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WO2004030665A1 - Composition de gel transparent destine a l'administration de sodium de diclofenac a travers la peau - Google Patents

Composition de gel transparent destine a l'administration de sodium de diclofenac a travers la peau Download PDF

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Publication number
WO2004030665A1
WO2004030665A1 PCT/GB2003/004398 GB0304398W WO2004030665A1 WO 2004030665 A1 WO2004030665 A1 WO 2004030665A1 GB 0304398 W GB0304398 W GB 0304398W WO 2004030665 A1 WO2004030665 A1 WO 2004030665A1
Authority
WO
WIPO (PCT)
Prior art keywords
transparent gel
gel composition
composition according
diclofenac
diclofenac sodium
Prior art date
Application number
PCT/GB2003/004398
Other languages
English (en)
Inventor
Francisco Jose Evaristo Stefano
Original Assignee
Thalas Group Incorporated
Paget, Hugh, Charles, Edward
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 Thalas Group Incorporated, Paget, Hugh, Charles, Edward filed Critical Thalas Group Incorporated
Priority to AU2003269266A priority Critical patent/AU2003269266A1/en
Publication of WO2004030665A1 publication Critical patent/WO2004030665A1/fr

Links

Classifications

    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • Transparent gel composition for the administration of diclofenac sodium through the skin
  • the present invention relates to a transparent gel composition for the transder al administration of diclofenac.
  • anti-inflammatory agents are used, which can be divided in two main groups: non-steroidal anti-inflammatory drugs (NSAIDs) and steroidal anti- inflammatory drugs.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • steroidal anti-inflammatory drugs NSAIDs
  • the anti-inflammatory compound diclofenac, that belongs to the first group, is one of most used pharmaceutical compounds all over the world.
  • This compound is administered "per os", via injection, or by rectal or topical administration, according to the circumstances. Nevertheless, when the diclofenac is administered orally, it usually develops several adverse side effects as, for example, severe gastrointestinal problems.
  • transdermal administration offers important advantages, mainly because of its simplicity and because of its administration is not invasive. Additionally, this route reaches the circulating blood without the "first pass" through the digestive system and the liver, where, in many cases, a significant proportion of the drug is metabolised and inactivated.
  • compositions for topical administration that comprise variable concentrations of anti- inflammatory agents.
  • diclofenac as well as the majority of the non-steroidal anti- inflammatories is limited because of the slow permeation rate that these compounds have through the skin.
  • This limitation has been overcome in some cases, through the addition of the so called "permeation enhancers".
  • the preparation of a diclofenac gel presents the disadvantage that, although the water solubility of diclofenac is approximately 1.5%, when the excipients of common use in this type of formulations are added, this compound tends to crystallise.
  • the selection of the excipients in general and of the permeation enhancer in particular has a high relevance in the development of a transparent gel for the transdermal administration of diclofenac through the skin.
  • diclofenac sodium is dissolved with difficulty in water and an oily base and, for this reason, the preparations for external use that contain this compound are usually prepared as dispersions of diclofenac sodium.
  • transdermal absorption is not good when the preparations are in a dispersion state. Therefore, in the literature, several techniques to dissolve diclofenac sodium using different additives have been described.
  • permeation enhancers to be used in preparations for transdermal administration, the following being the most common: oleic acid and its salts, lower alkyl esters associated with alkanes (C ⁇ C 3 ) (EP 0267617), oleic acid and/or 2-ethyl-hexanediol (WO 87/03490) and l-dodecylhexahydro-2H-azepin-2-one ("Azone”) (EP 0251425), included here as references. Additionally, ethanol, propyleneglycol and other alcohols, long chain fatty acids, etc., have been proposed (R. W. Baker and J.
  • diclofenac sodium one of the best permeation enhancers to be used in a transdermal gel composition having topical, local or systemic effect is oleyl alcohol.
  • this compound is insoluble in the aqueous solution that contains the excipients commonly used.
  • an heterogeneous system with two well defined phases was obtained.
  • diclofenac sodium was added to the above described formulation, a clear homogeneous gel was obtained.
  • the gel composition mentioned above not only has been demonstrated to be, in a completely unexpected way, homogeneous and transparent, without signs of heterogeneity or emulsion, but also has been demonstrated to have special permeation properties.
  • Oleyl alcohol not only proved to be a particularly suitable permeation enhancer, but also, in an unexpected way, the increase in its concentration did not produce an increase in the amount of diclofenac that permeated through the skin. In this manner, in the permeation experiments studied, it was found that an increase in the amount of oleyl alcohol from 1.5 to 3% do not produce changes in the amount of diclofenac that permeates the skin.
  • the present invention provides a transparent gel composition, for the topical, local or systemic administration of diclofenac through the skin wherein said composition comprises diclofenac sodium in a concentration of 4.2% or higher, preferably 5% or higher, and a mixture of oleyl alcohol and isopropyl alcohol in a ratio in the range 0.02 - 0.125, preferably 0.25 - 0.1, more preferably 0.025 and 0.05. A most preferred ratio is between 0.04 and 0.05.
  • the gel of the invention comprises diclofenac in a concentration of S-
  • a particularly preferred composition of the invention comprises oleyl alcohol in a percentage of the total weight of the composition in the range 0.75% to 3%, e.g. 1.5%, and isopropyl alcohol in a percentage of the total weight of the composition in the range 15% to 60%, e.g. 30%.
  • Propyleneglycol is a preferred optional component, preferably in an amount in the range 2 to 20%, e.g. 8%.
  • the composition may comprise, additionally, any one or more of vehicles, fragrances and thickeners, which are pharmaceutically and cosmetically acceptable .
  • the gel composition of the invention comprises also a chelating agent of bivalent ions such as copper, iron and manganese ions, in particular sodium edetate, which is particularly preferred because it improves the physical stability of the composition while preventing the development of a yellowish colour.
  • the gel composition of the invention comprises, at least one of the following compounds: propyleneglycol, methocel (hydroxypropylmethylcellulose) , methylparaben (p- methylhydrobenzoate) , fragrance, sodium edetate and deionised water.
  • a particular composition of the invention may comprise, as percentages of the total weight of the composition: diclofenac sodium 5%, isopropanol 30%, propyleneglycol 8%, oleyl alcohol 1.5%, Methocel K-15 1.3%, methylparaben 0.1%, fragrance 0.1%, EDTA 0.01% and deionised water up to 100%.
  • a process for preparing a transparent gel composition of the invention as described above which comprises the steps of dispersing hydroxypropylmethylcellulose in deionised water, mixing diclofenac sodium with the remaining components and pouring the dispersion of hydroxypropylmethylcellulose in water over the obtained mixture.
  • the gel composition of the invention may be prepared, for example, in the following way: Methocel K-15
  • the gel is a single phase composition.
  • the gel composition of this example was prepared as follows: 1.3 g of Methocel K-15 (hydroxypropylmethylcellulose) are dispersed in a sufficient amount of deionised water. Isopropanol, oleyl alcohol, propyleneglycol, methylparaben, diclofenac sodium and the fragrance are mixed in a suitable recipient. Then, the dispersion of Methocel in water is poured with constant stirring over the other solution, forming in this way an homogeneous and clear gel.
  • Methocel K-15 hydroxypropylmethylcellulose
  • the gel composition of this example was prepared in the same way as in Example 1.
  • the gel composition of this example was prepared in the same way as in Example 1.
  • Measurements were performed in triplicate using vertical type cells, with continuous stirring, in a water bath with controlled temperature (34°C) .
  • the cells that were used also known as diffusion Franz cells
  • the cells that were used have two chambers: a lower or receptor one in which the receptor solution is placed (phosphate buffer solution at pH 7.4) and an upper or donor one in which the solution to be assayed is placed.
  • a lower or receptor in which the receptor solution is placed
  • an upper or donor one in which the solution to be assayed is placed.
  • a magnetic stirring bar was also placed into the receptor chamber.
  • In the donor chamber 0.5 g of the gel to be studied was placed, ensuring a perfect contact between the semi-solid and the skin.
  • the receptor chamber was fixed to the donor chamber by means of a paraffin film, while the latter was also sealed with a similar film, to ensure that the assay was performed under occlusive conditions.
  • 2 ml samples of the receptor solution were taken at 2, 4, 6, 8 and 24 hours from the beginning of the assay and the diclofenac content of them was analysed with a suitable HPLC technique. The extraction of the samples was accompanied by replenishment with fresh receptor media.
  • the obtained values were used to calculate the amount of drug permeated, expressing the results as ⁇ g/cm 2 .
  • the diclofenac sodium gel without oleyl alcohol was prepared as follows: 1.3 g of Methocel K-15 (hydroxypropylmethylcellulose) were dispersed in 55.5 ml of deionised water. Isopropanol, propyleneglycol, methylparaben, diclofenac sodium and the fragrance were mixed in a suitable recipient. Then, the dispersion of Methocel in water is poured with constant stirring over the other solution, forming in this way an homogeneous and transparent gel.
  • Methocel K-15 hydroxypropylmethylcellulose
  • the gels that contain diclofenac sodium within this example were prepared as follows: 1.3 g of Methocel K-15 (hydroxypropylmethylcellulose) are dispersed in 55.5 ml of deionised water. Isopropanol, oleyl alcohol, propyleneglycol, methylparaben, diclofenac sodium and the fragrance are mixed in a suitable recipient. Then, the dispersion of Methocel in water was poured with constant stirring over the other solution, forming in this way an homogeneous and colorless gel. The gel corresponding to formulation 1 was prepared similarly to the corresponding gel of the previous example.
  • a diclofenac sodium gel, of formulation 3 or 4, prepared as disclosed in example 5 was applied three times a day during seven days on the forearm of 10 healthy volunteers. A total of 21 applications were made to each volunteer (two applications were made on the first day) . All subjects completed the study and were evaluated periodically for signs of local irritation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition de gel transparent destiné à une administration par voie topique, locale ou systémique de diclofénac à travers la peau, qui comprend du sodium de diclofénac à une concentration supérieure ou égale à 5% et un mélange d'alcool oléique et d'alcool isopropylique à un rapport compris entre 0,020 et 0,12. Cette composition comprend également des excipients acceptables du point de vue pharmaceutique. L'invention comprend également un procédé de préparation de ladite composition.
PCT/GB2003/004398 2002-10-07 2003-10-07 Composition de gel transparent destine a l'administration de sodium de diclofenac a travers la peau WO2004030665A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003269266A AU2003269266A1 (en) 2002-10-07 2003-10-07 Transparent gel composition, for the administration of diclofenac sodium through the skin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ARP020103777A AR036755A1 (es) 2002-10-07 2002-10-07 Una composicion en forma de gel transparente para la administracion de diclofenac sodico a traves de la piel
ARP020103777 2002-10-07

Publications (1)

Publication Number Publication Date
WO2004030665A1 true WO2004030665A1 (fr) 2004-04-15

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Family Applications (1)

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PCT/GB2003/004398 WO2004030665A1 (fr) 2002-10-07 2003-10-07 Composition de gel transparent destine a l'administration de sodium de diclofenac a travers la peau

Country Status (3)

Country Link
AR (1) AR036755A1 (fr)
AU (1) AU2003269266A1 (fr)
WO (1) WO2004030665A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008030359A3 (fr) * 2006-09-06 2008-07-31 Isw Group Inc Compositions topiques
EP2055298A1 (fr) * 2007-10-30 2009-05-06 Novartis AG Composition topique
WO2010008600A1 (fr) * 2008-07-16 2010-01-21 Dermworx Incorporated Système d'apport de médicament topique
WO2010116382A3 (fr) * 2009-04-08 2011-04-07 Cadila Healthcare Limited Compositions pharmaceutiques stables de diclofénac
WO2012110971A3 (fr) * 2011-02-17 2012-11-01 Promed Exports Pvt. Ltd. Procédé et composition pour retarder la sorption de conservateurs dans des matières plastiques
WO2014009793A1 (fr) 2012-07-11 2014-01-16 Glycores 2000 S.R.L. Solution de diclofénac destinée à un usage externe
US11000495B2 (en) 2014-09-10 2021-05-11 GSK Consumer Healthcare S.A. Topical diclofenac sodium compositions
WO2023180792A1 (fr) 2022-03-25 2023-09-28 Glycores 2000 Srl Composition pharmaceutique topique à activité anti-inflammatoire et analgésique et ses utilisations
EP4342449A1 (fr) * 2022-09-21 2024-03-27 Haleon CH SARL Compositions de gel monophasiques hydroalcooliques pour l administration topique de diclofénac
EP4342450A1 (fr) * 2022-09-21 2024-03-27 Haleon CH SARL Formulations topiques hydroalcooliques de diclofénac

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0788794A1 (fr) * 1994-08-09 1997-08-13 TSUMURA & CO. Composition pour preparation a usage externe
EP0879597A1 (fr) * 1996-02-07 1998-11-25 TSUMURA & CO. Solution aqueuse transparente de diclofenac sodique, compositions medicinales, et utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0788794A1 (fr) * 1994-08-09 1997-08-13 TSUMURA & CO. Composition pour preparation a usage externe
EP0879597A1 (fr) * 1996-02-07 1998-11-25 TSUMURA & CO. Solution aqueuse transparente de diclofenac sodique, compositions medicinales, et utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FREGANY A MOHAMMED: "TOPICAL PERMEATION CHARACTERISTICS OF DICLOFENAC SODIUM FORM NACMC GELS IN COMPARISON WITH CONVENTIONAL GEL FORMULATIONS", DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, NEW YORK, NY, US, vol. 27, no. 10, 2001, pages 1083 - 1097, XP009015688, ISSN: 0363-9045 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008030359A3 (fr) * 2006-09-06 2008-07-31 Isw Group Inc Compositions topiques
EP2214642B1 (fr) 2007-10-30 2017-05-03 Novartis Consumer Health S.A. Composition topique
WO2009056522A1 (fr) * 2007-10-30 2009-05-07 Novartis Ag Composition topique
US20100286268A1 (en) * 2007-10-30 2010-11-11 Novartis Ag Topical composition
JP2011500863A (ja) * 2007-10-30 2011-01-06 ノバルティス アーゲー 局所用組成物
EP2055298A1 (fr) * 2007-10-30 2009-05-06 Novartis AG Composition topique
KR101531729B1 (ko) * 2007-10-30 2015-06-25 노파르티스 아게 국소 조성물
WO2010008600A1 (fr) * 2008-07-16 2010-01-21 Dermworx Incorporated Système d'apport de médicament topique
US9050293B2 (en) 2008-07-16 2015-06-09 Juventio, Llc Small molecule solubilization system
WO2010116382A3 (fr) * 2009-04-08 2011-04-07 Cadila Healthcare Limited Compositions pharmaceutiques stables de diclofénac
JP2012523408A (ja) * 2009-04-08 2012-10-04 カディラ・ヘルスケア・リミテッド ジクロフェナクの安定な医薬組成物
WO2012110971A3 (fr) * 2011-02-17 2012-11-01 Promed Exports Pvt. Ltd. Procédé et composition pour retarder la sorption de conservateurs dans des matières plastiques
WO2014009793A1 (fr) 2012-07-11 2014-01-16 Glycores 2000 S.R.L. Solution de diclofénac destinée à un usage externe
US11000495B2 (en) 2014-09-10 2021-05-11 GSK Consumer Healthcare S.A. Topical diclofenac sodium compositions
WO2023180792A1 (fr) 2022-03-25 2023-09-28 Glycores 2000 Srl Composition pharmaceutique topique à activité anti-inflammatoire et analgésique et ses utilisations
EP4342449A1 (fr) * 2022-09-21 2024-03-27 Haleon CH SARL Compositions de gel monophasiques hydroalcooliques pour l administration topique de diclofénac
EP4342450A1 (fr) * 2022-09-21 2024-03-27 Haleon CH SARL Formulations topiques hydroalcooliques de diclofénac
WO2024062348A1 (fr) * 2022-09-21 2024-03-28 Haleon Ch Sarl Compositions de gel monophase hydroalcoolique pour l'administration topique de diclofénac
WO2024062349A1 (fr) * 2022-09-21 2024-03-28 Haleon Ch Sarl Formulations topiques hydroalcooliques de diclofénac

Also Published As

Publication number Publication date
AU2003269266A1 (en) 2004-04-23
AR036755A1 (es) 2004-09-29

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