WO2016159916A1

WO2016159916A1 - A foamy pharmaceutical formulation used in dermatological diseases

Info

Publication number: WO2016159916A1
Application number: PCT/TR2016/050094
Authority: WO
Inventors: Ilker TORLAK
Original assignee: Ogi̇g Sağlik Ürünleri̇ Ve Hi̇zmetleri̇ Sanayi̇ Ti̇caret Li̇mi̇ted Şi̇rketi̇
Priority date: 2015-03-31
Filing date: 2016-03-31
Publication date: 2016-10-06

Abstract

The invention relates to a foam formulation used in topical applications for prophylaxis and treatment of dermatological diseases that do not respond to initial treatment or are defined as persistent against suitable care, comprising at least one active agent, at least one solvent, at least one surfactant, at least one organic solvent, and water.

Description

METHOD AND APPARATUS OF NON-SQUARE INTRA PREDICTION FOR CHROMA COMPONENTS IN CODING SYSTEM WITH QUAD-TREE AND BINARY-TREE PARTITION

The Related Art

The invention relates to a combination pharmaceutical composition developed for topical applications used in prophylaxis and treatment of dermatological diseases that do not respond to initial treatment or are defined as persistent against suitable care.

The invention particularly relates to a combination pharmaceutical composition used in topical applications and comprising water, at least one active agent, at least one solvent, at least one organic solvent, and at least one surfactant.

The Prior Art

Skin is one of the largest organs in the body in terms of surface area and weight. Skin is formed of two layers as epidermis and dermis. Hypodermis or subcutaneous adipose tissue is located beneath the dermis. Skin has three basic functions as protection, regulation, and sensing. Injury affects all functions of the skin¹.

Skin is a protection organ. Primary function of the skin is to act as a barrier. Skin protects the body from mechanical impacts and pressure, temperature variations, microorganisms, radiation and chemicals.

Skin is a regulation organ. It regulates various aspects of the physiology. These include functions such as regulation of body temperature through perspiration and hairs and regulation of peripheral circulation and changes of fluid balance through perspiration. Furthermore, it acts as a store for vitamin D synthesis.

Skin is a sense organ. Skin contains a wide network of nerve cells that perceive and transmit the changes in the environment. There are different receptors for hot, cold, touching and pain. Damaging of these nerve cells is known as neuropathy and results in loss of sense in the affected areas. Patients with neuropathy do not feel any pain when they get injured and this increases the risk of more severe injuries or deterioration of the present injury. Dermatology deals with diagnosis and treatment of diseases transmitted by skin, hair, nail, mouth mucosa or sexually. Nowadays, allergic skin diseases are increasing more and more due to modern lifestyles and changing environmental conditions. Finding the causes of skin diseases such as Atopic Eczema, Contact Eczema, Urticaria (Hives) as well as the first line treatment to find out whether they are endogenous or exogenous are crucial in terms of preventing them from becoming chronic and recurring

Mainly, dermatological (skin) diseases can be listed as follows:

- Wart

- Pregnancy and skin

- Mange (Scabies) and its treatment

- Callus (hyperkeratosis)

- Herpes

- Excessive perspiration

- Vitiligo

- Hair diseases

- Blemish treatment

- Hair loss

- Psoriasis

- Spiloma and Hemangioma

- Acne (pimple)

- Eczema (uticaria)

Skin diseases can be split into several sections in order to get a general idea:

Skin diseases resulting from physical causes

Wounds caused by sharp, cutting or crushing objects, burns, cracks caused by cold, wounds caused by irritation of chemical substances can be included in this group².

Skin diseases caused by parasites

Mange, pediculosis and various fungal diseases are among the main diseases in this group. In addition, skin deformations caused by insects bites such as louse, bedbug and acarid can also be included in this group. Fungal diseases have an important place among the skin diseases. Approximately 10 % of the patients apply to dermatology clinics due to fungal diseases. Fungal diseases are classified as surface and deep fungal diseases. Surface fungal diseases

1 . Dermatophytoses

2. Candidiasis (monilia)

3. Pityriasis versicolor Dermatophytosis Infections

Dermatophytosis fungi cause tinea infection. They are transmitted by direct or indirect contact. They are surface fungal infections on keratinized tissues such as epidermis, hair and nail. Dermatophytoses:

1 . Trichophyton types cause disease on skin, hairs and nails.

2. Microsporum types cause disease on skin and hairs.

3. Epidermophyton types cause disease on skin and nails. Dermatophytoses are keratophilic and invade the keratin. Inflammation depends on metabolic products of fungus or late hypersensitivity. Dermatophytoses are classified as anthropophilic, zoophilic and geophilic by their presence in humans, soil or animals. Zoophilic fungi cause more severe inflammation compared to anthropophilic ones. Itching is the most significant complaint in skin fungal infections³'^{4 5}.

By settlement areas;

1 - Tinea capitis

2 - Tinea barba

3 - Tinea corporis

4 - Tinea cruris (inguinalis)

5 - Tinea pedis and T. manum

6 - Tinea incognito (atypical form)

Predisposing Factors:

1 . Moisture and dampness

2. Poor hygiene

3. Diabetes 4. Obesity

5. Use of systemic and topical steroid

6. Pregnancy

7. Immunosuppression

Clinical Forms:

Tinea capitis: It is surface fungal infection on the scalp and it is usually seen in pre - puberty periods. It is a fungal infection on the scalp mostly caused by trichophyton and microsporums. Fungal hyphas penetrate into and reproduce in hair shaft and follicle after a few days of incubation period following transmission. This reproduction leads to fraction of hair, squama and inflammatory response. The infection spreads centrifugally during 8 - 10 week period and it may affect an area up to 7 cm diameter. Alopecic patches (black dots) are found on the scalp in which there is one or more non - inflammable squama and fractured hair. Generally, it is encountered in school - age children⁶.

Tinea capitis; it has three types with different clinical features and courses as a - T.k. superficial, b - T.k. profound (kerion celsi) and c - T.k. favus.

Tinea Capitis Superficial: It is a type in which fungi are of non - inflammatory nature and also have human (anthropophilic) subtypes. It may occur as epidemics in schools due to its transmission by direct contact. It is colloquially known as "barber's itch" or "ringworm".

It starts as round or oval, small or large, greyish, scurfy macules or plates on the scalp. The hair in this area is observed to be fractured on follicular opening in a few weeks. This disease which is typically single - focal may occur multifocally. It doesn't cause permanent alopecia, because hair follicle isn't damaged^{78 9}.

Tinea Capitis Profound (Kerion Celsi): It is also known as inflammatory type. It is mostly caused by zoophilic (borne by cat, dog, sheep and goat) dermatophytes. The disease may start as T.k. superficial. The agent attacks the hair follicle and the surrounding and causes folliculitis and perifolliculitis in a short time. However, it mostly emerges as one or more watery, festering and partly crusty nodular lesions in different diameters. When the nodule is squeezed, fester comes out of hair follicular openings. It is referred to as kerion celsi for this characteristic. Inflammatory reaction develops in consequence of late presented sensitivity reaction against fungus elements. The hairs on the lesion can be drawn out smoothly by using tweezers. Cicatrice and permanent alopecia develop in the area of inflammation and maturation. Inflammation and lesion pain may arise in severe cases. Local adenoids become swollen and painful. Papular, vesicular, rarely pustular symptoms which are defined as id reaction particularly on the neck, face, shoulders and arms are seen in majority of patients.

Tinea Capitis Favus (Baldness): It is typically caused by Trichophyton schoenleinii and occasionally by T. violaceum. Clinically, it is characterized by fractured hair, cavity, yellow - green crust (scutulum, gode), atrophic cicatrice and weak, greyish and normal - length hair. It consists of scutulum fungus culture. It smells like mouse urine.

Tinea capitis diagnosis: It is confirmed when fungus agent is found on skin scratch or the local preparate made of hair. Systemic and topical antifungal agents should be administered together in all types of tinea capitis.

Tinea pedis: T. pedis which is also referred to as athletic foot is the most common fungal infection in society. It is typically seen in soldiers, sportsmen and dormitory students due to its transmissible nature. Wearing shoes for a long time, hyperhidrosis, humid and hot environments allows the disease to be localized easily. The disease which becomes still in cold seasons is aggravated in summer months again. The interdigital type is most commonly seen to start as itching and maceration between 4th and 5th fingers of the feet and spread to other fingers interdigitals. The hyperkeratotic squama type is generally asymptomatic. This type is also known as moccasin. There are slight erythema, hyperkeratoses and squamas on the sole and sides of the feet. In dyshidrosic type, there are vesicles and bullas on sides of the feet.

Tinea manum: It is typically seen on hands and mostly on the right hand. There are diffuses and dry squamas on the palm. It is most commonly caused by fungal infection on the feet. It is generally asymptomatic. The interdigital type characterized by maceration and erythema on the interdigitals and the dyshidrosic type characterized by vesicles on sides the hands are not rare. Definitive diagnosis should be made by contact, dermatitis, psoriasis, keratoderma, syphilis period 2 in fungal infections localized on the palms and soles and by erythrasma and candidiasis in the interdigital type.

Complications such as erysipelas and lymphangitis are pretty common in the course of T. pedis and T. manum. Tinea inguinalis (Tinea cruris): It is more commonly seen in men. It is in the form of itchy plaques which are localized one - sidedly or two - sidedly in the genito - crurale area (upper inner side of the thighs) and which have distinct edges and gradually expand. Scrotum is generally not affected as distinct from candidal infection of this area. There are bright and intense erythema, satellite papules and pustules with ragged edges in candidal infection of the inguinal area. Inguinal intertrigo is particularly seen in fat people. It doesn't have erythema as much as candidiasis; it isn't distinct - edged as inguinal tinea, and its microbiological assessment is negative. Erythrasma is a bacterial infection and its agent is Corynebacterium minutissimum. It gives off coralline fluorescent in Wood light. Healing in the middle, active inflamed edge and itching isn't observed on the lesion in erythrasma¹¹.

Tinea corporis (tinea circinata): It is colloquially known as tetter. It is mostly seen in the form round and sometimes oval or shapeless plaques in various diameters; its active edge expands while it is getting healed in the middle. Squama, erythema and inflammation are apparent in its periphery. A number of vesicles and pustules can be observed in severely inflamed cases. Satellite lesions may occur in time in the disease starting as a single lesion.

Tinea barba (sycosisparasitaria): It is an infection which is mostly caused by zoophilic fungi and seen in the beard and mustache area. It is typically characterized by one or more watery, festering and crusty nodular lesions in various diameters which start one - sidedly in the beard area. The hairs on the lesion can be drawn out easily. Regional adenoids get swollen and they hurt when touched. It is acknowledged as kerion celsi in the beard area with this appearance. Cicatrice and permanent alopecia develop in the inflammation and maturation area.

Sycosis barbae is characterized by staphylococcal folliculitis. Lupoid sycosis is a severe and chronic form of sycosis barbae; and the cicatrice in the middle is surrounded by papules and pustules and it is given the appearance of lupus vulgaris. Dermatophytosis folliculitis must be distinguished from Stf. aureus folliculitis. In fungal infections, hairs are typically fractured or fragile, and there are suppurative or granulomatous nodules. The hairs on these nodular areas can be drawn out easily with free of pain.

Pseudofolliculitis barbae results from stinging of curled hair shafts particularly on the gill and neck areas in people having hard and curled hairs such as black people. There are inflammatory papules on these areas. Secondary Stf. aureus infection should be ruled out if there are pustules¹². Tinea incognito: Surface fungal infections change their shape depending on the use of potent topical steroid, irritation or immunosuppression and they take a form apart from their characteristic features. Psoriasis, seborrheic dermatitis, nummular eczema and contact dermatitis diagnoses are made for fungal infections, then inflammation regresses at the early phase and the patients relieve by administering topical steroid. At later phases, local immunosuppression resulting from steroid allows the fungi to reproduce quickly.

Active distinct - edge characteristics expected to be seen in tinea corporis or cruris are lost. The difference between the middle and the edge of the lesions disappear. The infection may expand faster than expected. Papule and pustule formations become apparent. Fungus agent can be seen easily in the local preparate a few days after discontinuing the steroid.

Onychomycosis (Tinea unguium): It is mycotic infection on the nails. Dermatological diseases caused by microorganisms

Such organisms typically lead to dermatitises. Microorganisms may be localized easily on any skin deformation. Wounds, burns, mange, insect bites, eczemas and herpes may get suppurated easily. This is also referred to as "dermatitis". A mechanism apart from the abovementioned dermatites applies to lepra, lupus and syphilis which are among the diseases caused by microorganisms. Thus, they are referred to as specific inflammation or specific infection group¹³.

Allergic dermatological diseases

They are the most common dermatological diseases. Allergic skin diseases include serum disease, Quincke edema, uticaria, eczema, contact dermatitis. It is quite difficult to find out the cause of allergic skin diseases. For this purpose, the patient and his environment are investigated well. A variety of skin tests are conducted. If necessary, the patient is taken away from his environment. The reason for the allergy should be found out. The reasons may be pollens, various food substances, house dusts, some medicines or enterozoas. Heredity, body structure , nervousness or psychological reasons also play a big role in allergic diseases. Apart from such skin diseases; there might also be symptoms of various internal diseases on the skin. For example, various symptoms of diabetes can be seen on the skin (uticaria, hematoma, gangrene, etc.). In addition, malignant and non - malignant tumors can also be found on the skin. Skin cancer(s) is/are the least worst of all cancers. It can be fully recovered, as well.

Depending on the types of skin disease, various symptoms are found on skin. They include itching marks, papule (small blister), pustule (purulent blister), furuncle, ulcer, tubercule (small eminence), erythema (redness), hyperpigmentation (excess production of melanin), hypopigmentation (loss of skin color), desquamation (skin peeling), incrustation and neoplasia. One or more of these symptoms can be seen in a single skin disease. It is easy to diagnose skin diseases. For final diagnosis, a sample is taken from the patient and subjected to pathological examination. They are not always easy to treat; and they vary by the type of disease¹⁴.

One of the most common agents used in treatment of dermatological diseases is corticosteroids. In 1952, local corticosteroids came to be used widely in modern dermatological treatment after it was found out that local hydrocortisone is also effective in treatment of inflammatory dermatosis as cortisone which is administered systemically^{1 " 5}. In the next years, new derivatives to increase local activity have been produced. Differences were obtained in potency of steroid by modifying the ring structure and side chains. Adding halogen on the ninth position, introducing a double bond between the first two carbon atoms, and particularly the nature of side chains on the 21 st position increase its activity. The side effects reported have also increased upon increase in its frequency of use and introduction of stronger preparates in 1970's.

Strengths of the local corticosteroid preparates which are still in use are different. For example, halogen - free corticosteroids have low strength while halogenated corticosteroids have stronger effect⁷. However, preparates with stronger effect also have undesirable side effects. What we need is to decrease side effects of the treatment while increasing its potency.

There are new molecules claimed to achieve that goal. Mometasone furoate is alphamethyl 16 analog of beclomethasone. It comprises chlorine atoms in alpha 9 and position 21 and furan in position 17. Mometasone furoate having side effects comparable to betamethasone is a medium - strength steroid which is as strong as clobetasol furoate.^{16 " 21} Due to the potency being multi - factor problem, an equivalent dosage calculation that applies to local use hasn't been made so far unlike the systemic use. Local steroids are sorted and grouped by their potency. This sorting was previously made by treatment experience. This slow and expensive method is not suitable for determining the effects of new products. Nowadays, efficiency (potency) of local corticosteroids are sorted by vasoconstriction test, atrophy formation test and clinical experiments.^{2 5}'⁶'²² One of the sortings is MIMS (Monthly Index of Medical Specialization) sorting. Another one is Niedner sorting. Degrees of potency of local corticosteroid preparations affect their concentration. Accordingly, commercially available local corticosteroid preparations have concentrations varying between 1 % and 0.025 % (List: Table 3, below). When mometasone furoate is administered once a day in 0.1 % concentration, it is as efficient as betamethasone dipropionate or valerate administered twice a day.¹⁶²⁴

Corticosteroids have triple effect mainly primarily as anti - inflammatory, immunosuppressive and antiproliferative effects. Changes that occur on the skin upon administering local corticosteroid can be summarized as follows: 1 . Vasoconstriction

2. Reduction in inflammation

3. Decrease in cell mitosis

4. Epidermal thinning

5. Melanocyte inhibition

6. Inhibition of collagen synthesis

7. Epidermal barrier function disorder

8. Increase in epidermal beta receptor density

9. Inhibition of acantholysis As it is seen, some of the changes are undesirable effects. Vasodilatation probably caused by histamine and kinin by means of direct stabilization of inhibition and endothelium cells is eliminated and vasoconstriction emergesin production of prostaglandin. In this case, permissive effect of corticosteroids also has a role on catecholamines. Another significant effect is reduction of inflammation. Intradermal diapedesis of leukocyte with polymorphic nuclei is halted by steroids at the beginning of margination. This case is considered to develop depending on reduction in adhesion between the leucocytes and endothelial cells.

Antimitotic effects of local corticosteroids can be demonstrated with dermatosis progressing by squama and with on a normal human skin in vitro. Steroids are effective with inhibition at G2 phase of cellular cycle. Consequently, protein and collagen synthesis is inhibited.6,26,27 New generation methyl prednisolone aceponate and mometasone furoate are demonstrated to decrease collagen synthesis on a level with hydrocortisone.

Penetration of active substance into the skin is required for potency of local corticosteroids. Upon administering the preparation on the skin, the active substance transforms from transporter base into free state and then it is received by stratum corneum. Penetration of corticosteroids into stratum corneum doesn't only depend on relative water/oil solubility. Solubility of corticosteroids in the vehicle and solubility of the vehicle in stratum corneum affects this case. As in the case of propylene glycol/isopropyl myristate which is one of the most commonly used vehicles today, a transporter increases corticosteroid penetration. Efficiency of penetration and the preparate are increased by adding keratolytic active urea to a corticosteroid preparate at the rate of 10 % .

State of the skin is also important in penetration of corticosteroid into the skin. A skin with partially or completely damaged keratinized layer allows penetration and permeation of the active substance into the skin more quickly. Penetration occurs later in lichenification and undamaged skin.

Chemical configuration of the active substance affects penetration significantly. Particularly lipophilic corticosteroids such as mometasone penetrate into the skin better.

Age of the skin also plays an important role in penetration of corticosteroids. Barrier function the skin isn't developed completely in the children up to 6 - month old, so administration of corticoid must be made more carefully at these ages.

An important factor in terms of the effects of local corticosteroids is hydration of the administered area. Dampening the skin slightly before administration increases penetration by five times. When occlusion is made on the administered area, in other words that area is closed, moisture and heat go up. In the same time, corticosteroids are accumulated in the stratum corneum; thus, the desired effect is achieved for a long time.

Closed treatment; it is administered on dry lesions where local corticosteroid was administered openly before and no satisfactory response was received. Effect of the occlusion treatment is in parallel with the closing time. Some claim to achieve maximum penetration in a couple of hours through this method. Those who hold this opinion don't recommend closing for more than three or five hours. The area where closed treatment is to be administered must certainly be dry. Otherwise, it leads to development of moniliasis and folliculitis. Moreover, if another lesion is exudate, many organisms on the skin flora may easily reproduce and get into circulation and then cause development of common infectious eczematoid dermatitis. Therefore, dry lesions are preferable for closed treatment. Microorganisms on the skin flora may decrease potency of the local steroid.

Absorption levels of corticosteroid preparates administered on various areas of the body also varies by areas. For example, 1 % of the 1 % hydrocortisone solution administered on the forearm is absorbed while only 1 /7 of this amount is absorbed on the soles. Absorption is 6 times more on the face skin while it is 42 times more on the scrotal skin.

Corticosteroids are used locally in the form of lotion, cream and pomade. Three characteristics must be taken into account in local administration:

1 . Dosage of the preparate used,

2. Penetration sensitivity of the skin's administration area against corticosteroids

3. Dryness of the lesion.

Lotions are used in acute exudative cases; cream is used in subacute erythematous and edematous cases; corticosteroid preparates are used in the form of pomade in dry and lichenified chronic cases.

Native corticosteroids must be administered according to certain treatment principles. The administration should be made in the daytime if antiflammatory effect is desired, because epidermal proliferation kinetics is also subject to circadian rhythm; in addition, the administration is made in the evening to inhibit the reduced mitosis rate for antiproliferative effect.

Another therapeutic phenomenon is tachyphlaxis. Here, it is understood that effect of the medicine is decreasing despite continuing the treatment. In this case, another local corticosteroid is administered and this may bring success or the treatment is made intermittently. For example, local corticosteroid is administered for 3 days and then the moisturizer is administered for 3 days.

The treatment must always be initiated with the strongest preparate at the rate allowed by etiology, pathogenesis, dermatosis type and localization. Then the treatment is maintained with local corticosteroid enough to get dermatosis under control. As in the cases of systemic corticosteroids, probability of rebound phenomena must be taken into account when giving up the local treatment. Therefore, a local treatment must be given up gradually by using corticosteroid with lesser effect or prolonging the administration intervals more and more.34 Rebound phenomena can be prevented in combined betamethasone treatment with calcipotriol in psoriatic patients.34 Rebound phenomena is characterized by development of vasodilatation following vasoconstriction and its fixation, increase in inflammation, edema and pustulation.

Sides Effects of Corticosteroids

Sides effects of corticosteroids which are administered locally can be split into two groups as local and systemic. Their essential side effect is atrophy. This side effect rather arises after long - term administration on intertriginous areas. Formation of atrophy varies by the administration area, potency of steroid, administration of occlusion. As it is known, skin atrophy results from epidermal thinning and reduction of collagen tissue in vessel. Reduction of collagen tissue of the skin depends on inhibition of collagen biosynthesis. Epidermis thinning makes surface vessel plexy more explicit, so it may lead to development of new vessel, telangiectasis, particularly development of strias in puberty period. Sometimes, atrophy may disappear in about 6 months after giving up the local treatment.

Administration of retinoic acid and local steroid together may inhibit epidermal atrophy risk to a certain extent. Atrophy formation potency of mometasone is even lesser than that of betamethasone. Symptoms like acne rosacea may occur in the susceptible people in a couple of weeks or months especially after administration of fluorosteroids on the face. In this case, epidermal atrophy draws attention as well as the symptoms such as erythema, telangiectasia and papule. The symptoms are reversed gradually in a month after giving up the preparate. In addition, red papules which are all at the same stage of development appear on the face as a result of long - term use of fluorosteroids in normal non - susceptible people and this is followed by too many comedos that prevail in the case. Fluorocorticosteroids must not be used on the face in order to prevent such local complications and, if it is to be used, it must not be for more than a few days or one week. The local side effects may also include hyperkeratosis, hyperpigmentation, vitiligo due to acute vasoconstriction and delay in ulcerous and erosional lesion healing. Development of hypersensitivity due to locally administered corticosteroids is a rarely seen case. The number of phenomena reported recently is increasing more and more.42 - 46 Besides, glaucoma and subcapsular cataract development can be seen rarely in supraorbital administrations.

Systemic side effects may occur due to excessive use of local corticosteroid. In particular, it is asserted that long - term occlusion of fluorosteroids in adults and non - occlusion administration in children may cause suppression on hypothalamus - hypophysis axis. Recent studies indicate that 15 g halcinonide cream causes temporary suppression on serum Cortisol if administered to 50 % of the body with occlusion in psoriasis and without occlusion in normal cases. Suppressive potency of mometasone on hypophysis - adrenal axis is minimal particularly in children.

Clobetasol propionate which is another strongest local steroid is reported to cause development of iatrogenic Cushing syndrome and hirsutism if administered 20 g a day for 3 years. Side effects of local steroids are seen more commonly in babies due to their thin skin and high surface/volume rate. In addition to the side effects in adults, growth inhibition may also occur in babies.48 - 50 It is demonstrated that lower leg growth isn't inhibited in children in pre - puberty period who use inhalant fluticasone propionate.

Various preparates have been obtained by adding a number of additional substances to local corticosteroids. Additional substances include antiseptics, antibiotics, sulfonamides, salicylic acid, urea, oestrogens and antimycotics. Urea and salicylate have keratoplastic effect in optimal concentrations and they strengthen the corticosteroid's potency. Sometimes, antibiotic or antiseptic effect may be required for inflammatory superinfection dermatitis. However, allergic reactions are not rare in the cases of combination with antibiotics. If necessary, local steroid treatment combined with systemic antibiotic can be preferred.

Systemic Antifungal Medicines

Terbinafine dermatophytosis fungicide has fungistatic effect on Candidas. Squalene is an epoxidase inhibitor and it leads to accumulation of squalene inside fungus cells. It can be taken on an empty or full stomach. It is lipophilic and keratophilic. It is contraindicated in pregnancy and lactation.

Itracozanole has wide spectrum and it is effective on dermatophyte, Candida and m. furfur. It is also effective on deep and systemic mycoses. It suppresses ergosterol biosynthesis. It is highly lipophilic and keratophilic. The amount of use is 5 mg/kg/g per dose for children and 100 - 200 mg/g per dose for adults on a full stomach. It is contraindicated in pregnancy and lactation. Ketoconazole is effective ondermatophyte, Candida and m. furfur. It suppresses ergosterol biosynthesis. It may cause toxic hepatitis and reduce Cortisol and testosterone synthesis. The amount of use is 3 mg/kg/g per dose for children and 200 mg/g per dose for adults. It is contraindicated in pregnancy and lactation.

Fluconazole suppresses ergosterol biosynthesis. It can be used on an empty and full stomach. It penetrates into BOS, oil and keratin containing tissues for its being lipophilic and hydrophilic. It is effective on dermatophytosis and Candidas. Antiacids reduce its absorption. The amount of use is 1 - 2 mg/kg/g per dose for children and 50mg/g or 150 mg/hf per dose for adults. It is generally contraindicated to use in lactation and for babies under 1 - year old. The reference WO2014/201541 A1 is one of the patents in the art in literature. The relevant reference discusses non - aerosol frothy liquid composition suitable for topical embodiment. Glucoside and Oleth - 20 isn't used in this reference.

As a result, the above said drawbacks and the inadequacy of the prior art solutions about the subject have necessitated an improvement in the related technical field¹⁵.

Purpose of the Invention

The invention relates to a combination pharmaceutical composition used in topical applications, which meets the above said requirements, eliminates all of the drawbacks, and brings some additional advantages.

The primary purpose of the invention is to obtain a foamy pharmaceutical combination that can be applied topically and used in treatment of dermatological diseases. Foam formulations are usually easy to use, have lower density, and easy to spread compared to other topical dosage forms. As a result of having the invention in foam form, better spreading, quick drying, quick absorption are obtained and the invention is applied easily. Besides, the composition is odourless and provides a refreshing effect on the skin. Moreover, it can easily be applied on hair roots.

A purpose of the invention is to obtain a foam pharmaceutical composition having the characteristic of leaving the least possible residues or deposits following application. It does not leave an oily, slippery, and sticky layer following application. Another purpose of the invention is to provide a foamy pharmaceutical compound obtained with a dual system, instead of multiple complicated surfactants that cause irritation. Another purpose of the invention is to obtain a foamy, topically applicable pharmaceutical composition without using aerosols. In this way, the product according to the invention is obtained without harming the environment and increasing costs. A similar purpose of the invention is to provide topical use of active agents of various indications in foam dosage form in the same system. In this way, contribution is made to patient compliance.

The invention aims to form the pharmaceutical composition without the need for special heating - cooling etc. equipment during its production process.

Another purpose of the invention is to provide analytical convenience and thus ensure easy analysis, since the composition is in solution form. In order to achieve the above said purposes, the foam formulation according to the invention developed for topical applications used in prophylaxis and treatment of dermatological diseases that do not respond to initial treatment or are defined as persistent against suitable care; comprises at least one active agent,at least one solvent, at least one surfactant, at least one organic solvent, and water.

The structural and characteristic features of the invention and all of its advantages shall be understood better with the detailed description given below, and therefore, the assessment should be made by taking into account the said figures and detailed explanations. Detailed Description of the Invention

In this detailed description, the combination pharmaceutical composition used in topical applications and the preferred embodiments of said composition according to the invention are only disclosed for better understanding of the subject without forming any limiting effect.

The present invention relates to a dosage form in which the active agent is prepared in solution or suspension form and used in treatment of dermatological diseases. The formulation prepared in solution or suspension form is used in topical application in the form of foam, solution, or emulsion pomade with the help of the equipment used. The formulation according to the invention can also be produced in the form of a cream, gel, or liquid. The invention is a combination comprising at least one active agent, at least one solvent, water, at least one organic solvent, and at least one surfactant. The solvent is the substance ensuring dissolving of the active agent; and the surfactant is the substance ensuring formation of foam.

The system is a foam - generating dosage form, working independent from the active agent. Therefore, the invention would work even if the active agent is not present. However, addition of active agent is required for therapeutic activity. Preferably minoxidil is used as the active agent. Moreover, as the active agent, individuals or combinations selected from the group consisting of: Betamethasone dipropionate, clobetasol propionate, Mometasone furoate amcinonide, halsinoid, desoximetasone, Halometasone, triamcinolone acetonide, fluocinolone acetonide, Prednicarbat, hydrocortisone, butyrate Prednisolone, desonid Hydrocortisone, dexmetasone sodium, Diflucortolone valerate, Fluticasone propionate, Halcinonide, Halometasone monohydrate, Flumethasone pivalate, Methylprednizolon aceponate, ketoconazole, fluconazole, itraconazole, terbinafine, naftifine, oxiconazole, ciclopirox silver sulfadiazine (SSD), nitrofurasone, urea, salicylic acid, permethrin, ciclopirox olamine, acyclovir, benzoyl peroxide, minoxidil, isotretionin, tazarotene, bimatoprost, erythromycin, famciclovir, clindamycin, tretionin, chlorhexidine gluconate (CHG), polymyxin B sulfate, neomycin, povidone - iodide, mafenite, and gentamicin can be used.

As the solvent substance, preferably, monopropylene glycol, lactic acid, ethanol, and distilled water is used in the present invention. In addition to these, individuals or combinations selected from the group consisting of Sorbiton monooleate, Polysorbate derivatives, Cetylpyridine chloride, Polyoxyl 2 aleyl ether, Glyceryl monostearate, Stearic acid, Glycine, Glyceryl monostearate, Methyl cellulose, Polaxamer 407 or 188, Polyoxyl 40 stearate, Sodium lauryl sulfate, Carbomer, L - histidine, propylene glycol, PEG - 30 dipolyhydroxystereate, isohexadecane, C-12 - 15 alkyl benzoate polyhydroxystearic acid, ammonium acryloyldimethyltaurate/VP copolymer, dipalmitoyl hydroxypyrroline, Bois II (TM), cetyl alcohol, C 12 - 15 alkyl benzoate, caprylic/capric, triglyceride, tocopheril acetate, polyacrylamide, C-13 - 14 isoparaffine, ethoxy diglycol, phenoxyethanol, triethanolamine, light liquid paraffine, pemulen TR - 1 , carbopol ultrez, mannitol, ethyl alcohol and distilled water can also be used as solvents.

In the invention, preferably Lauryl Glucoside and Oleth - 20 are used as the surfactants. In addition to these, individuals or combinations selected from the group consisting of Sorbiton monooleate, Polysorbate derivatives, Cetylpyridine chloride, Polyoxyl 2 aleyl ether, Glyceryl monostearate, Stearic acid, Glycine, Glyceryl monostearate, Methyl cellulose, Polaxamer 407 or 188, Polyoxy140 stearate, Sodium lauryl sulfate, Carbomer, L - histidine, propylene glycol, PEG - 30 dipolyhydroxystereate, isohexadecane, C - 12 - 15 alkyl benzoate polyhydroxystearic acid, ammonium acryloyldimethyltaurate/VP copolymer, dipalmitoyl hydroxypyrroline, Bois II (TM), cetyl alcohol, C 12 - 15 alkyl benzoate, caprylic/capric, triglyceride, tocopheryl acetate, polyacrylamide, C - 13 - 14 isoparaffine, ethoxy diglycol, phenoxyethanol, triethanolamine, light liquid paraffine, pemulen TR - 1 , carbopol ultrez, mannitol, ethyl alcohol and distilled water can also be used as surfactants.

As an organic solvent, individuals or combinations selected from the group consisting of ethyl alcohol, isopropyl alcohol, and methyl alcohol can be used in the invention.

Moreover, essence can be used optionally in the relevant formulation.

Table 1 shows the preferred and usable by weight percentages of the raw materials used in the formulation.

Table 1. Substances used in the formulation

The production method of the foamy pharmaceutical composition of the invention can be carried out in various ways. In a preferred method for carrying out the invention;

First of all, water and solvent substances are taken into the same beaker, and stirred using a magnetic fish. When a clear solution is obtained; an active agent weighed separately is added and stirred.

After the active agent is dissolved, a surfactant is added into the beaker. Afterwards, it is stirred by a magnetic fish until it dissolves. After dissolution, preferably essence is added and stirred. After obtaining a homogeneous solution, pH is checked and the solution is filled into bottles. pH should be between 4 and 5.

EXAMPLE:

25.0 g distilled water, 5.0 g ethanol, 49.49 g propilene glycol, and 5.0 g lactic acid are weighed, added into the same beaker, and stirred with a magnetic fish for about 5 minutes. When a clear solution is obtained; Minoxidil weighed separately is added and stirred for about 10 minutes. After Minoxidil is dissolved, 10.0 g Lauryl Glucoside and 0.5 g Oleth - 20 is weighed and added into the beaker, stirred with magnetic fish for 30 minutes for dissolving. Afterwards 0.01 g essence is added. After obtaining a homogeneous solution, pH is checked and the solution is filled into bottles.

Table 2. Preferred and usable percentages by weight of the sample formulation

In the below given examples, various methods are seen in various combinations. EXAMPLES:

1 ) Minoxidil 5 % Foam formulation

^*q.s. : quantity sufficient

Production Stage: Phase 1

• Monopropylene glycol is weighed and heated up to 60 - 70 Ό.

• Minoxidil weighed separately is added on and stirred.

• Afterwards it is cooled down to room temperature.

Phase 2

· Oleth - 20 and Lauryl Glucoside are weighed and ethanol weighed in a desired amount is transferred into these two and dissolved therein.

Final Mixture

• Phase 1 and Phase 2 are mixed until a homogeneous solution is obtained.

• The solution is taken into a graduated cylinder and its volume is determined, and then water is added up to 95 % of the total volume. The solution is stirred again in a beaker.

• pH of the solution is measured, and lactic acid is added until desired pH value is reached (pH 4 - 5).

• Essence is added and mixed.

• pH is checked again.

· 2) Minoxidil 5 % Foam formulation

*q.s. : quantity sufficient

Production Stage: Phase 1

· Monopropylene glycol is weighed and heated up to 60 - 70 Ό.

• Minoxidil weighed separately is added on and stirred.

• Afterwards, it is cooled down to 35 - 40Ό.

Phase 2

• Oleth - 20 and Lauryl Glucoside are weighed and added into distilled water weighed in desired amount. Heated up to 60 - 70Ό and dissolve d.

• Afterwards, it is cooled down to 35 - 40Ό.

Final Mixture

• Phase 1 and Phase 2 are mixed while they are at the same temperature and a homogeneous solution is obtained.

· The solution is taken into a graduated cylinder and its volume is determined, and then ethanol is added up to 95 % of the total volume. The solution is stirred again in a beaker.

• Essence is added and stirred.

· pH is checked again. 3) Minoxidil 5 % Foam formulation

^*q.s. : quantity sufficient

Production Stage:

Phase 1

a) Monopropylene glycol is weighed and heated up to 60 - 70 Ό.

b) Minoxidil weighed separately is added on and stirred,

c) Afterwards it is cooled down to room temperature.

Phase 2

a) Oleth - 20 is weighed and added into distilled water weighed in desired amount, and then stirred.

b) Lauryl Glucoside is weighed and added into ethanol weighed in desired amount, and then mixed.

c) a and b are mixed with each other and a homogeneous solution is obtained. Final Mixture

a) Phase 1 and Phase 2 are mixed with each other.

b) pH of the solution is measured, and lactic acid is added until desired pH value is reached (pH 4 - 5).

c) Essence is added and stirred.

d) pH is checked again.

4) Minoxidil 5 % Foam formulation Active Agent; Minoxidil 5.00 g

Auxiliaries; Lactic Acid 10.00 g

Monopropylene 10.00 g

Glycol

Oleth - 20 10.00 g

Lauryl Glucoside 0.50 g

Ethanol ^*q.s.

Distilled Water 60.00 g

Essence 0.01 g

Total; 100 ml

^*q.s. : quantity sufficient

Production Stage:

Phase 1

• Weighed monopropylene glycol and distilled water are mixed.

• Minoxidil weighed separately is added on and mixed.

Phase 2

· Oleth - 20 and Lauryl Glucoside are weighed and lactic acid weighed in a desired amount is transferred into these two and dissolved therein.

Final Mixture

• Phase 1 and Phase 2 are mixed until a homogeneous solution is obtained.

• The solution is taken into a graduated cylinder, its volume is filled with ethanol, and stirred.

• pH is checked.

• Essence is added and stirred.

• pH is checked again.

5) Minoxidil 5 % Foam formulation

Active Agent; Minoxidil 5.00 g

Auxiliaries; Lactic Acid ^*q.s.

Monopropylene 5.00 g Glycol

Oleth - 20 10.00 g

Lauryl Glucoside 10.00 g

Ethanol 40.00 g

Distilled Water 20.00 g

Essence 0.01 g

Total; 100 ml

^*q.s. : quantity sufficient

Production Stage:

Phase 1

· Monopropylene glycol is weighed.

• Minoxidil weighed separately is added on and stirred.

Phase 2

• Oleth - 20 and Lauryl Glucoside are weighed and then transferred into ethanol and distilled water weighed in desired amounts, and dissolved therein. Final Mixture

• Phase 1 and Phase 2 are mixed with each other.

• Essence is added and stirred.

· pH is checked again.

During the application method and application of the foam formulation, attention should be paid to the spraying volume, foam provider apparatus, dosing required for indication, and the amount of active agent in the foam.

REFERENCES

1 . Ramsay DL, Weary PE. Primary care in dermatology: whose role should it be? J Am Acad Dermatol 1996;35(6):1005 - 8.

2. Fleischer AB Jr, Feldman SR, McConnell RC. The most common dermatologic problems identified by family physicians, 1990-1994. Fam Med 1997;29(9):648 - 52.

3. Kirsner RS, Federman DG. Lack of correlation between internists' ability in dermatology and their patterns of treating patients with skin disease. Arch Dermatol 1996;132(9):1043 - 6.

4. Gervert B, Maurer T, Berger T, et al. Primary care physicians as gatekeepers in managed care. Primary care physicians' and dermatologists' skills at secondary prevention of skin cancer. Arch Dermatol 1996;132(9):1030 - 8.

5. Johnson MT. On teaching dermatology to non - dermatologists. Arch Dermatol 1994;130:850 - 2. 6. Feldman SR, Fleischer AB, Chen JG. The gatekeeper model is inefficient for the delivery of dermatologic services. J Am Acad Dermatol 1999;40(3):426 - 32.

7. National Center for Health Statistics. Public use data tape documentation. 1990 National Ambulatory Medical Care Survey. Hyattsville, Md: US Department of Health and Human Services, Public Health Service, Centers for Disease Control, 1992.

8. Tenney JB, White KL, Williamson JW. National Ambulatory Medical Care Survey: background and methodology. National Center for Health Statistics. Vital Health Stat

1974;2:61 .

9. International classification of diseases, ninth revision, clinical modification, sixth edition. Salt Lake City: Med - Index Publications, 2003.

10. Greenberg HL, Shwayder TA, Bieszk N, Fivenson DP. Clotrimazole/ betamethasone diproprionate: a review of costs and complications in the treatment of common cutaneous fungal infections. Pediatr Dermatol 2002;19(1 ):78 - 81 . Review.

1 1 . Shaffer MP, Feldman SR, Fleischer AB. Use of clotrimazole/betamethasone diproprionate by family physicians. Fam Med 2000;32(8):561 - 5.

12. Reust CE. Longitudinal residency training: a survey of family practice residency programs. Fam Med 2001 ;33(10):740 - 5.

13. Cyr PR. Family practice center - based training in skin disorders: a photographic approach. Fam Med 1995;27(2):109 - 1 1 .

14. Gerbert B, Bronstone A, Maurer T, Berger T, McPhee SJ, Caspers N. The effectiveness of an Internet - based tutorial in improving primary care physicians' skin cancer triage skills. J Camcer Educ 2002;17(1 ):7 - 1 1 .

15. Gerbert B, Bronstone A, Wolff M, et al. Improving primary care residents' proficiency in the diagnosis of skin cancer. J Gen Intern Med 1998;13(2):91 - 7.

Claims

1. A foam formulation used in topical applications for treatment of dermatological diseases, characterized in that; it comprises:

- at least one active agent,

- at least one solvent,

- at least one surfactant,

- at least one organic solvent, and

- water.

2. The foam formulation according to Claim 1 , characterized in that; it comprises 0.001 - 50 % active agent by weight, 0.001 - 50 % solvent by weight, 0.001 - 50 % surfactant by weight, 0.001 - 50 % organic solvent by weight, and 0.001 - 50 % water by weight.

3. The foam formulation according to Claim 1 , characterized in that; said active agent comprises individuals or combinations selected from the group consisting of: Minoxidil, betamethasone dipropionate, clobetasol propionate, Mometasone furoate amcinonide, halsinoid, desoximetasone, Halometasone, triamcinolone acetonide, fluocinolone acetonide, Prednicarbat, hydrocortisone, butyrate Prednisolone, desonid Hydrocortisone, dexmetasone sodium, Diflucortolone valerate, Fluticasone propionate, Halcinonide, Halometasone monohydrate, Flumethasone pivalate, Methyl prednisolone aceponate, ketoconazole, fluconazole, itraconazole, terbinafine, naftifine, oxiconazole, ciclopirox silver sulfadiazine, nitrofurasone, urea, salicylic acid, permethrin, ciclopirox olamine, acyclovir, benzoyl peroxide, minoxidil, isotretionin, tazarotene, bimatoprost, erythromycin, famciclovir, clindamycin, tretionin, chlorhexidine gluconate, polymyxin B sulphate, neomycin, povidone - iodide, mafenite, and gentamicin.

4. The foam formulation according to Claim 1 , characterized in that; said solvent comprises individuals or combinations selected from the group consisting of: monopropylene glycol, lactic acid, ethanol, distilled water, Sorbiton monooleate, Polysorbate derivatives, Cetylpyridine chloride, Polyoxyl 2 aleyl ether, Glyceryl monostearate, Stearic acid, Glycine, Glyceryl monostearate, Methyl cellulose, Polaxamer 407 or 188, Polyoxyl 40 stearate, Sodium lauryl sulfate, Carbomer, L - histidine, propylene glycol, PEG - 30 dipolyhydroxystereate, isohexadecane, C12-15 alkyl benzoate polyhydroxystearic acid, ammonium acryloyldimethyltaurate/VP copolymer, dipalmitoyl hydroxypyrroline, Bois II (TM), cetyl alcohol, C12-15 alkyl benzoate, caprylic/capric, triglyceride, tocopheril acetate, polyacrylamide, C13-14 isoparaffine, ethoxy diglycol, phenoxyethanol, triethanolamine, light liquid paraffine, pemulen TR - 1 , carbopol ultrez, mannitol, ethyl alcohol, and distilled water.

5. The foam formulation according to Claim 1 , characterized in that; said surfactant comprises individuals or combinations selected from the group consisting of: Lauryl glucoside, Oleth - 20, Sorbiton monooleate, Polysorbate derivatives, Cetylpyridine chloride, Polyoxyl 2 aleyl ether, Glyceryl monostearate, Stearic acid, Glycine, Glyceryl monostearate, Methyl cellulose, Polaxamer 407 or 188, Polyoxyl 40 stearate, Sodium lauryl sulfate, Carbomer, L - histidin, propylene glycol, PEG - 30 dipolyhydroxystereate, isohexadecane, C- 12 - 15 alkyl benzoate polyhydroxystearic acid, ammonium acryloyldimethyltaurate/VP copolymer, dipalmitoyl hydroxypyrroline, Bois II (TM), cetyl alcohol, C12 - 15 alkyl benzoate, caprylic/capric, triglyceride, tocopheryl acetate, polyacrylamide, C13 - 14 isoparaffine, ethoxy diglycol, phenoxyethanol, triethanolamine, light liquid paraffine, pemulen TR - 1 , carbopol ultrez, mannitol, ethyl alcohol, and distilled water.

6. The foam formulation according to Claim 1 , characterized in that; said organic solvent comprises individuals or combinations selected from the group consisting of ethyl alcohol, isopropyl alcohol, and methyl alcohol.

7. The foam formulation according to Claim 1 , characterized in that; it comprises essence.

8. The foam formulation according to Claims 1 to 7, characterized in that; it is applied in cream, gel, or liquid form.