Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

• the present invention relates to a film coated tablet comprising vildagliptin/vildagliptin HCI and metformin HCI and at least one pharmaceutically acceptable excipient.
• the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.
• Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors.
• Type 1 and Type 2 There are two main types of diabetes; Type 1 and Type 2:
• Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy. People with Type 1 diabetes must use insulin injections to control their blood glucose.
• Type 2 diabetes the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweight. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
• Vildagliptin is a dipeptidyl dipeptidase-IV (DPP-IV) inhibitor developed for use in the treatment of type 2 diabetes (non-insulin dependent diabetes).
• DPP-IV dipeptidyl dipeptidase-IV
• vildagliptin inhibits the degradation of the dipeptidyl dipeptidase-IV enzyme, thereby inhibiting the effects of incretin hormones, glucagon-like peptide-1 (GLP-1), and of glucose-dependent insulinotropic peptide (GIP).
• GLP-1 glucagon-like peptide-1
• GIP glucose-dependent insulinotropic peptide
• the chemical designation of vildagliptin is (S)- ⁇ [(3-hydroxyadamantan-1- yl)amino]acetyl ⁇ pyrrolidine-2-carbonitrile, with the chemical structure illustrated below in Formula 1.
• Vildagliptin is soluble in water and in organic polar solvents.
• Vildagliptin is marketed under the trademark Galvus ® in 50 mg dosage forms. It is used against diabetes mellitus, but particularly in treating type 2 diabetes.
• Metformin is antidiabetics having an orally-administrated biguanide structure.
• Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform.
• Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg. It is used singly or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.
• metformin hydrochloride is 1 ,1 -dimethylbiguanide hydrochloride, has the following chemical structure of Formula II.
• Combination product of vildagliptin and metformin hydrochloride is marketed under the trademark Eucreas® (50mg/850mg and 50mg/1000mg dosage forms of vildagliptin and metformin hydrochloride).
• Pharmaceutical formulations of combined respective active ingredients and the process for their preparation are disclosed in EP 1948149.
• Combination preparations of metformin and vildagliptin are described in WO 2007/041053.
• a tablet disclosed can contain, in addition to the active substances, usual excipients, for example fillers, binders, disintegrants, lubricants and colorants.
• lubricants examples include colloidal silica, magnesium trisilicate, starch, talc, calcium phosphate, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, cellulose and microcrystalline cellulose.
• EP2477660 (A1) discloses a pharmaceutical composition
• a pharmaceutical composition comprising an active agent metformin or its salt in combination with an active agent sitagliptin or vildagliptin or their salt, and a lubricant (more than 10 wt.%, based on the total weight of the composition).
• the lubricant is polyethylene glycol or a mixture of polyethylene glycol with at least one of the other lubricant.
• vildagliptin Both metformin HCI and vildagliptin have some structural problems. Stability-related problems do occur in many active agents, including vildagliptin, under the influence of ambient and physical conditions.
• Vildagliptin is an active agent that is highly-susceptible to air and humidity. When vildagliptin is exposed to air and humidity, it degrades structurally and develops chemical behavioral changes. The stability of vildagliptin products developed is not at a desired level and the shelf life thereof is shortened.
• vildagliptin is reactive against the excipients employed in developing formulations containing the same. This fact causes impurities to occur in the formulation and leads to the inclusion of undesired components into the formulation. Also, the compressibility of metformin is poor. Considering these, it is very difficult to create a formulation comprising vildagliptin and metformin HCI.
• vildagliptin or vildagliptin HCI and a mixture comprising metformin HCI was prepared.
• a tablet formulation was created to overcome the above problems with a certain proportion and selected excipients.
• the main object of the present invention is to provides a tablet comprising vildagliptin/vildagliptin HCI and metformin HCI capable of being compressed into a tablet having adequate size, hardness, rapid disintegration time and an acceptable dissolution profile.
• Another object of the present invention is to provide a tablet, considering the negative structural features of metformin HCI and vildagliptin, having effective treatment and high stability formulation and an effective process.
• a tablet comprises;
• the ratio of the mixture comprising metformin hydrochloride ( %95 DC, metformin granulate Direct Compressible grade %95) to vildagliptin or vildagliptin HCI is in the range of 15:1 to 22:1 , preferably 16:1 to 21 :1 by weight. The ratio helps to provide the desired dissolution profile and the desired stability.
• the amount of vildagliptin or vildagliptin HCI is between 1.0% and 10.0% by weight in the total formulation. Preferably, it is between 2.0% and 7.0% or 3.0% and 5.0% by weight in the total formulation.
• the amount of a mixture comprising metformin hydrochloride is between 60.0% and 87.0% by weight in the total formulation. Preferably, it is between 67.0% and 85.0% or 74.0% and 82.0% by weight in the total formulation.
• the amount of metformin hydrochloride is between 92.0% and 97.0% by weight in the mixture. Preferably, it is 95.0% by weight in the mixture.
• Metformin HCI is used big proportion that can lead to considerable problems during the preparation of formulation with regard to the uniformity of the content of active agent in the individual composition units. Because of problems uniformity of the content, the active substance may interact with several excipients. It reflects that content uniformity play important role in the dissolution of the drug. Also, in terms of physical properties, the compressibility of metformin is poor, and how to obtain a tablet or a capsule having an acceptable mechanical strength is an important problem in formulation development.
• a mixture comprising metformin HCI was prepared. So, it helps to provide the desired uniformity of the content and therefore it provides the desired dissolution profile. Also, the mixture ensures the desired compressibility and high physically. Thanks to the mixture comprising metformin HCI %95.0 DC, compressing of tablet can made by direct compression without extra process even if metformin had low compressibility.
• the mixture comprising metformin HCI %95 DC also comprises at least one pharmaceutically acceptable excipient.
• the excipients are selected from the group comprising fillers, binders, lubricants or mixtures thereof.
• a tablet comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising binders, fillers, disintegrants, lubricants, glidants, moisture absorbing agents, coating agents or mixtures.
• excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed.
• the formulations should have no physicochemical incompatibility between the active agents and the excipients.
• Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
• the amount of fillers is between 3.0% and 20.0% by weight in the total formulation. Preferably, it is between 4.0% and 10.0% or 10.0% and 20.0% or 10.0% and 16.0% by weight in the total formulation.
• the filler is microcrystalline cellulose or mannitol or mixtures thereof.
• Suitable binders are selected from the group comprising copovidone sodium carboxymethyl cellulose, crospovidone, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, agar, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
• the amount of binders is between 0.01% and 10.0% by weight in the total formulation.
• the binder is copovidone.
• Suitable disintegrants are selected from the group comprising croscarmellose sodium, low- substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodecyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
• the amount of disintegrants is between 0.1% and 5.0% by weight in the total formulation.
• the disintegrant is croscarmellose sodium.
• Suitable lubricants are selected from the group comprising from magnesium stearate, colloidal silicon dioxide, calcium stearate, zinc stearate, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, stearic acid, fatty acid, fumaric acid, glyceryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
• the amount of lubricants is between 0.01% and 3.0% by weight in the total formulation.
• the lubricant is magnesium stearate.
• Suitable glidants are selected from the group comprising talc, colloidal silicon dioxide, corn starch or mixtures thereof.
• the amount of glidants is between 0.01% and 3.0% by weight in the total formulation.
• the glidant is talc.
• Suitable moisture absorbing agents are selected from the group comprising calcium chloride, calcium sulfate, activated carbon, zeolites, silica gel or mixtures thereof. According to one embodiment of the present invention, the amount of moisture absorbing agents is between 0.001% and 1 .0% by weight in the total formulation.
• the moisture absorbing agent is calcium chloride. Also, it helps to provide the desired dissolution profile.
• Suitable coating agents are selected from the group comprising copovidone, polymethacrylates, polydextrose, polyalkylacrylates copolymers, triacetin, hydroxyl propyl methyl cellulose, colloidal silicon dioxide, lactose monohydrate, medium chain triglycerides, hydroxypropyl cellulose, white wax, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof.
• the amount of coating comprising coating agents is between 0.5% and 5.0% by weight in the total formulation. Preferably, it is between 1.5% and 3.5% by weight in the total formulation.
• the mixture comprising metformin HCI %95 DC also comprises at least one pharmaceutically acceptable excipient.
• the excipients are selected from the group comprising microcrystalline cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone (K30, K90), magnesium stearate, pregelatinized starch, crospovidone or mixtures thereof.
• the mixture comprising metformin HCI %95 DC also comprises microcrystalline cellulose and polyvinylpyrrolidone (K30, K90). Surprisingly, this provides the desired content homogeneity of metformin HCI, so it ensures the desired dissolution profile in the tablet.
• the tablet comprising copovidone, microcrystalline cellulose, mannitol, magnesium stearate, talc, calcium chloride, croscarmellose sodium or mixtures thereof.
• the tablet of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
• the tablet is obtained by using direct compression, it is a simple and low-cost production method was employed. Also, since vildagliptin is highly-susceptible to air and humidity, this method is advantage because it does not contain high humidity environment and it is fast.
• Example 1 The tablet formulation comprising vildagliptin and metformin HCI
• Example 2 The tablet formulation comprising vildagliptin and metformin HCI
• Example 3 The tablet formulation comprising vildagliptin and metformin HCI
• Example 4 The tablet formulation comprising vildagliptin and metformin HCI
• Example 5 The tablet formulation comprising vildagliptin and metformin HCI
• Example 6 The tablet formulation comprising vildagliptin and metformin HCI
• Example 7 The tablet formulation comprising vildagliptin and metformin HCI
• Example 8 The tablet formulation comprising vildagliptin and metformin HCI Process for the described above tablet formulation examples;
• Example 9 A mixture comprising metformin HCI %95 DC q.s: Quantity sufficient
• Example 10 A mixture comprising metformin HCI %95 DC q.s: Quantity sufficient
• Example 11 A mixture comprising metformin HCI %95 DC
• Example 12 A mixture comprising metformin HCI %95 DC

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• General Health & Medical Sciences (AREA)
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• Veterinary Medicine (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)

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• 2020
  • 2020-06-25 TR TR2020/09949A patent/TR202009949A1/tr unknown
• 2021
  • 2021-05-07 WO PCT/TR2021/050443 patent/WO2021262116A1/en unknown
  • 2021-05-07 EP EP21829623.4A patent/EP4171533A1/de active Pending

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