Sustained-release formulation comprising metformin or pharmaceutically acceptable salt thereof, and method for preparing same

Abstract

The present invention relates to a sustained-release formulation comprising metformin or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a sustained-release formulation having excellent dissolution properties and safety, the formulation comprising: as an active ingredient, metformin or a pharmaceutically acceptable salt thereof; and as sustained-release agents, Carbopol and hydroxypropylmethylcellulose.

Description

Sustained-release formulations comprising metformin or pharmaceutically acceptable salts thereof, and methods for manufacturing the same

[0001] The present invention relates to a sustained-release formulation comprising metformin or a pharmaceutically acceptable salt thereof. Specifically, the invention relates to a sustained-release formulation comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and carbopol and hydroxypropylmethylcellulose as sustained-release agents, wherein the formulation of the present invention has excellent dissolution characteristics and safety.

[0002]

[0003] Metformin is a biguanide-class diabetes medication. Glucose in the blood is stored in the liver in the form of glycogen and is broken down and released when blood sugar levels are low. Metformin inhibits the production of glucose in the liver, reduces glucose absorption in the intestines, and improves insulin sensitivity in the body. Increased insulin sensitivity leads to glucose being absorbed and utilized by peripheral tissues, thereby lowering blood sugar levels. Metformin can suppress appetite and promote weight loss in diabetic patients, and because it does not cause hypoglycemic side effects when used alone in general settings, it is the first-line drug used to treat type 2 diabetes. Furthermore, as it is frequently used as a combination drug with other classes of diabetes medications, it can be considered the most widely used diabetes treatment.

[0004] Side effects associated with the use of metformin include loss of appetite, abdominal distension, nausea, and diarrhea, occurring in 20 to 30 percent of patients. Most side effects are transient and often disappear after 2 to 3 weeks of administration; however, if symptoms such as diarrhea or severe abdominal distension persist, it is advisable to discontinue use. These side effects can be improved by using sustained-release formulations, which allow for a reduction in the minimum and / or sustained dose or fewer doses. However, sustained-release formulations generally have a higher excipient content compared to standard formulations, resulting in larger tablet sizes. This disadvantage may cause dysphagia in elderly and pediatric patients, which can lead to poor medication adherence.

[0005] Accordingly, the inventors developed a sustained-release formulation containing metformin or a pharmaceutically acceptable salt thereof, thereby reducing side effects that occur in existing formulations and completing the formulation of the present invention, which has excellent dissolution characteristics and safety.

[0006]

[0007] [Prior Art Literature]

[0008] [Patent Literature]

[0009] (Patent Document 0001) Korean Registered Patent No. 10-0791844

[0010] (Patent Document 0002) Korean Registered Patent No. 10-2229798

[0011]

[0012] The present invention aims to provide a pharmaceutical composition comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and carbopol and hydroxypropylmethylcellulose as sustained-release agents.

[0013] In addition, the present invention aims to provide a pharmaceutical composition comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, carbopol and hydroxypropylmethylcellulose as sustained-release agents, and ethylcellulose and hydroxypropylmethylcellulose as coating agents.

[0014] In addition, the present invention aims to provide a method for manufacturing a sustained-release formulation, comprising the steps of: manufacturing a wet granule containing metformin or a pharmaceutically acceptable salt thereof as an active ingredient; manufacturing a tablet by adding carbopol and hydroxypropylmethylcellulose as a sustained-release agent to the wet granule; and manufacturing a coated tablet by adding ethylcellulose and hydroxypropylmethylcellulose as a coating agent to the tablet.

[0015]

[0016] The present invention relates to a pharmaceutical composition comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient; and carbopol and hydroxypropylmethylcellulose as sustained-release agents.

[0017] In the composition of the present invention above, the weight % of the sustained-release agent relative to the active ingredient may be 60 or more, preferably 90 or more, and more preferably 120 or more.

[0018] In the composition of the present invention above, ethylcellulose and hydroxypropylmethylcellulose may be additionally included as coating agents.

[0019] In addition, the composition of the present invention may contain more ethyl cellulose than hydroxypropylmethylcellulose as a coating agent. The coating agent for the active ingredient may be included in an amount of 2 weight% or more, and preferably, the coating agent for the active ingredient may be included in an amount of 3 weight% or more.

[0020] In the composition of the present invention, an excipient, a binder, or a lubricant may be further included. The excipient may be microcrystalline cellulose, the binder may be polyvinylpyrrolidone, and the lubricant may be magnesium stearate.

[0021] In the composition of the present invention, the active ingredient may be metformin hydrochloride.

[0022] The present invention relates to a method for manufacturing a sustained-release formulation, comprising the steps of: manufacturing a wet granule containing metformin or a pharmaceutically acceptable salt thereof as an active ingredient; manufacturing a tablet by adding carbopol and hydroxypropylmethylcellulose as a sustained-release agent to the wet granule; and manufacturing a coated tablet by adding ethylcellulose and hydroxypropylmethylcellulose as a coating agent to the tablet.

[0023] In the manufacturing method of the present invention above, the weight % of the sustained-release agent relative to the active ingredient may be 60 or more, preferably 90 or more, and more preferably 120 or more.

[0024] In the manufacturing method of the present invention above, ethyl cellulose and hydroxypropylmethylcellulose may be additionally included as coating agents.

[0025] In addition, in the manufacturing method of the present invention, ethyl cellulose may be included as a coating agent in greater quantities than hydroxypropylmethylcellulose. The coating agent for the active ingredient may be included in an amount of 2 weight% or more, and preferably, the coating agent for the active ingredient may be included in an amount of 3 weight% or more.

[0026] In the manufacturing method of the present invention, the active ingredient may be metformin hydrochloride.

[0027] The present invention relates to a method for manufacturing a sustained-release formulation, comprising the steps of: preparing a wet granule comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, microcrystalline cellulose as an excipient, and polyvinylpyrrolidone as a binder; preparing a raw tablet by adding carbopol and hydroxypropylmethylcellulose as a sustained-release agent and magnesium stearate as a lubricant to the wet granule; and preparing a coated tablet by adding ethylcellulose and hydroxypropylmethylcellulose as a coating agent to the raw tablet.

[0028]

[0029] The present invention relates to a sustained-release formulation comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and carbopol and hydroxypropylmethylcellulose as sustained-release agents. The formulation of the present invention can reduce side effects caused by the active ingredient through delayed release. In addition, the formulation of the present invention has improved dissolution characteristics and safety.

[0030]

[0031] Figure 1 shows the results of dissolution experiments on the formulations of Examples 1 to 7.

[0032] Figure 2 shows the results of dissolution experiments on the formulations of Examples 8 to 12.

[0033] Figure 3 shows the results of a dissolution test on the coated tablets of Examples 13 to 16.

[0034] Figure 4 shows the results of a dissolution test on the coated tablets of Examples 17 to 19.

[0035] Figure 5 shows the results of a dissolution test in the gastrointestinal tract for the coated tablet of Example 18.

[0036] Figure 6 shows the results of dissolution experiments in the gastrointestinal tract for the coated tablets of Examples 17 and 20.

[0037]

[0038] The present invention is to be explained in more detail through the following examples, but the following manufacturing examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0039] As used herein, the term "pharmaceuticalally acceptable salt" refers to any acid-addition salt or base-addition salt that is non-toxic and harmless to the patient and whose side effects caused by said salt do not impair the beneficial efficacy of the compound of the present invention. Inorganic acids that form suitable salts include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, hydrobromide, hydroiodide, nitrous acid, or phosphoric acid, and organic acids that form suitable salts include glycolic acid, lactic acid, pyruvate, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, nicotinic acid, tosylic acid, camphosulfonic acid, naphthoic acid, acetic acid, trifluoroacetic acid, oxalic acid, manderic acid, propionic acid, citric acid, lactic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, carboxylic acid, vanillic acid, benzenesulfonic acid, p-toluenesulfonic acid, or methanesulfonic acid, and preferably oxalates, hydrochlorides, It may be benzenesulfonate, hemifumarate, succinate, hemimaleate, nicotinate, tosylate, glycolate, hemisulfonate, tartrate, maleate, aspartate, malate, citrate, malonate, phosphate, glutamate, camphosulfonate, 3-hydroxy-2-naphthoate, mesylate, or 4-hydroxybenzoate, but is not limited thereto. In the present invention, the preferred salt may be a hydrochloride.

[0040]

[0041] [Preparation Example 1]

[0042] Preparation of sustained-release formulations containing HPMC

[0043]

[0044] Metformin hydrochloride, microcrystalline cellulose, PVP K-30, and PVP K-90, each component of Tables 1 and 2 below, were mixed in a high-shear mixer and purified water was added to prepare granules using a conventional wet granulation method.

[0045] Subsequently, a sustained-release agent (HPMC) and magnesium stearate were added to the prepared granules, mixed, and compressed using a rotary tablet press to produce tablets. Using HPMC (hydroxypropylmethylcellulose) with various viscosities as the sustained-release agent, sustained-release formulations containing metformin were prepared according to the components and contents of Tables 1 and 2 below.

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] [Preparation Example 2]

[0052] Preparation of sustained-release formulations containing carbopol and HPMC

[0053]

[0054] Using carbopol and HPMC (hydroxypropylmethylcellulose) as sustained-release agents, a sustained-release formulation containing metformin was prepared according to the ingredients and content of Table 3 below in a manner similar to Preparation Example 1.

[0055]

[0056]

[0057]

[0058] [Preparation Example 3]

[0059] Preparation of sustained-release formulations according to the coating agent (EC / HPMC) content ratio

[0060]

[0061] Tablets of Examples 13 to 16 were prepared using the method of Preparation Example 1 with the ingredients and content of Table 4 below.

[0062]

[0063]

[0064]

[0065] For the above-mentioned raw tablet, a coated tablet was prepared using a coating agent having the components and content ratios of Table 5 below.

[0066] A coating solution was prepared by thoroughly stirring a solvent mixed with ethanol and purified water with the ingredients and content of Table 5 below, and coated tablets with uniform properties were prepared using a coating machine on the raw tablets of Examples 13 to 16 prepared above.

[0067]

[0068]

[0069]

[0070] [Preparation Example 4]

[0071] Preparation of sustained-release formulations based on coating agent content

[0072]

[0073] The formulations of Examples 8, 9, and 12 prepared in Preparation Example 2 above were made into tablets, and the coated tablets of Examples 17, 18, and 19 were prepared according to the content of the coating agent in Table 6 below.

[0074] In addition, the formulation of Example 12 above was made into a tablet, and the coated tablet of Example 20 was prepared according to the content of the coating agent in Table 6 below.

[0075]

[0076]

[0077]

[0078] The above ratio represents the weight percentage of the coating agent relative to the weight of the active ingredient, metformin hydrochloride.

[0079]

[0080] [Test Example 1]

[0081] Dissolution evaluation according to type of sustained-release agent (HPMC)

[0082]

[0083] To confirm the differences in release patterns according to HPMC viscosity and content, the following experiments were performed on the formulations of Examples 1 to 7. Control group 1 was tested using Diavex XR extended-release tablets 1000 mg.

[0084] The dissolution evaluation was performed using 1000 mL of a pH 6.8 solution identical to the dissolution solution in the dissolution section of "Metformin hydrochloride extended-release tablets" listed in the U.S. Pharmacopoeia, and the paddle method was used to confirm the drug release pattern suitable for biological conditions.

[0085] The above experimental results are shown in Tables 7 and 8 and Figure 1 below.

[0086]

[0087]

[0088]

[0089]

[0090]

[0091] As shown in Tables 7, 8 and Figure 1 above, it was confirmed that the formulations of Examples 1-7 containing HPMC exhibited a higher dissolution rate than the control drug.

[0092]

[0093] [Test Example 2]

[0094] Dissolution evaluation according to type of sustained-release agent (Carbopol / HPMC)

[0095]

[0096] Dissolution experiments were performed on the formulations of Examples 8 to 12 containing carbopol and HPMC. The control group was Diavex XR extended-release tablets 1000 mg. The above dissolution experiments were performed in the same manner as in Test Example 1.

[0097] The above experimental results are shown in Table 9 and Figure 2 below.

[0098]

[0099]

[0100]

[0101] As shown in Table 9 and Figure 2 above, it was confirmed that the dissolution rate decreases as the content of carbopol and HPMC increases. In addition, it was confirmed that the dissolution rate decreases when carbopol and HPMC are included together compared to when HPMC is used alone. Therefore, it can be seen that sustained release of a formulation containing metformin is possible when carbopol and HPMC are used together.

[0102]

[0103] [Test Example 3]

[0104] Elution evaluation based on coating agent type and content (EC / HPMC)

[0105]

[0106] Coated tablets of Examples 13 to 16 were prepared using a coating agent containing ethylcellulose (EC) and HPMC in Preparation Example 3. For the coated tablets, a dissolution test was performed in the same manner as in Test Example 1.

[0107] The above experimental results are shown in Table 10 and Figure 3 below.

[0108]

[0109]

[0110]

[0111] As shown in Table 10 and Figure 3 above, it was confirmed that the coated tablet of Example 14 (EC:HPMC 2:1) exhibited a release pattern similar to the control group and showed an excellent release pattern.

[0112] On the other hand, in the case of Example 13 (EC:HPMC 1:1) and Example 16 (EC only), it was confirmed that the dissolution rate was high or too low compared to the control group.

[0113] Therefore, it can be seen that HPMC exhibits a superior sustained-release pattern when the EC content is higher.

[0114]

[0115] [Test Example 4]

[0116] Elution evaluation based on coating agent content (EC / HPMC)

[0117]

[0118] Coated tablets of Examples 17 to 19 were prepared according to the content of the coating agent containing ethylcellulose (EC) and HPMC in Preparation Example 4 above. For the coated tablets, a dissolution test was performed in the same manner as in Test Example 1.

[0119] The above experimental results are shown in Table 11 and Figure 4 below.

[0120]

[0121]

[0122]

[0123] As shown in Table 11 and Figure 4 above, it was confirmed that Examples 17 to 19 exhibit sustained-release patterns, and Example 19 exhibited the best release pattern similar to the reference drug. The coated tablets of Examples 17 to 19 contain 64, 96, and 128 weight% of the sustained-release agents Carbopol and HPMC, respectively, with respect to the content of the active ingredient metformin hydrochloride.

[0124] Accordingly, it can be seen that when the sustained-release agents Carbopol and HPMC are included in an amount of 60% by weight or more, preferably 90% by weight or more, and most preferably 120% by weight or more with respect to the content of the active ingredient metformin hydrochloride, an excellent sustained-release pattern is exhibited.

[0125]

[0126] [Test Example 5]

[0127] Evaluation of dissolution in the gastrointestinal tract

[0128]

[0129] A dissolution evaluation experiment in the gastrointestinal tract was performed on the coated tablet of Example 18 above.

[0130] The release patterns were compared by eluting for 2 hours in a pH 1.2 eluent, which is similar to the environment of the stomach, and a pH 6.8 eluent, which is similar to the environment of the small intestine. The elution conditions were 1000 mL of eluent and the paddle method was performed at 50 rpm.

[0131] The above experimental results are shown in Fig. 5. As shown in Fig. 5, it was confirmed that there was no difference in dissolution of the coated tablet of Example 18 at pH 1.2 and pH 6.8. Therefore, it can be seen that the coated tablet of Example 18 can effectively control the release of the active ingredient under acidic conditions.

[0132]

[0133] [Test Example 6]

[0134] Evaluation of dissolution in the gastrointestinal tract

[0135]

[0136] Dissolution evaluation experiments in the gastrointestinal tract were performed on the coated tablets of Examples 17 and 20 above.

[0137] Based on the literature, the dissolution system was evaluated to mimic the continuous dissolution of a drug from the stomach to the small intestine according to the biological domain after administration (Toward Biopredictive Dissolution for Enteric Coated Dosage Forms, J. Al-Gousous et al., 2016). After dissolving for 120 minutes in a pH 1.2 dissolution solution similar to the stomach, it was dissolved for 600 minutes in a pH 6.5–6.95 dissolution system similar to the environment of the small intestine.

[0138] The above experimental results are shown in Fig. 6 and Table 12 below.

[0139]

[0140]

[0141]

[0142] As shown in Table 12 and Figure 6 above, the coated tablets of Examples 17 and 20 exhibited a sustained-release pattern similar to the control group, and Example 20 exhibited a superior sustained-release pattern compared to Example 17.

[0143] Examples 17 to 20 contain 3.9, 4.6, 5.4, and 7.2 weight percent of a coating agent, respectively, with respect to metformin hydrochloride, which is the active ingredient. Thus, it can be seen that in order to exhibit an excellent sustained-release pattern, it is desirable to include at least 2 weight percent of the coating agent, and more preferably at least 3 weight percent.

[0144]

[0145] [Test Example 7]

[0146] Evaluation of NDMA content in severe stability specimens

[0147]

[0148] 1.0 mL of the internal standard substance NDMA-d6 (1,000 μg / mL) was accurately weighed and methanol was added to make the solution exactly 10 mL to prepare an internal standard solution (1 μg / mL). 40 μL of the NDMA standard solution (5,000 μg / mL) was accurately weighed and methanol was added to make the solution exactly 10 mL to prepare a standard stock solution (20 μg / mL). 500 μL of the above standard stock solution was accurately weighed and methanol was added to make the solution exactly 10 mL to prepare a standard solution (1 μg / mL). The standard solution and the internal standard solution were each weighed as shown in Table 13 below, mixed, and then dichloromethane was added to make the solution exactly 10 mL to prepare a linear standard solution.

[0149]

[0150]

[0151]

[0152] More than 20 tablets were accurately weighed and ground into powder. An amount equivalent to approximately 500 mg of metformin was accurately weighed and placed in a 50 mL conical tube. 5 mL of 1 mol / L hydrochloric acid was added, and the mixture was shaken thoroughly immediately afterward. To the above liquid, 50 μL of internal standard solution (1 μg / mL) was accurately taken and added, followed by 5 mL of dichloromethane. After mixing thoroughly, the mixture was centrifuged at 4,000 rpm for 10 minutes. An appropriate amount of the dichloromethane layer (lower layer) was taken and filtered through a 0.22 μm membrane filter; the first 2 mL of the filtrate was discarded, and the subsequent filtrate was used as the test solution.

[0153] Tests were performed using the gas chromatography method with the test solution and standard solution. The amount of NDMA in the test solution was determined using a calibration curve obtained from the NDMA peak area versus the internal standard peak area of ​​the standard solution.

[0154] The results of the experiment performed on the coated tablet of Example 18 are shown in Table 14 below.

[0155]

[0156]

[0157]

[0158] As shown in Table 14 above, it was confirmed that the coated tablet of Example 18 did not show an increase in NDMA during room temperature storage and high-temperature harsh testing. Therefore, it can be seen that the coated tablet of the present invention does not have genotoxicity issues caused by NDMA.

Claims

1. Metformin or a pharmaceutically acceptable salt thereof as an active ingredient; and A pharmaceutical composition comprising carbopol and hydroxypropylmethylcellulose as sustained-release agents.

2. A pharmaceutical composition according to claim 1, wherein the weight % of the sustained-release agent relative to the active ingredient is 60 or more.

3. A pharmaceutical composition according to claim 1, wherein the weight % of the sustained-release agent relative to the active ingredient is 90 or more.

4. A pharmaceutical composition according to claim 1, wherein the weight % of the sustained-release agent relative to the active ingredient is 120 or more.

5. A pharmaceutical composition according to claim 1, further comprising ethylcellulose and hydroxypropylmethylcellulose as coating agents.

6. A pharmaceutical composition according to claim 5, wherein the coating agent comprises more ethyl cellulose than hydroxypropylmethylcellulose.

7. A pharmaceutical composition according to claim 5, comprising 2% by weight or more of a coating agent for the active ingredient.

8. A pharmaceutical composition according to claim 5, comprising 3 weight percent or more of a coating agent for the active ingredient.

9. A pharmaceutical composition according to claim 5, further comprising an excipient, a binder, or a lubricant.

10. A pharmaceutical composition according to claim 9, wherein the excipient is microcrystalline cellulose.

11. A pharmaceutical composition according to claim 9, wherein the binder is polyvinylpyrrolidone.

12. A pharmaceutical composition according to claim 9, wherein the lubricant is magnesium stearate.

13. A pharmaceutical composition according to claim 1, wherein the active ingredient is metformin hydrochloride.

14. A step of preparing wet granules comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient; A step of preparing a tablet by adding Carbopol and hydroxypropylmethylcellulose as sustained-release agents to the above wet granules; and A step of manufacturing a coated tablet by adding ethyl cellulose and hydroxypropylmethylcellulose as coating agents to the above-mentioned raw tablet. A method for manufacturing a sustained-release formulation comprising 15. A method for manufacturing a sustained-release formulation according to claim 14, wherein the weight % of the sustained-release agent relative to the active ingredient is 60 or more.

16. A method for manufacturing a sustained-release formulation according to claim 14, wherein the weight % of the sustained-release agent relative to the active ingredient is 90 or more.

17. A method for manufacturing a sustained-release formulation according to claim 14, wherein the weight % of the sustained-release agent relative to the active ingredient is 120 or more.

18. A method for manufacturing a sustained-release formulation according to claim 14, wherein the coating agent comprises more ethyl cellulose than hydroxypropylmethylcellulose.

19. A method for manufacturing a sustained-release formulation according to claim 14, comprising 2% by weight or more of a coating agent for the active ingredient.

20. A method for manufacturing a sustained-release formulation according to claim 14, comprising 3% by weight or more of a coating agent for the active ingredient.

21. A method for manufacturing a sustained-release formulation according to claim 14, wherein the active ingredient is metformin hydrochloride.

22. A step of preparing wet granules comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, microcrystalline cellulose as an excipient, and polyvinylpyrrolidone as a binder; A step of preparing a tablet by adding Carbopol and hydroxypropylmethylcellulose as sustained-release agents and magnesium stearate as a lubricant to the above wet granules; and A step of manufacturing a coated tablet by adding ethyl cellulose and hydroxypropylmethylcellulose as coating agents to the above-mentioned raw tablet. A method for manufacturing a sustained-release formulation comprising

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