Methods of Treating Dermatological Disorders and Inducing Interferon Biosynthesis With Shorter Durations of Imiquimod Therapy

Abstract

Pharmaceutical Formulations and Methods for the Topical and/or transdermal delivery of imiquimod, including creams, ointments and pressure-sensitive adhesive compositions to treat dermatological disorders, namely, viral infections, such as Type I or Type II Herpes simplex infections and genital and perianal warts, actinic keratosis and superficial basal cell carcinoma, and to induce interferon biosynthesis to achieve an antiviral effect, with shorter durations of therapy, than currently approved for imiquimod by the Food & Drug Administration (“FDA”).

1 . A method of topical and/or transdermal administration of imiquimod for treating a dermatological disorder in a mammal, which method comprises:
 (a) applying an effective amount of a formulation containing imiquimod on the skin of a mammal once a day at least 3 times a week on 3 different days for at least between about 8 weeks and 12 weeks; and   (b) allowing said imiquimod to remain in contact with the skin for a sufficient time following said application to permit an effective amount of the imiquimod to penetrate the skin to achieve the antiviral effect.   
   
   
       2 . A method of  claim 1 , wherein said formulation is applied for 8 weeks. 
   
   
       3 . A method of  claim 1 , wherein said formulation is applied for 9 weeks. 
   
   
       4 . A method of  claim 1 , wherein said formulation is applied for 10 weeks. 
   
   
       5 . A method of  claim 1 , wherein said formulation is applied for 11 weeks. 
   
   
       6 . A method of  claim 1 , wherein said formulation is applied for 12 weeks. 
   
   
       7 . A method of  claims 1 - 6 , wherein the formulation is applied once a day at least 4 times a week. 
   
   
       8 . A method of  claims 1 - 6 , wherein the formulation is applied once a day at least 5 times a week. 
   
   
       9 . A method of  claims 1 - 6 , wherein the formulation is applied once a day at least 6 times a week. 
   
   
       10 . A method of  claims 1 - 6 , wherein the formulation is applied once a day at least 7 times a week. 
   
   
       11 . A method of  claims 1 - 10 , wherein the formulation contains from greater than about 1% to about 5% imiquimod. 
   
   
       12 . A method of  claim 11 , wherein the formulation contains about 1.25% imiquimod. 
   
   
       13 . A method of  claim 11 , wherein the formulation contains about 1.5% imiquimod. 
   
   
       14 . A method of  claim 11 , wherein the formulation contains about 1.75% imiquimod. 
   
   
       15 . A method of  claim 11 , wherein the formulation contains about 2% imiquimod. 
   
   
       16 . A method of  claim 11 , wherein the formulation contains about 2.25% imiquimod. 
   
   
       17 . A method of  claim 11 , wherein the formulation contains about 2.5% imiquimod. 
   
   
       18 . A method of  claim 11 , wherein the formulation contains about 2.75% imiquimod. 
   
   
       19 . A method of  claim 11 , wherein the formulation contains about 3% imiquimod. 
   
   
       20 . A method of  claim 11 , wherein the formulation contains about 3.25% imiquimod. 
   
   
       21 . A method of  claim 11 , wherein the formulation contains about 3.5% imiquimod. 
   
   
       22 . A method of  claim 11 , wherein the formulation contains about 3.75% imiquimod. 
   
   
       23 . A method of  claim 11 , wherein the formulation contains about 4.0% imiquimod. 
   
   
       24 . A method of  claim 11 , wherein the formulation contains about 4.25% imiquimod. 
   
   
       25 . A method of  claim 11 , wherein the formulation contains about 4.5% imiquimod. 
   
   
       26 . A method of  claims 1 - 25 , wherein the dermatological disorder is a viral disease. 
   
   
       27 . A method of  claim 26 , wherein the viral disease is a Type I Herpes simplex infection. 
   
   
       28 . A method of  claim 26 , wherein the viral disease is a Type II Herpes simplex infection. 
   
   
       29 . A method of  claims 1 - 25 , wherein the dermatological disorder is external genital or perianal warts. 
   
   
       30 . A method of  claims 1 - 25 , wherein the dermatological disorder is actinic keratosis. 
   
   
       31 . A method of  claims 1 - 25 , wherein the dermatological disorder is superficial basal cell carcinoma. 
   
   
       32 . A method of  claims 1 - 31 , wherein the formulation further includes a fatty acid. 
   
   
       33 . A method of  claim 32 , wherein the fatty acid is isostearic acid. 
   
   
       34 . A method of  claim 32 , wherein the fatty acid is oleic acid. 
   
   
       35 . A method of  claim 32 , wherein the fatty acid is super purified oleic acid. 
   
   
       36 . A method of  claim 32 , wherein the fatty acid is linoleic acid. 
   
   
       37 . A method of  claims 1 - 36 , wherein the formulation is selected from the group consisting of a cream, ointment, gel, foam, lotion and adhesive-coated sheet material. 
   
   
       38 . A method of topical and/or transdermal administration of imiquimod to induce interferon biosynthesis in a mammal, which method comprises:
 (a) applying an effective amount of a formulation containing imiquimod on the skin of a mammal once a day at least 3 times a week on 3 different days for at least between about 8 weeks and 12 weeks; and   (b) allowing said imiquimod to remain in contact with the skin for a sufficient time following said application to permit an effective amount of the imiquimod to penetrate the skin to achieve the antiviral effect.   
   
   
       39 . A method of  claim 38 , wherein said formulation is applied for 8 weeks. 
   
   
       40 . A method of  claim 38 , wherein said formulation is applied for 9 weeks. 
   
   
       41 . A method of  claim 38 , wherein said formulation is applied for 10 weeks. 
   
   
       42 . A method of  claim 38 , wherein said formulation is applied for 11 weeks. 
   
   
       43 . A method of  claim 38 , wherein said formulation is applied for 12 weeks. 
   
   
       44 . A method of  claims 38 - 43 , wherein the formulation is applied once a day at least 4 times a week. 
   
   
       45 . A method of  claims 38 - 43 , wherein the formulation is applied once a day at least 5 times a week. 
   
   
       46 . A method of  claim 38 - 43 , wherein the formulation is applied once a day at least 6 times a week. 
   
   
       47 . A method of  claim 38 - 43 , wherein the formulation is applied once a day at least 7 times a week. 
   
   
       48 . A method of  claims 38 - 47 , wherein the formulation contains from greater than about 1% to about 5% imiquimod. 
   
   
       49 . A method of  claim 48 , wherein the formulation contains about 1.25% imiquimod. 
   
   
       50 . A method of  claim 48 , wherein the formulation contains about 1.5% imiquimod. 
   
   
       51 . A method of  claim 48 , wherein the formulation contains about 1.75% imiquimod. 
   
   
       52 . A method of  claim 48 , wherein the formulation contains about 2% imiquimod. 
   
   
       53 . A method of  claim 48 , wherein the formulation contains about 2.25% imiquimod. 
   
   
       54 . A method of  claim 48 , wherein the formulation contains about 2.5% imiquimod. 
   
   
       55 . A method of  claim 48 , wherein the formulation contains about 2.75% imiquimod. 
   
   
       56 . A method of  claim 48 , wherein the formulation contains about 3% imiquimod. 
   
   
       57 . A method of  claim 48 , wherein the formulation contains about 3.25% imiquimod. 
   
   
       58 . A method of  claim 48 , wherein the formulation contains about 3.5% imiquimod. 
   
   
       59 . A method of  claim 48 , wherein the formulation contains about 3.75% imiquimod. 
   
   
       60 . A method of  claim 48 , wherein the formulation contains about 4.0% imiquimod. 
   
   
       61 . A method of  claim 48 , wherein the formulation contains about 4.25% imiquimod. 
   
   
       62 . A method of  claim 48 , wherein the formulation contains about 4.5% imiquimod. 
   
   
       63 . A method of  claim 38 - 48 , wherein the formulation further includes a fatty acid. 
   
   
       64 . A method of  claim 63 , wherein the fatty acid is isostearic acid. 
   
   
       65 . A method of  claim 63 , wherein the fatty acid is oleic acid. 
   
   
       66 . A method of  claim 63 , wherein the fatty acid is super purified or refined oleic acid. 
   
   
       67 . A method of  claim 63 , wherein the fatty acid is linoleic acid. 
   
   
       68 . A method of  claims 38 - 67 , wherein the formulation is selected from the group consisting of a cream, ointment, gel, foam, lotion and adhesive-coated sheet material. 
   
   
       69 . A method of treating actinic keratosis with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to an area affected with actinic keratosis, once per day for fourteen (14) days, followed by no application for fourteen (14) days, followed by again applying an effective amount of the low dose imiquimod formulation to the area affected with the actinic keratosis once per day for fourteen (14) days for a total of twenty-eight (28) doses, to treat the actinic keratosis.   
   
   
       70 . A method of treating actinic keratosis with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 215%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to an area affected with actinic keratosis, once per day for twenty one (21) days, followed by no application for twenty one (21) days, followed by again applying an effective amount of the low dose imiquimod formulation to the area affected with the actinic keratosis once per day for twenty one (21) days for a total of forty-two (42) doses, to treat actinic keratosis.   applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to the warts, once per day, each day, for up to about 56 consecutive days or about 8 consecutive weeks or until clearance is observed, which ever occurs earlier to treat the warts.   
   
   
       71 . A method of treating warts, such as genital or perianal warts, with low dose ikmiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method, comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to the warts, once per day, each day, for up to about 56 consecutive days or about 8 consecutive weeks or until clearance is observed, which ever occurs earlier to treat the warts.   
   
   
       72 . A method of treating a dermatological area affected with a viral disorder with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to an area affected with the viral disorder, once per day for fourteen (14) days, followed by no application for fourteen (14) days, followed by again applying an effective amount of the low dose imiquimod formulation to the virally affected area once per day for fourteen (14) days for a total of twenty-eight (28) doses, to treat the viral disorder.   
   
   
       73 . A method of treating a dermatological area affected with a viral disorder with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to an area affected with the viral disorder, once per day for twenty one (21) days, followed by no application for twenty one (21) days, followed by again applying an effective amount of the low dose imiquimod formulation to the virally affected area once per day for twenty one (21) days for a total of forty-two (42) doses, to treat the viral disorder.   
   
   
       74 . A method of treating a dermatological area affected with a viral disorder with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to the viral disorder, once per day, each day, for up to about 56 consecutive days or about 8 consecutive weeks or until clearance is observed, which ever occurs earlier to treat the viral disorder.   
   
   
       75 . A method of  claims 69 - 74 , wherein the viral disease is a Type I Herpes simplex infection. 
   
   
       76 . A method of  claims 69 - 74 , wherein the viral disease is a Type II Herpes simplex infection. 
   
   
       77 . A method of  claims 69 - 76 , wherein the formulation contains about 2.0% imiquimod. 
   
   
       78 . A method of  claims 69 - 76 , wherein the formulation contains about 2.25% imiquimod. 
   
   
       79 . A method of  claims 69 - 76 , wherein the formulation contains about 2.5% imiquimod. 
   
   
       80 . A method of  claims 69 - 76 , wherein the formulation contains about 2.75% imiquimod. 
   
   
       81 . A method of  claims 69 - 76 , wherein the formulation contains about 3% imiquimod. 
   
   
       82 . A method of  claims 69 - 76 , wherein the formulation contains about 3.25% imiquimod. 
   
   
       83 . A method of  claims 69 - 76 , wherein the formulation contains about 3.5% imiquimod. 
   
   
       84 . A method of  claims 69 - 76 , wherein the formulation contains about 3.75% imiquimod. 
   
   
       85 . A method of  claims 69 - 76 , wherein the formulation contains about 4.0% imiquimod. 
   
   
       86 . A method of  claims 69 - 76 , wherein the formulation contains about 4.25% imiquimod. 
   
   
       87 . A method of  claims 69 - 76 , wherein the formulation contains about 4.5% imiquimod. 
   
   
       88 . A method of inducing effective interferon biosynthesis to achieve an antiviral affect with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to a dermatological area of a mammal once per day for fourteen (14) days, followed by no application for fourteen (14) days, followed by again applying an effective amount of the low dose imiquimod formulation to the area once per day for fourteen (14) days for a total of twenty-eight (28) doses, and   allowing said imiquimod to remain in contact with the dermatological area for a sufficient time following said application to permit an effective amount of the imiquimod to penetrate the skin to achieve effective interferon biosynthesis inducement and an antiviral effect.   
   
   
       89 . A method of inducing effective interferon biosynthesis to achieve an antiviral effect with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to a dermatological area, once per day for twenty one (21) days, followed by no application for twenty one (21) days, followed by again applying an effective amount of the low dose imiquimod formulation to the area affected with the area once per day for twenty one (21) days for a total of forty-two (42) doses, and   allowing said imiquimod to remain in contact with the dermatological area for a sufficient time following said application to permit an effective amount of the imiquimod to penetrate the skin to achieve effective interferon biosynthesis inducement and an antiviral effect.   
   
   
       90 . A method of inducing effective interferon biosynthesis to achieve an antiviral effect with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to a dermatological area, once per day, each day, for up to about 56 consecutive days or about 8 consecutive weeks, and   allowing said imiquimod to remain in contact with the dermatological area for a sufficient time following said application to permit an effective amount of the imiquimod to penetrate the skin to achieve effective interferon biosynthesis inducement and an antiviral effect.   
   
   
       91 . A method of  claims 88 - 90 , wherein the formulation contains about 2.0% imiquimod. 
   
   
       92 . A method of  claims 88 - 90 , wherein the formulation contains about 2.5% imiquimod. 
   
   
       93 . A method of  claims 88 - 90 , wherein the formulation contains about 2.75% imiquimod. 
   
   
       94 . A method of  claims 88 - 90 , wherein the formulation contains about 3% imiquimod. 
   
   
       95 . A method of  claims 88 - 90 , wherein the formulation contains about 3.25% imiquimod. 
   
   
       97 . A method of  claims 88 - 90 , wherein the formulation contains about 3.5% imiquimod. 
   
   
       98 . A method of  claims 88 - 90 , wherein the formulation contains about 3.75% imiquimod. 
   
   
       99 . A method of  claims 88 - 90 , wherein the formulation contains about 4.0% imiquimod. 
   
   
       100 . A method of  claims 88 - 90 , wherein the formulation contains about 425% imiquimod. 
   
   
       101 . A method of  claims 88 - 90 , wherein the formulation contains about 4.5% imiquimod. 
   
   
       102 . A method of  claims 88 - 101 , wherein the formulation is selected from the group consisting of a cream, ointment, gel, foam, lotion and adhesive-coated sheet material 
   
   
       103 . An imiquimod low dose composition for treating topically or transdermally a dermatological disorder with a shorter duration than currently approved for 5% w/w imiquimod by the Food & Drug Administration (“FDA”), said composition comprising:
 (a) imiquimod in an amount selected from the group consisting of 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% by weight based on the total weight of the composition, and   (b) a fatty acid, and optionally,   (c) an emollient,   (d) a thickener,   (e) an antioxidant,   (f) preservative,   (g) a solubilizing agent, and/or   (h) a humectant.   
   
   
       104 . A composition of  claim 103 , wherein the total amount of fatty acid present in the composition is between about 3 percent and about 45 percent by weight based on the total weight of a formulation. 
   
   
       105 . A composition of  claims 103 - 105 , wherein the formulation is selected from the group consisting of a cream, ointment, gel, foam, lotion and adhesive-coated sheet material. 
   
   
       106 . A composition of  claims 103 - 105  for use in accordance with the methods of  claims 1 - 99 . 
   
   
       107 . A method of inducing effective interferon biosynthesis with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to a dermatological area of a mammal once per day for fourteen (14) days, followed by no application for fourteen (14) days, followed by again applying an effective amount of the low dose imiquimod formulation to the area once per day for fourteen (14) days for a total of twenty-eight (28) doses, to induce effective interferon biosynthesis.   
   
   
       108 . A method for inducing effective interferon biosynthesis with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to a dermatological area once per day for twenty-one (21) days, followed by no application for twenty-one (21) days, followed by again applying an effective amount of the low dose imiquimod formulation to an area affected with actinic keratosis once per day for twenty-one (21) days for a total of forty-two (42) doses, to induce effective interferon biosynthesis.   
   
   
       109 . A method of inducing effective interferon biosynthesis with low dose imiquimod therapy for a shorter duration than currently approved for 5% imiquimod by the Food & Drug Administration (“FDA”), said method comprising:
 applying an effective imiquimod dose of a low dose imiquimod formulation, such as about 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% imiquimod % w/w, to a dermatological area once per day each day, for up to 56 consecutive days or about 8 consecutive weeks to induce effective interferon biosynthesis.   
   
   
       110 . A method of  claims 107 - 109 , wherein the formulation contains about 2.75% imiquimod. 
   
   
       111 . New A method of  claims 107 - 109 , wherein the formulation contains about 3% imiquimod. 
   
   
       112 . A method of  claims 107 - 109 , wherein the formulation contains about 3.25% imiquimod. 
   
   
       113 . A method of  claims 107 - 109 , wherein the formulation contains about 3.5% imiquimod. 
   
   
       114 . A method of  claims 107 - 109 , wherein the formulation contains about 3.75% imiquimod. 
   
   
       115 . A method of  claims 107 - 109 , wherein the formulation contains about 4.0% imiquimod. 
   
   
       116 . A method of  claims 107 - 109 , wherein the formulation contains about 4.25% imiquimod. 
   
   
       117 . A method of  claims 107 - 109 , wherein the formulation contains about 4.5% imiquimod. 
   
   
       118 . A method of  claims 107 - 109  wherein the formulation contains about 2.5% imiquimod.