WO2019072353A1

WO2019072353A1 - Topical pharmaceutical preparation of betamethasone, calcipotriol and rose oil for treatment of psoriasis

Info

Publication number: WO2019072353A1
Application number: PCT/EG2018/000007
Authority: WO
Inventors: Mohamed Zakria Ahmed Ali ELMASRY; Ahmed Ibrahim Mohamed ELMALLAH
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-10-11
Filing date: 2018-05-16
Publication date: 2019-04-18
Anticipated expiration: 2020-04-11

Abstract

The present invention pertains to a topical preparation of a combination comprising (a) betamethasone or other potent glucocorticoid or their salts, thereof, and (b) calcipotriol or other D3 analogs thereof in addition to (c) rose oil or one or more of refined components such as geraniol and citronellol. The pharmaceutical composition comprising such combination is intended to treat psoriasis and other immunological and allergic topical diseases use of such combination for preparation of a topical medicament in the form of ointment, cream, spray, lotion, gel foam, transdermal patch and topical solution. A preliminary clinical study has proved the high efficacy and rapid effect of the new patent formula with a considerable cure rate in treating psoriasis.

Description

Topical Pharmaceutical Preparation of Betamethasone, Calcipotriol and Rose Oil for Treatment of Psoriasis

Full detailed description of the invention / utility model

The full description of the invention includes:

(Previous art - the problem or shortcomings in the previous art - detailed description - the method of exploitation)

(1/4) Previous art:

Treatment options depend on the extent and severity as well as the health of the patient. They include topical treatments, light therapy and regular therapy (such as oral or injection therapy). All treatment methods can be used alone or in combination with each other.

A. Topical treatment: Topical treatments are the backbone for the treatment of psoriasis. Psoriasis is improved by topical corticosteroids and emollients, alternatives include vitamin D3, such as calcipouiol and calcitriol, as well as tar, and topical retinoids (tazal'otene).

Topical cortisone and vitamin D3 analogs are the preferred treatment among the various topical medicaments available for psoriasis. Phototherapy is another option for non-conventional disease. It is also used in combination with other treatment modalities in the case of severe types of psoriasis.

Corticosteroids such as triamcinolone, flucinoloneand betamethasone, are the cornerstone for the treatment of topical psoriasis. Used alone or in combination with other modalities, either topical or systemic. Corticosteroids are anti-inflammatory, and immune-suppressants

2 - Vitamin D3 derivatives: Calcitriol, Calcipotrioland Tacalcitol Contribute to normalization of hyperplasia of keratinocytes and regulates cell growth.

3. Salicylic acid, coal tar, and Anthralin, arekeratolytics. Salicylates can be used with other topical treatments such as topical cortisone and calcineurin inliibitors to increase the latter's absorption across the skin. Anthralin reduces keratinocytes, inhibits the activation of T cells, and recovers cell differentiation.

4- Calcineurin inhibitors: Tacrolimus and Pimecrolimus are calcineurin inhibitors that can be used to treat psoriasis in the face and between the folds and for moderate to severe psoriasis.

5. Retinoids: such as tazarotene B. for light therapy (phototherapy): UVA and B, can have beneficial effects on psoriatic skin presumably by changing some immune function. UVB light is used to treat psoriasis. Ultraviolet therapy and topical treatments can usually be combined

UVA is a treatment that combines oral medicine containing suralin with UVA

Systemic therapy (oral or injection) is used in moderate to severe psoriasis and in cases of psoriatic arthritis with psoriasis. They can be combined with other topical or systemic therapies.

Non-biological treatments: Usually oral medicine such as methotrexate, acetrine and cyclosporine.

Methotrexate is an immunosuppressive agent that prevents the synthesis of DNA to prevent cell proliferation. Cyclosporine acts by inhibiting T cell lymphocytes.

Biologic Treatments

1- Tumor Necrosis Factor alpha (TNF-alpha) inhibitors: certolizumab, etanercept, adalimumab and infliximab. In psoriasis and psoriatic arthritis, there is an excess production of TNF alphain the skin or joints. This leads to rapid growth of skin cells and / or joint, tissue damage. Prevention of TNF alpha production helps to stop inflammatory course of psoriasis.

2 - Interleukin 12 and 23 (IL-12/23) inhibitors: Ustekinumab) works through selective targeting interleukin 12 (IL-12) and interleukin 23 (IL-23). Interleukins- 12/23 are associated with psoriasis.

3. Interleukin 17 (IL-17) inhibitors: (Secukinumab). By interfering with IL-17, this drug inhibits the inflammatory course of psoriasis. This can lead to an improvement in symptoms for many people who take it.

4. T cell suppressor inhibitors: Abatacept andEfalizumab. They target T cells in the immune system. T cells are involved in inflammation in psoriasis and psoriasis.

(2/4) The problem or shortcomings in the previous art:

Although there is an abundance of different medications to treat psoriasis, none has been proven to be a curative. The degree of improvement varies between different treatment modalities, and the PASI score of 100 is rarely achieved This PASI score is an objective score for degree of success or failure of therapy. In addition, relapses are common to most of these drugs. Treatment can be continued longer. This can be a restriction that may require a change between different medications and use combination or use at varying intervals.

The cost of new biologic medications is very high and puts additional restrictions on use. Improvement with calcipotrioltreatment is delayed. In addition to these limitations, side effects vary among different drugs, and in some cases may require discontinuation £>f treatment or switching to other remedies. These limitations have led to the concept that many patients with psoriasis do not receive adequate treatment to control the disease. Here are some negative effects of different drugs.

Topical cortisone: Side effects include atrophy of the skin, enlargement of the capillaries, or secondary infection. Therefore, strong cortisone should not be used on the face or the skin folds sites. Systemic events occur when cortisone is used for long periods of time or at higher doses than normal doses. Such as Cushing's syndrome, high blood sugar. Vitamin D3 derivatives side effectsinclude: skin irritation, allergies, high blood calcium levels, and vitamin D toxicity. For doses exceeding 100 gm ointment / week calcipotriol can lead to hypercalcemia.

Tacrolimus and Pimecrolimus treatments have a common negative effect of skin senstization. Tazarotene can cause irritation and can cause burning or stinging. Sensitivity to the sun may occur.

Systematic treatment. Methotrexate: hepatotoxicity, renal insufficiency, thrombocytopenia, leukocyte deficiency and infection. In addition to, mouth ulcers, nausea, fatigue, chills. Acitretin: Side effects include dry lips, dry eyes, dermatitis, hair loss, and include more serious adverse effects of teratogenicity and liver toxicity.

Cyclosporine use is limited due to high blood pressure and expected renal impairment.

Ustekinumab: Upper respiratory infection, pharyngitis, headache, dizziness, fatigue, diarrhea, nausea, back pain, muscular pain, arthralgia, local injection, pain, bruising, irritation, itching, Infection (up to 27%)

Secukinumab: Although this drug has shown great efficacy for psoriasis compared with other biologic therapy and old treatments, it has frequent side effects include: sore throat, nose, diarrhea, upper respiratory infection, sinusitis, obstruction or runny nose, herpes Oral, hives, athlete's foot, tonsillitis, inflammatory bowel disease, ear infection, eye inflammation or conjunctivitis, increased liver transaminases.

(3/4) new in the subject of invention / utility model

The present invention deals with the use of a low concentration of betamethasone and Calcipotriol with rose oil designed in the form of topical pharmaceutical formulation to achieve greater clinical effectiveness and reduce the negative effects of Betamethasone and Calcipotriol. Rose oil is effective as well as has no side effects as the US Food and Drug Administration has recognized that the rose oil of safe substances (GRAS). Considering the mechanisms of rose oil and its components that proveditshigh potential as anti-psoriasis agent, this combination can add new hope for psoriasis patients to receive treatment for the following expected benefits:

A. Quick onset.

B. Complete disappearance of all symptoms in a few weeks

C. Synergy between the three components with high efficiency and minimal failure rate within a limited period of treatment.

D. Low concentrations of the ingredients results in Few negative effects.

E. Full curative treatment with no relapses (4/4) Detailed description

In general, topical psoriasis treatment has a lower efficacy rate than new biological medications.

Biological therapy, although more effective, is very expensive and has many negative effects.

The treatment with topical vitamin D3 such as Calcipotriol and calcitriol has become an integral part of the psoriasis treatment system. It has been shown to be effective either alone or with other treatments. These treatments however, suffer from adverse effects as previously mentioned. Corticosteroids has long been regarded as the first line of treatment for psoriasis. But have topical and systemic side effects associated with continuous use, at high or prolonged concentrations. Afixed combination of calcipotriol and betamethasone dipropionate in the form of ointment and foam are available. This combination still suffers from the side effects of each component as the concentration of each component in the composition is the same for single-component ointments. Rose oil or its refined components such as geraniol and citronellolare promising elements in the treatment of psoriasis. There are many reports on the proposed mechanisms. Rose oil has a remarkable role in promoting differentiation in keratinocytes, but not its spread, a key feature that helps improve psoriasis (1). In addition to this latter finding, rose oilmodulates TRPVl receptors which are implicated in psoriasis pathogenesis (2,3). A similar association was also reported between the proliferation of keratinocytes and TRPVl receptors (4). Based on these reports, the work of rose oil on TPRV1, can clearly explain the beneficial role of rose oil in the treatment of psoriasis. In addition, rose oil, by enhancing the unique keratinocyte differentiation adds a new weapon in the treatment of psoriasis. The proposed invention consists of formulation of a topical pharmaceutical preparation comprising: A) Corticosteroid,B) Calcipotriol or other analogues of vitamin D3. plusC) rose oil or one or more of the refined ingredients such as geraniol and citronellol. The glucocorticoid is Betamethasone dipropionate or other powerful glucocorticoid or their salts. The concentration in the preparation ranges of 0.005-0.05% (0.05-0.5 mg / g ointment or other forms), preferably from 0.05 to 0.25mg per gram of the formulation and preferably O.lmg. Other strong or less effective glucocorticoid can be used within similar concentrations with those Standard.

The second element in the formulation is Calcipotriol, a vitamin D3 derivative or similarvitamin D3 analogues. Calcipotriol concentration ranges from 0.001-0.005% (10-50 μg / g, ointment or other forms). Preferably the range should be 0.001-0.025% (10-25 μg / g). More preferably as 10 micrograms per gram of base formula (0.001%). The third element in the composition is rose oil or one or more of its extracted and refined ingredients such as geraniol and citronellol. Rose oil has multiple names such as (oil of Otto, Rose of Attar, Attar of roses) is oil extracted from petals of different types of roses. Rose oil can also be replaced with essential oils containing geraniol and citronellol. The most common chemical compounds found in rose oil are: citronellol, geraniol, nerol, lynalol, ethyl phenyl alcohol, farnicol, stearopetin, a- benin, β-benin, a- Ethyl acetate, nitronil acetate, granyl acetate, nitril acetate, eugenol, methyl eugenol, oxidate, a-damacinone, β-damacinone, benzaldehyde, benzyl alcohol, rhodenyl acetate and

phenylthylformate.

The concentration of rose oil in the topical formulation of the invention ranges from 0.2-10% of ointment or other topical forms base (10-100 mg / g). The concentration should preferably be 5-50 mg / g from the base of the formulation (0.5-5%). The best would be 30mg / g (3% of the ointment base). Concentrations of geraniol and / or citronellol are used in a similar concentration to their presence in rose oil. The pharmaceutical formulation, which includes this formulation, is the preparation of the formulation in the form of topical ointment, cream, spray, lotion, gel, foam, transdermal patch, shampoo, paste or topical solution. So, the base is suitable for topical application and allows good penetration in keratin layers and skin for psoriasis patient. The current invention provides the use of a topical base including a suitable and compatible penetration enhancer

The invention, which includes topical pharmaceutical preparation, aims to treat psoriasis in all its forms and severity, as well as other skin diseases such as immune diseases, allergies, burns and skin ulcers.

A double blind clinical trial was performed to compare the efficacy and safety ofthe invention ointment to a standard formulation of Betamethasone / Calcipotriol ointment as a Comparator.

The topical ointment formula in this invention consists of three components: Betamethasone, Calcipotriol and Rose Oil. The formula chosen to be tested here is an ointment formula based on the following ingredients Each gram of ointment formula (Calcipotriol hydrate, Betamethasone dipropionate and Rose oil) ointment contains 10.45 micrograms of Calcipotriol hydrates (equivalent to 10 micrograms of Calcipotriol) and 0.129 mg of betamethasone dipropionate (0.1 mg of betamethasone) and rose oil 30 mg in base ointment of mineral oils, a-tocopherol, butylhydroxytoluene, white soft paraffin, liquid paraffin, polyoxypropylenestearyl ether.

Comparator is a standard ointment of a combination of betamethasone and Calcipotriol. Each gram (Calcipotriol and betamethasone dipropionate) contains an ointment containing 52.18 micrograms of Calcipotriol hydrate (equivalent to 50 micrograms of Calcipotriol) and 0.643 mg of betamethasone dipropionate (0.5 mg of betamethasone) in an ointment base of mineral oils, a-tocopherol,

butylhydroxytoluene, white soft paraffin, liquid paraffin, polyoxypropylenestearyl ether.

The objective of the experiment was to evaluate and compare the effectiveness of the patent formula and compare it with the standard comparator. This randomized double blind study was performed on a parallel group of 36 patients with moderate to severe psoriasis in outpatient status divided into two groups with 18 patients.

Protocol: The two groups were randomly selected for either treatment. Patients were instructed to apply the ointment once a day. Patients were examined every two weeks (week 2 and 4). The duration of the study was limited to 4 weeks. It is recommended that Continuous glucocorticoid should not be extended after 4 weeks.

Effectiveness evaluation: The PASI score ( Psoriasis Area and Severity Index) has been used. The evaluation was based on the following: PASI 90 and PASI 100 are both important results for the success of treatment for psoriasis patients, indicating that the symptoms of the disease are vanished or almost complete clearance. PASI > 75% demonstrating good efficacy of treatmen PASI > 50% indicates an improvement in the condition that may require dosage adjustment. PASI<50% indicating treatment failure and alternative treatment should be used.

Safety assessments and adverse events: Patients were screened to monitor the safety of the skin. Side effects were assessed, and patients were asked whether they had any problems during treatment, nature, and severity of adverse effects. Patients' satisfaction with treatment was assessed by performing the DLQI questionnaire (Dermatology Life Quality Index) two weeks later and at the end of the treatment period (4 weeks).

And results and data in Tables 1, 2 and 3 in the current clinical trial study, and the application of the new formula showed significant progress over the use of standard Betamethasone / Calcipotriol ointment. And PASI 90 as an important measure of successful treatment by the European Medicines Agency (5) and the goal of optimal treatment for patients (6). After 4 weeks, patients treated with the new patent formula showed more than 77.8% achieving PASI 90 whereas only 16.7% of patients of the comparator group reported this

This is an extraordinary effectiveness of a topical preparation and, moreover, in such a short period of treatment (4 weeks). PASI score> 75% of the new patent composition group is significantly higher than the comparator group (77.8 versus 38.9%) and 94.5% versus 50% for the new formula compared to the comparator group after 2 weeks and 4 weeks respectively. The percentage of patient showing PASI index of less than 50% was 27.8% in the comparator group, while no patient in the patent ointment group showed this criterion. As previously mentioned, for the Betamethasone / Calcipotriol ointment, the maximum weekly dose should not exceed lOOg. Treatment is not recommended of more than 30% surface area of the body. As in the current patent, the concentration is only one fifth of the original ointment so could allow higher doses and more use on the surface ef the body safely.

The results obtained emphasized three important outcomes: first, the new formula is much more efficient than the comparator group alone; secondly, the beginning of rapid improvement in the new formula set; third, the superiority of the new patent topical preparation to achieve excellent results is rarely obtained through any of the modalities currently available.

In this study, only 4 patients in the patent formula group complained of itching and stinging. Although statistically insignificant, 6 patients of the comparator group complained of itching and irritation which were higher and reflected by a lower DLQI score. Evaluation of patient satisfaction after treatment and the effect of progress in relieving patient symptoms revealed a very good acceptance of the patient for the new formula Fifteen out of 18 patients showed an improvement in DLQI score with a 90% reduction in outcome. For the comparator group, only 2 (11.1%) showed this decrease. All patients in the patent group showed a decrease of greater than 75%, while in the comparison group only 9 patients reported this decrease.

In conclusion, this invention of a topical ointment to treat psoriasis, which includes addition of rose oil to a low concentration of betamethasone and Calcipotriol, is a perfect alternative to comparator ointment and even new biological medications. In this study, for the first time, the patent formula was proven to be effective and curative for psoriasis, whereas the concentration of corticosteroids and Calcipotriol used was significantly lower than that of the formulation being marketed. The first interesting outcome of this study is the rapid onset manifested as reported by the results and the alleviation of symptoms and achievement of high PASI scores. Another interesting result in the new patent formulation group is the complete clearance of all symptoms in a large number of patients in only 4 weeks of topical treatment. The results obtained have also exceeded many of the recently reported results of biological therapy as stated in many clinical trials.

The rapid successes and improved symptoms with the new formula and very few ADR, compared to the high potential cost of biological therapies and potential adverse effects, can all advocate the use of the current patent as a first line option to treat many types of psoriasis.

Definition of general terms

The general terms used here are defined in the following sense, unless particularly stated otherwise: The terms "contained" and "including" are used here in the open and unlimited sense unless otherwise specified. The term "combination" or "pharmaceutical combination" is defined here to refer either to a fixed formula in the form of a single dose unit or a separate entity combination of the different components. That is, each component of the composition can be used independently at the same time or separately within time periods and allow the combination of Individual medicines all in a separate form to show a cooperative effect and synergy.

The term "fixed combination" means that active ingredients or therapeutic agents, corticosteroids, vitamin D3 derivatives and rose oil are given to the patient simultaneously in the form of a single topical entity or dosage form. The term "separate combination" means that active ingredients or therapeutic agents, corticosteroids, vitamin D3, rose oil or its derivatives are given to the patient as separate entities or in different pharmaceutical dosage forms in a dose eithep-simultaneously, concurrently or sequentially without specific time limits.

- Calcipotriol and calcipotrieneare synonyms. (4/5) Method of use

1. The present invention deals with the preparation ofa topical formula in the form of ointment, cream, spray, gel, foam, transdermal patch, shampoo, topical paste or topical solution.

2 The combination has a low concentration of betamethasone and Calcipotriol with rose oil

3 The medicine containing the above-mentioned ingredients is used in the treatment of all types of psoriasis and all types of eczema and all types of burns and wounds.

4 Apply a thin layer on the affected area.

References - Enhancement of keratinocyte differentiation by rose absolute oil (2010). Kim JH, Choi DK, Lee SS, Choi SJ, Kim CD, Yoon TJ, Lee JH., AnnnDermatol., 22(3):255-61.

- Activation of the human transient receptor potential vanilloid subtype 1 by essential oils

(2010).Ohkawara S, Tanaka-Kagawa T, Furukawa Y, Nishimura T, Jinno H., Biol Pharm Bull., 33(8): 1434-7.

- Roles of transient receptor potential proteins ( RPs) in epidermal keratinocytes.f 2011 ). Denda M, Tsutsumi M.. Adv Exp Med Biol. 704:847-60.

- Glvcolic acid induces keratinocvte proliferation in a skin equivalent model via TRPVl activation (2010)Denda S. Denda M. Inoue K. Hibino T., J Dermatol Sci.: 57(2):108-13.

- European Medicines Agency (EMA) Committ e for Medicinal Products for Human Use (CHMP) Guidelines on clinical investigation of medicinal products indicated for the treatment of psoriasis. 2004. Available at:

http://www.ema.europa.eu/docs/en_GB/documentJibrary/Scientific_guideline/(link is external)- Mrowietz, U. Implementing treatment goals for successful long-term management of psoriasis. Journal of the European Academy of Dermatology and Venereology, 26: 12-20.

Claims

1. A topical pharmaceutical preparation composed of (A) Betamethasone or other strong glucocorticoids or their salts; (B) Calcipotriol or other D3 counterparts; (C) Rose oil or one or more refined ingredients such asgeraniol and citronellol.

2. Composition according to element 1 where the glucocorticoid is betamethasone dipropionate or other strong glucocorticoid or their salts.

3. Composition according to any of the elements 1 and 2 where the concentration ranges from 0.005- 0.05% (0.05-0.5 mg per gram of ointment or other forms).

4. Composition according to elements 1-3 where vitamin D3 include Calcipotriol, calcitriolor tacalcitol.

5. Composition according to element 4 where the counterpart of vitamin D3 is Calcipotriol

6. Concentration according to elements 4 and 5, where the concentration of Calcipotriol ranges from 0.001-0.005% (10-50 μg / g of composition)

7. Composition According to any of the elements 1-6, include rose oil or one or more of its refined ingredients.

8. The composition according to the protection element No. 7, where the refined components of rose oil include geraniol and citronellol.

9. Composition according to elements 7 and 8, where the concentration of rose oil between 0.2-10% (2- 100 mg / g) rose oil or an appropriate concentration of refined ingredients such as geraniol and citronellol.

10. Composition according to any one of the elements 1-9, for the treatment of psoriasis, skin diseases, immune and allergic diseases, burns, ulcers and skin.

11. A pharmaceutical formulation according to elements of 1-10 is a topical formulation in the form of ointment, cream, spray, gel or foam, transdermal patch, shampoo, topical paste or topical solution.

12. Composition according to the protection element number 11 where the base contains an absorption enhancer.