Field of the Invention

The present invention is related to the compositions which are suitable for use in diseases of nipple and areola. More specifically, the present invention is related to the compositions comprising lanolin, Chamomilla Recutita (Matricaria) juice, Mimosa Tenuiflora shell extract and Calendula Officinalis extract.

Background of the Invention

The importance of the breastfeeding has been widely accepted for the physiologic and psychological development of the newborns. However, since the breastfeeding problems during the lactation period usually results in delactation, the health of the baby and his/her relationship with the mother are adversely affected. In that regard, the major problems experienced by nursing mothers are the skin conditions in nipple and areola in particular.

The said skin conditions occurs with the breastfeeding-related physical damage in the nipple or areola tissue. Such physical damages can be accompanied by infections, however, there are times when they follow a course without any infection accompanied.

Rhagade, a disease of nipple/areola without infection, is a manifestation of a postpartum inflammatory disease. Symptoms such as crack, abrasion, pain, rash, edema, scabbing occur in the area of inflammation.

On the other hand, the physical damage of the skin leads to secondary bacterial and/or fungal infections if left untreated. Staphylococcus aureus is the most common cause of the bacterial infections. It settles in the milk duct due to the damage in the nipple and causes serious diseases such as mastitis or breast abscess. In fungal infections, Candida albicans overgrows in the affected tissue and leads to mastitis. In these types of infections, oral candidiasis is seen in the breastfed babies.

In the state of art, lanolin is known for its topical use based on the principle of moist wound healing in the treatment of traumatic nipples / areola. [ Riordan , J. (1985). The effectiveness of topical agents in reducing nipple soreness of breastfeeding mothers. J Hum Lact, 1, 36-41]. Lanolin is still practically used by women based on its extensive experience, proving its satisfactory results in terms of providing care. Furthermore, nurses and lactation experts continue to recommend the use of lanolin. However, as shown in recent studies, the predominant idea is that lanolin increases the risk for infection and causes more severe infections as mentioned [Sasaki, B. C., Pinkerton, K., & Leipeit, A. (2014). Does lanolin use increase the risk for infection in breastfeeding women? Clinical Lactation, 5(1), 28-32].

From another point of view, it is important to develop non-toxic, causing less adverse effects, safe, non-irritating, and environment-friendly and cost-effective therapeutic formulations for the skin diseases of nipple and areola considering the vulnerable immune systems of postpartum mothers and newborns. In this respect, rapidly growing and widely accepted herbal and supplementary medical treatments are needed. However, careless taking of herbal mixtures or interactions thereof with the prescribed drugs might cause unknown effects and serious problems. For this reason, for the safety of both mothers or newborns, the use of active natural products should be preferred to their potential reliability.

In addition, emollient selection is quite important for herbal formulations, particularly for the formulations in the emulsion form. Emollients are advantageous for their physico chemical parameters such as viscosity, surface tension, spreadability and pour/blurring point and enable herbal oils to be used in the formulations easily with minimum effort.

As a result, there is a need in the art for herbal compositions with antifungal and antibacterial features that can overcome the abovementioned problems, maintaining the efficacy and stability of the active pharmaceutical ingredients. The said composition should comprise herbal supplements which do not exclude the useful features of lanolin and prevent lanolin-related infections. The invention achieves those goals with the compositions according to claim 1.

Brief Description of the Invention

The present invention is related to a topical composition comprising Lanolin, Chamomilla Recutita juice, Mimosa Tenuiflora shell extract and Calendula Officinalis extract. Wherein the ratio of Lanolin \Chamomilla Recutita juice is in the range of 1 :10 and 1 :1 by weight, which is advantageous.

It is also advantageous to use at least one emulsifier to ensure the desired stability of the compositions of the invention. Preferably, the said emulsifier agent is selected from a group comprising cetearyl alcohol, cetyl alcohol, polyglyceryl-3- stearate citrate and mixtures thereof. It is observed that the said stability is improved when a triglyceride is used. Preferably, the said glyceride is selected from a group comprising the oils of Shea, Helianthus Annuus, Zea Mays, Prunus Amigdalus Dulcis plants and mixtures thereof. The composition of the invention further comprise at least one additional agent selected from a group comprising moisturizer, thickener, humectant, antioxidant, preservative and pH regulator. The said moisturizer agent can be selected from a group comprising behenyl alcohol, glyceryl caprate, glyceryl caprylate, caprylyl glycol and mixtures thereof. The said thickener agent can be selected from a group comprising Cera Alba, xanthan gum or combinations thereof. The said humectant is preferably glycerin.

The topical composition of the invention is presented in the form of cream, foam, gel, lotion or ointment. The composition is preferably in the form of cream or ointment, more preferably in cream form.

The components present in the composition of the invention can be present in the following ratios by weight:

More preferred formulation of the composition of the invention is disclosed in the present description.

From another perspective, the invention is related to the use of the above-mentioned topical composition for diseases or disorders of nipple and/or areola. The said disease or disorder of nipple and areola can be selected from a group comprising dermatitis, eczema, vasospasm, mastitis and rhagade.

In another aspect, the invention is related to the method of preparation of the topical composition and consists of the following steps: a. Introducing of a hydrophilic phase comprising Chamomilla Recutita juice, b. Introduction of a lipophilic phase comprising Lanolin, Mimosa Tenuiflora shell extract and Calendula Officinalis extract,

c. Mixing hydrophilic phase and lipophilic phase together with an emulsifier.

It’s also found that an emulsifier which is used as part of the method and in particular an emulsifier which is selected from a group comprising cetearyl alcohol, cetyl alcohol, polyglyceryl-3-stereate, glyceryl stereate, citrate and mixtures thereof provides the desired stability.

Detailed Description of the Invention

The present invention presents a composition comprising lanolin as well as Mimosa Tenuiflora shell extract, Calendula Officinalis extract and Chamomilla Recutita juice with skin regeneration activities for use in skin disorders of nipple and areola especially in skin disorders of nipple and areola that are seen during lactation and breastfeeding periods.

The most important reason for the composition of the present invention to comprise Chamomilla Recutita juice is due to its capacity of preventing the lanolin-related antibacterial and antifungal infections as explained above. The term Chamomilla Recutita juice as used in the present invention means any extract of Chamomilla Recutita or more preferably the extract derived from the flower thereof.

It is known that Chamomilla Recutita has antimicrobial and drying effects in the ulcers with discharge, accelerating the recovery process [Glowania, HJ., Raulin, C., Swoboda, M. (1987). Effect of chamomile on wound healing-a clinical double-blind study. Z Hautkr, Sep 1;62(17):1262, 1267-71 ]. Moreover, it is also proved that Chamomilla Recutita has antimicrobial activities against staphylococcus and Candida microorganisms that cause infected skin diseases of nipple and areola [Aggag, ME., Yousef, RT. (1972). Study of antimicrobial activity of chamomile oil. Planta Med. Sep;22(2):140-4]. Therefore Chamomilla Recutita and lanolin show complementary effects particularly in the infected ulcers when used in combination. Yet, these substances need to be developed with the following components to have the features of fighting the microorganisms with wider spectrum and treating the conditions such as irritation and edema. For this reason, the invention suggests additionally the use of Mimosa Tenuiflora shell extract and Calendula Officinalis extract in the composition presented herein. It is found that Mimosa Tenuiflora shell extract is beneficial for the skin diseases of nipple and areola. The shell extract of Mimosa Tenuiflora is a product of traditional South America medicine for healing ulcers and burns. This plant shell comprises saponins, lipids, phytosterols, metoxichalcones, cuculcanins and tanins that are efficient against free radicals as well as providing antibacterial, antimycotic, astringent effects. Furthermore, in the microbiological activity profile studies the antibacterial and antimycotic features as well as the inhibition effect of Mimosa Tenuiflora shell extract on gram-positive (Staphylococcus aureus) and fungi proliferation are established. Calendula Officinalis extract has synergic interaction with M. tenuiflora extract due to the anti-inflammatory, anti-edema, antibacterial, antioxidant activities of triterpene diol esters that stimulate epithelium generation in skin lesions.

For this reason, the inventors have found a composition providing wider-spectrum antimycotic, antibacterial and antimicrobial features, rapid wound healing features, preventing irritation and having stability when the said herbal supplements are used with lanolin within the combination presented herein. In the preferred embodiments, the ratio of lanolin: Chamomilla Recutita juice is in the range of 1 :10 and 1 :1 by weight, which yielded outstanding results.

Preferably, biological additives are used in the composition of the present invention considering the sensitive immune systems of newborns and mothers. The term“biological additive” as used herein means any compound that is derived from a natural source such as animal, bacteria and yeast and has medical or beneficial effect. In this regard, biological additives might be the extracts and hydrous mixtures, oils and pollens of flowers, seeds, germs, shells or leaves of plants.

In a preferred embodiment of the present invention, the composition may comprise biological additive which is lecithin. Lecithin is a mixture of choline, choline esters, oil acids, glycerol, glycolipid, triglyceride, phosphoric acid and phosphatidylcholine which are the natural components of human milk. When used as additive, it is effective on clogged milk ducts. Another herbal additive is Maiva Syivestris extract which is known as mallow and externally used in poultice form for the wound treatment in traditional medicine. Preferably, Aloe Barbadensis can also be used in the present invention. Aloe Barbadensis contributes to the healing of the wounds by increasing the collagen amount in the skin and it is also involved in modulator system with its anti-inflammatory affects. In a preferred embodiment of the present invention, the said composition further comprises at least one triglyceride. The term“triglyceride” as used herein solely means any oil in solid or liquid form derived from the plants. The triglycerides used in the present invention are selected to overcome emulsion difficulties. Furthermore, since they are “natural”, they provide advantage for using the compound safely.

In a preferred embodiment, the said trglyceride shea is selected from a group comprising Helianthus Annuus, Zea Mays, Prunus Amigdalus Dulcis oils and mixtures thereof.

The major functions of triglycerides in the composition of the present invention are the emollient effect, however the chemical features of the said plants are also effective for healing the targeted diseases.

The chemical components isolated from shea oil have been reported to have anti inflammatory, emollient and humectant properties. Shea oil melts down at body temperature and has good water-binding features. Helianthus Annuus (Sunflower) is used for the wounds and skin lesions that usually take long to heal. Prunus Amigdalus Dulcis (Almond) is usually topically applied for skin care and liniments. Prunus Amigdalus Dulcis is also used for the production of natural cosmetics as an ointment base.

In another preferred embodiment of the present invention, the compound comprises at least one moisturizer (emollient) agent. The said moisturizer agent is selected from a group comprising beheny alcohol, glyceryl caprate, glyceryl caprylate, caprylyl glycol and mixtures thereof. These chemicals have moisturizing abilities as well as multifunctional cosmetic features such as wetting, viscosity regulator, antimicrobial, solubilizer. Emulsification efficacy of moisturizing agents depends on their concentration. The moisturizing agents help reduce mechanic work load and heat energy, contributing to the production of a homogeneous and stable emulsion.

In another embodiment of the present invention, the composition further comprises a thickener agent. Appropriate selection of the thickener agent, i.e. rheological additives improves product in terms of production, storage stability and administration. Rheological additives affect the stability and viscosity features of dosage form, thus are quite important in either liquid or semi-liquid formulations. The features that are regulated with rheological additives include but is not limited to viscosity, flow rate, stability depending on the viscosity variations in time and ability to suspend the particles in such compositions.

In a preferred embodiment, the said thickener agent is selected from a group comprising Cera Alba, xanthan gum or combinations thereof. While Cera Alba is known as beeswax, it is a natural rheology regulator. Xanthan gum, on the other hand, is a polysaccharide of high molecular weight formed by pure culture fermentation between carbohydrate and Xanthomonas campestris.

In a preferred embodiment of the present invention, the said thickener agent is Cera Alba. Cera Alba (beeswax) is necessary for applications where non-toxicity and biodegradation is very important. Cera Alba is preferably present in the range of 1% and 5% by weight of the total composition.

In a preferred embodiment of the present invention, the composition further comprises an emulsifier. Emulsifiers enhances kinetic stability of an emulsion. In a preferred embodiment, the said emulsifier is selected from a group comprising cetearyl alcohol, cetyl alcohol, polyglyceryl-3-stearate, glyceryl stearate citrate and mixtures thereof. Cetearyl alcohol, cetyl alcohol in this group are classified as fatty alcohols and used in oil- in-water emulsions, providing a soft feeling for the skin.

In another embodiment of the present invention, the composition further comprises a humectant. Humectants are composites that help keep skin moisturised. In cosmetics, humectants can be used in topical dosage forms to increase the solubility of the active components of the chemical compositions thus increasing the penetration abilities of the said active components to the skin along with their activity periods. The composition of the present invention comprises a humectant which is glycerin.

According to a preferred embodiment, the components present in the composition of the present invention is provided in Table 1 by their preferred ratios by weight.

Table 1

The composition of the present invention is preferably in a form intended for topical application. Specifically, preferred topical forms are cream, foam, gel, lotion and ointment. The said composition is more preferably in the form of cream or ointment.

The composition of the present invention can be used for the treatment of diseases related to nipple and areola. The said disease related to nipple and areola is selected from a group comprising dermatitis, eczema, vasospasm, mastitis, edema and rhagad. Furthermore, the present invention is related to the production of a composition comprising Mimosa Tenuiflora shell extract, Calendula Officinalis extract and Chamomilla Recutita juice, combined with lanolin.

The method of the said production comprises the following steps: a. Introducing a hydrophilic phase comprising Chamomilla Recutita juice, b. Introducing a lipophilic phase comprising Lanolin, Mimosa Tenuiflora shell extract and Calendula Officinalis extract,

c. Mixing hydrophilic phase and lipophilic phase together with an emulsifier.

The emulsifying agent mentioned herein was selected from cetearyl alcohol, cetyl alcohol, polygyceryl-3-stereate and glyceryl stearate citrate, which was observed to be advantageous. Because it is important that the hydrophilic and lipophilic phases are homogeneously mixed to provide long-term physical stability and as shown in the examples the agents herein provide the desired stability.

In a preferred embodiment, during the manufacture of the composition of the present invention, hydrophilic phase components comprising Aloe Barbadensis leaf juice powder, chelating agent, Chamomilla Recutita juice, Maiva Syivestris extract, propanediol are mixed, while separately prepared another second phase comprising glycerin and xanthan gum is added to hydrophilic phase. Lipophilic phase components comprising Shea oil, Mimosa Tenuiflora shell extract, Calendula Officinalis extract, Prunus Amygdalus Dulcis oil, cetyl alcohol, cetearyl alcohol, lecithin, Polyglyceryl-3-Stearate, lanolin and cera alba are mixed in the dissolvent. Hydrophilic phase second phase mixture and lipophilic phase is heated up to 70 °C. At this stage, two phases are combined and mixed for 10 minutes until emulsion is obtained. The product is cooled and the last phase components comprising caprylyl glycol, glyceryl caprylate, phenetyl alcohol are added below 40 °C.

Present inventors subjected the composition they obtained to a series of physicochemical tests. These tests are explained by means of the examples below and they are not intended to limit the scope of protection of the invention.

Examples

Example 1

In another preferred embodiment, the composition is prepared so as to comprise the following components by weight (%):

Example 2

Physicochemical and microbiological data of the obtained formulation are provided in Table below. Table 3

Example 3

Stability test: Method: The composition was stored at various temperatures (4 °C, 25 °C, 40 °C and in weekly thermal shock 4 °C / 40 °C) for 3 months and its stability was evaluated at certain time points (t: 0, day 15, month 1 , month 3). 4 samples that correspond to control days were analyzed for each environmental status. Samples were evaluated at each control time by keeping one sample sealed all the time and others open. Thermal shock was applied once a week in two stages starting in the cooler followed by cooler/heater.

For example, organoleptic and chemical-physical properties at room temperature (25 °C) remained unchanged. Expected and usual changes inherent in the raw materials were not observed under hot and cold conditions. The composition was sealed tightly in order to prevent it from oxidation and possible chemical-physical or temperature-related changes and stored at room temperature.

Conclusion: The composition is stable under reasonable storage conditions (room temperature: 25°C) while used for commercial purposes or in its container for more than 30 months (preserves its chemical and physical properties until the date of expiry). Example 4 Patch test:

Possible irritation effect of the composition was evaluated according to Draize classification. Method: The test was applied to 25 male-female patients between the ages 18-70 that were selected according to the inclusion criteria, i.e. a) well general state of health b) absence of dermatopathy c) absence of ongoing pharmacological treatment d) acceptance of not changing the ordinary daily routine and e) absence of atopy in anamnesis, in order to provide outpatient treatment.

Application of the Examples

According to the ordinary use of the composition, it was applied as a leave on or 10% standard concentration rinse-off composition. Liquid composition was applied to the skin at 20 pi dose. Solid and semi solid composition was applied at a dose of 20 pg. Finn chamber (plastic that contains 7 mm aluminum disc and absorbent paper discs) is a patch test device that provides good occlusion. For liquid compositions, Finn chamber contains blotting papers that were immersed in a certain amount (20 pi) of the sample that will be tested. For solid compositions, the compositions (20 pg) that will be tested are directly applied to the skin.

Application of the Test

The relevant area on the skin (surface of the back) was cleansed using 70% alcoholic solution.

The composition was applied at an amount of 0.02 g or ml/cm2 skin.

The relevant area of the skin was covered by the Finn chamber.

Composition was maintained in contact with the skin for 24 hours.

Finn chamber was removed.

Skin reactions were analyzed at minute 15, hour 1 and 24 after removing the Finn chamber.

Conclusion: There were no edema and erythema in the patients after the test.