Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin
First Claim
1. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)7-O-hexanoic acid conjugate, said composition:
- (a) comprising a water-in-oil (w/o) microemulsion including;
(i) a lipophilic component; and
(ii) a hydrophilic component; and
(iii) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)7-O-hexanoic acid conjugates; and
(b) having an HLB value between 3 and 7.
4 Assignments
0 Petitions
Accused Products
Abstract
A therapeutic formulation comprising a microemulsion of a therapeutic agent in free and/or conjugatively coupled form, wherein the microemulsion comprises a water-in-oil (w/o) microemulsion including a lipophilic phase and a hydrophilic phase, and has a hydrophilic and lipophilic balance (HLB) value between 3 and 7, wherein the therapeutic agent may for example be selected from the group consisting of insulin, calcitonin, ACTH, glucagon, somatostatin, somatotropin, somatomedin, parathyroid hormone, erythropoietin, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, non-naturally occurring opioids, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminease, adenosine deaminase, ribonuclease, trypsin, chymotrypsin, papain, Ara-A (Arabinofuranosyladenine), Acylguanosine, Nordeoxyguanosine, Azidothymidine, Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine Floxuridine, 6-Mercaptopurine, Doxorubicin, Daunorubicin, or I-darubicin, Erythromycin, Vancomycin, oleandomycin, Ampicillin; Quinidine and Heparin. In a particular aspect, the invention comprises an insulin composition suitable for parenteral as well as non-parenteral administration, preferably oral or parenteral administration, comprising insulin covalently coupled with a polymer including (i) a linear polyalkylene glycol moiety and (ii) a lipophilic moiety, wherein the insulin, the linear polyalkylene glycol moiety and the lipophilic moiety are conformationally arranged in relation to one another such that the insulin in the composition has an enhanced in vivo resistance to enzymatic degradation, relative to insulin alone. The microemulsion compositions of the invention are usefully employed in therapeutic as well as non-therapeutic, e.g., diagnostic, applications.
147 Citations
61 Claims
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1. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)7-O-hexanoic acid conjugate, said composition:
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(a) comprising a water-in-oil (w/o) microemulsion including;
(i) a lipophilic component; and
(ii) a hydrophilic component; and
(iii) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)7-O-hexanoic acid conjugates; and
(b) having an HLB value between 3 and 7. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
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11. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)7-O-hexanoic acid conjugate, said composition:
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(a) comprising a water-in-oil (w/o) microemulsion comprising;
(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;
(ii) a hydrophilic component comprising propylene glycol;
(iii) a surfactant component comprising lecithin and tween 80; and
(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)7-O-hexanoic acid conjugates in an aqueous solution; and
(b) having an HLB value between 3 and 7. - View Dependent Claims (12, 13, 14, 15, 16, 17, 18)
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19. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)7-O-hexanoic acid conjugate, said composition:
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(a) comprising a water-in-oil (w/o) microemulsion including;
(i) one or more lipophilic components selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids, and trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols;
(ii) a hydrophilic component comprising propylene glycol;
(iii) a surfactant comprising lecithin in a vegetable oil and/or tween 80; and
(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)7-O-hexanoic acid conjugates in a buffer solution; and
(b) having an HLB value between 3 and 7. - View Dependent Claims (20, 21, 22, 23, 24, 25, 26, 27, 36)
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28. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)7-O-hexanoic acid conjugate, said composition:
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(a) comprising a water-in-oil (w/o) microemulsion including;
(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;
(ii) a hydrophilic component comprising propylene glycol;
(iii) a surfactant comprising lecithin and mannitol; and
(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)7-O-hexanoic acid conjugates in a buffer solution; and
(b) having an HLB value between 3 and 7. - View Dependent Claims (29, 30, 31, 32, 33, 34, 35)
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37. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)7-O-hexanoic acid conjugate, said composition:
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(a) comprising a water-in-oil (w/o) microemulsion including;
(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;
(ii) a hydrophilic component comprising propylene glycol;
(iii) two or more surfactants, including lecithin and polyoxyethylene sorbitan monooleate; and
(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)7-O-hexanoic acid conjugates in a buffer solution; and
(b) having an HLB value between 3 and 7. - View Dependent Claims (38, 39, 40, 41, 42, 43, 44, 45)
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46. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)7-O-hexanoic acid conjugate, said composition:
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(a) comprising a water-in-oil (w/o) microemulsion including;
(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;
(ii) a hydrophilic component comprising propylene glycol esters;
(iii) two or more surfactants, including lecithin and sodium octanoate; and
(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)7-O-hexanoic acid conjugates in a buffer solution; and
(b) having an HLB value between 3 and 7. - View Dependent Claims (47, 48, 49, 50, 51, 52, 53)
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54. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)7-O-hexanoic acid conjugate, said composition:
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(a) comprising a water-in-oil (w/o) microemulsion including;
(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;
(ii) a hydrophilic component comprising propylene glycol esters;
(iii) a surfactant comprising lecithin; and
(iv) a therapeutically effective amount o insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)7-O-hexanoic acid coniugates in a buffer solution; and
(b) having an HLB value between 3 and 7. - View Dependent Claims (55, 56, 57, 58, 59, 60, 61)
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Specification