TR202008542A2 - FILM COATED TABLET PREPARATION PROCESS WITH LINAGLIPTIN AND METFORMIN - Google Patents

Abstract

The present invention; relates to a process for preparing a film-coated tablet containing linagliptin and metformin HCl to have the desired stability and dissolution profile. The present invention also relates to a simple, fast, cost-effective, time-saving and industrially suitable process.

Description

DESCRIPTION FILM COATED TABLET PREPARATION PROCESS WITH LINAGLIPTIN AND METFORMIN Field of Invention The present invention; The desired stability and strength of a film-coated tablet containing inagliptin and metformin HCl. It relates to a process for preparing it to have a dissolution profile. Available The invention is also simple, fast, cost-effective, time-saving and industrial. It also relates to an appropriate process.

State of the Art Diabetes mellitus, where insulin action is reduced or absent as a result of secretion changes It is a group of carbohydrate metabolism disorders in which insulin and/or insulin activity are reduced. Type 1 There are two main types of diabetes: Type 2 and Type 2. Type 1 diabetes is caused by damage to the insulin-producing cells (beta cells) of the pancreas. occurs. In type 1 diabetes, the pancreas produces little or no insulin, so sugar, It cannot enter body cells to be used as energy. People with type 1 diabetes, blood sugar should use insulin injections to control it.

In type 2 diabetes, the pancreas produces insulin, but the insulin produced is either insufficient or not properly produced. has no effect. This type of diabetes is most common in people over 40 years of age and overweight. Medicine 2 diabetes can sometimes be controlled with a combination of diet, weight control, and exercise.

However, a treatment consisting of oral glucose-lowering drugs or insulin injections applicable.

Linagliptin is used for type 2 or non-insulin dependent diabetes. glycemic control A selective, orally administered, xanthine-based supplement used as an adjunct to diet and exercise to increase It is a dipeptidyl peptidase-4 (DPP-4) inhibitor. DPP-4 inhibitors break down incretin hormone It acts by blocking the effect of DPP-4, an enzyme that inhibits glucagon-like in the body Two types of incretins called peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) hormone is present. These hormones are naturally produced by the body in response to food intake. as produced. Its job is to help the body produce more insulin only when it is needed. to help and reduce the amount of glucose produced by the liver when not needed.

Linagliptin acts by binding to DPP-4 and preventing its cleavage to GLP-1 and GIP.

Thus, the levels of these hormones in the body increase, thereby controlling blood sugar. effects also increase. methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione and its chemical structure is in Formula I is shown.

Formula I Metformin is an orally administered antidiabetic with a biguanide structure. metformin hydrochloride is a white to off-white crystalline compound and readily soluble in water and acetone, It is practically insoluble in ether and chloroform. Oral doses of metformin are usually it can change. Alone or with sulfonylurea, alpha-glucosidase inhibitors or insulin used in combination.

The chemical name of metformin hydrochloride is 1,1-dimethylbiguanide hydrochloride and its chemical structure shown in Formula II below.

H3C\|\IIJLHJLNH2 Formula II Combination of linagliptin with metformin HCl is an even more effective treatment of type II diabetes. offers treatment. Linagliptin in combination with metformin, United States USA by Boehringer Ingelheim under the brand name Jentadueto® is marketed. It is a pharmaceutical product containing pregelatinized starch, copovidone, corn starch and magnesium stearate. composition is described. The prior art tells us that Iinagliptin with a primary or secondary amino group is unstable and taught that it creates incompatibility, degradation or extraction problems. Prior art references state that Iinagliptin free base is combined with metformin HCl. using basic amino acids to avoid chemical degradation stands on it. stabilized the said Iinagliptin against degradation, along with more pharmaceutical excipients pharmaceutical composition containing a nucleophilic and/or basic agents to is explained. Also in the patent is a basic amino acid L-, which may be suitable as a stabilizer. explains the use of arginine.

The use of stabilizers not only provides the desired stability, but also Linagliptin. It is also isolated from destabilizing substances that may occur during the preparation of the formulation. However, there is still a need for a physically and chemically stable composition.

Surprisingly, in the present invention, there are physical and chemical compounds containing Iinagliptin and metformin. process of preparing stable pharmaceutical composition eliminates the above-mentioned problem. found to be removed.

Detailed Description of the Invention The present invention; containing linagliptin and metformin HCl and has good content uniformity and desired physical and to provide a process for preparing a film tablet with chemical stability. aims. The process in question is simple, fast, cost-effective, time-saving. and industrially suitable method.

Another object of the present invention is to eliminate the problems of the prior art and to is to bring additional advantages over the prior art.

Another object of the present invention is the desired dissolution containing Iinagliptin and metformin HCl. presenting a process for preparing a film tablet with profiles.

The term "Inagliptin" as used throughout the specification includes not only linagliptin but also Also, other pharmaceutically acceptable salt of Iinagliptin pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable acceptable polymorphs or pharmaceutically acceptable prodrugs. covers.

Linagliptin, amorphous Iinagliptin, crystalline Iinagliptin with polymorphic form A, polymorphic form Crystalline Iinagliptin with B and polymorphic form C with anhydrous form A, anhydrous form B available as crystalline Iinagliptin or mixtures thereof. Preferably Iinagliptin, anhydrous form A and anhydrous form B. These forms of linagliptin are considerably higher than the amorphous form. is stable.

The preparation process of the formulation and the amount of active ingredients in the formulation are very different. Therefore, it is important for the stability problems of Iinagliptin.

According to one embodiment of the present invention, a film-coated tablet containing Iinagliptin and metformin is a process for its preparation; where the process includes the following steps: a) Containing metformin HCl and at least one pharmaceutically acceptable excipient, a mixture called first mix is prepared, b) A mixture called second mix is prepared, containing linagliptin and meglumine, C) A granulation solution is prepared.

When the film-coated tablet is prepared by the above-mentioned process, it is effective during production. does not result in losses in substances or excipients and provides the desired good content uniformity. it has been seen to provide. This situation indicates that content uniformity plays an important role in dissolution of the drug. Meglumine belongs to the class of organic compounds known as hexose. These are the six unit of sugar. They are monosaccharides in which there is a part containing carbon. Meglumine is water soluble and pH It is an organic base used as a setting agent and solubilizer.

In general, Iinagliptin is not very stable when used with metformin HCl.

Since the use of metformin HCl increases the acidic level of the environment, it improves the stability of Iinagliptin. loses. In particular, in solid dosage forms, Iinagliptin containing the amine group is combined with many excipients. or may react with impurities of excipients. In this invention, the mixture containing Iinagliptin Surprisingly, the use of meglumine in the preparation of the (second mix) film-coated tablet It gives high stability to Iinagliptin in its form and thus the desired dissolution in the tablet. It has been found to provide the rate. The second mixture does not contain any excipients.

According to one embodiment of the present invention, the first mixture is considered to be at least one pharmaceutical. contains excipient which is excipient is a binder and a dispersant.

According to one embodiment of the present invention, the granulation solution contains a binder.

Since Metformin HCl is used in high amounts, it is necessary to prepare a homogeneous mixture. The desired result is obtained when a binder is used.

Suitable binder; copovidone, povidone, hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, alginate, sodium alginate, glycyrrhizin, polymethacrylates, poloxamer, polyacrylamide, aluminum hydroxide, bentonite, Iaponit, cetostearyl alcohol, polyoxyethylene-alkyl ethers, polydextrose, polyethylene oxide, xylitol, sucrose stearate or mixtures thereof.

According to one embodiment of the present invention, the binder is copovidone.

Metformin HCl is delivered in individual composition units during preparation of the formulation. in large quantities, which can cause significant problems with the content uniformity of the active substance. is used. Due to the problem of content uniformity, the active substance is mixed with a few excipients. can interact. This situation indicates that content uniformity plays an important role in dissolution of the drug. it shows that you are playing. The correct dispenser use ensures content uniformity. helps and therefore provides the desired dissolution profile According to one embodiment of the present invention, the dispenser; corn starch, sodium starch glycolate, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxypropyl cellulose, methyl cellulose, chitosan, starch, pregelatinized starch or selected from the group containing mixtures of these.

According to one embodiment of the present invention, the dispersant is corn starch.

According to one embodiment of the present invention, a film-coated tablet containing Iinagliptin and metformin The process for its preparation includes the following steps: a) A mixture (first mix) containing metformin HCl, copovidone and corn starch is prepared, b) A mixture (second mixture) containing linagliptin and meglumine is prepared, 0) A granulation solution is prepared by dissolving copovidone in water.

According to one embodiment of the present invention, a film-coated tablet containing linagliptin and metformin The process for its preparation also includes the following steps: d) First mix and second mix to geometric dilution with granulation solution. subjected to and wet granules are obtained, e) The granule is sifted wet, f) It is dried and then sieved, Geometric dilution and wet granulation processes according to one embodiment of the present invention used. Content uniformity is ensured by geometric dilution and wet granulation.

Increased content uniformity contributes to a marked increase in bioavailability.

Improving the uniformity of the content also means that the amount of active substance is too high. It is advantageous to avoid toxicity in the unlikely event that it may occur.

Geometric dilution, an inert substance that dilutes or binds the drug, and an appropriate amount It is a pharmaceutical process in which a diluent and a small amount of a drug are thoroughly mixed. This process is the It ensures an even distribution throughout the final product obtained.

When mixing a small amount of medication with a large amount of another ingredient or diluent geometric dilution process is used. In this method, a smaller amount of drug, It is placed in the mortar in equal amounts with the other ingredients. until the two ingredients are well mixed. crushed and powdered.

According to one embodiment of the present invention, a film-coated tablet containing linagliptin and metformin The process for its preparation also includes the following steps: 9) In step (f), a dispersant is added and mixed, h) A glidant is eliminated and added to the mixture in step (g), i) A lubricant is added and mixed, i) The mixture is pressed to form tablets, k) Tablets are coated with coating agents Especially when two active substances are combined in one final dosage form, these two active substances are very When used in different quantities, the problem of homogeneity, powder viscosity and compressibility present invention, especially thanks to step (g,h,i) The advantages are even more significant.

Suitable glidant; from the group consisting of colloidal silicon dioxide, talc or mixtures thereof. is selected.

According to one embodiment of the present invention, the glidant is colloidal silicon dioxide.

Appropriate Iubrican; magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium Iauril sulfate, magnesium lauryl sulfate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, stearic acid, polyethylene glycol, paraffin or their selected from a group containing mixtures of

According to one embodiment of the present invention, the lubricant is magnesium stearate.

According to one embodiment of the present invention, dispersive corn starch, glidant colloidal silicon dioxide and Iubrican magnesium stearate.

According to one embodiment of the present invention, a film-coated tablet containing Iinagliptin and metformin The process for its preparation also includes the following steps: 9) Adding and mixing the cornstarch in step (f), h) Eliminating colloidal silicon dioxide and adding it to the mixture in step (g), i) Adding and mixing magnesium stearate, i) Pressing the mixture to form tablets, k) Coating the tablets with coating agents.

According to one embodiment of the present invention, half of the corn starch used as the dispersant (a) and the remaining half is added in step (g). This allows the desired dissolution profile to be obtained. helps to.

Suitable coating materials; polymethacrylates, hydroxypropyl methylcellulose, triacetin, glycerol triacetin, talc, red iron dioxide, yellow iron dioxide, propylene glycol, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidon, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), all types of Opadry®, pigments, dyes, from the group consisting of titanium dioxide, macrogol, coloring matter or mixtures thereof is selected.

Coating agents according to one embodiment of the present invention are hydroxypropyl methylcellulose, talc, red iron dioxide, yellow iron dioxide, titanium dioxide, propylene glycol or their are mixtures.

According to one embodiment of the present invention, the hardness of the film-coated tablet depends on the mechanical strength of the formulation. important for stability. The hardness of the film-coated tablet is more than 150 N, preferably 150 N - 400 N In this invention there is talk of preparing a film-coated tablet containing linagliptin and metformin HCl. The process is stable. Combination; meglumine, copovidone, corn starch, magnesium Incompatibility, degradation or degradation with certain excipients such as stearate, colloidal silicon dioxide Does not show extraction problems.

In one embodiment of the invention, the film-coated tablet obtained by the process described in the invention is a total The tablet contains the following; 005% - 10.0 by weight linagliptin 700% - 90.0% by weight metformin HCl 10% -100% meglumine by weight, 20 - 80% corn starch by weight, 0.1 - 30 wt% colloidal silicon dioxide 0.1 - 30% by weight magnesium stearate 0.1 - 4.0% by weight coating.

In one embodiment of the invention, the film-coated tablet obtained by the process described in the invention is a total The tablet contains the following; 0.1% - 1.0 by weight linagliptin 800 - 85.0% by weight metformin HCl 10 - 30% meglumine by weight 30% - 4.0% corn starch by weight 0.2 - 1.0% by weight colloidal silicon dioxide 0.2 - 1.0% by weight magnesium stearate Example 1: Film-coated tablet formulation containing Linagliptin and metformin Ingredients By weight (%) Metformin HCl 82.47 .E E› Cornstarch 3.22 Copovidone 494 E Linagliptin 0.41 E â" Meglumin 1.98 c Copovidone 4.12 Magnesium stearate 0.82 TOTAL 100 Example 2: Film-coated tablet formulation containing linagliptin and metformin E Metformin HCl 82.61 3 Cornstarch 3.22 -E Kopovidone 4.94 E Linagliptin 0.21 E â" Meglumin 1.98 c Copovidone 4.12 Magnesium stearate 0.82 TOTAL 100 Process for Example 1 or 2; Metformin HCl is a drug containing half the copovidone and half the corn starch. mix (first mix) is prepared, A mixture (second mix) containing linagliptin and meglumine is prepared.

The remaining half of the copovidone is dissolved in water to form a granulation solution. is prepared.

First mix and second mix to geometric dilution with granulation solution. subjected to and wet granules are obtained, The granule is wet sifted, It is dried and then sieved, In step (f), the remaining half of the corn starch is added and mixed, Colloidal silicon dioxide is sieved and the mixture is added in step (g), Add magnesium stearate and mix The mixture is pressed to form tablets, Tablets are coated with coating agents

Claims (12)

REQUESTS A process for the preparation of a film-coated tablet containing linagliptin and metformin; feature; The process includes the steps of a) preparing a mixture (first mixture) containing metformin HCl and at least one pharmaceutically acceptable excipient, b) preparing a mixture (second mixture) containing linagliptin and meglumine, c) preparing a granulation solution. It is a film-coated tablet preparation process according to claim 1, and its feature is; the first mixture contains as at least one pharmaceutically acceptable excipient, a binder and a dispersant. It is a film-coated tablet preparation process according to claim 1, and its feature is; is that the granulation solution contains a binder dissolved in water. It is a film-coated tablet preparation process according to claim 2 or 3, and its feature is; binder copovidone, povidone, hydroxylpropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, alginate, sodium alginate, glycyrrhizine, polymethacrylates, poloxamer, polyacryltonide, alumina, hydroxide, benocyltonide, polyoxyethylene-alkyl ethers, polydextrose, polyethylene oxide, xylitol, sucrose stearate or mixtures thereof. It is a film-coated tablet preparation process according to claim 2, and its feature is; The binder is copovidone. It is a film-coated tablet preparation process according to claim 2, and its feature is; dispersant is selected from the group consisting of corn starch, sodium starch glycolate, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxypropyl cellulose, methyl cellulose, chitosan, starch, pregelatinized starch or their mixtures. It is a film-coated tablet preparation process according to claim 2, and its feature is; the dispersant is corn starch. It is a film-coated tablet preparation process according to claim 1, and its feature is; The process includes the steps of a) preparing a mixture (first mixture) containing metformin HCl, copovidone and corn starch, b) preparing a mixture containing linagliptin and meglumine (second mixture), c) preparing a granulation solution by dissolving copovidone in water. 9. It is a film-coated tablet preparation process according to claim 1 or 8, its feature is; The process includes the steps of d) Geometric dilution of the first mixture and the second mixture with the granulation solution and obtaining wet granules, e) Wet sieving the granule, f) Drying and sieving. 10. It is a film-coated tablet preparation process according to claim 9, its feature is; The process also includes the steps of 9) adding a dispersant and mixing in step (f), h) sieving the glidant and adding to the mixture in step (g), i) adding and mixing the lubricant, i) pressing the mixture to form tablets, k) coating the tablets with coating agents. . 11. It is a film-coated tablet preparation process according to claim 10, and its feature is; dispersant is corn starch, glidantin is colloidal silicon dioxide, lubricant is magnesium stearate. 12. It is a film-coated tablet preparation process according to claim 1 and its feature is; tablet hardness is 150, more preferably between 300 N and 350 N.