Importance of single or blended polymer types for controlled in vitro release and plasma levels of a somatostatin analogue entrapped in PLA/PLGA microspheres.

The aim of the work was to develop biodegradable microspheres for controlled delivery of the somatostatin analogue vapreotide and maintenance of sustained plasma levels over 2–4 weeks after a single injection in rats. Vapreotide was microencapsulated into end-group capped and uncapped low molecular weight poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) by spray-drying and coacervation. Microspheres were prepared from single and blended (1:1) polymer types. The microparticles were characterized for peptide loading, in vitro release and pharmocokinetics in rats. Spray-drying and coacervation produced microspheres in the size range of 1–15 and 10–70 μm, respectively, and with encapsulation efficiencies varying between 46% and 87%. In vitro release of vapreotide followed a regular pattern and lasted more than 4 weeks, time at which 40–80% of the total dose were released. Microspheres made of 14-kDa end-group uncapped PLGA50:50 or 1:1 blends of this polymer with 35 kDa end-group uncapped PLGA50:50 gave the best release profiles and yielded the most sustained plasma levels above a pre-defined 1 ng/ml over approximately 14 days. In vitro/in vivo correlation analyses showed for several microsphere formulations a linear correlation between the mean residence time in vivo and the mean dissolution time (r=0.958) and also between the amount released between 6 h and 14 days and the AUC6h–14d (r=0.932). For several other parameters or time periods, no in vitro/in vivo correlation was found. This study demonstrates that controlled release of the vapreotide is possible in vivo for a duration of a least 2 weeks when administered i.m. to rats. These results constitute a step forward towards a twice-a-month or once-a-month microsphere-formulation for the treatment of acromegaly and neuroendocrine tumors

In vitro and in vivo evaluation of a somatostatin analogue released from PLGA microspheres

The purpose of this study was to design poly(lactide-co-glycolide) (PLGA) microspheres for the continuous delivery of the somatostatin analogue, vapreotide, over 2–4 weeks. The microspheres were produced by spray-drying and the desired characteristics, i.e. high encapsulation efficiency and controlled release over 2–4 weeks, achieved through optimizing the type of polymer, processing solvent, and co-encapsulated additive. The in vitro release was tested in fetal bovine serum preserved with 0.02% of thiomersal. Furthermore, formulations were injected intramuscularly into rats to obtain pharmacokinetic profiles. Encapsulation efficiency was between 34 and 91%, depending on the particular formulation. The initial peptide release (within 6 h) was lowest, i.e. 1 ng/ml) over 21–28 days in rats was the one made with end-group uncapped PLGA 50:50, the solvent acetic acid and the additive polyethyleneglycol. In conclusion, the optimization of formulation parameters allowed us to produce vapreotide-loaded PLGA microspheres of suitable characteristics for therapeutic use

Transport of the Organic Cation N1-Methylnicotinamide by the Rabbit Proximal Tubule. I. Accumulation in the Isolated Nonperfused Tubule1'2

Prinffii in U.S.A. ABBREVIATIONS: TEA, tetraethylammonium; NMN, N1-methylnicotinamide; PAH, p-aminohippurate; T/M, tubular cell water over medium concentration ratio; HPLC, high performance liquid chromatography

Transport of the Organic Cation N1-Methylnicotinamide by the Rabbit Proximal Tubule. II. Reabsorption and Secretion in the Isolated Perfused 1 2

ABSTRACT The mechanisms involved in the transport of the organic cation N1-methylnicotinamide (NMN) were investigated in the isolated perfused rabbit S2 proximal tubule

Analysis of the influence of polymer characteristics and core loading on the in vivo release of a somatostatin analogue

Peptides and proteins have received much attention in recent years as candidate drugs. Vapreotide (RC-160) is a somatostatin analogue used for the therapy of hormone-dependent tumors and endocrine disorders. Like other peptides, it cannot be administered by the oral route and its plasma half-life is relatively short after parenteral administration. For these reasons, its use would be greatly enhanced by a sustained delivery system capable of maintaining controlled plasma levels of the peptide over an extended period of time. Poly(d,l-lactide-co-glyco (PLGA) are biocompatible biodegradable materials useful for a variety of applications, including the design of controlled-release systems for pharmaceutical agents. RC-160 pamoate loaded implants are proposed in this work as a means for controlling the drug release. Various PLGA were studied as biodegradable drug carriers and their in vivo release profiles were examined. Poly(d,l-lactide-co-glycolide) implants containing RC-160 were prepared by an extrusion method and the drug release was evaluated in vivo in rats using a radioimmunoassay method. The effects on the release profile, obtained by varying molecular weight, lactide/glycolide ratio and core loading were studied. The effects of polymer end groups were also investigated. Gel permeation chromatography was employed to characterize the loss in molecular weight of the different polymers after extrusion and γ-sterilization. It was found that drug loading, polymer molecular weight, copolymer composition and end group modifications were critical factors affecting the in vivo release properties. However, even though complex problems still exist, controlled release of peptides from biodegradable PLGA matrices can be achieved

Development and evaluation in vivo of a long-term delivery system for vapreotide, a somatostatin analogue

In recent years peptides and proteins have received much attention as candidate drugs. For many peptides, particularly hormones, it is desirable to release the drug continuously at a controlled rate over a period of weeks or even months. Polylactic acid and poly(lactic-co-glycolic) acid are well known biocompatible biodegradable materials with wide applications including the design of controlled-release systems for pharmaceutical agents. Polylactic acid implants containing vapreotide were prepared by an extrusion method and drug release was evaluated in vivo in rats using an RIA method The development of an injectable, biodegradable depot formulation of a somatostatin analogue (vapreotide) is described which ensures satisfactory peptide blood level in rats over ~250 days. A modification of this formulation by means of a wear coating allows minimisation of the initial burst a feature rarely discussed.</p

A water-soluble prodrug of cyclosporine A for ocular application: A stability study

UNIL088 is a water-soluble prodrug of cyclosporine A (CsA) developed for topical eye delivery. Such a prodrug has to fulfil two paradoxical requirements as it must be rapidly hydrolysed under physiological conditions but also retain a long shelf-life in aqueous media. This study has been conducted to explore the stability of UNIL088 formulated as an eyedrop solution. The stability study of the prodrug was performed over a pH range of 5–7 at 20 °C and at various ionic strengths. The molecule was more stable at pH 5 than at pH 7 with conversion rate constant of 3.2 × 10−3 and 26.0 × 10−3 days−1, respectively. The effect of temperature was studied at four different temperatures and activation energy was determined. Conversion of UNIL088 followed a pseudo-first-order kinetic with an activation energy of 79.4 kJ mol−1. Due to its low solubility, CsA generated precipitated in the solution. The average size of CsA precipitates, determined by photon spectroscopy, was 0.22 and 1.08 μm at 7 and 14 days, respectively. The hydrolysis mechanism was partially elucidated by identification of the intermediate pSer-Sar-CsA