Transbuccal peptide delivery: stability and in vitro permeation studies on endomorphin-1.

The purpose of this study was to investigate the feasibility of buccal delivery of a model peptide, endomorphin-1 (ENI), using stability and in vitro permeation studies. ENI is a recently isolated mu-opiate receptor agonist with high selectivity and specificity for this receptor subtype. Stability studies were conducted in various buffers and the drug was shown to be stable in both acidic and basic buffer systems. In the presence of full thickness porcine buccal epithelium, ENI was unstable with only 23.4+/-15.7% intact drug present after 6 h. The region responsible for this degradation was found to coincide with the major barrier region of the buccal epithelium as delineated through stability experiments in the presence of partial thickness buccal epithelium. Various peptidase inhibitors were used to isolate the enzyme(s) responsible for this degradation. Diprotin-A, a potent inhibitor of dipeptidyl peptidase IV, provided significant inhibition of the degradation of ENI in the presence of buccal epithelium. In vitro permeation studies revealed that the permeability coefficient of ENI across porcine buccal epithelium was 5.67+/-4.74x10(-7) cm/s. The enzymatic degradation of ENI was found not to be rate limiting to the drug's permeation across buccal epithelium, as diprotin-A did not increase the permeation of ENI. Sodium glycocholate as well as sodium taurocholate were also ineffective in enhancing the permeation of ENI across porcine buccal epithelium.

The influence of plasticizer molecular weight on spreading droplet size of HPMC aqueous solutions using an indirect method.

Film coating is a complex process that involves many factors. To ensure spreading and/or film capability, plasticizers are added. The role of different molecular weights of polyethylene glycol on the behavior of hydroxypropylmethylcellulose (HPMC) with different grades was determined and compared with values for the film without the plasticizer using a real method for spreading. The droplet size, distribution, and shape were analyzed as the criterion. The results show that the polymer grades and plasticizer types are important in droplet size formation.

Evaluation of poly(acrylic acid-co-ethylhexyl acrylate) films for mucoadhesive transbuccal drug delivery: factors affecting the force of mucoadhesion.

Based on the premise that similar surface properties between the adhesive and the substrate would yield a strong adhesive bond, copolymers of acrylic acid (AA) and 2-ethylhexyl acrylate (EHA), P(AA-co-EHA), were designed and synthesized for buccal mucoadhesion. A series of linear copolymers with varying feed ratios of the two monomers (AA and EHA) were synthesized through free radical copolymerization at 69+/-0.5 degrees C using azobis(isobutyronitrile) (AIBN) as initiator. The reactions were carried out in THF under nitrogen for 24 h. The glass transition temperatures, T(g), of the copolymers were determined using DSC. The adhesion studies were conducted to determine the effects of copolymer composition, contact time between the substrate and the adhesive, and crosshead speed on mucoadhesive performance of the copolymer films using a computer interfaced Instron material testing system. The glass transition temperature of the copolymers decreased with increasing EHA content. Wet glass surface as substrate was shown not to be a good substrate model for adhesion determination studies. The copolymer composed of 46:54 mol.% AA:EHA (an almost 1:1 ratio in the repeat units) yielded the highest mucoadhesive force in contact with porcine buccal mucosa which was significantly greater (P<0.05) than that of poly(acrylic acid) (PAA) (used as positive control). The mucoadhesive force for all copolymers studied was significantly (P<0.05) greater than that of the negative control (backing material without copolymer film) except for the EHA homopolymer. Crosshead speed increased mucoadhesive force linearly and had a more pronounced effect on the mucoadhesive performance than time of contact between the adhesive and the substrate.

Transbuccal permeation of a nucleoside analog, dideoxycytidine: effects of menthol as a permeation enhancer.

The use of a safe and effective permeation enhancer is paramount to the success of a buccal drug delivery system intended for systemic drug absorption. The enhancing effects of menthol (dissolved in an aqueous buffer in the absence of co-enhancers) on buccal permeation of a model hydrophilic nucleoside analog, dideoxycytidine (ddC), were investigated. In vitro transbuccal permeation of ddC was examined using freshly obtained porcine buccal mucosa. The experiments were carried out in side-bi-side flow through diffusion cells. Permeation enhancement studies were performed with varying concentrations of l-menthol dissolved in Krebs buffer solutions containing ddC. Partition coefficient experiments were carried out to probe into the mechanism of permeation enhancing properties of l-menthol and DSC studies were conducted to determine if there is a eutectic formation between ddC and l-menthol at various concentrations. Permeation of ddC increased significantly (P<0.05) in the presence of l-menthol independent of the concentration of the terpene. The apparent 1-octanol/buffer partition coefficient (log K(p)) of ddC was significantly (P<0.05) increased in presence of l-menthol and was also independent of the enhancer concentration. However, the tissue/buffer partition coefficient (log K'(p)) data showed a concentration dependent increase of log K'(p) in presence of l-menthol. Since log K'(p) is a measure of drug binding to the tissue in addition to drug partitioning, binding of ddC to the buccal tissue may provide an explanation for the concentration dependent increase in these values.

Transbuccal delivery of acyclovir: I. In vitro determination of routes of buccal transport.

PURPOSE: To determine the major routes of buccal transport of acyclovir and to examine the effects of pH and permeation enhancer on drug permeation. METHODS: Permeation of acyclovir across porcine buccal mucosa was studied by using side-by-side through diffusion cells at 37 degrees C. The permeability of acyclovir was determined at pH range of 3.3 to 8.8. Permeability of different ionic species was calculated by fitting the permeation of data to a mathematical model. Acyclovir was quantified using HPLC. RESULTS: Higher steady state fluxes were observed at pH 3.3 and 8.8. The partition coefficient (1-octanol/buffer) and the solubility of acyclovir showed the same pH dependent profile as that of drug permeation. In the presence of sodium glycocholate (NaGC) (2-100 mM), the permeability of acyclovir across buccal mucosa was increased 2 to 9 times. This enhancement was independent of pH and reached a plateau above the critical micelle concentration of NaGC. The permeabilities of anionic, cationic, and zwitterionic species were 3.83 X 10-5, 4.33 X 10-5, and 6.24 x 10-6 cm/sec, respectively. CONCLUSIONS: The in vitro permeability of acyclovir across porcine buccal mucosa and the octanol-water partitioning of the drug were pH dependent. A model of the paracellular permeation of the anionic, cationic, and zwitterionic forms of acyclovir is consistent with these data. The paracellular route was the primary route of buccal transport of acyclovir, and the enhancement of transbuccal transport of acyclovir by sodium glycocholate (NaGC) appeared to operate via this paracellular route.

Buccal mucosa as a route for systemic drug delivery: a review.

Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable. It is the objective of this article to review buccal drug delivery by discussing the structure and environment of the oral mucosa and the experimental methods used in assessing buccal drug permeation/absorption. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based delivery systems

Transbuccal delivery of acyclovir (II): feasibility, system design, and in vitro permeation studies.

PURPOSE: To design a buccal mucoadhesive system for systemic delivery of acyclovir using a novel mucoadhesive, copolymers of acrylic acid and poly(ethylene glycol), and to determine the feasibility of transbuccal delivery of acyclovir using this system. METHODS: The buccal delivery system was prepared using an adhesive, a copolymer of acrylic acid and poly(ethylene glycol) monomethylether monomethacrylate, and an impermeable membrane to prevent excessive washout by saliva and to attain unidirectional release. Acyclovir was loaded into the copolymer film prior to lamination of backing material. In vitro drug release studies were conducted in isotonic McIlvaine buffer solution. Buccal permeation of acyclovir was investigated using porcine buccal mucosa with side-by-side flow through diffusion cells at 37;C. Acyclovir was quantified using HPLC. RESULTS: Buccal permeation of acyclovir from the mucoadhesive delivery system was controlled for up to 20 hours with a time lag (t(lag)) of 10.4 hours and a steady state flux of 144.2 microg/cm(2)/h. With the incorporation of NaGC into the system t(lag) was shortened to 5.6 hours with an enhanced steady state flux of 758.7 microg/cm(2)/h. Sustained delivery of acyclovir across bucccal mucosa using this mucoadhesive system was maintained for up to 22 hours. CONCLUSIONS: The mucoadhesive system of P(AA-co-PEG) was shown to be a good candidate for controlled oral mucosal delivery of acyclovir. Buccal delivery of acyclovir was proven feasible based on in vitro permeation studies.