WO2022190030A1 - A topical formulation for the treatment of skin diseases - Google Patents
A topical formulation for the treatment of skin diseases Download PDFInfo
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- WO2022190030A1 WO2022190030A1 PCT/IB2022/052152 IB2022052152W WO2022190030A1 WO 2022190030 A1 WO2022190030 A1 WO 2022190030A1 IB 2022052152 W IB2022052152 W IB 2022052152W WO 2022190030 A1 WO2022190030 A1 WO 2022190030A1
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- YXHRQQJFKOHLAP-FVCKGWAHSA-M sodium;2-[[(4r)-4-[(3r,5r,8r,9s,10s,12s,13r,14s,17r)-3,12-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 YXHRQQJFKOHLAP-FVCKGWAHSA-M 0.000 description 1
- BRMSVEGRHOZCAM-UHFFFAOYSA-M sodium;2-dodecanoyloxyethanesulfonate Chemical compound [Na+].CCCCCCCCCCCC(=O)OCCS([O-])(=O)=O BRMSVEGRHOZCAM-UHFFFAOYSA-M 0.000 description 1
- UAJTZZNRJCKXJN-UHFFFAOYSA-M sodium;2-dodecoxy-2-oxoethanesulfonate Chemical compound [Na+].CCCCCCCCCCCCOC(=O)CS([O-])(=O)=O UAJTZZNRJCKXJN-UHFFFAOYSA-M 0.000 description 1
- CRPCXAMJWCDHFM-UHFFFAOYSA-M sodium;5-oxopyrrolidine-2-carboxylate Chemical compound [Na+].[O-]C(=O)C1CCC(=O)N1 CRPCXAMJWCDHFM-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940100459 steareth-20 Drugs 0.000 description 1
- 229940073743 steareth-20 methacrylate Drugs 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000003351 stiffener Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 230000036561 sun exposure Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 239000010677 tea tree oil Substances 0.000 description 1
- 229940111630 tea tree oil Drugs 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- ICUTUKXCWQYESQ-UHFFFAOYSA-N triclocarban Chemical compound C1=CC(Cl)=CC=C1NC(=O)NC1=CC=C(Cl)C(Cl)=C1 ICUTUKXCWQYESQ-UHFFFAOYSA-N 0.000 description 1
- 229960001325 triclocarban Drugs 0.000 description 1
- 229960003500 triclosan Drugs 0.000 description 1
- 229940057400 trihydroxystearin Drugs 0.000 description 1
- UUJLHYCIMQOUKC-UHFFFAOYSA-N trimethyl-[oxo(trimethylsilylperoxy)silyl]peroxysilane Chemical compound C[Si](C)(C)OO[Si](=O)OO[Si](C)(C)C UUJLHYCIMQOUKC-UHFFFAOYSA-N 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 229960000314 zinc acetate Drugs 0.000 description 1
- 235000013904 zinc acetate Nutrition 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 229940043825 zinc carbonate Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 229960001939 zinc chloride Drugs 0.000 description 1
- 239000011746 zinc citrate Substances 0.000 description 1
- 235000006076 zinc citrate Nutrition 0.000 description 1
- 229940068475 zinc citrate Drugs 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 229940012185 zinc palmitate Drugs 0.000 description 1
- LRXTYHSAJDENHV-UHFFFAOYSA-H zinc phosphate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LRXTYHSAJDENHV-UHFFFAOYSA-H 0.000 description 1
- 229910000165 zinc phosphate Inorganic materials 0.000 description 1
- 229940077935 zinc phosphate Drugs 0.000 description 1
- 229940100142 zinc pidolate Drugs 0.000 description 1
- 229940043810 zinc pyrithione Drugs 0.000 description 1
- OWVLYQRCCIEOPF-QHTZZOMLSA-L zinc;(2s)-5-oxopyrrolidine-2-carboxylate Chemical compound [Zn+2].[O-]C(=O)[C@@H]1CCC(=O)N1.[O-]C(=O)[C@@H]1CCC(=O)N1 OWVLYQRCCIEOPF-QHTZZOMLSA-L 0.000 description 1
- PICXIOQBANWBIZ-UHFFFAOYSA-N zinc;1-oxidopyridine-2-thione Chemical compound [Zn+2].[O-]N1C=CC=CC1=S.[O-]N1C=CC=CC1=S PICXIOQBANWBIZ-UHFFFAOYSA-N 0.000 description 1
- VIFYIFQGOLPNHA-UHFFFAOYSA-L zinc;dioxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [Zn+2].[O-]S([O-])(=O)=S VIFYIFQGOLPNHA-UHFFFAOYSA-L 0.000 description 1
- GJAPSKMAVXDBIU-UHFFFAOYSA-L zinc;hexadecanoate Chemical compound [Zn+2].CCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCC([O-])=O GJAPSKMAVXDBIU-UHFFFAOYSA-L 0.000 description 1
- ZPEJZWGMHAKWNL-UHFFFAOYSA-L zinc;oxalate Chemical compound [Zn+2].[O-]C(=O)C([O-])=O ZPEJZWGMHAKWNL-UHFFFAOYSA-L 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
Definitions
- the present disclosure generally relates to the field of topical compositions.
- the present disclosure provides a topical formulation that includes zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof.
- the compositions of the present disclosure may find utility in treatment of rashes and skin conditions/diseases.
- Skin infections are common and may be caused by bacteria, fungi or viruses. Breaks in the skin integrity, particularly those that inoculate pathogens into the dermis, frequently cause or exacerbate skin infections. Bacterial skin infections caused by corynebacteria, staphylococci, streptococcal skin infections, and human papillomavirus skin infections. The many dermatomycoses (skin infections caused by fungi or yeasts), onychomycosis and Candida infections occur in moist areas, such as the vulva, mouth, penis, skinfolds and diaper area.
- Infections by bacteria, viruses, or fungi can also cause a rash. These rashes vary depending on the type of infection. For instance, candidiasis, a common fungal infection, causes an itchy rash that generally appears in skin folds. Whereas diaper rash is often caused by irritation to the skin due to contact withcan, stool, and detergent. Sometimes it can be caused by yeast infections, bacterial infections, or even due to an allergy to diaper material.
- Zinc alone or as an adjuvant, has been found useful in many dermatological infections owing to its modulating actions on macrophage and neutrophil functions, natural killer cell/phagocytic activity, and various inflammatory cytokines. Although numerous compositions have been reported so far, they suffer from one or more shortcomings, particularly, from the perspective of preventing and/or treating skin conditions/disorders.
- One of the objects of the present disclosure is to provide a composition that may overcome the limitations associated with the conventional compositions.
- Another object of the present disclosure is to provide a composition that exhibits superior storage stability and functional reciprocity.
- Further object of the present disclosure is to provide a composition that is easy to prepare and is economical.
- Yet another object of the present disclosure is to provide a composition that finds utility in treatment for a wide variety of skin diseases/conditions.
- Still another object of the present disclosure is to deliver the active agents either simultaneously or concurrently or concomitantly to a subject for treatment of the skin disease.
- the present invention provides novel pharmaceutical compositions comprising compounds of the invention suitable formulated for treating skin diseases resulting from skin inflammation, infections, allergy and other related pathogenesis thereof.
- the present invention is directed to pharmaceutical compositions, comprising compound of formula I or a pharmaceutically acceptable Zinc salt, derivative thereof,
- RH independently represents oxide, undecyclenate, pyrithione, acetate, carbonate, lactate, chloride, bromide, malonate, oxalate, tartarate, citrate, pidolate, phosphate, nitrate, sulphate, thiosulphate, palmitate, gluconate, acetate, carnosine, Mg +2 , magnesium oxide, magnesium stearate, magnesium silicate, magnesium sulphate, magnesium chloride, magnesium bromide, magnesium acetate, magnesium lactate, magnesium pidolate, magnesium thiosulphate, magnesium sulphate, Ag + , silver oxide, silver lactate, silver chloride, silver bromide, silver pidolate, silver phosphate, silver nitrate, silver sulphate, silver thiosulphate, tetra-silver tetra-oxide, Cu +2 , copper sulfate pentahydrate, copper sulfate, copper malonate, copper citrate
- the present invention is directed to pharmaceutical compositions, comprising compound of formula II or a pharmaceutically acceptable salt, derivative, prodrug thereof,
- Ri, R2, R3 independently represents lauric acid (C12:0), monoglycerides [MG], monocaprin (MG C10:0), glycerol monolaurate (MG 02:0), oleic acid (08:1), elaidic acid (trans-C18:l), linoleic acid (08:2), linolenic acid (08:3), monocaprylate, monooleate, myristoleic acid, glycerol monocaprylate, C8:0, 00:0, 02:0, 04:0, 06:0, 08:0, 08:1, trans-08:l, 08:2, 08:3, C6:0, C8:0, 00:0, 02:0, 04:0, 06:0, 08:0, 04:1, 06:1, 08:1, trans-C18:l, 08:2, trans-C18:2, 08:3, C20:4, [MGs] 00:0, 02:0, 01:0, 02:0, 03:0,
- RH independently represents zinc Oxide, Zn +2 , zinc undecyclenate, zinc pyrithione, zinc acetate, zinc carbonate, zinc lactate, zinc chloride, zinc bromide, zinc malonate, zinc oxalate, zinc tartarate zinc citrate, zinc pidolate, zinc phosphate, zinc nitrate, zinc sulphate, zinc thiosulphate, zinc palmitate e, Mg +2 , magnesium oxide, magnesium stearate, magnesium silicate, magnesium sulphate, magnesium chloride, magnesium bromide, magnesium acetate, magnesium lactate, magnesium pidolate, magnesium thiosulphate, magnesium sulphate, Ag + , silver oxide, silver lactate, silver chloride, silver bromide, silver pidolate, silver phosphate, silver nitrate, silver sulphate, silver thiosulphate, tetra-silver tetra-oxide, Cu +2 , copper sulfate pentahydrate, copper
- the pharmaceutical composition comprises of dilaurylglyceryl fumarate (DGLF) a compound of formula II or a pharmaceutically acceptable salt, or a hydrate or a solvate or a prodrug thereof, as an active agent which treats an inflammatory-related condition along with one or more anti-irritant agents; antiseptic agent, emollients/ moisturizing agent, emulsifier, solvents, co-solvent pH modifier and other pharmaceutical acceptable carrier or excipient is used in the topical formulation.
- DGLF dilaurylglyceryl fumarate
- DGLF dilaurlglyceryl fumarate
- DGLS dilaurylglyceryl succinate
- DGLC dilauryl glyceryl caprylate
- the present invention provides a composition for treatment for a wide variety of skin diseases and inflammation.
- the composition when applied to affected skin, provides protection from the exogenous factor which flare up the skin inflammation, smother the affected skin, promote the healing process, improves the pH of the skin and skin flora and thus helps in restoration and regeneration of the skin barrier within short period of application.
- the pharmaceutical composition is used for treating skin disorders caused by skin inflammation due to exogenous and endogenous factors.
- Skin disorders include dermatitis mainly contract dermatitis, allergic dermatitis, diaper or napkin rashes in adult and babies, psoriasis and pruritus.
- kits comprising the pharmaceutical compositions disclosed herein.
- the kit may comprise instructions related to use of the composition for treating and preventing skin inflammation and diseases such as hyperpigmentation, dermatitis mainly contract dermatitis, allergic dermatitis, diaper or napkin rashes in adult and babies, psoriasis and pruritus.
- an active agent or “a therapeutic agent” refers not only to a single active agent but also to a combination of two or more different active agents
- a dosage form refers to a combination of dosage forms as well as to a single dosage form, and likes, or any combinations thereof.
- formulation refers to the drug/active ingredient in combination with one or more additional other agents and pharmaceutically acceptable excipients. This term includes orally administrable formulations as well as formulations administrable by other means.
- compositions that can be administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
- pharmaceutically acceptable refers to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U S. Food and Drug administration
- “Pharmacologically active” as in a pharmacologically active derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
- active agent or “therapeutic agent”, encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
- active agent or “therapeutic agent” includes compounds of Formula I or formula II, and pharmaceutically acceptable salts, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such compounds of formula I and formula II as used in the present pharmaceutical composition can be present in the form of pharmaceutically acceptable salts, esters, (i.e., the methyl and ethyl esters of the acids of compound to be used as prodrugs, solvated, hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound.
- Non-limiting examples of compound of formula II includes:
- DGLF dilaurylglyceryl fumarate
- DGLS dilaurylglyceryl succinate
- DGLC dilauryl glyceryl caprylate
- skin disorder areas refereed herein include skin conditions such as dermatitis, allergic contact dermatitis, psoriasis, diaper rash, eczema, and skin injuries/damage by wounds, burns, and fecal and urinary incontinence.
- These Human skins pH value is very important factor and it is somewhere between 4.5 and 6. In case of a newborn baby's skin and older adults the pH is neutral (pH 7). Skin disorders are reported when the pH value goes into the alanine range.
- the present disclosure generally relates to the field of topical compositions.
- the present disclosure provides a topical formulation that includes zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof.
- the compositions of the present disclosure may find utility in treatment of rashes and skin conditions/diseases.
- the present disclosure generally relates to the field of topical compositions.
- An aspect of the present disclosure provides a composition including: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof.
- the composition is formulated as a topical formulation.
- the composition comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1:1 to 10:1.
- the composition comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1:1 to 7: 1.
- the composition further comprises an active agent selected from: a topical antibacterial agent, a topical antifungal agent, a topical steroid, a vitamin or derivatives thereof, an amino acid or derivatives thereof, a fatty acid or derivatives thereof and combinations thereof.
- an active agent selected from: a topical antibacterial agent, a topical antifungal agent, a topical steroid, a vitamin or derivatives thereof, an amino acid or derivatives thereof, a fatty acid or derivatives thereof and combinations thereof.
- the composition further comprises an excipient.
- the excipient can be any or a combination of: a diluent, an emollient, a humectant, a preservative, a solvent, natural oils, essential oils, a fragrance, a fatty acid or derivative thereof, an amino acid or metabolite or derivative thereof, a surfactant, a solubilizer and a stabilizer.
- the composition is formulated as a topical cream formulation.
- the composition comprises: zinc salt in an amount ranging from 1% w/v to 35% w/v; dexpanthenol or salt or hydrate or solvate thereof in an amount ranging from 1% w/v to 20% w/v; an emollient in an amount ranging from 10% to 40% w/w; a humectant in an amount ranging from 5% to 30% w/w; a surfactant in an amount ranging from 2% to 30% w/w; and water in an amount ranging from 10% w/v to 60% w/v.
- the emollient is selected from white petrolatum, mineral oil, light mineral oil, isopropyl myristate, cetyl alcohol, beeswax, white beeswax, paraffin wax, hard paraffin wax, cetomacrogol, sumac wax, polawax shea butter and combinations thereof.
- the humectant is selected from glycerin, glycerol, propylene glycol, butylene glycol, sorbitol, polyethylene glycol, coconut oil, olive oil, jojoba oil, super refined castor oil and combinations thereof.
- the surfactant is selected from Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, Span 20, Span 40, Span 60, Span 80, lauramide DEA, cocamide DEA, cocamide MEA, glyceryl monostearate, stearic acid, polyethylene glycol ether of cetearyl alcohol, cetostearyl alcohol, lauroyl polyoxyl-32 glycerides, fatty alcohols, glycerol monooleate, glyceryl monostearate, emulsifying wax and combinations thereof.
- the composition further comprises a preservative in an amount ranging from 0.03% to 5% w/w. In an embodiment, the composition further comprises an antioxidant in an amount ranging from 0.03% to 5% w/w. In an embodiment, the composition further comprises a skin penetration enhancer in an amount ranging from 0.1% to 5% w/w.
- Another aspect of the present disclosure provides a method of preparing a topical formulation, said formulation comprising zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof, the method comprising the steps of: (a) melt mixing an emollient, a humectant and a first surfactant to prepare a water immiscible phase; (b) preparing a zinc salt dispersion by mixing zinc salt and a second surfactant in water having temperature ranging from 55°C to 90°C; (c) mixing the water immiscible phase with the zinc salt dispersion to obtain a uniform semisolid mixture; (d) preparing a dexpanthenol solution by dissolving dexpanthenol in water; (e) adding the dexpanthenol solution to the semisolid mixture upon the semisolid mixture reaching at a room temperature ranging from 20°C to 50°C with stirring to obtain a uniform mixture; (f) optionally, mixing any or a combination
- the advantageous topical formulations of the present disclosure form a layer on the skin, wherein zinc salt exhibits anti-infective property, while dexpanthenol exhibits healing property and accordingly, the formulations of the present disclosure can find utility in treatment of a wide variety of skin conditions/diseases/disorders.
- combination therapy or “combined treatment” or “in combination” as used herein denotes any form of concurrent or concomitantly or co-administration of active agents for treating wide varieties of skin diseases/conditions such as rashes, candidiasis, diaper rash and the likes.
- moistureturizers can be 3 types such as humectants, emollients, and occlusive.
- viscosity modifiers means to change the thickness or texture of pharmaceutical ingredients. Viscosity modifiers, include thickeners, texturizers, gelation agents and stiffening agents Some viscosity modifiers can be used to convert liquids to gels, pastes or powders. A viscosity modifier decreases the thickness of a liquid to improve pour ability and ultimately make it more palatable.
- treating and “treatment” as used herein refers to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage caused thereby.
- “treating” a subject/patient as described herein encompasses treating a wide variety of skin conditions such as rashes, candidiasis, diaper rash and the likes, which may be caused by allergens or organisms (like bacteria, virus, fungi etc.).
- Diaper rash is the most common form of contact dermatitis in childhood. Occlusion of the groin with diapers allows increased concentration of moisture in the area eventually leading to the breakdown of the underlying skin.
- the skin in the diaper area is predisposed to irritation by the prolonged contact with irritants, such as urine and feces, as well as by diaper occlusion, which leads to an increase in hydration and skin pH.
- diaper rash is usually mild and transient, bacteria or fungi sometimes invade the damaged skin, causing a severe diaper rash requiring medical evaluation and treatment especially in adults who are bed ridden.
- Skin infections are common and may be caused by bacteria, fungi or viruses. Breaks in the skin integrity, particularly those that inoculate pathogens into the dermis, frequently cause or exacerbate skin infections. Bacterial skin infections caused by corynebacteria, staphylococci, streptococcal skin infections, and human papillomavirus skin infections. The many dermatomycoses (skin infections caused by fungi or yeasts), onychomycosis and Candida infections occur in moist areas, such as the vulva, mouth, penis, skm folds and diaper area. [00052] Infections by bacteria, viruses, or fungi can also cause a rash. These rashes vary depending on the type of infection.
- candidiasis a common fungal infection, causes an itchy rash that generally appears in skm folds. Whereas diaper rash is often caused by irritation to the skin due to contact with urine, stool, and detergent. Sometimes it can be caused by yeast infections, bacterial infections, or even due to an allergy to diaper material.
- dosage form denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to elicit a desired therapeutic response.
- controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate.
- controlled release includes sustained release, non-immediate release and delayed release formulations.
- sustained release (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time.
- compositions and formulations of the present disclosure can afford a unique treatment option for a wide variety of skin conditions/disorders, and particularly, for treating diaper rash, wherein zinc salt exhibits anti-infective property, antioxidant, anti-inflammatory properties and forms a protective barrier, while dexpanthenol exhibits healing property, provides moistures, hydration, prevents loss of moisture from skin. Dermatological effects of the topical use of dexpanthenol increases fibroblast proliferation and accelerates re-epithelialization in wound healing. Accordingly, the compositions of the present disclosure including zinc salt and dexpanthenol exhibit strong functional reciprocity and synergy.
- the composition may include calamine with dexpanthenol or calamine in combination with zinc salt or calamine in combination with zinc salt and dexpanthenol and with one or more excipients.
- Calamine protects the skin and acts as astringent and soothing agent that helps in relieve itching. They also slow down bacterial growth, and prevent manifestation of infection.
- Camphor, menthol, pramoxine, zinc salt are other known soothing agents.
- An aspect of the present disclosure provides a composition including: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof.
- the composition is formulated as a topical formulation.
- composition of the present disclosure comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1 : 1 to 10: 1.
- the composition of the present disclosure comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1:1 to 7: 1.
- the composition of the present disclosure comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1.5 : 1 to 5 : 1.
- the composition of the present disclosure comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1.5:1 to 4 : 1.
- the composition comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio of about 4: 1.
- the composition comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio of about 2: 1.
- Present invention provides topical composition for treating skin diseases comprising zinc oxide, a micronutrient that participates in various cellular functions and in wound repair. It also help in the reduction in overall severity of signs and symptoms, particularly blistering, soreness, itching, and tingling, sensation in skin disorders.
- Zn is trace element abundantly present in skin with a concentration gradient from the upper stratum corneum layer to the basal layer, Zn it is important metal for the maintenance of healthy skin and wound healing.
- Zinc is auto debridement, anti-infective action, and promotion of epithelialization, zinc salt enhances re-epithelialization of wounds and the mode of delivery of zinc is probably critical for achieving the beneficial healing effect of zinc.
- the composition of the present invention comprising zinc salt and dexpanthenol is effective in the management of skin rashes, candidiasis, diaper rashes and other skin allergies and skin infection.
- the composition has antioxidant, anti-inflammatory, anti-androgenic, photo- protective, anti-ageing, and antibacterial properties. It supports in re epithelialization, elastic regenerative and would healing.
- the composition improves the integrity of stratum corneum, and reduces water loss from skin to maintaining it softness and elasticity. Further, the composition increases fibroblast proliferation which accelerated re-epithelialization in wound healing. Furthermore, the composition acts as a topical protectant and provides moisturizer to the skin.
- dexpanthenol leads to increased mobility of stratum corneum molecular components. Specifically, dexpanthenol interacts with lipid segments of the extracellular lamellae and protein residues in the corneocytes in stratum corneum and thus compensates for reduced hydration by retaining/increasing molecular fluidity.
- Other active agents used in the composition such as amino acids, vitamins, sun blocks, sun screen, antimicrobial agents, steroid, and fatty acids fastens the wound healing, prevents photo damage and skin ageing, inhibit microbial growth in the skin, and fastens wound healing process.
- immunosuppressant phosphodiesterase (PDE) inhibitors, anti-inflammatory agent, Janus kinase (JAK) Inhibitor
- PDE phosphodiesterase
- JK Janus kinase
- composition suppress the inflammatory components responsible for flaring up of allergic symptoms associated with skin rashes and skin infections.
- topical agents create a protective barrier over the skin and reduce the impact of external irritants thus are more effective than monotherapy.
- Cysteamme an aminothiol compound physiologically synthetized in human body cells, is known as depigmentmg agent. Skin hyperpigmentation is caused by an excessive production of melanin.
- Composition comprising cysteamine when applied topically it can scavenge free radicals and lighten skin that’s been darkened as a result of post-inflammatory hyperpigmentation, sun exposure and melasma.
- Composition comprising calamine soothes the skin irritation.
- the composition further comprises an active agents selected from: topical antibacterial agent, topical antifungal agent, topical steroid, immunosuppressant, PDE inhibitors- (PDE 4, PDE 3 and PDE 5), JAK Inhibitor, sun blocks/UV-filters, vitamin or derivatives thereof, an amino acid or derivatives thereof, a fatty acid or derivatives thereof and combinations thereof.
- an active agents selected from: topical antibacterial agent, topical antifungal agent, topical steroid, immunosuppressant, PDE inhibitors- (PDE 4, PDE 3 and PDE 5), JAK Inhibitor, sun blocks/UV-filters, vitamin or derivatives thereof, an amino acid or derivatives thereof, a fatty acid or derivatives thereof and combinations thereof.
- non-limiting examples of suitable topical steroidal agents include corticosteroids, hydrocortisone, hydroxyltriamcinolone, alphamethyl, dexamethasone, dexamethasone-phosphate, beclomethasone, dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone, diacetate, diflucortolone, valerate, fluadrenolone, fluclarolone, acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocmonide, flucortine, butylester, fluocortolone, fluprednidene (fluprednylidene)acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocor
- non-limiting examples of topical antifungal include miconazole, econazole, ketoconazole, sertaconazole, itraconazole, voriconazole, clioquinol, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, saperconazole, clotrimazole, haloprogin, butenafine, tolnaftate, nystatin, amorolfme, naftifine, griseofulvin, cysteamine hydrochloride and their pharmaceutically acceptable salts and prodrugs thereof.
- non- limiting examples of immunosuppressants include Azathioprine, Mycophenolic acid, Leflunomide, Teriflunomide, Ciclosporin, Pimecrolimus, tacrolimus, voclosporin, lenalidomide, pomalidomide, thalidomide, apremilast, sirolimus, everolimus, ridaforolimus, temsirolimus, umirolimus, zotarolimus, baricitinib, blisibimod, nilotinib, filgotinib, tofacitimb, upadacitimb, abatacept, belatacept, etanercept pegsunercept, aflibercept, alefacept, rilonacept and their pharmaceutically acceptable salts and prodrugs thereof.
- non-limiting examples of PDE 4 inhibitors include apremilast, arofylline, atizoram, benafentrine, catramilast, CC-1088, CDP-840, CGH-2466, cilomilast, cipamfylline, crisaborole, denbutylline, difamilast, drotaverine, etazolate, filaminast, glaucine, HT- 0712, ICI-63197 indimilast, irsogladine, lavamilast, lirimilast, lotamilast, luteolin, mesierinone, mesembrine, mesopram, oglemilast, piclamilast, pumafentrine, revamilast, Ro 20-1724, roflumilast, rolipram, ronomilast, RPL-554, RS-25344, tetomilast, tofimilast,
- non-limiting examples of PDE 3 Inhibitors include Adibendan, amrinone (inamrinone), anagrelide, benafentrine, bucladesine, carbazeran, cilostamide, cilostazol, enoximone, imazodan, KMUP-1, meribendan, milrinone, olprinone, parogrelil , pimobendan, pumafentrine , quazinone, RPL-554, siguazodan, trequinsin, vesnarinone, zardaverine and their pharmaceutically acceptable salts and prodrugs thereof.
- non-limiting examples of PDE 5 Inhibitors include PDE 5 inhibitors acetildenafil, aildenafil, avanafil, beminafil, benzamidenafil, dasantafil, icariin, gisadenafil, homosildenafil, lodenafil, mirodenafil, MY-5445, Nitrosoprodenafil, Norcarbodenafil, SCH-51866, Sildenafil, Sulfoaildenafil, T-0156, Tadalafil, Udenafil, Vardenafil and their pharmaceutically acceptable salts and prodrugs thereof.
- JAK Inhibitor examples include abrocitinib, baricitinib, filgotinib, momelotinib, oclacitinib, peficitinib, ruxolitinib, tofacitinib, tasocitinib, CP- 690550, upadacitinib, atiprimod, AZD-1480, baricitinib, chz868, cucurbitacin i (elatericin B, JSI- 124) CYT387 lestaurtimb, NSC-7908, NSC-33994, pacritmib, peficitinib, ruxolitinib, SD-1008, cercosporamide, decernotinib (VX-509), peficitinib, TCS-21311, WHI-P 15 ZM-39923, ZM- 449829 and their pharmaceutically acceptable salts and prodrugs
- sun blocks/UV-filters p-Aminobenzoic acid, padimate O, phenylbenzimidazole sulfonic acid, cinoxate, dioxybenzone, oxybenzone, homosalate, menthyl anthramlate, octocrylene, octyl methoxycmnamate, octyl salicylate, sulisobenzone, trolamine salicylate, avobenzone, ecamsule, titanium dioxide, zinc salt and their pharmaceutically acceptable salts and prodrugs thereof.
- vitamins include: vitamin A and their derivatives retinol, retinaldehyde, retinyl esters, oxoretinoids, retinyl palmitate and retinyl acetate, vitamin C and their derivatives L-ascorbic acid, ascorbyl palmitate, and magnesium ascorbyl phosphate, Vitamin B3/Niacinamide and their derivatives, vitamin B-5 /pantothenic acid and their derivatives, Vitamin E / a-tocopherol and their derivatives, Vitamin K/phytonadione and their derivatives, calciferols and their derivatives, or a combination thereof.
- non-limiting examples of antimicrobial ag ents include: chlorhexidine salts, such as iodopropynyl formic acid fourth, double imidazoles ureine, chlorhexidine gluconate, chlorhexidine acetate, isethionic acid chlorhexidine and hydrochloric acid chlorhexidine, benzalkonium chloride, butyl hydroxytoluene, benzethonium chloride, triclocarban, poly hexamethylene biguanide, hexadecylpyridinium chloride, methylbenzethonium chloride, halogenated phenolic resin, triclosan, parachlorometaxylenol, ethyl alcohol, propyl alcohol or a combination thereof.
- chlorhexidine salts such as iodopropynyl formic acid fourth, double imidazoles ureine, chlorhexidine gluconate, chlorhexidine acetate, isethionic acid
- non-limiting examples of amino acid derivatives or metabolites include: nor-leucine, nor- valine, L-alloisoleucine, L-threoisolucine D, L, or DL-leucine-containing di- and tri-peptides, D,L, or DL- valine-containing di- and tri-peptides, D,L, or DL-isoleucme-containing di- and tri-peptides, nitrogen-free analogues of branched chain amino acids, branched chain alpha-keto acids, isovaleryl-CoA, isovalerylcamitine, isovaleryglycine, isovaleric acid, beta-methylcrotonyl- CoA, beta-methylcrotonylcarnitine, beta-methylcrotonylglycine, beta-methylcrotonic acid, beta- methylglutaconyl-CoA, beta-methylglutaconylcarnitine, beta-methylglutaconylglyc
- the composition includes an excipient.
- the excipients can be any or a combination of: a diluent, an emollient, a humectant, a preservative, a solvent, a fragrance, a fatty acid or derivative thereof, an ammo acid or metabolite or derivative thereof, a surfactant, a solubilizer and a stabilizer.
- the composition may be formulated as a semi-solid or liquid dosage form.
- dosage forms includes suspension, solution, emulsion, cream, ointment, lotion, gel and the likes.
- the composition is formulated as a topical cream formulation.
- the composition comprises: zinc salt in an amount ranging from 1% w/v to 35% w/v; dexpanthenol or salt or hydrate or solvate thereof in an amount ranging from 1% w/v to 20% w/v; an emollient in an amount ranging from 10% to 40% w/w; a humectant in an amount ranging from 5% to 30% w/w; a surfactant in an amount ranging from 2% to 30% w/w; and water in an amount ranging from 10% w/v to 60% w/v.
- the composition of the present disclosure comprises an emollient in an amount ranging from 12% to 35% w/w. In an alternative embodiment, the composition of the present disclosure comprises an emollient in an amount ranging from 15% to 30% w/w.
- Non- limiting examples of emollient includes, PPG- 15 stearyl ether, lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, octyl stearate, mineral oil, isocetyl stearate, isopropyl myristate, cetyl alcohol, beeswax, paraffin wax, sumac wax, shea butter, Ceraphyl 424 (myristyl myristate), octyl dodecanol, dimethicone (Dow Corning 200-100 cps), phenyl trimethicone (Dow Corning 556), Dow Coming 1401 (cyclomethicone and dimethiconol), and cyclomethicone (Dow Corning 344), and Miglyol 840 (manufactured by Huls; propylene glycol dicaprylate/dicaprate) and combinations thereof.
- the emollient is selected from white petrolatum, mineral oil, isopropyl myristate, cetyl alcohol, beeswax, paraffin wax, sumac wax, shea butter and combinations thereof.
- Emollients are also soothing agents which are rapidly absorbed into the skm and are often used in hair-covered areas.
- Antimicrobial activity of a given essential oil may depend on one or two of the major constituents.
- the ratio in which the main active constituents are present may not be the only factor responsible for the inherent activity of essential oils, but the interactions between these and minor constituents in the oils are also important.
- Essential oils possess important volatile compounds with diverse bioactivities including antimicrobial potential.
- the antimicrobial properties of EOs are mostly related to the individual susceptibility of bacteria.
- the composition of the present disclosure comprises essential oils in an amount ranging from 2% to 50% w/w. In an alternative embodiment, the composition of the present disclosure comprises essential oils in an amount ranging from 2% to 20% w/w.
- the non-limiting examples of essential oils is selected from Light Mineral Oil, olive oil, coconut oil, shea butter, glycerol mono oleate, lavender oil natural, peppermint oil, lavender oil, tea tree oil, bergamot oil, chamomile oil, jasmine oil, ylang ylang oil, eucalyptus oil, lemon oil, cinnamon oil, lemon grass oil, clary sage oil, lavender oil, eucalyptus, rosemary oil, clove oil, frankincense oil, oregano oil, grapefruit oil and combinations thereof.
- the composition of the present disclosure comprises humectant in an amount ranging from 5% to 25% w/w. In an alternative embodiment, the composition of the present disclosure comprises the humectant in an amount ranging from 7% to 20% w/w. In an embodiment, the humectant is selected from glycerin, glycerol, propylene glycol, butylene glycol, sorbitol, polyethylene glycol, coconut oil, olive oil, jojoba oil and combinations thereof.
- the composition of the present disclosure comprises a surfactant in an amount ranging from 2% to 25% w/w. In an alternative embodiment, the composition of the present disclosure comprises a surfactant in an amount ranging from 4% to 25% w/w.
- surfactants useful in the compositions of the present disclosure include anionic surfactants, nonionic surfactants, amphoteric surfactants and mixtures thereof.
- Anionic surfactants useful herein include, but are not limited to, sarcosme type surfactants or sarcosmates; taurates such as sodium methyl cocoyl taurate; alkyl sulfates such as sodium trideceth sulfate or sodium lauryl sulfate; sodium lauryl sulfoacetate; sodium lauroyl isethionate; sodium laureth carboxylate; sodium dodecyl benzenesulfonate and mixtures thereof.
- Nonionic surfactants that can be used in the compositions of the present disclosure include, but are not limited to, Polyvinylpyrrolidone (PVP), compounds produced by the condensation of alkylene oxide groups with an organic hydrophobic compound which may be aliphatic or alkyl-aromatic in nature.
- PVP Polyvinylpyrrolidone
- suitable nonionic surfactants include, but are not limited to, alkyl polyglucosides; block copolymers such as ethylene oxide and propylene oxide copolymers e.g. Poloxamers; ethoxylated hydrogenated castor oils; Alkyl polyethylene oxide e g.
- amphoteric surfactants useful in the compositions of the present disclosure include, but are not limited to, derivatives of aliphatic secondary and tertiary amines in which the aliphatic radical can be a straight chain or branched and wherein one of the aliphatic substituents contains from about 8 to about 18 carbon atoms and one contains an anionic water- solubilizing group, e.g., carboxylate, sulfonate, sulfate, phosphate, or phosphonate.
- anionic water- solubilizing group e.g., carboxylate, sulfonate, sulfate, phosphate, or phosphonate.
- amphoteric surfactants include, but are not limited alkylimino-diproprionates, alkylamphoglycinates (mono or di), alkylamphoproprionates (mono or di), alkylamphoacetates (mono or di), N-alkyl b-aminoproprionic acids, alkylpolyamino carboxylates, phosphorylated imidazolines, alkyl betaines, alkylamido betaines, alkylamidopropyl betaines, alkyl sultaines, alkylamido sultaines, and mixtures thereof.
- amphoteric surfactant is selected from the group consisting of alkylamidopropyl betaines, amphoacetates such as sodium lauroamphoacetate and mixtures thereof. Mixtures of any of the above mentioned surfactants can also be employed.
- the surfactant is selected from Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, Span 20, Span 40, Span 60, Span 80, lauramide DEA, cocamide DEA, cocamide MEA, glyceryl monostearate, stearic acid, polyethylene glycol ether of cetearyl alcohol, cetostearyl alcohol, lauroyl polyoxyl-32 glycerides, fatty alcohols, glycerol monooleate, glyceryl monostearate, emulsifying wax and combinations thereof.
- Non-ionic surfactants act as good emulsifying agents and stabilizers or stabilizing agents.
- solubilizer examples include alcohols such as ethanol, sugars such as sorbitol, polyethylene glycols such as PEG-400, propylene glycol, cyclodextrms, sodium lauryl sulphate and other solubilizer agents or surfactant or a combination thereof.
- the composition further comprises an emulsifier.
- an emulsifier include agar, starch, pectin, bentonite hectorite, veegum, cetyl alcohol, glyceryl stearate, cereth-20, steareth-20, glycerol mono oleate, polawax, stearic acid 50, glyceryl monostearate, Ceteareth 20, polyoxyl 20 cetostearyl ether, isopropyl myristate, polyoxyethylene 8 beewax, Tween 60, Span 80, GSM 40 and a combination thereof.
- emulsifier or emulsifying agents include tragacanth, sodium lauryl sulfate, cetostearyl alcohol, sodium dioctyl sulfosuccinate, and polymers known as the spans and tweens impart stability to the emulsion.
- cetostearyl alcohol is used as emulsion stabilizer.
- composition may include a viscosity modifier.
- examples include glyceryl stearate, GSM 40, poloxamer, cetostearyl alcohol 50 and the likes.
- the composition further includes any or a combination of: a skin penetration enhancer, a preservative, an antioxidant, a moisturizing agent, a film former/waterproofing agent, a polyhydric alcohol, amino acids or metabolites or derivatives thereof, a fatty acid or derivatives thereof, a pH adjuster/chelating agent, a rheology modifying agent, a fragrance, a colorant, and a vitamin.
- the composition includes a preservative in an amount ranging from 0.01% to 5% w/w, preferably, ranging from 0.03% w/v to 5% w/v, more preferably, ranging from 0.03% w/v to 3% w/v and most preferably, ranging from 0.03% w/v to 1% w/v.
- preservatives useful in the compositions of the present disclosure include methyl paraben, propyl paraben, p-hydroxybenzoic acid esters, quaternary ammonium compounds such as benzalkonium chloride, sodium benzoate, benzyl alcohol, butanol, ethanol, isopropyl alcohol and the likes.
- the composition includes an antioxidant in an amount ranging from 0.01% to 5% w/w, preferably, ranging from 0.03% w/v to 5% w/v, more preferably, ranging from 0.03% w/v to 3% w/v and most preferably, ranging from 0.03% w/v to 1% w/v..
- anti oxidants useful in the compositions of the present disclosure include sodium metabisulfite, vitamin A, tocopherol, ascorbic acid or salt or derivative thereof, tartaric acid or salt or derivative thereof, retinyl palmitate, Sesamol, thiol derivatives, Butylated Hydroxy Anisole (BHA), Butylated Hydroxyl Toluene (BHT), and mixtures thereof.
- any other anti-oxidant(s) as known to or appreciated by a person skilled in the art can also be used to serve its/their intended purpose as laid down in embodiments of the present disclosure.
- the composition includes a skin penetration enhancer in an amount ranging from 0.1% to 5% w/w.
- skin penetration enhancer useful in the compositions of the present disclosure include sulphoxides such as dimethylsulphoxide, DMSO, Azones such as laurocapram, pyrrolidones such as 2-pyrrolidone, alcohols and alkanols such as ethanol, or decanol, glycols such as propylene glycol and combinations thereof.
- the skin penetration enhancer is diethylene glycol monoethyl ether.
- polyhydric alcohols useful in the compositions of the present disclosure include polyhydric alkanes, polyhydric alkane esters, polyalkene glycols, and mixtures thereof.
- Polyhydric alkanes can be propylene glycol, glycerin, glycerol, butylene glycol, hexylene glycol, 1,3- propanediol and the likes, but not limited thereto.
- Polyhydric alkane esters can be dipropylene glycol, ethoxydiglycol and the likes, but not limited thereto.
- Polyalkene glycols can be polyethylene glycol, polypropylene glycol and the likes, but not limited thereto.
- compositions of the present disclosure include polyhydric alcohol in an amount ranging from 5% w/v to 30% w/v, preferably, in an amount ranging from 5% w/v to 25% w/v, and more preferably, in an amount ranging from 5% w/v to 20% w/v.
- the hyaluronic acid has the ability to draw moisture from the environment to the skin delivering long-lasting moisture without clogging pores. By increasing skin's surface hydration, hyaluronic acid helps soften and smooth skin texture while also to improving the appearance of your skin's plumpness and firmness.
- the amino acids or metabolites or derivatives thereof include(s), but not limited to, glycine, glutamine, asparagine, arginine, lysine in biologically active enantiomeric forms, L-camitine, choline, betaine, taurine, glycosaminoglycans including hyaluronic acid, chondroitin sulfate, glucosamine, L-glucosamine, heparins and mixtures thereof.
- the composition includes hyaluronic acid or salt or derivative thereof in an amount ranging from 0.02% w/v to 3% w/v, preferably, ranging from 0.05% w/v to 2% w/v, more preferably, ranging from 0.1 % w/v to 1 % w/v and most preferably, ranging from 0.1% w/v to 0.5% w/v.
- stabilizers useful in the compositions of the present disclosure include, but not limited to, gums, agar, propylene glycol, and taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins and mixtures thereof.
- the fatty acid(s) or derivatives thereof include(s), but not limited to, fatty acids with Cl to C30 carbons, which includes long chain fatty acids; saturated or unsaturated fatty acids and derivatives thereof (monounsaturated fatty acids (MUFAs) C18:ln- 12c, C16:ln-5, C16:4n-1 and the polyunsaturated fatty acids (PUFAs) C16:3n-4, C20:3n-3, C20:4n-6, C21:5n-3 and C18:2n-9c,12t); hydrogenated fatty acids; fatty acid glycerides; polyoxyethylated oleic glycerides; monoglycerides and diglycerides; mono-, bi- or tri-substituted glycerides; glycerol mono-oleate esters; glycerol mono-caprate; glyceryl monocaprylate; dicaprylate; laurate, mono
- MUFAs mono
- the fatty acid derivatives are the compounds of formula II, examples include any or a combination of: diglyceryl lauryl fumarate (DGEF), diglyceryl lauryl succinate, diglyceryl capryl succinate, and diglyceryl capryl fumarate. These are used as a carrier for topical formulation of zinc salt in combination with dexpanthenol with one or more other active agents as disclosed in the exemplified compositions.
- DGEF diglyceryl lauryl fumarate
- diglyceryl lauryl succinate diglyceryl capryl succinate
- diglyceryl capryl fumarate diglyceryl capryl fumarate
- Topical therapeutic efficacy is highly dependent on skin conditions, physicochemical properties of the active substance and vehicle/formulation characteristics because of their significant impact on drug release and permeation.
- the topical formulation is formulated to mitigate any oxidation reactions of ingredient used in the products, leading to deterioration including odor formation, color change, and physical and/or chemical instability which can affect the quality, efficacy, and shelf-life of topical formulations and improve the topical or transdermal delivery of the active agents.
- the moisturizing agent(s) includes, but are not limited to lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, butylene glycol, sodium PCA, Carbowax 200, Carbowax 400, Carbowax 800, D-Panthenol, Olive oil, Coconut Oil, Lavender oil Natural, jojoba oil, soybean oil and combinations thereof.
- the film former/waterproofing agent(s) includes, but are not limited to acrylates/Ci2-22 alkylmethacrylate copolymer, C30-38 olefm/isopropyl maleate/methylacrylate copolymer, polyethylene, waxes, vinylpyrrolidone/dimethiconylacrylate/ polycarbamyl polyglycol ester, butylated polyvinylpyrrolidone, polyvinylpyrrolidone/hexadecane copolymer, polyvinylpyrrolidone/eicosene copolymer, tricontanyl polyvinylpyrrolidone, Brassica Campestris/Aleuritis Fordi Oil copolymer, aminofunctional silicones, decamethyl cyclopentasiloxane and trimethylsiloxysilicate, octadecene/ methylacrylate copolymer and combinations thereof.
- the pH adjuster or chelating agent(s) includes, but are not limited to sodium hydroxide, triethanolamine, EDTA salt and combinations thereof.
- the pH of the skin normally ranges from 4 to 6.
- the pH values of the topical composition were maintained similar to the skin’s normal pH value.
- the rheology modifying agent(s) include, but are not limited to acrylates crosspolymer, acrylates/Cio-30 alkylacrylate crosspolymer, polyacrylic acid, sodium polyacrylate, polyacrylate, acrylates/vinyl ester copolymer, PVP/decene copolymer, styrene/MA copolymer, acetamide MEA, acrylamides copolymer, acrylates copolymer, acrylates/steareth-20 methacrylate copolymer, acrylates/beheneth-25 methacrylate copolymer, PEG-150/decyl alcohol/SMDI copolymer, PVP, PVM/MA decadiene crosspolymer, carbomer, PEG crosspolymer, acrylates/palmeth-25 acrylates copolymer, polysaccharide, polyether-1, sodium magnesium silicate, bentonite, trihydroxystearin, hydroxy
- the fragrance(s) includes, but are not limited to alcohols, aldehydes, ketones, esters, ethers, acetates, nitriles, terpene hydrocarbons, nitrogenous or sulfurous heterocyclic compounds and essential oils.
- synthetic plant and animal oils and exudates comprising complex mixtures of various chemical components are also known for use as "fragrance materials” .
- the individual perfume raw materials which comprise a known natural oil can be found by reference to Journals commonly used by those skilled in the art such as “Perfume and Flavourist” or “Journal of Essential Oil Research", or those listed in reference texts such as the book by S.
- fragrance houses Firmenich, International Flavors & Fragrances, Givaudan, Symrise
- fragrance materials useful herein include pro-fragrances such as acetal pro- fragrances, ketal pro- fragrances, ester pro-fragrances, hydrolyzable inorganic-organic pro- fragrances, and mixtures thereof.
- the colorant(s) includes, but are not limited to FD&C Red No. 40, FD&C Yellow No. 5 and combinations thereof.
- the vitamin(s) includes, but are not limited to vitamin A, thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, vitamin C, vitamin E, Vitamin B10 and their derivatives or combinations thereof.
- excipients that may be used in the composition to serve an intended purpose
- one or more excipients may also serve more than one function, obviating the need of inclusion of separate excipients for the specified purpose.
- any other excipient known to or appreciated by a skilled person can also be used to realize the advantageous compositions of the present disclosure. Examples of useful excipients which can optionally be added to the composition are described in the Handbook of Pharmaceutical Excipients, 3rd edition, Edited by A. H. Kibbe, published by: American Pharmaceutical Association, Washington DC, ISBN: 0- 917330-96-X, and in Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond C Rowe - Publisher: Science and Practice.
- the topical formulation can be prepared into various forms such as but not limited to solids, liquids, suspensions, semisolids such as creams, gels, lotions, pastes or sticks, powders and finely dispersed liquids such as sprays or mists.
- the composition is formulated as a topical cream.
- glyceryl monooleate when used, it dramatically improves spreadability of the formulation. Further, glyceryl monooleate forms a barrier film that significantly improves water repellency of the formulation.
- Rash creams are intended to reduce the dermatitis and it should remain present on the skin for extended period of time showing its action even when the patient/subject urinates. So, it is ideal to prepare the formulation with water repellant property.
- the advantageous formulation of the present disclosure includes ingredients that are hydrophobic in nature and hence, naturally exhibits hydrophobicity.
- lauric acid present in the coconut oil acts as an anti-microbial agent on the skin, while olive oil and glyceryl monooleate have emollient properties; and coconut oil and jojoba oil afford anti-inflammatory and healing properties. Accordingly, the formulations (and compositions) of the present disclosure can find utility in treatment of wide varieties of skin conditions.
- an aspect of the present disclosure provides a method of preparing a topical formulation, said formulation comprising zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof, the method comprising the steps of: (a) melt mixing an emollient, a humectant and a first surfactant to prepare a water immiscible phase; (b) preparing a zinc salt dispersion by mixing zinc salt and a second surfactant in water having temperature ranging from 55°C to 90°C; mixing the water immiscible phase with the zinc salt dispersion to obtain a uniform semisolid mixture; (d) preparing a dexpanthenol solution by dissolving dexpanthenol in water; (e) adding the dexpanthenol solution to the semisolid mixture upon the semisolid mixture reaching at a room temperature ranging from 20°C to 50°C with stirring to obtain a uniform mixture; (f) optionally, mixing any or a
- compositions realized in accordance with embodiments of the present disclosure can find utility in treatment of a wide variety of skin conditions/disorders including rashes, candidiasis, diaper rash and the likes, which may be caused by allergens or organisms (like bacteria, virus, fungi etc.). It could be noted that the components of the compositions realized in accordance with embodiments of the present disclosure exhibit high degree of functional reciprocity, wherein zinc salt exhibits anti-infective property and forms a protective barrier, while dexpanthenol exhibits healing property.
- an embodiment of the present disclosure provides a method of treatment of a skin condition in a subject, said method comprising administering to a subject in need thereof an effective amount of a composition comprising: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof.
- the composition is formulated as a topical formulation.
- the skin condition is selected from rashes, candidiasis and diaper rash.
- compositions for use in treatment of a skin condition comprising: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof.
- the composition is formulated as a topical formulation.
- the skin condition is selected from rashes, candidiasis and diaper rash.
- Yet another embodiment of the present disclosure provides use of a composition for manufacture of a medicament for treatment of a skin condition, said composition comprising zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof.
- the composition is formulated as a topical formulation.
- the skin condition is selected from rashes, candidiasis and diaper rash.
- compositions for treatment of a skin condition comprising: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof.
- the composition is formulated as a topical formulation.
- the skin condition is selected from rashes, candidiasis and diaper rash.
- compositions of the present disclosure afford increased therapeutic effects, and reduced adverse effects, making these pharmaceutical compositions extremely effective therapeutics, especially in the treatment of skin diseases/conditions.
- Therapeutic levels of the combined drugs will vary from individual to individual and progression stage of disease.
- the combination medications in the appropriate amounts and intervals effective to treat skin disorders or diseases will necessarily be monitored both clinically and chemically by the medical experts or trained physicians.
- the patient may receive the specific dosage over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years and the like.
- compositions of the present disclosure in unit dosage form for ease of administration and uniformity of dosage.
- the specifications of the dosage unit forms of the present disclosure are dependent on the unique characteristics of the composition and the particular therapeutic effect to be achieved.
- Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients.
- Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995).
- the invention provides a method for treating allergic diseases/conditions, said method includes: providing a container that is suitable for storing the topical formulation for pharmaceutical use, the container comprising an applicator that is capable of dispensing a pharmaceutically effective dose of the topical formulation and spreading an approximately uniform amount of the topical formulation on a target area; loading the applicator with the dose of the topical formulation, and administering the dose of the topical formulation to the treatment area by uniform manual spreading.
- the container is a squeeze sensitive container
- the applicator is a flow through applicator which delivers the topical formulation to the target area when a user applies sufficient pressure on the container.
- the topical formulation is delivered using a transdermal delivery system designed to deliver the composition to the skin and into systemic circulation.
- the transdermal delivery system may be matrix type, liquid or gel reservoir type.
- topical delivery systems can be designed to deliver the active ingredient to local tissue.
- Non-limiting examples of transdermal delivery systems include: iontophoresis, voltage-gradient iontophoresis, electroporation, sonophoresis, magnetophoresis, dermal patches (vapor patches, adhesive patches) nano carriers, needled and needle-less shots, microneedles, thermal ablation, microdermabrasion, electroporation, radiofrequency usage, microporation, use of thermal techniques, micro and radio waves, electro-mechanical devices, nano deliveries and cavitational ultrasound techniques and injectors such as jet injectors, powderject, Implaject®, Crossjet®, Imitrex® and likes.
- Transdermal delivery systems deliver the active ingredient in a discrete dosage form from a skin-sticker patch or other transdermal methods/device by crossing through the skin layers to the systemic circulation.
- TDDS patches can be a single- and multiple layered devices, vapor patches, drug and polymer matrix characteristic-based products, as well as reservoir-based delivery systems.
- the patches may include polymeric membrane to control the drug release rate, which depends on the polymer properties, permeability coefficient, membrane thickness and the adhesive.
- the adhesive-dispersion type TDDS/devices uses polymer, such as polyisobutylene or polyacrylate, as the adhesive polymer with specific permeability thus controls the drug diffusion rate.
- the topical composition is a transdermal patch filled with the precise dose of drug and stuck to the skin for easy delivery of the drug into the blood circulation with help from enhancers.
- suitable polymers, permeation enhancers and solvents are employed. Examples include chitosan, a polysaccharide, hyaluronic acid, synthetic polymer- based hydrogels are prepared from polyacryhcs and polyacrylamide.
- Binary system-based fatty acids i.e. propylene glycol-oleic acid and 1,4-butane diol-linoleic acid, N, N-dimethyl-m-toluamide, calcium thioglycolate, eucalyptol, di-o-methyl-P-cyclodextrin, sodium caprylate mixed with glyceryl triglyceride, short chain glyceryl monocaprylate, imidic cyclic urea, cyclopentadecalactone, cyclodextrins, water, isopropyl alcohol, MCT 70, Transcutol P, and the likes can also be employed.
- the microneedles are used in combination with sonophoresis electroporation or iontophoresis to control the drug release rate and to provide improved delivery.
- Table 1 Compositions for zinc oxide and dexpanthenol topical cream
- Step (i) Water immiscible phase obtained in Step (i) above was added to the ZnO dispersion obtained in Step (ii) and mixed to get a uniform semisolid mixture.
- Dexpanthenol solution a part (8%) of the batch quantity water was taken in a vessel and dexpanthenol was dissolved therein to prepare a dexpanthenol solution.
- the uniform semisolid mixture was allowed to cool down to room temperature of about 30°C and then the dexpanthenol solution was mixed therewith.
- Lavender oil and BKC were added thereto, and final weight was adjusted with water to prepare topical cream formulation.
- Topical cream formulation was prepared using the composition as provided in Table 2 below. Topical cream formulation was prepared following the same method as described in the above example. Table 2: Composition for zinc oxide and dexpanthenol topical cream
- Topical cream formulation was prepared using the composition as provided in Table 3 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 3 Composition for zinc oxide and dexpanthenol topical cream
- Topical cream formulation was prepared using the composition as provided in Table 4 below. Topical cream formulation was prepared following the same method as described in the above example.
- Table 4 Composition for zinc oxide and dexpanthenol topical cream
- Topical cream was prepared using the composition as provided in Table 5 below.
- Table 5 Compositions for topical cream
- Topical cream formulations were prepared using the composition as provided in Table 6 below.
- Table 6 Compositions for zinc oxide and dexpanthenol topical cream
- Topical cream formulation was prepared using the composition as provided in Table 7 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 7 Composition for zinc oxide and dexpanthenol topical cream
- Table 8 3 Month stability data for ACGOO ICO 140021 (P)
- Topical cream formulation was prepared using the composition as provided in Table 9 below. Topical cream formulation was prepared following the same method as described in above example.
- Step 1 White petrolatum, Jojoba oil, Coconut oil, White bees wax, Polawax were charged into a heating vessel and allowed to dissolve
- Step 2 Take 25 % in batch quantity of water and heat up to 70°C-80°C and disperse Calamine to get homogenous phase
- Step 3 Add water immiscible phase obtained in Step 1 to the dispersion obtained in Step 2 and allowed to mix to get uniform semi solid phase
- Step 4 Take 8% batch quantity of water and dissolve dexpanthenol uniformly
- Step 5 Let the temperature of the semisolid phase obtained in Step 3, reach to 30°C slowly and then add dexpanthenol solution to get homogenous phase
- Step 6 Adjust the final weight with water
- Topical cream formulation was prepared using the composition as provided in Table 10 below. Topical cream formulation was prepared following the same method as described in above example.
- Topical cream formulation was prepared using the composition as provided in Table 11 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 11 Composition for topical cream
- Topical cream formulation was prepared using the composition as provided in Table 12 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 12 Composition for zinc oxide and dexpanthenol topical cream [000150] BATCH ACG001C0140015 & 16 (P)
- Topical cream formulations were prepared using the compositions as provided in Table 13 below. Topical cream formulations were prepared following the same method as described in above example.
- Table 13 Compositions for zinc oxide and dexpanthenol topical cream
- Step 1 White petrolatum, Light mineral oil, Jojoba oil, Olive oil, coconut oil, White bees wax, Hard paraffin wax, and Emulsifying wax were charged into a heating vessel and allowed to dissolve
- Step 2 Take 25% in batch quantity of water and heat up to 70°C-80°C and disperse ZnO to get homogenous phase
- Step 3 Add water immiscible phase obtained in Step 1 to the dispersion obtained in Step 2 and allowed to mix to get uniform semi solid phase
- Step 4 Take Transcutol P and dissolve DGLF completely using magnetic stirrer for 30 minutes
- Step 5 Let the temperature of the semisolid phase obtained in Step 3, reach to 30°C slowly and then add DGLF solution to get homogenous phase
- Step 6 Take 8% batch quantity of water and dissolve dexpanthenol uniformly
- Step 7 Add dexpanthenol solution to semisolid phase obtained in step 5 to get homogenous phase
- Step 8 Adjust the final weight with water [000153] BATCH ACG001C0140013& 14 (P)
- Topical cream formulation was prepared using the composition as provided in Table 14 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 14 Compositions for topical cream
- Topical cream formulation was prepared using the composition as provided in Table 15 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 15 Composition for zinc oxide and dexpanthenol topical cream Water
- Topical cream formulation was prepared using the composition as provided in Table 16 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 16 Compositions for topical cream
- Topical cream formulation was prepared using the composition as provided in Table 17 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 17 Compositions for topical cream
- Topical cream formulation was prepared using the composition as provided in Table 18 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 18 Composition for topical cream
- Topical cream formulation was prepared using the composition as provided in Table 20 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 20 Compositions for topical cream
- Topical cream formulation was prepared using the composition as provided in Table 21 below. Topical cream formulation was prepared following the same method as described in above example.
- Table 21 Composition for topical cream
- Topical cream formulation was prepared using the composition as provided in Table 22 below. Topical cream formulation was prepared following the same method as described in above example.
- Topical cream formulation was prepared using the composition as provided in Table 23 below. Topical cream formulation was prepared following the same method as described in above example.
- Topical cream formulation was prepared using the composition as provided in Tables 24- 27 below.
- Table 24 Composition for topical cream
- Table 25 Composition for topical cream
- Table 26 Composition for topical cream
- Table 27 Composition for topical cream
- Topical cream formulation was prepared using the composition as provided in Tables 27 to 30 and according to the process in general as disclosed below.
- Step 1 Charge white petrolatum, Light mineral oil, Jojoba oil, Coconut oil, Shea butter, Glycerol mono Stearate 40, Polawax and Butylhydroxytoluene into a heating vessel and allow to dissolve at 70°C-80°C.
- Step 2 Take 20 % in batch quantity of water and heat up to 70°C-80°C and disperse ZNO to get homogenous phase.
- Step 3 Add water immiscible phase obtained in Step 1 to the dispersion obtained in Step 2 and mix to get uniform semi solid phase.
- Step 4 Take 5% batch quantity of water and dissolve Benzalkonium chloride uniformly.
- Step 5 Take 5% batch quantity of water, propylene glycol and dissolve D-panthenol uniformly.
- Step 6 Let the temperature of the semisolid phase obtained in Step 3, reach to 30°C slowly and then add benzalkonium chloride solution and dexpanthenol solution to get homogenous phase.
- Step 7 Add Lavender oil natural to the above semisolid obtained at step 6.
- Step 8 Adjust the final weight with water and filled into the container.
- Table 28 Composition for topical cream comprising Cysteamme hydrochloride and Zn Sulphate.
- Topical cream formulation was prepared using the composition as provided in Tables 31 and according to the process disclosed below.
- Non-aqueous phase was prepared by melting GMS 40, shea butter, cetyl alcohol, cetostearyl alcohol 50 and melted by heating to temperature 80 °C
- Aqueous phase was prepared by dissolving all water-soluble ingredients such as Zinc sulphate, dexpanthenol, propylene glycol, alpha-tocopherol and EDTA into purified water.
- Drug phase was prepared by adding cysteamme hydrochloride to 5% batch quantity of water
- Table 29 Composition for topical cream comprising Cysteamine hydrochloride and Zn sulphate.
- Topical cream formulation was prepared using the composition as provided in Tables 32 and according to the process disclosed below.
- Step 1 Charge ceteareth 20, isopropyl myristate, shea butter, glycerol mono stearate 40, cetyl alcohol, cetostearyl alcohol 50 and butylhydroxytoluene into a heating vessel and allow to dissolve at 70°C-80°C.
- Step 2 Take 50 % in batch quantity of water and heat up to 70°C-80°C and dissolve EDTA, zinc sulphate and xanthan gum uniformly.
- Step 3 Take 5% batch quantity of water and dissolve cysteamine hydrochloride uniformly.
- Step 4 Take 8% batch quantity of light mineral oil and dissolve lecithin at 70°C-80°C.
- Step 5 Let the temperature of mixture obtained at step 4 to reach room temperature slowly and then add cysteamine hydrochloride solution obtained in Step 3 to step 4 and allow to mix completely.
- Step 6 Add water phase obtained in step 2 to the oil phase obtained in step 1 at 70°C-80°C and mix well for 15 mins and let the temperature reach to 30°C slowly and then add drug phase obtained at step 5 and mix to get uniform semi solid phase.
- Step 7 Take propylene glycol and dissolve D-panthenol uniformly.
- Step 8 Take 1% batch quantity of light mineral oil and dissolve a- tocopherol uniformly.
- Step 9 Add step 7 and step 8 to step 6 to get homogenous phase.
- Step 7 Add phenoxy ethanol to the above semisolid obtained at step 9.
- Step 8 Adjust the final weight with water and filled into the container.
- the topical formulation is intended to reduce the dermatitis associated with diaper or nappy rashes thus it important for the formulation to be present at the area of application for a longer duration.
- the skin in the area of application is constantly exposed to urine and stools. Therefore, the topical formulation of present invention is prepared with water repellant properties by selecting hydrophobic ingredients for the formulation preparation.
- the Formulations are prepared using water immiscible ingredients such as hydrocarbons (Petrolatum, mineral oil and others as disclosed above in the paragraphs and examples, fatty acid alcohols, various natural oils (Olive oils, coconut oil and other), waxes (Polawax, white bees wax, hard paraffin wax and others) to impart the water repellent property to the composition and water (105 to 20%) to disperse ZNO.
- hydrocarbons Petrolatum, mineral oil and others as disclosed above in the paragraphs and examples, fatty acid alcohols, various natural oils (Olive oils, coconut oil and other), waxes (Polawax, white bees wax, hard paraffin wax and others) to impart the water repellent property to the composition and water (105 to 20%) to disperse ZNO.
- the multi-functional excipients used in the formulation such as coconut oil have moisturizing effect as well as antimicrobial effect, it reduces the presence of bacteria, fungi & virus on the skin due to the presence the fatty acid such as lauric acid.
- the spreadability profile of the topical formulation is achieved by adjusting the ratios of waxes and oils used in the formulation.
- the ratios of waxes and oils in 1 :4 ratio was found to achieve desired spreadability to improve the ease of application especially, at gluteal region where the tissue is soft and sensitive was studied.
- percentage of waxes is more than 10 % w/w
- the spreadability decreased in various degrees depending upon the type of waxes being used and when the percent is less than 10% w/w the composition is slippery and sticky.
- the desired spreadability of the composition observed when the percentage of waxes in the composition is ⁇ 10 % w/w of the total weight of the composition.
- Zinc oxide (ZnO) in the composition if not milled before incorporating into the formulation results in grittiness.
- a well-grounded or milled ZnO, prior to incorporating it into the formulation is essential to elicit its bacteriostatic effect quickly. Therefor the ZnO was grounded at least for 30 minutes.
- the polawax and GMS 40 works as emulsifiers to bring homogeneity in the formulation. Mixing of the formulations for extended period of time (not less than 30 minutes) was observed as essential to improving homogeneity of the topical composition.
- ZnO remains non-ionic, undissolved or in suspended state, thus, preventing systemic absorption and the formulation is stable and remain on the skin for a longer period of time when application due to its water repellence property, thereby, extending the action of ZnO at the site of application.
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Abstract
Aspects of the present disclosure provides a topical formulation that includes zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof. The composition may include one or more other active agents. The compositions of the present disclosure may find utility in treatment of rashes and skin conditions/diseases. Another aspect of the present disclosure provides a method of preparing the topical formulation that includes zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof.
Description
A TOPICAL FORMULATION FOR THE TREATMENT OF SKIN DISEASES
FIELD OF THE INVENTION
[0001] The present disclosure generally relates to the field of topical compositions. In particular, the present disclosure provides a topical formulation that includes zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof. The compositions of the present disclosure may find utility in treatment of rashes and skin conditions/diseases.
BACKGROUND OF THE INVENTION
[0002] Skin infections are common and may be caused by bacteria, fungi or viruses. Breaks in the skin integrity, particularly those that inoculate pathogens into the dermis, frequently cause or exacerbate skin infections. Bacterial skin infections caused by corynebacteria, staphylococci, streptococcal skin infections, and human papillomavirus skin infections. The many dermatomycoses (skin infections caused by fungi or yeasts), onychomycosis and Candida infections occur in moist areas, such as the vulva, mouth, penis, skinfolds and diaper area.
[0003] Infections by bacteria, viruses, or fungi can also cause a rash. These rashes vary depending on the type of infection. For instance, candidiasis, a common fungal infection, causes an itchy rash that generally appears in skin folds. Whereas diaper rash is often caused by irritation to the skin due to contact with urme, stool, and detergent. Sometimes it can be caused by yeast infections, bacterial infections, or even due to an allergy to diaper material.
[0004] Skin and soft tissue infections remain among the most frequently encountered infections, and their severity ranges from mild cellulitis to severe, necrotizing infections with high incidences of morbidity and mortality. Most commonly, these disorders result from skin lesions in a susceptible host, but sometimes develop following hematogenous spread from a previously unknown focus. New, promising agents, with activity against multi-drug resistant gram-positive and gram-negative organisms, are aimed at filling the gap in the treatment of complicated skin infections.
[0005] Zinc, alone or as an adjuvant, has been found useful in many dermatological infections owing to its modulating actions on macrophage and neutrophil functions, natural killer cell/phagocytic activity, and various inflammatory cytokines. Although numerous compositions
have been reported so far, they suffer from one or more shortcomings, particularly, from the perspective of preventing and/or treating skin conditions/disorders.
[0006] The unmet need for improved compositions and methods that can be used to treat a wide variety of skin diseases/disorders. A need is also felt of improved formulations that are easy to apply and improve outcomes. The present disclosure satisfies the existing needs, at least in part, and overcomes one or more disadvantages of the conventional approaches.
OBJECTS OF THE INVENTION
[0007] One of the objects of the present disclosure is to provide a composition that may overcome the limitations associated with the conventional compositions.
[0008] Another object of the present disclosure is to provide a composition that exhibits superior storage stability and functional reciprocity.
[0009] Further object of the present disclosure is to provide a composition that is easy to prepare and is economical.
[00010] Yet another object of the present disclosure is to provide a composition that finds utility in treatment for a wide variety of skin diseases/conditions.
[00011] Still another object of the present disclosure is to deliver the active agents either simultaneously or concurrently or concomitantly to a subject for treatment of the skin disease.
SUMMARY OF GI 11 INVENTION
[00012] The present invention provides novel pharmaceutical compositions comprising compounds of the invention suitable formulated for treating skin diseases resulting from skin inflammation, infections, allergy and other related pathogenesis thereof.
[00013] In one aspect, the present invention is directed to pharmaceutical compositions, comprising compound of formula I or a pharmaceutically acceptable Zinc salt, derivative thereof,
Zn + RH Formula I
RH independently represents oxide, undecyclenate, pyrithione, acetate, carbonate, lactate, chloride, bromide, malonate, oxalate, tartarate, citrate, pidolate, phosphate, nitrate, sulphate, thiosulphate, palmitate, gluconate, acetate, carnosine, Mg+2, magnesium oxide, magnesium stearate, magnesium silicate, magnesium sulphate, magnesium chloride, magnesium bromide, magnesium acetate, magnesium lactate, magnesium pidolate, magnesium thiosulphate, magnesium sulphate, Ag+, silver oxide, silver lactate, silver
chloride, silver bromide, silver pidolate, silver phosphate, silver nitrate, silver sulphate, silver thiosulphate, tetra-silver tetra-oxide, Cu+2, copper sulfate pentahydrate, copper sulfate, copper malonate, copper citrate, copper oxalate, copper tartarate copper lactate, copper chloride, copper bromide, copper pidolate, copper phosphate, copper nitrate, copper thiosulphate, Al+3aluminium oxide, aluminium palmitate, aluminum stearate, aluminum chloride, aluminum oxychloride, aluminum barium silicate, Aluminum magnesium hydroxide stearate aluminum propionate aluminum dipropionate, aluminum aceto propionate, aluminum citro propionate, aluminum lacto propionate, aluminum tartaro propionate, aluminum aceto dipropionate, aluminum citro dipropionate, aluminum lacto dipropionate, and aluminum tartaro dipropionate, iodine, gold nanoparticles, or silver nanocrystal thereof in an ionic form or as a salt form or as a physical mixture form.
[00014] In one aspect, the present invention is directed to pharmaceutical compositions, comprising compound of formula II or a pharmaceutically acceptable salt, derivative, prodrug thereof,
Formula II wherein,
Ri, R2, R3 independently represents
lauric acid (C12:0), monoglycerides [MG], monocaprin (MG C10:0), glycerol monolaurate (MG 02:0), oleic acid (08:1), elaidic acid (trans-C18:l), linoleic acid (08:2), linolenic acid (08:3), monocaprylate, monooleate, myristoleic acid, glycerol monocaprylate, C8:0, 00:0, 02:0, 04:0, 06:0, 08:0, 08:1, trans-08:l, 08:2, 08:3, C6:0, C8:0, 00:0, 02:0, 04:0, 06:0, 08:0, 04:1, 06:1, 08:1, trans-C18:l, 08:2, trans-C18:2, 08:3, C20:4, [MGs] 00:0, 02:0, 01:0, 02:0, 03:0, [MGs] 01:0, 02:0, 03:0, C20:4, C8:0, 00:0, 02:0, 04:0, 06:1, 08:1, [MGs] C8:0, 00:0, 02:0, 04:0, 06:1, or 08:1; within the proviso,
C x:y is defined such that x is the number of carbons in the primary alkyl chain and y is the number of degrees of unsaturation; n = 0 to 80;
RH independently represents zinc Oxide, Zn+2, zinc undecyclenate, zinc pyrithione, zinc acetate, zinc carbonate, zinc lactate, zinc chloride, zinc bromide, zinc malonate, zinc oxalate, zinc tartarate zinc citrate, zinc pidolate, zinc phosphate, zinc nitrate, zinc sulphate, zinc thiosulphate, zinc palmitate e, Mg+2, magnesium oxide, magnesium stearate, magnesium silicate, magnesium sulphate, magnesium chloride, magnesium bromide, magnesium acetate, magnesium lactate, magnesium pidolate, magnesium thiosulphate, magnesium sulphate, Ag+, silver oxide, silver lactate, silver chloride, silver bromide, silver pidolate, silver phosphate, silver nitrate, silver sulphate, silver thiosulphate, tetra-silver tetra-oxide, Cu+2, copper sulfate pentahydrate, copper sulfate, copper malonate, copper citrate, copper oxalate, copper tartarate copper lactate, copper chloride, copper bromide, copper pidolate, copper phosphate, copper nitrate, copper thiosulphate, Al+3aluminium oxide, aluminium palmitate, aluminum
stearate, aluminum chloride, aluminum oxychloride, aluminum barium silicate, Aluminum magnesium hydroxide stearate aluminum propionate aluminum dipropionate, aluminum aceto propionate, aluminum citro propionate, aluminum lacto propionate, aluminum tartaro propionate, aluminum aceto dipropionate, aluminum citro dipropionate, aluminum lacto dipropionate, and aluminum tartaro dipropionate, Iodine, gold nanoparticles, or silver nanocrystal.
[00015] In certain embodiment, the pharmaceutical composition comprises of dilaurylglyceryl fumarate (DGLF) a compound of formula II or a pharmaceutically acceptable salt, or a hydrate or a solvate or a prodrug thereof, as an active agent which treats an inflammatory-related condition along with one or more anti-irritant agents; antiseptic agent, emollients/ moisturizing agent, emulsifier, solvents, co-solvent pH modifier and other pharmaceutical acceptable carrier or excipient is used in the topical formulation.
[00021] The present invention provides a composition for treatment for a wide variety of skin diseases and inflammation. The composition, when applied to affected skin, provides protection from the exogenous factor which flare up the skin inflammation, smother the affected skin, promote the healing process, improves the pH of the skin and skin flora and thus helps in restoration and regeneration of the skin barrier within short period of application.
[00022] The pharmaceutical composition is used for treating skin disorders caused by skin inflammation due to exogenous and endogenous factors. Skin disorders include dermatitis mainly contract dermatitis, allergic dermatitis, diaper or napkin rashes in adult and babies, psoriasis and pruritus.
[00023] Herein the application also provides a kit comprising the pharmaceutical compositions disclosed herein. The kit may comprise instructions related to use of the composition for treating and preventing skin inflammation and diseases such as hyperpigmentation, dermatitis mainly contract dermatitis, allergic dermatitis, diaper or napkin rashes in adult and babies, psoriasis and pruritus.
T)F,T ATT ,FT) DESCRIPTION OF THF INVENTION
Definitions
[00024] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. It is also understood that the
terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
[00025] It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, “an active agent” or “a therapeutic agent” refers not only to a single active agent but also to a combination of two or more different active agents, “a dosage form” refers to a combination of dosage forms as well as to a single dosage form, and likes, or any combinations thereof.
[00026] The term “formulation” or “composition” as used herein refers to the drug/active ingredient in combination with one or more additional other agents and pharmaceutically acceptable excipients. This term includes orally administrable formulations as well as formulations administrable by other means.
[00027] The term “pharmaceutically acceptable” means the material incorporated into a composition that can be administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U S. Food and Drug administration
[00028] “Pharmacologically active” (or simply “active”) as in a pharmacologically active derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
[00029] The term “active agent” or “therapeutic agent”, encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds. In one aspect “active agent” or “therapeutic agent”, includes compounds of Formula I or formula II, and pharmaceutically acceptable salts, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such compounds of formula I and formula II as used in the present pharmaceutical composition can be present in the form of pharmaceutically acceptable salts, esters, (i.e., the methyl and ethyl esters of the acids of compound to be used as prodrugs, solvated, hydrated. The solvation can be affected in the course of the manufacturing process or can take place
i.e. as a consequence of hygroscopic properties of an initially anhydrous compound. Non-limiting examples of compound of formula II includes:
[00034] dilauryl glyceryl caprylate (DGLC)
[00035] The terms “treating” and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage. Thus, “treating” a patient as described herein encompasses treating skin inflammation and skin injury or damage caused to the stratum corneum layer in general dermatosis. The inflammation and injury result in dermatitis specifically contract dermatitis, allergic dermatitis, diaper or napkin rashes/dermatitis in adult and babies, psoriasis, dry skin, pruritus, wound, lesion, blister and laceration.
[00036] The terms “skin disorder” areas refereed herein include skin conditions such as dermatitis, allergic contact dermatitis, psoriasis, diaper rash, eczema, and skin injuries/damage by wounds, burns, and fecal and urinary incontinence. These Human skins pH value is very important factor and it is somewhere between 4.5 and 6. In case of a newborn baby's skin and older adults the pH is neutral (pH 7). Skin disorders are reported when the pH value goes into the alanine range. The present disclosure generally relates to the field of topical compositions. In particular, the present disclosure provides a topical formulation that includes zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof. The compositions of the present disclosure may find utility in treatment of rashes and skin conditions/diseases.
[00037] The present disclosure generally relates to the field of topical compositions.
[00038] An aspect of the present disclosure provides a composition including: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof. In an embodiment, the composition is formulated as a topical formulation.
[00039] In an embodiment, the composition comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1:1 to 10:1. In an alternative embodiment, the composition comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1:1 to 7: 1.
[00040] In an embodiment, the composition further comprises an active agent selected from: a topical antibacterial agent, a topical antifungal agent, a topical steroid, a vitamin or derivatives thereof, an amino acid or derivatives thereof, a fatty acid or derivatives thereof and combinations thereof.
[00041] In accordance with an embodiment of the present disclosure, the composition further comprises an excipient. The excipient can be any or a combination of: a diluent, an emollient, a humectant, a preservative, a solvent, natural oils, essential oils, a fragrance, a fatty acid or derivative thereof, an amino acid or metabolite or derivative thereof, a surfactant, a solubilizer and a stabilizer.
[00042] In an embodiment, the composition is formulated as a topical cream formulation.
[00043] In accordance with an embodiment of the present disclosure, the composition comprises: zinc salt in an amount ranging from 1% w/v to 35% w/v; dexpanthenol or salt or hydrate or solvate thereof in an amount ranging from 1% w/v to 20% w/v; an emollient in an amount ranging from 10% to 40% w/w; a humectant in an amount ranging from 5% to 30% w/w; a surfactant in an amount ranging from 2% to 30% w/w; and water in an amount ranging from 10% w/v to 60% w/v.
[00044] In an embodiment, the emollient is selected from white petrolatum, mineral oil, light mineral oil, isopropyl myristate, cetyl alcohol, beeswax, white beeswax, paraffin wax, hard paraffin wax, cetomacrogol, sumac wax, polawax shea butter and combinations thereof. In an embodiment, the humectant is selected from glycerin, glycerol, propylene glycol, butylene glycol, sorbitol, polyethylene glycol, coconut oil, olive oil, jojoba oil, super refined castor oil and combinations thereof. In an embodiment, the surfactant is selected from Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, Span 20, Span 40, Span 60, Span 80, lauramide DEA, cocamide DEA, cocamide MEA, glyceryl monostearate, stearic acid, polyethylene glycol ether of cetearyl alcohol, cetostearyl alcohol, lauroyl polyoxyl-32 glycerides, fatty alcohols, glycerol monooleate, glyceryl monostearate, emulsifying wax and combinations thereof.
[00045] In an embodiment, the composition further comprises a preservative in an amount ranging from 0.03% to 5% w/w. In an embodiment, the composition further comprises an antioxidant in an amount ranging from 0.03% to 5% w/w. In an embodiment, the composition further comprises a skin penetration enhancer in an amount ranging from 0.1% to 5% w/w.
[00046] Another aspect of the present disclosure provides a method of preparing a topical formulation, said formulation comprising zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof, the method comprising the steps of: (a) melt mixing an emollient, a humectant and a first surfactant to prepare a water immiscible phase; (b) preparing a zinc salt dispersion by mixing zinc salt and a second surfactant in water having temperature ranging from 55°C to 90°C; (c) mixing the water immiscible phase with the zinc salt dispersion to obtain a uniform semisolid mixture; (d) preparing a dexpanthenol solution by dissolving dexpanthenol in water; (e) adding the dexpanthenol solution to the semisolid mixture upon the semisolid mixture reaching at a room temperature ranging from 20°C to 50°C with stirring to obtain a uniform mixture; (f) optionally, mixing any or a combination of: a fragrance and a preservative with the uniform mixture; and (g) making up the weight of the formulation with water to obtain the topical formulation.
[00047] The advantageous topical formulations of the present disclosure form a layer on the skin, wherein zinc salt exhibits anti-infective property, while dexpanthenol exhibits healing property and accordingly, the formulations of the present disclosure can find utility in treatment of a wide variety of skin conditions/diseases/disorders.
[00048] The term “combination therapy" or "combined treatment" or "in combination" as used herein denotes any form of concurrent or concomitantly or co-administration of active agents for treating wide varieties of skin diseases/conditions such as rashes, candidiasis, diaper rash and the likes.
[00049] The term “moisturizers” as used herein can be 3 types such as humectants, emollients, and occlusive.
[00050] The term “viscosity modifiers” means to change the thickness or texture of pharmaceutical ingredients. Viscosity modifiers, include thickeners, texturizers, gelation agents and stiffening agents Some viscosity modifiers can be used to convert liquids to gels, pastes or powders. A viscosity modifier decreases the thickness of a liquid to improve pour ability and ultimately make it more palatable. The terms “treating” and “treatment” as used herein refers to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage caused thereby. Thus, “treating” a subject/patient as described herein encompasses treating a wide variety of skin conditions such as rashes, candidiasis, diaper rash and the likes, which may be caused by allergens or organisms (like bacteria, virus, fungi etc.). Diaper rash is the most common form of contact dermatitis in childhood. Occlusion of the groin with diapers allows increased concentration of moisture in the area eventually leading to the breakdown of the underlying skin. The skin in the diaper area is predisposed to irritation by the prolonged contact with irritants, such as urine and feces, as well as by diaper occlusion, which leads to an increase in hydration and skin pH. Although diaper rash is usually mild and transient, bacteria or fungi sometimes invade the damaged skin, causing a severe diaper rash requiring medical evaluation and treatment especially in adults who are bed ridden.
[00051] Skin infections are common and may be caused by bacteria, fungi or viruses. Breaks in the skin integrity, particularly those that inoculate pathogens into the dermis, frequently cause or exacerbate skin infections. Bacterial skin infections caused by corynebacteria, staphylococci, streptococcal skin infections, and human papillomavirus skin infections. The many dermatomycoses (skin infections caused by fungi or yeasts), onychomycosis and Candida infections occur in moist areas, such as the vulva, mouth, penis, skm folds and diaper area.
[00052] Infections by bacteria, viruses, or fungi can also cause a rash. These rashes vary depending on the type of infection. For instance, candidiasis, a common fungal infection, causes an itchy rash that generally appears in skm folds. Whereas diaper rash is often caused by irritation to the skin due to contact with urine, stool, and detergent. Sometimes it can be caused by yeast infections, bacterial infections, or even due to an allergy to diaper material.
[00053] Prolonged exposure to urine and feces leads to a more alkaline diapered skin pH, resulting in changes in microbial colonization, activation of fecal protease and lipase enzymes, and stratum corneum impairment. Additionally, friction against the skin and maceration can lead to a breakdown of the skin barrier and increased permeability to potential irritant substances. These factors predispose the skin to microbial invasion and inflammation. Particularly Candida albicans and other pathogenic bacteria, such as Staphylococcus aureus, (b-hemolytic) Streptococcus sp., E. coli, and Bacteroides sp. are commonly associated with such conditions.
[00054] The term “dosage form” denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to elicit a desired therapeutic response.
[00055] The term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate. The term “controlled release” as used herein includes sustained release, non-immediate release and delayed release formulations.
[00056] The term “sustained release” (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time.
[00057] The present disclosure is, in part, on the premise of surprising observation of the inventors of the present disclosure that the compositions and formulations of the present disclosure can afford a unique treatment option for a wide variety of skin conditions/disorders, and particularly, for treating diaper rash, wherein zinc salt exhibits anti-infective property, antioxidant, anti-inflammatory properties and forms a protective barrier, while dexpanthenol exhibits healing property, provides moistures, hydration, prevents loss of moisture from skin. Dermatological effects of the topical use of dexpanthenol increases fibroblast proliferation and accelerates re-epithelialization in wound healing. Accordingly, the compositions of the present disclosure including zinc salt and dexpanthenol exhibit strong functional reciprocity and synergy. In certain embodiment, the composition may include calamine with dexpanthenol or calamine in combination with zinc salt or calamine in combination with zinc salt and dexpanthenol and with one or more excipients. Calamine protects the skin and acts as astringent and soothing agent that helps in relieve itching. They also slow down bacterial growth, and
prevent manifestation of infection. Camphor, menthol, pramoxine, zinc salt are other known soothing agents.
[00058] An aspect of the present disclosure provides a composition including: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof. In an embodiment, the composition is formulated as a topical formulation.
[00059] The composition of the present disclosure comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1 : 1 to 10: 1.
[00060] Alternatively, the composition of the present disclosure comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1:1 to 7: 1. [00061] Still alternatively, the composition of the present disclosure comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1.5 : 1 to 5 : 1. [00062] Still alternatively, the composition of the present disclosure comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio ranging from 1.5:1 to 4 : 1. [00063] In an embodiment, the composition comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio of about 4: 1.
[00064] In an embodiment, the composition comprises zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof in a weight ratio of about 2: 1.
[00065] Present invention provides topical composition for treating skin diseases comprising zinc oxide, a micronutrient that participates in various cellular functions and in wound repair. It also help in the reduction in overall severity of signs and symptoms, particularly blistering, soreness, itching, and tingling, sensation in skin disorders. Zn is trace element abundantly present in skin with a concentration gradient from the upper stratum corneum layer to the basal layer, Zn it is important metal for the maintenance of healthy skin and wound healing. Zinc is auto debridement, anti-infective action, and promotion of epithelialization, zinc salt enhances re-epithelialization of wounds and the mode of delivery of zinc is probably critical for achieving the beneficial healing effect of zinc. [00066] The composition of the present invention comprising zinc salt and dexpanthenol is effective in the management of skin rashes, candidiasis, diaper rashes and other skin allergies and skin infection. The composition has antioxidant, anti-inflammatory, anti-androgenic, photo- protective, anti-ageing, and antibacterial properties. It supports in re epithelialization, elastic regenerative and would healing. The composition improves the integrity of stratum corneum, and reduces water loss from skin to maintaining it softness and elasticity. Further, the composition increases fibroblast proliferation which accelerated re-epithelialization in wound healing.
Furthermore, the composition acts as a topical protectant and provides moisturizer to the skin. Further, dexpanthenol leads to increased mobility of stratum corneum molecular components. Specifically, dexpanthenol interacts with lipid segments of the extracellular lamellae and protein residues in the corneocytes in stratum corneum and thus compensates for reduced hydration by retaining/increasing molecular fluidity. Other active agents used in the composition such as amino acids, vitamins, sun blocks, sun screen, antimicrobial agents, steroid, and fatty acids fastens the wound healing, prevents photo damage and skin ageing, inhibit microbial growth in the skin, and fastens wound healing process. Use of immunosuppressant, phosphodiesterase (PDE) inhibitors, anti-inflammatory agent, Janus kinase (JAK) Inhibitor, in the composition suppress the inflammatory components responsible for flaring up of allergic symptoms associated with skin rashes and skin infections. These topical agents create a protective barrier over the skin and reduce the impact of external irritants thus are more effective than monotherapy. Cysteamme, an aminothiol compound physiologically synthetized in human body cells, is known as depigmentmg agent. Skin hyperpigmentation is caused by an excessive production of melanin. Composition comprising cysteamine when applied topically it can scavenge free radicals and lighten skin that’s been darkened as a result of post-inflammatory hyperpigmentation, sun exposure and melasma. Composition comprising calamine soothes the skin irritation.
[00067] General topical agents such as corticosteroids, anti-inflammatory agents/immunosuppressant antimicrobials gents and others are known to have potent and quick effects on symptoms of skin allergies. The excessive, continuous use of these agents have reported several adverse effects such as skin pigmentations, skin atrophy and bacterial resistance, which may affect the positive effects of the treatment. Hence, present invention provides an option of combining certain of these beneficial active agents with zinc salt and dexpanthenol in a manner to avert any adverse events.
[00068] In an embodiment, the composition further comprises an active agents selected from: topical antibacterial agent, topical antifungal agent, topical steroid, immunosuppressant, PDE inhibitors- (PDE 4, PDE 3 and PDE 5), JAK Inhibitor, sun blocks/UV-filters, vitamin or derivatives thereof, an amino acid or derivatives thereof, a fatty acid or derivatives thereof and combinations thereof.
[00069] In an embodiment, non-limiting examples of suitable topical steroidal agents include corticosteroids, hydrocortisone, hydroxyltriamcinolone, alphamethyl, dexamethasone, dexamethasone-phosphate, beclomethasone, dipropionate, clobetasol valerate, desonide,
desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone, diacetate, diflucortolone, valerate, fluadrenolone, fluclarolone, acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocmonide, flucortine, butylester, fluocortolone, fluprednidene (fluprednylidene)acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone, diacetate, fluradrenalone, acetonide, medrysone, amciafel, amcmafide, betamethasone, chlorprednisone, chlorprednisone acetate, clocortelone, clescmolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone, valerate, hydrocortisone, cyclopentylproprionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone, and their pharmaceutically acceptable salts and pro- drugs thereof. [00070] In an embodiment, non-limiting examples of topical antifungal include miconazole, econazole, ketoconazole, sertaconazole, itraconazole, voriconazole, clioquinol, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, saperconazole, clotrimazole, haloprogin, butenafine, tolnaftate, nystatin, amorolfme, naftifine, griseofulvin, cysteamine hydrochloride and their pharmaceutically acceptable salts and prodrugs thereof.
[00071] In an embodiment, non- limiting examples of immunosuppressants include Azathioprine, Mycophenolic acid, Leflunomide, Teriflunomide, Ciclosporin, Pimecrolimus, tacrolimus, voclosporin, lenalidomide, pomalidomide, thalidomide, apremilast, sirolimus, everolimus, ridaforolimus, temsirolimus, umirolimus, zotarolimus, baricitinib, blisibimod, nilotinib, filgotinib, tofacitimb, upadacitimb, abatacept, belatacept, etanercept pegsunercept, aflibercept, alefacept, rilonacept and their pharmaceutically acceptable salts and prodrugs thereof.
[00072] In an embodiment, non-limiting examples of PDE 4 inhibitors include apremilast, arofylline, atizoram, benafentrine, catramilast, CC-1088, CDP-840, CGH-2466, cilomilast, cipamfylline, crisaborole, denbutylline, difamilast, drotaverine, etazolate, filaminast, glaucine, HT- 0712, ICI-63197 indimilast, irsogladine, lavamilast, lirimilast, lotamilast, luteolin, mesembrenone, mesembrine, mesopram, oglemilast, piclamilast, pumafentrine, revamilast, Ro 20-1724, roflumilast, rolipram, ronomilast, RPL-554, RS-25344, tetomilast, tofimilast, YM- 976, zardaverine, ibudilast, roflumilast and their pharmaceutically acceptable salts and prodrugs thereof.
[00073] In an embodiment, non-limiting examples of PDE 3 Inhibitors include Adibendan, amrinone (inamrinone), anagrelide, benafentrine, bucladesine, carbazeran, cilostamide, cilostazol, enoximone, imazodan, KMUP-1, meribendan, milrinone, olprinone, parogrelil , pimobendan,
pumafentrine , quazinone, RPL-554, siguazodan, trequinsin, vesnarinone, zardaverine and their pharmaceutically acceptable salts and prodrugs thereof.
[00074] In an embodiment, non-limiting examples of PDE 5 Inhibitors include PDE 5 inhibitors acetildenafil, aildenafil, avanafil, beminafil, benzamidenafil, dasantafil, icariin, gisadenafil, homosildenafil, lodenafil, mirodenafil, MY-5445, Nitrosoprodenafil, Norcarbodenafil, SCH-51866, Sildenafil, Sulfoaildenafil, T-0156, Tadalafil, Udenafil, Vardenafil and their pharmaceutically acceptable salts and prodrugs thereof.
[00075] In an embodiment, non-limiting examples of JAK Inhibitor include abrocitinib, baricitinib, filgotinib, momelotinib, oclacitinib, peficitinib, ruxolitinib, tofacitinib, tasocitinib, CP- 690550, upadacitinib, atiprimod, AZD-1480, baricitinib, chz868, cucurbitacin i (elatericin B, JSI- 124) CYT387 lestaurtimb, NSC-7908, NSC-33994, pacritmib, peficitinib, ruxolitinib, SD-1008, cercosporamide, decernotinib (VX-509), peficitinib, TCS-21311, WHI-P 15 ZM-39923, ZM- 449829 and their pharmaceutically acceptable salts and prodrugs thereof.
[00076] In an embodiment, non-limiting examples of sun blocks/UV-filters p-Aminobenzoic acid, padimate O, phenylbenzimidazole sulfonic acid, cinoxate, dioxybenzone, oxybenzone, homosalate, menthyl anthramlate, octocrylene, octyl methoxycmnamate, octyl salicylate, sulisobenzone, trolamine salicylate, avobenzone, ecamsule, titanium dioxide, zinc salt and their pharmaceutically acceptable salts and prodrugs thereof.
[00077] In an embodiment, non-limiting examples of vitamins include: vitamin A and their derivatives retinol, retinaldehyde, retinyl esters, oxoretinoids, retinyl palmitate and retinyl acetate, vitamin C and their derivatives L-ascorbic acid, ascorbyl palmitate, and magnesium ascorbyl phosphate, Vitamin B3/Niacinamide and their derivatives, vitamin B-5 /pantothenic acid and their derivatives, Vitamin E / a-tocopherol and their derivatives, Vitamin K/phytonadione and their derivatives, calciferols and their derivatives, or a combination thereof.
[00078] In an embodiment, non-limiting examples of antimicrobial ag ents include: chlorhexidine salts, such as iodopropynyl formic acid fourth, double imidazoles ureine, chlorhexidine gluconate, chlorhexidine acetate, isethionic acid chlorhexidine and hydrochloric acid chlorhexidine, benzalkonium chloride, butyl hydroxytoluene, benzethonium chloride, triclocarban, poly hexamethylene biguanide, hexadecylpyridinium chloride, methylbenzethonium chloride, halogenated phenolic resin, triclosan, parachlorometaxylenol, ethyl alcohol, propyl alcohol or a combination thereof.
[00079] In an embodiment, non-limiting examples of amino acid derivatives or metabolites include: nor-leucine, nor- valine, L-alloisoleucine, L-threoisolucine D, L, or DL-leucine-containing di- and tri-peptides, D,L, or DL- valine-containing di- and tri-peptides, D,L, or DL-isoleucme-containing di- and tri-peptides, nitrogen-free analogues of branched chain amino acids, branched chain alpha-keto acids, isovaleryl-CoA, isovalerylcamitine, isovaleryglycine, isovaleric acid, beta-methylcrotonyl- CoA, beta-methylcrotonylcarnitine, beta-methylcrotonylglycine, beta-methylcrotonic acid, beta- methylglutaconyl-CoA, beta-methylglutaconylcarnitine, beta-methylglutaconylglycme, beta- methylglutaconic acid,beta-hydroxy-beta-methylglutaryl-CoA, beta-hydroxy-beta- methylglutarylcarnitine, beta-hydroxy-beta-methylglutarylglycine, beta-hydroxy-beta- methylglutaric acid, acetyl-CoA, acetylcarnitine, acetylglycine, acetoacetyl-CoA, acetoacetylcarnitme, acetoacetylglycme, isobutyryl-CoA, lsobutyrylcarmtine, lsobutyrylglycme, isobutyric acid, methylacrylyl-CoA, methylacrylylcarnitine, methylacrylylglycine, methylacrylic acid, beta-hydroxyisobutyryl-CoA, beta-hydroxy isobutyrylcarnitine, beta hydroxyisobutyrylglycine, beta-hydroxyisobutyric acid, methylmalonate semialdehyde, propionyl- CoA, propionylcarnitine, propionylglycine, propionic acid, D-methylmalonyl-CoA, L- methylmalonyl-CoA, DL-methylmalonyl-CoA, D-methylmalonylcamitine, L- methylmalonylcarnitme, DL-methylmalonylcarnitine, D-methylmalonylglycine, L- methylmalonylglycine, DL-methylmalonylglycine, methylmalonic acid, succinyl-CoA, succinylcarnitine, succinylglycine, succinic acid, alpha-methylbutyryl-CoA, alpha- methylbutyrylcarnitine, alpha-methylbutyrylglycine, alpha-methylbutyric acid, tiglyl-CoA, tiglylcarnitine, tiglylglycme, tiglic acid, alpha-methyl-beta-hydroxybutyryl-CoA, alpha-methyl- beta-hydroxybutyrylcarnitine, alpha-methyl-beta-hydroxybutyrylglycine, alpha-methyl-beta- hydroxybutyric acid, alpha-methylacetoacetyl-CoA, alpha-methylacetoacetylcarnitine, alpha- methylacetoacetylglycine, alpha-methylacetoacetic acid, and combinations thereof.
[00080] In an embodiment, the composition includes an excipient. The excipients can be any or a combination of: a diluent, an emollient, a humectant, a preservative, a solvent, a fragrance, a fatty acid or derivative thereof, an ammo acid or metabolite or derivative thereof, a surfactant, a solubilizer and a stabilizer.
[00081] The composition may be formulated as a semi-solid or liquid dosage form. Non limiting examples of dosage forms includes suspension, solution, emulsion, cream, ointment, lotion, gel and the likes. In an embodiment, the composition is formulated as a topical cream formulation.
[00082] In accordance with an embodiment of the present disclosure, the composition comprises: zinc salt in an amount ranging from 1% w/v to 35% w/v; dexpanthenol or salt or hydrate or solvate thereof in an amount ranging from 1% w/v to 20% w/v; an emollient in an amount ranging from 10% to 40% w/w; a humectant in an amount ranging from 5% to 30% w/w; a surfactant in an amount ranging from 2% to 30% w/w; and water in an amount ranging from 10% w/v to 60% w/v.
[00083] In an embodiment, the composition of the present disclosure comprises an emollient in an amount ranging from 12% to 35% w/w. In an alternative embodiment, the composition of the present disclosure comprises an emollient in an amount ranging from 15% to 30% w/w. Non- limiting examples of emollient includes, PPG- 15 stearyl ether, lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, octyl stearate, mineral oil, isocetyl stearate, isopropyl myristate, cetyl alcohol, beeswax, paraffin wax, sumac wax, shea butter, Ceraphyl 424 (myristyl myristate), octyl dodecanol, dimethicone (Dow Corning 200-100 cps), phenyl trimethicone (Dow Corning 556), Dow Coming 1401 (cyclomethicone and dimethiconol), and cyclomethicone (Dow Corning 344), and Miglyol 840 (manufactured by Huls; propylene glycol dicaprylate/dicaprate) and combinations thereof. In an embodiment, the emollient is selected from white petrolatum, mineral oil, isopropyl myristate, cetyl alcohol, beeswax, paraffin wax, sumac wax, shea butter and combinations thereof. Emollients are also soothing agents which are rapidly absorbed into the skm and are often used in hair-covered areas.
[00084] Antimicrobial activity of a given essential oil may depend on one or two of the major constituents. The ratio in which the main active constituents are present may not be the only factor responsible for the inherent activity of essential oils, but the interactions between these and minor constituents in the oils are also important. Essential oils possess important volatile compounds with diverse bioactivities including antimicrobial potential. The antimicrobial properties of EOs are mostly related to the individual susceptibility of bacteria.
[00085] In an embodiment, the composition of the present disclosure comprises essential oils in an amount ranging from 2% to 50% w/w. In an alternative embodiment, the composition of the present disclosure comprises essential oils in an amount ranging from 2% to 20% w/w. In an embodiment, the non-limiting examples of essential oils is selected from Light Mineral Oil, olive oil, coconut oil, shea butter, glycerol mono oleate, lavender oil natural, peppermint oil, lavender oil, tea tree oil, bergamot oil, chamomile oil, jasmine oil, ylang ylang oil, eucalyptus oil, lemon oil, cinnamon oil, lemon grass oil, clary sage oil, lavender oil, eucalyptus, rosemary oil, clove oil, frankincense oil, oregano oil, grapefruit oil and combinations thereof.
[00086] In an embodiment, the composition of the present disclosure comprises humectant in an amount ranging from 5% to 25% w/w. In an alternative embodiment, the composition of the present disclosure comprises the humectant in an amount ranging from 7% to 20% w/w. In an embodiment, the humectant is selected from glycerin, glycerol, propylene glycol, butylene glycol, sorbitol, polyethylene glycol, coconut oil, olive oil, jojoba oil and combinations thereof.
[00087] In an embodiment, the composition of the present disclosure comprises a surfactant in an amount ranging from 2% to 25% w/w. In an alternative embodiment, the composition of the present disclosure comprises a surfactant in an amount ranging from 4% to 25% w/w. Examples of surfactants useful in the compositions of the present disclosure include anionic surfactants, nonionic surfactants, amphoteric surfactants and mixtures thereof. Anionic surfactants useful herein include, but are not limited to, sarcosme type surfactants or sarcosmates; taurates such as sodium methyl cocoyl taurate; alkyl sulfates such as sodium trideceth sulfate or sodium lauryl sulfate; sodium lauryl sulfoacetate; sodium lauroyl isethionate; sodium laureth carboxylate; sodium dodecyl benzenesulfonate and mixtures thereof. Nonionic surfactants that can be used in the compositions of the present disclosure include, but are not limited to, Polyvinylpyrrolidone (PVP), compounds produced by the condensation of alkylene oxide groups with an organic hydrophobic compound which may be aliphatic or alkyl-aromatic in nature. Examples of suitable nonionic surfactants include, but are not limited to, alkyl polyglucosides; block copolymers such as ethylene oxide and propylene oxide copolymers e.g. Poloxamers; ethoxylated hydrogenated castor oils; Alkyl polyethylene oxide e g. Polysorbates, and/or; fatty alcohol ethoxylates; polyethylene oxide condensates of alkyl phenols; products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diamine; ethylene oxide condensates of aliphatic alcohols; long chain tertiary amine oxides; long chain tertiary phosphine oxides; long chain dialkyl sulfoxides; and mixtures thereof. The amphoteric surfactants useful in the compositions of the present disclosure include, but are not limited to, derivatives of aliphatic secondary and tertiary amines in which the aliphatic radical can be a straight chain or branched and wherein one of the aliphatic substituents contains from about 8 to about 18 carbon atoms and one contains an anionic water- solubilizing group, e.g., carboxylate, sulfonate, sulfate, phosphate, or phosphonate. Examples of suitable amphoteric surfactants include, but are not limited alkylimino-diproprionates, alkylamphoglycinates (mono or di), alkylamphoproprionates (mono or di), alkylamphoacetates (mono or di), N-alkyl b-aminoproprionic acids, alkylpolyamino carboxylates, phosphorylated imidazolines, alkyl betaines, alkylamido betaines, alkylamidopropyl betaines, alkyl sultaines, alkylamido sultaines,
and mixtures thereof. In certain embodiments, the amphoteric surfactant is selected from the group consisting of alkylamidopropyl betaines, amphoacetates such as sodium lauroamphoacetate and mixtures thereof. Mixtures of any of the above mentioned surfactants can also be employed. In an embodiment, the surfactant is selected from Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, Span 20, Span 40, Span 60, Span 80, lauramide DEA, cocamide DEA, cocamide MEA, glyceryl monostearate, stearic acid, polyethylene glycol ether of cetearyl alcohol, cetostearyl alcohol, lauroyl polyoxyl-32 glycerides, fatty alcohols, glycerol monooleate, glyceryl monostearate, emulsifying wax and combinations thereof. Non-ionic surfactants act as good emulsifying agents and stabilizers or stabilizing agents. Examples of suitable solubilizer include alcohols such as ethanol, sugars such as sorbitol, polyethylene glycols such as PEG-400, propylene glycol, cyclodextrms, sodium lauryl sulphate and other solubilizer agents or surfactant or a combination thereof.
[00088] In an embodiment, the composition further comprises an emulsifier. Non limiting examples include agar, starch, pectin, bentonite hectorite, veegum, cetyl alcohol, glyceryl stearate, cereth-20, steareth-20, glycerol mono oleate, polawax, stearic acid 50, glyceryl monostearate, Ceteareth 20, polyoxyl 20 cetostearyl ether, isopropyl myristate, polyoxyethylene 8 beewax, Tween 60, Span 80, GSM 40 and a combination thereof. Further, some commonly used emulsifier or emulsifying agents include tragacanth, sodium lauryl sulfate, cetostearyl alcohol, sodium dioctyl sulfosuccinate, and polymers known as the spans and tweens impart stability to the emulsion. Preferably, cetostearyl alcohol is used as emulsion stabilizer.
[00089] Further the composition may include a viscosity modifier. Examples include glyceryl stearate, GSM 40, poloxamer, cetostearyl alcohol 50 and the likes.
[00090] In an embodiment, the composition further includes any or a combination of: a skin penetration enhancer, a preservative, an antioxidant, a moisturizing agent, a film former/waterproofing agent, a polyhydric alcohol, amino acids or metabolites or derivatives thereof, a fatty acid or derivatives thereof, a pH adjuster/chelating agent, a rheology modifying agent, a fragrance, a colorant, and a vitamin.
[00091] In an embodiment, the composition includes a preservative in an amount ranging from 0.01% to 5% w/w, preferably, ranging from 0.03% w/v to 5% w/v, more preferably, ranging from 0.03% w/v to 3% w/v and most preferably, ranging from 0.03% w/v to 1% w/v. Examples of preservatives useful in the compositions of the present disclosure include methyl paraben, propyl
paraben, p-hydroxybenzoic acid esters, quaternary ammonium compounds such as benzalkonium chloride, sodium benzoate, benzyl alcohol, butanol, ethanol, isopropyl alcohol and the likes.
[00092] In an embodiment, the composition includes an antioxidant in an amount ranging from 0.01% to 5% w/w, preferably, ranging from 0.03% w/v to 5% w/v, more preferably, ranging from 0.03% w/v to 3% w/v and most preferably, ranging from 0.03% w/v to 1% w/v.. Examples of anti oxidants useful in the compositions of the present disclosure include sodium metabisulfite, vitamin A, tocopherol, ascorbic acid or salt or derivative thereof, tartaric acid or salt or derivative thereof, retinyl palmitate, Sesamol, thiol derivatives, Butylated Hydroxy Anisole (BHA), Butylated Hydroxyl Toluene (BHT), and mixtures thereof. However, any other anti-oxidant(s), as known to or appreciated by a person skilled in the art can also be used to serve its/their intended purpose as laid down in embodiments of the present disclosure.
[00093] In an embodiment, the composition includes a skin penetration enhancer in an amount ranging from 0.1% to 5% w/w. Examples of skin penetration enhancer useful in the compositions of the present disclosure include sulphoxides such as dimethylsulphoxide, DMSO, Azones such as laurocapram, pyrrolidones such as 2-pyrrolidone, alcohols and alkanols such as ethanol, or decanol, glycols such as propylene glycol and combinations thereof. In an embodiment, the skin penetration enhancer is diethylene glycol monoethyl ether.
[00094] Examples of polyhydric alcohols useful in the compositions of the present disclosure include polyhydric alkanes, polyhydric alkane esters, polyalkene glycols, and mixtures thereof. Polyhydric alkanes can be propylene glycol, glycerin, glycerol, butylene glycol, hexylene glycol, 1,3- propanediol and the likes, but not limited thereto. Polyhydric alkane esters can be dipropylene glycol, ethoxydiglycol and the likes, but not limited thereto. Polyalkene glycols can be polyethylene glycol, polypropylene glycol and the likes, but not limited thereto. The compositions of the present disclosure include polyhydric alcohol in an amount ranging from 5% w/v to 30% w/v, preferably, in an amount ranging from 5% w/v to 25% w/v, and more preferably, in an amount ranging from 5% w/v to 20% w/v. The hyaluronic acid has the ability to draw moisture from the environment to the skin delivering long-lasting moisture without clogging pores. By increasing skin's surface hydration, hyaluronic acid helps soften and smooth skin texture while also to improving the appearance of your skin's plumpness and firmness.
[00095] In an embodiment, the amino acids or metabolites or derivatives thereof include(s), but not limited to, glycine, glutamine, asparagine, arginine, lysine in biologically active enantiomeric forms, L-camitine, choline, betaine, taurine, glycosaminoglycans including hyaluronic acid,
chondroitin sulfate, glucosamine, L-glucosamine, heparins and mixtures thereof. In an embodiment, the composition includes hyaluronic acid or salt or derivative thereof in an amount ranging from 0.02% w/v to 3% w/v, preferably, ranging from 0.05% w/v to 2% w/v, more preferably, ranging from 0.1 % w/v to 1 % w/v and most preferably, ranging from 0.1% w/v to 0.5% w/v.
[00096] Examples of stabilizers useful in the compositions of the present disclosure include, but not limited to, gums, agar, propylene glycol, and taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins and mixtures thereof.
[00097] In an embodiment, the fatty acid(s) or derivatives thereof include(s), but not limited to, fatty acids with Cl to C30 carbons, which includes long chain fatty acids; saturated or unsaturated fatty acids and derivatives thereof (monounsaturated fatty acids (MUFAs) C18:ln- 12c, C16:ln-5, C16:4n-1 and the polyunsaturated fatty acids (PUFAs) C16:3n-4, C20:3n-3, C20:4n-6, C21:5n-3 and C18:2n-9c,12t); hydrogenated fatty acids; fatty acid glycerides; polyoxyethylated oleic glycerides; monoglycerides and diglycerides; mono-, bi- or tri-substituted glycerides; glycerol mono-oleate esters; glycerol mono-caprate; glyceryl monocaprylate; dicaprylate; laurate, monolaurate; glyceryl palmitostearate; glyceryl behenate; diethyleneglycol palmitostearate; polyethyleneglycol stearate; polyoxyethyleneglycol palmitostearate; glyceryl mono palmitostearate; cetyl palmitate; polyethyleneglycol palmitostearate; dimethylpolysiloxane; mono- or di-glyceryl behenate; fatty acid derivatives such as diglyceryl lauryl fumarate (DGLF), diglyceryl lauryl succinate, diglyceryl capryl succinate, diglyceryl capryl fumarate; fatty alcohols associated with polyethoxylate fatty alcohols; cetyl alcohol; octyldodecanol; myristyl alcohol; isopropyl myristate, isopropyl palmitate, stearic acid, lauric acid, EPA, DHA, linoleic acid, linolemc acid, stearyl alcohol and mixture thereof.
[00098] In certain embodiment the the fatty acid derivatives are the compounds of formula II, examples include any or a combination of: diglyceryl lauryl fumarate (DGEF), diglyceryl lauryl succinate, diglyceryl capryl succinate, and diglyceryl capryl fumarate. These are used as a carrier for topical formulation of zinc salt in combination with dexpanthenol with one or more other active agents as disclosed in the exemplified compositions.
[00099] . Topical therapeutic efficacy is highly dependent on skin conditions, physicochemical properties of the active substance and vehicle/formulation characteristics because of their significant impact on drug release and permeation.
[000100] The topical formulation is formulated to mitigate any oxidation reactions of ingredient used in the products, leading to deterioration including odor formation, color change, and physical
and/or chemical instability which can affect the quality, efficacy, and shelf-life of topical formulations and improve the topical or transdermal delivery of the active agents.
[000101] In an embodiment, the moisturizing agent(s) includes, but are not limited to lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, butylene glycol, sodium PCA, Carbowax 200, Carbowax 400, Carbowax 800, D-Panthenol, Olive oil, Coconut Oil, Lavender oil Natural, jojoba oil, soybean oil and combinations thereof.
[000102] In an embodiment, the film former/waterproofing agent(s) includes, but are not limited to acrylates/Ci2-22 alkylmethacrylate copolymer, C30-38 olefm/isopropyl maleate/methylacrylate copolymer, polyethylene, waxes, vinylpyrrolidone/dimethiconylacrylate/ polycarbamyl polyglycol ester, butylated polyvinylpyrrolidone, polyvinylpyrrolidone/hexadecane copolymer, polyvinylpyrrolidone/eicosene copolymer, tricontanyl polyvinylpyrrolidone, Brassica Campestris/Aleuritis Fordi Oil copolymer, aminofunctional silicones, decamethyl cyclopentasiloxane and trimethylsiloxysilicate, octadecene/ methylacrylate copolymer and combinations thereof.
[000103] In an embodiment, the pH adjuster or chelating agent(s) includes, but are not limited to sodium hydroxide, triethanolamine, EDTA salt and combinations thereof. The pH of the skin normally ranges from 4 to 6. The pH values of the topical composition were maintained similar to the skin’s normal pH value.
[000104] In an embodiment, the rheology modifying agent(s) include, but are not limited to acrylates crosspolymer, acrylates/Cio-30 alkylacrylate crosspolymer, polyacrylic acid, sodium polyacrylate, polyacrylate, acrylates/vinyl ester copolymer, PVP/decene copolymer, styrene/MA copolymer, acetamide MEA, acrylamides copolymer, acrylates copolymer, acrylates/steareth-20 methacrylate copolymer, acrylates/beheneth-25 methacrylate copolymer, PEG-150/decyl alcohol/SMDI copolymer, PVP, PVM/MA decadiene crosspolymer, carbomer, PEG crosspolymer, acrylates/palmeth-25 acrylates copolymer, polysaccharide, polyether-1, sodium magnesium silicate, bentonite, trihydroxystearin, hydroxy stearate, aluminum-magnesium hydroxide stearate, acacia gum, xanthan gum, microcrystalline cellulose, cellulose gum and combinations thereof. [000105] In an embodiment, the fragrance(s) includes, but are not limited to alcohols, aldehydes, ketones, esters, ethers, acetates, nitriles, terpene hydrocarbons, nitrogenous or sulfurous heterocyclic compounds and essential oils. However, naturally occurring plant and animal oils and exudates comprising complex mixtures of various chemical components are also known for use as "fragrance materials" . The individual perfume raw materials which comprise a known natural oil can be found
by reference to Journals commonly used by those skilled in the art such as "Perfume and Flavourist" or "Journal of Essential Oil Research", or those listed in reference texts such as the book by S. Arctander, Perfume and Flavor Chemicals, 1969, Montclair, New Jersey, USA and re-published by Allured Publishing Corporation Illinois (1994). Additionally, some perfume raw materials are supplied by the fragrance houses (Firmenich, International Flavors & Fragrances, Givaudan, Symrise) as mixtures in the form of proprietary specialty accords. Non-limiting examples of the fragrance materials useful herein include pro-fragrances such as acetal pro- fragrances, ketal pro- fragrances, ester pro-fragrances, hydrolyzable inorganic-organic pro- fragrances, and mixtures thereof.
[000106] In an embodiment, the colorant(s) includes, but are not limited to FD&C Red No. 40, FD&C Yellow No. 5 and combinations thereof.
[000107] In an embodiment, the vitamin(s) includes, but are not limited to vitamin A, thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, vitamin C, vitamin E, Vitamin B10 and their derivatives or combinations thereof.
[000108] While one or more embodiments of the present disclosure enumerates and describes a list of excipients that may be used in the composition to serve an intended purpose, it should be appreciated that one or more excipients may also serve more than one function, obviating the need of inclusion of separate excipients for the specified purpose. Although several embodiments of the present disclosure names few of the commonly used excipients, any other excipient known to or appreciated by a skilled person can also be used to realize the advantageous compositions of the present disclosure. Examples of useful excipients which can optionally be added to the composition are described in the Handbook of Pharmaceutical Excipients, 3rd edition, Edited by A. H. Kibbe, published by: American Pharmaceutical Association, Washington DC, ISBN: 0- 917330-96-X, and in Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond C Rowe - Publisher: Science and Practice.
[000109] The topical formulation can be prepared into various forms such as but not limited to solids, liquids, suspensions, semisolids such as creams, gels, lotions, pastes or sticks, powders and finely dispersed liquids such as sprays or mists.
[000110] In an embodiment, the composition is formulated as a topical cream. During experimentation, it could also be noted that when glyceryl monooleate is used, it dramatically improves spreadability of the formulation. Further, glyceryl monooleate forms a barrier film that significantly improves water repellency of the formulation. Rash creams are intended to reduce the
dermatitis and it should remain present on the skin for extended period of time showing its action even when the patient/subject urinates. So, it is ideal to prepare the formulation with water repellant property. The advantageous formulation of the present disclosure includes ingredients that are hydrophobic in nature and hence, naturally exhibits hydrophobicity. It could also be noted that lauric acid present in the coconut oil acts as an anti-microbial agent on the skin, while olive oil and glyceryl monooleate have emollient properties; and coconut oil and jojoba oil afford anti-inflammatory and healing properties. Accordingly, the formulations (and compositions) of the present disclosure can find utility in treatment of wide varieties of skin conditions.
[000111] While any conventional method as known to skilled artisans can be used for preparing the topical formulations of the present disclosure, it could be noted that if Dexpanthenol is added at the initial stages of process for preparing the formulation, it tends to degrade, and hence, dexpanthenol should preferably at a later stage of formulation preparation. It could also be noted that the consistency of the formulation tends to enhance greatly when zinc salt is grounded/milled at least for 30 minutes.
[000112] Accordingly, an aspect of the present disclosure provides a method of preparing a topical formulation, said formulation comprising zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof, the method comprising the steps of: (a) melt mixing an emollient, a humectant and a first surfactant to prepare a water immiscible phase; (b) preparing a zinc salt dispersion by mixing zinc salt and a second surfactant in water having temperature ranging from 55°C to 90°C; mixing the water immiscible phase with the zinc salt dispersion to obtain a uniform semisolid mixture; (d) preparing a dexpanthenol solution by dissolving dexpanthenol in water; (e) adding the dexpanthenol solution to the semisolid mixture upon the semisolid mixture reaching at a room temperature ranging from 20°C to 50°C with stirring to obtain a uniform mixture; (f) optionally, mixing any or a combination of: a fragrance and a preservative with the uniform mixture; and (g) making up the weight of the formulation with water to obtain the topical formulation.
[000113] The compositions realized in accordance with embodiments of the present disclosure can find utility in treatment of a wide variety of skin conditions/disorders including rashes, candidiasis, diaper rash and the likes, which may be caused by allergens or organisms (like bacteria, virus, fungi etc.). It could be noted that the components of the compositions realized in accordance with embodiments of the present disclosure exhibit high degree of functional reciprocity, wherein zinc salt exhibits anti-infective property and forms a protective barrier, while dexpanthenol exhibits healing property.
[000114] Accordingly, an embodiment of the present disclosure provides a method of treatment of a skin condition in a subject, said method comprising administering to a subject in need thereof an effective amount of a composition comprising: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof. In an embodiment, the composition is formulated as a topical formulation. In an embodiment, the skin condition is selected from rashes, candidiasis and diaper rash.
[000115] Further embodiments of the present disclosure provides a composition for use in treatment of a skin condition, said composition comprising: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof. In an embodiment, the composition is formulated as a topical formulation. In an embodiment, the skin condition is selected from rashes, candidiasis and diaper rash. [000116] Yet another embodiment of the present disclosure provides use of a composition for manufacture of a medicament for treatment of a skin condition, said composition comprising zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof. In an embodiment, the composition is formulated as a topical formulation. In an embodiment, the skin condition is selected from rashes, candidiasis and diaper rash.
[000117] Further embodiments of the present disclosure provides composition for treatment of a skin condition, said composition comprising: zinc salt and dexpanthenol or a salt or a hydrate or a solvate thereof. In an embodiment, the composition is formulated as a topical formulation. In an embodiment, the skin condition is selected from rashes, candidiasis and diaper rash.
[000118] The compositions of the present disclosure afford increased therapeutic effects, and reduced adverse effects, making these pharmaceutical compositions extremely effective therapeutics, especially in the treatment of skin diseases/conditions. Therapeutic levels of the combined drugs will vary from individual to individual and progression stage of disease. The combination medications in the appropriate amounts and intervals effective to treat skin disorders or diseases will necessarily be monitored both clinically and chemically by the medical experts or trained physicians.
[000119] Further, the patient may receive the specific dosage over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years and the like.
[000120] The choice of appropriate dosages for the drugs used in combination therapy according to the present disclosure can be determined and optimized by the skilled artisan, e.g., by observation of the patient, including the patient's overall health, the response to the combination
therapy, and the like. Optimization, for example, may be necessary if it is determined that a patient is not exhibiting the desired therapeutic effect or conversely, if the patient is experiencing undesirable or adverse side effects that are too many in number or are of a troublesome severity. [000121] It is especially advantageous to formulate compositions of the present disclosure in unit dosage form for ease of administration and uniformity of dosage. The specifications of the dosage unit forms of the present disclosure are dependent on the unique characteristics of the composition and the particular therapeutic effect to be achieved. Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients. Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995).
[000122] In an embodiment, the invention provides a method for treating allergic diseases/conditions, said method includes: providing a container that is suitable for storing the topical formulation for pharmaceutical use, the container comprising an applicator that is capable of dispensing a pharmaceutically effective dose of the topical formulation and spreading an approximately uniform amount of the topical formulation on a target area; loading the applicator with the dose of the topical formulation, and administering the dose of the topical formulation to the treatment area by uniform manual spreading. In some embodiment, the container is a squeeze sensitive container, and the applicator is a flow through applicator which delivers the topical formulation to the target area when a user applies sufficient pressure on the container.
[000123] In another embodiment, the topical formulation is delivered using a transdermal delivery system designed to deliver the composition to the skin and into systemic circulation. The transdermal delivery system may be matrix type, liquid or gel reservoir type. In some embodiments, topical delivery systems can be designed to deliver the active ingredient to local tissue.
[000124] Non-limiting examples of transdermal delivery systems include: iontophoresis, voltage-gradient iontophoresis, electroporation, sonophoresis, magnetophoresis, dermal patches (vapor patches, adhesive patches) nano carriers, needled and needle-less shots, microneedles, thermal ablation, microdermabrasion, electroporation, radiofrequency usage, microporation, use of thermal techniques, micro and radio waves, electro-mechanical devices, nano deliveries and cavitational ultrasound techniques and injectors such as jet injectors, powderject, Implaject®,
Crossjet®, Imitrex® and likes. Transdermal delivery systems deliver the active ingredient in a discrete dosage form from a skin-sticker patch or other transdermal methods/device by crossing through the skin layers to the systemic circulation. TDDS patches can be a single- and multiple layered devices, vapor patches, drug and polymer matrix characteristic-based products, as well as reservoir-based delivery systems. The patches may include polymeric membrane to control the drug release rate, which depends on the polymer properties, permeability coefficient, membrane thickness and the adhesive. The adhesive-dispersion type TDDS/devices uses polymer, such as polyisobutylene or polyacrylate, as the adhesive polymer with specific permeability thus controls the drug diffusion rate.
[000125] In some embodiment the topical composition is a transdermal patch filled with the precise dose of drug and stuck to the skin for easy delivery of the drug into the blood circulation with help from enhancers. In certain aspects, suitable polymers, permeation enhancers and solvents are employed. Examples include chitosan, a polysaccharide, hyaluronic acid, synthetic polymer- based hydrogels are prepared from polyacryhcs and polyacrylamide. Poly(2-hydroxyethyl methacrylate (p-HEMA), methyl methacrylate copolymers (Eudragit®), poly-N-vinylamide, povidone, and ±lactic acid oligomers (DLLO), polyurethanes (PUs), polyurethane elastomer hydrogels, acrylates, silicones, polyisobutylenes, Polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), polyacryhcs, Trihydroxy bile salts, monosodium glycolate, taurocholate sodium, dihydroxy salts, deoxycholate sodium, sodium glyco-deoxycholate and sodium taurodeoxycholate are also used as permeation enhancers. Binary system-based fatty acids, i.e. propylene glycol-oleic acid and 1,4-butane diol-linoleic acid, N, N-dimethyl-m-toluamide, calcium thioglycolate, eucalyptol, di-o-methyl-P-cyclodextrin, sodium caprylate mixed with glyceryl triglyceride, short chain glyceryl monocaprylate, imidic cyclic urea, cyclopentadecalactone, cyclodextrins, water, isopropyl alcohol, MCT 70, Transcutol P, and the likes can also be employed. [000126] In certain embodiments, the microneedles are used in combination with sonophoresis electroporation or iontophoresis to control the drug release rate and to provide improved delivery.
NON-LIMITING EXEMPLARY COMPOSITIONS [000127] BATCH ACG001C0140043(P) and ACG001C0140044(P)
[000128] Method of preparation of zinc oxide and dexpanthenol topical cream i. Water immiscible phase was prepared by charging White petrolatum, Light mineral oil, Olive oil, Coconut oil, Shea butter, Glycerol monooleate, White bees wax, Cetosteary alcohol, SPAN 60 and BHT into a heating vessel and melt mixing them. ii. ZnO dispersion: a part (25%) of the batch quantity water was taken in a vessel and heated to a temperature of 70°C-80°C; then ground/milled zinc oxide and Tween 60 were added to the heated water to prepare a ZnO dispersion. lii. Water immiscible phase obtained in Step (i) above was added to the ZnO dispersion obtained in Step (ii) and mixed to get a uniform semisolid mixture. lv. Dexpanthenol solution: a part (8%) of the batch quantity water was taken in a vessel and dexpanthenol was dissolved therein to prepare a dexpanthenol solution. v. The uniform semisolid mixture was allowed to cool down to room temperature of about 30°C and then the dexpanthenol solution was mixed therewith. vi. Finally, Lavender oil and BKC were added thereto, and final weight was adjusted with water to prepare topical cream formulation.
[000129] BATCH ACG001C0140040(P)
[000130] Topical cream formulation was prepared using the composition as provided in Table 2 below. Topical cream formulation was prepared following the same method as described in the above example.
Table 2: Composition for zinc oxide and dexpanthenol topical cream
[000131] BATCH ACG001C0140039
[000132] Topical cream formulation was prepared using the composition as provided in Table 3 below. Topical cream formulation was prepared following the same method as described in above example.
[000133] BATCH ACG001C0140038
[000134] Topical cream formulation was prepared using the composition as provided in Table 4 below. Topical cream formulation was prepared following the same method as described in the above example.
[000135] BATCH ACG001C0140037
[000136] Topical cream was prepared using the composition as provided in Table 5 below.
[000137] BATCH ACG001C0140034
[000138] Topical cream formulations were prepared using the composition as provided in Table 6 below.
Table 6: Compositions for zinc oxide and dexpanthenol topical cream
[000139] BATCH ACG001C0140021 (P)
[000140] Topical cream formulation was prepared using the composition as provided in Table 7 below. Topical cream formulation was prepared following the same method as described in above example.
[000141] BATCH ACG001C0140020
[000142] Topical cream formulation was prepared using the composition as provided in Table 9 below. Topical cream formulation was prepared following the same method as described in above example.
[000143] Manufacturing procedure:
Step 1: White petrolatum, Jojoba oil, Coconut oil, White bees wax, Polawax were charged into a heating vessel and allowed to dissolve
Step 2: Take 25 % in batch quantity of water and heat up to 70°C-80°C and disperse Calamine to get homogenous phase
Step 3: Add water immiscible phase obtained in Step 1 to the dispersion obtained in Step 2 and allowed to mix to get uniform semi solid phase Step 4: Take 8% batch quantity of water and dissolve dexpanthenol uniformly Step 5: Let the temperature of the semisolid phase obtained in Step 3, reach to 30°C slowly and then add dexpanthenol solution to get homogenous phase Step 6: Adjust the final weight with water
[000144] BATCH ACG001C0140019
[000145] Topical cream formulation was prepared using the composition as provided in Table 10 below. Topical cream formulation was prepared following the same method as described in above example.
[000146] BATCH ACG001C0140018
[000147] Topical cream formulation was prepared using the composition as provided in Table 11 below. Topical cream formulation was prepared following the same method as described in above example.
[000148] BATCH ACG001C0140017(P)
[000149] Topical cream formulation was prepared using the composition as provided in Table 12 below. Topical cream formulation was prepared following the same method as described in above example.
Table 12: Composition for zinc oxide and dexpanthenol topical cream
[000150] BATCH ACG001C0140015 & 16 (P)
[000151] Topical cream formulations were prepared using the compositions as provided in Table 13 below. Topical cream formulations were prepared following the same method as described in above example.
[000152] Manufacturing procedure:
Step 1: White petrolatum, Light mineral oil, Jojoba oil, Olive oil, Coconut oil, White bees wax, Hard paraffin wax, and Emulsifying wax were charged into a heating vessel and allowed to dissolve
Step 2: Take 25% in batch quantity of water and heat up to 70°C-80°C and disperse ZnO to get homogenous phase
Step 3: Add water immiscible phase obtained in Step 1 to the dispersion obtained in Step 2 and allowed to mix to get uniform semi solid phase
Step 4: Take Transcutol P and dissolve DGLF completely using magnetic stirrer for 30 minutes Step 5: Let the temperature of the semisolid phase obtained in Step 3, reach to 30°C slowly and then add DGLF solution to get homogenous phase Step 6: Take 8% batch quantity of water and dissolve dexpanthenol uniformly Step 7: Add dexpanthenol solution to semisolid phase obtained in step 5 to get homogenous phase Step 8: Adjust the final weight with water
[000153] BATCH ACG001C0140013& 14 (P)
[000154] Topical cream formulation was prepared using the composition as provided in Table 14 below. Topical cream formulation was prepared following the same method as described in above example.
[000155] BATCH ACG001C0140012 (P)
[000156] Topical cream formulation was prepared using the composition as provided in Table 15 below. Topical cream formulation was prepared following the same method as described in above example.
[000157] BATCH ACG001C0140010 & 11(P)
[000158] Topical cream formulation was prepared using the composition as provided in Table 16 below. Topical cream formulation was prepared following the same method as described in above example.
[000159] BATCH ACG001C0140007& 8 (P)
[000160] Topical cream formulation was prepared using the composition as provided in Table 17 below. Topical cream formulation was prepared following the same method as described in above example.
[000161] BATCH ACG001C0140006
[000162] Topical cream formulation was prepared using the composition as provided in Table 18 below. Topical cream formulation was prepared following the same method as described in above example.
[000163] BATCH ACG001C014005
[000164] Topical cream formulation was prepared using the composition as provided in Table 20 below. Topical cream formulation was prepared following the same method as described in above example.
Table 20: Compositions for topical cream
[000165] BATCH ACG001C014004
[000166] Topical cream formulation was prepared using the composition as provided in Table 21 below. Topical cream formulation was prepared following the same method as described in above example.
[000167] BATCH ACG001C0140003
[000168] Topical cream formulation was prepared using the composition as provided in Table 22 below. Topical cream formulation was prepared following the same method as described in above example.
[000169] BATCH ACG001C0140002(P)
[000170] Topical cream formulation was prepared using the composition as provided in Table 23 below. Topical cream formulation was prepared following the same method as described in above example.
[000171] BATCH ACG001C0140038
[000172] Topical cream formulation was prepared using the composition as provided in Tables 24- 27 below.
[000173] Batch No. ACG001C0140045 (P)
[000174] Batch No.:ACG001C0140046 (P)
[000175] Topical cream formulation was prepared using the composition as provided in Tables 27 to 30 and according to the process in general as disclosed below.
[000176] Manufacturing Process:
Step 1: Charge white petrolatum, Light mineral oil, Jojoba oil, Coconut oil, Shea butter, Glycerol mono Stearate 40, Polawax and Butylhydroxytoluene into a heating vessel and allow to dissolve at 70°C-80°C.
Step 2: Take 20 % in batch quantity of water and heat up to 70°C-80°C and disperse ZNO to get homogenous phase.
Step 3: Add water immiscible phase obtained in Step 1 to the dispersion obtained in Step 2 and mix to get uniform semi solid phase.
Step 4: Take 5% batch quantity of water and dissolve Benzalkonium chloride uniformly.
Step 5: Take 5% batch quantity of water, propylene glycol and dissolve D-panthenol uniformly. Step 6: Let the temperature of the semisolid phase obtained in Step 3, reach to 30°C slowly and then add benzalkonium chloride solution and dexpanthenol solution to get homogenous phase.
Step 7: Add Lavender oil natural to the above semisolid obtained at step 6.
Step 8: Adjust the final weight with water and filled into the container.
Table 28: Composition for topical cream comprising Cysteamme hydrochloride and Zn Sulphate.
[000177] Topical cream formulation was prepared using the composition as provided in Tables 31 and according to the process disclosed below.
[000178] Manufacturing procedure:
1. Non-aqueous phase was prepared by melting GMS 40, shea butter, cetyl alcohol, cetostearyl alcohol 50 and melted by heating to temperature 80 °C
2. Aqueous phase was prepared by dissolving all water-soluble ingredients such as Zinc sulphate, dexpanthenol, propylene glycol, alpha-tocopherol and EDTA into purified water.
3. The above aqueous phase was heated to 80 °C
4. Aqueous phase prepared in the step 2 was added to Step 1 and stirred until smooth semi solid consistency was obtained
5. Drug phase was prepared by adding cysteamme hydrochloride to 5% batch quantity of water
6. Lecithin was dissolved in the light mineral oil and the drug phase prepared in the above step was added to it and stirred for 15 minutes
7. Drug phase obtained in Step 5 was mixed to the semi-solid phase and continued stirring until homogenous phase obtained.
[000179] Topical cream formulation was prepared using the composition as provided in Tables 32 and according to the process disclosed below.
[000180] Manufacturing Process:
Step 1: Charge ceteareth 20, isopropyl myristate, shea butter, glycerol mono stearate 40, cetyl alcohol, cetostearyl alcohol 50 and butylhydroxytoluene into a heating vessel and allow to dissolve at 70°C-80°C.
Step 2: Take 50 % in batch quantity of water and heat up to 70°C-80°C and dissolve EDTA, zinc sulphate and xanthan gum uniformly.
Step 3: Take 5% batch quantity of water and dissolve cysteamine hydrochloride uniformly.
Step 4: Take 8% batch quantity of light mineral oil and dissolve lecithin at 70°C-80°C.
Step 5: Let the temperature of mixture obtained at step 4 to reach room temperature slowly and then add cysteamine hydrochloride solution obtained in Step 3 to step 4 and allow to mix completely. Step 6: Add water phase obtained in step 2 to the oil phase obtained in step 1 at 70°C-80°C and mix well for 15 mins and let the temperature reach to 30°C slowly and then add drug phase obtained at step 5 and mix to get uniform semi solid phase.
Step 7: Take propylene glycol and dissolve D-panthenol uniformly.
Step 8: Take 1% batch quantity of light mineral oil and dissolve a- tocopherol uniformly.
Step 9: Add step 7 and step 8 to step 6 to get homogenous phase.
Step 7: Add phenoxy ethanol to the above semisolid obtained at step 9.
Step 8: Adjust the final weight with water and filled into the container.
Merits of the Present Invention:
[000181] In the present invention the topical formulation is intended to reduce the dermatitis associated with diaper or nappy rashes thus it important for the formulation to be present at the area of application for a longer duration. The skin in the area of application is constantly exposed to urine and stools. Therefore, the topical formulation of present invention is prepared with water repellant properties by selecting hydrophobic ingredients for the formulation preparation. The Formulations are prepared using water immiscible ingredients such as hydrocarbons (Petrolatum, mineral oil and others as disclosed above in the paragraphs and examples, fatty acid alcohols, various natural oils (Olive oils, coconut oil and other), waxes (Polawax, white bees wax, hard paraffin wax and others) to impart the water repellent property to the composition and water (105 to 20%) to disperse ZNO. [000182] The multi-functional excipients used in the formulation such as coconut oil have moisturizing effect as well as antimicrobial effect, it reduces the presence of bacteria, fungi & virus on the skin due to the presence the fatty acid such as lauric acid. Further the coconut oil and jojoba oil in the composition have anti-inflammatory properties and support in healing of wounds. The olive oil and glyceryl monooleate used in the composition acts as emollient.
[000183] The spreadability profile of the topical formulation is achieved by adjusting the ratios of waxes and oils used in the formulation. The ratios of waxes and oils in 1 :4 ratio was found to achieve desired spreadability to improve the ease of application especially, at gluteal region where the tissue is soft and sensitive was studied. During the process it was observed that when percentage of waxes is more than 10 % w/w, the spreadability decreased in various degrees depending upon the type of waxes being used and when the percent is less than 10% w/w the composition is slippery and sticky. The desired spreadability of the composition observed when the percentage of waxes in the composition is <10 % w/w of the total weight of the composition. Spreadability is further enhanced by incorporating a multifunctional excipient such as glyceryl monooleate which helps to provide occlusive layer that forms the barrier on the skin to improves water repellency and spreadability of the formulation significantly. Dexpanthenol used in the composition is known for its healing property and other features as described in the earlier paragraphs.
[000184] Zinc oxide (ZnO) in the composition if not milled before incorporating into the formulation results in grittiness. A well-grounded or milled ZnO, prior to incorporating it into the formulation is essential to elicit its bacteriostatic effect quickly. Therefor the ZnO was grounded at least for 30 minutes.
[000185] The polawax and GMS 40 works as emulsifiers to bring homogeneity in the formulation. Mixing of the formulations for extended period of time (not less than 30 minutes) was observed as essential to improving homogeneity of the topical composition.
[000186] At the given pH of the formulation, ZnO remains non-ionic, undissolved or in suspended state, thus, preventing systemic absorption and the formulation is stable and remain on the skin for a longer period of time when application due to its water repellence property, thereby, extending the action of ZnO at the site of application.
Challenges in the development of the topical formulation/composition:
[000187] During the topical composition/formulation development process, it was observed that dexpanthenol degraded when it was added at its initial stage of the manufacturing process. Therefore, the order of adding the dexpanthenol during the process was changed and it was added at final stages of the manufacturing process and at room temperature which stabilized dexpanthenol in the composition. Further, in the process it was noticed that dexpanthenol in the topical composition was unstable in the absence of a stabilizer necessitating the overages. Addition of propylene glycol retarded the degradation of dexpanthenol thus, avoiding the necessity of the incorporation of overages. Further, the consistency of the topical formulation increased when zinc salt in the composition was grounded at least for 30 minutes.
[000188] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
Claims
1. A composition comprising: zinc salt, dexpanthenol or a salt or a hydrate or a solvate thereof, said composition being formulated as a topical formulation.
2. A composition comprising zinc salt, dexpanthenol, formula II or a salt or a hydrate or a solvate thereof, said composition being formulated as a topical formulation.
3. The composition as claimed in claim 1 , wherein the zinc salt is selected from zinc oxide or zinc sulfate.
4. The composition as claimed in claim 2, wherein the formula II is selected from dilaurylglycerylfumarate, dicaprylglycerylfumarate or dilaurylglyceryl succinate.
5. A composition comprising zinc salt, dexpanthenol, cysteamine or a salt or a hydrate or a solvate thereof, said composition being formulated as a topical formulation.
6. The composition as claimed in claim 5, wherein the zinc salt is selected from zinc oxide or zinc sulfate.
7. A composition comprising zinc salt, dexpanthenol, cysteamine a salt or a hydrate or a solvate, formula II or a salt or a hydrate or a solvate thereof, said composition being formulated as a topical formulation.
8. The composition as claimed in claim 7, wherein the zinc salt is selected from zinc oxide or zinc sulfate.
9. The composition as claimed in claim 7, wherein the formula II is selected from dilaurylglycerylfumarate, dicaprylglycerylfumarate or dilaurylglyceryl succinate.
10. The composition as claimed in claim 1, claim 2, claim 5, claim 7, wherein the composition further comprises an active agent selected from the group comprising: a topical antibacterial agent, immunosuppressant, PDE inhibitors, JAK Inhibitor, sun blocks, sunscreen, essential oils, a topical antifungal agent, a topical steroid, vitamin or derivative thereof, an amino acid or derivative thereof, a fatty acid or derivative thereof and combinations thereof.
11. The composition as claimed in claim 1, claim 2, claim 5, claim 7, wherein the composition further comprises an excipient.
12. The composition as claimed in claim 11, wherein the excipient is selected from any or a combination of a diluent, an emollient, a humectant, a preservative, a solvent, natural oils, essential oils, a fragrance, an emulsifier, a preservative, an antioxidant, a penetration enhancer a fatty acid or derivative thereof, an amino acid or metabolite or derivative thereof, a surfactant, a solubilizer and a stabilizer or a combination thereof.
13. The composition as claimed in claim 1, wherein the composition is formulated as a topical cream, lotion, solution, gel, ointment, emulsion, spray formulation.
14. The composition as claimed in claim 12, wherein the emollient is selected from white petrolatum, mineral oil, isopropyl myristate, cetyl alcohol, beeswax, paraffin wax, cetomacrogol, sumac wax, shea butter and combinations thereof.
15. The composition as claimed in claim 12, wherein the humectant is selected from glycerin, glycerol, propylene glycol, butylene glycol, sorbitol, polyethylene glycol, coconut oil, olive oil, jojoba oil, castor oil and combinations thereof.
16. The composition as claimed in claim 12, wherein the surfactant is selected from Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, Span 20, Span 40, Span 60, Span 80, Tween 60, lauramide DEA, cocamide DEA, cocamide MEA, Kolliphor 20, Kolliphor 40, Kolliphor 60, Kolliphor 80, glyceryl monostearate, stearic acid, polyethylene glycol ether of cetearyl alcohol, cetostearyl alcohol, lauroyl polyoxyl-32 glycerides, fatty alcohols, glycerol monooleate, glyceryl monostearate, emulsifying wax and combinations thereof.
17. The composition as claimed in claim 12, wherein the stabilizer is propylene glycol.
18. The composition as claimed in claim 12, wherein the composition further comprises of a emulsifier for improving the homogeneity of the composition wherein the emulsifier is selected from polawax and GMS 40.
19. The composition as claimed in claim 12, wherein the composition further comprises a preservative wherein the preservative is selected from methyl paraben, propyl paraben, p-
hydroxybenzoic acid esters, quaternary ammonium compounds such as benzalkonium chloride, sodium benzoate, benzyl alcohol, butanol, ethanol and isopropyl alcohol..
20. The composition as claimed in claim 7, wherein the composition further comprises an antioxidant wherein the antioxidant is selected from anti- oxidants useful in the compositions of the present disclosure include sodium metabisulfite, vitamin A, tocopherol, ascorbic acid, tartaric acid, retinyl palmitate, sesamol, Butylated Hydroxy Anisole (BHA) and Butylated Hydroxyl Toluene (BHT). .
21. The composition as claimed in claim 7, wherein the composition further comprises a skin penetration enhancer wherein the penetration enhancer is selected from sulphoxides such as dimethylsulphoxide, DMSO, azones, laurocapram, pyrrolidones, 2-pyrrolidone, alcohols, alkanols , ethanol, decanol, glycols, propylene glycol.
22. The composition as claimed in claim 10, wherein the active agent is selected from corticosteroids, hydrocortisone, hydroxyltriamcinolone, alphamethyl, dexamethasone, dexamethasone-phosphate, beclomethasone, cysteamine hydrochloride, calamine, dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone, diacetate, diflucortolone, valerate, fluadrenolone, fluclarolone, acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine, butylester, fluocortolone, fluprednidene (fluprednylidene)acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylpredmsolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone, diacetate, fluradrenalone, acetonide, medrysone, amciafel, amcinafide, betamethasone, chlorprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone, valerate, hydrocortisone cyclopentylproprionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone, miconazole, econazole, ketoconazole, sertaconazole, itraconazole, voriconazole, clioquinol, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, saperconazole, clotrimazole, haloprogin, butenafme, tolnaftate, nystatin, amorolfme, naftifme, griseofulvin, azathioprme, mycophenolic acid, leflunomide, teriflunomide, ciclosporin, pimecrolimus, tacrolimus, voclosporin, lenalidomide,
pomalidomide, thalidomide, apremilast, sirolimus, everolimus, ridaforolimus, temsirolimus, umirolimus, zotarolimus, baricitinib, blisibimod, nilotinib, filgotinib, tofacitmib, upadacitinib, abatacept, belatacept, etanercept pegsunercept, aflibercept, alefacept, rilonacept, apremilast, arofylline, atizoram, benafentrine, catramilast, CC-1088, CDP-840, CGH-2466, cilomilast, cipamfylline, crisaborole, denbutylline, difamilast, drotaverine, etazolate, filaminast, glaucine, HT-0712, ICI-63197 indimilast, irsogladine, lavamilast, lirimilast, lotamilast, luteolin, mesembrenone, mesembrine, mesopram, oglemilast, piclamilast, pumafentrine, revamilast, Ro 20-1724, roflumilast, rolipram, ronomilast, RPL-554, RS-25344, tetomilast, tofimilast, YM- 976, zardaverine, ibudilast, roflumilast, adibendan, amrinone (inamrinone), anagrelide, benafentrine, bucladesine, carbazeran, cilostamide, cilostazol, enoximone, imazodan, KMUP- 1 , menbendan, milrinone, olprinone, parogrelil , pimobendan, pumafentrine , quazinone, RPL- 554, siguazodan, trequinsin, vesnarinone, zardaverine, acetildenafil, aildenafil, avanafil, beminafil, benzamidenafil, dasantafil, icariin, gisadenafil, homosildenafil, lodenafil, mirodenafil, MY-5445, Nitrosoprodenafil, Norcarbodenafil, SCH-51866, Sildenafil, Sulfoaildenafil, T-0156, Tadalafil, Udenafil, Vardenafil, abrocitinib, baricitinib, filgotinib, momelotimb, oclacitmib, peficitmib, ruxolitimb, tofacitmib, tasocitmib, CP-690550, upadacitinib, atiprimod, AZD-1480, baricitinib, chz868, cucurbitacin i (elatencin B, JSI-124) CYT387 lestaurtinib, NSC-7908, NSC-33994, pacritimb, peficitinib, ruxolitinib, SD-1008, cercosporamide, decernotinib (VX-509), peficitinib, TCS-21311, WHI-P 15 ZM-39923, ZM- 449829, p-Aminobenzoic acid, Padimate O, phenylbenzimidazole sulfonic acid, cinoxate, dioxybenzone, oxybenzone, homosalate, menthyl anthramlate, octocrylene, octyl methoxycinnamate, octyl salicylate, sulisobenzone, trolamine salicylate, avobenzone, ecamsule, titanium dioxide, vitamin A and their derivatives retinol, retmaldehyde, retinyl esters, oxoretinoids, retinyl palmitate and retinyl acetate, vitamin C and their derivatives L-ascorbic acid, ascorbyl palmitate, and magnesium ascorbyl phosphate, Vitamin B3/Niacinamide and their derivatives, vitamin B-5 /pantothenic acid and their derivatives, Vitamin E / a-tocopherol and their derivatives, Vitamin K/phytonadione and their derivatives,, calciferols and their derivatives, nor-leucme, nor-valine, L-alloisoleucine, L-threoisolucine D, L, or DL-leucine- containing di- and tri-peptides, D,L, or DL- valine-containing di- and tri-peptides, D,L, or DL- isoleucine-containing di- and tri-peptides, nitrogen-free analogues of branched chain amino acids, branched chain alpha-keto acids, isovaleryl-CoA, isovalerylcarnitine, isovaleryglycine, isovaleric acid, beta-methylcrotonyl-CoA, beta-methylcrotonylcarnitine, beta-
methylcrotonylglycine, beta-methylcrotonic acid, beta- methylglutaconyl-CoA, beta- methylglutaconylcarnitine, beta-methylglutaconylglycine, beta- methylglutaconic acid,beta- hydroxy-beta-methylglutaryl-CoA, beta-hydroxy-beta- methylglutarylcarnitine, beta- hydroxy-beta-methylglutarylglycine, beta-hydroxy-beta- methylglutaric acid, acetyl-CoA, acetylcarnitine, acetylglycine, acetoacetyl-CoA, acetoacetylcarnitine, acetoacetylglycine, isobutyryl-CoA, isobutyrylcarnitme, isobutyrylglycine, isobutyric acid, methylacrylyl-CoA, methylacrylylcarnitine, methylacrylylglycine, methylacrylic acid, beta-hydroxyisobutyryl- CoA, beta-hydroxyisobutyrylcamitine, beta- hydroxyisobutyrylglycine, beta- hydroxyisobutyric acid, methylmalonate semialdehyde, propionyl-CoA, propionylcarnitine, propionylglycine, propionic acid, D-methylmalonyl-CoA, L- methylmalonyl-CoA, DL-methylmalonyl-CoA, D-methylmalonylcarnitine, L- methylmalonylcarnitine, DL-methylmalonylcarnitine, D-methylmalonylglycine, L- methylmalonylglycine, DL-methylmalonylglycine, methylmalonic acid, succinyl-CoA, succinylcarnitine, succinylglycine, succinic acid, alpha-methylbutyryl-CoA, alpha- methylbutyrylcarnitine, alpha-methylbutyrylglycine, alpha-methylbutyric acid, tiglyl-CoA, tiglylcarnitme, tiglylglycme, tiglic acid, alpha-methyl-beta-hydroxybutyryl-CoA, alpha- methyl- beta-hydroxybutyrylcarnitine, alpha-methyl-beta-hydroxybutyrylglycine, alpha- methyl-beta- hydroxybutyric acid, alpha-methylacetoacetyl-CoA, alpha- methylacetoacetylcarnitine, alpha- methylacetoacetylglycine, alpha-methylacetoacetic acid, and combinations thereof.
23. A method of treating a skin condition in a patient in need thereof comprising administering to a subject a therapeutically effective amount of the composition of any of the preceding claims.
24. Use of the pharmaceutical composition of any of the preceding claims in preparation of a medicament for the treatment of a skin condition in patient in need thereof.
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US20020041854A1 (en) * | 2000-05-19 | 2002-04-11 | Anke Hadasch | Cosmetic compositions in powder form comprising a binder, and make-up and cosmetic care methods |
US20050070551A1 (en) * | 2002-02-15 | 2005-03-31 | Julius Remenar | Novel crystalline forms of conazoles and methods of making and using the same |
WO2018096497A1 (en) * | 2016-11-28 | 2018-05-31 | Cellix Bio Private Limited | Compositions and methods for the treatment of fungal infections |
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US20020041854A1 (en) * | 2000-05-19 | 2002-04-11 | Anke Hadasch | Cosmetic compositions in powder form comprising a binder, and make-up and cosmetic care methods |
US20050070551A1 (en) * | 2002-02-15 | 2005-03-31 | Julius Remenar | Novel crystalline forms of conazoles and methods of making and using the same |
WO2018096497A1 (en) * | 2016-11-28 | 2018-05-31 | Cellix Bio Private Limited | Compositions and methods for the treatment of fungal infections |
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