Multi-day delivery of biologically active substances

Abstract

Compositions and methods for modifying biologically active substances to achieve multi-day delivery of such substances, particularly through oral or parenteral administration, are disclosed. The compositions include the biologically active substance conjugated to a carrier having a suitably long half life, typically more than one day, wherein the conjugate optionally contains a spacer linking the carrier to the biologically active substance. Pharmaceutical formulations of the conjugates are also disclosed, as are methods of extending delivery of a single dose of a biologically active substance for more than one day.

What is claimed: 
     
         1 . An oral pharmaceutical dosage form comprising a drug linked to a carrier through a spacer, wherein: (1) the drug includes one or more of an amino group, a hydroxyl group or a carboxyl group to which the carrier is linked via the spacer; (2) the carrier comprises one or more carotenoids, medium-chain or long-chain fatty acids, phospholipids, oils, triglycerides or sphingomyelins; and (3) the bond linking the spacer to the drug is hydrolyzable or enzymatically cleavable to release the drug in the gastrointestinal tract of a patient ingesting the dosage form. 
     
     
         2 . The oral pharmaceutical dosage form of  claim 1 , wherein the drug is selected from hydromorphone, zetia, lipitor, crestor, atacand, ethinyl estradiol, 17 beta-estradiol, levonorgestrel, norgestimate, norethisterone and rotigotine. 
     
     
         3 . The oral dosage form of  claim 1 , which has a half life in a patient's body of more than one day. 
     
     
         4 . The oral dosage form of  claim 1 , wherein the drug is released from the spacer-carrier into the patient's body. 
     
     
         5 . The oral dosage form of  claim 1 , wherein an effective amount of the drug is delivered to the patient for more than one day following administration of a single dose of the oral dosage form to the patient. 
     
     
         6 . The oral dosage form of  claim 1 , wherein the spacer increases or decreases the half life of the oral dosage form, as compared with an equivalent oral dosage form prepared without the spacer. 
     
     
         7 . The oral dosage form of  claim 1 , wherein the spacer comprises one or more diols, diamines, diacids, aminoacids, aminoalcohols, hydroxyacids, dithiols, hydroxythiols, aminothiols, mercaptocarboxylates, dialkylsulfates, phosphate diesters, and phosphate triesters. 
     
     
         8 . The oral dosage form of  claim 7 , wherein the spacer comprises citric acid, tartaric acid succinic acid, glutaric acid, glycine, polyethylene glycol or modified polyethylene glycol. 
     
     
         9 . The oral dosage form of  claim 1 , comprising a daily dosage of less than about 100 milligrams of the drug. 
     
     
         10 . A pharmaceutical composition comprising (1) the oral dosage form of  claim 1 , (2) a form of the drug not linked to the carrier and (3) optionally, one or more excipients for facilitating controlled release of the drug not linked to the carrier. 
     
     
         11 . The pharmaceutical composition of  claim 10 , comprising one or more other active agents. 
     
     
         12 . A method of extending delivery of a single dose of a drug to beyond one day from administration of the dose to a patient, comprising:
 (a) linking the drug to a carrier through a spacer to form a drug-spacer-carrier conjugate; and   (b) orally administering the conjugate to the patient, whereby the conjugate delivers the drug to the patient for more than one day from administration of a single dose of the conjugate.   
     
     
         13 . The method of  claim 12 , wherein the drug includes an amino group, a hydroxyl group or a carboxyl group and the method comprises linking the drug through a spacer to the carrier by way of the amino group, the hydroxyl group, or the carboxyl group present on the drug. 
     
     
         14 . The method of  claim 12 , wherein: (1) the drug is hydromorphone, zetia, lipitor, crestor, atacand, ethinyl estradiol, 17 beta-estradiol, levonorgestrel, norgestimate, norethisterone, or rotigotine; (2) the carrier comprises one or more carotenoids, medium-chain or long-chain fatty acids, phospholipids, oils, triglycerides or sphingomyelins; and (3) the bond between the drug and the spacer is hydrolyzable or enzymatically cleavable to release the drug in the gastrointestinal tract of a patient ingesting the conjugate. 
     
     
         15 . The method of  claim 12 , wherein the drug is released from the conjugate to enter the patient's body. 
     
     
         16 . The method of  claim 12 , wherein the spacer comprises one or more diols, diamines, diacids, aminoacids, aminoalcohols, hydroxyacids, dithiols, hydroxythiols, aminothiols, mercaptocarboxylates, dialkylsulfates, phosphate diesters, and phosphate triesters. 
     
     
         17 . The method of  claim 16 , wherein the spacer comprises citric acid, tartaric acid succinic acid, glutaric acid, glycine, polyethylene glycol or modified polyethylene glycol. 
     
     
         18 . The method of  claim 12 , wherein the single dose of the drug is less than about 100 milligrams.