Description

SUSTAINED-RELEASE FORMULATION COMPRISING METFORMIN ACID SALT

Technical Field

[1] The present invention relates to sustained-release formulation comprising metformin acid salt.

[2]

Background Art

[3] Metformin as a biguanide agent for treating diabetes mellitus is used in the form of hydrochloride salt. Metformin as an agent for treating non-insulin-dependent diabetes is used alone in case that diet therapy is not sufficient or also used together with sulfonylurea agent in case that only the sulfonylurea agent is not sufficient.

[4] The physical and chemical properties and so on of metformin hydrochloride and other metformnin salts are disclosed in WO 99/29314. It is difficult to deal with metformin hydrochloride while preparing pharmaceuticals. The reason is that metformin hydrochloride, a white adhesive powder, having a very high aqueous solubility (>300 mg/ml, > 230 mg/ml as metformin) needs a plenty of sustained-release polymer in order to prepare sustained-release formulation, moreover it accompanies a high hygroscopicity (25°C/95 % RH, at least 20% absorption after 6 hours, a high compaction susceptibility). Therefore, the problems that the formulation size becomes very large due to said physical and chemical properties of metformin hydrochloride under the necessity of a plenty of sustained-release excipients are occurred.

[5]

Disclosure of Invention Technical Problem

[6] The object of the present invention is to provide a pharmaceutical composition comprising metformin acid salt as an active ingredient, which can increase the convenience of the patients' administration as well as the preparation of the pharmaceuticals and facilitate the preparation of sustained-release metformin formulation by minimizing the final formulation size.

[7] The size of the final formulation could be reduced by replacing metformin hydrochloride with other metformin acid salts as an active ingredient. The reason is that said other metformin acid salts have similar molecular weights and lower aqueous solubility compared to metformin hydrochloride. Accordingly, it is possible to use less amount of the sustained-release excipient while preparing the formulation.

[8]

Technical Solution

[9] The present invention provides the composition for treating or preventing diabetes mellitus and related diseases thereof, which comprises metformin acid salt as an active ingredient and sustained-release excipients and further comprises a pharmaceutically acceptable carrier.

[10] The aqueous solubility of metformin acid salt of the present invention is not more than 230 mg/ml as metformin, preferably metformin acid salt is selected form metformin succinate and metformin oxalate. The pharmaceutical composition of the present invention comprising metformin acid salt and a pharmaceutically acceptable carrier is prepared in the form of a sustained-release formulation. The sustained-release formulation of the present invention may additionally comprise other agents for treating diabetes mellitus, preferably may be a complex sustained-release formulation which is a combination of metformin acid salt and sulfonylurea drug.

[H]

Advantageous Effects

[12] Metformin succinate and metformin oxalate as metformin acid salt according to the present invention show notably sustained release patterns in a drug release due to the lower solubility compared to that of the metformin hydrochloride while using the same amount of sustained-release excipient. Accordingly, in the preparation of a metformin formulation with these salts, it is easy to control of metformin release with less amount of sustained-release agent than metformin hydrochloride. At results, it is possible to remarkably reduce the size of a tablet so that patients can easily take the drugs and the preparation process can be simplified and less cost compared to previous sustained- release metformin formulation.

[13]

Brief Description of the Drawings

[14] Fig. 1 shows the results of the dissolution test of examples 3, 4 and comparative example depending on time at pH 6.8. (n=6)

[15] Fig. 2 shows the results of the dissolution test of examples 3, 5, 6, 7, and comparative example depending on time at pH 6.8. (n=6)

[16] Fig. 3 shows the concentration of drug in rat's blood of examples 1, 6, and comparative examaple depending on time at pH 6.8. (n=6)

[17]

Best Mode for Carrying Out the Invention

[18] As a sustained-release excipient for a sustained-release formulation of the present invention, hydroxypropylmethyl cellulose, acrylic acid and derivatives thereof or Eudragits may be used. The preferable administration path of the sustained-release for-

mulation is an oral administration. A tablet or a capsule may be exemplified as a mean for such administration. The formulation can be prepared by mixing an active ingredient and a carrier and then, tableting the mixed product. In this case, the proper example of used carrier may include a disintegrant such as sodium starch glycogate, crospovidone, starch, glucose and mannitol; a filler and an extender such as lactose, calcium phosphate and silicic acid derivatives; a binder such as polyvinyl pyrrolidone, carboxymethyl cellulose and other cellulose derivatives and gelatine; a lubricant such as talc, calcium stearate, magnesium stearate, and solid polyethylene glycol and so on. A hard or soft gelatine capsule comprising an active ingredient without or with the carrier can be also prepared by a conventional method. It is preferable that the pharmaceutical composition comprises 200mg to lOOOmg of metformin acid salt per dose unit as an active ingredient.

[19]

Mode for the Invention

[20] The present invention will be described in greater detail with reference to the following examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[21]

[22] The preparation of merformin acid salt

[23] Example 1: Preparation of metformin succinate

[24] Metformin hydrochloride (10.0 g, 60.4 mmol) and sodium hydroxide (2.42g, 60.4 mmol) were added to purified water (30ml) and stirred for 30 min and the solution was concentrated under reduced pressure at 40~45°C. Then the resulting product was added to 20 % ethanol (100 ml) and dissolved in a reactor. Succinic acid (7.09g, 60.4 mmol) dissolved in 120 ml of ethanol in another reactor was added to the reactor which contained the solution of metformin. The resulting solution was stirred for 2 hours at not more than 1O ⁰ C, filtrated and washed with ethanol (20 ml), then dried for 6 hours at 6O ⁰ C to obtain 10.2 g of the title compound.

[25] ¹ H NMR (D ₂ O) : δ 2.28 (s, 4H), 2.93 (s, 12 H)

[26] Example 2: The preparation of metformin oxalate

[27] According to the same method as example 1 except for replacing succinic acid with oxalic acid, 8.2g of the title compound was obtained.

[28] ¹³ C NMR (D ₂ O): δ 37.57 (methylamine-C), 158.52 (C=N), 160.17 (C=N), 173.46

(carboxyl-C)

[29]

[30] The preparation of pharmaceutical composition of metformin acid salt

[31] In order to confirm the effect of the sustained-release of acid salt according to the

present invention, we prepared the sustained-release formulation of metformin acid salt comprising 430 g hydroxypropylmethyl cellulose (40% -45%) as a sustained-release excipient in examples 3 and 4.

[32] [33] Example 3: The preparation of pharmaceutical composition of metformin succinate [34]

Composition

1. metformin succinate 568.5g

( 39Og corresponding amount as metformin)

2. hydroxypropylmethyl cellulose 100,000 cps 43Og

3. lactose 30g

4. polyvinyl pyrrolidone K30 35g

5. magnesium stearate 5g

6. purified water (20Og)

[35] Metformin succinate, hydroxypropylmethyl cellulose, lactose and polyvinyl pyrrolidine were added in a mixer and mixed all together. After that, purified water was added and mixed. The mixed composition was dried in a fluidized bed dryer and screened by sieve in size of 50 mesh. To that, magnesium stearate was added, mixed and a tablet was tableted (1068.5 mg per tablet).

[36] [37] Example 4: The preparation of pharmaceutical composition of metformin oxalate. [38]

Composition

1. metformin oxalate 661.9g

(39Og corresponding amount as metformin)

2. hydroxypropylmethyl cellulose 100,000 cps 43Og

3. lactose 30g

4. polyvinyl pyrrolidone K30 35g

5. magnesium stearate 5g

6. purified water (20Og)

[39] According to the same method as example 3 except for replacing metformin succinate with metformin oxalate as an active ingredient, a tablet was prepared (1161.9 mg per tablet).

[40] [41] In examples of 5 and 6, it is intended to show that the present invention accomplished to increase the basis adaptability and obtain the effect of cutting cost by reducing a tablet size by means of decreasing the amount of hydroxypropylmethyl cellulose as a sustained-release excipient with using metformin acid salt prepared in example 1.

[42] [43] Example 5: The preparation of pharmaceutical composition of metformin succinate wherein the amount of sustained-release excipient was reduced to 30% by weight based on total weight.

[44]

Composition

1. metformin succinate 568.5g

( 390g corresponding amount as metformin)

2. hydroxypropylmethyl cellulose 100,000 cps 28Og

3. lactose 30g

4. polyvinyl pyrrolidone K30 35g

5. magnesium stearate 5g

6. purified water (20Og)

[45] The amount of hydroxypropylmethyl cellulose as a sustained-release excipient was decreased to 30% by weight based on total weight (about 28Og) by the same method of example 3 to obtain a tablet (918.5 mg per tablet).

[46] [47] Example 6: The preparation of pharmaceutical composition of metformnin succinate wherein the amount of sustained-release excipient was reduced to 14% by weight based on total weight.

[48]

Composition

1. metformin succinate 568.5g

( 39Og corresponding amount as metformin)

2. hydroxypropylmethyl cellulose 100,000 cps l05g

3. lactose 30g

4. polyvinyl pyrrolidone K30 35g

5. magnesium stearate 5g

6. purified water (20Og)

[49] The amount of hydroxypropylmethyl cellulose as a sustained-release excipient was decreased to 14% by weight based on total weight (about 105g) by the same method of example 3 to obtain a tablet (743.5 mg per tablet).

[50] [51] Example 7: The preparation of complex sustained-release formulation of pharmaceutical composition which is a combination of the composition of example 6 and glimepiride.

Composition

1. metformin succinate 568.5g

( 39Og corresponding amount as metformin)

2. hydroxypropylmethyl cellulose 100,000 cps 105

3. lactose 3Og

4. polyvinyl pyrrolidone K30 35g

S. magnesium stearate 58

6. purified water (200g)

Coating preparation

7. glimcpiride 2.Og

8. hydroxypropylmethyl cellulose 100,000 cps 24.9g

9. polyethylene glycol 4.9g

10. titanium dioxide I 7g

11. sodium lauryl sulfate l-5g

[53] The pharmaceutical compound of example 6 was coated by the mixed solution of glimepiride, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide, sodium lauryl sulfate to obtain a tablet (778.5 mg per tablet).

[54] [55] Comparative example [56] Comparative example 1 : The preparation of pharmaceutical composition of metformin hydrochloride comprising 43% by weight of sustained-release excipient base on total wieght of a tablet.

[57]

Composition

1. metformin hydrochloride 500.0g

( 39Og corresponding amount as metformin)

2. hydroxypropylmethyl cellulose 100,000 cps 43Og

3. lactose 30g

4. polyvinyl pyrrolidone K30 35g

S. magnesium stearate 5g

6. purified water (20Og)

[58] The pharmaceutical composition was prepared by the same method as example 3 except for using metformin hydrochloride as an active ingredient.

[59] [60] Experimental examples [61] Experimental example 1 : Measurement of solubility of metformin acid salt [62] In order to confirm the solubility in water of aqueous active ingredients, we performed a solubility test of metformin acid salt described as below and the test was

performed by measuring each solubility of salts prepared in examples 1, 2 and previous salt (metformin chloride). To 30 ml purified water, the salts prepared in above examples and metformin chloride were sufficiently added and stirred at room temperature (22+5 ⁰ C). Then, the amount of metformin was measured at a fixed time by getting a sample. The results are shown in table 1.

[63] Table 1 [Table 1]

[64] As seen in table 1, the solubility of metfromin acid salt of the present invention is remarkably lower compared to metformin chloride.

[65] [66] Experimental example 2: Measurement of dissolution rate of metformin acid salt [67] In order to confirm the effect of continued release of the water-soluble active ingredient, we performed a dissolution test of metformin described as below and the test was performed by measuring dissolution rate of each formulation prepared in examples 3, 4 and comparative example. The dissolution test was performed according to the method of dissolution 2 described in United States Pharmacopoeia (USP) by using 900 ml of simulating serous fluid of pH 6.8 at 37 ⁰ C. The amount of metformin was measured by sampling the dissolution at each time (n=6). The results are shown in Fig. 1 and table 2.

[68] Table 2 [Table 2]

[69] As seen in Fig. 1 and table 2, the dissolution rate of metformin acid salt prepared in examples 3 and 4 by using the same amount of the sustained-release excipient as in comparative example was remarkably lowered than that of comparative example. This represents the effect of new acid salt prepared in examples 3 and 4.

[71] Experimental example 3: Measurement of dissolution rate of a tablet according to the change of the amount of sustained-release excipients for metformin acid salt [72] In order to confirm the effect of continued release of a water-soluble active ingredient according to the decrease of sustained-release excipient, we performed a dissolution test of metformin described as below and the test was performed by measuring the amount of metformin dissolved in each formulation prepared in examples 3, 5, 6, 7 and comparative example. The dissolution test was performed according to the method of dissolution 2 described in United States Pharmacopoeia (USP) by using 900 ml of simulating serous fluid of pH 6.8 at 37 ⁰ C. The amount of metformin was measured by sampling the dissolution at each time (n=6). The results are shown in Fig. 2 and table 3.

[73] Table 3 [Table 3]

[74] We compared all dissolution rates in each case of examples 3, 5, 6 and comparative example with decreasing the amount of sustained-release excipient in phase. As seen in Fig. 2 and table 3, the dissolution rates in comparative example and example 6 whose composition comprised only 14 % of sustained-release excipient, were similar each other. Moreover, a complex sustained-release formulation prepared in example 7 had a similar release-pattern to comparative example. This indicates that the size of a tablet may be remarkably reduced by decreasing the amount of sustained-release agents used in the preparation of the formulation such as examples 6 and 7.

[75] [76] Experimental example 4: Measurement of drug concentration in blood of rat [77] In order to investigate pharmacokinetic properties of the water-soluble active ingredient, after jugular vein cannulation to about 6-7 weeks rats, a given number of rats were orally administered of each of metformin hydrochloride and pharmaceutical compositions prepared in examples 1 and 6, and comparative example. Then, the concentration of the active ingredient was measured at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 9 hours by sampling 0.4ml of blood. The results are described in Fig. 3 and table 4.

[78] Table 4

[Table 4]

[79] In the Fig. 3 and table 4, we investigated pharmaceutical properties of the water- soluble active ingredients of metformin hydrochloride and examples 1 and 6, and comparative example. From the area under the curve (AUC), at results, we found that bioavailabilities of the compositions of examples 1 and 6 are superior to those of metformin hydrochloride and composition of comparative exmaple. This fact proves that the bioavailability of the sustained-release formulation comprising new acid salt of is excellent.