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PubMedDate not supplied

Impact of liposomes as delivery systems in veterinary medicine.

The development of drug resistance and the inability of the drug to reach the location of the etiologic agents are major challenges for anti-infective and cancer therapies. As the development of new drugs with improved pharmacodynamic and pharmacokinetic properties is a slow and difficult process, drug delivery systems appear as promising alternatives. Liposomes are lipid vesicles formed when phospholipids are exposed to an aqueous environment. They arrange themselves in bilayers and close up, forming a vesicle. During this process they capture the aqueous phase of the dispersion, and any substance dissolved in it, within the vesicle. Liposomes have remarkable features that make them an almost ideal delivery system. They are biodegradable, with few side effects, can deliver drugs with different physico-chemical properties together and can be formulated for different routes of administration. The potential to modify the pharmacokinetic behaviour of encapsulated drugs to deliver them selectively to the site of action is the most important feature of liposomes as drug delivery systems. Liposomes are already used in human medicine for he treatment of bacterial, viral and parasitic diseases, and cancer. They have also been proven useful as immunoadjuvants and vaccines. Liposomes are used in certain avian vaccines. The possible uses of liposomes and their impact in veterinary medicine in the treatment of infectious diseases and cancer as well as in the prevention of diseases are discussed in the present article.

Animal Diseases↗
PubMed2001

Collagen minipellet as a controlled release delivery system for tetanus and diphtheria toxoid.

The use of biodegradable polymer matrices as a single-dose vaccine delivery system was investigated using tetanus toxoid (TT) and diphtheria toxoid (DT). BALB/c mice were immunized with TT or DT in different formulations including individual, in minipellet and aluminum hydroxide (alum), and the antibody responses were monitored for 48 weeks. Antigens entrapped in minipellet elicited higher antibody responses compared to those obtained with individual antigens and antigens adsorbed to alum and the antibody levels remained elevated over 48 weeks. In addition, minipellet formulations induced the same subclasses of antibodies induced by alum formulations. These results raise the possibility to obtain optimal and long-lasting immune responses by a single administration of minipellet formulations.

Adjuvants, Immunologic↗
PubMedDate not supplied

Bioadhesive fluorescent microspheres as visible carriers for local delivery of drugs. II: Uptake of insulin-loaded PCEFB/PLGA microspheres by the gastrointestinal tract.

Uptake of novel inherently fluorescent microspheres composed of a luminescent polyanhydride, poly[p-(carboxyethylformamido)-benzoic anhydride] (PCEFB), and poly(lactide-co-glycolide) (PLGA) (2:1, weight ratio) by the gastrointestinal tract was evaluated by fluorescent microscopy. Oral efficiency of the incorporated insulin also was determined by measuring reduction of plasma glucose levels after feeding diabetic rats with a single dose of the microspheres. We found that PCEFB/PLGA microspheres could adhere to the intestinal epithelium and traverse the absorptive cells. A large number of the spheres were observed in spleen, whereas few were detected in liver within the evaluated period of time. Apparent reduction of the plasma glucose levels was observed over a span of 6 h postfeeding. The unique properties of the delivery system such as biodegradability, bioadhesivity, and inherently luminescent characteristics render it an ideal "visible" tracer for monitoring oral fate of polymeric microspheres.

Adhesives↗
PubMedDate not supplied

Microencapsulation of gentamicin in biodegradable PLA and/or PLA/PEG copolymer.

Biodegradable carriers containing gentamicin for local treatment of bone infection were developed. This paper describes the preparation and in vitro evaluation of these biodegradable implants. Poly-L-lactic acid (PLA) and poly-L-lactic acid:polyethylene glycol (PLA/PEG) disk implants containing gentamicin sulphate were obtained by compression of microspheres prepared by a double emulsion process. The mean particle size distribution of the microspheres, based on volume, ranged from 95-270 microm. The gentamicin sulphate loading of the microspheres, after a methylene chloride-water extraction procedure, exceeded 90% of the theoretical value. In vitro dissolution studies on the microspheres and implants with drug loadings 10-40% w/w indicated that the rate of drug release from both PLA and PLA/PEG implants increased, with an increase in drug loading. The release of gentamicin from microspheres was dependent on the properties of PLA and/or PLA/PEG. The PLA/PEG copolymer was more hydrophilic than the PLA homopolymer, and with a smaller pH change in the microenvironment with polymer being degraded. In comparison, the PLA/PEG implant released antibiotic faster and had a larger inhibitory zone based on the Bauer-Kirby experiments used to test the inhibitory activity of antimicrobial devices. Experimental results showed that the biodegradable PLA/PEG gentamicin delivery system had a potential for prophylaxis of post-operative infection.

Anti-Bacterial Agents↗
PubMed2001

Effect of cross-linking on the in vitro release kinetics of doxorubicin from gelatin implants.

Doxorubicin is one of the most potent anti-tumor agents used generally in the treatment of bone cancer. Like other cancer chemotharepeutics, it produces undesirable side effects such as cardiotoxicity, which is especially severe when administrated via the conventional intravenous route. In order to minimize the systemic toxicities and to make this drug more suitable for the treatment of bone cancer, an implantable delivery system with cross-linked gelatin as the biodegradable matrix material was developed. This delivery system could possibly improve targeting of the drug as well as sustain the rate of release of the drug to the tumor. Glutaraldehyde was used as a cross-linking agent. Incorporation of glutaraldehyde in the matrix was needed to maintain the mechanical strength of the implant and to sustain the rate of release of the drug from the implant. Besides cross-linking the gelatin matrix, glutaraldehyde was found to cross-link the free amino group of doxorubicin. The effect of cross-linker concentration on the stability of the drug in the implant and on the rate and extent of release were also evaluated. In conclusion, cross-linked gelatin implants were developed for the local delivery of doxorubicin.

Antibiotics, Antineoplastic↗
PubMed2003

Genipin-crosslinked gelatin microspheres as a drug carrier for intramuscular administration: in vitro and in vivo studies.

Gelatin microspheres have been widely evaluated as a drug carrier. Nevertheless, gelatin dissolves rather rapidly in aqueous environments, making the use of the polymer difficult for the production of long-term delivery systems. This adverse aspect requires the use of a crosslinking agent in forming nonsoluble networks in microspheres. However, the use of crosslinking agents such as formaldehyde and glutaraldehyde can lead to toxic side effects owing to residual crosslinkers. In an attempt to overcome this problem, a naturally occurring crosslinking agent (genipin) was used to crosslink gelatin microspheres as a biodegradable drug-delivery system for intramuscular administration. Glutaraldehyde was used as a control. In the in vitro study, the morphology, dynamic swelling, and antienzymatic degradation of test microspheres were evaluated. In the in vivo study, the biocompatibility and degradability of test microspheres were implanted in the skeletal muscle of a rat model via intramuscular injection. The results obtained in the study suggested that crosslinking of gelatin microspheres with glutaraldehyde or genipin may produce distinct crosslinking structures. The water transport mechanism in both the glutaraldehyde- and genipin-crosslinked gelatin microspheres exhibit anomalous behavior ranging from Fickian to Case-II extremes. The increase of the swelling diameter for the genipin-crosslinked microspheres was significantly less than that observed for the glutaraldehyde-crosslinked microspheres. In the animal study, it was found that the degree in inflammatory reaction for tissues implanted with the genipin-crosslinked microspheres was significantly less than that implanted with the glutaraldehyde-crosslinked microspheres. Additionally, the degradation rate of the genipin-crosslinked microspheres was significantly slower than their glutaraldehyde-crosslinked counterparts. These results indicated that the genipin-crosslinked gelatin microspheres may be used as a long-acting drug carrier for intramuscular administration.

Animals↗
PubMed2002

In vivo release of vancomycin from biodegradable beads.

The current delivery system of antibiotics for the treatment of osteomyelitis uses polymethylmethacrylate (PMMA) beads as a local drug-release agent. The nonbiodegradable nature of the PMMA, however, necessitates a second operation to remove the beads. This article explores the alternative of using biodegradable polymers as antibiotic beads for a long-term drug release in vivo. To manufacture an antibiotic bead, lactide-glycolide copolymers were mixed with vancomycin. The mixture was compressed and sintered at 55 degrees C to form beads 8 mm in diameter. An in vivo animal model was proposed to characterize the elution rate of antibiotic over a 55-day period. Biodegradable beads released high concentrations of antibiotic (well above the breakpoint sensitivity concentration) in vivo for the period of time needed to treat bone infection; that is, 4-6 weeks. A bacterial inhibition test was also carried out to determine the relative activity of the released antibiotics. The diameter of the sample inhibition zone ranged from 8 to 18 mm, which is equivalent to 9.1 to 100% of relative activity. In addition, the antibiotic concentration of systemic blood was found to be very low. Antibiotic-impregnated biodegradable beads may have a potential role in the prevention and management of surgical infections.

Animals↗
PubMed2005

Use of biodegradable PLGA microspheres as a slow release delivery system for the Boophilus microplus synthetic vaccine SBm7462.

The synthetic anti-Boophilus microplus vaccine SBm7462 derived from the tick intestinal protein, Bm86, induced a protective immune response when emulsified in saponin and used in cattle. Using a mice model, and with the objective of improving the vaccine by continual peptide release, it was encapsulated in PLGA 50:50 microspheres and inoculated in BALB/c mice to assess the immunological response by detection of anti-peptide IgGs. Comparative studies were made with the peptide emulsified in saponin and with another synthetic vaccine, and the microsphere/peptide was characterized for efficiency of encapsulation, in vitro release profile, morphology, size, peptide integrity after encapsulation and stability in different pHs. The findings showed that saponin enhances a better immune response from SBm7462 and that the PLGA 50:50 microspheres are suitable for use with this peptide.

Animals↗
PubMed2004

In vivo study of biodegradable alginate antibiotic beads in rabbits.

The authors investigated the lyophilized poly-L-lysine-coated alginate antibiotic delivery system in vivo for the treatment of musculoskeletal infections. The sodium alginate was mixed with vancomycin, coated with poly-L-lysine and lyophilized to form 3 mm in diameter biodegradable antibiotic beads. The antibiotic beads were implanted in the distal femoral cavities of rabbits for in vivo investigation. The local concentration of vancomycin was well above the minimal inhibitory concentration of Staphylococcus aureus for 21 days. The release was most marked during the first two days. The diameters of sample inhibition zone ranged from 8 to 16 mm, the relative activity of vancomycin ranged from 12.5% to 100%. The blood level of vancomycin reached its peak (46.0 mg/l) two days after implantation and fell to 3.2 mg/l at two weeks. It was undetectable after three weeks. There was no increase in the concentration of blood urea nitrogen and serum creatinine after the implantation. Histological observations showed that bead materials were biodegradable, resorbed slowly and only cause mild host reaction. This study offers a biodegradable delivery system of antibiotics to treat musculoskeletal infections.

Alginates↗
PubMedDate not supplied

Microencapsulation and the grafting of genetically transformed cells as therapeutic strategies to rescue degenerating neurons of the CNS.

A number of approaches have been developed to deliver growth factors within the central nervous system of adult mammals. Initially a variety of neurotrophic factors were administered either by single intracerebroventricular or local injections directly into brain tissues or via permanently installed cannulae for chronic administrations. More recently delivery systems including conjugates, biodegradable and non-biodegradable implants and microspheres as well as genetically engineered cells have been introduced in order to provide a prolonged supply of neurotrophic factors and to prevent their enzymatic degradation. In this review we examine a variety of means of delivering neurotrophic factors (mainly nerve growth factor) with the primary focus upon the use of microencapsulated neurotrophins and cells genetically modified to produce them. In addition, this review highlights some difficulties and future trends in the development of novel delivery systems hopefully more suitable for investigations in different areas of neuroscience.

Animals↗
PubMed2006

Biodegradable scleral implants as new triamcinolone acetonide delivery systems.

The goal of this study was to develop ocular scleral implants able to release triamcinolone acetonide (TA) overall several months. Scleral discs were manufactured by a compression-molding method using a new synthetic polymer, poly(methylidene malonate) (PMM2.1.2), as matrix. Implants with good mechanical properties adapted for in vivo implantation have been obtained when using high M(w) PMM2.1.2 (100,000 - 150,000 Da) associated with ethoxylated derivatives of stearic acid (Simulsol) or oligomers of methylidene malonate as plasticizer. After implantation in rabbit eyes, scleral implants showed a good ocular biocompatibility. Indeed, the clinical follow-up and ocular inflammation parameters, such as inflammatory cell number and protein content in aqueous humor, demonstrated that implants were well tolerated and did not provoke abnormal inflammation. Implants were able to release significant concentrations of TA in the vitreous and the sclera throughout 5 weeks.

Absorbable Implants↗
PubMed1998

Intramural injection of biodegradable microspheres as a local drug-delivery system to inhibit neointimal thickening in a rabbit model of balloon angioplasty.

Restenosis remains the major limitation of coronary angioplasty. The objective of this study was to develop microspheres able to be delivered at the angioplasty site for long-term drug release and to test their effects in a model of balloon angioplasty. Polylactic-co-glycolide acid microspheres (5-10 microm in diameter) were prepared by using an oil-in-water emulsion-solvent evaporation method. In vitro experiments with hydrocortisone-loaded microspheres revealed a hydrocortisone release for 4 weeks. We studied the in vivo effect of injection of microspheres into the arterial wall of New Zealand White rabbits by using a perforated balloon. Deep penetration of microspheres in the arterial wall was documented immediately after angioplasty. Intimal hyperplasia was assessed in iliac arteries 4 weeks after angioplasty. The morphometric analysis was performed in four groups of animals; the first group was subjected only to conventional angioplasty (control, n = 10), whereas the other three groups after conventional angioplasty were received perforated balloon angioplasty with saline (n = 10), microspheres (n = 10), or hydrocortisone-loaded microspheres (n = 7). Intramural injection of saline did not induce greater intimal hyperplasia compared with control (0.17 +/- 0.03 vs. 0.18 +/- 0.03 mm2, respectively). Microspheres injection was associated with a trend toward a greater degree of intimal hyperplasia that did not reach statistical significance. Hydrocortisone-loaded microspheres were associated with a significant reduction in intimal hyperplasia compared with unloaded microspheres (0.16 +/- 0.02 vs. 0.26 +/- 0.03 mm2, respectively). The polylactic-co-glycolide acid microspheres are well tolerated, easily injected into the arterial wall, and the increase of intimal hyperplasia is easily inhibited by release of hydrocortisone for 4 weeks after initial injury.

Angioplasty, Balloon↗
PubMed1987

Biodegradable microspheres: polyacryl starch microparticles as a delivery system for the antileishmanial drug, sodium stibogluconate.

Liver parasite burdens of Leishmania donovani in the mouse have been determined after treatment with intravenous administration of sodium stibogluconate in the free or carrier form. The carrier form, in which the drug was covalently bound to polyacryl starch microparticles, was up to 100x more effective than the free form in this murine model of visceral leishmaniasis. Empty microparticles had no effect on liver parasite burdens and the enhanced in-vivo antileishmanial activity of the carrier form of the drug was apparently due to passive drug delivery to the infected liver.

Animals↗
PubMed2004

Sustained polymeric delivery of gene silencing antisense ODNs, siRNA, DNAzymes and ribozymes: in vitro and in vivo studies.

Small interfering RNA (siRNA), antisense oligonucleotides (ODNs), ribozymes and DNAzymes have emerged as sequence-specific inhibitors of gene expression that may have therapeutic potential in the treatment of a wide range of diseases. Due to their rapid degradation in vivo, the efficacy of naked gene silencing nucleic acids is relatively short lived. The entrapment of these nucleic acids within biodegradable sustained-release delivery systems may improve their stability and reduce the doses required for efficacy. In this study, we have evaluated the potential in vitro and in vivo use of biodegradable poly (D,L-lactide-co-glycolide) copolymer (PLGA) microspheres as sustained delivery devices for ODNs, ribozyme, siRNA and DNA enzymes. In addition, we investigated the release of ODN conjugates bearing 5'-end lipophilic groups. The in vitro sustained release profiles of microsphere-entrapped nucleic acids were dependent on variables such as the type of nucleic acid used, the nature of the lipophilic group, and whether the nucleic acid used was single or double stranded. For in vivo studies, whole body autoradiography was used to monitor the bio-distribution of either free tritium-labelled ODN or that entrapped within PLGA microspheres following subcutaneous administration in Balb-c mice. The majority of the radioactivity associated with free ODN was eliminated within 24 h whereas polymer-released ODN persisted in organs and at the site of administration even after seven days post-administration. Polymer microsphere released ODN exhibited a similar tissue and cellular tropism to the free ODN. Micro-autoradiography analyses of the liver and kidneys showed similar bio-distribution for polymer-released and free ODNs with the majority of radioactivity being concentrated in the proximal convoluted tubules of the kidney and in the Kupffer cells of the liver. These findings suggest that biodegradable PLGA microspheres offer a method for improving the in vivo sustained delivery of gene silencing nucleic acids, and hence are worthy of further investigation as delivery systems for these macromolecules.

Animals↗
PubMed1997

Tumor treatment by sustained intratumoral release of cisplatin: effects of drug alone and combined with radiation.

PURPOSE: The effect of intratumoral delivery of cisplatin to a mouse tumor model (RIF-1) by means of a biodegradable polymer implant with and without radiation was studied. METHODS AND MATERIALS: The polymer bis (p-carboxyphenoxy) propane-sebacic acid (CPP:SA; 80:20) and its degradation products have been characterized. Polymer rods (8 x 0.5 mm) containing 17% cisplatin by weight were prepared by extrusion, and the in vitro degradation rate measured. The implants were placed into mouse tumors and their effect (with and without radiation) on tumor growth delay studied. The levels of Pt in the mouse kidney, tumor, and blood plasma at selected intervals after implant were also determined. These results were compared with those obtained when cisplatin was delivered systemically. RESULTS: When cisplatin was delivered by the polymer implants, higher levels were present in the tumor for longer time periods (cf. systemic delivery of the drug). For both nonirradiated and irradiated tumors, those treated with the polymer implants had significantly longer tumor growth delays compared to nonimplanted controls and to systematically treated tumors. CONCLUSIONS: The results show that intratumoral delivery of cisplatin is more efficient than systemic delivery. Using the biodegradable polymer implant, higher doses of cisplatin can be tolerated by the animal as the drug is localized within the tumor, and the high levels of the drug in the tumor can be maintained for an extended period of time. When radiation is given in conjunction with cisplatin, the tumor response is supraadditive for all modes of cisplatin administration but is potentiated to a greater extent when cisplatin is delivered through the polymer implant. The greatest effect is seen for treatment with cisplatin delivered by polymer implant combined with fractionated radiation.

Animals↗
PubMed2005

Microencapsulation peptide and protein drugs delivery system.

Many methods were used to devise peptide and protein drugs delivery system (DDS). Because of their relatively large size, they have low transdermal bioavailabilities. In systemic delivery of proteins, biodegradable material as parenteral depot formulation occupy an important place because of several aspects like protection of sensitive proteins from degradation, prolonged or modified release, pulsatile release patterns. The main objective in developing controlled release protein injectables is avoidance of regular invasive doses which in turn provide patient compliance, comfort as well as control over blood levels. This review article presents the outstanding contributions in field of microencapsulation as protein delivery systems and different approaches of protein delivery are described. Then discusses how these advances may be applied to resolve the challenges face the development of microcapsule for the controllable delivery of protein drugs.

Alginates↗
PubMed2001

Intranasal vaccination against plague, tetanus and diphtheria.

Plague is an extremely virulent and potentially lethal infection caused by the bacterium Y. pestis. The current vaccine used to immunise against plague often fails to engender solid (100%) protection against inhalational infection with Y. pestis. Similarly, logistical factors favour the development of non-parenteral immunisation protocols to counter plague. Recently an improved parenteral vaccination strategy for plague, based on the recombinant subunit approach, has entered clinical trails. The Yersinia pestis subunit antigens (F1 and V) have been successfully incorporated into novel vaccine delivery systems such as biodegradable microspheres composed of poly-L-(lactide) (PLLA). Intranasal and intratracheal administration of PLLA microencapsulated F1 and V serves to protect experimental animals from inhalational and subcutaneous challenge with virulent Y. pestis bacilli. Liposomes have also been used to improve the immunogenicity of intranasally administered Y. pestis antigens, and the effectiveness of this approach to plague immunisation has been evaluated. Tetanus and diphtheria still cause many deaths worldwide. The maintenance of protective immunity to diphtheria and tetanus requires booster injections of the currently licensed toxoid vaccines. Consequently, many people remain unprotected. Improved coverage may well result from the development of effective non-invasive vaccines that could be readily distributed and potentially self-administered. To this end, the intranasal and inhalational routes of administration have been extensively investigated. Tetanus and diphtheria toxoids have been delivered intranasally to experimental animals using a wide variety of adjuvants (enterotoxin derivatives), penetration enhancers (cyclodextrins, bile salts, surfactants, cationic polymers) and delivery systems (microspheres and liposomes). As compared with parenteral vaccination, nasal immunisation has been shown favourably effective in small animal models, and a limited number of early phase clinical trails. As a caveat to this, adjuvantisation of toxoid/subunit molecules appears to be a requisite for elicitation of appreciable immunological responses, following nasal administration of acellular immunogens. Testing in larger animal models and humans is needed to ascertain if the promising results obtained in rodents can be reciprocated without compromising safety.

Administration, Intranasal↗
PubMed2005

The enzymatic degradation and swelling properties of chitosan matrices with different degrees of N-acetylation.

In the design of chitosan-based drug delivery systems and implantable scaffolds, the biodegradation rate of the chitosan matrix represents a promising strategy for drug delivery and the function of carriers. In this study, we have investigated the degradation of chitosan with different degrees of N-acetylation, with respect to weight loss, water absorption, swelling behavior, molecular weight loss of bulk materials, and reducing sugar content in the media. Chitosan matrices were prepared by compression molding. The results revealed that the initial degradation rate, equilibrium water absorption, and swelling degree increased with decreasing degree of deacetylation (DD) and a dramatic rise began as DD of the chitosan matrix decreased to 62.4%. Chitosan matrices with DD of 52.6%, 56.1%, and 62.4% had the weight half-life of 9.8, 27.3, and more than 56 days, respectively, and the weight half-life of average molecular weight 8.4, 8.8, and 20.0 days, respectively. For chitosan matrices with DD of 71.7%, 81.7%, and 93.5%, both types of half-life exceeded 84 days because of the much slower degradation rate. The dimension of chitosan matrices during degradation was determined by the process of swelling and degradation. These findings may help to design chitosan-based biomedical materials with predetermined degradation timed from several days to months and proper swelling behaviors.

Absorption↗