CN1805738A - Extended-release tablets of metformin - Google Patents

Abstract

The present invention relates to extended-release unit dosage formulations of metformin or its pharmaceutically acceptable salt thereof and the process for their preparation.

Description

Sustained-release metformin tablets

technical field

The present invention relates to a sustained-release unit dose preparation of metformin (metformin) or a pharmaceutically acceptable salt thereof, and a preparation method thereof.

Background technique

In recent years, extended-release pharmaceutical dosage forms have received much attention, and it is highly desirable to use them to provide patients with a constant amount of pharmaceutical preparations. The properties of the delivery system are controlled by the nature and dosage of the drug, the desired release profile and physiological factors. For example, it is challenging to develop a sustained release system for large doses of water soluble drugs with a narrow absorption distribution window (limited to the stomach and/or upper intestine).

Sustained-release dosage forms not only increase compliance due to less frequent dosing, but also reduce the severity and frequency of side effects because they maintain essentially constant blood levels and avoid fluctuations associated with conventional immediate-release formulations.

Metformin has been widely used to lower blood glucose in patients with non-insulin-dependent diabetes mellitus (NIDDM). However, as a short-acting drug, metformin requires two or three daily doses. A distinct advantage of sustained-release metformin dosage forms is less frequent dosing.

Side effects associated with metformin use are frequently gut-gastric related, such as anorexia, nausea, vomiting, and occasional diarrhea. These side effects can be partly avoided by reducing the initial and/or maintenance dose or using sustained release dosage forms.

Metformin is inherently poorly permeable in the lower portion of the gastrointestinal tract, resulting in its absorption in the upper portion of the gastrointestinal tract. It has high solubility in water (>300 mg/ml at 25°C). These parameters lead to difficulties in providing a sustained release of drug from a formulation, with attendant problems associated with controlling the initial bursting of the formulation. The dissolution rate of such highly soluble drugs is reduced by embedding the drug in a polymer matrix or coating the drug with a polymeric barrier membrane through which the drug must diffuse for release and absorption.

This approach may be advantageous for low-dose drugs, since large amounts of polymer are required, but disadvantageous for drugs administered on the order of a few hundred milligrams per day.

Metformin hydrochloride is commercially available, currently under the tradenames Glucophage(R) (regular) and Glucophage XR (sustained release tablet) from Bristol Mayers Squibb. Glucophage's regular tablets contain 500 mg, 800 mg and 1000 mg of metformin hydrochloride. Glucophage XR tablets (500 mg metformin hydrochloride, sustained release) contain two dual hydrophilic matrix systems as described in U.S. Patent 6,457,521, which relates to the preparation of a biphasic controlled release system for the release of metformin . This patent describes a two-phase system comprising an inner solid particulate phase containing the drug and a sustained release material, and an outer solid continuous phase containing the sustained release material. When in contact with the release medium, the drug released from the particles in the inner phase is transferred through the outer solid continuous phase and released into the upper gastrointestinal tract.

However, the total tablet weight for each tablet containing 500 mg of active ingredient is about 1000 mg, since a considerable amount of polymer is required to control the release rate of the drug. When prepared according to the method of the invention, a scale-up formulation containing 1000 mg of drug weighs at least 2 grams. This is unacceptably large for human consumption. Two 500 mg strength tablets are required for administration of metformin at a daily adult dose of 1000 mg.

Metformin is a highly water-soluble drug that flows poorly and compresses poorly and, therefore, cannot be compressed in its pure form. In addition, it is a high dose drug and therefore has a particularly high tendency to capping during tablet manufacture. Said capping not only leads to a loss of yield, but also impairs its quality. Such a high drug content does not allow large variations in the amount of excipients.

Many attempts have been made to obtain directly compressed tablets by compressing the drug with suitable excipients that facilitate handling and improve the properties of the product. However, direct compression is limited to cases where the drug is crystalline in structure and has physical properties suitable for forming a pharmaceutically acceptable tablet. However, in cases where the active ingredient cannot be directly compressed, it is necessary to add one or more excipients. Because excipients added to the formulation increase the size of the tablet, the direct compression method is practically limited to formulations containing low doses of active ingredient. Furthermore, the capping tendency is particularly high in the case of direct compression containing high doses of active ingredient.

Such an attempt was made in US Patent 6,117,451, which describes the use of specific excipients in specific size and density ranges to improve the flow and compressibility of metformin hydrochloride. These excipients were mixed with metformin and the resulting mixture was directly compressed. In this patent, wet granulation is used to convert the powder mixture into granules with the proper fluidity and cohesiveness required for tablets. The method comprises mixing powders in a suitable mixer and then adding a granulating liquid to the mixed powders under shear to obtain granules. These wet masses are then screened through suitable sieves and dried. Wet granulation also produces variable release properties depending on the degree of polymer hydration. Furthermore, the use of organic solvents leads to the problem of residual solvents.

US Patent 5,955,106 discloses a method comprising granulating metformin and a hydrocolloid-forming retarding agent with an aqueous solvent to form a granular product, and drying the granular product. Hydrocolloid retarders, when in contact with an aqueous medium, swell and form a gel matrix that erodes to release the drug.

Sustained release metformin compositions have also been made using other technologies. US Patent 6,340,475 describes an oral dosage form in which the drug is incorporated into a polymer matrix consisting of a hydrophilic polymer which absorbs water and swells to a sufficiently large size To promote retention of the dosage form in the stomach. The swollen polymer matrix remains intact for a period of time sufficient to allow release of substantially all of the drug before the matrix dissolves.

However, there remains a need for a metformin dosage form that can introduce high doses and is easy to manufacture and that provides sustained release. There is also a need for methods that can impart good flow and compressibility to the mixture, address capping issues, and provide the desired sustained release.

The present inventors have discovered a sustained release pharmaceutical composition of metformin which maintains blood level concentrations of therapeutic amounts of the drug in the patient's body for a sufficient period of time and which can be formulated as a monolithic matrix for prolonged periods Slow release of active ingredients.

Contents of the invention

In one aspect, sustained release metformin tablets are formulated as a monolithic matrix containing metformin, a rate controlling polymer and other pharmaceutically acceptable excipients.

In another aspect, there is provided a sustained release metformin tablet comprising a high dose of metformin and having an acceptable size to facilitate oral administration.

Sustained-release metformin tablets, on the other hand, comprise a monolithic system that releases highly soluble metformin at a relatively constant rate over an extended period of time, which is easy to manufacture.

In yet another aspect, there is provided a sustained release metformin tablet comprising 5-25% w/w rate controlling polymer. The use of a lower amount of rate controlling polymer than previously known formulations ensures that the overall weight of the dosage form is lower and that a single dosage unit is sufficient to provide a therapeutic dose of drug. Sustained-release tablets therefore offer the benefit of greater patient convenience and compliance.

In one aspect there is provided a sustained release tablet which releases metformin in a controlled manner over a period of 24 hours, especially over a period of 12 hours.

In another aspect, there is provided an 850 mg strength sustained release metformin tablet comprising 5-25% w/w rate controlling polymer and other pharmaceutically acceptable excipients.

In another aspect, there is provided a 1000 mg strength sustained release metformin tablet comprising 5-25% w/w rate controlling polymer and other pharmaceutically acceptable excipients.

In a general aspect, there is provided a monolithic sustained release tablet containing 500-1000 mg of metformin, wherein the total weight of the tablet does not exceed 1500 mg.

In another general aspect, there is provided a method of preparing sustained release tablets of metformin or a non-toxic acid addition salt thereof, the method comprising mixing the components followed by roller compaction or compression. The compacts are suitably sized and compressed into tablets.

In another general aspect, there is provided an 850 mg strength sustained release metformin tablet prepared by roller compaction.

In another general aspect, there is provided a 1000 mg strength sustained release metformin tablet prepared by roller compaction.

Roller compaction generally involves a screening step that results in a narrow particle size distribution with few particles at the extreme ends of the size range. Roll compaction offers several other advantages, such as obtaining a mixture with a uniform particle size range, improving flow properties, aiding in dust control, increasing bulk density, and controlling particle hardness.

In another aspect, there is provided a sustained release metformin tablet comprising:

a. about 500-1000 mg of metformin,

b. 5-25% w/w rate controlling polymer, and

c. Other pharmaceutically acceptable excipients.

In another aspect, a method of preparing a sustained release tablet of metformin comprises:

e. mixing metformin, 5-25% w/w rate controlling polymer and other pharmaceutically acceptable excipients,

f. compaction/pressing,

g. grinding or crushing the compacted/compressed material in step (b) into granules, and

h. Lubricate and compress the granules to form tablets.

According to our pending Indian patent application, 1002/DEL/2001 (incorporated herein by reference in its entirety), the humidity of metformin can be adjusted to further improve flow properties prior to mixing with rate controlling polymers and other excipients. Alternatively, metformin can be mixed with a rate-controlling polymer and/or other excipients, followed by humidity adjustment.

Accordingly, methods of preparing sustained-release metformin tablets include:

a. Regulate the humidity of metformin,

b. mixed with 5-25% w/w rate controlling polymer and other pharmaceutically acceptable excipients,

c. Compaction/pressing,

d. grinding or crushing the compacted/compressed material in step (b) into granules, and

e. Lubricate and compress the granules to form tablets.

Therefore, another method of preparing sustained-release metformin tablets involves:

a. mixing metformin, 5-25% w/w rate controlling polymer and other pharmaceutically acceptable excipients,

b. Regulating the humidity of the mixture,

c. Compaction/pressing,

d. grinding or crushing the compacted/compressed material in step (b) into granules, and

e. Lubricate and compress the granules to form tablets.

According to one embodiment of the present invention, there is provided a method of preparing a sustained release tablet of metformin. Therein the tablet has better strength, aesthetic appeal, desired profile and yield, and enables the incorporation of very high doses of drug without making the tablet unacceptably large and difficult to swallow.

In another aspect, a method of treating non-insulin dependent diabetes is provided to a patient in need thereof, said method comprising administering a sustained release metformin tablet comprising:

a. about 500-1000 mg of metformin,

b. 5-25% w/w rate controlling polymer, and

c. Other pharmaceutically acceptable excipients.

The sustained release tablet may also include one or more of sulfonylurea, insulin, glitazone, alpha-glucosidase inhibitor, meglitinide, fibrate, star Statin, squalene synthesis inhibitor and angiotensin converting enzyme inhibitor.

Detailed ways

Monolithic systems (such as sustained-release dosage forms) consisting of hydrophilic polymers and other excipients are convenient and cost-effective.

The term "monolithic matrix" as used herein refers to a drug-containing matrix formed by uniformly dispersing or dissolving the drug in a suitable polymer. Monolithic systems can be prepared by direct compression, wet and dry granulation methods. In this dosage form, the diffusion of drug through the matrix is the rate limiting step. The rate of release from the matrix generally follows the square root of time. In monolithic formulations made of hydrophilic polymers, drug release is controlled by the rate at which the polymer matrix swells.

Metformin can be used in the form of acid addition salts of inorganic or organic acids. Such acids are for example, but not limited to, hydrochloric acid, formic acid, acetic acid, malic acid, tartaric acid or fumaric acid.

In each tablet, Metformin can account for 1000 mg.

The rate controlling polymer may be selected from cellulose derivatives, starch or its derivatives, alginates, acrylic and methacrylic acid derivatives, polyethylene oxide, gums, carbohydrate based polymers and similar Material.

Cellulose derivatives can be selected from ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, carboxy Sodium methylcellulose or similar material. These polymers may be used alone or in combination.

The acrylic polymer may be, for example, a carboxyvinyl polymer commercially available under the tradename Carbopol(R) (B.F. Goodrich, USA). The carbohydrate based polymer may be selected from xanthan gum, tragacanth gum, karaya gum, guar gum, gum arabic, gellang gum, locust bean gum and the like. The rate controlling polymer comprises 5-25% w/w of the formulation.

Pharmaceutically acceptable excipients can be selected from diluents, binders, lubricants, glidants and flavoring agents, which are physically and chemically compatible with metformin and help to optimize Tablet hardness, friability, drug dissolution and manufacturing method.

The diluent may be selected from any such pharmaceutically acceptable excipients which lend bulk to the composition and improve its compressibility. These diluents may be selected from starch and starch derivatives, dicalcium phosphate, calcium sulfate, sorbitol, microcrystalline cellulose, lactose, dextrose, mannitol, alginates, alkaline earth metal salts, clays, polyethylene glycols or similar material.

The binder may be selected from starch, mannitol, polyvinylpyrrolidone, carboxymethylcellulose, hydroxyalkylcellulose, dextrin, carbohydrate gums, alginate, polyacrylic acid, polyvinyl alcohol and similar materials or mixture.

Lubricants may be selected from talc, magnesium stearate, stearates of other alkaline earth metals (such as zinc stearate and calcium stearate, etc.), sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, stearyl fumaric acid Sodium, glyceryl monostearate, polyethylene glycol and similar materials.

Glidants may be selected from colloidal silicon dioxide, talc and similar materials.

The mixture is compacted by roller pressing. Alternatively, the mixture can be compressed to form slugs. One embodiment involves compacting or compressing the metformin alone or after mixing it with a rate controlling polymer and/or excipient.

The compacted or compressed material is crushed/ground and sieved to the desired particle size using a suitable mill (eg vibratory granulator/multimil/Fitzmil).

These granules are lubricated with a lubricant and compressed into tablets.

Metformin can be mixed with one or more antidiabetic agents, if desired, prior to the compaction step. Suitable antidiabetic agents include those selected from the group consisting of sulfonylureas (such as glyburide, glipizide, glimepiride and gliclazide), alpha-glucosidase inhibitors (such as acarbose and alcohol), glitazones (such as rosiglitazone and pioglitazone), and mixtures of two or more of the above antidiabetic agents.

The following examples illustrate various embodiments but do not limit the claims in any way.

Example 1 Element Weight (mg)/tablet Metformin hydrochloride 1000.00 Sodium carboxymethyl cellulose 25.00   Microcrystalline Cellulose 85.00 Hydroxypropylmethylcellulose 275.00 Magnesium stearate 3.75 Colloidal silica 16.25 water 45.00 in total 1450.00

step:

1. Weigh the above ingredients and sieve through a suitable sieve.

2. Mix metformin hydrochloride with microcrystalline cellulose in a mixer and spray with the required amount of purified water.

3. Mix the mixture in step 2 with sodium carboxymethylcellulose, hydroxypropylmethylcellulose, magnesium stearate and part of the colloidal silicon dioxide.

4. Screen the mass in step 3 and then compact it using a roller compactor.

5. The compacted material is properly sized.

6. The sized granules are lubricated and compressed into tablets.

Example 2 Element Weight (mg)/tablet

Metformin hydrochloride 850.00 Sodium carboxymethyl cellulose 21.25   Microcrystalline Cellulose 72.25 Hydroxypropylmethylcellulose 233.75 Magnesium stearate 3.1875 Colloidal silica 13.8175 water 38.25 in total 1232.5

Steps: the steps given in Example 1.

Table 1 provides the release profiles of the tablets prepared according to Examples 1 and 2.

Table 1: Release profiles of the tablets of Examples 1 and 2 in phosphate buffer at pH 6.8/900ml/USP Apparatus II/50rpm time (hours) The drug release percentage (%) of the tablet of embodiment 1 The drug release percentage (%) of the tablet of embodiment 2 0.5 twenty three twenty one 1.0 33 30 2.0 46 45 4.0 63 66 6.0 76 79 8.0 85 87 10.0 91 95 12.0 94 96

Example 3 Element Weight (mg)/tablet Metformin hydrochloride 1000.00 Sodium carboxymethyl cellulose 25.00   Microcrystalline Cellulose 36.50 Hydroxypropylmethylcellulose 325.00

Magnesium stearate 3.00 Colloidal silica 15.5 water 45.00 in total 1450.00

Steps: the steps given in Example 1.

Example 4 Element Weight (mg)/tablet Metformin hydrochloride 1000.00 Dicalcium phosphate 205.00 Hydroxypropylmethylcellulose 175.00 Magnesium stearate 5.00 Colloidal silica 10.00 Talc 5.00 water 20.00 in total 1420.00

Steps: the steps given in Example 1.

Table 2 provides the release profiles of the tablets prepared according to Examples 3 and 4.

Table 2: Release profiles of the tablets of Examples 3 and 4 in phosphate buffer at pH 6.8/900ml/USP Apparatus II/50rpm time (hours) The drug release percentage (%) of the tablet of embodiment 3 The drug release percentage (%) of the tablet of embodiment 4 0.5 18 twenty one 1.0 28 31 2.0 41 47 4.0 59 67 6.0 70 80 8.0 79 90 10.0 86 94 12.0 88 96

Furthermore, it is contemplated that any single feature, or combination of optional features, of the inventive variations described herein may be expressly excluded from the claimed invention, so described as a negative limitation. Accordingly, the invention is defined by the appended claims.

Claims (61)

1. dimethyldiguanide tablet that continue to discharge comprises:

The metformin of a. about 500-1000 milligram,

B.5-25% the control rate aggregation thing of w/w and

C. other pharmaceutically acceptable excipient.

2. continuous release tablet as claimed in claim 1 is characterized in that, it comprises 850 gram metformin.

3. continuous release tablet as claimed in claim 1 is characterized in that, it comprises 1000 gram metformin.

4. continuous release tablet as claimed in claim 1 is characterized in that, wherein metformin is the form of alkali or the form of pharmaceutically acceptable salt.

5. continuous release tablet as claimed in claim 4 is characterized in that, wherein pharmaceutically acceptable salt is hydrochlorate, fumarate, hydrobromate, succinate or embonate.

6. continuous release tablet as claimed in claim 5 is characterized in that wherein pharmaceutically acceptable salt is a hydrochlorate.

7. continuous release tablet as claimed in claim 1, it is characterized in that described control rate aggregation thing is selected from cellulose derivative, starch or derivatives thereof, alginate, acrylic or methacrylic acid derivative, poly(ethylene oxide), natural gum and based on the polymer of carbohydrate.

8. continuous release tablet as claimed in claim 7 is characterized in that, described control rate aggregation thing is selected from cellulose derivative.

9. continuous release tablet as claimed in claim 8, it is characterized in that described cellulose derivative is selected from ethyl cellulose, methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or its mixture.

10. continuous release tablet as claimed in claim 9 is characterized in that, described cellulose derivative is the mixture of hydroxypropyl emthylcellulose and sodium carboxymethyl cellulose.

11. continuous release tablet as claimed in claim 1 is characterized in that, described other pharmaceutically acceptable excipient comprises diluent, binding agent, lubricant, fluidizer and flavoring agent.

12. continuous release tablet as claimed in claim 11, it is characterized in that described binding agent is selected from starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl cellulose, dextrin, carbohydrate glue, alginate, polyacrylic acid, polyvinyl alcohol or its mixture.

13. continuous release tablet as claimed in claim 11 is characterized in that, described diluent is a microcrystalline Cellulose.

14. continuous release tablet as claimed in claim 11 is characterized in that, described lubricant is a magnesium stearate.

15. continuous release tablet as claimed in claim 11 is characterized in that, described fluidizer is a colloidal silica.

16. continuous release tablet as claimed in claim 1 is characterized in that, the gross weight of described tablet is no more than 1500 milligrams.

17. continuous release tablet as claimed in claim 1 is characterized in that, described tablet controllably discharged metformin in 12 hours.

18. continuous release tablet as claimed in claim 1 is characterized in that, described tablet discharged metformin in 24 hours.

19. continuous release tablet as claimed in claim 1, it is characterized in that described tablet also comprises one or more sulfonylureas, insulin, lattice row ketone, Alpha-glucosidase inhibitor, Ge Lienai, Bei Te, Si Dating, zamene synthetic inhibitor and angiotensin converting enzyme inhibitor.

20. a method for preparing the dimethyldiguanide tablet that continues to discharge comprises:

A. mix the control rate aggregation thing of metformin, 5-25% w/w and other pharmaceutically acceptable excipient,

B. compacting/compacting,

C. the material of compacting/compacting in the step (b) is ground or pulverize into granule and

D. lubricate and suppress described granule and form tablet.

21. method as claimed in claim 20 is characterized in that, described continuous release tablet contains 850 milligrams of metformin.

22. method as claimed in claim 20 is characterized in that, described continuous release tablet contains 1000 milligrams of metformin.

23. method as claimed in claim 20 is characterized in that, wherein metformin is the form of alkali or the form of pharmaceutically acceptable salt.

24. method as claimed in claim 23 is characterized in that, wherein pharmaceutically acceptable salt is hydrochlorate, fumarate, hydrobromate, succinate or embonate.

25. method as claimed in claim 24 is characterized in that, wherein pharmaceutically acceptable salt is a hydrochlorate.

26. method as claimed in claim 20, it is characterized in that described control rate aggregation thing is selected from cellulose derivative, starch or derivatives thereof, alginate, acrylic or methacrylic acid derivative, poly(ethylene oxide), natural gum and based on the polymer of carbohydrate.

27. method as claimed in claim 26 is characterized in that, described control rate aggregation thing is selected from cellulose derivative.

28. method as claimed in claim 27, it is characterized in that described cellulose derivative is selected from ethyl cellulose, methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or its mixture.

29. method as claimed in claim 28 is characterized in that, described cellulose derivative is the mixture of hydroxypropyl emthylcellulose and sodium carboxymethyl cellulose.

30. method as claimed in claim 20 is characterized in that, described other pharmaceutically acceptable excipient comprises diluent, binding agent, lubricant, fluidizer and flavoring agent.

31. method as claimed in claim 30, it is characterized in that described binding agent is selected from starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl cellulose, dextrin, carbohydrate glue, alginate, polyacrylic acid, polyvinyl alcohol or its mixture.

32. method as claimed in claim 30 is characterized in that, described diluent is a microcrystalline Cellulose.

33. method as claimed in claim 30 is characterized in that, described lubricant is a magnesium stearate.

34. method as claimed in claim 30 is characterized in that, described fluidizer is a colloidal silica.

35. method as claimed in claim 20 is characterized in that, described tablet prepares by compacting.

36. method as claimed in claim 20 is characterized in that, described tablet prepares by the roller compacting.

37. method as claimed in claim 20 is characterized in that, the gross weight of described tablet is no more than 1500 milligrams.

38. method as claimed in claim 20 is characterized in that, described tablet controllably discharged metformin in 12 hours.

39. method as claimed in claim 20 is characterized in that, described tablet discharged metformin in 24 hours.

40. method as claimed in claim 20, it is characterized in that described tablet also comprises one or more sulfonylureas, insulin, lattice row ketone, Alpha-glucosidase inhibitor, Ge Lienai, Bei Te, Si Dating, zamene synthetic inhibitor and angiotensin converting enzyme inhibitor.

41. the dimethyldiguanide tablet of the lasting release of a monoblock comprises:

The metformin of a. about 500-1000 milligram,

B.5-25% the control rate aggregation thing of w/w and

C. other pharmaceutically acceptable excipient.

42. continuous release tablet as claimed in claim 41 is characterized in that, it comprises 850 gram metformin.

43. continuous release tablet as claimed in claim 41 is characterized in that, it comprises 1000 gram metformin.

44. continuous release tablet as claimed in claim 41 is characterized in that, wherein metformin is the form of alkali or the form of pharmaceutically acceptable salt.

45. continuous release tablet as claimed in claim 44 is characterized in that, wherein pharmaceutically acceptable salt is hydrochlorate, fumarate, hydrobromate, succinate or embonate.

46. continuous release tablet as claimed in claim 45 is characterized in that, wherein pharmaceutically acceptable salt is a hydrochlorate.

47. continuous release tablet as claimed in claim 41, it is characterized in that described control rate aggregation thing is selected from cellulose derivative, starch or derivatives thereof, alginate, acrylic or methacrylic acid derivative, poly(ethylene oxide), natural gum and based on the polymer of carbohydrate.

48. continuous release tablet as claimed in claim 47 is characterized in that, described control rate aggregation thing is selected from cellulose derivative.

49. continuous release tablet as claimed in claim 48, it is characterized in that described cellulose derivative is selected from ethyl cellulose, methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or its mixture.

50. continuous release tablet as claimed in claim 49 is characterized in that, described cellulose derivative is the mixture of hydroxypropyl emthylcellulose and sodium carboxymethyl cellulose.

51. continuous release tablet as claimed in claim 41 is characterized in that, described other pharmaceutically acceptable excipient comprises diluent, binding agent, lubricant, fluidizer and flavoring agent.

52. continuous release tablet as claimed in claim 51, it is characterized in that described binding agent is selected from starch, mannitol, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxy alkyl cellulose, dextrin, carbohydrate glue, alginate, polyacrylic acid, polyvinyl alcohol or its mixture.

53. continuous release tablet as claimed in claim 51 is characterized in that, described diluent is a microcrystalline Cellulose.

54. continuous release tablet as claimed in claim 51 is characterized in that, described lubricant is a magnesium stearate.

55. continuous release tablet as claimed in claim 51 is characterized in that, described fluidizer is a colloidal silica.

56. continuous release tablet as claimed in claim 41 is characterized in that, the gross weight of described tablet is no more than 1500 milligrams.

57. continuous release tablet as claimed in claim 41 is characterized in that, described tablet controllably discharged metformin in 12 hours.

58. continuous release tablet as claimed in claim 41 is characterized in that, described tablet discharged metformin in 24 hours.

59. continuous release tablet as claimed in claim 41, it is characterized in that described tablet also comprises one or more sulfonylureas, insulin, lattice row ketone, Alpha-glucosidase inhibitor, Ge Lienai, Bei Te, Si Dating, zamene synthetic inhibitor and angiotensin converting enzyme inhibitor.

60. the patient for the needs treatment provides the method for the diabetes of the non--insulin dependency of treatment, described method comprises the dimethyldiguanide tablet that continues release, and described tablet comprises:

A. more than 500 milligrams metformin,

B.5-25% the control rate aggregation thing of w/w and

C. other pharmaceutically acceptable excipient.

61. method as claimed in claim 60, it is characterized in that described tablet also can comprise one or more sulfonylureas, insulin, lattice row ketone, Alpha-glucosidase inhibitor, Ge Lienai, Bei Te, Si Dating, zamene synthetic inhibitor and angiotensin converting enzyme inhibitor.