Safe and effective drug formulation used for the treatment of psoriasis

Abstract

The formulation of the topical cream that is used for the treatment of skin diseases such as psoriasis and eczema includes clobetasol propionate as a corticosteroid for anti-inflammatory action, salicylic acid for keratolytic action, urea for skin hydration and keratolytic action, and retinoic acid or its derivatives to prevent hyperpigmentation and antimycotic action.

Description

[0001] SAFE AND EFFECTIVE DRUG FORMULATION USED FOR THE TREATMENT OF PSORIASIS

[0002] Technical Field

[0003] This invention relates to a topical dermal drug formulation used for the treatment of skin diseases such as psoriasis and eczema.

[0004] Bacground of the Invention

[0005] Psoriasis is a common skin disease with physical and psychological challenges. As with similar dermatoses, the visible disfigurement and appearance of the skin eruption can create a negative reaction at close social contact, which can increase the psychological burden of the disease. The prevalence of psoriasis is 2% in Europe and 4% in North America. Prevalence increases linearly throughout the life. At 18 years of age, the prevalence is almost ten times higher than in newborns. The vast majority of patients, 70-80%, usually consult a physician with mild psoriasis that may benefit from topical treatment. It is considered that exposure to sun depending on the climate and ethnicity influence the prevalence of psoriasis. However, it is evaluated in different scientific studies that different hereditary and environmental factors may also play a role.

[0006] Topical treatments are usually chosen during the treatment of the patient. Following the introduction of topical hydrocortisone by Sulzberger and Witten in 1952, the use of potent topical steroids in treatment became widespread. However, the relatively recent launch of monoclonal antibodies to treat various disease algorithms has led to significant therapeutic advances in dermatology, especially for the treatment of psoriasis. Although many biologic agents have had some success in treating lesions in the initial phase, no current biologic therapy has been proved to be curative. Therefore, the use of biologic agents in the long-term treatment of the disease remains controversial. Thus, the topical therapies, including topical corticosteroids, are still the most common approaches used in the initial and maintenance treatment of psoriasis. Topical treatment options can be administered as monotherapy or in combination with other agents.

[0007] Brief Description Of The Invention

[0008] The formulation of the invention is a new combination product with four active ingredients targeting different activities such as suppression of inflammation, desquamation of lesions, moisturization of the skin and prevention of discoloration.

[0009] The formulation of the invention is intended to provide treatment of tissue disorders due to psoriasis and eczema thanks to the synergistic effect of the four active ingredients in its content, and to prevent relapse or to extend it over a long period of time and thus to increase the comfort of life by restoring the patient to a normal tissue appearance.

[0010] Detailed Description Of The Invention

[0011] The topical cream formulation of the invention is for use in the elimination of adverse effects (hyperkeratotic layer, crusting, discoloration, dry skin, etc.) on the skin due to psoriasis, and it is main feature is to provide superiority in the treatment thanks to the use of the same in combination with synergistic additive effect.as well as the independent effects of the corticosteroid and / or its derivatives, salicylic acid and / or its derivatives, retinoic acid and / or its derivatives, urea and / or its derivatives contained in the formulation.

[0012] The topical cream formulation of the invention is a new combination product with four active ingredients. These active ingredients have been selected for different purposes such as suppressing inflammation, desquamation of lesions, moisturizing the skin and preventing discoloration and they are used in the treatment of skin diseases such as psoriasis and eczema.

[0013] The formulation of the topical cream of the invention that is used for the treatment of psoriasis includes clobetasol propionate as a corticosteroid for anti-inflammatory action, salicylic acid for keratolytic action, urea for skin hydration and keratolytic action, and retinoic acid or derivatives thereof to prevent hyperpigmentation.

[0014] The active ingredients in the formulation of the topical cream of the invention enable treatment of tissue disorders due to the disease with synergistic effect and prevent recurrence of the disease permanently or for a long time.

[0015] Following the completion of preclinical animal studies, the formulation of the topical cream of the invention was developed with lower concentrations of active ingredients compared to marketed products. It is a rational approach to prefer the use of drugs in treatment at as low effective concentrations as possible. The safety, tolerability and efficacy of the topical cream, which is the formulation of the invention, have been investigated in a Phase 1 clinical study in psoriasis patients and healthy volunteers and its efficacy and safety have been proven.

[0016] In the formulation of the topical cream of the invention containing reduced amounts of active ingredients, the active ingredients are also selected in appropriate ratios for synergistic effect. According to this approach, the weight ratio of clobetasol propionate / retinoic acid selected as corticosteroid is 15 to 40, preferably 25 to 40, preferably about 35; the weight ratio of urea / salicylic acid is 1.5 to 3, preferably about 2. The corticosteroid in the composition of the topical cream formulation of the invention is clobetasol propionate and its weight ratio in the formulation is at the rate of 0.03-0.04%, preferably 0.035%. In the reference literature (Martindale: The Complete Drug Reference:), clobetasol propionate is indicated for use at 0.05%, and it is approximately 1.5 times of the ratio which is stated as the most preferred condition in the formulation of the invention (0.050 / 0.035%).

[0017] Urea or its derivatives in the composition of the topical cream formulation of the invention is 1-15%, preferably 9.5%. by weight in the formulation. The reference literature (Martindale: The Complete Drug Reference:) specifies a usage at the rate of 5-25% for urea and the rate specified for the formulation of the invention is less than two-fifths of the maximum rate specified in the reference literature (9.48 / 25).

[0018] Salicylic acid or its derivatives in the composition of the topical cream formulation of the invention is at the rate of 1-6%, preferably 4-5%, more preferably 4.5%, and most preferably 4.75% by weight in the formulation. In the reference literature (Martindale: The Complete Drug Reference:), usage at the rate of 2-6% is indicated for salicylic acid, and the rate in the most preferred condition indicated in the formulation of the invention is approximately three-fifths of the maximum rate indicated in the reference literature (4.75 / 6).

[0019] Retinoic acid or its derivatives in the composition of the topical cream formulation of the invention is at the rate of 0.001-0.01%, preferably 0.001-0.005%, more preferably 0.001-0.002% by weight in the formulation. All-trans-retinoic acid (ATRA, tretinoin, Formula 1), 13 -cis— retinoic acid (isotretinoin, Formula 2), retinol (Formula 3), 11-czs-retinoic acid (Formula 4) and 9-cz.v-retinoic acid (alitretinoin, Formula 5) may be selected as retinoic acid and retinoic acid derivatives. In the retinoic acid reference literature (Martindale: The Complete Drug Reference:), the rate of tretinoin for hyperpigmentation is specified as 0.02-0.05%, and this is approximately seventeen times of the rate in the most preferred condition of the formulation of the invention (0.02 / 0.0012). In the patent application, the term retinoic acid is used to mean retinoic acid and all its derivatives such as tretinoin, isotretinoin, alitretinoin.

[0020] Vitamin E or its derivatives used as antioxidants in the composition of the topical cream formulation of the invention is at the rate of 0.01-0.1%, preferably 0.05% by weight.

[0021] Chlorocresol used as an antimicrobial preservative in the composition of the topical cream formulation of the invention is at the rate of 0.1-0.2%, preferably 0.15% by weight, and vitamin E acetate used as an antioxidant is at the rate of 0.05%.

[0022] The topical formulation of the invention may be in the form of cream, ointment, lotion, foam and gel. The characteristic of the topical formulation of the invention is that it is an oil-in-water (Y / S) emulsion. In the formulated Y / S emulsion, the oil phase as an emulgator contains a mixture of glyceryl stearate + PEG- 100 stearate (Arlacel 165), glycerol monostearate and / or their combinations at the rate of 3-5% by weight. In the formulation, Arlacel is used at the rate of approximately 4% and glycerol monostearate is used at the rate of approximately 0.35%. The total emulsifier is approximately 4-4.5%.

[0023] Note: Numerical values indicated in the specification and the claims should be considered with a tolerance of ± 10%. The weight ratios of the ingredients are given as weight / weight according to the formulation amount.

[0024] In the formulated Y / S emulsion, the water phase may contain pH adjusters, one or more antimicrobial preservatives, humectants and cosolvents. Sodium hydroxide, citric acid and sodium citrate were chosen as pH adjusters, chlorocresol as antimicrobial preservative, glycerol monostearate as humectant, and propylene glycol as cosolvent. The composition contains tocopherol acetate (vitamin E) as an antioxidant.

[0025] The substances included in the formulation and their intended use are indicated in Table 1.

[0026] Table 1. The ingredients included in topical cream formulation and their intended use

[0027] Urea and salicylic acid in the topical pharmaceutical composition are soluble in the water phase of the Y / S emulsion, clobetasol propionate and retinoic acid and / or its derivatives are soluble in the cream phase of the Y / S emulsion form. The production method of the topical pharmaceutical composition includes the following steps: a) Preparation of a water phase containing urea and salicylic acid and citric acid, trisodium citrate dihydrate, sodium hydroxide and chlorocresol, c) Preparation of oil phase by mixing liquid petrolatum, white beeswax, cetostearyl alcohol, glyceryl stearate + PEG- 100 stearate, glyceryl monostearate, d) Preparation of cream base by mixing oil phase and water phase, e) Addition of antioxidant substance with clobetasol propionate, retinoic acid or derivatives, f) Packaging

[0028] The topical cream formulation is indicated in Table 2. This formulation was used in the clinical study.

[0029] Table 2. Topical cream formulation

[0030] The topical cream formulation is prepared as follows:

[0031] Water phase: Propylene glycol is added to heated distilled water and stirred until it becomes homogeneous. Add citric acid, trisodium citrate dihydrate and sodium hydroxide are added into the mixture. Chlorocresol, urea and salicylic acid are added and dissolved.

[0032] Oil Phase: Liquid petroleum jelly is heated, white beeswax, cetostearyl alcohol, Arlacel 165 and glyceryl monostearate is added and dissolved completely.

[0033] Cream Base: Oil phase and water phase is mixed at the same temperature. Clobetasol -17 propionate, retinoic acid and vitamin E acetate are added thereon.

[0034] The safety, tolerability and clinical efficacy of the topical cream formulation forming the subject of invention containing reduced amounts of the active substance were demonstrated in the Phase 1 clinical study described below.

[0035] The topical cream formulation was applied twice a day for two weeks in healthy subjects (n=12) and patients diagnosed with plaque psoriasis (n=6) according to a randomized, double -blind, singlecenter, placebo -controlled Phase 1 clinical study plan. And the placebo product (n=6) was administered in 6 healthy subjects.

[0036] Patients with plaque psoriasis were evaluated by a dermatologist and it was requested to have a Physician Global Assessment (PGA) score >3 (moderate psoriasis) at screening.

[0037] Findings: A total of 31 adverse events occurred during the study in 13 participants, including 9 healthy subjects, 3 healthy subjects receiving placebo and one psoriatic patient. The most common adverse events were reactions at the site of administration, including erythema, exfoliation, itching and burning sensation. During the basic assessment, one patient had a PGA score of 3 (moderate) and five patients had a PGA score of 4 (severe). On the 14thday of the treatment, four patients experienced grade-two and two patients experienced grade-three improvements compared to baseline. This finding indicates that patients moved from moderate and severe disease to mild disease and almost a complete clearance (score 2 or 1).

[0038] There was no significant change in IL- 17, IL-23 and TNF-a levels throughout the study.

[0039] Results: As the results of the Phase 1 study in 18 healthy volunteers and 6 patients with plaque psoriasis showed a favorable safety and tolerability profile for the formulation; the Phase 2 clinical study was initiated in patients with mild to moderate plaque psoriasis.

Claims

CLAIMS1. A topical formulation for use in the treatment of skin diseases such as psoriasis and eczema, characterized in that it comprises clobetasol propionate at the rate of 0.03-0.04%, salicylic acid at the rate of 1-6%, preferably 4-5%, more preferably 4.75% by weight, urea at the rate of 1-15%, preferably 9.5% by weight, retinoic acid at the rate of 0.001-0.005%, preferably 0.001-0.002% by weight according to the weight of the formulation, at least one antioxidant and hydrophilic and lipophilic substance as excipients.

2. A topical pharmaceutical composition according to claim 1, comprises clobetasol propionate at the rate of 0,03-04% by weight, retinoic acid at the rate of 0.001-0.002 by weight, urea at the rate of 9.5% by weight and salicylic acid at the rate of 1-6%, preferably 4-5% by weight.

3. A topical pharmaceutical composition according to claim 2, comprises clobetasol propionate retinoic acid at the rate of 0.035% by weight according to the formulation weight, wherein the weight ratio of clobetasol propionate / retinoic acid is 25 to 40, preferably 30.

4. A topical pharmaceutical composition according to any one of the claims 1 to 3, characterized in that it is an oil-in-water (Y / S) emulsion.

5. A topical pharmaceutical composition according to any one of claims 1 to 3, the oil phase of the Y / S emulsion comprises, as an emulsifier, a mixture of Glyceryl Stearate r PEG-100 Stearate, glycerol monostearate and / or combinations thereof by weight in total between 3-5%, 3.5-4.5%, Glyceryl Stearate t- PEG- 100 Stearate mixture and glycerol monostearate at the rate of 0.3-0.5%.

6. A topical pharmaceutical composition according to any one of claims 1 to 3, wherein the water phase of the Y / S emulsion comprises at least one pH adjusting agent, at least one antimicrobial preservative, moisturizer and cosolvent.

7. A topical pharmaceutical composition according to any one of claims 1 to 3, wherein urea and salicylic acid are soluble in the water phase of the Y / S emulsion.

8. A topical pharmaceutical composition according to any one of claims 1 to 3, wherein clobetasol propionate and retinoic acid Y / S are soluble in the oil phase of the emulsion.

9. A topical pharmaceutical composition according to claims 1 to 2, it comprises tocopherol acetate as an antioxidant agent.

10. A method for producing a topical drug formulation according to claim 1, it comprises the following steps: a) Preparation of a water phase containing urea and salicylic acid and citric acid, trisodium citrate dihydrate, sodium hydroxide and chlorocresol, c) Preparation of oil phase by mixing liquid petrolatum, white beeswax, cetostearyl alcohol, glyceryl stearate PEG- 100 stearate mixture, glyceryl monostearate, d) Preparation of cream base by mixing oil phase and water phase,e) Addition of antioxidant substance with clobetasol propionate, retinoic acid or derivatives, f) packaging.

11. A topical pharmaceutical composition according to claim 1, characterized in that being cream, ointment, lotion, foam, gel formulations.

12. A topical pharmaceutical composition according to claim 1 for used in the treatment of psoriasis.

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