KR20090013736A - Sustained-release formulation comprising metformin acid salt - Google Patents

Abstract

A sustained-release formulation comprising metformin acid addition salt is provided to remarkably reduce the size of tablet and facilitate the drug intaking of patient by using a small amount of release-sustaining agent, and simplify the manufacturing process. The sustained-release formulation comprises metformin acid addition salt having solubility in water of 230 mg/ml or less as metformin and pharmaceutically acceptable carriers, and is formulated as tablet or capsule, wherein the metformin acid addition salt is metformin succinate or metformin oxalate; and the carrier is hydroxypropylmethyl cellulose, acrylic acid and its derivative or eudragit.

Description

Sustained-release formulation comprising metformin acid salt

The present invention relates to a sustained release preparation comprising metformin acid addition salt.

Metformin, a biguanide-based diabetes treatment, is commercially available in the form of hydrochloride. Metformin is used alone as a therapeutic agent for insulin-independent diabetes, or in combination with a sulfonylurea system even when sulfonylurea alone is insufficient.

WO 99/29314 disclosed in the prior art discloses the physicochemical properties of metformin hydrochloride and other metformin salts. Metformin hydrochloride is a white, tacky powder with a very high aqueous solubility (> 300 mg / mL,> 230 mg / mL as metformin), which requires a large amount of sustained-release polymer and, concomitantly hygroscopic ( hygroscopicity (25 ℃ / 95% RH, hygroscopicity over 20% after 6 hours, high compressibility) is a problem that is difficult to handle in the manufacture of pharmaceuticals. Due to the physicochemical properties of metformin hydrochloride, there is a problem in that a large amount of the sustained-release excipient is required when formulating the release control system, thereby increasing the size of the formulation.

An object of the present invention relates to the composition of a formulation capable of sustaining the release of metformin salt with a relatively low amount of sustained-release excipient, while having a similar molecular weight compared to metformin hydrochloride, and having a relatively low solubility in water. By developing a formulation composition comprising metformin acid addition salts with low solubility, the size of the final formulation can be reduced to increase patient comfort, facilitate the preparation of controlled release formulations of metformin, and increase the convenience in manufacturing pharmaceuticals. To provide a pharmaceutical composition comprising the metformin acid addition salt as an active ingredient.

 The present invention provides a composition for treating or preventing diabetes and related diseases comprising metformin acid addition salts and sustained-release excipients as an active ingredient and additionally a pharmaceutically acceptable carrier.

The metformin acid addition salt of the present invention has a solubility in water of up to 230 mg / ml as metformin, preferably metformin succinate or metformin oxalate. Pharmaceutical compositions of the present invention comprising metroformamic acid addition salts and pharmaceutically acceptable carriers are prepared in the form of sustained release preparations. The sustained release formulation of the present invention may be a sustained release formulation further comprising another antidiabetic agent, and is preferably a complex sustained release formulation of metroformamic acid addition salt and sulfonylurea-based drug.

Metformin succinate and metformin oxalate, which are acid addition salts of metformin according to the present invention, have significantly lower solubility in water compared to metformin hydrochloride, resulting in a significantly delayed dissolution pattern in dissolution of the formulation when the same amount of sustained-release excipient is used. You can see it. Therefore, in the preparation of the metformin formulations using these salts, the sustained release of the metformin formulations is facilitated by using a lower amount of sustained release agent than metformin hydrochloride. As a result, the size of the tablets can be significantly reduced, making it easier for patients to take medicines, and the manufacturing process can be simplified and cheaper than conventional metformin sustained release agents.

Sustained-release excipients used in the sustained-release preparation of the present invention include hydroxypropylmethylcellulose, acrylic acid and its derivatives or eudragits. Preferred dosage forms of the sustained release preparations of the invention are oral administration, and such means of administration include tablets or capsules. Tablets may be prepared by mixing the active ingredient with a carrier followed by tableting, examples of suitable carriers used include disintegrants such as sodium starch glyconate, crospovidone, starch, sugars, and mannitol; Fillers and extenders such as lactose, calcium phosphate and silicic acid derivatives; Binders such as polyvinyl pyrrolidone, carboxymethyl cellulose and other cellulose derivatives, and gelatin; Lubricating agents such as talc, calcium stearate, magnesium stearate and solid polyethylene glycols. In addition, hard or soft gelatin capsules containing the active ingredient without or together with the carrier may be prepared according to conventional methods. In this case, the active ingredient of the pharmaceutical composition may include 200 mg to 1000 mg per dosage unit as an acid addition salt of metformin.

The following examples further illustrate the invention described herein and are not intended to limit the scope of the invention.

Metformin acid Addition salt  Produce

Example 1 Preparation of Metformin Succinate

Metformin hydrochloride (10.0 g, 60.4 mmol) and sodium hydroxide (2.42 g, 60.4 mol) were added to 30 ml of purified water, stirred for 30 minutes, and the solution was concentrated under reduced pressure at 40 to 45 ° C. After dissolving and dissolving 100 ml of 20% ethanol in the reactor, succinic acid (7.09 g, 60.4 mmol) was dissolved in 120 ml of ethanol in another vessel and introduced into a reactor of metformin hydrochloride solution. After stirring for 2 hours at 10 ° C or less, filtered and washed with 20 ml of ethanol, and dried for 6 hours at 60 ° C to give 10.2 g of the compound.

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

Example 2: Preparation of Metformin Oxalate

Succinic acid of Example 1 was converted to oxalic acid to prepare in the same manner to obtain 8.2 g of the compound.

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

                  173.46 (carboxyl-C)

Metformin acid Addition salt  Preparation of Pharmaceutical Composition

In Examples 3 and 4, the sustained release of the acid addition salt according to the present invention was prepared by preparing a sustained-release preparation of metformin acid addition salt with the amount of hydroxypropylmethylcellulose as 430 g (40% to 45%) as a sustained-release excipient. To see the effect.

Example 3 Preparation of a Pharmaceutical Composition of Metformin Succinate

Metformin succinate, hydroxypropylmethyl cellulose, lactose and polyvinyl pyrrolidone were added to the mixer and mixed, and then fed into the mixer with purified water. The association was dried in a fluid bed dryer, sized in a sieve of 50 mesh size, mixed with magnesium stearate and compressed to a weight of 1068.5 mg per definition.

Example 4 Preparation of a Pharmaceutical Composition of Metformin Oxalate

In the same manner as in Example 3, the drug was changed to metformin oxalate to prepare a weight of 1161.9 mg per limit.

In Examples 5 to 6 by using the metformin acid addition salt prepared in Example 1 to reduce the amount of the sustained-release excipient hydroxypropyl methyl cellulose step by step to reduce the tablet size intended for the present invention In addition, it was intended to show the cost saving effect.

Example 5 Preparation of a Pharmaceutical Composition of Metformin Succinate with Sustained Release Excipients Reduced to 30% by Weight

In the same manner as in Example 3, the amount of the sustained-release excipient hydroxypropylmethylcellulose was reduced to 30% (about 280 g) to prepare a weight of 918.5 mg per limit.

Example 6 Preparation of a Pharmaceutical Composition of Metformin Succinate with Sustained Release Excipients Reduced to 14% of the Total Tablet Weight

In the same manner as in Example 3, the amount of the sustained-release excipient hydroxypropylmethylcellulose was reduced to 14% (about 105 g) to prepare a weight of 743.5 mg per limit.

Example 7: Preparation of a pharmaceutical composition of a composite sustained release formulation of the composition of Example 6 and glymepiride

To the pharmaceutical composition prepared in Example 6, it was prepared with a mixture of glymepiride, hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide, sodium lauryl sulfate to prepare 778.5 mg per limit.

[Comparative Example]

Comparative Example 1: Preparation of the metformin hydrochloride pharmaceutical composition containing 43% of the sustained-release excipient relative to the total tablet weight

In the same manner as in Example 3 was prepared by replacing the main drug with metformin hydrochloride.

Experimental Example

Experimental Example 1 Measurement of Solubility of Metforminic Acid Addition Salt

In order to confirm the water-solubility of the water-soluble active ingredient, the solubility test of the metformin acid addition salt was carried out as follows for Example 1, Example 2, and the existing salt (methformin hydrochloride). At room temperature (22 ± 5oC), the salt and metformin hydrochloride prepared in the above examples were sufficiently added to 30 ml of purified water and stirred to collect a sample at a predetermined time, and the content of metformin was measured. The results are shown in Table 1.

As can be seen from Table 1, the metformin acid addition salt of the present invention had a significantly lower solubility than metformin hydrochloride.

Experimental Example 2: Measurement of the dissolution rate of metformin acid addition salt

In order to confirm the sustained release effect of the water-soluble active ingredient, the dissolution test of metformin was performed on the formulations prepared in Examples 3, 4 and Comparative Examples as follows. Elution experiments were carried out using 900 ml of simulated solution at pH 6.8 at 37 ° C. and following the Elution 2 method described in the US Pharmacopoeia. The eluate was taken at each time period and the content of metformin was measured (n = 6). The results are shown in FIGS. 1 and 2.

1 and Table 2, it can be seen that the dissolution rate of metformin acid addition salt prepared using the same weight sustained-release excipient as in Example 3, Example 4, Comparative Example is significantly lower than the dissolution rate of Comparative Example. This can be seen as the effect of the new acid addition salts prepared in Examples 3 and 4.

Experimental Example 3 Measurement of Dissolution Rate of Tablets with Changes of Sustained-release Excipients of Metforminic Acid Addition Salts

In order to confirm the sustained release effect of the slow release excipient of the water-soluble active ingredient, the dissolution test of metformin was carried out for the formulations prepared in Examples 3, 5, 6, 7 and Comparative Examples as follows. Was carried out. Dissolution experiments were carried out using 900 ml of simulated solution at pH 6.8 at 37 ° C. and according to the Elution 2 method described in the US Pharmacopoeia. The eluate was taken at each time period and the content of metformin was measured (n = 6). The results are shown in FIG. 2 and Table 3.

In FIGS. 2 and 3, the dissolution rates of the tablets prepared by gradually reducing the sustained-release excipients as in Examples 3, 5, 6, and Comparative Example were compared, and the comparative example and the sustained-release agent were 14%. The dissolution rate is very similar to Example 6 used only. In addition, the dissolution pattern similar to that of the comparative example was also observed for the sustained release composite prepared in Example 7. This means that by reducing the sustained-release agent as in Example 6, Example 7, it is possible to significantly reduce the size of the tablet.

       Experimental Example 4 Measurement of Blood Drug Concentration in Rats

In order to examine the pharmacokinetic properties of the water-soluble active ingredient, the pharmaceutical composition prepared in metformin hydrochloride, Example 1, Example 6, and Comparative Example was prepared after cannulation in the jugular administration of 6-7 week old rats. 0.4 ml of blood was collected every 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 9 hours after oral administration to a certain number of mice to determine the concentration of the active ingredient. The results are shown in [Figure 3] and [Table 4].

3 and Table 4, the pharmacokinetic properties of the water-soluble active ingredient of metformin hydrochloride, Examples 1, 6, and Comparative Example showed that the compositions of Examples 1 and 6 were more effective than metformin hydrochloride and the compositions of Comparative Example. The bioavailability is excellent from the area under the curve (AUC). This demonstrates the good bioavailability of the sustained release formulations for freshly prepared acid addition salts.

Figure 1 shows the dissolution test results with time at pH 6.8 of Examples 3 and 4 and Comparative Examples. (n = 6)

Figure 2 shows the dissolution test results with time at pH 6.8 of Example 3 and Example 5, Example 6, Example 7, and Comparative Example. (n = 6)

3 shows blood drug concentrations with time in rats of Examples 1 and 6 and Comparative Examples. (n = 6)

Claims (5)

A sustained release preparation comprising metformin acid addition salt having a solubility in water as metformin of 230 mg / ml or less and a pharmaceutically acceptable carrier. The sustained-release preparation according to claim 1, wherein the metformin acid addition salt is metformin succinate or metformin oxalate. The sustained-release preparation according to claim 1, wherein the carrier is hydroxypropylmethyl cellulose, acrylic acid and derivatives thereof, or eudragits. The sustained release preparation according to claim 1, which is a tablet or capsule. The sustained release preparation of claim 1, further comprising a sulfonylurea-based drug.

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