EP2448576A2 - Composition pharmaceutique augmentant la solubilité - Google Patents

Composition pharmaceutique augmentant la solubilité

Info

Publication number
EP2448576A2
EP2448576A2 EP10757644A EP10757644A EP2448576A2 EP 2448576 A2 EP2448576 A2 EP 2448576A2 EP 10757644 A EP10757644 A EP 10757644A EP 10757644 A EP10757644 A EP 10757644A EP 2448576 A2 EP2448576 A2 EP 2448576A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
weight
telmisartan
range
amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10757644A
Other languages
German (de)
English (en)
Inventor
Mahmut Bilgic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bilgic Mahmut
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP2448576A2 publication Critical patent/EP2448576A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to pharmaceutical compositions having problems of solubility and stability and the medical use and the preparation method of these compositions.
  • the present invention provides a combination which is effective in the treatment of essential hypertension.
  • This effect provided by a combination in accordance with the invention is named as “desired effect” during the patent.
  • Defined combination comprises telmisartan as an antihypertensive agent.
  • Hypertension is the condition in which the blood pressure is higher than normal values.
  • Hypertension can be classified as essential (primer) or secondary hypertension. Hypertension which is not related to any known medical reason is named as essential hypertension; the elevation of blood pressure caused by another reason as renal disease and tumors is named as secondary hypertension.
  • TPR total peripheric resistance
  • hypertension is known to be a hereditary disease in high percentage.
  • Hypertension is a serious disease and without treatment, consequences can reach to life- threatening sizes. Hypertension without treatment is an important risk factor for the disease as cerebrovascular accident (paralysis), miocard infarct (heart attack), hypertensive cardiomiopathie (congestive heart failure), cardiac dilatation, heartbeat disorder, atherosclerosis which can cause ischemic heart disease, coronary arterial disease, arterial aneurism, hypertensive retinopathy (retina damage), hypertensive nephropathy (chronical kidney failure), hypertensive encephalopathy (confusion, headache, convulsion), bleeding in brain blood vessel and thrombosis.
  • cerebrovascular accident paralysis
  • miocard infarct hemocard infarct
  • hypertensive cardiomiopathie congestive heart failure
  • cardiac dilatation heartbeat disorder
  • atherosclerosis which can cause ischemic heart disease, coronary arterial disease, arterial aneurism, hypertensive retinopathy (retina damage), hypertensive
  • telmisartan angiotensin II receptor antagonists
  • diuretics which increase the activity of angiotensin II receptor antagonists.
  • Chemical name of telmisartan is 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazole]-l'- yl)methyl]-[l,r-bifenyl]-2-carboxylic acid. (Formula 1).
  • Telmisartan is firstly described in the patent numbered EP502314 Bl (In patent family, patents numbered EP0552765 Bl, US5591762 A, US5594003 A, US5602127 A and US5614519 A are included). In the patent, processes for preparing telmisartan, pharmaceutical compositions comprising telmisartan and angiotensin antagonist activity of telmisartan are also mentioned.
  • Telmisartan is a strong, long acting and non-peptide angiotensin II receptor antagonist and it is used in the treatment of hypertension.
  • Angiotensin II is synthesized from angiotensin I with a reaction catalyzed by angiotensin converting enzyme (ACE).
  • Angiotensin II has effects as vasoconstriction, excitation of aldosterone synthesis and secretion, cardiac excitation and the enhancement of sodium back absorption from kidney tubulus.
  • Telmisartan inhibits effects of angiotensin II by selectively blocking binding to ATI receptor in many tissues as vascular smooth muscle and adrenal gland. For this reason, mechanism of action of telmisartan is independent from routes wherein synthesis of angiotensin II occurs.
  • AT2 receptors are found in many tissues. However, it is not known that AT2 receptor is related to cardiovascular homeostasy.
  • the ATI receptor affinity of telmisartan is more than its AT2 receptor affinity.
  • the present invention is directed to obtain an effective composition which provides the desired effect based on the strong antihypertensive effect of telmisartan.
  • an aspect of the invention is to provide a formulation in accordance with the invention comprising a pharmaceutically acceptable, non-toxic and therapeutically effective amount of telmisartan and to formulate this agent in the form of tablet.
  • Telmisartan is an active agent displaying polymorphism.
  • the polymorphs of telmisartan are also faced with solubility problems.
  • Polymorph B of telmisartan is described in patent application numbered WO0043370 Al which is characterized with an endothermic pick seen at 183 ⁇ 2 0 C after DSC analysis .In the application, it is described that polymorph B is turned to polymorph A under temperature and moisture effect. Solubility of said two polymorphs is low.
  • particle size reduction One of the known techniques applied to address the solubility problem of poorly soluble drugs such as telmisartan is particle size reduction. Because the dissolution rate of a particulate solid depends on the surface area and the surface area increases as the particle size reduces, reducing particle size may increase dissolution rate.
  • particle size reduction may not always be effective at increasing the dissolution rate of a drug. Because, many hydrophobic drugs have a strong tendency to agglomerate while being transformed into larger particles during the dosage form manufacturing process depending on an overall decrease in effective surface area.
  • nanoparticulate technology Another technique applied to increase the surface area is nanoparticulate technology. But, there are some barriers faced during the processes for obtaining nanoparticles such as technical and mechanical limitation of breaking the drug particles into the size of nano particles and the stabilization of these small drug particles in the dosage form.
  • Basic agent a basic agent having a telmisartan molar ratio between 1:1 - 10:1, b) Surfactant or emulsifier in an amount of approximately 1-20% of the final composition,
  • telmisartan a pharmaceutical composition is described to increase solubility of telmisartan wherein the composition comprises,
  • compositions proposed in the above patents and patent applications head to the use of surfactant and emulsifier to remedy the solubility problem.
  • pharmaceutical compositions produced by an incomplex production method to overcome solubility problem of telmisartan.
  • crystalline telmisartan sodium salt characterized with a melting point of 245 ⁇ 5 0 C and that preparation process of crystalline telmisartan sodium salt obtained by acid addition salts formed with hydrochloric acid, hydrobromic acid, toluensulphonic acid and methanesulfonic acid; are described.
  • telmisartan salts (ammonium, choline, ters-butyl amine, arginin, meglumin, ethanolamine, piperazine, diethylamine, sulphuric acid, maleic acid, tartaric acid, citric acid, fumaric acid, oxalic acid, benzenesulphonic acid, naphthalene-2-sulphonic acid, tris-(hydroxymethyl)amine) and/or its polymorphs (telmisartan potassium) and its preparation processes are described.
  • telmisartan salts and their polymorphs are described in consideration of exhibiting higher solubility than free form. However, no proof is submitted whether these salts really provide a pharmaceutical composition with high solubility and stability or not, and a formulation is not proposed for most of them.
  • present invention presents a novel composition and an incomplex production method to provide targeted therapeutic efficiency of telmisartan which have solubility problem and which can be stable in only basic medium.
  • composition of this invention proposes to address the solubility problem of telmisartan without the need of using surfactant and emulsifier.
  • the characteristic of the invention is adding ammonium during the preparation of formulation to increase telmisartan' s solubility and to ensure its stability and spontaneous generation of telmisartan ammonium salt which has a solubility higher than free acid without using another additional process.
  • Pharmaceutical formulations according to the present invention include trometamine as stabilizing agent in order to increase stability Obtained composition is a composition having improved solubility and stability properties and is effective in the treatment of hypertension.
  • the present invention relates to a process for preparation of pharmaceutical composition
  • a process for preparation of pharmaceutical composition comprising a therapeutically effective amount of telmisartan for use in the manufacture of a medicament for the treatment of essential hypertension, characterized in that ammonia is used during the preparation of composition.
  • the manufacturing process which provides a formulation so as to obtain the desirable effect is as follows:
  • a gran ⁇ lation solution is obtained by adding and dissolving telmisartan, tromethamine and optionally at least one pharmaceutically acceptable excipient, preferably a binder in the solution of ammonia mixed with a suitable pure solvent or solvent mixture, preferably water;
  • - granulation is made by spraying granulation solution on a pharmaceutically acceptable diluents preferably on mannitol or sorbitol;
  • the final mixture is obtained by addition of at least one pharmaceutically acceptable excipient, preferably a lubricant after drying granules obtained in previous steps at 50°C to have maximum 2% of moisture and sieving the final mixture is then mixed to obtain a homogeneous mixture and fed to the tablet press machine
  • the tablets are coated.
  • the present invention is directed to obtain a composition which provides the desired effect depending on antihypertensive effect of telmisartan.
  • a solubility problem was arised during the studies conducted for this purpose as mentioned before.
  • An in-complex method should be generated to overcome the solubility problem of telmisartan and the incompatibility problem between substances forming the composition and on the other hand, therapeutically effective amount of active agents and suitable amount of excipients should be found to provide the desired effect of the telmisartan composition.
  • composition comprising telmisartan wherein ammonia is used during the preparation provides optimum activity for the treatment of essential hypertension.
  • telmisartan in certain ratios, a sufficient amount of ammonia, and tromethamine and optionally at least one pharmaceutically acceptable excipient selected from a group of substances comprising diluent, binder, disintegrant, lubricant and glidant provides optimum efficiency for the treatment of essential hypertension.
  • telmisartan The solubility problem of telmisartan is solved with a composition wherein the content of the composition is established according to the solubility properties of the substance and with an incomplex production method.
  • the pharmaceutical composition comprises telmisartan as active ingredient in the form of free acid.
  • telmisartan contacts with ammonia which is added to composition for increasing solubility and ensuring stability, telmisartan ammonium salt is obtained spontaneously. In this way there is no need for further process to obtain telmisartan ammonium salt.
  • Tromethamine adding to the pharmaceutical composition is also increasing the stability of composition.
  • a granulation solution is obtained by adding telmisartan, tromethamine as a stabilizing agent and optionally at least one pharmaceutically acceptable excipient, preferably a binder, in the solution of ammonia mixed with a suitable pure solvent or solvent mixture, preferably water.
  • granulation is made by spraying this granulation solution on a pharmaceutically acceptable diluents, preferably on mannitol or sorbitol.
  • the final mixture is obtained by addition of at least one pharmaceutically acceptable excipient, preferably a lubricant after drying granules obtained in previous steps at 50°C to have maximum 2% of moisture and sieving.
  • the final mixture is fed into the tablet press machine after mixing homogeneously.
  • Tablets are optionally coated with a film coating.
  • Tablets obtained with this method exhibit 80% solubility in the dissolution medium in first 20 minutes.
  • telmisartan in an amount in the range of 0.1-40% by weight, ammonia in an amount in the range up to 10% by weight, tromethamine in an amount in the range of 0.1-20% by weight and use of at least one pharmaceutically acceptable excipient selected from additives as diluent, binder, dispenser, lubricant and glidant when needed; which are preferred to obtain the desired therapeutic activity.
  • diluents can be selected from a group comprising lactose, microcrystalline cellulose, starch, pre-gelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, caoline, lactilol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol.
  • sorbitol or mannitol is used.
  • Diluent is present in an amount preferably in the range of 0-95% by weight and more preferably 5-85% by weight.
  • binders are selected from starches (as potato starch, corn starch, wheat starch), sugars as sucrose, glucose, dextrose, lactose, maltodextrine, natural and synthetic gums (as acacia), gelatin, cellulose derivative (as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellylose), polyvinylpyrrolidone, polyethylene glycol, wax, calcium carbonate, calcium phosphate, alcohols (as sorbitol, xilitol, mannitol) and water.
  • polyvinylpyrrolidone povidone
  • binder is present preferably in the range of 0-10% by weight, more preferably 0.1-5% by weight.
  • disintegrants are selected from starch (corn starch, potato starch) sodium starch glycolate, pre-gelatinized starch, cellulose derivative (as croscarmellose sodium or microcrystalline cellulose), polyvinylpyrrolidone, crospovidone, alginic acid, sodium alginate, clays (as xanthane gum or veegum), ion-exchange resins, food acids and effervescent systems based on alkali carbonate compounds.
  • disintegrant is present preferably in the range of 0-10% by weight, more preferably 0.1-5% by weight.
  • lubricants are selected from metallic stearates (as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (as sodium stearyl fumarate), fatty acids (as stearic acids), fatty alcohols, glyceryl behenate, mineral oil, paraffines, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates (as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc.
  • magnesium stearate is used.
  • lubricant is present preferably in the range of 0-10% by weight, more preferably
  • glidants are selected from silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, calcium phosphate tribasic, metallic stearates, metallic lauryl sulfates and calcium silicate. In pharmaceutical formulation, glidant is present in the range of less than 1% by weight.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques présentant des problèmes de solubilité, le procédé de préparation de ces compositions et l'utilisation médicale de celles-ci.
EP10757644A 2009-07-02 2010-06-25 Composition pharmaceutique augmentant la solubilité Withdrawn EP2448576A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR200905146 2009-07-02
PCT/TR2010/000124 WO2011002423A2 (fr) 2009-07-02 2010-06-25 Composition pharmaceutique augmentant la solubilité

Publications (1)

Publication Number Publication Date
EP2448576A2 true EP2448576A2 (fr) 2012-05-09

Family

ID=43066962

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10757644A Withdrawn EP2448576A2 (fr) 2009-07-02 2010-06-25 Composition pharmaceutique augmentant la solubilité

Country Status (2)

Country Link
EP (1) EP2448576A2 (fr)
WO (1) WO2011002423A2 (fr)

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI9210098B (sl) 1991-02-06 2000-06-30 Dr. Karl Thomae Benzimidazoli, zdravila, ki te spojine vsebujejo, in postopek za njihovo pripravo
US5602127A (en) 1991-02-06 1997-02-11 Karl Thomae Gmbh (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists
DE4225756A1 (de) 1992-01-22 1994-03-10 Thomae Gmbh Dr K Benzimidazole, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
US5594003A (en) 1991-02-06 1997-01-14 Dr. Karl Thomae Gmbh Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists
US5614519A (en) 1991-02-06 1997-03-25 Karl Thomae Gmbh (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists
DE19901921C2 (de) 1999-01-19 2001-01-04 Boehringer Ingelheim Pharma Polymorphe von Telmisartan, Verfahren zu deren Herstellung und deren Verwendung zur Herstellung eines Arzneimittels
DE10153737A1 (de) 2001-10-31 2003-05-28 Boehringer Ingelheim Pharma Kristallines Natriumsalz des Telmisartans, Verfahren zu dessen Herstellung und dessen Verwendung zur Herstellung eines Arzneimittels
DE10244681A1 (de) 2002-09-24 2004-04-08 Boehringer Ingelheim International Gmbh Neue feste Telmisartan enthaltende pharmazeutische Formulierungen und deren Herstellung
EP1824833A2 (fr) 2004-11-11 2007-08-29 LEK Pharmaceuticals D.D. Preparation de sels de telmisartan avec une solubilite amelioree
WO2006063737A1 (fr) * 2004-12-17 2006-06-22 Boehringer Ingelheim International Gmbh Therapie combinatoire impliquant le telmisartan et l'hydrochlorothiazide
US20070116759A1 (en) * 2005-11-22 2007-05-24 Gershon Kolatkar Pharmaceutical compositions of telmisartan
SI22297A (sl) 2006-06-23 2007-12-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Priprava soli telmisartana
US20090142398A1 (en) * 2007-11-21 2009-06-04 Pharmascience Inc. Novel pharmaceutical compositions comprising a disintegration matrix

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011002423A2 *

Also Published As

Publication number Publication date
WO2011002423A2 (fr) 2011-01-06
WO2011002423A3 (fr) 2011-03-03

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