Studies On Novel Polymer Matrixes And Enhancement Of Lactate Esters On The Percutaneous Penetration Of Drugs In Transdermal Drug Delivery System

Pressure sensitive adhesives (PSAs) in transdermal drug delivery system (TDDS) not only are used to bond transdermal drug delivery devices to the outermost layer of the skin, but also are applied to act as a reservoir of drugs or penetration enhancers. As for pressure sensitive adhesives, the multilayer-molecular structures, such as constitutional unit, structure and configuration of the polymer chains, aggregation and crosslinking structure et al., have significant impact on drug release, stability, loading amount and so on. Therefore, the structure control of PSAs is important for TDDS. Fortunately, the reversible addition-fragmentation chain transfer (RAFT) polymerization method has recently been developed to prepare polymers with well-defined structure and low polydispersity.In this paper, RAFT polymerization had been used to prepare a series of PSAs with well-defined structure. First, several carbazyl dithiocarbamates as RAFT agents were prepared by an improved aqueous phase method based on a nucleophilic substitution reaction between sodium carbazole-carbodithioate and alkyl halides at room temperature, including N-carbazole-carbodithioate (BCBD), 1-phenylethyl N-carbazole-carbodithioate (PCBD), cumyl N-carbazolylcarbodithioate (CCBD), tert-butyl N-carbazolecarbodithioate (TBBD), as well as di(thiocarbazolyl) disulfide (DTCD). Then, 2-cyanoprop-2-yl N-carbazolylcarbodithioate (CYCBD) and 4-cyanovalericacid N-carbazolylcarbodithioate (CVCBD) were synthesized based on a substitution reaction between DTCD and azobisisobutyronitrile or azobis(cyanovaleric acid). After the studies on the relative effectiveness of these carbazyl RAFT agents in the RAFT polymerizations, CYCBD with the best control ability was selected as RAFT reagent to initiate copolymerization of acrylate monomers. Ethyl acrylate,butyl acrylate and 2-ethylhexyl acrylate were chosen as the soft monomers, methyl acrylate, methyl methacrylate and styrolene as the hard monomers andβ-hydroxyethyl methacrylate as the crosslink monomers. The structure of the prepared block copolymers were characterized by GPC and 1HNMR. The mechanical properties such as initial bonding strength, cohesion and adhesion were measured according to the related Chinese Standard. At last, ibuprofen, methyl nicotinate and 5-fluorouracil were chosen as drug model to estimate the drug release behavior in the obtained PSAs in vitro and the results show that these PSAs can be used to control drug release.Another objective of this thesis was to develop a novel organic-inorganic hybrid polymeric gel that is suitable for the bioadhesive film applied on skin as TDDS. The film-forming gels were prepared by using poly(vinyl alcohol) as base material,γ-(glycidyloxypropyl) trimethoxysilane (GPTMS) as cross-linker, glycerol as plasticizer and (N-vinyl pyrrolidone) as a tackifier. The mechanical properties, skin adhesion properties, swelling properties and water vapor permeability of the films prepared from different formulations of hybrid gels were studied. The miscibility and the thermal properties of films were investigated by using FT-IR, DSC, SEM and XRD. In addition, release and permeation characteristics of drugs form the resultant films were studied by using hydrophilic 5-fluorouracil and hydrophobic ibuprofen as the model drugs. All results show that the incorporation of GPTMS into the PVA can significantly enhance film mechanical strength and improve film skin adhesion properties of the film, decrease the crystalline regions of PVA and enhance the drug release. Moreover, skin irritation of the hybrid films was investigated in vivo in human subjects, and the results show that the films cause non-irritation to skin after topical application for 120 hours. The organic-inorganic hybrid polymer gel possesses very good properties for application in the skin and may provide a novel and promising formulation for transdermal drug delivery system.Finally, a series of lactate esters was synthesized and their enhancement on the skin permeation of four kinds of drugs with different physicochemical properties in propylene glycol or PSAs was also studied, including ibuprofen, salicylic acid, dexamethasone and 5-fluorouracil. All results indicated that lactate esters can exert a significant influence on the transdermal delivery of the model drugs and there is a structure-activity relationship between the tested lactate esters and their enhancement effects. The results also suggested that the lactate esters with the chain length of fatty alcohol moieties of 10-12 are more effective enhancers.