TR201605929A1 - THERAPEUTIC FORMULATIONS FOR THE TREATMENT OF DIABETES - Google Patents

Abstract

The present invention includes; diabetes mellitus, especially non-insulin dependent diabetes (Type 2 diabetes) and obesity for use in the symptomatic and / or therapeutic treatment of diabetes; The present invention relates to a pharmaceutical composition (s) comprising the appropriate antidiabetic agent of the biguanide group and / or the pharmaceutically acceptable derivatives thereof and / or the pharmaceutically acceptable derivatives of the pharmaceutically acceptable sulfonylurea group having antihyperglycemic activity.

Description

DESCRIPTION: THERAPEUTIC FORMULATIONS FOR THE TREATMENT OF DIABETES FIELD OF THE INVENTION The present invention; diabetes mellitus, especially non-insulin dependent diabetes (Type 2 diabetes) and for use in the symptomatic and/or therapeutic treatment of obesity diabetes; Appropriate active substance and/or pharmaceutical with antidiabetic properties from the biguanide group as pharmaceuticals with antihyperglycemic activity Appropriate active substance with antidiabetic properties from the acceptable sulfonylurea group and/or combination therapy with pharmaceutically acceptable derivatives relates to pharmaceutical composition(s).

In addition, the present invention; Appropriate antidiabetic agent from the biguanide group in substance Metformin, N,N-dimethylimidodicarboiimidic diamide (Formula 1) and/or pharmaceutical acceptable derivatives; Appropriate antidiabetic properties from the sulfonylurea group active ingredient Gliclazide, N-[[(hexahydrocyclopenta[c]pyrrole-Z(1H)-yl)amino]carbonyl]-4- methylbenzenesulfonamide (Formula II) and/or pharmaceutically acceptable derivatives and in combination as active ingredients in appropriate pharmaceutical forms relates to the pharmaceutical composition(s) for which it is used.

Formula 1: CHÄEÄNHQ In addition, the invention relates to Metforin and/or its pharmaceutically acceptable derivatives and Gliclazide. Formula ll: and/or pharmaceutically acceptable derivatives used in combination pharmaceutical compositions suitable for oral, topical and parenteral administration formulations and symptomatic and/or therapeutic uses. PRIOR ART (KNOWN STATE OF THE ART) Beta cells of the pancreas under normal conditions when the level of glucose (sugar) in the blood rises. secretion of the hormone insulin by the cells, the energy they need by the cells glucose must enter the cell and be used in order to provide if it insulin is awake.

diabetes mellitus; absence, deficiency or peripheral ineffectiveness of insulin in the human body together with the disorder of carbohydrate, fat and protein metabolism, which occurs as a result of It is a chronic disease in which many factors play a role in the etiology of chronic hyperglycemia. known as metabolic disease.

In people with diabetes, the insulin produced by the pancreas is either insufficient or the insulin is not targeted. It cannot show its effect sufficiently in the tissues. As a result of this; in blood and urine glucose level increases, excessive glucose levels in the blood damage tissues and cells. cause dysfunction and failure. Long-term effects of diabetes mellitus May occur with specific complications that develop progressively, These complications microvascular complications (potentially blinding retinopathy with renal failure) at risk of nephropathy and/or foot ulcers, amputation, which may result in neuropathy) and macrovascular complications (myocardial infarction, stroke, and peripheral artery disease) can be examined in two groups. Therefore, patients with diabetes It carries a risk for cardiovascular, peripheral vascular and cerebrovascular diseases.

There are three main types of diabetes mellitus: Type 1 diabetes mellitus, Type 2 diabetes mellitus and classified as diabetes resulting from other specific defects (WHO/NCD/NCS/99.2).

In Type 1 Diabetes (Insulin Insulin), which usually occurs in children and young ages (< 30 years) Dependent Diabetes)_; The pancreas produces little or no insulin. type 1 diabetes Patients absolutely need insulin at every stage of the disease.

Adult-onset diabetes and approximately 901% of all diabetes cases are type 2 diabetes Non-Independent Diabetes). In addition to the insufficiency in insulin production, it also occurs in the surrounding tissues. There is resistance to insulin. To effectively control the amount of glucose in the blood The pancreas needs to secrete more insulin.

Therapeutic treatment of diabetes mellitus and especially non-insulin dependent diabetes (Type 2 diabetes) Some drugs used in the treatment: i Biguanide o Sulfonylurea o Ct-glucosidase inhibitor o Prandial glucose regulator i Thiazolidinediones (Glitazones) i Incretin mimetics/ GLP-1 analogues o DPP-4 inhibitors (Gliptins) biguanides; oral used for the treatment of diabetes mellitus or occult diabetes antihyperglycemic drugs. Biguanide-derived antihyperglycemic agents insulin-dependent They are widely used in non-diabetic diabetes mellitus. Metformin is in the structure of dimethylbiguanide and is an antihyperglycemic agent of the biguanide class. is the agent. Orally administered metformin to reduce plasma glucose level In addition to reducing glucose formation, it also increases insulin sensitivity in the tissue. It inhibits gluconeogenesis and, to a lesser extent, peripheral insulin resistance, especially in the liver. reducing effect. It is an antidiabetic that does not cause hypoglycemia and causes mild weight loss.

Antidiabetic agents of many acid addition salts, including metformin and its hydrochloride salt. its use is stated in the patent document numbered US 3,174,901.

Metformin has a low risk of hypoglycemia. Metformin also reduces cholesterol from LDL and It also reduces triglyceride levels. In addition, polycystic ovary syndrome and alcoholic It is also used in non-liver disorders. Pancreatic cancer and other cancer There are also studies on the prevention of types.

Sulfonylureas; They increase the release of stored insulin from pancreatic ß cells. This they do not affect insulin synthesis in reciprocal [3 cells. Biphasic insulin release affect the first phase. They lower the serum glucagon level.

In pancreatic ß cells; ATP dependent-potassium channels located on the channel By binding to sulfonylurea receptors and blocking (reducing potassium output to the outside) insulin they increase saline. In chronic application, it can also reduce insulin sensitivity in target cells. they increase. They also cause hypoglycemia in normal people. They increase the use of lactate in tissues and reduce lactate levels. They are antilipolytic. All high in plasma albumin they are connected in proportion. All but chlorpropamide are significantly metabolized in the liver. they are made. All sulfonylureas carry the basic S-phenyl sulfone urea structure. gliclazide, It has an antiaggregant effect on platelets.

Gliclazide; It is a sulfonylurea hypoglycemic substance. Gliclazide normalizes glycemia. the common point of vascular complications of patients with diabetes, It also fights microthrombosis. Gliclazide. a sustained glycemia 24 hours a day provides stability. Normalizes fasting glycemia and can be used in post-prandial or reactive prevents hyperglycemia.

The effect of gliclazide against microthrombosis is seen in 3 ways. platelets in the blood reduces its aggregation and activity. abnormally attached to the walls of thin blood vessels prevents fibrin aggregation. It prevents the vasoconstriction effect of adrenaline. Gliclazide It is rapidly absorbed from the gastrointestinal tract. The plasma half-life is 10-12 hours. Gliclazide°in A large amount is metabolized in the liver. An obvious hypoglycemic effect of metabolites there is none. Its metabolites and some gliclazide are excreted in the urine.

Biguanide and sulfonylurea providing controlled release in patent document EP1107763 A combination of tablets containing group drugs is mentioned. DESCRIPTION OF THE INVENTION The present invention; diabetes mellitus, especially non-insulin dependent diabetes (Type 2 diabetes) and for use in the symptomatic and/or therapeutic treatment of obesity diabetes; Appropriate active substance and/or pharmaceutical with antidiabetic properties from the biguanide group as pharmaceuticals with antihyperglycemic activity Appropriate active substance with antidiabetic properties from the acceptable sulfonylurea group and/or combination therapy with pharmaceutically acceptable derivatives relates to pharmaceutical composition/s.

Another aspect of the present invention is; from the biguanide group for oral use Appropriate active substance with antidiabetic properties and/or pharmaceutically acceptable derivatives of pharmaceutically acceptable antihyperglycemic activity Appropriate active substance with antidiabetic properties from the sulfonylurea group and/or combination therapy with pharmaceutically acceptable derivatives and pharmaceutically by the preparation of pharmaceutical compositions containing acceptable excipients. It is related to.

In the invention, the other active substance with antidiabetic properties in the biguanide group is phenformin, preferably among buformin, metformin and/or pharmaceutically acceptable derivatives selected as metformin hydrochloride.

In the invention, an antidiabetic drug from the sulfonylurea group with antihyperglycemic activity active ingredient acetohexamide, chlorpropamide, tolbutamide, tolazamide, glipizide, gliclazide, glibenclainide, glimepiride, gluquidone and/or pharmaceutically acceptable preferably selected as gliclazide among its derivatives.

In the invention, the term "pharmaceutically acceptable derivatives" is defined as pharmaceutically acceptable. Suitable salts, esters, solvates, hydrates, complexes, polymorts, enantiomers, prodrugs, acid addition salts, analogs, isomers, racemates, amides, enantiomer salts, basic salts, conjugates, tautomers, anhydrates, anhydrides, bases, one or more of acids, ethers, crystalline and amorphous forms or free forms is expressed.

The pharmaceutical composition for oral administration may be in solid or liquid dosage forms.

These dosage forms are; tablet (chewable, mouth-soluble, dispersible, water-dispersible, film coated, bilayer, multilayer, enteric coated, mini, controlled release, sustained release, immediate release, extended release, delayed release, modified saline, modified release), capsule (hard, soft, enteric-coated, film-coated, controlled-release, sustained-release, immediate release, extended release, delayed release, modified release, modified release), powder, granule, caplet, disc, mouth soluble film, bulk powder (multi-dose), pellet, sachet, water dispersible powder, water dispersible granule, effervescent tablet, effervescent granule, effervescent powder form, gel, pill, syrup, solution, suspension, elixir, drop, position, emulsion or as a dosage form such as a spray.

The pharmaceutical formulation(s) of the invention may contain one or more layers. Sufficient To ensure the therapeutic effect and to minimize the side effects, the release of the drug should be reduced. layer/s are changed, modified, controlled, extended, continuous, with one or more of the immediate or delayed release pharmaceutical dosage forms can be formulated.

Its pharmacokinetic properties are not suitable for use expectations, eg half-life short-lived, rapid/high peak with undesirable effects concentration, which has not good bioavailability due to various reasons, etc. for drugs By changing the pharmaceutical forms, the release patterns in the gastrointestinal tract are aimed at the purpose. More optimized preparations are being developed. These have been changed many times, They are referred to as controlled, slowed and extended release formulations.

The compositions of modified release formulations are important for their function.

Modified-release drug formulations, although they may be more expensive, short half-life, peak, in which adherence to treatment is important for treatment success For drugs that reach concentration rapidly, with varying pharmacokinetics, They are useful and ultimately reduce the cost of treatment. Modified release systems They are classified as transdermal systems and oral systems. delayed release In systems, the release of the active substance from the system occurs in a certain region. Generally It is used for enteric coated tablets.

To increase the stability of the enteric coating formulation, to prevent acid-induced degradation. It is expressed as the substance or substance mixture used for These enteric coatings before it starts to decompose, it resists stomach acid and at the same time, it It provides a slow drug release in the upper part of the small intestine or in the upper part of the small intestine.

Direct compression, wet or dry granulation in the preparation of tablet(s) of the invention applicable.

Direct coinpression of the pulverized material without disturbing the physical structure of the material. It is obtained by compression. Widely used as a direct compaction tool The excipient studied in this way is microcrystalline cellulose (Avicel, FMC).

Direct compression of the tablets without changing the physical nature of the material It consists of obtaining the shaped material by compression.

In this method, drugs and excipients are mixed, for example, using a V-type mixer. and the tablet is compressed in a tablet press. It is the simplest and fastest method, but this method In order to be used, the powder or granule mass must be fluid and printable.

Process steps: -Premix -Adding slider and a short shuffle -Tablet printing Many techniques are used in the preparation of dosage forms. one of them granulation method. Granulation; as the growth of fine dust particles granulation for pharmaceutical purposes; a preparation for tableting This is the stage of filling hard gelatin capsules or granules as a final product. It is also applied because of its use by being placed in a package.

The purpose of the granulation is to give the unit drug % of the particles of the powder substance participating in the mixture. It is to form a unit of weight that will be equivalent to the quantities. Pharmaceutical powder mixes (active substance or auxiliary substances) in a unit by preventing their separation. It is necessary to ensure that they remain in a homogeneous form, this is achieved by granulation. possible.

The methods to be chosen in granulation can be classified in 3 main categories: wet granulation, dry granulation and other granulation methods.

Age Granulation: In the wet granulation method, high speed fluidized bed granulation, spray drying and extrusion pelletizing methods are used. Mourning In granulation, the active ingredient and the binder (solution) are mixed for a certain period of time. sieved and dried in a fluidized bed dryer. This dried mixture is the other filling. It is mixed with the ingredients until it reaches a certain homogeneity. My wife's last 3-5 slider is added in minutes. Samples are taken from the final mixture obtained and sent to the laboratory. sent. According to the results of the laboratory, for tablet compression or for the desired pharmaceutical form. stages can be passed.

Age granulation methods: 1. Age granulation method (Classical method) 2. Granulation by fluidized bed method 3. Granulation by Spray-Drying method 4. Microgranulation method . Extrusion-Spheronization method 6. Method of preparing granules with high-level mixers The wet granulation process is as follows: - Grinding of the active substance (if necessary), - Mixing with powder substances, - Ensuring the aggregation of the particles of the powder mixture with the addition of binder, The process is called granulation.) - Screening of agglomerated particles as wet, - Drying of the sifted powder mixture is common in the drying process using bed dryers, - Dry grinding after drying, - Homogenizing in double conical or V type mixers - Adding lubricant to this resulting mixture and mixing for another 5 minutes, (This the mixture is called the final product.) - It is the transition to tablet pressing or the stages for the desired pharmaceutical form.

Dry Granulation: In the dry granulation method, pre-compression and inter-roll compression methods are used. In dry granulation, it is usually 1/3 of the lubricant is mixed with other powder mixtures. This is because dust gets into the cylinders. prevents it from sticking. The remainder of the lubricant is added to the mix after dry granulation. and stirred for 3-5 minutes. Samples are taken from the final mixture formed after the mixture and It is sent to the laboratory for various tests. According to the laboratory results, tablet compression or The steps can be passed for the desired pharmaceutical form.

When tablet contents are sensitive to moisture or when exposed to high temperatures during drying. when they cannot tolerate temperatures and the tablet contents do not have sufficient hereditary binding or hard forging to form granules when they have cohesive properties (slugging) can be used. This method is dry granulation, precompression or double compression. called method. It eliminates many processing steps, but however, weight measurement, mixing, hard forging, dry sieving, lubrication and It includes compression operations. Active ingredient, dilution (if needed) and part of the lubricant is blended. One of the active substance or diluent cohesion should have features. Significant amount in the pulverized material contains air; Under pressure, this air is removed from the powder material and produces a very dense the structure is created. The longer the time allowed for the air to escape, the better the tablet. or a lump is obtained.

The process steps of preparing tablet mixture by dry granulation method are as follows: 0 The active substance and binder and fillers are ground.

O The grinded powder mixture is compressed between the rollers and briquetted. o The powder mixture in the form of briquettes is crushed, ground and sieved. o The sifted powder mixture is subjected to a short mixing. 0 A lubricant is added to the mixture with a certain granule size, a short mixing is made. 0 Tablet printing is sent.

The pharmaceutical bilayer tablet formulation for oral administration in the present invention; In addition to suitable active ingredients, at least one lubricant, at least one buffering agent, at least one binder, at least one colorant, at least one release controlling agent, at least one glidaide and at least one one or more selected from the group consisting of at least one granulation solvent describes a composition that may contain an excipient.

In the invention, the "lubricant" is the flow of a powder mixture that reduces or inhibits friction. It is expressed as agent or agent mixtures that improve its properties. slider aspect; 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, tripalmityl, 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 their mixtures can be used.

Magnesium stearate and/or polyethylene glycol are preferably used in the invention. in the find The amount of lubricant used is 001-20%, preferably 0.1-8% by weight.

In the invention, the term "buffering agent" refers to substances that regulate the acidity and basicity of the composition. is expressed as. As a buffering agent; citric acid anhydrous, sodium citrate dihydrate, sodium phosphate, sodium dihydrogen phosphate, potassium citrate, phosphoric acid, ammonium hydroxide, citric acid, diisopropanolamine, sodium carbonate, sodium silicate, disodium orthophosphate, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium aluminate, diethanol amine, sodium alginate, ethylenediamine, meglumine, hydrochloric acid, lactic acid, sodium citrate, sodium hydroxide, triethanolamine, trolamine, sodium benzoate, sodium hydrogen carbonate, calcium hydrogen phosphate dihydrate or mixtures thereof can be used. Calcium hydrogen phosphate dihydrate is preferably used in the invention. in the find the amount of buffering agent used is 10-80%, preferably 40-70% by weight.

The term "binder" in the invention; keeping the ingredients together, tablets, pellets or ensuring that the granules are formulated with the required mechanical strength and low active dosage. expressed as substances or mixtures of substances used to give volume to units of is being done. As binder, pregelatinized corn starch, pregelatinized starch, hydroxy propyl starch, gelatin, microcrystalline cellulose, cellulose, gums, polyvinyl pyrrolidone, polymethacrylates, sodium carboxymethyl cellulose, starch, paraffins, stearic acid, gums, methyl cellulose, ethyl cellulose, polyethyleneglycol, magnesium aluminum silicate, carboxy methylcellulose, hydroxy propylcellulose, hydroxy ethylcellulose, propylene glycol, polyoxyethylene- polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, polysaccharides, polaxamers, alginic acids, collagen, albumin, crospovidone, povidone, copovidone, maltodextrin, hydroxypropyl methyl cellulose or mixtures thereof can be used. Preferably, hydroxypropyl methyl cellulose is used in the invention. in the find The amount of binder used is 0.1-20%, preferably 0.8-5% by weight.

In the invention, the term "colorant" is a pleasant-looking and optically intermediate between the two formulations. are expressed as substances that provide discrimination. As a colorant iron oxide such as, but not limited to, yellow iron oxide, red iron oxide pigments, ß-carotene, red beet powder, chlorophyll, tartrazine, yellow orange, quinoline yellow, erythrosine, titanium dioxide pigments, caramel, sunset blond or mixtures thereof can be used. Red iron oxide is preferably used in the invention. used in the invention the amount of colorant is 0.01-5%, preferably 0.1-1% by weight.

As "release controlling agent" in the invention; polyvinyl acetate phthalate, polyethylene glycol-polyvinyl alcohol copolymer, polyacrylic acid derivatives, polysaccharide derivatives, methacrylate polymer, polymethacrylate, ethyl methacrylate copolymer, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, polylactic acid, polylactic acid copolymer, polyvinylpyrrolidone, polyvinylalcohol, glyceride, polyethylene oxide, glyceryl behenate, methacrylic acid copolymer, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate, carboxy methyl ethyl cellulose, sodium carboxy methyl cellulose, ethyl cellulose, methyl acrylate, ethylacrylate, methylmethacrylate, ethylmethacrylate, acrylic and inethacrylic acid esters, sodium alginate, hypromellose phthalate, hypromellose acetate succinate, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propyanate phthalate, cellulose acetate phthalate, cellulose acetate Trimelitate, gelatin, celak, xanthan gum or mixtures of these can be used. in the find preferably hydroxypropyl methyl cellulose is used. sway control used in the invention the amount of dissolving agent is 01-65%, preferably 1-25% by weight.

The term "glidant" in the invention; Tablet pressing immediately allows the flow of material into the matrix space. It is expressed as a substance with extra small particles and low density that facilitates it.

As a glidant; talc, magnesium stearate, hydrogenated vegetable oil, calcium stearate, stearic acid, colloidal silicon dioxide, sodium stearylfumate, polyoxyethyleneglycol, leucine, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, silica, colloidal anhydrous silica, polyethyleneglycol, cellulose derivatives, starch or their mixtures can be used. in the find preferably colloidal silicon dioxide is used. Amount of glidant used in the invention Purified water, ethyl alcohol, methyl alcohol, isopropyl as granulation solvent in the invention Alcohols such as alcohol, butyl alcohol, methylene chloride or their mixtures can be used.

Purified water is preferably used as the granulation solvent in the invention.

Pharmaceutical using the active ingredients of the present invention in combination dose range of formulations suitable for their composition; metformiri and/or 1000mg; 10-350mg for gliclazide and/or pharmaceutically acceptable derivatives In the invention, Metforin and/or its pharmaceutically acceptable derivatives and Gliclazide and/or pharmaceutically acceptable derivatives in combination modified-release pharmaceutical doublet for oral administration of pharmaceutical compositions The layered tablet formulation includes: A) The layer containing Metformin Hydrochloride; - approximately 10-99.9% by weight of Metformin Hydrochloride - one or more sliders of approximately 0.01-20% by weight B) The layer containing gliclazide; - approximately 0.1-35% by weight of Gliclazide - about 10-80% by weight of one or more buffering agents - one or more binders, approximately 0.1-20% by weight - about 0.01-5% by weight of one or more colorants - one or more controlled release agents in an amount of approximately 0.1-65% by weight - about 0.01-25% by weight of one or more glidants - one or more sliders of approximately 001-20% by weight -sufficient amount of granulation fluid The invention is mainly used as an antidiabetic drug from the biguanide group for oral use. appropriate active ingredient and/or pharmaceutically acceptable derivatives from the group of pharmaceutically acceptable sulfonylureas with antihyperglycemic activity Appropriate active substance with antidiabetic properties and/or considered as pharmaceutical. combination therapy with acceptable derivatives and suitable pharmaceutically acceptable relates to the preparation of pharmaceutical composition(s) containing excipients. find it It is essential that pharmaceutical compositions be in the form of double-layered tablets. Aforementioned biguanide of pharmaceutical bilayer tablet formulations preferably of one layer. antidiabetic agent from the group, and the other layer is from the sulfonylurea group. It is essential that it contains an agent with antidiabetic properties. The tablets thus obtained are surprising. somewhat stable behavior in terms of physical and chemical stability. has exhibited. In addition, to ensure adequate therapeutic effect and minimize side effects. They have been found to be surprisingly effective for

Examples of the features of the invention are given below, but not limited to the following: Metformin and/or pharmaceutically acceptable derivatives with Gliclazide and/or pharmaceuticals containing pharmaceutically acceptable derivatives in combination Modified-release pharmaceutical bilayer tablet for oral administration of compositions Its formulation includes the following; A) The layer containing Metforine Hydrochloride; - approximately 10-99.9% by weight of Metformin Hydrochloride - approx. 0.01-20% by weight magnesium stearate B) The layer containing gliclazide; - approximately 0.1-35% by weight of Gliclazide - approximately 10-80% by weight of calcium hydrogen phosphate dihydrate - approx. 0.1-20% by weight hydroxypropyl methyl cellulose - approximately 0.01-5% by weight of your dirt with iron oxide - approx. 0.1-65% by weight hydroxypropyl methyl cellulose - approximately 0.01-25% by weight of colloidal silicoii dioxide - approximately 0.01-20% by weight of magnesium stearate and/or polyethylene glycol Metformin and/or pharmaceutically acceptable derivatives with Gliclazide and/or pharmaceuticals containing pharmaceutically acceptable derivatives in combination Pharmaceutical bilayer tablet with modified saline for oral administration of compositions Its formulation includes the following; A) The layer containing Metformin Hydrochloride; - approximately 200-1500mg of Metformin Hydrochloride - about 0.1-15mg magnesium stearate B) The layer containing gliclazide; - approximately 10-350mg of Gliclazide - about 50-8001ng calcium hydrogen phosphate dihydrate - approx. 0.1-40mg hydroxypropyl methyl cellulose - about 0.1-10mg of red iron oxide - approx. 5 -240mg hydroxypropyl methyl cellulose - about 0.1-15mg colloidal silicon dioxide - about 0.1-85mg magnesium stearate and/or polyethylene glycol Production process: Metformin Hydrochloride Layer: Raw materials are weighed according to the production formula. Metformin Hydrochloride granule drying loss is controlled. Pure water is added until proper drying loss is achieved and humidification is done. Drying loss of Metformin Hydrochloride granule is between 1-2% should be. Preferably if the drying loss of metformin hydrochloride granule is less than 1%.] drying loss is between 1%.] and 1.8%. humid granules are sieved through a sieve. The moistened and sieved granules are mixed. Magnesium After the stearate has been sieved, it is added to the appropriate mixer and mixed.

Gliclazide T layer: Raw materials are weighed according to the production formula. Gliclazide, hydroxypropyl methyl cellulose, Red iron oxide (partial) and calcium hydrogen phosphate dihydrate are sieved through the sieve.

Eliminated Gliclazide, hydroxypropyl methyl cellulose, red iron oxide (partial) and Calcium hydrogen phosphate dihydrate raw materials are transferred to the granulation boiler and is mixed. The amount of distilled water determined in the formula is added slowly to the powder mixture. wet granulation process is performed. Granulation steps: Granulation liquid is added.

The mass is mixed. The crusher is operated to break the lumps. Adequacy of granulation controlled by mixing. If necessary, some more pure water can be added.

The wet granule obtained after granulation until the appropriate drying loss is obtained. dried. If large lumps are observed, the semi-dry granules are sieved and left to dry again. The dried granules are sieved. Hydroxypropyl methyl cellulose and colloidal silicon dioxide, polyethylene glycol and the remaining red iron oxide are sieved through the sieve.

The sieved mixture is added onto the dried granules. The resulting mixture is mixed with a mixer. transferred and mixed. After sifting the magnesium stearate through the sieve, added and mixed.

Powder mixtures of Metformin Hydrochloride and gliclazide, double layered with suitable physical properties. (bilayer) is printed as tablets.

Claims (1)

REQUESTS . Combination therapy of the appropriate active substance and/or pharmaceutically acceptable derivatives with antidiabetic properties from the biguanide group for oral use with the appropriate antidiabetic active substance and/or pharmaceutically acceptable derivatives from the pharmaceutically acceptable sulfonylurea group with antihyperglycemic activity and pharmaceutically acceptable Preparation of pharmaceutical composition(s) containing suitable excipients. . It is the pharmaceutical composition/s specified in the claim 1 and its feature is; It is the selection of the other antidiabetic active ingredient in the biguanide group among phenformin, buformin, metformin and/or pharmaceutically acceptable derivatives. . It is the pharmaceutical composition/s specified in claim 17 and its feature is; The other active ingredient in the biguanide group with antidiabetic properties is metformin hydrochloride. . It is the pharmaceutical composition/s specified in Claim 1 and its feature is; is to select the antidiabetic active ingredient from the sulfonylurea group with antihyperglycemic activity among acetohexamide, chlorpropamide, tolbutamide, tolazamide, glipizide, gliclazide, glibenclamide, glimepiride, gluquidone and/or pharmaceutically acceptable derivatives. . It is the pharmaceutical composition/s listed in 1 and its feature is; The antidiabetic active ingredient in the sulfonylurea group with antihyperglycemic activity is preferably gliclazide. . Modified release pharmaceutical bilayer tablet formulation for oral administration of pharmaceutical compositions containing metformin and/or pharmaceutically acceptable derivatives in combination with Gliclazide and/or pharmaceutically acceptable derivatives comprising: A) The layer containing Metformin Hydrochloride; - about 10-99.9% by weight of Metformin Hydrochloride - about 0.01-20% by weight of one or more lubricants B) Gliclazide-containing layer; - about 0.1-35% by weight Gliclazide - about 10-80% by weight of one or more buffering agents - about 0%. 1-20 wt% of one or more binders - about 001 - 5% by weight of one or more colorants - about 0%. 1-65 weight percent one or more controlled-release agents - one or more glidants, approximately 001-25% by weight - one or more lubricants, approximately 001-20% by weight - sufficient amount of granulation fluid Metformin and/or pharmaceutically acceptable A modified release pharmaceutical bilayer tablet formulation for oral administration of pharmaceutical compositions containing gliclazide and/or its pharmaceutically acceptable derivatives in combination with their acceptable derivatives comprises: A) The layer containing Metformin Hydrochloride; - approximately 10-99.9% by weight of Metformin Hydrochloride - approximately 001-20% by weight of magnesium stearate B) Gliclazide-containing layer; - about 0%. 1-35 wt.% Gliclazide - approx. 10-80 wt.% calcium hydrogen phosphate dihydrate - approx. 0.1-20 wt.% hydroxypropyl methyl cellulose - approx. 001 -5 wt.% red iron oxide - approx. 0%. 1-65 weight percent hydroxypropyl methyl cellulose - approximately 001-25% by weight colloidal silicon dioxide - approximately 001-20% by weight magnesium stearate and/or polyethylene glycol. It is the pharmaceutical composition/s specified in claim 6 and its feature is; 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, tripalmityl, 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. It is the pharmaceutical composition/s specified in Claim 87 and its feature is; the lubricant is preferably magnesium stearate and/or polyethylene glycol. It is the pharmaceutical composition/s specified in Claim 6 and its feature is; buffer agent citric acid anhydrous, sodium citrate dihydrate, sodium phosphate, sodium dihydrogen phosphate, potassium citrate, phosphoric acid, ammonium hydroxide, citric acid, diisopropanolamine, sodium carbonate, sodium silicate, disodium orthophosphate, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium aluminate, diethanol amine, sodium alginate, ethylenediamine, meglumine, hydrochloric acid, lactic acid, sodium citrate, sodium hydroxide, triethanolamine, trolamine, sodium benzoate, sodium hydrogen carbonate, calcium hydrogen phosphate dihydrate or their mixtures. It is the pharmaceutical composition/s specified in Claim 10 and its feature is; preferably the buffering agent is calcium hydrogen phosphate dihydrate. It is the pharmaceutical composition/s specified in Claim 6 and its feature is; binder pregelatinized corn starch, pregelatinized starch, hydroxy propyl starch, gelatin, microcrystalline cellulose, cellulose, gums, polyvinyl pyrrolidone, polymethacrylates, sodium carboxy methyl cellulose, starch, paratins, polycrystalline cellulose, aluminum glycol, ethylene glycol methyl cellulose, gums, ethylene ethyl methyl cellulose, gums, ethylene ethyl methyl cellulose, silicate, carboxy methylcellulose, hydroxy propylcellulose, hydroxy ethylcellulose, propylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, polysaccharides, polaxamers, alginic acids, collagen, albumin, crospovidone, crospovidone, hydroxy copovytrodone, crospovidone cellulose or their mixtures. It is the pharmaceutical composition/s specified in claim 12, characterized in that the binder is preferably hydroxypropyl methyl cellulose. It is the pharmaceutical composition/s specified in claim 6 and its feature is; colorant including, but not limited to, iron oxide pigments such as yellow iron oxide, red iron oxide, ß-carotene, red beetroot powder, chlorophyll, tartrazine, yellow orange, quinoline yellow, erythrosine, titanium dioxide pigments, caramel, sunset yellow, or mixtures thereof. is chosen among them. It is the pharmaceutical composition/s specified in Claim 14 and its feature is; The colorant is preferably the pharmaceutical composition/s specified in Claim 6, and its feature is; polyvinyl acetate phthalate, polyethylene glycol-polyvinyl alcohol copolymer, polyacrylic acid derivatives, polysaccharide derivatives, methacrylate polymer, polymethacrylate, ethyl methacrylate copolymer, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, polylactic acid-ethyl acrylate copolymer, polyvinyl acetate phthalate, release controlling agent , polyvinylpyrrolidone, polyvinylalcohol, glyceride, polyethylene oxide, glyceryl behenate, inethacrylic acid copolymer, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate, carboxy methyl ethyl cellulose, sodium carboxy ethyl cellulose, sodium carboxy methyl ethyl cellulose, sodium carboxy methyl ethyl cellulose, inethacrylate methyl thallate acrylate cellulose, ethylacrylate, ethyl acetate, ethyl acetate , acrylic and inethacrylic acid esters, sodium alginate, hypromellose phthalate, hypromellose acetate succinate, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propiyanate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, gelatin, celac, xanthan gum. It is the pharmaceutical composition/s specified in Claim 16 and its feature is; preferably the release controlling agent is hydroxypropyl methyl cellulose. It is the pharmaceutical composition/s specified in Claim 67 and its feature is; glidantine talc, magnesium stearate, hydrogenated vegetable oil, calcium stearate, stearic acid, colloidal silicon dioxide, sodium stearylfumarate, polyoxyethyleneglycol, leucine, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, silica, colloidal anhydrous silica, polyethyleneglycol, cellulose derivatives, starch or their mixtures. It is the pharmaceutical composition/s specified in claim 18 and its feature is; the glidantine is preferably colloidal silicon dioxide. It is the pharmaceutical composition/s specified in claim 6 and its feature is; The granulation solvent is selected from purified water, alcohols such as ethyl alcohol, methyl alcohol, isopropyl alcohol, butyl alcohol, methylene chloride or their mixtures. It is the pharmaceutical composition/s specified in claim 20 and its feature is; the granulation solvent is preferably agitated water. It is the pharmaceutical composition/s specified in the request and its feature is; dosage form(s) of tablet (chewable, oro-soluble, dispersible, water-dispersible, film-coated, bi-layer, multi-layer, enteric-coated, mini, controlled-release, sustained-release, immediate-release, extended-release, delayed-release, modified-release, modified-release ), capsule (hard, soft, enteric coated, film coated, controlled release, sustained release, immediate release, extended release, delayed release, modified release, modified release), powder, granule, caplet, disc, oral soluble film, bulk powder (multi-dose), pellet, sachet, water-dispersible powder, water-dispersible granule, effervescent tablet, effervescent granule, effervescent powder form, gel, pill, syrup, solution, suspension, elixir, drop, position, emulsion or spray is chosen among them. It is a pharmaceutical composition/s according to any of the above claims and its feature is; dose range of formulations suitable for pharmaceutical compositions where active ingredients are used in combination; 200-2700mg for metformin and/or pharmaceutically acceptable derivatives; 10-350mg for gliclazide and/or its pharmaceutically acceptable derivatives. It is the pharmaceutical composition/s specified in Claim 1 and its feature is; The dosage form(s) is preferably a double-layered tablet. It is the pharmaceutical composition/s specified in claim 1 and its feature is; is the selection from one or more of one or more of the layer/s modified, modified, controlled, extended, sustained, immediate or delayed release pharmaceutical dosage forms to achieve control of its release. It is the pharmaceutical composition/s specified in the list 1 and its feature is; The obtained pharmaceutical composition is in the form of a modified release pharmaceutical bilayer tablet. It is a pharmaceutical composition/s according to any of the above claims and its feature is; It is indicated for the symptomatic and/or therapeutic treatment of diabetes mellitus, particularly non-insulin dependent diabetes (Type 2 diabetes) and obesity diabetes.