111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20100029781Al
`
`(19) United States
`c12) Patent Application Publication
`Morris
`
`(10) Pub. No.: US 2010/0029781 A1
`Feb. 4, 2010
`(43) Pub. Date:
`
`(54) METHODS FOR PREPARATION OF
`ANTI-ACNE FORMULATION AND
`COMPOSITIONS PREPARED THEREBY
`
`(76)
`
`Inventor:
`
`Jerome A. Morris, Erie, CO (US)
`
`Correspondence Address:
`ALLERGAN, INC.
`2525 DUPONT DRIVE, T2-7H
`IRVINE, CA 92612-1599 (US)
`
`(21) Appl. No.:
`
`12/478,377
`
`(22) Filed:
`
`Jun.4,2009
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/058,751, filed on Jun.
`4, 2008.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 311136
`(2006.01)
`A61P 17110
`(52) U.S. Cl. ........................................................ 514/646
`ABSTRACT
`(57)
`
`The present invention provides methods to make solvent(cid:173)
`microparticle (SMP) topical formulations for bioactive drugs.
`The formulations, which are aqueous gels containing undis(cid:173)
`solved solid drug, include a drug in a solution which can
`permeate the stratum corneum layer of the epidermis and the
`drug in an undissolved microparticulate solid form that does
`not readily cross the stratum corneum. The solid form is
`retained in or above the stratum corneum to serve as a reser(cid:173)
`voir or to provide drug action in the supracorneum zone. The
`fine, particulate solid component of the invention can confer
`a smooth, nongritty feel against the skin.
`
`1
`
`AMN1008
`
`

`

`US 2010/0029781 AI
`
`Feb.4,2010
`
`1
`
`METHODS FOR PREPARATION OF
`ANTI-ACNE FORMULATION AND
`COMPOSITIONS PREPARED THEREBY
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`[0001] This application claims the benefit of U.S. provi(cid:173)
`sional patent application Ser. No. 61/058,751, filed on Jun. 4,
`2008, and which is incorporated herein by reference in its
`entirety.
`
`BACKGROUND
`
`[0002] Formulations systems adapted for delivery of bio(cid:173)
`active drugs to the skin and via the skin must be designed to
`address the barrier properties of skin and of skin-related
`structures, such as lesion surfaces, inflamed skin, scabs, scar
`tissue, and the like Formulations for drug delivery to or via
`skin include cosmetic, transdermal, and topical systems. The
`optimal delivery strategy for administering pharmaceuticals
`to, and via, the skin varies among various types of formula(cid:173)
`tions depending upon the target tissues. Cosmetic applica(cid:173)
`tions, where the target tissue is the skin surface, are designed
`to provide for negligible drug penetration past the stratum
`corneum, the layer of dead cells on the surface of the epider(cid:173)
`mis. For transdermal applications, where the goal is to intro(cid:173)
`duce the drug to the entire body by way of the skin, steady
`state, high efficiency drug delivery through the epidermal and
`dermal layers via the capillary bed to the bloodstream and
`thus systemically to the patient is preferred. However, for
`topical delivery, minimal systemic absorption is preferred, as
`the target tissue is at or near the skin surface, and topical
`agents may furthermore have undesirable side effects when
`absorbed systemically. However, the bioactive agent must
`nevertheless penetrate sufficiently to expose the dermal and
`subdermal tissue to effective doses of the agent, as the target
`tissue may be several millimeters below the skin surface. For
`instance, in the treatment of acne, the inflamed sebaceous
`glands are located in dermal and subdermal layers, but not in
`deeper musculature. In the treatment of viral lesions such as
`from Herpes Simplex, viral populations may be similarly
`located.
`In order to adequately dose viable epidermis and
`[0003]
`dermis, relatively 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., due to the often-broad distribu(cid:173)
`tion of the malcondition over a substantial surface area of the
`body and the need to achieve effective in vivo concentrations
`of the bioactive drug throughout a tissue layer that can be at
`least several millimeters in depth. For example, acne, viral
`skin lesions, fungal infections, and other dermatological dis(cid:173)
`ease states can involve substantial areas of the body's surface.
`Also, it is often advantageous to be able to deliver the bioac(cid:173)
`tive drug over a period of time, such that a desired level of the
`drug in the target tissue is achieved for a period of time
`sufficient to achieve the desired result, e.g., killing most of a
`population of infectious bacterial or fungal cells. Some der(cid:173)
`matological conditions, such as acne, require multiple deliv(cid:173)
`ery strategies because they have multiple delivery require(cid:173)
`ments, such as killing skin surface bacteria while also
`penetrating deep into inflamed sebaceous glands to kill bac(cid:173)
`teria in that locus.
`[0004] One topical formulation for the treatment of acne
`that has found wide acceptance is Aczone®, a topical formu-
`
`lation of the bioactive drug dapsone that is in the physical
`form of an aqueous gel containing dapsone both in solution
`and in the solid phase. Commercially available with a 5%
`concentration of dapsone, this gel material also includes Car(cid:173)
`homer 980 as a thickener, methylparaben as a preservative,
`diethyleneglycol monoethyl ether (DGME) as a cosolvent,
`and sodium hydroxide for pH adjustment. A notable feature
`of Aczone is that the bioactive drug dapsone is not totally
`dissolved in the vehicle, but also is present in microparticu(cid:173)
`late, dispersed form. Thus, the Aczone formulation is in the
`nature of a solvent-microparticle (SMP) topical gel formula(cid:173)
`tion that contains dapsone both in dissolved form and in solid
`microparticulate form, which is advantageous for treatment
`of acne, as the dissolved material is readily and immediately
`available for absorption into dermal and subdermal tissue,
`while the solid microparticulate form persists on the surface
`of the skin after application and is only slowly released for
`absorption. It may be absorbed, for example, by dissolution in
`skin oils and perspiration and subsequent permeation on a
`molecular level. The rate of absorption of dapsone from the
`solid microparticulate state can be controlled, at least in part,
`by the specifics of the microparticulate form of the solid
`material, e.g., the size, size distribution, shape, surface/vol(cid:173)
`ume ratio, polymorphic crystalline form, and hydration or
`solvation of the dapsone microparticles. For example, as is
`well known in the art, larger particles tend to dissolve or
`disperse more slowly due to the lower surface area/volume
`ratio in comparison with smaller but similarly shaped particu(cid:173)
`lates.
`In U.S. Pat. Nos. 5,863,560 and 6,060,085, topical
`[0005]
`or dermatological compositions (formulations) containing
`bioactive drugs such as dapsone or acyclovir, and others, are
`provided for treatment of various skin diseases. These patents
`also provide methods of preparation of aqueous gels contain(cid:173)
`ing both dissolved and solid particulate forms of the bioactive
`drug, wherein the drug is at least moderately soluble in at least
`some organic solvents but only sparingly soluble, or
`insoluble, in water. These methods involve dissolving the
`drug in a solvent that has at least some solubility in water, then
`partially precipitating the drug in solid form by addition of
`water. This method results in the production of particulates
`from the sparingly soluble drug whose physical form is gov(cid:173)
`erned by the specifics of the technique used to carry out the
`precipitation, such as concentration, identity of the solvent,
`relative amount of water added, the presence of other ingre(cid:173)
`dients, the time period over which precipitation occurs, the
`temperature, post-precipitation handling, and other variables.
`Many of these variables are likely to be influenced by the
`scale on which the step of precipitation is carried out, and the
`degree of control that can be exercised. Therefore, procedures
`that may work well on a small scale can nevertheless cause
`problems when attempting to scale up to industrial produc(cid:173)
`tion of the topical formulation.
`
`SUMMARY
`
`[0006] Embodiment of the invention described herein are
`directed to novel methods for preparation of solvent-micro(cid:173)
`particle (SMP) topical formulations including a bioactive
`drug, and to the formulations prepared by various embodi(cid:173)
`ments the inventive method. A specific example of a drug that
`is suitable for use in this type of topical SMP formulation is
`dapsone, which is indicated for treatment of acne, among
`other malconditions, by topical application. A topical SMP
`formulation prepared by an embodiment of a method of the
`
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`

`US 2010/0029781 AI
`
`Feb.4,2010
`
`2
`
`invention includes a bioactive agent in two physical states: a
`dissolved form of a drug that can permeate the stratum cor(cid:173)
`neum layer of the epidermis and become available in tissues
`of the living dermal layer, and a solid form of a drug that does
`not readily cross the stratum corneum of the epidermis and
`thus persists on the exterior surface of the epidermis The solid
`form can be retained in or above the stratum corneum, where
`it can serve as a reservoir of a drug for eventual permeation of
`the skin, or can provide drug action in the supracorneum zone,
`for example killing bacteria disposed on the skin surface. The
`solid form can be of a size and form adapted to confer a
`smooth, soft feeling when applied topically to human skin.
`The solid form of the drug may be any one of multiple poly(cid:173)
`morphic forms of a single drug, or can include more than one
`polymorph.
`[0007]
`In various embodiments of the invention, a method
`of preparing a solvent-microparticle topical gel formulation
`comprising a bioactive drug, wherein the formulation com(cid:173)
`prises the drug dissolved in a liquid and the drug in a micro(cid:173)
`particulate solid form dispersed in the liquid, the method
`comprising first forming the liquid by combining an organic
`solvent and water, and then contacting the drug in a micro(cid:173)
`particulate solid form with the liquid, such that the micropar(cid:173)
`ticulate solid form does not entirely dissolve in the liquid; and
`dissolving a thickener in the liquid at a concentration suffi(cid:173)
`cient to form a gel, is provided.
`[0008]
`In another embodiment of the invention, a method of
`preparing a solvent-microparticle topical gel formulation
`comprising a bioactive drug is provided wherein, prior to the
`step of contacting the microparticulate solid form with the
`liquid, forming a solution of the drug in the liquid, wherein
`the drug is substantially completely dissolved in the liquid.
`[0009]
`In another embodiment, a topical SMP formulation
`prepared by a method of the invention is provided.
`[0010]
`In another embodiment, a second drug can be
`included in a topical SMP formulation prepared by a method
`of the invention In various embodiments, methods of prepar(cid:173)
`ing a topical SMP formulation of the invention comprising a
`second drug are provided.
`[0011]
`In various embodiments, the amount of the drug in
`microparticulate solid form dispersed in a unit volume of the
`liquid is no more than about six times the amount of the drug
`dissolved in the unit volume of the liquid.
`[0012]
`In various embodiments, the topical composition is
`a semi-solid aqueous gel, wherein a drug is dissolved in the
`gel such that the drug has the capacity to cross the stratum
`corneum layer of the epidermis and become available at least
`in the living dermal tissue, and wherein the composition also
`contains the drug in a microparticulate state that does not
`readily cross the stratum corneum of the epidermis In various
`embodiments, the topical composition is a semi-solid or gel(cid:173)
`like vehicle that can include a preservative, active surfactants
`or emulsifiers antioxidants, or sunscreens, or any combina(cid:173)
`tion thereof
`In some embodiments, the solid form of the active
`[0013]
`agent is a amorphous solid. In other embodiments, the solid
`form of the active agent is a flake. In still other embodiments,
`the solid form of the active agent is a crystal. In various
`embodiments, the invention provides compositions with
`desirable physical properties, such as a smooth, non-gritty
`feeling against the skin of a patient.
`
`DETAILED DESCRIPTION
`
`[0014] As used herein, "dapsone" refers to the chemical
`compound dapsone having
`the
`elemental
`formula
`C 12H 12N2 0 2S, structure
`
`known as bis( 4-aminophenyl)sulfone, including its hydrates,
`solvates, tautomers, and salts; also known as 4,4'-sulfonylbis(cid:173)
`benzeneamine, 4,4'-sulfonyldianiline, and diaphenylsulfone;
`and dapsone analogs; and dapsone related compounds. "Dap(cid:173)
`sone analogs" refers to chemical compounds that have similar
`chemical structures and thus similar therapeutic potential to
`dapsone such as the substituted bis(4-aminophenyl)-sul(cid:173)
`fones. "Dapsone related compounds" refers to chemical com(cid:173)
`pounds that have similar therapeutic potential, but are not as
`closely related by chemical structure to dapsone such as the
`substituted 2,4-diamino-5-benzylpyrimidines.
`[0015] A "drug," "active agent," "bioactive agent," or
`"pharmaceutical," as the terms are used herein, refer to a
`medicinal compound, organic, organometallic, or inorganic,
`that can be used for treatment of a malcondition wherein
`topical application of the material is medically indicated.
`[0016] As used herein, "gel" refers to a colloid in a more
`solid form than a solution; a jelly-like material formed by the
`coagulation or gelation of a colloidal liquid; many gels have
`a fibrous matrix and fluid filled interstices: gels can be vis(cid:173)
`coelastic as well as viscous, and in various embodiments gels
`can resist some mechanical stress without deformation.
`[0017] As used herein, the term "microparticulate" or
`"microparticle" refers to any solid form of an active agent,
`including dapsone, provided that the average particle size is
`on the micron scale, that is, less than 1 mm, and that there are
`substantially no particles of size larger than 1 mm in a sample
`of the solid. By "average particle size" is meant an average of
`the particle diameters of all the particles in a population of the
`particles. By "particle diameter" of an individual particle is
`meant, if the particle is substantially spherical, the diameter
`of the sphere; if the particle is elongated or of irregular shape,
`an average of diameters along all axes. The average particle
`size can be on the order of microns (1-1 0 microns), tens of
`microns (11-1 00 microns), or hundreds of microns (1 01-999
`microns), or it can be submicron. Typically, average particle
`sizes in an SMP formulation of the invention are around
`10-500 microns. The microparticulate active agent described
`herein can be in any solid shape, such as flakes or crystals or
`amorphous particles.
`[0018] By the terms "dissolved" or a "solution" is meant a
`molecular solution of a substance, the substance being a solid
`in pure form at room temperature, in a liquid, wherein indi(cid:173)
`vidual molecules of the substance are separated from each
`other in the liquid solution, as is well known in the art. Few if
`any long-lasting interactions between molecules of the sub(cid:173)
`stance take place in the solution phase, and the molecules of
`the substance are surrounded by molecules of the materials
`making up the liquid.
`
`3
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`US 2010/0029781 AI
`
`Feb.4,2010
`
`3
`
`[0019] By the terms "suspended," "suspension," "dis(cid:173)
`persed," and "dispersion" are meant a physical state wherein
`finely particulate solid particles are mixed with a liquid, but
`are not dissolved in the liquid. There are many significant and
`long-term associations between individual molecules of the
`suspended or dispersed substance within the particles. Mol(cid:173)
`ecules of the substances making up the liquid may permeate
`the particles, but the particles retain a cohesive structure,
`wherein aggregations of molecules of the solid substance
`persist. Upon standing, these particles may be acted on by the
`force of gravity, causing them to accumulate at the bottom of
`a vessel containing the suspension or dispersion.
`[0020] The microparticulate solid can be any polymorph of
`a given drug, or can be a mixture of multiple polymorphs. It
`can include hydrates, solvates, tautomers, salts or molecular
`complexes of the drug. By a "molecular complex" of a drug is
`meant a form of the drug wherein the active molecule is in a
`defined molecular association with a carrier, for example a
`cyclodextrin complex of a drug. For example, when the drug
`is dapsone, various polymorphic forms such as Form I or
`Form III can be used.
`[ 0021] The microparticulate solid may have been milled or
`ground to achieve smaller sized particles. As used herein, the
`terms "milling" and "grinding" refer to the action ofbreaking
`a solid material into smaller pieces. The grinding of solid
`matters occurs under exposure of mechanical forces that
`trench the structure by overcoming of the interior bonding
`forces. After the grinding the state of the solid is changed: the
`grain size, the grain size disposition and the. grain shape.
`[0022] As used herein, "preservative" refers to any sub(cid:173)
`stance which prevents bacterial growth, mold growth, fer(cid:173)
`mentation, oxidation, or molecular decomposition, or any
`combination thereof.
`"Therapeutically effective amount" refers to an
`[0023]
`amount of a drug, or a combination of more than one drug or
`an amount of a formulation including the drug or the combi(cid:173)
`nation, effective to treat dermatological condition in a patient.
`[0024] The term "topical" as used herein refers to the route
`of administration of a dermatological composition that
`involves direct application to the exterior body part being
`treated, the skin, or a lesion on the body exterior where skin
`has decomposed such as a scab, plaque or open sore. Typi(cid:173)
`cally, areas of the body suitable for application of the derma(cid:173)
`tological composition include the skin of the face, throat,
`neck, scalp, chest, back, ears, and other skin sites. Application
`to mucosal surfaces is not included in the term "topical" as
`used herein.
`[0025] As used herein, the term "treat", "treatment", or
`"treating" includes prophylaxis of the specific disorder or
`condition, or alleviation of the symptoms associated with a
`specific disorder or condition and/or preventing, ameliorat(cid:173)
`ing, inhibiting or eliminating the symptoms.
`[0026] Embodiments of the invention described herein pro(cid:173)
`vides topical SMP gel formulations and methods to prepare
`the formulations. Embodiments of the topical SMP formula(cid:173)
`tions include a liquid component, the liquid component
`including a mixture of water and an at least partially water(cid:173)
`soluble solvent. The solvent can be an organic solvent, for
`example the solvent can include diethyleneglycol monoethyl
`ether (DGME), N-methylpyrrolidone (NMP), N,N-dimethyl(cid:173)
`formamide, N,N-dimethylacetamide (DMA), dimethylsul(cid:173)
`foxide (DMSO), or any other substantially non-toxic solvent
`suitable for application to human skin, wherein the solvent
`has at least some water solubility. Or, combinations of any of
`
`these solvents can be used. Additional examples include etha(cid:173)
`nol, propylene glycol, glycerol, diethyleneglycol, triethyl(cid:173)
`eneglycol, polyethylene glycol, propylene carbonate, pyrroli(cid:173)
`done,
`N-methyl
`pyrrolidone,
`dimethylsulfoxide,
`triethanolamine, 1 ,4-butanediol, triacetin, diacetin, dimethyl
`isosorbide, and the like, alone or in combination. The solvent
`and the water can be present in various relative amounts in the
`liquid. The solvent need not be miscible with water in all
`proportions, but when mixed at the particular ratio selected
`for a formulation, the water and the solvent should form a
`single phase. at room temperature.
`[0027] Water is typically the predominant component of
`the liquid. For example, the solvent can make up about
`10-40% of the liquid by weight, with the remainder of the
`liquid component as described herein being water. Deionized
`water or distilled water can be used in a method of the inven(cid:173)
`tion. The water can be sterilized, for example by ultrafiltration
`or by boiling, to remove any infectious organisms that could
`be present. The water can be substantially free of dissolved
`solids, such as salts or other contaminants. USP grade water
`can be used.
`[0028] Other solvents that can be used in conjunction with
`water to form the liquid of the inventive method include, but
`are not limited to: benzyl alcohol, denatured alcohol, metha(cid:173)
`nol, isopropyl alcohol, water, propanol, acetone, chlorobu(cid:173)
`tanol, methyl ethyl ketone, sorbitan monolaurate, sorbitan
`monooleate, sorbitan monopalmitate, butanol, butyl alcohol,
`diglycerides, dipropylene glycol, eugenol, diacetin, dietha(cid:173)
`nolamine, monoacetin, monoglycerides, PEG vegetable oil,
`N,N-dimethylformamide, N-methyl formamide, N-methy(cid:173)
`lacetamide, N,N-dimethylacetamide, or combinations
`thereof.
`[0029] Glycol ethers are organic solvents that are moder(cid:173)
`ately soluble to miscible with water and can be as a solvent in
`formation of a liquid used in a method of the invention. A
`glycol ether is an ether formed from at least one glycol and at
`least one lower alkyl alcohol. Preferably the glycol is selected
`from an alkylene glycol such as ethylene glycol, propylene
`glycol, or butylene glycol. The ether portion of the glycol
`ether is a radical of a lower alkyl alcohol such as a C 1 to C6
`alcohol. Preferably, the ether portion alcohol is selected from
`methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alco(cid:173)
`hol, butyl alcohol, or isobutyl alcohol.
`[0030] Examples of glycol ethers under the classification of
`ethylene glycol ethers include ethylene glycol monopropyl
`ether (propoxyethanol), ethylene glycol mono butyl ether (bu(cid:173)
`toxyethanol), diethylene glycol monoethyl ether ( ethoxydig(cid:173)
`lycol, DGME), diethylene glycol monobutyl ether (butoxy(cid:173)
`diglycol),
`diethylene
`glycol monoisopropyl
`ether
`(isopropyldiglycol), and diethylene glycol monoisobutyl
`ether (isobutyl diglycol).
`[0031] Glycol ethers under the classification of propylene
`glycol ethers include propylene glycol monomethyl ether,
`dipropylene glycol monomethyl ether (PPG-2 methyl ether),
`tripropylene glycol monomethyl ether (PPG-3 methyl. ether),
`propylene glycol n-propyl ether, dipropylene glycol n-propyl
`ether (PPG-2 propyl ether), propylene glycol monobutyl
`ether, dipropylene glycol monobutyl ether (PPG-2 butyl
`ether), propylene glycol monoisobutyl ether, and dipropylene
`glycol dimethyl ether. In one embodiment of the invention the
`solvent is ethoxydiglycol. In another embodiment, the sol(cid:173)
`vent is methoxydiglycol. Additional suitable exemplary gly(cid:173)
`col ethers are disclosed, e.g., in Aldrich Handbook of Fine
`Chemicals, 2003-2004 (Milwaukee, Wis.).
`
`4
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`US 2010/0029781 AI
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`Feb.4,2010
`
`4
`
`In one embodiment, formulations of the invention
`[0032]
`can have a glycol ether. present in about 20.0 wt. %to about
`40.0 wt. %. In another embodiment, formulations of the
`invention cab have a glycol ether present in about 20.0 wt.%
`to about 35.0 wt. %. In another embodiment, formulations of
`the invention can have a glycol ether present in about 25.0 wt.
`%to about 40.0 wt. %. In yet another embodiment, formula(cid:173)
`tions of the present invention can have a glycol ether present
`in about 25.0 wt.% to about 35.0 wt.% of the composition.
`More specifically, compositions of the present invention have
`a glycol ether present in about 25.0 wt.% of the composition.
`[0033] A drug is present in the SMP formulation, both
`dissolved and dispersed in the liquid component. An example
`of a drug for use in a method of the invention is dapsone.
`Another example is acyclovir or ganciclovir. A drug is present
`in the topical SMP formulation in two distinct physical forms.
`First a solution or dissolved form of the drug is present in the
`SMP formulation, wherein the drug substance is dissolved in
`the liquid comprising the water and. the solvent. Therefore
`the drug has at least a limited solubility in the liquid of the
`SMP formulation. This dissolved form of the drug can per(cid:173)
`meate the stratum corneum layer of the epidermis and
`become available in the living dermal tissue when the formu(cid:173)
`lation is applied to human skin. The second physical form of
`the drug in the SMP formulation is a microparticulate solid
`form that is not dissolved in the liquid, but rather is dispersed
`or suspended in the liquid of the formulation. Therefore the
`drug is not completely soluble in the liquid comprising water
`and a solvent at the concentration of drug and the composition
`ofliquid used. The formulation can be in gel form due to the
`presence of a thickener as discussed below. This solid micro(cid:173)
`particulate form does not readily cross the stratum corneum
`of the epidermis when the formulation is applied to human
`skin. Instead, the solid form is retained in or above the stratum
`corneum to serve as a reservoir for eventual absorption
`through the stratum corneum into the living dermal tissue, or
`to provide drug action in the supracorneum zone, or both. The
`fine, microparticulate solid component can confer a smooth,
`nongritty feel against the skin. For example, flakes or amor(cid:173)
`phous solids of relatively small average particle diameter can
`provide a smooth skin feel or texture.
`[0034] Examples of drugs that can be used in a formulation
`prepared by a method of the invention include, in addition to
`dapsone, acyclovir, and ganciclovir: salicylic acid, resorci(cid:173)
`nol, resorcinol acetate, benzoyl peroxide, sulfur, retinol, ret(cid:173)
`inoic acid, citric acid, an alpha hydroxy acid, retinal, phar(cid:173)
`maceutically acceptable salts thereof, and combinations
`thereof. Specifically, the active agent can be at least one of
`adapalene, azaleic acid, erythromycin salnacedin, inocoter(cid:173)
`one acetate, or isotretenoin anisatil.
`In various embodiments of the invention, the drug
`[0035]
`can be a glucocorticoid. Glucocorticoids include, e.g.,
`betamethasone dipropionate, betamethasone valerate, clobe(cid:173)
`tasol propionate, diflorasone diacetate, halobetasol propi(cid:173)
`onate, amcinonide, desoximetasone, fluocinonide, fluocino(cid:173)
`nide acetonide, halcinonide,
`triamcinolone acetonide,
`flurandrenolide, hydrocortisone valerate, hydrocortisone
`butyrate, mometasone furoate, aclometasone dipropionate,
`desonide, dexamethasone sodium phosphate, and fluocino(cid:173)
`lone acetonide.
`In various embodiments of the invention, the drug
`[0036]
`can be calcipotriene, a retinoid, anthralin, coal tar, salicylic
`acid, or a combination thereof.
`
`In various embodiments of the invention, the drug
`[0037]
`can be an antibiotic agent. As used herein, an "antibiotic
`agent" refers to any compound having activity against either
`Gram-positive or Gram-negative organisms (i.e., inhibits. the
`growth or destroys the development of either Gram-positive
`or Gram-negative organisms). Stedman's Medical Dictio(cid:173)
`nary, Illustrated, (25th Ed.), Williams & Wilkins: Baltimore
`(1990) and Mosby's Medical, Nursing, & Allied Health Dic(cid:173)
`tionary, (5th Ed.), Mosby: St. Louis (1998).
`[0038] Any suitable antibiotic agent can be employed, pro(cid:173)
`vided the antibiotic. agent effectively inhibits the growth or
`destroys the development of either Gram-positive or Gram(cid:173)
`negative organisms and the antibiotic agent remains stable in
`the formulation. Preferably, the stability is over a prolonged
`period of time, e.g., up to about 3 years, up to about !year, or
`up to about 6 months, typically experienced in the manufac(cid:173)
`turing, packaging, shipping, and/or storage of the composi(cid:173)
`tion. Suitable antibiotic agents are disclosed, e.g., in Physi(cid:173)
`cian's Desk. Reference
`(PDR), Medical Economics
`Company (Montvale, N.J.), (53rd Ed.), 1999; Mayo Medical
`Center Formulary, Unabridged Version, Mayo Clinic (Roch(cid:173)
`ester, Minn.), January 1998; Merck Index, An Encyclopedia
`of Chemicals, Drugs, and Biologicals, (11th Ed.), Merck &
`Co., Inc. (Rahway, N.J.), 1989;. University of Wisconsin
`Antimicrobial Use Guide, http://www.medsch.wisc.edu/clin(cid:173)
`sci/amcg/amcg.html; Introduction on the Use of the Antibi(cid:173)
`otics Guideline, Descriptions of Specific Antibiotic Classes,
`Thomas Jefferson University, http://jeffiine.tju.edu/CWIS/
`OAC/antibiotics_guide/intro.html; and references. cited
`therein.
`[0039] Suitable classes of antibiotic agents include, e.g.,
`~-lactams, aminoglycosides, antifungal agents, and combi(cid:173)
`nations thereof. Suitable antibiotic agents include, e.g., cilas(cid:173)
`tatin, clavulanic acid, folinic acid, probenecid, pyridoxine,
`sulbactam, dapsone, ethambutol, isoniazid, pyrazinamide,
`rifampin, streptomycin, capreomycin, ethionamide, para
`aminosalicylic acid, cycloserine, ciprofloxacin, nalidixic
`acid, norfloxacin, ofloxacin, imipenam, meropenem, cilista(cid:173)
`tin, cefadroxil, cefazolin, cephalexin, cephalothin, cefaclor,
`cefamandole, cefonicid, cefoxitin, cefuroxine, cefoperazone,
`cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, moxalac(cid:173)
`tam, cefepine, bacitracin, vancomycin, aztreonam, amoxicil(cid:173)
`lin, clavulanic acid, benzathine, penicillin g, penicillin v,
`ampicillin, carbenicillin. indamyl, carbenicillin, mezlocillin,
`piperacillin, ticarcillin, cloxacillin, dicloxacillin, floxacillin,
`methicillin, nafcillin, oxacillin, colistmethate, polyrnixin b,
`trimethoprim,
`cotrimoxazole, mafenide,
`sulfadiazine,
`sodium
`sulfacetamide,
`sulfacytine,
`sulfadiazine,
`sul(cid:173)
`famethoxazole, sulfapyridine, sulfasalazine, sulfisoxazole,
`chloramphenicol, clindamycin, spectinomycin, azithromy(cid:173)
`cin, clarithromycin, erythrmoycin, erythromycin estolate,
`spiramycin, chlortetracycline, demeclocycline, doxycycline,
`minocycline, oxytetracycline, amikacin, kanamycin, neomy(cid:173)
`cin, streptomycin, tobramycin, nitrofurantoin, griseofulvin,
`potassium iodide, fluconazole, itraconazole, ketoconazole,
`miconazole, clotrimazole, amphotericin b, nystatin, niclosa(cid:173)
`mide, nifurtimox, piperazine, praziquantel, pyrantel pamo(cid:173)
`ate, ascariasis, pinworm, thiabendazole, amodiaquine, chlo(cid:173)
`roquine, hydroxychloroquine, mefloquine, primaquine,
`pyrimethamine, quinidine gluconate, fansidar, diloxanide
`furoate, melarsoprol, nifurtimox, paromomycin, pentami(cid:173)
`dine, sodium stibogluconate, suramin, metronidazole, foscar(cid:173)
`net, 3-deoxythmidin-2-ene, dideoxycytosine, dideoxyi(cid:173)
`nosine, lamivudine, azidothymidine, indinavir, ritonavir,
`
`5
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`5
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`saquinavir, acyclovir, idoxuridine, ribavirin, vidarabine,
`amantidine, rinantidine, pharmaceutically acceptable salts
`thereof, and combinations thereof Specifically, the antibiotic
`agent can be dapsone, erythromycin, tetracycline, clindamy(cid:173)
`cin, cephalosporin, pharmaceutically. acceptable salts
`thereof, or a combination thereof. In a preferred embodiment,
`the antibiotic agent is dapsone. When the compositions are in
`use (i.e., when the. composition is placed upon the skin of a
`patient (e.g., human)), the dapsone can be in continuous con(cid:173)
`tact with the skin surface of the patient.
`[0040] Specifically, the antibiotic can be at least one of
`Arnphomycin, Apramycin, Avilamycin, Azithromycin, Baci(cid:173)
`tracin, Bactiracin Zinc, Clarithromycin, Clindamycin, Clin(cid:173)
`damycin Hydrochloride, Clindamycin Palmitate Hydrochlo(cid:173)
`ride, Clindamycin Phosphate, Dirithromycin, Erythromycin,
`Erythromycin Acistrate, Erthromycin Estolate, Erthryomy(cid:173)
`cin Ethlylsuccinate, Erthryomycin Gluceptate, Erythromycin
`Lactobionate, Erthromycin Propionate, Erthromycin Stear(cid:173)
`ate, Fosfomycin, Fosfomycin Tromethamine, Josamycin,
`Kitasamycin, Lexithromycin, Lincomycin, Limcomycin
`Hydrochloride, Metronidazole Hydrochloride, Metronida(cid:173)
`zole Phosphate, Mirincamycin Hydrochloride, Paldimycin,
`Paulomycin, Pirlimycin Hydrochloride, Ranimycin, Relo(cid:173)
`mycin, Roxithromycin, Spectinomycin Hydrochloride, Spi(cid:173)
`ramycin