CA2265461C - Compositions and methods for topical application of therapeutic agents - Google Patents

Compositions and methods for topical application of therapeutic agents Download PDF

Info

Publication number
CA2265461C
CA2265461C CA002265461A CA2265461A CA2265461C CA 2265461 C CA2265461 C CA 2265461C CA 002265461 A CA002265461 A CA 002265461A CA 2265461 A CA2265461 A CA 2265461A CA 2265461 C CA2265461 C CA 2265461C
Authority
CA
Canada
Prior art keywords
pharmaceutical
microparticulate
dissolved
composition
gel
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.)
Expired - Lifetime
Application number
CA002265461A
Other languages
French (fr)
Other versions
CA2265461A1 (en
Inventor
David W. Osborne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Sales LLC
Original Assignee
ViroTex Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by ViroTex Corp filed Critical ViroTex Corp
Publication of CA2265461A1 publication Critical patent/CA2265461A1/en
Application granted granted Critical
Publication of CA2265461C publication Critical patent/CA2265461C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • 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
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/12—Antivirals

Abstract

The present invention generally relates to pharmaceutical compositions that enable control of drug delivery properties and the development of optimal drug delivery strategies customized for particular drugs and particular diseases. The composition includes a dissolved pharmaceutical that has the capacity to permeate the stratum corneum layer of the epidermis and become available systemically, and pharmaceutical in a microparticulate state that does not readily cross the stratum corneum of the epidermis. The dissolved and microparticulate pharmaceuticals may be the same or different pharmaceuticals.
Methods for the preparation and use of the compositions are also provided. In a preferred embodiment, the invention finds particular use in a formulation for the topical application of dapsone for the treatment of acne. In another preferred embodiment, the invention finds particular use for the treatment of herpes lesions.

Description

?20CA 02265461 1999-03-09W0 98/10746 PCT/US97-/15919-1-COMPOSITIONS AND METHODS FOR TOPICAL APPLICATION OFTHERAPEUTIC AGENTSFIELD OF THE INVENTIONThe present invention relates to novel dermatological compositions that exhibitreadily optimized solubility and systemic drug delivery properties for applying drugs andtherapeutic agents to the skin of humans and animals and methods for their preparation andUSC.BACKGROUND OF THE INVENTIONWhile the skin has long been considered the preferred route of administration forcosmetic applications and dermatological therapies, the introduction of transderrnalnitroglycerin patches initiated use of the skin as a route for administering systemic drugtherapy. Three types of known product applications which employ the barrier properties ofthe skin for drug delivery include cosmetic, topical, and transdermal applications. Theoptimal delivery strategy for administering pharmaceuticals via the skin varies amongindividual pharmaceuticals and among different disease states.Cosmetic applications are limited to negligible drug penetration past the stratumcomeum. Thus, any carrier that minimizes penetration or that aids excipient retention withinor onto the stratum comeum would be of tremendous advantage. For transdermalapplications, steady state drug delivery is preferred. Steady state delivery requires the use ofrate-controlling membranes that slow systemic breakthrough of highly permeable drugs suchas nitroglycerin. This type of control can be achieved by using matrix type patches thatmodify delivery rates by using polymer adhesives and solvents. For topical delivery, minimal?20CA 02265461 1999-03-09WO 98/10746 PCT/US97l15919systemic breakthrough is always preferred. In order to adequately dose the viable epidermisand dermis, however, large amounts of drug must cross the intact skin barrier, i.e. the stratumcomeum, or the lesional delivery barrier, i.e. scab, plaque, etc.Some dermatological conditions, such as acne, require multiple delivery strategiesbecause they have multiple delivery requirements. Acne is chronic pilosebaceous unitin?ammation associated with the face and trunk usually occurring in adolescence due tocomplex interactions of androgens and bacteria. For the adolescent, circulating androgenresults in significantly increased sebum production. The sebaceous glands dramaticallyenlarge and excrete more sebum than the immature pilosebaceous canals can accommodate.Simultaneously, anaerobic bacteria (Propionibacterium acnes) that feed upon the sebum,converting triglycerides to fatty acids, dramatically increase in number due to an increase involume of the nutrition source. The increase in constrictedlimmature ducts and bacterialwaste products results in plugged follicles and typical acne in?ammation. Acne severity for aparticular anatomical location parallels the number of sebaceous glands per unit of skin.Acne, which is often treated with antibiotics, is one condition where a highlyspecialized topical drug delivery is needed. Ideally, a topical antimicrobial would beprimarily delivered into the pilosebaceous unit, with only minimal active crossing of the skinbarrier. Intact stratum comeum lines the upper third of the pilosebaceous unit, and it is intothis upper third of the hair follicle that the sebaceous duct secretes sebum. Thus, a needexists for an acne treatment that maximizes antimicrobial drug levels in the upper third of thepilosebaceous unit.?20CA 02265461 1999-03-09wo 98/10746 PCT/US97/15919Additionally, when an anti-in?ammatory agent is used to treat acne, it is important toincrease the level of drug that will cross the intact stratum comeum lining the upper third ofthe pilosebaceous unit. By de?nition, in?ammation is the response of the viable epidermis toirritants and sensitizers. In order to reduce the amount of in?ammation, the activepharmaceutical must penetrate past the stratum comeum and interfere with the cascade ofinflammatory events. Ideally, delivery of an anti-in?ammatory for acne requires that steady-state levels be sustained. To date, the ideal delivery system that provides antimicrobial agentsabove the stratum comeum while providing anti-in?ammatory agents below the stratumcomeum has not been implemented.Other dermatological conditions, such as herpes lesions, require multiple deliverystrategies because the barrier properties of the lesion dramatically change in the course of thedisease. Starting with the prodrome and progressing through the formation of vesicles, thelesion has an intact stratum comeum delivery barrier, and thus, maximum penetration of thedrug is necessary. While in place, the stratum comeum delays penetration to the target tissueand sustains the time that the dissolved active drug resides in the target tissue. During thisstage of the lesion, microparticulate drug will not signi?cantly cross the intact stratumcomeum, and thus, has no real effect in treatment of the lesion. Once the herpes lesionvesicles rupture, the stratum comeum is no longer in place, and the dissolved drug rapidlysweeps past the target tissue, providing minimal or insigni?cant bene?t. However, from thetime that the vesicle ruptures and through to the complete formation of the scab, themicroparticulate drug is deposited directly at the target area, where it can slowly be releasedfor sustained and significant therapeutic bene?t. Thus, in order to adequately dose the viable?20CA 02265461 1999-03-09W0 98/ 10746 PCT/US97/ 15919epidermis from the prodrome through the time of scab formation in a herpes lesion, twodistinctly different drug delivery strategies must be implemented.While the dermatological conditions of acne and herpes lesions serve as conceptualexamples of how therapeutic approaches can require dramatically different drug deliverypro?les, all skin diseases are best treated by a particular drug delivery strategy tailoredspeci?cally to the pharmaceutical and the particular disease. Some diseases are best treatedusing pulsed or spiked delivery in which high levels of drug are delivered in a short period oftime. This type of treatment saturates receptor sites and provides maximum microbial or viralreplication inhibition, thus providing optimal therapy for certain diseases. Conversely, acosmetic, topical, or transderrnal product that provides steady state active pharmaceuticaldelivery while minimizing excipient delivery provides the preferred skin delivery pro?le forother diseases. Thus, a carrier system that can be adjusted to optimize the delivery profile forthe pharmacology of the active drug and the nature of the disease state is needed to advancethe effectiveness of pharmaceutical products applied to the skin.SUMMARY OF THE INVENTIONThe present invention concerns a pharmaceutical carrier system comprising adermatological composition that is a semi-solid aqueous gel, wherein a pharmaceutical isdissolved in the gel such that the pharmaceutical has the capacity to cross the stratumcorneum layer of the epidermis and become available systemically, and wherein thecomposition also contains pharmaceutical in a microparticulate state that does not readilycross the stratum corneum of the epidermis. The ratio of microparticulate pharmaceutical todissolved pharmaceutical is adjustable, but is preferably five or less. The microparticulate?10U20CA 02265461 1999-03-09W0 98/10746 PCT/US97/15919pharmaceutical and the dissolved pharmaceutical may be the same drug, or they may bedifferent drugs.Methods for preparing the compositions of the present invention are also shown. Inaddition, methods for treating dermatological conditions that include topically applying thedermatological compositions of the invention are shown. More particularly, the inventionconcerns methods for treating dermatological conditions or diseases such as acne, herpeslesions, and dermatitis. Antimicrobial agents having anti-in?ammatory properties such asdapsone are used to treat acne. Antiviral agents or antiviral agents in combination with localanesthetics are used to treat herpes lesions, and anti-in?ammatory agents are used to treatdermatitis.DESCRIPTION OF THE PREFERRED EMBODIMENTSThe present invention comprises compositions for application to the skin that canform microparticulate drug precipitates in adjustable ratios of microparticulate drug todissolved drug, methods for the formation of said compositions, and methods for treatment ofskin conditions using said compositions. The advantages of the present invention areappreciated in the treatment of skin conditions or diseases by using cosmetics or topicalpharmaceuticals, and in the systemic treatment of illness by using transdermalpharmaceuticals. The present invention is particularly effective in the treatment of acne withantimicrobial actives known to possess anti-in?ammatory properties such as dapsone. Theinvention also ?nds particular use in the treatment of herpes lesions and dermatitis.In one embodiment, the present invention is directed to a novel pharmaceutical carriersystem comprising a dermatological composition that is a semisolid aqueous gel, wherein the?20CA 02265461 1999-03-09W0 98/ 10746 PCT/U S97/ 15919composition exhibits an optimal balance between a dissolved pharmaceutical that is availableto cross through the stratum comeum to become systemically available, and amicroparticulate pharmaceutical that is retained in or above the stratum comeum to serve as areservoir or to provide drug action in the supracomeum zone. The microparticulatepharmaceutical and the dissolved pharmaceutical may be the same or different drugs. Themicroparticulate pharmaceutical may comprise a crystalline precipitant or an amorphousprecipitant.Optimal balance is accomplished by having a semisolid gel carrier system in whichmicroparticulate pharmaceutical precipitates are formed in reproducible ratios with respect tothe dissolved pharmaceutical. For the composition to have a wide range of applicability, themicroparticulate to dissolved pharmaceutical ratio preferably should be no greater than ?ve,at therapeutic levels of applied active pharmaceutical.A composition having a microparticulate to dissolved pharmaceutical ratio of lessthan two may provide the greatest amount of pharmaceutical available for immediate partitionout of the stratum comeum and into the viable epidermis. This should provide minimumreservoir capacity, but may not maintain sustained delivery or provide maximum activity inthe supracomeum zone. A composition having a microparticulate to dissolvedpharmaceutical ratio of two or greater may have a reduced amount of drug available forimmediate partition out of the stratum comeum and into the viable epidermis. This providesmaximum reservoir capacity, and maintains sustained delivery, providing maximum activityin the supracomeum zone. For the present invention, the ratio for microparticulate drug todissolved drug should be no greater than 50, preferably no greater than 10, and most?20CA 02265461 1999-03-09W0 98/ 10746 PCT/U S97! 15919preferably no greater than 5. Drug delivery from the microparticulate/dissolvedpharmaceutical formulation may be optimized to provide higher levels of drug to thesupracomeum zone, while maintaining the level of drug partitioning out of the stratumcomeum and into the viable epidermis, despite 10-fold increases in the amount ofpharmaceutical applied to the skin.The compositions of the present invention comprise semi-solid and gel-like vehiclesthat include a polymer thickener, water, preservatives, active surfactants or emulsi?ers,antioxidants, sunscreens, and a solvent or mixed solvent system. The solvent or mixedsolvent system is important to the formation of the microparticulate to dissolvedpharmaceutical ratio. The formation of the microparticulate, however, should not interferewith the ability of the polymer thickener or preservative systems to perform their functions.Polymer thickeners that may be used include those known to one skilled in the art,such as hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetic andpharmaceutical industries. Preferably, the hydrophilic or hydroalcoholic gelling agentcomprises “CARBOPOL®” (B.F. Goodrich, Cleveland, OH), “HYPAN®” (KingstonTechnologies, Dayton, NJ), “NATROSOL®” (Aqualon, Wilmington, DE), “KLUCEL®”(Aqualon, Wilmington, DE), or “STABILEZE®” (ISP Technologies, Wayne, NJ).Preferably, the gelling agent comprises between about 0.2% to about 4% by weight of thecomposition. More particularly, the preferred compositional weight percent range for“CARBOPOL®” is between about 0.5% to about 2%, while the preferred weight percentrange for “NATROSOL®” and “KLUCEL®” is between about 0.5% to about 4%. The?U20CA 02265461 1999-03-09W0 98/ 10746 PCTIU S97/ 15919preferred compositional weight percent range for both “HYPAN®” and “STABILEZE®” isbetween about 0.5% to about 4%.“CARBOPOL®” is one of numerous cross—linked acrylic acid polymers that are giventhe general adopted name carbomer. These polymers dissolve in water and form a clear orslightly hazy gel upon neutralization with a caustic material such as sodium hydroxide,potassium hydroxide, triethanolamine, or other amine bases. “KLUCEL®” is a cellulosepolymer that is dispersed in water and forms a uniform gel upon complete hydration. Otherpreferred gelling polymers include hydroxyethylcellulose, cellulose gum, MVE/MAdecadiene crosspolymer, PVM/MA copolymer, or a combination thereof.Preservatives may also be used in this invention and preferably comprise about 0.05%to 0;5% by weight of the total composition. The use of preservatives assures that if theproduct is microbially contaminated, the formulation will prevent or diminish microorganismgrowth. Some preservatives useful in this invention include methylparaben, propylparaben,butylparaben, chloroxylenol, sodium benzoate, DMDM Hydantoin, 3-Iodo—2—Propylbutylcarbamate, potassium sorbate, chlorhexidine digluconate, or alcombination thereof.Titanium dioxide may be used as a sunscreen to serve as prophylaxis againstphotosensitization. Alternative sunscreens include methyl cinnamate. Moreover, BHA maybe used as an antioxidant, as well as to protect ethoxydiglycol and/or dapsone fromdiscoloration due to oxidation. An alternate antioxidant is BHT.Pharmaceuticals for use in all embodiments of the invention include antimicrobialagents, anti-in?ammatory agents, antiviral agents, local anesthetic agents, corticosteroids,destructive therapy agents, antifungals, and antiandrogens. In the treatment of acne, active?20CA 02265461 1999-03-09W0 98/10746 PCT/US97/15919pharmaceuticals that may be used include antimicrobial agents, especially those having anti-in?ammatory properties such as dapsone, erythromycin, minocycline, tetracycline,clindamycin, and other antimicrobials. The preferred weight percentages for theantimicrobials are 0.5% to 10%. In the topical treatment of herpes lesions, activepharmaceuticals that may be used include antiviral or local anesthetic agents. Aconcentration of about 1.0% to 10% by weight is preferred for nucleoside analogues such asacyclovir, famciclovir, penciclovir, valacyclovir, and ganciclovir.Local anesthetics include tetracaine, tetracaine hydrochloride, lidocaine, lidocainehydrochloride, dyclonine, dyclonine hydrochloride, dimethisoquin hydrochloride, dibucaine,dibucaine hydrochloride, butambenpicrate, and pramoxine hydrochloride. A preferredconcentration for local anesthetics is about .025% to 5% by weight of the total composition.Anesthetics such as benzocaine may also be used at a preferred concentration of about 2% to25% by weight.Corticosteroids that may be used include betamethasone dipropionate, ?uocinoloneacetonide, betamethasone valerate, triamcinolone acetonide, clobetasol propionate,desoximetasone, di?orasone diacetate, amcinonide, ?urandrenolide, hydrocortisone valerate,hydrocortisone butyrate, and desonide are recommended at concentrations of about 0.01% to1.0% by weight. Preferred concentrations for corticosteroids such as hydrocortisone ormethylprednisolone acetate are from about 0.2% to about 5.0% by weight.Destructive therapy agents such as salicylic acid or lactic acid may also be used. Aconcentration of about 2% to about 40% by weight is preferred. Cantharidin is preferablyutilized in a concentration of about 5% to about 30% by weight. Typical antifungals that may?20CA 02265461 1999-03-09W0 93/10745 PCT/US97/15919-10-be used in this invention and their preferred weight concentrations include: oxiconazolenitrate (0.1% to 5.0%), ciclopirox olamine (0.1% to 5.0%), ketoconazole (0.1% to 5.0%),miconazole nitrate (0.1% to 5.0%), and butoconazole nitrate (0.1% to 5.0%). For the topicaltreatment of seborrheic dermatitis, hirsutism, acne, and alopecia, the active pharmaceuticalmay include an antiandrogen such as ?utamide or fmasteride in preferred weight percentagesof about 0.5% to 10%.Typically, treatments using a combination of drugs include antibiotics in combinationwith local anesthetics such as polymycin B sulfate and neomycin sulfate in combination withtetracaine for topical antibiotic gels to provide prophylaxis against infection and relief ofpain. Another example is the use of minoxidil in combination with a corticosteroid such asbetamethasone diproprionate for the treatment of alopecia ereata. The combination of ananti-in?ammatory such as cortisone with an antifungal such as ketoconazole for the treatmentof tinea infections is also an example.In one embodiment, the invention comprises a dermatological composition havingabout 0.5% to 4.0% carbomer and about 0.5% to 10% of a pharmaceutical that exists in botha dissolved state and a microparticulate state. The dissolved pharmaceutical has the capacityto cross the stratum comeum, whereas the microparticulate pharmaceutical does not.Addition of an amine base, potassium hydroxide solution, or sodium hydroxide solutioncompletes the formation of the gel. More particularly, the pharmaceutical may includedapsone, an antimicrobial agent having anti-in?ammatory properties. A preferred ratio ofmicroparticulate to dissolved dapsone is ?ve or less.?H20CA 02265461 1999-03-09W0 98/10746 PCT/US97I159l9-]]-In another embodiment, the invention comprises about 1% carbomer, about 80-90%water, about 10% ethoxydiglycol, about 0.2% methylparaben, about 0.3% to 3.0% dapsoneincluding both microparticulate dapsone and dissolved dapsone, and about 2% causticmaterial. More particularly, the carbomer may include “CARBOPOL® 980” and the causticmaterial may include sodium hydroxide solution.In a preferred embodiment, the composition comprises dapsone and ethoxydiglycol,which allows for an optimized ratio of microparticulate drug to dissolved drug. This ratiodetermines the amount of drug delivered, compared to the amount of drug retained in orabove the stratum corneum to function in the supracomeum domain. The system of dapsoneand ethoxydiglycol may include puri?ed water combined with “CARBOPOL®” gellingpolymer, methylparaben, propylparaben, titanium dioxide, BHA, and a caustic material toneutralize the “CARBOPOL®.”Another preferred embodiment of this invention relates to a composition for thetreatment of herpes lesions comprising a semisolid aqueous gel; a ?rst pharmaceutical in thegel, partially in a microparticulate form and partially in a dissolved form, where optimizeddelivery for early state lesions is provided when the pharmaceutical is dissolved andoptimized delivery for later state lesions is provided when the pharmaceutical is in amicroparticulate form; and a second pharmaceutical dissolved in the gel which providesbene?t throughout lesion progression. In a preferred embodiment, the composition comprisesacyclovir and 1-methyl-2-pyrrolidone, which allows for an optimized ratio ofmicroparticulate drug to dissolved drug for the treatment of herpes lesions. Acyclovir may bepresent in dissolved and microparticulate forms. The ratio determines the amount of drug?20CA 02265461 1999-03-09WO 98/10746 PCT/US97/15919-12-delivered up to the point of lesion vesicle formation, as compared to the amount of drugavailable to be deposited into the lesion once the vesicles rupture. The drug delivery systemof acyclovir and 1-methyl-2-pyrrolidone may include puri?ed water combined withKLUCEL® hydroxypropyl cellulose gelling polymer, methylparaben, and propylparaben.In another preferred embodiment, a combination drug system of acyclovir andtetracaine HCl may be formulated with 1-methyl-2-pyrrolidone to provide both antiviral andlocal anesthetic activity. Tetracaine HCl is a local anesthetic that alters membrane functionand blocks pain. In a preferred embodiment, acyclovir comprises 5% by weight of thecomposition. The system of acyclovir, tetracaine HCl, and l-methyl-2-pyrrolidone caninclude puri?ed water, sodium lauryl sulfate, KLUCEL® hydroxypropyl cellulose gellingpolymer, methylparaben, and propylparaben. The combination of a local anesthetic withsodium lauryl sulfate has been shown to be an effective therapy for herpes lesions. Thecombination of the nucleoside analogue acyclovir with the anesthetic/late stage antiviralcombination tetracaine HCl and sodium lauryl sulfate should provide complete topicaltherapy for herpes lesions.The relative percentages for each of the reagents used in the present invention mayvary depending upon the desired strength of the target formulation, gel viscosity, and thedesired ratio of microparticulate to dissolved pharmaceutical. Unless otherwise designated,all reagents listed above are commonly known by one of ordinary skill in the art and arecommercially available from pharmaceutical or cosmetic excipient suppliers.The present invention also provides methods for preparing the dermatologicalcompositions described above. In a general form, the method for producing a dermatological?20CA 02265461 1999-03-09W0 98/10746 PCT/US97/15919-13-gel composition having dissolved drug and microparticulate drug precipitates comprises thesteps of completely dissolving a pharmaceutical in a solvent or solvent mixture; adding andadequately dispersing a polymeric thickener in water; and combining the dissolvedpharmaceutical with the dispersed polymeric thickener. Alternatively, water may be slowlyadded to the dissolved pharmaceutical, followed by the addition of a polymeric thickener.Ethoxydigylcol and l-methyl—2-pyrollidone are preferred solvents for use in this invention.In one preferred embodiment‘, the method for preparing a dermatological compositionhaving dissolved and microparticulate pharmaceutical comprises the steps of forming ahomogenous dispersion by stirring purified water vigorously enough to form a vortex andsifting gel polymer into the vortex formed in the water while continuing to stir; forming apharmaceutical component by dissolving methyl paraben and propylparaben inethoxydiglycol by mixing to form a solution, and mixing an active pharmaceutical with thesolution until the pharmaceutical dissolved; mixing the pharmaceutical component with thehomogenous dispersion to form a microparticulate pharmaceutical dispersion; and adding acaustic material. The active pharmaceutical may comprise any of the types mentioned above.In a preferred embodiment, the active pharmaceutical comprises dapsone. In anotherpreferred embodiment, the active pharmaceutical comprises acyclovir or acyclovir incombination with tetracaine or tetracaine HCl.The order in which reagents are combined may be important, depending on theparticular reagents necessary for the target mixture. For example, after a pharmaceutical suchas dapsone is dissolved in a solvent such as ethoxydiglycol, water may be slowly added to thedapsone in the ethoxydiglycol solution, or the dapsone in ethoxydiglycol solution may be?20CA 02265461 1999-03-09W0 98/ 10746 PCT/US97/ 15919-14-added to the water with mixing. Adding the dapsone in ethoxydiglycol solution to water mayresult in less polydispersity in the size of the microparticulates than adding water to thedapsone in ethoxydiglycol solutions.The carbomer is generally dispersed in the water component of the formulation, whilethe remaining ingredients will be dissolved or dispersed in whichever of the two componentsare best for dissolving or dispersing the ingredient. For example, it is suggested to dissolvemethylparaben, propylparaben, and BHA in ethoxydiglycol. After the ethoxydiglycolcomponent and water component are combined, neutralizer is added to formulate the gel.Finally, in another embodiment of the invention, methods for the treatment ofdermatological conditions by topical application of the compositions of this invention areshown. These methods are useful in the treatment of diseases such as acne, herpes lesions,seborrhea dermatitis, hirsutism, and alopecia. In a preferred embodiment, a method for thetreatment of dermatological conditions comprises applying topically a gel compositioncomprising a dissolved pharmaceutical that has the capacity to cross the stratum comeum ofthe epidermis and become systemically available, and a microparticulate pharmaceutical thathas only minimal capacity to cross the stratum comeum in its microparticulate state. In oneembodiment, the dissolved pharmaceutical and microparticulate pharmaceutical compriseabout 1.0% to 10% antiviral agent. In another embodiment, the dissolved pharmaceutical andmicroparticulate pharmaceutical comprise about 0.5% to 10% antiandrogen.In a preferred embodiment, a method for the treatment of acne comprises applyingtopically a gel composition that comprises a dissolved anti—in?ammatory pharmaceutical anda microparticulate antimicrobial pharmaceutical, wherein the dissolved anti-in?ammatory?H20CA 02265461 1999-03-09W0 98/ 10746 PCT/US97/15919-15-pharmaceutical crosses the stratum comeum of the epidermis and is absorbed into the lowertwo-thirds of the pilosebaceous unit, while the microparticulate antimicrobial pharmaceuticalis primarily delivered into the upper third of the pilosebaceous unit, crossing the stratumcomeum of the epidermis only minimally. Preferably, the dissolved pharmaceutical andmicroparticulate pharmaceutical comprise dapsone.In another preferred embodiment, a method for the treatment of herpes lesionscomprises applying topically a semisolid gel composition that comprises a semisolid aqueousgel; a ?rst pharmaceutical in the gel, which exists in a partially microparticulate form and apartially dissolved form, providing for optimized delivery for early state lesions whendissolved and optimized delivery for later state lesions when present as a microparticulate;and a second pharmaceutical dissolved in the gel, providing bene?t throughout progression ofthe lesion. Preferably, the first pharmaceutical comprises a nucleoside analogue, and thesecond pharmaceutical comprises a local anesthetic. In a preferred embodiment, thenucleoside analogue comprises acyclovir, penciclovir, famciclovir, valacyclovir, organciclovir, and the local anesthetic comprises tetracaine, dyclonine, dibucaine, or a saltthereof, such as tetracaine HCI, dyclonine HCl, or dibucaine HCI. More preferably, acyclovircomprises 5% by weight of the composition, and tetracaine HCl comprises 2-5% by weight.The following examples are provided to enable those of ordinary skill in the art tomake and use the methods and compositions of the invention. These examples are notintended to limit the scope of what the inventors regard as their invention. Additionaladvantages and modi?cations will be readily apparent to those skilled in the art.?20CA 02265461 1999-03-09WO 98/10746 PCT/US97/15919-16-Examples 1 through 6 describe methods for the preparation of compositions of theinvention that include microparticulate crystalline dapsone, dissolved dapsone, andcombinations of the two. The examples offer illustrations of methods that can be used tocontrol the ratio of dissolved to microparticulate pharmaceuticals in the ?nal product. Sincemicroparticulate pharmaceuticals are retained above the stratum comeum having negligiblepenetration and dissolved pharmaceuticals penetrate the stratum comeum, controlling theratios between the two epidermal areas is important in developing a composition having anoptimal delivery route for administering pharmaceuticals via the skin.Example 7 describes a method for the preparation of compositions of this inventionusing two different pharmaceuticals in combination, resulting in one pharmaceuticaldissolved in the composition and the other present in a microparticulate state, such that twoepidermal areas may be treated with two different drugs. Example 8 provides a method forpreparing a composition having a pharmaceutical partially in a microparticulate state andpartially dissolved, combined with a different dissolved pharmaceutical. Examples 9-1 1provide evaluations of the compositions and methods described herein.EXAMPLE 1The following example provides a method for producing a topical therapeutic agent inwhich the pharmaceutical component is a combination of dissolved and microcrystallinedapsone. Because of the nature of the microcrystalline dapsone in the ?nal product ofExample 1, microcrystalline dapsone will be retained in or above the stratum comeum andwill therefore serve as a reservoir or provide drug action in the supracomeum zone. Thedissolved dapsone will pass through the stratum comeum. The method of Example 1 can also?20CA 02265461 1999-03-09W0 98/ 10746 PCT/U S97! 15919-17-be used to produce a composition of this invention that includes other pharmaceuticals suchas those described above.A polymer thickener component was prepared by charging 85.7 grams of puri?edwater to a vessel suitable to contain 100 grams of ?nished semisolid product, and slowlysifting one gram of “CARBOPOL® 980” into a vortex formed by rapidly stirring the puri?edwater. When a homogeneous dispersion of “CARBOPOL® 980” and water was formed,stirring was reduced to minimize air entrapment. Next, an active pharmaceutical componentwas prepared by charging an appropriately sized container with 10.0 g of ethoxydiglycol. 0.2g of methylparaben and 0.1 g of propylparaben were added to the ethoxydiglycol and mixeduntil all of the crystalline solid was dissolved. 1.0 g dapsone was added to the ethoxydiglycoland mixed until the drug was completely dissolved.The polymer thickener component was added to the pharmaceutical component withmixing, and immediately resulted in the formation of crystalline microparticles. Once thedispersion was homogenous, 2.0 grams of a 10% w/w aqueous sodium hydroxide solutionwere added to neutralize the CARBOPOL® 980 and form the gel.EXAMPLE 2The following example provides another topical therapeutic agent in which thepharmaceutical component is dissolved dapsone. The method of Example 2 can also be usedto produce a composition of this invention that includes other pharmaceuticals.To prepare the composition of Example 2, the procedure of Example 1 was followedusing the following speci?c weights of reagents. All dapsone was dissolved in the ?nalproduct gel, and thus, crystalline microparticles did not form when the polymer thickener?H20CA 02265461 1999-03-09WO 98/10746 PCT/US97/15919-18-component was added to the pharmaceutical component. All reagent weights are shown per100 grams of product.Component wt/100 g productPolvmer Thickener ComponentWater 86.67 g“CARBOPOL 980” 9 1.0 gActive Pharmaceutical ComponentEthoxydiglycol 10.0 gMethylparaben 0.2 gPropylparaben 0.1 gDapsone 0.03 g/ Caustic/Amine Component10% w/w Sodium Hydroxide 2.0 gEXAMPLE 3The following example provides yet another topical therapeutic agent in which thepharmaceutical component is dissolved dapsone. The method of Example 3 can also be usedto produce a composition of this invention that includes other pharmaceuticals such as thosedesignated in this application.The procedure of Example 1 was followed using reagents in the amounts designatedbelow. All of the dapsone was dissolved in the ?nal product gel, thus crystallinemicroparticles did not form upon adding the polymer thickener component to thepharmaceutical component. All reagent weights are shown per 100 grams of product.?E20CA 02265461 1999-03-09W0 98/10746 PCT/US97/15919- 19 -Component wt/100 g productPolymer Thickener ComponentWater 86.6 g“CARBOPOL 980” 1.0 gActive Pharmaceutical ComponentEthoxydiglycol 10.0 gMethylparaben 0.2 gPropylparaben 0.1 gDapsone 0.1 gCaustic/Amine Component10% w/w Sodium Hydroxide 2.0 gEXAMPLE 4The following example provides yet another topical therapeutic agent in which thepharmaceutical component is dissolved dapsone. The method of Example 4 can also be usedto produce a composition of this invention that includes other pharmaceuticals such as thosedesignated in this application.The procedure of Example 1 was followed using reagents in the amounts designatedbelow. All reagent weights are shown per 100 grams of product.Component wt/100 g productPolymer Thickener ComponentWater 86.4 g“CARBOPOL 980” 1.0 g?20CA 02265461 1999-03-09WO 98/10746 PCT/U S97/ 15919-20-Active PharmaceuticalEthoxydiglycol 10.0 gMethylparaben 0.2 gPropylparaben 0.1 gDapsone 0.3 gCaustic/Amine Component10% w/w Sodium Hydroxide 2.0 gEXAMPLE 5The following example provides yet another topical therapeutic agent in which thepharmaceutical component is a combination of dissolved and microcrystalline dapsone.Because of the nature of the microcrystalline dapsone in the ?nal product of Example 5, itwill be primarily retained in or above the stratum comeum and will therefore serve as areservoir or provide drug action in the supracomeum zone. The method of Example 5 canalso be used to produce a composition of this invention that includes other pharmaceuticalssuch as those designated in this application.The procedure of Example 1 was followed using reagents in the amounts designatedbelow. All reagent weights are shown per 100 grams of product.Component wt/100 g productPolymer Thickener ComponentWater 86.2 g“CARBOPOL 980” 1.0 g?CA 02265461 1999-03-09wo 98/10746 PCT/US97/15919-2]-Active Pharmaceutical ComponentEthoxydiglycol 10.0 gMethylparaben 0.2 gPropylparaben 0.1 g5 Dapsone 0.5 gCaustic/Amine Component10% w/w Sodium Hydroxide 2.0 gEXAMPLE 6The following example provides a method for producing a topical therapeutic agent in10 which the pharmaceutical component is a combination of dissolved and microcrystallinedapsone. Because of the nature of the microcrystalline dapsone in the ?nal product ofExample 6, it will be retained in or above the stratum comeum and will therefore serve as areservoir or provide drug action in the supracomeum zone. The method of Example 6 canalso be used to produce a composition of this invention that includes other pharmaceuticals15 such as those designated in this application.The procedure of Example 1 was followed using reagents in the amounts designatedbelow. All reagent weights are shown per 100 grams of product.Component wt/100 g productPolymer Thickener Component20 Water 83.7 g“CARBOPOL 980” 1.0 g?H20CA 02265461 1999-03-09W0 98/ 10746 PCT/US97/15919- 22 -Active Pharmaceutical ComponentEthoxydiglycol 10.0 gMethylparaben 0.2 gPropylparaben 0.1 gDapsone 3.0 gCaustic/Amine Component10% w/w Sodium Hydroxide 2.0 gEXAMPLE 7Example 7 describes a method for preparing a composition of this invention thatincludes a microparticulate crystalline pharmaceutical, dapsone, in combination with adifferent dissolved pharmaceutical, dyclonine HCl. Since microparticulate pharmaceuticalsare retained above the stratum comeum having negligible penetration and dissolvedpharmaceuticals penetrate the stratum corneum, using different drugs for the two forms(microparticulate and dissolved) enables treating the two epidermal areas with differentdrugs. This allows further options to develop optimal delivery routes for administeringpharmaceuticals via the skin.An active pharmaceutical component was prepared by charging an appropriately sizedcontainer with 15.0 g of ethoxydiglycol. 0.3 g methylparaben and 0.15 g of propylparabenwere added to the ethoxydiglycol and mixed until all of the crystalline solid was dissolved.1.5 g of dapsone were added to the ethoxydiglycol and mixed until the drug was completelydissolved.?20CA 02265461 1999-03-09“'0 93/10745 PCT/US97l15919-23-An active pharmaceutical component which would remain dissolved was prepared bycharging an appropriately sized container with 127.8 grams of puri?ed water. 1.5 grams ofdyclonine HCl was added to the water with mixing until all of the drug was completelydissolved.The solvent phase was added to the aqueous phase and crystalline microparticles ofdapsone were immediately formed. 3.75 grams of “NATROSOL”® 250 PHARM wereadded to form a topical gel containing microcrystalline dapsone and dissolved dyclonine HCl.The presence of microcrystalline dapsone was con?rmed by optical microscopy.EXAMPLE 8Example 8 describes a method for preparing a composition of this invention thatincludes a pharmaceutical partially in a microparticulate form and partially in a dissolvedform in combination with a different dissolved pharmaceutical. The composition ?ndsparticular use in the treatment of herpes lesions. The pharmaceutical in both dissolved andmicroparticulate forms provides optimized delivery for early stage lesions when dissolvedand optimized delivery for later stage lesions when present as a microparticulate. The otherdissolved pharmaceutical provides bene?t throughout the lesion progression.An active pharmaceutical component was prepared by charging an appropriately sizedcontainer with 44.0 g of l—methyl-2-pyrrolidone. 0.16 g methylparaben and 0.08 gpropylparaben as preservatives were added to the 1-methyl-2-pyrrolidone and mixed until allthe crystalline solid dissolved. 8.0 g 1 N NaOH was mixed with the l-methyl-2-pyrrolidoneand preservative mixture prior to the addition of 4.0 g acyclovir. Upon heating to?H20CA 02265461 1999-03-09WO 98/10746 PCT/U S97/ 15919-24-approximately 50°C, all of the added materials dissolved to form a single phase clearsolution.An active pharmaceutical component which would remain dissolved was prepared bycharging an appropriately sized container with 17.36 g puri?ed water. 4.0 g tetracaine HC1and 0.8 g of sodium lauryl sulfate was added to the water with mixing until all of the solidswere dissolved.The solvent phase was added to the aqueous phase and crystalline microparticles ofacyclovir were immediately formed. 1.60 grams of KLUCEL® HF hydroxypropyl cellulose _were added to form a topical gel containing microcrystalline acyclovir, dissolved acyclovir,and dissolved tetracaine HC1 and sodium lauryl sulfate. The presence of microcrystallineacyclovir was con?rmed by optical microscopy.EXAMPLE 9-EVALUATIONExample 9 evaluates the compositions of examples 1-6 and demonstrates thatincreasing the dapsone content of this invention’s composition from 0 to 0.3% increases theamount of dapsone that permeates into the skin, whereas further increasing dapsone above0.3% results in microparticulate dapsone that remains above the stratum comeum orsupracorneum zone. Therefore, the amount of dapsone that permeates into the skin does notincrease incrementally for compositions having increased dapsone above 0.3%.In example 9, experiments were performed by loading excised human skin on astandard Franz type vertical diffusion cell having a 15 mm ori?ce, 7.0 ml volume, andequipped with a Hanson Helix stirrer using a phosphate buffered saline/ethoxydiglycolmixture as the receptor phase. The full thickness of human abdominal skin was removed?20CA 02265461 1999-03-09W0 98/10746 PCT/US97/15919-25-from a cadaver within 24 hours of death. The subcutaneous tissue was removed using a #22scalpel blade. The tissue was cut into 5 X 15 cm sections with care being taken to avoidcontamination of the stratum comeum with subcutaneous fat. Each 5 X 15 cm section wasplaced in a sterile plastic bag and stored on wet ice until being placed in the freezer(maximum transport time 2 hours). A single 5 X 15 cm section of skin was removed from thefreezer on the day of an in-vitro skin permeation study. The skin was thawed, rinsed, patteddry with a tissue, and loaded on the Franz diffusion cell. Samples were dosed with 10 mg ofthe formulation i.e. ?nite dosing. Receptor solutions were assayed by reverse phase HPLCusing UV detection.The cumulative drug concentration in the receptor solution was monitored over a 72hour period. The data in Table 1 shows the mean quantities of drug transported forquadruplicate in-vitro skin permeation experiments in which each formulation was evaluatedusing the same donor skin on each of four different days. As seen in Table l; the cumulativeamount of dissolved dapsone that was transported across the stratum comeum increased untilthe dapsone level at which the formation of microparticulate dapsone was reached, i.e. up to0.3 weight percent dapsone. At concentrations above 0.3 %, the amount of dissolved drugdid not increase, and the amount of drug delivered remained the same. Thus, the excess drug(above 0.3 weight percent) was retained in the stratum comeum or supracomeum zone.For this drug delivery system, the microparticulate to dissolved pharmaceutical ratioof 1.5 to 15 resulted in increasing amounts of drug available for antimicrobial action in thesupracomeum zone, while maintaining a set amount of dapsone available for anti-in?ammatory activity in the viable epidermis.?20CA 02265461 1999-03-09W0 98/10745 PCT/US97/15919_ 25 -Table 1.Dapsone Concentration in Receptor Solution Followingin-vitro Dosing of 10 mg of Topically Applied SemisolidDapsone Semisolid Example pg Dapsonc/1 .77cm2 % of Applied DoseConcentration Number by 72 hrs transported by 72 hrs(% w/w)0.03 2 0.35=e0.1 ll01 3 073iQ3 70.3 4 2.6 i 2.2 80.5 5 2.2 d: 0.8 41.0 1 2.9 i 1.7 33.0 _ 6 3.3 i 2.5 1EXAMPLE 10--EVALUATIONExample 10 demonstrates the importance of using the [optimum microparticulate todissolved pharmaceutical ratio. The results in 'l‘able 2 show that for the same amount ofapplied drug, the amount of drug in the supracomeum zone can be optimized by improvingthe microparticulate to dissolved pharmaceutical ratio.In example 10, the procedures of example 9 were used, including Franz diffusion celland experimental technique, however 1% dapsone formulations were compared. Formulationnumber 1 was manufactured according to example 1 and contained 1% dapsone and 10%ethoxydiglycol having a microparticulate drug/dissolved drug ratio of 5. Formulation number?20CA 02265461 1999-03-09W0 98/10746 PCT/US97/15919-27-2 had the composition 1% dapsone, 25% ethoxydiglycol, 70.7% water, 1% “CARBOPOL980,” 0.2% methylparaben, 0.1% propylparaben, and 2% sodium hydroxide solution (10%w/w). For fonnulation number 2, all of the dapsone is dissolved with no microparticulatedrug present.Approximately 10 mg of product was rubbed into the skin, and after 72 hours, the skinsurface was tape stripped to remove all supracomeum drug. The skin was cut into smallpieces and extracted while the receptor solution was directly assayed. For formulationnumber 1 (microparticulate to dissolved drug ratio equal to 5) 68 1 4% of the applied doseremained in the supracomeum zone, while only 52 i 3% of formulation 2 (particulate todissolved drug ratio = 0) remained in the supracomeum zone. Each value is the mean oftriplicate experiments.Table 2.Distribution of Dapsone in Different Skin Layersby 72 hrs of in-vitro Permeation StudyFormulation 1% DDS Hydrogel in 10% DGME 1% DDS Hydrogel in 25% DGME(microcrystal form) (soluble form)Receptor 0.92% :l: 0.14 l.29%;t 0.24Surface residual 68.42% i 3.84 52.51% 1: 2.88Stratum comeum l5.54%i 4.12 32.l5%i 6.16Dermal 13.59%: 2.15 14.06%: 7.31Total recovery 60.7% :1: 5.3 53.7%:t 7.7?H20CA 02265461 1999-03-09WO 98/10746 PCT/US97/15919-28-EXAMPLE 11-—EVALUATIONExample 1] demonstrates that a 2% acyclovir solution in 1-methyl-2 pyrrolidoneprovides the same level of intact skin delivery as a 5% acyclovir gel formulation that containsapproximately 2% dissolved acyclovir and 3% microparticulate acyclovir. These deliveryresults are compared with the Spruance (1986 Antimicrobial Agents and Chemotherapy, Vol.29, No. 5, Pgs. 730-732) standard acyclovir intact skin delivery formulation comprised of 5%acyclovir dissolved in 95% dimethyl sulfoxide (DMSO). The 95/5 DMSO/acyclovir standardformulation is known to be 60-fold more permeable than the commercially availableZOVIRAX® Ointment (5% acyclovir in a polyethylene glycol base).In example 1 1, the procedures of example 9 were used except that 50-500 microliterdoses of formulations were applied to dermatomed human skin which was not frozen untilafter 48 hours post-mortem. The formulation of example 8 which contains 5% acyclovir (ofwhich approximately 40% is dissolved and 60% is in a microparticulate form) was testedalong with a 2% acyclovir in 1-methyl-2—pyrrolidone. In direct comparison with the 95/ 5DMSO/acyclovir skin delivery standard, both the 5% acyclovir combination gel of example 8and the 2% acyclovir in 1-methyl—2-pyrrolidone solution delivered 20-25% of the acyclovirdelivery standard. The presence of crystalline microparticulate drug does not increase thedelivery of acyclovir across intact skin. The delivery of the dissolved acyclovir is consideredoptimized since it was more than 10-fold greater than skin delivery of acyclovir from thecommercialized ZOVIRAX® formulation.?CA 02265461 1999-03-09W0 98/10746 PCT/US97/15919-29-Those skilled in the art will recognize that, while specific embodiments have beenillustrated and described, various modi?cations and changes may be made without departingfrom the spirit and scope of the invention.

Claims (31)

CLAIMS:
1. A dermatological composition comprising:
a semisolid aqueous gel;
a pharmaceutical dissolved in said gel, wherein said dissolved pharmaceutical has the capacity to cross the stratum corneum layer of the epidermis and become available systemically; and a microparticulate pharmaceutical dispersed in said gel, wherein said microparticulate pharmaceutical does not crass the stratum corneum of the epidermis in its microparticulate state.
2. The composition of claim 1, wherein said gel comprises carbomer, hydroxyethylcellulose, hydroxypropylcellulose, cellulose gum, MVE/ME decadiene crosspolymer, or PVM/MA copolymer.
3. The composition of claim 1, wherein said gel comprises a cross-linked acrylic acid polymer dissolved in an aqueous phase and a caustic material.
4. The composition of claim 1, wherein said microparticulate pharmaceutical is a crystalline precipitant.
5. The composition of claim 1, wherein said microparticulate pharmaceutical is an amorphous precipitant.
6. The composition of claim 1, wherein said dissolved pharmaceutical and microparticulate pharmaceutical comprise an antimicrobial agent, anti-inflammatory agent, antiviral agent, local anesthetic, corticosteroid, destructive therapy agent, antifungal agent, or antiandrogen agent.
7. The composition of claim 1, wherein the ratio of microparticulate pharmaceutical to dissolved pharmaceutical is no greater than 5.
8. The composition of claim 1, wherein said microparticulate pharmaceutical and dissolved pharmaceutical comprise the same pharmaceutical.
9. The composition of claim 1, wherein said microparticulate pharmaceutical and dissolved pharmaceutical comprise different pharmaceuticals.
10. A dermatological composition, comprising a semisolid aqueous gel having about 0.5% to 4.0% carbomer; about 0.5% to 10% pharmaceutical, wherein said pharmaceutical comprises a dissolved pharmaceutical having the capacity to cross the stratum corneum of the epidermis and become systemically available and a microparticulate pharmaceutical lacking the ability to cross the stratum corneum of the epidermis in its microparticulate state; and an amine base, sodium hydroxide solution, or potassium hydroxide solution.
11. The dermatological composition of claim 10, wherein said pharmaceutical comprises dapsone.
12. The dermatological composition of claim 11, wherein the microparticulate to dissolved pharmaceutical ratio is no greater than 5.
13. The composition of claim 10, wherein said pharmaceutical comprises an antimicrobial agent, antiviral agent, anti-inflammatory agent, local anesthetic, corticosteroid, destructive therapy agent, antifungal agent, or antiandrogen agent.
14. A dermatological gel composition including microparticulate pharmaceutical and dissolved pharmaceutical, which comprises:
about 1 % carbomer;
about 83.7 to 86.4% water;
about 10% ethoxydiglycol;
about 0.2% methylparaben;
up to about 3% dapsone in a microparticulate and dissolved state;
and about 2 % sodium hydroxide solution.
15. The dermatological composition of claim 14, wherein the ratio of microparticulate to dissolved dapsone is no greater than 5.
16. A dermatological gel composition for the treatment of herpes lesions comprising:
a semisolid aqueous gel;
a first pharmaceutical in said gel, partially in a microparticulate form and partially in a dissolved form, wherein said first pharmaceutical provides optimized delivery for early state lesions when dissolved and optimized delivery for later state lesions when present as a microparticulate; and a second pharmaceutical dissolved in said gel, wherein said second pharmaceutical provides benefit throughout lesion progression.
17. The composition of claim 16, wherein said first pharmaceutical comprises a nucleoside analogue, and said second pharmaceutical comprises a local anesthetic.
18. The composition of claim 17, wherein said nucleoside analogue is selected from the group consisting of acyclovir, penciclovir, famciclovir, valacyclovir, and ganciclovir.
19. The composition of claim 17, wherein said local anesthetic is selected from the group consisting of tetracaine, tetracaine HCI, dyclonine, dyclonine HCI, dibucaine, and dibucaine HCI.
20. The composition of claim 17, wherein said nucleoside analogue is acyclovir, which comprises 5% by weight of the composition.
21. The composition of claim 17, wherein said local anesthetic is tetracaine HCI, which comprises 5% by weight of the composition.
22. A dermatological composition for the treatment of herpes lesions comprising acyclovir and 1-methyl-2-pyrrolidone in a semisolid aqueous gel, wherein said acyclovir is present in dissolved and microparticulate forms.
23. A use of a semisolid gel composition, wherein said composition comprises:
a semisolid aqueous gel; a first pharmaceutical in said gel, partially in a microparticulate form and partially in a dissolved form, wherein said first pharmaceutical provides optimized delivery for early state lesions when dissolved and optimized delivery for later state lesions when present in a microparticulate; and a second pharmaceutical dissolved in said gel, wherein said second pharmaceutical provides benefit throughout lesion progression; for the treatment of dermatological conditions.
24. The use of claim 23, wherein said first pharmaceutical comprises an antimicrobial agent, anti-inflammatory agent, antiviral agent, local anesthetic agent, corticosteroid, destructive therapy agent, antifungal agent, or antiandrogen agent.
25. The use of claim 23, wherein said first pharmaceutical comprises dapsone.
26. A use for treating disease of an aqueous gel composition for topical application, said composition comprising a dissolved pharmaceutical that has the capacity to cross the stratum corneum of the epidermis and become systemically available, and a microparticulate pharmaceutical that has only minimal capacity to cross the stratum corneum in its microparticulate state.
27. The use of claim 26, wherein said dissolved pharmaceutical and said microparticulate pharmaceutical comprise about 1.0% to 10% antiviral agent.
28. The use of claim 26, wherein said dissolved pharmaceutical and said microparticulate pharmaceutical comprise about 0.5 to 10% antiandrogen.
29. A use of a gel composition comprising a dissolved anti-inflammatory pharmaceutical and a microparticulate antimicrobial pharmaceutical, wherein said dissolved anti-inflammatory pharmaceutical is capable of crossing the stratum corneum of the epidermis and being absorbed into the lower two-thirds of the pilosebaceous unit, while said microparticulate antimicrobial pharmaceutical is adapted to be primarily delivered into the upper third of the pilosebaceous unit, crossing the stratum corneum of the epidermis only minimally, for treating acne.
30. The use of claim 29, wherein said anti-inflammatory pharmaceutical and said antimicrobial pharmaceutical comprise dapsone.
31. A method for the preparation of a dermatological gel composition wherein said composition includes dissolved and microparticulate pharmaceutical, comprising the steps of:
forming a homogenous dispersion by stirring purified water vigorously enough to form a vortex and sifting gel polymer into the vortex formed in the water while continuing to stir;
forming a pharmaceutical component by dissolving methyl paraben and propylparaben in ethoxydiglycol by mixing to form a solution, and mixing an active pharmaceutical with said solution until said pharmaceutical dissolves;
mixing said pharmaceutical component with said homogeneous dispersion to form a microparticulate pharmaceutical dispersion; and adding a caustic material.
CA002265461A 1996-09-11 1997-09-10 Compositions and methods for topical application of therapeutic agents Expired - Lifetime CA2265461C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/712,454 1996-09-11
US08/712,454 US5863560A (en) 1996-09-11 1996-09-11 Compositions and methods for topical application of therapeutic agents
PCT/US1997/015919 WO1998010746A1 (en) 1996-09-11 1997-09-10 Compositions and methods for topical application of therapeutic agents

Publications (2)

Publication Number Publication Date
CA2265461A1 CA2265461A1 (en) 1998-03-19
CA2265461C true CA2265461C (en) 2004-11-30

Family

ID=24862185

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002265461A Expired - Lifetime CA2265461C (en) 1996-09-11 1997-09-10 Compositions and methods for topical application of therapeutic agents

Country Status (11)

Country Link
US (3) US5863560A (en)
EP (1) EP0957900B1 (en)
JP (2) JP4276298B2 (en)
AT (1) ATE258426T1 (en)
AU (1) AU737365B2 (en)
CA (1) CA2265461C (en)
DE (1) DE69727398T2 (en)
DK (1) DK0957900T3 (en)
ES (1) ES2212128T3 (en)
PT (1) PT957900E (en)
WO (1) WO1998010746A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10201517B2 (en) 2010-10-21 2019-02-12 Galderma Laboratories, L.P. Brimonidine gel compositions and methods of use

Families Citing this family (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030157036A1 (en) * 2002-02-20 2003-08-21 Osborne David W. Topical dapsone for the treatment of acne
US5863560A (en) * 1996-09-11 1999-01-26 Virotex Corporation Compositions and methods for topical application of therapeutic agents
US6787157B1 (en) * 1998-03-10 2004-09-07 Abbott Laboratories Multiphase active ingredient-containing formulations
US6294188B1 (en) 1998-07-09 2001-09-25 Aviana Biopharm Inc. Methods involving changing the constitutive and stimulated secretions of the local reproductive system of women
CA2399229A1 (en) * 2000-01-31 2001-08-02 Collaborative Technologies, Inc. Surfactant free topical compositions and method for rapid preparation thereof
US20040002482A1 (en) * 2000-08-30 2004-01-01 Dudley Robert E. Androgen pharmaceutical composition and method for treating depression
US6503894B1 (en) * 2000-08-30 2003-01-07 Unimed Pharmaceuticals, Inc. Pharmaceutical composition and method for treating hypogonadism
US20040092494A9 (en) * 2000-08-30 2004-05-13 Dudley Robert E. Method of increasing testosterone and related steroid concentrations in women
US20020193321A1 (en) * 2000-12-12 2002-12-19 Mohan Vishnupad Dual dispenser for aesthitically acceptable delivery of anhydrous skin treatment compositions
US6998421B2 (en) 2001-06-07 2006-02-14 Biozone Laboratories, Inc. Compounds and methods for inhibition of phospholipase A2 and cyclooxygenase - 2
US6495596B1 (en) 2001-03-23 2002-12-17 Biozibe Laboratories, Inc. Compounds and methods for inhibition of phospholipase A2 and cyclooxygenase-2
US6475526B1 (en) 2001-06-05 2002-11-05 Jeffrey B. Smith Zinc containing compositions for anti-viral use
US20040072810A1 (en) 2001-11-07 2004-04-15 Besins International Belgique Pharmaceutical composition in the form of a gel or a solution based on dihydrotestosterone, process for preparing it and uses thereof
US20030144362A1 (en) * 2002-01-28 2003-07-31 Utterberg David S. High viscosity antibacterials for cannulae
US20050042240A1 (en) * 2002-01-28 2005-02-24 Utterberg David S. High viscosity antibacterials
WO2003092704A1 (en) * 2002-04-30 2003-11-13 Mochida Pharmaceutical Co., Ltd. External preparation enhanced in systemic property of vidarabine
US20040086469A1 (en) * 2002-10-30 2004-05-06 Osborne David W. Protectant for UV-induced skin damage
US6855341B2 (en) * 2002-11-04 2005-02-15 Jeffrey B. Smith Anti-viral compositions and methods of making and using the anti-viral compositions
US20080274209A1 (en) * 2002-11-04 2008-11-06 Integritas Pharma, Inc. Methods of treating inflammation
JP4591746B2 (en) * 2002-12-03 2010-12-01 大正製薬株式会社 Water-soluble topical composition containing sparingly soluble antiviral components
US20050037033A1 (en) * 2003-05-23 2005-02-17 Program For Appropriate Technology In Health Microbicidal compositions and methods and use
US7186416B2 (en) * 2003-05-28 2007-03-06 Stiefel Laboratories, Inc. Foamable pharmaceutical compositions and methods for treating a disorder
US20060229258A1 (en) * 2003-07-30 2006-10-12 Daniela Serikaku Steroidal compositions containing hydroxycarboxylic acids and methods of using the same
MXPA06001713A (en) * 2003-08-13 2007-01-26 Qlt Usa Inc Emulsive composition containing dapsone.
US20060204526A1 (en) * 2003-08-13 2006-09-14 Lathrop Robert W Emulsive composition containing Dapsone
US20050191338A1 (en) * 2004-01-30 2005-09-01 Lifeng Kang Transdermal drug delivery composition comprising a small molecule gel and process for the preparation thereof
WO2006004759A2 (en) * 2004-06-29 2006-01-12 Mcclellan Stephanie N Topical compositions for anti-aging
US20060024372A1 (en) * 2004-07-29 2006-02-02 Utterberg David S High viscosity antibacterials
WO2006036936A2 (en) * 2004-09-27 2006-04-06 Bridge Pharma, Inc. The s-isomer of 2-{2-[n-(2-indanyl)-n-phenylamino]ethyl}piperidine and other dermal anesthetic agents
US20060079558A1 (en) * 2004-09-27 2006-04-13 Bridge Pharma. Inc. R-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine and other dermal anesthetics
US7264314B2 (en) 2004-10-27 2007-09-04 Brennan Miles B Adrenocorticotropic hormone analogs and related methods
US20070088012A1 (en) * 2005-04-08 2007-04-19 Woun Seo Method of treating or preventing type-2 diabetes
WO2006113796A2 (en) * 2005-04-20 2006-10-26 Xylos Corporation Microbial cellulose materials for use in transdermal drug delivery system
US20060271262A1 (en) * 2005-05-24 2006-11-30 Mclain Harry P Iii Wireless agricultural network
US8389469B2 (en) * 2005-06-06 2013-03-05 The Rockefeller University Bacteriophage lysins for Bacillus anthracis
US8846154B2 (en) 2005-06-07 2014-09-30 S.C. Johnson & Son, Inc. Carpet décor and setting solution compositions
US20100154146A1 (en) 2008-07-02 2010-06-24 S.C. Johnson & Son, Inc. Carpet decor and setting solution compositions
US7582291B2 (en) * 2005-06-30 2009-09-01 The Rockefeller University Bacteriophage lysins for Enterococcus faecalis, Enterococcus faecium and other bacteria
ITMI20051417A1 (en) * 2005-07-22 2007-01-23 Mipharm S P A TOPIC FORMULATION IN THE FORM OF GEL CONTAINING AS ACTIVE CYCLOVIT AND LIDOCAINE INGREDIENTS
US20090176743A1 (en) * 2005-07-29 2009-07-09 Priscilla Schaffer Methods for treating or preventing reactivation of a latent herpesvirus infection
EP1917355B1 (en) 2005-08-24 2010-12-08 The Rockefeller University Ply-gbs mutant lysins
US20070071705A1 (en) * 2005-09-29 2007-03-29 De Oliveira Monica A M Topical anti-microbial compositions
WO2007044976A2 (en) 2005-10-12 2007-04-19 Unimed Pharmaceuticals, Llc Improved testosterone gel and method of use
JP2007320886A (en) * 2006-05-31 2007-12-13 Isp Japan Kk Hydrogel-like sheet agent and its production method
WO2008011161A2 (en) * 2006-07-21 2008-01-24 Bridge Pharma, Inc. Dermal anesthetic compounds
US8586010B2 (en) 2008-02-27 2013-11-19 Allergan, Inc. Dapsone to treat rosascea
US20100029781A1 (en) * 2008-06-04 2010-02-04 Morris Jerome A Methods for preparation of anti-acne formulation and compositions prepared thereby
EP2571984A2 (en) 2008-10-10 2013-03-27 Lusomedicamenta, S.A. Antibacterial phage peptides and methods of use thereof
AU2010211456B2 (en) 2009-02-06 2016-05-26 Technophage, Investigação E Desenvolvimento Em Biotecnologia, S.A. Antibacterial phage, phage peptides and methods of use thereof
US20110117182A1 (en) * 2009-07-30 2011-05-19 Allergan, Inc. Combination of dapsone with other anti-acne agents
US8999302B1 (en) 2009-10-22 2015-04-07 Aplicare, Inc. Skin dye protectant formulations
PT104837A (en) 2009-11-24 2011-05-24 Technophage Investiga O E Desenvolvimento Em Biotecnologia S A PACKAGES OF FACTS ENTEROC? CICOS AND M? ALL FOR ITS USE
CN102869345B (en) 2010-03-17 2015-02-11 诺瓦利克有限责任公司 Pharmaceutical composition for treatment of increased intraocular pressure
CA2811472C (en) 2010-09-17 2019-08-27 Tecnifar-Industria Tecnica Farmaceutica, S.A. Antibacterial phage, phage peptides and methods of use thereof
EP2444063A1 (en) 2010-10-20 2012-04-25 Novaliq GmbH Liquid pharmaceutical compositions for the delivery of active ingredients
CN115887627A (en) 2011-04-21 2023-04-04 洛克菲勒大学 Streptococcus bacteriophage lysin for gram-positive bacteria detection and treatment
JP6039145B2 (en) * 2011-05-25 2016-12-07 ノバリック ゲーエムベーハー Topical pharmaceutical compositions based on semi-fluorinated alkanes
BR112013034059A2 (en) * 2011-06-30 2016-09-06 Allergan Inc retinoid topical compositions and processes for treating skin conditions
WO2013141730A1 (en) 2012-03-19 2013-09-26 Tecnifar-Indústria Técnica Farmacêutica, S.A. Compositions comprising cocktails of antibacterial phages and uses thereof for the treatment of bacterial infections
DK3181119T3 (en) 2012-09-12 2019-09-16 Novaliq Gmbh SEMIFLUORED ALKAN COMPOSITIONS TO USE IN TREATMENT OF KERATOCONJUNCTIVITIS SICCA
EP2922528B1 (en) 2012-11-20 2017-05-31 Allergan, Inc. Topical dapsone and dapsone/adapalene compositions and methods for use thereof
US9012402B1 (en) 2014-06-11 2015-04-21 James Blanchard Gel for topical delivery of NSAIDs to provide relief of musculoskeletal pain and methods for its preparation
WO2016019336A1 (en) 2014-07-31 2016-02-04 Allergan, Inc. Comparative efficacy and tolerability of dapsone 5% in adult versus adolescent females with acne vulgaris
JP6602964B2 (en) 2015-09-30 2019-11-06 ノバリック ゲーエムベーハー Semifluorinated compounds and compositions thereof
CN113662928A (en) 2015-09-30 2021-11-19 诺瓦利克有限责任公司 Semi-fluorinated compounds for ophthalmic administration
CA3003610A1 (en) * 2015-11-04 2017-05-11 Allergan, Inc. Methods of treatment of acne vulgaris using topical dapsone compositions
ES2763121T3 (en) 2016-06-23 2020-05-27 Novaliq Gmbh Topical administration method
MX2019003363A (en) 2016-09-22 2019-10-02 Novaliq Gmbh Pharmaceutical compositions for use in the therapy of blepharitis.
AU2017329983B2 (en) 2016-09-23 2022-05-05 Novaliq Gmbh Ophthalmic compositions comprising ciclosporin
BR112019021917A8 (en) 2017-04-21 2023-03-21 Novaliq Gmbh IODINE COMPOSITIONS
CN110650734A (en) 2017-05-12 2020-01-03 诺瓦利克有限责任公司 Pharmaceutical compositions comprising semifluorinated alkanes for the treatment of conditions associated with contact lenses
US9895359B1 (en) 2017-06-07 2018-02-20 Arcutis, Inc. Inhibition of crystal growth of roflumilast
US10821075B1 (en) 2017-07-12 2020-11-03 James Blanchard Compositions for topical application of a medicaments onto a mammalian body surface
CN111372566A (en) 2017-09-27 2020-07-03 诺瓦利克有限责任公司 Ophthalmic composition comprising latanoprost for treating ocular diseases
WO2019068763A1 (en) 2017-10-04 2019-04-11 Novaliq Gmbh Ophthalmic compositions comprising f6h8
US20210062137A1 (en) 2017-12-22 2021-03-04 The Rockefeller University Recombinant pseudomonas aeruginosa lysins
US11576893B2 (en) 2018-03-02 2023-02-14 Novaliq Gmbh Pharmaceutical compositions comprising nebivolol
KR102404412B1 (en) 2018-09-27 2022-05-31 노바리크 게엠베하 topical sunscreen formulations
WO2020074697A1 (en) 2018-10-12 2020-04-16 Novaliq Gmbh Ophthalmic composition for treatment of dry eye disease
WO2020181395A1 (en) 2019-03-14 2020-09-17 Crescita Therapeutics Inc. Rinse-off compositions and uses thereof for delivery of active agents
US11746352B2 (en) 2019-12-30 2023-09-05 Eligo Bioscience Microbiome modulation of a host by delivery of DNA payloads with minimized spread
AU2021214399A1 (en) 2020-01-31 2022-08-25 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half-life
US11617773B2 (en) 2020-04-08 2023-04-04 Eligo Bioscience Elimination of colonic bacterial driving lethal inflammatory cardiomyopathy
CN115427565A (en) 2020-04-08 2022-12-02 艾力格生物科技有限公司 Prevention, treatment, or cure of microbiome-related diseases or disorders by modulating microbiota function by gene therapy of microbiomes
WO2021250284A1 (en) 2020-06-12 2021-12-16 Eligo Bioscience Specific decolonization of antibiotic resistant bacteria for prophylactic purposes
WO2022003209A1 (en) 2020-07-03 2022-01-06 Eligo Bioscience Method of containment of nucleic acid vectors introduced in a microbiome population
WO2022144382A1 (en) 2020-12-30 2022-07-07 Eligo Bioscience Chimeric receptor binding proteins resistant to proteolytic degradation
WO2022169615A1 (en) 2021-02-05 2022-08-11 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
WO2023057599A1 (en) 2021-10-07 2023-04-13 Eligo Bioscience Methods involving bacteroides strain replacement
WO2023057598A1 (en) 2021-10-07 2023-04-13 Eligo Bioscience Methods involving bacterial strain replacement

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3867533A (en) * 1968-12-20 1975-02-18 Basf Wyandotte Corp Preparation of aqueous gel compositions containing a water-insoluble organic ingredient
US4731359A (en) * 1980-04-21 1988-03-15 University Of Southern California Prolonged action drug formulation
US4507287A (en) * 1983-06-20 1985-03-26 Dixon Glen J Preparation and method for the treatment of acne
US4853439A (en) * 1987-10-09 1989-08-01 Gaf Corporation Water-soluble complexes of water-insoluble organic compounds
US5180576A (en) * 1991-08-30 1993-01-19 Church & Dwight Co., Inc. Anticalculus dentifrices
GB2260080A (en) * 1991-10-04 1993-04-07 Rhone Poulenc Rorer Ltd Gelled alginate compositions
AU670777B2 (en) * 1992-04-16 1996-08-01 Ortho Pharmaceutical Corporation Aqueous gel vehicles for retinoids
IL104283A (en) * 1992-12-30 1996-12-05 Agis Ind 1983 Ltd Non-emulsion antiviral topical pharmaceutical composition comprising acyclovir an aqueous gel agent and an alkali oleate
GB9408545D0 (en) * 1994-04-29 1994-06-22 Zyma Sa Compositions
KR970705394A (en) * 1994-09-06 1997-10-09 다께다 가즈히코 AN OINTMENT PREPARATION
US5565188A (en) * 1995-02-24 1996-10-15 Nanosystems L.L.C. Polyalkylene block copolymers as surface modifiers for nanoparticles
US5863560A (en) * 1996-09-11 1999-01-26 Virotex Corporation Compositions and methods for topical application of therapeutic agents

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10201517B2 (en) 2010-10-21 2019-02-12 Galderma Laboratories, L.P. Brimonidine gel compositions and methods of use

Also Published As

Publication number Publication date
JP2001500863A (en) 2001-01-23
PT957900E (en) 2004-06-30
ATE258426T1 (en) 2004-02-15
DE69727398D1 (en) 2004-03-04
AU737365B2 (en) 2001-08-16
EP0957900A1 (en) 1999-11-24
DK0957900T3 (en) 2004-06-01
AU4261097A (en) 1998-04-02
DE69727398T2 (en) 2004-11-25
US6060085A (en) 2000-05-09
CA2265461A1 (en) 1998-03-19
EP0957900B1 (en) 2004-01-28
US5863560A (en) 1999-01-26
ES2212128T3 (en) 2004-07-16
WO1998010746A1 (en) 1998-03-19
US6620435B1 (en) 2003-09-16
JP2006096774A (en) 2006-04-13
JP4276298B2 (en) 2009-06-10

Similar Documents

Publication Publication Date Title
CA2265461C (en) Compositions and methods for topical application of therapeutic agents
JP2001500863A5 (en)
US5219877A (en) Lauryl alcohol as skin penetration enhancer for topical imidazole agents
AU621589B2 (en) Topical metronidazole formulations and therapeutic uses thereof
EP2052714B1 (en) Topical gel delivery systems for treating skin disorders
US5110809A (en) Antifungal gel formulations
EP1510213B1 (en) Penetration enhancing and irritation reducing systems comprising testosterone
CA2271139C (en) Percutaneous delivery system
US6017520A (en) Penetration enhancement of topically applied therapeutic formulations
EP0471872A1 (en) Antifungal gel formulations
EP1409022B1 (en) Pharmaceutical mousse composition comprising salicylic acid
US20100196454A1 (en) Dressing formulations to prevent and reduce scarring
KR20070072482A (en) Organo-gel formulations for therapeutic applications
AU3211999A (en) An acidified composition for topical treatment of nail and skin conditions
IE57733B1 (en) Topical drug release system
JPS6135166B2 (en)
WO2000038732A1 (en) Hyaluronate lyase used for promoting penetration in topical agents
EP0305380B1 (en) Novel topical metronidazole formulations
AU768046B2 (en) Compositions and methods for topical application of therapeutic agents
Chukwumerije et al. Studies on the efficacy of methyl esters of n-alkyl fatty acids as penetration enhancers
NZ235054A (en) Gel formulation comprising imidazole antifungal agent and a 17-ester steroid anti-inflammatory agent with a co-solvent system and a gelling agent
TW202310826A (en) Topical anesthetic agent-clay composite compositions
KR20170008763A (en) Hydroalcoholic system for nail treatment
JPH0358941A (en) Percutaneous absorbable pharmaceutical
PT95175A (en) Process for the preparation of pharmaceutical compositions containing an imidazole and a corticosteroid in the form of a gel for topical administration with antifungal action

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20170911