JP2014231511A - Bilayer tablet containing repaglinide and metformin and method of producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a bilayer tablet containing repaglinide and metformin.SOLUTION: The bilayer tablet comprises a first layer containing repaglinide or a pharmaceutically acceptable salt thereof, and a second layer containing metformin or a pharmaceutically acceptable salt thereof.

Description

  The present invention relates to a bilayer tablet containing repaglinide and metformin, and more particularly, to a bilayer tablet containing repaglinide and metformin, which is a hypoglycemic complex. More specifically, in a pharmaceutical composition containing repaglinide and metformin, the release patterns of the two drugs do not interfere with each other, so that the elution pattern of each drug when administered in vivo is respectively It relates to a bilayer tablet having an dissolution pattern similar to that of a single drug. The present invention also relates to a bilayer tablet containing repaglinide and metformin, which contains concentrated glycerin so as not to cause separation between layers due to external factors in production, storage and distribution.

  In general, sulfoneurea drugs are often used as oral hypoglycemic agents for the treatment of diabetes. However, since sulfoneurea drugs have a long action time and promote insulin secretion regardless of the blood glucose state, the frequency of hypoglycemia is high. When treated with sulfoneurea drugs for a long time, The β-cell response becomes insensitive, and paradoxically, a high concentration of sulfoneurea inhibits insulin biosynthesis.

  There is repaglinide as a drug that can compensate for the disadvantages of such sulphonurea drugs, and this repaglinide is a meglitinide drug and has a shorter duration of action than sulphonurea drugs. Less stimulates cells and has fewer side effects such as hypoglycemia and weight gain. Repaglinide can be stably used even in patients with abnormal kidneys, since the main excretion route is bile excretion, not renal excretion.

  Metformin (1,1-dimethylbihydride hydrochloride) is a drug used as a primary therapeutic agent for diabetic patients, and is a biguanide drug that suppresses liver glucose synthesis and improves insulin resistance in peripheral tissues. .

  On the other hand, in UKPDS49, as diabetes progresses, glycemic control becomes difficult only with monosulfone urea, metformin, or insulin alone, and 50% of patients become 3 years after diagnosis of diabetes. Results showed that 75% of patients require combination therapy (Non-patent Document 1). In addition, the rational use of oral drugs can not only reduce the need for repeated administration of additional insulin injections, but can also maintain a low level of glycated hemoglobin, resulting in vascular complications. It is said that it is useful for prevention of symptom (nonpatent literature 2).

  In particular, in relation to such combination therapy, repaglinide, which has an insulin secretion promoting mechanism and has less pancreatic irritation than sulfoneurea, reduces insulin resistance, and is widely used as a primary drug for diabetes. Can be achieved in a single dosage form, and when repaglinide is used in combination with metformin, which is widely used as a primary agent for the treatment of type 2 diabetes, each administration of repaglinide and metformin alone There is a study result that fasting blood glucose (FPG) and glycated hemoglobin (HbA1c) were significantly decreased (Non-patent Document 3).

  According to such research results, Patent Document 1 discloses a pharmaceutical composition containing metformin and repaglinide, but this document only discloses the pharmacological effects obtained by the combined use of the two drugs. No specific pharmaceutical dosage form is disclosed.

  Patent Document 2 discloses a pharmaceutical composition containing metformin and repaglinide. In this document, a pre-formation containing repaglinide is produced, and then mixed with metformin granules. A method of locking is disclosed, but this time teaches that the relative humidity of a pre-formulation containing repaglinide must be kept below 25%.

  However, in the production of a two-component composite agent, it is not desirable in the actual production process to separately prepare a pre-formulation containing a specific component and maintain the relative humidity below a specific value. Thus, there is a demand for a new manufacturing method that can be manufactured without particularly considering humidity.

US Pat. No. 6,677,358 International Application Publication WO2008 / 037807 Pamphlet

The Journal of the American Medical Association, 281 (21), 2005-12. Diabetologia 2003: 46 (suppl 1) Diabetes Care. 1999: 22: 119-124

  An object of the present invention is a pharmaceutical composition containing repaglinide and metformin, and unlike the prior art, a bilayer tablet that can be produced without special consideration for humidity during the production process and a method for producing the same It is to provide.

  Another object of the present invention is that, when it is constituted into a two-layer tablet with repaglinide and metformin, there is a knowledge that interlayer separation is likely to occur during production, storage and distribution, and means for preventing such interlayer separation. The present invention provides a novel bilayer tablet containing concentrated glycerin and a method for producing the same.

  As means for solving the above problems, the present invention provides the following technical solution principle.

A first layer containing repaglinide or a pharmaceutically acceptable salt thereof;
And a second layer containing metformin or a pharmaceutically acceptable salt thereof.

  In the bilayer tablet, the bilayer tablet is characterized in that the first layer or the second layer contains concentrated glycerin as an anti-separation agent.

  In the bilayer tablet, there is provided the bilayer tablet, wherein the first layer contains concentrated glycerin.

A method for producing a bilayer tablet comprising a first layer containing repaglinide and a second layer containing metformin,
(A) producing a granule constituting the first layer containing repaglinide;
(B) producing granules constituting the second layer containing metformin;
(C) tableting the granules constituting the second layer,
(D) In the method for producing a bilayer tablet, the granules constituting the first layer are put on the tablet tableted in the step (c) to make a bilayer tablet.
The first layer or the second layer includes a concentrated glycerin.

  According to the present invention, a pharmaceutical composition comprising repaglinide and metformin is manufactured, and a bilayer tablet similar in dissolution pattern to each single component is manufactured without special consideration for humidity during the manufacturing process In particular, it is possible to achieve the effect of preventing the interlayer separation phenomenon that is likely to occur in bilayer tablets of repaglinide and metformin.

1 shows a schematic structure of a bilayer tablet according to the present invention. The dissolution test result of repaglinide in the bilayer tablet according to the present invention is shown. The dissolution test result of metformin in the bilayer tablet which concerns on this invention is shown.

  The bilayer tablet according to the present invention comprises repaglinide or a pharmaceutically acceptable salt thereof in the first layer, and metformin or a pharmaceutically acceptable salt thereof in the second layer. To do. Below, the characteristic and kind of each component which comprise the bilayer tablet of this invention are demonstrated concretely.

(First layer)
The first layer of the bilayer tablet according to the present invention can contain repaglinide or a pharmaceutically acceptable salt thereof. The first layer can be manufactured with granules containing repaglinide, and after manufacturing the binding solution, the repaglinide, basic additive, and anti-separation agent are dissolved in the binding solution and separately pharmaceutically acceptable. The excipient is mixed and kneaded with the binder solution, dried, sieved with a mesh sieve to produce wet granules, and then the pharmaceutically acceptable excipient is post-mixed to produce granules.

Specific examples of the basic excipient according to the present invention include NaHCO ₃ , CaCO ₃ , MgCO ₃ , KH ₂ PO ₄ , K ₂ HPO ₃ , basic inorganic substances such as calcium trichloride, arginine, Examples include lysine, histidine, meglumine, aluminum magnesium silicate, aluminum magnesium metasilicate, salts thereof, and mixtures thereof, preferably NaHCO ₃ , CaCO ₃ , MgCO ₃ and mixtures thereof. Not.

  The presence of the basic additive can increase the solubility of repaglinide, which is a poorly soluble drug, and can ultimately increase the bioavailability of repaglinide.

  The binding solution can be produced by dissolving a pharmaceutically acceptable binding agent in purified water, and the type of binding agent is not particularly limited, but includes povidone K30, poloxamer 405, alginic acid, sodium alginate, sodium carboxymethylcellulose, One or more compounds selected from the group consisting of ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, starch and pregelatinized (pregelatinized) starch.

  In particular, as a characteristic configuration of the present invention, the first layer can contain concentrated glycerin, but according to the study of the present inventor, when forming a bilayer tablet with repaglinide and metformin, an interlayer separation phenomenon occurs. The knowledge that it is easy to do was obtained, and it turned out that another means for preventing this was necessary. Thereby, when concentrated glycerin is added to the first layer, it is possible to prevent the interlayer separation phenomenon of the bilayer tablet without special consideration, for example, without considering the humidity during the manufacturing process. Obtained knowledge.

  Further, pharmaceutically necessary excipients for producing the first layer granules include anhydrous calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, and red iron oxide, but are not limited thereto. Not. In addition, the first layer can be mixed with a pharmaceutically acceptable disintegrant, a lubricant, and other optional excipients. The disintegrant includes alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystals Cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized (pre-gelatinized) starch, starch glycolate, and one or more compounds selected from the group consisting of starch, Agents include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hardened vegetable oil, polyethylene glycol, sodium benzoate And a group of talc Is one or more compounds selected, but the embodiment is not limited thereto. The other excipients and auxiliary agents are diluents, colorants, anti-tacking agents, or mixtures thereof, but are not limited thereto.

  Also, the first layer may further contain a surfactant in order to improve the sparingly soluble nature of repaglinide. Surfactants can improve aqueous granulation, facilitate tablet ejection after compression, and promote accelerated dissolution of pharmacologically active ingredients. Representative examples of surfactants that can be used include, but are not limited to, sodium lauryl sulfate, poloxamers, polysorbates, and mixtures thereof. As an example of the present invention, the surfactant is preferably present only in the repaglinide layer in order to improve stability, but is not limited thereto.

In one preferred embodiment, the first layer is based on the weight of the first layer: (a) about 0.25% to about 1% by weight of repaglinide, more preferably 1% by weight, (b) base About 0.5% to about 3% by weight of an additive, (c) about 0.5% to about 3% by weight of an interlayer separation inhibitor,
(d) about 80% to about 99.5% by weight of diluent, (e) about 0.5% to about 5% by weight of binder, and (f) about 5% to about 15% by weight of disintegrant. %, (G) lubricant from about 0.5% to about 3% by weight, and (h) colorant up to 0.1% by weight, more preferably from about 0.05% to about 0.1%. An amount of% wt% can be included.

(Second layer)
The second layer of the bilayer tablet according to the present invention contains metformin. For example, the second layer is manufactured by mixing wet solution of metformin with povidone K30 dissolved in ethanol and water, drying it, and sieving with a mesh sieve to produce wet granules, then adding magnesium stearate and mixing. can do. The second layer can optionally contain diluents and other optional excipients and adjuvants. Examples of disintegrants include hydroxypropyl cellulose, crospovidone, sodium starch gluconate, croscarmellose sodium, etc. And can be appropriately selected from commonly used disintegrants. Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, talc, glyceryl fatty acid esters, glycerol dibehenate, and the like. It is possible to select appropriately.

  In particular, the second layer of the present invention can contain concentrated glycerin as an interlayer separation inhibitor. According to the inventor's research, when a bilayer tablet is composed of repaglinide and metformin, it has been found that a delamination phenomenon is likely to occur, and that another means for preventing this is necessary. . Thereby, when concentrated glycerin is added to the first layer, it is possible to prevent the interlayer separation phenomenon of the bilayer tablet without special consideration, for example, without considering the humidity during the manufacturing process. Obtained knowledge.

  That is, in the present invention, concentrated glycerin can be contained in the first layer and / or the second layer, thereby effectively preventing interlayer separation of the bilayer tablet composed of repaglinide and metformin.

  In one preferred embodiment, the second layer is 45% to 98% by weight of metformin and about 0.5% to 3% by weight of anti-separation agent, diluent, disintegration based on the weight of the second layer. Ingredients for the production of granules such as agents may be included in amounts of about 2% to about 55% by weight and lubricants in amounts of about 0.5% to 3% by weight.

(Double-layer tableting)
The bilayer tablet according to the present invention is a bilayer tablet in which a granule containing repaglinide or a pharmaceutically acceptable salt thereof is a first layer and a granule containing metformin or a pharmaceutically acceptable salt thereof is a second layer. And, concentrated glycerin is used as an interlayer separation preventing agent that prevents the first layer and the second layer from being separated. In particular, the basic additive and concentrated glycerin contained in the first layer can improve the stability, achieve an excellent elution pattern, and prevent interlayer separation.

The bilayer tablet according to the present invention can be produced by the following steps.
(a) A step of producing granules constituting the first layer containing repaglinide.
(b) A step of producing granules constituting the second layer containing metformin.
(c) Tableting the granules constituting the second layer.
(d) A step of putting granules constituting the first layer on the tablet compressed in the step (c) and compressing into a bilayer tablet.

  In particular, the present invention is characterized in that in step (a) or step (b), agricultural glycerin is included.

  Various processes by manufacture of the bilayer tablet concerning this invention can be performed by a normal process.

  The following examples further illustrate the present invention. However, the following examples are for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1
Production of granules containing repaglinide In order to produce granules containing repaglinide, a binding solution prepared by dissolving povidone K30 and poloxamer 407 in water with the composition shown in Table 1 below is prepared. Repaglinide, meglumine and concentrated glycerin are dissolved in this binding solution. Separately, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, and red iron oxide are mixed, then kneaded with a mixture of repaglinide dissolved therein, dried, and sieved with a mesh sieve to produce wet granules. Then, croscarmellose sodium and magnesium stearate were added and mixed to produce repaglinide granules.

Production of Granules Containing Metformin Hydrochloride A composition as shown in Table 1 below was prepared by kneading and drying a combined solution of Povidone K30 in ethanol and water in Metformin hydrochloride, and sieved with a mesh sieve to produce wet granules. Thereafter, magnesium stearate is added and mixed to produce metformin hydrochloride granules.

  Using a bilayer tableting machine, metformin hydrochloride granules are made into the first layer, repaglinide granule layer is made into the second layer, and the bilayer tablet is compressed to give the corresponding amount of 2 mg of repaglinide and the corresponding amount of metformin hydrochloride 500 mg. A bilayer tablet composite formulation was completed.

Example 2
Production of granules containing repaglinide In order to produce granules containing repaglinide, a binding solution prepared by dissolving povidone K30 and poloxamer 407 in water with the composition shown in Table 2 below is prepared. Repaglinide and meglumine are dissolved in this binding solution. Separately, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, and red iron oxide are mixed, then kneaded with a mixture of repaglinide dissolved therein, dried, and sieved with a mesh sieve to produce wet granules. Then, croscarmellose sodium and magnesium stearate were added and mixed to produce repaglinide granules.

Manufacture of granules containing metformin hydrochloride The composition shown in Table 2 is mixed with metformin hydrochloride, povidone K30, a combined solution of concentrated glycerin dissolved in ethanol and water, dried and sieved through a mesh sieve to produce wet granules. Then, magnesium stearate is added and mixed to produce metformin hydrochloride granules.

  Using a bilayer tablet press, the metformin hydrochloride granule is made into the second layer, the repaglinide granule layer is made into the first layer, the bilayer tablet is tableted, and the amount of repaglinide 2 mg and the amount of metformin hydrochloride 500 mg A bilayer tablet composite formulation was completed.

Example 3
Production of granules containing repaglinide To produce granules containing repaglinide, a binding solution prepared by dissolving povidone K30 and poloxamer 407 in water with the composition shown in Table 3 below is prepared. Repaglinide, meglumine and concentrated glycerin are dissolved in this binding solution. Separately, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, and red iron oxide are mixed, then kneaded with a mixture of repaglinide dissolved therein, dried, and sieved with a mesh sieve to produce wet granules. Then, croscarmellose sodium and magnesium stearate were added and mixed to produce repaglinide granules.

Manufacture of granules containing metformin hydrochloride In the composition shown in Table 3 below, metformin hydrochloride is mixed with povidone K30, a combined solution of concentrated glycerin dissolved in ethanol and water, dried, sieved through a mesh sieve and wet granules After production, magnesium stearate is added and mixed to produce metformin hydrochloride granules.

  Using a bilayer tablet press, the metformin hydrochloride granule is made into the second layer, the repaglinide granule layer is made into the first layer, the bilayer tablet is tableted, and the amount of repaglinide 2 mg and the amount of metformin hydrochloride 500 mg A bilayer tablet composite formulation was completed.

Comparative Example 1
Production of granules containing repaglinide To produce granules containing repaglinide, a binding solution prepared by dissolving povidone K30 and poloxamer 407 in water with the composition shown in Table 4 below is prepared. Repaglinide and meglumine are dissolved in this binding solution. Separately, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, and red iron oxide are mixed, then kneaded with a mixture of repaglinide dissolved therein, dried, and sieved with a mesh sieve to produce wet granules. Then, croscarmellose sodium and magnesium stearate were added and mixed to produce repaglinide granules.

Manufacture of granules containing metformin hydrochloride After preparing a wet granule by kneading and drying a combined solution of povidone K30 in ethanol and water in metformin hydrochloride with the composition shown in Table 4 below, the mixture is sieved with a mesh sieve. Then, magnesium stearate is added and mixed to produce metformin hydrochloride granules.

  Using a bilayer tablet press, the metformin hydrochloride granule is made into the second layer, the repaglinide granule layer is made into the first layer, the bilayer tablet is tableted, and the amount of repaglinide 2 mg and the amount of metformin hydrochloride 500 mg A bilayer tablet composite formulation was completed.

Comparative Example 2
Production of granules containing repaglinide To produce granules containing repaglinide, a binding solution prepared by dissolving povidone K30 and poloxamer 407 in water with the composition shown in Table 5 below is prepared. Repaglinide, meglumine and glycerin are dissolved in this binding solution. Separately, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, and red iron oxide are mixed, then kneaded with a mixture of repaglinide dissolved therein, dried, and sieved with a mesh sieve to produce wet granules. Then, croscarmellose sodium and magnesium stearate were added and mixed to produce repaglinide granules.

Production of Granules Containing Metformin Hydrochloride After preparing a wet granule by kneading a metformin hydrochloride with a combined solution of povidone K30 dissolved in ethanol and water with the composition shown in Table 5 and sieving with a mesh sieve. Then, magnesium stearate is added and mixed to produce metformin hydrochloride granules.

  Using a bilayer tablet press, the metformin hydrochloride granule is made into the second layer, the repaglinide granule layer is made into the first layer, the bilayer tablet is tableted, and the amount of repaglinide 2 mg and the amount of metformin hydrochloride 500 mg A bilayer tablet composite formulation was completed.

Experimental example 1
A friability test and a hardness test were performed according to Examples 1 to 3 and Comparative Examples 1 and 2. The friability test is one method for expressing the physical strength of a tablet. The amount of powder generated when a tablet is dropped from a certain height while being put in a cylinder and rotated at a certain speed or breakage. Measure and measure the degree to be done. Judgment is based on the ability of the tablet to withstand breakage during handling, packaging, and shipping. Ten tablets manufactured in each Example and Comparative Example were placed in a cylinder of a friability tester and operated for 4 minutes at a speed of 25 rpm, and then the state of the tablets was confirmed.

The test results were evaluated as follows.
(Double-circle): There is no tablet which interlayer-separated in the test tablet or the edge | tip lacked.
◯: There are no tablets separated from each other in the test tablet, but there are no more than two tablets with missing edges.
Δ: One or more tablets separated from each other in the test tablet, and two or more tablets lacking edges.
X: Two or more tablets separated from each other in the test tablet, and three or more tablets lacking in edges.

  The hardness test is a test for measuring the breaking strength of a tablet (unit: kgf).

  As a test method, the hardness is measured by placing the tablet in a load cell compartment on the long axis in a hardness measuring instrument. Ten tablets in each example and comparative example were tested in the above manner.

The test results were evaluated as follows.
A: Ten tablets having a hardness of 18 kgf or more in the test tablets.
○: 7 or more tablets having a hardness of 18 kgf or more in the test tablets.
Δ: 5 or more tablets having a hardness of 18 kgf or more in the test tablets.
X: Less than 5 tablets having a hardness of 18 kgf or more in the test tablets.

  The results are shown in Table 6 (results of friability test) and Table 7 (results of hardness test).

  As can be seen from the above table, in Examples 1 and 3 in which concentrated glycerin was added to the first layer, unlike the other examples, the phenomenon that the edge portion of the tablet was broken little by little during the friability test, There was no delamination phenomenon. Further, in Example 2 in which concentrated glycerin was added to the second layer, there was a tablet in which the edge portion of the tablet lacked in the first layer part, but the interlayer separation phenomenon did not occur. Compared to Examples 1 and 2, the friability was very good. It is presumed that repaglinide granules and metformin hydrochloride granules with concentrated glycerin increased cohesion between the particles and showed better results than the other products in the friability test, thereby preventing delamination it is conceivable that. Also in the hardness test, Examples 1 and 3 containing concentrated glycerin in the first layer were very excellent in hardness, and Comparative Examples 1 and 2 not containing concentrated glycerin were poor in hardness.

Experimental example 2
From the above experimental example, it was found that the bilayer tablet containing concentrated glycerin showed very good physical properties in the friability and hardness experiments. However, when such friability and hardness are very excellent, a desired elution pattern may not be obtained, so an elution test was performed on the examples of the present invention.

Dissolution Test Examples 1-3 repaglinide, Comparative Examples 1 and 2 and NovoNorm Tab. ^TM 2mg (control drug, Novo Nordisk Corporation) implementing the dissolution test by reference to elution item "repaglinide Tablets" of USP against did. After the test, the test solutions were taken at 5, 10, 15, and 30 minutes to confirm the dissolution rate. The results are shown in Table 8 and FIG.

  The elution rates in Examples 1 and 3 show the same results as the control drug. As a result of comparison with Comparative Example 1 containing no concentrated glycerin, the elution rate is about 10% at 5 minutes and the elution rate is about 10 minutes at 10 minutes. It was about 9% higher. Moreover, it turned out that the comparative example 2 showed the elution rate about 3 to 4% lower than Examples 1 and 3 in 5 and 10 minutes.

(2) Dissolution Test Examples 1 to 3 of metformin, Comparative Examples 1 and 2 and Diabex Tab. ^TM 500mg (control drug, Daewoong Pharmaceutical Co., Ltd.) was eluted item "metformin hydrochloride tablets" of BP reference against The dissolution test was conducted. After the test, the test solutions were taken at 5, 10, 15, and 30 minutes to confirm the dissolution rate, and the results are shown in Table 9 and FIG.

  It turned out that the elution rate in Examples 1-34 shows an equivalent elution rate compared with a control drug. Accordingly, it has been found that it is desirable to add concentrated glycerin in order to improve the friability, hardness, and dissolution rate of the preparation during the production of the bilayer tablet of the combined preparation of repaglinide and metformin hydrochloride.

Claims (4)

  A bilayer tablet comprising a first layer containing repaglinide or a pharmaceutically acceptable salt thereof and a second layer containing metformin or a pharmaceutically acceptable salt thereof.   The bilayer tablet according to claim 1, wherein the first layer or the second layer contains concentrated glycerin as an anti-separation agent.   The bilayer tablet according to claim 2, wherein the first layer contains concentrated glycerin. A method for producing a bilayer tablet comprising a first layer containing repaglinide and a second layer containing metformin,
(a) producing a granule constituting the first layer containing repaglinide;
(b) producing a granule constituting the second layer containing metformin;
(c) tableting the granules constituting the second layer,
(d) In the method for producing a bilayer tablet in which the granules constituting the first layer are put on the tablet tableted in the step (c) and compressed into a bilayer tablet,
The first layer or the second layer contains concentrated glycerin.

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