CA2601694A1 - Enhancement of macrolide penetration through human skin - Google Patents

Abstract

The addition of a skin modifying agent to a macrolide having molecular weight between 500 and 1200 Daltons unexpectedly improves the delivery of the macrolide through human skin when compared to the drug mixed with alcohol alone. The skin modifying agent can be formulated with suitable excipients to form a lotion, ointment, cream, or gel for treating psoriasis and other skin disorders.

Description

ENHANCEMENT OF MACROLIDE PENETRATION THROUGH HUMAN
SKIN

CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit of U.S. Provisional Application No.
60/661,031 filed March 14, 2005. This application, in its entirety, is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates to the field of topical drug delivery and more specifically to the field of enhancing topical delivery of macrolides for treatment of skin disorders. In particular, the invention relates to the delivery of physiologically active molecules with molecular weights between 500 Daltons and 1200 Daltons.

BACKGROUND OF THE INVENTION

[0003] The administration of drugs and other biological materials to the bloodstream via a transdermal route of administration has received much attention in recent years. The skin of an average adult covers more than two square meters of surface area and receives about one-third of all blood circulating through the body. It is elastic, rugged, and generally self-generating. Human skin consists of two layers: the epidermis (which is a composite of multiple layers including the stratum corneum), and the dermis.
The stratum corneum (S.C.) represents the rate-limiting step in diffusion of chemical through the skin. The S.C. is composed of dead, keratinized, metabolically inactive cells which are closely packed together, and consists of an amorphous matrix of mainly lipoid and nonfibrous protein within which keratin filaments are distributed. The cells of the S.C. generally contain 20%
water, while the cells below, in the stratum germinativum, contain 70% water.
The S.C. does not become hydrated readily. Thus, transdermal permeation is primarily controlled by diffusion through the S.C.

[0004] There are several major reasons for the interest in transdermal delivery of drugs:

[0005] elimination of uncertainties of absorption from, and irritation to, the gastrointestinal tract which arise when drugs are administered orally;

[0006] bypassing the portal circulation, thereby eliminating first-pass metabolism in the liver; this is extremely important for drugs with short half-lives, or with potential unwanted actions on the liver:

[0007] localized delivery of medication to the intended target site;

[0008] delivery of medication directly into the systemic circulation at a constant rate (similar to intravenous infusion);

[0009] infrequent dosing (daily, weekly or longer) for certain drugs;

[0010] ease of use; foster patient compliance.

[0011] However, present transdermal delivery systems often have major drawbacks. For example, they are restricted to low-molecular weight drugs and those with structures having the proper lipophilic/hydrophilic balance.
High molecular weight drugs or drugs with too high or low hydrophilic balance often cannot be incorporated into current transdermal systems in concentrations high enough to overcome their impermeability through the stratum corneum. Specifically, the literature has shown that chemical transdermal delivery systems, where the skin is undamaged or unaltered, are limited to drugs having a molecular weight of less than 500 Daltons, for example, see JD Bos and MM Meinardi, The 500 Dalton Rule for the Skin Penetration of Chemical Compounds and Drugs 1: Exp. Dermatol. Jun 2000;
9(3): 165-9.

[0012] Transdermal delivery is generally restricted to those small molecule medications requiring delivery rates less than 10 mg/day. In order to obtain higher blood levels, the rate of drug delivery must be increased. There have been many proposals to accomplish the higher rate of drug delivery via the use of absorption promoters and by the development of prodrugs that can be more readily absorbed. Examples of existing absorption enhancers include dimethyl sulfoxide (DMSO), ethylene glycol, hexanol, fatty acid and esters, and pyrrolidone derivatives, among others. One such enhancer compound which has received much attention is Azone (N-dodecyl azacycloheptan-2-one).

[0013] Use of such penetration enhancers has been made for a variety of small molecule drugs as has been demonstrated. Prior art patents of relevance to penetrating enhancers of physiologically active agents include U.S. Pat. Nos. 3,551,554 which describes dimethyl sulfoxide, U.S. Pat. No.
3,989,816 discloses 1-substituted azacycloheptane-2-one; U.S. Pat. No.
4,132,781 discloses a topical antibiotic plus 2-pyrrolidone or an n-lower alkyl-2-pyrrolidone, U.S. Pat. No. 4,017,641 also describes 2-pyrrolidone but with propylene glycol; others of interest are U.S. Pat. Nos. 3,903,256, 4,343,798, 4,046,886, 3,934,013; 4,070,462; 4,130,643, 4,130,667, 4,289,764;
4,070,462; 3,527,864; 3,535,422, 3,598,123, 3,952,099, 4,379,454, 4,286,592; 4,299,826; 4,314,557; 4,343,798; 4,335,115; 3,598,122;
4,405,616, 3,896,238, 3,472,931 and 4,557,934.

[0014] Applicants have previously developed a new class of compounds which are derivatives of 1,3-dioxanes and 1,3-dioxolanes for use as skin penetration enhancing compounds. These compounds, which have been made commercially available under the trademark SEPA , are described in detail in U.S. Pat. No. 4,861,764. Work with the dioxolane enhancers has been described in several literature and patent publications. For example, Samour, et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 16: 183-184 (1989); Marty, et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 16:179-(1989); Marty, et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 17:415-(1990); Michniak, et al., Drug Delivery 2:117-122 (1995); Marty, et al., -Abstract of Paper Presented at American Association of Pharmaceutical Scientists, Washington, D.C., Mar. 26-28, 1990.

[0015] Specific examples of SEPAO enhancers can be found in U.S.
Patents 5,976,566 and 5,968,919 where the topical delivery of non-steroidal anti-inflammatory drugs and hormones are demonstrated. The active molecules for each of these examples have molecular weights that range from approximately 200 Daltons to about 400 Daltons. In an article published in the June/July 2004 issue of Pharmaceutical Formulation and Quality, delivery, via SEPAO, of fat- and water-soluble small molecules, and proteins and biologics is discussed. In addition this article discusses delivery of a peptiae of 1200 mol. wt. through the skin. Unexpectedly, Applicants have discovered that the SEPAO enhancers can enhance delivery of macrolides with molecular weights larger than the 500 MW upper limit previously believed to exist for chemical penetration enhancement.

SUMMARY OF THE INVENTION

[0016] The present invention has as a principal object to provide a stable topical composition effective for the treatment of skin disorders with a macrolide. In one embodiment, the invention can include a corticosteroid in addition to the macrolide.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The compositions of the invention are intended for topical non-invasive application to the skin, providing non-systemic, localized absorption of the macrolide active ingredient, and any other co-active ingredients for treatment of skin disorders. The composition of the present invention can be applied as needed to the affected part of the skin. For example it can be applied one to four times a day.
[0016] Examples of the macrolide.active ingredient which is advantageously administered by the topical formulations of this invention include macrolides with molecular weights greater than 500 Daltons, for example 600 Daltons, and more preferably 700 Daltons and less than 1200 Daltons, for example 1100 Daltons, and more prefereably 1050 Daltons.
Specifically, these macrolides can include tacrolimus, pimecrolimus, sirolimus, ascrolimus, everolimus, ascomycins such as ascomycin, dunaimycins such as dunaimycin, rapamycins such as rapamycin, prolylrapamycin, 32-desmethylrapamycin, 32-desmethoxyrapamycin and other lactone based compounds. Suitable macrolides include the chemical whose structure is:

H

"3C!D, CHg H ...

~ .. "S'H2O
~ ON
C0a, R#gC0= 4QHg [0019] Additional suitable macrolides include 17-allyl-1,14-dihydroxy-12-[2-(4-hyd roxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-d imethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1 Ø4,9]octacos-18-ene-2,3,10,16-tetraone and FK 506.
[0020] The macrolide can be present in amounts ranging from 0.01-5.0 wt.% relative to the weight of the composition, preferably 0.01-2.0 wt.%
relative to the total composition. For example, the macrolide can be present in the follow wt. % relative to the weight of the composition: 0.01, 0.05, 0.1, 0.5, 1, or 1.5.
[0021] Examples of some of the skin disorders that can be treated with the composition include psoriasis, eczema, atopic dermatitis, erythema, pelagra, allergic contact dermatitis, poison ivy, poison oak, poison sumac and other skin disorders.
[0022] The penetration of the active ingredient through the skin is preferably enhanced to an acceptable level by including in the composition an effective amount of a skin penetration enhancing compound in the form of a skin modifying agent of the substituted 1,3-dioxacyclopentane and substituted 1,3-dioxacyclohexane types disclosed in U.S. Pat. No. 4,861,764, the disclosure of which is incorporated herein in its entirety by reference thereto, or the corresponding substituted acetal compound. Representative examples of the skin penetration enhancing compounds include:

[0023] 2-substituted 1,3-dioxolanes of the formula (I):

R Ro O R

1. (I) 2-substituted 1,3-dioxanes of the formula (II):

O

R Ro 2. (II) substituted-acetals of the formula (III):
O R'1 R

O R'2 3. (III) [0024] In the above formulas (I), (II) and (III) R preferably represents a C7 to C14 hydrocarbyl group, Ro, Ri, R2, R3, R4, R5, and R6, each, independently, represent hydrogen or a C, to C4 alkyl group. R', and R'2, each, independently, represent C, to C4 alkyl group.
[0025] The hydrocarbyl group for R may be a straight or branched chain alkyl, alkenyl or alkynyl group, especially alkyl or alkenyl. Preferably, R
represents a C7 to C12 aliphatic group; especially C7 to Clo aliphatic group.
Examples of suitable alkyl groups include, for example, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 2-methyl-octyl, 4-ethyl-decyl, methyl-decyl, and the like. The straight chain alkyl groups, such as n-heptyl, n-octyl, n-nonyl and n-decyl, are especially preferred. Examples of alkenyl groups include, for example, 2-hexenyl, 2-heptenyl, 2-octenyl, 2-nonenyl, 2',6'-dimethyl-2',6'-heptadienyl, 2',6'-dimethyl-2'heptaenyl, and the like.
The R
group may also be substituted by, for example, halo, hydroxy, carboxy, carboxamide and carboalkoxy.
[0026] The C, to C4 alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and the like. The preferred alkyl groups for Ro, and for R, to R6 and for R', and R'2 are alkyl having 1 or 2 carbon atoms, most especially ethyl. Ro, and R, to R6 may also, preferably, all be hydrogen.
[0027] Specific skin modifying agents include, for example, 2-n-pentyl-1,3-dioxolane, 2-n-heptyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxolane, 2-n-undecyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxane, 2-n-undecyl-1,3-dioxane, 2-n-heptylaldehyde-acetal, 2-n-octyl-aldehyde-acetal, 2-n-nonylaldehyde-acetal, 2-n-decylaldehyde-acetal, 3,7-dimethyl-2,6-octadienal (citral), citronal and the like. 2-n-nonyl-1,3-dioxolane is especially preferred and is commercially available from MacroChem Corporation of Lexington, Mass., under the trademark SEPAO.
[0028] Examples of other skin penetration enhancers and co-solvents that may be added in addition to the skin modifying agent include dimethyl sulfoxide (DMSO), polyethylene glycol monolaurate, ethylene glycol, alkyl lactams, long chain amides, hexanol, fatty acids and their esters, and pyrrolidone derivatives.
[0029] The solubilizing and/or absorption-promoting agents that can be used in the present invention means an agent which can dissolve the active or actives or their pharmaceutically acceptable salts with a concentration of at least 0.01 % relative to the total weight of the composition, and further promote the absorption of the active(s) or their pharmaceutically acceptable salts through skin. In other words, the solubilizing and/or absorption-promoting agent affords solubilizing and absorbing abilities to the active(s) or their pharmaceutically acceptable salts. Examples of absorption promoters and/or solubilizers inciude: alkane dicarboxylic esters such as alkane dicarboxylic dialkyl esters (dimethyl adipate, diethyl adipate, diisopropyl adipate, diethyl pimelate, diethyl sebacate, dipropyl sebacate etc.); and higher alkane carboxylic alkyl esters (isopropyl myristate, ethyl myristate, etc.).

[0030] The amount of the skin modifying agent is selected to provide the desired delivery rate for the active compound by taking into consideration such additional factors as, product stability, side effects, carrier system and the like. Generally, depending on the particular delivered compound and other vehicles, amounts of the skin modifying agent in the range of from about 2.0 to 25%, preferably from about 2 or 3 or 4 to 12 or 15 or 20 percent, especially from about 5 to 10 percent, of the composition, will provide optimal flux rate and 24 hour payload of the active ingredient. Usually, for gel formulations the amount of enhancer compound may be lower than for cream formulations, such as from about 2 to 10 percent of the formulation.
[0031] The compositions are generally formulated as gels, especially aqueous-alcoholic gels. However, other forms, such as, for example, lotions, creams, mousses, aerosols, ointments, lubricants, lacquers, patches, solutions, tinctures, and the like, may be used so long as when applied to the affected area of the skin the formulation will stay in place, i.e., without run-off, for sufficient time, to permit an individual to spread and retain the composition over and on the affected area.
[0032] The vehicle for any of the forms of the compositions of the invention may also include glycol, e.g., propylene glycol, butylene glycol, hexylene glycol, etc. (except in the case of the third embodiment described above), lower alcohol, e.g., ethanol, isopropanol, and, usually, water. In addition, of course, the skin penetration enhancing dioxolane, dioxane or acetal is included in the formulations in an amount effective to enhance the penetration of the active ingredient through the skin, including the stratum corneum.
[0033] Accordingly, a suitable vehicle or carrier system for a composition comprising a macrolide and a skin modifying agent can be an aqueous or non-aqueous alcoholic carrier containing sufficient alcohol, especially ethanol and/or isopropanol and, often, glycol, e.g., propylene glycol, to solubilize the macrolide and be miscible with the skin modifying agent. Generally, however, depending on the amounts of agent and macrolide in the formulations an aqueous or non aqueous alcoholic carrier can contain from about 1 to about 99% by weight, for example 15 to about 85%, or 30 to about 70%, or 35 to about 55% by weight of the composition of ethyl alcohol and/or isopropyl alcohol. Mixtures of ethanol and isopropanol in proportions providing the desired solubility of the macrolide and compatibility with the enhancer can also be used.
[0034] Again, the total amount of the aqueous or non-aqueous, alcoholic carrier will depend on the amount of macrolide, amount and type of enhancer, and the form of the composition, e.g., gel, cream, ointment, etc. Usually amounts of the aqueous or non-aqueous alcoholic carrier within the range of from about 1% to about 98% such as between about 20 and 95%, or between 70% and 90% by weight may be used. For example, in one embodiment, the aqueous carrier can contain water between 15 and about 89% by weight, for example 20 to about 80%, or from 25 to about 70% or from about 30 to about 60 % by weight of the composition. Mixtures of water and alcohol, e.g.
ethanol, propanol, ethylene glycol, propylene glycol can be used in ratios of water:alcohol ranging from 20:80 to about 90:10, such as about 40:60, about 45:55, about 50:50 about 55:45 about 60:40.
[0035] In some compositions which are in the form of a gel, a thickening agent, such as hydroxypropyl cellulose, can be included as a gelling agent.
However, any other pharmaceutically acceptable thickening/gelling agent may be used. For example, mention may be made of other cellulosic ethers, polymeric thickening agents, e.g., acrylic acid polymers, Carbopol®
thickeners, etc., xanthan gum, guar gum, and the like, as well as inorganic thickeners/gelling agents. The amount of the thickening agent is not particularly critical and can be selected to provide the desired product consistency or viscosity to allow for easy application to the skin but which will not be too watery or loose so that it will stay where applied. Generally, depending on its molecular weight, amounts of thickening agent up to about 5%, such as, for example, from 0.1 to about 2%, of the composition will provide the desired effect.
[0036] As is well known in this art, it is possible to include other ingredients in the formulations for particular aesthetic and/or functional effects. For example, the formulations may, optionally, include one or more moisturizers for hydrating the skin and emollients for softening and smoothing the skin.
Glycerin is an example of such a suitable moisturizing additive. When present the additive will usually be incorporated in an amount of up to about 5 percent by weight of the composition, for example, from about 0.1 to 5%.

[0037] The carrier can also include a lipophilic component which can comprise from about 1% to about 60% of the total weight of the composition, such as about I to about 30% or about 1 to about 10%.
[0038] Lipophilic components of the formulation can be fatty acid material.
"Fatty acid material" may include blends of fatty acids, typically containing fatty acid moieties with chain lengths of from C8 to C30. The fatty acid material may also contain relatively pure amounts of one chain length fatty acid moiety. Suitable fatty acids from which fatty acid/nonionic surfactant base mixtures may be derived include pelargonic, lauric, myristic, palmitic, stearic, isostearic, oleic, linoleic, ricinoleic, arachidic, behenic and erucic acids. Although normally saturated, suitable fatty acid materials may contain unsaturated fatty acid moieties, and may contain fatty acid moieties having a degree of substitution, such as e.g. hydroxy fatty acids. The chain length of the components of the fatty acid material also determines the rheological properties of the resultant skin composition base. A fatty acid material mix containing relatively high proportions of stearic and palmitic acid moieties has been found to be particularly suitable for use for manufacturing skin creams and lotions which may be used in temperate to hot climates, while fatty acid material mixtures containing relatively high amounts of lower chain length fatty acid moieties (e.g. more than 50% of the fatty acid moiety having a chain length of C8-C14) may also be suitable for the preparation of skin compositions for use in relatively cold climates.
[0039] Additional additives in the compositions can include skin care actives which are acidic in aqueous solution, such as for example fatty acids, such as alpha hydroxy fatty acids including lactic acid and glycolic acid; as well as peroxides such as hydrogen peroxide, vitamins such as vitamin B3, and polysaccharides such as chitosan; particularly preferred alpha hydroxy fatty acids are lactic acid and glycolic acid.
[0040] Emollient materials may also serve as cosmetically acceptable additives. These may be in the form of silicone oils and synthetic esters.
The*
emollient material may be a silicone oil, an ester or a mixture of these.
Amounts of the emollients may range anywhere from 0.1 to 20%, such as between I and 5% by weight of the final composition.

[0041] Silicone oils may be divided into the volatile and non- volatile variety.
The term "volatile" as used herein refers to those materials which have a measurable vapour pressure at ambient temperature. Volatile silicone oils are preferably chosen from cyclic or linear polydimethyl siloxanes containing from 3 to 9, preferably from 4 to 5 silicon atoms. Linear volatile silicone materials generally have viscosities less than about 5 centistokes at 25 C., while cyclic materials typically have viscosities of less than about 10 centistokes.
[0042] Non-volatile silicone oils useful as an emollient material include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers. The essentially non-volatile polyalkyl siloxanies useful herein include, for example, polydimethyl siloxanes with viscosities of from about 5 to about 25 million centistokes at 25 C.
[0043] Silicone emulsifying agents can include dimethicone copolyols.
These can include polydimethylsiloxanes modified to include polyether side chains. Other modifications to the side chains can result in nonionic, anionic, cationic, amphoteric, and zwitterionic pendant moieties.
[0044] Among the ester emollients are:
1. Alkenyl or alkyl esters of fatty acids having 10 to 20 carbon atoms. Examples thereof include isoarachidyl neopentanoate, isononyl isononanoate, oleyl myristate, oleyl stearate, and oleyl oleate.
2. Ether-esters such as fatty acid esters of ethoxylated fatty alcohols.
3. Polyhydric alcohol esters. Ethylene glycol mono and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poly- fatty acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are satisfactory polyhydric alcohol esters.
4. Wax esters such as beeswax, spermaceti, myristyl myristate, stearyl stearate and arachidyl behenate.
5. Sterol esters of which cholesterol fatty acid esters are examples thereof.
[0045] The compositions of the present invention may be prepared and formulated as emulsions. Emulsions are typically heterogenous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 ,um in diameter. (Idson, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199; Rosoff, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p.
245; Block in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 2, p. 335; Higuchi et al., in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are often biphasic systems comprising of two immiscible liquid phases intimately mixed and dispersed with each other. In general, emulsions may be either water in oil (w/o) or of the oil in water (o/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase the resulting composition is called a water in oil (w/o) emulsion.
Alternatively, when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase the resulting composition is called an oil in water (o/w) emulsion. Emulsions may contain additional components in addition to the dispersed phases and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase.
Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants may also be present in emulsions as needed. Pharmaceutical emulsions may also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil in water in oil (o/w/o) and water in oil in water (w/o/w) emulsions. Such complex forrriuiatioi-is o-fien provide certain advantages that simple binary emulsions do not. Multiple emulsions in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous provides an o/w/o emulsion.
[0046] Emulsions are characterized by little or no thermodynamic stability.
Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion may be a semisolid or a solid, as is the case of emulsion-style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that may be incorporated into either phase of the emulsion.
Emulsifiers may broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199).
[0047] Useful oils can include vegetable and hydrogenated vegetable oils including safflower oil, castor oil, coconut oil, cottonseed oil, menhaden oil, apim kernel oil, palm oil, peanut oil, soybean oil, jojoba oil, linseed oil, rice bran oil, pine oil, sesame oil, and sunflower seed oil and their hydrogenated varieties. Additional useful oils can include animal fats and oils such as cod liver oil, and lanolin and its derivatives, mineral oil and petrolatum.
[0048] Synthetic surfactants, also known as surface active agents, can be used in the carrier in forming emulsions and have been reviewed in the literature (Rieger, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 285; Idson, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199).
Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants used may be classified into different classes based on the nature of the hydrophilic group into: nonionic, aniv, iic, cationic, zwitterionic and amphoteric (Rieger, in "Pharmaceutical Dosage Forms,"

Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 285).
[0049] Common nonionic surfactants are polyoxyethylene ester and ether surfactants, a specific example of which is Tween 60. Other suitable nonionic surfactants are described in McCutcheons "Detergents and emulsifiers", North American edition (1986), published by Allured Publishing Corporation, the contents of which are specifically incorporated herein by reference. Examples of common nonionic surfactants can be derived from condensation reactions between long chain alcohols (C8-C30) with sugar or starch polymers. Other useful nonionic surfactants are the condensation products of alkylene oxides with fatty acids (alkylene oxide esters of fatty acids, or alkylene oxide diesters of fatty acids), or the condensation products of alkylene oxides and fatty alcohols (alkylene ethers of fatty alcohols).
[0050] Other useful nonionic emulsifying agents include sugar esters, poly esters, alkoxylated sugar esters and polyesters, C1-C30 fatty acid esters of C1-30 fatty alcohols, alkoxylated derivatives of C1-C30 fatty acid esters of Cl-30 fatty alcohols, alkoxylated ethers of C1-30 fatty alcohols, polyglyceryl esters of C1-C30 fatty acids, C1-C30 esters or ethers of polyols, alkyl phosphate, polyoxyalkylene fatty ether phosphates, fatty acid amides, acyl lactylates and mixtures thereof.
[0051] Exemplary cationic emulsifying agents are those disclosed in McCutheon's, Detergents and Emulsifiers, North American Edition (1986), the contents of which are hereby incorporated by reference in their entirety.
Useful cationic surfactants include cationic ammonium salts such as quaternary ammonium salts and amino-amides.
[0052] Useful anionic emulsifying agents include alkoxyl isethionates, alkyl and alkyl ether sulfates and salts thereof, alky and alkyl ether phosphates and salts thereof, alkyl methyl taurates and soaps of fatty acids.
[0053] An ionic polyamide polymer containing acrylamidopropanesulfonic acid (AMPS) and/or its salts as a comonomer may be used as an ionic polymeric stabilizing agent. These polymers can be formed from a variety of monomers including acrylamide and methacrylamide, which may be unsubstituted or substituted with one or two alkyl groups (preferably Cl to C5), or N-vinyl pyrrolidone. In one emuodiment the acrylate amide and methacrylate amide are monomers in which the amide nitrogen is unsubstituted, or substituted with one or two Cl to C5 alkyl groups (preferably methyl, ethyl, or propyl), for example, acrylamide, methacrylamide, N-methacrylamide, N-methylmethacrylamide, N,N-dimethylmethacrylamide, N-isoproprylacrylamide, N-isopropylemthacrylamide, and N,N-dimethylacrylamide. In another embodiment the polyacrylarnide-AMPS
copolymer is the product given the CTFA designation polyacrylamide (and) isoparrafin (and) Iaureth-7, available under the Trade name Sepigel 305 from Seppic Corporation (Fairfield, N.J.). In another embodiment a copolymer of ammonium AMPS and N-vinylpyrrolidone, commercially under the trade name Aristoflex , can be used. In a particular embodiment a mixture containing sodium AMPS (also known as acryloyid imethyltau rate) copolymer, isohexadecane, and polysorbate 80, commercially available under the trade name Simulgel 600 is used. Mixtures of two or more ionic polymeric stabilizing agents may also be used.
[0054] The ionic stabilizing agents of the present invention are included in an amount sufficient to prevent visible separation of the composition. The stabilizers are generally present in a concentration of about 0.1 to about 10%
by weight. One of skill in the art will also recognize that the amount of ionic polymeric stabilizing agent necessary will deperid upon the hydrophobic and hydrophilic phases, intended use, intended storage, and use conditions, and other optional ingredients which maybe used within the composition as well as the mixing conditions and mixing apparatus used to prepare the emulsion or dispersion.
[0055] The ionic polymeric stabilizing agents of the present invention allow for the formation of a stable composition at lower concentrations of alcohol than compositions without these ionic stabilizing agents. In one embodiment, the ionic polymeric stabilizing agent is present from between about 1 and about 10 percent, for example, from about 2 to about 8 percent by weight of the composition.
[0056] Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. Antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid aiid sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin.
[0057] The compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, steroids, local anesthetics or anti-inflammatory agents, skin conditioning agents such as oils and vitamins or may contain additional materials useful in physically formulating various dosage forms of the composition of present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
[0058] Suitable steroids can include a co-active ingredient such as a corticosteroid. Examples of some suitable corticosteroids include: clobetasol propionate, betamethasone dipropionate, betamethasone valerate, diflucortolone valerate, fluticasone valerate, hydrocortisone 17-butyrate, mometasone furoate, methylprednisolone aceponate, aclometasone dipropionate, clobetasone butyrate, fluocinolone acetonide, triamcinolone acetonide, hydrocortisone and other useful cotricosteroids and their analogs including salts. Other co-active ingredients useful in treating skin disorders can also be used with the macrolide and can include anti-inflammatories, non-steroidal anti-inflammatories, antifungals, antibiotics, anti-infectives, and skin protectants such as sunscreen components. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.q., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings flavorings and/or aromatic substances and the like.
[0059] The effects of the topical compositions according to the invention are further illustrated by way of the following representative examples which in no way are intended to limit the scope of the invention.

EXAMPLES
Example 1-3:
[0060] These Examples compare the percutaneous absorption through human cadaver skin of FK506 from alcoholic formulations containing 0.5 wt.%

FK506, and either 0, 5%, or 10% of SEPA 0009 (2-n-nonyl-1,3 dioxalane) with the remainder comprising 200 proof ethanol.
[0061] The tests are run in standard static cells with phosphate buffered saline (PBS) solution as the receptor fluid (surface area =0.635 cm2, skin temperature = 32 C ). The following table 1 indicates the formulations used in Examples 1-3. Each test was run for 24 hours under non-occluded conditions with a finite dose of the test formulation.

Example 1 Example 2 Example 3 wt.% FK 506 0.5 0.5 0.5 wt.% SEPA0009 0 5 10 Ethanol (200 Proof) 99.5 94.5 89.5 [0062] The results obtained are reported in Table 2 as cumulative % of dose delivered for the three formulations. The values reported represent average values for 24samples with the exception of the 4 hr values which represent averages of 16 samples. The cumulative % dose delivered was significantly higher at each time point for each formulation containing the 1,3 dioxolane.

TIME (hr.) EXAMPLE 1 EXAMPLE 2 EXAMPLE 3 0 0.000 0.000 0.000 4 0.320 0.584 0.466 8 0.695 1.471 1.600 24 1.970 4.888 5.420 Examples 4-5 and Comparative Examples A-C
[0063] These Examples compare the percutaneous absorption through human cadaver skin of FK506 from alcoholic formulations containing 0.5 wt.%
FK506, and either 0, 5%, 10% of SEPA 0009 (2-n-nonyl-1,3 dioxalane), or 5% or 10% dimethyl sulfoxide (DMSO) with the remainder comprising 200 proof ethanol.

Ex. A Ex. 4 Ex. 5 Comp. Ex. Comp. Ex. C
B
wt.% FK 506 0.5 0.5 0.5 0.5 0.5 wt.% SEPA0009 0 5 10 0 0 wt.% DMSO 0 0 0 5.0 10.0 Ethanol (200 99.5 94.5 89.5 94.5 89.5 Proof) [0064] The tests are run in standard static cells with phosphate buffered saline (PBS) solution as the receptor fluid (surface area =0.635 cm2, skin temperature = 32 C ). Table 3 indicates the formulations used in Examples 4-5 and Comparative Examples A-C. Each test was run for 24 hours under non-occluded conditions with a finite dose of the test formulation.
[0065] The results obtained are reported in Tables 4 and 5 as Flux and as cumulative % of dose delivered for the five formulations. The values reported represent average values for 12 samples. The flux and cumulative % dose delivered was significantly higher at each time point for each formulation containing the 1,3 dioxolane.

TABLE 4 - Flux (mg/sq.cm/hr) Time Comp. Ex. Comp Ex.
hr Comp. Ex. A Example 4 Example 5 B C

4 0.002 0.061 0.088 0.006 0.007 16 0.002 0.067 0.130 0.000 0.001 TABLE 4 - Cumulative Amt. (% of applied dose) Comp. Ex. Comp. Ex. Comp Ex.
Time hr A Example 4 Example 5 B C

8 0.032 0.949 1.420 0.097 0.112 24 0.072 2.180 4.822 0.097 0.129 Comparative Examples D-G:
[0066] These Examples compare the percutaneous absorption through human cadaver skin of Cyclosporine A from alcoholic formulations containing 4.0 wt% of Cyclosporine A, and either 0, 5%, or 10% of DMSO or 10% of SEPA 0009 (2-n-nonyl-1,3 dioxalane) with the remainder comprising 200 proof ethanol.
[0067] The tests are run in standard static cells with phosphate buffered saline (PBS) solution as the receptor fluid (surface area =0.635 cm2, skin temperature = 32 C ). The following table 6 indicates the formulations used in Comparative Examples D-G. Each test was run for 24 hours under non-occluded conditions with a finite dose of the test formulation.

Comp. Ex. Comp. Ex. E Comp. Ex. F Comp. Ex.
D G
wt.% Cyclosporine 4.0 4.0 4.0 4.0 wt.% DMSO 0 5 10 0 wt. % SEPA0009 0.0 0.0 0.0 10.0 wt. % Ethanol (200 96.0 91.0 86.0 86.0 Proof) [0068] The results obtained are reported in Table 7 as cumulative % of dose delivered for the four formulations. The values reported represent average values for 12 samples. From the tables it is clear that none of the formulations appears to deliver measurable amounts of Cyclosporine A.

TIME (hr.) Comp. Ex. Comp. Ex. E Comp. Ex. F Comp. Ex.
D G
0 0.000 0.000 0.000 0.000 4 0.000 0.000 0.000 0.000 8 0.000 0.000 0.000 0.000 24 0.000 0.000 0.000 0.000

Claims (21)

1. A topical composition comprising:
.cndot. a macrolide or a pharmaceutically acceptable salt thereof, having a MW of greater than 500 and less than 1200; and a compound comprising:
- a C7 to C14 - hydrocarbyl substituted 1,3 - dioxalane, 1,3 -dioxane, or acetal thereof.

2. The composition of claim 1, wherein the macrolide includes tacrolimus or a pharmaceutically acceptable salt thereof.

3. The composition of claim 1, wherein the macrolide includes pimecrolimus or a pharmaceutically acceptable salt thereof.

4. The composition of claim 1, wherein the macrolide comprises tacrolimus, pimecrolimus, sirolimus, ascrolimus, rapamycin, prolylrapamycin, 32-desmethylrapamycin, 32-desmethoxyrapamycin, ascomycin, dunaimycin, everolimus or a pharmaceutically acceptable salt thereof.

5. The composition of claim 1, wherein the compound comprises 2-n-nonyl-1,3-dioxolane.

6. The composition of claim 2, wherein the compound comprises 2-n-nonyl-1,3-dioxolane.

7. The composition of claim 1, wherein the macrolide comprises 0.01- 5.0 wt.% relative to the total composition.

8. The composition of claim 1 wherein the compound comprises 4-15 wt.% relative to the total composition.

9. The composition of claim 1 further comprising a steroid.

10. The composition of claim 9 further comprising a corticosteroid.

11. The composition of claim 10 wherein the corticosteroid comprises clobetasol propionate, betamethasone dipropionate, betamethasone valerate, diflucortolone valerate, fluticasone valerate, hydrocortisone 17-butyrate, mometasone furoate, methylprednisolone aceponate, aclometasone dipropionate, clobetasone butyrate, fluocinolone acetonide, triamcinolone acetonide, or hydrocortisone.

12. The composition of claim 1, wherein the composition is a skin cream, a gel, an ointment, a lacquer, lotion, a patch, a solution or a tincture.

13. A method of treating a skin disorder comprising:
.cndot. applying a therapeutically effective amount of a composition comprising:
- a macrolide or a pharmaceutically acceptable salt thereof, having a MW of greater than 500 and less than 1200.;
and .cndot. a skin modifying agent comprising:
- a C7 to C14 - hydrocarbyl substituted 1,3 - dioxalane, 1,3 -dioxane, or acetal thereof.

14. The method of claim 13 wherein the macrolide comprises 0.01- 5.0 wt.% relative to the total composition.

15. The method of claim 13 wherein the compound comprises 4-15 wt.%
relative to the total composition.

16. The method of claim 13 wherein the compound comprises 2-n-nonyl-1,3-dioxolane.

17. The method of claim 13 wherein the macrolide comprises tacrolimus.

18. The method of claim 13, further comprising:
.cndot. covering the site of the disorder after applying the composition.

19. The method of claim 18 wherein the site is covered using a bandage.

20. The method of claim13 wherein the skin disorder comprises psoriasis, eczema, atopic dermatitis, erythema, pelagra, allergic contact dermatitis, poison ivy, poison oak, or poison sumac.

21