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At least 811 records · Page 45Linked to original sources
PubMed2001

Pharmacokinetic model for in vivo/in vitro correlation of intravitreal drug delivery.

A pharmacokinetic model of intravitreal drug delivery has been developed for describing the elimination and distribution of ocular drugs in the posterior segments of the eye. The model, based on Fick's second law of diffusion, assumes the cylindrical vitreous body with three major pathways for elimination: the posterior aqueous chamber, the retina/choroids/sclera (RCS) membrane and the lens posterior capsule. The model parameters such as the diffusion coefficient and the partition coefficient of the drug in the vitreous body and its surrounding tissues, the posterior lens capsule and the retina/choroids/sclera membrane, can be determined from in vitro membrane penetration experiments using respective rabbit tissues. The time course of in vivo mean concentration of the drug in the rabbit vitreous body following intravitreal drug delivery well agreed with the profile calculated from the present pharmacokinetic model for both membrane-controlled polymeric devices and biodegradable rod-matrix systems. The pharmacokinetic model suggests that the major route of elimination of drug molecules released from the vitreous implant is through the posterior aqueous humor because of the absence of a barrier membrane. However, the elimination through the RCS membrane cannot be overlooked because of the large diffusion area of the RCS membrane. The vitreous body concentration of the drug released from biodegradable vitreous implants can be predicted from the in vivo release rate-time profile by the present pharmacokinetic model.

Animals↗
PubMed2003

Characterization of methacrylated inulin hydrogels designed for colon targeting: in vitro release of BSA.

PURPOSE: To characterize methacrylated inulin hydrogels with respect to their release properties. METHODS: Proteins (bovine serum albumin or lysozyme) were used as model drugs and were loaded during or after hydrogel formation. Parameters such as the drug loading method, the molecular weight of the proteins, the initial drug loading concentration, the hydrogel feed composition, degree of substitution, and size of the hydrogel were investigated by determining the release of the model proteins from the hydrogels in a phosphate buffer solution. The biodegradable properties were investigated by studying the release of bovine serum albumin in a solution of inulinase. RESULTS: In vitro protein release from methacrylated hydrogels was influenced by factors such as the drug loading procedure and the molecular weight and loading concentration of the proteins. The feed composition and degree of substitution of inulin seem to be crucial in controlling both the extent and the rate of release. Protein release was clearly enhanced in the presence of inulinase, indicating the biodegradable properties of methacrylated inulin hydrogels. CONCLUSIONS: Several hydrogels show interesting properties with respect to the development of a colon-specific drug delivery system.

Colon↗
PubMed1996

Efficacy of intralesionally administered cisplatin-impregnated biodegradable polymer for the treatment of 9L gliosarcoma in the rat.

OBJECTIVE: Use of biodegradable polymers for the local delivery of chemotherapy is a promising new strategy in the treatment of high-grade gliomas. We examine the benefit of local delivery of cisplatin, via biodegradable polymer, in the treatment of intracranial glioma in rats. This treatment is compared against intralesionally administered free cisplatin and systemic cisplatin. METHODS: The Fischer 344 9L gliosarcoma rat model was used with a cannula placed in the right frontal lobe. On Day 0, 5 x 10(3) 9L gliosarcoma cells were infused. Treatment was initiated on Day 7. In Experiment 1, polymer alone was infused intralesionally to rule out any inherent toxic or tumoricidal properties. In Experiment 2, polymer impregnated with 0.5, 5.0, and 25 mg/m2 cisplatin was infused intralesionally. In Experiment 3, the most effective dose of drug containing polymer was compared against a similar dose of intralesionally administered free cisplatin and the systemic administration of cisplatin. RESULTS: In Experiment 1, polymer alone demonstrated no inherent toxic or tumoricidal properties. In Experiment 2, polymer impregnated with 0.5 mg/m2 was 100% effective in eradicating intracranial tumor with minimal histological evidence of toxicity. At the 5.0 and 25 mg/m2 doses, local brain toxicity was significant. In Experiment 3, at Day 60, 8 of 12 animals treated with polymer containing 0.5 mg/m2 cisplatin were alive and tumor free. This compared with 3 of 13 tumor-free survivors for the group treated with intralesionally administered free cisplatin, and 0 of 13 and 0 of 11 survivors for the 50 and 100 mg/m2 intraperitoneally administered doses, respectively. CONCLUSION: The local instillation of cisplatin-impregnated biodegradable polymer, allowing the sustained release of high-dose chemotherapy locally, seems to be effective treatment for intracranial 9L gliosarcoma in the rat. Treatment was superior to intralesionally administered free or systemic cisplatin.

Animals↗
PubMedDate not supplied

Spray-dried albumin microspheres for the intra-articular delivery of dexamethasone.

This work deals with the preparation of corticosteroid-loaded albumin microspheres designed for intra-articular administration. Dexamethasone was chosen as the model drug and bovine serum albumin was used as the biodegradable, natural polymer. Albumin microspheres were produced by spray drying, a 'one-step' technique seldom used in the preparation of microparticulate drug delivery systems with particle sizes < 10 microns. The effects of both polymer/drug ratio used in the formulations and the different heat-stabilization conditions were evaluated on morphology, size, solubility characteristics, drug loading and 'in vitro' drug release of the microparticles.

Dexamethasone↗
PubMed2001

Enzyme loaded biodegradable microspheres in vitro ex vivo evaluation.

Prolidase is a naturally occurring enzyme involved in the final stage of protein catabolism. Deficient enzyme activity causes prolidase deficiency (PD), a rare autosomal recessive inherited disorder whose main manifestations are chronic, intractable ulcerations of the skin, particularly of lower limbs. Although several attempts have been made towards the treatment of this pathology, a cure for this disease has yet to be found. The purpose of this work is to evaluate the possibility of enzyme replacement therapy through prolidase microencapsulation in biodegradable microspheres. The poly(D,L-lactide-co-glycolide) (PLGA) prolidase loaded microparticulate systems have been prepared utilizing the w-o-w double emulsion solvent evaporation method. They have been characterized "in vitro" by morphological analysis, total protein content and an in vitro dissolution test of active protein. "Ex vivo" evaluation of prolidase activity from the microspheres has been performed on cellular extracts of cultured skin fibroblasts from healthy subjects (controls) and from patients affected by PD. The results reported in this work on prolidase from pig kidney (available on the market) demonstrate the positive role of microencapsulation as a process of enzymatic activity stabilization inside PLGA microspheres achieving both in vitro and ex vivo active enzyme release. This formulation can be proposed as a parenteral depot drug delivery system.

Adult↗
PubMed2006

Synthesis and characterization of poly-alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide]-g-poly(L-lactide) biodegradable copolymers as drug carriers.

A series of biodegradable amphiphilic graft polymers were successfully synthesized by grafting poly(L-lactide) (PLLA) sequences onto a water-soluble polymer poly-alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide] (PHEA) backbone. We established the feasibility of preparing these novel graft polymers by the ring-opening polymerization initiated by the macroinitiator PHEA bearing hydroxyl groups without adding any catalyst. The successful grafting of PLLA sequences onto the PHEA backbone was verified by combined size exclusion chromatography (SEC) and multiangle laser light scattering (MALLS) analysis. The chemical structures of graft polymers were characterized by FTIR and (1)H NMR. The critical micelle concentration (CMC) of the graft polymer was determined by fluorescence probe technique using pyrene. By controlling the feed ratio of the macroinitiator to the monomer, graft polymers with different branch lengths can be obtained. Using the 3-(4,5 dimethylthiozol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, the graft copolymer has been proved to have low cytotoxicity. Based on the amphiphilicity of the graft copolymers, nanoparticular drug delivery systems were prepared by the direct dissolution method and the dialysis method. The anticancer drug Tegafur was encapsulated into polymeric nanoparticles, and in vitro drug release behavior was investigated. Transmission electron microscopy (TEM) images demonstrate that these nanoparticles are regularly spherical in shape. The particle size and distribution of the nanoparticles were measured.

Animals↗
PubMed2000

A poly(ortho ester) designed for combined ocular delivery of dexamethasone sodium phosphate and 5-fluorouracil: subconjunctival tolerance and in vitro release.

A viscous hydrophobic poly(ortho ester) (POE) has been developed as a biocompatible, biodegradable sustained release system for selected cases of glaucoma filtering surgery. Dexamethasone and 5-fluorouracil (5-FU) are frequently administered together post-operatively, for their anti-fibroblastic and anti-inflammatory properties, respectively. A combined sustained release of both drugs could be advantageously used. Drug release kinetics were studied using specially designed thermostated cells. Subconjunctival tolerance was evaluated on New Zealand albino rabbits by clinical evaluation. Due to its basicity, the addition of dexamethasone sodium phosphate (DEX-P) stabilized the polymer and prolonged 5-FU in vitro release from 2 to 4 days. Both therapeutic agents were released concomitantly, according to a linear profile. The presence of 5-FU only slightly affected the overall subconjunctival tolerance of POE in rabbits, whereas the addition of DEX-P markedly improved POE tolerance by reducing the hyperemia of the conjunctiva to a minimal grade.

Animals↗
PubMed2002

Robust and prolonged gene expression from injectable polymeric implants.

We introduce an injectable system for the formation of a biodegradable DNA-containing implant that releases DNA over a 2-month period to provide a robust and prolonged gene expression at the site. Sustained delivery of the appropriate plasmid DNA resulted in sustained expression of luciferase, the persistent appearance of secreted alkaline phosphatase in the serum and small blood vessel formation in the vicinity of the implant from the delivery of the development endothelial locus-1 gene. Local expression of development endothelial locus-1 protein promotes the development of blood vessels to meet the metabolic demands of new tissue and is a paradigm for the delivery of other growth factors that act locally to aid tissue regeneration. This delivery system involves simple preparation procedures and can be injected directly into the site, hence should be a useful approach to plasmid-based gene transfer for vaccination and tissue engineering.

Absorbable Implants↗
PubMed1998

Membrane fusion and rupture in liposomes: effect of biodegradable pH-sensitive surfactants.

Biodegradable pH-sensitive surfactants (BPS) are a unique family of easily metabolized compounds that demonstrate pH-dependent surface activity. These agents, in combination with other delivery systems, have demonstrated effects in enhancing transnucleic acid activity. The increased activity has been hypothesized to occur from a release of endosomal contents. Simply, the BPS delivery system containing nucleic acids enters the cell through an endocytotoic process. It encounters an acidic pH and becomes surface active leading to defects in the endosomal membrane. In the current study, an in vitro model membrane was used to better understand the liposome defect mechanisms that BPS elicit. Using this system, it is shown that BPS can induce both liposome fusion and rupture depending upon the pH and mole ratio of BPS to membrane lipids. Futhermore, liposome fusion induced by BPS was dependent on the total numbers of liposome particles while rupture was independent of interacting liposome particles. The generated data indicate that BPS agents act differently from other typical surface active agents and fuosgenic compounds. Instead of facilitating membrane fusion through the hexagonal II phase, BPS appeared to contribute and participate in the membrane fusion at different stages.

Biodegradation, Environmental↗
PubMed1991

Nanoparticles and liposomes: a state of the art.

The loading of drugs into ultrafine host vesicles or colloidal capsules in the nanometer size range is an acknowledged technique for the optimization of controlled drug delivery. The main purpose will always be to design inert auxiliary accompanying materials; to use body-friendly and biodegradable excipients; and to miniaturize the drug carrier system dramatically in order to get good stability, excellent absorption, quantitative tissular transfer and, therefore, the expected pharmacodynamic activity. Furthermore, side effects and foreign body irritation should be avoided and a good local and systemic tolerance during and after medication should be a condition sine qua non. The actual state of the art is shown with 4 practical application examples, namely: a cellular uptake by endocytosis and a specific lysosomotropic cell transfer with cell tracer-loaded nanoparticles; the strong immunosuppressive stimulation of nanocapsules--as new adjuvants--when loaded with viral or other antigens; the better blood-brain barrier transfer of an antiparkinson drug when covalently bound to special liposomes; and the use of minivesicles for controlled site-specific anticancer drug release (tumor targeting). In the future, we must find a possibility to deliver the correct dose of the drug precisely to the diseased target organs, tissues or cells of destination, without flooding the organism with massive drug doses. One technologic answer could be the minicarrier concept with specific pathfinders and aspecific pretargeters that serve as switchmen to guide the drug-loaded carrier to the organs, with precise spot landing.

Animals↗
PubMed2006

[Investigation of biodegradable materials as polymeric gene carriers].

This is a study on the biodegradable polymers as gene controlled-released coatings for gene transfer. The PELA (poly (Dl-lactic acid)-co-poly (ethylene glycol), and PLGAE (poly (lactic acid)-co-poly (ethylene glycol)-co-poly (glycolic acid) random copolymer) were synthesized and prepared as the coatings of plasmid pCH110 in the transfection. All kinds of factors affecting the loading efficiency, cytotoxicity, transfection efficiency and the course of the degradation and release in vitro were discussed. The average diameters of microspheres of PELA and PLGAE were 1-3 microm and 0.72 microm respectively. The loading efficiency levels of them were 62% and 70% respectively. The transfection efficiency levels of two kinds of pCH110 delivery system for COS-1 cells were higher and two of them had few cytotoxicity. After transfection, the X-gal assay was performed and reported positive for 96 h. The biodegradable polymeric materials as gene carriers possess their potential superiority.

Biocompatible Materials↗
PubMed2003

Water-soluble biodegradable cationic polyphosphazenes for gene delivery.

Polyphosphazenes bearing cationic moieties were synthesized from poly(dichloro)phosphazene, which in turn was obtained by thermal polymerization of hexachlorocyclotriphosphazene in 1,2,4-trichlorobenzene. Next, either 2-dimethylaminoethanol (DMAE) or 2-dimethylaminoethylamine (DMAEA) side groups were introduced by a substitution reaction. The polymers were purified by dialysis against water and tetrahydrofuran, lyophilized and evaluated as polymeric transfectants. The polyphosphazenes were able to bind plasmid DNA yielding positively charged particles (polyplexes) with a size around 80 nm at a polymer/DNA ratio of 3:1 (w/w). The polyphosphazene-based polyplexes were able to transfect COS-7 cells in vitro with an efficiency comparable to a well-known polymeric transfectant [poly(2-dimethylaminoethyl methacrylate), pDMAEMA]. The toxicity of both polyphosphazenes was lower than pDMAEMA. The transfection efficiency for the poly(DMAE)phosphazene-based polyplexes was about threefold higher in the absence of serum than in the presence of 5.0% fetal bovine serum. This is probably caused by unfavorable interactions of the polyplexes with serum proteins. In contrast, the poly(DMAEA)phosphazene-based polyplexes showed a threefold lower transfection activity in the absence of serum. For this system, serum proteins likely masked the toxicity of the polyplexes, as shown by the XTT cell viability assay and confocal laser scanning microscopy studies. Preliminary degradation studies indicate that the polymers were indeed degradable. The half-life at pH 7.5 and 37 degrees C was around 7 days for poly(DMAE)phosphazenes and 24 days for poly(DMAEA)phosphazenes. This study shows that polyphosphazenes are a suitable and promising new class of biodegradable polymeric carriers for gene delivery.

Animals↗
PubMed2005

Characterization and biocompatibility of organogels based on L-alanine for parenteral drug delivery implants.

The development of simple and efficient drug delivery systems for the sustained release of peptides/proteins and low molecular weight hydrophilic molecules is an ongoing challenge. The purpose of this work was to prepare and characterize novel biodegradable in situ-forming implants obtained via the self-assembly of L-alanine derivatives in pharmaceutical oils. Six different amphiphilic organogelators based on L-alanine were synthesized. These derivatives could successfully gel various vegetable and synthetic oils approved for parenteral administration. Gelation was thermoreversible, and phase transition temperatures depended on gelator structure, concentration and solvent. Hydrogen bonds and van der Waals interactions were shown to be the main forces implicated in network formation. Selected formulations were then injected subcutaneously in rats for preliminary assessment of biocompatibility. Histopathological analysis of the surrounding tissues revealed mild, chronic inflammation and an overall good biocompatibility profile of the implants over the 8 wk evaluation period. This study demonstrates that in situ-forming organogels represent a potentially promising platform for sustained drug delivery.

Alanine↗
PubMed2004

Arthroscopic meniscal repair with an absorbable screw: results and surgical technique.

The results of a new method for arthroscopic all-inside meniscus repair using a biodegradable cannulated screw (Clearfix meniscal screw) were assessed in a medium-term follow-up prospective study. The Clearfix meniscal screw system consists of delivery cannulae, screw driver, and screw implants. After tear debridement, a screw is located on the driver and passed through the cannula to the insertion site, holding the two sides of the tear together under linear compression. Forty-eight patients (48 repairs) with a mean age of 32.7 years were included in the study. Ligament stabilizing procedures were done in 39 patients (81%) who had anterior cruciate ligament deficient knees. Only longitudinal lesions in the red/red or red/white zone were repaired. Follow-up averaged 19 months, with a range from 12 to 48 months. Patients were evaluated using clinical examination, the "Orthopaedische Arbeitsgemeinschaft Knie (OAK)" knee evaluation scheme and magnetic resonance imaging (MRI). Criteria for clinical success included absence of joint-line tenderness, absence of swelling and a negative McMurray test. Postoperatively, there were no complications directly associated with the device. Twelve of 48 repaired menisci (25%) were considered failures according to the above-mentioned criteria. According to the OAK knee evaluation scheme, 38 patients (79%) had an excellent or good result. MRI, however, showed persisting grade III or IV lesions in 35 patients (73%). Analysis showed that age, length of tear, and simultaneous anterior cruciate ligament reconstruction did not affect the clinical outcome. In contrast, risk factors for failure of meniscus repair are chronicity of injury, location of tear more than 3 mm from the meniscosynovial junction and meniscus side (medial).

Absorbable Implants↗
PubMed2004

Continuous release of rh-interferon alpha-2a from triglyceride matrices.

The use of biodegradable polymeric matrices as controlled release systems is known to be associated with various drawbacks. The objective of this study was to develop an alternative delivery system based on triglycerides, thereby aiming for sustained continuous protein release. Tristearin implants containing lyophilised rh-interferon alpha-2a (IFN-alpha) and varying amounts of polyethylene glycol 6000 (PEG) were prepared by compression. Release studies exhibited that more than 90% of the incorporated IFN-alpha can be liberated in a continuous way over 1 month from systems containing 10% PEG. Integrating hydroxypropyl-beta-cyclodextrin (HP-beta-CD) into the matrices proved to stabilise IFN-alpha and led to a higher and faster protein release due to solubilising effects. The protein was released in virtually monomeric form. Scanning electron microscopy (SEM) and mercurial porosimetry revealed the matrices forming an interconnected pore network.

Delayed-Action Preparations↗
PubMed2003

In vivo bone and soft tissue response to injectable, biodegradable oligo(poly(ethylene glycol) fumarate) hydrogels.

This study was designed to assess in vivo bone and soft tissue behavior of novel oligo(poly(ethylene glycol) fumarate) (OPF) hydrogels using a rabbit model. In vitro degradation of the OPF hydrogels was also investigated in order to compare with in vivo characteristics. Four groups of OPF hydrogel implants were synthesized by alternation of crosslinking density, poly(ethylene glycol) (PEG) block length of OPF, and cell-binding peptide content. The in vitro degradation rate of OPF hydrogels increased with decreasing crosslinking density of hydrogels, which was characterized by measuring weight loss and swelling ratio of hydrogels and medium pH change. Examination of histological sections of the subcutaneous and cranial implants showed that an uniform thin circumferential fibrous capsule was formed around the OPF hydrogel implants. Quantitative evaluation of the tissue response revealed that no statistical difference existed in capsule quality or thickness between implant groups, implantation sites or implantation times. At 4 weeks, there was a very limited number of inflammatory and multinuclear cells at the implant-fibrous capsule interface for all implants. However, at 12 weeks, OPF hydrogels with PEG block length of number average molecular weight 6090+/-90 showed extensive surface erosion and superficial fragmentation that was surrounded by a number of inflammatory cells, while OPF hydrogels with PEG block length of number average molecular weight 930+/-10 elicited minimal degradation. Constant fibrous capsule layers and number of inflammatory cells were observed regardless of the incorporation of cell-binding peptide and crosslinking density of OPF hydrogels with PEG block length of number average molecular weight 930+/-90. These results confirm that the degradation of implants can be controlled by tailoring the macromolecular structure of OPF hydrogels. Additionally, histological evaluation of implants proved that the OPF hydrogel is a promising material for biodegradable scaffolds in tissue engineering.

Animals↗
PubMed1998

In vitro degradation study of polyester microspheres by a new HPLC method for monomer release determination.

Biodegradable polyesters have increasing importance as materials used for the preparation of microspheres. The knowledge of their degradation process is important to prepare microparticulate delivery systems with suitable drug release rates. In this work an in vitro degradation study of empty and drug loaded microspheres is described. Three different polyesters were used: two poly-d, l-lactides of different molecular weight and a poly-d, l-lactide-co-glycolide (50:50). Diazepam has been chosen as the model drug. Solvent evaporation and spray-drying were used as preparation methods. To study the polymer degradation process, a new HPLC method is proposed for the direct and (in the case of the copolymer) simultaneous determination of the monomer(s): lactic acid (LA) and glycolic acid (GA). SEM and particle size analysis highlight the different characteristics of the particles, depending on their preparation method: spray-dried spheres result to be always smaller with respect to particles obtained by solvent evaporation. The results obtained indicate in particular that: the preparation methods play an important role in determining the degradation behaviour of microspheres, as unloaded spray-dried particles are characterized by a higher monomer release rate with respect to microspheres obtained by solvent evaporation; PLGA spheres degrade faster than PDLLA microparticles, according to the higher hydrophilicity of the copolymer; the two monomers are released at a different rate in the case of PLGA (faster for GA, slower for LA); the presence of diazepam increases the polymer degradation rate, with respect to empty particles.

Biocompatible Materials↗