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WO2008147245A2 - Composition pharmaceutique de proxodolol à libération contrôlée - Google Patents

Composition pharmaceutique de proxodolol à libération contrôlée Download PDF

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Publication number
WO2008147245A2
WO2008147245A2 PCT/RU2007/000619 RU2007000619W WO2008147245A2 WO 2008147245 A2 WO2008147245 A2 WO 2008147245A2 RU 2007000619 W RU2007000619 W RU 2007000619W WO 2008147245 A2 WO2008147245 A2 WO 2008147245A2
Authority
WO
WIPO (PCT)
Prior art keywords
proxodolol
pharmaceutical composition
composition according
hypromellose
following number
Prior art date
Application number
PCT/RU2007/000619
Other languages
English (en)
Russian (ru)
Other versions
WO2008147245A3 (fr
Inventor
Sergei Danilovich Juzhakov
Robert Georgievich Glushkov
Viktor Vladimirovich Chistyakov
Natalya Vyacheslavovna Aristovskaya
Original Assignee
Otkrytoe Aktsionernoe Obschestvo 'otechestvennye Lekarstva'
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 Otkrytoe Aktsionernoe Obschestvo 'otechestvennye Lekarstva' filed Critical Otkrytoe Aktsionernoe Obschestvo 'otechestvennye Lekarstva'
Publication of WO2008147245A2 publication Critical patent/WO2008147245A2/fr
Publication of WO2008147245A3 publication Critical patent/WO2008147245A3/fr

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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
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the field of pharmacy.
  • the invention relates to a new controlled release preparation based on the active ingredient of proxodolol or its pharmaceutically acceptable salts.
  • Proxodolol or butylamine hydroxypropoxyphenoxymethyl methyloxadiazole has the chemical name 5 - [2 - (3 - tert - butylamino - 2 - hydroxypropoxy) phenoxymethyl] - 3 - methyl - 1, 2, 4 - oxadiazole hydrochloride and the structural formula:
  • Proxodolol or butylamine hydroxypropoxyphenoxymethyl methyloxadiazole may be used in the form of a base or pharmaceutically acceptable salts.
  • Proxodolol is a non-selective alpha and beta blocker; It has a hypotensive, antianginal and antiarrhythmic effect (refers to class II antiarrhythmics).
  • Proxodolol is available in the form of tablets, solution for injection and eye drops. The indicated dosage forms are used according to the following indications - arterial hypertension, angina pectoris (prophylaxis), arrhythmias; compensated chronic heart failure (in the composition
  • proxodolol is available commercially only in the form of immediate release tablets or drops (Drug Encyclopedia 2005, p.736).
  • the use of proxodolol in the form of eye drops is described, for example, in RF patents ⁇ N22173123, 2128486, 2191013.
  • proxodolol orally at 10 mg 3-4 times a day, with good tolerance, the dose is gradually increased by 10-20 mg / day, to a daily dose of 80-120 mg, the maximum daily dose is 240 mg.
  • Retardation (delayed release of active substances), including pharmacologically active substances with a relatively short half-life in the body, allows you to get the appropriate composition of prolonged action and due to a more even level in the blood to avoid, in addition, side effects, as well as improve the accuracy of patients dosage instructions.
  • Controlled release dosage forms are known in the art.
  • RF patent N ° 2127587 describes a method for preparing a solid dosage form for oral administration, comprising preparing a solid substrate containing the active ingredient, preparing an aqueous dispersion of an acrylic copolymer, coating
  • the coating provides controlled release of the active ingredient.
  • an acrylic copolymer a plasticized mixture of ammonium methacrylate copolymers, which are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, is used.
  • the coating applied to the substrate is cured at a temperature above the glass transition temperature of the plasticized mixture of acrylic copolymers for at least 24 hours.
  • Retardation of pharmaceutically active substances can also be achieved through the formation of special granules.
  • Such particles contain a sugar-based core, the therapeutic material can be incorporated directly into it, or sprayed on top, or distributed differently over the surface of the particle.
  • the particles are then coated with a suitable coating material, such as wax or varnish.
  • the release of therapeutic material upon coating failure is controlled by adjusting the coating thickness or coating composition. Examples of therapeutic formulations of collapsible particles are disclosed in US Pat. No. 3,939,259.
  • These formulations are prepared by placing a portion of the uncoated particles containing a therapeutically active material in a rotating vat and contacting the particles with a sufficient amount of a coating solution, namely a zein shellac solution , for coating granules. The coating operation is repeated until the zein-alkali coating reaches a suitable thickness in order to prevent destruction during a selected period of time after ingestion. Groups of particles with different coatings intended for disintegration at different times are combined into capsules or tablets, thereby producing modified release therapeutic preparations of the active ingredient.
  • a coating solution namely a zein shellac solution
  • SUBSTITUTE SHEET (RULE 26) requirements.
  • the release rate of the active substance depends on the ionic strength. A change in ionic strength can even lead to the so-called dose dumping. In this case, the entire amount of the active substance is released in a very short time, which can lead to undesirable and even dangerous high levels of the active substance in the blood.
  • controlled-release proxodolol dosage forms can be prepared efficiently and conveniently using a mixture of one or more swelling or gelling components, an active ingredient and a pharmaceutically acceptable excipient.
  • the drug provides immediate release of part of the dose of the active substance necessary to create a therapeutic effect, the rest is released for a long time.
  • the objective of the invention is the creation of an effective dosage form with controlled release, with stable kinetic indicators of delivery of the active substance and allowing to maintain the stability of proxodolol over a long shelf life.
  • the present invention provides controlled release compositions comprising: a) an active ingredient consisting of proxodolol or a pharmaceutically acceptable salt thereof; b) at least one swellable or gelling component; c) suitable excipients.
  • suitable swelling or gelling agents include: polyvinylpyrrolidone, polyethylene oxide, polymers or copolymers of acrylic acid, polyethylene glycols, alginates, cellulose and derivatives (ethers and salts). Hydroxypropyl cellulose, in particular hypromellose (METNOCEL®) or hypromellose (BENECEL® MP 824), is particularly preferred.
  • SUBSTITUTE SHEET substances, disintegrants, binders, diluents, colorants and the like.
  • the following substances can be used: dextrin, lactose, microcrystalline cellulose, calcium stearate, silicon dioxide, sucrose, glucose, sodium chloride, starch, sodium bicarbonate, crospovidone, magnesium stearate, water, silica gel, sodium chloride, talc, glycine, polyethylene oxide , aerosil, gelatin, mannitol, sorbitol, titanium dioxide.
  • a significant advantage of the proposed composition is the ability to prepare solid dosage forms using conventional and inexpensive methods. For example, tabletting after preliminary wet granulation. After this, the tablets can be film-coated by conventional methods.
  • Opadray II can be used: polyvinyl alcohol, macrogol, titanium dioxide E 171, talc.
  • composition per tablet proxodolol 120 mg
  • Hypromellose (METNOSEL®) - 0.0015 g
  • the mass of the tablet core 0.25 g
  • Tests of drugs were carried out according to an open, randomized and cross-sectional scheme. Each rabbit alternately received the test drug (one 120 mg tablet) and the comparison drug (3 tablets of 40 mg) once. The time interval between taking medications is
  • SUBSTITUTE SHEET (RULE 26) Sample selection. Blood samples in a volume of 1.5 ml were taken from the ear vein of rabbits in polypropylene tubes before use of the drug (zero sample) and 0.25, 0.5, 0.67, 1, 1.5, 2, 3, 4 (6, 8, 24, 30) hours after administration proxodolol (prolonged proxodolol). After centrifugation at 14 TWQ. 0.5 ml of serum were taken rpm, frozen and stored until analysis at a temperature of -20 0 C.
  • the method of extracting the drug 100 ⁇ l of 2.5 N NaOH was added to 500 ⁇ l of blood serum, 4 ml of chloroform was extracted with vigorous shaking. After centrifugation, the organic layer was separated and evaporated to dryness under a stream of nitrogen. The residue was dissolved with shaking in 100 ⁇ l of sodium pentyl sulfonate solution (pH 3), 50 ⁇ l was introduced into the chromatographic column. The recovery of proxodolol from serum was 80%. The detection limit is 0.03 ⁇ g / ml serum.
  • Tables 1 and 2 show the concentrations of proxodolol ( ⁇ g / ml) in the blood serum of rabbits when taking the compared dosage forms, calculated average values, standard errors and confidence (95%) intervals.
  • proxodolol Concentrations of proxodolol ( ⁇ g / ml) when using proxodolol tablets prolonged at a dose of 43.6 mg / kg
  • proxodolol Concentrations of proxodolol ( ⁇ g / ml) when using standard proxodolol tablets at a dose of 43.6 mg / kg
  • Table 3 and 4 show the main pharmacokinetic parameters of Smake, Tmax, MRT, AUC, etc., calculated from concentration curves, reflecting the degree, absorption rate and elimination of the drug when using the compared dosage forms of proxodolol.
  • Pharmacokinetic parameters of prolonged proxodolol
  • the concentration profile of proxodolol when using prolonged-release tablets (with controlled release) is significantly different from the pharmacokinetic curve obtained when using proxodolol tablets.
  • the maximum concentration (Smake) of proxodolol is recorded after 0.73 hours from the moment of administration of proxodolol, for a prolonged form - after 1.5 hours.
  • the average Smake value for proxodolol is 0.87 ⁇ g / ml, for the prolonged form - 0.51 ⁇ g / ml.
  • the mean retention time (MRT) parameter was 3.2 and 17.2 hours, respectively. Significant differences are also observed in the AUC parameter, which reflects the degree of absorption.
  • AUC 0- ⁇ is 5.15, for the comparison drug - 1.82 mcg / ml / hour.
  • the ratios of the values of the maximum concentrations to the areas under the Smaks / AUS pharmacokinetic curve (parameter reflecting the absorption rate) for the test and reference tablets are 0.122 and 0.635 h, respectively, 1 i.e., the absorption rate of the reference drug is higher than that of prolonged form.
  • Relative bioavailability calculated as the ratio of the areas under the concentration-time pharmacokinetic curves (AUC), at
  • AUC Proxodolol i.e. when using the dosage form of proxodolol with a modified release, the degree of absorption of the drug increases by 3 times.
  • proxodolol from a prolonged dosage form is characterized by a slower absorption from the gastrointestinal tract (with a decrease in maximum concentrations), a significant increase in the degree of absorption and a prolongation of the circulation period of the drug in the bloodstream (14.8 versus 2.4 hours).
  • Use Opadray II (series 85) (ND 42-14219-06): polyvinyl alcohol, macrogol, titanium dioxide E 171, talc. The coating is carried out until a tablet with a shell weighing 0.257 g.
  • proxodolol when administered orally at a dose of 50 mg / kg (dose corresponding to an ED50 2 hours after administration) provides an effective blockade of beta-adrenergic receptors (blocking the positive chronotropic and depressant effects of isoproterenol by at least 25%) for 8 hours.
  • a comparative study of beta-adrenergic blocking activity and duration of action of controlled-release proxodolol tablets (120 mg each), conventional tablets (40 mg each) and the substance of the drug was carried out when used in ze 150 mg / kg.
  • SUBSTITUTE SHEET (RULE 26) the chronotropic effect of isoproterenol. It was found that 2 hours after oral administration of proxodolol tablets of 120 mg, ordinary tablets of 40 mg and the substance of the drug in the same dose (150 mg / kg), the positive chronotropic effect of isoproterenol is blocked on average, respectively, by 92.65 and 100% and 24 hours after the administration of the studied drugs by 69.27 and 23%
  • proxodolol preparation provides an effective blockade of beta-adrenergic receptors within 24 hours after its administration, which gives reason to attribute it to long-acting beta-blockers.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention relève du domaine de la médecine et en particulier de la pharmacie et concerne spécifiquement une nouvelle préparation présentant des caractéristiques cinétiques stables quant à l'administration d'une substance active. Les formes médicamenteuses de proxodolol à libération contrôlée peuvent être préparées efficacement et facilement au moyen d'un mélange composé d'un ou plusieurs composants de gonflement ou gélifiants, d'un ingrédient actif et d'une charge pharmaceutiquement acceptable. On utilise de préférence une préparation se présentant sous la forme de comprimés contenant 120 mg de proxodolol, de l'hypromellose et des charges pharmaceutiquement acceptables telles que la cellulose microcristalline, le stéarate de calcium et l'aérosil. Les nouvelles formes pharmaceutiques à libération de proxodolol appropriée permettent de réduire le nombre de prises quotidiennes tout en maintenant constante la teneur en ingrédient actif dans une dose thérapeutique.
PCT/RU2007/000619 2007-06-01 2007-11-13 Composition pharmaceutique de proxodolol à libération contrôlée WO2008147245A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2007120431 2007-06-01
RU2007120431/15A RU2356532C2 (ru) 2007-06-01 2007-06-01 Фармацевтическая композиция проксодолола с контролируемым высвобождением

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WO2008147245A2 true WO2008147245A2 (fr) 2008-12-04
WO2008147245A3 WO2008147245A3 (fr) 2009-06-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9459187B2 (en) 2011-03-04 2016-10-04 Becton, Dickinson And Company Blood collection device containing lysophospholipase inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014070A1 (fr) * 1994-11-02 1996-05-17 Janssen Pharmaceutica N.V. Compositions orales a liberation prolongee a base de cisapride
WO2000021525A2 (fr) * 1998-10-14 2000-04-20 Novartis Ag Composition pharmaceutique a liberation durable et procede de liberation d'un agent pharmaceutiquement actif

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014070A1 (fr) * 1994-11-02 1996-05-17 Janssen Pharmaceutica N.V. Compositions orales a liberation prolongee a base de cisapride
WO2000021525A2 (fr) * 1998-10-14 2000-04-20 Novartis Ag Composition pharmaceutique a liberation durable et procede de liberation d'un agent pharmaceutiquement actif

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9459187B2 (en) 2011-03-04 2016-10-04 Becton, Dickinson And Company Blood collection device containing lysophospholipase inhibitor
RU2623049C2 (ru) * 2011-03-04 2017-06-21 Бектон, Дикинсон энд Кампани Устройство для взятия крови, содержащее ингибитор лизофосфолипазы

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Publication number Publication date
WO2008147245A3 (fr) 2009-06-04
RU2356532C2 (ru) 2009-05-27
RU2007120431A (ru) 2008-12-10

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