MXPA00004340A - Skin penetration enhancing components - Google Patents

Abstract

The present invention relates to a topical formulation for the treatment of a dermatological condition which comprises a macrocyclic lactone antibiotic, immunosuppressive 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.

Description

COMPONENTS OF INCREASED SKIN PENETRATION The present invention relates to an effective treatment for psoriasis and other dermatological conditions using an immunosuppressive agent applied topically. The preferred formula does not allow the agent to appear in the blood or other circulatory system at a significant level.

The dermatological conditions can be uncomfortable and embarrassing for the patient, so that s requires a safe and effective treatment. Some dermatological conditions are caused by an immune or superactive system. Examples are psoriasis, alopecia, lichen planus, lupus erythematosus, pyoderma gangrenosum, vitiligo, and graft disease against the host. Others may be due to pustular or bacterial skin infections.

The dermatological conditions caused by a superactive immunity 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, As acne vulgaris and subcurative hydranitis can be treated with macrolide antibiotics, for example erythromycin acitromycin and clarithromycin. The agents mentioned above can be applied by means of creams and topical lotions taken orally.

Psoriasis affects 2.4% of the population and current understanding of the pathogenesis of the disease since it is initially driven by immunocytes. These and the keratinocytes are mutually assimilated and activated through the production of cytosines, TGFa, IL-6 and IL-8 lymphocytes This leads to a hyperproliferative epidermis with a 3-hour fast cycle of the transient amplifying compartment d keratinocytes.

FK506 is a macrolide antibiotic which shows part of homology with sirolimus. Research and models have shown that it has some efficacy in the treatment of contact dermatitis, atopic eczema and to a lesser extent psoriasis. Cyclosporine 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 collateral effects resulting from systemic administration.

Other forms of treatment of determatological conditions may include the use of topical steroids because these have undesirable effects such as purpura and irreversible atrophy.

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

The macrocyclic lactone antibiotic rampamycin for example is described in European Patent A-05333433 and has been used topically to treat such skin disorders with psoriasis and dermatitis. However, no attempt has been made to reduce the amount of rampamycin translocated through the skin to the systemic system. Nor is there any discussion of reducing the levels of circulating rampamicin or another macrolide drug at the same time as it provides a therapeutically effective treatment for a variety of skin disorders.

We have found that this can be achieved by adding a permeation modulator to such drugs. Permeation enhancers are well known as a class of drug translocation facilitators, but the purpose of these is to increase the flow of drugs through the drug. of the skin . A permeation modulator, however, has the facility to allow the drug to penetrate the skin, particularly the stratum corneum, without passing significantly through the epidermis to systemic systems (eg, lymph or blood 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, these are often not specified in their action which leads to undesirable side effects. It will therefore be desirable to develop a topical delivery formula for an immunosuppressive agent which preferably treats the diseased sites only and avoids a significant systemic exposure so as to reduce harmful side effects.

Sirolimus is a macrocyclic lactone antibiotic produced by the organism Strepto icine Hygroscopicus; This is known because it has potent immunosuppressive activities. Sirolimus acts through a specific agglutination of a cytosolic immunophilin family called FK binding proteins (FKBP). The FKBP complex sirolimus acts as at least three sites. First, by blocking the activation d phosphorylation of p70 s6 kinase, an enzyme that acts on the subunit of S6 ribosomal protein 40S, thus reducing the efficiency of the translation. Second, by avoiding the activation of the specific elongation factors required for protein synthesis. Third, it inhibits the enzyme activity of the kinase-dependent cyclin cdk-cyclin E complex from which it forms one of the tight controls of the Gl / S transition in the cell division mediant to inhibit the normal decline of the inhibitor p27 cdk which can follow IL-2 stimulation. Sirolimus has an advantage over other immunosuppressive agents in the treatment of psoriasis since it has an inhibitory effect on the proliferation of keratinosito. In vitro experiments have shown that this inhibitory effect takes place varying from 3-10μg / ml. A wider range can be used for example from 1 to 20μg / ml, but an effective range is 5-8μg / ml.

According to the first aspect of the invention, s provides a topical formula for the treatment of a dermatological condition which comprises a macrocyclic lactone antibiotic or an immunosuppressive macrolide or a pharmacologically active analog, derivative or prodrug thereof characterized in that it also comprises a modulator of permeacy and the permeation modulator and the macrocyclic lactone antibiotic, the immunosuppressive macrolide and the pharmacologically active analog, derivative or prodrug are present and relative amounts so that when a therapeutic amount is applied to the skin, a minimal systemic effect is produced .

By the term "minimal systemic effect" it is meant that the amount of the detectable active principal in the blood stream is preferably 0.3 ng / nl about 4 to 2 hours after administration, more preferably down to 0.1 ng / ml over the same period.

Preferably the macrocyclic lactone antibiotic is selected from erythromycin, acryromycin clarithromycin. These macrocyclic lactone antibiotics are effective in treating bacterial skin infections and pustules such as acne vulgaris.

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

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

Conveniently the permeation modulator is used in conjunction with a solvent system which includes an aromatic alcohol such as a phenyl alkanol or a biologically acceptable d benzene derivative, with or without the combination of monoglycerides and / or fatty acid ester (e.g. isopropy myristate). Other solvents used include benzaldehyde benzylbenzoate and acetone. The combination of the solvent and the permeation modulator also optimizes the passage of the immunosuppressant macrolide or the macrocyclic lactone antibiotic through the stratum corneum.

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

Preferably, the above-mentioned ranges of macrocyclic lactone or immunosuppressive macrolide antibiotic or an analogous or prodrug derivative thereof are used in an agent comprising a permeation modulator; wherein the concentration of the permeation modulator is from 0.1% to 60% po weight. More preferably the concentration of the modulator of permeation is from either 0.1% to 39.9% or 40% to 80% by weight. Even more preferably the concentration of the modulator of permeation is either from 0.1% to 19.9%, 20% to 39.9 % or 40% to 60% Preferably the above-mentioned ranges of macrocyclic lactone or permeability modulator and immunosuppressant antibiotic are used in the formula in conjunction with a solvent system; where the concentration of the solvent system is from 5% to 90% by weight. More preferably the concentration of the solvent system is either from 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 formula. If the formula is to be used topically, it must be of an appropriate consistency. Thus, thickening agents such as cetostearyl alcohol or the commercially available white soft paraffin medical grade can be added. These can reduce the penetration of the immunosuppressive agent but these are required for an effective application. The formulas of the invention are particularly suitable for the treatment of scalp conditions.

In addition to the liquid and solid carriers set forth above, the formulas of the invention may additionally include one of the following: flavoring agent, lubricants, solubilizers, suspension agents, fillers and sliders.

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

The invention will now be described by way of illustration only with reference to the following examples tables and figures accompanying the description.

Figure 1 is a graphical representation of the effect on the flow (μg / hr / cm2) of sirolimus (y) through the stratum corneum by varying the proportion of capric acid and benzyl alcohol, where x is the percentage of acid Capric in benzyl alcohol.

Figure 2 is a graphical representation of the effect on the flow (μg / hr / cm2) of sirolimus (y) through the stratum corneum by varying the proportion of octanoic acid and benzyl alcohol, where x is the percentage acid octanoic in benzyl alcohol.

Figure 3 is a graphical representation of the effect on the flow (μg / hr / cm2) of sirolimus (y) through the stratum corneum by varying the proportion of oleic acid and benzyl alcohol, where x is the percentage of the acid oleic in benzyl alcohol.

Figure 4 is a graphical representation of the effect on the flow (μg / hr / cm2) of sirolimus (y) through stratum corneum by varying the concentration of sirolimus (mg / ml) (x) while maintaining constant proportion of capric acid and benzyl acid.

Figure 5 is a graphical representation of the results of the clinical score (y) determined after the application of the sirolimus () formula of the control (::: in Example 3.

Figure 6 is a graphical representation of the difference in clinical score after application with the sirolimus formula in Example 3, where y is the number of subjects in each group. A positive rating (x shows improvement with the use of the active formula.

Figures 1 to 4 were obtained by in vitro experimentation. The results were used to optimize the concentration of sirolimus and the proportion of permeation enhancer and solvent used in the experiments in vivo.

Example 1 A formula of 8% sirolimus and 92% d a capric acid vehicle (50%) was formed with the benzyl alcohol (fifty%) . This was tested in a single application experiment on four individuals with normal skin. The venous blood samples were taken at 4, 7 and 24 hours after application and no significant levels of sirolimus were detected using MSGCMS which is able to detect sirolimus levels down to 0.1 ng / ml.

In parallel, the skin biopsies were taken from the individuals after 7 hours. The biopsy samples were glued to a glass slide and sectioned serially horizontally in four layers each 0.00 millimeters thick and extracted with acetonitrile. The results are given in Table 1.

Table 1 shows sirolimus tissue concentrations seven hours after the application of capric acid: benzyl alcohol (50:50) containing sirolimus at 8%. The horizontal skin sections were each 0. millimeter. Therefore, for the example, the section of the designated foot 2 was the skin's horizontal layer of 0.7-1. millimeters of the surface of the skin.

Example 2 A formula of sirolimus (2.2%) in a vehicle comprising 40% isopropyl myristate, 10% benzyl alcohol and 50% capric acid was tested in single application experiments on three individuals with normal skin. The venous blood samples were taken at 4, 7 and 24 hours after the application and no significant levels of sirolimus were detected using MSGCMS.

After 7 hours biopsi samples were taken from two of the individuals. These were bisected in parallel with the surface to give a lower half and an upper half, which correspond approximately to the epidermis and to the dermis. The skin was homogenized with acetonitrile and the concentration of sirolimus was determined by HPLC. The results are given in Table 2.

Table 2 shows the concentrations of sirolimus tissue 7 hours after the application of capric acid isopropyl myristate: benzyl alcohol (50:40:10) containing sirolimus at 2.2%.

Example 3 A comparison of the right blind and double side effect of topically applying sirolimus in the com formulas described in examples 1 and 2, to 24 patients with a chronic plaque psoriasis (over 3 months) was carried out (22 d 24 patients were eventually analyzed). A single target plate was treated for the first six weeks with the lowest potency formula of Example 2. After this active treatment was increased to the highest potency formula of Example 1 for 6 weeks unless a clear improvement One side has happened.

The study included adults with chronic plac psoriasis, clearly demarcated and stable and, 2, very similar contralateral comparable plate of around d 50 cm2 in area on the opposite sides of the body. The subjects were all over 18 years of age, and were able to apply the creams and had no significant medical problems. The transaminases were no more than twice the upper normal limit and the subjects were selected to avoid what they might have a vacation in the sunlight during the 6-1 weeks of the trial.

Before the trial was started, there was a 2-week washout period in which only soft emollients were applied to the target lesions.

The treatment was randomized and double blinded. The hands were completely washed between the daily application of the test formulas. The active formula was consistently applied to a plate while a control comprising only the base vehicle was consistently applied to the plate on the opposite side. Where possible, the arm or elbows were selected as target areas since transverse contamination at these sites is less feasible. The evaluations were made at 0 weeks, 2 weeks, 4 weeks and weeks on the low power treatment and at 8, 10 and 1 on the formula of 12 and above, provided that there were no signs or laboratory evidence of toxicity. The clinical score was made at each time and the areas plotted at the end of the treatment. The biopsies of the active lesions and control were carried out at the end of the treatment or at withdrawal. Biopsies were not made and an adverse effect such as a reaction to the application occurred as this would influence the measures that were being evaluated.

The lesions were also evaluated at intervals of four days with a subjective rating on a scale of 0-8 for erythema, thickening and scaling. Objective measures of improvement were carried out on both lesions at the end of each treatment period (low and high formulas) These included pulsed ultrasound scanning measurements of the thickness of the lesion and erythema measured with erythema reflectance, both were averaged over five areas in each psoriatic lesion and were validated using a previous study which was carried out using betametasoma as a reference.

At each visit, the complete blood count, biochemistry, including urea, electrolytes, liver enzymes, bilirubin, calcium, magnesium, uric acid, glucose, amylase, muscle enzymes, lipids, were measured. cholesterol . Sirolimus levels were carried out every two weeks during therapy. Samples for sirolimus levels were stored at -80 ° and sent to a central reference laboratory for analysis by LC / MS / MS by Wyeth Ayerst Research.

In the biopsies, the epidermal thickness was measured and the immunoperoxidase immunoisoxidase was done using the following antibodies to count the cells in a blind form: Therefore, the Ki-67 antibody was used to give a measure of hyperproliferation in the epidermis and the CD4 helper lymphocytes were used to give a measure of autoimmune activity which drives psoriasis.

The cell count in the tissues was automated using an image analysis aided by computer (Seescan). The data were analyzed by the Student T test for paired data and the Wilcoxon test.

The comparison of the active final scores against placebo achieved significance at 0.032 for the T test or the Wilcoxon test for 0.0457, see Table 3 and Figures 5 and 6. The erythema measurements and the ultrasound records were not significantly different. Three of the twenty-two patients developed sensitivity to contact in the topical preparations one with benzyl alcohol, one with sirolimus and one with both of these.

Antibody tests with Ki-67 showed a significant reduction of the proliferation cells from the main one of 83 / mm3 in control to 55 / mm3 with sirolimus (rampamycin) to give a significance of P-0.027 (Test T) Using the cells CD4 control values were 61 / mm3 and against 32.7 / mm3 it means values after rampamicin to give a significance of P-0.0026 (Test T). The test was mismatched due to missing samples.

Table 3 shows the clinical response to topical sirolimus. The clinical score is measured on a scale of 0-24 with higher values indicating an improved result, the thickness of ultrasound in millimeters and the measurement of erythema in arbitrary units.

These results show that the penetration of sirolimus from a formula described above occurs. It is thought that increased adsorption will occur through the scalp to effectively treat psoriasis of the scalp.

Claims (23)

R E I V I N D I C A C I O N S

1. A topical formula for the treatment of a dermatological condition which comprises a macrocyclic d-lactone antibiotic, an immunosuppressive macrolide or a pharmacologically active analogue, a derivative or a prodrug thereof; characterized in that it further comprises a permeation modulator and the permeation modulator and the macrocyclic or macrocyclic antibiotic or macrolide or the pharmacologically active analog, derivative or prodrug thereof are present in relative amounts so that when a therapeutic amount is applied to the skin it is produced a minimal systemic effect.

2. A formula, as claimed in clause 1, characterized in that it comprises up to 10% by weight of macrocyclic lactone antibiotic or the immunosuppressive analogue or macrolid, derivative or prodrug thereof; The permeation modulator is present at 1 to 60% by weight.

3. A formula, as claimed in any of clauses 1 or 2, characterized in that the macrocyclic lactone antibiotic is selected from erythromycin, azithromycin and clarithromycin.

4. A formula, as claimed in any of clauses 1 or 2, characterized in that the immunosuppressant macrolide is selected from sirolimus FK506 or SD ASM 981.

5. A formula, as claimed in any of the preceding clauses, characterized in that the permeation modulator is an alkanoic acid or alkenic acid.

6. A formula, as claimed in clause 5, characterized in that the alkanoic acid or the alkidic acid is selected from capric acid, octanoic oleic acid such as acid or acids of intermediate chain length

7. A formula, as claimed in any of the preceding clauses, characterized in that the dermatological condition is selected from psoriasis alopecia, eczema dermatitis, lichen planus, lupus erythematosus pyoderma gangrenosum, vitiligo, graft disease against host d, infections of skin with pustules, bacterial skin infections or acne vulgaris.

8. A formula, as claimed in clause 7, characterized in that the dermatological condition and eczema dermatitis and the concentration of antibiotic of macrocyclic lactone or of immunosuppressive macrolide is from 0.05% to 2% by weight.

9. A formula, as claimed in any of the preceding clauses, characterized in that the permeation modulator is used in conjunction with a solvent system.

10. A formula, as claimed in clause 9, characterized in that the solvent system comprises aromatic alcohol or a biologically acceptable benzene derivative, with or without a mixture of monoglycerides and / or fatty acid ester.

11. A formula, as claimed in any of clauses 9 or 10, characterized in that the permeation modulator comprises capric acid and the solvent system comprises benzyl alcohol.

12. A formula, as claimed in any of clauses 8 to 11, characterized in that the concentration of the solvent system is from 5% to 90% by weight.

13. A formula, as claimed in any of the preceding clauses, characterized in that it comprises a thickening agent.

14. A formula, as claimed in clause 13, characterized in that the thickener is selected from white soft paraffin, yellow soft paraffin alcohol, cetyl alcohol, stearyl alcohol, divalent carboxylic acid soaps and carnauva wax.

15. A topical formula for the treatment of a dermatological condition which comprises an immunosuppressant macrolid or a pharmacologically active analog, or derivative or a prodrug thereof; characterized by the fact that it also comprises a permeation modulator; and the permeation and macrolide modulator or the pharmacologically active analog, derivative or prodrug thereof are present in relative amounts so that when a therapeutic amount is applied to the skin a minimal systemic effect is produced.

16. A formula, as claimed in clause 15, characterized in that the immunosuppressive macrolide is selected from sirolimus FK506 or SDZ ASM 981.

17. A formula, as claimed in clause 16, characterized by the immunosuppressive macrolide and sirolimus.

18. The use in the manufacture of a topical composition for the treatment of a dermatological condition of a macrocyclic lactone antibiotic or an immunosuppressant macrolid or a pharmacologically acceptable analog, or derivative or prodrug thereof, characterized in that it also comprises a permeation modulator and the permeacy modulator and the antibiotic of macrocyclic lactone or immunosuppressant macrolid or the pharmacologically active analog, derivative or prodrug thereof are present in relative amounts so that when a therapeutic amount is applied to the foot a minimal systemic effect is produced.

19. The use, as claimed in clause 18, characterized in that the macrocyclic lactone antibiotic or the immunosuppressant macrolide is present in up to 10% by weight of the composition.

20. The use of an immunosuppressant macrolide, or macrocyclic lactone antibiotic or a pharmacologically active analogue, a derivative or prodrug thereof in the preparation of a topical formula, as claimed in any of clauses 1 to 17.

21. A method for the treatment of a skin or mucosal disease comprising applying the same a topical composition comprising a macrocyclic d-lactone antibiotic or an immunosuppressive macrolide or a pharmacologically acceptable analog, a derivative or prodrug thereof characterized in that it comprises a permeacy modulator and the permeation modulator and the macrocyclic lactone or immunosuppressive macrolide antibiotic or the pharmacologically acceptable analogue, derivative or prodrug thereof are present in relative amounts so that when a therapeutic amount is applied to the skin a minimal systemic effect.

22. A method, as claimed in clause 21, characterized in that the macrocyclic lactone antibiotic or the immunosuppressant macrolide is present in up to 10% by weight of the composition.

23. A method, as claimed in clauses 21 or 22, characterized in that the immunosuppressant macrolide is used. SUMMARY The present invention relates to a topical formula for the treatment of a dermatological which comprises a macrocyclic lactone antibiotic, an immunosuppressant macrolid or a biologically active analog, derivative or a prodrug thereof, characterized in that it also comprises a permeation modulator and the The permeation modulator and the macrolitic lactone or macrolide or the biologically active analogue, derivative or prodrug thereof are present in relative amounts so that when a therapeutic amount is applied to the skin a minimal systemic effect is produced. The immunosuppressant macrolid can be sirolimus. The dermatological conditions can be uncomfortable and embarrassing for the patient, so that s requires a safe and effective treatment. Some dermatological conditions are caused by an immune or superactive system, examples are psoriasis, alopecia, lichen planus, lupus erythematosus, pyoderma gangrenosum, vitiligo and graft disease against host. Others may be due to pustular or bacterial skin infections.