Methyl Starch); available from Penwest Pharmaceuticals Co. , Patterson, N.Y.  10512 of Solka Floe⑧ (cellulose floc, N · 18) This paper size is applicable to China National Standard (CNS) A4 (210 χ 297 mm) ------------------ -^ --------- ^ (Please read the notes on the back before filling this page) A7 1227144 __B7__ V. Description of the invention () F ·); Available from Foremost Whey Products, Banaboo, WI 53913 and DMV Corp., Vehgel, Holland, spray-dried lactose® (lactose, N · F ·, spray-dried); and available from Colorcon, Inc. Sta-Rx 1500® (Starch 1500) (Pregelatinized Starch, N., West Point, PA 19486) F. , Made by pressure). In general, the formulation can be prepared as a diluent made by direct pressure, such as by wet granulation of spray-dried lactose, or by pre-mixed direct addition by methods known in the art. It is prepared by pressing the diluent. In particular embodiments, the components of the sustained release excipient may be manufactured in advance. However, in other embodiments, the active drug can be added to the excipient ingredients and the mixture can be melted and granulated to form a gramxlaticm. Finally, when a surfactant is used, a dissolved or dispersed surfactant containing thiazepin and or oxybutynin can be added directly to the ingredient mixture. In other specific embodiments of the present invention, the inert diluent obtained by direct pressurization used with the sustained-release pharmaceutical excipients of the present invention is an increased microcrystalline cellulose, as disclosed in J.  Staniforth, B.  Sherwood and E.  Hunter filed U.S. Patent Application Serial No. 08 / 370,576 in the name of "Pharmaceutical Excipient Having Improved compressibility" filed on January 9, 1995, which is fully incorporated herein by reference. For reference, the added microcrystalline cellulose described therein is commercially available from Penwest Pharmaceuticals Co. under the "Prosolv" brand name.  〇19 This paper size applies the Chinese National Standard (CNS) A4 specification (210 x 297 mm) ------------- 1 ------ Order -------- -Line 1 ^^ · (Please read the precautions on the back before filling in this page) A7 1227144 _B7 Sun · Surface · __-_ '1 " 1 · ΝΙ_ 细 ΐ1 · 1 —'-— One, five, the description of the invention () (Please read the notes on the back of 53 before filling out this page) • -An effective amount of a pharmaceutically acceptable surfactant can also be added to the above excipient ingredients, or added when the drug is added to increase Bioavailability of drugs. An example of a suitable surfactant is docusate sodium, which is present in an amount up to about 15% by weight of the solid dosage form. A particularly preferred surfactant is sodium lauryl sulfate, which is present in an amount of about 15% by weight of the solid dosage form. In a specific embodiment, the surfactant is dissolved in a suitable solvent, such as water, and is then added to a mixture of sustained-release excipients and drugs. This allows the surfactant to wet the particles of the excipients to This allows the precipitate to be small and not aggregate when the solvent evaporates the drug particles. It is possible to obtain granules of a drug and a surfactant which are finely and homogeneously dispersed in an excipient. In a specific embodiment of the present invention, for example, wherein the drug is azathione and or oxybutynin, the surfactant is from about 1% to about 5%, or from about 1% to about 1 by weight of the final product. It is added in an amount of 5%, however, the upper limit of the surfactant contained may be limited to 15%. A limiting factor is the need to provide a pharmaceutically acceptable formulation for the final product. For example, in the case of tablets, the upper limit of the surfactant dose contained is produced by the production of a pharmaceutically acceptable tablet For example, tablets having a friability of less than about 1% and a hardness of 6 to 8 kg. The surfactants useful in the present invention generally include pharmaceutically acceptable anionic surfactants, cationic surfactants, amphoteric (amphiphilic / amphiphilic) surfactants, and nonionic surfactants. Suitable pharmaceutically acceptable anionic surfactants include, for example, monovalent alkanes 20 ^ Paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) ~ A7 1227144 _____B7__ 5. Description of the invention () (please first (Please read the notes on the back and fill in this page again.) Glutamates, fatty acid-polypeptide condensates, sulfates, alkyl sulfates (including sodium lauryl sulfate (SLS)), ethoxylated alkyl sulfates, ester-linked sulfonates (including docusate sodium ) Or dioctyl sodium sodium bisulfate (DSS)), alpha olefin sulfonates, and phosphorylated alcohols. Suitable pharmaceutically acceptable cationic surfactants include, for example, monoalkylquaternary ammonium salts, dialkylquaternary ammonium compounds, aminoamines, and aminoimines. Suitable pharmaceutically acceptable amphoteric (amphiphilic / amphiphilic) surfactants include, for example, N-substituted alkylamines, N-substituted betaines, sulfobetaines, and N-alkyl 6-aminopropionate. Other suitable surfactants for use with the present invention include polyethylene glycols in the form of esters or ethers. Examples include polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid from castor oil, or polyethoxylated fatty acid from castor oil or polyethoxylated fatty acid from hydrogenated castor oil. Surfactants available on the previous page are known under the trade names Cremophor, Myrj, Polyoxyl 40 stearate, Emest 2675, Lipal 395, and PEG 3350. p Η modifiers promote drug release from the matrix, and from about 1% to about 50%, from about 1% to about 25%, from about 1% to about 15%, or from about 1% to about 15% by weight of the final dosage form It is present in an amount of about 1% to about 10%. In a preferred embodiment, the ρ Η adjusting agent is an organic acid. Example 21 The paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) A7 1227144 __B7 ____ 5. Description of the invention (Such as citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid or lactic acid. (Please read the notes on the back before filling this page) -Line The dissociable gel strength enhancer that can be used with the present invention can be monovalent or polyvalent metal cations. Preferred salts are inorganic salts, including sulfates, chlorides, borates, bromides, citrates, acetates, lactates, and the like of various alkali and / or alkaline earth metals. Specific examples of suitable dissociable gel strength enhancers include: calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate , Chlorine Ming ·, Samarium Chloride, Sodium Citrate, Sodium Acetate, Calcium Lactate, Magnesium Sulfate and Sodium Fluoride. Polyvalent metal cations can also be used in the present invention. However, the dissociable gel strength enhancer is divalent. Particularly preferred salts are calcium sulfate and sodium chloride. The dissociable gel strength enhancer of the present invention is added in an amount effective to obtain the required enhanced gel strength due to the cross-linking action of gelling agents (such as heteropolysaccharide gum and homopolysaccharide gum). In other specific embodiments, the dissociable gel strength enhancer is included in the sustained release excipient of the present invention, and the sustained release excipient is between about 1% to about 20 by weight. And is present in an amount between about 0.5% to about 16% by weight of the final dosage form. . In a specific preferred embodiment of the present invention, the sustained-release matrix of the present invention comprises a sustained-release excipient comprising about 1 to about 9% by weight of a heteropolysaccharide gum and a homopolysaccharide gum. A gelling agent, a dissociable gel strength enhancer at about 0 to about 20% by weight, and an inert medical diluent at about 1 to about 89% by weight. In other embodiments, the sustained release excipient comprises about 10 to about 75. Gelatin 22% by weight Paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) " --- 1227144 • A7 --------- B7____ 5. Description of the invention () Agent, about 2 to about 15% by weight of a dissociable gel strength enhancer, and about 30 to about 75% by weight of an inert pharmaceutical diluent. In still other specific embodiments, the sustained release excipient contains about 30 to about 75 weight percent of a gelling agent, about 5 to about 10 weight percent of a dissociable gel strength enhancer, and about 15 To about 65% by weight of an inert pharmaceutical diluent. The sustained release excipient of the present invention (whether or not a dissociable gel strength enhancer is selectively added) can further improve its properties by incorporating a hydrophobic substance, which will reduce the hydration of the gum and Does not interfere with the hydrophilic matrix. In other specific embodiments of the present invention, this is achieved by forming a sustained release excipient into a granular form with a dispersion or solution of a hydrophobic substance before incorporating the drug. The hydrophobic polymer may be selected from alkyl celluloses, such as ethyl cellulose, other hydrophobic fibrous materials, polymers or copolymers derived from acrylates or methacrylates, copolymers of acrylates or methacrylates , Corn mash, wax, shellac, hydrogenated vegetable oil, and any other technically acceptable pharmaceutically acceptable hydrophobic substance. The amount of hydrophobic substance added to the sustained release excipient is such that it can effectively slow down the hydration of the gum without disturbing the hydrophilic matrix formed when exposed to environmental liquids. In a particularly preferred embodiment of the present invention, the hydrophobic substance is added to the sustained release excipient in an amount of about 1 to about 20% by weight. The solvent of the hydrophobic substance may be an aqueous solvent or an organic solvent, or a mixture of the two. In a specific embodiment, when the sustained release excipient of the present invention has been prepared in advance, it is possible to mix the sustained release excipient with the drug in, for example, a high-shear mixer. In some particularly preferred embodiments, the medicine 23 paper size applicable standard (CNS) A4 i grid (210 x 297 public love) a -------------% (please first Read the notes on the back and fill in this page) Order --------- line 1227144 A7 _____ B7___ V. Description of the invention () is a benzothiazide that is effective for treating circulating diseases and hypertension, A particularly preferred dihydropyridine system is thiazepin. The effective formulation of thiazemone generally includes a daily dose of from about 30 to about 500 mg, preferably from about 12 mg to about 480 mg. In a particularly preferred embodiment of the invention, the dosage form for a 24 hour formulation includes a dose of thiazolidone in an amount of 120 mg, 180 mg, 240 mg, or 3 0 0 mg; dosages for 12 hour formulations are 60 mg, 90 mg and 120 mg. In certain other preferred embodiments, the drug is oxybutynin, which is effective for treating urinary diseases. Oxybutyn effective formulations for 12-hour formulations typically include from about 2.5 mg to about 50 mg, e.g. from about 2. A daily dose of 5 mg to about 25 mg, and for 24 hours Formulation 尙 includes a daily dose of from about 5 mg to about 50 mg. Before the mixture is compressed into a solid dosage form such as a lozenge, an effective amount of any generally accepted pharmaceutical lubricant, including calcium or magnesium soaps, is preferably added to the mixture of ingredients. An example of a suitable lubricant is stearic acid.  Magnesium, based on the weight of the solid dosage form of about 0. An amount of 5 to about 3% is present. A particularly preferred lubricant is sodium stearyl fumarate, NF, which is commercially available under the tradename Pruv® from Penwest Pharmaceuticals Co. The sustained-release excipients of the present invention have consistent packing characteristics in a range of different particle size distributions, and can be directly pressurized after adding drugs and lubricating powders, or traditional wet granulation To make the final dosage form (for example, lozenges). 24 (Please read the precautions on the back before filling out this page)-I--IIII Order · -------- · This paper size applies to China National Standard (CNS) A4 (210 X 297 Public Love) 1227144. A7 ___B7 _ 5. Description of the invention () The properties and characteristics of the specific excipient system prepared according to the present invention depend in part on the individual properties of the homopolysaccharide and heteropolysaccharide composition, in terms of polymer solubility and glass transition temperature It depends on the multiplication between different homopolysaccharides and heteropolysaccharides, and the interaction between homopolysaccharides and heteropolysaccharides and inert carbohydrates on the interaction between the dissolved liquid and the excipient. The combination of a gelling agent (ie, a mixture of xanthan gum and locust bean gum) and an inert diluent, whether or not dissociable gel strength enhancers and hydrophobic polymers are added, can provide a ready-to-use sustained release Formulation products, in which the formulator only needs to mix the desired active drug, pΗ regulator, surfactant, and optional lubricant with excipients, and then press the mixture into a slowly released lozenge. The excipient may include a physical admix of gum and a soluble excipient, such as pressurized sucrose, lactose, or dextrose, although it is preferred to use pure sucrose, pure lactose , Or pure dextrose (ie, those in a crystalline state), etc., the gum is made into particles or agglomerated to form excipients. The granular form has certain advantages, including its ability to optimize fluidity and compressibility; it can be made into lozenges, formulated in capsules, extruded and rounded with the active drug to form small medicines. Wait. The pharmaceutical excipients prepared according to the present invention can be prepared using any assembly technique to obtain an acceptable excipient product. In wet granulation technology, a desired amount of heteropolysaccharide gum, homopolysaccharide gum, and an inert diluent are mixed together, and then a moisturizer such as water, propylene glycol 'glycerol, alcohols, or the like is added. To make a humidified mass. Next, the humidified 25 (Please read the precautions on the back before filling out this page) (CNS) A4 specifications (210 X 297 mm) 1227144 Δ7 Α7 _ a _B7 _ 5. Description of the invention () The lumps are dry. The dried agglomerates are ground into particles using conventional equipment. Therefore, the excipient product is directly usable. The pre-manufactured sustained release excipient is preferably free-flowing and directly pressurizable. Therefore, the excipient can be mixed with a therapeutically active drug and a selective lubricant in a desired ratio (dry granulation method). Alternatively, 'all or part of the excipient can be subjected to wet granulation with the active ingredient' and then made into lozenges. When the final product to be prepared is a lozenge, then the entire mixture is present in an amount sufficient to make a batch of uniform lozenges, under normal pressure (ie, about 2000 to 1600 psi) , Into the traditional production-grade ingot making machine to make tablets. However, the mixture must not be pressurized to such an extent that it will still be difficult to hydrate upon subsequent exposure to gastric fluids. As a method of manufacturing lozenges, one of the direct pressure methods is limited to the size of lozenges. If the amount of active ingredient is high, pharmaceutical formulators may choose to granulate the active ingredient with other excipients by wet granulation to obtain a tablet of comparable size with the correct compact strength. Generally, the amount of fillers / binding agents or excipients required for wet granulation is less than that of direct pressure manufacturing. This is because the wet granulation process, to a certain extent, has been Provides some of the physical properties required for lozenges. When the drug is thiazepine, the average lozenge size of the round lozenge is preferably between about 300 mg and about 750 mg, and the capsule lozenge is between about 700 Mg to 1,000 mg. The average particle size range of the granulated excipients of the present invention is preferably between about 50 microns and about 400 microns, and more preferably between about 1 8 5 26. This paper size applies to Chinese National Standards (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling this page) -------- ^ --------- line 1227144 A7 ------ B7__ V. Description of the invention () Micrometer to about 265 micrometers. The particle size of the particles is not so strict, and the important parameter is: the average particle size of the particles must be. Allows the production of directly pressurizable excipients to form pharmaceutically acceptable lozenges. The compactness and bulk required for the particles of the present invention are generally between about 0.3 to about 0. 8 g / ml, the average density is about 0. 5 to about 0. 7 g / ml. For best results, the tablets made by the granulation method of the present invention have a hardness between about 5 and about 20 kg. The particles produced in accordance with the present invention have an average outflow rate of about 25 to about 40 grams per second. Lozenges compacted using an instrumented rotary ingot mill have been found to have a strength structure that is not affected by the inert sugar component. Scanning electron micrographs of the surface of a large number of lozenges have provided qualitative evidence of a large amount of plastic deformation caused by compression, which occurred on both the lozenge surface and across the cracked surface, and also showed evidence of surface holes. Holes, initial solvent infiltration and solution exudation may occur. In certain embodiments of the invention, the lozenge is coated with a sufficient amount of a hydrophobic polymer to allow the formulation to further regulate the release of the drug. The hydrophobic polymer contained in the coating layer of the tablet may be the same substance 'or a different substance than the hydrophobic polymer which is selectively used to granulate the persistent excipient. In other specific embodiments of the present invention, the lozenge coating layer may include an enteric coating material to be added to or replace the hydrophobic polymer coating layer. Examples of suitable casing polymers include: cellulose acetate phthalate, hydroxypropyl methylcellulose gallate, polyvinyl acetate, methacrylic acid copolymer, shellac, hydroxypropyl methylcellulose Succinate, vinegar 27 S——No paper and national standard "? — (CNS) A—4 specifications (210 X 297 mm) '— ~ ^ (Please read the precautions on the back before filling this page) πpack n 11 n- flu fnn · ϋ m wire A7 1227144 _ B7___ 5. Description of the invention () Acid cellulose triphenylhexacarboxylate, and any of the above mixtures. An example of a suitable commercially available casing material is a substance with the trade name Eudragit ™ L30D55. In other embodiments, the dosage form may be coated with a hydrophilic coating to add to or replace the coating. An example of a suitable substance that can be used in this type of hydrophilic coating is propylmethyl-cellulose (e.g., Opadry, commercially available from Colorcon, West Point, PA). The coatings can be applied in any of the pharmaceutically acceptable ways known to those skilled in the art. For example, in one embodiment, the coating is applied via a fluidized bed or in a coating pan. For example, the coated tablet can be dried in a coating pan at a temperature of about 60 to 70 ° C for about 3-4 hours. The solvent of the hydrophobic polymer or the casing coating layer may be organic, aqueous, or a mixture of an organic solvent and an aqueous solvent. The organic solvent may be, for example, isopropyl alcohol, ethanol, and the like, with or without water. In other specific embodiments of the present invention, a support platform is applied to the tablets made according to the present invention. Appropriate support platforms are well known to those skilled in the art. An example of a suitable support platform is set forth, for example, in U.S. Patent No. 4,8 3 9, 177, which is incorporated herein by reference. In this patent, the support platform is partially coated on the lozenge and consists of a polymeric substance that is insoluble in an aqueous liquid. For example, the support platform can be designed to maintain the non-permeable nature of the therapeutically active drug when delivered. The support platform can be applied to lozenges, which are coated, for example, by pressurizing the coating on a portion of the surface of the lozenge, and coated with a polymer material containing the support platform over the entire surface. ) A4 size (210 X 297 mm) ------------------- ^ ---------- ^ ^ (Please read the notes on the back first Fill out this page again) 1227144 A7 B7 —-.   · Ι _. . . . . . . . . . ". . . . . . . . . . .  . . . . . . . . . . . . . . _ 丨 丨 11 '11 Exposure 5. Description of the invention () Part or part of the tablet surface, or the tablet is immersed in a polymer solution. If applied by pressure, the support platform has a thickness of, for example, about 2 mm, and if applied by spray coating or dip coating, the thickness of the support platform is about 1 0 //. Generally speaking, in a specific embodiment of the present invention, in which a hydrophobic polymer or an enteric coating is applied to a lozenge, the weight increase of the coated lozenge is from about 1% to about 20%, In certain specific embodiments, it is preferably from about 5% to about 10%. Substances effective for hydrophobic coatings and substances supporting the platform of the present invention include: derivatives of acrylic acid (such as esters of acrylic acid, methacrylic acid, and copolymers thereof), cellulose and derivatives thereof (such as ethyl acetate) Cellulose), polyvinyl alcohol, and the like. In certain embodiments of the present invention, the core of the lozenge includes an additional dose of the drug, which is contained in a hydrophobic coating or an enteric coating, or is coated on the lozenge core (excluding the hydrophobic coating). Layer or casing coating layer) on the outer surface of the coating layer (overcoating), or as a second coating layer on the surface of the base coating layer containing a hydrophobic layer or casing coating layer. This situation may be desirable, for example, when the formulation is first exposed to gastric fluid, a loading dose of a therapeutically active agent is required to provide a therapeutically effective blood content of the active agent. The loading amount of the drug contained in the coating layer may be, for example, about 10% to about 40% of the total amount of the drug contained in the formulation. In a preferred embodiment of the invention, the final formulation provides a bimodal or heterogeneous plasma content when the drug is azathione. 29 This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before filling this page) : A7 1227144 ____B7___ Five 'Description of the Invention () In a preferred embodiment, when the drug is thiazepine, the formulation of the present invention provides sulfur to reach sulfur within about 4 to about 10 hours after the oral administration of the dosage form to the patient. The first time (T max # 1) of the peak plasma concentration of azosterone. In a particularly preferred embodiment, the first time to reach the peak plasma concentration occurs about 6 to about 8 hours after oral administration. In a preferred embodiment, the maximum plasma concentration (C max # 1) of dithiazem (diltiazem) at the first time Tmax is about 50 to about 1,000 nanograms / ml. In the oral sustained release dosage form, a dose of 240 mg of azathione. In other preferred embodiments, the sustained release azathione formula provides a second peak plasma concentration (Cmax # 2), which occurs About 10 to about 16 hours after oral administration of the dosage form to the patient (Ding max # 2) In some preferred embodiments, the second peak plasma concentration (Cmax # 2) occurs within about 12 to about 14 hours (Tmax # 2) after the dosage form is administered to the patient orally. In a specific embodiment, the maximum plasma concentration of thiazolidone at C max # 2 is from about 60 to about 90 nanograms / ml, with each of 240 mg of thiazolidone administered at 2 4 During the hour. In a particularly preferred embodiment, the sustained release thiazolidinone formulation provides Cmax # 1 of W5Q (for the purposes of the present invention, it is defined as the first C max (C max # 1) The width of the plasma concentration curve at 50% height, based on the trough taken from C min between C max # 1 and Cmax # 2 値) from about 0.5 to about 4 hours, preferably From about 1 to about 3 hours. 30 Scaling Standard Spun Scarf Family Standard (CNS) A4 Secret (210 X 297 Public Love) One-(Please read the precautions on the back before filling this page) -Pack ---- ---- Order --------- Line 1 A7 1227144 ___ BT ^ _ V. Description of the Invention () In a specific and preferred embodiment, the sustained-release sulfur nitrogen® ketone formula provides C max # 2 of W5Q ( For the purposes of the present invention, it is defined as the width of the plasma concentration curve at 50% height of the first C max (C max # 2), which is based on the C min between C max # 1 and C max # 2 The troughs taken are from about 0.5 to about 8 hours, preferably from about 2 to about 6 hours. In a particularly preferred embodiment, the sustained-release thioazepine formulation of the present invention provides a ratio of Cmax # 1 to Cmax # 2 which is from about 0. 1: 1 to about 1.5: 1, preferably from about 0. 7: 1 to about 1 · 2: 1. Based on the dosage of azathione in the sustained-release oral formulation of the present invention, it is generally easy to determine C max # 1, C max # 2, T max for different doses of azathione over a period of 12 or 24 hours. # 1 和 T max # 2 0 In a specific preferred embodiment of the present invention, when the drug is oxybutynin, this formulation provides a time to reach the peak plasma concentration (T max) of oxybutynin, which It is within about 5 to about 15 hours, preferably within about 8 to about 12 hours. Soluble to highly soluble drugs suitable for use in the present invention include: antihistamines (eg, azatadine maleate), brompheniramine maleate, carbene maleate Carbinoxamine maleate, chlorpheniramine maleate, dexchlorpheniramine maleate, diphenhydramine hydrochloride (31 ΪPaper size is applicable to Chinese national standards) CNS) A4 size (210 X 297 H ~ '. -------------------- Order ---------- Line (Please read the notes on the back before filling this page) A7 1227144 _B7____ V. Description of the invention () diphenhydramine hydrochloride), doxylamine succinate, metdilazine hydrochloride, promethazine, trimeprazine tartrate, citrate festival Dtt tripelennamine citrate, benzamidine diamine, and triprolidine hydrochloride); antibiotics (e.g., penicillin potassium, cloxacillin sodium, dichlorononicillin sodium, that Nafcillin sodium, oxacillin sodium, carbenicillin indanyl sodium, oxytetracycline hydrochloride, tetracycline hydrochloride, clindamycin hydrochloride ), Clindamycin hydrochloride, clindamycin palmitate, lincomycin hydrochloride, novobiocin sodium, nitrofurantion sodium, mezonida hydrochloride Metronidazole hydrochloride); anti-tuberculosis agents (such as isonicotinylhydrazine); cholinergic agents (such as ambemmium chloride, ammonium chloride, bethanecol chloride), bromine Neostigmine bromide, pyridostigmine bromide); anti-mushroom tests (for example, anisotropine methylbromide), clidinium bromide bromide), dicyclomine hydrochloride, hexocyclium methylsulfate, Homatropine methylbromide, hyoscyamine sulfate, bromamine methantheline bromide), hydrobromide sclerotium bromide (32 paper sizes apply Chinese National Standard (CNS) A4 specifications (210 X 297 mm) (please read the precautions on the back before filling out this page)) ----- Order ---------- line A7 1227144 B7__ 5. Description of the invention () hyoscine hydrobromide), oxyphenonium bromide, propantheline bromide , Didihexethyl chloride); sympathomimetics (bitolterol mesylate), ephedrine, ephedrine hydrochloride, orciprenaline sulfate, hydrochloric acid Phenylpropanolamine, pseudoephedrine hydrochloride, ritodrine hydrochloride, salbutamol sulfate, terbutaline sulfate); anti-sympathetic drugs (such as phenoxybenzamine hydrochloride) Various types of autonomic drugs (such as nicotine); iron preparations (such as ferrous gluconate, ferrous sulfate); hemostatic agents (such as aminocaproic acid) ), Disopyramide phosphate, flecainide acetate, procainamide hydrochloride, propanolol hydrochloride, quinidine gluconate ( quinidine gluconate), timolol maleate, tocainide hydrochloride, vera hydrochloride Verapamil hydrochloride); antihypertensive agents (eg, captopril, clonidine hydrochloride, hydralazine hydrochloride, mecamylamine hydrochloride) hydrochloride), metoprolol tartrate): vasodilators (such as papaverine hydrochloride); non-steroidal anti-inflammatory agents (such as choline salicylate, magnesium salicylate, meclofenamate ) Sodium, Naproxen (naproxen 33 This paper size applies to the Chinese National Standard (CNS) A4 specifications (210 X 297 mm) (Please read the precautions on the back before filling out this page) | Install ------- -Order --------- line 1227144 • ΚΙΒ7 _ 5. Description of the invention (_) sodium, tolmetin sodium); anticonvulsants (for example, phenobarbital) Sodium, phenytoin sodium, troxidone, ethosuximide, sodium valproate); tinting agents (for example, acetophenazine maleate) , Salt and proma promazine hydrochloride), thioridazine hydrochloride, trifluoroperazine hydrochloride, lithium clavulanate, molindone hydrochloride, thiothixine hydrochloride ); Stimulants (for example, benzophenamine hydrochloride, dextroamphetamine sulfate, dextroamphetamine phosphate, diethylamine phenylacetone hydrochloride, fenfluramine hydrochloride, methamphetamine hydrochloride Gianphenphenamine, methylphenidate hydrochloride, phendimetrazine tartrate, benzomorpholine hydrochloride, carfiline citrate; barbitrates (for example, Sodium starch barbiturate, butyl barbiturate, secobarbital sodium); sedatives (eg, hydroxyethoxymazine hydrochloride, meprylon) •, cough Agents (for example, potassium iodide); antiemetics (for example, benzquinamide hydrochloride, metoclopropamide hydrochloride ), Tricresylamine hydrochloride); gastrointestinal drugs (such as ranitidine hydrochloride); heavy metal antagonists (such as penicillamine, penicillamine hydrochloride); antithyroid drugs ( For example, Mesimazol (34 paper sizes are applicable to Chinese National Standard (CNS) A4 (210x 297 mm) (Please read the notes on the back before filling out this page) — — — — — — — I ^ · I 1 ----- ^ A7 1227144 ____ B7_________ 5. Description of the invention () methimazole)); urogenital smooth muscle relaxants (such as flaxoxate hydrochloride); vitamins (such as thiamine hydrochloride, ascorbic acid); not Classified medicaments (e.g. amantadine hydrochloride, cholchicine, etidronate disodium, leucovorin bromide, methylene blue, potassium chloride, chlorophosphorus定 (pralidoxime chloride)). The above listed agents are not intended to be the only ones. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples illustrate various aspects of the invention. However, these examples are not to be construed as limiting the scope of the patentable invention of the present invention in any way. Example 1-2 Effect of Drug: Gum Ratio on Formula In Examples 1-2, the sustained release excipient according to the present invention is first prepared, followed by the addition of a drug (thiazepine in this example) and A pH adjuster (in this case, fumaric acid), and finally the final mixture is made into a tablet. The sustained release excipient was dry blended with the required amounts of xanthan gum, locust bean gum, and dextrose in a high speed mixer / granulator for three minutes. When using a shredder / pusher, add water to the dry blended mixture and perform pelletizing for an additional three minutes. Next, the granulated product is dried in a fluidized bed dryer to an LOD (drying loss) of less than about 10% by weight (e.g., about 4 to 7% LOD). Then, use a 20 mesh sieve to grind and distribute the granules to a 35-sheet paper size ϋ Chinese National Standard (CNS) A4 (210 X 297 mm) --- (Please read the precautions on the back first (Fill in this page again) Install -------- Order ---------- Line 1227144 A7 B7 Ingredients 1.  Xanthan Gum 2.  Locust Bean Swell 3.  Dextrose 4.  Water 5. Description of the invention (in the granulator. The ingredients of the granules of Examples 1-2 are shown in Table 1 below. Table 1 Preparation amount of sustained release excipient (%)-Example 1 amount (%)- Example 2 20 12 30 18 50 70 30 25 Next, the required amounts of thiazepine, fumaric acid, and an appropriate amount of water were mixed in a propeller type mixer for five minutes to form a slurry ( shiny). Then, the slurry was added to the continuous release excipient at a one-minute interval in the granulator, which was performed with a low-speed pusher. Then, a shredder and a pusher were used for 2 minutes at high speed The mixture is granulated (extra water and granulation time can be used to form the appropriate granules), and the resulting granules are dried in a fluidized bed dryer until its L 0 DL system is below 5%, and Mill with a hammer forward at 2000 to 300 Or pm. The milled particles are then placed in a V-blender with sodium lauryl sulfate and stirred for an additional three minutes. A suitable ingot Lubricant (Pruv®, sodium stearyl fumarate, NF, commercially available from Penwest P Harmaceuticals Co.) was added, and the mixture was stirred for an additional three minutes. Then, the obtained granules were pressed into a tablet using a capsule-shaped punch. This final mixture was made into a tablet of about 768 Mg. The ingredients of the tablets of Example 1 to 2 are shown in the following Table 2: 36 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling (This page)-Packing -------- Order --------- Line 1 1227144 B7 V. Description of the invention () Table 2 Lozenge Formula One Example 1-2 Ingredient Amount (%) Amount (Mg / tablet) 1. Sustained-release vehicle 52. 1 400. 0 2Sulfur and nitrogen 31. 3 240. 0 3. Fumaric acid 5. 2 40. 0 4. Sodium lauryl sulfate 10. 4 80. 0 5.  Pmv® (stearyl fumarate 1. 0 8. 0 nanometers) 6. Water * 27. 5 0. 0 * Removed during processing The final tablet has a tablet weight of 678 mg and a hardness of 15 K p. Then, dissolution test was performed on the tablets of Examples 1-2. The dissolution test was performed in 900 ml of water in an automated USP dissolution apparatus (Paddle II, 100 rpm), and the amount of drug released was via ultraviolet Analysis. The dissolution results in this test tube are shown in Figure 1 and Table 3 below. Table 3 Time (hours) Example 1 Dissolution) Example 2 (% mmi 〇 0. 0 〇. 〇37 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) -------- ^ ------- -$ 1 1227144 A7 B7 V. Description of the invention (1 13. 4 8. 3 2 19. 0 12. 4 4 28. 4 18. 4 8 40. 9 29. 0 12 52. 3 38. 2 16 63. 1 44. 4 2 0 70. 1 49. 9 24 78. 2 55. 3 From the results provided in Figures 1 and 3, it is clear that the release rate of thiazepine is slower as the amount of gum in the formulation increases. Examples 3-4 Effects of the ratio of gum = dextrose In Examples 3-4, the sustained release excipient was prepared according to the procedure described in Example-2. The components of the sustained release excipients of Examples 3 to 4 are shown in Table 4 below: Table 4 Ingredients Amount: (%)-Example 3 Amount (%)-Example 41 1. Xanthan gum 12 20 2. Locust Bean Gum 18 30 3 · Dextrose 70 50 4 · Water * 25 35 * After being removed during processing, the thiazemone tablet is prepared as follows: The required amount of thiazemone, transbutene The diacid and the sustained release excipient were placed in a granulator and mixed for three minutes at low speed. Put 38 on the pusher (please read the precautions on the back before filling this page) ------------- Order --- This paper size applies to China National Standard (CNS) A4 (210 X 297) Love) A7 1227144 _ B7 _____ — ---------- -------------------- 1 'V. Description of the invention () During low speed, Water is added at 2 minute intervals (extra water and granulation time can be used to form appropriate granules). The granules obtained are then dried in a fluidized bed dryer until their LOD ratio is below 5% 'and using a sieve # 0 0 50 with a hammer forward at 2000 to 3000 rpm Milled. The milled granules were then placed in a V-blender with sodium lauryl sulfate and stirred for 10 minutes. A suitable tablet lubricant (Pmv®, sodium stearyl fumarate, NF, commercially available from Penwest Pharmaceuticals Co. ) Was added, and the mixture was stirred for an additional 5 minutes. Then, the obtained pellets were pressed into a tablet by using a capsule-shaped punch. This final mixture is made into tablets of about 750 mg. The ingredients of the tablets of Examples 3 to 4 are shown in the following Table 5: Table 5 Ingredients of Formulation Example 3-4 of Floss Formula Amount (%) _ Amount (mg / tablet) 1. Sustained release excipients 53,3 400. 0 2 Thiaziridone 32. 0 240. 0 3. Fumaric acid 8. 0 60. 0 4. Sodium lauryl sulfate 5. 3 40. 0 5.  Pmv® (stearyl transbutene di 1. 3 10. 0 sodium) 6. Water * 27. 5 0. 0 was removed during processing.The final lozenge had 7 5 0. 0 mg tablet weight and 15 Kp hardness. Then, the dissolution test was performed on the tablets of Examples 3 to 4. The dissolution test was performed on 39 papers in accordance with China National Standard (CNS) A4 & (210 X 297 mm) ~ " -------- --- · installation -------- tr ---------- line · (Please read the precautions on the back before filling this page) 1227144 A7 B7 V. Description of the invention 250 ml of buffer (p Η 6) was performed in an automated US P dissolution apparatus (Paddle III, 15 CPM), and the drug release amount (please read the precautions on the back before filling this page) The analysis was performed by ultraviolet analysis. The dissolution results in this test tube are shown in the following Figure 2 and Table 6. Table 6 Time (hours) Example 3 (% dissolved funeral) Example 4 (% dissolved) 0 0. 0 0. 0 1 20. 1 14. 3 3 36. 5 25. 2 8 64. 7 45. 5 12 88. 3 57. 2 16 102. 2 67. 4 24 103. 6 86. 2 From the results provided in Figure 2 and Table 6, it is clear that when the amount of gum relative to the amount of dextrose increases, the drug release is observed to slow down relatively. Examples 5-6 Effects of Types of Surfactants In Examples 5-6, sustained release excipients were prepared according to the procedures described in Examples 1-2. The components of the sustained release excipients of Examples 5-6 are shown in Table 7 below: Table 7 Ingredients Amount (%)-Examples 5-6 1. Xanthan gum 40 12 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm) 1227144 A7 B7 V. Description of the invention (2) Locust bean gum 18 3. Dextrose 70 4. Water * 25 * After being removed during the treatment, the thiazepine ketone tablets are prepared as follows: The required amounts of thiazolidinone, fumaric acid and an appropriate amount of water are mixed in a propeller type mixer Five minutes to form a slurry. The slurry was then added to the sustained release excipient in the granulator at one minute intervals, which was performed with a low speed impeller. Next, the mixture is granulated with a shredder and a pusher at high speed for 2 minutes (extra water and granulation time can be used to form appropriate granules), and the obtained granules are dried in a fluidized bed dryer Medium, until its LOD series is below 5%, and mill with 2000 to 3000 rp m forward with a hammer. The milled granules of Example 5 were then placed in a V-blender with sodium lauryl sulfate, and the milled granules of Example 6 were placed in a V-shape with docusate sodium Stir and stir for an additional 10 minutes. A suitable tableting lubricant (Pnw®, sodium stearyl fumarate, NF) is commercially available from Penwest Pharmaceuticals Co. ) Was added and the mixture was stirred for another three minutes. Then, the obtained granules were pressed into a tablet using a capsule-shaped punch. This final mixture is made into tablets of about 8 4 8 mg. The ingredients of the tablets of Examples 5-6 are shown in the following Table 8: Table 8 Formulation of tablets-Examples 5-6 41 This paper size applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm) (Please read the precautions on the back before filling this page) -------- ^ ---------- ^^ A7 1227144 _B7 V. Description of the invention () Composition (%) (implementation) Example amount (%) (Example 5) 6) 1. Sustained release excipients47. 2 47. 2 2 Thiazepine 28. 3 28. 3 3. Fumaric acid 14. 2 14. twenty four. Sodium lauryl sulfate 9. 4 N / A 5. Docusate sodium (Docusate N / A 9. 4 Sodium) 6Pmv® (stearyl transbutene di 0. 9 0. 9 Sodium) 7. Water * 26. 5 26. 5 * Amount removed during processing (mg / sharp (mg / lozenge)) (Example 5) (Example 6) 1. Sustained-release vehicle 400. 0 400. 0.2 2 Thiazemone 240. 0 240. 0 3. Fumaric acid 120. 0 120. 0 4. Sodium lauryl sulfate 80. 0 N / A 5Pmv® (stearyl transbutene di N / A 80. 0 sodium) 6. Water * 8. 0 8. 0 -------- ^ --------- 1 (Please read the notes on the back before filling this page) The final tablet has 8 4 8. 0 mg tablet weight and 15 K p hardness. Then, dissolution test was performed on the tablets of Examples 5 to 6. The dissolution test was performed in 900 ml of water in an automated USP dissolution apparatus (Paddle II, 100 rpm), and the drug release amount was measured by ultraviolet rays. Analysis. The dissolution results in this test tube are shown in Figure 3 and Table 9 below. 42 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1227144 A7 B7 V. Description of the invention (time (hours) Table 9 Example 5 (% dissolution) Example 6 (% dissolution) 0 0 . 0 0. 0 1 14. 0 12. 2 2 19. 3 18. 9 4 31. 3 29. 8 8 49. 5 47. 6 12 62. 7 61. 4 16 77. 0 73. 0 2〇 88. 5 83. 5 24 98. 6 89. 2 (Please read the precautions on the back before filling this page) Sustained-release excipients are the sustained-release excipients according to Example 1 Examples 7-8 Table 10 Amount (%)-Example 7-8 12 43 From the results provided in Fig. 3 and Table 9, it is obvious that the release rates of thiazemone are similar for sodium lauryl sulfate and docusate sodium in equal proportion. However, the formulation is indeed better with sodium lauryl sulfate. Examples 7-8 Effect of surfactant content The ingredients prepared in the procedure described in Examples 7-8-2 are not more than the following Table 10 Ingredients 1. Xanthan Gum-Packing -------- Order ---------- Line 1 Paper Size Applicable to Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 1227144 A7 B7 V. Description of the invention () 2. Locust Bean Gum 18 3. Dextrose 70 4 · Water * 25 * After being removed during the treatment, the thiazepine ketone tablet is prepared as follows: The required amount of thiazepine ketone, fumaric acid and an appropriate amount of water are advanced A mixer-type mixer was mixed for five minutes to form a slmry. The slurry was then added to the continuous release excipient in the granulator at one minute intervals, which was performed with a low speed pusher. Next, the mixture is granulated with a shredder and a pusher at high speed for 2 minutes (extra water and granulation time can be used to form appropriate granules), and the obtained granules are dried in a fluidized bed dryer Medium until its L 0 D series is below 5% and milled forward with a hammer at 2000 to 3000 rpm. The milled particles were then placed in a V-blender with sodium lauryl sulfate and stirred for 10 minutes. A suitable tableting lubricant (Pmv®, sodium stearyl fumarate, NF, commercially available from Penwest Pharmaceuticals Co.) was added and the mixture was stirred for an additional three minutes. Then, the obtained pellets were pressed into a tablet using a capsule-shaped punch. This final mixture is made into tablets of approximately 768 mg. The ingredients of the tablets of Examples 7-8 are shown in the following Table 11: Table 11 1 Table formulation 1 Example 7-8 ingredients.  Amount (%) (Example amount (%) (Example 44) This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) (Please read the precautions on the back before filling out this page) | -------- Order -------- · Line j A7 1227144 _B7 V. Description of the invention () 7) 8) 1. Sustained-release vehicle 52. 1 54. 9 2.Thiazetone 31. 3 33. 0 3. Fumaric acid 5. 2 5. 5 4. Sodium lauryl sulfate 10. 4 5. 5 5 Pruv® (Stearyl Butene Di 1. 0 1. 1 Sodium) 6 · Water * 27. 5 27. 5 * Removed during processing (Please read the precautions on the back before filling out this page) Ingredient Amount (mg / Lozenge (mg / Lozenge)) (Example 7) (Example 8) 1. Sustained-release vehicle 400. 0 400. 0.2 2 Thiazemone 240. 0 240. 0 3. Fumaric acid 40. 0 40. 0 4. Sodium lauryl sulfate 80. 0 40. 0 5.  Pnw® (stearyl transbutene di 8. 0 8. (Sodium 0) The final lozenge of Example 7 has 76.8. A tablet weight of 0 mg and a hardness of 15 K p. The final lozenge of Example 8 has 7 2 8. The tablet weight of 0 milligrams applies to the Chinese paper standard (CNS) A4 (210 X 297 mm) at 45 paper sizes. 1227144 A7 B7 V. Description of the invention (and the hardness of 15 κ P. (Please read the back of the paper first) Note: Please fill in this page again.) Then, dissolution test was performed on the tablets of Examples 7-8. The dissolution test was performed in 900 ml of water in an automated USP dissolution apparatus (Paddle II, 100 rpm), and The amount of drug released was analyzed by UV analysis. The dissolution results in this test tube are shown in Figure 4 and Table 12 below. Table 1 2 Time (hours) Example 7 (% dissolution) Example 8 (° / 〇 Dissolved) 〇0. 0 0. 0 1 13. 4 18. 5 2 19. 0 28. 2 4 28. 4 40. 1 8 40. 9 56. 1 12 52. 3 67. 6 16 63. 1 77. 7 2 0 70. 1 83. 8 24 78. 2 90. 5 From the results provided in Fig. 4 and Table 12, it is clear that the release rate of thioazetone is inversely proportional to the surfactant content. Example 9-Effect of fumaric acid content In Examples 9-10, a sustained release excipient was prepared according to the procedure described in Examples 1-12. Example 9 The ingredients of the one-form agent are shown in the following table 13: 46 10 Sustained release The paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 1227144 A7 B7 V. Description of the invention (Ingredient 12 18 70 25 Table 1 (%)-Example 9 ii. 1. Xanthan Gum 2 Locust Bean Gum 3 Dextrose 4. Water * * After being removed during the process, the thiazepine acetonite is prepared as follows: The required amount of thiazepine, fumaric acid, and an appropriate amount of water are mixed in a propeller type mixer. Minutes to form a slurry. The purple was then added to the holding release vehicle in a granulator at one minute intervals, which was performed with a low speed pusher. Next, the mixture is granulated with a shredder and a pusher at high speed for 2 minutes (extra water and granulation time can be used to form appropriate granules), and the obtained granules are dried in a fluidized bed dryer Medium, until its LOD series is below 5%, and milled forward with a hammer at 2000 to 3000 rpm. The milled granules were then placed in a V-blender with sodium lauryl sulfate and stirred for 10 minutes. A suitable ingot lubricant (Pmv®, sodium stearyl fumarate, NF, commercially available from Penwest Pharmaceuticals Co.) was added and the mixture was stirred for an additional three minutes. Then, the obtained pellets were pressed into a tablet using a capsule-shaped punch. This final mixture is made into tablets of about 8 4 8 mg. Example 9 The composition of the 10 tablets is shown in the following Table 14: Table 1 4 47 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------- -^ --------- (Please read the precautions on the back before filling out this page) 1227144 A7 B7 V. Description of the Invention (Ingredients, Tablets Formula 1 Example 9-10 Amount (%) (Example Amount (%) (Example 9) 1.  Sustained release excipients 2.  Thiazepine 3.  Fumaric acid4.Sodium lauryl sulfate 5.  Pmv® (Sodium stearyl fumarate) * Sodium stearyl fumarate 6. Water * * Removed during processing 47. 2 28. 3 14. 2 9. 4 0. 9 10) 52. 1 31. 3 5. 2 10. 4 1. 0 26. 5 26. 5 (Please read the precautions on the back before filling out this page) Ingredient 1.  Sustained release excipients 2.  Thiazepine 3.  Fumaric acid 4.  Sodium lauryl sulfate 5 · Pruv® * (mg / lozenge) amount (mg / lozenge) (Example 9) 400. 0 240. 0 120. 0 80. 0 8. 0 (Example 11 0) 400. 0 240. 0 40. 0 80. 0 8. 0: Sodium The final lozenge of Example 9 had a lozenge weight of 84.8 mg and a hardness of 15 Kp. The final lozenge of Example 10 had a lozenge weight of 76.8 mg and a hardness of 15 Kp. Then, dissolution test was performed on the tablets of Example 9-10. The dissolution test was performed in 900 ml of water in an automated US P dissolution apparatus (Paddle II, 100 rpm), and the drug release amount was based on After 48 paper sizes, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applied. 1227144 A7 B7 V. Description of invention (Analysis by UV analysis. The dissolution results in this test tube are shown in Figure 5 and Table 1 below Table 1. Time (hours) Example 9 (% dissolved) Example 1 0 (% dissolved) 0 0. 0 0. 0 1 14. 0 13. 4 2 19. 3 19. 0 4 31. 3 28. 4 8 49. 5 40. 9 12 62. 7 52. 3 16 77. 0 63. 1 2 0 88. 5 70. 1 24 98. 6 78. 2 (Please read the precautions on the back before filling this page) From the results provided in Figure 5 and Table 1, it is obvious that the release rate of the drug is increased when the amount of fumaric acid in the formula increases. increase. Examples 11-12 Addition of Special Granular Drugs In Examples 1-12, the sustained release excipients were prepared according to the procedures described in Examples 1-12. The ingredients of the sustained release excipients of Examples 1 1 and 12 are shown in Table 16 below: Ingredient 1.  Xanthan Gum 2.  Locust Bean Gum Table 16 Amount (〇 / 〇-Example 11-12 12 18 49 This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 1227144 ____B7 _ V. Description of the invention () 3) . Dextrose 70 4 · Water * 25 * After being removed during the treatment, the thiazepine tablet was prepared as follows. In Example 11, the required amount of thiazepine, fumarate The acid and an appropriate amount of water were mixed in a propeller-type mixer for five minutes to form a slurry. The slurry was then added to the sustained release excipient in a granulator at one minute intervals, which was performed on a low speed impeller. Next, the mixture is granulated with a shredder and a pusher at high speed for 2 minutes (extra water and granulation time can be used to form appropriate granules), and the obtained granules are dried in a fluidized bed dryer Medium until its LOD actinide is below 5% and milled forward with a hammer at 2000 to 3000 rp m. The milled granules were then placed in a V-blender with sodium lauryl sulfate and stirred for 10 minutes. A suitable tableting lubricant (Pmv®, sodium stearyl fumarate, NF, commercially available from Penwest Pharmaceuticals Co.) was added and the mixture was stirred for an additional three minutes. Then, the obtained pellets were pressed into a tablet by using a capsule-shaped punch. This final mixture is made into a tablet of about 848 mg. In Example 12, a portion of diltiazem, fumaric acid, and an appropriate amount of water were mixed in a propeller type mixer for five minutes to form a slurry. The slurry was then added to the sustained release excipient in a granulator at one minute intervals, which was performed with a low speed pusher. Next, use a shredder and a pusher at high speed for 2 minutes to make the mixed 50 paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----------- load- ------- Order ---------- Line (Please read the precautions on the back before filling this page) 1227144 A7 B7 V. Description of the invention Granulation time can be used to form appropriate granules), and then the granules obtained are dried in a fluidized bed dryer until its LOD ratio is below 5%, with a hammer forward at 2000 to 300 rpm Milled. The milled granules were then placed in a V-blender with sodium lauryl sulfate and stirred for 10 minutes. A suitable ingot lubricant (Pnmv®, sodium stearyl fumarate, NF, commercially available from Penwest Pharmaceuticals Co.) was added, and the mixture was stirred for an additional three minutes. Then, the obtained granules were pressed into a tablet using a capsule-shaped punch. This final mixture is made into tablets of about 8 4 8 mg. The ingredients of the tablets of Example 1 1-12 are shown in the following Table 17: Table 17 7 Formulation of the tablet 1 Example 11-12 The amount of ingredient σ〇u Example 1 amount) (Example 1 1) 2 ) 1. Sustained release excipients47. 2 47. 2 2 · Thionazinone (granular) 28. 3 18. 4 3 · Thiazepine (especially granular) N / A 9. 9 4. Fumaric acid 14. 2 14. 2 5 sodium lauryl sulfate 9. 4 9. 4 6. Pruv® (stearyl fumarate 0. 9 0. 9 sodium) 7. Water * 26. 5 25. 0 * Removed during processing Ingredient i (mg / tablet) Amount (mg / tablet (Example 11)) (Example 12) 1. Sustained-release vehicle 400. 0 400. 0 2 · Thiazazone (granular) 240. 0 156. 0 51 This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) (please read the precautions on the back before filling in this page)

Equipment -------- Order ---------- Line I A7 1227144 __B7 V. Description of the invention () 3. Thiaziridone (especially granular) N / A 84.0 4. Butan Maleic acid 120.0 120.0 5. Sodium lauryl sulfate 80.0 80.0 6 · Pruv® * 8.0 8.0 (Please read the notes on the back before filling this page) * The final ingot of sodium stearyl fumarate Example 1 1 The agent has a lens weight of 84.8 mg and a hardness of 15 Kp. The final lozenge of Example 12 had a lozenge weight of 84.8 mg and a hardness of 15 Kp. Then, dissolution test was performed on the tablets of Examples 1 to 12. The dissolution test was performed in 900 ml of water in an automated USP dissolution apparatus (Paddle II, 100 rpm), and the drug release amount was based on The analysis was performed by ultraviolet analysis. The dissolution results in this test tube are shown in Figure 6 and Table 18 below. Table 18 Time (hours) Example 1 1 (¾ dissolved) MM11 2 (¾ dissolved) 0 0.0 0.0 1 14.2 32.6 2 19.3 35.5 4 31.3 48.7 8 49.5 66.4 12 62.7 78.5 16 77.0 85.2 20 88.5 89.2 24 98.6 94.6 From the results provided in Figure 6 and Table 18, it appears that the addition of a particularly granular thiazemone would cause about 35% of the initial burst. Obviously, adding a percentage of the special granular drug will provide an initial rapid release, as shown in Figure 75. Over time, the sulfur content in the dosage forms of Examples 1 1 and 12 is 52. The Chinese paper standard (CNS) ) A4 specification (210 X 297 mm) —---- A7 B7 Amount (%)-Example 1 3 — 1 «12 18 70 25 1227144 V. Description of the invention () Azazone's% release rate was confirmed . Example 1 3 — 1 8 Coated tablets of Eudragit L30D55 with sodium hydride Sodium Hydrate 1 In Examples 1 3-18, the sustained release excipients were in accordance with the procedures described in Examples 1 to 2 To prepare. The ingredients of the sustained release excipients of Examples 1 3 to 18 are shown in the following Table 19: Table 1 9 Ingredients 1. Xanthan Gum 2. Locust Bean Gum 3. Dextrose 4. Water * * During the treatment period After removal, thiazepine tablets are prepared as follows:

Mix the required amounts of thiazepine, fumaric acid and sustained release excipients in a granulator at low speed for three minutes, then add an appropriate amount of water at two minute intervals, which is driven at low speed器 proceed. Next, the obtained slurry is granulated with a shredder and a pusher at a high speed of 7.5 minutes (extra water and granulation time can be used to form appropriate granules), and the obtained granules are dried in a fluid In a bed dryer, until its LOD series is below 5%, use a sieve # 0050 to grind with a hammer forward from 200 to 3000 rpm. The milled granules were then placed in a V-blender with sodium lauryl sulfate and stirred for 10 minutes. A suitable ingot lubricant (pruv®, sodium stearyl fumarate, N 53 (Please read the precautions on the back before filling this page) ^ -------- ^ ---- ------ Line 1 paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) • KI 1227144 _ Β7 _ 5. Description of the invention () F, commercially available from Penwest Pharmaceuticals Co •) was added and the mixture was stirred for an additional 5 minutes. Then, the obtained granules were pressed into a tablet using a capsule-shaped punch. This final mixture is made into tablets of about 750 mg. The ingredients of the tablets of Example 1 3-1 8 are shown in the following table 20: Table 20 Formulation of tablets 1 Example 13-18 Ingredient amount (%) 1. Sustained release excipient 53.3 2 · Sulfur nitrogen Ketone (granular) 32.0 3. Fumaric acid 8.0 4. Sodium lauryl sulfate 5.3

5. Pruv® (sodium stearyl fumarate U) 6 · Water * 27.0 * Mill / Lozenges removed during processing 1 · Sustained release excipient 400.0 2 · Thiazetone (granular) ) 240.0 3 · Fumaric acid 60.0 54 ί Paper size national standard (cns) A4 specification (21〇χ 297 公 爱 _)-(Please read the precautions on the back before filling this page) Binding ----- ----- Line ·· A7 1227144 ______B7___ 5. Description of the invention () 4 · Sodium lauryl sulfate 40.0 5 · Pruv® (Sodium stearyl fumarate) 10.0 The final lozenge has 7 5 0 · 0 mg The weight of the tablet and the hardness of 15 KP. Then, the core lozenge was coated with Eudragit L30D55 aqueous suspension with sodium hydroxide to obtain a weight increase of 3%, 5%, 7%, and 9% (Examples 15 to 18) based on the total weight of the lozenge. . The aqueous suspension was prepared according to the following procedure: A 1.0 N sodium hydroxide solution was prepared by adding 4.0 g of sodium hydroxide to 50 ml of pure water in a volumetric flask, And stir for 5 to 15 minutes. Next, add pure water to the necessary volume and mix again. The talc suspension is prepared by slowly adding 9.31 grams of triethyl citrate to 20.54 grams of pure water while stirring. While stirring continuously, 2 2-2 grams of talc was added to the container at intervals of 3 minutes, and the container was stirred until a suspension was formed. Next, Eudragit was passed through a # 40 mesh sieve and 294.52 grams was weighed to prepare an Eudemgit suspension. Using a dropper, 1.78 grams of a 1.0 N sodium hydroxide solution was added to Eudragit while stirring, and the mixture was stirred for 30 to 60 minutes. When the Eudragit suspension is stirred, the talc suspension is added over a period of five minutes and stirred for 30 to 60 minutes.

The dissolution test was performed on the tablets of Examples 1 3 to 18. The dissolution test was performed in an automated US 55 in 250 ml of buffer (pH 6). This paper is in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----------- ^ -------- ^ ---------- (Please read the precautions on the back before filling this page) A7 1227144 ___ B7_ 5. Explanation of the invention () P dissolution instrument (Paddle II, 15CPM), and the drug release amount is analyzed by ultraviolet analysis method. The dissolution results in this test tube are shown in the following Figure 8 and Table 21: Table 2 1 ------------ · Packing (Please read the precautions on the back before filling this page) Time (hours Example 1 6 Example 1 7 ___ »Example 1 8 Lot B (5% coated lot B (7% coated lot B (9% coated))) 0 0.0 0.0 0.0 1 1.9 0.4 0.4 3 13.8 11.1 8.9 8 44.1 36.3 27.5 12 63.4 54.4 41.8 16 82.4 77.7 56.8 24 98.3 99.6 84.6 From the results provided in Figure 8 and Table 21, it is obvious that: • Line 0. Time (hour Example 1 3 Implementation Example 1 4 __ Example 1 5 Lot No. A (Uncoated Lot No. B (No Coated Lot No. A (3% coated))) 〇 0.0 0.0 0.0 1 18.4 18.0 5.4 3 32.6 32.8 16.0 8 59.8 60.2 48.9 12 80.5 77.9 68.2 16 92.3 93.9 89.6 24 93.7 98.4 99.0 When the amount (by weight) of the coating is increased, the release rate will decrease. Example 1 9 2 2 0 Eudragit RS30D / RL30D (50/50) (A certain The standard of ammonium acrylate paper is applicable to China National Standard (CNS) A4 (210 x 297 mm) 1227144 a7 _ B7__ V. Description of the invention () The water-emulsion dispersion) Jing Duoxiang of coated tablets was prepared in Example 19-2 0 according to the procedure described in Examples 1 to 2. Examples 19 and 20 The ingredients of the sustained-release excipients are shown in Table 2 below: Table 2 2 Ingredient Amount)-Example m η 1. Xanthan Gum 12 2 · Locust Bean Gum 18 3. Dextrose 70 4. Water * 25 * After being removed during the treatment, thiazepine tablets are prepared as follows: The required amounts of thiazepine, fumaric acid and sustained release excipients are mixed in a granulator at a low speed. Minutes, followed by the addition of an appropriate amount of water at a two-minute interval, which was performed with a low-speed impeller. Next, the obtained slurry was granulated with a shredder and impeller at high speed for 6 minutes (extra water And the granulation time can be used to form the appropriate granules) 'The granules obtained are then dried in a fluidized bed dryer until its LOD is less than 5%, and using a sieve # 0 0 5 0 with a hammer Mill forward at 2000 to 300 rpm. The milled granules were then placed in a V-blender with sodium lauryl sulfate and stirred for 10 minutes. A suitable ingot lubricant (Pηιν®, sodium stearyl fumarate ' ' NF " commercially available from Penwest Pharmaceuticals Co.) was added ' and the mixture was stirred for an additional 3 minutes. Then, use a 57-capsule paper size in the form of Chinese National Standard (CNS) A4 (210 X 297 mm) (please read the precautions on the back before filling this page) t -------- ^ --------- A7 1227144 ____B7___ 5. Description of the invention () The punch will press the obtained granules into tablets. This final mixture is made into tablets of about 50 mg. The ingredients of Example 19-20 tablets are shown in Table 23 below: Table 2 3 Formulation of tablets 1 Example 19 Amount of ingredients (%) Amount (mg / tablet) 1. Sustained release Excipients 53.3 400.0 2 · thiazepine (granular) 32.0 240.0 3. fumaric acid 8.0 60.0 4 · sodium lauryl sulfate 5.3 40.0 5 · Pruv® (stearyl transbutene di 1.3 10.0 sodium ) 6. Water * 27.0 0.0 * Removed during processing. The final lozenge has a lozenge weight of 750.0 mg and a hardness of 15 K p. The core lozenge was then coated with an aqueous suspension of Euckagit RS30D / RL30D (50/50) with sodium hydroxide to obtain an 8% weight increase based on the total weight of the lozenge. The aqueous suspension is prepared by the following procedure:

The Endragit RS / RL suspension was prepared by mixing 1000 grams of Eudragit RS with 1000 grams of Eudragit RL. The talc suspension is prepared by applying 1 2 · 0 g of citric acid 58 paper size to the Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page ) 0 · II I--I 1 Order · II 111-1227144 A7 _____B7 ___ 5. Description of the invention () Triethyl ether is obtained by slowly adding 3 38 · 0 grams of pure water while stirring. While continuing to stir, 50.0 grams of talc was added to the container at intervals of 3 minutes. The valley was disturbed until a suspension was formed. Next 'while stirring the Eudragit suspension, the talc suspension is added over a period of five minutes, the resulting mixture is stirred for 30 to 60 minutes and filtered through a 40 mesh screen. The dissolution test was performed on the tablets of Examples 19-20. The dissolution test was performed in 900 ml of 0.1NHC 1 in an automated USP dissolution apparatus (Paddle II, 100 rpm), and the amount of drug released was via ultraviolet light. Analysis. The dissolution results in this test tube are shown in the following Figure 9 and Table 2 4: Table 2 4 Time (hours) Example 19 (8% coating) M Gang 1 4 Coating (Please read the precautions on the back before filling (This page) ο 3 5 8 0 2 4 6 0 4 IX IX I—I 1—Η ΟΟ ΟΟ ly 5 3 9 3 8 9 1- 2 ο 1- rML · ········· 3 · 1 1 54415666 C2457899999 05.6.24.5.9.2.6.5.3 0.0 · 1 46.7.42.7.7.1 CC124567789 Installation -------- Order ----- From the results provided in Figure 9 and Table 24, It is clear that the coating reduces the release rate. Example 2 1-2 3 The effect of coating tablets with cellulose cellulose B 59 The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 1227144 · a7 ____B7 __ "-V. Description of the invention () (Please read the precautions on the back before filling out this page) In Examples 2 1-2 3, the 'sustained release excipients were prepared according to the procedures described in Examples 1-2. Example 2 1-2 The ingredients of the sustained release excipients of 3 are shown in the following Table 2 5: Table 2 5 Component j-Example m 1. Xanthan Gum 12 2 · Locust Bean Gum 18 3 · Dextrose 70 4 · Water * 25 * After being removed during the treatment, the azathione tablet was prepared as follows: The required amounts of azathione, fumaric acid, and sustained release excipients were mixed in a granulator at low speed for three minutes Then, an appropriate amount of water is added at a two-minute interval, which is performed with a low-speed pusher. Then, the obtained slurry is granulated with a shredder and a pusher at high speed for 3 minutes (extra water and Granulation time can be used to form appropriate granules), and the granules obtained are then dried in a fluidized bed In a desiccator until its LOD is below 5% and milled using a sieve # 0050 with a hammer forward at 200 to 3000 rpm. The milled granules are then placed in a laurel Sodium sulphate in a V-blender and stirred for 10 minutes. A suitable ingot lubricant (Pmv®, sodium stearyl fumarate, NF, commercially available from Penwest Pharmaceuticals Co.) was used. Add and stir the mixture for an additional 3 minutes. Then, use a capsule of 60 paper sizes to apply Chinese National Standard (CNS) A4 (210 X 297 mm) 1227144 A7 • A / __ _B7 __—- 5 2. Description of the invention () A punch machine presses the obtained granules into a tablet. The final mixture is made into a tablet of about 750 mg. Example 2 1-2 of 3 The ingredients are shown in the following Table 26. Table 2 6 Lozenge Formula-Example 2 1-Ingredient Amount) g (grams / tablets) 1 · Sustained-release excipient 53.3 400.0 2 · Thiazetone (granule) Shape) 32.0 240.0 3 · Fumaric acid 8.0 60.0 4 · Sodium lauryl sulfate 5.3 40.0 5 · Pruv® (Stearyl fumaric acid ) 1.3 10.0 6. Water * 29.0 0.0 * removed during processing

The final tablet had a tablet weight of 75.0 mg and a hardness of 15 KP. Then, the core tablets were coated with ethylcellulose / Opadry (80/20) aquatic solution to obtain 4% and (based on Example 2 2 and 2 3 respectively) based on the total weight of the tablets. ) To increase weight. The aqueous dispersion was prepared by the following procedure: First, 60 grams of Opadry and 340 grams of water were mixed in a suitable container. While the mixing was continued, 944 g of ethyl cellulose was added to the Opadry dispersion, and the resulting mixture was stirred for 30 to 60 minutes. The dissolution test was performed on the tablets of Examples 2 1-2 3. The dissolution test was performed in 250 ml of buffer (ρ Η 6) in an automated us 61? National Standard (CNS) A4 specification (210 X 297 cm). Li) '----- ^ 11 outfit --- I ---- order ----- (please read the precautions on the back before filling out this page) Trip 4 A7 1227144 ______B7_ ___________ 1- 5. Description of the invention ( ) P dissolution instrument (Paddle III, bCPM), and the drug release amount is analyzed by ultraviolet analysis method. The dissolution results in this test tube are shown in the following Figure 10 and Table 2 7: Table 2 7 Mo (hours) Example 2 1 Example 2 2 Example 12- ^ (without coating) (4% coating (6% coating) 〇0.0 0.0 0.0 1 8.8 4.1 0.5 3 39.1 29.8 2.6 8 69.0 61.2 58.2 12 85.1 86.7 95.5 16 106.6 99.8 101.3 24 107.0 101.9 101.5 Based on the results provided in Figure 1 0 and Table 2 7 It is clear that as the amount of coating increases, the release rate decreases. Example 2 4-2 5 Effect of adding excipients outside the manufacturing granules In Examples 2 4-25, the sustained release excipients were prepared according to the procedures described in Examples 1 to 2. Examples 2-2 5 The components of the sustained release excipients are shown in the following Table 28: Table 28 Amount (%)-Example? . 4 volume-example? $ 12 12 62 This paper size is applicable to Chinese National Standard (CNS) A4 ^ (210 X 297 mm) "-(Please read the precautions for back purchase before filling this page) ^ -------- ^ ---------- Ingredients 1. Xanthan gum 1227144 A7 B7 5. Description of the invention () 2. Locust bean gum 18 18 3 · Dextrose 70 70 4. Water * 25 25 * During processing After being removed, the lozenges were prepared according to the ingredients in Table 29 and the procedure is as follows: Table 2 9 Ingredients (%) Implementation mg / Lozens (%) Implementation mg / Sharp Example 24 Agent Example 25 24 m Example 25 1. Sustained release excipients 49.2 400.0 53.3 400.0 2 · Thiazemone HC1 (intragranular granular) 19.2 156.0 32.0 240.0 3 · Thiazemone HC1 (particularly granular) 10.3 84.0 Ν / Α N / A 4.Reverse Butenedioic acid 14.8 120.0 8.0 60.0 5. Surfactant (SLS · Λ 4.9 40.0 5.3 40.0) 6. Sodium stearyl fumarate, NF 1.6 13.0 1.3 10.0 7. Water * * Removed during processing 27.0 0.0 27.0 0.0 Example 2 4 The final lozenge has a lozenge weight of 83.0 mg and a hardness of 15 Kp. Example 2 5 The final tablet has a tablet weight of 75.0 mg. 63 The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ^ -------- ^- --------. (Please read the precautions on the back before filling out this page) A7 1227144 _B7__ 5. Description of the invention () _ and the hardness of 1 5 K p. The formulation of Examples 2 4-2 5 was prepared as follows: Distribute the required amounts of (1), (2), and (4) to a granulator and mix at low speed for three minutes; when performed with a low speed pusher 'Add (7) at two minute intervals; granulate the mixture with a shredder and a pusher at a high speed of 7.5 minutes (extra water and granulation time can be used to form appropriate granules); make The granulated mixture is dried in a fluidized bed dryer until its LOD ratio is below 5%; the dried granules are milled using a sieve # 005 0 forward with a hammer at 2000 to 3000 rp m; milled The granules and (5) or (3 & 5) were placed in a V-blender and stirred for 10 minutes; (6) was added to the V-blender and stirred for 5 minutes. The final mixture is then pressed into a tablet using a capsule-shaped punch. Eudragit® L30D55 coated dispersion with sodium hydroxide was prepared as follows: A · 1.0N sodium hydroxide was prepared by adding 4.0 grams of sodium hydroxide to a 100 ml volumetric flask; then 50 milliliters of pure water and a magnetic stir bar are added to the flask, and the contents of the flask are mixed for 5 to 15 minutes; the stir bar is removed and the volume is QS and mixed to prepare it. B. Preparation of talc suspension by weighing 20. 54 grams of pure water in a suitable container; slowly adding 9.31 grams of triethyl citrate while stirring the pure water ; Then, when the mixture is stirred, add 2 2 · 2 grams of talc into the container at 2 minute intervals (the mixture 64 this standard applies to China National Standard (CNS) A4 specifications (210 X 297 mm)) I '. ^ -------- Order ---------. (Please read the notes on the back before filling this page) A7 1227144 ______B7__ 5. Description of the invention () The compound is stirred until Until a suspension is formed). C. Eudragit® L30D55 suspension is prepared by passing the EudragitLSODSS coating dispersion through a # 40 mesh sieve; weighing 2 9 4. 5 2 grams of sieved Eudragit® L30D55 and placing it in a suitable container; Using a dropper, while stirring the mixture, 3.56 grams of a 1 • 0 N sodium hydroxide (step A) solution was added; it was made by stirring the mixture for 30 to 60 minutes. D. Preparation of the final coating suspension by adding Eudragit® L30D55 suspension (step C) while stirring the talc suspension (step B) for a period of five minutes; stirring the mixture 30 to 60 Made in minutes. The lozenge is coated to obtain a 4% increase in weight based on the total weight of the lozenge. The lozenge is coated by making the coated lozenge into a clear gelatin capsule. The plasma profile of Example 24 The in vivo test of the tablet of Example 24 was performed in healthy volunteers using a two-way random publicly marked crossover design in a group of 12 subjects Subjects and they were dosed in a fasted state and compared to CARDIZEM CD®. The results are shown in the following Figure 11 and Table 3 0: Table 3 0 Shijian Example 2 4 Fasting Cardizem-CD Fasting must be _ (nanograms / liter) (Taigram / ml 0 0.00 0.00 65 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------ ^ ----------------- -. (Please read the notes on the back before filling this page) A7 1227144 ___ B7 V. Description of the invention () 1 0.65 0.00 2 4.72 0.00 4 31.02 19.65 6 62.45 83.08 7 63.27 60.98 8 65.45 50.79 9 64.20 42.52 10 65.39 38.43 12 77.30 42.56 14 82.86 52.58 15 81.91 56.40 16 80.17 57.48 18 70.09 57.73 20 57.59 51.97 24 42.21 43.48 3 0 24.82 28.73 36 10.97 12.8 48 2.55 3.78 The curve between Example 2 4 and CARDIZEM CD ^ > 2 40 mg The ratio of the lower region is 1.16: 1. The ratio of the average Cmax between Example 25 and CARDIZEMCD2 40 mg is 116: 1. Results: Figure 11 and Example 2 4 demonstrate a live The dual-mode plasma content of the body, CARDIZEM CD® is also a blend of two different bead formulas The plasma content of the dual mode was confirmed in Example 2. The plasma type of Example 25 was used for the in vivo test of the tablet of Example 25, which is based on the health of 66 national paper standard (CNS) A4 specifications (21 × χ297). Love) ------------ Installation -------- Order --- (Please read the precautions on the back before filling this page) 1227144 A7 _ B7 V. Description of the invention (_ ) Of volunteers using a two-way random publicly-labeled interaction design '12 subjects per group and they were dosed in a fasting state 'compared to CARDIZEM CD®. The results are shown below Figure 1 2 and Table 3 1 ·· Table 3 1 Time Example Fasting Cardizem-CD Test Hours) (Tg / ml) (Ng / milli) 01246789

02456804068 IX IX IX IX 1-1000000OOOO 0.00 0.30 6.55 35.43 77.71 76.91 70.88 66.18 64.98 71.90 65.48 62.72 60.60 48.87 38.95 33.10 20.93 10.14 2.52 0.00 0.05 0.40 5.48 66.02 58.31 47.29 39.31 35.51 38.55.41.66. Note on the back, please fill in this page again) The ratio of the area under the curve between Example 25 and CARDIZEM CD2 40 mg is 1.16: 1. The average C max ratio between Example 25 and CARDIZEM CD2 40 mg is 1 67. This paper is compliant with China National Standard (CNS) A4 (210 X 297 mm P " A7 1. Huangyuan) Gum 12 25 2 · Locust bean gum 18 25 3. Calcium sulfate N / A 10 4. Ethyl cellulose N / A 5 5. Dextrose 70 35 6 · Water * 25 N / A 7. Ethanol * N / A 20 Removed during processing 1227144 _B7___ V. Description of the invention () • 26: 1 ° 糸 吉 果 · Figure 12 and Example 2 5 confirms a dual-mode plasma content in vivo, CARDIZEM CD® also consists of two Mixtures of bead formulations treated in different ways confirm dual-mode plasma levels. Examples 2 6 and 27 7 Effects of Different Excipients In Examples 2 6 and 27, the sustained release excipients were according to Examples 1 to 2 Prepared according to the procedure described in Examples. The components of the sustained release excipients of Examples 2 6 and 27 are shown in the following Table 3 2: Table 3 2 Ingredient Amount (%)-Example 26 Amount (%)-Example 2 7 After the formulation in Table 3 3, the azathione tablet is prepared as follows: The required amount of thiazepine, fumaric acid and an appropriate amount of 68 papers Degree applies to China National Standard (CNS) A4 specification (210 X 297 mm) ^ -------- ^ ----------. (Please read the precautions on the back before filling this page ) 1227144 a7 _ B7__ V. Description of the invention () The release excipient is placed in a granulator and mixed at low speed for three minutes. Water is added to the continuous release excipient at a two-minute interval while the pusher is running at low speed. Medium (extra water and granulation time can be used to form the appropriate granules). The granules obtained are then dried in a fluidized bed dryer until its LOD is below 5%, and a hammer is used to advance 2 Milled from 0.000 to 300,000 rpm. The milled granules were then placed in a V-blender with sodium lauryl sulfate and stirred for 10 minutes. A suitable ingot lubricant (Pruv®, Sodium stearyl fumarate, NF, commercially available from Penwest Pharmaceuticals Co.) was added and the mixture was stirred for an additional 5 minutes. The resulting granules were then 'using a capsule-shaped punch The tablets are pressed into tablets. This final mixture is made into tablets of about 750 mg. The ingredients of the tablets of Examples 2 6 and 27 are shown in Table 3 3 below: Table 3 3 Ingredients Example 2 6 Example 2 6 Example 2 7 Example 2 7% mg / Lozenge% mg / Lozenge Agent 1. Sustained release excipient 53.3 400.0 53.3 400.0 2 Thiazolone HC1 32.0 240.0 32.0 240.0 3 Fumaric acid 8.0 60.0 8.0 60.0 4 Surfactant (SLS 5.3 40.0 5.3 40.0) 5 Stearic acid Based on fumaric acid 1.3 0.0 30.0 0.0 Sodium 6. Water * 27.0 0.0 30.0 0.0 was removed during processing. The final lozenge of Example 26 had a lozenge weight of 75.0 mg and a hardness of 15 Kp. The final tablet of Example 2 has a tablet size of 75.0 mg and a weight of 69. The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----------- ^ -------- ^ ---------- (Please read the precautions on the back before filling this page) A7 1227144 _B7__ 5. Description of the invention () Amount and hardness of 1 5 κ P . Then, dissolution tests were performed on the tablets of Examples 26 and 27. The dissolution test was performed in 250 ml of a buffer solution (pΗ6) in an automated US P dissolution apparatus (Paddle III type, 15 CPM). The amount of drug released is analyzed by UV analysis. The dissolution results in this test tube are shown in Figures 13 and 34 below. Table 3 4 Time (hour) Example 25 (% dissolution) Example 2 6 dissolution) 0.0 0.0 0.0 1.0 18.4 12.6 3.0 32.6 23.9 8.0 59.8 45.9 12.0 80.5 60.3 16.0 92.3 71.8 24.0 93.7 91.4 Slower dissolution pattern than Example 25. Results The dissolution rate can be adjusted by using different grades of excipients. Example 2 8-2 9 The effect of gum in the formula: the effect of the drug ratio In Examples 2 8-29, first, the sustained-release excipient was prepared according to the present invention, followed by the addition of a drug (oxybutynin) and adjustment of pH (Citric acid in this case), and then the final mixture is made into lozenges. 70 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ----------- installation -------- order --------- -Line I ^ Γ (Please read the precautions on the back before filling this page) • A7 1227144 -____— V. Description of the invention () The preparation of the sustained release excipient is made of xanthan gum and locust bean gum , Dextrose, and sulphuric acid # 5 are distributed to a high-shear mixer / granulator, ethyl cellulose is distributed to a container containing ethanol, and ethyl cellulose / ethanol mixture is distributed to xanthan gum , Locust bean gum, dextrose and calcium sulfate, and granulate to form appropriate granules' The mixture is dried in a fluidized bed dryer, and the dried mixture is milled to form appropriate granules. The ingredients of the sustained-release excipients of Examples 2 8 to 29 are shown in the following Table 35: Table 3 5 Preparation of sustained-release excipients Ingredients Amount (%)-Examples? Η 1. Xanthan Gum 20 15 2 · Locust Bean Gum 30 15 3 · Dextrose 40 60 4. Calcium Sulfate 10 10 5. Water * 20-30 20-30 is removed during the process and then the required amount Oxybutynin and sodium stearyl fumarate are passed through a 25 mesh sieve, sifted oxybutynin and sustained release excipients are dispensed into a V-blender and stirred for 10 minutes , Add sodium stearyl fumarate to the blended mixture of oxybutynin and a sustained release excipient and stir for an additional 5 minutes, and then use a 5/1 6 ”round shape tooling The final blended final product is pressed into a tablet. This final mixture is made into a tablet of about 1 7 9.4 mg. Examples 2 8-2 71 ¥ ^ The size applies to Chinese National Standard (CNS) A4 (210 x 297) (Mm) ^ " — 1 ^ -------- 1 ---------. (Please read the notes on the back before filling out this page) A7 1227144 ____B7__ 5. Description of the invention () The ingredients of the 9 tablets are shown in the following Tables 3 6 and 37: Table 3 6 Tablet Formulation Example 2 8 Ingredient _ Amount (%) Amount (mg / tablet) 1. Sustained release excipient 9 2.9 166.7 2. Oxybutyn HC1 5.6 10.0 3. Sodium stearyl fumarate 1.5 2.7 Tablet weight. 179.4 Hardness (K p) 5 Table 3 7 Tablet Formula One Example 2 9 Ingredient amount (% ) Amount (mg / tablet) 1. Sustained release excipient 92.9 166.7 2. Oxybutyn HC1 5.6 10.0 3. Stearyl fumarate _ 1.5 2.7 Tablet weight 179.4 Hardness (K p) 5 ( Please read the notes on the back before filling this page) The final tablet has a tablet weight of 1 7 9.4 mg and a hardness of 5 Kp. Then, the tablet of Examples 2 8-2 9 was tested for dissolution. In this test tube The dissolution results are shown in the following table 38. Table 38 Hours in the calendar month) Example 2 8 (% dissolution) Example 2 Q (¾dissolved) 72 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1227144 A7 _B7 V. Description of the invention () 0.0 0.0 0.0 2.0 44.4 33.6 4.0 67.6 42.5 6.0 86.6 57.4 8.0 103.0 72.5 12.0 108.7 88.9 20.0 108.7 92.8 2 9 Drug: gum ratio with 1: 8 · 3 From the results provided in Table 38, it is clear that the release rate of oxybutynin is slower when the ratio of drug: gum in the formulation is increased. Examples 3 0-3 1 Effect of gum: dextrose ratio In Examples 30-31, the sustained release excipients were prepared according to the procedures described in Examples 2 8 and 29. The components of the sustained release excipients of Examples 3 0 and 31 are shown in Table 3 9 below: Table 3 9 Preparation amount of sustained release excipients Amount of Example 30 0 Amount (%)-Example 3 丄1. Xanthan Gum 20 15 2. Locust Bean Gum 30 15 3. Dextrose 40 60 4. Calcium Sulfate 10 10 5. Water * 20-30 20-30 * Removed during processing. Next, oxybutynin tablets The formulation is prepared as follows: Pass the required amount of oxybutynin and sodium stearyl fumarate through a 25 mesh screen, pass the sieve oxybutynin and the sustained release excipient 73 papers Dimensions are applicable to China National Standard (CNS) A4 specifications (210 X 297 male f) ------------ install --- II (Please read the precautions on the back before filling this page) tr-- -------- Line f · 1227144 A7 _B7__ V. Description of the invention () Distribute to a V-shaped stirrer and stir for 10 minutes, add the sieved sodium stearyl fumarate to aoxia Bunin and the sustained-release excipient blended mixture and stirred for an additional 5 minutes, and then the final blended final product was pressed into tablets using a 5/1 6 "round shape tooling. This Final mixture About 1 7 9.4 mg of lozenges. The ingredients of the lozenges of Examples 30 to 31 are shown in the following Tables 40 and 41: Table 40 0 Lozenge Formula One Example 30 The amount of ingredients (%) (Mg / deposit) 1. Sustained-release excipient 92.9 166.7 2. Oxybutyn HC1 5.6 10.0 3. Sodium stearyl fumarate 1.5 2.7 Tablets Weight Hardness (K p) Table 4 1 179.4 5 Lozenge Formula One Example 31 Ingredient amount (%) Amount (mg / lozenge) 1. Sustained release excipient 92.9 166.7 2. Oxybutyn HC1 5.6 10.0 3. Sodium stearyl fumarate 1.5 2.7 Tablet weight 179.4 Hardness (K p) 5 The final tablet has a tablet weight of 17 9.4 mg and a hardness of 5 Kp. Then, dissolution tests were performed on the tablets of Examples 30-31. This 74 II-* IIIIII 1 ^ · 11111111 · (Please read the precautions on the back before filling in this page) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 1227144 A7 _B7_ V. Description of the invention The results are shown in Table 4 2 below. Table 4 2 Time (hours) Example 3 0 (% dissolved) Example 3 1 (% dissolved Solution) 0.0 0.0 0.0 2.0 44.4 33.6 4.0 67.6 42.5 6.0 86.6 57.4 8.0 103.0 72.5 12.0 108.7 88.9 20.0 108.7 92.8 It is obvious from the results provided in Table 4 2 that when the amount of gum in the formula is relative to dextrose A relative decrease in the release of oxybutynin was observed with increasing amounts. Example 3 Effect of 2-3 5 Succinic acid In Examples 3 2-3, a sustained release excipient was prepared according to the procedure described in Examples 2 8 and 29. The components of the sustained release excipients of Examples 3 2 and 3 3 are shown in Table 4 3 below: Table 4 3 Ingredient Amount (%)-Example 3 2 —3 3 1. Xanthan Gum 25 75 Paper Size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ Installation -------- Order ----- (Please read the note on the back first Please fill in this page again) 4 1227144 A7 B7 V. Description of the invention () 2. Locust bean gum 25 3. Dextrose 35 4. Calcium sulfate 10 5 · Ethyl cellulose 5 6. Water * 20-30 * In processing After being removed, the oxybutynin lozenges were prepared as follows: Pass the required amount of Norabutin., Oxybutynin and sodium stearyl fumarate through a 25 mesh screen and pass through a sieve The succinic acid and sustained release excipients were dispensed into a V-blender and stirred for 10 minutes. Sifted oxybutynin was added to the blended mixture of succinic acid and sustained release excipients and stirred for an additional 5 minutes. Add the sieved sodium stearyl fumarate to the blended mixture of oxybutynin, succinic acid and sustained release excipients and stir for an additional 5 minutes. Then, use 5/16, and round shape Profiled final blended end product will be made pressurized lozenges. The final mixture of Example 3 2 was made into a sharpening agent of about 251 · 0 mg, and the final mixture of Example 33 was made into a tablet of about 296 · 0 mg. The ingredients of the tablets of Example 3 2-3 3 are shown in the following Tables 4 4 and 4 5: Table 4 4 Mirror Formulation Example 1 2-Quantities (mg / tablet 76 ϋ ㉛ home standard (CNS ) A4 S (210 X 297 public "1 '--- ^ ^ -------- ^ ------ (Please read the precautions on the back before filling this page) 4 A7 1227144 _____B7 V. Description of the invention (1) 1. Sustained release excipient 93.2 234.0 2. Succinic acid N / AN / A 3. Oxybutyn HC1 6 15.0 4. Sodium stearyl fumarate 0.8 2.0 Tablet weight 251 Hardness ( Κ p) 8 The final lozenge has a lozenge weight of 2 51 • 0 mg and a hardness of 8 ρ. Table 45 Lozenge Formula-Example 3 3 Ingredient Amount (%) Amount (mg / Lozenge) 1. Sustained Release excipient 92.9 166.7 2. Succinic acid 15.2 45.0 3. Oxybutyn HC1 5.1 15.0 4. Sodium stearyl fumarate 0.7 2.0 Tablet weight 296.0 Hardness (K p) 8 (Please read the back Note: Please fill in this page again.) -------- Order ------ The final tablet has a tablet weight of 2 9 6.0 mg and a hardness of 8 κ P. Then, for Example 3 2- 3 3 tablets for dissolution test. This test tube dissolves The solution results are shown in the following table 4 6. Table 4 6 77 This paper size applies the Chinese National Standard (CNS) A4 specification (210 x 297 mm) A7 1227144 _B7__ V. Description of the invention () Time (hours) Example 3 2 (% dissolved) Example 3 3 (% dissolved) 0.0 0.0 0.0 2.0 1.3 8.9 4.0 2.1 12.9 6.0 4.7 24.0 8.0 11.3 34.0 12.0 25.9 44.0 20.0 43.9 59.5 From the results provided in Table 4 6 it is clear that The addition of succinic acid can aid the solubility of the drug, thereby increasing the release rate. In Examples 3 4-35, the sustained release excipient was prepared according to the procedures described in Examples 2 8 and 29. Examples 3 4 and The ingredients of the sustained release excipients 3 to 5 are shown in the following Table 4 7: Table 47 Ingredient Amount (%)-Example 3 4-3 5 1. Xanthan Gum 25 2. Locust Bean Gum 25 3. Dextrose Sugar 35 4. Gold sulfate 10 5. Ethyl cellulose 5 6. Water * 20-30 * Removed during processing Next, oxybutynin tablets are prepared as follows: The required amount of sustained-release excipient is shaped Agent, succinic acid and oxybutynin 78 paper sizes are applicable to Chinese National Standard (CNS) A4 (210 X 2 97 mm) (Please read the unintentional matter on the back before filling out this page) -------- Order ---------- Line 1227144 .A7 B7 V. Description of the invention () Dispensed into a granulator, they were dry-mixed for three minutes at low speed with a propeller with chopped blades in the closed position. Water is added at one minute intervals, and the mixture is granulated at a high speed for 3 minutes (extra water and granulation time can be used to form appropriate granules). The mixture is then dried in a fluidized bed dryer Until its L 0D ratio is below 5%, and use a paddle to mill the dried granules at 2 000 to 3000 r pm. The milled granules and sodium stearyl fumarate were placed in a V-blender and stirred for 10 minutes. Then, the blended mixture was pressed into a lozenge using a compression profile of 5/16 "round shape. The final mixture of Example 34 was made into a tablet of about 2 9 6.0 mg, and The final mixture was made into tablets of about 2 6.0 mg. The ingredients of the tablets of Examples 3 4 to 3 5 are shown in Tables 4 8 and 4 9 below.

Table 48 Tablet Formulation Example 1 4 Component amount (%) Amount (mg / 1 1. Sustained release excipient 79.1 234.0 2. Succinic acid 15.2 45.0 3. Oxybutyn HC1 5.1 15.0 4. Stearyl based Sodium butenedioate 0.7 2.0 5 · water * 30-45 N / A Lozenge weight hardness (K p 296.0 The final lozenge was removed during processing with a tablet weight of 2 9 6.0 mg and a hardness of 8 Kp. 79 tablets Paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1227144 A7 _B7 V. Description of the invention () Table 4 9 Formulation of the first embodiment 3_5 Ingredient amount (%) Amount (mg / tablet) 1 Sustained release excipients 88.0 234.0 2. Succinic acid 5.6 15.0 3. Oxybutyn HC1 5.6 15.0 4. Sodium stearyl fumarate 0.8 2.0 5. Water * 30-45 N / A Tablet weight 266.0 Hardness (K p) 8 * Removed during processing The final tablet has a tablet weight of 2 6 6.0 mg and a hardness of 8 K p. Then, the tablets of Examples 3 4-3 5 were tested for dissolution. This test tube The internal dissolution results are shown in the following table 50. Table 5 0

Time (hours) 眚 Example 3 2 Dissolution) Example 3 3 U Dissolution Angle II 0.0 0,0 0.0 2.0 9.2 5.8 4.0 13.7 7.9 6.0 21.2 11.7 8,0 34.2 23.4 12.0 49.1 37.4 18.0 63.9 57.5 From the results provided, it is clear that the higher the amount of succinic acid in the formulation, the faster the release rate. 80 This paper size applies to China National Standard (CNS) A4 (210 x 297 mm)

tr i I

I

1227144 A7 ___B7___ 5. Description of the Invention (') Example 3 Preparation of Ethyl Cellulose / OPADRY® Coatings by Using Ethyl Cellulose (SURELEASE ”/ OPADRY® (80/20) Water Piece Dispersion Coating Tablets The procedure is as follows: First, weigh 40 grams of water in a suitable container, add 60 grams of OPADRY® to the water while stirring, and continue mixing. When mixing the OPADRY® dispersion, add 9 3 3 grams of ethylcellulose dispersion (Surelease®) is added and allowed to stir for 30 to 60 minutes. The final dispersion is used to coat the tablets to obtain 3 to 5% based on the total weight of the tablets The weight increase. In Examples 36, the sustained release excipients were prepared according to the procedures described in Examples 2 8 and 29. The ingredients of the sustained release excipients of Example 36 are shown in Table 5 1 below. Middle: Table 5 1 J component (%)-Example 3 6 1. Xanthan Gum 25 2. Locust Bean Gum 25 3 · Dextrose 35 4. Calcium Sulfate 10 5. Ethyl Cellulose 5 6. Water * 20 -30 is removed during processing. Next, oxybutynin tablets are prepared as follows: The required amount of sustained release excipient, Acid and Oxybutynin 81 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 Gongchu) A7 1227144 _B7__ 5. Description of the invention () When equipped in a granulator, they are used to close The propellers of the shredded blades are dry-mixed at low speed for three minutes. Water is added at one minute intervals, and the mixture is granulated at high speed for three minutes (extra water and granulation time can be used to form (Appropriate granules), and then the mixture is dried in a fluidized bed dryer until its LOD ratio is below 5%, and the dried granules are milled using paddles at 2 000 to 3000 r pm. The milled granules and sodium stearyl fumarate were placed in a V-blender and stirred for 10 minutes. Then, the blended shape was compressed using a 5/16 "round shape. The mixture was pressed to make a tablet. The final mixture of Example 36 was made into a tablet of about 2 9 6.0 mg. The composition of the tablet of Example 36 was shown in Table 5 2 below: Table 5 2 Formulation of tablets Example 3 6 Ingredient Amount (%) Amount (mg / tablet) 1. Continued release excipient 79.1 234.0 2. Succinic acid 15.2 45.0 3. Oxybutyn HC1 5.1 15.0 4. Sodium stearyl fumarate 0.7 2.0 5. Water 1 30-45 N / A Tablet weight 296.0 Hardness (K p) 8 --- 1--11 ^ ---- I ---- I (Please read the notes on the back before filling this page) 1 During the processing, the final tablet has 2 9 6.0 mg The weight of the tablets and the hardness of 8 Kp. 1 82 This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 1227144 A7 B7 V. Description of the invention (Then, the dissolution test was performed on the tablets of Example 36. The dissolution results in this test tube are shown In the following table 53. Table 5 3 Time (hours) 0.0 2.0 4.0 6.0 8.0 12.0 20.0 Example 1 0.0 26.8 32.1 35.8 40.1 54.2 72.2 Example 2 0.0 7.1 10.3 14.9 20.2 27.4 53.2 Example 3 0.0 1.7 2.8 5.5 9.0 15.1 32.7 From the results provided in Table 53, it is clear that the release rate decreases as the amount of coating (by weight) increases. In Example 3, the sustained release excipient was prepared according to the procedures described in Examples 2 8 and 29. The components of the sustained release excipient of Example 37 are shown in Table 5 4 below: Table 5 4 ( Please read the precautions on the back before filling this page.) -------- Order ---------- Line k 83 1227144 A7 B7 V. Description of the invention (Ingredient 1. Xanthan gum · 2, locust bean gum 3. dextrose 4. calcium sulfate 5. ethyl cellulose 6. water * * amount removed during processing (%) · Example 3 7 25 25 35 10 5 20-30 (Please read the precautions on the back before filling out this page) FI Tablet Formulation Example 1 7 Ingredients 1. Sustained-release excipient 2. Oxybutyn HC1 3. Fumaric acid 4. Pruv ^ (mg / tablet) 166.7 15 30 2 Order ----------. Total weight (core) 213.7 The final tablet has 2 1 3.7 mg of tablets Weight. Then, dissolution test was performed on the tablets of Example 3 7 and compared with Ditropan XL. The dissolution results in this test tube are shown in Table 5 5 below. Table 5 5 84 This paper size applies the Chinese National Standard (CNS) A4 specifications (210 x 297 mm) 1227144 B7 V. Description of the invention ()% Dissolution / release time (hours) DitropanXL 149-141 0 0.0 0.0 1 1.9 5.9 2 3.5 8.5 4 13.4 15.7 8 36.1 43.50 12 60.7 72.1 18 85.0 86.9 Reply 98.4 98.0 Other oxybutynin formulations, in which the P Η adjuster contains fumaric acid, is shown in Table 5 6 Table 5 6 Ingredient mg / tablet (range) or% (if specified) 1 Sustained release excipients 170-234 mg 2. fumaric acid 15-60 mg 3. oxybutynin HC1 5, 10 , 15 mg 4. Silicon dioxide 0-2% 5. Sodium stearyl fumarate 1-2% The examples provided above are not intended to be absolute. For those skilled in the art, many other variations of the present invention are obvious and are included in the scope of the attached patent application. 85 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 χ 297 public love)

Claims (1)

1227144 S cs D8 6. Scope of patent application 1. A preparation method of oral solid form for sustained release of bioavailability of soluble to highly soluble therapeutically active drugs, comprising: a) preparing a sustained release Granules comprising a gelling agent, the gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum that can be cross-linked with the heteropolysaccharide gum when exposed to environmental liquids; b) adding sustained treatment to the sustained-release granules An effective amount of a drug having a solubility of more than about 10 grams per liter, and a pH adjuster containing an organic acid, which accelerates the release of the drug from the dosage form; and c) granulates the mixture of step b) It is compressed and compressed into a solid dosage form which provides sustained release of the drug after oral administration to a human patient. 2. The method according to item 1 of the scope of the patent application, wherein the sustained-release particles further comprise up to about 20% by weight of an ionizable gel strength enhancer. 3. The method according to item 1 of the scope of patent application, wherein the sustained-release particles further comprise about 1% to about 89% by weight of an inert diluent. 4 The method according to item 1 of the scope of patent application, wherein the continuous release The particles further comprise a surfactant. 5. The method according to item 1 of the patent application range, wherein the sustained-release particles further comprise about 1% to about 20% by weight of a hydrophobic substance. 06. The method according to item 1 of the patent application range, wherein the continuous release 1 This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mol) (Please read the note on the back ^: transcribe this page) Packing 1227144 B8 C8 D8 6. The scope of patent application • The particles are based on Prepared by dry granulation. 7. The method according to item 1 of the scope of patent application, wherein the sustained-release granules are prepared by a wet granulation method. 8. The method according to item 1 of the scope of patent application, wherein the heteropolysaccharide gum is xanthan gum, and the homopolysaccharide gum is locust bean gum. 9. The method according to item 1 of the scope of patent application, wherein the organic acid is selected from the group consisting of citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid, and combinations thereof In the group of people. 10. The method according to item 1 of the scope of patent application, wherein the organic acid is fumaric acid. 11. The method according to item 1. of the scope of patent application, wherein the drug is benzothiazine. 12. The method according to item 11 of the scope of patent application, wherein the benzothiazine is diltiazem or a pharmaceutically effective salt thereof. 13. The method according to item 1 of the scope of patent application, which provides continuous release of the drug for at least about 12 hours after oral administration to a human patient. 14. The method according to item 13 of the scope of patent application, wherein the sulfur nitrogen ketone is present in an amount of about 60 mg to about 120 mg. 15. The method according to item 1 of the scope of patent application, which provides continuous release of the drug for at least about 24 hours after oral administration to a human patient. 16. The method according to item 15 of the scope of patent application, wherein the thio nitrogen masking ketone is present in an amount of about 120 mg to about 300 mg. Π The method according to item 1 of the scope of patent application, wherein the drug is an antispasmodic agent. 2 This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) (Please read the notes on the back and fill out this page first) Packing 1227144 B8 C8 D8 VI. Patent Application Scope 18 · According to Patent Application Scope 17 The method according to item 1, wherein the anti-leaning drug is oxybutynin or a pharmaceutically acceptable salt thereof. The method according to item 1 of the scope of patent application, wherein the antispasmodic agent is oxybutynin salt. Oxybutynin chloride 〇2〇. The method according to item 19 of the application, wherein the oxybutynin is present in an amount of about 2.5 mg to about 25 mg. 21-The method according to item 20 of the scope of the patent application, wherein the Olympus 1 Bunin is present in an amount of about 5 mg to about 50 mg. 22. The method according to item 3 of the scope of patent application, wherein the inert diluent is selected from the group consisting of monosaccharides, disaccharides, polyols, and mixtures thereof. 23. The method according to item 3 of the scope of patent application, wherein the ratio of the inert diluent to the gelling agent is about 1: 3 to about 3: 1. 24. The method according to item 23 of the scope of patent application, wherein the ratio of the drug to the gelling agent is about 1: 5 to about 5: 1. 25. The method according to claim 2, wherein the dissociable gel strength enhancer is selected from the group consisting of alkali metal, alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate and lactic acid In the group of salt. -26-The method according to item 2 of the scope of patent application, wherein the dissociable gel strength enhancer includes calcium sulfate. 27. The method according to item 4 of the scope of patent application, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate and a pharmaceutically effective sodium docusate 3 297 mm) 1227144 B8 C8 D8 6. In the group consisting of docusate sodium. 28. The method according to item 5 of the application, wherein the hydrophobic substance is ethyl cellulose. 29. The method according to item 12 of the scope of patent application, wherein the dosage form provides an initial peak concentration of thiazepine (C max # 1) within about 4 to about 10 hours after oral administration of the dosage form, followed by the occurrence of The second peak concentration (Cmax # 2) within about 10 to about 16 hours after oral administration of the dosage form provides a therapeutic effect for at least about 24 hours after oral administration to a human patient. 30. The method according to item 29 of the scope of patent application, wherein the time to reach the first peak plasma concentration of azathione (T max # 1) is within about 6 to about 8 hours after the dosage form is orally administered to the patient occur. 31. The method according to item 29 of the scope of patent application, wherein the maximum plasma concentration (Cmax # 1) of azathione at the first Tmax is about 50 to about 100 per 24 mg dose of thiazemone Ng / ml. 32. The method according to item 29 of the application, wherein the second peak plasma concentration (Cmax # 2) occurs within about 12 to about 14 hours after the dosage form is orally administered to the patient (Tmax # 2). 33. A method according to item 32 of the scope of patent application, wherein the maximum blood concentration of azathione at Cmax # 2 is about 60 to about 90 nanograms per milliliter per 240 grams of azathione. 34 · The method according to item 29 of the scope of patent application, wherein based on the trough taken as C min between Cmax # 1 and Cmax # 2, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the note on the back ^^ 塡 write this page) Loading line 0 ^ 88 ^ ABCD 1227144 VI. Application for patent scope. The width of the plasma concentration curve at 50% height of Cmax # 1 is from about 0.5 To about 4.0 hours. 35. The method according to item 29 of the scope of patent application, wherein the width of the plasma concentration curve at 50% height of Cmax # l is based on the low trough value taken as Cmin between Cmax # 1 and Cmax # 2. To about 3 hours. 36. The method according to item 29 of the scope of patent application, wherein the width of the plasma concentration curve at 50% height of C max # 2 is based on the low trough value taken as C min between C max # 1 and Cmax # 2 From about 0.5 to about 8 hours. 37. The method according to item 29 of the scope of patent application, wherein the width of the plasma concentration curve at 50% height of Cmax # 2 is based on the low trough value taken as C min between C max # 1 and Cmax # 2 About 2 to about 6 hours. 38. The method according to item 29 of the application, wherein the ratio of Cmax # 1 to Cmax # 2 is from about 0.5: 1 to about 1.5: 1. 39. The method according to item 38 of the scope of patent application, wherein the ratio of Cmax # 1 to C max # 2 is about 0.7: 1 to about 1.2: 1. 40. A sustained-release oral solid dosage form comprising a mixture of: a therapeutically effective amount of a drug having a solubility of more than about 10 g / litre; a pΗ regulator of about 1 to about 50%, It contains organic acids; and a kind of sustained-release particles containing a kind of glue. The paper size is applicable to Chinese National Standard (CNS) A4 specifications (210 X 297 cm) (Please read the notes on the back first.) (This page) Pack 1227144 B8 C8 D8 6. Scope of patent application • gelling agent, the gelling agent contains a heteropolysaccharide gum and a homopolysaccharide gum that can be cross-linked with the heteropolysaccharide gum when exposed to environmental liquids; of which the drug The ratio to the gelling agent is from about 10: 1 to about 1:10; the dosage form provides continuous release of the drug after oral administration to a human patient, and the pH adjusting agent accelerates the release of the drug from the dosage form. 41. The dosage form according to item 40 of the application, wherein the gelling agent further comprises a dissociable gel strength enhancer. 42. The dosage form according to any one of claims 40 or 41 in the scope of the patent application, wherein the dosage form provides continuous release of the drug for at least about 12 hours after oral administration. 43. The dosage form according to any one of claims 4Q or 41 of the scope of the patent application, wherein the dosage form provides continuous release of the drug for at least about 24 hours after oral administration. 44. The dosage form according to item 41 of the application, wherein the dissociable gel strength enhancer is selected from the group consisting of alkali metal, alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate and In the group of lactate. 45. The dosage form according to item 44 of the application, wherein the dissociable gel strength enhancer comprises calcium sulfate. 46. The dosage form according to any one of claims 40 or 41 in the scope of the patent application, wherein the heteropolysaccharide gum is xanthan gum and the homopolysaccharide gum is locust bean gum. 47. The dosage form according to any one of claims 40 or 41 in the scope of the patent application, wherein the organic acid is selected from the group consisting of citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid, and Among the groups composed of these combinations, 6 paper sizes are applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1227144 A8 BS C8 D8 Application for a poor patent scope 48 · According to No. 40 or 41 of the scope of patent application The dosage form of any one of the above, wherein the solid dosage form is in the form of granules. 49. A dosage form according to any one of claims 40 or 41 in the scope of the patent application, wherein the drug is azathione or a pharmaceutically effective salt thereof. (Please read the notes on the back to complete this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)