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EP2231119A1 - Pharmaceutical foams - Google Patents

Pharmaceutical foams

Info

Publication number
EP2231119A1
EP2231119A1 EP08860575A EP08860575A EP2231119A1 EP 2231119 A1 EP2231119 A1 EP 2231119A1 EP 08860575 A EP08860575 A EP 08860575A EP 08860575 A EP08860575 A EP 08860575A EP 2231119 A1 EP2231119 A1 EP 2231119A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically active
glycerides
composition
propellant
active ingredient
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Withdrawn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
EP08860575A
Other languages
German (de)
French (fr)
Inventor
Giancarlo Ceschel
Gabriele Vecchi
Flavia Giuliana Tinti
Carlo Oliani
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.)
Monteresearch-Pharmaceutical Development Service
Original Assignee
Monteresearch-Pharmaceutical Development Service
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 Monteresearch-Pharmaceutical Development Service filed Critical Monteresearch-Pharmaceutical Development Service
Publication of EP2231119A1 publication Critical patent/EP2231119A1/en
Withdrawn legal-status Critical Current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
    • A61K9/0012—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • the present invention relates to pharmaceutical compositions that are applied as a foam.
  • compositions for topical application which have improved absorbency by the skin particularly human skin.
  • the invention provides improved surfactant formulations useful in pharmaceutical compositions that are applied as foams.
  • This invention therefore provides the use of combination of non-hydrogenated lecithin and other surfactants as ingredients for foams having pharmaceutical uses.
  • non-hydrogenated lecithin and polyglycolyzed glycerides has been found particularly advantageous to enhance the absorption of active ingredients into the skin from pharmaceutical formulations applied as a foam.
  • the invention further provides pharmaceutical formulations applicable as a foam containing a combination of non- hydrogenated lecithin and other surfactants.
  • Topical applications of pharmaceutical active ingredients are widely used and have the benefits, when compared to oral or i.v. administration, that gastric/renal side effects can be limited and higher doses can be applied.
  • Active pharmaceutical ingredients of several classes are formulated and applied as ointments, creams, gels, lotions, topical solutions.
  • Lotion and gel topical dosage forms have the disadvantage that extended rub-in may be required and may leave oily residues.
  • the solution form has the disadvantage that it readily runs off the site of application, and therefore it is difficult to apply controlled amounts of the solution.
  • Foams and aerosols are dosage forms applied from a pressurised canister and containing one or more active pharmaceutical ingredients that, upon valve actuation, are released from the container as a fine dispersion of liquid and/or solid materials in a gaseous medium such as from an aerosol.
  • foams as means of topical administration of pharmaceutical active ingredients is described in US Patent Application publication number 2007/77208, European Patent Application EP502502A, and the American Journal of Drug delivery 2003, 1, 73; Expert Opinion on Drug Delivery, 3, 799 and references cited therein). Due to physico-chemical processes taking place once the foam is applied on the skin, drug delivery rate is generally higher than that obtainable by application of solutions or emulsions of the active ingredient.
  • formulations for application as a foam typically contain a liquid carrier, a propellant, an emulsifier for dispersion of the active ingredient in the liquid carrier.
  • Other additives may be included in the formulation for several reasons depending on the nature of the active ingredient; for example additives may be included to enhance percutaneous penetration, to improve foam formation and stability (emulsifiers) and to assure microbiological purity over time.
  • the formulation is such that it can be pressurised within a container and expelled from the container as a spray when a valve is activated to allow release of the foam from the container.
  • Formulation ingredients can have a significant effect on percutaneous absorption of the pharmaceutical active ingredient and on overall efficacy of the drug action. It has now been found that the use of non-hydrogenated lecithin's and their derivatives in combination with other surfactants have unexpected synergistic effects in improving the active ingredient delivery rate of pharmaceutical formulations topically applied as foam.
  • Lecithins and their derivatives may be synthetic or naturally occurring and lecithins of natural origin are mixtures composed mainly of phosphatidylcholine and other phospholipids Lecithins are known to moisturise skin and mucosal tissues and facilitate penetration of active ingredients into the skin
  • Lecithin and partially hydrogenated lecithin are used as excipient for topical pharmaceutical formulations comprising, among others, moisturising creams (United States patent 6316428), emulsions for nasal administration (United States Patent 5179079) and creams to treat psoriasis (United States Patent Application 2002012648, United States Patent 5945409). They have also been proposed for use in foams containing anti-inflammatory agents
  • Glycerides such as caprylocaproyl macrogolglycerides (commercially available as Labrasol) are used as emulsifiers and as absorption enhancers in pharmaceutical and cosmetic formulations, both for topical and oral administration (e.g. Clinical pharmacology and therapeutics 2000, 68, 114).
  • compositions in the form of foams comprising a combination of non-hydrogenated lecithin and/or its derivatives and glycerides, particularly caprylocaproyl macrogolglycerides, allow enhanced topical absorption of pharmaceutically active ingredients.
  • the present invention provides the use of a mixture of non-hydrogenated lecithin and one or more glycerides as a surfactant in a foamable composition comprising a pharmaceutical active ingredient for topical application.
  • the invention provides a composition
  • a composition comprising i) a pharmaceutically active ingredient for topical application ii) a liquid carrier iii) a propellant iv) a surfactant comprising a mixture of non-hydrogenated lecithin and one or more glycerides or their derivatives.
  • the invention provides a pressurised container equipped with a contents release valve containing a composition comprising i) a pharmaceutically active ingredient for topical application ii) a liquid carrier iii) a propellant iv) a surfactant comprising a mixture of non-hydrogenated lecithin and one or more glycerides or their derivatives.
  • the invention provides the topical treatment by application to skin of a foam comprising i) a pharmaceutically active ingredient for topical application ii) a liquid carrier iii) a propellant iv) a surfactant comprising a mixture of non-hydrogenated lecithin and one or more glycerides or their derivatives.
  • the preferred glycerides are caprylcaproyl macrogol glycerides.
  • one or more antioxidants may be included in the formulation to improve the stability of the formulation over time.
  • active ingredient 'active agent', 'at least one pharmaceutically active compound' and 'pharmaceutically active agent' are used interchangeably herein and refer to a substance having a pharmaceutical, pharmacological or therapeutic effect.
  • Pharmaceutically acceptable salt of an active compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Carrier' refers to a composition which has only excipient properties or components required to carry an active agent, but which itself has no pharmaceutical or therapeutic effect.
  • the at least one pharmaceutically active compound comprises a combination of active agents.
  • Any combination of active agents suitable for topical administration can be used in the compositions of the present invention.
  • the combination of active agents comprises at least two agents selected from an antibacterial agent and an antifungal agent.
  • a topical delivery composition in a pressurised container comprises up to 15 % wt of at least one pharmaceutically active compound, or its pharmaceutically acceptable salt; from about 83 % to about 97.9 % wt of a carrier; and from about 2 % to about 7 % wt of an aerosol propellant selected from the group consisting of a hydrocarbon or a hydroflurocarbon, a chloroflurocarbon, and a mixture thereof.
  • compositions of the present invention are present in a pressurized container comprising a homogenous mixture of from about 0.1 % to about 10 % wt of a pharmaceutically active ingredient, or its pharmaceutically acceptable salt from about 83 % to about 97.9 % wt of a carrier, and from about 2 % to about 79 % wt of an aerosol propellant selected from the group consisting of a hydrocarbon, a hydrofluorocarbon and a mixture thereof and a surfactant system comprising non-hydrogenated lecithin and a glyceride.
  • the maximum amount of propellant used is often determined by its miscibility with other components in the composition to form a mixture, such as a homogeneous mixture.
  • the minimal level of propellant used in the composition is often determined by the desired foam characteristics and its ability to substantially or completely evacuate the container.
  • Water and optionally a pH-adjusting agent generally comprise the remaining portion as a carrier.
  • the amount of water present ranges from about 10 % to about 95 % wt, preferably from about 10 % to about 90 % wt more preferably from about 20 % to about 90 % wt with from about 30 % to about 40 % wt or alternatively from about 80 % to about 95 % wt.
  • the pressurized container is a one-piece aluminium container in which the inner surface is lined with a chemically inert lining.
  • a preferred inner surface lining is polyamide-imide (PAM) lacquer.
  • PAM polyamide-imide
  • the container is fitted with an upright or inverted valve and a conventional foam spout actuator.
  • the invention is applicable for the topical administration of any pharmaceutically active material. It has been found that the invention is particularly useful with at least one pharmaceutically active material chosen from anti-inflammatory, myorelaxing, antimicotic, antihistaminics, antibiotics, local anesthesics and analgesic active pharmaceutical ingredients and combinations thereof.
  • the invention is also useful for the topical delivery of steroidal and non-steroidal anti-inflammatory pharmaceutical agents as well as non steroidal inflammatory active materials such as diclofenac, nimesulide, ketoprofene.
  • the active ingredient is hydrocortisone acetate.
  • the active ingredient is sodium butyrate.
  • the active ingredient is econazole.
  • Non-hydrogenated lecithin as used herein includes synthetic lecithins and their derivatives and also includes naturally occurring lecithin and the non-hydrogenated versions of lecithin of natural and synthetic lecithin and their derivatives.
  • Lecithin refers to a material which is a phosphatide on naturally occurring or synthetic phosphatides can be used.
  • Phosphatidylcholine is the preferred form of lecithin and is a derivative of glycerine esterified with a choline ester of phosphoric acid and two fatty acid groups which may be the same or different.
  • the fatty acids are saturated or unsaturated fatty acids, having 16-20 carbons and containing up to 4 double bonds.
  • Natural lecithins can be extracted from vegetable matter (e.g. sunflower seeds, soybeans, safflower seeds and cottonseed), animal (e.g. egg yolk) or lecithins of synthetic origin can be used.
  • the preferred structure of the lecithin will depend upon the nature of the pharmaceutical active ingredient.
  • a definition of lecithin may be found in Stedman's medical dictionary 21 $t ed., page 8791 which defines lecithin as any of a group of phospholipids which upon hydrolysis yield two fatty acid molecules and a molecule each of glycerophosphoric acid and choline. There are therefore several varieties of lecithin.
  • Lecithin is a mixture of the diglycerides of stearic, palmitic, and oleic acids, and palmitoleic, linoeic, linolenic, and arachidonic acids, linked to the choline ester of phosphoric acid.
  • Soybean lecithin is a preferred lecithin and may contain the following acids; palmitic, stearic, palmitoleic, oleic, linoleic, linolenic and arachidonic. In some lecithins both fatty acids are saturated while others contain only unsaturated fatty acids for example, oleic, linoleic or arachidonic.
  • lecithins In other lecithins one fatty acid is saturated, the other unsaturated.
  • Lecithins are found in nervous tissue, hepatic tissue, cardiac tissue, in egg yolks and in soy which constitutes the most common and economical source of phosphatidylcholine. Accordingly any reference herein to non-hydrogenated lecithin or phosphatidylcholine is intended to include any combination of non-hydrogenated lecithin-like phospholipids compounds.
  • examples of other phospholipids which can be used in accordance with the present invention include phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and phosphatidic acid.
  • a mixture of any of the above phospholipids may also be used in the present invention. Mixtures of these phospholipids are present in a natural soy lecithins.
  • glyceride refers to an ester of glycerol with carboxylic acids and includes mono-, di - and tri-glycerides and mixtures thereof. Glyceride includes synthetic and naturally occurring glycerides and derivatives thereof.
  • polyglycolised glyceride refers to esters of glycerol that have been ethoxylated or propoxylated. These materials can be complex mixtures of compounds derived from the reaction of glycerol and/or its derivatives, ethylene and/or propylene oxide and carboxylic acids which may themselves be mixtures of carboxylic acids.
  • polyglycolyzed glyceride refers to specific mixtures of mono-, di- and triglycerides and polyethylene glycol mono and diesters, obtained either by partial alcoholysis of hydrogenated vegetable oils using polyethylene glycol.
  • the "polyglycolyzed glycerides” may be saturated or unsaturated and may be complexes of ethoxylated glycerides and polyethylene glycol esters.
  • the saturated polyglycolyzed glyceride is a glyceryl caprylate/caprate and PEG-8 (polyethylene glycol) caprylate/caprate complex commercially available as Labrosol is a preferred material.
  • the polyglycolyzed glycerides of the present invention have Hydrophilic Lipophilic Balance (HLB) values of between and including 6 and 14 typically the free glycerol content is less than 3%.
  • HLB Hydrophilic Lipophilic Balance
  • suitable polyglycolyzed glycerides include Labrafac.RTM.CM 10, Labrafil.RTM.M 10, Labrafil.RTM. NA10, Labrafac.RTM.CM 12, Labrasol.RTM. (Labrafac.RTM.CM 14) and the like.
  • polyglycolyzed glycerides examples include Labrafac.RTM.CM 6, Labrafil.RTM. WL2609 BS, Labrafac.RTM.CM 8, Labrafac.RTM.CM10, Labrafil.RTM.M 10, Labrafil.RTM. NA10, Labrafac.RTM. CM12, and Labrasol.RTM. (Labrafac.RTM. CM 14).
  • Preferred polyglycolyzed glycerides having HLB values of between 6 and 14 inclusive, and containing medium chain (C 8 - C 10 ) triglycerides, are Labrafac.RTM.
  • Analogs and derivatives of the above polyglycolyzed glycerides are also suitable for use in the compositions and methods of the present invention. To the extent that these analogs and derivatives are similar in structure to or are readily obtained by chemical modification of the polyglycolyzed glycerides. While substantially retaining the physical properties of the polyglycolyzed glycerides, such analogs and derivatives are intended to be included among the compositions and methods of the present invention.
  • the term “foam” refers to finely dispersed suspensions of liquid and/or solid materials in a gaseous medium, the suspension being released from pressurized containers as droplet dosage foams upon actuation of the valve of the container.
  • the present invention therefore provides various pharmaceutically active topical compositions applied as foams based on the finding that the combined use of non-hydrogenated lecithin and glycerides, particularly polyglycolyzed glycerides produce a synergistic effect resulting in an enhanced absorption of the active pharmaceutical ingredient by the skin and an easier delivery of the drug.
  • the topical compositions of the present inventions are solutions or suspensions suitable to be delivered as a foam or droplets from a pressurised container upon actuation of a valve.
  • the foam preferably contains the active pharmaceutical ingredient in a concentration between 0.5 and 10% weight/volume together with non-hydrogenated lecithin in concentration between 0.1 % and 10%, and glycerides in concentration between 5% and 30%.
  • the non-hydrogenated lecithin is present in a concentration between 0.1 % and 5 % and the glyceride is in a concentration between 8% and 15%.
  • the non-hydrogenated lecithin is present in a concentration between 0.3% and 0.5% and the glyceride is present in a concentration between 9 % and 11 % the balance of the formulation being other additives and a carrier such as water.
  • the foam compositions can be applied for absorption on the skin of humans or animals or, varying the ingredient ratios as suitable, vaginal, rectal, buccal mucose.
  • the invention is particularly useful with formulations in which the active pharmaceutical ingredient is one or more of anti-inflammatory, myorelaxing, antifungal, antihistamines, antibiotic, local aesthetic and analgesic agents.
  • the invention in particular is useful in the provision of a topically applied composition for delivery of steroidal and non-steroidal anti-inflammatory pharmaceutical agents, in particular the active pharmaceutical ingredients can comprise, but are not limited to, diclofenac, hydrocortisone acetate, nimesulide, ketoprofene, tiocolchicoside and sodium butyrate.
  • compositions may contain additional components such as perfumes, bacteriostatic agents (e.g. benzyl alcohol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and analogues), anti-oxidants (e.g. tocoferol acetate, butyl hydroxy anisole, butyl hydroxyl toluene and analogues).
  • bacteriostatic agents e.g. benzyl alcohol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and analogues
  • anti-oxidants e.g. tocoferol acetate, butyl hydroxy anisole, butyl hydroxyl toluene and analogues.
  • Non-hydrogenated lecithin and/or its derivatives is used.
  • Non-hydrogenated lecithins do not require elaborated purification treatments, and provide a cost-effective solution for the production of pharmaceutical foams which is particularly suitable for industrial production.
  • transdermal permeability of the active pharmaceutically ingredient used in the formulations was evaluated using Franz cells permeation test using porcine inner ear epidermis as the septum between the formulation (donor compartment) and the receptor phase chamber.
  • porcine epidermis is the preferred model as it displays permeation properties similar to those of human skin (International Journal of Pharmaceutics 2007, 331 , 139).
  • the compartment had 4.8 ml_ capacity.
  • the receptor chamber is encircled in a jacket in which water is circulated at 37 ⁇ 1 0 C.
  • the samples of skin are taken from the inner ear of the pig as soon as sacrificed and dipped, for 24 h, in a solution buffer at pH. 7.4 held at 4 0 C.
  • the connectival parts are removed by surgical technique and the remaining skin is cut in squares of 2x2 cm. The squares obtained are conserved until use at 20 0 C.
  • the test is conducted by positioning the porcine skin between the donor compartment and the receptor chamber with the external surface towards the upper compartment.
  • the foam pharmaceutical formulation is placed inside the donor compartment.
  • the receptor chamber is then filled up with phosphate buffer at pH 7.4. 2 ml of the buffer solution are then sampled at regular time intervals and analysed for the content of the active pharmaceutical ingredient, when a sample is removed the initial volume of the solution is restored with phosphate buffer heated at 37°C. The samples thus obtained are stored at to 4°C until the quantitative analysis is performed.
  • the test is repeated 9 times for every formulation and the samples obtained are analysed by HPLC.
  • the chromatographic conditions used for the determination of the active ingredient were as follows.
  • diclofenac sodium salt is dispersed in purified water under stirring, until complete dissolution is obtained.
  • Non-hydrogenated phosphatidilcoline (lecithin) is dissolved in purified water and then introduced into the main container together with the flavouring agent and stirred for 15-20 minutes.
  • the formulation is then diluted to the required volume with purified water and stirred for 15-20 minutes with pH control (limits: 7-9).
  • the solution is then filtered under pressure.
  • the desired weight of the solution is placed into a canister provided with a valve and then a propellant gas is pumped into the canister, to pressurise the formulation and provide 5 wt % propellant.
  • the propellant gas was a mixture of 80 % isobutane and 20 % n-butane.
  • the formulation was produced in a manner similar to that described in Example 1 , with variations of some excipients and of the active ingredient.
  • Example 3- hydrocortisone Foam The formulation was produced in a manner similar to that described in Example 1 , with variations of some excipients and of the active ingredient; composition of the solution, expressed percentage was
  • caprylocaproyl macrogol glycehdes (Labrasol) 5.000 7 non-hydrogenated phosphatidylcholine (lecithin) 0.300
  • Example 4- thiocolchicoside Foam The formulation was produced in a manner similar to that in Example 1 , except that the lecithin was not employed, the formulation had the following composition in percentage terms
  • the formulation was produced in a similar manner to that described in Example 1.
  • the final composition of the solution, expressed in %. was 1 Econazole 3.000

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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

Foams for the topical application of pharmaceutical active ingredients are based on a surfactant combination of non-hydrogenated lecithin and glycerides or their derivatives, the use of the surfactant combination results in improved absorption of the active ingredient by the skin.

Description

PHARMACEUTICAL FOAMS
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions that are applied as a foam. In particular it relates to such compositions for topical application which have improved absorbency by the skin particularly human skin. The invention provides improved surfactant formulations useful in pharmaceutical compositions that are applied as foams. This invention therefore provides the use of combination of non-hydrogenated lecithin and other surfactants as ingredients for foams having pharmaceutical uses. In particular the use of non-hydrogenated lecithin and polyglycolyzed glycerides has been found particularly advantageous to enhance the absorption of active ingredients into the skin from pharmaceutical formulations applied as a foam. The invention further provides pharmaceutical formulations applicable as a foam containing a combination of non- hydrogenated lecithin and other surfactants.
BACKGROUND INFORMATION
Topical applications of pharmaceutical active ingredients are widely used and have the benefits, when compared to oral or i.v. administration, that gastric/renal side effects can be limited and higher doses can be applied. Active pharmaceutical ingredients of several classes are formulated and applied as ointments, creams, gels, lotions, topical solutions. Lotion and gel topical dosage forms have the disadvantage that extended rub-in may be required and may leave oily residues. The solution form has the disadvantage that it readily runs off the site of application, and therefore it is difficult to apply controlled amounts of the solution.
Topical application of pharmaceuticals in the form of aerosols and foams is also known. Foams and aerosols are dosage forms applied from a pressurised canister and containing one or more active pharmaceutical ingredients that, upon valve actuation, are released from the container as a fine dispersion of liquid and/or solid materials in a gaseous medium such as from an aerosol.
The use of foams as means of topical administration of pharmaceutical active ingredients is described in US Patent Application publication number 2007/77208, European Patent Application EP502502A, and the American Journal of Drug delivery 2003, 1, 73; Expert Opinion on Drug Delivery, 3, 799 and references cited therein). Due to physico-chemical processes taking place once the foam is applied on the skin, drug delivery rate is generally higher than that obtainable by application of solutions or emulsions of the active ingredient.
In addition to the pharmaceutically active ingredient, formulations for application as a foam typically contain a liquid carrier, a propellant, an emulsifier for dispersion of the active ingredient in the liquid carrier. Other additives may be included in the formulation for several reasons depending on the nature of the active ingredient; for example additives may be included to enhance percutaneous penetration, to improve foam formation and stability (emulsifiers) and to assure microbiological purity over time. The formulation is such that it can be pressurised within a container and expelled from the container as a spray when a valve is activated to allow release of the foam from the container.
Formulation ingredients can have a significant effect on percutaneous absorption of the pharmaceutical active ingredient and on overall efficacy of the drug action. It has now been found that the use of non-hydrogenated lecithin's and their derivatives in combination with other surfactants have unexpected synergistic effects in improving the active ingredient delivery rate of pharmaceutical formulations topically applied as foam.
Lecithins and their derivatives may be synthetic or naturally occurring and lecithins of natural origin are mixtures composed mainly of phosphatidylcholine and other phospholipids Lecithins are known to moisturise skin and mucosal tissues and facilitate penetration of active ingredients into the skin
Lecithin and partially hydrogenated lecithin are used as excipient for topical pharmaceutical formulations comprising, among others, moisturising creams (United States patent 6316428), emulsions for nasal administration (United States Patent 5179079) and creams to treat psoriasis (United States Patent Application 2002012648, United States Patent 5945409). They have also been proposed for use in foams containing anti-inflammatory agents
Glycerides such as caprylocaproyl macrogolglycerides (commercially available as Labrasol) are used as emulsifiers and as absorption enhancers in pharmaceutical and cosmetic formulations, both for topical and oral administration (e.g. Clinical pharmacology and therapeutics 2000, 68, 114).
United States Patent 4,760,096 describes the use of lecithins in the presence of caprylocaproyl triglycerides for enhanced skin moistuπsation in preparations such as skin creams, face creams, lotions or ointments but no particular synergetic effect was obtained by use of this combination for the formulations described. .
SUMMARY OF THE INVENTION
In accordance with the present invention, it has been found that pharmaceutical preparations in the form of foams comprising a combination of non-hydrogenated lecithin and/or its derivatives and glycerides, particularly caprylocaproyl macrogolglycerides, allow enhanced topical absorption of pharmaceutically active ingredients.
The present invention provides the use of a mixture of non-hydrogenated lecithin and one or more glycerides as a surfactant in a foamable composition comprising a pharmaceutical active ingredient for topical application.
In a further embodiment the invention provides a composition comprising i) a pharmaceutically active ingredient for topical application ii) a liquid carrier iii) a propellant iv) a surfactant comprising a mixture of non-hydrogenated lecithin and one or more glycerides or their derivatives.
In a further embodiment the invention provides a pressurised container equipped with a contents release valve containing a composition comprising i) a pharmaceutically active ingredient for topical application ii) a liquid carrier iii) a propellant iv) a surfactant comprising a mixture of non-hydrogenated lecithin and one or more glycerides or their derivatives.
In another embodiment the invention provides the topical treatment by application to skin of a foam comprising i) a pharmaceutically active ingredient for topical application ii) a liquid carrier iii) a propellant iv) a surfactant comprising a mixture of non-hydrogenated lecithin and one or more glycerides or their derivatives.
The preferred glycerides are caprylcaproyl macrogol glycerides.
In a further embodiment of the present invention one or more antioxidants may be included in the formulation to improve the stability of the formulation over time. Unless the context requires otherwise the terms active ingredient 'active agent', 'at least one pharmaceutically active compound' and 'pharmaceutically active agent' are used interchangeably herein and refer to a substance having a pharmaceutical, pharmacological or therapeutic effect.
Pharmaceutically acceptable salt of an active compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
'Carrier' refers to a composition which has only excipient properties or components required to carry an active agent, but which itself has no pharmaceutical or therapeutic effect.
In another aspect the at least one pharmaceutically active compound comprises a combination of active agents. Any combination of active agents suitable for topical administration can be used in the compositions of the present invention. Preferably the combination of active agents comprises at least two agents selected from an antibacterial agent and an antifungal agent.
The present invention provides various pharmaceutically active topical delivery compositions. In one embodiment a topical delivery composition in a pressurised container comprises up to 15 % wt of at least one pharmaceutically active compound, or its pharmaceutically acceptable salt; from about 83 % to about 97.9 % wt of a carrier; and from about 2 % to about 7 % wt of an aerosol propellant selected from the group consisting of a hydrocarbon or a hydroflurocarbon, a chloroflurocarbon, and a mixture thereof.
In a preferred embodiment the compositions of the present invention are present in a pressurized container comprising a homogenous mixture of from about 0.1 % to about 10 % wt of a pharmaceutically active ingredient, or its pharmaceutically acceptable salt from about 83 % to about 97.9 % wt of a carrier, and from about 2 % to about 79 % wt of an aerosol propellant selected from the group consisting of a hydrocarbon, a hydrofluorocarbon and a mixture thereof and a surfactant system comprising non-hydrogenated lecithin and a glyceride.
When the above composition is released i.e. dispensed from a pressurized container, a foam is formed.
The maximum amount of propellant used is often determined by its miscibility with other components in the composition to form a mixture, such as a homogeneous mixture. The minimal level of propellant used in the composition is often determined by the desired foam characteristics and its ability to substantially or completely evacuate the container. Water and optionally a pH-adjusting agent generally comprise the remaining portion as a carrier. The amount of water present ranges from about 10 % to about 95 % wt, preferably from about 10 % to about 90 % wt more preferably from about 20 % to about 90 % wt with from about 30 % to about 40 % wt or alternatively from about 80 % to about 95 % wt.
Preferably the pressurized container is a one-piece aluminium container in which the inner surface is lined with a chemically inert lining. A preferred inner surface lining is polyamide-imide (PAM) lacquer. Typically the container is fitted with an upright or inverted valve and a conventional foam spout actuator.
The invention is applicable for the topical administration of any pharmaceutically active material. It has been found that the invention is particularly useful with at least one pharmaceutically active material chosen from anti-inflammatory, myorelaxing, antimicotic, antihistaminics, antibiotics, local anesthesics and analgesic active pharmaceutical ingredients and combinations thereof. The invention is also useful for the topical delivery of steroidal and non-steroidal anti-inflammatory pharmaceutical agents as well as non steroidal inflammatory active materials such as diclofenac, nimesulide, ketoprofene. In a preferred embodiment, the active ingredient is hydrocortisone acetate. In a further embodiment, the active ingredient is sodium butyrate. In a preferred embodiment, the active ingredient is econazole.
DETAILED DESCRIPTION OF THE INVENTION
Non-hydrogenated lecithin as used herein includes synthetic lecithins and their derivatives and also includes naturally occurring lecithin and the non-hydrogenated versions of lecithin of natural and synthetic lecithin and their derivatives. "Lecithin" refers to a material which is a phosphatide on naturally occurring or synthetic phosphatides can be used. Phosphatidylcholine is the preferred form of lecithin and is a derivative of glycerine esterified with a choline ester of phosphoric acid and two fatty acid groups which may be the same or different. Preferably the fatty acids are saturated or unsaturated fatty acids, having 16-20 carbons and containing up to 4 double bonds. Natural lecithins can be extracted from vegetable matter (e.g. sunflower seeds, soybeans, safflower seeds and cottonseed), animal (e.g. egg yolk) or lecithins of synthetic origin can be used. The preferred structure of the lecithin will depend upon the nature of the pharmaceutical active ingredient. A definition of lecithin may be found in Stedman's medical dictionary 21 $t ed., page 8791 which defines lecithin as any of a group of phospholipids which upon hydrolysis yield two fatty acid molecules and a molecule each of glycerophosphoric acid and choline. There are therefore several varieties of lecithin. Lecithin is a mixture of the diglycerides of stearic, palmitic, and oleic acids, and palmitoleic, linoeic, linolenic, and arachidonic acids, linked to the choline ester of phosphoric acid. Soybean lecithin is a preferred lecithin and may contain the following acids; palmitic, stearic, palmitoleic, oleic, linoleic, linolenic and arachidonic. In some lecithins both fatty acids are saturated while others contain only unsaturated fatty acids for example, oleic, linoleic or arachidonic. In other lecithins one fatty acid is saturated, the other unsaturated. Lecithins are found in nervous tissue, hepatic tissue, cardiac tissue, in egg yolks and in soy which constitutes the most common and economical source of phosphatidylcholine. Accordingly any reference herein to non-hydrogenated lecithin or phosphatidylcholine is intended to include any combination of non-hydrogenated lecithin-like phospholipids compounds. Examples of other phospholipids which can be used in accordance with the present invention include phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and phosphatidic acid. A mixture of any of the above phospholipids may also be used in the present invention. Mixtures of these phospholipids are present in a natural soy lecithins.
The term glyceride as used herein refers to an ester of glycerol with carboxylic acids and includes mono-, di - and tri-glycerides and mixtures thereof. Glyceride includes synthetic and naturally occurring glycerides and derivatives thereof. The term polyglycolised glyceride refers to esters of glycerol that have been ethoxylated or propoxylated. These materials can be complex mixtures of compounds derived from the reaction of glycerol and/or its derivatives, ethylene and/or propylene oxide and carboxylic acids which may themselves be mixtures of carboxylic acids.
The term "polyglycolyzed glyceride" as used herin refers to specific mixtures of mono-, di- and triglycerides and polyethylene glycol mono and diesters, obtained either by partial alcoholysis of hydrogenated vegetable oils using polyethylene glycol. The "polyglycolyzed glycerides" may be saturated or unsaturated and may be complexes of ethoxylated glycerides and polyethylene glycol esters. In a particular embodiment, the saturated polyglycolyzed glyceride is a glyceryl caprylate/caprate and PEG-8 (polyethylene glycol) caprylate/caprate complex commercially available as Labrosol is a preferred material. The polyglycolyzed glycerides of the present invention have Hydrophilic Lipophilic Balance (HLB) values of between and including 6 and 14 typically the free glycerol content is less than 3%. Examples of suitable polyglycolyzed glycerides include Labrafac.RTM.CM 10, Labrafil.RTM.M 10, Labrafil.RTM. NA10, Labrafac.RTM.CM 12, Labrasol.RTM. (Labrafac.RTM.CM 14) and the like.
Examples of polyglycolyzed glycerides include Labrafac.RTM.CM 6, Labrafil.RTM. WL2609 BS, Labrafac.RTM.CM 8, Labrafac.RTM.CM10, Labrafil.RTM.M 10, Labrafil.RTM. NA10, Labrafac.RTM. CM12, and Labrasol.RTM. (Labrafac.RTM. CM 14). Preferred polyglycolyzed glycerides having HLB values of between 6 and 14 inclusive, and containing medium chain (C8 - C10) triglycerides, are Labrafac.RTM. CM6, Labrafac.RTM.CM8, Labrafac.RTM. CM10, Labrafac.RTM. CM12, and Labrasol.RTM. (Labrafac.RTM. CM 14). Analogs and derivatives of the above polyglycolyzed glycerides are also suitable for use in the compositions and methods of the present invention. To the extent that these analogs and derivatives are similar in structure to or are readily obtained by chemical modification of the polyglycolyzed glycerides. While substantially retaining the physical properties of the polyglycolyzed glycerides, such analogs and derivatives are intended to be included among the compositions and methods of the present invention.
As used herein, the term "foam" refers to finely dispersed suspensions of liquid and/or solid materials in a gaseous medium, the suspension being released from pressurized containers as droplet dosage foams upon actuation of the valve of the container.
The present invention therefore provides various pharmaceutically active topical compositions applied as foams based on the finding that the combined use of non-hydrogenated lecithin and glycerides, particularly polyglycolyzed glycerides produce a synergistic effect resulting in an enhanced absorption of the active pharmaceutical ingredient by the skin and an easier delivery of the drug.
In particular, the topical compositions of the present inventions are solutions or suspensions suitable to be delivered as a foam or droplets from a pressurised container upon actuation of a valve. The foam preferably contains the active pharmaceutical ingredient in a concentration between 0.5 and 10% weight/volume together with non-hydrogenated lecithin in concentration between 0.1 % and 10%, and glycerides in concentration between 5% and 30%. Preferably, the non-hydrogenated lecithin is present in a concentration between 0.1 % and 5 % and the glyceride is in a concentration between 8% and 15%. More preferably, the non-hydrogenated lecithin is present in a concentration between 0.3% and 0.5% and the glyceride is present in a concentration between 9 % and 11 % the balance of the formulation being other additives and a carrier such as water.
The foam compositions can be applied for absorption on the skin of humans or animals or, varying the ingredient ratios as suitable, vaginal, rectal, buccal mucose.
The invention is particularly useful with formulations in which the active pharmaceutical ingredient is one or more of anti-inflammatory, myorelaxing, antifungal, antihistamines, antibiotic, local aesthetic and analgesic agents. The invention in particular is useful in the provision of a topically applied composition for delivery of steroidal and non-steroidal anti-inflammatory pharmaceutical agents, in particular the active pharmaceutical ingredients can comprise, but are not limited to, diclofenac, hydrocortisone acetate, nimesulide, ketoprofene, tiocolchicoside and sodium butyrate.
Optionally the compositions may contain additional components such as perfumes, bacteriostatic agents (e.g. benzyl alcohol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and analogues), anti-oxidants (e.g. tocoferol acetate, butyl hydroxy anisole, butyl hydroxyl toluene and analogues).
An additional benefit of the present invention is that non-hydrogenated lecithin and/or its derivatives is used. Non-hydrogenated lecithins do not require elaborated purification treatments, and provide a cost-effective solution for the production of pharmaceutical foams which is particularly suitable for industrial production.
The enhanced skin permeability achieved using foams containing a combination of non- hydrogenated lecithins and glycerides particularly polyglycolyzed glycerides in comparison to the results obtained using the separate components is demonstrated by the results in the following experimental report.
Permeability Study
The transdermal permeability of the active pharmaceutically ingredient used in the formulations was evaluated using Franz cells permeation test using porcine inner ear epidermis as the septum between the formulation (donor compartment) and the receptor phase chamber.
For these studies porcine epidermis is the preferred model as it displays permeation properties similar to those of human skin (International Journal of Pharmaceutics 2007, 331 , 139).
In the study three Franz cells were used, each having a compartment donor of 9 mm diameter corresponding to a diffusional area of 64 mm2. The compartment had 4.8 ml_ capacity. The receptor chamber is encircled in a jacket in which water is circulated at 37 ± 10C. The samples of skin are taken from the inner ear of the pig as soon as sacrificed and dipped, for 24 h, in a solution buffer at pH. 7.4 held at 40C. Subsequently the connectival parts are removed by surgical technique and the remaining skin is cut in squares of 2x2 cm. The squares obtained are conserved until use at 200C. The test is conducted by positioning the porcine skin between the donor compartment and the receptor chamber with the external surface towards the upper compartment. The foam pharmaceutical formulation is placed inside the donor compartment. The receptor chamber is then filled up with phosphate buffer at pH 7.4. 2 ml of the buffer solution are then sampled at regular time intervals and analysed for the content of the active pharmaceutical ingredient, when a sample is removed the initial volume of the solution is restored with phosphate buffer heated at 37°C. The samples thus obtained are stored at to 4°C until the quantitative analysis is performed.
The test is repeated 9 times for every formulation and the samples obtained are analysed by HPLC.
The chromatographic conditions used for the determination of the active ingredient were as follows.
Mobile phase: acetonitrile (65%), phosphate buffer at pH 3, 5 (35%). Flow: 1,2 ml/min,;
Pressure: 1 ,52 5.51 Kpsi λ = 278nm; TR = milimeter Column: C-18 micron Lichrospher 1.
For other active ingredients analyses were performed using suitable variations.
The Flow and the coefficient of permeability (Kp) were found to be as follows - diclofenac foam with non-hydrogenated lecithin only: Flow in g/cm2 h = 144,23; Kp= 0.03231- diclofenac foam with non-hydrogenated lecithin and labrasol: Flow in g/cm2 h= 155,08; Kp = 0.03545
The examples which follow are included only to illustrate, without limiting, the scope of the invention.
Example 1- diclofenac Foam
In a suitable container diclofenac sodium salt is dispersed in purified water under stirring, until complete dissolution is obtained. The Labrasol, benzyl alcohol, potassium sorbate and alfa tocoferyl acetate, previously dispersed in Polysorbate 80, and are then added and stirred until dissolved.
Non-hydrogenated phosphatidilcoline (lecithin) is dissolved in purified water and then introduced into the main container together with the flavouring agent and stirred for 15-20 minutes.
The formulation is then diluted to the required volume with purified water and stirred for 15-20 minutes with pH control (limits: 7-9). The solution is then filtered under pressure. The desired weight of the solution is placed into a canister provided with a valve and then a propellant gas is pumped into the canister, to pressurise the formulation and provide 5 wt % propellant.
The propellant gas was a mixture of 80 % isobutane and 20 % n-butane.
The composition of the solution in percentage was
1 diclofenac sodium salt (corresponding to 3,000 of the base)
2 non-hydrogenated phosphatidilcholine (lecithin) 0.300 3 caprylocaproyl macrogol glycerides (Labrosol) 10.000
4 benzyl Alcool 0.500
5 potassium sorbate 0.100
6 Polysorbate 80 0.100
7 alfa tocoferyl acetate 0.100 8 scent 1.000
9 purified Water up to 100.000
Example 2- ketoprofene Foam
The formulation was produced in a manner similar to that described in Example 1 , with variations of some excipients and of the active ingredient. The final composition of the solution, in percentage, was
1 ketoprofene acid 3.000
2 trometamina 5.400
3 non-hydrogenated Phosphatidylcholine (lecithin) 0.200 4 caprylocaproyl macrogol glycerides (Labrasol ®) 10.000
5 benzyl alcool 0.500
6 potassium sorbate (preservative) 0.100
7 polysorbate 80 6.000
8 alfa tocoferyl acetate 0.100 9 scent 1.000
10 purified water up to 100.000 and it was placed in the canister with the propellant gas following the same procedure as in Example 1.
Example 3- hydrocortisone Foam The formulation was produced in a manner similar to that described in Example 1 , with variations of some excipients and of the active ingredient; composition of the solution, expressed percentage was
I hydrocortisone acetate 0.558 2 polysorbate 80 6.000
3 benzyl alcool 0.5
4 polyacrylamide copolymer (thickener) 1.000
5 glycerol 3.000
6 caprylocaproyl macrogol glycehdes (Labrasol) 5.000 7 non-hydrogenated phosphatidylcholine (lecithin) 0.300
8 methyl- p- hydroxybenzoate (preservative) 0.150
9 propyl-p-hydroxyibenzoate (preservative) 0.050
10 a lfa tocoferyl acetate 0.100
I I scent 1.000 12 purified water up to 100.000 and it was placed in the canister with the propellant gas following the same procedure as in Example 1.
Example 4- thiocolchicoside Foam The formulation was produced in a manner similar to that in Example 1 , except that the lecithin was not employed, the formulation had the following composition in percentage terms
1 tiocolchicoside 10.000
2 sodium hydroxide 0.400
3 non-hydrogenated phosphatidylcholine (lecithin) 0.200 4 caprylocaproyl Macrogol glycerides 5.000
5 potassium sorbate (preservative) 0.100
6 polysorbate 80 6.000
7 benzyl alcool 0.500
8 alfa tocoferyl acetate 0.100 9 scent 1.000
10 Purified water up to 100.000 and it was placed in the canister with the propellant gas following the same procedure as in Example 1.
Example 5- econazole Foam
The formulation was produced in a similar manner to that described in Example 1. The final composition of the solution, expressed in %. was 1 Econazole 3.000
2 sodium hydroxide 0.405
3 non-hydrogenated phosphatidylcholine (lecithin) 0.300
4 Caprylocaproyl Macrogol glycerides 10.000 5 benzyl alcool 0.500
6 potassium sorbate 0.100
7 polysorbate 80 2.000
8 alfa tocoferyl acetate 0.100
9 scent 1.000 10 purified water up to 100.000 and it was placed in the canister with the propellant gas following the same procedure as in Example 1.

Claims

1. A composition comprising i) a pharmaceutically active ingredient for topical application ii) a liquid carrier iii) a propellant iv) a surfactant comprising a mixture of non-hydrogenated lecithin and one or more glycerides and derivatives thereof v) from 20% to 95% of water based on the weight of the composition.
2. A pressurised container equipped with a contents release valve containing a composition comprising i) a pharmaceutically active ingredient for topical application ii) a liquid carrier iii) a propellant iv) a surfactant comprising a mixture of non-hydrogenated lecithin and one or more glycerides and derivatives thereof v) from 20% to 95% of water based on the weight of the composition.
3. The topical treatment by application to skin of a foam comprising i) a pharmaceutically active ingredient for topical application ii) a liquid carrier iii) a propellant iv) a surfactant comprising a mixture of non-hydrogenated lecithin and one or more glycerides and derivatives thereof v) from 20% to 95% of water based on the weight of the composition.
4. A system according to any of claims 1 to 3 in which one or more antioxidants are included in the formulation.
5. A system according to any of the preceding claims in which the glyceride comprises caprylcaproyl macroglycerides.
6. A system according to any of the preceding claims in which the pharmaceutically active ingredient is a combination of active agents comprising at least two agents selected from an antibacterial agent, and an antifungal agent, anaesthetic, anti-inflammatory, anti-histaminic.
7. A system according to any of the preceding claims comprising a topical delivery composition in a pressurised container which comprises up to 15 % wt of at least one pharmaceutically active compound, or its pharmaceutically acceptable salt, from 83 % to 97.9 % wt of a carrier and from 2 % to 7 % wt of an aerosol propellant and from 20% to 95% wt of water.
8. A system according to claim 7 wherein the propellant comprises of a hydrocarbon, a hydrofluorocarbon, or a chlorofluorocarbon, or mixtures thereof.
9. A system according to any of the preceding claims further comprising a pH adjusting agent.
10. A system according to any of the preceding claims in which the amount of water ranges from 30 % to 40 % wt.
11. A system according to any of the preceding claims in which the pharmaceutically active material is chosen from anti-inflammatory, myorelaxing, antimicotic, antihystaminics antibiotics, local anesthesics and analgesic active pharmaceutical ingredients.
12. A system according to claim 11 in which the pharmaceutically active material is a steroidal or non-steroidal anti-inflammatory pharmaceutical agents.
13. A system according to any of the preceding claims in which the pharmaceutically active material is hydrocortisone acetate.
14. A system according to any of the preceding claims in which the pharmaceutically active material is sodium butyrate.
15. A system according to any of the preceding claims in which the pharmaceutically active ingredient is econazole.
16. A system according to any of the preceding claims in which the foam contains the active pharmaceutical ingredient in a concentration between 0.5 and 10% weight/volume together with non-hydrogenated lecithin in a concentration between 0.1% and 10%, and glycerides in concentration between 5% and 30%.
17. A system according to claim 16 in which the non-hydrogenated lecithin is present in a concentration between 0.1% and 5% and the glyceride is in a concentration between 8% and 15%.
18. A system according to any of the preceding claims further containing components selected from perfumes, bacteriostatic agents and anti-oxidants.
EP08860575A 2007-12-12 2008-11-30 Pharmaceutical foams Withdrawn EP2231119A1 (en)

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US9358209B2 (en) 2010-10-26 2016-06-07 Exeltis Usa Dermatology, Inc. Econazole composition and methods of treatment therewith
US9205093B2 (en) * 2012-09-11 2015-12-08 Gary Marder Hydrocortisone nanotechnological delivery system

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