Huagang Chen

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.

Preparation of biodegradable poly(+/-)lactide microparticles using a spray-drying technique.

Abstract— Drug containing biodegradable poly(±)lactide microparticles were prepared by using a spray‐drying technique. Formulations containing model drugs in either a dissolved (progesterone) or dispersed state (theophylline) were spray‐dried. The spray‐drying method was less dependent on the solubility characteristics of the drug when compared with traditional microencapsulation techniques such as phase separation or solvent evaporation techniques. Differential scanning calorimetry and scanning electron microscopy were used to characterize the microparticles. The drug release profiles were characterized by a rapid release phase (burst effect) followed by a slow release phase, the extent of each phase being dependent on the drug loading.

Preparation and characterization of microspheres containing the anti-inflammatory agents, indomethacin, ibuprofen, and ketoprofen

Abstract The anti-inflammatory agents, indomethacin, ibuprofen, and ketoprofen, were encapsulated by the solvent evaporation method using polymers such as ethylcellulose, poly(ϵ-caprolactone), poly(methyl methacrylate), polystyrene, and Eudragit RS and RL. In vitro dissolution studies, scanning electron microscopy, and differential scanning calorimetry were used to characterize the microspheres. In contrast to the release of ibuprofen and ketoprofen, the release of indomethacin from ethylcellulose microspheres was too slow for oral use even at high drug loadings. The indomethacin release could be increased by using more permeable polymers or polymer blends. The rates of polymer and drug precipitation during microsphere formation were dependent upon the organic solvent selected. When chloroform was selected as the organic solvent, the drug precipitated before the polymer and indomethacin crystals were visible on the microsphere surface. With methylene chloride, the polymer precipitated before the drug, and drug crystals were not observed. The analysis of the microspheres by differential scanning calorimetry was inconclusive since the drugs dissolved in the molten polymer during the heating step. Indomethacin-poly(ϵ-caprolactone) microspheres were prepared by a melt-dispersion technique without the use of organic solvents.

The effect of the addition of low molecular weight poly(dl-lactide) on drug release from biodegradable poly(dl-lactide) drug delivery systems

Abstract Biodegradable films and microspheres were prepared from blends of high and low molecular weight poly( dl -lactide) with molecular weights of 120,000 and 2000, respectively, by solvent casting and an emulsification-solvent evaporation method. Salicylic acid, caffeine, and quinidine were chosen as model compounds. Differential scanning calorimetry and scanning electron microscopy were used to characterize the films and microspheres. The addition of low molecular weight poly( dl -lactide) clearly accelerated the release of drug from both films and microspheres. Biodegradable drug delivery systems were prepared with durations of action between several hours to months by varying the amount of low molecular weight poly( dl -lactide). This technique allowed control over the drug release with a single, biodegradable homopolymer. In the case of quinidine, interactions with the carboxyl groups of poly( dl -lactide) occurred and complicated the release pattern.

INDOMETHACIN POLYMERIC NANOSUSPENSIONS PREPARED BY MICROFLUIDIZATION

Abstract Polymeric nanosuspensions containing indomethacin were prepared by a microfluidization-solvent evaporation method. The nanosuspensions were evaluated with respect to total drug content, drug content in the polymer and aqueous phase, particle size, drug crystallization in the aqueous phase, in vitro drug release, and stability to flocculation in 0.1 N HCl and pH 7.4 phosphate buffer. Nanosuspensions with a total drug content of 35 mg indomethacin/ml nanosuspension could be prepared without drug crystallization. More than 98% of the drug were found within the polymer phase. Unwanted drug crystallization in the aqueous phase depended on the drug loading, the drug-polymer compatibility, the organic solvent, and the type and amount of surfactant used. Indomethacin was released rapidly from ethyl cellulose nanoparticles within 15 minutes. Nanoparticles intended to provide drug release over longer periods of time were obtained by using mixtures of ethyl cellulose and poly (methyl methacrylate). In pH 7.4 buffer, anionic, nonionic and macromolecular stabilizers protected the nanosuspensions against flocculation while nonionic surf octants were good stabilizers in 0.1 N HCl.

Pseudoephedrine HCl microspheres formulated into an oral suspension dosage form

Abstract Pseudoephedrine HCl, a highly water-soluble drug, was entrapped within polymeric microspheres by either an oil-in-water (dispersion or cosolvent method) or a water-in-oil-in-water (multiple emulsion method) emulsion-solvent evaporation method. Acceptable drug loadings were achieved with the three methods. The microspheres were characterized by dissolution studies, scanning electron microscopy and differential scanning calorimetry. The microsphere structure or porosity depended strongly on the polymer selected and, to a lesser extent, on the method of preparation. The drug was partly soluble in cellulosic polymers (ethyl cellulose, cellulose acetate butyrate) but insoluble in poly(methyl methacrylate) and poly( d,l -lactide). The microspheres were formulated into an oral suspension dosage form, using concentrated sucrose or sorbitol solutions, glycerol, propylene glycol or Neobee M-5 oil as suspending vehicles. The amount of drug leached into the storage vehicle leveled off after 2–3 weeks and did not change significantly during further storage. After six months, between 77 and 93% of the original drug loading was still present within the microspheres. The storage of the microspheres in the vehicles had little influence on the drug release profiles.

Spontaneous formation of drug-containing acrylic nanoparticles

Nanoparticles containing ibuprofen, indomethacin or propranolol were formed spontaneously after the addition of solutions of the drugs and acrylic polymers (Eudragit RS or RL 100) in the water-miscible solvents, acetone or ethanol, to water without sonication or microfluidization. The colloidal dispersions were stabilized by quaternary ammonium groups and did not require the addition of surfactants or polymeric stabilizers. The nanoparticles were compared to nanoparticles prepared either by a microfluidization-solvent evaporation method with a water-immiscible organic solvent, methylene chloride, or by a melt method with respect to particle size and redispersibility of freeze- or spray-dried samples. Nanoparticles prepared by microfluidization or the melt method were easily redispersed while Eudragit RS nanoparticles prepared by spontaneous emulsification were not redispersible. Flexible films were formed from the nanosuspensions after the addition of 15 per cent triethyl citrate, a water-soluble plasticizer. The release of propranolol from the films increased with increasing proportion of RL, but was independent of the order of mixing of the two polymers or nanosuspensions during film preparation. The drug release from indomethacin films was increased by adding water-soluble polymers to the nanosuspension.

Formation of Sustained Release Wax Matrices Within Hard Gelatin Capsules in a Fluidized Bed

AbstractSustained release wax matrices were formed within hard gelatin capsules during fluidization in a hot air stream. The capsules were filled with drug (propranolol HC1 or dieophylline) – wax (Precirol ATO-5 or Gelucire 50/13) powder blends and suspended in a fluidized bed to induce fusion of the wax. Upon cooling, wax matrices with embedded drug were formed in the ends of die capsules. The use of blends of waxes with different HLB values allowed good control over the drug release pattern. The drug release from the matrices was independent of the pH of the dissolution medium. Differential scanning calorimetry was used to study the physical state of the drugs in the matrices. Propranolol HC1 was insoluble and completely dispersed in the wax matrix while theophylline was partially dissolved in the wax.

Microencapsulation of Antimicrobial Ceftiofur Drugs

Polymeric microparticles containing two ceftiofur salts as antimicrobial agents for intramammary application in dry cows were prepared by modified o/w-solvent evaporation methods (dispersion or cosolvent method) or by a w/o/w-multiple emulsion solvent evaporation method. The microspheres were characterized with respect to drug loading, drug release, and morphological properties. The three methods resulted in high encapsulation efficiencies. The choice of organic solvent/solvent mixture strongly affected the structure of the microparticles; both matrix and reservoir-type structures with different porosities were obtained. Scaling up to larger batch sizes resulted in microspheres with a faster drug release. The addition of water-miscible cosolvents to the water-immiscible polymer solution allowed the preparation of microparticles from a drug solution rather than a drug dispersion. Microparticles prepared by the cosolvent method could be separated after shorter time intervals from the aqueous phase; the microspheres had a denser matrix with finely dispersed drug crystals and a slower drug release when compared with microspheres prepared by the dispersion method, which had a more porous structure with larger embedded drug crystals. The cosolvent and dispersion methods present a simple alternative to the w/o/w-solvent evaporation method for the encapsulation of water-soluble drugs with an external water phase.

Hydrolysis of Cellulose Acetate and Cellulose Acetate Butyrate Pseudolatexes Prepared by a Solvent Evaporation-Microfluidization Method

AbstractAqueous colloidal Cellulose acetate dispersions have recently been introduced as an alternative to organic polymer solutions for the coating of osmotically active cores with a semipermeable membrane. Cellulose esters are known to hydrolytically degrade in an aqueous environment. This study followed the chemical degradation of pseudolatexes of the cellulose esters, cellulose acetate and cellulose acetate butyrate, over time and as a function of temperature. The pseudolatexes were prepared by a microfluidization-solvent evaporation method. The hydrolysis of the cellulose esters was followed by determining the pH and the amount of the acidic degradation products, acetic and butyric acid, in the aqueous phase of the polymer dispersions with an HPLC assay. The degradation followed a pseudo first-order equation and rate constants and activation energies were calculated. In addition to chemical instability, agglomeration and gelling of the colloidal particles occurred. The pseudolatexes were stable at 4°...