New prospective in treatment of Parkinson's disease: studies on permeation of ropinirole through buccal mucosa.

The aptitude of ropinirole to permeate the buccal tissue was tested using porcine mucosa mounted on Franz-type diffusion cells as ex vivo model. Drug permeation was also evaluated in presence of various penetration enhancers and in iontophoretic conditions. Ropinirole, widely used in treatment of motor fluctuations of Parkinson's disease, passes the buccal mucosa. Flux and permeability coefficient values suggested that the membrane does not appear a limiting step to the drug absorption. Nevertheless, an initial lag time is observed but the input rate can be modulated by permeation enhancement using limonene or by application of electric fields. Absorption improvement was accompanied by the important reduction of the lag time; at once the time required to reach the steady state plasma concentration was drastically decreased. On the basis of these results we could assume that clinical application of ropinirole by buccal delivery is feasible.

Synthesis and in vitro studies on a potential dopamine prodrug.

Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of blood-brain barrier (BBB) which is a selective interface that excludes most water-soluble molecules from entering the brain. Neutral amino acids permeate the BBB by specific transport systems. Condensation of dopamine with neutral amino acids could afford potential prodrugs able to interact with the BBB endogenous transporters and easily enter the brain. The synthesis and characterization of the dopamine derivative 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (7) is described. The chemical and enzymatic stability of 7 was evaluated. The molecular weight (300 Da) and Log Papp (0.76) indicated that the physico-chemical characteristics of compound 7 are adequate to cross biological membranes. Compound 7 was enzymatically cleaved to free dopamine in rat brain homogenate (t1/2 = 460 min). In human plasma, the t1/2 of 7 was estimated comparable to that reported for L-DOPA. In view of a possible oral administration of 7, studies of its chemical behavior under conditions simulating those of the gastrointestinal tract showed that no dopamine production occurred; furthermore, 7 is able to permeate through a simulated intestinal mucosal membrane. The collected data suggest that compound 7 could beconsidered a very valuable candidate for subsequent in vivo evaluation.

Carbamazepine transbuccal delivery: the histo-morphological features of reconstituted human oral epithelium and buccal porcine mucosae in the transmucosal permeation.

Transbuccal drug delivery is an attractive way of administration since several well-known advantages are provided, especially with respect to peroral management. Carbamazepine (CBZ) is an anticonvulsant which is useful in controlling neuropathic pain, and it is currently administered by peroral route, although its absorption and bioavailability is limited due to various factors. The oral cavity could be an interesting site for transbuccal CBZ delivery due to two properties: slow administration of constant low drug doses and less dose-related side effects. However, in transbuccal absorption a major limitation could be the low permeability of the mucosa which results in low drug bioavailability; thus the aptitude of the drug to penetrate the buccal mucosa has to be assessed by using tissue models resembling human normal mucosa. In our experience, CBZ well permeates mucosal membranes. In order to assess the efficacy of CBZ transbuccal delivery and to verify the reliability of these tissues in permeability testing before and after the passage of CBZ, the histo-morphological features of reconstituted human oral (RHO) epithelium (E) and buccal porcine mucosae were investigated. Significant histological changes due to CBZ passage were observed both in RHO-E and porcine mucosa. The main findings detected in RHO samples were cellular swellings with a signet ring-like appearance, nuclear swelling, prominent nucleoli lined against the nuclear membrane and the presence of keratohyalin granules. The most striking finding regarding porcine buccal mucosa was a cytoplasmic vacuolization, mainly involving the basal layer.

Transbuccal tablets of carbamazepine: formulation, release and absorption pattern.

Tranbsuccal drug administration is an attractive method, as it has several advantages especially with respect to peroral delivery. Here we report: i) the aptitude of carbamazepine (CBZ) to penetrate porcine buccal mucosa and reconstituted human oral (RHO) epithelium; ii) three different tablet formulations for transbuccal administration; iii) the drug release rate from tablets. CBZ permeation through the buccal mucosa was investigated by using two different bi-compartmental open models: Franz cells for porcine buccal mucosa and Transwell diffusion cells system for RHO epithelium. Results, expressed as drug flux (Js) and permeability coefficients (Kp), indicated that CBZ well penetrates the membrane and arrives in the acceptor phase. Js and Kp resulted 7x10(-2) mg/cm2h and 0.23 cm/h for in vitro experiments and 1.81 x 10(-2) mg/cm2h and 4.57 x 10(-2) cm/h for ex vivo experiments. The flux is extensively affected by the membrane thickness. The CBZ release from three different formulations of tablets, prepared with loaded microspheres, loaded matrices, and conventional compressed physical mixture of components was studied. Using the new formulated "non-conventional" tablets prolonged drug release was obtained. Loaded matrix tablets discharged CBZ faster than microsphere tablets (17% and 12% in about 2.5 h respectively). Results indicate the possibility of administering CBZ on buccal mucosa.