Evaluation of the swelling, hydration and rupturing properties of the swelling layer of a rupturable pulsatile drug delivery system.

The objective of this study was to investigate the swelling characteristics of various swellable polymers in swelling layers that induce the rupturing of an outer polymer coating in pulsatile drug delivery systems (DDS). An apparatus was designed to measure simultaneously the swelling energy/force and water uptake of discs, made of polymers. The swelling energy of several excipients decreased in the following order: croscarmellose sodium (Ac-Di-Sol) > low-substituted hydroxypropyl cellulose (L-HPC) > sodium starch glycolate (Explotab) > crospovidone (Kollidon CL) > hydroxypropyl methylcellulose (Methocel K100M). A linear correlation existed between the swelling energy and the water uptake. The swelling behavior of Ac-Di-Sol depended on the ionic strength and the pH of the medium due to a competition for free water and the acidic nature of this polymer. Analysis of the time-dependent swelling force data with a previously developed exponential equation confirmed a diffusion-controlled swelling force development, predominantly controlled by the penetration rate of the medium. The swelling behavior and the rupture of the outer polymeric coating of a pulsatile DDS were demonstrated in simulation tests.     

Stability of poly(D,L-lactide-co-glycolide) and leuprolide acetate in in-situ forming drug delivery systems.

In-situ forming drug delivery systems are prepared by dissolving a drug and a biodegradable polymer (poly(D,L-lactide-co-glycolide), PLGA) in a biocompatible organic solvent (In-situ implant, ISI) or further emulsified into an external phase (oil or aqueous solution), resulting in oil-in-oil or oil-in-water emulsions (In-situ forming microparticles, ISM). The chemical stability of PLGA and the drug is a major concern. In this study, the stability of PLGA and leuprolide acetate in the in-situ forming systems and lyophilized sponges was investigated. The degradation of PLGA increased with increasing storage temperature and water content in the biocompatible solvents. A faster degradation occurred in polar protic solvents (2-pyrrolidone, PEG 400, triethyl citrate) than in polar aprotic solvents (N-methyl-2-pyrrolidone, DMSO, triacetin, ethyl acetate). The presence of leuprolide acetate significantly accelerated PLGA degradation, especially in solution state. PLGA was stable in oily suspensions at 4 degrees C and degraded only slightly faster than solid powder at 25 degrees C. No interaction between the oils and the PLGA was observed as indicated by an unchanged T(g) of approx. 47 degrees C. PLGA underwent a slight degradation at 4 degrees C after 150 days in water and saturated sodium chloride solution. The degradation was slower in saturated sodium chloride solution than in water at 25 degrees C. Residual acetic acid in lyophilized sponges facilitated the PLGA degradation in contrast to dioxane. Leuprolide acetate did not affect the PLGA stability negatively. However, lidocaine significantly enhanced the polymer degradation in the sponges. Finally, leuprolide acetate was chemically stable in the sponges, the oils and the polymer solutions in suspension state, but unstable (aggregation) when dissolved in the polymer solutions and stored at 25 degrees C and 40 degrees C.     

Dissolution rate improvement of poorly water-soluble drugs obtained by adsorbing solutions of drugs in hydrophilic solvents onto high surface area carriers.

The dissolution rate of the model drugs carbamazepine and nifedipine was improved by adsorbing solutions of the drugs in hydrophilic non-volatile or volatile solvents onto carriers with a large surface area. This was accomplished by dissolving the drug in methanol or the non-toxic hydrophilic liquids PEG 400 or 2-pyrrolidone, and adsorbing these solutions onto the surface of silica (Aerosil) or crosslinked polyvinylpyrrolidone (Kollidon CL-M). The solvent binding capacities decreased in the order of methanol, PEG 400, 2-pyrrolidone for Aerosil 200, 300, 380 and for Kollidon CL-M. Kollidon bound less liquid than Aerosil because of the smaller surface area. Differential scanning calorimetry measurements showed higher interactions between drugs and Kollidon compared to Aerosil, suggesting a low aggregation of precipitated drug particles. The drug release from the adsorbent systems was enhanced when compared to micronized drug and independent of the drug loading in the investigated range. The drugs were also dissolved in various liquid, paste-like or solid solubilisers (polyoxyl-40-hydrogenated castor oil (Cremophor RH 40), macrogol-15-hydroxystearate (Solutol HS), poloxamers (Lutrol F68, Pluronic F87NF and Pluronic L44NF) and adsorbed onto Kollidon. These adsorbent systems also exhibited an increased dissolution rate when compared to pure drug.     

Polymeric Microspheres Prepared by Spraying into Compressed Carbon Dioxide

Purpose. The objective was to prepare polymeric microparticles by atomizing organic polymer solutions into a spray chamber containing compressed CO₂ (PCA-process) and to study the influence of various process parameters on their morphological characteristics. Methods. The swelling of various pharmaceutically acceptable polymers [ethyl cellulose, poly(methyl methacrylate), poly(-caprolactone), poly(dl-lactide), poly(l-lactide) and poly(dl-lactide-glycolide) copolymers] in CO₂ was investigated in order to find polymers which did not agglomerate during the spraying process. Poly(l-lactide) (L-PLA) microparticles were prepared by spraying the organic polymer solution into CO₂ in a specially designed spraying apparatus. The effect of various process (pressure and temperature of the CO₂ phase, flow rate) and formulation (polymer concentration) variables on the morphology and particle size of L-PLA-microparticles was investigated. Results. Polymers with low glass transition temperatures agglomerated even at low temperatures. The formation of microparticles was favored at moderate temperatures, low polymer concentrations, high pressures and high flow rates of CO₂. High polymer concentrations and low flow rates resulted in the formation of polymeric fibers. Colloidal L-PLA particles could also be prepared with this technique in a surfactant-free environment. Initial studies on the microencapsulation of drugs resulted in low encapsulation efficiencies. Conclusions. The PCA method is a promising technique for the preparation of drug-containing microparticles. Potential advantages of this method include the flexibility of preparing microparticles of different size and morphology, the elimination of surfactants, the minimization of residual organic solvents, low to moderate processing temperatures and the potential for scale-up.     

Aqueous HPMCAS coatings: effects of formulation and processing parameters on drug release and mass transport mechanisms.

The major aim of the present work was to study the effects of various formulation and processing parameters on the resulting drug release kinetics from theophylline matrix pellets coated with aqueous hydroxypropyl methylcellulose acetate succinate (HPMCAS) dispersions. The plasticizer content, coating level and curing conditions significantly affected the release patterns in 0.1 M HCl, whereas no major effects were observed in phosphate buffer, pH 7.4. Due to the significant size of the HPMCAS particles (being in the micrometer range), their coalescence was particularly crucial and not complete upon coating. Consequently, at low coating levels continuous water-filled channels connected the bead cores with the release medium through which the drug could rapidly diffuse, resulting in high release rates even at low pH. In contrast, at high coating levels such continuous connections did not exist (due to the increased number of polymer particle layers), and drug release was controlled by diffusion through the macromolecular network resulting in much lower release rates in 0.1 M HCl. Importantly, pellet curing at elevated temperature and ambient relative humidity or exposure to elevated relative humidity at room temperature did not significantly alter the microstructure of the coatings, leading to only slightly decreased drug release rates. In contrast, pellet curing at elevated temperature combined with elevated relative humidity induced significant further polymer particle coalescence, resulting in a change of the underlying drug release mechanism and significantly reduced drug release rates.     

In situ gelling, bioadhesive nasal inserts for extended drug delivery: in vitro characterization of a new nasal dosage form.

The purpose of this study was the preparation and characterization of sponge-like, in situ gelling inserts based on bioadhesive polymers. Hydrophilic polymers (carrageenan, Carbopol, chitosan, hydroxypropyl methylcellulose (HPMC) K15M and E5, sodium alginate, sodium carboxy methylcellulose (NaCMC), polyvinyl pyrrolidone (PVP) 90, xanthan gum) were dissolved with/without the model drug oxymetazoline HCl in demineralized water and lyophilized into small inserts. The drug release, water uptake, mechanical properties, X-ray diffraction and bioadhesion potential of the nasal inserts were investigated. A sponge-like structure of nasal inserts was formed with amorphous, but not with crystalline polymers during the freeze-drying process. The insert hardness increased with the glass transition temperature of the polymer (PVP25相似文献   

Compression of pellets coated with various aqueous polymer dispersions

Pellets coated with a new aqueous polyvinyl acetate dispersion, Kollicoat SR 30 D, could be compressed into tablets without rupture of the coating providing unchanged release profiles. In contrast, the compression of pellets coated with the ethylcellulose dispersion, Aquacoat ECD 30, resulted in rupture of the coating and an increase in drug release. Plasticizer-free Kollicoat SR coatings were too brittle and ruptured during compression. The addition of only 10% w/w triethyl citrate as plasticizer improved the flexibility of the films significantly and allowed compaction of the pellets. The drug release was almost independent of the compression force and the pellet content of the tablets. The inclusion of various tabletting excipients slightly affected the drug release, primarily because of a different disintegration rate of the tablets. The core size of the starting pellets had no influence on the drug release. Pellets coated with the enteric polymer dispersion Kollicoat 30 D MAE 30 DP [poly(methacrylic acid, ethyl acrylate) 1:1] lost their enteric properties after compression because of the brittle properties of this enteric polymer. Coating of pellets with a mixture of Kollicoat MAE 30 DP and Kollicoat EMM 30 D [poly(ethyl acrylate, methyl methacrylate) 2:1] at a ratio of 70/30 and compaction of the pellets resulted in sufficient enteric properties.     

Influence of plasticization time, curing conditions, storage time, and core properties on the drug release from Aquacoat-coated pellets

Theophylline or chlorpheniramine maleate pellets were coated with an aqueous ethylcellulose dispersion, Aquacoat. The influence of the plasticization time, curing conditions, storage time, and core properties on the drug release were investigated. The plasticization time (time between plasticizer addition to the polymer dispersion and the spraying process) did not affect the drug release, when the water-soluble plasticizer triethyl citrate, was used because of its rapid uptake by the colloidal polymer particles. In contrast, with the water-insoluble plasticizer acetyltributyl citrate (ATBC), plasticization time (1/2 h vs 24 h) influenced the drug release, the longer plasticization time resulted in a slower drug release because of a more complete plasticizer uptake prior to the coating step. However a thermal aftertreatment of the coated pellets at eleylated temperatures (curing step) reduced/eliminated the effect of the plasticization time with ATBC. In general, curing reduced the drug release and resulted in stable drug release profiles. The time period between the coating and the curing step was not critical when the pellets were cured for a longer time. The structure of the pellet core (high dose matrix vs low dose layered pellet) strongly affected the drug release. A slow, zero-order drug release was obtained with high dose theophylline pellets, while a more rapid, first-order release pattern was obtained with low dose theophylline-layered nonpareil pellets.     

Drug release from beads coated with an aqueous colloidal ethylcellulose dispersion, Aquacoat, or an organic ethylcellulose solution.

The objective was to investigate several factors (composition of the coating formulation, the type and pH of the release medium and curing conditions), which influence the drug release from beads coated with either the aqueous ethylcellulose dispersion, Aquacoat or an organic ethylcellulose solution. The chlorpheniramine maleate release from Aquacoat-coated beads was faster in pH 7.4 buffer than in 0.1 N HCl. Increasing the curing time and curing temperature decreased the drug release in pH 7.4 buffer but did not affect the release in 0.1 N HCl. In contrast, the drug release from beads coated with the ethanolic ethylcellulose solution was not affected by the curing step, the release medium or the addition of sodium lauryl sulfate. Scanning electron microscopy and contact angle measurements explained the release data. The differences in the drug release behavior of aqueous--and organic solvent--ethylcellulose--coated beads could be attributed to the differences in the film formation process.     

Constant Potassium Chloride Release from Microporous Membrane-Coated Tablets Prepared with Aqueous Colloidal Polymer Dispersions

To achieve constant drug release and to avoid the use of organic solvents, potassium chloride tablets were coated with aqueous latexes containing dispersed pore-formers with pH-dependent solubility characteristics. The pore-forming agent, dibasic calcium phosphate, was insoluble in the latex but soluble at low pH. Upon contact with simulated gastric fluids, it leached out rapidly to form a rate-controlling, microporous membrane. The release of potassium chloride was linear with time up to 75–80% drug released. It increased with increasing level of pore-former and decreasing membrane thickness but was independent of the degree of agitation and the pH of the dissolution medium after leaching of the pigments. Upon storage at different relative humidities, moisture uptake of the film coat and variations in the release profiles over time were minimal.