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- W1497771180 abstract "Repetitive oral administration of tablets to companion animals is particularly challenging andthere is a continuing need for alternative options such as long acting injections or implants.Therefore, properties of sustained release injectables formed in-situ for use in dogs wereinvestigated. These formulations comprise a biocompatible solvent in which thebiodegradable PLA/PLGA polymers and the lipophilic anti-infective NOA449851, derivative ofmilbemycin against the parasite Dirofilaria immitis are dissolved. These formulationscoagulate into solid implants on contact with aqueous fluids after i.m. or s.c. injection,thereby releasing the incorporated drug slowly over a period of weeks to months. Thistechnology has several attractive features such as simplicity of concept, ease ofmanufacturing as well as use of FDA approved polymers.Dissolution tests were performed to investigate in-vitro drug release characteristics frominjectable formulations varying in polymer type, polymer concentration, active ingredientconcentration and solvent composition. At high drug loads, release properties wereindependent of polymer type. However, in case of very low drug loads, drug release wascontrolled by polymer properties. Major releasing mechanism was found to be drug diffusionand therefore was influenced by drug concentration. Significant reduction of initial burst wasobserved when polymer concentration was increased. Also the solvent compositioninfluenced in-vitro drug release. Especially a significant reduction of the initial burst wasobserved when a fraction of the main solvent triacetin was substituted with hydrophilicco-solvents such as ethanol absolute or anhydrous glycerol, while a lipophilic co-solventsuch as Miglyol 812 did increase the initial drug release. Solvent composition, depending onits affinity to the dissolution medium, influences the rate of fluid-convection, the hardeningprocess of the polymers, the internal structure of the implant and therefore its drug releaserate.Raman and IR spectroscopy revealed that the active ingredient was incorporated in theamorphous conformation in all investigated batches. No evidence of any interaction betweenthe active ingredient and the polymeric matrix could be detected.Tolerability and pharmacokinetic properties of six sustained release injectables formedin-situ, varying in polymer concentration and solvent composition were explored aftersubcutaneous administration to Beagle dogs. The high viscosity of the formulations andconsequently the poor syringeability turned out to be a critical issue. Viscosity of theformulations was decreased by reducing the polymer concentration and by varying thecomposition of the solvent mixture. All investigated formulations were very good tolerated bythe animals. In agreement with in-vitro investigations, reduction of polymer concentrationgave rise to increased initial drug release. Presence of hydrophilic co-solvents reducedmaximum drug concentration in dog plasma profiles. The active ingredient NOA449851 wasdetectable in blood of experimental animals over 450 days after subcutaneous injection ofsustained release formulations. However, very high inter-animal variations were found forsome formulations and important differences in AUC values were calculated, despite thesame amount of drug injected to each dog. These differences could be explained by possibleencapsulation of the subcutaneous implant with connective tissue.The degree of correlation between the in-vitro dissolution parameters and the in-vivopharmacokinetic data was investigated. Cmax was positively correlated to cumulative in-vitrodrug release at Tmax, however not in a significant manner. In general, for this type of dosageform and drug, no satisfactory IVIVC are observed. The model used for in-vitro drug releasetesting neglect probably some crucial aspects of physiological conditions governing in-vivorelease and cannot replace biological systems.Stability studies were performed for three sustained release injectables formed in-situ duringsix months storage at the four selected temperatures 5°C, 25°C, 30°C and 40°C. Theformulations were based on PLA polymers, active ingredient NOA449851, solvent triacetinand in case of one formulation, co-solvent ethanol absolute. An HPLC-method was utilizedfor determination of the active ingredient content. No differences between the threeformulations were observed. The content of active ingredient slightly decreased with timeand temperature. Molecular weights of PLA polymers were determined with GPC. Decreasein molecular weight was significantly increased with storage temperature and time. Theseresults are in agreement with the findings of Wang et al. [Wang et al., 2003]. No significantinfluence of co-solvent ethanol absolute on the PLA stability could be measured. However,presence of active ingredient seemed to decrease hydrolysis process of PLA polymer,probably by competitively attracting water molecules responsible for polymer degradation.NIR data analysis of solvent triacetin showed spectral changes for wavelengths at 1900 nm.These spectral changes were consistent in every analyzed spectra set as solvent triacetinwas in excess in all investigated samples. Influence of solvent effect could not be removedby study design, as no specific wavelength could be attributed to PLA polymers.Surprisingly, in-vitro drug releases from a formulation tested directly after manufacturing andafter six months storage at 40°C were found to be similar, despite the important reduction ofthe molecular weight of the PLA polymers. This confirms a drug release mechanism mainlycontrolled by drug diffusion through the matrix and not erosion controlled.Microspheres and sustained release injectables formed in-situ are both technologiesintended for parenteral application, planned to achieve a long lasting drug release. In bothtechnologies, the sustained effect is caused by biodegradable PLA/PLGA polymer matrix inwhich the active ingredient is embedded. In order to investigate the influence of thepreparation method of the polymer matrix on the release of the drug substance,microparticles batches were prepared for comparison with regards to in-vitro releaseproperties. For all tested microsphere batches, drug release was independent on type ofbiodegradable polymer. A bigger fraction of active ingredient was released from themicroparticles at high drug loads. In every investigated case, drug release from sustainedrelease injectables formed in-situ was faster and to a much larger extent than from relatedmicroparticles. As possible explanation of the slower release from microparticles may be thedenser packing of the polymer matrix compared to the in-situ formed implants. Themicrospheres polymer matrix is solidified before injection by applying a much more efficientsolvent extraction procedure then the implants which only solidifies slowly at the site ofinjection. For that reason, diffusion controlled drug release is slower from the more denselypacked microsphere matrix.Sustained release injectables formed in-situ showed, under in-vitro as well as in-vivoconditions, a prolonged active ingredient release, confirming that this drug deliverytechnology is a suitable approach to achieve a controlled long term release of the lipophilicanti infective NOA449851. This technology fulfills, for this particular compound, some basicrequirements such as a good tolerability, controlled release of the active ingredient over along period of time as well as an acceptable stability of formulation during storage for severalmonths at low temperature conditions. Release properties of the active ingredient could bemodified by changing composition of the formulation and possible detrimental burst effectscould be suppressed by careful selection of polymer concentration and solvent mixture.Especially, the latter finding, the suppression of a burst effect can be considered as asignificant improvement of the in-situ implant technology. It is to be expected that in thefuture, development of new implantable systems will, increasingly, help reducing cost fordrug therapy, potentate medical treatments and, simultaneously enhance patient compliance." @default.
- W1497771180 created "2016-06-24" @default.
- W1497771180 creator A5060850239 @default.
- W1497771180 date "2006-01-01" @default.
- W1497771180 modified "2023-09-26" @default.
- W1497771180 title "Sustained release injectables formed in-situ for veterinary use" @default.
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