TR201610368A2 - CITAGLIPTIN PHOSPHATE ANHYDRUS FORMULATIONS WITH ADVANCED RESOLUTION SPEED - Google Patents

Abstract

The present invention relates to the field of pharmaceutical technology and is a film tablet formulation comprising sitagliptin phosphate in anhydrous form as active ingredient, microcrystalline cellulose as an adjuvant, calcium hydrogen phosphate anhydrous, croscarmellose sodium, sodium stearyl fumarate, magnesium stearate and coating material prepared by direct compression method. characterized in that; a) 31 - 32% by weight of sitagliptin phosphate in anhydrous form as active ingredient, b) 14 - 16% by weight of microcrystalline cellulose as diluent.

Description

Technical Area The present invention relates to the field of pharmaceutical technology and has an improved dissolution rate. Pharmaceutical in the form of film-coated tablets containing the active ingredient sitagliptin phosphate anhydrous describes the formulations.

Previous Technique The active substance of sitagliptin was first described in the patent number U86699871 of Merck. has been made. Sitagliptin phosphate monohydrate is in patent number US7326708 belonging to Merck company. background is explained. The molecular structure of sitagliptin phosphate anhydrous is given below. (trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1zl) (anhydrous). sitagliptin Phosphate anhydrous is a white or almost white crystalline powder that does not become hygroscopic.

Soluble in water and N,N-dimethylformamide; slightly soluble in methanol; ethanol, acetone and sparingly soluble in acetonitrile; It is insoluble in isopropanol and isopropyl acetate.

Sitagliptin, dipeptidyl-peptidase-IV (DPP-IV) used in the treatment of type 2 diabetes mellitus It is the first member of a new group of drugs called inhibitors to be approved by the FDA.

DPP-IV inhibitors are used in the treatment of type 2 diabetes mellitus; glucagon-like peptide DPP-incretin hormones such as I (GLP-1) and glucose-dependent insulinotropic peptide (GIP) they do. These hormones are produced naturally by the body in response to food intake. they are produced. Its functions are to increase the body's ability to produce more insulin only when necessary. to help it produce and when it is not needed, it is produced by the liver to reduce the amount of glucose. Sitagliptin is an active hormone with intact integrity By increasing their concentration, these hormones have more of an effect on controlling blood sugar. they make it effective. This is non-insulin dependent diabetes mellitus (NIDDM). 'An important development in the treatment and prevention of Type 2 diabetes, also known as offers.

Sitagliptin is used orally. Sitagliptin is currently commercially available in 25 mg, 50 mg and 100 mg. It is sold under the name Januvia of Merck company in the form of film tablets at doses of mg. is offered.

Sitagliptin phosphate salts typically fall into the intended administration form, namely oral tablets, pharmaceutical diluents, excipients compatible with conventional pharmaceutical practice or as a mixture with carrier substances. Active pharmaceutical for oral administration component eg lactose, starch, sucrose, glucose, microcrystalline cellulose, magnesium stearate, it can be combined with dicalcium phosphate, calcium sulfate, maiiiiitol, sorbitol and the like. From this binders, lubricants, dispersants and Coloring agents may be added. Lubricants used in tablet dosage forms sodium oleate, sodium stearyl fuinrate, magnesium stearate, sodium benzoate, sodwm acetate, sodium chloride and the like and dispersants starch, methyl cellulose, croscarmellose European patent EP1654263 B1 from Merck, sitagliptin dihydrogeuphosphate describes the crystal moiiohydrate of the salt and the process for its preparation. In patents, 100 Directly to obtain film tablet formulations containing mg Sitagliptin dihydrogen phosphate compression method and compression method between cylinders were used. Direct printing method 32% by weight, using sitagliptin dihydrogenphosphate monohydrate, % by weight 31.95% by weight microcrystalline cellulose, 31.95% by weight mannitol (or by weight) formulation is explained. Active ingredient sitagliptin dihydrogenphosphate moiiohydrate, microcrystalline cellulose, mannitol (or dicalcium phosphate) and croscarmellose 'First mixed and then The mixture was lubricated with magnesium stearate and pressed into tablets, and lastly tablets Covered with Opadry White film. Generally, the active ingredients are the hydrate forms. Its solubility, dissolution rate and bioavailability are lower than the anhydrous form. Active ingredient The monohydrate form of sitagliptin dihydrogenphosphate salt, which is used as Because of the (HzO) molecule, the molecules are connected to each other with tighter bonds, so the anhydrous It has lower solubility in vitro than its form. Hydrogen bonds in the structure, slower dissolution than the anhydrous (anhydrous) form It causes the speed to show and the absorption to decrease. Therefore, improved dissolution There is a need for sitagliptin phosphate anhydrous formulations with high speed. pharmaceutical composition containing sitagliptin hydrochloride salt, crystallization inhibitor and excipient is explained. Amorphous sitagliptin hydrochloride salt and crystallization inhibitor solvent After it is prepared in The solid form obtained is mixed with the excipient. Polyvinylpyrrolidone as crystallization inhibitor, Microcrystalline cellulose was used as an excipient. Pharmaceutical formulation by weight polyvinylpyrrolidone, 30-35% by weight microcrystalline cellulose, 20-30% by weight lactose and/or mannitol, which is preferred as a diluent, at a rate of 3.5-8% by weight. croscarmellose sodium, 0.5% to 5% by weight magnesium selected as lubricant stearate and/or sodium stearyl fumarate, 0.01% to 0.0.4% by weight as antioxidants prepared with selected butyl hydroxytoluene and preferably other excipients. In tablet coating Opadry is used. In the wet granulation process used in this patent, the active substance such as particles sticking to each other and difficult to process in the tablet machine. may encounter problems. This situation indicates that the impurity values in stability tests This causes the dissolution profiles to appear low. Also mourn During the granulation process, the soaking process creates a problem in the dissolution of the active substance, may cause the solubility to decrease over time. However, in the direct printing method Since there is no heating and humidification stage, the dissolution rate and dissolution rate are higher.

Therefore, better dispersion time and dissolution can be achieved by applying the direct compression method. It has an improved dissolution rate in order to obtain stable products with different profiles. Sitagliptin phosphate anhydrous formulations are needed.

As an element of the present invention, the formulation was prepared by the direct printing method. Direct printing method, using less equipment and using less energy, Tablet production can be done in a shorter time compared to other methods. low cost and production and packaging with the direct printing method, which is an easy-to-apply method. durable, adequate hardness formulations are obtained. Also, granulation Impurity formation, which is a problem encountered in the method, causes a decrease in dissolution rates. available. With formulations prepared by the direct compression method, stability tests are more with improved dissolution rate showing good disintegration time and dissolution profiles Sitagliptin phosphate anhydrous formulations have been obtained.

In our invention, the anhydrous form of sitagliptin phosphate salt was used as the active substance.

The phosphate anhydrous form of sitagliptin was compared with the monohydrate form in vitro. It has been found that the resolution is higher in the medium. in the monohydrate structure sitagliptin, as the molecules are connected to each other with tighter bonds due to hydrogen bonds. The m0n0hydrate form shows a slower dissolution rate than the anhydrate form. Thus, more Pharmaceutical containing the active ingredient sitagliptin phosphate anhydrous with a high dissolution rate film tablet formulations were obtained.

In the formulation subject to the present invention, croscarmellose sodium was used as a dispersant.

It is used in croscarmellose sodium tablets at a concentration of 0.5-5.0%. nontoxic and It is an ioiiiirritant substance. However, if taken in high amounts, it can have a laxative effect.

NaCMC with the use of croscarmellose sodium, cross-linked NaCMC or sodium starch A shorter disintegration time was obtained compared to glycolate. In addition, the subject of the invention Sodium stearyl fumarate and magnesium stearate were chosen as lubricants in the formulation.

As a result of the trials, sodium stearyl fumarate and inagnezyuin stearate together It has been concluded that its use has a superior slider feature.

Calcium in anhydrous form as a filler in the formulation of the present invention hydrogen phosphate is used. Chemical, physical and physiological properties of the experiments In terms of the active substance, sitagliptin phosphate is a filler that is closest to anhydrous. Calcium hydrogen phosphate anhydris was chosen as the In addition, high calcium hydrogen phosphate Ingestion of large amounts may cause gastrointestinal irritation. Therefore, in the present invention The amount of calcium hydrogen phosphate was kept at an acceptable level.

In the present invention, it is used with microcrystalline cellulose, mannitol and lactose for diluent selection. experiments have been made. Microcrystalline cellulose, both to aid printing and mixing It has superiority over others in terms of gaining a good fluency. Also, in the formulation The amount of microcrystalline cellulose used significantly affects the dispersion time.

As a result of the experiments, it was found that the amount of microcrystalline cellulose was high. It has been observed that using it delays the dispersion time. Disintegration of tablets, dissolution Delay of dispersion time, as it is an important parameter affecting the rate of dissolution it also causes a decrease in the speed. Therefore, in the formulation subject to the invention, Improved dissolution rate by using 14% - 16% microcrystalline cellulose content. Sitagliptin phosphate alihydrus formulations have been obtained. As a result of our studies, we found, surprisingly, sitagliptin in anhydrous form as the active ingredient. phosphate, inocrystalline cellulose as excipient, calcium hydrogen phosphate anhydrous, croscarinellose sodium, sodium stearyl fumarate, magnesium stearate and coating material film tablet formulation containing and prepared by direct compression method; a) 0/0 3] - 32% sitagliptin in anhydrous form as active ingredient b) 14% - 16% by weight of microcrystalline cellulose as the diluting agent It has an improved dissolution rate that gives the most appropriate dissolution result with its content. Sitagliptin phosphate anhydrous formulation was obtained.

Detailed description of the invention The subject of the invention is sitagliptin phosphate in anhydrous form as an active substance, an auxiliary substance. as microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, direct printing containing sodium stearyl fumarate, magnesium stearate and coating material of the film tablet formulation prepared by the method, as active ingredient 31 by weight - 0/0 32 Sitagliptin phosphate in anhydrous form, 14% to 16% by weight as diluent It is characterized by containing a high proportion of microcrystalline cellulose.

In the film tablet formulations according to the present invention, the active substance and excipients The amounts of sitagliptin in the core tablet are shown in Table 1.

The examples given in Table 1 are given to explain the present invention in detail, but The scope of the invention is not limited to these examples.

Table 1. Amounts of active substance and excipients in the core tablet Components Unit formula (mg) Active ingredient Example l Sitagliptin phosphate anhydrous (100 mg of Sitagliptin) Excipients Microcrystalline cellulose 0/0 14 - 16% Calcium Hydrogen Phosphate, _ anhydrous Croscarinellose Sodium 1.5% - 2.5% Sodium Stearyl Fumarate 2% - 4% Magnesium Stearate 1% - 2% Production method used for the preparation of stable tablet core according to the present invention contains the following steps. l) Raw materials are weighed in accordance with the production formula. 2) Sitagliptin Phosphate Anhydrus, Microcrystalline Cellulose, Calcium Hydrogen Phosphate Anhydrus, Croscarmellose Sodium is sieved through a sieve and until a homogeneous mixture is obtained. until mixed. 3) Then, Sodium Stearyl Fumarate is added to the mixture after it is sieved through the sieve. is mixed. 4) Next, sieved Magnesium Stearate is added to the mixture and again is mixed.

) The powder mix, which has been mixed, conforms to the specifications in the tablet printing machine. printed as. 6) Core tablets are coated in accordance with specifications. This coating layer is a or more auxiliary items.

3 doses of product containing 25 mg, 50 mg and 100 mg Sitagliptin with the formulation given in Table 1. developed. The formulation is anhydrous at a rate of 31% - 32% by weight as the active ingredient. Sitagliptin phosphate in its form, 14% to 16% by weight microcrystalline as diluent cellulose, 46% to 48% by weight calcium hydrogen phosphate as filler anhydrous, 1.5 - 2.5% by weight croscarmellose sodium as a dispersant, lubricant 2% - 4% by weight sodium stearyl fumarate and 1% - 2% by weight Contains magnesium stearate. Direct press method was used as the production method.

Unlike the formulation studied in Example 1, the active ingredient sitagliptin phosphate anhydrous amount has been increased to 47%-48% by weight. Direct printing method as production method is applied. 25 mg, 50 mg and 100 mg Sitagliptin with the formulation studied in Example 2 A product containing 3 doses has been developed.

Table 2. Amounts of active substance and excipients in the core tablet Components Unit formula (mg) Active ingredient 1 . one (100mg of Sitagliptm) Sitagliptin phosphate anhydrous 47% - 48% Excipients Microcrystalline cellulose 14% - 16% Calcium Hydrogen Phosphate, Aiihydrus Croscarmellose Sodium 1.5% - 2.5% Sodium Steari] Fumarate 2% - 4% Magnesium Stearate 1% - 2% Unlike the formulation used in Example 1, only sitagliptin is substituted for phosphate anhydrus. sitagliptin phosphate monohydrate was used. The auxiliary contained in the formulation in Example 1 same items are used. Direct printing used in Example 1 as a production method By using the method, products containing 25 mg, 50 mg and 100 mg Sitagliptin were obtained.

Table 3. Amounts of active substance and excipients in the core tablet Components Unit formula (mg) Active ingredient _ _ I (100mg of Sitagliptin) Sitagliptin phosphate monohydrate Excipients Microcrystalline cellulose 14% - 16% Calcium Hydrogen Phosphate, anhydrous Croscarmellose Sodium 1.5% - 2.5% Sodium Stearyl Fumarate 2% - 4% Magnesium Stearate 1% - 2% The direct printing method used in Example 1 was used as the production method. in example 1 Unlike the formulation used, the amount of diluent is kept low. microcrystalline Using a small amount of cellulose both reduced the fluidity of the mixture and Table 4. Amounts of active substance and excipients in the core tablet Components Unit formula (mg) Active ingredient _ _ I (100mg of Sitagliptin) Sitagliptin phosphate anhydrous 31% - 32% Excipients Microcrystalline cellulose 4% - 6% Calcium Hydrogen Phosphate, anhydrous Croscarmellose Sodium 4.5% - 5.5% Sodium Stearyl Fumarate 4% - 6% Magnesium Stearate 3% - 5% The formulation described in the European patent of Merck EP1654263 B1 prepared using

Direct printing method was used as the production method. Inventive in example l.” different from the formulation, the active ingredient sitagliptin dihydrogenphosphate monohydrate used. It is preferred to use only magnesium stearate as lubricant.

Adding mannitol to the formulation as an excipient causes problems in terms of stability. caused it to happen. In addition, the amount of microcrystalline cellulose as a diluent is high. has been retained. It was found that the high amount of microcrystalline cellulose delayed the dispersion time. has been observed.

Table 5. Amounts of active substance and excipients in the core tablet Components Unit formula (0/0) Active ingredient . _ . (100mg of Sitagliptin) Sita tin dihydroenphosphate monohydrate Excipients Mannitol 31.95% Croscarmellose Sodium 2% Magnesium Stearate 2% worked with the formulation. Differently active substance in the formulation used in Example 1 The amorphous form of sitagliptin was used, and lactose and butyl form were used as auxiliary substances. hydroxytoluene is added to the formulation. 6% added as crystallization agent polyvinylpyrrolidone caused prolonged dispersion time and crystallized from amorphous form. It has created problems in stability in the transition to shape.

Table 6. Amounts of active substance and excipients in the core tablet Components Unit formula (0/0) Active ingredient 1 _ . (100mg of Sitagliptin) Sitagliptin hydrochloride, amorphous 25% Excipients Polyvinylpyrrolidone 6% Microcrystalline cellulose 34% Lactose 26.98% Croscarinellose sodium 7% Magnesium stearate 1% Butyl hydroxytoluene 002% Two of the Sitagliptin 100 mg film tablet products obtained according to Example 1 and Example 2-3-4-5-6 Dissolution studies were carried out under different accelerated stability conditions.

According to the trials, the active substance and auxiliary substances contained in the formulation in Example 1 the preparation of the substances by using the specified percentage ranges and the production method Optimal dissolution according to Example 2-3-4-5-6 by applying the direct compression method Sitagliptin phosphate anhydrous formulation with improved dissolution rate resulting in has been reached. The dissolution results in minutes are compared in Table 7 and Table 8.

It was prepared with the formulations specified in Table 7, Example 1 and Example 2-3-4-5-6. Sitagliptin 100 mg film-coated tablet products at conditions of accelerated stability (4OOC ± 2°C/75 ± 5% RH) in an aquatic environment with the dissolution medium described in the European Pharynacopeia (Water + 100 rpm, 900 ml, basket) dissolution profiles were compared. Europe In the Farniakopesi, the dissolution specification is “at least 80% at the end of 20 minutes. condition” is determined.

Table 7. Dissolution results for Sitagliptin 100 mg film tablet Samples Dissol'i'ion “ o (40°C ± 2°C/75 ± 5% RH) Examples Water + 100 rpm, 900 ml, basket *The dissolution specification in the European Pharmacopoeia is stated as “at least 800% after 20 minutes”.

It was prepared with the formulations specified in Table 8, Example 1 and Example 2-3-4-5-6. Sitagliptin 100 mg film-coated tablet products at conditions of accelerated stability (40°C ± 2°C/75 ± 5% RH) obtained dissolution profiles were compared. The ratios given in Table 8 are pH. 6.8 Phosphate + 100 rpm, 900 ml, obtained in a basket environment.

Table 8. Dissolution results for Sitagliptin 100 mg film tablet samples Dissolution 'V0 (40°C ± 2°C/75 ± 5% RH) Examples pH 6.8 Phosphate + 100 rpm, 900 ml, basket According to the dissolution results obtained in the aquatic environment indicated in Table 7, the European All formulations with the condition "at least 800% after 20 minutes" specified in the Pharmacopoeia Although it is provided for appears to dominate.

Example of dissolution results obtained in pH 6.8 Phosphate medium specified in Table 8

Claims (1)

REQUESTS 1) It is a film tablet formulation prepared by direct compression method, containing sitagliptin phosphate in anhydrous form as an active ingredient, microcrystalline cellulose, calcium hydrogen phosphate anhydrous as an auxiliary substance, croscarmellose sodium, sodium stearyl fumarate, magnesium stearate and coating material. a) 31% - 32% by weight of sitagliptin phosphate in the form of anhydrous as an active ingredient, b) 14% - 16% by weight of microcrystalline cellulose as a diluting agent.