Preparation, Characterization, and In Vitro Evaluation of 1- and 4-Month Controlled Release Orntide PLA and PLGA Microspheres

Kostanski, Janusz W.; Thanoo, B. Chithambara; DeLuca, Patrick P.

doi:10.1081/pdt-100102043

Cited by 45 publications

(20 citation statements)

References 25 publications

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“…Table 1 lists currently marketed formulations, indications for use, and duration of action. These depot formulations can deliver a sustained dose in vivo for varying periods of time, from weeks to months, [1][2][3][4][5][6] primarily owing to low degradation rates of the bulk eroding PLA and PLGA polymers.…”

Section: Introductionmentioning

confidence: 99%

A model-dependent approach to correlate accelerated with real-time release from biodegradable microspheres

2005

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The purpose of this study was to determine the feasibility of applying accelerated in vitro release testing to correlate or predict long-term in vitro release of leuprolide poly(lactideco-glycolide) microspheres. Peptide release was studied using a dialysis technique at 37°C and at elevated temperatures (50°C-60°C) in 0.1M phosphate buffered saline (PBS) pH 7.4 and 0.1M acetate buffer pH 4.0. The data were analyzed using a modification of the Weibull equation. Peptide release was temperature dependent and complete within 30 days at 37°C and 3 to 5 days at the elevated temperatures. In vitro release profiles at the elevated temperatures correlated well with release at 37°C. The shapes of the release profiles at all temperatures were similar. Using the modified Weibull equation, an increase in temperature was characterized by an increase in the model parameter, α, a scaling factor for the apparent rate constant. Complete release at 37°C was shortened from 30 days to 5 days at 50°C, 3.5 days at 55°C, 2.25 days at 60°C in PBS pH 7.4, and 3 days at 50°C in acetate buffer pH 4.0. Values for the model parameter β indicated that the shape of the release profiles at 55°C in PBS pH 7.4 (2.740) and 50°C in 0.1M acetate buffer pH 4.0 (2.711) were similar to that at 37°C (2.677). The E a for hydration and erosion were determined to be 42.3 and 19.4 kcal/mol, respectively. Polymer degradation was also temperature dependent and had an E a of 31.6 kcal/mol. Short-term in vitro release studies offer the possibility of correlation with long-term release, thereby reducing the time and expense associated with longterm studies. Accelerated release methodology could be useful in the prediction of long-term release from extended release microsphere dosage forms and may serve as a quality control tool for the release of clinical or commercial batches.

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Section: Introductionmentioning

confidence: 99%

A model-dependent approach to correlate accelerated with real-time release from biodegradable microspheres

2005

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“…The lack of testosterone suppression for the 503 microspheres was expected because very little release from these microspheres was detected in vitro [26]. The initial suppression of testosterone in these two groups could be ascribed to the release of free Orntide adsorbed to the microspheres' surface or ascribed to stress during administration; stress also affected serum levels in the animals in the control group.…”

Section: Resultsmentioning

confidence: 97%

“…All microsphere batches resulted in significant decrease of testosterone levels compared with control groups. Statistically, the 503H (2) and 503H ( Cumulative Orntide AUCs were compared with in vitro release profiles previously obtained with a dialysis method [26]. Assuming that Orntide acetate has a very short biological half-life and that the peptide does not stimulate an antibody reaction, then the cumulative Orntide.AUC should reflect the in vivo release from sustained-release Orntide formulations.…”

Section: Resultsmentioning

confidence: 99%

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Evaluation of orntide microspheres in a rat animal model and correlation to in vitro release profiles

et al. 2000

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Orntide acetate, a novel luteinizing hormone-releasing hormone (LHRH) antagonist, was prepared and evaluated in vivo in 30-day and 120-day sustained delivery formulations using a rat animal model. Orntide poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l-lactide) (PLA) microspheres were prepared by a dispersion method and administered subcutaneously in a liquid vehicle to rats at 2.2 mg Orntide/kg of body weight (30-day forms) or 8.8 mg Orntide/kg (120-day forms). Serum levels of Orntide and testosterone were monitored by radioimmunoassays, and a dose-response study at 4 doses (3, 2.25, 1.5, and 1.75 mg Orntide/kg) was conducted to determine the effective dose of Orntide. Microspheres with diameters between 3.9 and 14 µ were prepared. The onset and duration of testosterone suppression varied for different microsphere formulations and were influenced both by polymer properties and by microsphere characteristics. Microspheres prepared with 50:50 and 75:25 copolymers effectively sustained peptide release for 14 to 28 days, whereas an 85:15 copolymer and the PLA microspheres extended the pharmacological response for more than 120 days. Increase in drug load generally accelerated peptide release from the microspheres, resulting in higher initial serum levels of Orntide and shorter duration of the release. In general, apparent release was faster in vivo than under in vitro conditions. Orntide microspheres effectively suppressed testosterone in rats, providing rapid onset of release and extended periods of chemical castration. Testosterone suppression occurred immediately after microsphere administration without the initial elevation seen with LHRH superagonists.

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“…These formulations sustain drug levels in vivo for varying periods of time. 16 A previously published study showed that male rats treated with 120-day orntide microspheres were able to produce offspring upon cessation of treatment. 17 The goal of the present study was to assess the return to fertility in male rats, post treatment of a 1-year PLA microsphere dosage form of orntide, in comparison to untreated vehicle control and younger breeders.…”

Section: Introductionmentioning

confidence: 99%

Assessment of fertility in male rats after extended chemical castration with a GnRH antagonist

D’Souza

Selmin

Murty

et al. 2004

AAPS J

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Preparation, Characterization, and In Vitro Evaluation of 1- and 4-Month Controlled Release Orntide PLA and PLGA Microspheres

Abstract: Orntide acetate was successfully incorporated into PLA and PLGA ms and the 1- and 4-month in vitro release profiles were achieved by polymer selection and optimization of the manufacturing parameters.

Cited by 45 publications

References 25 publications

A model-dependent approach to correlate accelerated with real-time release from biodegradable microspheres

A model-dependent approach to correlate accelerated with real-time release from biodegradable microspheres

Evaluation of orntide microspheres in a rat animal model and correlation to in vitro release profiles

Assessment of fertility in male rats after extended chemical castration with a GnRH antagonist

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