Hans P. Merkle

Evaluation of laminated muco-adhesive patches for buccal drug delivery

Abstract The aim of this study is the development and evaluation of adhesive patches for buccal administration, consisting of two-ply laminates of an impermeable backing layer and a hydrocolloid polymer layer containing the drug. The patches were prepared by a casting procedure using viscous aqueous solutions of drug and hydrocolloid polymers, and subsequent drying. The polymers used were hydroxyethylcellulose, hydroxypropylcellulose, poly(vinylpyrrolidone) and poly(vinylalcohol). The integrity of the laminate is based on adhesive bonds between the hydrocolloid layer and an agarose layer grafted to one side of the backing layer sheet. After mucosal contact, firm adhesion to the mucosal surface is established by interactions of the swollen polymer and the buccal mucus layer. The duration of mucosal adhesion in vivo is affected by the type of polymer used, its viscosity grade, the polymer load per patch, and the drying procedure for preparation. A wide range of drug release rates can be achieved by varying these parameters. Drug release rates are controlled by polymer dissolution kinetics.

Comparative study of intravenous, nasal, oral and buccal TRH administration among healthy subjects

Four different modes of TRH application (400 μg iv, 1 mg nasal, 10 mg buccal and 40 mg oral) were investigated in young healthy subjects for evaluation of thyrotropin (TSH) and prolactin (PRL) stimulation. Plasma TSH, PRL, T4, T3, thyroxine-binding-globulin (TBG) were measured by radioimmunoassay. There were significant increases of TSH and PRL following TRH stimulation by all test forms. Bolus injection of TRH led to maximal TSH and PRL plasma levels within 20 min to 30 min, compared with 30 min to 45 min following nasal administration. Buccal and oral application produced more prolonged TSH and PRL increases, achieving plateau levels after 120 min to 180 min. Stimulated PRL levels were higher in women than in men. Uniformity of PRL response was better after iv or nasal than buccal and oral TRH stimulation. Known side effects were lower after nasal than iv TRH application. Buccal and oral administration provoked no side effects. Nasal TRH application seems to be a well suited test form for TSH and PRL stimulation.

Drug Delivery of Peptides: The Buccal Route

Peptides and proteins are currently emerging as a major class of future drugs. So far the research in this field is mainly focused on basic research covering isolation, synthesis, analysis, and biological and clinical effects. However, increasing attention is now also given to considerations regarding suitable dosage forms and routes of absorption. It is widely accepted that the most common dosage forms and routes, i.e. solid dosage forms for peroral application and sterile preparations for parenteral application, will not provide a realistic basis for a widespread use of these drugs in the future. This is because (i) most oligopeptides and proteins are not readily absorbed in the gastrointestinal tract, e.g. due to the presence of proteolytic enzymes and the low permeability of the gut membranes to such often hydrophilic compounds. And also (ii) parenteral application, certainly, is of limited suitability to long term treatments and frequent use of drugs.

Release kinetics of polymeric laminates for transdermal delivery: Experimental evaluation and physical modelling

Abstract This presentation deals with the evaluation of a polymeric laminate for transdermal delivery of nitroglycerin. The investigated four-ply laminate was composed of (a) an impermeable backing layer, (b) a polymer film serving as the major drug depot, (c) a microporous membrane with the pores being filled with different non-polar media, and (d) an adhesive film to achieve close contact to the skin. Additionally, an identical system without a microporous membrane was investigated. Both in vivo and in vitro studies demonstrated that drug release could be controlled using different media to fill the pores of the microporous membrane. In vivo and in vitro data were in good correlation for the membrane systems only. However, no correlation was observed for the membrane free matrix system. This was attributed to system control with the membrane systems and skin control with the simple matrix system. Further studies regarding the system control mechanism of the membrane systems revealed a rather complex control pattern. In essence, it was found that in the initial stage drug release was significantly controlled by the uptake of humidity from the skin into the polymer film, leading to an increasing diffusivity of the drug in the polymer matrix. Moreover, a change of the drugs partitioning in the system resulted in a partial shift of the drug load into the adhesive layer. In its final stage drug release was partially controlled by the penetration of the drug through the pores of the microporous membrane. Because of the complex release pattern, physical modelling of the system required numerical methods. For computation the code DISPL was used which was slightly modified in order to account for concentration discontinuities across boundaries. Time variable diffusion and partition coefficients could be implemented after appropriate modifications of the original code were made. A preliminary evaluation demonstrated that numerical modelling will provide a useful tool in the preformulation stage of transdermal systems. Its use will shorten time and cost for developing such dosage forms.

Intrinsic diffusion coefficients of drugs in pressure-sensitive adhesive polymer masses

Abstract The determination of diffusion coefficients in pressure-sensitive adhesive polymers is a prerequisite to evaluate suitable adhesive polymers for transdermal patches. This paper reports on a membrane permeation technique through laminates composed of a pressure-sensitive adhesive layer and a microporous membrane for mechanical support, allowing easy handling of the adhesive without problems due to sticking. In order to determine intrinsic diffusion coefficents, the effects of the adjacent aqueous diffusion layers and of the microporous membrane were factored out by simultaneous data analysis of different adhesive layer thicknesses. To standardize the drugs thermodynamic activity, all experiments were carried out with saturated drug dispersions. The drugs investigated were three verapamil analogs, i.e. gallopamil, anipamil, and the verapamil carboxylic acid analog. To illustrate the method, experiments with different pressure-sensitive adhesives were carried out in which the effects of drug and polymer structure on diffusivity were clearly demonstrated. The effects of cross-linking, of polar and non-polar additives, and of initial drug loading were also studied, resulting in moderate or negligible effects on drug diffusivity. In agreement with theory, it was finally demonstrated that the contribution of the aqueous diffusion layers to the overall permeability of the laminates was significant when highly permeable adhesives were studied.