WO1998010746A1

WO1998010746A1 - Compositions and methods for topical application of therapeutic agents

Info

Publication number: WO1998010746A1
Application number: PCT/US1997/015919
Authority: WO
Inventors: David W. Osborne
Original assignee: Virotex Corporation
Priority date: 1996-09-11
Filing date: 1997-09-10
Publication date: 1998-03-19
Also published as: AU4261097A; CA2265461A1; DK0957900T3; PT957900E; AU737365B2; US6060085A; ATE258426T1; DE69727398T2; CA2265461C; JP2001500863A; JP2006096774A; JP4276298B2; US5863560A; EP0957900A1; DE69727398D1; US6620435B1; ES2212128T3; EP0957900B1

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

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.

BACKGROUND OF THE INVENTION While the skin has long been considered the preferred route of administration for

cosmetic applications and dermatological therapies, the introduction of transdermal

nitroglycerin 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 administering pharmaceuticals via the skin varies among

individual pharmaceuticals and among different disease states.

Cosmetic applications are limited to negligible drug penetration 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 breakthrough 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 adhesives 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 production. The sebaceous glands dramatically

enlarge 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 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 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. 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 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 properties 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 co eum 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

co eum, and thus, has no real effect in treatment of the lesion. Once the herpes lesion

vesicles rupture, the stratum co eum 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 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 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

5 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 saturates receptor sites and provides maximum microbial or viral

replication inhibition, thus providing optimal therapy for certain diseases. Conversely, a

lo cosmetic, topical, or transdermal product that provides steady state active pharmaceutical

delivery while minimizing excipient delivery provides the preferred skin delivery profile for

other diseases. 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.

l s 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

dissolved in the gel such that the pharmaceutical has the capacity to cross the stratum

comeum layer of the epidermis and become available systemically, and wherein the

20 composition also contains pharmaceutical in a microparticulate state that does not readily

cross the stratum comeum of the epidermis. The ratio of microparticulate pharmaceutical to

dissolved pharmaceutical is adjustable, but is preferably five or less. The microparticulate pharmaceutical and the dissolved pharmaceutical may be the same dmg, 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 treating dermatological conditions or diseases such as acne, herpes

lesions, and dermatitis. Antimicrobial agents having anti-inflammatory properties such as

dapsone are used to treat acne. Antiviral agents or antiviral agents in combination with local

anesthetics are used to treat herpes lesions, and anti-inflammatory agents are used to treat

dermatitis.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention comprises compositions for application to the skin that can

form microparticulate d g precipitates in adjustable ratios of microparticulate d g to

dissolved dmg, 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 effective in the treatment of acne with

antimicrobial actives known to possess anti-inflammatory properties such as dapsone. 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 dermatological composition that is a semisolid aqueous gel, wherein the composition exhibits an optimal balance between a dissolved pharmaceutical that is available

to cross through the stratum comeum to become systemically available, and a

microparticulate pharmaceutical that is retained in or above the stratum comeum to serve as a

reservoir or to provide drug action in the supracomeum zone. The microparticulate

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 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 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 comeum and into the viable epidermis. This should provide minimum

reservoir capacity, but may not maintain sustained delivery or provide maximum activity in

the supracomeum zone. A composition having a microparticulate to dissolved

pharmaceutical ratio of two or greater may have a reduced amount of dmg available for

immediate partition out of the stratum comeum and into the viable epidermis. This provides

maximum reservoir capacity, and maintains sustained delivery, providing maximum activity

in the supracomeum zone. For the present invention, the ratio for microparticulate drug to

dissolved dmg should be no greater than 50, preferably no greater than 10, and most preferably no greater than 5. Dmg delivery from the microparticulate/dissolved

pharmaceutical formulation may be optimized to provide higher levels of dmg to the

supracomeum zone, while maintaining the level of dmg partitioning out of the stratum

comeum and into the 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

pharmaceutical ratio. The formation of the microparticulate, however, should not interfere

with 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 and

pharmaceutical industries. Preferably, the hydrophilic or hydroalcoholic gelling agent

comprises "CARBOPOL®" (B.F. Goodrich, Cleveland, OH), "HYPAN®" (Kingston

Technologies, 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 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 "NATROSOL®" 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%.

"CARBOPOL®" is one of numerous cross-linked acrylic acid polymers that are given

the general adopted name carbomer. 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 gelling polymers include hydroxyethylcellulose, cellulose gum, MVE/MA

decadiene 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 the

product is microbially contaminated, the formulation will prevent or diminish microorganism

growth. Some preservatives 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 sunscreens 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 invention include antimicrobial

agents, anti-inflammatory agents, antiviral agents, local anesthetic agents, corticosteroids,

destmctive therapy agents, antifungals, and antiandrogens. In the treatment of acne, active pharmaceuticals that may be used include antimicrobial agents, especially those having 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 .025% to 5% by weight of the total composition.

Anesthetics such as benzocaine 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

methylprednisolone acetate are from about 0.2% to about 5.0% by weight.

Destmctive 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

utilized 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 l0%.

Typically, treatments using a combination of drugs include antibiotics in combination

with local anesthetics such as polymycin B sulfate and neomycin sulfate in combination 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 -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 dermatological 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 comeum, whereas the microparticulate pharmaceutical does not.

Addition of an amine base, potassium hydroxide solution, or sodium hydroxide solution

completes the formation of the gel. More particularly, the pharmaceutical may include

dapsone, an antimicrobial agent having anti-inflammatory properties. A preferred ratio of

microparticulate to dissolved dapsone is five or less. 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% dapsone

including both microparticulate dapsone and dissolved dapsone, and about 2% caustic

material. More particularly, the carbomer may include "CARBOPOL® 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 dmg. This ratio

determines the amount of dmg delivered, compared to the amount of dmg retained in or

above the stratum comeum to function in the supracomeum domain. The system of dapsone

and ethoxydiglycol may include purified water combined with "CARBOPOL®" gelling

polymer, 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, partially in a microparticulate form and partially in a dissolved form, where optimized

delivery for early state lesions is provided when the pharmaceutical is dissolved and

optimized delivery for later state lesions is provided when the pharmaceutical is in a

microparticulate form; and a second pharmaceutical dissolved in the gel which provides

benefit throughout lesion progression. In a preferred embodiment, the composition comprises

acyclovir and l-methyl-2-pyrrolidone, which allows for an optimized ratio of

microparticulate dmg to dissolved dmg for the treatment of herpes lesions. Acyclovir may be

present in dissolved and microparticulate forms. The ratio determines the amount of dmg delivered up to the point of lesion vesicle formation, as compared to the amount of dmg

available to be deposited into the lesion once the vesicles rupture. The dmg delivery system

of acyclovir and l-methyl-2-pyrrolidone may include purified water combined with

KLUCEL® hydroxypropyl cellulose gelling polymer, methylparaben, and propylparaben.

In another preferred embodiment, a combination dmg 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 embodiment, acyclovir comprises 5% by weight of the

composition. The system of acyclovir, tetracaine HCl, and l-methyl-2-pyrrolidone can

include purified water, sodium lauryl sulfate, KLUCEL® hydroxypropyl cellulose gelling

polymer, methylparaben, and propylparaben. The combination 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

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 pharmaceutical. 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 preparing the dermatological

compositions described above. In a general form, the method for producing a dermatological gel composition having dissolved dmg and microparticulate dmg precipitates comprises the

steps of completely dissolving a pharmaceutical in a solvent or solvent mixture; adding and

adequately dispersing a polymeric thickener in water; and combining the dissolved

pharmaceutical with the dispersed polymeric thickener. Alternatively, water may be slowly

added to the dissolved pharmaceutical, followed by the addition of a polymeric thickener.

Ethoxydigylcol and 1 -methyl-2-pyrollidone are preferred solvents for use in this invention.

In one preferred embodiment, the method for preparing a dermatological composition

having dissolved and microparticulate pharmaceutical comprises 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 the

solution until the pharmaceutical dissolved; mixing the pharmaceutical component with the

homogenous dispersion to form a microparticulate pharmaceutical dispersion; and adding a

caustic material. The active pharmaceutical may comprise any of the types mentioned above.

In a preferred embodiment, the active pharmaceutical comprises dapsone. In another

preferred embodiment, the active pharmaceutical comprises acyclovir or acyclovir in

combination with tetracaine or tetracaine HCl.

The order in which reagents are combined may be important, depending on the

particular reagents necessary for the target mixture. For example, after a pharmaceutical such

as dapsone is dissolved in a solvent such as ethoxydiglycol, water may be slowly added to the

dapsone in the ethoxydiglycol solution, or the dapsone in ethoxydiglycol solution may be added to the water with mixing. Adding the dapsone in ethoxydiglycol solution to water may

result in less polydispersity in the size of the microparticulates than adding water to the

dapsone in ethoxydiglycol solutions.

The carbomer is generally dispersed in the water component of the formulation, while

the remaining ingredients will be dissolved or dispersed in whichever of the two components

are best for dissolving or dispersing the ingredient. For example, it is suggested to dissolve

methylparaben, propylparaben, and BHA in ethoxydiglycol. After the ethoxydiglycol

component and water component are combined, neutralizer is added to formulate the gel.

Finally, in another embodiment of the invention, methods for the treatment of

dermatological conditions by topical application of the compositions of this invention are

shown. 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 the

treatment of dermatological conditions comprises applying topically a gel composition

comprising a dissolved pharmaceutical that has the capacity to cross the stratum co eum of

the epidermis and become systemically available, and a microparticulate pharmaceutical that

has only minimal capacity to cross the stratum comeum in its microparticulate state. In one

embodiment, the dissolved pharmaceutical and microparticulate pharmaceutical comprise

about 1.0% to 10% antiviral agent. In another embodiment, the dissolved pharmaceutical and

microparticulate pharmaceutical comprise 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 and

a microparticulate antimicrobial pharmaceutical, wherein the dissolved anti-inflammatory pharmaceutical crosses the stratum comeum of the epidermis and is absorbed into the lower

two-thirds of the pilosebaceous unit, while the microparticulate antimicrobial pharmaceutical

is primarily delivered into the upper third of the pilosebaceous unit, crossing the stratum

comeum of the epidermis only minimally. Preferably, the dissolved pharmaceutical and

microparticulate pharmaceutical comprise dapsone.

In another preferred embodiment, a method for the treatment of herpes lesions

comprises applying topically a semisolid gel composition that comprises a semisolid aqueous

gel; a first pharmaceutical in the gel, which exists in a partially microparticulate form and a

partially dissolved form, providing for 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 the gel, providing benefit throughout progression of

the lesion. Preferably, the first pharmaceutical comprises a nucleoside analogue, and the

second pharmaceutical comprises a local anesthetic. In a preferred embodiment, the

nucleoside analogue comprises acyclovir, penciclovir, famciclovir, valacyclovir, or

ganciclovir, and the local anesthetic comprises tetracaine, dyclonine, dibucaine, or a salt

thereof, such as tetracaine HCl, dyclonine HCl, or dibucaine HCl. More preferably, acyclovir

comprises 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 to

make and use the methods and compositions of the invention. These examples are not

intended to limit the scope of what the inventors regard as their invention. Additional

advantages and modifications will be readily apparent to those skilled in the art. Examples 1 through 6 describe methods for the preparation of compositions of the

invention that include microparticulate crystalline dapsone, dissolved dapsone, and

combinations of the two. The examples offer illustrations of methods that can be used to

control the ratio of dissolved to microparticulate pharmaceuticals in the final product. Since

microparticulate pharmaceuticals are retained above the stratum comeum having negligible

penetration and dissolved pharmaceuticals penetrate the stratum comeum, controlling the

ratios between the two epidermal areas is important in developing a composition having an

optimal delivery route for administering pharmaceuticals via the skin.

Example 7 describes a method for the preparation of compositions of this invention

using two different pharmaceuticals in combination, resulting in one pharmaceutical

dissolved in the composition and the other present in a microparticulate state, such that two

epidermal areas may be treated with two different drugs. Example 8 provides a method for

preparing a composition having a pharmaceutical partially in a microparticulate state and

partially dissolved, combined with a different dissolved pharmaceutical. Examples 9-1 1

provide evaluations of the compositions and methods described herein.

EXAMPLE 1

The following example provides a method for producing a topical therapeutic agent in

which the pharmaceutical component is a combination of dissolved and microcrystalline

dapsone. Because of the nature of the microcrystalline dapsone in the final product of

Example 1 , microcrystalline dapsone will be retained in or above the stratum comeum and

will therefore serve as a reservoir or provide dmg action in the supracomeum zone. The

dissolved dapsone will pass through the stratum comeum. The method of Example 1 can also be used to produce a composition of this invention that includes other pharmaceuticals such

as those described above.

A polymer thickener component was prepared by charging 85.7 grams of purified

water to a vessel suitable to contain 100 grams of finished semisolid product, and slowly

sifting one gram of "CARBOPOL® 980" into a vortex formed by rapidly stirring the purified

water. When a homogeneous dispersion of "CARBOPOL® 980" and water was formed,

stirring was reduced to minimize air entrapment. Next, an active pharmaceutical component

was prepared by charging an appropriately sized container with 10.0 g of ethoxydiglycol. 0.2

g of methylparaben and 0.1 g of propylparaben were added to the ethoxydiglycol and mixed

until all of the crystalline solid was dissolved. 1.0 g dapsone was added to the ethoxydiglycol

and mixed until the dmg was completely dissolved.

The polymer thickener component was added to the pharmaceutical component with

mixing, and immediately resulted in the formation of crystalline microparticles. Once the

dispersion was homogenous. 2.0 grams of a 10% w/w aqueous sodium hydroxide solution

were added to neutralize the CARBOPOL® 980 and form the gel.

EXAMPLE 2

The following example provides another topical therapeutic agent in which the

pharmaceutical component is dissolved dapsone. The method of Example 2 can also be used

to produce a composition of this invention that includes other pharmaceuticals.

To prepare the composition of Example 2, the procedure of Example 1 was followed

using the following specific weights of reagents. All dapsone was dissolved in the final

product gel, and thus, crystalline microparticles did not form when the polymer thickener component was added to the pharmaceutical component. All reagent weights are shown per

100 grams of product.

Component wt/100 g product

Polymer Thickener Component

Water 86.67 g

"CARBOPOL 980" 1.0 g

Active Pharmaceutical Component

Ethoxydiglycol 10.0 g

Methylparaben 0.2 g

Propylparaben 0.1 g

Dapsone 0.03 g

Caustic/Amine Component

10% w/w Sodium Hydroxide 2.0 g

EXAMPLE 3

The following example provides yet another topical therapeutic agent in which the

pharmaceutical component is dissolved dapsone. The method of Example 3 can also be used

to produce a composition of this invention that includes other pharmaceuticals such as those

designated in this application.

The procedure of Example 1 was followed using reagents in the amounts designated

below. All of the dapsone was dissolved in the final product gel, thus crystalline

microparticles did not form upon adding the polymer thickener component to the

pharmaceutical component. All reagent weights are shown per 100 grams of product. Component wt/100 g product

Polymer Thickener Component

Water 86.6 g

"CARBOPOL 980" 1.0 g

Active Pharmaceutical Component

Ethoxydiglycol 10.0 g

Methylparaben 0.2 g

Propylparaben 0.1 g

Dapsone 0.1 g

Caustic/ Amine Component

10% w/w Sodium Hydroxide 2.0 g

EXAMPLE 4

pharmaceutical component is dissolved dapsone. The method of Example 4 can also be used

designated in this application.

below. All reagent weights are shown per 100 grams of product.

Component wt/100 p product

Polymer Thickener Component

Water 86.4 g

"CARBOPOL 980" 1.0 g Active Pharmaceutical

Ethoxydiglycol 10.0 g

Methylparaben 0.2 g

Propylparaben 0.1 g

Dapsone 0.3 g

Caustic/ Amine Component

10% w/w Sodium Hydroxide 2.0 g

EXAMPLE 5

pharmaceutical component is a combination of dissolved and microcrystalline dapsone.

Because of the nature of the microcrystalline dapsone in the final product of Example 5, it

will be primarily retained in or above the stratum comeum and will therefore serve as a

reservoir or provide dmg action in the supracomeum zone. The method of Example 5 can

also be used to produce a composition of this invention that includes other pharmaceuticals

such as those designated in this application.

below. All reagent weights are shown per 100 grams of product.

Component wt/100 g product

Polymer Thickener Component

Water 86.2 g

"CARBOPOL 980' 1.0 g Active Pharmaceutical Component

Ethoxydiglycol 10.0 g

Methylparaben 0.2 g

Propylparaben 0.1 g

Dapsone 0.5 g

Caustic/Amine Component

10% w/w Sodium Hydroxide 2.0 g

EXAMPLE 6

Example 6, it will be retained in or above the stratum co eum and will therefore serve as a

reservoir or provide dmg action in the supracomeum zone. The method of Example 6 can

also be used to produce a composition of this invention that includes other pharmaceuticals such as those designated in this application.

below. All reagent weights are shown per 100 grams of product.

Component wt/100 % product

Polymer Thickener Component

Water 83.7 g

"CARBOPOL 980" 1.0 g Active Pharmaceutical Component

Ethoxydiglycol 10.0 g

Methylparaben 0.2 g

Propylparaben 0.1 g

Dapsone 3.0 g

Caustic/ Amine Component

10% w/w Sodium Hydroxide 2.0 g

EXAMPLE 7

Example 7 describes a method for preparing a composition of this invention that

includes a microparticulate crystalline pharmaceutical, dapsone, in combination with a

different dissolved pharmaceutical, dyclonine HCl. Since microparticulate pharmaceuticals

are retained above the stratum comeum having negligible penetration and dissolved

pharmaceuticals penetrate the stratum comeum, using different dmgs for the two forms

(microparticulate and dissolved) enables treating the two epidermal areas with different

dmgs. This allows further options to develop optimal delivery routes for administering

pharmaceuticals via the skin.

An active pharmaceutical component was prepared by charging an appropriately sized

container with 15.0 g of ethoxydiglycol. 0.3 g methylparaben and 0.15 g of propylparaben

were 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 dmg was completely

dissolved. An active pharmaceutical component which would remain dissolved was prepared by

charging an appropriately sized container with 127.8 grams of purified water. 1.5 grams of

dyclonine HCl was added to the water with mixing until all of the drug was completely

dissolved.

The solvent phase was added to the aqueous phase and crystalline microparticles of

dapsone were immediately formed. 3.75 grams of "NATROSOL"® 250 PHARM were

added to form a topical gel containing microcrystalline dapsone and dissolved dyclonine HCl. The presence of microcrystalline dapsone was confirmed by optical microscopy.

EXAMPLE 8

Example 8 describes a method for preparing a composition of this invention that

includes a pharmaceutical partially in a microparticulate form and partially in a dissolved

form in combination with a different dissolved pharmaceutical. The composition finds

particular use in the treatment of herpes lesions. The pharmaceutical in both dissolved and

microparticulate forms provides optimized delivery for early stage lesions when dissolved

and optimized delivery for later stage lesions when present as a microparticulate. The other

dissolved pharmaceutical provides benefit throughout the lesion progression.

container with 44.0 g of l-methyl-2-pyrrolidone. 0.16 g methylparaben and 0.08 g

propylparaben as preservatives were added to the l-methyl-2-pyrrolidone and mixed until all

the crystalline solid dissolved. 8.0 g 1 N NaOH was mixed with the 1 -methyl-2-pyrrolidone

and preservative mixture prior to the addition of 4.0 g acyclovir. Upon heating to approximately 50°C, all of the added materials dissolved to form a single phase clear

solution.

An active pharmaceutical component which would remain dissolved was prepared by

charging an appropriately sized container with 17.36 g purified water. 4.0 g tetracaine HCl

and 0.8 g of sodium lauryl sulfate was added to the water with mixing until all of the solids

were dissolved.

acyclovir 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 HCl and sodium lauryl sulfate. The presence of microcrystalline

acyclovir was confirmed by optical microscopy.

EXAMPLE 9 -EVALUATION Example 9 evaluates the compositions of examples 1-6 and demonstrates that

increasing the dapsone content of this invention's composition from 0 to 0.3% increases the

amount of dapsone that permeates into the skin, whereas further increasing dapsone above

0.3% results in microparticulate dapsone that remains above the stratum comeum or

supracomeum zone. Therefore, the amount of dapsone that permeates into the skin does not

increase incrementally for compositions having increased dapsone above 0.3%.

In example 9, experiments were performed by loading excised human skin on a

standard Franz type vertical diffusion cell having a 15 mm orifice, 7.0 ml volume, and

equipped with a Hanson Helix stirrer using a phosphate buffered saline/ethoxydiglycol

mixture as the receptor phase. The full thickness of human abdominal skin was removed from a cadaver within 24 hours of death. The subcutaneous tissue was removed using a #22

scalpel blade. The tissue was cut into 5 X 15 cm sections with care being taken to avoid

contamination of the stratum comeum with subcutaneous fat. Each 5 X 15 cm section was

placed in a sterile plastic bag and stored on wet ice until being placed in the freezer

5 (maximum transport time 2 hours). A single 5 X 15 cm section of skin was removed from the

freezer on the day of an in- vitro skin permeation study. The skin was thawed, rinsed, patted

dry with a tissue, and loaded on the Franz diffusion cell. Samples were dosed with 10 mg of

the formulation i.e. finite dosing. Receptor solutions were assayed by reverse phase HPLC

using UV detection.

lo The cumulative dmg concentration in the receptor solution was monitored over a 72

hour period. The data in Table 1 shows the mean quantities of dmg transported for

quadmplicate in-vitro skin permeation experiments in which each formulation was evaluated

using the same donor skin on each of four different days. As seen in Table 1 , the cumulative

amount of dissolved dapsone that was transported across the stratum comeum increased until

i the dapsone level at which the formation of microparticulate dapsone was reached, i.e. up to

0.3 weight percent dapsone. At concentrations above 0.3 %, the amount of dissolved dmg

did not increase, and the amount of dmg delivered remained the same. Thus, the excess dmg

(above 0.3 weight percent) was retained in the stratum comeum or supracomeum zone.

For this dmg delivery system, the microparticulate to dissolved pharmaceutical ratio

0 of 1.5 to 15 resulted in increasing amounts of dmg available for antimicrobial action in the

supracomeum zone, while maintaining a set amount of dapsone available for anti-

inflammatory activity in the viable epidermis. Table 1.

Dapsone Concentration in Receptor Solution Following

in-vitro Dosing of 10 mg of Topically Applied Semisolid

Dapsone Semisolid Example μg Dapsone/1.77cm² % of Applied Dose Concentration Number by 72 hrs transported by 72 hrs

(% w/w)

0.03 2 0.35 ± 0.1 1 1

0.1 3 0.73 ± 0.3 7

0.3 4 2.6 ± 2.2 8

0.5 5 2.2 ± 0.8 4

1.0 1 2.9 ± 1.7 3

3.0 6 3.3 ± 2.5 1

EXAMPLE 10 -EVALUATION

Example 10 demonstrates the importance of using the optimum microparticulate to

dissolved pharmaceutical ratio. The results in Table 2 show that for the same amount of

applied dmg, the amount of drug in the supracomeum zone can be optimized by improving

the microparticulate to dissolved pharmaceutical ratio.

In example 10, the procedures of example 9 were used, including Franz diffusion cell

and experimental technique, however 1 % dapsone formulations were compared. Formulation

number 1 was manufactured according to example 1 and contained 1% dapsone and 10%

ethoxydiglycol having a microparticulate dmg/dissolved dmg ratio of 5. Formulation number 2 had the composition 1% dapsone, 25% ethoxydiglycol, 70.7% water, 1% "CARBOPOL

980," 0.2% methylparaben, 0.1% propylparaben, and 2% sodium hydroxide solution (10%

w/w). For formulation number 2, all of the dapsone is dissolved with no microparticulate

dmg present.

Approximately 10 mg of product was mbbed into the skin, and after 72 hours, the skin

surface was tape stripped to remove all supracomeum drug. The skin was cut into small

pieces and extracted while the receptor solution was directly assayed. For formulation

number 1 (microparticulate to dissolved dmg ratio equal to 5) 68 + 4% of the applied dose

remained in the supracomeum zone, while only 52 + 3% of formulation 2 (particulate to

dissolved dmg ratio = 0) remained in the supracomeum zone. Each value is the mean of

triplicate experiments.

Table 2.

Distribution of Dapsone in Different Skin Layers

by 72 hrs of in-vitro Permeation Study

Formulation 1 % DDS Hydrogel in 10% DGME 1% DDS Hydrogel in 25% DGME (microcrystal form) (soluble form)

Receptor 0.92% ± 0.14 1.29% ± 0.24

Surface residual 68.42%± 3.84 52.51%± 2.88

Stratum corneum 15.54% ± 4.12 32.15% ± 6.16

Dermal 13.59% ± 2.15 14.06% ± 7.31

Total recovery 60.7%± 5.3 53.7%± 7.7 EXAMPLE 11-EVALUATION

Example 1 1 demonstrates that a 2% acyclovir solution in l-methyl-2 pyrrolidone

provides the same level of intact skin delivery as a 5% acyclovir gel formulation that contains

approximately 2% dissolved acyclovir and 3% microparticulate acyclovir. These delivery

results 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 standard

formulation is known to be 60-fold more permeable than the commercially available

ZOVIRAX® Ointment (5% acyclovir in a polyethylene glycol base).

In example 1 1, the procedures of example 9 were used except that 50-500 microliter

doses of formulations were applied to dermatomed human skin which was not frozen until

after 48 hours post-mortem. The formulation of example 8 which contains 5% acyclovir (of

which approximately 40% is dissolved and 60% is in a microparticulate form) was tested

along with a 2% acyclovir in 1 -methyl-2-pyrrolidone. In direct comparison with the 95/5

DMSO/acyclovir skin delivery standard, both the 5% acyclovir combination gel of example 8

and the 2% acyclovir in 1 -methyl-2-pyrrolidone solution delivered 20-25% of the acyclovir

delivery standard. The presence of crystalline microparticulate dmg does not increase the

delivery of acyclovir across intact skin. The delivery of the dissolved acyclovir is considered

optimized since it was more than 10-fold greater than skin delivery of acyclovir from the

commercialized ZOVIRAX® formulation. Those skilled in the art will recognize that, while specific embodiments have been

illustrated and described, various modifications and changes may be made without departing

from the spirit and scope of the invention.

Claims

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 comeum layer of the epidermis and become

available systemically; and

a microparticulate pharmaceutical dispersed in said gel, wherein said microparticulate

pharmaceutical does not cross the stratum comeum 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, destmctive 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 comeum of the

epidermis and become systemically available and a microparticulate pharmaceutical lacking

the ability to cross the stratum comeum of the epidermis in its microparticulate state; and an

amine base, sodium hydroxide solution, or potassium hydroxide solution.

1 1. The dermatological composition of claim 10, wherein said pharmaceutical comprises

dapsone.

12. The dermatological composition of claim 1 1 , 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, destmctive

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

5 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.

lo 17. The composition of claim 16, wherein said first pharmaceutical comprises a

nucleoside analogue such as acylclovir, penciclovir, famciclovir, valacyclovir, or ganciclovir,

and said second pharmaceutical comprises a local anesthetic such as tetracaine, tetracaine

HCl, dyclonine, dyclonine HCl, dibucaine, or dibucaine HCl.

15 18. The composition of claim 17, wherein said acyclovir comprises 5% by weight of the

composition.

19. The composition of claim 17, wherein said tetracaine HCl comprises 5% by weight of

the composition.

0

20. 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.

21. A method for the treatment of dermatological conditions comprising applying

topically a semisolid gel composition, wherein said composition comprises:

a semisolid aqueous gel;

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

provides benefit throughout lesion progression.

22. The method of claim 21 , wherein said active pharmaceutical comprises an

antimicrobial agent, anti-inflammatory agent, antiviral agent, local anesthetic agent,

corticosteroid, destmctive therapy agent, antifungal agent, or antiandrogen agent.

23. The method of claim 21, wherein said active pharmaceutical comprises dapsone.

24. A method for treating disease comprising applying topically an aqueous gel

composition comprising a dissolved pharmaceutical that has the capacity to cross the stratum comeum of the epidermis and become systemically available, and a microparticulate

pharmaceutical that has only minimal capacity to cross the stratum comeum in its

microparticulate state.

25. The method of claim 24, wherein said dissolved pharmaceutical and said

microparticulate pharmaceutical comprise about 1.0% to 10% antiviral agent.

26. The method of claim 24, wherein said dissolved pharmaceutical and said

microparticulate pharmaceutical comprise about 0.5 to 10% antiandrogen.

27. A method for treating acne, which comprises applying topically a gel composition

comprising a dissolved anti-inflammatory pharmaceutical and a microparticulate

antimicrobial pharmaceutical, wherein said dissolved anti-inflammatory pharmaceutical

crosses the stratum comeum of the epidermis and is absorbed into the lower two-thirds of the

pilosebaceous unit, while said microparticulate antimicrobial pharmaceutical is primarily

delivered into the upper third of the pilosebaceous unit, crossing the stratum comeum of the

epidermis only minimally.

28. The method of claim 27, wherein said anti-inflammatory pharmaceutical and said

antimicrobial pharmaceutical comprise dapsone.

29. 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.