United States Patent [19J
`Osborne
`
`[54] COMPOSITIONS AND METHODS FOR
`TOPICAL APPLICATION OF THERAPEUTIC
`AGENTS
`
`[75]
`
`Inventor: David W. Osborne, The Woodlands,
`Tex.
`
`[73] Assignee: ViroTex Corporation, The Woodlands,
`Tex.
`
`[21]
`
`Appl. No.: 712,454
`
`[22]
`
`Filed:
`
`Sep. 11, 1996
`
`[51]
`
`[52]
`
`[58]
`
`[56]
`
`Int. Cl.6
`
`............................ A61K 9/10; A61K 47/32;
`A61K 47/38
`U.S. Cl. .......................... 424/484; 424/487; 424/488;
`514/944
`Field of Search ..................................... 424/484-488;
`514/944; 252/315.01, 315.7
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,731,359
`4,853,439
`5,180,576
`5,643,584
`5,705,194
`
`3/1988 Swarbrick.
`8/1989 Barabas .
`1!1993 Winston eta!. .
`7/1997 Farng eta!. .
`1!1998 Wong et a!. .
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US005863560A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,863,560
`Jan. 26, 1999
`
`FOREIGN PATENT DOCUMENTS
`
`0679390 A 11/1995 European Pat. Off ..
`4/1993 United Kingdom .
`2260080
`
`Primary Examiner-Edward 1. Webman
`Attorney, Agent, or Firm-Arnold White & Durkee
`
`[57]
`
`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 a phar(cid:173)
`maceutical 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 formu(cid:173)
`lation 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.
`
`10 Claims, No Drawings
`
`1
`
`AMN1016
`
`Mylan (IPR2019-01095) MYLAN1016, p. 001
`
`

`

`5,863,560
`
`1
`COMPOSITIONS AND METHODS FOR
`TOPICAL APPLICATION OF THERAPEUTIC
`AGENTS
`
`FIELD OF THE INVENTION
`The present invention relates to novel dermatological
`compositions that exhibit readily optimized solubility and
`systemic drug delivery properties for applying drugs and
`therapeutic agents to the skin of humans and animals and
`methods for their preparation and use.
`
`5
`
`2
`Additionally, when an anti-inflammatory agent is used to
`treat acne, it is important to increase the level of drug that
`will cross the intact stratum corneum lining the upper third
`of the pilosebaceous unit. By definition, inflammation is the
`response of the viable epidermis to irritants and sensitizers.
`In order to reduce the amount of inflammation, the active
`pharmaceutical must penetrate past the stratum corneum and
`interfere with the cascade of inflammatory events. Ideally,
`delivery of an anti-inflammatory for acne requires that
`10 steady-state levels be sustained. To date, the ideal delivery
`system that provides antimicrobial agents above the stratum
`corneum while providing anti-inflammatory agents below
`the stratum corneum has not been implemented.
`Other dermatological conditions, such as herpes lesions,
`require multiple delivery strategies because the barrier prop(cid:173)
`erties of the lesion dramatically change in the course of the
`disease. Starting with the prodrome and progressing through
`the formation of vesicles, the lesion has an intact stratum
`corneum delivery barrier, and thus, maximum penetration of
`the drug is necessary. While in place, the stratum corneum
`delays penetration to the target tissue and sustains the time
`that the dissolved active drug resides in the target tissue.
`During this stage of the lesion, microparticulate drug will
`not significantly cross the intact stratum corneum, and thus,
`25 has no real effect in treatment of the lesion. Once the herpes
`lesion vesicles rupture, the stratum corneum is no longer in
`place, and the dissolved drug rapidly sweeps past the target
`tissue, providing minimal or insignificant benefit. However,
`from the time that the vesicle ruptures and through to the
`30 complete formation of the scab, the microparticulate drug is
`deposited directly at the target area, where it can slowly be
`released for sustained and significant therapeutic benefit.
`Thus, in order to adequately dose the viable epidermis from
`the prodrome through the time of scab formation in a herpes
`35 lesion, two distinctly different drug delivery strategies must
`be implemented.
`While the dermatological conditions of acne and herpes
`lesions serve as conceptual examples of how therapeutic
`approaches can require dramatically different drug delivery
`40 profiles, all skin diseases are best treated by a particular drug
`delivery strategy tailored specifically to the pharmaceutical
`and the particular disease. Some diseases are best treated
`using pulsed or spiked delivery in which high levels of drug
`are delivered in a short period of time. This type of treatment
`45 saturates receptor sites and provides maximum microbial or
`viral replication inhibition, thus providing optimal therapy
`for certain diseases. Conversely, a cosmetic, topical, or
`transdermal product that provides steady state active phar(cid:173)
`maceutical delivery while minimizing excipient delivery
`50 provides the preferred skin delivery profile for other dis(cid:173)
`eases. Thus, a carrier system that can be adjusted to optimize
`the delivery profile for the pharmacology of the active drug
`and the nature of the disease state is needed to advance the
`effectiveness of pharmaceutical products applied to the skin.
`
`BACKGROUND OF THE INVENTION
`While the skin has long been considered the preferred
`route of administration for cosmetic applications and der(cid:173)
`matological therapies, the introduction of transdermal nitro- 15
`glycerin patches initiated use of the skin as a route for
`administering systemic drug therapy. Three types of known
`product applications which employ the barrier properties of
`the skin for drug delivery include cosmetic, topical, and
`transdermal applications. The optimal delivery strategy for 20
`administering pharmaceuticals via the skin varies among
`individual pharmaceuticals and among different disease
`states.
`Cosmetic applications are limited to negligible drug pen(cid:173)
`etration past the stratum corneum. Thus, any carrier that
`minimizes penetration or that aids excipient retention within
`or onto the stratum corneum would be of tremendous
`advantage. For transdermal applications, steady state drug
`delivery is preferred. Steady state delivery requires the use
`of rate-controlling membranes that slow systemic break(cid:173)
`through of highly permeable drugs such as nitroglycerin.
`This type of control can be achieved by using matrix type
`patches that modify delivery rates by using polymer adhe(cid:173)
`sives and solvents. For topical delivery, minimal systemic
`breakthrough is always preferred. In order to adequately
`dose the viable epidermis and dermis, however, large
`amounts of drug must cross the intact skin barrier, i.e. the
`stratum corneum, or the lesional delivery barrier, i.e. scab,
`plaque, etc.
`Some dermatological conditions, such as acne, require
`multiple delivery strategies because they have multiple
`delivery requirements. Acne is chronic pilosebaceous unit
`inflammation associated with the face and trunk usually
`occurring in adolescence due to complex interactions of
`androgens and bacteria. For the adolescent, circulating
`androgen results in significantly increased sebum produc(cid:173)
`tion. The sebaceous glands dramatically enlarge and excrete
`more sebum than the immature pilosebaceous canals can
`accommodate. Simultaneously, anaerobic bacteria
`(Propionibacterium aches) that feed upon the sebum, con(cid:173)
`verting triglycerides to fatty acids, dramatically increase in
`number due to an increase in volume of the nutrition source.
`The increase in constricted immature ducts and bacterial
`waste products results in plugged follicles and typical acne
`inflammation. Acne severity for a particular anatomical 55
`location parallels the number of sebaceous glands per unit of
`skin.
`Acne, which is often treated with antibiotics, is one
`condition where a highly specialized topical drug delivery is
`needed. Ideally, a topical antimicrobial would be primarily
`delivered into the pilosebaceous unit, with only minimal
`active crossing of the skin barrier. Intact stratum corneum
`lines the upper third of the pilosebaceous unit, and it is into
`this upper third of the hair follicle that the sebaceous duct
`secretes sebum. Thus, a need exists for an acne treatment
`that maximizes antimicrobial drug levels in the upper third
`of the pilosebaceous unit.
`
`SUMMARY OF THE INVENTION
`The present invention concerns a pharmaceutical carrier
`system comprising a dermatological composition that is a
`semi-solid aqueous gel, wherein a pharmaceutical is dis-
`60 solved in the gel such that the pharmaceutical has the
`capacity to cross the stratum corneum layer of the epidermis
`and become available systemically, and wherein the com(cid:173)
`position also contains pharmaceutical in a microparticulate
`state that does not readily cross the stratum corneum of the
`65 epidermis. The ratio of microparticulate pharmaceutical to
`dissolved pharmaceutical is adjustable, but is preferably five
`or less. The microparticulate pharmaceutical and the dis-
`
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`5,863,560
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`3
`solved pharmaceutical may be the same drug, or they may
`be different drugs.
`Methods for preparing the compositions of the present
`invention are also shown. In addition, methods for treating
`dermatological conditions that include topically applying
`the dermatological compositions of the invention are shown.
`More particularly, the invention concerns methods for treat(cid:173)
`ing dermatological conditions or diseases such as acne,
`herpes lesions, and dermatitis. Antimicrobial agents having
`anti-inflammatory properties such as dapsone are used to 10
`treat acne. Antiviral agents or antiviral agents in combina(cid:173)
`tion with local anesthetics are used to treat herpes lesions,
`and anti-inflammatory agents are used to treat dermatitis.
`
`4
`delivery from the microparticulate/dissolved pharmaceutical
`formulation may be optimized to provide higher levels of
`drug to the supracorneum zone, while maintaining the level
`of drug partitioning out of the stratum corneum and into the
`5 viable epidermis, despite 10-fold increases in the amount of
`pharmaceutical applied to the skin.
`The compositions of the present invention comprise semi-
`solid and gel-like vehicles that include a polymer thickener,
`water, preservatives, active surfactants or emulsifiers,
`antioxidants, sunscreens, and a solvent or mixed solvent
`system. The solvent or mixed solvent system is important to
`the formation of the microparticulate to dissolved pharma(cid:173)
`ceutical ratio. The formation of the microparticulate,
`however, should not interfere with the ability of the polymer
`15 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 hydroal(cid:173)
`coholic gelling agents frequently used in the cosmetic and
`pharmaceutical industries. Preferably, the hydrophilic or
`20 hydroalcoholic gelling agent comprises "CARBOPOL®"
`(B. F. Goodrich, Cleveland, Ohio), "HYPAN®" (Kingston
`Technologies, Dayton, N.J.), "NATROSOL®" (Aqualon,
`Wilmington, Del.), "KLUCEL®" (Aqualon, Wilmington,
`Del.), or "STABILEZE®" (ISP Technologies, Wayne, N.J.).
`25 Preferably, the gelling agent comprises between about 0.2%
`to about 4% by weight of the composition. More
`particularly, the preferred compositional weight percent
`range for "CARBOPOL®" is between about 0.5% to about
`2%, while the preferred weight percent range for "NATR0-
`30 SOL®" and "KLUCEL®" is between about 0.5% to about
`4%. The preferred compositional weight percent range for
`both "HYPAN®" and "STABILEZE®" is between about
`0.5% to about 4%.
`"CARBO POL®" is one of numerous cross-linked acrylic
`acid polymers that are given the general adopted name
`carbo mer. These polymers dissolve in water and form a clear
`or slightly hazy gel upon neutralization with a caustic
`material such as sodium hydroxide, potassium hydroxide,
`triethanolamine, or other amine bases. "KLUCEL®" is a
`cellulose polymer that is dispersed in water and forms a
`uniform gel upon complete hydration. Other preferred gel(cid:173)
`ling polymers include hydroxyethylcellulose, cellulose gum,
`MVE/MAdecadiene crosspolymer, PVM/MAcopolymer, 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 the
`product is microbially contaminated, the formulation will
`prevent or diminish microorganism growth. Some preserva(cid:173)
`tives useful in this invention include methylparaben,
`propylparaben, butylparaben, chloroxylenol, sodium
`benzoate, DMDM Hydantoin, 3-Iodo-2-Propylbutyl
`carbamate, potassium sorbate, chlorhexidine digluconate, or
`a combination thereof.
`Titanium dioxide may be used as a sunscreen to serve as
`prophylaxis against photosensitization. Alternative sun(cid:173)
`screens include methyl cinnamate. Moreover, BHA may be
`used as an antioxidant, as well as to protect ethoxydiglycol
`and/or dapsone from discoloration due to oxidation. An
`alternate antioxidant is BHT.
`Pharmaceuticals for use in all embodiments of the inven(cid:173)
`tion include antimicrobial agents, anti-inflammatory agents,
`antiviral agents, local anesthetic agents, corticosteroids,
`destructive therapy agents, antifungals, and antiandrogens.
`In the treatment of acne, active pharmaceuticals that may be
`used include antimicrobial agents, especially those having
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`The present invention comprises compositions for appli(cid:173)
`cation to the skin that can form microparticulate drug
`precipitates in adjustable ratios of microparticulate drug to
`dissolved drug, methods for the formation of said
`compositions, and methods for treatment of skin conditions
`using said compositions. The advantages of the present
`invention are appreciated in the treatment of skin conditions
`or diseases by using cosmetics or topical pharmaceuticals,
`and in the systemic treatment of illness by using transdermal
`pharmaceuticals. The present invention is particularly effec(cid:173)
`tive in the treatment of acne with antimicrobial actives
`known to possess anti-inflammatory properties such as dap(cid:173)
`sone. The invention also finds particular use in the treatment
`of herpes lesions and dermatitis.
`In one embodiment, the present invention is directed to a
`novel pharmaceutical carrier system comprising a dermato(cid:173)
`logical composition that is a semisolid aqueous gel, wherein
`the composition exhibits an optimal balance between a 35
`dissolved pharmaceutical that is available to cross through
`the stratum corneum to become systemically available, and
`a microparticulate pharmaceutical that is retained in or
`above the stratum corneum to serve as a reservoir or to
`provide drug action in the supracorneum zone. The micro- 40
`particulate pharmaceutical and the dissolved pharmaceutical
`may be the same or different drugs. The microparticulate
`pharmaceutical may comprise a crystalline precipitant or an
`amorphous precipitant.
`Optimal balance is accomplished by having a semisolid 45
`gel carrier system in which microparticulate pharmaceutical
`precipitates are formed in reproducible ratios with respect to
`the dissolved pharmaceutical. For the composition to have a
`wide range of applicability, the microparticulate to dissolved
`pharmaceutical ratio preferably should be no greater than 50
`five, at therapeutic levels of applied active pharmaceutical.
`A composition having a microparticulate to dissolved
`pharmaceutical ratio of less than two may provide the
`greatest amount of pharmaceutical available for immediate
`partition out of the stratum corneum and into the viable 55
`epidermis. This should provide minimum reservoir capacity,
`but may not maintain sustained delivery or provide maxi(cid:173)
`mum activity in the supracorneum zone. A composition
`having a microparticulate to dissolved pharmaceutical ratio
`of two or greater may have a reduced amount of drug 60
`available for immediate partition out of the stratum corneum
`and into the viable epidermis. This provides maximum
`reservoir capacity, and maintains sustained delivery, provid(cid:173)
`ing maximum activity in the supracorneum zone. For the
`present invention, the ratio for microparticulate drug to 65
`dissolved drug should be no greater than 50, preferably no
`greater than 10, and most preferably no greater than 5. Drug
`
`3
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`5,863,560
`
`5
`anti-inflammatory properties such as dapsone,
`erythromycin, minocycline, tetracycline, clindamycin, and
`other antimicrobials. The preferred weight percentages for
`the antimicrobials are 0.5% to 10%. In the topical treatment
`of herpes lesions, active pharmaceuticals that may be used
`include antiviral or local anesthetic agents. A concentration
`of about 1.0% to 10% by weight is preferred for nucleoside
`analogues such as acyclovir, famciclovir, penciclovir,
`valacyclovir, and ganciclovir.
`Local anesthetics include tetracaine, tetracaine
`hydrochloride, lidocaine, lidocaine hydrochloride,
`dyclonine, dyclonine hydrochloride, dimethisoquin
`hydrochloride, dibucaine, dibucaine hydrochloride,
`butambenpicrate, and pramoxine hydrochloride. A preferred
`concentration for local anesthetics is about 0.025% to 5% by
`weight of the total composition. Anesthetics such as ben(cid:173)
`zocaine may also be used at a preferred concentration of
`about 2% to 25% by weight.
`Corticosteroids that may be used include betamethasone
`dipropionate, fluocinolone acetonide, betamethasone
`valerate, triamcinolone acetonide, clobetasol propionate,
`desoximetasone, diflorasone diacetate, amcinonide,
`flurandrenolide, hydrocortisone valerate, hydrocortisone
`butyrate, and desonide are recommended at concentrations
`of about 0.01% to 1.0% by weight. Preferred concentrations
`for corticosteroids such as hydrocortisone or methylpred(cid:173)
`nisolone 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. A concentration of about 2% to about
`40% by weight is preferred. Cantharidin is preferably uti(cid:173)
`lized in a concentration of about 5% to about 30% by weight.
`Typical antifungals that may be used in this invention and
`their preferred weight concentrations include: oxiconazole
`nitrate (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
`topical treatment of seborrheic dermatitis, hirsutism, acne,
`and alopecia, the active pharmaceutical may include an
`antiandrogen such as flutamide or finasteride in preferred
`weight percentages of about 0.5% to 10%.
`Typically, treatments using a combination of drugs
`include antibiotics in combination with local anesthetics
`such as polymycin B sulfate and neomycin sulfate in com(cid:173)
`bination with tetracaine for topical antibiotic gels to provide
`prophylaxis against infection and relief of pain. Another
`example is the use of minoxidil in combination with a
`corticosteroid such as betamethasone diproprionate for the
`treatment of alopecia ereata. The combination of an anti(cid:173)
`inflammatory such as cortisone with an antifungal such as
`ketoconazole for the treatment of tinea infections is also an
`example.
`In one embodiment, the invention comprises a dermato(cid:173)
`logical composition having about 0.5% to 4.0% carbomer
`and about 0.5% to 10% of a pharmaceutical that exists in
`both a dissolved state and a microparticulate state. The
`dissolved pharmaceutical has the capacity to cross the
`stratum corneum, whereas the microparticulate pharmaceu(cid:173)
`tical does not. Addition of an amine base, potassium hydrox- 60
`ide solution, or sodium hydroxide solution completes the
`formation of the gel. More particularly, the pharmaceutical
`may include dapsone, an antimicrobial agent having anti(cid:173)
`inflammatory properties. A preferred ratio of microparticu(cid:173)
`late to dissolved dapsone is five or less.
`In another embodiment, the invention comprises about
`1% carbo mer, about 80-90% water, about 10%
`
`6
`ethoxydiglycol, about 0.2% methylparaben, about 0.3% to
`3.0% dapsone including both microparticulate dapsone and
`dissolved dapsone, and about 2% caustic material. More
`particularly, the carbomer may include "CARBOPOL®
`5 980" and the caustic material 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 ratio
`10 determines the amount of drug delivered, compared to the
`amount of drug retained in or above the stratum corneum to
`function in the supracorneum domain. The system of dap(cid:173)
`sone and ethoxydiglycol may include purified water com(cid:173)
`bined with "CARBOPOL®" gelling polymer,
`15 methylparaben, propylparaben, titanium dioxide, BHA, and
`a caustic material to neutralize the "CARBOPOL®."
`Another preferred embodiment of this invention relates to
`a composition for the treatment of herpes lesions comprising
`a semisolid aqueous gel; a first pharmaceutical in the gel,
`20 partially in a microparticulate form and partially in a dis(cid:173)
`solved form, where optimized delivery for early state lesions
`is provided when the pharmaceutical is dissolved and opti(cid:173)
`mized delivery for later state lesions is provided when the
`pharmaceutical is in a microparticulate form; and a second
`25 pharmaceutical dissolved in the gel which provides benefit
`throughout lesion progression. In a preferred embodiment,
`the composition comprises acyclovir and 1-methyl-2-
`pyrrolidone, which allows for an optimized ratio of micro(cid:173)
`particulate drug to dissolved drug for the treatment of herpes
`30 lesions. Acyclovir may be present in dissolved and micro(cid:173)
`particulate forms. The ratio determines the amount of drug
`delivered up to the point of lesion vesicle formation, as
`compared to the amount of drug available to be deposited
`into the lesion once the vesicles rupture. The drug delivery
`35 system of acyclovir and 1-methyl-2-pyrrolidone may
`include purified water combined with KLUCEL® hydrox(cid:173)
`ypropyl cellulose gelling polymer, methylparaben, and pro(cid:173)
`pylparaben.
`In another preferred embodiment, a combination drug
`system of acyclovir and tetracaine HCl may be formulated
`with 1-methyl-2-pyrrolidone to provide both antiviral and
`local anesthetic activity. Tetracaine HCl is a local anesthetic
`that alters membrane function and blocks pain. In a preferred
`45 embodiment, acyclovir comprises 5% by weight of the
`composition. The system of acyclovir, tetracaine HCl, and
`1-methyl-2-pyrrolidone can include purified water, sodium
`lauryl sulfate, KLUCEL® hydroxypropyl cellulose gelling
`polymer, methylparaben, and propylparaben. The combina-
`50 tion of a local anesthetic with sodium lauryl sulfate has been
`shown to be an effective therapy for herpes lesions. The
`combination of the nucleoside analogue acyclovir with the
`anesthetic/late stage antiviral combination tetracaine HCl
`and sodium lauryl sulfate should provide complete topical
`55 therapy for herpes lesions.
`The relative percentages for each of the reagents used in
`the present invention may vary depending upon the desired
`strength of the target formulation, gel viscosity, and the
`desired ratio of microparticulate to dissolved pharmaceuti(cid:173)
`cal. Unless otherwise designated, all reagents listed above
`are commonly known by one of ordinary skill in the art and
`are commercially available from pharmaceutical or cosmetic
`excipient suppliers.
`The present invention also provides methods for prepar-
`65 ing the dermatological compositions described above. In a
`general form, the method for producing a dermatological gel
`composition having dissolved drug and microparticulate
`
`40
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`5,863,560
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`8
`7
`drug precipitates comprises the steps of completely dissolv(cid:173)
`and a microparticulate antimicrobial pharmaceutical,
`ing a pharmaceutical in a solvent or solvent mixture; adding
`wherein the dissolved anti-inflammatory pharmaceutical
`and adequately dispersing a polymeric thickener in water;
`crosses the stratum corneum of the epidermis and is
`and combining the dissolved pharmaceutical with the dis(cid:173)
`absorbed into the lower two-thirds of the pilosebaceous unit,
`persed polymeric thickener. Alternatively, water may be 5
`while the microparticulate antimicrobial pharmaceutical is
`primarily delivered into the upper third of the pilosebaceous
`slowly added to the dissolved pharmaceutical, followed by
`the addition of a polymeric thickener. Ethoxydiglycol and
`unit, crossing the stratum corneum of the epidermis only
`1-methyl-2-pyrollidone are preferred solvents for use in this
`minimally. Preferably, the dissolved pharmaceutical and
`invention.
`microparticulate pharmaceutical comprise dapsone.
`In one preferred embodiment, the method for preparing a 10
`In another preferred embodiment, a method for the treat-
`dermatological composition having dissolved and micropar(cid:173)
`ment of herpes lesions comprises applying topically a semi(cid:173)
`ticulate pharmaceutical comprises the steps of forming a
`solid gel composition that comprises a semisolid aqueous
`gel; a first pharmaceutical in the gel, which exists in a
`homogenous dispersion by stirring purified water vigorously
`partially microparticulate form and a partially dissolved
`enough to form a vortex and sifting gel polymer into the
`vortex formed in the water while continuing to stir; forming 15 form, providing for optimized delivery for early state lesions
`when dissolved and optimized delivery for later state lesions
`a pharmaceutical component by dissolving methyl paraben
`when present as a microparticulate; and a second pharma(cid:173)
`and propylparaben in ethoxydiglycol by mixing to form a
`ceutical dissolved in the gel, providing benefit throughout
`solution, and mixing an active pharmaceutical with the
`progression of the lesion. Preferably, the first pharmaceutical
`solution until the pharmaceutical dissolved; mixing the
`20 comprises a nucleoside analogue, and the second pharma(cid:173)
`pharmaceutical component with the homogenous dispersion
`to form a microparticulate pharmaceutical dispersion; and
`ceutical comprises a local anesthetic. In a preferred
`adding a caustic material. The active pharmaceutical may
`embodiment, the nucleoside analogue comprises acyclovir,
`comprise any of the types mentioned above. In a preferred
`penciclovir, famciclovir, valacyclovir, or ganciclovir, and
`the local anesthetic comprises tetracaine, dyclonine,
`embodiment, the active pharmaceutical comprises dapsone.
`25 dibucaine, or a salt thereof, such as tetracaine HCl, dyclo(cid:173)
`In another preferred embodiment, the active pharmaceutical
`nine HCl, or dibucaine HCl. More preferably, acyclovir
`comprises acyclovir or acyclovir in combination with tetra(cid:173)
`comprises 5% by weight of the composition, and tetracaine
`caine or tetracaine HCl.
`HCl comprises 2-5% by weight.
`The order in which reagents are combined may be
`The following examples are provided to enable those of
`important, depending on the particular reagents necessary
`for the target mixture. For example, after a pharmaceutical 30
`ordinary skill in the art to make and use the methods and
`such as dapsone is dissolved in a solvent such as
`compositions of the invention. These examples are not
`intended to limit the scope of what the inventors regard as
`ethoxydiglycol, water may be slowly added to the dapsone
`their invention. Additional advantages and modifications
`in the ethoxydiglycol solution, or the dapsone in ethoxydig(cid:173)
`will be readily apparent to those skilled in the art.
`lycol solution may be added to the water with mixing.
`Adding the dapsone in ethoxydiglycol solution to water may 35
`Examples 1 through 6 describe methods for the prepara(cid:173)
`result in less polydispersity in the size of the microparticu(cid:173)
`tion of compositions of the invention that include micropar-
`lates than adding water to the dapsone in ethoxydiglycol
`ticulate crystalline dapsone, dissolved dapsone, and combi(cid:173)
`solutions.
`nations of the two. The examples offer illustrations of
`methods that can be used to control the ratio of dissolved to
`The carbomer is generally dispersed in the water campo- 40
`nent of the formulation, while the remaining ingredients will
`microparticulate pharmaceuticals in the final product. Since
`be dissolved or dispersed in whichever of the two compo(cid:173)
`microparticulate pharmaceuticals are retained above the
`nents are best for dissolving or dispersing the ingredient. For
`stratum corneum having negligible penetration and dis(cid:173)
`example, it is suggested to dissolve methylparaben,
`solved pharmaceuticals penetrate the stratum corneum, con(cid:173)
`propylparaben, and BHA in ethoxydiglycol. After the 45
`trolling the ratios between the two epidermal areas is impor(cid:173)
`ethoxydiglycol component and water component are
`tant in developing a composition having an optimal delivery
`combined, neutralizer is added to formulate the gel.
`route for administering pharmaceuticals via the skin.
`Finally, in another embodiment of the invention, methods
`Example 7 describes a method for the preparation of
`compositions of this invention using two different pharma-
`for the treatment of dermatological conditions by topical
`50 ceuticals in combination, resulting in one pharmaceutical
`application of the compositions of this invention are shown.
`These methods are useful in the treatment of diseases such
`dissolved in the composition and the other present in a
`as acne, herpes lesions, seborrhea dermatitis, hirsutism, and
`microparticulate state, such that two epidermal areas may be
`alopecia. In a preferred embodiment, a method for the
`treated with two different drugs. Example 8 provides a
`treatment of dermatological conditions comprises applying
`method for preparing a composition having a pharmaceuti-
`55 cal partially in a microparticulate state and partially
`topically a gel composition comprising a dissolved pharma(cid:173)
`dissolved, combined with a different dissolved pharmaceu(cid:173)
`ceutical that has the capacity to cross the stratum corneum
`of the epidermis and become systemically available, and a
`tical. Examples 9-11 provide evaluations of the composi(cid:173)
`tions and methods described herein.
`microparticulate pharmaceutical that has only minimal
`capacity to cross the stratum corneum in its microparticulate
`state. In one embodiment, the dissolved pharmaceutical and 60
`microparticulate pharmaceutical comprise about 1.0% to
`10% antiviral agent. In another embodiment, the dissolved
`pharmaceutical and microparticulate pharmaceutical com(cid:173)
`prise about 0.5% to 10% antiandrogen.
`In a preferred embodiment, a method for the treatment of
`acne comprises applying topically a gel composition that
`comprises a dissolved anti-inflammatory pharmaceutical
`
`The following example provides a method for producing
`a topical therapeutic is agent in which the pharmaceutical
`component is a combination of dissolved and microcrystal(cid:173)
`line dapsone. Because of the nature of the microcrystalline
`65 dapsone in the final product of Example 1, microcrystalline
`dapsone will be retained in or above the stratum corneum
`and will therefore serve as a reservoir or provide drug action
`
`EXAMPLE 1
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`5
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`Mylan (IPR2019-01095) MYLAN1016, p. 005
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`

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`5,863,560
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`5
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`9
`in the supracorneum zone. The dissolved dapsone will pass
`through the stratum corneum. The method of Example 1 can
`also be used to produce a composition of this invention that
`includes other pharmaceuticals such as