Roland Bodmeier

Gastroretentive drug delivery systems

A controlled drug delivery system with prolonged residence time in the stomach is of particular interest for drugs that i) are locally active in the stomach, ii) have an absorption window in the stomach or in the upper small intestine, iii) are unstable in the intestinal or colonic environment, or iv) exhibit low solubility at high pH values. This article gives an overview of the parameters affecting gastric emptying in humans as well as on the main concepts used to design pharmaceutical dosage forms with prolonged gastric residence times. In particular, bioadhesive, size-increasing and floating drug delivery systems are presented and their major advantages and shortcomings are discussed. Both single- and multiple-unit dosage forms are reviewed and, if available, results from in vivo trials are reported.

Solvent selection in the preparation of poly(dl-lactide) microspheres prepared by the solvent evaporation method

Abstract Poly( dl -lactide) (PLA) microspheres containing quinidine or quinidine sulfate were prepared by the solvent evaporation technique. The successful entrapment of drug within the microspheres was associated with: (a) a fast rate of precipitation of the polymer from the organic solvent phase; (b) a low water solubility of the drug in the aqueous phase; and (c) a high concentration of the polymer in the organic phase. The rate of polymer precipitation was strongly affected by the rate of diffusion of the organic solvent into the aqueous phase. Organic solvents of low water solubility resulted in a slow polymer precipitation, causing the drug to partition completely into the aqueous phase. Water-miscible organic solvents when added to the organic phase further enhanced the drug content in the microspheres. The construction of a solubility envelope for PLA and an envelope for microsphere formation based on the three-dimensional solubility parameter concept was found to be useful in the selection of suitable solvent mixtures and in the interpretation of solvent-non-solvent-polymer interactions and the formation of PLA microspheres.

HPMC-matrices for controlled drug delivery: a new model combining diffusion, swelling, and dissolution mechanisms and predicting the release kinetics.

AbstractPurpose. The purpose of this study was to investigate the drug release mechanisms from hydroxypropyl methylcellulose (HPMC)-matrices, and to develop a new model for quantitative predictions of controlled drug delivery. Methods. The dissolved mass of pure HPMC-matrices and the drug release rate from propranolol HCl-loaded HPMC-matrices were determined experimentally. Based on Ficks second law of diffusion for cylinders, the transport of water and drug were modeled considering (i) both radial and axial diffusion, (ii) concentration-dependent drug diffusivities, (iii) matrix swelling and (iv) HPMC dissolution. Results. Good agreement between theory and experiment (dissolved mass and drug release studies) was obtained, proving the validity of the presented model. The water and drug diffusivities are strongly dependent on the matrix swelling ratio. Diffusion, swelling and dissolution are the governing mechanisms involved in the overall drug release process. Conclusions. The practical benefit of the presented model is to identify the required shape and dimensions of drug-loaded HPMC-matrices in order to achieve desired release profiles, thus facilitating the development of new controlled drug delivery products. This will be demonstrated in a future study.

A novel approach to the oral delivery of micro- or nanoparticles.

A novel oral multiple-unit dosage form which overcame many of the problems commonly observed during the compression of microparticles into tablets was developed in this study. Micro- or nano-particles were entrapped in beads formed by ionotropic gelation of the charged polysaccharide, chitosan or sodium alginate, in solutions of the counterion, tripolyphosphate (TPP) or calcium chloride (CaCl2), respectively. The described technique did not change the physical properties of the microparticles, and it allowed a high microparticle loading (up to 98%). The ionic character of the polymers allowed pH-dependent release of the microparticles. Chitosan beads disintegrated and released the microparticles in 0.1 N HC1, while calcium alginate beads stayed intact in 0.1 N HC1 but rapidly disintegrated in simulated intestinal fluids. Coating the calcium alginate beads with cellulose acetate phthalate resulted in an enteric drug delivery system. Scanning electron microscopy and dissolution and disintegration tests were used to characterize the microparticle-containing beads. The disintegration time of the beads was studied as a function of the solution viscosity of the polysaccharide, gelation time, counterion concentration, and method of drying.

Mechanical, water uptake and permeability properties of crosslinked chitosan glutamate and alginate films

Abstract Films of chitosan glutamate and sodium alginate were obtained by a casting/solvent evaporation method, and crosslinked with their counterions, tripolyphosphate (TPP) and calcium chloride (CaCl 2 ), respectively. The crosslinked films were characterized with respect to the mechanical properties in the dry and wet state, water vapor transmission, water uptake in different media and permeability to model drugs. The crosslinked films were water-insoluble but permeable to water vapor. The water vapor transmission rate of chitosan films linearly decreased with increasing concentration of crosslinking agent. An optimum crosslinking agent concentration was found with alginate. Wet alginate films had lower puncture strength and higher elongation values when compared with dry films the mechanical properties were a function of the CaCl 2 concentration. In acidic medium, the swelling of the alginate films was independent of the CaCl 2 concentration. The permeability to chlorpheniramine maleate and guaifenesin varied with pH and CaCl 2 concentration. Chitosan films showed swelling and permeability characteristics, which were dependent on pH and on the concentration of the crosslinking agent. Diffusion of chlorpheniramine maleate through chitosan films increased with increasing concentration of glycerin.

ENCAPSULATION OF WATER-SOLUBLE DRUGS BY A MODIFIED SOLVENT EVAPORATION METHOD. I. EFFECT OF PROCESS AND FORMULATION VARIABLES ON DRUG ENTRAPMENT

Pseudoephedrine HCl, a highly water-soluble drug, was entrapped within poly (methyl methacrylate) microspheres by a water/oil/water emulsification-solvent evaporation method. An aqueous drug solution was emulsified into a solution of the polymer in methylene chloride, followed by emulsification of this primary emulsion into an external aqueous phase to form a water/oil/water emulsion. The middle organic phase separated the internal drug-containing aqueous phase from the continuous phase. Microspheres were formed after solvent evaporation and polymer precipitation. The drug content of the microspheres increased with increasing theoretical drug loading, increasing amounts of organic solvent, polymer and polymeric stabilizer, and decreased with increasing stirring time, increasing pH of the continuous phase and increased volume of the internal and external aqueous phase.

Tableting of coated pellets

Abstract Oral sustained/controlled release multiple unit dosage forms are becoming more popular when compared to single unit dosage forms. With regard to the final dosage form, the multiparticulates are usually formulated into single unit dosage forms such as filling them into hard gelatin capsules or compacting them into tablets. Although there is abundant literature available on the preparation of pellets and on coating technology, only a few dozen research articles have addressed the issue of compaction of coated pellets into tablets. This review provides an update on this research area and discusses the important formulation and process parameters necessary to obtain pellet-containing tablets, which, ideally, have the same properties, in particular drug release properties, as the individual coated pellets.

PREPARATION AND EVALUATION OF DRUG-CONTAINING CHITOSAN BEADS.

AbstractSulfadiazine beads were prepared by dropping drug-containing solutions of the positively charged polysaccharide, chitosan, into tripolyphosphate (TPP) solutions. The droplets instantaneously formed gelled spheres by ionotropic gelation, entrapping the drug within a three-dimensional network of the ionically linked polymer. To achieve maximum drug content, high payloads, short gelation times, low TPP concentrations, and a low internal to external phase ratio were required. The chitosan beads showed pH-dependent swelling and dissolution behavior. The beads swelled and dissolved in 0.1N HCl, while they stayed intact in simulated intestinal fluid. The release of sulfadiazine in 0.1N HCl decreased with increasing concentration of TPP, but was independent of the TPP concentration in intestinal fluids. The morphology of the beads was investigated by scanning electron microscopy. The porosity of the beads depended on the method of drying.

The preparation and evaluation of drug-containing poly(dl-lactide) microspheres formed by the solvent evaporation method

Several compounds such as caffeine, diazepam, hydrocortisone, progesterone, quinidine, quinidine hydrochloride, quinidine sulfate, and theophylline were evaluated for incorporation into poly(dl-lactide) (PLA) microspheres using the solvent evaporation technique. The process is generally limited to the entrapment of water-insoluble drugs. Adjustment of the pH of the aqueous phase to minimize drug solubility resulted in increased drug contents within the microspheres in the case of ionizable drugs. The release profile of quinidine from the microspheres was characterized by three different release phases, a lag time with no drug release, a burst effect of rapid drug release within a short period of time, and a slow release phase, respectively. The structure of the microsphere surface layer, which was a function of the pH of the aqueous phase at preparation, strongly influenced the rate and amount of drug released. Thermal analysis of quinidine-loaded microspheres revealed three thermal events, corresponding to the glass transition temperature of the polymer and to the recrystallization and melting of quinidine.

pH-independent release of a weakly basic drug from water-insoluble and -soluble matrix tablets.

Weakly basic drugs or salts thereof demonstrate pH-dependent solubility. The resulting release from conventional matrix tablets decreases with increasing pH-milieu of the gastrointestinal tract. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Two different polymers were used as matrix formers, the water-insoluble and almost unswellable ethylcellulose (EC), and the water-soluble and highly swellable hydroxypropyl methylcellulose (HPMC). Two different approaches to solve the problem of pH-dependent release of weakly basic drugs are demonstrated in this paper. The first one is based on the addition of hydroxypropyl methylcellulose acetate succinate (HPMCAS, an enteric polymer), the second one on the addition of organic acids such as fumaric, succinic or adipic acid to the drug-polymer system. The first approach failed to achieve pH-independent drug release, whereas the addition of organic acids to both matrix formers was found to maintain low pH values within the tablets during drug release in phosphate buffer (pH 6.8 or 7.4). Thus, the micro-environmental conditions for the dissolution and diffusion of the weakly basic drug were almost kept constant. The release of verapamil hydrochloride from tablets composed of ethylcellulose or HPMC and organic acids was found to be pH-independent.