Andrei Dashevsky

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.

Improvement of the encapsulation efficiency of oligonucleotide-containing biodegradable microspheres

The objective of this study was to encapsulate an oligonucleotide drug within poly(lactide) microparticles with high encapsulation efficiencies at high theoretical drug loadings by the solvent evaporation method. With the conventional W/O/W method, the encapsulation efficiency decreased with increasing internal water content, increasing stirring time prior to filtration of the microparticles and increasing drug loading. The encapsulation was improved by replacing methylene chloride with ethyl acetate, by using micronized drug powder instead of an internal aqueous phase or by adding electrolytes or nonelectrolytes to the external phase. With ethyl acetate, a pre-emulsification step into a smaller volume of external aqueous phase was necessary in order to avoid premature polymer precipitation and to obtain microparticles. The addition of salts (NaCl or MgCl(2)) or sorbitol to the external aqueous phase significantly improved the encapsulation efficiency, even at high theoretical drug loadings. The microparticles had a denser structure with a smooth, pore-free surface.

Reduction in burst release of PLGA microparticles by incorporation into cubic phase-forming systems

A high initial burst release of an phosphorothioate oligonucleotide drug from poly(lactide-co-glycolide) (PLGA) microparticles prepared by the w/o/w solvent extraction/evaporation was reduced by incorporating the microparticles into the following glycerol monooleate (GMO) formulations: 1) pure molten GMO, 2) preformed cubic phase (GMO+water) or 3) low viscosity in situ cubic phase-forming formulations (GMO+water+cosolvent). The in situ cubic phase-forming formulations had a low viscosity in contrast to the first two formulations resulting in good dispersability of the microparticles and good syringability/injectability. Upon contact with an aqueous phase, a highly viscous cubic phase formed immediately entrapping the microparticles. A low initial burst and a continuous extended release over several weeks was obtained with all investigated formulations. The drug release profile could be well controlled by the cosolvent composition with the in situ systems.

Drug release from and sterilization of in situ cubic phase forming monoglyceride drug delivery systems

Since a monoglyceride-based cubic phase is too viscous to be injected parenterally, mixtures of monoglyceride, water and water-miscible cosolvents were investigated as low viscosity injectable in situ cubic phase-forming formulations. Upon contact with the release medium, a highly viscous cubic phase formed rapidly and served as an extended release matrix for the oligonucleotide drug. Extended drug release was obtained with all formulations. The drug release followed the square root of time relationship indicating a diffusion-controlled release mechanism. The release depended on the type of cosolvent and followed the order of ethanol>PEG 300>2-pyrrolidone>DMSO. Higher water or monoglycerides contents decreased the drug release because of an increased viscosity and increased swollen matrix thickness. The bioburden of different commercially available monoglycerides and of the prepared in situ cubic phase-forming formulations met USP XXIII requirements. Monoglycerides can be successfully sterilized by gamma irradiation or by autoclaving and the in situ cubic phase-forming formulations by autoclaving and aseptic filtration. The monoglycerides and in situ cubic phase-forming formulations retained their phase behaviour and release properties after sterilization.

Polyvinyl acetate-based film coatings.

Polyvinyl acetate-based colloidal aqueous polymer dispersion Kollicoat(®) SR 30 D results in coatings characterized by moderate swelling behaviour, lipophilicity, pH-independent permeability for actives and high flexibility to withstand mechanical stress and is therefore used for controlled release coating. The colloidal aqueous polymer dispersion of Kollicoat(®) SR 30 D can be easily processed due to an optimal low minimum film forming temperature (MFT) of 18 °C without plasticizer addition and a thermal after-treatment (curing) of coated pellets. The drug release from Kollicoat(®) SR 30 D coated pellets was almost pH independent. Drug release could be easily adjusted by coating level or addition of soluble pore forming polymers. Physically stable Kollicoat(®) SR 30 D dispersions were obtained with the water-soluble polymers Kollidon(®) 30 and Kollicoat(®) IR up to 50% w/w. 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 tableting excipients slightly affected the drug release, primarily because of a different disintegration rate of the tablets. A combination of Kollicoat(®) SR 30 D and Kollicoat(®) IR with higher coating levels>10 mg/cm(2) is a relatively new alternative to OROS system which does not require drilling.

In Vitro and In Vivo Performance of a Multiparticulate Pulsatile Drug Delivery System

ABSTRACT The objective of this study was to investigate the in vitro and in vivo drug release performance of a rupturable multiparticulate pulsatile system, coated with aqueous polymer dispersion Aquacoat® ECD. Acetaminophen was used as a model drug, because in vivo performance can be monitored by measuring its concentration in saliva. Drug release was typical pulsatile, characterized by lag time, followed by fast drug release. Increasing the coating level of outer membrane lag time was clearly delayed. In vitro the lag time in 0.1 N HCl was longer, compared to phosphate buffer pH 7.4 because of ionisable ingredients present in the formulation (crosscarmelose sodium and sodium dodecyl sulphate). In vitro release was also longer in medium with higher ion concentration (0.9% NaCl solution compared to purified water); but independent of paddle rotation speed (50 vs.100 rpm). Macroscopically observation of the pellets during release experiment confirms that the rupturing of outer membrane was the main trigger for the onset of release. At the end of release outer membrane of all pellets was destructed and the content completely released. However, pellets with higher coating level and correspondingly longer lag time showed decreased bioavailability of acetaminophen. This phenomenon was described previously and explained by decreased liquid flow in the lower part of intestine. This disadvantage can be considered as a limitation for drugs (like acetaminophen) with high dose and moderate solubility; however, it should not diminish performance of the investigated system in principle.

Encapsulation of water-soluble drugs by an o/o/o-solvent extraction microencapsulation method

A new o/o/o-solvent extraction microencapsulation method based on less toxic solvents is presented in this study. The drug is dissolved/dispersed into a poly(D,L-lactide)/or poly (D,L-lactide-co-glycolide) (PLGA) solution in a water-miscible organic solvent (e.g., dimethylsulfoxide or 2-pyrrolidone) (o(1)), followed by emulsification into an oil phase (o(2)) (e.g., peanut oil). This emulsion is added to the external phase (o(3)) to solidify the drug-containing polymer droplets. The polymer solvent and the oil are extracted in an external phase (o(3)) (e.g., ethanol), which is a nonsolvent for the polymer and miscible with both the polymer solvent and the oil. One major advantage of this method is the reduced amount of solvent/nonsolvent volumes. In addition, very high encapsulation efficiencies were achieved at polymer concentration of 20%, w/w for all investigated polymers and o(1)/o(2) phase ratios with ethanol as the external (o(3)) phase. The encapsulation efficiency was very low (<20%) with water as external phase. The particle size of the microparticles increased with increasing polymer concentration and o(1)/o(2) phase ratio and larger microparticles were obtained with 2-pyrrolidone compared to dimethylsulfoxide as polymer solvent (o(1)). After an initial burst, in vitro drug release from the microparticles increased for the investigated polymer as follows: Resomer(®) RG 506>RG 756>R 206. A third more rapid release phase was observed after 6 weeks with Resomer(®) RG 506 due to polymer degradation. Similar drug release patterns were obtained with the o/o/o and w/o/w multiple emulsion methods because of similar porous structures. This new method has the advantages of less toxic solvents, much lower preparation volume and solvent consumption and high encapsulation efficiencies when compared to the classical w/o/w method.

Effect of water-soluble polymers on the physical stability of aqueous polymeric dispersions and their implications on the drug release from coated pellets

Purpose: To investigate the physical stability and drug release-related properties of the aqueous polymer dispersions Kollicoat® SR 30 D and Aquacoat® ECD (an ethylcellulose-based dispersion) in the presence water-soluble polymers (pore formers) with special attention to the potential flocculation of the polymer dispersions. Methods: A precise characterization of the flocculation phenomena in undiluted samples was monitored with turbidimetric measurements using the Turbiscan Lab-Expert. Theophylline or propranolol HCl drug-layered pellets were coated with Kollicoat® SR 30 D and Aquacoat® ECD by the addition of water-soluble polymers polyvinyl pyrrolidone (Kollidon® 30 and 90 F), polyvinyl alcohol–polyethylene glycol graft copolymer (Kollicoat® IR), and hydroxypropyl methylcellulose (Pharmacoat® 603 or 606) in a fluidized bed coater Glatt GPCG-1 and drug release was performed according to UPS paddle method. Results: Stable dispersions were obtained with both Kollicoat® SR 30 D (a polyvinyl acetate-based dispersion) and Aquacoat® ECD with up to 50% hydrophilic pore formers polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® IR) and polyvinyl pyrrolidone (Kollidon® 30). In general, Kollicoat® SR 30 D was more stable against flocculation than Aquacoat® ECD. Stable dispersions were also obtained with higher amounts of water-soluble polymer or by reducing the concentration of the polymer dispersion. Flocculated dispersions resulted in porous films and, thus, in a sharp increase in drug release. Conclusions: Kollicoat® SR 30 D was more resistant to flocculation upon addition of water-soluble polymers than Aquacoat® ECD. The continuous adjustment of drug release from Kollicoat® SR 30-coated pellets was possible with Kollicoat® IR amounts over a broad range.

Process and formulation variables affecting the performance of a rupturable capsule-based drug delivery system with pulsatile drug release.

The objective of this study was to optimize several process and formulation parameters, which influence the performance of a rupturable, pulsatile drug delivery system. The system consisted of a drug‐containing hard gelatin capsule, a swelling layer of croscarmellose (Ac‐Di‐Sol®) and a binder, and an outer ethylcellulose coating. Polyvinyl pyrrolidone (Kollidon 90F) was superior to HPMC and HPC as a binder for the swelling layer with regard to binding (adherence to capsule) and disintegration properties of the swelling layer. The capsule‐to‐capsule uniformity in the amount of swelling layer and outer ethylcellulose coating, which significantly affected the lag time prior to rupture of the capsule, was optimized by decreasing the batch size, and by increasing the rotational pan speed and the distance between the spray nozzle and the product bed. The type of baffles used in the coating pan also affected the layering uniformity. Fully‐filled hard gelatin capsules had a shorter lag time with a higher reproducibility compared to only half‐filled capsules, because the swelling pressure was directed primarily to the outer ethylcellulose coating and not to the inner capsule core. Stability studies revealed that the lag time of the capsules was stable over a 240‐day period when the moisture content was kept unchanged.

Poly vinyl acetate and ammonio methacrylate copolymer as unconventional polymer blends increase the mechanical robustness of HPMC matrix tablets

The objective was to investigate poly vinyl acetate (Kollicoat® SR 30 D) and ammonio methacrylate copolymer (Eudragit® RL 30 D) blends as coatings to increase the mechanical robustness of hydroxypropyl methylcellulose (HPMC) matrix tablets. Poly vinyl acetate (Kollicoat® SR 30 D - KSR) was selected for its flexibility and ammonio methacrylate copolymer (Eudragit® RL 30 D - ERL) because of its high permeability. Films based on KSR:ERL blends were prepared by casting or spraying aqueous dispersions of these polymers and were characterized by water uptake, dry mass loss and mechanical properties. KSR:ERL blends were investigated as coating materials to improve the robustness, mechanical strength and drug release from the HPMC matrix tablets containing propranolol HCl, caffeine and carbamazepine as model drugs. Both HPMC and the polymer coating affected the propranolol release. The release and the mechanical properties could be easily adjusted by varying the polymer blend ratio. The flexibility increased with increasing KSR content. At an 8% w/w coating level, a force of 3.2N was required to rupture the coating of the swollen tablet after 16h in the release medium; the coated tablets were thus robust to withstand gastrointestinal forces. The coating level (6%-10%, w/w) and dissolution agitation rate (50rpm to 150rpm) had no effect on the drug release. The water-insoluble carbamazepine was not released from the coated tablets as HPMC erosion, which is necessary for the release of a poorly water-soluble drug was hindered by the coating. The release of the water-soluble propranolol increased with increasing drug content and decreased with increasing HPMC content. CONCLUSION Poly vinyl acetate and ammonio methacrylate copolymer could be a proper polymer blend for coating HPMC matrix tablets to increase mechanical robustness, which characterized by its flexibility and permeability.