Sustained-release delivery of octreotide from biodegradable polymeric microspheres.

The study reports on the drug release behavior of a potent synthetic somatostatin analogue, octreotide acetate, from biocompatible and biodegradable microspheres composed of poly-lactic-co-glycolic acid (PLGA) following a single intramuscular depot injection. The serum octreotide levels of three Oakwood Laboratories formulations and one Sandostatin LAR(®) formulation were compared. Three formulations of octreotide acetate-loaded PLGA microspheres were prepared by a solvent extraction and evaporation procedure using PLGA polymers with different molecular weights.

Impurity formation studies with peptide-loaded polymeric microspheres Part I. In vivo evaluation.

The purpose of the present investigation was to assess the peptide related substances or impurities formed during incubation of drug loaded poly-(D,L-lactide-co-glycolide) (PLGA) and poly-(D,L-lactide) (PLA) microspheres under in vivo conditions. Sprague-Dawley rats were injected with separate batches of octreotide microspheres prepared by either an oil/water or oil/oil dispersion technique. At specified time points (days 14, 22, 30, and 41), animals were sacrificed and microsphere particles were recovered from the subcutaneous injection sites.

Impurity formation studies with peptide-loaded polymeric microspheres Part II. In vitro evaluation.

Since acylated peptide impurities were isolated from octreotide microspheres following incubation in an in vivo environment, the present investigation was undertaken to determine the dosage form dynamics responsible for facilitating acylation. In particular, microsphere batches made with poly(L-lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) 85:15 were studied for in vitro drug release, mass balance relationships, mass loss behavior, hydration uptake, and solid-state stability. Furthermore, native octreotide was incubated in a varying pH stability model (heat treated lactic acid solutions 42.

In vivo release kinetics of octreotide acetate from experimental polymeric microsphere formulations using oil/water and oil/oil processes.

The purpose of the present study was to characterize the in vivo release kinetics of octreotide acetate from microsphere formulations designed to minimize peptide acylation and improve drug stability. Microspheres were prepared by a conventional oil/water (o/w) method or an experimental oil/oil (o/o) dispersion technique. The dosage forms were administered subcutaneously to a rat animal model, and serum samples were analyzed by radioimmunoassay over a 2-month period.

Preparation and stability of poly(ethylene glycol) (PEG)ylated octreotide for application to microsphere delivery.

The purpose of this study was to prepare poly(ethylene glycol) (PEG)ylated octreotide and investigate the stability against acylation by polyester polymers such as poly(lactic acid) and poly(lactic-co-glycolic acid). Octreotide was modified by reaction with monomethoxy PEG-propionaldehyde (molecular weight 5,000) in the presence of sodium cyanoborohydride. The mono-PEGylated fraction was isolated by reversed-phase high-performance liquid chromatography (HPLC) and characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).

Identification of chemically modified peptide from poly(D,L-lactide-co-glycolide) microspheres under in vitro release conditions.

The purpose of this research was to study the chemical reactivity of a somatostatin analogue, octreotide acetate, formulated in microspheres with polymers of varying molecular weight and co-monomer ratio under in vitro testing conditions. Poly(D,L-lactide-co-glycolide) (PLGA) and poly(D,L-lactide) (PLA) microspheres were prepared by a solvent extraction/evaporation method. The microspheres were characterized for drug load, impurity content, and particle size.

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

The purpose of this study was to assess whether male rats whose testosterone levels were suppressed to castration levels (<0.5 ng/mL) for a 1-year period by the sustained delivery of orntide acetate, a GnRH antagonist, would return to fertility (ie, produce offspring) after serum testosterone returned to control levels. Male rats comprising a treatment group (orntide microspheres, dose = 27 mg/kg/y), a vehicle control group, and a control group of proven male breeders were used.

Effect of osmotic pressure in the solvent extraction phase on BSA release profile from PLGA microspheres.

This study investigated the influence of osmotic pressure in the organic solvent extraction phase on release profile of bovine serum albumin (BSA) from poly(lactide-co-glycolide) (PLGA) microspheres. BSA-loaded PLGA microspheres with a target load of 10% were prepared by a double emulsion phase separation method. All the microsphere batches were fabricated in the same conditions except that in the organic solvent (CH2Cl2) evaporation step.

Identification and determination of GnRH antagonist gelling at injection site.

The purpose of this study was to first observe whether orntide, a GnRH antagonist, gels at the injection site and if so, to develop and validate an extraction method to quantitate the peptide amount as well as assess chemical stability in the gel. After subcutaneous injection of a large dose of orntide acetate solution, a white gel and local traumatized effect were observed at the injection site. Orntide remaining at the injection site was recovered by tissue excision, homogenization and tissue protein precipitation with perchloric acid and quantified by high performance liquid chromatography (HPLC) following separation on a C18 column.

Return to fertility after extended chemical castration with a GnRH antagonist.

Background: Antagonistic analogues of GnRH for the treatment of prostate cancer may be used clinically in persons for whom return to fertility after such treatment is important or desirable. The purpose of this study was, therefore, to evaluate the effects of a long term treatment with orntide, a GnRH antagonist, on testosterone levels and fertility in male rats.

Methods: Two groups of male rats received either 120-day orntide microspheres (8.

Preparation, characterization and in vivo evaluation of 120-day poly(D,L-lactide) leuprolide microspheres.

A 120-day poly(D,L-lactide) (PLA) microsphere delivery system for a luteinizing hormone-releasing hormone (LHRH) analogue, leuprolide, was prepared and evaluated. Leuprolide microspheres were prepared with PLA (m.w.

Effect of gamma-irradiation on peptide-containing hydrophilic poly (d,l-lactide-co-glycolide) microspheres.

The effect of gamma-irradiation on the physicochemical properties of peptide-containing hydrophilic poly (d,l-lactide-co-glycolide) (PLGA) microspheres was evaluated. PLGA (50/50, Mw: 8,600) with free carboxylic end groups was used to make drug-loaded and placebo microspheres by a solvent extraction evaporation method. Both formulated and non-formulated microspheres were gamma-irradiated at 0, 1, 1.

Preparation, characterization, and in vitro evaluation of 1- and 4-month controlled release orntide PLA and PLGA microspheres.

Purpose: To prepare, characterize and evaluate in vitro sustained delivery formulations for a novel LHRH antagonist, Orntide acetate, using biodegradable microspheres (ms).

Methods: Poly(d,l-lactide) (PLA) and poly(d,l-lactide-co-glycolide) (PLGA) were characterized for molecular weight (Mw, Mn) using gel permeation chromatography (GPC) and content of free end carboxyl groups (acid number, AN) by a titration method. 1- and 4-month Orntide ms were prepared by a dispersion/solvent extraction/evaporation process and characterized for drug content (HPLC), bulk density (tapping method), particle size (laser diffraction method), surface morphology (scanning electron microscopy, SEM), and structural integrity of encapsulated peptide by Fourier Transform Matrix Assisted Laser Desorption mass spectrometry (FT-MALDI).

Extended release peptide delivery systems through the use of PLGA microsphere combinations.

The purpose of this study was to evaluate the utility of combining polymer matrices to overcome extended lag periods or unacceptably short durations of action intrinsic in the individual polymer systems. Leuprolide, an LHRH superagonist, was incorporated into a variety of poly(lactide-co-glycolide) (PLGA) matrices using a solvent extraction/evaporation method. The in vitro release of Leuprolide from these matrices was evaluated at pH 7.

Effect of processing parameters on the properties of peptide-containing PLGA microspheres.

The physico-chemical properties of biodegradable polylactide-co-glycolide (PLGA) microspheres containing the peptide salmon calcitonin (sCT) were affected by the processing parameters. The microsphere size increased with an increase in the viscosity of the polymer solution. Concentration of methanol and peptide in the dispersed phase had the most discernible effects with the combination causing external and internal porosity.

Biodegradable indium-111 labeled microspheres for in vivo evaluation of distribution and elimination.

Short-lived gamma emitting radioisotopes can be incorporated into polylactide/glycolide polymeric microspheres with various specific activities for possible use in understanding the in-vivo deposition, distribution and clearance of microparticulate drug carrier systems. The incorporated radiolabel is stable with negligible leaching out of the microspheres. These microspheres are suitable for studying the oral uptake of particles, lung distribution after inhalation delivery and evaluation of in-vivo fate following parenteral administration in systemic circulation or in specific tissue compartments.

Oral sustained-release drug delivery systems using polycarbonate microspheres capable of floating on the gastric fluid.

Polycarbonate microspheres loaded with aspirin, griseofulvin and p-nitroaniline were prepared by a solvent evaporation technique. High drug loading (> 50%) was achieved by this process. Drug-loaded microspheres were found to float on simulated gastric fluid and intestinal fluid.

Controlled release of oral drugs from cross-linked polyvinyl alcohol microspheres.

A new technique for the preparation of cross-linked polyvinyl alcohol (PVA) microspheres containing various drugs is described. An aqueous solution of PVA containing various concentrations of glutaraldehyde was dispersed as droplets in liquid paraffin using a suitable stabilizing agent. Cross-linking of PVA droplets with glutaraldehyde was induced by an acid catalyst (HCl) which was produced by the addition of small quantities of benzoyl chloride into the dispersion medium.

Cross-linked chitosan microspheres: preparation and evaluation as a matrix for the controlled release of pharmaceuticals.

Chitosan microspheres having good spherical geometry and a smooth surface were prepared by the glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in paraffin oil using dioctyl sulphosuccinate as the stabilizing agent. Microspheres having different degrees of swelling were made by varying the cross-linking density. Microspheres were prepared by incorporating theophylline, aspirin or griseofulvin.

Tantalum-loaded polyurethane microspheres for particulate embolization: preparation and properties.

Polyurethane microspheres having diameters in the range 150-1500 microns were prepared by condensation polymerization of toluene diisocyanate (TDI) with poly(tetramethylene glycol) (PTMG) of average mol wt 990 in an aqueous dispersion medium containing dioctyl sulphosuccinate (DOS) as the suspension stabilizer and 1,4-diazabicyclo[2.2.2]octane (DABCO) as the catalyst for polymerization.

Tantalum loaded silicone microspheres as particulate emboli.

Chloroform solutions of medical grade silicone resin were cured in an aqueous dispersion medium containing poly(vinyl alcohol) (PVA) as the drop stabilizer at 40-60 degrees C to generate smooth, spherical, elastic microspheres. The microspheres were encapsulated with tantalum powder to render them radiopaque. Tantalum loaded microspheres having diameter more than 1.

Hydrolysed microspheres from cross-linked polymethyl methacrylate (Hydrogel). A new embolic material for interventional neuroradiology.

Highly hydrophilic, perfectly smooth and spherical microspheres have been synthetized. These non-biodegradable microspheres absorb water in varying degrees and can be injected easily through microcatheters due to their slippery and compressible characteristics. The material was successfully used for embolization of 4 vascular intracranial tumours and 2 spinal vascular lesions in the cervical region, by superselective delivery.

Barium sulphate-loaded p(HEMA) microspheres as artificial emboli: preparation and properties.

Poly(2-hydroxyethyl methacrylate) p(HEMA) microspheres of good spherical geometry (diameter 90-1500 microns) encapsulated with 40-50% barium sulphate to impart radiopaque properties were prepared by a solvent evaporation process. These microspheres were cross-linked by reacting with hexamethylene diisocyanate (HMDI) or by gamma-irradiation in the presence of ethylene glycol dimethacrylate (EGDM) in n-heptane. Microspheres with a porous structure and a rough surface were also made by the incorporation of NaCl along with BaSO4.

Preparation and evaluation of radiopaque hydrogel microspheres based on PHEMA/iothalamic acid and PHEMA/iopanoic acid as particulate emboli.

Highly porous poly(2-hydroxyethyl methacrylate) (PHEMA) microspheres prepared by suspension polymerization of 2-hydroxyethyl methacrylate (HEMA) in presence of polymeric diluents such as poly(methyl methacrylate) (PMMA) in toluene and poly(tetramethylene glycol) (PTMG) were made radiopaque by esterification of the reactive hydroxyl groups with iothalamic acid and iopanoic acid, two radiopaque substances clinically used. Of the various solvents and catalysts examined, tetrahydrofuran (THF) and N,N'-dimethyl paratoluidine (DMPT) were found to be best for obtaining a high degree of conversion. More than 30 wt% iodine could be bound to the microspheres which made them sufficiently radiopaque to be imaged radiographically.