[go: up one dir, main page]

WO2011126352A2 - Médicament contre la tuberculose sur la base d'un complexe d'inclusion de cyclodextrine et de rifampicine ainsi qu'un procédé de fabrication correspondant. - Google Patents

Médicament contre la tuberculose sur la base d'un complexe d'inclusion de cyclodextrine et de rifampicine ainsi qu'un procédé de fabrication correspondant. Download PDF

Info

Publication number
WO2011126352A2
WO2011126352A2 PCT/KZ2011/000004 KZ2011000004W WO2011126352A2 WO 2011126352 A2 WO2011126352 A2 WO 2011126352A2 KZ 2011000004 W KZ2011000004 W KZ 2011000004W WO 2011126352 A2 WO2011126352 A2 WO 2011126352A2
Authority
WO
WIPO (PCT)
Prior art keywords
rifampicin
isoniazid
inclusion complex
mixture
sensitive polymer
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.)
Ceased
Application number
PCT/KZ2011/000004
Other languages
English (en)
Russian (ru)
Other versions
WO2011126352A3 (fr
Inventor
Кунназ Баймухановна МУРЗАГУЛОВА
Турарбек Амирханович РАКИШ
Марина Емельяновна КИМ
Калдыбай Джайловович ПРАЛИЕВ
Кайрат Мирзасалимович БЕКЕТО
Жанболат Илесович РУСТЕМБЕКОВ
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.)
Joint-Stock Co "ab Bekturov's Institute Of Chemical Sciences"
ROMAT PHARMACEUTICAL Co Ltd
Original Assignee
Joint-Stock Co "ab Bekturov's Institute Of Chemical Sciences"
ROMAT PHARMACEUTICAL Co Ltd
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 Joint-Stock Co "ab Bekturov's Institute Of Chemical Sciences", ROMAT PHARMACEUTICAL Co Ltd filed Critical Joint-Stock Co "ab Bekturov's Institute Of Chemical Sciences"
Priority to EA201201098A priority Critical patent/EA201201098A1/ru
Publication of WO2011126352A2 publication Critical patent/WO2011126352A2/fr
Publication of WO2011126352A3 publication Critical patent/WO2011126352A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • Anti-tuberculosis drug based on the inclusion complex of cyclodextrin with rifampicin and the method for its preparation
  • the invention relates to the pharmaceutical industry and can be used in medical institutions for the treatment of tuberculosis.
  • the disadvantage of this tool is its high toxicity (LD 5 o 280 mg / kg in rats) due to the simultaneous dissolution of rifampicin and isoniazid in the acidic environment of the stomach, leading to the formation of a toxic product of their interaction - isonicotylhydrazone rifampicin.
  • a drug for oral administration comprising a cyclodextrin inclusion complex (CC) with rifampicin and a CD inclusion complex with isoniazid in amounts of 5 to 50% of the total weight of rifampicin and isoniazid, respectively, and an additional orange dye and sweetener aspartame, as well as a method for its preparation, including processing cyclodextrin with rifampicin and treatment with cyclodextrin with isoniazid, then mixing the resulting inclusion complexes — CD with rifampicin, CD with isoniazid, followed by the addition of a dye and sweetener and packaging dry mix in sachets (application PCT / WO jNb 2005/074937, class A 61K 31/4965, 2005).
  • CC cyclodextrin inclusion complex
  • CD inclusion complex with isoniazid in amounts of 5 to 50% of the total weight of rifampicin and isoniazid, respectively, and an additional orange dye and
  • An object of the invention is to provide an anti-tuberculosis drug for oral administration that meets the standards of DOTs, a treatment acceptable to both adults and children, and a method for its preparation.
  • the technical result consists in minimizing the first stage of drug absorption while maintaining the bioavailability of rifampicin (complete dissolution of rifampicin) with toxicity (LD ⁇ 5000 mg / kg).
  • the technical result is achieved by an anti-TB drug consisting of two antibacterial components, the first of which is a inclusion complex of CD with rifampicin in a molar ratio of 1: 1, and the second is granular isoniazid with a pH-sensitive polymer, excipients and a mixture of moving substances (aerosil and calcium or magnesium stearate in their weight ratio 1: 1) in the following ratio of components, mg:
  • auxiliary substances use a sweetener, disintegrator, hepatoprotector, antioxidant in the following content, wt.% from the average weight of the tablet:
  • antioxidant - 0.43 - 1.25 as well as a method for its production, including treatment of CD with rifampicin, granulation of isoniazid with a pH-sensitive polymer with further mixing of the CD inclusion complex with rifampicin with granulated isoniazid, sweetener, disintegrator, hepatoprotector, antioxidant and dusting the resulting intermediate with a mixture of moving substances (aerosil and calcium or magnesium stearate 1: 1) and tableting.
  • all components are administered in the following ratio, mg:
  • the molar ratio in the inclusion complex of cyclodextrin with rifampicin is 1: 1
  • the second antibacterial agent is granular isoniazid with a pH-sensitive polymer, and as an auxiliary substance, a disintegrator, hepatoprotector, antioxidant and dusting the intermediate add a mixture of moving substances (calcium or magnesium stearate and aerosil 1: 1) at the claimed ratios.
  • the proposed method for the preparation of the drug differs from the prototype method in the molar ratio of the CD inclusion complex with rifampicin, granulation of isoniazid with a pH-sensitive polymer and further mixing with additionally introduced auxiliary substances - disintegrator, hepatoprotector, antioxidant and followed by dusting with a mixture of moving substances, taking into account the claimed ratios and further tableting of the intermediate.
  • a pH-sensitive polymer As a pH-sensitive polymer, a mixture of Eudragit L100 and polyvinyl acetate phthalate or shellac is used. Mannitol or aspartame are used as a sweetener, sodium croscarmellose or crospovidone of the Polyplasdon XL-10 brand are used as a disintegrant, ascorbic acid or vitamin E or succinic acid are used as antioxidants, and bifendate is used as a hepatoprotector.
  • Mannitol or aspartame are used as a sweetener
  • sodium croscarmellose or crospovidone of the Polyplasdon XL-10 brand are used as a disintegrant
  • ascorbic acid or vitamin E or succinic acid are used as antioxidants
  • bifendate is used as a hepatoprotector.
  • Example 1 Consistently sift all the components of the claimed drug.
  • 300 g of isoniazid with 40 g of Eudragit L 100 and 28 g of polyvinyl acetate phthalate are granulated, the granules are mixed in a high-speed mixer - granulator with 1430 g of the previously prepared cyclodextrin complex with rifampicin in a 1: 1 molar ratio for 8 minutes, then 780 g are added sequentially.
  • excipients 320 g of mannitol, 340 g of crospovidone brand Polyplasdon XL-10, 20 g of bifendate, 30 g of ascorbic acid and mixed for another 8 minutes, then the resulting mixture is poured into a double cone mixer, 50 g of a mixture of sliding substances are added (25 g of Aerosil and 25 g of magnesium stearate) and dust the intermediate for 20 minutes.
  • the mass content of auxiliary substances for a specific example with an average tablet weight of 255 mg is, wt.%: Mannitol - 12.15; crospovidone brand Polyplasdon XL-10 -13.33, bifendate -0.78, ascorbic acid - 1.17.
  • the obtained granulate is subjected to tabletting on a Manesta rotary tablet press, achieving the necessary technological parameters of the tablet — strength not less than 97.0%, disintegration less than 3 minutes, average tablet weight within normal limits.
  • the toxicity (LD 5 o on white mice and rats) of the claimed drug is 5000 mg / kg, the dispersion time is 20 s, and the dissolution of rifampicin reaches 100% in 0.1 M HCl in 15 minutes.
  • table 1 aspartame is used as a sweetener, in examples 5, 10, as a pH-sensitive shellac polymer, in examples 4, 7, a mixture of calcium stearate and aerosil is used as a moving substance, in example 9, croscarmellose sodium is used as a disintegrant, in example 10 as an antioxidant is vitamin E, in example 11, succinic acid, and in the remaining examples, analogously to example 1 described above.
  • the claimed drug allows you to minimize the first stage of its absorption while maintaining the bioavailability of rifampicin due to the dispersibility of the target product, the complete and separate dissolution of rifampicin and isoniazid in different environments of the gastrointestinal tract.
  • the proposed anti-tuberculosis drug based on the inclusion complex of cyclodextrin with rifampicin under the conditional code RIZEF-D passed preclinical tests in the laboratory of preclinical trials of the National Center for Examination of Medicines for acute toxicity and bioavailability of rifampicin.
  • Acute toxicity studies are carried out in accordance with the approved protocol ° D-09-27 / b on white outbred adult mice of both sexes weighing 25.0-30.0 g and rats of both sexes weighing 150.0-200.0 g.
  • a criterion Acceptable randomization is considered the absence of external signs of the disease and the homogeneity of the groups according to body weight ( ⁇ 20%).
  • body weight ⁇ 20%.
  • Table 2 presents data on groups of experimental animals for the study of acute toxicity of RIZEF-D.
  • mice With the introduction of the studied drug RIZEF-D at a dose of 5000 mg / kg, two of the six animals fell to mice, which is 33.3%. In the animal JSTe 6, by the end of the study, a decrease in body weight of 0.3 g was observed. The average total weight gain in the experimental group was +1.4. The increase in body weight in the experimental group of mice exceeded that of the control group by +0.3 g.
  • the inventive drug RIZEF-D-dispersible tablets are classified as low-toxic drugs, because their LD50 exceeds 5000 mg / kg for both animal species.
  • the average comparative pharmacokinetic profile of rifampicin in the blood plasma of rabbits after a single oral administration of RIZEF-D 60/30 (T) and RIFAHTI GN 60 mg (R) is shown in FIG. 1.
  • the time (t) per hour is indicated on the X axis, the maximum concentration of drugs C max in ⁇ g / ml on the ordinate axis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Medical Informatics (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Pulmonology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un médicament contre la tuberculose sur la base d'un complexe d'inclusion de cyclodextrine et de rifampicine ainsi qu'un procédé de fabrication correspondant. Cette invention se rapport à l'industrie pharmaceutique et peut s'utiliser dans des établissements médicaux pour traiter la tuberculose. Le médicament est constitué d'un complexe d'inclusion de cyclodextrine et de rifampicine avec un rapport molaire 1 :1, d'isoniazide granulé avec un polymère sensible au pH, de substances auxiliaires, à savoir un édulcorant, un désintégrateur, un hépatoprotecteur, un antioxydant et un mélange de substances lubrifiantes, à savoir un stéarate de calcium ou de magnésium et une silice sublimée, avec un rapport déclaré des composants; il permet de réduire au minimum la première étape d'absorption du médicament tout en préservant la biodisponibilité de la rifampicine à faible toxicité (dose limite (50) 5000 mg/kg) et, partant, de l'administrer aux patients, enfants ou adultes.
PCT/KZ2011/000004 2010-04-07 2011-03-29 Médicament contre la tuberculose sur la base d'un complexe d'inclusion de cyclodextrine et de rifampicine ainsi qu'un procédé de fabrication correspondant. Ceased WO2011126352A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EA201201098A EA201201098A1 (ru) 2010-04-07 2011-03-29 Противотуберкулезный препарат на основе комплекса включения циклодекстрина с рифампицином и способ его получения

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KZ2010/0417.1 2010-04-07
KZ20100417 2010-04-07

Publications (2)

Publication Number Publication Date
WO2011126352A2 true WO2011126352A2 (fr) 2011-10-13
WO2011126352A3 WO2011126352A3 (fr) 2011-12-01

Family

ID=44763441

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KZ2011/000004 Ceased WO2011126352A2 (fr) 2010-04-07 2011-03-29 Médicament contre la tuberculose sur la base d'un complexe d'inclusion de cyclodextrine et de rifampicine ainsi qu'un procédé de fabrication correspondant.

Country Status (2)

Country Link
EA (1) EA201201098A1 (fr)
WO (1) WO2011126352A2 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA02003596A (es) * 2000-08-09 2003-10-14 Panacea Biotec Ltd Composiciones farmaceuticas novedosas de farmacos anti tubercular y procedimiento para su preparacion.
US7001893B2 (en) * 2002-10-28 2006-02-21 Council Of Scientific And Industrial Research Inclusion complex of Rifampicin, an anti-tubercular drug, with β-cyclodextrin or 2-hydroxypropyl β-cyclodextrin and a process thereof

Also Published As

Publication number Publication date
EA201201098A1 (ru) 2013-03-29
WO2011126352A3 (fr) 2011-12-01

Similar Documents

Publication Publication Date Title
NZ503766A (en) Pharmaceutical preparation comprising clodronate as active ingredient and silicified microcrystalline cellulose as excipient
JP5517938B2 (ja) 安定なトラネキサム酸とアスコルビン酸含有医薬組成物
CA2874779C (fr) Composition pharmaceutique d'entecavir, et procede de fabrication
EP3437645A1 (fr) Comprimé enrobé d'un film et présentant une stabilité chimique élevée de son principe actif
WO2011074660A1 (fr) Préparation à élution stabilisée
JP5579066B2 (ja) 有効成分が境界を有してなる医薬固形製剤
EP2370061A2 (fr) Composition pharmaceutique contenant de l ézétimibe et de la simvastatine
AU2014295098B2 (en) Anti-tuberculosis stable pharmaceutical composition in a form of a coated tablet comprising granules of isoniazid and granules of rifapentine and its process of preparation
EP3020416A1 (fr) Comprimé à désagrégration ultrarapide et sa méthode de fabrication
WO2011126352A2 (fr) Médicament contre la tuberculose sur la base d'un complexe d'inclusion de cyclodextrine et de rifampicine ainsi qu'un procédé de fabrication correspondant.
EP2520300A1 (fr) Composition pharmaceutique pour administration orale
JP2020111532A (ja) ビタミンｂ１類を配合する固形製剤
EP2934494B1 (fr) Formulation pharmaceutique de n-[5-[2-(3,5-diméthoxyphényl)éthyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-diméthylpipérazin-1-yl]benzamide
KR101561345B1 (ko) 제어방출되는 프로피온산 계열의 약제학적 조성물
WO2019221215A1 (fr) Composition médicinale particulaire contenant de la lubiprostone
JP2016060731A (ja) 経口組成物
KR20210118164A (ko) 필름 코팅 조성물 및 고형 제제
Palparthi et al. Formulation and evaluation of cefpodoxime proxetil sustained release matrix tablets
Srilakshmi et al. FORMULATION AND EVALUATION OF MATRIX TABLETS OF METFORMIN HYDROCHLORIDE
EP3900708A1 (fr) Composition médicale à libération prolongée contenant du zaltoprofène
RU2420288C1 (ru) Фармацевтический состав с противотуберкулезным действием
CA2671778A1 (fr) Forme posologique a liberation immediate de bosentan et procede de fabrication de ladite forme posologique
JP2005320267A (ja) 小型のクラリスロマイシン高含有錠剤及びその製造方法
JP2007284394A (ja) 被覆固形製剤
HK1212229B (en) Pharmaceutical formulation of n- [5- [2-(3,5-dimethoxyphenyl) ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl]benzamide

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11766203

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 201201098

Country of ref document: EA

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11766203

Country of ref document: EP

Kind code of ref document: A2