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BR-PI0817478-B1 - ORALLY BIOAVAILABLE COMPOSITION, METHOD FOR PRODUCING AN ORALLY BIOAVAILABLE COMPOSITION, AND KIT

Abstract

The present invention is configured by a composition capable of carrying a therapeutic or diagnostic agent, typically in a non-orally available form, through the digestive tract environment such that the therapeutic or diagnostic agent is bioavailable. The composition may or may not be targeted to specific cellular receptors, such as hepatocytes. Therapeutic agents include, but are not limited to, insulin, calcitonin, serotonin, and other proteins. The targeting is performed with biotin- or metal-based targeting agents.

Inventors

  • JOHN R. LAU
  • BLAIR W. GEHO

Assignees

  • SDG, INC. (AN OHIO CORPORATION)

Dates

Publication Date
20260317
Application Date
20080926
Priority Date
20070928

Claims (12)

  1. 1. An orally bioavailable composition, characterized in that it comprises gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and lipid particle, wherein said liposome, liposome fragment, and lipid particle are generated from a mixture of lipid components comprising disadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol, said composition further comprising a therapeutic or diagnostic agent and a biotin-derived bleaching agent, wherein the biotin-derived bleaching agent is biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentamido phosphate). hexanamido)ethyl) or biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate, wherein said gelatin actively and reversibly interacts with one or more of said constituents, wherein 5% to 50% of said additional constituents exhibit an average diameter equal to or less than 20 nanometers.
  2. 2. Composition according to claim 1, characterized in that said lipid components are further selected from the group consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol oleate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phosphorac-(1-glycerol)] (sodium salt), and 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxoexahydro- 1H-thieno[3,4-d]imidazol-4-yl) pentanamido)ethyl triethylammonium phosphate.
  3. 3. Composition according to claim 2, characterized in that said therapeutic agent is selected from the group consisting of insulin, interferon, erythropoietin, parathyroid hormone, calcitonin, serotonin, rituximab, trastuzumab, uricase, tissue plasminogen activator, thymoglobin, a vaccine, heparin or a heparin analogue, anitrombin III, filgrastin, pramilitide acetate, exanatide, epifibatide, antivenoms, IgG, IgM, HGH, thyroxine, GLP-1, blood coagulation factors VII and VIII, a monoclonal antibody, and glycolipids that act as therapeutic agents.
  4. 4. Composition according to claim 1, characterized in that said therapeutic agent is insulin.
  5. 5. Composition according to claim 1, characterized in that it comprises an additional biotin-derived bleaching agent selected from the group consisting of N-hydroxysuccinimide (NHS) biotin (2,5-dioxopyrrolidin-1-yl 5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentanoate); sulfo-NHS-biotin (2,5-dioxo-3(trioxidanylthio)pyrrolidin-1-yl sodium 5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentanoate); long-chain N-hydroxysuccinimide biotin (2,5-dioxopyrrolidin-1-yl 6-(5-((3aS,6aR)-2-oxoexahydro- 1H-thieno[3,4-d]imidazol-4-yl) hexanoate); long-chain sulfo-N-hydroxysuccinimide biotin (2,5-dioxo-3-(trioxidanylthio) sodium pyrrolidin-1-yl 6- (5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentamido) hexanoate; Biocytin (acid 2-amino-6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentamido) hexanoic acid); sulfo-N-hydroxysuccinimide-S-S-biotin (2,5-dioxo-3-(trioxidanylthio) pyrrolidin-1-yl 3-((2-(4-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)butylamino) ethyl)disulfanyl) propanoate); biotin-BMCC (4-((2,5-dioxy-2,5-dihydro-1H- pyrrol-1-yl)methyl)-N-(4-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentanamide)butyl) cyclohexanecarboxamide); biotin-HPDP (5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)-N-(6-(3-(pyridin-2-yldisulfanyl)propanamido) hexyl)pentanamide); iodoacetyl-LC-biotin (N-(6-(2-iodoacetamide)hexyl)-5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide); biotin-hydrazide (5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentahydrazide); biotin-LC-hydrazide (N-(6-hydrazinyl-6-oxohexyl)-5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide); biocytin hydrazide (N-(5-amino-6-hydrazinyl-6-oxohexyl)-5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide); cadaverine biotin (N-(5-aminopentyl)-5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4- d]imidazol-4-yl)pentanamide); Carboxybiotin ((3aS,6aR)-4-(4-carboxybutyl)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-1-carboxylic acid);photobiotin (N-(3-((3-(4-azido-2-nitrophenylamino)propyl)(methyl)amino)propyl)- 5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide);p-aminobenzoyl biotin trifluoroacetate (2- (4-aminobenzamido)-6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazole- 4-yl)pentanamido)hexanoic); p-diazobenzoyl biocytin (4-(1-carboxy-5-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido) pentylcarbamoyl) benzenediazonium chloride); 12-((biotinyl)amino)dodecanoic acid (12-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentanamido) dodecanoic acid); 12-((biotinyl)amino)dodecanoic acid succinimidyl ester (2,5-dioxopyrrolidin-1-yl 12-(5- ((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)dodecanoate); S-biotinyl homocysteine (4-mercapto-2-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)butanoic acid); biocytin-X (2-amino-6-(6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexamide)hexanoic acid; biocytin x-hydrazine (N-(5-amino-6- hydrazinyl-6-oxohexyl)-6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido) hexamide); biotinethylenediamine (N-(2-aminoethyl)-5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide); biotin-XL (6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentanamido) hexanoic acid); biotin-X-ethylenediamine (N-(2-aminoethyl)-6-(5- ((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanamide); biotin-XX hydrazide (N-(6-hydrazinyl-6-oxohexyl)-6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanamide); biotin-XX-SE (2,5-dioxopyrrolidin-1-yl 6-(6- (5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanamido) hexanoate); biotin-XX, SSE (2,5-dioxo-1-(6-(6-(5-((3aS, 6aR) -2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamido) hexanamido) hexanoyloxy) sodium pyrrolidine-3-sulfonate; biotin-X-cadaverine (2,2,2-5-(6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido) hexanamido)pentan-1-amino trifluoroacetate); α-(t-BOC)biocytin (2-(tert-butoxycarbonylamino)-6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentanamido)hexanoic acid); N-(biotinyl)-N'-(iodoacetyl) ethylenediamine (N-(2-(2-iodoacetamido)ethyl-5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide); DNP-X-biocytin-X-SE (2,5-dioxopyrrolidin-1-yl 2-(6-(6-(2,4-dinitrophenylamino)hexanamido)hexanamido)- 6-(6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanamido) hexanoate (N-(6-); hydrazinyl-6-oxohexyl)-5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide); norbiotinamine hydrochloride (4-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl) butan-1-amino chloride); 3-(N-maleimidylpropionyl) biocytin (2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamide)-6-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanoic acid); ARP (N'-(2-(aminooxy)acetyl)-5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentahydrazide); biotin-1-sulfoxide (5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoic acid sulfoxide); biotin methyl ester (methyl 5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate); biotin-maleimide (6-(2,5-dioxy-2,5-dihydro-1H-pyrrol-1-yl)-N’-(5-((3aS,6aR)-2- oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl) hexahydrazide); biotin- poly(ethylene glycol) amine - aminomethyl polyethylene (5-((3aS,6aR)-2- oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate); (+) sodium salt of biotin 4-amidobenzoic acid (4-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido) sodium benzoate); Biotin 2-N-acetylamino-2-de0oxy-β-D-glucopyranoside (((2R,5S)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)-2,3,4,5,6-pentamethyltetrahydro-2H-pyran-2-yl)methyl 5-((3aS,6aR)- 2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate); Biotin α-D-N- acetylneuraminide ((2S,5R)-5-acetamido-4-hydroxy-3,3,4,5,6-pentamethyl- 2-((5-((3aS,6aR)-2-oxohexahydro-1H-thieno [3,4-d]imidazol-4-yl) pentanoyloxy) methyl)-6-(1,2,3-trihydroxypropyl) tetrahydro-2H-pyran-2-carboxylic acid; Biotin-α- L-fucoside (((2R,5S)-3,4,5-trihydroxy-2,3,4,5,6,6-hexamethyltetrahydro-2H-pyran-2-yl)methyl 5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate); Biotin lacto-N-bioside; ((2R,5S)-3-acetamido-5-hydroxy-6-(hydroxymethyl)-2,3,4,6-tetramethyl-4-((((2S,5R)-3,4,5-trihydroxy-6-(hydroxymethyl)- 2,3,4,5,6-pentamethyltetrahydro-2H-pyran-2-yl)methoxy)methyl) tetrahydro-2H-pyran- 2-yl)methyl 5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate ((2R,5S)-3-acetamido-5-hydroxy-6-(hydroxymethyl)-2,3,4,6-tetramethyl-4-((((2S,5R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2,3,4,5,6-pentamethyltetrahydro-2H-pyran-2-yl)methoxy)methyl) tetrahydro-2H-pyran-2-yl)methyl 5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate; Biotin- Lewis-A trisaccharide (2R,3R,5S)-5-((((2S,3S,5S)-3-acetamido-5-hydroxy-6-(hydroxymethyl)-2,4,6-trimethyl-4-((((2S,5R)-3,4,5-trihydroxy-6-(hydroxymethyl)- 2,3,4,5,6-pentamethyltetrahydro-2H-pyran-2-yl)methoxy) methyl)tetrahydro-2H-pyran-2-yl)methoxy)methyl)-3,4-dihydroxy-2,4,5,6,6-pentamethyltetrahydro-2H-pyran-2-yl 5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate; Biotin- Lewis-Y tetrasaccharide; ((2S,5S)-3-acetamido-4-((((2R,5S)-5-((((2R,5S)-4,5-dihydroxy-6-(hydroxymethyl)-2,3,4,5,6-pentamethyl-3-((((2S,5S)-3,4,5-trihydroxy- 2,3,4,5,6,6-hexamethyltetrahydro-2H-pyran-2-yl)methoxy)methyl)tetrahydro-2H-pyran-2-yl)methoxy)methyl)-3,4-dihydroxy-2,3,4,5,6,6-hexamethyltetrahydro-2H-pyran-2- yl)methoxy)methyl)-5-hydroxy-6-(hydroxymethyl)-2,3,4,5,6-pentamethyltetrahydro-2H-pyran-2-yl 5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate); Biotin-α-D-mannopyranoside (((1R,4R)-2,3,4-trihydroxy-5-(hydroxymethyl)-1,2,3,4,5-pentamethylcyclohexyl)methyl 5-((3aS,6aR)-2-oxoexahydro- 1H-thieno[3,4-d]imidazol-4-yl)pentanoate); biotin 6-O-phospho-α-D-mannopyranoside (((2R,5S)-3,4,5-trihydroxy-2,3,4,5,6-pentamethyl-6-(phosphonooxymethyl) tetrahydro-2H-pyran-2-yl)methyl 5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate; and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(biotinyl), iminobiotin derivatives of the aforementioned compounds, and mixtures thereof.
  6. 6. Composition according to claim 1, characterized in that said biotin-derived bleaching agent is biotin DHPE or biotin-X-DHPE and said therapeutic agent is insulin.
  7. 7. Method for producing an orally bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and a particle, wherein said liposome, liposome fragment, and particle are generated from a mixture of lipid components comprising disadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol, said composition further comprising a therapeutic or diagnostic agent and a biotin-derived bleaching agent, wherein said biotin-derived bleaching agent is biotin-X-DHPE or biotin DHPE, wherein 5% to 50% of said additional constituents exhibit an average diameter equal to or less than 20 nanometers, wherein said gelatin actively and reversibly interacts with one or more of said constituents, characterized in that it comprises the steps of: a. a. Mix said lipid components and said bleaching agent in an aqueous medium to form a first mixture through a microfluidization process; b. Add said therapeutic or diagnostic agent to said first mixture to form a second mixture; c. Add said second mixture to gelatin to form an associated gelatin mixture; d. Dry said associated gelatin mixture.
  8. 8. Method according to claim 7, characterized in that a. said lipid components are further selected from the group consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol oleate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl-sn-glycero-3-[phosphorac-(1-glycerol)] (sodium salt), and 2,3-diacetoxypropyl 2-(5- ((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentamido)ethyl triethylammonium phosphate; and b. said therapeutic agent is selected from the group consisting of insulin, interferon, erythropoietin, parathyroid hormone, calcitonin, serotonin, rituximab, trastuzumab, uricase, tissue plasminogen activator, thymoglobin, a vaccine, heparin or a heparin analogue, anitrombin III, filgrastin, pramilitide acetate, exanatide, epifibatide, antivenoms, IgG, IgM, HGH, thyroxine, GLP-1, blood coagulation factors VII and VIII, a monoclonal antibody, and glycolipids that act as therapeutic agents.
  9. 9. Method according to claim 8, characterized in that said therapeutic agent is insulin.
  10. 10. Composition according to claim 1, characterized in that said lipid components are 1,2-distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate, and cholesterol; and said therapeutic agent is insulin.
  11. 11. Kit, characterized in that it comprises: a. an orally bioavailable composition comprising gelatin and additional constituents, said constituents comprising a dynamically sized liposome, liposome fragment, and lipid particle, wherein said liposome, liposome fragment, and lipid particle are generated from a mixture of lipid components comprising disadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol, said composition further comprising a therapeutic or diagnostic agent and, optionally, a bleaching agent, wherein said biotin-derived bleaching agent is biotin-X-DHPE or biotin DHPE, wherein 5% to 50% of said additional constituents exhibit an average diameter equal to or less than 20 nanometers, wherein said gelatin actively and reversibly interacts with one or more of said constituents; eb. instructional material for administering said composition to a human being.
  12. 12. Kit according to claim 11, characterized in that it further comprises insulin for co-administration with said composition in said human being.

Description

FUNDAMENTALS OF THE INVENTION [001] One of the most preferred means of delivering a pharmaceutical product to an individual is in an oral formulation. However, oral formulations of many pharmaceutical compounds are often unavailable due to the pharmaceutical's incompatibility with the hostile environment of the digestive tract. This is particularly true in the case of pharmaceutical compounds such as peptides, proteins, certain small molecules, and nucleic acids. [002] An oral formulation of a protein such as insulin would be highly desirable. To present strategies for normalizing blood glucose levels in Type I and Type II diabetic patients using subcutaneous insulin administration in various time-release formulations, such as ultralente insulin and NPH humulin. The use of these formulations delays and subsequently controls insulin biodistribution by regulating drug release in tissues. Sustained insulin management leads to better glucose control and the need for fewer injections during the course of the disease. Unfortunately, multiple painful injections are still necessary because these formulations fail to provide sustained insulin levels in the diabetic individual. [003] Many other important medications are also not currently available in oral formulations. Examples include calcitonin, serotonin, parathyroid hormone, GLP-1, erythropoietin, various types of interferon, human growth hormone, monoclonal antibodies, and many others, the uses of which have been extensively discussed in the literature. [004] What is needed in the field of oral drug delivery is a composition that allows the oral release of a wide range of pharmaceutical products and other therapeutic agents. The present invention meets and addresses this need. BRIEF SUMMARY OF THE INVENTION [005] The present invention includes compositions that facilitate and/or enable the absorption of therapeutic products that are typically not orally bioavailable. In one embodiment, a composition of the invention works by associating with a therapeutic agent and accompanying the therapeutic agent through the intestinal lumen into the portal bloodstream and ultimately into the systemic circulation. In certain embodiments, the composition of the invention possesses many unique and advantageous properties. One of these properties is the ability to insert into intercellular spaces and pass through the mammalian intestine into the portal circulation. In certain embodiments, a composition of the invention can be targeted to specific cellular or extracellular receptors through one or more targeting agents. [006] In a typical embodiment, an orally bioavailable composition of the invention comprises gelatin and additional constituents. The additional constituents comprise a dynamically tailored liposome, liposome fragment, and lipid particles, wherein the lipid particle comprises at least one lipid component and the liposome or liposome fragment comprises at least two lipid components. The composition further comprises at least one therapeutic or diagnostic agent and, optionally, at least one bleaching agent. The gelatin actively and reversibly interacts with one or more of the constituents in the composition of the invention. [007] In certain embodiments, the lipid components are selected from the group consisting of MPB-PE, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol, cholesterol oleate, dihexadecyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, 1,2-dimyristoyl-sn-glycero-3-phosphate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dipalmitoyl- sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt), and 2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxoexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentanamido)ethyl triethylammonium phosphate. [008] In certain embodiments, the therapeutic agent is selected from the group consisting of insulin, interferon, erythropoietin, parathyroid hormone, calcitonin, serotonin, rituximab, trastuzumab, uricase, tissue plasminogen activator, thymoglobin, a vaccine, heparin or a heparin analogue, anitrombin III, filgrastin, pramilitide acetate, exanatide, epifibatide, antivenoms, IgG, IgM, HGH, thyroxine, GLP-1, blood coagulation factors VII and VIII, a monoclonal antibody, and glycolipids that act as therapeutic agents. [009] In a preferred embodiment, the therapeutic agent is insulin. [0010] In certain embodiments, the bleaching agent comprises a metal-derived bleaching agent or a biotin-derived bleaching agent. [0011] In a sub-embodiment, the metal-derived bleaching agent comprises a metal and at least one complexing agent. Preferably, the metal in the metal-derived bleaching agent is selected from the group consisting of a transition metal, an internal transition metal and an adjacent transition metal, and at least one complexing agent