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EP2571495A1 - Composition pharmaceutique à libération contrôlée à base de losartan - Google Patents

Composition pharmaceutique à libération contrôlée à base de losartan

Info

Publication number
EP2571495A1
EP2571495A1 EP11720522A EP11720522A EP2571495A1 EP 2571495 A1 EP2571495 A1 EP 2571495A1 EP 11720522 A EP11720522 A EP 11720522A EP 11720522 A EP11720522 A EP 11720522A EP 2571495 A1 EP2571495 A1 EP 2571495A1
Authority
EP
European Patent Office
Prior art keywords
weight
losartan
pharmaceutical composition
core
immediate release
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Withdrawn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
EP11720522A
Other languages
German (de)
English (en)
Inventor
Antonio Sereno Guerra
David Loeches Blas
Roberto Varas Fernandez-Molina
Estibaliz Del Cura Medina
José Miguel Rizo Martínez
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.)
Laboratorios Liconsa SA
Original Assignee
Laboratorios Liconsa SA
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 Laboratorios Liconsa SA filed Critical Laboratorios Liconsa SA
Priority to EP11720522A priority Critical patent/EP2571495A1/fr
Publication of EP2571495A1 publication Critical patent/EP2571495A1/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Withdrawn legal-status Critical Current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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a pharmaceutical controlled release
  • composition of losartan to its preparation process and its use for the prophylaxis and/or treatment of hypertension.
  • Losartan is the International Nonproprietary Name of 2-butyl-4-chloro-1 -[[2'- (1 H-tetrazol-5-yl)[1 ,1 '-biphenyl]-4-yl]methyl]-1 H-imidazole-5-methanol.
  • Losartan is a non-peptide angiotensin II receptor antagonist (Type ATi) and its structure corresponds to formula (I):
  • Losartan is marketed as potassium losartan which is used in regulating hypertension alone or in combination with other antihypertensive agents, including diuretics. It is also indicated to reduce stroke and left ventricular hypertrophy in hypertensive patients. Losartan also show effects in the prevention and treatment of renal failure, myocardial infraction, arrhythmia, heart failure and diabetic complications such as nephropathy in type II diabetic patients, and in the prevention of atherosclerosis and cardiovascular diseases. Losartan is commercially available as tablets for oral administration containing from 25 mg to 100 mg of the active ingredient, alone or in combination with hydrochlorothiazide. The typically dosing regimens are either once-daily or twice-daily.
  • the terminal half-life of losartan and its active metabolite is about 2 hours and 6-9 hours respectfully, and their median maximum concentration is about 1 hour and 3-4 hours respectfully.
  • Losartan is readily orally absorbed in about 33% in the gastrointestinal tract, particularly in the upper parts of the small intestine where its absorption windows is located, otherwise losartan and its active metabolite are evacuated with the intestinal transit without being correctly absorbed.
  • Epidemiologic studies have shown that in patients with hypertension, blood pressure follows a highly reproducible circadian pattern characterized by a decrease of the blood pressure during sleep, and a rapid increase in the early morning period. Therefore, the early morning period has been associated with both loss of blood pressure control and increased rates of myocardial infarction and stroke, especially during the first 4 to 6 hours after awakening (Cf. William B. White. "Clinical assessment of early morning blood pressure in patients with hypertension". Preventive Cardiology. 2007 Fall, vol.10, pp. 173-4).
  • the total amount of the hydrophilic polymers is about 50% by the weight of the composition, taking into account that when a mixture of both hydroxypropyl methylcellulose and polyethylene oxide is used, the weight ratio between them is 50:50.
  • a pharmaceutical composition which comprises a gastric retained core comprising a pharmaceutically effective amount of losartan and hydroxypropyl methylcellulose (HPMC) as a unique controlled release polymer, that is without any other controlled release polymer, and an immediate release layer comprising a pharmaceutically effective amount of losartan, has an appropriate dissolution profile which allows having effective plasmatic concentrations over 24 hours, and avoids the evacuation of the unabsorbed active ingredient by the intestinal transit. It is advantageous for the reduction of the risk of cardiovascular accidents, and for having a better control of blood pressure. Besides, the compositions of the present invention are also advantageous because of its extended timing uptake allowing a reduction of the dose intake, thereby increasing the acceptance by the patients of the oral administered posologies.
  • HPMC hydroxypropyl methylcellulose
  • an aspect of the present invention refers to a pharmaceutical
  • composition which comprises a gastric retained core, and an immediate release layer, where: the core comprises a pharmaceutically effective amount of losartan, or its pharmaceutically acceptable salts, and an amount of hydroxypropyl methylcellulose comprised between 5 and 25% by the weight of the composition as a unique controlled release polymer, together with one or more pharmaceutically acceptable excipients or carriers; and the immediate release layer comprises a pharmaceutically effective amount of losartan, or its pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable excipients or carriers.
  • Another aspect of the present invention refers to a process for the preparation of the pharmaceutical composition as defined above, which comprises (a) mixing losartan or its pharmaceutically acceptable salts, with hydroxypropyl methylcellulose, a filler, and a binder, followed by adding a glidant and a lubricant; (b) mixing losartan or its pharmaceutically acceptable salts with a filler, a binder, followed by adding a lubricant; (c) compressing the mixture of step (a); and (d) compressing the mixture of step (b) over the resultant core of step (c) to yield a tablet.
  • Another aspect of the present invention relates to the pharmaceutical composition as defined above for use in the prophylaxis and/or treatment of hypertension.
  • FIG. 1 shows the dissolution profile of losartan from the pharmaceutical compositions of Examples 1 (A), 2(x), 3(0) and 4(B). Units of the scheme are as follows: %D is the percentage of losartan dissolved and t is time in minutes.
  • FIG. 2 shows the dissolution profile of losartan from the marketed immediate release pharmaceutical composition containing 100 mg of the active ingredient (Cozaar). Units of the scheme are as follows: %D is the percentage of losartan dissolved and t is time in minutes.
  • a “pharmaceutically effective amount” of losartan or its salts refers to that amount which provides a therapeutic effect in various administration regimens.
  • a “pharmaceutically acceptable salt” of losartan refers to those salts which are, within the scope of medical judgement, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “percentage (%) by weight” refers to the percentage of each ingredient of the pharmaceutical composition in relation to the total weight of the pharmaceutical composition.
  • controlled release or "controlled delivery” refer to a delivery of the drug at a predetermined rate and/or location according to the needs of the body and disease states for a definite time of period.
  • gastric retained refers to a delivery of the drug by dispersion throughout the polymer and has difficulty in diffusing out of the polymer matrix. Therefore, the biological fluid diffuses into the matrix and causes its outer polymer region to swell, allowing release of the drug entrapped inside the polymer at a predictable rate.
  • the retained gastric dosage form contains hydrophilic polymers that swell to a size such that the dosage form is retained in the fed mode.
  • hydrophilic polymer refers to the partition coefficient P, which is the ratio of the equilibrium concentration of a compound in an organic phase to that in an aqueous phase.
  • a hydrophilic compound has a P value less than 1 .0, typically less than about 0.5, where P is the partition coefficient of the compound between octanol and water.
  • P is the partition coefficient of the compound between octanol and water.
  • polymer refers to a molecule containing a plurality of covalently attached monomer units, and includes branched, dendrimeric, star, and linear polymers. The term also includes homopolymer and copolymers, as well as uncrosslinked polymers and from slightly to moderately or substantially crosslinked polymers.
  • fed mode or “fasted state” refers to the digestive mode of a normal digestive process. The fed mode is typically induced by the presence of food in the stomach giving rise to continuous and regular contractions per minute while the pylorus is partially open. The partial opening of the pylorus causes a sieving effect in which liquids and small particles flow continuously from the stomach into the intestine, while particles exceeding about 1 cm in size are retained for approximately 4 to 6 hours.
  • ratio refers to the relation of amount of losartan of the core and the amount of losartan in the immediate release layer needed to have effective amounts of the active ingredient.
  • filler refers to a material which is used to increase the bulk, improve consistency and improve the handle.
  • Materials commonly used as fillers include, but are not limited to, dextrose, lactose, lactose monohydrate, fructose, mannitol, microcrystalline cellulose, starch, pregelatinized starch, powdered cellulose, silicied cellulose, sorbitol, sucrose and talc, or mixtures thereof.
  • binder refers to a material which imparts cohesiveness to powdered materials improving free-flowing qualities in the manufacture of the solid dosage form.
  • Materials commonly used as binders include, but are not limited to, starch, gelatin, sugars, sodium alginate, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, and calcium
  • carboxymethylcellulose or mixtures thereof.
  • the binder used is microcrystalline cellulose.
  • glidant refers to a material which improves the flow characteristics of powder mixtures in the dry state.
  • Materials commonly used as a glidant include, but are not limited to, magnesium stearate, colloidal silicon dioxide, precipitated silica, and talc, or mixture thereof.
  • lubricant refers to a material which prevent from adhesion of the tablet material to the surface of dies and punches, reduce inter-particle friction, facilitate the ejection of the tablets from the die cavity, and may improve the rate of flow of the tablet granulation.
  • Materials commonly used as a lubricant include, but are not limited to, talc, alkaline earth salts of stearic acid such as magnesium and calcium stearate, stearic acid, glyceryl behanate,
  • an aspect of the present invention refers to a
  • composition which comprises a gastric retained core where the amount of HPMC is comprised between 5 and 25% by the weight of the composition as a unique controlled release polymer, together with one or more pharmaceutically acceptable excipients or carriers, and an immediate release layer, where both layers comprises pharmaceutically effective amount of losartan, or its pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical composition of the present invention which comprises a core that the amount of HPMC is comprised between 5 and 25% by weight of the composition as a unique controlled release polymer and an active immediate release layer allow having an appropriate dissolution profile of the active ingredient maintaining effective plasmatic concentrations for over 24 hours.
  • HPMC hydrophilic polymer
  • HPMC content of HPMC comprised between 5 and 25% by weight of the composition as a unique controlled release polymer in the core of the pharmaceutical composition of the present invention, allows a balance of these both processes, that is swelling and erosion, having an appropriate dissolution profile that maintain effective concentrations of the active ingredient for over 24h.
  • the pharmaceutical composition of the present invention allows the dissolution of losartan in a short period of time, due to the present of the active immediate release layer.
  • the dissolution rate of losartan related to the immediate release layer of the present invention is slower than the dissolution rate of the marketed product Cozaar (Example 6 table 1 and Fig. 2).
  • losartan in marketed tablets are dissolved in about 25 minutes, while in the composition of the present invention the content of the immediate release layer is dissolved in about 60 minutes.
  • the target dissolution profile comprises that at least 35% by weight of losartan is retained in the dosage form after 1 hour and at least 70% by weight of losartan is dissolved from the dosage form after 12 hours of its oral
  • the above-mentioned composition of the present invention is further coated with an outer inert immediate release film-coating.
  • This film-coating is formed by a water-soluble material to cover up the active ingredient possessing objectionable tastes or odors, or in protecting materials sensitive to oxidation.
  • appropriate polymers to prepare the film- coating include soluble alkyl- or hydroxyalkylcellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
  • the film-coating polymer is selected from the group consisting of low-substituted hydroxypropylcellulose (L-HPC), and hydroxypropyl methylcellulose (HPMC), or their mixtures.
  • the film-coating polymer can be accompanied by plasticizers such as triethylcitrate (TEC), polyethylene glycol (PEG), cetyl and stearyl alcohol; surface-active agents such as sodium lauryl sulphate, polysorbate and poloxamer; pigments such as titanium dioxide, iron sesquioxide; lubricants such as talc, magnesium stearate or glyceril monostearate, and mixtures thereof.
  • the film-coating comprises hydroxypropylcellulose, and hydroxypropyl methylcellulose as a polymers, and titanium dioxide as a pigment.
  • Losartan can be in form of pharmaceutically acceptable salt of organic acids, inorganic acids or metals.
  • inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid.
  • organic acids include methansulfonic acid, trifluoromethansulfonic acid, ethansulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, citric acid, oxalic acid, acetic acid and maleic acid, among others.
  • appropriate metals include alkaline or alkaline earth alkaline such as sodium, potassium, magnesium, and calcium, among others.
  • the pharmaceutically acceptable salt of losartan is potassium salt.
  • the amount of HPMC in the gastric retained core is comprised between 5 and 25% by weight of the composition as a unique controlled release polymer.
  • the amount of HPMC in the gastric retained core is comprised between 6 and 23% by weight of the composition.
  • the amount of HPMC in the gastric retained core is comprised between 7 and 20% by weight of the composition.
  • the amount of HPMC in the gastric retained core is comprised between 8 and 15% by weight of the composition.
  • the amount of HPMC in the gastric retained core is 13% by weight.
  • compositions of the present invention contain losartan both in the gastric retained core and in the active immediate-release layer.
  • the ratio between the amount of losartan in the core and the amount of losartan in the immediate release layer is comprised between 30:70 and 70:30.
  • the weight ratio between the amount of losartan in the core and the amount of losartan in the immediate release layer is comprised between 40:60 and 60:40.
  • the weight ratio between the amount of losartan in the core and the amount of losartan in the immediate release layer is 50:50.
  • the above-mentioned weight ratio contributes to ensure that losartan is released from the composition of the present invention with the target dissolution profile, in order to achieve and maintain effective concentrations for over 24 hours. It is known that losartan and its active metabolite have linear pharmacokinetic in a dose range comprised between 10 and 200 mg. In a preferred
  • the total amount of losartan is comprised between 50 and 200 mg. In a more preferred embodiment the total amount of losartan is comprised between 70 and 150 mg . Preferably, the total amount of losartan is 100 mg.
  • the pharmaceutical composition of the present invention can contain additional pharmaceutical excipients. The excipients must be selected from those that do not degrade the active ingredient in order to prepare the orally administrable pharmaceutical composition of the invention.
  • compositions defined above comprise pharmaceutically acceptable excipients or carriers appropriate for their oral administration.
  • the gastric retained core comprises a filler, a glidant, a lubricant, a binder, or their mixtures.
  • the immediate release layer could be formed by excipients which help the formation of the active layer around the gastric retained core.
  • the immediate release layer comprises a filler, a lubricant, a binder, or their mixtures.
  • the gastric retained core of the composition of the present invention comprises: 5-30% by weight of potassium losartan; 5-25% by weight of hydroxypropyl methylcellulose; 15-50% by weight of filler; 0.1 -10% by weight of lubricant; 0.1 -5% by weight of glidant; and 2-20% by weight of binder; and the immediate release layer comprises: 5-20% by weight of potassium losartan; 2-30% by weight of filler; 5-20% by weight of binder; and 0.1 -5% by weight of lubricant, being the sum of components of the composition 100%.
  • the gastric retained core of the composition of the present invention comprises: 8-20% by weight of potassium losartan; 8-15% by weight of hydroxypropyl methylcellulose; 15-45% by weight of filler; 0.1 -5% by weight of lubricant; 0.1 -2% by weight of glidant; and 8-15% by weight of binder; and the immediate release layer comprises: 8-15% by weight of potassium losartan; 9-23% by weight of filler; 8-15% by weight of binder; and 0.1 -2% by weight of lubricant, being the sum of components of the composition 100%.
  • the gastric retained core of the composition of the present invention comprises: 12.6% by weight of potassium losartan; 12.8% by weight of hydroxypropyl methylcellulose; 22.7% by weight of mannitol; 0.7% by weight of magnesium stearate; 0.2% by weight of colloidal silicon dioxide; and 10% by weight of microcrystalline cellulose; and the immediate release layer comprises: 12.6% by weight of potassium losartan; 13.2% by weight of microcrystalline cellulose; 5.2% by weight of pregelatinized maize starch; 6.4% by weight of lactose; and 0.2% by weight of magnesium stearate.
  • losartan is orally administered as a monotherapy for the treatment of hypertension at doses of 50, 100 and 150 mg once-daily or twice-daily. It is shown that 150 mg dose give not greater effect than 50-1 OOmg.
  • physiopathologic studies have demonstrated that the frequency of
  • losartan is more relevant than the administered amount to the control of the effectively of the treatment (cf. Alan H. Gradman et al. "A randomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension". Hypertension, 1995, vol. 25, pp. 1345-1350; Domenic A. Sica et al . "Clinical pharmacokinetics of losartan", Clinical Pharmacokinet, 2005, vol. 44, pp. 797-814).
  • the pharmaceutical composition of the present invention is administered once-daily. This regimen is advantageous because allows a better control of the blood pressure and cardiovascular disorders, a simplicity of the oral administered posologies, together with a better
  • the pharmaceutical composition of the present invention can be prepared by conventional techniques that are well known in the pharmaceutical industry.
  • the gastric retained core and the immediate release layer can for example be fabricated by direct compression in punches and dies fitted to a rotary tablet press, or by ejection or compression molding, granulation followed by compression, or the formation of a paste that is then extruded into a mold or into an extrude which is then cut into short lengths.
  • the outer inert immediate release film-coating can be applied as a coating over the immediate release layer spraying, dipping, or pan-coating.
  • compositions of the present invention can be prepared by a process which comprises: which comprises: (a) mixing losartan or its pharmaceutically acceptable salts, with hydroxypropyl methylcellulose, a filler, and a binder, followed by adding a glidant, and a lubricant; (b) mixing losartan or its pharmaceutically acceptable salts with a filler, a binder, followed by adding a lubricant; (c) compressing the mixture of step (a); and (d) compressing the mixture of step (b) over the resultant core of step (c) to yield a tablet.
  • both compression steps of the gastric retained core and the immediate release layer is carried out by direct compression
  • step (d) comprising coating the tablets of step (d) by spraying an aqueous suspension which comprises an immediate release film-coating polymer; and drying the film-coating layer formed.
  • composition defined above for use in the prophylaxis and/or treatment of hypertension is also part of the invention.
  • This aspect could be also formulated as the use of the
  • Example 1 Tablet composition is as follow:
  • Hydroxypropyl cellulose 40.00 1 .16
  • immediate- methylcellulose 40.00 1 .16 release film- HPMC-606
  • TOTAL 100 100 means "as needed”; * Water removed after processing
  • Example 2 Tablet composition is as follow:
  • Hydroxypropyl cellulose 40.00 1 .16
  • immediate- methylcellulose 40.00 1 .16 release film- HPMC-606
  • TOTAL 100 100 means "as needed”; * Water removed after processing
  • Example 3 Tablet composition is as follow:
  • Hydroxypropyl cellulose 40.00 1 .16
  • immediate- methylcellulose 40.00 1 .16 release film- HPMC-606
  • TOTAL 100 100 means "as needed”; * Water removed after processing
  • Example 4 Tablet composition is as follow:
  • Hydroxypropyl cellulose 40.00 1 .16
  • Example 5 Process for the manufacture of the tablets of Examples 1 -4 5.1 . Process for the manufacture of the tablets of Example 4
  • Step 1 Potassium losartan, lactose and magnesium stearate were separately sieved through a sieve of 600 ⁇ .
  • Step 2 In a Cyclops mixer lactose and microcrystalline cellulose were added, and the resultant mixture was blended during 10 min. The resultant mixture of step 1 was removed from the mixer and stored in a polyethylene bag.
  • Step 3 In the Cyclops mixer potassium losartan and pregelatinized starch were successively added, and the resultant mixture was blended during 10 min. After that time, mixture of step 2 was added, and the resultant mixture was blended during 30 min. Magnesium stearate was finally incorporated, and blended during 5 min to obtain Mixture B.
  • Mixture A and mixture B were compressed to provide tablets of potassium losartan whose core contains mixture A and the immediate release layer contains mixture B.
  • Tablets were compressed on a Fette 102i rotary tablet press.
  • the rotor speed was 25.000 tablets per hour, and the compression force was about 1 .3KN for mixture A and 10KN for mixture B.
  • Obtained tablets had a median hardness of 100N and ⁇ 1 % of friability.
  • Titanium dioxide was added to the obtained dissolution and blended during 30 min. Finally, the obtained suspension was settled for 1 hour with an agitation pressure of 0.5 ⁇ 0.1 Bar. The film-coating were performed using a coating pan, at feed air temperature of 40 °C. The sprayed flow rate is 20 g/min. The final total weight of obtained tablets is 393 mg ⁇ 2. 5.2. Process for the manufacture of the tablets of Examples 1 -3
  • Example 6 Dissolution profile.
  • the target dissolution profile requires that the pharmaceutical composition of the present invention is swelled and retained under the stomach conditions where losartan is dissolved, and that the therapeutic concentration is achieved in the upper parts of the small intestine for a period of time about 24 hours.
  • the dissolution test was carried out to a solution of 900 ml_ at 37°C and at 50 rpm using a Pharmatest (PTWS, Germany) as a dissolution apparatus II USP according to the conditions described in the USP30 Pharmacopoeia.
  • Example 1 contains 22.32% HPMC in the core
  • Pharmaceutical composition of Example 2 contains 12.86% HPMC in the core
  • Pharmaceutical composition of Example 3 contains 9.08% HPMC in the core.
  • Pharmaceutical composition of Example 4 contains 6.05% HPMC in the core.
  • Comparative pharmaceutical composition of Cozaar contains 100 mg of potassium losartan, and HPMC in tablets of immediate release dosage form.
  • the dissolution profile results in Table 1 show that the pharmaceutical composition of the invention (Examples 1 -4) which comprises an amount of HPMC comprised between 5 and 25% by weight as a unique controlled release polymer in the gastric retained core and an active immediate release layer have the required dissolution profile.
  • the dissolution of losartan comprises that at least 35% by weight of losartan is retained in the dosage form after 1 hour and at least 70% by weight of losartan is dissolved from the dosage form after 12 hours after being orally administered.
  • Comparative pharmaceutical composition of Cozaar (not using HPMC as a controlled release polymer) gives rise to a different dissolution profile in comparison with the percentage of the weight of losartan which is dissolved by the immediate release layer.
  • Domenic A Sica et al. "Clinical pharmacokinetics of losartan", Clinical Pharmacokinet, 2005, vol . 44, pp. 797-814.

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Abstract

La présente invention concerne une composition pharmaceutique à libération contrôlée à base de losartan comprenant un noyau central gastrorésistant contenant du losartan et une quantité comprise entre 5 et 25 % en poids d'hydroxypropylméthylcellulose qui constitue l'unique polymère assurant la libération contrôlée. Ladite composition comprend également une couche active à libération immédiate contenant du losartan. L'invention concerne, en outre, le procédé de préparation de ladite composition et son utilisation en vue de la prophylaxie et du traitement de l'hypertension.
EP11720522A 2010-05-21 2011-05-20 Composition pharmaceutique à libération contrôlée à base de losartan Withdrawn EP2571495A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11720522A EP2571495A1 (fr) 2010-05-21 2011-05-20 Composition pharmaceutique à libération contrôlée à base de losartan

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP10382135A EP2392318A1 (fr) 2010-05-21 2010-05-21 Composition pharmaceutique à libération prolongée du losartan
PCT/EP2011/058229 WO2011144724A1 (fr) 2010-05-21 2011-05-20 Composition pharmaceutique à libération contrôlée à base de losartan
EP11720522A EP2571495A1 (fr) 2010-05-21 2011-05-20 Composition pharmaceutique à libération contrôlée à base de losartan

Publications (1)

Publication Number Publication Date
EP2571495A1 true EP2571495A1 (fr) 2013-03-27

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EP10382135A Withdrawn EP2392318A1 (fr) 2010-05-21 2010-05-21 Composition pharmaceutique à libération prolongée du losartan
EP11720522A Withdrawn EP2571495A1 (fr) 2010-05-21 2011-05-20 Composition pharmaceutique à libération contrôlée à base de losartan

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP10382135A Withdrawn EP2392318A1 (fr) 2010-05-21 2010-05-21 Composition pharmaceutique à libération prolongée du losartan

Country Status (7)

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EP (2) EP2392318A1 (fr)
AR (1) AR081400A1 (fr)
BR (1) BR112012029565A2 (fr)
MX (1) MX2012013362A (fr)
TW (1) TW201201800A (fr)
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WO (1) WO2011144724A1 (fr)

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WO2018002673A1 (fr) * 2016-07-01 2018-01-04 N4 Pharma Uk Limited Nouvelles formulations d'antagonistes du récepteur de l'angiotensine ii
CN119112811A (zh) * 2016-08-29 2024-12-13 北京科信聚润医药科技有限公司 一种氢氯噻嗪微片及其制备方法
IT201800011123A1 (it) 2018-12-14 2020-06-14 Dpl Pharma S P A Composizioni farmaceutiche orali solide per la somministrazione cronotropica di sartani

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US7413751B2 (en) 2001-10-25 2008-08-19 Depomed, Inc. Methods of treatment using a gastric retained losartan dosage
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MX2009004681A (es) * 2006-10-30 2009-08-19 Hanall Pharmaceutical Co Ltd Composicion compleja de liberacion controlada que comprende bloqueadores del receptor de angiotensina ii e inhibidores de hmg-coa-reductasa.

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EP2392318A1 (fr) 2011-12-07
WO2011144724A1 (fr) 2011-11-24
TW201201800A (en) 2012-01-16
AR081400A1 (es) 2012-08-29
UY33393A (es) 2011-12-30
BR112012029565A2 (pt) 2016-12-13
MX2012013362A (es) 2013-05-01

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