Control Of Drug Release Rate Research Articles

Precise control of PLG microsphere size provides enhanced control of drug release rate

An important limitation in the development of biodegradable polymer microspheres for controlled-release drug delivery applications has been the difficulty of specifically designing systems exhibiting precisely controlled release rates. Because microparticle size is a primary determinant of drug release, we developed a methodology for controlling release kinetics employing monodisperse poly( d,l-lactide-co-glycolide) (PLG) microspheres. We fabricated 20-, 40- and 65-μm diameter rhodamine-containing microspheres and 10-, 50- and 100-μm diameter piroxicam-containing microspheres at various loadings from 1 to 20%. In vitro release kinetics were determined for each preparation. Drug release depended strongly on microsphere diameter with 10- and 20-μm particles exhibiting concave-downward release profiles while larger particles resulted in sigmoidal release profiles. Overall, the rate of release decreased and the duration increased with increasing microsphere size. Release kinetics from mixtures of uniform microspheres corresponded to mass-weighted averages of the individual microsphere release kinetics. Appropriate mixtures of uniform microspheres were identified that provided constant (zero-order) release of rhodamine and piroxicam for 8 and 14 days, respectively. Mixing of uniform microspheres, as well as control of microsphere size distribution, may provide an improved methodology to tailor small-molecule drug-release kinetics from simple, biodegradable-polymer microparticles.

High molecular weight polyethylene oxides (PEOs) as an alternative to HPMC in controlled release dosage forms

High molecular weight polyethylene oxides (PEOs) have recently been proposed as an alternative to hydroxypropylmethylcellulose (HPMC) in controlled release matrix tablets. In this study, we compared the performance of PEO and HPMC polymers when employed in the Geomatrix® 1 Geomatrix® is a registered trademark of Skye Pharma AG, Muttenz, CH. 1 technology, a versatile, well-known method to achieve extended release of drugs at a constant rate. Four core formulations were prepared, containing a soluble drug (diltiazem) and, alternatively, PEO or HPMC of two different viscosity grades. These formulations have the same composition except for the polymer employed. Similarly, four barrier formulations were also prepared, which only differ in the kind of polymer employed. Three-layer Geomatrix® systems were then prepared using these core and barrier formulations. The release profiles of the different three-layer systems obtained were compared, to verify if PEO could efficiently replace HPMC in this type of dosage form. The results show that slower release rates can be obtained from the plain matrices containing HPMC compared to PEO, moreover HPMC, used in the barrier formulations, is generally more efficient in controlling drug release rate in three-layer Geomatrix systems.

Concomitant and controlled release of dexamethasone and 5-fluorouracil from poly(ortho ester)

A viscous bioerodible and hydrophobic poly(ortho ester) has been developed as a biocompatible, sustained drug release system for an ophthalmic application in intraocular proliferative disorders. The combination of wound healing modulators such as 5-fluorouracil and dexamethasone is a major advantage since these drugs act at different stages of these diseases. Since 5-fluorouracil is an acidic, water-soluble compound and dexamethasone exists in three chemical forms, i.e. the water-insoluble base, the highly hydrophobic acetate ester or the basic phosphate salt, it was of interest to investigate whether the physicochemical properties of the drugs have an influence on their release rates, and whether a concomitant and sustained release of both 5-fluorouracil and dexamethasone could be achieved. It has been found that lipophilicity and acidobasicity play a major role in controlling drug release rates and polymer degradation. The combination of 5-fluorouracil and dexamethasone phosphate allows a sustained and concomitant release of both drugs, due to the basic characteristics of the corticosteroid which stabilize the polymer. This system appears to be promising for concomitant and controlled drug delivery aimed at the pharmacological treatment of intraocular proliferative disorders.

Preparation and Evaluation of Beads Made of Different Calcium Alginate Compositions for Oral Sustained Release of Tiaramide

ABSTRACTThis study was undertaken to develop a sustained-release formulation of tiaramide (TAM), a nonsteroidal anti-inflammatory drug with a short half-life, using alginate of different chemical compositions. Alginate gel beads containing TAM were prepared using a gelation of alginate with calcium cations. Bead performance was evaluated in vitro for different dissolution media and beads were also subjected to coating. TAM release was dependent both on its solubility in dissolution medium and the guluronate residue content of the alginate used. The release rate was in the following order: in pH 1.2 < pH 6.8 < water. The fast release rate in pH 1.2 is the result of the high solubility of TAM in acidic medium. Beads based on alginate rich in guluronate residue had the lowest release rate, which can be attributed to the compact structure formed by guluronate residues through cooperative interaction with calcium ions. Alginate beads were administered to beagle dogs, and pharmacokinetic parameters (mean residence time [MRT], tmax, Cmax, and A UC) were calculated. In vivo results were in good agreement with in vitro dissolution characteristics. Beads with high guluronate content gave the best controlled results. In addition, coated beads showed a more satisfactory sustained-release pattern. Calcium alginate appears to be a potential carrier for controlling drug release rate, even for water-soluble drugs such as TAM.

Assessment of a dissolution vessel designed for use with floating and erodible dosage forms

A standard dissolution vessel was modified for the purpose of assessing more reliably the performance of floating dosage forms, particularly those which rely on erosional mechanisms to control drug release rate. The floating dosage form was placed under a supported stainless steel mesh, situated 72 mm from the base of the vessel, and the dissolution test carried out with the paddles set 10 mm above the mesh. The performance of the modified dissolution vessel was explored using two different floating dosage forms; liquid-filled HALO™-propranolol capsules with biphasic rapid and sustained-release characteristics and a rapid-release only floating dosage form consisting of lipidic granule-filled Macrotonin™ capsules. In the case of HALO™-propranolol capsules, performance of the novel dissolution vessel was compared with an existing dissolution method for floating dosage forms in which the paddles are set to the surface of the dissolution medium in the vessel, and the use of wire sinkers. The results showed that the modified dissolution vessel provided a more reproducible dissolution profile, eliminated the risk of floating dosage forms adhering to the paddles and simplified sampling procedures, while retaining the ability to differentiate between acceptable and unacceptable dissolution performance.

A one year controlled release implant for the luteinizing hormone releasing hormone superagonist RS-49947. II. Clinical performance results

A small macroporous nonerodible matrix implant supplying therapeutic levels of the decapeptide drug RS-49947 ([ d-Nal(2) 6,aza-Gly 10]-luteinizing hormone releasing hormone) for one year is described and analyzed. The implant is indicated for estrus or male sexual behavior suppression (reversible chemical castration), or for the treatment of sex hormone dependent diseases in the canine or feline. These small (55 mg) slab devices are implanted below the ventral surface skin of the animal through a small incision, and can be removed or replaced at the end of one year of therapy. The optimal system contains 41% of water soluble drug raw material (33.6% theoretical of RS-49947 free base) dispersed in Silastic 382 silicone elastomer. Plasma levels of drug and clinical performance parameters in the canine are presented for the optimal formulation and for formulations containing higher (44% drug solubles) and lower (39% drug solubles) percentages of drug raw material. Formulations containing 39% or 41% of drug raw material release in vivo by an unanticipated apparent zero order release mechanism. Comparison of clinical and in vitro data suggests that in vivo itmechanisms may control drug release rates from these systems. In vitro data for these implants are consistent with current knowledge of macroporous implants, while the in vivo data show anomalous drug release durations and profile shapes. Hypotheses for the differences between in vitro and in vivo drug release are presented. The drug raw material used to manufacture these implants exhibits a unique morphology, which may further complicate understanding of the in vivo release results. In vitro data for these systems give some insight into in vivo release, although the mechanisms of in vitro and in vivo drug release apparently differ.

A method for the preparation of polylactic acid microcapsules of controlled particle size and drug loading.

A solvent partition technique for the microencapsulation of hydrocortisone-polylactic acid has been developed for the preparation of microcapsules of controlled particle size distribution and drug loading. The method involves continuous injection of a drug-polymer solution with a syringe infusion pump into flowing mineral oil where microcapsules are formed as the solvent of the drug-polymer is partitioned into the mineral oil. Using preselected syringe needle size and mechanical control of the mineral oil flow rate at the needle tip, microcapsules of consistent particle sizes and desired drug loadings were prepared. Microcapsules of different internal structures were also prepared by varying the solvent system for the drug-polymer preparation. Dissolution studies showed that at the same drug loading, the rate of the percentage drug release increased with decreasing particle size, and that at similar particle size distributions, the rate increased with increasing drug loading. These results indicate that both the particle size distribution, and the drug loading must be controlled in a microencapsulation process to produce microcapsules of controlled drug release rate.

Control of Drug Release Rate by Use of Mixtures of Polycaprolactone and Cellulose Acetate Butyrate Polymers

AbstractChlorpromazine microspheres were prepared by an emulsion solvent evaporation technique using polycaprolactone and cellulose acetate butyrate as the matrix. The fluidity of the polymer solution was easily adjusted by use of mixtures of two polymers and thus provided a practical means to control the microsphere size. The In Vitro release pattern was easily changed by changing the ratios of these two polymers. An increase in polycaprolactone content of the polymer microsphere matrix brought about an increase in the release rate. Drug loading had no predictable effect on the dissolution rate, but smaller microspheres gave more rapid drug release due to the greater surface area.

Kinetics of drug release from polylactic acid-hydrocortisone microcapsules.

Polylactic acid microcapsules of similar particle size distribution containing various drug loadings of hydrocortisone were prepared. The microcapsules, which contained randomly dispensed drug particles, showed a dissolution pattern which consists of a fast first-stage and a slow second-stage drug release. Our studies showed that the kinetics of drug release from the microcapsules can be adequately described by a spherical matrix model based on a flux mechanism involving the diffusion of dissolved drug at the penetrating front of the dissolution medium. Drug loading played an important role in the control of drug release rate. An empirical relationship between drug loading and drug diffusibility through the polymeric matrix was developed and showed that the rate of drug release increased exponentially with the increase in drug loading. The microcapsules were further shown to exhibit increased rate of drug release in dissolution medium containing either cetylpyridium chloride or aerosol OT. The effect of the surfactants was attributed to surface tension lowering and improved wetting of the microcapsule particles.