SUNSCREEN FORMULATIONS

INTRODUCTION

Aspects of the present invention relate to ultraviolet (UV) radiation-protecting sunscreen formulations. Further aspects of the present invention relate to methods for preparing and using such formulations.

It has long been known that prolonged exposure to UV that reaches the surface of the earth can lead to the formation of erythema or light dermatoses, as well as to an increased incidence of skin cancers and accelerated skin ageing. It is well-documented that exposure to ultraviolet ("UV") radiation can result in a wide range of adverse health consequences. Excessive exposure to light of UV-B wavelengths (290-320 nm) can have both short- and longer-term effects. The immediate and primary consequence of unprotected UV-B exposure is erythema and sunburn. Childhood sunburns have been correlated with melanoma later in life. Light of UV-A wavelengths (320-400 nm) penetrates the skin deeper than UV-B, reaching both the epidermis and dermis. Repeated exposures to the shorter wavelength UV-A II rays (approximately less than about 340 nm) and the longer wavelength UV-A I rays (approximately longer than about 340 nm) have been associated with formation of fine lines and wrinkles, irregular skin pigmentation, weakening of the skin's immune system, and skin cancer. Other skin disorders associated with overexposure to UV radiation include non-melanoma skin cancers (i.e., basal cell carcinomas and squamous cell carcinomas), actinic keratoses, and premature ageing of the skin.

Topical sunscreening active agents can be grouped into two broad categories: organic and inorganic (physical) sunscreens. Commercially available sunscreen products contain from about 3 to about 26% of one or more UV-absorbing or blocking chemicals. When applied to the surface of the skin to form a thin film, e.g., about 10-15 pm in thickness, these chemicals act as a filter to diminish the penetration of UV radiation to the cells of the epidermis. These sunscreens are topically applied in a cream, oil, lotion, alcohol, or gel vehicle, and they are usually colorless because they do not contain any visible light-absorbing chemicals. The most widely used organic based sunscreens contain, for example, paraaminobenzoic acid (PABA), PABA esters (e.g., glyceryl PABA, amyldimethyl PABA and octyldimethyl PABA), benzophenones (oxybenzone and sulisobenzone), cinnamates (octylmethoxy cinnamate and cinoxate), salicylates (homomenthyl salicylate), anthranilates such as menthyl anthranilate, 2-ethylhexy1-2-cyano-3,3-dipheny1 acrylate, 2-phenylbenzimidazole-5-sulfonic acid, digalloyl trioleate, 3-(4-methylbenzylidene)camphor, 4-isopropyldibenzoylmethane, butylmethoxy dibenzoylmethane, and 2-ethyl-2-cyano-3,3'-diphenyl acrylate.

Sunscreen products absorb a certain percentage of light over a specified spectrum, thus preventing potentially harmful erythemal UV from reaching and damaging the skin. The sun protection factor ("SPF") listed on sunscreen products is related to this percentage and is intended to communicate the amount of erythemal UV attenuation. More particularly, a numerical SPF theoretically tells the user that he or she is protected X times longer than without sunscreen, where X is the label SPF. For example, an SPF 33 product would, theoretically, absorb 97% of erythemal UV radiation and allow 3% of unattenuated light to reach the skin. The user of such an SPF 33 product would conclude that he or she could stay out in the sun 33 times longer than without the sunscreen. However, because some sunscreen actives are not photostable, labeled SPF may not be indicative of the photoprotection actually provided, and thus misleads consumers to believe that they can safely stay out in sun for longer periods of time than that for which the sunscreen actually provides protection. Accordingly, photostable sunscreen formulations, whose labeling accurately communicates to consumers the degree of UV protection actually provided, would be beneficial. Also needed are sunscreen formulations that substantially maintain their SPF ratings over an exposure time period of a typical consumer.

One shortcoming of currently available sunscreen products is that SPF ratings are generated on the basis of sunscreen product exposure to artificial light spectra generated in a solar simulator. While convenient to the scientist testing a formulation, the SPF methodology does not satisfactorily provide an accurate measure of how the formulation will perform under actual conditions of use. Without being bound by theory, the deficiency is believed to result from wavelengths present in natural sunlight being missing in the artificial spectra, or being present in much lesser relative intensities than in natural sunlight, these wavelengths being responsible (at least in part) for degradation reactions in many sunscreens. These degradation reactions result in lesser amounts of effective sunscreen being present over the exposure time so that effective SPF drops with exposure time. These degradation reactions also generate free radicals, which are associated with adverse health consequences.

Various sunscreen formulations have been proposed, which include at least one active ingredient that is intended to reduce the intensity of UV radiation reaching the skin, thereby inhibiting the undesired effects on the skin. A number of compounds have been proposed for use as UV protectants in sunscreen formulations, especially soluble organic UV absorbers and insoluble micronized inorganic compounds, e.g., zinc oxide and titanium dioxide.

Avobenzone is an oil-soluble ingredient used in sunscreen products to absorb the full spectrum of UV-A rays. It is a dibenzoylmethane derivative. Its ability to absorb ultraviolet light over a wider range of wavelengths than many organic sunscreen agents has led to its use in many commercial preparations marketed as "broad spectrum" sunscreens. Avobenzone has an absorption maximum at 357 nm. Avobenzone is available as Parsol™ 1789, Eusolex™ 9020, Escalol™ 517, and others. Avobenzone has chemical names: 1-(4-Methoxyphenyl)-3-(4-tert-butylphenyl) propane-1,3-dione; and 4-(1,1-Dimethylethyl)-4'-methoxydibenzoylmethane. Avobenzone has a molecular formula C20H22O3 and a molecular weight of 310.39. Avobenzone can be used in concentrations up to 3% by weight, and 2-3% in combinations with other sunscreens. Avobenzone is insoluble in water and soluble in hot methanol. The formula of avobenzone is represented as structure (1).

Avobenzone is an active ingredient in commercial products including SHADE® marketed by Fulford, SPECTRABAN ULTRA® marketed by Stiefel Laboratories, SUNSET® by Merck, PHOTOBAN® by Micro Labs, SUNCROS® by Ranbaxy (Crosslands), etc.

Oxybenzone is a derivative of benzophenone. It forms colorless crystals that are readily soluble in most organic solvents. It is used as an ingredient in sunscreen and other cosmetics because it absorbs UV-B and short-wave UV-A rays. This organic compound has been shown to penetrate into the skin where it acts as a photosensitizer. Oxybenzone is available as Eusolex 4360, Escalol 567, etc. Oxybenzone has chemical names: (2-hydroxy-4-methoxyphenyl)- phenylmethanone; and 2-hydroxy-4-methoxybenzophenone. Oxybenzone has a molecular formula C14H1203 and a molecular weight of 228.24. Oxybenzone is practically insoluble in water, and freely soluble in alcohol and in toluene. Oxybenzone belongs to the category of UV-B filter (sunscreen). Oxybenzone can be used in concentrations of 2-6% by weight of a formulation. The formula of oxybenzone is represented as structure (2).

Oxybenzone is an active ingredient in commercial products including SHADE® marketed by Fulford, SPECTRABAN ULTRA® marketed by Stiefel Laboratories, UA AVO® marketed by Alkem Laboratories, GLYAHA HQ-SP® marketed by Shalaks Pharma, HYCLEAN® marketed by Ranbaxy Laboratories, SUNGRACE® marketed by Glenmark Pharma, etc.

Octocrylene is an ester formed by the condensation of a diphenylcyanoacrylate with 2-ethylhexanol. It is a viscous, oily liquid that is clear and colorless. The extended conjugation of the acrylate portion of the molecule absorbs UV-B and short-wave UV-A rays with wavelengths from 280 to 320 nm, protecting the skin from direct DNA damage. The ethylhexanol portion is a fatty alcohol, adding emollient and oil-like (water resistant) properties. This organic compound can penetrate into the skin where it acts as a photosensitizer. This results in an increased production of free radicals under illumination. Free radicals are known to induce indirect DNA damage and an increased concentration of free radicals might have contributed to the increased incidence of malignant melanoma in sunscreen-users compared to non-users. Octocrylene has chemical names: 2-ethylhexyl 2-cyano-3, 3-diphenyl-2-propenoate; and 2-ethylhexyl-2-cyano-3,3-diphenylacrylate. Octocrylene has a molecular formula C24H27NO2 and a molecular weight of 361.5. Octocrylene is soluble in most organic solvents, and insoluble in water. Octocrylene can be used up to 10% by weight of a formulation, more specifically 7-10% in combinations with other sunscreens. The formula of octocrylene is represented as structure (3).

Octocrylene is an active ingredient in commercial products including SUNGRACE® marketed by Glenmark Pharma, PHOTOBAN-30® marketed by Micro Labs, etc.

Bemotrizinol, sold as Tinosorb® S, is an oil soluble organic compound which is added to sunscreens to absorb UV rays. Bemotrizinol is a broad spectrum UV absorber, absorbing UV-B as well as UV-A rays. It has 2 absorption peaks, at 310 and 340 nm. It is highly photostable. Even after 50 MED (minimal erethemal dose) exposure, 98.4% remains intact. It helps prevent the photodegradation of other sunscreen actives like avobenzone. Bemotrizinol has strong synergistic effects on the SPF when formulated with bisoctrizole, ethylhexyl triazone or iscotrizinol. It is the most effective UV absorber available, measured by SPF. Bemotrizinol has a chemical name bis-ethylhexyloxyphenol methoxyphenyl triazine (BMET). Bemotrizinol has a molecular formula C38H49N3O5 and a molecular weight of 627.81. Bemotrizinol is used as sunscreen agent. Bemotrizinol can be used up to 5% by weight of a formulation. Bemotrizinol is soluble in polar cosmetic oils and insoluble in water. The formula of bemotrizinol is represented as structure (4).

Bisoctrizole is sold as Tinosorb® M, and is a benzotriazole based organic compound which is added to sunscreens to absorb UV rays. Bisoctrizole is a broad spectrum ultraviolet radiation absorber, absorbing UV-B as well as UV-A rays. It also reflects and scatters UV. Bisoctrizole is a hybrid UV absorber, the only organic UV filter produced as microfine organic particles (<200 nm) like microfine zinc oxide and titanium dioxide. Where other organic UV absorbers need to be dissolved in either the oil or water phase, bisoctrizole dissolves poorly in both. Bisoctrizole is added to the water phase of a sunscreen as a 50% suspension, while mineral micropigments are usually added to the oil phase. The bisoctrizole particles are stabilized by the surfactant decyl glucoside. Bisoctrizole shows very little photodegradation and has a stabilizing effect on other UV absorbers, octylmethoxycinnamate (octinoxate) in particular. When formulated into a sunscreen, bisoctrizole has minimal skin penetration, unlike some other organic sunscreen actives. Bisoctrizole has a chemical name 2,2-methanediylbis[6-(2H-benzotriazol-2-yl)-4-(2,4,4-trimethylpentan-2-yl)phenol]. Bisoctrizole has a molecular formula C41H5oN602 and a molecular weight of 658.88. Bisoctrizole can be used up to 5% by weight of a formulation. Bisoctrizole is dispersible in water and insoluble in cosmetic oils. The formula of bisoctrizole is represented as structure (5).

It is well known that ultraviolet radiation is harmful to human skin. Depending on the wavelength, the UV radiation causes different types of skin damage. UV-B radiation (about 290 to about 320 nm) is responsible for sunburn and can cause skin cancer. UV-A radiation (about 320 to about 400 nm), while producing tanning of the skin, contributes also to sunburn and the induction of skin cancers. Moreover, the harmful effects of the UV-B radiation may be aggravated by UV-A radiation. An effective sunscreen formulation preferably comprises both UV-A and UV-B filters, covering the full range of about 290 nm to about 400 nm, to prevent the human skin from the harmful effects of sunlight. The effects of UV-A are mainly mediated by free radicals, e.g., reactive oxygen species inducing different types of degradation to cellular DNA, lipids, and proteins. The visible indications are often the result of long-term, cumulative effects. This is why skin photoaging is associated with UV-A exposure. It is also known that normal outdoor UV-A radiation can be effective enough to cause the breakdown of the proteins collagen and elastin, leading to a loss of firmness and resilience of the skin. Therefore the UV-A protection in daily skin care is of significant relevance.

Numerous UV-B filters are approved by regulatory authorities for their use in sunscreen preparations, which are mainly derivatives of 3-benzylidenecamphor, ethylhexyl salicylate, and cinnamic acid esters, such as 2-ethylhexyl p-methoxycinnamate. A new class of organic UV filters is micronized triazine derivatives which are commonly used in admixture with cinnamic acid derivatives and/or dibenzoylmethane derivatives. Unfortunately, this UV filter combination employed in sunscreen compositions suffers from relatively rapid photodegradation with the consequence that the protection from sun damage is lost during exposure.

International Application Publication No. WO 02/17874 discloses the use of triazine derivatives used as sunscreen agents. It also discloses topical formulations comprising the derivatives.

The benzotriazole-type ultraviolet absorber is a known methylenebis (hydroxyphenyl-benzotriazole) derivative, and may be manufactured by a manufacturing process of, for example, US Patent Nos. 5,237,071 and 5,166,355, Japanese Laid-open Patent [Kokai] Publication No. H04-290877, etc.

In United Kingdom Patent Application 2303549 A, there is described a method of producing micronised, insoluble organic UV absorbers, as well as a sunscreen composition comprising: a) 0.1 to 15%, preferably 0.5 to 10% by weight, based on the total composition of a micronised formulation of an insoluble organic UV absorber, produced according to the disclosed method; and optionally b) a cosmetically acceptable carrier.

US Patent No. 5,733,531 discloses topical sun block formulations for shielding skin from ultraviolet radiation, and a composite sun blocking component thereof. Further, the sun blocking component of the formula includes an effective amount of a plurality of particles having diameters in the range of about 0.01-100 microns, each particle including a matrix and a UV-attenuating compound incorporated into the matrix.

IN Publication No. 1286/MUM/2005 discloses a stable sunscreen composition comprising: an organic UV-A sunscreen, an organic UV-B sunscreen and cosmetically acceptable vehicle wherein said UV-A sunscreen and UV-B sunscreen are kept isolated from each other by encapsulating one of said sunscreens in solid lipid encapsulate.

WO 2006/016975 discloses a photostable composition that provides protection from ultraviolet radiation comprising a triplet combination of sunscreens consisting of avobenzone, octocrylene and oxybenzone; optionally, a fourth sunscreen component selected from the group consisting of one or more sunscreens.

US Patent No. 6436376 discloses a regime/regimen for improvedly UV-photoprotecting human skin, hair and/or scalp against the deleterious effects of ultraviolet irradiation, comprising topically applying thereon an effective UV-photoprotecting amount of at least one UV-A and/or UV-B sunscreen such as avobenzone, octocrylene and oxybenzone, an amount of the copolymer tricontanyl PVP effective to significantly enhance the SPF value of said at least one UV-A and/or UV-B sunscreen, formulated into a topically applicable, cosmetically/dermatologically acceptable vehicle, diluent or carrier therefor.

Thus there remains, an unmet need to provide new, stable cosmetically acceptable sunscreen formulations that comprise a combination of organic UV absorbing agents which is absolutely free of inorganic UV absorbing agents. There remains a need for sunscreen formulations that accurately combine photoprotection under actual conditions of use for an extended period of exposure with enhanced stability, and the physicochemical stability and organoleptic properties of the formulation are maintained during storage. A need also exists for formulations that minimize skin irritation and prolong the duration of action of sunscreen protection, as compared to conventional sunscreen formulations.

SUMMARY

Aspects of the present invention relate to topical sunscreen formulations intended to be used for protection against the harmful effects caused from exposure to solar radiation.

In embodiments, the present invention relates to topical sunscreen formulations that are in the form of emulsions, such as creams or lotions.

In embodiments, the present invention relates to topical sunscreen formulations that provide extended protection against UV-A & UV-B rays.

In embodiments, the present invention relates to topical sunscreen formulations comprising organic UV radiation absorbing agents as active ingredients.

In embodiments, the present invention relates to topical sunscreen formulations comprising avobenzone, oxybenzone, octocrylene, bemotrizinol, and bisoctrizole.

In embodiments, the present invention relates to topical sunscreen formulations comprising avobenzone, oxybenzone, octocrylene, bemotrizinol, bisoctrizole and one or more pharmaceutically acceptable excipients, wherein the formulation has an SPF ranging from 30 to 50 and is effective against UV-A & UV-B rays.

In embodiments, the present invention relates to topical sunscreen formulations that comprise at least one antioxidant, at least one preservative, at least one film-forming agent, at least one non-tacky or non greasy agent.

In embodiments, the present invention relates to topical sunscreen formulations that provide SPF values of 30-50 to an individual using the formulation and active agents comprised in the formulation provide protection from UV radiation above 370 nm.

In embodiments, the present invention relates to topical sunscreen formulations that comprise additional SPF boosters.

In embodiments, the present invention relates to topical sunscreen formulations that are useful for the treatment of melasma, polymorphic light eruption (PMLE), photodamage and for prophylaxis against photoexposure.

In embodiments, the present invention relates to topical sunscreen formulations that are non-oily, cosmetically elegant, not comedogenic and water resistant in nature.

In embodiments, the present invention relates to topical sunscreen formulations having viscosities greater than about 30,000 centipoise and pH values about 5 to about 9.

In embodiments, the present invention relates to topical sunscreen formulations that provide a smooth feel when applied.

In embodiments, the present invention relates to topical sunscreen formulations that are free of fragrances.

In embodiments, the present invention relates to topical sunscreen formulations that are inorganic UV absorbing agents free and do not leave a white residue on the surface of the skin, after application.

In embodiments, the invention includes processes for preparing topical sunscreen formulations, embodiments comprising:

a) preparing an oil phase comprising the active ingredients oxybenzone, octocrylene, avobenzone and bemotrizinol, together with pharmaceutically acceptable excipients;

b) preparing an aqueous phase by combining a chelating agent, humectant and a polymer with water, mixing at temperatures of about 70°C to 80°C and optionally neutralizing the aqueous phase;

c) adding the oily phase to the aqueous phase with stirring, and homogenizing at high speeds;

d) adding an aqueous solution of bisoctrizole to the homogenized emulsion of step c);

e) adding an aqueous solution of a neutralizer to the emulsion obtained in step d); and

(f) mixing the emulsion obtained in step e) under vacuum, and allowing the mass to cool.

In embodiments, the invention includes forms of packaging for the sunscreen formulations, such that the characteristics of the formulations are maintained during storage for commercially relevant times and in packages suitable for commercial sale, which provide stability during storage or transportation.

DETAILED DESCRIPTION

As used herein, the term "avobenzone" includes the compound avobenzone, pharmaceutical^ acceptable salts and esters thereof, and any of polymorphs, solvates and hydrates thereof.

As used herein, the term "oxybenzone" includes the compound oxybenzone, pharmaceutically acceptable salts and esters thereof, and any of polymorphs, solvates and hydrates thereof.

As used herein, the term "octocrylene" includes the compound octocrylene, pharmaceutically acceptable salts and esters thereof, and any of polymorphs, solvates and hydrates thereof.

As used herein, the term "bemotrizinol" includes the compound bemotrizinol, pharmaceutically acceptable salts and esters thereof, and any of polymorphs, solvates and hydrates thereof.

As used herein, the term "bisoctrizole" includes the compound bisoctrizole, pharmaceutically acceptable salts and esters thereof, and any of polymorphs, solvates and hydrates thereof.

The term "pharmaceutically acceptable" refers to substances that are useful in preparing a pharmaceutical composition that are generally non-toxic and is not biologically undesirable, and includes those acceptable for veterinary use and/or human pharmaceutical use.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not a pharmacologically active ingredient, such as a filler, diluent, carrier, etc.

The excipients that are useful in preparing the pharmaceutical composition are generally safe, non- toxic, and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. This includes both one and more than one such excipients.

The term "composition" is intended to encompass a combination including active ingredients and pharmaceutically acceptable excipients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

The terms "formulation" or "dosage form" refer to finished pharmaceutical products that are suitable for administration, including, but not limited to, gels, creams, lotions, etc.

The term "optional" or "optionally" means that the subsequently described element, component or circumstance may or may not be present, so that the description includes instances where the element, component, or circumstance occurs and instances where it does not.

The term "stable" as used herein refers to physical stability and/or chemical stability of the active agent in a topical composition, wherein changes in the drug assay values and/or impurities content are less than about 10%, during stability study storage of the composition at 25°C and 60% relative humidity (RH), or 30°C and 65% RH, or 40°C and 75% RH, for durations such as 3, 6,12,18, or 24 months.

The term "topical administration" is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosa, as in, for example, the treatment of various skin disorders. Topical administration, in contrast to transdermal administration, provides a local rather than a systemic effect. Formulations for topical administration are suitable for use in contact with skin tissue without undue toxicity, incompatibility, instability, or adverse reactions with the skin or the active ingredient, e.g., avobenzone, oxybenzone, octocrylene, bemotrizinol, and bisoctrizole.

"Carrier" or "vehicle," as used herein, refer to carrier materials suitable for topical drug administration. Carriers and vehicles useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of a pharmaceutical formulation or drug delivery system in a deleterious manner. The topical formulations of the present invention are particularly suitable for topical administration. Formulations suitable for topical administration include liquid or semi-liquid preparations. Examples of liquid and semi-liquid preparations include, but are not limited to, topical solutions, liniments, lotions, creams, ointments or pastes and gels. Other topical ingredients used in the topical formulation are generally those commonly used and recognized by persons skilled in the art of topical formulations.

Topical sunscreen formulations of the present invention may contain aqueous or oily solutions or suspensions. They may be prepared by dissolving or dispersing a pharmaceutical active agent in a suitable solvent, which may also contain a bactericidal agent, a fungicidal agent, or any other suitable preservative, and may also include a surface active agent. Suitable solvents for the preparation of an oily solution include, without limitation, glycerol, diluted alcohols, and propylene glycol.

Lotions and liniments include those suitable for topical application to the skin, containing a bactericide. Creams, ointments, and pastes are semi-solid formulations made by mixing the pharmaceutical active with a greasy or non-greasy base. The topical formulation can be in finely-divided or powdered form and may be alone or in a aqueous or non-aqueous solution or suspension or Lotion. The topical formulation may be mixed with the greasy or non-greasy base with the aid of suitable machinery. The base may contain hydrocarbons. Examples of hydrocarbons include, but are not limited to, hard, soft, or liquid paraffins, glycerol, beeswax, metal soaps, mucilages, oils of natural origin (such as almond, corn, arachis, castor or olive oil), wool fat or its derivatives, fatty acids (such as stearic acid or oleic acid), or any combination thereof.

The formulation may also contain a surface active agent, such as an anionic, cationic or non-ionic surfactant. Examples of the surfactants include, but are not limited to, sorbitan esters or polyoxyethylene derivatives thereof (such as polyoxyethylene fatty acid esters) and glyceryl stearate, PEG 100 stearate, and cetyl alcohol.

Pharmaceutically acceptable excipients according to the present invention further include, for example, any one or more of polymers, plasticizers, vehicles or diluents, solvents, viscosity enhancers or thickening or gelling agents, film forming agents, emulsifiers, chelating agents, tonicity agents, wetting agents, neutralizers, non tacky/non greasing agents, anti tacking agents, antioxidants, preservatives, humectants, and any other excipients that are commonly used in topical pharmaceutical dosage form preparations.

Examples of solvents or vehicles useful in this invention include, but are not limited to, isopropyl palmitate, isopropyl myristate, mineral oils, dicapryl carbonate, water, petrolatum, etc.

Examples of emulsifiers useful in this invention include, but are not limited to, glyceryl monostearate, cetyl alcohol, liquid paraffins, lanolin alcohols, sorbitan monostearate (Span™ 60), sorbitan monooleate (Tween™ 80), lecithin, sorbitan monoesters, such as sorbitan monoleate, sorbitan monolaurate, sorbitan monopalmitate, and sorbitan monostearate, polysorbates, such as those prepared from lauric, palmitic, stearic and oleic acids, polysorbate 20, mononylphenyl ethers of polyethylene glycols, such as the monoxynols, polyoxyethylene monoesters, such as polyoxeethylene monostearate, polyoxyethylene monolaurate, and polyoxyethylene monoleate, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, poloxamers having a molecular weight between 2,000 and 8,000, triethanolamine, and ureas such as diazolidinyl urea.

Examples of chelating agents useful in this invention include, but are not limited to sodium and calcium salts of EDTA, such as disodium EDTA and calcium disodium EDTA.

Examples of gelling agents useful in this invention include, but are not limited to, carbomers (Carbopol™ products), polyethylene oxides, ammonium methacrylates, carrageenan, cellulose acetate phthalate aqueous products such as CAPNF from Eastman, carboxymethyl cellulose sodium, carboxy polymethylene, cellulose, cellulose acetates (microcrystalline), cellulose polymers, divinylbenzene styrene copolymers, ethyl celluloses, ethylene vinyl acetate, silicone, potyisobutylene, shellac, guar gum, guar rosin, cellulose derivatives such as hydroxyethyl celluloses, hydroxymethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, carboxymethyl celluloses, and methyl celluloses, hypromellose phthalates (hydroxypropyl methylcellulose phthalate), methyl acrylate, microcrystalline wax, polyvinyl alcohols, polyvinyl acetates, polyvinyl acetate phthalates such as Suretic from Colorcon, polyvinylpyrrolidones (PVP), PVP ethyl celluloses, acrylates, PEG/PVP, xanthan gum, trimethyl siloxysilicate, maleic acid/anhydride copolymers, polacrilin, poloxamers, polyethylene oxides, polyglactic acid/poly-l-lactic acid, terpene resin, locust bean gum, prolamines (e.g., zein), acrylic copolymers, polyurethane dispersions, gelatin (both type A and type B from various sources such as pigs, cattle, and fish), dextrin, starch, polyvinyl alcohol-polyethylene glycol copolymers, methyacrylic acid-ethyl acrylate copolymers such as Kollicoat polymers from BASF, methacrylic acid and methacrylate based polymers, e.g., poly(methacrylic acid) copolymers and methylmethacrylate copolymers, including Eudragit polymers from Evonik Industries (Eudragit E, L, NE, RL, RS, S100), esters of polyvinylmethylether/maleic anhydride copolymers such as Gantrez™ ES-425, Gantrez ES-225 available from ISP, and any mixtures thereof.

Other polymers are also suitable for use as solid gel-forming agents, depending on the solvent vehicle components, the drug, and the specific functional requirements of the given formulation.

Examples of neutralizers useful in this invention include, but are not limited to triethanolamine and other pharmaceutically acceptable neutralizing agents.

Examples of humectants/moisturizers useful in this invention include, but are not limited to: polyhydroxy alcohols such as sorbitol, glycerin, hexanetriol, propylene glycol, hexylene glycol, and the like; polyethylene glycols; sugars and starches; sugar and starch derivatives (e.g., alkoxylated glucose); D-panthenol; hyaluronic acid; lactamide monoethanolamine; acetamide monoethanolamine; 2-pyrrolidone-5-carboxylic acid; urea; and any mixtures thereof.

Examples of film forming agents useful in this invention include, but are not limited to vinyl polymers, eicosene co-polymers, butylated polyvinyl pyrrolidones, vinylpyrrolidone-dimethylaminoethylmethacrylate copolymers, triacontanyl PVP, polyquaternium-55, and any mixtures thereof.

Examples of antioxidants useful in this invention include, but are not limited to butylated hydroxytoluene (BHT), methyl parabens, propyl parabens, butylated hydroxyanisole (BHA), ascorbic acid (Vitamin C), propyl gallate, and alpha-tocopherol (Vitamin E), vitamin E acetate, and any mixtures thereof.

Examples of preservatives useful in this invention include, but are not limited to, alkyl esters of parahydroxybenzoic acid like methylparaben and propylparaben, benzoates, hydantoin derivatives, propionate salts, sorbic acid, benzyl alcohol, imidazolidinyl urea, sodium dehydroacetate, pentylene glycol, o-phenylphenol, sodium o-phenylphenol, chlorocresol, salicylic acid, sodium salicylate, magnesium salicylate, resorcin, chloroxylenol, thymol, triclosan, cresols, benzalkonium chloride, benzethonium chloride, cetylpyridium chloride, benzoic acid, sodium benzoate, sorbic acid, dehydroacetic acid, sodium dehydroacetate, chlorhexidine, chlorhexidine gluconate, chloramine T, triclocarban, iodopropynyl butylcarbanate, chlorobutanol, chlorphenesin, hinokitol, silver chloride, zinc pyrithione, alkyldiaminothylglycine hydrochloride, glycerol caprylate, and any mixtures thereof. Appropriate preservatives can be chosen to satisfy a preservative challenge test and to provide product stability.

Examples of non tacky/anti tacking agents useful in this invention include, but are not limited to aluminum starch octenylsuccinate, talc, aluminum stearate, zinc stearate, magnesium stearate, and any mixtures thereof.

Examples of SPF boosters include, but are not limited to cetyl dimethicone, dimethylsiloxane, polydimethylsiloxane and the like and any mixtures thereof.

The compositions of the present invention may also contain at least one emollient. Useful emollients include, but are not limited to, volatile silicone oils, non-volatile emollients, and mixtures thereof. Examples of volatile silicone oils useful herein include: Dow Corning 344, Dow Corning 345, and Dow Corning 200 (manufactured by Dow Corning Corp.), Silicone 7207 and Silicone 7158 (manufactured by the Union Carbide Corp.), SF 1202 (manufactured by General Electric), and SWS-03314 (manufactured by SWS Silicones, Inc.). Examples of non-volatile emollients include hydrocarbons (e.g., the Permethyl products), propoxylated alcohols, non-volatile silicone oils, and mixtures thereof. Non-volatile silicone oils useful as emollient materials include polyalkylsiloxanes, polyalklyarylsiloxanes, and polyethersiloxane copolymers.

In embodiments of the invention, other additives such as emollients, moisturizers, anti-wrinkle agents, anti-aging compounds, and the like can be included for their cosmetic or protective effects.

In an aspect, the invention includes sunscreen active agents that are UV-radiation absorbers or filters, which can be one or more of the following: avobenzone, oxybenzone, octocrylene, bemotrizinol, and bisoctrizole.

In an aspect, formulations of the invention include the sunscreen agent avobenzone in concentrations about 1 % to 5% by weight of the final formulation.

In an aspect, formulations of the invention include the sunscreen agent oxybenzone in concentrations about 1% to 7% by weight of the final formulation.

In an aspect, formulations of the invention include the sunscreen agent octocrylene in concentrations about 6% to 12% by weight of the final formulation.

In an aspect, formulations of the invention include the sunscreen agent bisoctrizole in concentrations about 4% to 10% by weight of the final formulation.

In an aspect, formulations of the invention include the sunscreen agent bemotrizinol in concentrations about 0.1 % to 6% by weight of the final formulation.

In an aspect, formulations of the invention include an anti-tacky/non-greasing agent in concentrations about 0.5% to 5% by weight of the final formulation.

In embodiments, formulations of the invention comprise bisoctrizole 7%w/w, octocrylene 10%w/w, oxybenzone 3%w/w, avobenzone 2%w/w, and bemotrizinol 5%w/w.

In embodiments, formulations of the invention comprise bisoctrizole 5%w/w, octocrylene 7%w/w, oxybenzone 2%w/w, avobenzone 2%w/w, and bemotrizinol 2%w/w.

In an aspect, the invention includes sunscreen agents as mentioned above which provide extended protection against UV radiation (UV-A and UV-B), e.g., over a broad spectrum of UV ranging from about 200 nm to about 400 nm.

In an aspect, the invention includes sunscreen formulations having viscosities higher than about 30,000 centipoise, or about 30,000 to about 100,000 centipoise.

In an aspect, the invention includes sunscreen formulations having pH values from about 5 to about 8.5, or about 5.5 to about 8.

In an aspect, the invention includes processes for preparing stable topical sunscreen formulations, embodiments comprising:

a) preparing an oil phase by combining glyceryl stearate, PEG 100 stearate, sorbrtan monostearate, isopropyl palmitate, dicaprylyl carbonate, shea butter, vitamin E acetate, cetyl alcohol, cetyl dimethicone and vinyl polymer/eicosene co-polymer and heating to about 70±5°C to form a melt, then sequentially adding octocrylene, oxybenzone, avobenzone, bemotrizinol, methyl paraben, propyl paraben , maintaining the temperature at 70±5°C;

b) preparing an aqueous phase by heating water to about 70±5°C and sequentially adding EDTA, propylene glycol, and carbomer-980, followed by stirring to achieve homogeneity while maintaining 70±5°C and optional neutralization of the aqueous phase;

c) adding the oil phase to the aqueous phase with stirring, followed by homogenizing at high speed;

d) dispersing aluminum starch octenylsuccinate in glycerin, followed by mixing with the material from step c) and cooling the mass to 40°C;

e) dispersing bisoctrizole in water and mixing with the material from step e);

f) dissolving trolamine in water, mixing with the material from step e), homogenizing and applying vacuum for neutralization of the mass; and

g) allowing the mass to cool to 27±3°C, with mixing.

In embodiments, stable topical sunscreen formulations of the present invention further comprise at least one preservative, in concentrations of about 0.1% to about 5% by weight of the total formulation. In embodiments, topical sunscreen formulations of the present invention further comprise at least one viscosity enhancer in concentrations of about 0.01% to about 3% by weight of the total formulation. In embodiments, stable topical sunscreen formulations of the present invention further comprise at least one surfactant, in concentrations of about 0.5% to about 7%, by weight of the total formulation.

In embodiments, stable topical sunscreen formulations of the present invention further comprise at least one humectant, in concentrations of about 5% to about 20%, by weight of the total formulation. In embodiments, the present invention provides stabilized topical sunscreen formulations by incorporation of at least one antioxidant. In embodiments, the content of antioxidant in formulations ranges from about 0.1% to about 5%, by weight of the total formulation.

Sunscreen formulations of the present invention can be part of a kit or device and be filled into tubes, jars, bottles, aerosol containers, and any other forms of packaging that will allow ease of application topically, such as to the face, hands, ears, torso, legs, and any other such superficial location. The formulations are meant to be applied topically, either manually or by using a convenient applicator, for patient compliance and ease of application. The dose, and number and frequency of applications can be decided by a person skilled in the art of treating conditions, such as a physician, a dermatologist, and the like.

In embodiments, the invention includes forms of packaging for the sunscreen formulations, such that UV radiation protecting characteristics of the formulations are maintained during transportation, storage, and use for commercially relevant times (e.g., 6 months, 12 months, 24 months, or intermediate or longer periods). The compositions may be packaged in tubes of glass, polymer, or metal materials. Metal tubes may be made of aluminum or plastics, as they provide ideal barriers for products needing maximum protection and shelf life. A metal tube is advantageous as it is non-porous, light in weight, sanitary, durable, versatile, non-refillable, decorative, easy to handle, has a long shelf life and is adaptable to modern mass production methods and to automatic packaging. It is suited for dispensing controlled portions of medicines.

Laminated tubes also may also be used for packaging. The features and advantages of laminated tubes include ability to retain smoothness, flexibility and softness, increase in product shelf life, excellent barrier properties, excellent sealability, resistance to print bleeding, tamper evident closures with nozzle seals available, and hot foil stamping. In embodiments, the invention provides sunscreen formulations, in packages suitable for commercial sale that provide stability during storage or transportation. The sunscreen formulations of the present invention are intended to provide effective levels of SPF for extended durations of time. HDPE tubes can also be used for packing the sunscreen formulations. Pre-printed monolayer plastic tubes made of 100% HDPE by extrusion processes, with snap-on tamper evident caps or flip top tamper evident caps made up of polypropylene by injection molding processes, are useful.

In vitro SPF values are determined by measuring the diffuse transmission in the UV-range using a Labsphere Ultraviolet Transmittance Analyser.

Certain specific aspects and embodiments of the invention will be explained in more detail with reference to the following examples, being provided only for purposes of illustration, and it is to be understood that the present invention is not deemed to be limited thereto.

EXAMPLE 1: Formulation of sunscreen (SPF 50).

Manufacturing process:

a) An oil phase comprising the active ingredients oxybenzone, octocrylene, avobenzone and bemotrizinol, together with pharmaceutically acceptable excipients was prepared.

b) An aqueous phase was prepared by combining a chelating agent, humectant and a polymer with water, mixing at temperatures about 70°C to 80°C and optional neutralization of aqueous phase.

c) The oily phase was added to the aqueous phase with stirring, and homogenized at high speeds.

d) An aqueous solution of bisoctrizole was added to a homogenized emulsion of step c).

e) An aqueous solution of a neutralizer was added to the emulsion obtained in step d).

(f) The emulsion obtained in step e) under vacuum was mixed, and the mass was allowed to cool.

EXAMPLE 2: Formulation of sunscreen (SPF 50).

Manufacturing process: similar to the process for Example 1. EXAMPLE 3: Formulation of sunscreen (SPF 50).

Manufacturing process: similar to the process for Example 1.

EXAMPLE 4: Formulation of sunscreen (SPF 50).

Manufacturing process: similar to the process for Example 1. EXAMPLE 5: Formulation of sunscreen (SPF 50).

Manufacturing process: similar to the process for Example 1. EXAMPLE 6: Formulation of sunscreen (SPF 50).

Manufacturing process: similar to the process for Example 1. EXAMPLE 7: Formulation of sunscreen (SPF 50).

Manufacturing Process: similar to the process for Example 1. EXAMPLE 8: Formulation of sunscreen (SPF 50).

Manufacturing process: similar to the process for Example 1.

The prepared formulations, filled into closed containers, were exposed to the stability testing conditions of 25°C and 60% relative humidity (RH), 30°C and 65% RH, and 40°C and 75% RH, for one, two, three and six months, and analysis at various storage points was carried out. Results are shown in Table 1, where the values are percentages of the label ingredient content. In the table, "OBE" is oxybenzone, "OCT" is octocrylene, "AVB" is avobenzene, "BOZ" is bisoctrizole, and "BTZ" is bemotrizanol.

EXAMPLE 9: Formulation of sunscreen (SPF 30).

Manufacturing process: similar to the process for Example 1. EXAMPLE 10: Formulation of sunscreen (SPF 30).


Manufacturing process: similar to the process for Example 1.

The prepared formulations, filled into closed containers, were exposed to the stability testing conditions 25°C and 60% relative humidity (RH), 30°C and 65% RH, and 40°C and 75% RH, for one and three months, and analysis at various storage points are shown in Table 2, where the values are percentages of the label ingredient content.

Table 2:

We claim:

1. A topical sunscreen formulation comprising avobenzone, oxybenzone, octocrylene, bemotrizinol, bisoctrizole and one or more pharmaceutically acceptable excipients, wherein the formulation has an SPF ranging from 30 to 50 and is effective against UV-A & UV-B rays.

2. The topical sunscreen formulation of claim 1, wherein: avobenzone is in the range from about 1% to about 5% w/w; oxybenzone is in the range from about 1% to about 7% w/w; octocrylene is in the range from about 6% to about 12% w/w; bemotrizinol is in the range from about 0.1% to about 6% w/w; and bisoctrizole is in the range from about 4% to about 10% w/w.

3. The sunscreen formulation according to claims 1 or 2, wherein excipients include one or more surfactants, one or more preservatives, one or more film-forming agents, one or more non-tacky agents or non greasy agents, one or more solvents, and one or more SPF boosters.

4. The sunscreen formulation according to claim 3, wherein: a surfactant comprises one or more of glyceryl stearate, PEG 100 stearate, and cetyl alcohol; a preservative comprises one or more of methyl paraben, propyl paraben, and sodium benzoate; a film-forming agent comprises one or more of vinyl polymers, eicosene co-polymers, and butylated polyvinylpyrrolidones; a non-tacky agent or non greasy agent comprises one or both of aluminum starch octenylsuccinate and aluminum stearate; a solvent comprises one or more of isopropyl palmitate, dicaprylyl carbonate, and propylene glycol, and a SPF booster comprises one or more of cetyl dimethicone, dimethylsiloxane, and polydimethylsiloxane.

5. The sunscreen formulation according to any of claims 1-4, wherein the composition is fragrant free and inorganic sunscreen agents free.

6. The sunscreen formulation according to any of claims 1-5, wherein the composition is in the form of an emulsion.

7. The sunscreen formulation according to any of claims 1-6, wherein the formulation comprises bisoctrizole about 7%w/w, octocrylene about 10%w/w, oxybenzone about 3%w/w, avobenzone about 2%w/w, and bemotrizinol about 5%w/w.

8. The sunscreen formulation according to any of claims 1-6, wherein the formulation comprises bisoctrizole about 5%w/w, octocrylene about 7%w/w, oxybenzone about 2%w/w, avobenzone about 2%w/w, and bemotrizinol about 2%w/w.

9. A process for preparing topical sunscreen formulations, the process comprising:

a) preparing an oil phase comprising the active ingredients oxybenzone, octocrylene, avobenzone, and bemotrizinol, together with one or more pharmaceutically acceptable excipients;

b) preparing an aqueous phase by combining a chelating agent, humectant and polymer with water, mixing at temperatures at about 70°C to 80°C and optionally adjusting the pH to a neutral value;

c) combining the oily phase of step a) with the aqueous phase of step b), with stirring, and homogenizing at high speeds;

d) adding an aqueous solution of bisoctrizole to a homogenized emulsion of step c);

e) adding an aqueous solution of a neutralizer to the emulsion obtained in step d); and

(f) mixing the emulsion obtained in step e) under vacuum, and allowing the mass to cool.

10. The sunscreen formulation comprising avobenzone, oxybenzone, octocrylene, bemotrizinol, bisoctrizole and one or more pharmaceutically acceptable excipients, substantially as described and illustrated herein.