Derivatized carbohydrates, compositions comprised thereof and methods of use thereof

Abstract

Derivatized carbohydrates are provided which can be used to form a variety of materials including solid delivery systems. The derivatized carbohydrates are generally carbohydrates, wherein at least a portion of the hydroxyl groups on the carbohydrate are substituted with a branched hydrophobic chain, such as a hydrocarbon chain, via, for example, an ether or ester linkage. The solid delivery systems can be used for delivery and release of a variety of substances, and are, for example, in the form of tablets for oral administration, or in the form of powders, microspheres or implants for intravenous, intradermal, transdermal, pulmonary or other route of administration. The derivatized carbohydrates can be processed to form a solid matrix having a substance, such as a therapeutic agent, incorporated therein. In one embodiment, the solid matrix is provided in a solid dose form which is capable of releasing a therapeutic substance in situ at various controlled rates.

1 . A substituted carbohydrate having the structure defined by a Formula selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       wherein, in each of Formula 1-4: 
 one or more of R 1-8  are independently NHR 9 , N(R 9 ) 2 , O(C═O)R 9 , or OR 9 , wherein R 9  is a branched, saturated or unsaturated, C3-C8 hydrocarbon; and  
 the remainder of R 1-8  are independently H, NHR 10 , N(R 10 ) 2 , O(C═O)R 10 , or OR 10 , wherein R 10  is a C1-C4 straight chain alkyl group.  
 
     
     
         2 . The substituted carbohydrate according to  claim 1   wherein one or more of R 1-8  are independently O(C═O)R 9 , and O(C═O)R 9  is the acid acyl group of an acid selected from the group consisting of isobutyrate, pivalate, 2,2-dimethylbutyrate, 3,3-dimethylbutyrate, and 2-ethyl butyrate;    wherein the remainder of R 1-8  are independently O(C═O)R 10 ; and    wherein R 10  is selected from the group consisting of methyl, ethyl, propyl and butyl.    
     
     
         3 . A substituted carbohydrate selected from the group consisting of trehalose hexa-3,3-dimethylbutyrate, trehalose diacetate-hexa-3,3-dimethylbutyrate, trehalose octa-3,3-dimethylbutyrate, lactose isobutyrate-heptaacetate, lactose 3-acetyl-hepta-3,3-dimethylbutyrate and lactose octa-3,3-dimethylbutyrate.  
     
     
         4 . A composition comprising a substituted carbohydrate according to  claim 1 ,  2 , or  3 , and a substance capable of being released from the composition.  
     
     
         5 . The composition according to  claim 4 , wherein the substituted carbohydrate is in the form of a solid matrix having the substance incorporated therein.  
     
     
         6 . The composition according to  claim 5 , further comprising at least one physiologically acceptable glass selected from the group consisting of carboxylate, nitrate, sulfate, bisulfate, a hydrophobic carbohydrate derivative, and combinations thereof.  
     
     
         7 . The composition according to  claim 5 , wherein the composition is in the form of a solid delivery system selected from the group consisting of lozenge, tablet, disc, film, suppository, needle, microneedle, microfiber, particle, microparticle, sphere, microsphere, powder, and an implantable device.  
     
     
         8 . The composition according to  claim 5 , wherein the substance is a pharmaceutically active chemical.  
     
     
         9 . The composition according to  claim 8 , wherein the substance is selected from the group consisting of lipids, proteins, peptides, peptide mimetics, hormones, saccharides, nucleic acids, and protein nucleic acid hybrids.  
     
     
         10 . The composition according to  claim 9 , wherein the proteins are selected from the group consisting of enzymes, growth hormones, growth factors, insulin, monoclonal antibodies, interferons, interleukins and cytokines.  
     
     
         11 . The composition according to  claim 5 , wherein the substance is immunogenic and is selected from the group consisting of live viruses, attenuated viruses, nucleotide vectors encoding antigens, bacteria, antigens, antigens plus adjuvants and haptens coupled to carriers.  
     
     
         12 . A method of making a solid delivery system, the method comprising processing a substituted carbohydrate according to  claim 1 ,  2 , or  3 , and a substance to be released therefrom, thereby to form a solid matrix having the substance incorporated therein.  
     
     
         13 . A method of making a solid delivery system, the method comprising: 
 a) forming or obtaining a substituted carbohydrate according to  claim 1 ,  2 , or  3 , which is capable of forming a vitreous glass; and    b) processing the substituted carbohydrate and a substance to be released therefrom, thereby to form a solid matrix having the substance incorporated therein.    
     
     
         14 . The method according to  claim 12  wherein the processing step comprises: 
 i) melting the substituted carbohydrate;  
 ii) incorporating the substance in the melt, wherein the melt temperature is sufficient to fluidize the substituted carbohydrate, and insufficient to substantially inactivate the substance; and  
 iii) quenching the melt.  
 
     
     
         15 . The method according to  claim 12  wherein the processing step comprises: 
 i) dissolving or suspending the substituted carbohydrate and the substance in a solvent effective in dissolving at least one of the substituted carbohydrate and the substance; and  
 ii) evaporating the solvent.  
 
     
     
         16 . The method according to  claim 13  wherein the forming comprises reacting free hydroxyl groups on a carbohydrate with at least one acid acyl group including a branched hydrocarbon chain thereon, thereby to form the substituted carbohydrate.  
     
     
         17 . The method according to  claim 12  wherein the method further comprises incorporating into the matrix at least one physiologically acceptable glass-forming material selected from the group consisting of carboxylate, nitrate, sulfate, bisulfate, a hydrophobic carbohydrate derivative and combinations thereof.  
     
     
         18 . The method according to  claim 12  wherein the method further comprises processing the matrix into a form selected from the group consisting of lozenge, tablet, disc, film, suppository, needle, microneedle, microfiber, particle, microparticle, sphere, microsphere, powder, and an implantable device.  
     
     
         19 . The method according to  claim 18  wherein the substance is a pharmaceutically active chemical.  
     
     
         20 . The method according to  claim 19  wherein the substance is selected from the group consisting of lipids, proteins, peptides, peptide mimetics, hormones, saccharides, nucleic acids, and protein nucleic acid hybrids.