Link:  Pharm/Biotech Resources

Title:  Skin penetration enhancing components

United States Patent:  6,958,153

Issued:  October 25, 2005

Inventors:  Ormerod; Anthony David (Aberdeen, GB); Winfield; Arthur (Kuwait University, KW)

Assignee:  Wyeth (Madison, NJ)

Appl. No.:  530375

Filed:  November 5, 1998

PCT Filed:  November 5, 1998

PCT NO:  PCT/GB98/03317

371 Date:  July 7, 2000

102(e) Date:  July 7, 2000

PCT PUB.NO.:  WO99/24036

PCT PUB. Date:  May 20, 1999

The present invention relates to a topical formulation for the treatment of a dermatological condition which comprises a macrocyclic lactone antibiotic, immunosuppresive macrolide or a biologically active analogue, derivative or pro-drug thereof; characterized in that it further comprises a permeation modulator and the permeation modulator and the macrocyclic lactone or macrolide or the biologically active analogue, derivative or pro-drug thereof are present in relative amounts such that when a therapeutic amount is applied to the skin a minimal systemic effect is produced. The immunosuppressive macrolide may be sirolimus.

This present invention relates to an effective treatment for psoriasis and other dermatological conditions using a topically applied immunosuppressive agent. The preferred formulation does not allow the agent to appear in the blood or other circulatory system at any significant level.

Dermatological conditions can be uncomfortable and embarrassing for the patient, so an effective safe treatment is required. Some dermatological conditions are caused by an overactive immune system, examples are psoriasis, alopecia, lichen planus, lupus erythematosus, pyoderma gangrenosum, vitiligo and graft versus host disease. Others can be due to bacterial or pustular skin infections.

Dermatological conditions caused by an overactive immune system can be treated by immunosuppressive macrolides, for example sirolimus (rapamycin), FK-506 (tacrolimus) or SDZ ASM 981. Those that are caused by bacteria or are deeper skin infections, such as acne vulgaris and hidranitis suppcurativa, can be treated by macrolide antibiotics, for example erythromycin, azithromycin and clarithromycin. The above agents may be applied by means of topical creams and lotions or taken orally.

Psoriasis affects 2.4% of the population and the current understanding of the pathogenesis of the disease is that it is driven initially by immunocytes. These and keratinocytes are mutually stimulated and activated through the production of cytokines, TGFa, IL-6 and IL-8 from lymphocytes. This leads to a hyperproliferative epidermis with rapid 36 hour cycling of the transient amplifying compartment of keratinocytes.

FK506 is a macrolide antibiotic which shows part homology with sirolimus. Research in models has shown that it has some efficacy in the topical therapy of contact dermatitis, atopic eczema and to a lesser degree psoriasis. Cyclosporin is also known to be effective in treating a wide range of skin diseases. However the usefulness of these drugs is limited by their potential side effects resulting from systemic administration.

Other forms of treatment of dermatological conditions may include using topical steroids but these have undesirable effects such as irreversible atrophy and purpura.

In the treatment of the human or animal body, one of the considerations is that any medicament shall as far as possible affect only the afflicted part. It is well known that amounts of circulating drug should be kept as low as possible to avoid unwanted mutations. A problem with the topical application of medicaments to the skin for example, is that the medicament tends to penetrate the skin and establish itself in the circulating blood system. This is not what is intended in the treatment of dermatological conditions.

The macrocyclic lactone antibiotic rapamycin for example as disclosed in EP-A-0533433 has already been used topically to treat such skin disorders as psoriasis and dermatitis. However no attempt has been made to reduce the amount of rapamycin translocated across the skin into the systemic system. Nor is there any discussion of the reduction of the levels of circulating rapamycin or other macrolide drug at the same time as providing therapeutically effective treatment for a variety of skin disorders.

We have now found that this may be achieved by the addition to such drugs of a permeation modulator. Permeation enhancers are well known as a class of drug translocation facilitors, but the purpose of these is to increase the drug flux across the skin. A permeation modulator however has the facility to allow the drug to penetrate the skin, and particularly the stratum corneum, without significantly passing through the epidermis into systemic systems (eg the blood or lymph systems).

It is also known that immunosuppressive agents taken orally and steroids applied topically can be used to treat dermatological conditions, such as psoriasis or eczema. However, they are often non-specific in their action which leads to undesirable side effects. Thus it would be desirable to develop a topical delivery formulation for an immunosuppressive agent which preferentially treats the diseased sites only and avoids significant systemic exposure; so reducing harmful side effects.

Sirolimus is a macrocyclic lactone antibiotic produced by the organism Streptomyces hygroscopicus; it is known to have potent immunosuppressive activities. Sirolimus acts through specific binding of a family of cytosolic immunophilins called the FK binding proteins (FKBP). The sirolimus FKBP complex acts at least three sites. Firstly, by blocking the phosphorylation activation of p70 s6 kinase, an enzyme acting on the 40S ribosomal subunit s6 protein, thereby reducing the efficiency of translation. Secondly by preventing activation of specific elongation factors required for protein synthesis. Thirdly, it inhibits enzyme activity of the cyclin dependent kinase cdk-cyclin E complex which forms one of the tight controls of the G1/S transition in cell division by inhibiting the normal decline of the p27 cdk inhibitor which would follow IL-2 stimulation. Sirolimus has an advantage over other immunosuppressive agents in the treatment of psoriasis as it has an inhibitory effect on keratinocyte proliferation. In vitro experiments have shown that this inhibitory effect takes place at concentrations ranging from 3-10 μg/ml. A broader range may be employed for example 1 to 20 μg/ml, but the more efficacious range is 5-8 μg/ml.

According to the first aspect of the invention, there is provided a topical formulation for the treatment of a dermatological condition which comprises a macrocyclic lactone antibiotic or immunosuppressive macrolide or a pharmacologically active analogue, derivative or pro-drug thereof; characterised in that it further comprises a permeation modulator and the permeation modulator and the macrocyclic lactone antibiotic, immunosuppressive macrolide or pharmacologically active analogue, derivative or pro-drug are present in relative amounts such that when a therapeutic amount is applied to the skin, a minimal systemic effect is produced.

By the term "minimal systemic effect", is meant that the amount of active principal detectable in the blood stream is preferably less than 0.3 ng/nl over 4 to 24 hours after administration, more preferably below 0.1 ng/ml over the same period.

Preferably the macrocyclic lactone antibiotic is selected from erythromycin, azithromycin or clarithromycin. These macrocyclic lactone antibiotics are effective for treating pustular and bacterial skin infections such as acne vulgaris.

Conveniently the immunosuppressive macrolide is selected from sirolimus, FK-506 or SDZ ASM 981. Sirolimus is a favoured alternative because it is also an effective antibiotic which is useful in the microbiological preservation of the formulation. The microbiological properties of sirolimus are also helpful in the treatment of scalp and flexural psoriasis, seborrhoeic dermatitis and in secondarily atopic eczema.

In preferred embodiments the permeation modulator may be an alkanoic or alkenic acid, preferably having 6 to 20 carbon atoms such as capric acid, octanoic acid, oleic acid or acids or such acids of intermediate chain length. The permeation modulator aids the penetration of the immunosuppressive macrolide or macrocyclic antibiotic through the stratum corneum, the principle barrier to the penetration of drugs. The stratum corneum is an aggregate of the stacked, flattened skeletons of keratin filled cells interspersed with lipid monolayer structures and water. The addition of the permeation modulator to the formulation results in the partial disruption of the barrier components, particularly the lipid structures. A gradient of the drug can then be produced across the stratum corneum particularly, which facilitates the diffusion of the immunosuppressive macrolide or macrocyclic lactone antibiotic across the stratum corneum into the living epidermis. The relative concentrations of the macrolide or antibiotic and the permeation modulator are chosen so that only partial penetration of the skin occurs; the macrocyclic lactone antibiotics or immunosuppressive macrolides reach the areas which require treatment but significant absorption of the said drugs into the systemic circulation is avoided thus reducing the likelihood of any systemic side effects.

Conveniently the permeation modulator is used in conjunction with a solvent system which includes an aromatic alcohol such as phenyl-alkanol or a biologically acceptable benzene derivative, with or without an admixture of monoglycerides and/or a fatty acid ester (e.g. isopropyl myristate). Other solvents. used, include benzaldehyde, benzyl benzoate and acetone. The combination of solvent and permeation modulator further optimises the passage of the immunosuppressive macrolide or the macrocyclic lactone antibiotic across the stratum corneum.

Preferably, the concentration of the macrocyclic lactone antibiotic or immunosuppressive macrolide is up to 10% by weight of the formulation. More preferably the concentration of the macrocyclic lactone antibiotic or immunosuppressive macrolide is either 0.5% to 5.9% or 6% to 12% by weight. Even more preferably the concentration of the macrocyclic antibiotic or immunosuppressive macrolide is either 1 to 5% or 6 to 8% by weight. A concentration of 0.05% to 2% is most preferable in the treatment of eczema. The term "% by weight" used herein refers to the "% by weight of the final formulation".

Preferably the above ranges of macrocyclic lactone antibiotic or immunosuppressive macrolide or analogue derivative or pro-drug thereof are used in an agent comprising a permeation modulator; wherein the concentration of the permeation modulator is 0.1% to 60% by weight. More preferably the concentration of the permeation modulator is either 0.1% to 39.9% or 40% to 80% by weight. Even more preferably the concentration of the permeation modulator is either 0.1% to 19.9%, 20% to 39.9% or 40% to 60%.

Preferably the above ranges of macrocyclic lactone antibiotic or immunosuppressive and permeation modulator are used in a formulation in conjunction with a solvent system; wherein the concentration of the solvent system is 5% to 90% by weight. More preferably the concentration of the solvent system is either 0.1% to 49.9% or 50% to 90% by weight. Even more preferably the concentration of the solvent system is either 0.1% to 19.9%, 20% to 39.9%, 40% to 69.9% or 70% to 90% by weight.

Preferably a thickening agent is present in the formulation. If the formulation is to be used topically, it should be of an appropriate consistency. Therefore, thickening agents such as cetostearyl alcohol or commercially available medical grade white soft paraffin may be added. These can reduce the penetration of the immunosuppressive agent but they are required for effective application. The formulations of the invention are particularly suitable for treatment of conditions of the scalp.

In addition to the liquid and solid vehicles set forth above, the formulations of the invention may additionally include one of the following: flavouring agents, lubricants, solubilizers, suspending agents, filler and glidants.

The formulation can also be dissolved or suspended in any pharmaceutically acceptable liquid carrier or vehicle such as water or a pharmaceutically acceptable oil or fat. Such a liquid carrier or vehicle can contain other pharmaceutically acceptable additives such as solubilizers, emulsifier, buffers, preservatives, suspending agents, thickening agents, colouring agents, viscosity regulators, stabilizers or osmo-regulators.
 

Claim 1 of 28 Claims

1. A topical formulation for the treatment of a dermatological condition which comprises a macrocyclic lactone antibiotic chosen from clarithromycin or an immunosuppressive macrolide chosen from sirolimus or SDZ ASM 981, and a permeation modulator which are present in relative amounts such that when a therapeutic amount is applied to the skin a minimal systemic effect is produced.

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