WO1998010746A1 - Compositions and methods for topical application of therapeutic agents - Google Patents

Compositions and methods for topical application of therapeutic agents Download PDF

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Publication number
WO1998010746A1
WO1998010746A1 PCT/US1997/015919 US9715919W WO9810746A1 WO 1998010746 A1 WO1998010746 A1 WO 1998010746A1 US 9715919 W US9715919 W US 9715919W WO 9810746 A1 WO9810746 A1 WO 9810746A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical
dissolved
microparticulate
composition
gel
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1997/015919
Other languages
English (en)
French (fr)
Inventor
David W. Osborne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ViroTex Corp
Original Assignee
ViroTex Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ViroTex Corp filed Critical ViroTex Corp
Priority to DE69727398T priority Critical patent/DE69727398T2/de
Priority to JP51377398A priority patent/JP4276298B2/ja
Priority to AU42610/97A priority patent/AU737365B2/en
Priority to EP97940944A priority patent/EP0957900B1/en
Priority to CA002265461A priority patent/CA2265461C/en
Priority to AT97940944T priority patent/ATE258426T1/de
Priority to DK97940944T priority patent/DK0957900T3/da
Publication of WO1998010746A1 publication Critical patent/WO1998010746A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • nitroglycerin patches initiated use of the skin as a route for administering systemic drug
  • the skin for drug delivery include cosmetic, topical, and transdermal applications.
  • steady state drug delivery is preferred.
  • Steady state delivery requires the use of
  • corneum or the lesional delivery barrier, i.e. scab, plaque, etc.
  • Some dermatological conditions such as acne, require multiple delivery strategies
  • topical antimicrobial would be
  • Intact stratum corneum lines the upper third of the pilosebaceous unit, and it is into
  • pilosebaceous unit pilosebaceous unit. Additionally, when an anti-inflammatory agent is used to treat acne, it is important to treat acne.
  • inflammation is the response of the viable epidermis to
  • the active In order to reduce the amount of inflammation, the active
  • microparticulate drug will not significantly cross the intact stratum
  • microparticulate drug is deposited directly at the target area, where it can slowly be released
  • This type of treatment saturates receptor sites and provides maximum microbial or viral
  • a carrier system that can be adjusted to optimize the delivery profile for
  • the present invention concerns a pharmaceutical carrier system comprising a
  • composition that is a semi-solid aqueous gel, wherein a pharmaceutical is
  • composition also contains pharmaceutical in a microparticulate state that does not readily
  • 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
  • compositions of the present invention are also shown.
  • compositions of the invention are shown. More particularly, the invention
  • Antimicrobial agents having anti-inflammatory properties such as
  • dapsone are used to treat acne.
  • anesthetics are used to treat herpes lesions, and anti-inflammatory agents are used to treat
  • the present invention comprises compositions for application to the skin that can
  • microparticulate d g precipitates in adjustable ratios of microparticulate d g to
  • the present invention is particularly effective in the treatment of acne with
  • antimicrobial actives known to possess anti-inflammatory properties such as dapsone.
  • invention also finds particular use in the treatment of herpes lesions and dermatitis.
  • the present invention is directed to a novel pharmaceutical carrier
  • composition comprising a dermatological composition that is a semisolid aqueous gel, wherein the composition exhibits an optimal balance between a dissolved pharmaceutical that is available
  • microparticulate pharmaceutical that is retained in or above the stratum comeum to serve as a
  • the pharmaceutical and the dissolved pharmaceutical may be the same or different drugs.
  • microparticulate pharmaceutical may comprise a crystalline precipitant or an amorphous
  • 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
  • than two may provide the greatest amount of pharmaceutical available for immediate partition
  • pharmaceutical ratio of two or greater may have a reduced amount of dmg available for
  • 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
  • compositions of the present invention comprise semi-solid and gel-like vehicles
  • the solvent or mixed solvent system includes antioxidants, sunscreens, and a solvent or mixed solvent system.
  • solvent system is important to the formation of the microparticulate to dissolved
  • Polymer thickeners that may be used include those known to one skilled in the art,
  • the hydrophilic or hydroalcoholic gelling agent is selected from the hydrophilic or hydroalcoholic gelling agent
  • 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
  • CARBOPOL® is one of numerous cross-linked acrylic acid polymers that are given
  • carbomer dissolve in water and form a clear or
  • KLUCEL® is a cellulose
  • 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%
  • the formulation will prevent or diminish microorganism
  • Some preservatives useful in this invention include methylparaben, propylparaben,
  • Titanium dioxide may be used as a sunscreen to serve as prophylaxis against
  • Alternative sunscreens include methyl cinnamate.
  • BHA may
  • An alternate antioxidant is BHT.
  • agents anti-inflammatory agents, antiviral agents, local anesthetic agents, corticosteroids,
  • destmctive therapy agents antifungals, and antiandrogens.
  • active pharmaceuticals include antimicrobial agents, especially those having anti-
  • inflammatory properties such as dapsone, erythromycin, minocycline, tetracycline,
  • antimicrobials are 0.5% to 10%.
  • actives In the topical treatment of herpes lesions, actives
  • compositions that may be used include antiviral or local anesthetic agents.
  • nucleoside analogues such as
  • acyclovir famciclovir, penciclovir, valacyclovir, and ganciclovir.
  • Local anesthetics include tetracaine, tetracaine hydrochloride, lidocaine, lidocaine
  • 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
  • Corticosteroids that may be used include betamethasone dipropionate, fluocinolone
  • hydrocortisone butyrate, and desonide are recommended at concentrations of about 0.01 % to
  • 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.
  • Cantharidin is preferably
  • 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%)
  • an antiandrogen such as flutamide or finasteride in preferred weight percentages
  • treatments using a combination of drugs include antibiotics in combination
  • tetracaine for topical antibiotic gels to provide prophylaxis against infection and relief of
  • Another example is the use of minoxidil in combination with a corticosteroid such as
  • betamethasone diproprionate for the treatment of alopecia ereata.
  • anti -inflammatory such as cortisone with an antifungal such as ketoconazole for the treatment
  • the invention comprises a dermatological composition having
  • the dissolved pharmaceutical has the capacity
  • the pharmaceutical may include
  • dapsone an antimicrobial agent having anti-inflammatory properties.
  • microparticulate to dissolved dapsone is five or less.
  • the invention comprises about 1% carbomer, about 80-90%
  • the carbomer may include "CARBOPOL® 980" and the caustic
  • the material may include sodium hydroxide solution.
  • the composition comprises dapsone and ethoxydiglycol
  • ethoxydiglycol may include purified water combined with "CARBOPOL®" gelling
  • herpes lesions comprising a semisolid aqueous gel; a first pharmaceutical in the
  • microparticulate form a microparticulate form
  • a second pharmaceutical dissolved in the gel which provides
  • the composition comprises
  • Acyclovir may be
  • the ratio determines the amount of dmg delivered up to the point of lesion vesicle formation, as compared to the amount of dmg
  • acyclovir and l-methyl-2-pyrrolidone may include purified water combined with
  • KLUCEL® hydroxypropyl cellulose gelling polymer methylparaben, and propylparaben.
  • tetracaine HCl may be formulated with 1 -methyl-2-pyrrolidone to provide both antiviral and
  • Tetracaine HCl is a local anesthetic that alters membrane function
  • acyclovir comprises 5% by weight of the
  • composition The system of acyclovir, tetracaine HCl, and l-methyl-2-pyrrolidone can
  • sodium lauryl sulfate has been shown to be an effective therapy for herpes lesions.
  • the present invention also provides methods for preparing the dermatological
  • the method for producing a dermatological gel composition having dissolved dmg and microparticulate dmg precipitates comprises the
  • water may be slowly
  • Ethoxydigylcol and 1 -methyl-2-pyrollidone are preferred solvents for use in this invention.
  • the method for preparing a dermatological composition in one preferred embodiment, the method for preparing a dermatological composition
  • having dissolved and microparticulate pharmaceutical comprises the steps of forming a
  • the active pharmaceutical may comprise any of the types mentioned above.
  • the active pharmaceutical comprises dapsone.
  • the active pharmaceutical comprises dapsone.
  • the active pharmaceutical comprises acyclovir or acyclovir in
  • 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
  • the carbomer is generally dispersed in the water component of the formulation, while
  • neutralizer is added to formulate the gel.
  • compositions of this invention are provided.
  • treatment of dermatological conditions comprises applying topically a gel composition
  • the dissolved pharmaceutical and microparticulate pharmaceutical comprise
  • microparticulate pharmaceutical comprise about 0.5% to 10% antiandrogen.
  • a method for the treatment of acne comprises applying
  • topically a gel composition that comprises a dissolved anti-inflammatory pharmaceutical and
  • microparticulate antimicrobial pharmaceutical wherein the dissolved anti-inflammatory pharmaceutical crosses the stratum comeum of the epidermis and is absorbed into the lower
  • microparticulate pharmaceutical comprise dapsone.
  • the first pharmaceutical comprises a nucleoside analogue
  • second pharmaceutical comprises a local anesthetic.
  • the second pharmaceutical comprises a local anesthetic.
  • nucleoside analogue comprises acyclovir, penciclovir, famciclovir, valacyclovir, or
  • the local anesthetic comprises tetracaine, dyclonine, dibucaine, or a salt
  • tetracaine HCl dyclonine HCl
  • dibucaine HCl acyclovir
  • tetracaine HCl comprises 2-5% by weight.
  • microparticulate crystalline dapsone dissolved dapsone
  • microparticulate pharmaceuticals are retained above the stratum comeum having negligible
  • ratios between the two epidermal areas is important in developing a composition having an
  • Example 7 describes a method for the preparation of compositions of this invention
  • composition dissolved in the composition and the other present in a microparticulate state, such that two
  • Example 8 provides a method for
  • the following example provides a method for producing a topical therapeutic agent in
  • the pharmaceutical component is a combination of dissolved and microcrystalline
  • Example 1 microcrystalline dapsone will be retained in or above the stratum comeum and
  • Example 1 The method of Example 1 can also be used to produce a composition of this invention that includes other pharmaceuticals such
  • a polymer thickener component was prepared by charging 85.7 grams of purified
  • the polymer thickener component was added to the pharmaceutical component with
  • the following example provides another topical therapeutic agent in which the
  • Example 2 The method of Example 2 can also be used
  • composition of this invention that includes other pharmaceuticals.
  • Example 3 The method of Example 3 can also be used
  • composition of this invention that includes other pharmaceuticals such as those
  • Example 1 The procedure of Example 1 was followed using reagents in the amounts designated
  • microparticles did not form upon adding the polymer thickener component to the
  • Example 4 The method of Example 4 can also be used
  • composition of this invention that includes other pharmaceuticals such as those
  • Example 1 The procedure of Example 1 was followed using reagents in the amounts designated
  • pharmaceutical component is a combination of dissolved and microcrystalline dapsone.
  • Example 5 can
  • composition of this invention that includes other pharmaceuticals
  • Example 1 The procedure of Example 1 was followed using reagents in the amounts designated
  • the following example provides a method for producing a topical therapeutic agent in
  • the pharmaceutical component is a combination of dissolved and microcrystalline
  • Example 6 it will be retained in or above the stratum co eum and will therefore serve as a
  • Example 6 can
  • composition of this invention that includes other pharmaceuticals such as those designated in this application.
  • Example 1 The procedure of Example 1 was followed using reagents in the amounts designated
  • CARBOPOL 980 1.0 g Active Pharmaceutical Component
  • Example 7 describes a method for preparing a composition of this invention that
  • microparticulate crystalline pharmaceutical includes a microparticulate crystalline pharmaceutical, dapsone, in combination with a
  • An active pharmaceutical component was prepared by charging an appropriately sized
  • the solvent phase was added to the aqueous phase and crystalline microparticles of
  • microcrystalline dapsone was 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 describes a method for preparing a composition of this invention that
  • composition finds
  • microparticulate forms provides optimized delivery for early stage lesions when dissolved
  • dissolved pharmaceutical provides benefit throughout the lesion progression.
  • An active pharmaceutical component was prepared by charging an appropriately sized
  • propylparaben as preservatives were added to the l-methyl-2-pyrrolidone and mixed until all
  • 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,
  • 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
  • the microparticulate to dissolved pharmaceutical ratio For this dmg delivery system, the microparticulate to dissolved pharmaceutical ratio
  • Dapsone Semisolid Example ⁇ g Dapsone/1.77cm 2 % of Applied Dose Concentration Number by 72 hrs transported by 72 hrs
  • Example 10 demonstrates the importance of using the optimum microparticulate to
  • the amount of drug in the supracomeum zone can be optimized by improving
  • microparticulate to dissolved pharmaceutical ratio
  • example 10 the procedures of example 9 were used, including Franz diffusion cell
  • Formulation number 2 had the composition 1% dapsone, 25% ethoxydiglycol, 70.7% water, 1% "CARBOPOL
  • Example 1 1 demonstrates that a 2% acyclovir solution in l-methyl-2 pyrrolidone
  • acyclovir dissolved in 95% dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • ZOVIRAX® Ointment (5% acyclovir in a polyethylene glycol base).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Anesthesiology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Virology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
PCT/US1997/015919 1996-09-11 1997-09-10 Compositions and methods for topical application of therapeutic agents Ceased WO1998010746A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
DE69727398T DE69727398T2 (de) 1996-09-11 1997-09-10 Zusammensetzungen und verfahren zur topischen anwendungen von wirkstoffen
JP51377398A JP4276298B2 (ja) 1996-09-11 1997-09-10 治療薬の局所適用のための組成物および方法
AU42610/97A AU737365B2 (en) 1996-09-11 1997-09-10 Compositions and methods for topical application of therapeutic agents
EP97940944A EP0957900B1 (en) 1996-09-11 1997-09-10 Compositions and methods for topical application of therapeutic agents
CA002265461A CA2265461C (en) 1996-09-11 1997-09-10 Compositions and methods for topical application of therapeutic agents
AT97940944T ATE258426T1 (de) 1996-09-11 1997-09-10 Zusammensetzungen und verfahren zur topischen anwendungen von wirkstoffen
DK97940944T DK0957900T3 (da) 1996-09-11 1997-09-10 Sammensætninger og fremgangsmåder til topisk påföring af terapeutiske midler

Applications Claiming Priority (2)

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

Publications (1)

Publication Number Publication Date
WO1998010746A1 true WO1998010746A1 (en) 1998-03-19

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Family Applications (1)

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

Country Status (11)

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

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WO2001054663A3 (en) * 2000-01-31 2001-12-20 Collaborative Technologies Inc Surfactant free topical compositions and method for rapid preparation thereof
WO2003092704A1 (fr) * 2002-04-30 2003-11-13 Mochida Pharmaceutical Co., Ltd. Preparation externe de vidarabine a propriete systemique amelioree

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US6620435B1 (en) 2003-09-16
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ATE258426T1 (de) 2004-02-15
US5863560A (en) 1999-01-26
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CA2265461C (en) 2004-11-30
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AU737365B2 (en) 2001-08-16
CA2265461A1 (en) 1998-03-19
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AU4261097A (en) 1998-04-02
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