KR20220165346A - Formulation comprising evogliptin with improved stability - Google Patents

Abstract

The present invention relates to a coated tablet with improved stability of evogliptin in a coating layer which comprises an inner layer comprising metformin, and a coating layer coated with the inner layer, wherein the coated tablet includes evogliptin or an acceptable salt thereof, and ethyl cellulose in the coating layer. A pharmaceutical composition according to the present invention can be expected to increase the shelf life by reducing the tablet size through minimizing the ratio of the evogliptin portion in the combination preparation and suppressing the generation of evogliptin related substances.

Description

Formulation comprising evogliptin with improved stability}

The present invention relates to a formulation containing evogliptin or an acceptable salt thereof, a dipeptidylpeptidase IV (DPP-IV) inhibitor, and metformin, in which the stability of evogliptin is improved.

DPP-IV inhibitors are drugs developed to treat or improve the therapeutic effect of type 2 diabetes patients. Currently, DPP-IV inhibitors on the market include Sitagliptin, Vildagliptin, and Saxagliptin. (Saxagliptin) and Evogliptin. DPP-IV inhibitors have a mechanism to control blood sugar by maintaining a high blood level of GLP-1, which plays an important role in maintaining glucose homeostasis, and has a stable blood sugar lowering effect, as well as side effects of existing diabetes treatments such as hypoglycemia and weight gain. improved.

Metformin is a biguanide type 2 diabetes drug that increases sensitivity to insulin in human peripheral tissues, inhibits glucose absorption in the intestine, inhibits hepatic gluconeogenesis, and inhibits fatty acid oxidation. It is related, and it is a drug administered to diabetic patients.

DPP-IV inhibitors and metformin are pharmaceutical compounds for the treatment of diabetes widely known in the art, and since the pharmaceutical compounds exert antidiabetic effects through different mechanisms, the combination of the two drugs has a good effect in the treatment of diabetic patients. It is known to perform.

Accordingly, the development of complexes containing DPP-IV inhibitors is actively being carried out, and representatively 'metformin and DPP-IV inhibitors', 'TZD series and DPP-IV inhibitors', 'SGLT-2 inhibitors and DPP-IV inhibitors' ' combination, and recently, a three-drug combination of 'metformin, a DPP-IV inhibitor and a SGLT-2 inhibitor', and a diabetes/hyperlipidemia combination of 'rosuvastatin and a DPP-IV inhibitor' are also being actively developed.

However, during the development of a DPP-IV inhibitor as a combination drug, not only the fact that the stability of the DPP-IV inhibitor is affected through interaction with other drugs, but also the amount or ratio of the isolation layer that inhibits the contact of the DPP-IV inhibitor It was discovered that this affects the stability of the DPP-IV inhibitor, and development of a formulation capable of minimizing the generation of pharmaceutically unacceptable related substances without decomposition even during long-term storage was attempted.

In the development of a combination drug, it is necessary to exhibit a release that is suitable for the drug to be absorbed into the body. There are cases in which application is difficult due to problems such as solvents.

The development direction of the combination preparation was developed in the form of a double-layer tablet or drug-coated tablet to overcome the difference in compatibility or release rate between drugs. Representative examples widely used clinically are Janumet XR, WO 2009-099734 A1, ^{Kombiglyze ® XR} , WO 2005-117841 A1, and Tenelia M sustained-release tablets. ^® MSR, Korean Registered Patent No. 10-1526825).

The inventors of the present invention also want to develop drug-coated tablets containing Evogliptin (Suganon ^® , Korean Registered Patent No. 10-1007497), a new DPP-IV inhibitor developed by the present applicant, in order to utilize the advantages of such drug-coated tablets. did To this end, the inventors of the present invention are polyvinyl alcohol or hydride, which is universally used as a coating base, as in the examples of WO 2009-099734 A1 (Janumet XR patent) and WO 2005-117841 A1 (Combiglise patent) An attempt was made to develop evogliptin drug-coated tablets by applying hydroxypropylmethylcellulose. During the research and development process, it was found that evogliptin changes to an amorphous form during coating and decreases stability, resulting in a rapid increase in related substances. Considering that it is essential in the pharmaceutical industry to develop a formulation capable of minimizing generation of related substances even during long-term storage, it can be said that this problem must be solved.

In particular, the sitagliptin fast-release layer formulation technology disclosed in WO 2009-099734 A1 (Janumet XR patent), which is a prior art, uses a solvent with low volatility. There is a big problem that can be completed, but Korean Patent Publication No. 10-2020-0021774 A suggests a method of preparing a coating solution by dissolving in a highly volatile organic solvent to solve the above problem, but this technology has the possibility of generating residual solvent. There arises a problem that may cause toxicity or permission problems according to. In addition, in recent years, the use of organic solvents has been discouraged for the safety of workers and eco-friendly processes.

Accordingly, the inventors of the present invention conducted research to improve the stability of evogliptin in the process of developing a combination of 'metformin and evogliptin', and as a polymer capable of suppressing the generation of evogliptin related substances in the coating layer, Ethyl cellulose was derived. Finally, an evogliptin coating composition obtained by dissolving or dispersing ethyl cellulose and an appropriate coating agent in purified water for stability improvement was discovered, and the present invention, which is highly usable for the development of a combination preparation with various drug groups, was completed.

WO 2009-099734 A1 WO 2005-117841 A1 Korean Registered Patent No. 10-1007497 Republic of Korea Patent Publication 10-2020-0021774 A

An object of the present invention is to provide a combination preparation containing metformin and evogliptin or an acceptable salt thereof, in which the stability of evogliptin is improved by suppressing the formation of related substances in evogliptin. .

In order to solve the above problems, the present invention is an inner layer containing metformin; and a coating layer coated with an inner layer, wherein the coating layer contains evogliptin or an acceptable salt thereof and ethyl cellulose, and the stability of evogliptin in the coating layer is improved.

The coated tablet of the present invention contains metformin in the inner layer, evogliptin or an acceptable salt thereof in the coating layer, and ethyl cellulose, which is a polymer, is coated together, and the coating layer of the present invention contains evogliptin or an acceptable salt thereof. The salt is present as evogliptin at 2.5 mg/T to 10 mg/T, and ethyl cellulose is present at 25 to 60% by weight of the total weight of the coating layer.

In the present invention, the 'pharmaceutically acceptable salt' of evogliptin refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid including an inorganic or organic base and an inorganic or organic acid. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc and the like. In particular, ammonium, calcium, magnesium, potassium or sodium salts are preferred. Solid salts may exist in one or more crystal structures and may also exist in the form of hydrates. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary or tertiary amines, substituted amines including naturally substituted amines, amine rings, or arginine, betaine, caffeine, choline, N,N '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, Hydrabamine, isopropylamine, lysine, methylglucamine, popolin, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. Basic ion exchange resins are included. Salts prepared from inorganic and organic acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, delic acid, methanesulfonic acid, muric acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, adipic acid and the like. Acetic acid, citric acid, hydrochloric acid, malic acid, phosphoric acid, succinic acid, tartaric acid or adipic acid are particularly preferred.

The present invention is characterized in that the stability of evogliptin or an acceptable salt thereof can be improved by including ethyl cellulose together with evogliptin or an acceptable salt thereof in a coating layer.

Evogliptin has a total related substance content of 2.0% by weight or less. Therefore, when the combined preparation containing metformin and evogliptin of the present invention is stored for 4 weeks under heat-severe conditions (60°C, HDPE bottle, closed), the total related substance content of evogliptin should be 2.0% by weight or less, Preferably it is 1.0% by weight or less.

The present invention solves the problem of deterioration in the stability of evogliptin, which can promote production of related substances, by including evogliptin and ethyl cellulose in the outer coating layer. That is, evogliptin dissolved in the coating solution may change into an amorphous form due to rapid solidification during the coating process, which may promote the production of evogliptin related substances. In the present invention, the production of related substances of evogliptin was suppressed by including ethyl cellulose in the coating solution.

In the present invention, a coating agent may be included in the coating solution. When ethyl cellulose is applied to the coating layer, it is possible to suppress the generation of related substances by minimizing the plasticity of the evogliptin coating layer. In the present invention, a specific coating agent is included in the coating solution so that this problem does not occur. Preferably, the coating base of the present invention is medium chain triglyceride, oleic acid, polyvinyl alcohol, hydroxypropylmethylcellulose, talc, titanium oxide, glyceryl monocaprylocaprate, sodium lauryl sulfate, lecithin, xanthan gum, polyethylene glycol and these It may be selected from the group consisting of mixtures of.

In addition, the inner layer of the present invention includes metformin or a pharmaceutically acceptable salt thereof, and 'pharmaceutically acceptable salt' refers to a non-toxic pharmaceutically acceptable base including an inorganic or organic base and an inorganic or organic acid; A salt prepared from an acid is possible, and a hydrochloride salt is preferred. Metformin or a pharmaceutically acceptable salt thereof included in the inner layer of the present invention is present in an amount ranging from about 75 to 85% by weight of the total weight of the inner layer.

In addition, one or more binders, preferably hydroxypropylcellulose, may optionally be present in the inner layer of the present invention in an amount ranging from 1 to 10% by weight of the total weight of the inner layer; Optionally, at least one release controlling agent, preferably methacrylic acid copolymer, hydroxypropylmethylcellulose, carbomer or a mixture thereof, is present in an amount of 12 to 25% of the total weight of the inner layer. may be present in an amount in the range of weight percent; Optionally, one or more lubricants, preferably magnesium stearate, may be present in an amount ranging from 0.2 to 2% by weight of the total weight of the inner layer.

In addition, the inner layer in the present invention does not affect the stability of evogriptin. Therefore, in addition to metformin, binguanides such as phenformin; glucosidase inhibitors such as acarbose and miglitol; insulin, insulin secretagogues or insulin sensitizers; meglitinides such as repaglinide and nateglinide; sulfonylurea drugs such as glimepiride, glyburide, gliclazide, chloropropamide, and glipizide; binguanide/glyburide combinations such as glucovans; thiazolidinedione drugs such as triglitazone, isaglitazone, pioglitazone, piraglitazar, englitazone, darglitazone, isaglitazone, leglitazar, rivoglitazone, and liraglutide; PPAR-alpha agonists; PPAR-gamma agonists; PPAR alpha/gamma dual agonists; glycogen phosphorylase; inhibitors of fatty acid binding protein (aP2); glucagon-like peptide (GLP-1), or other agonists of the GLP-1 receptor; and SGLT-2 inhibitors such as dapagleflozin and various types of antidiabetic agents known in the art.

In addition, the present invention

a) providing an inner layer tablet;

b) forming a coating layer (containing a drug) with a coating solution containing evogliptin or an acceptable salt thereof, ethyl cellulose and a coating agent, and coating the tablet with the coating layer formulation; and

c) there is provided a method for manufacturing a coated tablet comprising the step of drying the coated tablet to form the coated tablet of the present invention.

The inner layer used in the coated tablet of the present invention may be prepared by various processes and the order of adding excipients, preferably through a wet granulation process and a tableting process.

The coating solution according to the present invention can be prepared with the composition shown in [Table 2], including evogliptin tartrate and 20 cP of ethyl cellulose in purified water.

The coated tablets of the present invention are useful for the treatment of mammals, such as humans, canines and felines, for type II diabetes.

The coated tablet according to the present invention has the advantage of improving stability and securing a sufficient shelf life by suppressing generation of related substances of evogliptin by applying ethyl cellulose to the coating layer. In addition, by applying evogliptin to the coating layer, the tablet size reduction effect can be obtained through minimizing the ratio of the evogliptin part in the combination preparation.

1 is a graph showing the results of analyzing related substances of evogliptin in the stability test of Examples and Comparative Examples according to the present invention.
2 is a scanning electron microscope image of a real photograph and a cross-section of a tablet of Example 1, and it can be confirmed through the cross-sectional image that a coating layer is formed.

Hereinafter, examples will be described in detail to aid understanding of the present invention.

All terms used in the present invention, unless specifically defined, are used in the same meaning as commonly understood in the related field of the present invention. In addition, the examples and experimental examples recorded to aid understanding of the present invention are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited thereto. In addition to the preferred methods or samples described herein, similar or equivalents thereof are also included in the scope of the present invention.

<Examples 1 to 7> Preparation of combination preparation according to the present invention

Step 1: Preparation of inner layer containing metformin

1) Preparation of granules

After well dispersing methacrylic acid copolymer, hydroxypropyl cellulose and red iron oxide in a mixture of purified water and ethanol shown in Table 1 below, spraying on metformin hydrochloride in a fluid bed granulator was followed by granulation, drying and sizing.

2) Post mixing

The sized product of 1) was put into a mixer, hydroxypropylmethylcellulose and carbomer were mixed, and sieved was lubricated with magnesium stearate to prepare a final mixture.

3) tableting

The final mixture of 2) was compressed into tablets using a rotary tablet press (PR1000, PTK-GB, Korea) to prepare tablets (inner layer) having a total weight of 1270.4 mg.

Step 2: Preparation of a coating layer containing evogliptin

1) Preparation of coating solution

A coating solution was prepared by putting the ingredients in Table 2 below, including evogliptin tartrate and ethyl cellulose, in purified water in a stirrer and completely dispersing them.

2) Coating of the outer layer (coating layer)

The coating solution prepared in 1) was sprayed and dried on the inner-layer tablet containing metformin prepared in step 1 in a coating machine (Diosna, Germany) to obtain coated tablets having a total weight of 1,330.4 mg, respectively, as in Examples 1 to 7. did

Examples 1 to 7 contained evogliptin tartrate, ethyl cellulose, talc, Allura Red AC aluminum lake, and glyceryl monocaprylocaprate. In Examples 1 to 3, the amount of ethyl cellulose was varied. Examples 4 to 5 additionally contain polyvinyl alcohol and hydroxypropylmethylcellulose, respectively, compared to Example 1, and Examples 6 to 7 are those in which the amount of evogliptin was changed compared to Example 1.

<Comparative Examples 1 to 7> Preparation of composite preparations not containing ethyl cellulose in the coating layer

Step 1: Preparation of inner layer containing metformin

An inner layer containing metformin was prepared in the same manner as in step 1 of Example 1.

Step 2: Preparation of a coating layer containing evogliptin

Tablets coated with the composition shown in Table 3 in the same manner as in Step 2 of Example 1 according to the present invention were obtained and used as Comparative Examples 1 to 7.

Comparative Examples 1 to 7 are for confirming the effect of ethyl cellulose included in the drug coating layer on the stability of evogliptin. That is, Comparative Examples 1 and 5 to 7 are tablets containing polyvinyl alcohol used in the drug coating layer in WO 2005-117841 A1 (CombiGlyze patent), and Comparative Example 2 is a tablet containing WO 2009-099734 A1 (JanumexR patent) ) is a tablet containing hydroxypropylmethylcellulose used in the drug coating layer. In particular, Comparative Examples 1 and 2 exclude ethyl cellulose from the compositions of Examples 4 and 5, respectively. Further, Comparative Example 3 is a tablet containing hydroxypropylmethylcellulose acetate succinate, and Comparative Example 4 is a tablet containing a methacrylate copolymer (Eudragit ^® E100) in a coating layer.

<Experimental Example 1> Stability test (thermal stress conditions and accelerated conditions)

The preparations prepared in Examples 1 to 7 and Comparative Examples 1 to 7 were stored in a sealed HDPE bottle at 60° C., and the total amount of related substances was evaluated at the start, 2 weeks and 4 weeks, and shown in Table 4 and FIG. showed up

In addition, the preparations prepared in Examples 1 and 4 according to the present invention were stored in a sealed HDPE bottle at 40 ° C. and 75% RH, and the amount of total related substances was evaluated at the time of initiation, 1 month, 2 months and 6 months. The results are shown in Table 5.

As can be seen from the results in Table 4, it can be seen that the amount of related substances produced varies greatly depending on the presence or absence of ethyl cellulose in the coating layer. Examples 1 to 3 are compositions containing only ethyl cellulose as a main coating material, and have an excellent effect of inhibiting generation of related substances. That is, Examples 1 to 3 were confirmed to be sufficiently stable under heat stress conditions, and in Example 2, the generation rate of related substances slightly increased according to the amount of ethyl cellulose. Example 3 did not show a significant change even with the increase in ethyl cellulose. In addition, Example 4 showed a similar rate of generation of related substances to Example 1 even though polyvinyl alcohol was included in addition to ethyl cellulose, and it was confirmed that it was sufficiently stable even after 6 months of accelerated testing. It was confirmed that sufficient stability can be secured under heat stress conditions even when the amount of evogliptin is changed.

In contrast, Comparative Examples 1, 2, and 5 to 7 are compositions containing only polyvinyl alcohol or hydroxypropylmethylcellulose as a main coating material, respectively, and related substances are generated very quickly due to high plasticity, so they are unsuitable as evogliptin coating compositions Do. In addition, the tablets containing hydroxypropylmethylcellulose acetate succinate in the coating layer in Comparative Example 3 and the tablets containing methacrylate copolymer (Eudragit ^® E100) in the coating layer in Comparative Example 4 also generate related substances very quickly, Evogliptin is unsuitable as a coating composition.

Therefore, in the present invention, by applying ethyl cellulose to the coating layer to suppress generation of related substances of evogliptin, it is possible to improve stability and secure a sufficient shelf life.

Claims (6)

an inner layer comprising metformin; and
Coating layer coated with the inner layer
A coated tablet with improved stability of evogliptin in the coating layer, comprising evogliptin or an acceptable salt thereof, or ethyl cellulose in the coating layer. The coated tablet with improved stability of evogliptin in the coating layer according to claim 1, wherein the evogliptin or an acceptable salt thereof is present in the coating layer in an amount of 2.5 mg/tablet to 10 mg/tablet as evogliptin. The coated tablet with improved stability of evogliptin in the coating layer according to claim 1, wherein the ethyl cellulose is present in an amount of 25 to 60% by weight based on the total weight of the coating layer. The method of claim 1, wherein the coating base included in the coating layer is medium chain triglyceride, oleic acid, polyvinyl alcohol, hydroxypropylmethylcellulose, talc, titanium oxide, glyceryl monocaprylocaprate, sodium lauryl sulfate, lecithin, xanthan gum A coated tablet with improved stability of evogliptin in the coating layer, characterized in that it is selected from the group consisting of polyethylene glycol and mixtures thereof. The coated tablet according to claim 4, wherein the stability of evogliptin in the coating layer is improved, to which a coating solution prepared by dissolving or dispersing evogliptin or an acceptable salt thereof, ethyl cellulose, and a coating base in purified water is applied. a) preparing granules containing metformin, mixing a binder, a release controlling agent and a lubricant and tableting to provide an inner-layer tablet;
b) forming a coating layer with a coating solution containing evogliptin or an acceptable salt thereof, ethyl cellulose and a coating agent, and coating the tablet with the coating layer formulation; and
c) a method for producing a coated tablet comprising the step of drying the coated tablet to form a coated tablet of the present invention.

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