WO2008118762A1 - Procédés et emballages visant à améliorer la sécurité pendant l'utilisation d'imiquimod pour traiter des enfants atteints de troubles de la peau - Google Patents

Procédés et emballages visant à améliorer la sécurité pendant l'utilisation d'imiquimod pour traiter des enfants atteints de troubles de la peau Download PDF

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WO2008118762A1
WO2008118762A1 PCT/US2008/057758 US2008057758W WO2008118762A1 WO 2008118762 A1 WO2008118762 A1 WO 2008118762A1 US 2008057758 W US2008057758 W US 2008057758W WO 2008118762 A1 WO2008118762 A1 WO 2008118762A1
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imiquimod
child
percent
providing information
method further
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PCT/US2008/057758
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English (en)
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WO2008118762A9 (fr
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Herbert B. Slade
James H. Lee
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Graceway Pharmaceuticals, Llc
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Publication of WO2008118762A1 publication Critical patent/WO2008118762A1/fr
Publication of WO2008118762A9 publication Critical patent/WO2008118762A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • This invention pertains to enhancing the safety of using pharmaceutical formulations containing 1-isobutyl-1 H-imidazo[4,5-c]-quinolin-4-amine, i.e., imiquimod, to treat children diagnosed with skin disorders. More particularly, it pertains to methods and packages containing creams, ointments, foams, gels, lotions, salves, pressure sensitive adhesive coatings or adhesive-coated sheet materials, which contain imiquimod, that (i) enhance skin penetration of drugs to treat dermatological disorders, namely, molluscum contagiosum, viral infections, such as Type I or Type Il Herpes simplex infections, e.g., condyloma acuminata, genital warts and perianal warts, actinic keratosis, and superficial basal cell carcinoma, and (ii) induce interferon biosynthesis, with enhanced safety by providing precautions and warnings that systemic absorption of imiquimod and other effects, namely, a decrease in median white blood
  • U.S. Patent No. 4,751 ,087 discloses the use of a combination of ethyl oieate and glyceryl monolaurate as a skin penetration enhancer for nitroglycerine, with all three components being contained in the adhesive layer of a transdermal patch, wherein this U.S. patent is incorporated herein by reference in its entirety.
  • U.S. Patent No. 4,411 ,893 discloses the use of N,N-dimethyldodecylamine-N- oxide as a skin penetration enhancer in aqueous systems, wherein this U.S. patent is incorporated herein by reference in its entirety.
  • U.S. Patent No. 4,722,941 discloses readily absorbable pharmaceutical compositions that comprise a pharmacologically active agent distributed in a vehicle comprising an absorption-enhancing amount of at least one fatty acid containing 6 to 12 carbon atoms and optionally a fatty acid monoglyceride. Such compositions are said to be particularly useful for increasing the absorption of pharmacologically active bases, wherein this U.S. patent is incorporated herein by reference in its entirety.
  • U.S. Patent No. 4,746,515 discloses a method of using glyceryl monolaurate to enhance the transdermal flux of a transdermal ⁇ deliverable drug through intact skin, wherein this U.S. patent is incorporated herein by reference in its entirety.
  • U.S. Patent No. 5,238,944 discloses topical formulations and transdermal delivery systems containing 1-isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine, wherein this U.S. patent is incorporated herein by reference in its entirety.
  • the present invention is directed to overcoming certain drawbacks and shortcomings associated with imiquimod therapy when treating children diagnosed with skin disorders, through the discovery of novel methods and packages containing topical imiquimod pharmaceutical products that enhance the safety of imiquimod when used to treat children.
  • the possible imiquimod systemic absorption in children when treated with topical imiquimod may manifest itself as, for example: (a) peak serum imiquimod concentrations in children between about 2 and about 12 years of age following both single and multiple doses at about ⁇ 2 ng/ml; (b) median multiple-dose peak serum drug levels of approximately about 0.2 ng/ml or about 0.5 ng/ml in children ages from about 2 to about 5 years who receive imiquimod doses of about 12.5 mg (one packet) or about 25 mg (two packets), respectively; (c) median multiple dose serum drug levels of about 0.1 ng/ml, about 0.15 ng/ml, or about 0.3 ng/ml in children ages between about 6 and about 12 years who receive imiquimod doses of 12.5 mg, 25 mg, or 37.5 mg (three packets), respectively; (d) a median decrease in the white blood cell ("WBC”) count, such as a median WBC count decreased
  • the present invention provides methods and packages, to enhance the safety profile of imiquimod when used as topical therapy to treat children diagnosed with skin disorders, which comprises (i) providing information, such as to the child, a prescribing or treating physician, a treating nurse or guardian of the child, that systemic absorption of imiquimod may result in the child receiving imiquimod therapy, and (ii) providing further information to the child, the prescribing or treating physician, the treating nurse or the child's guardian, that the child should be monitored as safety and precautionary measures; namely, serum imiquimod levels, median white blood cell counts and median absolute neutrophil counts may be examined during the course of imiquimod therapy.
  • imiquimod is generally safe to use with children ages 2 to 12
  • the current invention nevertheless contemplates providing information to the children, the childrens' guardians, e.g., parents, the treating nurses, the prescribing/treating physicians or other health care officials, that consideration should be given to tapering or stopping imiquimod treatment, or reducing the imiquimod dose or frequency of imiquimod administration, in the event that (a) serum imiquimod concentrations exceed more than about 2 ng/mL, (b) there is a decrease in median white blood cell counts by at least about 1.4*109/1- and/or (c) there is a decrease in median absolute neutrophil counts by at least about 1.42*109/L, until the symptoms have subsided, as safety and precautionary measures.
  • Examples of dermatological disorders contemplated by the present invention include (i) molluscum contagiosum possibly caused by a poxvirus of the (i) Molluscipox virus genus, (ii) viral infections, such as Type I or Type Il Herpes simplex infections, e.g., condyloma acuminata, genital warts and perianal warts, actinic keratosis, and superficial basal cell carcinoma, and (iii) induce interferon biosynthesis.
  • Examples of topical imiquimod formulations suitable for use in accordance with the present invention include creams, ointments, foams, gels, lotions, salves, pressure sensitive adhesive coatings and adhesive-coated sheet materials.
  • the present invention also provides a substantially non-irritating pharmaceutical formulation for topical and/or transdermal administration of the imiquimod, which formulation comprises:
  • a pharmaceutically acceptable vehicle for imiquimod which vehicle comprises a fatty acid, such as isostearic acid, linoieic acid, oleic acid, super purified oleic acid (an oleic acid having low polar impurities such as peroxides) and a combination thereof, in a total amount of about 3 percent to about 45 percent by weight based on the total weight of the formulation.
  • the formulation is further characterized in that when tested in the hairless mouse skin model described in U.S. Patent No. 5,238,944, the formulation provides a penetration of the agent of at least about 10% ⁇ and preferably at least about 15%) of the total amount of the agent contained in the formulation in 24 hours.
  • the salient elements of a pharmaceutical formulation according to the invention are (a) imiquimod and (b) a fatty acid, e.g., isostearic, linoieic, super purified oleic or oleic acid and mixtures thereof.
  • a pharmaceutical formulation of the invention can be in any form known to the art, such as a cream, an ointment, a foam, a gel, a lotion or a pressure-sensitive adhesive composition, each form containing the necessary elements in particular amounts and further containing various additional elements.
  • a cream of the invention preferably contains about 2 percent to about 4 percent by weight of imiquimod based on the total weight of the cream; about 5 percent to about 25 percent by weight of fatty acid, based on the total weight of the cream; and optional ingredients such as emollients, emulsifiers, thickeners, and/or preservatives.
  • An ointment of the invention contains an ointment base in addition to imiquimod and fatty acid.
  • An ointment of the invention preferably contains about 2 percent to about 4 percent by weight imiquimod; about 3 percent to about 45 percent, more preferably about 3 percent to about 25 percent by weight fatty acid; and about 40 percent to about 95 percent by weight ointment base, all weights being based on the total weight of the ointment.
  • an ointment of the invention can also contain emulsifiers, emollients and thickeners.
  • a pressure-sensitive adhesive composition of the invention contains imiquimod, fatty acid, and an adhesive.
  • the adhesives utilized in a pressure sensitive adhesive composition of the invention are preferably substantially chemically inert to imiquimod.
  • a pressure sensitive adhesive composition of the invention preferably contains about 2 percent to about 4 percent by weight imiquimod; about 10 percent to about 40 percent by weight, more preferably of about 15 percent to about 30 percent by weight, and most preferably about 20 percent to about 30 percent by weight of fatty acid; all weights being based on the total weight of the pressure sensitive adhesive composition.
  • pressure sensitive adhesive compositions of the invention can also contain one or more skin penetration enhancers.
  • the total amount of skin penetration enhancer(s) present in a pressure sensitive adhesive composition of the invention is preferably about 3 percent to about 25 percent by weight, and more preferably about 3 percent to about 10 percent by weight based on the total weight of the pressure sensitive adhesive composition.
  • a pressure sensitive adhesive coated sheet material of the invention can be made from a pressure-sensitive adhesive composition of the invention in the form of an article such as a tape, a patch, a sheet, or a dressing.
  • a formulation of the present invention may be used to topically and/or transdermal ⁇ administer imiquimod for effectively treating viral infections, for example, Type I or Type Il Herpes simplex infections, actinic keratosis and superficial basal cell carcinoma for a shorter duration of time and with the same or increased number of applications per week, as compared to current imiquimod topical therapy.
  • a formulation of the present invention containing between greater than about 1% and about 5% imiquimod may be applied from three to seven times per week (once per day) for 8 to 12 weeks to treat viral infections, for example, Type I or Type Il Herpes simplex infections, actinic keratosis and superficial basal cell carcinoma.
  • viral infections for example, Type I or Type Il Herpes simplex infections, actinic keratosis and superficial basal cell carcinoma.
  • formulations containing between greater than about 1% and about 5% imiquimod are preferred, formulations containing about 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% are more preferred and that formulations containing about 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0% are most preferred.
  • the present invention contemplates applying an effective amount of imiquimod for a shorter period of time than currently approved by the FDA. More specifically, the present invention contemplates applying an effective amount of imiquimod from three to seven times or more per week to an area in need of imiquimod treatment for about 8 to about 12 weeks, and more preferably between about 4, about 5, about 6 and about 7 times a week for about 8, about 9 or about 10 weeks.
  • the phrase "substantially non-irritating" designates formulations that do not cause unacceptable skin irritation in conventional repeat skin irritation tests in albino rabbits such as that described in Draize et al., "Appraisal of the Safety of Chemicals in Food, Drugs and Cosmetics", prepared by the Division of Pharmacology of the Food and Drug Administration, published originally in 1959 by the Association of Food and Drug Officials of the United States, Topeka, Kans. (2nd printing 1965), incorporated herein by reference.
  • the present invention provides pharmaceutical formulations such as creams, ointments, foams, gels, lotions and adhesive coatings that contain imiquimod and a fatty acid such as isostearic, linoleic, super purified oleic acid or oleic acid and mixtures thereof.
  • the formulations of the invention provide desirable skin penetrability of the imiquimod.
  • the compound imiquimod is a known antiviral agent that is also known to induce interferon biosynthesis. It can be prepared using the method disclosed in U.S. Pat. No. 4,689,338, the disclosure of which is incorporated herein by reference. The compound can be used to treat viral infections such as Type I or Type Il Herpes simplex infections and genital warts.
  • the compound is an interferon inducer suggests that it, and therefore formulations containing it, might be useful in the treatment of numerous other diseases, such as rheumatoid arthritis, warts, eczema, hepatitis B, psoriasis, multiple sclerosis, essential thrombocythaemia, and cancer, such as basal cell carcinoma and other neoplastic diseases.
  • the amount of imiquimod present in a formulation of the invention will be an amount effective to treat the targeted disease state to prevent the recurrence of such a disease or to promote immunity against such a disease.
  • the amount is preferably about 0.5 percent to about 9 percent by weight based on the total weight of a formulation, more preferably between greater than about 1% and about 5% imiquimod, and more preferably between about 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5%, and most preferred between about 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0%. .
  • a fatty acid such as isostearic acid, linoieic acid, super purified oleic acid, oleic acid or a mixture thereof is incorporated into a formulation of the invention.
  • the total amount of fatty acid present in a formulation is preferably about 3 percent to about 45 percent by weight based on the total weight of a formulation. It should be understood that when oleic acid is selected as a fatty acid, that stability may present issue. Thus, stabilizers, such as anti-oxidants and the like may be required to preserve pharmaceutical elegance and stability over the life of the oleic formulation.
  • a pharmaceutical formulation of the invention can be in a form such as a cream, an ointment, a foam, a gel, a lotion, a pressure-sensitive adhesive composition, or other forms known to those skilled in the art, each particular form containing imiquimod and fatty acid in particular amounts, and optionally containing various additional elements.
  • the preferred amounts of drug and fatty acid, and the amounts and types of optional elements used in formulations of the invention are discussed below with particular reference to creams, ointments and adhesive compositions.
  • a cream according to the invention contains 1-isobutyl-1 H-imidazo[4,5-c]quinolin- 4-amine and fatty acid.
  • the amount of 1-isobutyl-1 H-imidazo[4,5-c]-quinolin-4-amine present in a cream is preferably about 0.5 percent to about 9 percent by weight, and more preferably about 1 percent to about 5 percent by weight, based on the total weight of the cream.
  • the total amount of fatty acid present in a cream of the invention is preferably about 3 percent to about 45 percent by weight, and more preferably about 5 percent to about 25 percent by weight, based on the total weight of the cream.
  • a cream of the invention can contain emollients, emulsifiers, thickeners, and/or preservatives.
  • Emollients such as long chain alcohols, e.g., cetyl alcohol, stearyl alcohol and cetearyl alcohol; hydrocarbons such as petrolatum and light mineral oil; or acetylated lanolin can be included in a cream of the invention.
  • a cream can contain one or more of these emollients.
  • the total amount of emollient in a cream of the invention is preferably about 5 percent to about 30 percent, and more preferably about 5 percent to about 10 percent by weight based on the total weight of the cream.
  • Emulsifiers such as nonionic surface active agents, e.g., polysorbate 60 (available from ICI Americas), sorbitan monostearate, polyglyceryl-4 oleate, and polyoxyethylene(4)iauryl ether or trivalent cationic a cream of the invention.
  • a cream can contain one or more emulsifiers. Generally the total amount of emulsifier is preferably about 2 percent to about 14 percent, and more preferably about 2 percent to about 6 percent by weight based on the total weight of the cream.
  • compositions such as Veegum.TM.K (available from R. T. Vanderbilt Company, Inc.), and long chain alcohols (i.e. cetyl alcohol, stearyl alcohol or cetearyl alcohol) can be used.
  • a cream can contain one or more thickeners. The total amount of thickener present is preferably about 3 percent to about 12 percent by weight based on the total weight of the cream.
  • Preservatives such as methyl paraben, propylparaben and benzyl alcohol can be present in a cream of the invention.
  • the appropriate amount of such preservative(s) is known to those skilled in the art.
  • an additional solubilizing agent such as benzyl alcohol, lactic acid, acetic acid, stearic acid or hydrochloric acid can be included in a cream of the invention.
  • the amount present is preferably about 1 percent to about 12 percent by weight based on the total weight of the cream.
  • a cream of the invention can contain a humectant such as glycerin, skin penetration enhancers such as butyl stearate, and additional solubilizing agents.
  • a single ingredient can perform more than one function in a cream, i.e., cetyl alcohol can serve both as an emollient and as a thickener.
  • a cream consists of an oil phase and a water phase mixed together to form an emulsion.
  • the amount of water present in a cream of the invention is about 45 percent to about 85 percent by weight based on the total weight of the cream.
  • the oil phase of a cream of the invention can be prepared by first combining the 1-isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine and the fatty acid (if the cream contains benzyl alcohol it can also be added at this point) and heating with occasional stirring to a temperature of about 50 0 C. to 85°C. When the 1-isobutyl-1 H-imidazo[4,5-c]quinolin-4- amine appears to be completely dissolved, the remaining oil phase ingredients are added and heating is continued until dissolution appears to be complete.
  • the water phase can be prepared by combining all other ingredients and heating with stirring until dissolution appears to be complete.
  • the creams of the invention are generally prepared by adding the water phase to the oil phase with both phases at a temperature of about 65°C. to 75°C.
  • the resulting emulsion is mixed with a suitable mixer apparatus to give the desired cream.
  • An ointment of the invention contains an ointment base in addition to 1-isobutyl- 1 H-imidazo[4,5-c3quinolin-4-amine and fatty acid.
  • the amount of 1-isobutyl-1 H-imidazo[4,5-c]-quinolin-4-amine present in an ointment of the invention is preferably about 0.5 percent to about 9 percent, and more preferably about 0.5 percent to about 5 percent by weight based on the total weight of the ointment.
  • the total amount of fatty acid present in an ointment of the invention is preferably about 3 percent to about 45 percent, and more preferably about 3 percent to about 25 percent based on the total weight of the ointment.
  • a pharmaceutically acceptable ointment base such as petrolatum or polyethylene glycol 400 (available from Union Carbide) in combination with polyethylene glycol 3350 (available from Union Carbide) can be used.
  • the amount of ointment base present in an ointment of the invention is preferably about 60 percent to about 95 percent by weight based on the total weight of ointment.
  • an ointment of the invention can also contain emollients, emulsifiers and thickeners.
  • emollients, emulsifiers, and thickeners and the preferred amounts thereof described above in connection with creams are also generally suitable for use in an ointment of the invention.
  • An ointment according to the invention can be prepared by combining 1-isobutyl- 1 H-imidazo[4,5-c]quinolin-4-amine with fatty acid and heating with occasional stirring to a temperature of about 65°C. When the 1-isobutyl-1 H-imidazo[4,5-c]-quinolin-4-amine appears to be completely dissolved, the remaining ingredients are added and heated to about 65.°C. The resulting mixture is mixed with a suitable mixer while being allowed to cool to room temperature.
  • a pressure-sensitive adhesive composition of the invention contains 1-isobutyl- 1 H-imidazo[4,5-c]-quinolin-4-amine, fatty acid, and a pressure sensitive adhesive polymer.
  • the amount of 1-isobutyl-1 H-imidazo[4,5-c]-quinolin-4-amine present in a pressure sensitive adhesive composition of the invention is preferably about 0.5 percent to about 9 percent by weight, and more preferably about 3 percent to about 7 percent by weight based on the total weight of the adhesive composition.
  • the amount of fatty acid present is preferably about 10 percent to about 40 percent by weight, more preferably about 15 percent to about 30 percent by weight, and most preferably about 20 percent to about 30 percent by weight, based on the total weight of the adhesive composition.
  • the adhesive polymer utilized in a pressure sensitive adhesive composition of the invention is substantially chemically inert to 1-isobutyl-1 H- imidazo[4,5-c]quino]in-4-amine.
  • the adhesive polymer is preferably present in an amount of about 55 percent to about 85 percent by weight based on the total weight of the composition.
  • Suitable adhesive polymers include acrylic adhesives that contain, as a major constituent (i.e., at least about 80 percent by weight of all monomers in the polymer), a hydrophobic monomeric acrylic or methacryiic acid ester of an alkyl alcohol, the alkyl alcohol containing 4 to 10 carbon atoms. Examples of suitable monomers are those discussed below in connection with the "A Monomer". These adhesive polymers can further contain minor amounts of other monomers such as the "B Monomers” listed below.
  • Preferred adhesives include acrylic pressure-sensitive adhesive copolymers containing A and B Monomers as follows: Monomer A is a hydrophobic monomeric acrylic or methacryiic acid ester of an alkyl alcohol, the alkyl alcohol containing 4 to 10 carbon atoms, preferably 6 to 10 carbon atoms, more preferably 6 to 8 carbon atoms, and most preferably 8 carbon atoms.
  • a Monomers examples include n-butyl, n- pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloctyl, isooctyl and 2- ethylhexyl acrylates.
  • the most preferred A Monomer is isooctyl acrylate.
  • Monomer B is a reinforcing monomer selected from the group consisting of acrylic acid; methacryiic acid; alkyl acrylates and methacrylates containing 1 to 3 carbon atoms in the alkyl group; acrylamide; methacrylamide; lower alkyl-substituted acrylamides (i.e., the alkyl group containing 1 to 4 carbon atoms) such as tertiary-butyl acrylamide; diacetone acrylamide; n-vinyl-2-pyrrolidone; vinyl ethers such as vinyl tertiary-butyl ether; substituted ethylenes such as derivatives of maleic anhydride, dimethyl itaconate and monoethyl formate and vinyl perfluoro-n-butyrate.
  • acrylic acid methacryiic acid
  • acrylamide methacrylamide
  • the preferred B Monomers are acrylic acid, methacryiic acid, the above-described alkyl acrylates and methacrylates, acrylamide, methacrylamide, and the above-described lower alkyl substituted acrylamides.
  • the most preferred B Monomer is acrylamide.
  • the pressure-sensitive adhesive copolymer containing A and B Monomers as set forth above preferably contains the A Monomer in an amount by weight of about 80 percent to about 98 percent of the total weight of all monomers in the copolymer.
  • the A Monomer is more preferably present in an amount by weight of about 88 percent to about 98 percent, and is most preferably present in an amount by weight of about 91 percent to about 98 percent.
  • the B Monomer in such a copolymer is preferably present in the pressure-sensitive adhesive copolymer in an amount by weight of about 2 percent to about 20 percent, more preferably about 2 percent to about 12 percent, and most preferably 2 to 9 percent of the total weight of the monomers in the copolymer.
  • the adhesive copolymer comprises about 60 to about 80 percent by weight (and preferably about 70 to about 80 percent by weight) of the above-mentioned hydrophobic monomeric acrylic or methacrylic acid ester of an alkyi alcohol (i.e., Monomer A described above) based on the total weight of all monomers in the copolymer; about 4 to about 9 percent by weight based on the total weight of all monomers in the copolymer of a reinforcing monomer selected from the group consisting of acrylic acid, methacrylic acid, an alky!
  • an alkyi alcohol i.e., Monomer A described above
  • acryiate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group, acrylamide, methacrylamide, a lower alkyl- substituted acrylamide, diacetone acrylamide and N-vinyl-2-pyrrolidone; and about 15 to about 35 percent by weight (and preferably about 15 to about 25 percent by weight) of vinyl acetate based on the total weight of all monomers in the copolymer.
  • the preferred acrylic or methacrylic acid ester is isooctyl acryiate and the preferred reinforcing monomer is acrylamide.
  • the above described adhesive copolymers are known, and methods of preparation therefor are well known to those skilled in the art, having been described for example, in U.S. Pat. No. 24,906 (Ulrich), the disclosure of which is incorporated herein by reference.
  • the polymerization reaction can be carried out using a free radical initiator such as an organic peroxide (e.g., benzoylperoxide) or an organic azo compound (e.g., 2,2'-azobis(2 I 4-dimethy!pentanenitri!e), available under the trade designation "Vazo 52" from DuPont).
  • a free radical initiator such as an organic peroxide (e.g., benzoylperoxide) or an organic azo compound (e.g., 2,2'-azobis(2 I 4-dimethy!pentanenitri!e), available under the trade designation "Vazo 52" from DuPont).
  • a free radical initiator such as an organic peroxide (e.g., be
  • a pressure sensitive adhesive composition of the invention can also contain one or more skin penetration enhancers such as glyceryl monoiaurate, ethyl oieate, isopropyl myristate, diisopropyl adipate and N,N-dimethy!dodecylamine-N-oxide, either as a single ingredient or as a combination of two or more ingredients.
  • the skin penetration enhancer(s) preferably form a substantially homogeneous mixture with the pressure sensitive adhesive polymer or copolymer.
  • the total amount of skin penetration enhancer(s) present in a pressure sensitive adhesive composition of the invention is preferably about 3 percent to about 25 percent by weight, more preferably about 3 percent to about 10 percent by weight based on the total weight of the adhesive composition.
  • the skin penetration enhancer is a single ingredient, it is preferably a skin penetration enhancer such as isopropyl myristate, diisopropyl adipate, ethyl oieate, or glyceryl monoiaurate.
  • a combination skin penetration enhancer is used, it is preferably a combination such as: ethyl oieate with glyceryl monoiaurate; ethyl oieate with N, N- dimethyldodecylamine-N-oxide; glyceryl monoiaurate with N,N-dimethyldodecylamine- N-oxide; and ethyl oieate with both glyceryl monoiaurate and N, N- dimethyidodecylamine-N-oxide.
  • a pressure-sensitive adhesive composition of the invention can be prepared by combining dry adhesive, 1-isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine, fatty acid, and skin penetration enhancer(s) with an organic solvent.
  • the preferred organic solvents are methanol and ethyl acetate.
  • the total solids content of the adhesive coating is preferably in the range of about 15 percent to about 40 percent, and more preferably in the range of about 20 to about 35 percent based on the total weight of the adhesive coating. The resulting mixture is shaken or mixed for a period of about 20 to 72 hours.
  • the 1-isobutyl-1 H-imidazo[4,5-c]-quinolin-4- amine be in micronized form (i.e., particle size of 1-2 microns in diameter).
  • the mixture can be heated during shaking.
  • the 1-isobutyl-1 H-imidazo-4,5-c]quinolin-4-amine is combined with the fatty acid and shaken at 40 0 C until there appears to be complete dissolution. The remaining ingredients are added and the mixture is shaken for a period of about 20 to 72 hours.
  • the pressure-sensitive adhesive compositions described above are preferably coated onto one surface of a suitable backing of sheet material, such as a film, to form a pressure-sensitive adhesive coated sheet material.
  • a pressure-sensitive adhesive coated sheet material of the invention can be prepared by knife coating a suitable release liner to a predetermined uniform thickness with a wet adhesive formulation. This adhesive coated release liner is then dried and laminated onto a backing using conventional methods.
  • Suitable release liners include conventional release liners comprising a known sheet material, such as a polyester web, a polyethylene web, or a polystyrene web, or polyethylene-coated paper, coated with a suitable silicone-type coating such as that available under the trade designation Daubert 164Z, from Daubert Co.
  • the backing can be occlusive, non-occlusive or a breathable film as desired.
  • the backing can be any of the conventional materials for pressure-sensitive adhesive tapes, such as polyethylene, particularly low density polyethylene, linear low density polyethylene, high density polyethylene, randomly-oriented nylon fibers, polypropylene, ethylene-vinylacetate copolymer, polyurethane, rayon and the like.
  • Backings that are layered, such as polyethylene-aluminum-polyethylene composites are also suitable.
  • the backing should be substantially non-reactive with the ingredients of the adhesive coating.
  • the presently preferred backing is low density polyethylene.
  • the pressure-sensitive adhesive coated sheet material of the invention can be made in the form of an article such as a tape, a patch, a sheet, a dressing or any other form known to those skilled in the art.
  • an article in the form of a patch is made from an adhesive coated sheet material of the invention and applied to the skin of a mammal.
  • the patch is replaced as necessary with a fresh patch to maintain the particular desired therapeutic effect of the 1-isobutyl-1 H-imida2o[4,5-c]qutnoiin-4-amine.
  • a 25-30 percent solids solution of the isooctyl acrylate:acry!amide (93:7) adhesive copolymer in ethyl acetate/methanoi (90:10) was coated onto a two-sided release liner using a knife-coater and coating at 0.5 mm in thickness.
  • the adhesive- coated laminate was dried first at 82°C for 3 minutes and then at 116°C for 3 minutes. The dried adhesive coating was then stripped off the release liner and placed in a glass bottle. The foregoing procedure results in a reduction of the amount of any residual monomer in the adhesive copolymer.
  • a master batch was prepared by combining 621.0 g of isooctyl acrylate, 41.4 g of acrylamide, 165.6 g of vinyl acetate, 1.656 g of 2,2'-azobis(2,4-dimethyipentanenitrile) (available from the DuPont Company as Vazo.TM.52), 884.52 g of ethyl acetate and 87.48 g of methanol.
  • a 400 g portion of the resulting solution was placed in an amber quart bottle. The bottle was purged for two minutes with nitrogen at a flow rate of one liter per minute. The bottle was sealed and placed in a rotating water bath at 45°C for twenty-four hours to effect essentially complete polymerization.
  • the copolymer was diluted with 250 g of ethyl acetate/methanol (90/10) to 26.05% solids and had a measured inherent viscosity of 1.27 dl/g in ethyl acetate at a concentration of 0.15 g/dl. Its Brookfield viscosity was 5580 centipoise.
  • a cream according to the present invention was prepared from the following ingredients:
  • the water phase was added to the oil phase.
  • the mixture was mixed with a homogenizer for 13 minutes then put into a cool water bath and mixed with a 3 inch propeller for 40 minutes (the temperature was 29°C).
  • the resulting cream was placed in glass jars.
  • Brij TM. 30 polyoxyethylene(4) lauryl ether is available from IC! Americas, Inc.
  • a cream according to the present invention was prepared from the following ingredients:
  • Witconol TM. 14 (po!yglyceryl4 oleate) is available from Witco Chemical Corp. Organics
  • the 1-isobuty!-1 H-imidazo[4,5-c]quinolin-4-amine and theisostearic acid were weighed into a glass jar and heated with occasional stirring until the amine was dissolved (the temperature reached 68°C).
  • To this solution was added, the petrolatum, mineral oil, aluminum stearate, cetyl alcohol, Witconol.TM.14, acetytated lanoline and propylparaben.
  • the mixture was heated to 75°C.
  • the methylparaben and water were combined and heated until the paraben dissolved (the temperature reached 61 0 C).
  • the Veegum.TM.K was added to the aqueous solution and heated at 75 0 C.
  • An ointment according to the present invention was prepared from the following ingredients:
  • Example 11 Using the general procedure of Example 11 an ointment containing the following ingredients was prepared.
  • Creams of the present invention were prepared using the ingredients shown in Table 3. The Example 1 except that benzyl alcohol was used with the isostearic acid to dissolve the 1- isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine.
  • a cream according to the present invention was prepared from the following ingredients:
  • the isostearic acid and 0.8 g of 1-isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine were combined in a glass jar and heated with stirring until the amine had dissolved.
  • the remaining oi! phase ingredients were added to this solution and the mixture was heated to about 70 0 C.
  • the aqueous phase ingredients were weighed into a separate beaker and heated with stirring until the amine and the parabens had dissolved. With both phases at about 70 0 C, the water phase was added to the oi! phase and mixed with a propeller until the mixture cooled to room temperature.
  • the formulation was coated at a thickness of 20 mils onto a 5 mil Daubert 164Z liner.
  • the laminate was oven dried for 3 minutes at 105 0 F., for 2 minutes at 185°F., and for 2 minutes at 210 0 F.
  • the resulting adhesive coating contained 59.1 percent 93:7 isooctyl acrylate:acylamide adhesive copolymer, 15.0 percent isostearic acid, 20.0 percent ethyl oleate, 3.0 percent glyceryl monolaurate and 2.9 percent 1-isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine.
  • the material was then laminated with 3 mil low density polyethylene backing and die cut into 2.056 cm.sup.2 patches.
  • Example 17 Using the general method of Example 17 the formulations shown below were prepared. 1-lsobutyl-1 H-imidazo[4,5-c]quinolin-4-amine that had been ground with a mortar and pestle was used. The adhesive was the 93:7 isooctyi acrylate: acrylamide copolymer prepared in PREPARATIVE METHOD 1 above. The solvent was 90:10 ethyl acetate: methanol. All formulations were mixed at room temperature.
  • Example 18 A formulation with the same components in the same proportions as Example 18 was prepared using a different method.
  • the 1-isobutyl-1 H-imidazo[4,5-c]-quinolin-4- amine was combined with the oleic and isostearic acids and shaken at 40 0 C. until there was complete dissolution of the 1-isobutyl-1 H-imidazo-[4,5-c]quinolin-4-amine.
  • the remaining ingredients were added and shaken a 40 0 C. for 72 hours. Patches measuring 2.056 cm.sup.2 were prepared by the general method of Example 17.
  • Aldara® Cream commercially available via prescription and manufactured by 3M i
  • the objective is to evaluate the efficacy of imiquimod cream, 5% (imiquimod) for the treatment of moJluscum contagiosum (MC) lesions in pediatric subjects when the cream was applied 3 times per week (3x/wk) for up to 16 weeks.
  • the efficacy of imiquimod is evaluated by assessing MC lesion clearance.
  • the primary efficacy parameter is complete clearance of all MC lesions (complete clinical resolution) from treatment initiation to the week 18/efficacy visit.
  • Secondary efficacy parameters include partial clearance, defined as ⁇ 50% reduction from the baseline lesion count, and the change in total lesion count. Time to complete clearance is also compared between treatment groups.
  • the secondary objective is to evaluate the safety of imiquimod. Safety assessments are conducted throughout the study.
  • AEs adverse events
  • LSRs local skin reactions
  • MC lesions and application area locations are recorded on a body diagram. Subjects report to the clinic at treatment weeks 2, 4, 8, 12, and 16, and post treatment at week 18 for efficacy assessments, and week 28 for end- of-study procedures. At each study visit, MC lesions are counted and recorded, and safety procedures are performed. Also, the subject's diary is reviewed for compliance. Subjects return at week 18 for the primary efficacy and post treatment safety assessments. All subjects who did not clear their MC lesions as well as subjects who did not complete the 16 weeks of treatment are to report to the clinic at week 28 for final safety and efficacy assessments.
  • Eligible subjects have >2 clinically verified MC lesions (at least half had >5 lesions) not located on buttocks, or inguinal region or on hands only and are 2 to 12 years old.
  • Imiquimod cream 5%, 1 to 3 sachets applied to MC lesions, topical.
  • MC lesions are treated 3x/wk for up to 16 weeks, or until determined that all MC lesions are cleared.
  • the vehicle cream, 1 to 3 packets, is applied to MC lesions, topical.
  • the primary dataset is analyzed for efficacy and safety is the intent-to-treat (!TT) dataset, consisting of all randomized subjects.
  • a per-protocoi (PP) dataset is also analyzed for efficacy.
  • the PP dataset includes data from subjects who have an assessment of the primary variable, apply at least two thirds of the required doses, and are free from major protocol violations.
  • Treatment groups are compared with respect to the primary variable (complete clearance rate at the week 18 study visit) by means of the Cochran-Mantel-Haenzsel (CMH) Test, which adjusts for multiple study centers.
  • CMH Test is also performed for the secondary efficacy variable: partial clearance rate.
  • the median cumulative exposure for imiquimod subjects during the study is 587.5 mg imiquimod (range, 12.5 to 1662.5 mg).
  • the median number of doses received is 44.0 (range, 1 to 64).
  • imiquimod is found to be safe in children ages 2 to 12 with MC when dosed 3x/wk for up to 16 weeks. According to this study, imiquimod is not statistically significantly more effective than vehicle cream when dosed 3x/wk for up to 16 weeks with respect to complete and partial clearance of MC lesions.
  • Aldara® (imiquimod) Cream 5%, is supplied in single-use packets which contain 250 mg of the cream. It is commercially available to patients by prescription as a box of 12 packets NDC 29336-610-12. !t is recommended to store Aldara® Cream at 4 - 25 0 C (39 - 77°F) and avoid freezing.
  • Aldara® (imiquimod 5%) Cream is an immune response modifier for topical administration. Each gram contains 50 mg of imiquimod in an off-white oil-in-water vanishing cream base consisting of isostearic acid, cetyl alcohol, steary!
  • imiquimod is 1-(2- methylpropy!)-1H-imidazo[4,5-c]quinolin-4-arnine.
  • Imiquimod has a molecular formula of CuHi 6 N 4 and a molecular weight of 240.3.

Abstract

L'invention concerne des emballages pharmaceutiques et des procédés visant à améliorer la sécurité pendant l'utilisation d'imiquimod pour traiter des enfants atteints de troubles de la peau. Plus particulièrement, le profil de sécurité d'utilisation de l'imiquimod est accentué en fournissant des informations aux enfants, aux tuteurs des enfants, y compris aux parents et aux professionnels de soins de santé, qu'une absorption systémique d'imiquimod et d'autres effets peuvent être observés lorsqu'une thérapie à l'imiquimod est utilisée pour traiter des enfants âgés de 2 à 12 ans environ. Des exemples d'absorption systémique comprennent des concentrations inférieures à environ 2 ng/mL d'imiquimod dans le sérum ; une diminution de la numération médiane de leucocytes d'environ 1,4*109/L ou une diminution de la numération médiane absolue des neutrophiles d'environ 1,42*109/L. Une administration topique et/ou transdermique d'imiquimod, y compris sous forme de crèmes, pommades, gels, lotions, salves et compositions adhésives autocollantes pour traiter des troubles dermatologiques chez des enfants, à savoir le molluscum contagiosum, les infections virales, telles que les infections d'herpes simplex de type I ou de type II et le condylome acuminé, les verrues génitales et les verrues périanales, la kératose actinique et l'épithélioma basocellulaire superficiel, et pour induire une biosynthèse d'interféron.
PCT/US2008/057758 2007-03-23 2008-03-20 Procédés et emballages visant à améliorer la sécurité pendant l'utilisation d'imiquimod pour traiter des enfants atteints de troubles de la peau WO2008118762A1 (fr)

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EP2453747A1 (fr) * 2009-07-13 2012-05-23 Medicis Pharmaceutical Corporation Formulations d'imiquimod à intensité de dosage plus faible et régimes posologiques courts pour traiter des verrues génitales et périanales
US8598196B2 (en) 2008-08-18 2013-12-03 Medicis Pharmaceutical Corporation Methods of treating dermatological disorders and inducing interferon biosynthesis with shorter durations of imiquimod therapy
EP3347000A4 (fr) * 2015-09-11 2019-03-27 Phio Pharmaceuticals Corp. Procédés de traitement de troubles et d'affections cutanés en utilisant des haptènes

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US8598196B2 (en) 2008-08-18 2013-12-03 Medicis Pharmaceutical Corporation Methods of treating dermatological disorders and inducing interferon biosynthesis with shorter durations of imiquimod therapy
US9271973B2 (en) 2008-08-18 2016-03-01 Medicis Pharmaceutical Corporation Methods of treating dermatological disorders and inducing interferon biosynthesis with shorter durations of imiquimod therapy
EP2453747A1 (fr) * 2009-07-13 2012-05-23 Medicis Pharmaceutical Corporation Formulations d'imiquimod à intensité de dosage plus faible et régimes posologiques courts pour traiter des verrues génitales et périanales
EP2453747A4 (fr) * 2009-07-13 2012-12-05 Medicis Pharmaceutical Corp Formulations d'imiquimod à intensité de dosage plus faible et régimes posologiques courts pour traiter des verrues génitales et périanales
US8642616B2 (en) 2009-07-13 2014-02-04 Medicis Pharmaceutical Corporation Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts
US9078889B2 (en) 2009-07-13 2015-07-14 Medicis Pharmaceutical Corporation Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts
AU2010274097B2 (en) * 2009-07-13 2016-06-16 Medicis Pharmaceutical Corporation Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts
US9980955B2 (en) 2009-07-13 2018-05-29 Medicis Pharmaceutical Corporation Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts
US10238645B2 (en) 2009-07-13 2019-03-26 Medicis Pharmaceutical Corporation Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts
US10918635B2 (en) 2009-07-13 2021-02-16 Medicis Pharmaceutical Corporation Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts
US11850245B2 (en) 2009-07-13 2023-12-26 Medicis Pharmaceutical Corporation Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts
EP3347000A4 (fr) * 2015-09-11 2019-03-27 Phio Pharmaceuticals Corp. Procédés de traitement de troubles et d'affections cutanés en utilisant des haptènes

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