Compositions and methods for topical application and transdermal delivery of an oligopeptide

Abstract

The invention relates to the transdermal application of oligopeptides for reducing synaptic transmission in tissues of an animal. In one aspect, this invention relates to compositions comprising an oligopeptide and optionally a carrier comprising a positively charged “backbone” having positively charged branching or “efficiency” groups, as described herein. Most preferably the positively charged carrier is a long-chain positively charged polypeptide or a positively charged nonpeptidyl polymer, for example, a polyalkyleneimine. The invention further relates methods for producing a biologic effect of reducing synaptic transmission in a tissue by topically applying an effective amount of such a composition, preferably to the skin, of a subject or patient in need of such treatment. This invention also provides kits for preparing or formulating a composition that comprises the oligopeptide and optionally a carrier, as well as such additional items that are needed to produce a usable formulation, or a premix that may in turn be used to produce such a formulation.

What is claimed is: 
     
         1 . A composition comprising an oligopeptide of from 6 to about 20 amino acids, said oligopeptide comprising the amino acid sequence of SEQ ID NO: 1, the composition further comprising a positively charged carrier having attached positively charged branching groups independently selected from -(gly) n1 -(arg) n2 , HIV-TAT, Antennapedia PTD, and fragments of HIV-TAT or of Antennapedia PTD or mixtures thereof, in which the subscript n1 is an integer of from 0 to about 20, and the subscript n2 is independently an odd integer of from about 5 to about 25. 
     
     
         2 . A composition according to  claim 1  wherein SEQ ID NO: 1 comprises the C-terminal end of the oligopeptide. 
     
     
         3 . A composition according to  claim 2  wherein the N-terminal end of the oligopeptide comprises from 3 to about 14 neutral amino acids. 
     
     
         4 . A composition according to  claim 3  wherein the N-terminal end of the oligopeptide comprises 4 aspartate molecules. 
     
     
         5 . A composition according to  claim 1  wherein SEQ ID NO: 1 comprises the N-terminal end of the oligopeptide. 
     
     
         6 . A composition according to  claim 5  wherein the C-terminal end of the oligopeptide comprises from 3 to about 14 neutral amino acids. 
     
     
         7 . A composition according to  claim 6  wherein the C-terminal end of the oligopeptide comprises 4 aspartate molecules. 
     
     
         8 . A composition according to  claim 1  wherein the oligopeptide is derivatized. 
     
     
         9 . A composition according to  claim 8  wherein the oligopeptide is derivatized with a molecule selected from the group consisting of an acetyl group, a palmitoyl group. 
     
     
         10 . A composition according to  claim 1  wherein the oligopeptide is recombinately produced. 
     
     
         11 . A composition according to  claim 1  wherein the composition is a cream, lotion, ointment, gel or liquid. 
     
     
         12 . A composition according to  claim 11  wherein the composition further comprises a buffer. 
     
     
         13 . A composition according to  claim 1  wherein the composition is a controlled release composition. 
     
     
         14 . A composition according to  claim 1  wherein the composition further comprises saline. 
     
     
         15 . A composition according to  claim 14  wherein the composition further comprises a buffer. 
     
     
         16 . A composition according to  claim 1  in which the positively charged carrier comprises a second oligopeptide having positively charged branching groups independently selected from -(gly) n1 -(arg) n2  in which the subscript n1 is an integer of from about 0 to about 20 and the subscript n2 is independently an odd integer of from about 5 to about 25. 
     
     
         17 . A composition according to  claim 16  in which the subscript n1 is an integer of from 0 to about 8. 
     
     
         18 . A composition according to  claim 16  in which the subscript n1 is an integer of from about 2 to about 5. 
     
     
         19 . A composition according to  claim 16  in which the subscript n2 is an odd integer of from about 7 to about 17. 
     
     
         20 . A composition according to  claim 16  in which the subscript n2 is an odd integer from about 7 to about 13. 
     
     
         21 . A composition according to  claim 16  in which the carrier comprises a second oligopeptide having attached positively charged branching groups selected from HIV-TAT and fragments thereof. 
     
     
         22 . A composition according to  claim 21  in which the branching groups are positively charged HIV-TAT fragments that have the formula (gly) p -RGRDDRRQRRR-(gly) q , (gly) p -YGRKKRRQRRR-(gly) q , or (gly) p -RKKRRQRRR-(gly) q , wherein the subscripts p and q are each independently an integer of from 0 to 20. 
     
     
         23 . A composition according to  claim 1  in which the positively charged branching groups comprise at least about 0.05% by weight of the total carrier weight. 
     
     
         24 . A composition according to  claim 1  in which the positively charged branching groups comprise from about 0.5% to about 45% by weight of the total carrier weight. 
     
     
         25 . A composition according to  claim 1  in which the positively charged branching groups comprise from about 0.1% to about 30% by weight of the total carrier weight. 
     
     
         26 . A composition according to  claim 1  in which the backbone comprises a positively charged oligopeptide. 
     
     
         27 . A composition method according to  claim 26  in which the backbone comprises a positively charged polylysine. 
     
     
         28 . A composition according to  claim 27  in which the polylysine has a molecular weight of from about 10,000 to 1,500,000. 
     
     
         29 . A composition according to  claim 27  in which the polylysine has a molecular weight of from about 25,000 to about 1,200,000. 
     
     
         30 . A composition according to  claim 27  in which the polylysine has a molecular weight of from about 100,000 to about 1,000,000. 
     
     
         31 . A composition according to  claim 1  in which the backbone comprises a positively charged nonpeptidyl carrier. 
     
     
         32 . A composition according to  claim 31  in which the backbone comprises a positively charged polyalkyleneimine. 
     
     
         33 . A composition according to  claim 32  in which the polyalkyleneimine is a polyethyleneimine. 
     
     
         34 . A composition according to  claim 33  in which the polyethyleneimine has a molecular weight of from about 10,000 to about 2,500,000. 
     
     
         35 . A composition according to  claim 33  in which the polyethyleneimine has a molecular weight of from about 100,000 to about 1,800,000. 
     
     
         36 . A composition according to  claim 33  in which the polyethyleneimine has a molecular weight of from about 500,000 to about 1,400,000. 
     
     
         37 . A method for reducing symptoms associated with a medical condition selected from the list consisting of dystonia, muscle spasms, autonomic nerve disorders, cerebrel palsy, Parkinson's disease, tremors, epilepsy, inner ear disorders, muscles disorders, nerve entrapment disorders, hyperhidrosis, acne, mucous, secretions, psoriasis, diabetes related cutaneous disorders, wound healing, mammary gland disorders, hair growth, urologic disorders, neuropshychiatric disorders, cancer and hypercalcemia comprising administering a therapeutically effective amount of the composition of  claim 1 . 
     
     
         38 . A method according to  claim 37  further comprising administering the composition to a region of the body selected from the group consisting of scalp, face, neck, shoulders, arms, axilla, hands, palms of the hands, back, legs, feet and soles of the feet. 
     
     
         39 . A method according to  claim 38  in which the medical condition subjective or clinical hyperhidrosis. 
     
     
         40 . A method according to  claim 39  in which the composition is administered to the axilla. 
     
     
         41 . A method according to  claim 39  in which the composition is administered to the face. 
     
     
         42 . A method according to  claim 39  in which the composition is administered to the forehead. 
     
     
         43 . A method according to  claim 39  in which the composition is administered to the palms of the hand. 
     
     
         44 . A method according to  claim 39  in which the composition is administered to the soles of the feet. 
     
     
         45 . A compound comprising an oligopeptide of from 7 to about 20 amino acids, said oligopeptide comprising the amino acid sequence of SEQ ID NO: 1. 
     
     
         46 . The compound according to  claim 45  wherein the oligopeptide is from 8 to about 20 amino acids. 
     
     
         47 . The compound according to  claim 45  wherein the oligopeptide is from 9 to about 20 amino acids. 
     
     
         48 . The compound according to  claim 45  wherein the oligopeptide is from 10 to about 20 amino acids. 
     
     
         49 . A method for reducing symptoms associated with a medical condition selected from the list consisting of dystonia, muscle spasms, autonomic nerve disorders, cerebrel palsy, Parkinson's disease, tremors, epilepsy, inner ear disorders, muscles disorders, nerve entrapment disorders, hyperhidrosis, acne, mucous, secretions, psoriasis, diabetes related cutaneous disorders, wound healing, mammary gland disorders, hair growth, urologic disorders, neuropshychiatric disorders, cancer and hypercalcemia comprising administering a therapeutically effective amount of the compound of  claim 45 . 
     
     
         50 . A method according to  claim 49  further comprising administering the compound to a region of the body selected from the group consisting of scalp, face, neck, shoulders, arms, axilla, hands, palms of the hands, back, legs, feet and soles of the feet. 
     
     
         51 . A method according to  claim 50  in which the medical condition subjective or clinical hyperhidrosis. 
     
     
         52 . A method according to  claim 51  in which the compound is administered to the axilla. 
     
     
         53 . A method according to  claim 51  in which the compound is administered to the face. 
     
     
         54 . A method according to  claim 51  in which the compound is administered to the forehead. 
     
     
         55 . A method according to  claim 51  in which the compound is administered to the palms of the hand. 
     
     
         56 . A method according to  claim 51  in which the compound is administered to the soles of the feet. 
     
     
         57 . A kit for topically administering to a subject an effective amount of the composition comprising an oligopeptide of from 6 to about 20 amino acids, said oligopeptide comprising the amino acid sequence of SEQ ID NO: 1, the kit comprising said composition and a positively charged carrier having attached positively charged branching groups independently selected from -(gly) n1 -(arg) n2 , HIV-TAT. Antennapedia PTD, and fragments of HIV-TAT or of Antennapedia PTD or mixtures thereof, in which the subscript n1 is an integer of from 0 to about 20, and the subscript n2 is independently an odd integer of from about 5 to about 25 compound of  claim 45 . 
     
     
         58 . A kit according to  claim 57  further comprising a custom applicator. 
     
     
         59 . A kit according to  claim 58  in which the custom applicator is designed for use by a health care professional. 
     
     
         60 . A kit according to  claim 58  in which the custom applicator is designed for self-administration by a subject. 
     
     
         61 . A kit according to  claim 57  comprising a pre-formulated composition comprising the compound and the carrier. 
     
     
         62 . A kit according to  claim 57  in which the compound and the carrier are separately formulated for combining prior to administration. 
     
     
         63 . A kit according to  claim 57  in which the compound is contained in a device for administering the compound to a subject via the skin. 
     
     
         64 . A kit according to  claim 63  in which the device is a skin patch. 
     
     
         65 . A kit according to  claim 57  wherein the carrier further comprises a polymeric backbone having attached positively charged branching groups, wherein the association between the carrier and the compound is non-covalent. 
     
     
         66 . A kit according to  claim 65  wherein the attached positively charged branching groups are independently selected from -(gly) n1 -(arg) n2 , IIIV-TAT and fragments thereof, and Antennapedia PTD or mixtures thereof, in which the subscript n1 is an integer of from 0 to about 20, and the subscript n2 is independently an odd integer of from about 5 to about 25. 
     
     
         67 . A kit according to  claim 66  in which the compound is contained in a device for administering the oligopeptide to a subject via the skin. 
     
     
         68 . A kit according to  claim 67  in which the device is a skin patch.