EP1865896A1 - Enhancement of macrolide penetration through human skin - Google Patents
Enhancement of macrolide penetration through human skinInfo
- Publication number
- EP1865896A1 EP1865896A1 EP06738155A EP06738155A EP1865896A1 EP 1865896 A1 EP1865896 A1 EP 1865896A1 EP 06738155 A EP06738155 A EP 06738155A EP 06738155 A EP06738155 A EP 06738155A EP 1865896 A1 EP1865896 A1 EP 1865896A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- macrolide
- skin
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
Definitions
- This invention relates to the field of topical drug delivery and more specifically to the field of enhancing topical delivery of macrolides for treatment of skin disorders.
- the invention relates to the delivery of physiologically active molecules with molecular weights between 500 Daltons and 1200 Daltons.
- the administration of drugs and other biological materials to the bloodstream via a transdermal route of administration has received much attention in recent years.
- the skin of an average adult covers more than two square meters of surface area and receives about one-third of all blood circulating through the body. It is elastic, rugged, and generally self- generating.
- Human skin consists of two layers: the epidermis (which is a composite of multiple layers including the stratum corneum), and the dermis.
- the stratum corneum represents the rate-limiting step in diffusion of chemical through the skin.
- the S. C. represents the rate-limiting step in diffusion of chemical through the skin.
- the S. C. is composed of dead, keratinized, metabolically inactive cells which are closely packed together, and consists of an amorphous matrix of mainly lipoid and nonfibrous protein within which keratin filaments are distributed.
- the cells of the S. C. generally contain 20% water, while the cells below, in the stratum germinativum, contain 70% water. The S. C. does not become hydrated readily. Thus, transdermal permeation is primarily controlled by diffusion through the S.C.
- transdermal delivery systems often have major drawbacks. For example, they are restricted to low-molecular weight drugs and those with structures having the proper lipophilic/hydrophilic balance. High molecular weight drugs or drugs with too high or low hydrophilic balance often cannot be incorporated into current transdermal systems in concentrations high enough to overcome their impermeability through the stratum corneum.
- the literature has shown that chemical transdermal delivery systems, where the skin is undamaged or unaltered, are limited to drugs having a molecular weight of less than 500 Daltons, for example, see JD Bos and MM Meinardi, The 500 Dalton Rule for the Skin Penetration of Chemical Compounds and Drugs. 1 : Exp. Dermatol. Jun 2000; 9(3): 165-9.
- Transdermal delivery is generally restricted to those small molecule medications requiring delivery rates less than 10 mg/day. In order to obtain higher blood levels, the rate of drug delivery must be increased.
- absorption promoters include dimethyl sulfoxide (DMSO), ethylene glycol, hexanol, fatty acid and esters, and pyrrolidone derivatives, among others.
- DMSO dimethyl sulfoxide
- ethylene glycol ethylene glycol
- hexanol hexanol
- fatty acid and esters fatty acid and esters
- pyrrolidone derivatives among others.
- Azone N-dodecyl azacycloheptan-2- one.
- Applicants have previously developed a new class of compounds which are derivatives of 1 ,3-dioxanes and 1 ,3-dioxolanes for use as skin penetration enhancing compounds. These compounds, which have been made commercially available under the trademark SEPA ® , are described in detail in U.S. Pat. No. 4,861 ,764. Work with the dioxolane enhancers has been described in several literature and patent publications. For example, Samour, et al., Proc. Int. Symp. Control. ReI. Bioact. Mater. 16: 183-184 (1989); Marty, et al., Proc. Int. Symp. Control. ReI. Bioact. Mater.
- the present invention has as a principal object to provide a stable topical composition effective for the treatment of skin disorders with a macrolide.
- the invention can include a corticosteroid in addition to the macrolide.
- compositions of the invention are intended for topical noninvasive application to the skin, providing non-systemic, localized absorption of the macrolide active ingredient, and any other co-active ingredients for treatment of skin disorders.
- the composition of the present invention can be applied as needed to the affected part of the skin. For example it can be applied one to four times a day.
- these macrolides can include tacrolimus, pimecrolimus, sirolimus, ascrolimus, everolimus, ascomycins such as ascomycin, dunaimycins such as dunaimycin, rapamycins such as rapamycin, prolylrapamycin, 32- desmethylrapamycin, 32-desmethoxyrapamycin and other lactone based compounds.
- Suitable macrolides include the chemical whose structure is:
- Additional suitable macrolides include 17-allyl-1 ,14-dihydroxy-12-[2- (4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21 ,27-tetramethyl-11 ,28-dioxa-4-azatricyclo[22.3.1 .0. 4>9 ]octacos-18- ene-2,3,10,16-tetraone and FK 506.
- the macrolide can be present in amounts ranging from 0.01-5.0 wt.% relative to the weight of the composition, preferably 0.01-2.0 wt.% relative to the total composition.
- the macrolide can be present in the follow wt. % relative to the weight of the composition: 0.01 , 0.05, 0.1 , 0.5, 1 , or 1.5.
- Examples of some of the skin disorders that can be treated with the composition include psoriasis, eczema, atopic dermatitis, erythema, pelagra, allergic contact dermatitis, poison ivy, poison oak, poison sumac and other skin disorders.
- the penetration of the active ingredient through the skin is preferably enhanced to an acceptable level by including in the composition an effective amount of a skin penetration enhancing compound in the form of a skin modifying agent of the substituted 1 ,3-dioxacyclopentane and substituted 1 ,3-dioxacyclohexane types disclosed in U.S. Pat. No. 4,861 ,764, the disclosure of which is incorporated herein in its entirety by reference thereto, or the corresponding substituted acetal compound.
- Representative examples of the skin penetration enhancing compounds include: [0023] 2-substituted 1 ,3-dioxolanes of the formula (I):
- R preferably represents a C 7 to Cu hydrocarbyl group
- R 0 , R-i, R2, R3, R4, R5, and Re each, independently, represent hydrogen or a Ci to C 4 alkyl group
- R'i and R f 2 each, independently, represent Ci to C 4 alkyl group.
- the hydrocarbyl group for R may be a straight or branched chain alkyl, alkenyl or alkynyl group, especially alkyl or alkenyl.
- R represents a C 7 to C12 aliphatic group; especially C 7 to C 10 aliphatic group.
- suitable alkyl groups include, for example, n-hexyl, n-heptyl, n- octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 2-methyl-octyl, 4-ethyl-decyl, 8- methyl-decyl, and the like.
- the straight chain alkyl groups such as n-heptyl, n-octyl, n-nonyl and n-decyl, are especially preferred.
- alkenyl groups include, for example, 2-hexenyl, 2-heptenyl, 2-octenyl, 2-nonenyl, 2 l ,6'-dimethyl-2 ⁇ 6 I -heptadienyl I 2 ⁇ 6'-dimethyl-2 I heptaenyl, and the like.
- the R group may also be substituted by, for example, halo, hydroxy, carboxy, carboxamide and carboalkoxy.
- the C 1 to C 4 alkyl group may be, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, and the like.
- the preferred alkyl groups for R 0 , and for Ri to R 6 and for R'i and R' 2 are alkyl having 1 or 2 carbon atoms, most especially ethyl.
- Ro, and Ri to Re may also, preferably, all be hydrogen.
- Specific skin modifying agents include, for example, 2-n-pentyl-1 ,3- dioxolane, 2-n-heptyl-1 ,3-dioxolane, 2-n-nonyl-1 ,3-dioxolane, 2-n-undecyl-1 ,3- dioxolane, 2-n-nonyl-1 ,3-dioxane, 2-n-undecyl-1 ,3-dioxane, 2-n- heptylaldehyde-acetal, 2-n-octyl-aldehyde-acetal, 2-n-nonylaldehyde-acetal, 2-n-decylaldehyde-acetal, 3,7-dimethyl-2,6-octadienal (citral), citronal and the like.
- 2-n-nonyl-1 ,3-dioxolane is especially preferred and is commercially available from MacroChem
- Examples of other skin penetration enhancers and co-solvents that may be added in addition to the skin modifying agent include dimethyl sulfoxide (DMSO), polyethylene glycol monolaurate, ethylene glycol, alkyl lactams, long chain amides, hexanol, fatty acids and their esters, and pyrrolidone derivatives.
- DMSO dimethyl sulfoxide
- polyethylene glycol monolaurate ethylene glycol
- alkyl lactams ethylene glycol
- long chain amides hexanol
- hexanol hexanol
- fatty acids and their esters include pyrrolidone derivatives.
- the solubilizing and/or absorption-promoting agents that can be used in the present invention means an agent which can dissolve the active or actives or their pharmaceutically acceptable salts with a concentration of at least 0.01 % relative to the total weight of the composition, and further promote the absorption of the active(s) or their pharmaceutically acceptable salts through skin.
- the solubilizing and/or absorption- promoting agent affords solubilizing and absorbing abilities to the active(s) or their pharmaceutically acceptable salts.
- absorption promoters and/or solubilizers include: alkane dicarboxylic esters such as alkane dicarboxylic dialkyl esters (dimethyl adipate, diethyl adipate, diisopropyl adipate, diethyl pimelate, diethyl sebacate, dipropyl sebacate etc.); and higher alkane carboxylic alkyl esters (isopropyl myristate, ethyl myristate, etc.).
- the amount of the skin modifying agent is selected to provide the desired delivery rate for the active compound by taking into consideration such additional factors as, product stability, side effects, carrier system and the like.
- compositions are generally formulated as gels, especially aqueous-alcoholic gels.
- lotions, creams, mousses, aerosols, ointments, lubricants, lacquers, patches, solutions, tinctures, and the like may be used so long as when applied to the affected area of the skin the formulation will stay in place, i.e., without run-off, for sufficient time, to permit an individual to spread and retain the composition over and on the affected area.
- the vehicle for any of the forms of the compositions of the invention may also include glycol, e.g., propylene glycol, butylene glycol, hexylene glycol, etc. (except in the case of the third embodiment described above), lower alcohol, e.g., ethanol, isopropanol, and, usually, water.
- glycol e.g., propylene glycol, butylene glycol, hexylene glycol, etc.
- lower alcohol e.g., ethanol, isopropanol
- the skin penetration enhancing dioxolane, dioxane or acetal is included in the formulations in an amount effective to enhance the penetration of the active ingredient through the skin, including the stratum corneum.
- a suitable vehicle or carrier system for a composition comprising a macrolide and a skin modifying agent can be an aqueous or non-aqueous alcoholic carrier containing sufficient alcohol, especially ethanol and/or isopropanol and, often, glycol, e.g., propylene glycol, to solubilize the macrolide and be miscible with the skin modifying agent.
- an aqueous or non aqueous alcoholic carrier can contain from about 1 to about 99% by weight, for example 15 to about 85%, or 30 to about 70%, or 35 to about 55% by weight of the composition of ethyl alcohol and/or isopropyl alcohol.
- Mixtures of ethanol and isopropanol in proportions providing the desired solubility of the macrolide and compatibility with the enhancer can also be used.
- the total amount of the aqueous or non-aqueous, alcoholic carrier will depend on the amount of macrolide, amount and type of enhancer, and the form of the composition, e.g., gel, cream, ointment, etc.
- amounts of the aqueous or non-aqueous alcoholic carrier within the range of from about 1% to about 98% such as between about 20 and 95%, or between 70% and 90% by weight may be used.
- the aqueous carrier can contain water between 15 and about 89% by weight, for example 20 to about 80%, or from 25 to about 70% or from about 30 to about 60 % by weight of the composition. Mixtures of water and alcohol, e.g.
- ethanol, propanol, ethylene glycol, propylene glycol can be used in ratios of wateralcohol ranging from 20:80 to about 90:10, such as about 40:60, about 45:55, about 50:50 about 55:45 about 60:40.
- a thickening agent such as hydroxypropyl cellulose
- a thickening agent such as hydroxypropyl cellulose
- any other pharmaceutically acceptable thickening/gelling agent may be used.
- the amount of the thickening agent is not particularly critical and can be selected to provide the desired product consistency or viscosity to allow for easy application to the skin but which will not be too watery or loose so that it will stay where applied. Generally, depending on its molecular weight, amounts of thickening agent up to about 5%, such as, for example, from 0.1 to about 2%, of the composition will provide the desired effect.
- the formulations may, optionally, include one or more moisturizers for hydrating the skin and emollients for softening and smoothing the skin.
- Glycerin is an example of such a suitable moisturizing additive.
- the additive will usually be incorporated in an amount of up to about 5 percent by weight of the composition, for example, from about 0.1 to 5%.
- the carrier can also include a lipophilic component which can comprise from about 1% to about 60% of the total weight of the composition, such as about 1 to about 30% or about 1 to about 10%.
- Lipophilic components of the formulation can be fatty acid material.
- “Fatty acid material” may include blends of fatty acids, typically containing fatty acid moieties with chain lengths of from C8 to C30.
- the fatty acid material may also contain relatively pure amounts of one chain length fatty acid moiety.
- Suitable fatty acids from which fatty acid/nonionic surfactant base mixtures may be derived include pelargonic, lauric, myristic, palmitic, stearic, isostearic, oleic, linoleic, ricinoleic, arachidic, behenic and erucic acids.
- suitable fatty acid materials may contain unsaturated fatty acid moieties, and may contain fatty acid moieties having a degree of substitution, such as e.g.
- the chain length of the components of the fatty acid material also determines the rheological properties of the resultant skin composition base.
- a fatty acid material mix containing relatively high proportions of stearic and palmitic acid moieties has been found to be particularly suitable for use for manufacturing skin creams and lotions which may be used in temperate to hot climates, while fatty acid material mixtures containing relatively high amounts of lower chain length fatty acid moieties (e.g. more than 50% of the fatty acid moiety having a chain length of C8-C14) may also be suitable for the preparation of skin compositions for use in relatively cold climates.
- Additional additives in the compositions can include skin care actives which are acidic in aqueous solution, such as for example fatty acids, such as alpha hydroxy fatty acids including lactic acid and glycolic acid; as well as peroxides such as hydrogen peroxide, vitamins such as vitamin B3, and polysaccharides such as chitosan; particularly preferred alpha hydroxy fatty acids are lactic acid and glycolic acid.
- skin care actives which are acidic in aqueous solution, such as for example fatty acids, such as alpha hydroxy fatty acids including lactic acid and glycolic acid; as well as peroxides such as hydrogen peroxide, vitamins such as vitamin B3, and polysaccharides such as chitosan; particularly preferred alpha hydroxy fatty acids are lactic acid and glycolic acid.
- Emollient materials may also serve as cosmetically acceptable additives. These may be in the form of silicone oils and synthetic esters.
- the emollient material may be a silicone oil, an ester or a mixture of these. Amounts of the emollients may range anywhere from 0.1 to 20%, such as between 1 and 5% by weight of the final composition.
- Silicone oils may be divided into the volatile and non- volatile variety. The term "volatile” as used herein refers to those materials which have a measurable vapour pressure at ambient temperature. Volatile silicone oils are preferably chosen from cyclic or linear polydimethyl siloxanes containing from 3 to 9, preferably from 4 to 5 silicon atoms.
- Non-volatile silicone oils useful as an emollient material include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers.
- the essentially non-volatile polyalkyl siloxanies useful herein include, for example, polydimethyl siloxanes with viscosities of from about 5 to about 25 million centistokes at 25° C.
- Silicone emulsifying agents can include dimethicone copolyols. These can include polydimethylsiloxanes modified to include polyether side chains. Other modifications to the side chains can result in nonionic, anionic, cationic, amphoteric, and zwitterionic pendant moieties. [0044] Among the ester emollients are:
- Alkenyl or alkyl esters of fatty acids having 10 to 20 carbon atoms examples thereof include isoarachidyl neopentanoate, isononyl isononanoate, oleyl myristate, oleyl stearate, and oleyl oleate.
- Ether-esters such as fatty acid esters of ethoxylated fatty alcohols.
- Ethylene glycol mono and di-fatty acid esters diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poiy- fatty acid esters, ethoxylated glyceryl monostearate, 1 ,3-butylene glycol monostearate, 1 ,3-butylene glycol distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are satisfactory polyhydric alcohol esters.
- Wax esters such as beeswax, spermaceti, myristyl myristate, stearyl stearate and arachidyl behenate.
- Sterol esters of which cholesterol fatty acid esters are examples thereof.
- compositions of the present invention may be prepared and formulated as emulsions.
- Emulsions are typically heterogenous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 ⁇ in diameter.
- Emulsions are often biphasic systems comprising of two immiscible liquid phases intimately mixed and dispersed with each other.
- emulsions may be either water in oil (w/o) or of the oil in water (o/w) variety.
- aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase the resulting composition is called a water in oil (w/o) emulsion.
- an oily phase when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase the resulting composition is called an oil in water (o/w) emulsion.
- Emulsions may contain additional components in addition to the dispersed phases and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase.
- Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and antioxidants may also be present in emulsions as needed.
- compositions may also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil in water in oil (o/w/o) and water in oil in water (w/o/w) emulsions.
- Such complex formulations often provide certain advantages that simple binary emulsions do not.
- Multiple emulsions in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion.
- a system of oil droplets enclosed in globules of water stabilized in an oily continuous provides an o/w/o emulsion.
- Emulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion may be a semisolid or a solid, as is the case of emulsion-style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that may be incorporated into either phase of the emulsion.
- Emulsifiers may broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in “Pharmaceutical Dosage Forms," Liebemnan, Rieger and Banker (Eds.), 1988, volume 1 , p. 199).
- Useful oils can include vegetable and hydrogenated vegetable oils including safflower oil, castor oil, coconut oil, cottonseed oil, menhaden oil, aplm kernel oil, palm oil, peanut oil, soybean oil, jojoba oil, linseed oil, rice bran oil, pine oil, sesame oil, and sunflower seed oil and their hydrogenated varieties.
- Additional useful oils can include animal fats and oils such as cod liver oil, and lanolin and its derivatives, mineral oil and petrolatum.
- Synthetic surfactants also known as surface active agents, can be used in the carrier in forming emulsions and have been reviewed in the literature (Rieger, in “Pharmaceutical Dosage Forms,” Lieberman, Rieger and Banker (Eds.), 1988, volume 1 , p. 285; Idson, in “Pharmaceutical Dosage Forms,” Lieberman, Rieger and Banker (Eds.), 1988, volume 1 , p. 199).
- Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion.
- hydrophile/lipophile balance The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations.
- HLB hydrophile/lipophile balance
- surfactants used may be classified into different classes based on the nature of the hydrophilic group into: nonionic, anionic, cationic, zwitterionic and amphoteric (Rieger, in “Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1 , p. 285).
- Common nonionic surfactants are polyoxyethylene ester and ether surfactants, a specific example of which is Tween 60.
- nonionic surfactants are described in McCutcheons "Detergents and emulsifiers", North American edition (1986), published by Allured Publishing Corporation, the contents of which are specifically incorporated herein by reference.
- Examples of common nonionic surfactants can be derived from condensation reactions between long chain alcohols (C8-C30) with sugar or starch polymers.
- Other useful nonionic surfactants are the condensation products of alkylene oxides with fatty acids (alkylene oxide esters of fatty acids, or alkylene oxide diesters of fatty acids), or the condensation products of alkylene oxides and fatty alcohols (alkylene ethers of fatty alcohols).
- Other useful nonionic emulsifying agents include sugar esters, poly esters, alkoxylated sugar esters and polyesters, C1-C30 fatty acid esters of C1-30 fatty alcohols, alkoxylated derivatives of C1-C30 fatty acid esters of C1- 30 fatty alcohols, alkoxylated ethers of C1-30 fatty alcohols, polyglyceryl esters of C1-C30 fatty acids, C1-C30 esters or ethers of polyols, alkyl phosphate, polyoxyalkylene fatty ether phosphates, fatty acid amides, acyl lactylates and mixtures thereof.
- Exemplary cationic emulsifying agents are those disclosed in McCutheon's, Detergents and Emulsifiers, North American Edition (1986), the contents of which are hereby incorporated by reference in their entirety.
- Useful cationic surfactants include cationic ammonium salts such as quaternary ammonium salts and amino-amides.
- Useful anionic emulsifying agents include alkoxyl isethionates, alkyl and alkyl ether sulfates and salts thereof, alky and alkyl ether phosphates and salts thereof, alkyl methyl taurates and soaps of fatty acids.
- An ionic polyamide polymer containing acrylamidopropanesulfonic acid (AMPS) and/or its salts as a comonomer may be used as an ionic polymeric stabilizing agent.
- AMPS acrylamidopropanesulfonic acid
- polymers can be formed from a variety of monomers including acrylamide and methacrylamide, which may be unsubstituted or substituted with one or two alkyl groups (preferably C1 to 05), or N-vinyl pyrrolidone.
- the acrylate amide and methacrylate amide are monomers in which the amide nitrogen is unsubstituted, or substituted with one or two C1 to C5 alkyl groups (preferably methyl, ethyl, or propyl), for example, acrylamide, methacrylamide, N- methacrylamide, N-methylmethacrylamide, N,N-dimethylmethacrylamide, N- isoproprylacrylamide, N-isopropylemthacrylamide, and N 1 N- dimethylacrylamide.
- C1 to C5 alkyl groups preferably methyl, ethyl, or propyl
- polyacrylamide-AMPS copolymer is the product given the CTFA designation polyacrylamide (and) isoparrafin (and) laureth-7, available under the Trade name Sepigel 305 from Seppic Corporation (Fairfield, NJ. ).
- a copolymer of ammonium AMPS and N-vinylpyrrolidone commercially under the trade name Aristoflex®, can be used.
- a mixture containing sodium AMPS (also known as acryloyldimethyltaurate) copolymer, isohexadecane, and polysorbate 80 commercially available under the trade name Simulgel 600 is used. Mixtures of two or more ionic polymeric stabilizing agents may also be used.
- the ionic stabilizing agents of the present invention are included in an amount sufficient to prevent visible separation of the composition.
- the stabilizers are generally present in a concentration of about O.1 to about 10% by weight.
- One of skill in the art will also recognize that the amount of ionic polymeric stabilizing agent necessary will depend upon the hydrophobic and hydrophilic phases, intended use, intended storage, and use conditions, and other optional ingredients which maybe used within the composition as well as the mixing conditions and mixing apparatus used to prepare the emulsion or dispersion.
- the ionic polymeric stabilizing agents of the present invention allow for the formation of a stable composition at lower concentrations of alcohol than compositions without these ionic stabilizing agents.
- the ionic polymeric stabilizing agent is present from between about 1 and about 10 percent, for example, from about 2 to about 8 percent by weight of the composition.
- Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation.
- Antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid arid sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin.
- compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels.
- the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, steroids, local anesthetics or anti-inflammatory agents, skin conditioning agents such as oils and vitamins or may contain additional materials useful in physically formulating various dosage forms of the composition of present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
- Suitable steroids can include a co-active ingredient such as a corticosteroid.
- suitable corticosteroids include: clobetasol propionate, betamethasone dipropionate, betamethasone valerate, diflucortolone valerate, fluticasone valerate, hydrocortisone 17-butyrate, mometasone furoate, methylprednisolone aceponate, aclometasone dipropionate, clobetasone butyrate, fluocinolone acetonide, triamcinolone acetonide, hydrocortisone and other useful cotricosteroids and their analogs including salts.
- co-active ingredients useful in treating skin disorders can also be used with the macrolide and can include antiinflammatories, nonsteroidal anti-inflammatories, antifungals, antibiotics, anti-infectives, and skin protectants such as sunscreen components.
- antiinflammatories nonsteroidal anti-inflammatories
- antifungals antibiotics
- anti-infectives and skin protectants
- skin protectants such as sunscreen components.
- auxiliary agents e.q., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings flavorings and/or aromatic substances and the like.
- PBS phosphate buffered saline
- the following table 1 indicates the formulations used in Examples 1-3. Each test was run for 24 hours under non-occluded conditions with a finite dose of the test formulation.
- PBS phosphate buffered saline
- the following table 6 indicates the formulations used in Comparative Examples D-G. Each test was run for 24 hours under non- occluded conditions with a finite dose of the test formulation.
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Abstract
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Application Number | Priority Date | Filing Date | Title |
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US66103105P | 2005-03-14 | 2005-03-14 | |
PCT/US2006/009065 WO2006099390A1 (en) | 2005-03-14 | 2006-03-14 | Enhancement of macrolide penetration through human skin |
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EP1865896A1 true EP1865896A1 (en) | 2007-12-19 |
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EP06738155A Withdrawn EP1865896A1 (en) | 2005-03-14 | 2006-03-14 | Enhancement of macrolide penetration through human skin |
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EP (1) | EP1865896A1 (en) |
JP (1) | JP2008533153A (en) |
KR (1) | KR20070121746A (en) |
CN (1) | CN101203198A (en) |
AU (1) | AU2006223080A1 (en) |
CA (1) | CA2601694A1 (en) |
IL (1) | IL185962A0 (en) |
MX (1) | MX2007011283A (en) |
WO (1) | WO2006099390A1 (en) |
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US10265265B2 (en) | 2007-03-15 | 2019-04-23 | Drug Delivery Solutions Limited | Topical composition |
WO2009101412A1 (en) * | 2008-02-13 | 2009-08-20 | Cipla Limited | Topical pharmaceutical composition |
JP2011102260A (en) * | 2009-11-11 | 2011-05-26 | Takada Seiyaku Kk | Tacrolimus external preparation |
EP2671583A4 (en) * | 2011-01-31 | 2014-09-03 | Univ Osaka | Externally-used drug for treating skin disorder and method for producing same |
CA2834710A1 (en) * | 2011-05-16 | 2012-11-22 | Dale L. Pearlman | Compositions and methods for the treatment of skin diseases |
US8580286B2 (en) | 2012-03-16 | 2013-11-12 | Dale L. Pearlman | Compositions and methods for the treatment of skin diseases |
US9211397B2 (en) * | 2012-12-19 | 2015-12-15 | Senju Usa, Inc. | Patch for treatment of eyelid disease containing clobetasol |
CN103127140B (en) * | 2013-01-25 | 2014-09-10 | 江苏圣宝罗药业有限公司 | Compound external use drug curing psoriasis |
AU2016325446B2 (en) | 2015-09-24 | 2021-05-13 | Drexel University | Novel compositions and methods for treating or preventing dermal disorders |
CN105663027B (en) * | 2016-04-01 | 2018-12-18 | 中国人民解放军广州军区武汉总医院 | Sirolimus external preparation, preparation method and the usage |
RU2741504C2 (en) | 2016-04-04 | 2021-01-26 | Драг Деливери Солюшнз Лимитед | Composition for local application containing tacrolimus |
EP3542788A1 (en) | 2018-03-19 | 2019-09-25 | MC2 Therapeutics Limited | Topical composition comprising calcipotriol and betamethasone dipropionate |
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US4861764A (en) * | 1986-11-17 | 1989-08-29 | Macro Chem. Corp. | Percutaneous absorption enhancers, compositions containing same and method of use |
US5028431A (en) * | 1987-10-29 | 1991-07-02 | Hercon Laboratories Corporation | Article for the delivery to animal tissue of a pharmacologically active agent |
US6787342B2 (en) * | 2000-02-16 | 2004-09-07 | Merial Limited | Paste formulations |
-
2006
- 2006-03-14 EP EP06738155A patent/EP1865896A1/en not_active Withdrawn
- 2006-03-14 MX MX2007011283A patent/MX2007011283A/en not_active Application Discontinuation
- 2006-03-14 CN CNA2006800166123A patent/CN101203198A/en active Pending
- 2006-03-14 AU AU2006223080A patent/AU2006223080A1/en not_active Abandoned
- 2006-03-14 KR KR1020077023494A patent/KR20070121746A/en not_active Application Discontinuation
- 2006-03-14 CA CA002601694A patent/CA2601694A1/en not_active Abandoned
- 2006-03-14 JP JP2008501951A patent/JP2008533153A/en active Pending
- 2006-03-14 WO PCT/US2006/009065 patent/WO2006099390A1/en active Application Filing
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CN101203198A (en) | 2008-06-18 |
MX2007011283A (en) | 2008-03-13 |
CA2601694A1 (en) | 2006-09-21 |
WO2006099390A1 (en) | 2006-09-21 |
KR20070121746A (en) | 2007-12-27 |
IL185962A0 (en) | 2008-02-09 |
JP2008533153A (en) | 2008-08-21 |
AU2006223080A1 (en) | 2006-09-21 |
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