TR2022013357A2 - ORAL THERAPEUTIC FORMULATIONS - Google Patents

Abstract

The present invention; In adults with type 2 diabetes mellitus, in addition to diet and exercise to improve glycemic control, in patients not adequately controlled with the maximum tolerated dose of metformin alone, metformin in combination with other medicinal products for the treatment of diabetes, including insulin, and in patients adequately controlled with these medicinal products Suitable active ingredient(s) and/or pharmaceutically acceptable derivatives with antidiabetic properties in the group of dipeptidyl peptidase-4 (DPP-IV) inhibitors, in the group of dipeptidyl peptidase-4 (DPP-IV) inhibitors, as monotherapy, for use in combination in patients who are not already treated with the combination of linagliptin and metformin in separate tablets. It relates to pharmaceutical composition/s containing treatment alone or in combination with appropriate active ingredient/s with antidiabetic properties in the biguanide group and/or pharmaceutically acceptable derivatives.

Description

DESCRIPTION ORAL THERAPEUTIC FORMULATIONS The present invention; In adults with type 2 diabetes mellitus, in addition to diet and exercise to improve glycemic control, in patients not adequately controlled with the maximum tolerated dose of metformin alone, with metformin in combination with other medicinal products for the treatment of diabetes, including insulin, and in patients not adequately controlled with these medicinal products In combination, for use in patients already treated with the combination of linagliptin and metformin in separate tablets, appropriate active substance/s and/or pharmaceutically acceptable derivatives with antidiabetic properties in the group of dipeptidyl peptidase-4 (DPP-IV) inhibitors are used alone as monotherapy. or pharmaceutical composition/s containing combined treatment with suitable active substance/s with antidiabetic properties in the biguanide group and/or pharmaceutically acceptable derivatives thereof. Present invention; Linagliptin, 8-[(3R)-3-Aminopiperidin-1-yl]-7-(but-2-in-1-yl)-, which has antidiabetic properties in the group of dipeptidyl peptidase-4 (DPP-4) inhibitors It is included in the biguanide group with 3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione (Formula 1) and/or its pharmaceutically acceptable derivatives. It relates to the pharmaceutical composition/s in which the active ingredient with antidiabetic properties is Metformin, N,N-dimethylimidodicarbonimidic diamide (Formula 11) and/or its pharmaceutically acceptable derivatives, Linagliptin is used alone as monotherapy or in combination with other suitable active agent/s. . Formula 1: GH3 GH3 NHz Formula 11: Also invention; It also includes formulations of pharmaceutical compositions suitable for oral administration and prophylactic and/or symptomatic and/or therapeutic uses of pharmaceutical compositions using linagliptin and/or its pharmaceutically acceptable derivatives as monotherapy or in combination with metformin and/or its pharmaceutically acceptable derivatives. PRIOR ART (STATE OF THE ART) When the glucose (sugar) level in the blood increases, under normal conditions, the insulin hormone is secreted by the beta cells of the pancreas, and the glucose must enter the cells and be used in order for the cells to provide the energy they need; Insulin stimulates this. Diabetes mellitus; It is defined as a chronic metabolic disease that occurs as a result of the absence, insufficiency or peripheral ineffectiveness of insulin in the human body, accompanied by carbohydrate, fat and protein metabolism disorders, and progresses with chronic hyperglycemia, in which many factors play a role in its etiology. In individuals with diabetes, the insulin produced by the pancreas is either insufficient or insulin cannot sufficiently exert its effect on target tissues. As a result; Glucose levels in blood and urine increase, excessive glucose levels in blood damage tissues and cells, causing their dysfunction and failure. Long-term effects of diabetes mellitus may occur with progressively developing specific complications. These complications can be examined in two groups: microvascular complications (such as retinopathy, which can lead to potential blindness, nephropathy and/or foot ulcer, which can result in renal failure, neuropathy that carries the risk of amputation) and macrovascular complications (such as myocardial infarction, stroke and peripheral artery disease). Therefore, patients with diabetes are at risk for cardiovascular, peripheral vascular and cerebrovascular diseases. There are three main types of diabetes mellitus: It is classified as Type 1 diabetes mellitus, Type 2 diabetes mellitus and diabetes resulting from other specific defects (WHO/NCD/NCS/992). In Type 1 Diabetes (Insuline Dependent Diabetes), which generally occurs in children and young ages (< 30 years old); The pancreas either cannot secrete insulin at all or secretes very little. Type 1 diabetic patients absolutely need insulin at every stage of the disease. Approximately 90.1% of all adult-onset diabetes cases are type 2 diabetes (Non-Insulin Dependent Diabetes). Along with the deficiency in insulin production, there is resistance to insulin in the surrounding tissues. In order to effectively control the amount of glucose in the blood, more insulin must be secreted from the pancreas. Some drugs used in the therapeutic treatment of diabetes mellitus and especially non-insulin-dependent diabetes (Type 2 diabetes): o Biguanide o Sulfonylurea o Ot-glucosidase inhibitor o Prandial glucose regulator o Thiazolidinediones (Glitazones) o Incretin mimetics/ GLP-1 analogs o DPP-4 inhibitors (Gliptins). Dipeptidylpeptidase-4 (DPP-4) inhibitors; Inhibiting the DPP-4 enzyme, which ensures rapid degradation of the GLP-1 molecule in the postprandial period, and increasing the levels of GLP-1 and GIP, which are endogenous and natural incretins, are another new antidiabetic drug group. DPP-4 inhibition prevents the rapid degradation of incretins and appears to be a promising therapeutic target in the treatment of Diabetes mellitus (DM). DPP-4 inhibitors show their anti-hyperglycemic effects by prolonging the concentrations and effects of incretins. DPP-4 inhibitors are orally active, low molecular weight molecules that can inhibit more than 90% of plasma DPP-4 activity for more than 24 hours. These agents increase active incretin levels by preventing rapid degradation. Thus, they are effective in the treatment of early-stage DM in which the pancreatic insulin reserve is not completely exhausted due to the increase in endogenous incretin. The group of dipeptidylpeptidase-4 (DPP-4) inhibitors includes sitagliptin, alogliptin, saxagliptin, vildagliptin, evogliptin, linagliptin, anagliptin, teneligliptin, trelagliptin, gemigliptin, dutogliptin, omarigliptin. The risk of hypoglycemia seen with sulfonylurea therapy appears to be lower with DPP-4 inhibitors. Risks such as bone fracture, congestive heart failure, and weight gain, which are seen with thiazolinediones, have not been found in studies. In light of this current data, they seem safer in terms of side effects. (DPP-4 Inhibitors and Diabetes Mellitus Treatment - Assistant Professor Ugur Bilge Osman Gazi University Faculty of Medicine) Biguanides; They are oral antihyperglycemic drugs used for the treatment of diabetes mellitus or prediabetes. Biguanide-derived antihyperglycemic agents are widely used in non-insulin-dependent diabetes mellitus. Metformin has a dimethylbiguanide structure and is an antihyperglycemic agent from the biguanide class. Metformin, taken orally to reduce plasma glucose levels, not only reduces hepatic glucose formation but also increases insulin sensitivity in the tissue. It acts especially by reducing gluconeogenesis in the liver and, to a lesser extent, by reducing peripheral insulin resistance. It is an antidiabetic that does not cause hypoglycemia and causes mild weight loss. The aim of diabetes treatment should be to avoid the acute osmotic symptoms of hyperglycemia, to both control and stabilize blood sugar in the long term, to prevent/postpone complications, and while doing these, not to impair the patient's quality of life. There are multiple factors in the pathophysiology of diabetes, such as insulin resistance, insulin deficiency, glucagon excess, GLP-1/GIP deficiency-resistance, and cytokines secreted from adipose tissue. This reveals the need to develop new treatments. Treatment agents that have been approved in recent years can be listed as DPP-4 enzyme inhibitors, GLP-1 analogs, SGLT-2 (Sodium Glucose Transporter 2) inhibitors, and new analog insulins. (New Systemic Treatment Approaches in Diabetes - Assist. Prof. Dr. Mustafa Kulaksizoglu) In type 2 diabetes, as a result of the natural process, monotherapies are replaced by combination treatments over time. Insulin sensitizing and insulin secretagogue drugs are combined in accordance with the pathophysiological basis of the disease. Considering the cost and experience period, combinations with metformin should be preferred. Depending on the patient's characteristics, metformin can often be combined with SU, GLN, DPP4-I, PIO or SGLT2-I. (T emd diagnosis, treatment and follow-up guide for diabetes mellitus and its complications-2018). The aim is to increase the success of treatment by increasing the patient's compliance with the treatment as well as the effectiveness. Dispersible compositions, preparation processes and their use in diabetes treatment are mentioned. A stable pharmaceutical composition comprising metformin or its salt and one or more alkalisers is disclosed. and describes fixed-dose combinations of a common drug such as Metformin. The composition further includes one or more pharmaceutical excipients, basic agents such as buffering agents to stabilize the DPP-4 inhibitor in question against degradation. Different polymorphs of a compound have different properties in terms of melting point, solubility, density, optical and electrical properties, vapor pressure and solid state stability. Polymorphism; It can occur as a result of processes such as crystallization from different solvents at different speeds and temperatures, precipitation, evaporation, crystallization from molten mass, grinding, lyophilization, spray drying. The active ingredient and excipients in the solid drug form exist in different crystal shapes and amorphous forms. The different crystal structures observed in the structures of different polymorphs may lead to differences in solubility and dissolution profiles. Polymorphs must be stable throughout their shelf life. DESCRIPTION OF THE INVENTION The present invention; In adults with type 2 diabetes mellitus, in addition to diet and exercise to improve glycemic control, in patients not adequately controlled with the maximum tolerated dose of metformin alone, with metformin in combination with other medicinal products for the treatment of diabetes, including insulin, and in patients not adequately controlled with these medicinal products In combination, for use in patients already treated with the combination of linagliptin and metformin in separate tablets, appropriate active substance/s and/or pharmaceutically acceptable derivatives with antidiabetic properties in the group of dipeptidyl peptidase-4 (DPP-IV) inhibitors are used alone as monotherapy. or pharmaceutical composition/s containing the combination treatment with suitable active substance/s with antidiabetic properties in the biguanide group and/or pharmaceutically acceptable derivatives thereof. Another aspect of the present invention; Pharmaceutical compositions containing the treatment of dipeptidyl peptidase-4 (DPP- and/or its pharmaceutically acceptable derivatives for oral administration, as monotherapy or in combination with the appropriate active substance with antidiabetic properties in the biguanide group and/or its pharmaceutically acceptable derivatives. In the invention, the appropriate active substance with antidiabetic properties in the group of dipeptidyl peptidase 4 (DPP-4) inhibitors includes, but is not limited to, vildagliptin, evogliptin, saxagliptin, sitagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, dutogliptin, omarigliptin. and/or its pharmaceutically acceptable derivatives, preferably linagliptin, and/or its pharmaceutically acceptable derivatives, preferably linagliptin. In the invention, the active substance(s) with antidiabetic properties in the biguanide group used as the active ingredient are, but are not limited to, phenformin, metformin; is selected from butformin and/or its pharmaceutically acceptable derivatives, preferably metformin hydrochloride. In the invention, the term "pharmaceutically acceptable derivatives" means suitable pharmaceutically acceptable salts, esters, solvates, hydrates, complexes, polymorphs, enantiomers, prodrugs, acid addition salts, analogues, isomers, racemates, amides, enantiomer salts, basic salts, conjugates. It can be formulated with one or more of the following: tautomers, anhydrates, anhydrides, bases, acids, ethers, crystalline and amorphous forms, or free forms. The pharmaceutical composition prepared for oral administration may be in solid or liquid dosage forms. These dosage forms; tablet (uncoated, chewable, orodispersible, dispersible, water-dispersible, film-coated, single-layer, double-layer, disintegrating-coated, mini-tablet, controlled-release, sustained-release, immediate-release, extended-release, delayed-release, modified-release, buccal ), capsule (hard, soft, enteric-coated, film-coated, controlled-release, sustained-release, immediate-release, extended-release, delayed-release, modified-release), powder, dry powder, granule, caplet, disc, orodissolving film, bulk powder (multi-dose), pellet, sachet, water-dispersible powder, water-dispersible granule, effervescent tablet, effervescent granule, effervescent powder, microcapsule, dental tablets, pill, syrup, solution, suspension, elixir, drop, position, emulsion or spray. Can be formulated into dosage form. Interlocking asymmetric aggregates used directly as medicine or as a preliminary step in the preparation of tablets are called granules. The granulated core may be more or less porous, spherical or cylindrical. It consists of multiple small nuclei. They are aggregates of different particle sizes prepared with powder substances in various shapes and appearances. Some advantages of using powder or granules in the preparation of tablets are as follows: o Making the powder mixture into a free-flowing form, o Giving a common and single density to the mixture consisting of different powder substances, o Creating a homogeneous mixture that does not separate, o Improving the compressibility of the active substance and the compression mass, o To be able to control the release rate of the active substance, o To ensure homogeneous distribution and unit dose accuracy, To prevent dust and contamination risk and to prevent dose loss due to dust The pharmaceutical formulation of the invention may contain one or more layers. To provide control of the release of the drug to ensure adequate therapeutic effect and minimize side effects, the sheets may be formulated with one or more of a modified, controlled, extended, sustained, immediate or delayed release pharmaceutical dosage forms. Tablet/s prepared for oral use may contain one or more coatings. Coated tablets; It is generally prepared in the form of formulas containing the active ingredient in the core, partially in the core and partially in the coating, or only in the coating. Coating materials must be physiologically harmless and not incompatible with the active ingredient. Coating types; They can be listed as sugar coating, film coating and enteric coating. Sugar-coated tablets are compressed tablets that have a coating made of sugar. The coating in question may be colored and is extremely useful for covering active substances that have an offensive taste or odor and for protecting materials that are sensitive to oxidation. Film-coated tablets are compressed tablets coated with a thin layer or film applied using a water-soluble material. In this regard, a number of polymeric materials with film-forming properties can be used. Film coatings have the same general properties as sugar coatings, but bring with them the important additional advantage of significantly reducing the time required for the coating process. Purposes of Coating; ° Protection of the active ingredient against light, oxygen and moisture ° Masking of the undesirable odor and taste of the active ingredient ° Improving the aesthetic appearance of the tablet ° Obtaining colored tablets with very little dyestuff ° Increasing the easy swallowability of the tablet by the patient ° Increasing mechanical durability during production, packaging and transportation ° Protection of the active substance against digestive secretions ° Avoiding side effects, such as stomach irritation ° Facilitating the recognition of the drug, thus increasing the safety in drug use ° Increasing the stability of the active substance ° Regulating the controlled release characteristics. Its pharmacokinetic properties do not comply with the usage expectations, for example, it has a short half-life, reaches rapid/high peak concentrations in a way that may cause undesirable effects, does not have good bioavailability due to various reasons, etc. By changing the pharmaceutical forms of drugs, preparations are being developed whose release patterns in the gastrointestinal tract are made more suitable for the purpose. These are often referred to as modified, controlled, slowed and extended release formulations. The compositions of modified-release formulations are important for their functions. Although modified-release drug formulations may be more expensive, they are more useful for drugs with short half-lives, rapid reaching peak concentrations, and variable pharmacokinetics, where patient compliance with treatment is important for treatment success, and ultimately they reduce the cost of treatment. Modified release systems are classified as transdermal systems and oral systems. In delayed release systems, the release of the active substance from the system occurs in a certain region. It is generally used for enteric coated tablets. Enteric coatings are defined as substances or mixtures of substances used to increase the stability of the formulation and prevent acid-induced decomposition. These enteric coatings resist stomach acid before they begin to decompose and also provide a slow drug release in the lower part of the stomach or upper part of the small intestine. In the preparation of tablet/s in the invention, direct compression, wet or dry granulation can be applied. Direct compression consists of compressing the pulverized material without damaging the physical structure of the material. The excipient that has been widely studied as a direct compression medium is microcrystalline cellulose. (Avicel, FMC) Many techniques are used in the preparation of dosage forms. One of these is the granulation method. Granulation; It is defined as the growth of fine powder particles. Granulation for pharmaceutical purposes; It is a preliminary preparation stage for tableting, it is also applied for the purpose of filling into hard gelatin capsules or placing the granule in a package as a final product. The purpose of granulation is to create a unit with a weight equivalent to the percentage of the unit drug of the particles of the powder substance participating in the mixture. It is necessary to ensure that pharmaceutical powder mixtures (active ingredients or excipients) remain homogeneous within a unit by preventing them from separating, and this is possible with granulation. The methods to be chosen in granulation can be classified into 3 main categories: wet granulation, dry granulation and other granulation methods. Wet Granulation: In the wet granulation method, high-speed fluidized bed granulation, spray drying and extrusion pelletizing methods are used. In wet granulation, the active ingredient and binder (solution) are mixed for a certain period of time, sieved as wet and dried in a fluidized bed dryer. This dried mixture is mixed with other filling materials until a certain homogeneity is reached. Slider is added in the last 3-5 minutes of the mixture. Samples are taken from the final mixture and sent to the laboratory. Depending on the laboratory results, tablet printing or the desired pharmaceutical form steps can be taken. Moist granulation methods: 1. Moist granulation method (Classical method) 2. Granulation by fluid bed method 3. Granulation by Spray-Drying method 4. Microgranulation method. Extrusion-Spheronization method 6. Granule preparation method with high alignment mixers. The wet granulation process follows the following order: ° Grinding the active ingredient (if deemed necessary), ° Mixing with powder materials, ° Ensuring the particles of the powder mixture clump together by adding binder, (This process is called granulation.) ° Sifting the clumped particles as wet, ° Drying the sieved powder mixture. Using fluidized bed dryers widely in the drying process, ° Dry grinding after the drying process, ° Homogenizing in double cone or V type mixers, ° Adding lubricant to this mixture and mixing for another 5 minutes, (This mixture is called the final product.) ° Tablet pressing. or proceeding with the steps for the desired pharmaceutical form. Dry Granulation: In the dry granulation method, pre-compression and inter-cylinder compression methods are used. In dry granulation, generally 1/3 of the lubricant in the formula is mixed with other powder mixtures. This is because it prevents dust from sticking to the rollers. The rest of the lubricant is added to the mixture after dry granulation and mixed for 3-5 minutes. Samples are taken from the final mixture after mixing and sent to the laboratory for various tests. According to the laboratory results, tablet printing or appropriate steps for the desired pharmaceutical form can be started. Capsules; gelatin, cellulose esters, polyvinyl alcohol, etc., for administering single doses of medication. They are containers made of one of the materials. Doses, solid and semi-prepared substances, and liquid drugs that do not dissolve the capsule can be placed in the capsules. Capsules are generally divided into two; hard/two-piece capsules and soft capsules. Hard capsules consist of two parts: the container and the lid. Powders that taste bitter, are difficult to swallow, and deteriorate quickly in the air, and drugs that require rapid absorption are intended to be given in capsules. The main ingredient of hard gelatin capsules consists of high-quality gelatin, which is a macromolecular protein. Hard gelatin capsules are prepared from a mixture of gelatin, gum Arabic, dye and water using special techniques and special machines. Hard capsules are prepared by the dipping method. The principle of this method is to dip rods made of stainless steel into the melted capsule wall solution and form a capsule wall film on the surface of these rods. Gelatin, dyes, preservatives and water are the substances that form the hard gelatin capsule wall. Hard capsules can be filled with powder, granules, pellets, tablets, liquids and semi-solid forms. There are two basic requirements for any formulation filled into capsules. The formulation must be filled into the capsule at the correct dose and the active ingredient must be released from the capsule in sufficient quantity to treat the patient. In order to prepare hard gelatin capsule formulations, active ingredients, fillers, substances that improve flow properties, glidants, dispersions, lubricants, dispersants and surfactants are used. Pharmaceutical dosage forms containing pharmaceutical hard gelatin capsules; It contains two or more active ingredients in different physical forms such as powder, granules, pellets, beads, mini tablets and tablets. Soft capsules: They are single-piece round, ellipse and tube-shaped capsules prepared with a mixture of gelatin, glycerin, sorbitol, gum arabic and water. After the necessary items are placed, they are closed so that they cannot be opened. Soft capsules are prepared by surrounding a liquid content with a gelatin capsule wall. They are more flexible than hard capsules. Soft capsules can be round, oval, oblong (rectangular rod) or tube shaped. They consist of one piece. Soft gelatin capsules are generally filled with liquid drug forms in the form of solutions or suspensions. However, semi-solids and powders can also be filled. The manufacture of soft capsules is suitable for insoluble substances, low-dose active substances, compounds with high activity, oxygen-sensitive substances, and bad-tasting substances. In the production of soft gelatin capsules, preparation of the capsule wall, filling with material and closing the capsule consist of a series of sequential processes. The pharmaceutical formulation prepared for oral use in the present invention; Suitable pharmaceutically acceptable active ingredients, as well as at least one diluent, at least one basic agent, at least one binder, at least one lubricant, at least one glidant, at least one solvent, at least one film coating agent, at least one film The binder describes the composition comprising at least one anti-tackifier, at least one plasticizer and at least one pigment. In the invention, the term "diluent/filler"; It is expressed as substances or mixtures of substances used to make tablets or capsules practical for production and in a size suitable for patient use. As a diluent; lactose, maltose, sucrose, dextrin, mannitol, lactilol, xylitol, sorbitol, isomalt, microcrystalline cellulose, dextrose, dextrate, pregelatinized starch, modified starch, corn starch, lactose anhydrous, lactose monohydrate, dibasic calcium phosphate, hydroxy propyl methylcellulose, tribasic calcium phosphate, polyhydric alcohols or cellulose ethers, calcium hydrogen phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, maltodextrin, calcium carbonate, kaolin, sodium hydroxide or mixtures thereof may be used. In the present invention, pregelatinized starch is preferably used as the diluent in a ratio of approximately 5-55% w/w. As the basic agent in the invention; sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, primary amines, secondary amines, tertiary amines, cyclic amines, calcium glycerophosphate, calcium gluconate, calcium acetate, N,N, dibenzylethylenediamine, diethanolamine, ethylenediamine, amino sugars (meglumine, glucamine , chondrosamine/V-acetylglucosamine, Glucosamine, L-daunosamine, galactosamine, D-mannosamine, mycosamine, kanosamine, neosamine C, N-methyl-L-glucosamine, mycaminose, muramic acid and streptamine), disodium hydrogen orthophosphate, sodium aluminate, calcium. carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium sulfate, monosodium glutamate, polacrillin sodium, sodium alginate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium acetate, magnesium silicate, magnesium aluminate or mixtures of these can be used. In the present invention, preferably meglumine is used as the basic agent at a ratio of approximately 0.01-5% w/w. The term "binder" in the invention; They are defined as substances or mixtures of substances used to hold the ingredients together, to ensure that tablets, pellets or granules are formulated with the required mechanical strength, and to give volume to low active dosage units. As a binding agent; pregelatinized corn starch, pregelatinized starch, hydroxy propyl starch, gelatin, microcrystalline cellulose, cellulose, gums, polyvinyl pyrrolidone, polymethacrylates, sodium carboxy methyl cellulose, starch, paraffins, stearic acid, gums, methyl cellulose, ethyl cellulose, polyethylene glycol, yum aluminum silicate , carboxy methylcellulose, hydroxy propylcellulose, hydroxy ethylcellulose, propylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, polysaccharides, polyxamers, alginic acids, collagen, albumin, crospovidone, povidone, copovidone, lactose monohydrate, maltodextrin, hypromellose or mixtures thereof may be used. In the present invention, copovidone is preferably used as the binder/s in a ratio of approximately 0.1-35% w/w. The term "glidant" in the invention; It is expressed as a low-density substance with extra small particles that facilitates the flow of the material into the matrix space at the time of tablet pressing. As glidant; talc, magnesium stearate, hydrogenated vegetable oil, calcium stearate, stearic acid, colloidal silicon dioxide, sodium stearylfumarate, polyoxyethylene glycol, leucine, lethal, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, silica, colloidal anhydrous silica, silica colloidal hydrate, polyethyleneglycol, cellulose derivatives, starch or mixtures thereof may be used. In the present invention, silica colloidal hydrate is used as a glidant at a ratio of 0.01-9% w/w. In the invention, "lubricants" are defined as agents or mixtures of agents that improve the flow properties of a powder mixture that reduces or prevents friction. As lubricant; talc, calcium stearate, magnesium stearate, aluminum stearate, polyethylene glycol, tristearin, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silicon dioxide, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, oleic acid, tripalmythyl, potassium oleate, hydrogenated vegetable oils, leucine, alanine, glycine, caprylic acid, glyceryl behenate, glyceryl palmitostearate, sodium benzoate, sodium acetate, fumaric acid, zinc stearate, zinc oleate, zinc palmitate, paraffins, fatty alcohols or mixtures thereof can be used. In the present invention, magnesium stearate is preferably used as the lubricant at a ratio of approximately 0.01-15% w/w. Solvents include purified water, ethanol, alcohols such as methyl alcohol, isopropyl alcohol, butyl alcohol, acetone, diacetone, polyols, polyethers, esters, alkyl ketones, methylene chloride, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether. , diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran, or mixtures thereof may be used. In the present invention, purified water and/or ethanol are preferably used as solvents. In the invention, the term "film coating agent" is defined as substances or mixtures of substances used to protect the formulation content against degradation by moisture in the air and to provide ease of swallowing unpleasant-tasting forms. As a coating agent; methyl cellulose, hydroxyethylcellulose, hydroxybutylcellulose, hydroxypropylmethylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, carboxymethylethylcellulose, sodium carboxymethyl amylopectin, polyvinyl acetate phthalate, polyoxyethylene glycol, macrogol, polyvinyl alcohol (opadry types), polyvinyl acetal diethyl aminoacetate, clay methacrylate copolymer, methacrylic acid copolymer, hydroxypropyl methyl cellulose acetate, dioxy methyl cellulose succinate, carboxy methyl ethyl cellulose, polyacrylic acids, methacrylic acid copolymers, methyl acrylate, ethylacrylate, methylmethacrylate, ethylmethacrylate, acrylic and methacrylic acid esters, hypromellose, hypromellose phthalate, hypromellose acetate succin horse, hydroxymethyl cellulose succinate acetate, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propyanate phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate trimellitate, gelatin, selak, castor oil, chitosan, alginic acid, carrageenan, titanium dioxide, galactomannones, tragacanth, indian glue , gum arabic, guar gum, xanthan gum, talc, red iron oxide or mixtures of these may be used. In the invention, the term "pigment" is defined as substances that give a pleasant appearance and provide optical differentiation between two formulations. As pigments, but not limited to, iron oxide pigments such as yellow iron oxide, red iron oxide, ß-carotene, red beet powder, chlorophyll, taitrazine, yellow orange, quinoline yellow, erythrosine, titanium dioxide, caramel or mixtures of these can be used. In the present invention, preferably red iron oxide and/or yellow iron oxide and/or titanium dioxide are used as pigments in a ratio of approximately 0.01-30% w/w. In the invention, the term "plasticizer" is defined as substances used to increase the flexibility of the coating, reduce the risk of film breakage and increase the adhesion of the film to the core. They must be compatible with the polymer and must not be volatile. As a plasticizer; polyethylene glycols (macrogol), glycerin, propylene glycol, acetyl citrate, arnyl oleate, myristyl acetate, butyl oleate, butyl stearate, triacetin, diethylphthalate, acetylated monoglycerides or mixtures thereof can be used. In the present invention, polyethylene glycols (macrogol) are preferably used as plasticizers at a ratio of approximately 0.05-25% w/w. In the invention, the term "film-forming agent" is defined as the components required to form a binder, a film, such as a thin layer or cover. As a filmmaking agent; polyvinyl alcohol-partially hydrolyzed, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene oxide, hypromellose, macrogol, gelatin or mixtures thereof can be used. In the present invention, hydroxypropyl methyl cellulose is preferably used as the film-forming agent at a ratio of approximately 0.5-85% w/w. As an anti-adhesion agent in the invention; talc, colloidal silicon dioxide (Aerosil, Syloid, Cab-O-Sil), magnesium stearate, corn starch, magnesium trisilicate or mixtures of these can be used. Talc is preferably used in the invention. The amount of anti-adhesion agent used in the invention is 0.01-15% by weight. The flow properties of powders, particle sizes, shapes and surface morphology are very important in the preformulation stage and can affect the content uniformity, homogeneity and dissolution rate of the formulation. Particle size and distribution can affect formulation characteristics, finished product specification and bioavailability of the product. For example, the sedimentation and loculation rate of suspensions depends on the particle size. Additionally, in suspensions, crystal growth is more common in active substances with a wide particle size distribution range. Particle size and distribution are very important, especially in tablet and capsule technology. The particle size of active substances whose absorption is limited by the dissolution rate affects the absorption. As the particle size of powders changes, their specific surface areas also change. As a result, the dissolution rate of the drug in body fluids changes. The taste of the drug is also related to particle size. In preparing the solution formulation of a bitter-tasting drug for oral administration, it is not desirable to reduce the particle size too much. Because as the particles become smaller, the number of dissolved molecules increases. Determination of particle size and distribution is very important in the preformulation and formulation stages of a product. Particle size distribution for Linagliptin and/or its pharmaceutically acceptable derivatives used as the active ingredient of the pharmaceutical formulation in the invention, 0.1 for d(0.1) - Particle size distribution for Metformin and/or its pharmaceutically acceptable derivatives used as the active ingredient of the pharmaceutical formulation in the invention , was measured in the range of 15-95 µm for d(0.9). The invention essentially relates to the preparation of pharmaceutical composition(s) using Linagliptin and/or its pharmaceutically acceptable derivatives in combination with Metformin and/or its pharmaceutically acceptable derivatives for oral use. The composition further comprises one or more pharmaceutical excipients, basic agents to stabilize said active ingredient and/or pharmaceutical form against degradation by eliminating incompatibilities with the excipient, degradation problems or extraction problems. It is essential that the pharmaceutical composition(s) of the invention be in the form of tablets, tablets in capsules, capsules in capsules, pellets in capsules and/or powders in capsules for oral use. Since pharmaceutical excipients such as binders, diluents, anti-adhesion agents, glidant, lubricant and the like may adversely interact with the compound, a basic agent vehicle is required for effective pharmaceutical dosage form. Therefore, one or more basic agents used to improve the stability of the formulation can overcome problems such as incompatibility, poor stability, degradation, etc. with a stable oral pharmaceutical composition in the Linagliptin/Metformin combination. As a result, by using a suitable basic agent in these pharmaceutical compositions, protection against decomposition and degradation was achieved with a surprising effect. Thus, the pharmaceutical formulation/s obtained surprisingly exhibited a very stable behavior in terms of physical and chemical stability. They have also been found to be surprisingly effective in providing adequate therapeutic effect and minimizing side effects. In particular, it has been found that these problems can be overcome in these pharmaceutical compositions by the use of amino sugar and/or alkalizer as a basic agent. Therefore, by using a suitable amino sugar and/or alkalizer in these pharmaceutical compositions, protection against decomposition and degradation can be provided with a surprise effect. The amount of linagliptin in pharmaceutical compositions containing the appropriate active ingredient of the present invention and/or its pharmaceutically acceptable derivatives is adjusted between 1-25 mg, preferably 2.5 mg, according to the needs and the expert's evaluation. Linagliptin and/or its pharmaceutically acceptable derivatives in the present invention is a mixture of polymorphs A and B. A representative mixture of polymorph A and B has an X-ray powder diffraction pattern containing X-ray powder diffraction (XRPD) peaks. A BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Shows the X-ray powder diffraction (XRPD) pattern of Linagliptin. The following formulation examples illustrate the invention, but do not limit it in any way. The composition for oral administration, containing 1-25 mg Linagliptin and 100-3000 mg Metformin in tablet formulation, includes: - Linagliptin at approximately 0.01-5% w/w - Metformin at approximately 1-95% w/w - approximately, % 5-55% w/w pregelatinized starch -approximately, 0.01-5% w/w meglumine -approximately, 0.1-35% w/w copovidone -approximately, 0.01-9% w/w silica colloidal hydrate -approximately, Magnesium stearate at 0.01-15% w/w - one or more coating agent(s) at approximately 0.1-15% w/w (this coating includes hydroxypropyl methyl cellulose, titanium dioxide, talc, macrogol, yellow iron oxide and red iron contains oxide) -sufficient amount of ethanol and/or pure water. The composition, containing 1-25 mg Linagliptin and 100-3000 mg Metformin in tablet formulation for oral administration, contains the following: -approximately, 75-450 mg pregelatinized starch -approximately, 2-30 mg meglumine -approximately, 0.5-20 mg silica colloidal hydrate -approximately, 01-15 mg magnesium stearate -approximately, 5-85 mg one or more coating agent(s) (this coating contains hydroxypropyl methyl cellulose, titanium dioxide, talc, macrogol, yellow iron oxide and red iron oxide. ) -sufficient amount of ethanol and/or pure water. Production process: Raw materials are weighed in accordance with the production formula. Some of the pregelatinized starch is mixed with Linagliptin, Meglumine is added and sieved through the sieve. Metformin is sieved through the same sieve and mixed in the granulation mixer. Kopovidone is mixed in the Ethanol-Pure Water mixture until homogeneous. The granulation process is carried out by adding the granulation solution to the powder mixture. The granulation mixture is dried in the oven. After drying, the resulting mixture is sieved. Some of the pregelatinized starch and Silica Colloidal Hydrate are sieved and added to the granulation mixture and mixed. Magnesium Stearate is sieved and added to the mixture and mixed. The resulting final mixture is printed with the appropriate punch. Coating materials are mixed in Pure Water until homogeneous, and a film coating solution is obtained. Core tablets are coated with the coating solution prepared in appropriate proportions. TR

Claims (1)

1.STEMS. Suitable active ingredient(s) with antidiabetic properties and/or pharmaceutically acceptable derivatives in the group of dipeptidyl peptidase-4 (DPP-4) inhibitors for oral use. Suitable active ingredient(s) with antidiabetic properties and/or pharmaceutically acceptable derivatives in the biguanide group and/or pharmaceutically acceptable derivatives thereof. It relates to the pharmaceutical composition(s) comprising the combination treatment with . . It is the pharmaceutical composition/s specified in claim 1 and its feature is; The appropriate active substance with antidiabetic properties in the group of dipeptidyl peptidase-4 (DPP-4) inhibitors is selected from vildagliptin, evogliptin, saxagliptin, sitagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, dutogliptin, omarigliptin and/or pharmaceutically acceptable derivatives. is to be selected. . It is the pharmaceutical composition/s specified in claim 2 and its feature is; The appropriate active substance with antidiabetic properties in the group of dipeptidyl peptidase-4 (DPP-4) inhibitors is preferably linagliptin. . Pharmaceutical composition(s) as in claim 1, characterized in that the appropriate active substance(s) with antidiabetic properties in the biguanide group are selected among phenformin, metformin and butformin and/or pharmaceutically acceptable derivatives. . It is a pharmaceutical composition/s according to claim 4, characterized in that the suitable active ingredient/s with antidiabetic properties in the biguanide group is preferably metformin. . It is a pharmaceutical composition(s) according to any one of claims 1-3, characterized in that it is in a film-coated tablet formulation. . 7. A pharmaceutical composition according to any one of claims 1-6, characterized in that it contains linagliptin, preferably 1000 mg. . Pharmaceutical composition(s) according to any of the above claims, characterized in that said composition contains, in addition to suitable pharmaceutically acceptable active ingredients, at least one diluent, at least one basic agent, at least one binder, at least one lubricant, at least one glidant, at least one It contains at least one solvent, at least one film coating agent, at least one film-forming agent, at least one anti-adhesive, at least one plasticizer and at least one pigment. . It is a tablet formulation for oral administration, and its feature is that the composition containing 1-25 mg Linagliptin and 100-3000 mg Metformin contains the following: - Linagliptin at a ratio of approximately 0.01-5% w/w - Metformin at a ratio of approximately 1-95% w/w - approx. 5-55% w/w pregelatinized starch - ca. 0.01-5% w/w meglumine - ca. 0.1-35% w/w copovidone - ca. 0.01-9% w/w silica colloidal hydrate -magnesium stearate at approximately 0.01-15% w/w -one or more coating agent(s) at approximately 0.1-15% w/w (this coating may include hydroxypropyl methyl cellulose, titanium dioxide, talc, macrogol, yellow Contains iron oxide and red iron oxide.) -sufficient amount of ethanol and/or pure water. It is a tablet formulation for oral administration and its feature is that the composition containing 1-25 mg Linagliptin and 100-3000 mg Metformin contains the following: -approximately, 75-450 mg pregelatinized starch -approximately, 2-30 mg meglumine -approximately, 0.5-20 mg silica. colloidal hydrate - approximately 01-15 mg magnesium stearate - approximately 5-85 mg one or more coating agent(s) (this coating contains hydroxypropyl methyl cellulose, titanium dioxide, talc, macrogol, yellow iron oxide and red iron oxide .) -sufficient amount of ethanol and/or pure water. The composition according to claim 1, for use in the treatment of type 2 diabetes mellitus, in addition to diet and exercise, to provide glycemic control. TR