WO2011072481A1 - Controlled release tablet formed by multiple particles - Google Patents

Abstract

A controlled release tablet formed by multiple particles is disclosed. The controlled release tablet is prepared by compressing the mixtures of two or more drug particles and adjuvant particles without drug. The controlled release tablet does not disintegrate or swell under the routine measure condition of dissolution. The drug release of said tablet is controlled to be stable.

Description

 Particle combination controlled release tablet

 The invention belongs to the field of pharmaceutical preparations, and relates to a novel controlled release tablet prepared by combining the same drug particles of one or more carriers, and does not disintegrate or dissolve under common release conditions. And the drug release is almost unaffected by the release conditions. technical background

 The concept of drug delivery system (DDS) emerged in the early 1970s and became a hot topic in formulation research in the 1980s. Slow and controlled release formulations were the initial stages of DDS development. The slow and controlled release preparation has the following characteristics: 1) For drugs with short half-life or frequent administration, the number of times of administration can be reduced, such as ordinary preparations 3 times a day, and the preparation of sustained-release or controlled-release preparation can be changed once a day; The blood concentration is stable, avoiding peaks and valleys, and is beneficial to reducing the side effects of the drug, and is particularly suitable for treating drugs with narrow windows.

 The sustained release preparation and the controlled release preparation are separated, and the Chinese Pharmacopoeia 2005 edition has clear regulations on both. The sustained release preparation refers to a preparation which continuously releases the drug for a long period of time after administration to achieve a long-acting effect, wherein the drug release is mainly a first-order speed process. The controlled release preparation refers to a preparation in which the medicine can be automatically released at a predetermined rate within a predetermined time to maintain the blood concentration constant for a long period of time in an effective concentration range. The release rate of the controlled release formulation is more stable than that of the sustained release formulation.

 The slow and controlled release preparations can be mainly divided into two types: skeleton type and reservoir type. The release mechanism is mainly divided into: 1) release type; 2) diffusion type; 3) dissolution type; 4) osmotic pressure type; 5) ion Exchange role class. The controlled release preparations prepared according to various release principles have their own advantages and disadvantages. For example, the dissolution principle is only suitable for those drugs with less solubility in water. The principle of dissolution is too many uncontrollable factors in the receptor, and it is difficult to control the release kinetics, osmotic pressure. The principle is only suitable for drugs with good water solubility and stable solution, and the technical complexity is high. The controlled release tablets prepared by the ion exchange principle have a small application range, a small drug loading amount and easy to affect the internal environment of the receptor, and the diffusion principle is relatively small. The invention has the advantages of easy preparation, economy and various methods, and is suitable for both water-soluble medicines and water-insoluble medicines, and can prepare both skeleton preparations and membrane-controlled storage preparations.

The controlled release preparations currently on the market are mainly controlled tablets, mainly osmotic pump type and skeleton type, for example: osmotic pump type with nifedipine controlled release tablets, glipizide controlled release tablets, skeleton type nifedipine oral skeleton Controlled Release Tablets, Metoprolol Tartrate Controlled Release Tablets, Nisodipine Controlled Release Core Tablets and Rosatidine Hydrochloride Acetate Gel Skeleton piece. The above-mentioned skeleton type preparation is generally prepared by using HPMC as a skeleton material, and the release rate depends on the diffusion speed of the drug through the gel layer and the dissolution rate of the gel, since HPMC itself is a hydrophilic gel and is not suitable for a water-soluble drug. For the more water-soluble drugs, the osmotic pump type is generally adopted. The osmotic pump type controlled release tablets belong to the membrane-controlled storage type preparation, and the preparation process is complicated and the cost is high; the release rate at the end is declining due to factors such as the core drug concentration being lower than its saturation. In addition, the amount of the drug contained in the membrane-controlled depot preparation is larger than that of the conventional preparation, and errors or membrane damage during the preparation process may cause the drug depot to rupture and cause toxic side effects caused by excessive release.

 Therefore, it is urgent to invent a simple and practical invention, which is suitable for preparing a water-soluble strong drug into a controlled release tablet, and adopting the technology to prepare a correspondingly cost-effective and safely controlled release preparation. Summary of the invention

 One of the objects of the present invention provides a controllable release tablet which is economical and safe to use. The controlled release tablet is a particle combined controlled release tablet which does not disintegrate, does not dissolve under common release conditions, and has no drug release characteristics. Affected by conventional factors.

 SUMMARY OF THE INVENTION A second object of the present invention is to provide a particle-controlled controlled release tablet preparation technique comprising an active ingredient which is a water-soluble and short half-life drug.

 "Particle combined controlled release tablets" refers to the design and preparation of a variety of particles, and then according to the particle's drug strength, drug release properties and other indicators to achieve stable controlled release characteristics, the particles are combined, compressed into tablets, obtained Under the common release conditions, the controlled release tablets do not disintegrate, do not dissolve, and the drug release is not affected by the release conditions.

 The release studies in vitro release media and in vivo simulated media showed that the appearance of the tablets remained unchanged during the drug release period of 0-12 hours under pseudo-physiological conditions, and even the tablets were soaked in the release medium. The time is extended to a week and remains unchanged.

 The controlled release tablet is made of one or more medicated granules including granules, eucalyptus (spheres), inclusions, and other granules containing no medicinal particles and no drug.

 The common release conditions: 1 determination method: basket method, paddle method; 2 rotation speed: 20- l OOrpm; 3 release medium: artificial gastric juice, artificial intestinal juice, water; 4 release medium pH: 4-9; 1度/。 The content of the inorganic salt is about 1% - 5%, the surfactant content of about 0. 1 ° /. 0。 5%, ethanol content of about 10% - 15%, sodium carboxymethyl cellulose content of 0. 5» /. -1%; 6 Appearance of the shape of the tablet: Die, coated tablets, film defects.

The controlled release tablet can be made into a small piece having a diameter of about 2 to 3 Μ, and is filled into a hard plastic enamel to prepare a capsule. The controlled release film coating film is a cellulose coating film of aqueous pores, and the aqueous pores are fine pores left by the hydrophilic porogen dissolved in the release medium, which can ensure the rapid release of the drug from the tablet at the initial stage of release. Released in the middle. The amount of the porogen is related to the amount of the tablet and the weight gain of the coating, i.e., the amount of film forming material used. The amount of film-forming material (coating weight gain) is positively correlated with the amount of porogen, the proportion of pore-forming material increases, the weight gain of coating increases, and the use of film-forming materials increases; the proportion of porogen decreases, and the weight gain of coating decreases. The use of film forming materials is reduced. The synergy ensures the release of the panicles in the self-controlled release tablets of the drug.

 The commonly used sustained-release matrix tablets can be classified into a hydrophilic gel matrix sheet, an insoluble matrix sheet, and an aerobic skeleton sheet. The core of the controlled release sheet belongs to an insoluble matrix sheet, and the core of the matrix sheet is composed of two or more kinds of particles combined and pressed, and the core of the matrix sheet has a certain hardness after being pressed into a sheet, and the medium is released in vitro. And in the simulated medium in the body, it shows the characteristics of no disintegration and no dissolution.

 The active ingredient contained in the controlled release tablet is a water-soluble drug selected from the group consisting of sodium ferulate, erythromycin thiocyanate, sodium ampicillin, chloramphenicol, fosfomycin sodium, rhein, apomorphine hydrochloride, hydrochloric acid. Dihydroetorphine, hydromorphone hydrochloride, trimetazidine hydrochloride, acetylcysteine, ethosylamine, quinine dihydrochloride, adenosine triphosphate, sorbitol, chlorpheniramine maleate, maleic acid Thiololol, taurine, diethylamine salicylate, doxycycline hydrochloride, penicillamine, benzalkonium bromide, sodium phenobarbital, sodium citrate, sodium calcium edetate, sulfuric acid Gentamicin, carbachol, cefuroxime sodium, sodium cromoglycate, L-carnitine, acetyl-L-carnitine and its salts, propionyl L-carnitine and its salts. Preferred are trimetazidine hydrochloride, L-carnitine, acetyl-L-carnitine and salts thereof, propionyl L-carnitine and salts thereof.

 The auxiliary material of the controlled release tablet comprises a filler, a release retarder, a binder, a lubricant, wherein the filler is selected from the group consisting of microcrystalline cellulose, dextrin, talc, mannitol, calcium sulfate, calcium hydrogen phosphate, and Pressed starch, preferably talc; wherein the release retarder is selected from the group consisting of hydroxypropionyl cellulose, alginate, chitosan, stearic acid, beeswax, bran wax, stearyl alcohol, glyceryl monostearate , mercaptoacrylic acid copolymer, non-toxic polyvinyl chloride, silicone rubber, ethylene-vinyl acetate copolymer, preferably stearic acid, hydroxypropyl cellulose, methacrylic acid copolymer; adhesive selected from gelatin, gum arabic , dextrin, shellac, starch, hydroxypropyl ketone cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol, polyethylene glycol, polymethacrylic acid Resin, preferably hydroxypropyl fluorenyl cellulose, poly methacrylic resin; lubricant selected from magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate (magnesium), preferably stearic acid Magnesium acid

The retarder in the controlled release tablet material can block the release of the drug through the skeleton type, and is an important factor affecting the release performance of the tablet. The controlled release tablet retarder has a hydrophilic polymer material and water insoluble polymerization. Materials, waxy materials, acrylic materials, different particles used in different retarders, pressed into tablets to work together to achieve controlled release requirements.

The controlled release tablet auxiliary material has a filler and a retarder, and the release property of the particle can be adjusted by changing the ratio of the filler and the retarder, thereby adjusting the release property of the tablet core, and increasing the content of the retarder. The more obvious the release effect, the slower the release; the smaller the amount, the smaller the release ability and the faster the release. The ratio of the filler to the blocker is 0. 05-20: 1 , preferably 0. ² 5-4: 1.

 The dosages, prescriptions and preparation processes of the different granules used for preparing the controlled release tablets are different. According to the drug content, the granules containing the drug can be divided into 1% _100% granules, medicinal Q. 1%-1% granules, blank 1度/。 The granules, and the drug containing 1% - 100% of the coated granules, containing 0. 1 ° /. -11⁄2 granules and blank granules are non-coated granules. Such a design is based on ensuring that the drug maintains a stable release rate throughout the release process.

 The coating liquid selected for the coated granules is selected from one or more of the following materials: ethyl cellulose, fluorenyl cellulose, polymethacrylic acid polymer, cellulose acetate phthalate, polyvinyl decanoate , cellulose acetate trimellitate, preferably ethyl cellulose. DRAWINGS

 Fig.1 Release curve of controlled release tablets of trimetazidine hydrochloride with different particle combinations (1)

 Fig.2 Release curve of different granules combined with trimetazidine hydrochloride controlled release tablets ( 2 )

 Fig.3 Optimized particle combination dry-release curve of trimetazidine hydrochloride controlled release tablets in different release mediaFig.4 Optimized particle combination release profile of trimetazidine hydrochloride controlled release tablets at different measured speedsFig.5 Optimized particle combination The release profile of the oxazine controlled release tablets in different pH waters is shown in Fig. 6. Optimized particle combination release curve of trimetazidine hydrochloride controlled release tablets in different internal environment waters (1) Fig. 7 Optimized particle combination of trimeta hydrochloride. The release profile of Qin controlled release tablets in different internal environment waters ( 2 ) Fig. 8 Optimized particle combination release profile of different coatings of trimetazidine hydrochloride controlled release tablets

 The invention is further described in conjunction with the examples, which are intended to illustrate the invention and not to limit the scope of the invention. Related Examples A combination of controlled doses of trimetazidine hydrochloride tablets was prepared using trimetazidine hydrochloride as a model drug.

1 basic particle prescription A particle (calculated in lg, containing about 25% of the drug)

 Prescription: mg

 Trimetazidine Hydrochloride 250

 Stearic acid 200

 Compressible starch 450

 Eudragit E100 40

 Cellulose acetate phthalate 60

B particles (calculated in lg, containing about 0.5% of the drug)

 Prescription: mg

 Trimetazamine Hydrochloride 5

 Stearic acid 350

 Talc 600

 Carboxymethyl cellulose sodium 45

C particles (calculated in lg, containing about 0% of the drug)

 Prescription: mg

 Trimetazamine Hydrochloride 0

 Stearic acid 600

 Microcrystalline cellulose 370

 Hydroxypropylmethylcellulose 30

2 basic particle preparation process

 A particle process:

 1) The main drug, trimetazidine hydrochloride, is placed in an appropriate amount of Eudragit E100 (5%) solution, stirred and mixed, and stearic acid is crushed through an 80 mesh sieve for use;

 2) Weigh stearic acid and compressible starch according to the prescription amount, and mix and paste;

 3) 2) the resulting mixture is added in small amounts, and stirred a plurality of times to add 1) the obtained drug-impregnated binder to make a soft material;

4) Extrusion granulation, the granules were placed in an oven at 50 ° C for 3 hours, and the 20 mesh sieve was taken out; 5%-0. 8 _{0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0}

 6) After the coating, the A particles are placed in an oven at 50 ° C for 1 hour, taken out, and passed through a 20 mesh sieve.

 B particle process

 1) Put the drug trimetazidine hydrochloride in an appropriate amount of 0.5% CMC-Na solution, stir the mixed sentence, and crush the stearic acid powder through the 80 mesh sieve for use;

 2) Weigh the stearic acid and talcum powder according to the prescription;

 3) adding 1) the mixture to the obtained drug-impregnated binder in a small amount of a plurality of times to prepare a soft material;

 4) Extrusion granulation, the granules were placed in an oven at 50 ° C for 3 hours, and the 20 mesh sieve was taken out.

 C particle process

 1) Stearic acid is crushed through an 80 mesh sieve for use;

 2) Weigh the stearic acid and microcrystalline cellulose according to the prescription;

 3) 2) The mixture obtained by adding a small amount of stirring to an appropriate amount of 0.5% CMC-Na solution to make a soft material; 4) extrusion granulation, the granules are placed in an oven at 50 ° C for 3 hours, and the 20 mesh sieve is taken out. That is.

3 combined pellets pressed into tablets

Example 1

 Combination 1: A, B, C mixed and pressed but not coated, alone A pellets, B pellets alone, the release profile of the tablets in water is shown in Figure 1;

 Release curve analysis: From Figure 1, A particle coating was separately compressed, and the obtained tablets reached the release balance in 8 hours; B particles were separately compressed, and the obtained tablets reached the release balance in 4 hours; A, B mixed tablets, The equilibrium time of the obtained tablets was close to 12 hours, and the overall structure of the tablets formed by the mixed pellets controlled the release of the drug, suggesting the rationality of the "particle combination" design. Example 2

 Combination 2: A granule coating and other granules are mixed and tableted after tableting, A granule coating and other granules are mixed. Tablets after tableting are not coated, A granules are not coated and other granules are mixed. The tablet after the tablet is not coated, and the water release curve is shown in Figure 2;

Release curve analysis: Figure 2, after the particle A is coated, after it is pressed with other particles, the release curve Compared with the tablets which are not coated with A granules, they have a significant sustained release effect, and are generally closer to the tablet recoating; and after the A granules are coated, the tablets are mixed with other granules, and the tablets are coated. The controlled release characteristics are more significant, suggesting the rationality of the A particle coating. Example 3

 Combination 3: that is, the optimized embodiment, the particle parameters, the selection of the coating liquid, the coating amount and other important parameters are optimized, the optimization results are as follows, and the dry release study under common release conditions is shown in Figure 3-8;

 1) Weigh the appropriate amount of A, B, C particles, the specific gravity of A, B, C particles is 2: 2: 3, weigh 1% of the total weight of magnesium stearate, and mix well with the three particles, tableting;

 2) Tableting, each tablet contains about 35mg, and the tablet weight is 490mg-500mg;

 3) Pill prescription

 Prescription: mg

 Trimetazamine Hydrochloride 35. 7

 Stearic acid 207. 7

 Talc 84. 0

 Hydroxypropyl ketone cellulose 6. 3

 Eudragi t E100 5. 7

 Cellulose acetate phthalate 8. 4

 Microcrystalline cellulose 77. 7

 Carboxymethyl cellulose sodium 6. 3

 Compressible starch 63

 Magnesium stearate 0. 5

4, tablet coating

The coating liquid is 1.0% ethyl cellulose and 0.3% polyethylene glycol 4000 in anhydrous ethanol solution, coating weight gain

5, tablet release research

Three batches of samples were taken and placed in a dissolution vessel of 1000 mL of medium, and the slurry temperature was measured at 37 ° C. The 12-hour release of the three batches of samples was measured. Other conditions for the determination of release are as follows: 1) Different release media: water, artificial gastric juice, artificial intestinal fluid; (see Figure 3)

 2) Different speeds in water: 30 rpm, 50 rpm, 100 rpm; (see Figure 4)

 3) Different pH in water: pH 4. 0, pH 6. 8. pH 9. 0; (see Figure 5)

 4) Different aqueous medium environment: 15% ethanol, 0.5% sodium dodecyl sulfate (SDS) solution, 5% sodium chloride, 1% CMC-Na solution (see Figure 6, Figure 7)

 5) Different coating conditions: coated tablets, semi-coated tablets, and pieces; (see Figure 8)

6 release curve analysis

 1) The ideal controlled release tablet should be completely released in 12 hours, and the release curve conforms to the zero-order characteristic. The average release time (MDT) is 3.90 hours. The MDT range of the controlled release release study is 2. 99小时。 The mean value is 3.97 hours (n = 18), wherein in the 1% CMC-Na solution was 5. 63 hours, the MDT of the tablets was 2.99 hours, indicating the controlled release tablets It is basically in compliance with the release requirements of controlled release tablets under the conditions of common release assays.

 2) From Figure 3, the MDT of the tablets in artificial gastric juice, water and artificial intestinal juice were 3. 97, 4. 07, 4. 48 hours, respectively, indicating that the release of the drug in artificial gastric juice was slightly faster than in water and artificial intestinal juice. However, the overall release curve characteristics of each solution are similar, and the release end point is basically the same in artificial gastric juice and in the other two media, and the cumulative release rate in 12 hours is more than 90%, suggesting that the drug in the tablet is in the whole digestive tract in the body. Fully and controllable release in the system.

 3) From Figure 4, the overall characteristics of the release curve from 20 rpm to 100 rpm are similar, but the release of the larger rotation speed is slightly advanced. The MDT is 4. 07, 3. 82, 3. 58 hours at 20 rpm, 50 rpm, and 100 rpm, respectively. It indicates that the rotation speed is increased, and the average release time of the controlled release sheet is slightly reduced. The hydrophilic porogen of the tablet rapidly produces a porogenic effect, so that the release of the anterior segment is rapid, but because the hydrophilic drug in the tablet is more soluble in water, the difference in the release rate caused by the rotational speed is not obvious, and from the perspective of release, at different rotational speeds The characteristics of the overall release curve are basically the same, so it can be inferred that the release characteristics of the tablet mainly depend on the nature of the tablet itself, and the correlation with the disturbance of the release medium of the tablet is not obvious, suggesting that the patient with gastrointestinal motility disease can still be taken without restriction;

4) From Fig. 5, pH 4.0. 0, the drug release rate is faster in the front and middle segments, and the velocity decreases significantly in the posterior segment, but the release end point is basically the same as the pH 6.8 and pH 9. 0, within 12 hours. More than 90% release. Therefore, the release of the tablet is not affected by the pH of the release medium, suggesting that the release characteristics of the tablet are not affected by changes in digestive acid reduction; 5) From Figure 6, the release of the film is not affected by changes in the environment of the solution, and the release of the 15% ethanol solution, the 5% sodium chloride solution and the distilled water is substantially the same, and the MDT is 3. 6 3. 89, 3, respectively. Over 79 hours, more than 90% release in 12 hours, suggesting that the tablet can be safely used after drinking and in high sodium salt diets;

 6) From Figure 7, the release characteristics of the film in the 0.5% SDS solution and water are basically the same, MDT is 3.93, 4. 17 hours, and more than 90% release in 12 hours, it is inferred that the release of the film is not affected by the surface. The effect of the active agent. However, the release rate in the 1% CMC-Na solution decreased slightly (MDT was 5.63 hours), and it was concluded that the viscosity of the medium had a certain effect on drug release, but the effect was not significant from the overall characteristics of the release curve, and was released for 12 hours. Close to 90%. The above suggestion that the tablet is limited by the viscosity of the digestive juice and bile (surface activity) in the digestive system;

 7) From Fig. 8, the tablets were released faster than the tablets with half of the coated film, and the MDT was 2.99, and 3.37 hours, respectively. The release profile of the coating film at half removal was close to that of the complete coating (MDT of 3.76 hours), confirming that the tablet is safer than other membranes, and that the tablet can still be damaged when the coating of the tablet is slightly damaged. Play a slow release effect;

 8) In the above release study, the film did not rupture or disintegrate during the whole measurement process, and the tablet still has considerable hardness, indicating the advantage that the tablet does not disintegrate or dissolve under common release conditions. The film does not disintegrate, dissolve, and release the drug throughout the digestive system without being affected by the internal environment.

Claims

Rights request

 A controlled release tablet according to the invention, characterized in that the controlled release tablet is formed by combining and pressing two or more kinds of particles of the same drug and excipient particles containing no drug, and the controlled release tablet is in a common release degree. Under the measurement conditions, it does not disintegrate, does not dissolve, and the drug release is not easily affected by various conventional factors.

 2. The particle-controlled controlled release tablet according to claim 1, wherein the controlled release tablet has a coating film.

 3. The particle-controlled controlled release tablet according to claim 2, wherein the coating liquid for preparing the coating film is selected from one or more of the following materials: ethyl cellulose, methyl cellulose, sulfhydryl group Acrylic copolymer, cellulose acetate phthalate, polyvinyl phthalate, cellulose acetate trimellitate.

 4. The particle-controlled controlled release tablet according to claim 2, wherein the pharmaceutically acceptable plasticizer added to the coating film is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, coconut oil, castor oil, and corn oil. One or more of glycerin monoacetate, triacetin, dibutyl alginate, and dibutyl phthalate.

 The controlled release tablet according to claim 2, wherein the coating film is a coating film of an aqueous channel.

 6. The particle-controlled controlled release tablet according to claim 5, wherein the pore-porous hydrophilic material of the aqueous channel coating film is selected from the group consisting of povidone, polyvinyl alcohol, polyethylene glycol, hydroxypropylmethylcellulose, One or more of sucrose, sodium chloride, and a surfactant.

 7. The particle-controlled controlled release tablet according to claim 1, wherein the controlled release tablet has a matrix core.

 8. The particle combination controlled release tablet according to claim 7, wherein the matrix core is a sustained release matrix core

 9. The particle-controlled controlled release tablet according to claim 1, wherein the drug is a water-soluble drug.

 The combination controlled release tablet according to claim 9, wherein the water-soluble drug is selected from the group consisting of sodium ferulate, azithromycin, ampicillin sodium, chloramphenicol, fosfomycin sodium, rhein, and hydrochloric acid. Apomorphine, dihydroetorphine hydrochloride, hydromorphone hydrochloride, acetylcysteine, ethosamine, quinine dihydrochloride, disodium adenosine triphosphate, chlorpheniramine maleate, timolol maleate , taurine, diethylamine salicylate, doxycycline hydrochloride, penicillamine, benzalkonium bromide, sodium phenobarbital, sodium citrate, sodium calcium edetate, gentamicin sulfate Carbachol, cefuroxime sodium, sodium cromoglycate, trimetazidine hydrochloride, L-carnitine, acetyl-L-carnitine and its salts, propionyl L-carnitine and its salts.

The controlled release tablet according to claim 9, wherein the water-soluble drug is selected from the group consisting of trimetazidine and a salt thereof, L-carnitine and a salt thereof, acetyl L-carnitine and a salt thereof, and propionyl group. L-carnitine and its salts.

The controlled release tablet according to claim 1, wherein the auxiliary material of the controlled release tablet comprises a filler, a retarder, a binder, and a lubricant.

 The controlled release tablet according to claim 12, wherein the filler is selected from the group consisting of microcrystalline cellulose, dextrin, talc, mannitol, calcium sulfate, calcium hydrogen phosphate, and compressible starch.

 The controlled release tablet according to claim 12, wherein the retarder is selected from the group consisting of hydroxypropylmethylcellulose, alginate, chitosan, stearic acid, beeswax, bran wax, hard Aliphatic alcohol, glyceryl monostearate, methacrylic acid copolymer, non-toxic polyvinyl chloride, ethylene-vinyl acetate copolymer.

 The controlled release tablet according to claim 12, wherein said binder is selected from the group consisting of gelatin, gum arabic, dextrin, shellac, starch, hydroxypropylcellulose, and carboxymethylcellulose. , mercapto cellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol, polyethylene glycol, acrylic resin.

 The controlled release tablet according to claim 12, wherein the lubricant is selected from the group consisting of magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, and lauryl sulfate. Magnesium

 The ratio of the filler to the retarder is from 0.05 to 20:1.

 The ratio of the filler to the retarder is from 0.25 to 4:1.

 19. The granule combination controlled release tablet of claim 1 wherein said granule comprises coated granules and non-coated granules.

 The granule-combined controlled release tablet according to claim 19, wherein the coated granule is a granule having a drug content of 1% to 100°/», and the non-coated granule is a granule or a blank granule having a drug content of 0.

 The controlled release tablet according to claim 19, wherein the coating liquid of the coated granule is selected from one or more of the following materials: ethyl cellulose, fluorenyl cellulose, methacrylic acid copolymer , cellulose acetate phthalate, polyethyl phthalate phthalate, cellulose acetate trimellitate.