WO2017072668A1

WO2017072668A1 - Topical anti-hyperpigmentation composition

Info

Publication number: WO2017072668A1
Application number: PCT/IB2016/056429
Authority: WO
Inventors: Sanjay U NIPANIKAR; Anisha S KANJILAL; Sanjeevan S KANJILAL
Original assignee: Ari Healthcare Pvt. Ltd.
Priority date: 2015-10-31
Filing date: 2016-10-26
Publication date: 2017-05-04

Abstract

The present disclosure relates to a topical anti-hyperpigmentation composition and a process for preparation thereof. The topical anti-hyperpigmentation composition comprises extract of Glycyrrhiza glabra, extract of Rubia cordifolia, extract of Symplocos racemosa, extract of Terminalia arjuna, extract of Myristica fragrans and Kanaka taila. The topical anti-hyperpigmentation composition is suitable for lightening hyperpigmented skin, relieving symptoms of acne, post acne dark spots, skin rashes, naevus, melasma, eczema and dermatitis.

Description

TOPICAL ANTI-HYPERPIGMENTATION COMPOSITION

FIELD

The present disclosure relates to a topical anti-hyperpigmentation composition and a process for preparation thereof. BACKGROUND

Skin disorders are relatively common in large segments of the population globally. For example, melasma, naevus, hyperpigmentation, acne, eczema and dermatitis are relatively common skin disorders. With the increase in the world's ageing population, exposure to various pollutants, use of chemically laced substances and medications, hormonal changes, unhealthy eating habits, exposure to sun and their cumulative effects over a long period of time lead to age spots or "sun-induced freckles", due to which there is a concomitant increase in the occurrence of skin disorders.

Skin disorders like hyperpigmentation and other conditions of uneven skin pigmentation are usually viewed as undesirable and unattractive. For instance, the occurrence of acne, rashes, scratch marks or injuries to the skin can result in post-inflammatory hyperpigmentation characterized by the presence of unwanted dark spots on the face or other parts of the body.

Hyperpigmentation is characterized by darkening of an area of the skin, caused by overproduction of a pigment in the skin known as melanin. Hyperpigmentation refers to areas of skin where excess melanin has been produced and deposited, causing skin patches that appear darker than the surrounding skin.

Hyperpigmentation of skin is caused as a result of (1) an abnormally high concentration of melanocyte producing melanin or (2) when melanocytes are hyperactive. For instance, sun exposure stimulates the production of melanin. Although, hyperpigmentation can affect anyone, it is more prevalent among certain ethnic groups such as Asian, Mediterranean, African, or Latin. Hyperpigmentation can affect any part of the body including face, hands, and neck.

There are many skin care products available for treating skin disorders and conditions, such as acne and age spots. The chemical ingredients in many of these products are irritating or even harmful to the skin. Alternative compounds for lightening skin color are also available. However, most of the synthetic compounds in use have side effects and it has been reported that such compositions provide only temporary effects and hyperpigmentation recurs, if the use of such composition is discontinued. CN101756876(A) recites a freckle removing facial mask comprising Angelica sinensis, Angelica dahuricae, Bletilla striata and Glycyrrhiza uralensis. However, the facial mask lacks specific active ingredients which are effective in reducing redness which is caused by acne or eczema. CN 102188562(A) recites a formula of Chinese medicine for removing scars of acnes and the preparation method thereof. The formula comprises Poriacocos (Wolfiporia extensa), and pearl powder. However the formula is only limited to lightening of scars caused by acne. Further, the known skin care formulations are not capable of alleviating the symptoms of post acne dark spots, skin rashes, naevus, melasma, eczema and dermatitis.

Therefore, there exists a need for a natural solution that provides desirable results for overcoming the above mentioned drawbacks and that is devoid of side effects. OBJECTS

Some of the objects of the present disclosure, of which at least one embodiment herein satisfies, are as follows:

An object of the present disclosure is to ameliorate one or more problems of the prior art or to at least provide a useful alternative. Another object of the present disclosure is to provide an effective topical composition for lightening hyperpigmented skin.

Still another object of the present disclosure is to provide an effective topical composition which is also effective in relieving symptoms of acne, post acne dark spots, skin rashes, naevus, melasma, eczema and dermatitis. Yet another object of the present disclosure is to provide an effective topical composition which provides synergistic effect.

Still another object of the present disclosure is to provide an effective topical composition which is stable, devoid of any side effects and is nontoxic. Yet another object of the present disclosure is to provide a topical composition which provides smooth application without substantial friction and provides ease of application.

Still another object of the present disclosure is to provide a topical composition wherein the active ingredients are uniformly distributed. Yet further object of the present disclosure is to provide a topical composition which is calming and has characteristic pleasant fragrance.

Still another object of the present disclosure is to provide a process for the preparation of the topical composition which is simple and cost effective.

Other objects and advantages of the present disclosure will be more apparent from the following description which is not intended to limit the scope of the present disclosure.

SUMMARY

The present disclosure relates to a topical anti-hyperpigmentation composition and a process for preparation thereof.

The topical anti-hyperpigmentation composition comprises extract of Glycyrrhiza glabra in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition; extract of Rubia cordifolia in an amount ranging from 0.05 wt% to 10 wt% of the total weight of the composition; extract of Symplocos racemosa in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition; extract of Terminalia arjuna in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition; extract of Myristica fragrans in an amount ranging from 0.01 wt% to 30 wt% of the total weight of the composition; Kanaka taila (oil) as Ayurvedic classical formulation in an amount ranging from 0.01 wt% to 40 wt% of the total weight of the composition; at least one fluid medium in an amount ranging from 45 wt% to 95 wt% of the total weight of the composition; and at least one pharmaceutically acceptable excipient. The extract of Glycyrrhiza glabra, extract of Rubia cordifolia, extract of Symplocos racemosa, extract of Terminalia arjuna, and extract of Myristica fragrans is an extract obtained from at least one solvent selected from the group consisting of alcoholic, hydro-alcoholic, aqueous, ether, ethyl acetate, acetone, propylene glycol, hexane, mixture of water, ethyl acetate and acetone, and mixture of acetone, ethyl alcohol and hexane. The pharmaceutically acceptable excipient is at least one selected from the group consisting of at least one gelling agent in an amount ranging from 0.05 wt% to 7 wt% of the total weight of the composition; at least one preservative in an amount ranging from 0.01 wt% to 0.6 wt% of the total weight of the composition; at least one antioxidant in an amount ranging from 0.01 wt% to 1 wt% of the total weight of the composition; at least one pH modifying agent in an amount ranging from 0.01 wt% to 5 wt% of the total weight of the composition; at least one fragrance in an amount ranging from 0.01 wt% to 10 wt% of the total weight of the composition; at least one emulsifying agent in an amount ranging from 0.05 wt% to 5 wt% of the total weight of the composition; at least one anti-foaming agent in an amount ranging from 0.01 wt% to 5 wt% of the total weight of the composition; at least one cleansing agent in an amount ranging from 0.01 wt% to 5 wt% of the total weight of the composition; at least one emollient in an amount ranging from 0.05 wt% to 10 wt% of the total weight of the composition; at least one humectant in an amount ranging from 0.05 wt% to 10 wt% of the total weight of the composition; and at least one chelating agent in an amount ranging from 0.01 wt% to 0.1 wt% of the total weight of the composition.

Further, there is provided a process for the preparation of the topical anti-hyperpigmentation composition. The process comprises preparing a gel phase by mixing at least one gelling agent and at least one chelating agent with at least one fluid medium to obtain a gel. An oil phase is prepared by mixing at least one cleansing agent and at least one emollient, followed by addition of the Kanaka taila and at least one anti-oxidant at a temperature in the range of 65 °C to 85 °C. An aqueous phase is prepared by mixing at least one humectant, at least one preservative, the extract of Rubia cordifolia, the extract of Symplocos recemosa, the extract of Terminalia arjuna, and at least one emulsifying agent with at least one fluid medium at a temperature in the range of 65 °C to 85 °C. The oil phase is admixed into the aqueous phase under stirring at a temperature in the range of 65 °C to 85 °C, followed by the addition of at least one anti-foaming agent to form an emulsion. The so formed emulsion is admixed to the gel phase with continuous stirring, followed by the addition of the extract of Myristica fragrans, and at least one pH modifying agent adjusting pH in the range of 5 to 7, to form a cream. The cream is cooled at a temperature in the range of 30 °C to 35 °C and adding at least one fragrance to the cooled cream to obtain fragranced topical anti-hyperpigmentation composition of the present disclosure. The extract of Glycyrrhiza glabra is added while preparing an oil phase when the extract of Glycyrrhiza glabra is at least one extract selected from the group consisting of alcoholic, hydro-alcoholic, aqueous, ether, ethyl acetate, acetone, hexane, mixture of water, ethyl acetate, and acetone, and mixture of acetone, ethyl alcohol and hexane. The extract of Glycyrrhiz glabra is added while admixing so formed emulsion into the so formed gel phase when the extract of Glycyrrhiza glabra is a propylene glycol extract. BRIEF DESCRIPTION OF ACCOMPANYING DRAWING

The anti-hyperpigmentation composition of the present disclosure will now be described with the help of the accompanying drawing, in which:

Figures 1 and 2 illustrate the histological observations of melanocytes in the epidermis of skin of male and female mice respectively, after 28 days of application of control (C).

Figures 3 and 4 illustrate the histological observations of melanocytes in the epidermis of skin of male and female mice respectively, after 28 days of application of standard drug (hydroquinone; S).

Figures 5 and 6 illustrate the histological observations of melanocytes in the epidermis of skin of male and female mice respectively, after 28 days of application of test item-1 (Tl). Figures 7 and 8 illustrate the histological observations of melanocytes in the epidermis of skin of male and female mice respectively, after 28 days of application of test item-2 Kanaka taila (T2).

DETAILED DESCRIPTION

Skin disorders are relatively common in large segments of the population globally. For example, melasma, naevus, hyperpigmentation, acne, eczema and dermatitis are relatively common skin disorders. Skin disorders like hyperpigmentation and other conditions of uneven skin pigmentation are usually viewed as undesirable and unattractive. For instance, the occurrence of acne, rashes, scratch marks or injuries to the skin can result in postinflammatory hyperpigmentation characterized by the presence of unwanted dark spots on the face or other parts of the body.

There are many skin care products available for treating skin disorders and conditions, such as acne and age spots. Chemical ingredients in many of these products are irritating or even harmful to the skin. Alternative compounds for lightening skin color are also available. However, most of the synthetic compounds in use have side effects and it has been reported that such compositions provide only temporary effects and hyperpigmentation returns if the use of such composition is discontinued.

The present disclosure envisages a topical anti-hyperpigmentation composition comprising a plurality of medicinal plant based extracts and classical Ayurvedic formulation. These biological extracts are value added products when used along with the Kanaka taila (oil), i.e., the classical Ayurvedic formulation. The topical composition as disclosed in the present disclosure is effective for prevention and/or treatment of hyperpigmentation and is also effective in relieving the symptoms of acne, post acne dark spots, skin rashes, naevus, melasma, eczema, dermatitis and various other skin diseases/disorders. In accordance with one aspect of the present disclosure, there is provided a topical anti- hyperpigmentation composition. The topical anti-hyperpigmentation composition comprises extract of Glycyrrhiza glabra in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition; extract of Rubia cordifolia in an amount ranging from 0.05 wt% to 10 wt% of the total weight of the composition; extract of Symplocos racemosa in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition; extract of Terminalia arjuna in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition; extract of Myristica fragrans in an amount ranging from 0.01 wt% to 30 wt% of the total weight of the composition; Kanaka taila (oil) as Ayurvedic classical formulation in an amount ranging from 0.01 wt% to 40 wt% of the total weight of the composition; at least one fluid medium in an amount ranging from 45 wt% to 95 wt% of the total weight of the composition; and at least one pharmaceutically acceptable excipient. The extract of Glycyrrhiza glabra, extract of Rubia cordifolia, extract of Symplocos racemosa, extract of Terminalia arjuna, and extract of Myristica fragrans is an extract obtained from at least one solvent selected from the group consisting of alcoholic, hydro-alcoholic, aqueous, ether, ethyl acetate, acetone, propylene glycol, hexane, mixture of water, ethyl acetate and acetone, and mixture of acetone, ethyl alcohol and hexane.

Alternatively, there is provided a topical anti-hyperpigmentation composition. The topical anti-hyperpigmentation composition comprises extract of Glycyrrhiza glabra in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition; extract of Rubia cordifolia in an amount ranging from 0.05 wt% to 10 wt% of the total weight of the composition; extract of Symplocos racemosa in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition; extract of Terminalia arjuna in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition; extract of Myristica fragrans in an amount ranging from 0.01 wt% to 30 wt% of the total weight of the composition; Kanaka taila (oil) as Ayurvedic classical formulation in an amount ranging from 0.01 wt% to 40 wt% of the total weight of the composition; at least one fluid medium in an amount ranging from 45 wt% to 95 wt% of the total weight of the composition; and at least one pharmaceutically acceptable excipient. The extract of Glycyrrhiza glabra is an extract obtained from at least one solvent selected from the group consisting of propylene glycol, mixture of water, ethyl acetate and acetone, and mixture of acetone, ethyl alcohol and hexane.

In one embodiment of the present disclosure, the propylene glycol extract of Glycyrrhiza glabra is used for the preparation of the topical anti-hyperpigmentation composition.

In another embodiment of the present disclosure, the mixture of acetone, ethyl alcohol, and hexane extract of Glycyrrhiza glabra is used for the preparation of the topical anti- hyperpigmentation composition.

Glycyrrhiza glabra, commonly known as liquorice and licorice, is native to southern Europe and parts of Asia but is also known to grow in the sub- tropical and warm temperate regions of the world, northern Africa and western Asia.

Rubia cordifolia, commonly known as common madder and samanga can be found growing in areas ranging from Africa to tropical Asia, China, Japan and Australia. In Africa, it is found from Sudan and Ethiopia to South Africa. Symplocos racemosa is native to Asia (including Myanmar and Nepal), Australia and America.

Myristica fragrans which is commonly known as nutmeg grows abundantly in Guangdong and Yunnan in China, Taiwan, Indonesia, Malaysia, Grenada in the Caribbean, Sri Lanka and South America. Terminalia arjuna is commonly known as Kakubha, Partha, Shvetavaha, and Sadad. It is native to Asia particularly Myanmar and Sri Lanka. Kanaka taila is an age old Ayurvedic Classical formulation and has been used for external application. It contains Glycyrrhiza glabra, Callicarpa macrophylla, Rubia cordifolia, Nymphaea stellata, Mesuaferrea and Sesame Oil.

In accordance with embodiments of the present disclosure, the fluid medium can be at least one selected from the group consisting of water, alcohol, ether, acetone, methyl acetate, chloroform, propane, butane, hexane, dichloromethane, dichloroethane, freons, and polyethylene glycol (PEG).

The pharmaceutically acceptable excipient is at least one selected from the group consisting of:

i. at least one gelling agent in an amount ranging from 0.05 wt% to 7 wt% of the total weight of the composition;

ii. at least one preservative in an amount ranging from 0.01 wt% to 0.6 wt% of the total weight of the composition;

iii. at least one antioxidant in an amount ranging from 0.01 wt% to 1 wt% of the total weight of the composition;

iv. at least one pH modifying agent in an amount ranging from 0.01 wt% to 5 wt% of the total weight of the composition;

v. at least one fragrance in an amount ranging from 0.01 wt% to 10 wt% of the total weight of the composition;

vi. at least one emulsifying agent in an amount ranging from 0.05 wt% to 5 wt% of the total weight of the composition;

vii. at least one anti-foaming agent in an amount ranging from 0.01 wt% to 5 wt% of the total weight of the composition;

viii. at least one cleansing agent in an amount ranging from 0.01 wt% to 5 wt% of the total weight of the composition;

ix. at least one emollient in an amount ranging from 0.05 wt% to 10 wt% of the total weight of the composition;

x. at least one humectant in an amount ranging from 0.05 wt% to 10 wt% of the total weight of the composition; and

xi. at least one chelating agent in an amount ranging from 0.01 wt% to 0.1 wt% of the total weight of the composition.

The gelling agent is at least one selected from the group consisting of agar agar, carbomer, glucomannan gum powder, xanthan gum powder, methylcellulose, poloxamers, bentonite, gelatin, and sodium carboxymethylcellulose.

The preservative is at least one selected from the group consisting of sodium hydroxymethylglycinate, benzoin powder, citric acid powder, green tea extract, potassium sorbate, and parabens. The antioxidant is at least one selected from the group consisting of tocopherol acetate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, ascorbyl palmitate, citric acid, propyl gallate, sodium metabisulfite and methionine.

The pH modifying agent is at least one selected from the group consisting of potassium hydroxide, sodium hydroxide, diethylamine, citric acid, and lactic acid.

The fragrance is at least one selected from the group consisting of splendid compound, French bouquet, citrus breeze, white musk, avocado, green apple, cremia, gold aloe rose, and J & J.

The emulsifying agent is at least one selected from the group consisting of tragacanth, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, glyceryl monostearate, sodium oleate, and polyoxyethylene sorbitan monooleate. The anti-foaming agent is at least one selected from the group consisting of dimethicone, and simethicone.

The cleansing agent is at least one selected from the group consisting of stearic acid, lauric acid, myristic acid, oleic acid, and palmitic acid.

The emollient is at least one selected from the group consisting of cetostearyl alcohol, sterol, lecithin, paraffin wax, stearic acid, fatty acid ester, and lanolin derivatives.

The humectant is at least one selected from the group consisting of glycerine, propylene glycol, petrolactum, mineral oil, triethylene glycol.

The chelating agent is at least one selected from the group consisting of disodium ethylenediamine tetraacetic acid, diethylene triamine penta acetic acid, and N,N- bis(carboxymethyl)glycine.

In accordance with the embodiments of present disclosure, the pH of the topical anti- hyperpigmentation composition is in the range of 5 to 7. In accordance with the embodiments of present disclosure, each dose of the topical anti- hyperpigmentation composition is in the range of 100 to 500 mg/1.5 cm of skin and is administered 2 to 4 times per day.

The plant parts used in the topical formulation of the present disclosure can be derived from the barks, roots, tubers, stigma, kernels, exudates, stolons, rhizome, leaves, seeds, nuts, berries, fruits, stems and flowers of the plants are commercially purchased from the market as value added products and therefore, the specific source of the product is unknown.

Typically, the plant extracts can be alcoholic extracts, ester extracts, acetone extracts, hydroalcoholic extracts, aqueous extracts, ether, ethyl acetate, propylene glycol, hexane, mixture of water, ethyl acetate and acetone, mixture of acetone, ethyl alcohol and hexane, and combination thereof.

In accordance with another aspect of the present disclosure, there is provided a process for preparing a topical anti-hyperpigmentation composition. The process for preparing the topical composition of the present disclosure, involves the preparation of a gel phase, an aqueous phase, an oil phase, an emulsion and a cream. i. The gel phase can be prepared by mixing at least one gelling agent and at least one chelating agent with at least one fluid medium to obtain a gel. ii. The oil phase can be prepared by mixing at least one cleansing agent and at least one emollient, followed by addition of the Kanaka taila and at least one anti-oxidant at a temperature in the range of 65 °C to 85 °C. iii. The aqueous phase can be prepared by mixing at least one humectant, at least one preservative, the extract of Rubia cordifolia, the extract of Symplocos recemosa, the extract of Terminalia chebula, and at least one emulsifying agent with at least one fluid medium at a temperature in the range of 65 °C to 85 °C. iv. The emulsion can be prepared by admixing oil phase obtained in step (ii) into the aqueous phase obtained in step (iii) under stirring at a temperature in the range of 65 °C to 85 °C, followed by the addition of at least one anti-foaming agent to form an emulsion. v. The cream is prepared by admixing the emulsion obtained in step (iv) into the gel phase obtained in step (i) with continuous stirring, followed by the addition of the extract of Myristica fragrans, and at least one pH modifying agent adjusting pH in the range of 5 to 7, to form a cream. The cream is cooled at a temperature in the range of 30 °C to 35 °C and at least one fragrance is added to the cooled cream to obtain fragranced topical anti- hyperpigmentation composition of the present disclosure. The extract of Glycyrrhiza glabra is added while preparing an oil phase when the extract of Glycyrrhiza glabra is at least one extract selected from the group consisting of alcoholic, hydro-alcoholic, aqueous, ether, ethyl acetate, acetone, hexane, mixture of water, ethyl acetate and acetone, and mixture of acetone, ethyl alcohol and hexane. The extract of Glycyrrhiza glabra is added while admixing so formed emulsion into the so formed gel phase when the extract of Glycyrrhiza glabra is a propylene glycol extract.

Alternatively in step (v), the cream is prepared by admixing the emulsion obtained in step (iv) into the gel phase obtained in step (i) with continuous stirring, followed by the addition of the extract of Myristica fragrans, and at least one pH modifying agent adjusting pH in the range of 5 to 7, to form a cream. The cream is cooled at a temperature in the range of 30 °C to 35 °C and at least one fragrance is added to the cooled cream to obtain fragranced topical anti- hyperpigmentation composition of the present disclosure. The extract of Glycyrrhiza glabra is added while preparing an oil phase when the extract of Glycyrrhiza glabra is at least one selected from the group consisting of mixture of water, ethyl acetate, and acetone extract, and mixture of acetone, ethyl alcohol and hexane extract. The extract of Glycyrrhiza glabra is added while admixing so formed emulsion into the so formed gel phase when the extract of Glycyrrhiza glabra is a propylene glycol extract.

The topical anti-hyperpigmentation composition of the present disclosure is prepared in the controlled dehumidified conditions such as relative humidity: 40 ± 5 % RH; and temperature: 25 °C ± 2 °C. The topical medicinal composition exerts its action by a combination of mechanisms such as:

Tyrosinase inhibitory Activity: Glycyrrhiza glabra possesses inhibitory effect on tyrosinase enzyme, thus helps in hyperpigmentation disorders.

Skin-lightening Activity: Myristica fragrans possesses inhibitory effect on melanin biosynthesis, thus helps in skin lightening activity. Glycyrrhiza glabra and Rubia cordifolia also possess skin lightening activity. Skin nourishing Activity: Glycyrrhiza glabra and Rubia cordifolia possess skin moisturizing effect.

Ant-oxidant Activity: Terminalia arjuna and Myristica fragrans possess anti-oxidant activity.

- Anti-inflammatory activity: Symplocos racemosa and Terminalia arjuna possess anti-inflammatory activity.

Anti-microbial Activities: Glycyrrhiza glabra, Symplocos racemosa, Terminalia arjuna and Myristica fragrans possess anti-microbial activity.

The topical anti-hyperpigmentation composition of the present disclosure has better skin whitening/ de-pigmenting activity, melanocyte reducing capacity, no adverse clinical signs and no mortality. Thus the topical anti-hyperpigmentation composition is safe and can be effectively used for alleviating the symptoms of hyperpigmentation, melasma, cholasma and various skin pigmentation disorders.

The term "an effective amount" refers to the amount of the topical composition of the present disclosure that is required to confer one of the above-described effects, like reducing pigmentation marks, reducing dark spots, post acne dark spots, relieving the symptoms of acne, melasma, neavous, dermatitis, eczema and various other skin diseases/disorders, etc. The effective amount depends on many factors including the indication of being treated, the overall condition of the patient, excipient/s used for formulation and the possibility of co- using with other treatment/s. The dose amount and its frequency may vary according to the age, body weight, condition and response of the individual subject.

The topical anti-hyperpigmentation composition of the present disclosure has a rapid and long lasting effect, is non-toxic and has no side effects. Moreover, it also has a good stability and is suitable for mass production. The topical anti-hyperpigmentation composition of the present disclosure has pleasant fragrance, provides smooth application without substantial friction with the active ingredients uniformly distributed, is stable and can be easily applied.

The scope of the present invention is not only limited to Glycyrrhiza glabra, Rubia cordifolia, Symplocos racemosa, Terminalia arjuna, Myristica fragrans and products derived there from but also extends to botanically closely related plants specially belonging to same family, preferably belonging to same genus, still preferably belonging to same species having substantially similar phenotypic and genotypic characteristics.

The ingredients of the composition also possess anti-bacterial, anti-fungal, anti-inflammatory and anti-microbial properties and therefore help in providing relief to patients with hyperpigmentation, acne, rashes, naevus, melasma, eczema, dermatitis and various other skin diseases/disorders.

In addition to the topical composition described above, the extracts of the above plants may also be formulated as a sustained and/or controlled release composition. In accordance with the embodiments of the present disclosure, the topical medicinal composition can be in a dosage form selected from the group consisting of lotion, cream, ointment, paste, powder, oil, salve, gel and balm. Furthermore, the topical composition according to the present disclosure can be in the form of a preparation that facilitates topical application, such as a cream, foam, powder (lepa), emulsion, and liquid.

The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial scale.

EXPERIMENTAL DETAILS

Experiment-1A: Preparation of the topical anti-hyperpigmentation composition in accordance with present disclosure (with propylene glycol extract of Glycyrrhiz glabra)

A topical anti-hyperpigmentation composition in the form of a cream was prepared by using the extracts of Glycyrrhiza glabra, Rubia cordifolia, Symplocos racemosa, Terminalia arjuna, Myristica fragrans, and Kanaka taila, which were commercially purchased from the market as value added products and are in an unrecognizable form. i. Gel phase preparation: A gel phase was prepared by mixing 0.7 g of Acrypol 934 and 0.1 g of disodium ethylenediamine tetraacetic acid with 34.87 g of purified water to obtain a gel. ii. Oil phase preparation: An oil phase was prepared by mixing 1.5 g of stearic acid and 2 g of cetostearyl alcohol, followed by the addition of 4 g of kanaka taila and 0.1 g of butylated hydroxytoluene at 75 °C. iii. Aqueous phase preparation: An aqueous phase was prepared by mixing 3 g of glycerine, 5 g of propylene glycol, 0.2 g of methyl paraben, 0.1 g of propyl paraben, 1 g of hydroalocoholic extract of Rubia cordifolia, 2 g of hydroalocoholic extract of Symplocos racemosa, 2 g of hydroalcoholic extract of Terminalia arjuna, and 1.5 g of poly oxye thy lene sorbitan monolaurate with pre -heated 34.88 g of purified water at 75 °C. iv. Preparation of emulsion: The oil phase obtained in step (ii) was admixed into the aqueous phase obtained in step (iii) under homogenization at 50 °C, followed by the addition of 1 g of dimethicone to form an emulsion. v. Preparation of cream: The emulsion obtained in step (iv) was admixed to the gel phase obtained in step (i) with continuous stirring, followed by the addition of 2 g of propylene glycol extract of Glycyrrhiza glabra, 3 g of propylene glycol extract of Myristica fragrans, and 0.85 g of potassium hydroxide 50 % solution to form a cream with pH 6. The so formed cream was cooled to 30 °C to obtain cooled cream and 0.2 g of J & J fragrance was added to the cooled cream with stirring to obtain a topical anti-hyperpigmentation cream. The topical anti-hyperpigmentation cream was prepared in the controlled dehumidified conditions provided herein below:

Relative humidity: 40 ± 5 % RH; and

Temperature: 25 °C ± 2 °C.

Experiment- IB: Preparation of the topical anti-hyperpigmentation composition in accordance with present disclosure (with mixture of acetone, ethyl alcohol, and hexane extract of Glycyrrhiza glabra)

The process for preparation of the topical anti-hyperpigmentation cream was similar to experiment-lA except for the addition of extract of Glycyrrhiza glabra. In experiment-IB, the extract of Glycyrrhiza glabra used was a extract of the mixture of acetone, ethyl alcohol, and hexane which was added in step (ii) i.e., oil phase preparation instead of propylene glycol extract of Glycyrrhiza glabra as used in experiment-lA which was added in step (v) i.e., preparation of cream.

Experiment-2A: Characterization of the topical anti-hyperpigmentation composition prepared in accordance with the present disclosure A] Testing de-pigmentation activity of the topical anti-hyperpigmentation composition prepared in accordance with experiment- 1 A of the present disclosure in mice

Vehicle control (C) did not have the active ingredients. Standard drug (S) was Hydroquinone 4% w/w and it was directly purchased from the local market. Test item-1 (Tl) was prepared in accordance with experiment- 1A of the present disclosure and Test item-2 (T2) is Kanaka taila. The ingredients and their amounts used to prepare C, Tl, and T2 are summarized in Table-1.

Table-1: List and amounts of ingredients used in C, Tl and T2

Procedure:

De-pigmentation study of the topical anti-hyperpigmentation composition was carried out on mice. Animals were grouped one day prior to the experiment as given in Table 2.

Table 2: Grouping and Study design

The mice were shaved and Vaseline wax was applied overnight on the shaved area and prior to the first day of treatment. Vaseline wax was washed with 0.9 % warm saline before initiating de-pigmentation study of the topical anti-hyperpigmentation composition. The control (C), Standard drug (S), Test item-1 (Tl) and Test item-2 Kanaka taila (T2) as described in Experiment-1A were applied twice a day, topically on the shaved skin area of mice for a consecutive period of 28 days (4 weeks). If the hair grows back, it was shaved at regular intervals. During de -pigmentation activity, mice were screened for adverse clinical signs once a day and for mortality twice a day. No adverse clinical signs or mortality were detected in the mice. The clinical signs and mortality observed after the end of 28 days are given in Table 3.

Table 3: Adverse clinical signs and Mortality of male and female mice

(w/w)

T2 80 NAD NAD Nil Nil

(v/w)

n = 5; NAD = No Abnormalities Detected

Further, the mice were also assessed for skin irritation on Draize 's scale immediately after application of the C, S, Tl and T2, till the completion of study. All four samples, i.e., C, S, Tl and T2 were found to be non-irritating on the mice skin. The observations for skin irritation index are given in Table-4 and standard Draize 's scale for skin irritation is given as Appendix-I for reference.

Table 4: Skin Irritation Index

Appendix-I: (Draize Scale for Skin Irritation Index)

Furthermore, the animals were also assessed for skin whitening of the same skin area to which the C, S, Tl and T2 were applied using Von Luschan's chromatic scale. The scoring of the C, S, Tl and T2 were done at the applied area on Dayl and thereafter once a week during the 28 days period. The observations for skin whitening are given in Table 5 and Table 6. Also, the standard Von Luschan's Chromatic scale is given as Appendix-II for reference. Table 5: Skin whitening index by Von Luschan's Chromatic Scale Male Animals

n=5; Values are in Mean+SD; *p<0.05 compared to vehicle control on respective days; a:p<0.05 G2 vs G3; b:p<0.05 G2 vs G4; c:p<0.05 G4 vs G3

It is evident from the Table 5 that, the skin whitening/ de -pigmenting activity of Tl in male mice is significantly superior as compared to that of T2 and S.

Table 6: Skin whitening index by Von Luschan's Chromatic Scale Female Animals

It is evident from the Table 6 that, the skin whitening/ de -pigmenting activity of Tl in female mice is significantly superior as compared to that of T2 and S. Appendix-II: VON LUSCHAN'S CHROMATIC SCALE

Based on the results of the study, it can be concluded that Tl, T2 and S are safe and possess skin whitening/ de-pigmenting activity. Enhanced skin whitening/ de -pigmenting activity by Tl is observed as compared to that of T2 and S. Thus, Tl is safe and can be effectively used for the treatment of hyperpigmentation, melasma, cholasma and various skin pigmentation disorders.

After the completion of 28 days of the de-pigmentation study on mice, all the mice were sacrificed by carbon-di-oxide asphyxiation on the 29^th day and subjected to external and internal gross necropsy observations. No abnormalities were detected in necropsy for all four samples, i.e., C, S, Ti and T2. The necropsy observations for all 4 samples are given in Table-7.

Table-7: Necropsy observation of male and female mice

5; NAD = No Abnormalities Detected It is seen from the Table-7 that, no abnormalities are detected in necropsy for the tested items on mice.

Further, the skin (where all the samples were applied) of mice from all the samples were collected and preserved in 10 % neutral buffered formalin. Histopathology of skin was evaluated by using Fontana-Masson Silver stain. Melanocytes were counted at different fields in the skin sections by using the micrometric method. The percent reduction in melanocytes of the skin epidermis of mice is given in Table 8 and Figures 1 to 8.

Table 8: Mean percent melanocytes of male and female animals

n=5; Values are in Mean + SD; *p<0.05 compared to vehicle control; a:p<0.05 G2 vs G3; c:p<0.05 G4 vs G3

Figures 1 and 2 depict the histological observations of melanocytes in the epidermis of skin of male and female mice respectively, after 28 days of application of control (C). Figures 3 and 4 depict melanocyte reduction in the epidermis of skin of male and female mice respectively, after 28 days of application of standard drug (hydroquinone; S). Figures 5 and 6 depict melanocyte reduction in the epidermis of skin of male and female mice respectively, after 28 days of application of test item-1 (Tl). Figures 7 and 8 depict melanocyte reduction in the epidermis of skin of male and female mice respectively, after 28 days of application of test item-2 (T2). It is clearly seen from the Figures 1 to 8 that S, Tl and T2 showed reduced melanocytes in the skin epidermis of mice as compared to C. Further, among S, Tl and T2, the reduction of melanocytes is highest in case of Tl, which resulted in enhanced skin whitening/ depigmentation activity. Experiment-2B: Characterization of the topical anti-hyperpigmentation composition prepared in accordance with experiment- IB of the present disclosure

Similar results for Test item-3 (T3) in terms of skin whitening/ de -pigmenting activity, melanocyte reducing capacity, no adverse clinical signs and no mortality were observed as shown in experiment-2A. Based on the above studies, it is evident that Tl and T3 of the present disclosure has better skin whitening/ de-pigmenting activity, melanocyte reducing capacity, no adverse clinical signs and no mortality as compared to C, S and T2. Thus, Tl and T3 are safe and can be effectively used for the treatment of hyperpigmentation, melasma, cholasma and various skin pigmentation disorders. TECHNICAL ADVANCES AND ECONOMICAL SIGNIFICANCE

The present disclosure described herein above has several technical advantages including, but not limited to, the realization of: an effective topical composition providing lightening of hyperpigmented skin;

an effective topical composition which also alleviates the symptoms of acne, post acne dark spots, skin rashes, naevus, melasma, eczema and dermatitis;

an effective topical composition providing synergistic effect;

a stable topical composition; and

an effective topical composition that is devoid of any side effects and is nontoxic.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The use of the expression "at least" or "at least one" suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results.

Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.

The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.

While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.

Claims

CLAIMS:

1. A topical anti-hyperpigmentation composition comprising: i. extract of Glycyrrhiz glabra in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition,

ii. extract of Rubia cordifolia in an amount ranging from 0.05 wt% to 10 wt% of the total weight of the composition;

iii. extract of Symplocos racemosa in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition;

iv. extract of Terminalia arjuna in an amount ranging from 0.01 wt% to 20 wt% of the total weight of the composition;

v. extract of Myristica fragrans in an amount ranging from 0.01 wt% to 30 wt% of the total weight of the composition;

vi. Kanaka taila (oil) as Ayurvedic classical formulation in an amount ranging from 0.01 wt% to 40 wt% of the total weight of the composition; vii. at least one fluid medium in an amount ranging from 45 wt% to 95 wt% of the total weight of the composition; and

viii. at least one pharmaceutically acceptable excipient.

wherein said extract of Glycyrrhiza glabra, said extract of Rubia cordifolia, said extract of Symplocos racemosa, said extract of Terminalia arjuna, and said extract of Myristica fragrans, is an extract obtained from at least one solvent selected from the group consisting of alcoholic, hydro-alcoholic, aqueous, ether, ethyl acetate, acetone, propylene glycol, hexane, mixture of water, ethyl acetate and acetone, and mixture of acetone, ethyl alcohol and hexane.

2. The topical anti-hyperpigmentation composition as claimed in claim 1 , wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of:

ii. at least one preservative in an amount ranging from 0.01 wt% to 0.6 wt% of the total weight of the composition; iii. at least one antioxidant in an amount ranging from 0.01 wt% to 1 wt% of the total weight of the composition;

3. The topical anti-hyperpigmentation composition as claimed in claim 1, wherein said at least one fluid medium is selected from the group consisting of water, alcohol, ether, acetone, methyl acetate, chloroform, propane, butane, hexane, dichloromethane, dichloroethane, freons, and polyethylene glycol (PEG).

4. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one gelling agent is selected from the group consisting of agar agar, carbomer, glucomannan gum powder, xanthan gum powder, methylcellulose, poloxamers, bentonite, gelatin, and sodium carboxymethylcellulose.

5. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one preservative is selected from the group consisting of sodium hydroxymethylglycinate, benzoin powder, citric acid powder, green tea extract, potassium sorbate, and parabens.

6. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one antioxidant is selected from the group consisting of tocopherol acetate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, ascorbyl palmitate, citric acid, propyl gallate, sodium metabisulfite, and methionine.

7. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one pH modifying agent is selected from the group consisting of potassium hydroxide, sodium hydroxide, diethylamine, citric acid, and lactic acid.

8. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one fragrance is selected from the group consisting of splendid compound, French bouquet, citrus breeze, white musk, avocado, green apple, cremia, gold aloe rose, and J & J.

9. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one emulsifying agent is selected from the group consisting of tragacanth, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, glyceryl monostearate, sodium oleate and polyoxyethylene sorbitan monooleate.

10. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one anti-foaming agent is selected from the group consisting of dimethicone, and simethicone.

11. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one cleansing agent is selected from the group consisting of stearic acid, lauric acid, myristic acid, oleic acid, and palmitic acid.

12. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one emollient is selected from the group consisting of cetostearyl alcohol, sterol, lecithin, paraffin wax, stearic acid, fatty acid ester, and lanolin derivatives.

13. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one humectant is selected from the group consisting of glycerine, propylene glycol, petrolactum, mineral oil, and triethylene glycol.

14. The topical anti-hyperpigmentation composition as claimed in claim 2, wherein said at least one chelating agent is selected from the group consisting of disodium ethylenediamine tetraacetic acid, diethylene triamine penta acetic acid, and N,N- bis(carboxymethyl)glycine.

15. The topical anti-hyperpigmentation composition as claimed in claim 1 or claim 2, wherein the pH of said topical anti-hyperpigmentation composition is in the range of 5 to 7.

16. The topical anti-hyperpigmentation composition as claimed in claim 1 or claim 2, wherein each dose of said composition is in the range of 100 to 500 mg/ 1.5 cm of skin, administered 2 to 4 times per day.

17. A process for preparing the topical anti-hyperpigmentation composition as claimed in claim 2; said process comprising the following steps:

i. preparing a gel phase by mixing said at least one gelling agent and said at least one chelating agent with said at least one fluid medium to obtain a gel;

ii. preparing an oil phase by mixing said at least one cleansing agent and said at least one emollient, followed by addition of said Kanaka taila and said at least one anti-oxidant at a temperature in the range of 65 °C to 85 °C;

iii. preparing an aqueous phase by mixing said at least one humectant, said at least one preservative, said extract of Rubia cordifolia, said extract of Symplocos racemosa, said extract of Terminalia arjuna, and said at least one emulsifying agent with said at least one fluid medium at a temperature in the range of 65 °C to 85 °C;

iv. admixing said oil phase obtained in step (ii) into said aqueous phase obtained in step (iii) under stirring at a temperature in the range of 65 °C to 85 °C, followed by the addition of said at least one anti-foaming agent to form an emulsion;

v. admixing said emulsion obtained in step (iv) into said gel phase obtained in step (i) with continuous stirring, followed by the addition of said extract of Myristica fragrans, and said at least one pH modifying agent adjusting pH in the range of 5 to 7, to form a cream; and

vi. cooling said cream obtained in step (v) to a temperature in the range of 30 °C to 35 °C and adding said at least one fragrance to said cooled cream with stirring to obtain fragranced cream,

wherein said extract of Glycyrrhiza glabra is added in step (ii) when said extract of Glycyrrhiza glabra is at least one selected from the group consisting of mixture of water, ethyl acetate, and acetone extract, and mixture of acetone, ethyl alcohol and hexane extract,

wherein said extract of Glycyrrhiza glabra is added in step (v) when said extract of Glycyrrhiza glabra is a propylene glycol extract.