Preparation and evaluation of microspheres prepared from novel polyester-ibuprofen conjugates blended with non-conjugated ibuprofen.

A novel polyester, poly(glycerol-adipate-co-omega-pentadecalactone) (PGA-co-PL), was conjugated with a model drug, ibuprofen, through the free hydroxyl groups of the former and the free carboxyl group of the latter at various levels of substitution. The conjugated material was processed into microspheres by both emulsion solvent evaporation and spray-drying methods. Samples of conjugated material were also blended with non-conjugated drug and the microspheres produced were evaluated by various methods. Morphologically, the microspheres produced were satisfactory. However, there was some initial burst drug release from all samples, probably due to the presence of non-conjugated drug. Subsequent drug release was very slow due to the relative stability of the covalent bonding of the drug-polyester conjugate. Stability tests showed that storage at high relative humidity resulted in increased burst release.

Synthesis and evaluation of novel polyester-ibuprofen conjugates for modified drug release.

Ibuprofen was conjugated at different levels to a novel polyester, poly(glycerol-adipate-co-omega-pentadecalactone) (PGA-co-PL), via an ester linkage to form a prodrug. The conjugates were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), infrared (IR), gel permeation chromatography (GPC), ultraviolet (UV), and high-performance liquid chromatography (HPLC). The conjugates had a molecular weight between 18 and 24 kDa, and there was a suppression of the free hydroxyl groups within the conjugated polymer. DSC scans showed a lowering of the melting point (T(m)) when compared with the polyester alone and a difference in the number and area of T(m) peaks. Drug release studies showed an initial burst release (13-18%) followed thereafter by very slow release (maximum 35% after 18 days). Continuous work may produce ester-linked conjugates that are sufficiently labile to allow for complete release of ibuprofen over the time period studied.

Evaluation of ibuprofen-loaded microspheres prepared from novel copolyesters.

The utility of two novel linear random copolyesters to encapsulate and control the release of ibuprofen, via microspheres, was investigated. Various manufacturing parameters, including temperature, disperse phase volume and polymer:ibuprofen ratios were altered during the microsphere production. The effects of these changes on the morphological characteristics of the microspheres, yield, drug loading, encapsulation efficiency and drug release rates were examined. The diameter of the microspheres ranged from 36 to 89 microm and showed both smooth and ridged surfaces. Microsphere diameter was probably determined by the internal phase volume, while surface morphology was controlled by manufacturing temperature. Greater encapsulation efficiency was obtained by increasing the polymer:ibuprofen ratio and by reducing the internal phase volume. For all batches there was an initial burst drug release into phosphate buffer (pH 7.4) over the first 2-4h, which was followed by a much slower release rate over the remaining time period. Drug release rates during both these phases were dependent upon the amount and nature of the polymer in the microspheres, noting that the more hydrophilic polymer provided faster release rates. Ibuprofen solubility appeared to play a dominant role in controlling release, although both encapsulation efficiency and microsphere morphology were also contributing factors.

Compressed xanthan and karaya gum matrices: hydration, erosion and drug release mechanisms.

Directly compressed matrices were produced containing either xanthan gum or karaya gum as a release-controlling agent. These swellable hydrophilic natural gums were used to control the release of varying proportions of two model drugs, caffeine and diclofenac sodium, which have different solubilities in aqueous medium. Gum erosion, hydration and drug release studies were carried out using a dissolution apparatus (basket method) at two agitation speeds. Xanthan gum displayed a high degree of swelling due to water uptake and a small degree of erosion due to polymer relaxation. Neither agitation speed nor drug solubility had any significant effect on water uptake, but matrices with the lower proportion of gum produced a lesser degree of hydration. In contrast, karaya gum displayed a much lower hydration capacity and a higher rate of erosion, both markedly affected by agitation speed. Drug release from xanthan and karaya gum matrices depended on agitation speed, solubility and proportion of drug. Both xanthan and karaya gums produced near zero order drug release with the erosion mechanism playing a dominant role, especially in karaya gum matrices.

Development and evaluation of a multiple-unit oral sustained release dosage form for S(+)-ibuprofen: preparation and release kinetics.

Mini-matrix tablets containing S(+)-ibuprofen have been prepared by the wet granulation method. The hydrophilic matrix was formed with either xanthan gum, karaya gum or hydroxymethylcellulose (HPMC) together with a choice of additives from lactose, Encompress(R), Avicel(R) PH101, talc and Lubritab(R). Multiple unit dosage forms (MUDFs) were subsequently obtained by encapsulating the mini-matrix tablets into hard gelatin capsules. Preparation, in vitro release profiles and release kinetics are presented.

Solvent influence on spray-dried biodegradable microspheres.

Microspheres of fixed poly(D,L-lactic acid) (PDLLA) composition--Resomer R104:R202H (30:70)--containing 20% w/w rifampicin have been spray-dried from a range of acetonic, halogenated, and solvent mixtures thereof under constant process conditions to examine the influence of solvent selection on microsphere characteristics. Solubility of the polymer composite in the studied solvents determined the kinetics of polymer deposition during drying. Viscosity studies provided an indirect index of solvent power in ascending order: acetone (ACT) < dichloromethane (DCM) < chloroform (CFM) < halothane (HAL). Accordingly, poorer acetonic solvents produced a more open, porous matrix of increased mean diameter, whereas DCM, CFM and HAL generated more coherent matrices of greater density and elevated glass transition temperature, which significantly retarded drug release. Yield generally increased in parallel with solvent strength and microsphere density consistent with the proposed generalized particle formation mechanism. Residual solvent also increased with particle density, both parameters being interrelated and dictated by the inherent affinity of the polymer composite for individual solvents. In turn, the position of glass transition temperature (Tg) and the quantity of associated polymer stress-relaxation were a direct function of amount and persistence of organic residue. The magnitude of these changes determined the relative rates and extents of microsphere ageing, as measured by drug release studies. In general, rate of drug release increased with Tg, after corrections were made for specific surface area (r2 = 0.963). Overall, solvent choice for spray-drying has a remarkable influence on microsphere characteristics and, accordingly, technological as well as toxicological considerations should be paid during selection of same.

Modulation of rifampicin release from spray-dried microspheres using combinations of poly-(DL-lactide).

Microspheres containing 20% w/w rifampicin (RIF) with smooth morphology have been readily prepared from combinations of low, R104 (Mw, 2000) and moderate, R202H (Mw, 9000), molecular weight poly(D,L-lactide) (PDLLA) as a means to modulate drug release from either polymer when used alone. These have been characterized with respect to their drug loading, granulometry, in vitro drug release and thermal behaviour. Particle size distributions were Gaussian, whereby mean microsphere diameter was found to increase from 2.11 to 2.98 microns as the proportion of more viscous R202H increased, whilst > 95% of particles were < 10 microns, irrespective of the polymer blend used. Use of a reduced inlet temperature for spray-drying gave uncharacteristically high production yields in the range of 55.8-80.7% for the process. Encapsulation efficiencies were quantitative with the weight proportion of drug co-dissolved (p < 0.05), yielding microspheres of high and predictable RIF loading. In vitro drug release revealed a dramatic shift in release profile between 40 and 60% R104. Closer examination in this range showed the predicted pattern of increased release rate as the fraction of more hydrophilic R104 increased. However, disproportionate differences were evident between 44 and 48% R104. From the apparent temperature dependent drug release, the criticality of matrix composition was attributed to the coincidence of matrix softening with the dissolution medium temperature and consequent hydration, which, at a finite composition, resulted in a controlled auto-hydration mechanism. Dramatic dependence of release rate with dissolution methodology was accountable to the fact that drug release was considerably quicker where microspheres remained suspended and individualized with the USP paddle method as opposed to aggregated with the shaking bath methodology. In conclusion, the utility of blending racemic PDLLA to modulate drug release and the convenience of spray-drying as a technique to produce microspheres of predictable character have been demonstrated. The temperature-dependent release exhibited may have application in the site-specific delivery of drugs where local increased biochemical activity promotes drug release in response to an increased pharmacological need.

Evaluation of biodegradable rifampicin-bearing microsphere formulations using a stability-indicating high-performance liquid chromatographic assay.

The validation of a rapid and selective stability-indicating high-performance liquid chromatographic procedure for the determination of rifampicin (RIF) and its decomposition products in aqueous solution is described. Direct injection and column switching HPLC procedures have been compared and, owing to the increased sensitivity and precision, the latter has been applied to the study of RIF stability in the presence of isoascorbic acid at pH 7.4. The time-dependent hydrolytic decomposition of RIF to 3-formyl rifamycin SV (RSV) was found to be biexponential. Log concentration versus time plots of RIF and RSV decomposition were found to be parallel, indicating a pseudo equilibrium decomposition process. This feature allowed corrections for the amounts lost to secondary reactions to be calculated when the assay was applied to the determination of release characteristics of RIF from biodegradable poly-d, l-lactide-co-glycolide microspheres.

Relationship between swelling, erosion and drug release in hydrophillic natural gum mini-matrix formulations.

The swelling, erosion and solvent front penetration properties of mini-matrices containing xanthan (X), locust bean (LB) and karaya (K) gums were examined, analysed and related to the overall in vitro release kinetics of diclofenac sodium, used as a model drug. Mini-matrices were produced with drug:gum ratios of 1:1 as well as formulations of drug and X in combinations of 2:1, 2:3 and 1:2. The rank order of decreasing swelling index (SI) in both axial and radial dimensions was X?K?LB and each gum showed almost Fickian swelling behaviour. The solvent front penetration rates were consistent with the rates of swelling. However, the order of decreasing drug release and erosion rates was LB>X>K and all formulations demonstrated anomalous (non-Fickian) drug release kinetics. Therefore Fickian drug diffusion and polymer erosion were both occurring simultaneously. The dominant mechanism depended on the nature and content of the gum, as well as the stage in the dissolution time period. There was a loss of matrix integrity in formulations containing a high drug:gum ratio.

Dissolution of theophylline from film-coated slow release mini-tablets in various dissolution media.

The dissolution of an experimental formulation of film-coated slow release theophylline mini-tablets has been investigated using the USP paddle apparatus in test media at pH 1.2 (hydrochloric acid), pH 5.4 and 7.4 (phosphate buffers) at 37 degrees C. Monitoring of in-vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in less than 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in-vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasize the usefulness of an animal model for assessment of in-vivo drug release and subsequent absorption, during the development of modified release dosage forms.