Alexandra Rothen-Weinhold

Release of BSA from poly(ortho ester) extruded thin strands

A solventless procedure was used where powdered polymer and micronized protein were intimately mixed and then extruded into 1 mm strands that were cut to the desired length. The polymers used were poly(ortho esters) specifically designed to allow extrusion in the neighborhood of 70 degrees C. At these temperatures many proteins maintain activity in the dry state. In vitro erosion and BSA release results indicate that after a fairly long lag-time, BSA release and polymer erosion occur concomitantly indicating an erosion-controlled process. The lag-time could be eliminated by the addition to the mixture prior to extrusion between 1 and 5 wt% poly(ethylene glycol) or its methoxy derivatives. The lag-time could also be eliminated by using an AB-block copolymer where A is poly(ortho ester) and B is poly(ethylene glycol).

Poly(ortho esters) : their development and some recent applications

Poly(ortho esters) have been under development since the early 1970s and four families of such polymers have been described. Of most interest are poly(ortho ester) III and poly(ortho ester) IV. Poly(ortho ester) III is a semisolid material that has been shown to be highly biocompatible and is currently being investigated as an adjunct to glaucoma filtering surgery and other ocular applications. However, the polymerization is difficult to control and is not readily scaled up. Poly(ortho ester) IV can be easily prepared in a highly reproducible manner, is very stable provided moisture is rigorously excluded and has also been shown to be highly biocompatible. It is currently under development for a variety of applications, such as ocular delivery, protein release, post-operative pain treatment and post-operative cancer treatment.

Injection-molding versus extrusion as manufacturing technique for the preparation of biodegradable implants

Polylactic acid (PLA) is a biocompatible and biodegradable material with wide utility for many applications, including the design of controlled-release systems for pharmaceutical agents. The factors determining the degradation kinetics of these systems include the composition and the molecular mass of the polymer, the morphology and the structure of the device, and the influence of thermal processes. The processing of the polymer determines the structure and design of the device, and influences to a high degree its morphology, namely its microporous structure, polymeric chain orientation and crystallinity.In this work, we aimed to compare the influence of two different implant manufacturing techniques, extrusion and injection-molding, on the in vitro degradation of the polymeric matrix. Both kinds of implants were loaded with a somatostatin analogue. Decrease in molecular weight, and polydispersity evolution during an accelerated in vitro degradation test were studied by size exclusion chromatography. Morphological changes in the polymeric matrix during degradation were followed after defined time intervals by means of scanning electron microscopy. Crystallinity studies were performed by differential scanning calorimetry and by X-ray analysis. Peptide stability in the polymeric matrix after both manufacturing methods was evaluated. Peptide release profiles, obtained in vitro during a week dissolution test, from both implant samples, were studied. It was shown that both molecular weight and polydispersity decreased after extrusion or injection-molding. This decrease was more pronounced with the latter technique. Crystallinity studies demonstrated that the crystalline network was not destroyed after both manufacturing methods. Peptide release profiles obtained in vitro were in good accordance with scanning electron microscopy. It was found that both manufacturing techniques had to be considered, although the extruded implants degraded more rapidly in vitro than the injection-molded ones.

Formation of peptide impurities in polyester matrices during implant manufacturing

Most peptides are susceptible, in vivo, to proteolytic degradation, and it is difficult to formulate and to deliver them without loss of biological activity. In addition, it is often desirable to release them continuously and at a controlled rate over a period of weeks or months. For these reasons, a controlled release system is suitable. Poly(lactic acid) (PLA) is a biocompatible and biodegradable material that can be used for many applications, including the design of injectable controlled release systems for pharmaceutical agents. Development of these delivery systems presents challenges in the assessment of stability, specially for peptide drugs. By means of an extrusion method, long-acting poly(lactic acid) implants containing vapreotide, a somatostatin analogue, were prepared. The nature of the main degradation product obtained after implant manufacturing was elucidated. It was found that the main peptide impurity was a lactoyl lactyl-vapreotide conjugate. Because lactide are found in small quantities in most commercially available PLA, the influence of residual lactide in the polymeric matrix, on the formation of peptide impurities during manufacturing, was specially investigated. This work demonstrates that the degree of purity of the carrier is of great importance with regard to the formation of peptide impurities.

Development of poly(ortho esters) and their application for bovine serum albumin and bupivacaine delivery

The preparation of drug delivery devices using solventless fabrication procedures is of significant interest and two such procedures are described. In one such procedure, powdered polymer and micronized protein are intimately mixed and then extruded into 1 mm strands that are cut to the desired length. The polymers used were specifically designed to allow extrusion at temperatures where proteins maintain activity in the dry state. In vitro erosion and BSA release show that BSA release and polymer erosion occur concomitantly indicating an erosion-controlled process. There is a lag-time, but that can be eliminated by the addition to the mixture prior to extrusion small amounts of poly(ethylene glycol) or its methoxy derivatives. The lag-time could also be eliminated by using an AB-block copolymer where A is poly(ortho ester) and B is poly(ethylene glycol). Another means of using solventless fabrication methods is to use a semi-solid material into which drugs can be mixed at room temperature and the semi-solid injected. Data on BSA and bupivacaine release are presented.

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 approximately 250 days. A modification of this formulation by means of a wear coating allows minimisation of the initial burst a feature rarely discussed.

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

Abstract 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.

Formulation and technology aspects of conrolled drug delivery in animals

In the veterinary field, the development of new routes of administration or new delivery systems capable of controlling the release of drugs are of considerable interest. Because of the large number of food-producing animals and the unique problems associated with the administration of drugs to these animals, the potential markets are huge and will only be fully realized if improvements to old dosage forms lead to practical and effective formulations. This review intends to summarize the state of the art in the field of veterinary controlled and/or prolonged release systems.

Stability studies of a somatostatin analogue in biodegradable implants.

In recent years, peptides and proteins have received much attention as drug candidates. For many polypeptides, particularly hormones, it is desirable to release the drug continuously at a controlled rate over a period of weeks or even months, and thus a controlled release system is needed. Polylactic acid (PLA) is a biocompatible and biodegradable material with wide utility for many applications, including the design of controlled release systems for pharmaceutical agents. Pharmaceutical development of these delivery systems presents new problems in the area of stability assessment, especially for peptide drugs. In this study, we aimed to investigate the influence of different steps, during the manufacturing of an implant, on peptide stability in the polymeric matrix. Polylactic acid implants containing vapreotide, a somatostatin analogue, were prepared by extrusion. The effects of time, extrusion and temperature on the peptide stability were studied. The influence of various gamma sterilization doses, as well as the conditions under which the implants were irradiated, were also investigated. Peptide stability in the polymeric matrix was evaluated at various temperatures and at various time intervals up to 9 months.

Controlled and/or prolonged parental delivery of peptides from the hypothalmic pituitary axis

In recent years, advances in genetic engineering and in several other fields have led to the development of many new pharmaceutically active polypeptides. Because many of these polypeptides have extremely short plasma half-lives and are not active orally, the development of new delivery routes of administration or new delivery systems capable of controlling the release of these materials in their active forms are of considerable interest. Controlled release products for parenteral applications, such as implants or microparticulate systems have gained increasing importance and appropriate delivery systems for peptides have become the subject of intensive research. Therefore, the therapeutic and commercial potential of these peptides will only be fully realized if these advances are accompanied by improvements in the design of dosage forms leading to practical and effective formulations. The intent of this review is to summarize the work done in the field of controlled and/or prolonged release systems for peptides from the hypothalamic pituitary axis and their analogs. The potential in controlled and/or prolonged peptide delivery and the particularity of various kind of controlled delivery systems are discussed.