Chemical and physical methods to enhance drug delivery through biological membranes

Discovery of a new pharmacologically active molecule able to determine pharmacological effects favoring the cure of diseases or the attenuation of the associated symptoms is only the first step in the drug developmental process. The delivery of a defined amount of active principle to the target site at a determined time or duration is as important as its discovery. In order to realize the optimal therapeutic outcomes, a delivery system should be designed to achieve the optimal drug concentration at a predetermined rate and at the desired site. Moreover, in the drug developmental process should be considered the influence of drug physicochemical properties on passive diffusion process through biological membranes. Biological membranes are composed of small amphiphilic molecules, phospholipids with two hydrophobic chains and cholesterol or other related structures, which associate into lipid bilayers in aqueous media. Drug molecules must possess some lipophilicity to be able to permeate biological membranes as hydrophilic part of biological membranes are commonly thought to be less important for drug absorption. In general, drug solubility and subsequently its ability to permeate biological membranes since only dissolved drug molecules are able to penetrate them, is among the main physicochemical properties to evaluate in formulation of new and known chemical entity. Poor aqueous solubility of drugs is an important factor essentially associated to their limited oral bioavailability but it is also able to hinder drug delivery via non-oral routes such as buccal, ocular, nasal, pulmonary, rectal, ungual and vaginal route. Numerous methods have been proposed to enhance aqueous solubility of poorly soluble drugs and to enhance the drug permeation through biological membranes often by the design of innovative systems for the controlled release of drugs. The aim of this research work was the development of suitable semisolid formulations for transungual and transdermal drugs delivery and of tablets for oral and vaginal extended-release. To develop a transungual drug delivery a combination of iontophoresis and chemical enhancers was used in order to enhance the solubility and the permeation of an antimycotic drug (nystatin) through hoof bovine membranes chosen as experimental model. A polymeric monolithic hydrogel was prepared to control the transdermal release of diltiazem hydrochloride, an antihypertensive drug with high hydrophilicity. As topical vaginal drug delivery by once daily bioadhesive vaginal tablets might be an important approach for the treatment of candidiasis, in the present study high viscosity polymers were used to control the release of clotrimazole from tablets, and both chemical enhancers and cyclodextrin were used to increase the apparent water solubility of this drug. Finally, a metformin extended-release dosage form by floating gastroretentive approach was designed. Gastroretentive dosage forms were prepared by using an hydrophilic polymer and a gas-forming agent to obtain a low density dosage form able to float above gastric fluid for a prolonged period of time. While the system is floating on gastric content, the drug will be released slowly at desiderate rate from the system.