[go: up one dir, main page]

WO2005067941A1 - Formulation topique d’aciclovir - Google Patents

Formulation topique d’aciclovir Download PDF

Info

Publication number
WO2005067941A1
WO2005067941A1 PCT/IB2005/000118 IB2005000118W WO2005067941A1 WO 2005067941 A1 WO2005067941 A1 WO 2005067941A1 IB 2005000118 W IB2005000118 W IB 2005000118W WO 2005067941 A1 WO2005067941 A1 WO 2005067941A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
esters
topical pharmaceutical
acyclovir
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/IB2005/000118
Other languages
English (en)
Spanish (es)
Inventor
Maria Jacqueline Sepulveda
Carlos Guillermo Von Plessing
Galo Cardenas
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.)
Universidad de Concepcion
EPIC Ltda
Original Assignee
Universidad de Concepcion
EPIC Ltda
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 Universidad de Concepcion, EPIC Ltda filed Critical Universidad de Concepcion
Publication of WO2005067941A1 publication Critical patent/WO2005067941A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61P31/12—Antivirals

Definitions

  • the objective of the present invention is the development of a topical formulation, useful in the treatment of dermal and mucosal viral infections.
  • This composition contains as active ingredient 9- (2-hydroxymethoxymethyl) guanine, a compound that is known in the art as “acyclovir” and also N, O-carboxymethyl chitosan, which promotes the absorption of the active substance.
  • Acyclovir and its salts derived from esters are widely known for their antiviral action, which is widely explained in GB1523865 which is currently in the public domain.
  • EP 0 044 543 B1 describes an acyclovir formulation in which the vehicle is an oil / water mixture, which contains at least 30% water-miscible polyvalent alcohol.
  • Another related application is WO97 / 34607 which describes a topical formulation, where the vehicle is a formulation similar to European application 44543, but in this case the formulation of this invention patent application is characterized in that the vehicle being used is found in an oil-in-water emulsion containing at least 10% polyethylene glycol / monoethylether commercially known as Transcutol ® (Gattefosse SA).
  • the present patent application relates to a topical formulation for the administration of acyclovir.
  • the composition contains a chitosan derivative as an element that promotes the absorption of the active substance through the skin.
  • the chitosan derivative used is N, O-carboxymethyl chitosan (NOCMC).
  • NOCMC N, O-carboxymethyl chitosan
  • US4619995 N, O-carboxymethyl chitosan
  • the degree of substitution is typically between 0.6-1.0.
  • the NOCMC is soluble in solutions whose pH is above 6 and under 2.
  • NOCMC is soluble in water, is derived from a natural and biodegradable polysaccharide, so it has excellent characteristics to be used as an absorption promoter in this topical formulation.
  • the topical formulation to be protected comprises from 1 to 10% w / w acyclovir for any of its salts or esters, from 1 to 40% w / w NOCMC and from 20 to 40% water, incorporated into the mixture in any oil phase
  • the lipid component of the emulsion is constituted by known substances and is emulsified with the aqueous component in accordance with the processes known for this purpose in the state of the art.
  • One or more emulsifying agents can be added as an ingredient to the lipid phase, this component can be fatty or oily, and its function is to grant stability to the emulsion over time.
  • the oil phase ingredients of this pharmaceutical composition have been predominantly selected on the basis of desired cosmetological characteristics in the final product, provided that the solubility of acyclovir in the oil phase and the aqueous phase is limited.
  • Some lipid substances that can be used for this formulation can be of linear or branched chemical structure, mono or dialkyl esters of fatty acid esters such as, isopropylmiristate and isopropylpalmitate, mixtures of the cetyl group and the stearyl alcohol group known by the name of Cromadol ® , which have high molecular weight and lipids such as white paraffins or liquid paraffins and other mineral oils.
  • Agents that allow an emulsion to be obtained include cetyl alcohols, sodium lauryl sulfate, stearyl alcohol, polyoxyethylene alkyl ethers such as Brij ® 72 and 721 (ICI, United Kingdom) and polyoxiestearyl esters such as Steareth 2 or 21. All these compounds may be used to obtain the desired emulsion in this topical formula.
  • the aqueous phase of the composition may also contain other components such as glycerin and glycol. These components are added to the aqueous phase to be used in the emulsion in order to increase the solubility of acyclovir in the aqueous phase.
  • glycerin and glycol are added to the aqueous phase to be used in the emulsion in order to increase the solubility of acyclovir in the aqueous phase.
  • glycol is a peculiar skin dehydrator. This point is particularly important when the preparation is to be applied to areas of skin that are not healthy as in the case of conditions caused by Herpes lablalis.
  • N, O-carboxymethyl chitosan it has been found, and it is the purpose of this invention, that the addition of N, O-carboxymethyl chitosan to the remaining ingredients of the formulation, in that percentage (1 to 40% w / w of N, O-carboxymethyl chitosan), it can reduce the presence of glycol in the formulation, specifically below 30% and even eliminated, while increasing the cosmetological and pharmaceutical efficacy of the formulation thanks to the ability of N, O-carboxymethyl.
  • Chitosan to act as a promoter of the absorption of the active substance through the skin.
  • N, O-carboxymethyl chitosan has a water solubility that is particularly useful in helping the formation of oil-water emulsions.
  • Composition ranges (w / w) used for the formulation and administration of acyclovir according to the present invention include: N, O-carboxymethyl chitosan 1- 40%, acyclovir 0.5-10%, cetroesaric alcohol 3-10%, 5-15% mineral oil, Steareth-21 2-5%, 0.1-1% sodium lauryl sulfate, and purified water required to reach 100%.
  • preservatives such as: p-oxybenzoates, benzoate Sodium, benzalkonium chloride, and others can be added to this formulation as a precautionary supplement in case of long-term storage.
  • a process for preparing the aforementioned formulation is also part of this invention. This process consists in stirring acyclovir or any of its salts or esters, N, O, carboxymethyl chitosan, the excipients constituted by the oil phase and the aqueous phase until the formation of the oil / water emulsion.
  • oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of acyclovir in most of the oils used in pharmaceutical emulsions formulations is very low.
  • the cream should preferably be a non-greasy product that does not stain and is washable, with a consistent consistency to prevent it from leaking out of the tubes or other containers.
  • Monobasic or dibasic, straight or branched chain alcohol esters can be used, such as isocetyl di-isoadipate, propylene glycol diester and coconut fatty acids, isopropyl myristate, isopropyl palmitate, butyl stearate or mixed acid ester 2- ethylhexanoic with a mixture of cetyl or stearyl alcohols, all three being last preferred for this pharmaceutical formulation. These can be used alone or in combination, depending on the required properties. Alternatively, high melting point lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils, can be used.
  • acyclovir may initially be incorporated completely in conjunction with the N, O-carbaoxymethyl chitosan in the aqueous portion, in which it may form a solution or a mixture of solution / suspension and then emulsify With the base of ointment.
  • acyclovir can be included in the emulsifying ointment, before emulsifying it with the aqueous phase.
  • the apparatus used for the formation of an emulsion is a turboemulsifier, which allows agitation under vacuum conditions, thus avoiding the incorporation of air and subsequent bubble formation in the final cream.
  • the topical formulation of the present invention patent application is prepared to be used for the treatment and prevention of viral infections by Herpes sp.
  • the tests carried out indicate that it is useful in cases of Herpes labialis and Herpes genitalis.
  • the formulation should be applied to the skin 2 to 5 times daily, preferably 3 or 4 times. It is obvious that the formulation referred to in this application for invention has been conceived for the particular administration of acyclovir and its derivatives, but this base formula can easily be adapted for the topical administration of other acyclovir analogue topical antiviral drugs such as, famciclovir, penciclovir, valacyclovir, and their synergistic combinations with other antivirals.
  • Part of this invention is the method of treating viral infections, particularly Herpes sp, which comprises the administration of a topical application formulation.
  • the oil phase was prepared by melting at 60 ° C solid petrolatum, beeswax and ketostearyl alcohol.
  • the aqueous phase was prepared with sodium lauryl sulfate, glycerin, methyl and propylparaben and water in which acyclovir has been heated to 70 ° C and suspended, subsequently added to the oil phase.
  • the mixing of the phases was slow under stirring and the whole system subjected to heat, once equilibrium was reached, the composition is cooled to room temperature.
  • the cream once formed was packaged in 10g tubes.
  • the cream described in example 1 was compared with the commercial cream Zovirax ® (GlaxoSmithKIine, Brentford, United Kingdom) using a Franz cell to measure permeation through artificial membrane and rat skin.
  • the artificial membrane and rat skin were mounted in Franz's cell, with a contact surface of 2.0 cm 2 . To this surface an amount of cream equal to 900-960mg was applied.
  • a Soerensen solution of pH 7.4 was used as a receiving solution for a period of 8 hours.
  • Several fractions were collected every 0.2h. The collected fractions were analyzed by the reverse phase high resolution liquid chromatography method described in J. Of Chromatography B, 791 (2003) 257-363.
  • the permeation test results are shown in the following tables.
  • Table 3 Pharmacokinetic parameters of the invented formulation obtained from rat skin tests.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L’invention concerne une formulation pharmaceutique destinée à l’administration topique d’aciclovir, cette composition peut être utilisée dans le traitement préventif et thérapeutique d’infections virales. La formulation compte la présence d’un dérivé de quitosan en tant que promoteur d’absorption du principe actif, de préférence le N, O, carboxyméthyle quitosan.
PCT/IB2005/000118 2004-01-08 2005-01-07 Formulation topique d’aciclovir Ceased WO2005067941A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CL2004000027 2004-01-08
CL27-2004 2004-01-08

Publications (1)

Publication Number Publication Date
WO2005067941A1 true WO2005067941A1 (fr) 2005-07-28

Family

ID=34754197

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/000118 Ceased WO2005067941A1 (fr) 2004-01-08 2005-01-07 Formulation topique d’aciclovir

Country Status (1)

Country Link
WO (1) WO2005067941A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010109433A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale antivirale et son procédé de fabrication

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4619995A (en) * 1984-12-24 1986-10-28 Nova Chem Limited N,O-carboxymethyl chitosan and preparative method therefor
SU1375113A3 (ru) * 1980-07-18 1988-02-15 Дзе Велкам Фаундейшн Лимитед (Фирма) Способ получени эмульсии 9-(2-оксиэтоксиметил)гуанина "Ацикловир
RU2128503C1 (ru) * 1992-09-09 1999-04-10 А/С Геа Фармасьютиск Фабрик Антивирусная фармацевтическая эмульсия типа масло в воде
WO2003043612A1 (fr) * 2001-11-21 2003-05-30 Besins International Belgique Poudre filmogene micronisee comprenant une substance active
RU2214820C2 (ru) * 2001-09-25 2003-10-27 Дж.Б. Кемикалс Энд Фармасьютикалс Лтд. Таблетированная фармацевтическая композиция

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1375113A3 (ru) * 1980-07-18 1988-02-15 Дзе Велкам Фаундейшн Лимитед (Фирма) Способ получени эмульсии 9-(2-оксиэтоксиметил)гуанина "Ацикловир
US4619995A (en) * 1984-12-24 1986-10-28 Nova Chem Limited N,O-carboxymethyl chitosan and preparative method therefor
RU2128503C1 (ru) * 1992-09-09 1999-04-10 А/С Геа Фармасьютиск Фабрик Антивирусная фармацевтическая эмульсия типа масло в воде
RU2214820C2 (ru) * 2001-09-25 2003-10-27 Дж.Б. Кемикалс Энд Фармасьютикалс Лтд. Таблетированная фармацевтическая композиция
WO2003043612A1 (fr) * 2001-11-21 2003-05-30 Besins International Belgique Poudre filmogene micronisee comprenant une substance active

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010109433A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale antivirale et son procédé de fabrication

Similar Documents

Publication Publication Date Title
KR890000493B1 (ko) 국소외용 약학적 조성물의 제조방법
ES2393761T3 (es) Espuma farmacéutica de ácido graso
ES2282325T3 (es) Composicion de emulsion de aceite en agua (o/w) y metodo pra su preparacion.
NL8201413A (nl) Farmaceutische preparaten voor plaatselijke toepassing en werkwijzen voor het bereiden en toepassen van deze preparaten.
US4963555A (en) Formulations of heterocyclic compounds
EP0044543B1 (fr) Formulations topiques à base de 9(2-hydroxyéthoxyméthyl) guanine
ES2590258T3 (es) Preparación antiinflamatoria y analgésica para uso externo
WO2000001390A1 (fr) Formulations topiques d'aciclovir
KR0168436B1 (ko) 비스테로이드계 소염진통제를 함유하는 수중유형 유화 조성물
LV10912A (lv) 9-(2-Oksietoksi) metilguaninu(acikloviru) vai ta sali vai esteri saturosa farmaceitiska emulsija ellaudeni ar antiviralu aktivitati
JP2007533606A (ja) ダプソンを含む乳化組成物
ES2944263T3 (es) Agente tópico para administración transdérmica
WO2005067941A1 (fr) Formulation topique d’aciclovir
CA2074503C (fr) Formulation pharmaceutique contenant du penciclovir
EP0593562B1 (fr) Composition topique contenant du penciclovir
JPH0735330B2 (ja) 外用クリ−ム組成物
IE902819A1 (en) Pharmaceutical formulation
US6469015B1 (en) Pharmaceutical formulation
JP7646342B2 (ja) 外用医薬組成物
WO1997045123A1 (fr) Formulations pharmaceutiques topiques comprenant de l'aciclovir
ES2280045T3 (es) Composiciones farmaceuticas de la vendustina.
WO2022178604A1 (fr) Composition pharmaceutique topique moussante
SK145696A3 (en) Topical preparation containing aciclovir and preparation method thereof
HK1012242B (en) Topical composition containing penciclovir
WO2003092704A1 (fr) Preparation externe de vidarabine a propriete systemique amelioree

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Ref document number: DE

WWE Wipo information: entry into national phase

Ref document number: 06076508

Country of ref document: CO

122 Ep: pct application non-entry in european phase