Details for Patent: 5,817,644

Title:	Targeting of dosages of medicine and therapeutic agents
Abstract:	A method of treating a disease or condition in a human treatable by a medicine and/or therapeutic agent which may be transported by an agent to the site in need of treatment in the body and which agent may also transport the medicine and/or therapeutic agent to the liver (by for example, the transport agent binding to receptors on the liver) is provided comprising: (a) administering an effective non-toxic amount of a first agent which does not bind to receptors at the site in need of treatment but which binds with receptors of the liver thereby "down regulating" the liver; and, (b) thereafter administering an effective non-toxic amount of a medicine and/or therapeutic agent and an effective amount of a second agent which is a transport agent and is a different agent from the first agent which binds to the site in need of treatment and would be capable of binding to the sites of the liver if the liver had not been "down regulated" so that its binding capacity for the second agent has been substantially reduced by the up-take by the liver of the first agent administered under sub-paragraph (a) by for example, binding with the scavenger receptors of the liver.
Inventor(s):	Gustafson; Stefan (Mississauga, CA)
Assignee:	Hyal Pharmaceutical Corporation (Mississauga, CA)
Filing Date:	Dec 07, 1995
Application Number:	08/568,489
Claims:	1. A method of treating a disease or condition in a human treatable by a medicinal or therapeutic agent which may be transported by an agent to the site in need of treatment in the body and which agent may also transport the medicinal or therapeutic agent to the liver comprising: (a) administering an effective non-toxic amount of a first agent which does not bind to receptors at the site in need of treatment but which binds with receptors of the liver thereby "down regulating" the liver, wherein the first agent selected from glycosaminoglycans, except forms of hyaluronic acid; Keratan sulphate; and acetylated low density lipoproteins: and, (b) thereafter administering during the time the liver receptors are down-regulated by the first agent, an effective non-toxic amount of a medicinal or therapeutic agent and an effective amount of a second agent which is a transport agent and is a different agent from the first agent and which second agent binds to the site in need of treatment and would be capable of binding to the sites of the liver if the liver had not been "down regulated" so that its binding capacity for the second agent has been substantially reduced by the up-take by the liver of the first agent administered under sub-paragraph (a) by binding with the scavenger receptors of the liver, wherein the second agent is selected from a form of hyaluronic acid. 2. The method of claim 1 wherein the first agent is a glycosaminoglycan which is not a form of hyaluronic acid having a molecular weight less than 750,000 daltons. 3. The method of claim 1 wherein the first agent is chondroitin sulphate. 4. The method of claim 3 wherein the second agent (transport agent) is a form of hyaluronic acid having a molecular weight less than 750,000 daltons. 5. The method of claim 4 wherein the form of hyaluronic acid is selected from the group consisting of hyaluronic acid (hyaluronan) and a pharmaceutically acceptable salt thereof. 6. The method of claim 4 wherein the amount of chondroitin sulphate exceeds about 3-5 mg./kg of the human. 7. The method of claim 1, 3, or 6 wherein the second agent is an effective amount of the form of hyaluronic acid having a molecular weight less than 750,000 daltons. 8. A method of protecting the liver from taking up medicinal or therapeutic agents toxic to the liver and which are to be administered to a patient comprising: (a) administering an effective amount of a first agent which does not bind to receptors at the site in need of treatment but which binds with receptors of the liver thereby "down regulating" the liver, wherein the first agent selected from glycosaminoglycans, except forms of hyaluronic acid; Keratan sulphate; and acetylated low density lipoproteins; and, (b) thereafter administering during the time the liver receptors are down-regulated by the first agent, an effective amount of a medicinal or therapeutic agent and an effective amount of a second agent which is a transport agent and is a different agent from the first agent and which second agent is a transport agent which binds to the site in need of treatment and would be capable of binding to the sites of the liver if the liver had not been "down regulated" so that its binding capacity for the second agent has been substantially reduced by the up-take by the liver of the first agent administered under sub-paragraph (a) by binding with the scavenger receptors of the liver, said second agent being selected from a form of hyaluronic acid. 9. The method of claim 8 wherein the first agent is chondroitin sulphate and the second agent is a form of hyaluronic acid. 10. The method of claim 9 wherein the form of hyaluronic acid is selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof having a molecular weight less than 750,000 daltons. 11. The method of claim 10 wherein the amount of chondroitin sulphate exceeds 3-5 mg./kg. 12. The method of claim 11 wherein the effective amount of the form of hyaluronic acid exceeds 0.1 mg. 13. The method of claim 8 or 9wherein the effective amount of the form of hyaluronic acid has a molecular weight less than 750,000 daltons. 14. A dosage kit for maximizing the amount of medicinal or therapeutic agent to be delivered to a site in the body in need of treatment and for protecting the liver from taking up the medicinal or therapeutic agent when the medicinal or therapeutic agents must be delivered to treat sites other than the liver, comprising: (a) an effective dosage amount of a first agent which does not bind to receptors at the site in need of treatment but which binds with receptors of the liver to thereby "down regulate" the liver, wherein the first agent selected from glycosaminoglycans, except forms of hyaluronic acid; Keratan sulphate; and acetylated low density lipoproteins; (b) a separate effective dosage amount, separate from the dosage amount in subparagraph (a), comprising an effective non-toxic amount of a medicinal or therapeutic agent and an effective amount of a second agent which is a transport agent and is a different agent from the first agent and which second agent binds to the site in need of treatment and would be capable of binding to the sites of the liver if the liver is not down regulated so that its binding capacity for the second agent has been substantially reduced by the up-take by the liver of the first agent when the second agent is administered after the dosage amount under sub-paragraph (a) is administered, said second agent being selected from a form of hyaluronic acid. 15. The dosage kit of claim 14 wherein the first agent is chondroitin sulphate and the second agent is a form of hyaluronic acid. 16. The dosage kit of claim 15 wherein the form of hyaluronic acid is selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof having a molecular weight less than 750.000 daltons. 17. The dosage kit of claim 16 wherein the amount of chondroitin sulphate exceeds about 3-5 mg. of the body. 18. The dosage kit of claim 17 wherein the amount of the form of hyaluronic acid exceeds 0.1 mg. 19. The dosage kit of claim 14 or 15 wherein the form of hyaluronic acid has a molecular weight less than 750,000 daltons. 20. A method of treating a disease or condition in a human treatable by a medicinal or therapeutic agent which may be transported by an agent to the site in need of treatment in the body and which agent may also transport the medicinal or therapeutic agent to the liver comprising: (a) administering an effective non-toxic amount of a first agent which does not bind to receptors at the site in need of treatment but which binds with receptors of the liver thereby "down regulating" the liver, wherein the first agent selected from glycosaminoglycans, except forms of hyaluronic acid; Keratan sulphate; and acetylated low density lipoproteins; and, (b) thereafter administering during the time the liver receptors are down-regulated by the first agent, an effective non-toxic amount of a medicinal or therapeutic agent which is substantially less than the amount normally considered effective and an effective amount of a second agent which is a transport agent and is a different agent from the first agent and which second agent would bind to the site in need of treatment and would be capable of binding to the sites of the liver if the liver had not been "down regulated" so that its binding capacity for the second agent has been substantially reduced by the up-take by the liver of the first agent administered under sub-paragraph (a) by binding with the scavenger receptors of the liver and which effective non-toxic amount of the second agent is in an effective amount which is substantially less than the amount normally considered effective, wherein the second agent is selected from a form of hyaluronic acid. 21. The method of claim 20 wherein the first agent is a glycosaminoglycan which is not a form of hyaluronic acid. 22. The method of claims 20 or 21 wherein the first agent is chondroitin sulphate. 23. The method of claim 22 wherein the second agent (transport agent) is a form of hyaluronic acid having a molecular weight less than 750,000 daltons. 24. The method of claim 23 wherein the form of hyaluronic acid is selected from the group consisting of hyaluronic acid (hyaluronan) and a pharmaceutically acceptable salt thereof having a molecular weight less than 750,000 daltons and greater than 150,000 daltons. 25. The method of claim 23 wherein the amount of chondroitin sulphate exceeds about 3-5 mg./kg of the human. 26. The method of claim 20 or 25 wherein the second agent is an effective amount exceeding about 20 .mu.g/kg of body weight of the patient of the form of hyaluronic acid having a molecular weight less than 750,000 daltons. 27. A method of protecting the liver from taking up medicinal or therapeutic agents toxic to the liver comprising: (a) administering an effective amount of a first agent which does not bind to receptors at the site in need of treatment but which binds with receptors of the liver thereby "down regulating" the liver, wherein the first agent selected from glycosaminoglycans, except forms of hyaluronic acid; Keratan sulphate; and acetylated low density lipoproteins; and, (b) thereafter administering during the time the liver receptors are down-regulated by the first agent, an effective amount of a medicinal or therapeutic agent which is substantially less than the amount normally used and an effective amount of a second agent which is a transport agent and is a different agent from the first agent and which second agent is a transport agent which binds to the site in need of treatment and would be capable of binding to the sites of the liver if the liver had not been "down regulated" so that its binding capacity for the second agent has been substantially reduced by the up-take by the liver of the first agent administered under sub-paragraph (a) by binding with the scavenger receptors of the liver and which effective amount of the second agent is in an effective amount which is substantially less than the amount normally considered effective, wherein the second agent is selected from a form of hyaluronic acid. 28. The method of claim 27 wherein the first agent is chondroitin sulphate and the second agent is a form of hyaluronic acid. 29. The method of claim 28 wherein the form of hyaluronic acid is selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof having a molecular weight less than 750,000 daltons. 30. The method of claim 29 wherein the amount of chondroitin sulphate exceeds 3-5 mg./kg. 31. The method of claim 30 wherein the effective amount of the form of hyaluronic acid exceeds 0.1 mg. 32. The method of claim 27 or 30 wherein the effective amount of the form of hyaluronic acid has a molecular weight less than 750,000 daltons and is an amount exceeding about 20 .mu.g/kg of body weight of a patient. 33. A dosage kit for maximizing the amount of medicinal or therapeutic agent to be delivered to a site in the body in need of treatment and for protecting the liver from taking up the medicinal or therapeutic agent when medicinal or therapeutic agents must be delivered to treat sites other than the liver, comprising: (a) an effective dosage amount of a first agent which does not bind to receptors at the site in need of treatment but which binds with receptors of the liver to thereby "down regulate" the liver, wherein the first agent selected from glycosaminoglycans, except forms of hyaluronic acid; Keratan sulphate; and acetylated low density lipoproteins; (b) a separate effective dosage amount, separate from the dosage amount in subparagraph (a) comprising an effective non-toxic amount of a medicinal or therapeutic agent which is substantially less than the amount normally considered effective and an effective amount of a second agent which is a transport agent and is a different agent from the first agent and which second agent would bind to the site in need of treatment and would be capable of binding to the sites of the liver if the liver is not down regulated so that its binding capacity for the second agent has been substantially reduced by the up-take by the liver of the first agent when administered after the dosage amount under sub-paragraph (a) is administered and which effective non-toxic amount of the second agent is in an effective amount which is substantially less than the amount normally considered effective, wherein the second agent is selected from a form of hyaluronic acid. 34. The dosage kit of claim 33 wherein the first agent is chondroitin sulphate and the second agent is a form of hyaluronic acid. 35. The dosage kit of claim 34 wherein the form of hyaluronic acid is selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof having a molecular weight less than 750,000 daltons. 36. The dosage kit of claim 35 wherein the amount of chondroitin sulphate exceeds about 3-5 mg. 37. The dosage kit of claim 36 wherein the amount of the form of hyaluronic acid exceeds 0.1 mg. 38. The dosage kit of claim 33 or 36 wherein the effective amount of the form of hyaluronic acid has a molecular weight less than 750,000 daltons. 39. A method of preventing metastases in a person suffering from cancer comprising: (a) administering an effective amount of a first agent which does not bind to receptors at the site in need of treatment but which binds with receptors of the liver thereby "down regulating" the liver, wherein the first agent selected from glycosaminoglycans, except forms of hyaluronic acid; Keratan sulphate; and acetylated low density lipoproteins; and, (b) thereafter administering during the time the liver receptors are down-regulated by the first agent, an effective amount of a medicinal or therapeutic agent and an effective amount of a second agent which is a transport agent and is a different agent from the first agent and which second agent is a transport agent which binds to the site in need of treatment and transports to the interstitial fluid, lymph and nodes and would be capable of binding to the sites of the liver if the liver had not been "down regulated" so that its binding capacity for the second agent has been substantially reduced by the up-take by the liver of the first agent administered under sub-paragraph (a) by binding with the scavenger receptors of the liver, wherein the second agent is selected from a form of hyaluronic acid. 40. The method of claim 39 wherein the first agent is chondroitin sulphate and the second agent is a form of hyaluronic acid. 41. The method of claim 40 wherein the form of hyaluronic acid is selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof having a molecular weight less than 750,000 daltons. 42. The method of claim 41 wherein the amount of chondroitin sulphate exceeds 3-5 mg./kg. 43. The method of claim 42 wherein the effective amount of the form of hyaluronic acid exceeds 0.1 mg. 44. The method of claim 39 or 40 wherein the effective amount of the form of hyaluronic acid has a molecular weight less than 750,000 daltons. 45. The method of claim 39, 40, 41 or 42, wherein the medicinal or therapeutic agent is selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID) and a cytotoxic agent and combinations thereof.