# US 5,707,641 A · Formulations comprising therapeutically-active proteins or polypeptides > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,707,641 A - Document ID: US5707641A - Status: Granted - Kind: A - Application number: 08/322,154 - Filed: 1994-10-13 - Granted: 1998-01-13 - Earliest claimed: 1994-10-13 - Assignees: Pharmaderm Research & Development Ltd. - Inventors: Avi Gertner; Yosef Rubinstein - Web page: https://patentgrep.com/patent/US5707641A ## CPC - A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids - A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)} - A61K 9/7023: {Transdermal patches and similar drug-containing composite devices, e.g. cataplasms (galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006)} - A61K 38/26: Glucagons - A61K 38/28: Insulins - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract A pharmaceutical formulation which is adapted particularly for transdermal administration, and which comprises an aqueous emulsion or dispersion including, in addition to the aqueous phase, at least ingredients (a) and (b) of ingredients (a), (b) and (c): (a) as active ingredient, at least one therapeutically active protein or polypeptide; (b) at least one pharmaceutically acceptable emulsifier; (c) an oil phase comprising or consisting essentially of at least one ester of an aliphatic hydroxy compound containing 1-12 carbon atoms and 1-4 alcoholic hydroxy groups with an aliphatic carboxylic acid containing 8-24 carbon atoms and 1-3 carboxylic acid groups; provided that the therapeutic activity of the active ingredient in the formulation is such that the presence or the therapeutic effect of the active ingredient is detectable in the bloodstream within less than two hours after commencing transdermal administration, and further provided that when the active ingredient comprises insulin, the insulin is subjected to a pretreatment under predetermined conditions, prior to incorporation in the formulation. ## Claims ### Claim 1 A pharmaceutical formulation which is adapted particularly for transdermal administration, and which comprises an aqueous emulsion or dispersion including, in addition to the aqueous phase, at least the following ingredients (a), (b) and (c): (a) an active ingredient which comprises insulin; (b) at least one pharmaceutically acceptable emulsifier; (c) an oil phase comprising at least one ester of an aliphatic hydroxy compound containing 1-12 carbon atoms and 1-4 alcoholic hydroxy groups with an aliphatic carboxylic acid containing 8-24 carbon atoms and 1-3 carboxylic acid groups; provided that the therapeutic activity of said active ingredient is such that the presence or the therapeutic effect of said active ingredient is detectable in the bloodstream in less than two hours after commencing transdermal administration of said formulation, and further provided that said insulin has been subjected to a pretreatment under predetermined conditions above refrigeration temperature, prior to incorporation in said formulation, said pretreatment being sufficient to produce said therapeutic activity. ### Claim 2 (depends on 1) A pharmaceutical formulation according to claim 1, wherein the activity of the insulin therein is such that in a bioassay based on subcutaneous injection of no more than 0.2 iu insulin/kg in healthy rabbits, including a control bioassay, the formulation is capable of exhibiting a peak of reduction of the blood glucose concentration, compared with the control, within no more than one hour from the time of injection. ### Claim 3 (depends on 2) A pharmaceutical formulation according to claim 2, wherein said peak of reduction is at least 50% below the control value of blood glucose concentration. ### Claim 4 (depends on 1) A pharmaceutical formulation according to claim 1, wherein said at least one ester is selected from the group consisting of monoglycerides, diglycerides and triglycerides of monocarboxylic acids selected from the group consisting of saturated monocarboxylic acids and monocarboxylic acids containing ethylenic unsaturation. ### Claim 5 (depends on 1) A pharmaceutical formulation according to claim 1, wherein said pharmaceutically acceptable emulsifier contains at least one esterified carboxylic group in its structure. ### Claim 6 (depends on 5) A pharmaceutical formulation according to claim 5, wherein said pharmaceutically acceptable emulsifier is selected from the group consisting of lecithin and polyoxyethylene sorbitan monocarboxylate esters. ### Claim 7 A pharmaceutical formulation which is adapted particularly for transdermal administration, and which comprises at least one carrier, diluent or adjuvant, together with insulin as active ingredient, provided that said insulin has been subjected to a pretreatment under predetermined conditions above refrigeration temperature sufficient to cause its therapeutic activity to be such that the presence or the therapeutic effect of said active ingredient is detectable in the bloodstream in less than two hours after commencing transdermal administration of said formulation; and provided further that said formulation does not contain didecanoyl-.alpha.-phosphatidyl choline. ### Claim 8 (depends on 7) A pharmaceutical formulation according to claim 7, wherein the activity of the insulin therein is such that in a bioassay based on subcutaneous injection of no more than 0.2 iu insulin/kg in healthy rabbits, including a control bioassay, the formulation is capable of exhibiting a peak of reduction of the blood glucose concentration, compared with the control, within no more than one hour from the time of injection. ### Claim 9 (depends on 8) A pharmaceutical formulation according to claim 8, wherein said peak of reduction is at least 50% below the control value of blood glucose concentration. ### Claim 10 (depends on 1) A matrix for transdermal administration of at least one active ingredient which comprises insulin, which comprises a porous, absorbent, perforate and flexible monolaminar or polylaminar solid support, having absorbed thereon a pharmaceutical formulation according to claim 1. ### Claim 11 (depends on 7) A matrix for transdermal administration of a pharmaceutical formulation containing insulin, which comprises a porous, absorbent, perforate and flexible monolaminar or polylaminar solid support, having absorbed thereon a pharmaceutical formulation according to claim 7. ### Claim 12 (depends on 1) A method for controlling glucose concentration in the blood of a diabetic patient, which comprises transdermally administering to said patient a pharmaceutical formulation according to claim 1. ### Claim 13 (depends on 12) A method according to claim 12, wherein said transdermal administration is effected by applying to the skin of the patient a matrix which comprises a porous, absorbent, perforate and flexible monolaminar or polylaminar solid support, having absorbed thereon said pharmaceutical formulation. ### Claim 14 (depends on 7) A method for controlling glucose concentration in the blood of as diabetic patient, which comprises administering to the patient a pharmaceutical formulation according to claim 7. ### Claim 15 (depends on 14) A method according to claim 14, wherein said pharmaceutical formulation is administered to the patient transdermally. ### Claim 16 (depends on 15) A method according to claim 15, wherein said transdermal administration is effected by applying to the skin of the patient a matrix which comprises a porous, absorbent, perforate and flexible monolaminar or polylaminar solid support, having absorbed thereon said pharmaceutical formulation. ### Claim 17 A pharmaceutical formulation which is adapted particularly for transdermal administration, and which comprises an aqueous emulsion or dispersion including, in addition to the aqueous phase, at least the following ingredients (a) and (b): (a) an active ingredient comprising insulin; and (b) at least one pharmaceutically acceptable emulsifier; provided that the formulation excludes didecanoyl-.alpha.-phosphatidyl choline, that the therapeutic activity of said active ingredient in said formulation is such that the presence or the therapeutic effect of said active ingredient is detectable in the bloodstream in less than two hours after commencing transdermal administration of said formulation, and provided that said insulin has been subjected to a pretreatment under predetermined conditions above refrigeration temperature, prior to incorporation of said insulin in said formulation, said pretreatment being sufficient to produce said therapeutic activity. ### Claim 18 (depends on 17) A pharmaceutical formulation according to claim 17, wherein the activity of said insulin is such that in a bioassay based on subcutaneous injection of no more than 0.2 iu insulin/kg in healthy rabbits, including a control bioassay, said formulation is capable of exhibiting a peak of reduction of the blood glucose concentration, compared with the control, within no more than one hour from the time of injection of said formulation. ### Claim 19 (depends on 18) A pharmaceutical formulation according to claim 18, wherein said peak of reduction is at least 50% below the control value of blood glucose concentration. ### Claim 20 (depends on 17) A pharmaceutical formulation according to claim 17, wherein said at least one ester is selected from the group consisting of monoglycerides, diglycerides and triglycerides of monocarboxylic acids selected from the group consisting of saturated monocarboxylic acids and monocarboxylic acids containing ethylenic unsaturation. ### Claim 21 (depends on 17) A pharmaceutical formulation according to claim 17, wherein said pharmaceutically acceptable emulsifier contains at least one esterified carboxylic group in its structure. ### Claim 22 (depends on 21) A pharmaceutical formulation according to claim 21, wherein said pharmaceutically acceptable emulsifier is selected from the group consisting of lecithin and polyoxyethylene sorbitan monocarboxylate esters. ### Claim 23 (depends on 17) A matrix for transdermal administration of insulin, which comprises a porous, absorbent, perforate and flexible monolaminar or polylaminar solid support, having absorbed thereon a pharmaceutical formulation according to claim 17. ### Claim 24 (depends on 17) A method for controlling glucose concentration in the blood of as diabetic patient, which comprises administering to the patient a pharmaceutical formulation according to claim 17. ### Claim 25 (depends on 24) A method according to claim 24, wherein said pharmaceutical formulation is administered to said patient transdermally. ### Claim 26 (depends on 25) A method according to claim 25, wherein said transdermal administration is effected by applying to the skin of said patient a matrix which comprises a porous, absorbent, perforate and flexible monolaminar or polylaminar solid support, having absorbed thereon said pharmaceutical formulation. ### Claim 27 A pharmaceutical formulation which is adapted particularly for transdermal administration, and which comprises an aqueous emulsion or dispersion including, in addition to the aqueous phase, an active ingredient which comprises insulin which is stably dissociated into dimers and/or monomers and/or in which insulin-metal bonds are split or weakened, and substituted insulin or short-acting insulin preparations, wherein the therapeutic activity of said active ingredient is such that the presence or the therapeutic effect of said active ingredient is detectable in the bloodstream in less than two hours after commencing transdermal administration of said formulation.