MXPA06011585A - Pimecrolimus foam composition containing hexylene glycol, optionally oleyl alcohol, dimethylisosorbide and/or medium chain triglycerides - Google Patents

Abstract

Pharmaceutical foam compositions substantially free of ethanol and comprising pimecrolimus in a carrier vehicle comprising a mixture of oily solvents amounting to at least 40%of the total weight of the composition and consisting of:i) hexylene glycol;ii) optionally oleyl alcohol;and iii) dimethylisosorbide and/or medium chain triglycerides;and additionally:iv) when oleyl alcohol is absent, water in an amount of less than 25%;v) at least one consistency agent;vi) at least one preservative;and vii) at least one surfactant/emulgator;and propellant gas for foaming;and optionally further conventional excipients. They are indicated for use in the treatment of various skin, nail and mucosal diseases.

Description

COMPOSITION OF PIMECROLI US FOAM CONTAINING HEXILENGLICOL. OPTIONALLY OLEILIC ALCOHOL. Pf ETHICALSORBIDE AND / OR TRIGLYCERIDES OF MEDIUM CHAIN This invention relates to pharmaceutical compositions, for use in particular in the treatment of skin diseases. It relates to a pharmaceutical composition comprising the anti-inflammatory ascomycin derivative pimecrolimus in the form of a foam. WO 2004/016289 discloses pharmaceutical compositions substantially free of ethanol and water comprising an ascomycin in a carrier vehicle comprising a mixture of three components amounting to at least 40% of the total weight of the compositions and consisting of: i) a alkanol of 3 to 8 carbon atoms; ii) a fatty alcohol; and iii) an additional solvent selected from: a) an alkane ester of alkane carboxylic acid or alkyl ester of alkane carboxylic acid and / or b) a hydrophilic co-compound and c) a triglyceride; and optionally additional conventional excipients. Although these compositions are essentially liquid or semisolid single-phase, it is also envisioned in that description that the liquid phase can form the liquid component of a foam formulation.

It has now been found that, surprisingly, foams comprising the ascomycin pimecrolimus in a particular type of formulation not described as such herein and having a high oil content, although optionally including a small amount of water added, are particularly beneficial. Specifically, the invention relates to a foam pharmaceutical composition substantially free of ethanol and comprising pimecrolimus in a carrier vehicle comprising a mixture of oily solveni which account for at least 40% of the total weight of the composition and which consists of: i) hexylene glycol; I) optionally oleyl alcohol; and iii) dimethyl isosorbide and / or medium chain triglycerides; and additionally: iv) when the oleyl alcohol is absent, water in an amount less than 25%; v) at least one consistency agent; vi) at least one conservator; and vii) at least one surfactant / emulsifier; and propellant gas for foaming; and optionally additional conventional excipients; hereinafter briefly called "the composition of the invention". Thus, at least 40% of the total weight of the composition consists of hexylene glycol, oleyl alcohol, dimethyl isosorbide and / or medium chain triglycerides.

In a subgroup the composition of the invention is substantially free of ethanol and water and comprises pimecrolimus in a carrier vehicle comprising a mixture of three components of oily solvents amounting to at least 40% of the total weight of the composition and consisting of: i ') hexylene glycol; I ') optionally oleyl alcohol; and iii1) dimethyl isosorbide and / or medium chain triglycerides; and additionally: v ') at least one consistency agent; vi ') at least one conservator; and vii ') at least one surfactant / emulsifier; and propellant gas for foaming; and optionally additional conventional excipients; In a preferred subgroup thereof the carrier vehicle for pimecrolimus consists of: i ') hexylene glycol; ii ') optionally oleyl alcohol; and iii ') dimethyl isosorbide and / or medium chain triglycerides; and additionally: v ') hydroxypropyl cellulose and / or stearyl alcohol; vi ') p-hydroxybenzoic acid ester with ethylene glycol phenyl ether; and vii ') glyceryl monostearate and nonionic sugar esters; and propellant gas for foaming. In another subgroup, the composition of the invention is substantially free of ethanol and comprises macroimemus in a carrier vehicle comprising a mixture of two components of oily sorts which amount to at least 40% of the total weight of the composition and which consists of: i ") hexylene glycol, and iii ') dimethyl isosorbide and / or medium chain Vriglycerides; and additionally: iv ") water in an amount less than 25%; v") at least one consistency agent; vi ") at least one conservative, and vii") at least one surfactant / emulsifier; and a propellant gas for foaming; and optionally additional conventional excipients. In a preferred subgroup thereof the carrier vehicle for pimecrolimus consists of: i ") hexylene glycol, and iii") medium chain triglycerides and optionally dimethylisosorbide; and additionally: iv ") water in an amount less than 25%; v") polyvinylpyrrolidone and stearyl alcohol; vi ") p-hydroxybenzoic acid ester with ethylene glycol phenyl ether; and vii") glyceryl monostearate and lecithin; and propellant gas for foaming. The composition of the invention is effective irrespective of the condition of the skin, nails or mucosa, is tolerated, stable and has particularly interesting penetration properties. It preserves and improves the beneficial penetration properties of more complex or non-homogeneous formulations such as emulsions or suspensions based on water or hydrocarbons, which is particularly convenient in terms of ease of administration and compliance by the patient. It has the advantage that it consists of few components, it is easy to prepare and well tolerated in the human skin. Pimecrolimus is the compound of formula l: (Example 66a in EP 427680), that is,. { [1 E- (1 R, 3R, 4S)] 1 R, 9S, 12S, 13R, 14S, 17R, 18E, 21S, 23S, 24R, 25S, 27R} -12- [2- (4-c / oro-3-methoxycyclohexyl) -1-methylvinyl] -17-etrl-1, 14-dihydroxy-23,25-dimethoxy-13, 19.2, 27-tetramethyl- 1, 28-dioxa-4-azatricyclo [22.3.1 .0 (4,9)] octacss-18-ene-2,3,? 0, 16-tetraone. The glycoxy hexyion preferably is in an amount from about 1% to about 10% when component ii) is present, and preferably in an amount from about 2% to about 20%, preferably from about 5% to about 10%. when component iv) is present. The oleyl alcohol, when present, is preferably in an amount from about 1% to about 20%.

The added water, when present, is preferably in an amount from about 1% to about 20%, especially from about 5% to about 15%. The dimethyl isosorbide is preferably in an amount from about 35% to about 90% when component ii) is present, and from about 0% to about 20%, preferably from about 0% to about 10% when component iv) is I presented. Medium chain triglycerides are preferably in an amount of from about 5% to about 20% when the component ii) is present, and from about 50% to about 80%, preferably from about 60%) to about 70% when the present component iv). The consistency agents may be conventional, for example as described in WO 2004/016289. Preferably they are hydroxypropylcellulose or polyvinylpyrrolidone, and / or stearyl alcohol; when component ii) is present, they are preferably in an amount from about 0.1% to about 5%, for example hydroxypropylcellulose from about 0.2% to about 1% together with stylaric alcohol from about 1% to about 5%; when present component iv), preferably they are in an amount from about 1% to about 10%, for example polyvinylpyrrolidone from about 1% to about 5% together with stearyl alcohol from about 3% to about 10%. The preservatives may be conventional, for example as described in WO 2004/016289, preferably they are esters of p-hydroxybenzoic acid (parabens), for example an ester of p-hydroxybenzoic acid with ethylene glycol phenyl ether, such as Phenonip®. Preferably they are in an amount from about 0.1% to about 0.5%. The surfactants / emulsifiers for foaming may be conventional, for example cationic, nonionic or anionic, for example cetrimide, lecithin, soaps and silicones. Commercially available surfactants such as Tween® are also suitable. Glyceryl monostearate, lecithin and non-ionic sugar ester are preferred, such as System SP-30 and SP-70. When component ii) is present, the amount of surfactant / emulsifier is from about 0.5% to about 5%, for example, glyceryl monostearate from about 1% to about 3%, together with System SP-30 and SP-70, each one from about 0.5% to about 2%. When present compound iv), the capacity of the emulsifier / emulsifier is from about 0.5% to about 20%, for example glyceryl monostearate from about 1% to about 3%, together with lecithin from about 5% to about 20%. The propellant gas for foaming is, for example, any harmless gas conventionally used as a propellant, such as butane or propane, or a mixture of butane and propane, for example, in the ratio of about 80/20. "Substantially free of ethanol" and "substantially free of water" means that neither ethanol nor water is added, respectively, as an intentional constituent part of the composition of the invention. However, for example, a small amount of moisture, for example up to about 1% water, may be present, for example as an intrinsic purity in one of the excipients used, or as part of the active ingredient when it is, for example a hydrate, for example when the crystal form A of pimecrolimus is used. "%" means in the present percent on a weight basis by weight (w / w). "Tofal weight of the composition" is to be understood as referring to the total weight including surfactant / emulsifier, but without propellant gas. A particularly beneficial aspect of the composition of the invention is that although the components of the above oily solvenides are solubilizing agents, they additionally have enhanced penetration properties, thus helping to maintain the formulation both simple and effective. "Treatment" as used in the present includes prevention, namely prophylactic as well as curative treatment. The component of the active agent can be in free form or in pharmaceutically acceptable salt form if such forms exist. The invention thus provides a formulation for application to a body surface such as a foam, comprising the active ingredient pimecrolimus and a foamable carrier vehicle as defined above. The active ingredient may be present as an integral part of the formulation, or some components may be maintained separately from other ingredients of the formulation and be combined therewith during the formation of the foam. The formulation comprises a foaming agent (particularly, at least one surfactant / emulsifier) which is capable of promoting the production of a foam structure. The invention also provides, therefore, a foamable carrier and an active ingredient with some components of the carrier packaged separately therefrom, which are mixed with the other components during the foaming process. The foam can be exposed to the atmosphere so as to dry in a coating, or it can be covered by conventional dressings. The composition of the invention is applied to the site of the body of interest in the form of a foam and, therefore, it is necessary that the composition undergoes a process of foaming anis of the application to the body. In the foaming process, gas is forced into or formed within the formulation to trap small gas bubbles in it, thus forming foam. Any suitable gas or gas producing system can be used to produce the foam, for example, buffalo, propane and niferous oxide, but other gases are also suitable. Normally the foam is produced by conventional means such as by aerosol technology. The composition can be stored in any convenient container until required. Generally, the container is designed to preserve the sterile nature of the formulation. The container will be conveniently provided with means for foaming the composition when required. The invention then also provides a closed container containing a composition of the invention, capable of ejecting the formulation in the form of a foam. For example, the container may be an aerosol can, which contains a pressurized gas which in use causes the production of the foam. Alternatively, the gas can be produced by a chemical reaction when two different ingredients are mixed, contained, for example, in two portions of a sachet. The closed container may have separate deposits for the foamable carrier or parts thereof and the active ingredient. Thus, the foamable carrier or parts thereof and the active ingredient are stored separately and mixed together in suitable proportions during the foaming process. The invention also provides an apparatus for producing a foam for application to a body surface of a composition of the invention, which comprises: a) a closed container having a reservoir containing the foamable carrier or parts thereof, and a reservoir containing the active ingredient and the carrier resins of the carrier; and b) means for producing a foam from the foamable carrier. Optionally, additional foaming agents can be mixed with the foamable carrier. The gel can be sterilized and this is generally desirable for medical use. The sterilization can take place by subjecting the composition to autoclaving, for example, at temperatures from about 100 ° C to about 125 ° C, for example for less than 30 minutes. The advantages of applying a topical product in the form of a foam include: - easy and fast application; - can conform to superficial irregularities; - isolation of the diseased area; - Cooling of the felts; - antibacterial action to prevent infection; - biocompatibility with tissues; and / or - maintenance of a humid environment. This produced foam can subsist for a period of time of, for example, 3 to 24 hours, as some of the gas trapped in the foam structure escapes. The foamed composition is gradually dried to produce a sheet of foam which still retains a basic foam structure and which can cover the site to which the foam was applied. This sheet of foam can be left in place as a proiecfora cover. The composition of the invention will normally be applied directly to the site of the body of interest in the form of a foam produced from a suitable device, such as an aerosol, immediately prior to administration. It is possible to previously produce an amount of the foamed composition which is then applied to the body site by any suitable means, for example by hand or spatula. The composition of the invention may optionally comprise additional conventional excipients, such as plasticizers, humectants (eg, glycerol, prophan-1, 2-diol, polypropylene glycol and other polyhydric alcohols), free radical scavengers, antioxidants, viscosity adjusting agents , iinids and colorants, for example as described in "Lexikon der Hílfsstoffe für Pharmazie, Kosmeíik und angrenzende Gebieie", HP Fiedler, Cantor Verlag Aulendsrf edition, Aulendorf, 5th edition (2002). The composition of the invention is indicated for use in the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases. The terms "skin" and "cutaneous" should be broadly understood to also include diseases of, for example, nails or mucous membranes. Examples of immunogenic diseases include alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and eczematous dermatitis, seborrheic dermatitis, lichen planus, pemfigus, bullous pemphigoid, epidermolysis hullosis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, and lupus erythematosus. Examples of skin diseases include dermatomyositis, leucoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, acne, autoimmune diseases such as chronic rheumatoid arthritis, scleroderma and the like. The invention also provides a composition as defined above for use in the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases. It also provides a method for treating inflammatory and hyperproliferative skin diseases or cutaneous manifestations of immunologically mediated diseases, which comprises administering a composition of the invention to a patient in need thereof. Still further, it provides the use of a composition of the invention in the preparation of a medicament for the treatment of inflammatory and hyperproliferal skin diseases and cutaneous manifestations of immunoiologically-mediated diseases. It further provides the use of a carrier vehicle as defined above to increase the penetration of pimecrolimus into human skin, nails or mucous membranes. The composition of the invention can be prepared in a conventional manner by handling the components to a pharmaceutical composition. For example, the composition of the invention can be obtained by dissolving pimecrolimus in hexylene glycol and / or oleyl alcohol or medium chain triglycerides, and other components, for example, dimethyl isosorbide and the additional excipients, can be added at the appropriate time as is conventional. The following Examples illustrate the invention. The compounds are in free, ie neutral, or base form unless otherwise specified. Example 1 . Foam Component Quantity (g) Pimecrolimus 1 .0 1) Acetyl solvents: i) hexylene glycol 2.5 ii) oleyl alcohol 2.5 iii) dimefilisosorbide (ArlasoIveR) 77.2 medium chain triglycerides (oil) 10.0 2) Consisinance agents: hydroxypropylcellulose (Klucel MF) 0.5 stearyr alcohol 2.0 3) Preservative: PhenonipR (an ester of p-hydroxybenzoic acid 0.3 with ethylene glycol phenyl ether) 4) Surfactants / emulsifiers: glyceryl monostearate 2.0 System SP-30 and SP-70 1.0 (each) (= non-ionic sugar esters, mild emulsifiers) Total 100.00 5) Propellant: 80/20 butane / propane The preparation is in accordance with conventional manufacturing processes for a foam. Example 2: Foam Component Quantity (g) Pimecrolimus 1 .0 1) Oily solvents: i) hexylene glycol 10.0 ii) medium chain glycerides (oil) 59.7 2) Water 10.0 5 3) Consistency Agents: polyvinylpyrrolidone (PVP K90) 2.0 stearyl alcohol 5.0 4) Preservative: Phenonip® (an acid ester) p-hydroxybenzoic 0.3"1 ° with ethylene glycol phenyl ether) 5) Surfactants / emulsifiers: glyceryl monostearate 2.0 lecithin 1 0.0 Tofal 100.00 6) Propelenie: 80/20 bulano / propane The preparation is in accordance with conventional manufacturing processes for a foam. Example 3: Foam 0 Regarding Example 2, whereby as solvent i) only 5.0 g of hexylene glycol is used, and as solvent ii) 5.0 g of dimethyl isosorbide are included in addition to the triglycerides.

Claims (9)

1. CLAIMS 1. A pharmaceutical foam composition substantially free of ethanol and comprising pimecrolimus in a carrier vehicle comprising a mixture of oily solvents which amount to at least 40% of the total weight of the composition and which consists of; i) hexylene glycol; ii) optionally oleyl alcohol; and iii) dimethyl isosorbide and / or medium chain triglycerides; and additionally: iv) when oleyl alcohol is absent, water in an amount less than 25%; v) at least one consensual agency; vi) at least one conservator; and vii) at least one surfactant / ethnulsifier; and gas propelenie for foaming; and optionally additional conventional excipients. A composition according to claim 1, substantially free of ethanol and water and comprising pimecrolimus in a carrier vehicle comprising a mixture of three oily solvent components amounting to at least 40% of the total weight of the composition and consisting of: i :) hexylene glycol; ii ') oleyl alcohol; and iii ') dimethyl isosorbide and / or medium chain triglycerides; and additionally: v!) at least one consistency agent; vi ') at least one conservator; and vii ') at least one tensioner / emulsifier; and propellant gas for foaming; and optionally additional conventional excipients. 3. A composition according to claim 1, comprising pimecroiimus in a carrier vehicle comprising a mixture of two components of solvent solvents which add up to at least 40% of the total weight of the composition and consisting of: i ") hexylene glycol; and iii ') dimethylisosorbide and / or medium chain triglycerides, and additionally: iv ") water in an amount less than 25%; v ") at least one consistency agent; vi") at least one conservative; and vii ") at least one surfactant / emulsifier, and a propellant gas for foaming, and optionally additional conventional excipients 4. A composition according to claim 1 or 2, comprising pimecrolimus in a carrier vehicle consisting of: ') hexylide glycoli;) oleyl alcohol; and iii') dimethyl isosorbide and / or medium chain triglycerides, and additionally: v ') hydroxypropyl cellulose and / or stearyl alcohol; vi ') ester of p-hydroxybenzoic acid with ethylene glycol ether; and vii ') glyceryl monostearate and nonionic sugar esters; and propellant gas for foaming. 5. A composition according to claim 1 or 3, comprising pimecrolimus in a carrier vehicle consisting of: i ") hexylene glycol, and iii") medium chain glycerides and optionally dimethylisosorbide; and additionally: iv ") water in an amount less than 25%; v") polyvinyl pyrrolidone and esaryle alcohol; vi ") ester of p-hydroxybenzoic acid with phenylene glycol, and vii") glyceryl monostearate and lecithin; and propellant gas for foaming. 6. A composition according to any of claims 1 to 3, for use in the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases. 7. A method for tracing inflammatory and hyperproliferative skin diseases or cutaneous manifestations of immunologically mediated diseases which comprises administering a composition according to any of claims 1 to 3 to a patient who requires it. 8. Use of a composition according to any of claims 1 to 3, in the preparation of a medicament for the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases. 9. Use of a carrier vehicle as defined in any of claims 1 to 3, to increase the penetration of pimecrolimus into human skin, nails or mucous membranes.