Biodegradable microcapsules: Acceleration of polymeric excipient hydrolytic rate by incorporation of a basic medicament

Maulding, H.V.; Tice, Thomas R.; Cowsar, Donald R.; Fong, J. W.; Pearson, Jane E.; Nazareno, J.P.

doi:10.1016/0168-3659(86)90071-4

Cited by 96 publications

(26 citation statements)

References 6 publications

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“…In fact, polyester hydrolysis can be described by an autocatalytic degradative mechanism, the kinetics of which is a function of pH (20) and literature documented that faster hydrolysis of ester bonds occurs in a basic environment (7)(8)(9)21). At early stages, PLGA microspheres tend to be a closed system in which hydration proceeds very fast (i.e., within minutes; 22), even if a small amount of water is absorbed due to the hydrophobic nature of the polymer (23).…”

Section: Resultsmentioning

confidence: 99%

“…In particular, when uncapped PLGA is used to microencapsulate a basic drug, two opposite mechanisms of interaction with opposite outcomes have been reported, namely, -basic drugs shield the polymer terminal carboxylic residues, thereby decelerating the catalytic effect of the acidic chain ends on polymer degradation (4-6) -basic drugs behave as catalysts in the hydrolytic cleavage of the polymer chain ester bonds, thereby accelerating polymer degradation (7)(8)(9) In a previous work, 7-and 15-day acting risperidone PLGA microspheres were formulated by a dispersion method and characterized in vitro and in vivo (10). These results suggested that the presence of risperidone accelerates the degradation rate of PLGA polymers.…”

Section: Introductionmentioning

confidence: 99%

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Accelerated Polymer Biodegradation of Risperidone Poly(d, l-Lactide-Co-Glycolide) Microspheres

2012

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Abstract. The influence of a tertiary amine, namely risperidone (pKa07.9) on the degradation of poly(D, L lactide-co-glycolide) (PLGA) microspheres was elucidated. Risperidone and blank microspheres were fabricated at two lactide/glycolide ratios, 65:35 and 85:15. The microspheres were characterized for drug loading by high-performance liquid chromatography, particle size by laser diffractometry, and surface morphology by scanning electron microscopy. Polymer degradation studies were carried out with drugloaded microspheres and blank microspheres in presence of free risperidone in 0.02 M PBS containing 0.02% Tween®80 at 37°C. Molecular weight was monitored by gel permeation chromatography. Risperidone and blank microspheres had similar size distribution and were spherical with a relatively nonporous smooth surface. The presence of risperidone within the microspheres enhanced the hydrolytic degradation in both polymeric matrices with faster degradation occurring in 65:35 PLGA. The molecular weight decreased according to pseudo-first-order kinetics for all the formulations. During the degradation study, the surface morphology of drug-loaded microspheres was affected by the presence of risperidone and resulted in shriveled microspheres in which there appeared to be an intrabatch variation with the larger microspheres being less shriveled than the smaller ones. When blank microspheres were incubated in free risperidone solutions, a concentration-dependent effect on the development of surface porosity could be observed. Risperidone accelerates the hydrolytic degradation of PLGA, presumably within the microenvironment of the drug-loaded particles, and this phenomenon must be taken into consideration in designing PLGA dosage forms of tertiary amine drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Accelerated Polymer Biodegradation of Risperidone Poly(d, l-Lactide-Co-Glycolide) Microspheres

2012

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“…In contrast, for basic compounds, two effects accelerated or slowed down depends on the relative importance of the two effects. [46][47][48][49][50][51] To elucidate this point, an sized amorphous polymers will not yield hollow structures, but morphological changes similar to the case of the largesized devices will be observed. 46 …”

Section: Additivesmentioning

confidence: 99%

Hydrolytic degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids

Li¹

1999

J. Biomed. Mater. Res.

597

417

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During the past decade, important advances have been made in the understanding of the hydrolytic degradation characteristics of aliphatic polyesters derived from lactic acid (LA) and glycolic acid (GA). Degradation of large poly(LAGA) (PLAGA) polymers is autocatalyzed by carboxyl end groups initially present or generated upon ester bond cleavage. Faster internal degradation and degradation-induced morphological and compositional changes are three of the most important findings deduced from the behaviors of various PLAGA polymers. This review presents the state of the art in this domain. The research efforts are focused on detailing the degradation mechanism and the effects of various factors on the degradation of PLAGA polymers. An attempt is also made to elaborate a scheme that can be used to predict degradation characteristics of these polymers from their initial composition and morphology.

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“…Both Risperidone and Olanzapine are weakly basic nucleophiles that will be encapsulated in a polyester based polymer containing carboxylic end groups [COOH]. Due to the known reactivity of other basic drugs with the PLGA polymer [12,19], it is critical to understand the impact of Risperidone and Olanzapine on degradation of the 65 : 35 PLGA polymer, as it influences the dosage form performance in vivo. Ensuring that polymer properties like molecular weight are suitable for incorporating a basic drug while retaining sustained delivery characteristics are some important aspects that should be assessed in parallel with dosage form design.…”

Section: (I) Ensuring That the Right Amount Of Drug Loading Is Presenmentioning

confidence: 99%

“…Depending on the polymer type and the incorporated therapeutic agent, the polymeric dosage form can provide sustained drug levels for varying durations in vivo [10,11]. Indeed, research has shown that these therapeutic agents have varying physicochemical properties that could alter polymer degradation and thereby alter drug release profiles [12][13][14][15][16]. This highlights the need to investigate the effect of a drug on polymer degradation as it can be critical with respect to product performance, as cited by several authors [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Degradation of Lactide-co-Glycolide Polymer with Basic Nucleophilic Drugs

D’Souza

Faraj

Dorati

et al. 2015

Advances in Pharmaceutics

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The purpose of this study was to examine the degradative effect of weakly basic nucleophilic drugs on a lactide-co-glycolide (PLGA) polymer in a microsphere formulation. Biodegradable PLGA microspheres of two second-generation atypical antipsychotics, Risperidone and Olanzapine, were manufactured using a solvent extraction/evaporation technique. The effect of drug content, buffer pH and temperature on polymer molecular weight and degradation, were examined via a series of experiments and compared against a control (Placebo PLGA microspheres). In comparison to Placebo microspheres, significant polymer molecular weight reduction was observed upon encapsulation of varying levels of either Risperidone or Olanzapine. There was excellent correlation between the extent of molecular weight reduction during manufacture and the amount of encapsulated drug in the microspheres. Subsequent studies on polymer degradation showed: the following (a) the Placebo and Olanzapine microspheres followed pseudo first order kinetics, (b) Risperidone microspheres exhibited biphasic degradation profiles, and (c) polymer degradation was dependent on temperature, not pH. The findings of these studies show that encapsulation of weakly basic nucleophile type drugs into PLGA can accelerate the biodegradation of the PLGA and have major implications on the design of polymeric microsphere drug delivery systems.

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Biodegradable microcapsules: Acceleration of polymeric excipient hydrolytic rate by incorporation of a basic medicament

Cited by 96 publications

References 6 publications

Accelerated Polymer Biodegradation of Risperidone Poly(d, l-Lactide-Co-Glycolide) Microspheres

Accelerated Polymer Biodegradation of Risperidone Poly(d, l-Lactide-Co-Glycolide) Microspheres

Hydrolytic degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids

Enhanced Degradation of Lactide-co-Glycolide Polymer with Basic Nucleophilic Drugs

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