EP0679390A2 | 1995-11-02 | |||
GB2260080A | 1993-04-07 |
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 crosslinked 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, antiinflammatory 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 05% 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. |
11. | 11 The dermatological composition of claim 10, wherein said pharmaceutical comprises dapsone. |
12. | 12 The dermatological composition of claim 1 1 , wherein the microparticulate to dissolved pharmaceutical ratio is no greater than 5. |
13. | 13 The composition of claim 10, wherein said pharmaceutical comprises an antimicrobial agent, antiviral agent, antiinflammatory agent, local anesthetic, corticosteroid, destmctive therapy agent, antifungal agent, or antiandrogen agent. |
14. | 14 A dermatological gel composition including microparticulate pharmaceutical and dissolved pharmaceutical, which comprises: about. |
15. | % 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. |
16. | % sodium hydroxide solution. |
17. | 15 The dermatological composition of claim 14, wherein the ratio of microparticulate to dissolved dapsone is no greater than 5. |
18. | 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. | 19 The composition of claim 17, wherein said tetracaine HCl comprises 5% by weight of the composition. |
20. | 20 A dermatological composition for the treatment of herpes lesions comprising acyclovir and 1 methyl2pyrrolidone in a semisolid aqueous gel, wherein said acyclovir is present in dissolved and microparticulate forms. |
21. | 21 A method for the treatment of dermatological conditions comprising applying topically a semisolid gel composition, wherein said composition comprises: a semisolid aqueous gel; a first pharmaceutical in said gel, partially in a microparticulate form and partially in a dissolved form, wherein said first pharmaceutical provides optimized delivery for early state lesions when dissolved and optimized delivery for later state lesions when present as a microparticulate; and a second pharmaceutical dissolved in said gel, wherein said second pharmaceutical provides benefit throughout lesion progression. |
22. | 22 The method of claim 21 , wherein said active pharmaceutical comprises an antimicrobial agent, antiinflammatory agent, antiviral agent, local anesthetic agent, corticosteroid, destmctive therapy agent, antifungal agent, or antiandrogen agent. |
23. | 23 The method of claim 21, wherein said active pharmaceutical comprises dapsone. |
24. | 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. | 25 The method of claim 24, wherein said dissolved pharmaceutical and said microparticulate pharmaceutical comprise about 1.0% to 10% antiviral agent. |
26. | 26 The method of claim 24, wherein said dissolved pharmaceutical and said microparticulate pharmaceutical comprise about 0.5 to 10% antiandrogen. |
27. | 27 A method for treating acne, which comprises applying topically a gel composition comprising a dissolved antiinflammatory pharmaceutical and a microparticulate antimicrobial pharmaceutical, wherein said dissolved antiinflammatory pharmaceutical crosses the stratum comeum of the epidermis and is absorbed into the lower twothirds 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. | 28 The method of claim 27, wherein said antiinflammatory pharmaceutical and said antimicrobial pharmaceutical comprise dapsone. |
29. | 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. |
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
The following example provides yet another topical therapeutic agent in which the
pharmaceutical component is dissolved dapsone. The method of Example 4 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 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
The following example provides yet another 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 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.
The procedure of Example 1 was followed using reagents in the amounts designated
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
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 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.
The procedure of Example 1 was followed using reagents in the amounts designated
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.
An active pharmaceutical component was prepared by charging an appropriately sized
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.
The solvent phase was added to the aqueous phase and crystalline microparticles of
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/1.77cm 2 % 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.
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