Sustained release of risperidone from biodegradable microspheres prepared by in-situ suspension-evaporation process.

Risperidone-loaded poly (D,L-lactide-co-glycolide) (PLGA) microspheres were prepared with a suspension-evaporation process with an aqueous suspension containing an in situ-formed aluminum hydroxide inorganic gel (SEP-AL process) and evaluated for encapsulation efficiency, particle size, surface morphology, glass transition temperature, in vitro drug release profile, and in vivo behavior. The SEP-AL microspheres were compared with conventional oil-in-water (O/W) emulsion solvent evaporation method using polyvinylalcohol (PVA) as an emulsifier (CP-PVA process). The microspheres were spherical in shape. DSC measurements showed that risperidone crystallinity was greatly reduced due to the homogeneous distribution of risperidone in PLGA microspheres. In vitro drug release profile from the microspheres showed a sigmoidal pattern of negligible initial burst up to 24h and minimal release (time-lag) for 7 days. After the lag phase, slow release took a place up to 25 days and then rapid release occurred sharply for 1 week. In vivo rat pharmacokinetic profile from the microspheres showed very low blood concentration level at the initial phase (up to 24h) followed by the latent phase up to 21 days. At the 3rd week, main phase started and the blood concentration of the drug increased up to the 5th week, and then gradually decreased. The risperidone-loaded PLGA microspheres produced by SEP-AL process showed excellent controlled release characteristics for the effective treatment of schizophrenia patients.

Drug-organic electrolyte complexes as controlled release systems.

A water-insoluble complex between diltiazem HCl and Na deoxycholate was prepared to achieve sustained release dosage forms. Physicochemical characterization of the drug complex was carried out with differential scanning calorimetry, (1)H-nuclear magnetic resonance, and Fourier transform infrared spectroscopy. These techniques showed that the characteristic peaks in both the drug and the complexing agent (protonated amine and carboxylate) disappeared and new peaks appeared upon formation of the ionic complex. The release of diltiazem from drug-complex tablets was sustained for a long period of time (>24 h) and was dependent on the pH of the dissolution medium. However, the dependence of drug release on pH was eliminated at pH 6-8 and minimized at pH 1.5 when drug-complex powders were incorporated in hydroxypropylmethylcellulose (HPMC) drug carriers. Unlike the release of diltiazem HCl from HPMC drug carriers, drug release from drug-complex/HPMC tablets was linear or near linear irrespective of the viscosity grade of the polymer (E15 to K4M). This is due to a shift in the controlling mechanism of drug release from drug diffusion to erosion of polymer. Also, drug release kinetics was not significantly affected by the water solubility of cationic drugs (diltiazem HCl, verapamil HCl, propranolol HCl, and labetalol HCl) ranging from 1.6 to 62% and the type of amine (i.e., secondary or tertiary). The same release characteristics were observed from the complexes between anionic drugs (Na salicylate, naproxen Na, and tolmetin Na) and benzathine diacetate as found from the complexes between cationic drugs and Na deoxycholate.

Noncross-linked copolymers of dimethylaminoethyl methacrylate and methacrylic acid as oral drug carriers.

The purpose of this study was to synthesize new water-soluble ampholytic copolymers consisting of tertiary amine and carboxylic acid pendent groups for oral drug carriers. The polymers were prepared with a 1:1 molar ratio of dimethylaminoethyl methacrylate and methacrylic acid by free radical polymerization. After polymerization, polymer rods were recovered, dissolved (or swollen) in de-ionized water, and freeze-dried before obtaining fine powders. Drug release experiments with various drugs, representing a variety of drug solubility and types of amine, were carried out with compressed tablets (total weight of 600 mg) containing a variety of basic drugs in pH's of 1.5 and 7. Surprisingly, zero-order release kinetics even from a tablet geometry has been obtained with drug loading ranging from 20-50%. Drug release in pH 7 maintains a zero-order rate up to 80-85% release after a slight initial burst, whereas in pH 1.5 one may not find the initial burst and zero-order kinetics is extended up to 90-95% release. Drug release becomes faster in pH 1.5 than pH 7 due to the faster rate of protonation of the tertiary amine in acidic conditions. The release of basic drugs in pH 1.5 is not significantly different even with varying solubility and types of amine (primary, secondary, and tertiary). However, different drug release profiles in pH 7 are observed with different types of amine and solubility.

Controlled release from triple layer, donut-shaped tablets with enteric polymers.

The purpose of this research was to evaluate triple layer, donut-shaped tablets (TLDSTs) for extended release dosage forms. TLDSTs were prepared by layering 3 powders sequentially after pressing them with a punch. The core tablet consisted of enteric polymers, mainly hydroxypropyl methylcellulose acetate succinate, and the bottom and top layers were made of a water-insoluble polymer, ethyl cellulose. Drug release kinetics were dependent on the pH of the dissolution medium and the drug properties, such as solubility, salt forms of weak acid and weak base drugs, and drug loading. At a 10% drug loading level, all drugs, regardless of their type or solubility, yielded the same release profiles within an acceptable level of experimental error. As drug loading increased from 10% to 30%, the drug release rate of neutral drugs increased for all except sulfathiazole, which retained the same kinetics as at 10% loading. HCl salts of weak base drugs had much slower release rates than did those of neutral drugs (eg, theophylline) as drug loading increased. The release of labetalol HCl retarded as drug loading increased from 10% to 30%. On the other hand, Na salts of weak acid drugs had much higher release rates than did those of neutral drugs (eg, theophylline). Drug release kinetics were governed by the ionization/erosion process with slight drug diffusion, observing no perfect straight line. A mathematical expression for drug release kinetics (erosion-controlled system) of TLDSTs is presented. In summary, a TLDST is a good design to obtain zero-order or nearly zero-order release kinetics for a wide range of drug solubilities.