Challenges in polymer therapeutics: state of the art and prospects of polymer drugs.
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Animals↗
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Results for “Biodegradable Delivery Systems”
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Piroxicam release from spray-dried biodegradable microspheres.
Poly(D,L-lactide) (DL-PLA) and poly(D,L-lactide-co-glycolide) (DL-PLGA) microspheres containing a non-steroidal anti-inflammatory model drug, piroxicam, were prepared by a spray drying process. The microspheres were characterized for surface morphology by scanning electron microscopy, particle size distribution by laser diffraction spectrometry, drug content and in vitro drug release. The diameters of the microspheres ranged from 1 to 15 microns. The DL-PLA particles appeared to be more spherical and smooth than the DL-PLGA particles, which showed a more undulated surface. Piroxicam content in the microspheres was 10%. A very high encapsulation efficiency of 99.0% was achieved with both polymers. In vitro release studies were carried out in a flow-through cell. The in vitro release rate of the drug from the DL-PLA microspheres was very slow. Less than 20% of the loaded drug was released within 10 d. The release mechanism was diffusion controlled and followed a square root of time relationship. Only a very small initial burst effect was observed. In contrast, the DL-PLGA microspheres provided a much faster drug release: about 50% was released within the first 5 h of the experiment. The mechanism for piroxicam release from the DL-PLA microspheres is not matrix erosion, but mainly drug diffusion through the intact polymer barrier. For the DL-PLGA microspheres, a pore diffusion release mechanism is proposed.
Biodegradation, Environmental↗
Biodegradable poly(lactic-co-glycolic acid) microparticles for injectable delivery of vaccine antigens.
Injectable biodegradable polymeric particles (usually microspheres) represent an exciting approach to control the release of vaccine antigens to reduce the number of doses in the immunization schedule and optimize the desired immune response via selective targeting of antigen to antigen presenting cells. After the first couple of decades of their study, much progress has been made towards the clinical use of antigen-loaded microspheres. Poly(lactide-co-glycolic acids) (PLGAs) have been studied most commonly for this purpose because of their proven safety record and established use in marketed products for controlled delivery of several peptide drugs. PLGA microspheres have many desirable features relative to standard aluminum-based adjuvants, including the microspheres' ability to induce cell-mediated immunity, a necessary requirement for emergent vaccines against HIV and cancer. This review examines several impediments to PLGA microparticle development, such as PLGA-encapsulated antigen instability and deficiency of animal models in predicting human response, and describes new trends in overcoming these important issues. PLGA microparticles have displayed unprecedented versatility and safety to accomplish release of one or multiple antigens of varying physical-chemical characteristics and immunologic requirements, and have now met numerous critical benchmarks in development of long-lasting immunity after a single injected dose.
Animals↗
Influences of excipients on in vitro release and in vivo performance of tetanus toxoid loaded polymer particles.
Protein instability during microencapsulation has been one of the major hurdles of biodegradable polymer particles-based vaccine delivery systems. In the present work, effect of serum albumin, sucrose and sodium bicarbonate on surface morphology, entrapment efficiency, in vitro release and in vivo performance tetanus toxoid (TT) loaded PLA particles were investigated. Use of serum albumin as well as high concentration of protein antigen ( approximately 60mg/ml) helped in protecting the immunoreactivity of the antigen during primary emulsification step of particle formulation. Incorporation of sucrose in the internal aqueous phase led to the reduction in encapsulation efficiency of TT from 43.8+/-4.3% to 27.3+/-3.6% in PLA particles and resulted with formation of particles having irregular surface characteristics. Addition of sodium bicarbonate along with sucrose during primary emulsion led to slight improvement in encapsulation efficiency of TT (34.3+/-3.2%) but affected the in vivo performance in terms of serum anti-TT antibody titers from single point immunization. Restoration of osmotic balance by adding equivalent amount of sucrose in external aqueous phase helped in preventing multiple emulsion instability and subsequently improved the encapsulation efficiency of TT to 63.1+/-4.2%. Maximum entrapment efficiency of TT up to 69.2+/-5.1% was achieved when serum albumin, sucrose and sodium bicarbonate were used in internal aqueous phase and sucrose was used in the external aqueous phase. Polymer particles entrapping tetanus toxoid along with optimal stabilizers showed burst release of immunoreactive antigen (>40% in early period) and elicited high and sustained anti-TT antibody titers from single point intramuscular immunization. Anti-TT antibody titers were further enhanced upon immunization of admixture of PLA particles and alum. Choice and use of stabilizers during particle formulation thus need careful considerations not only to protect the immunoreactivity of the antigen, but also to produce stable, uniform particles for optimal in vivo performances.
Adjuvants, Immunologic↗
Biodegradable microspheres alone do not stimulate murine macrophages in vitro, but prolong antigen presentation by macrophages in vitro and stimulate a solid immune response in mice.
The purpose of this study was to analyze the potential of various types of biodegradable microspheres (MS) (i) to activate in vitro cell line-derived macrophages (RAW 264.7, Mphi), and primary peritoneal and bone marrow-derived mouse Mphi, to prolong the release and presentation of microencapsulated synthetic malaria antigens by Mphi after uptake of antigen-loaded MS, and (ii) to stimulate an immune response in mice against a microencapsulated synthetic malaria antigen. The MS were made of various types of poly(lactide-co-glycolide) (PLGA) or chitosan cross-linked with tripolyphosphate. PLGA, but not chitosan MS, were efficiently ingested by Mphi. Upon exposure to the various MS types, Mphi increased only the production of reactive oxygen intermediates (ROI), while the production of nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), and the expression of cyclooxigenase-2 (COX-2), inducible NO synthase (iNOS), the cell surface markers MHC class I and II, and CD 86 remained unaffected. In vitro release of the microencapsulated antigen from PLGA50:50 MS followed a pulsatile pattern and extended over 14 weeks. This prolonged antigen release was also mirrored in the significantly prolonged antigen presentation over more than 7 days by Mphi after uptake of antigen-loaded PLGA MS. Finally, antigen-loaded PLGA MS induced a solid immune response in mice after a single s.c.-injection, which was only slightly inferior to the antibody titers measured with the control formulation with Montanide ISA720. These results suggest that MS are well tolerated by Mphi. The prolonged antigen presentation by Mphi, as measured in vitro, along with the capacity to induce a strong immune response in animals emphasize that biodegradable MS are a very promising delivery system for both preventive and immunotherapeutic vaccines.
Animals↗
Encapsulation of antigenic extracts of Salmonella enterica serovar. Abortusovis into polymeric systems and efficacy as vaccines in mice.
The properties of drug-vaccine delivery systems based on the use of biodegradable polymers, and its application in the control of experimental infection by Salmonella enterica serovar. Abortusovis (SAO), are described in this manuscript. Micelles of major membrane antigens from SAO (HSao extract) can be encapsulated in microparticles of poly(epsilon-caprolactone) or in nanoparticles of Gantrez polymer. The encapsulation process was optimized by the combined use of cyclodextrins. The resulting particles contained unaltered significant amounts of the antigenic complex. To establish the protective value of these subunit vaccines, particles were injected in one single dose (20 microg of HSao) subcutaneously in BALB/c mice in order to observe the protection conferred against experimental infection with the virulent strains S. Abortusovis 15/5. Control non-immunized animals resulted infected, as well as the group that received unloaded or HSao loaded into microparticles. In contrast, nanoparticles conferred a significant protection when compared to unvaccinated controls, similar to that induced by the attenuated commercial vaccine Rv6. In conclusion, protection against experimental infection in mice after one single shoot, and its potential for mucosal vaccination suggest that HSao-nanoparticles may represent a serious alternative to the conventional attenuated vaccines against S. Abortusovis.
Animals↗
The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices.
A considerable research has been conducted on drug delivery by biodegradable polymeric devices, following the entry of bioresorbable surgical sutures in the market about two decades ago. Amongst the different classes of biodegradable polymers, the thermoplastic aliphatic poly(esters) like poly(lactide) (PLA), poly(glycolide) (PGA), and especially the copolymer of lactide and glycolide, poly(lactide-co-glycolide) (PLGA) have generated immense interest due to their favorable properties such as good biocompatibility, biodegradability, and mechanical strength. Also, they are easy to formulate into different devices for carrying a variety of drug classes such as vaccines, peptides, proteins, and micromolecules. Also, they have been approved by the Food and Drug Administration (FDA) for drug delivery. This review discusses the various traditional and novel techniques (such as in situ microencapsulation) of preparing various drug loaded PLGA devices, with emphasis on preparing microparticles. Also, certain issues about other related biodegradable polyesters are discussed.
Biocompatible Materials↗
Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method.
The surface and internal morphology, drug distribution and release kinetics at 22 degrees C of polyesters such as PCL (polycaprolactone) and PLGA (poly(DL-lactic-co-glycolic acid)) 65:35 microspheres containing BSA (bovine serum albumin) have been investigated in order to understand the relationship amongst morphology, drug distribution and in vitro release profiles and to develop controlled release devices for marine fishes in tropical area. CLSM (confocal laser scanning microscope) micrographs reveal that the polyvinylalcohol (PVA as an emulsifier) concentration in the external water phase strongly influences drug distribution within microspheres and release profiles. The presence of PVA in the internal water phase enhances the stabilization of inner water droplets against coalescence. This results in a more uniform drug distribution and a slower BSA release. Different oil-phase volumes and polymer concentrations yield different solvent exchange and precipitation mechanisms, which lead to different morphologies. A low oil-phase volume yields microspheres with a porous matrix and defective skin surface, which gives a high initial BSA burst as well as a fast release profile. Microspheres fabricated from a low polymer concentration have less defective skin surface, but with a less tortuous inner matrix which results in a more rapid BSA release. A higher BSA loading yields a larger concentration gradient between the emulsion droplet and the continuous water phase as well as between the microspheres and the in vitro medium. The former results in a lower encapsulation efficiency, whereas the latter yields a faster initial burst and a more rapid release profile. High stirring speed can reduce microsphere size, but decreases the yield of microspheres.
Biodegradation, Environmental↗
Biodegradable block copolymers.
Recently, block copolymers have got tremendous impetus on the ongoing research in the area of drug delivery technology, due to their capability to provide a biomaterial having a broad range of amphiphilic characteristics, as well as targeting the drugs to specific site. This article is an attempt to review applications of block copolymers in surface modification, drug targeting, nano and microparticles, hydrogels, micelles etc. The physicochemical properties of block copolymers and various synthetic routes for block copolymers are also discussed.
Animals↗
Biodegradable polyphosphazenes for drug delivery applications.
Biodegradable polymers such as poly(alpha-hydroxy acids), poly(anhydrides), poly(ortho esters), poly(amino acids) and polyphosphazenes have raised considerable interest as short-term medical implants due to their transient nature. Among these, polyphosphazenes are a relatively new class of polymers, quite distinct from all the biodegradable polymers synthesized so far, due to their synthetic flexibility and versatile adaptability for applications. These are high molecular weight, essentially linear polymers with an inorganic backbone of alternating phosphorous and nitrogen atoms bearing two side groups attached to each phosphorous atom. Controlled tuning of physico-chemical properties, including biodegradability, can be achieved in this class of polymers via macromolecular substitutions. Biodegradable polyphosphazenes, due to their hydrolytic instability, nontoxic degradation products, ease of fabrication and matrix permeability, are an excellent platform for controlled drug delivery applications. This review discusses the mode of degradation and drug delivery applications of biodegradable polyphosphazenes.
Animals↗
Determination of protein loading in biodegradable polymer microspheres containing tetanus toxoid.
Various methods to determine loading of vaccine in biodegradable polymer microspheres encapsulating tetanus toxoid were evaluated. The microspheres were composed of poly (D-lactic acid) (PLA) and poly (DL-lactic-co-glycolic acid) (PLGA). Dissolution of microspheres in organic solvents such as methylene chloride, chloroform, or dimethyl sulfoxide and extraction of vaccine antigen or total protein with phosphate buffered saline gave variable results which depended upon the characteristics of the microspheres, such as type of polymer, excipients used in the microspheres and formulation conditions. Microspheres made from low molecular weight PLGA polymer and showing a large burst release exhibited up to 25% extraction of antigen whereas microspheres made from PLA microspheres with low burst release showed < 1% extraction. Extraction of total protein with 0.1 N NaOH and 5% sodium dodecyl sulfate showed results similar to those obtained with organic solvent extraction method. Partial digestion of microspheres with 6 N HCl at 60 degrees C for 20 h resulted in approximately 30% loss in TT protein by micro-bicinchoninic acid (BCA) assay. The major problem with this method was strong reactions in the micro-BCA assay of stabilizers, particularly sugars (glucose, sucrose) used in the microsphere formulations. Complete digestion of microspheres with 6 N HCl at 110 degrees C for 20 h or with 13.5 N NaOH at 121 degrees C for 1 h and quantitation of amino acids by a modified ninhydrin assay showed reproducible results on the protein loading in the microspheres. However, this method was affected by the presence of stabilizers, such as gelatin, which contain amino acids. Further, sucrose concentrations higher than 10% caused interference in the ninhydrin assay on samples hydrolyzed with 6 N HCl. In contrast, hydrolysis with 13.5 N NaOH did not show any interference by sucrose. Stabilizers used outside the microspheres for lyophilization purposes may be removed by washing the microspheres before loading determination or by dialysis but stabilizers used inside the microspheres would still cause interference. For reliable determination of total protein in the microspheres containing vaccines, we suggest complete digestion of microspheres with acid or base followed by amino acid analysis by colorimeteric assays such as ninhydrin method or using amino acid analyzers. The method needs to be optimized for each type of formulation to eliminate interference by the excipients. Alternatively, total protein nitrogen in the microspheres may be determined by the Kjel-dahl method if no amino acids or other nitrogen containing stabilizer is used inside the microspheres.
Antigens, Bacterial↗
New biodegradable hydrogels based on a photocrosslinkable modified polyaspartamide: synthesis and characterization.
alpha,beta-Poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), a synthetic water-soluble biocompatible polymer, was derivatized with glycidyl methacrylate (GMA), in order to introduce in its structure chemical residues having double bonds and ester groups. The obtained copolymer (PHG) contained 29 mol% of GMA residues. PHG aqueous solutions at various concentrations ranging from 30 to 70 mg/ml were exposed to a source of UV rays at lambda 254 nm in the presence or in the absence of N,N'-methylenebisacrylamide (BIS); the formation of compact gel phases was observed beginning from 50 mg/ml. The obtained networks were characterized by FT-IR spectrophotometry and swelling measurements which evidenced the high affinity of PHG hydrogels towards aqueous media at different pH values. In vitro chemical or enzymatic hydrolysis studies suggested that the prepared samples undergo a partial degradation both at pH 1 and pH 10 and after incubation with enzymes such as esterase, pepsin and alpha-chymotrypsin. Finally, the effect of irradiation time on the yield and the properties of these hydrogels was investigated and the sol fractions coming from irradiated samples, properly purified, were characterized by FT-IR and 1H-NMR analyses.
Acrylamides↗
Porous biodegradable microparticles for delivery of pentamidine.
The primary objective of this study was to develop a method for the preparation of porous biodegradable controlled release formulation of poly(lactide/glycolide) (PLGA). The model drug used for this study was pentamidine. Scanning electron microscopy pictures showed that these microparticles are highly porous and spherical in shape. A comparison of particle size reveals a similar median particle size (54-68 microm) in all six batches. The particles are all smaller than 90 microm. Differential scanning calorimetry thermograms revealed that pentamidine was mostly present in the crystalline form in the microparticles and did not dissolve in PLGA. The efficiency of encapsulation of pentamidine was higher than 58% in all six batches. The amount of drug released from these microparticles was at least 12% within the first 60 min. At least 50% of the total drug was released within the first 4 h. Drug release from these microparticles continued for up to 12 h. This faster drug dissolution was due to the highly porous surface. This highly porous surface will allow large molecules to release at a much faster rate than the regular microcapsules/microspheres.
Biodegradation, Environmental↗
A novel family of L-amino acid-based biodegradable polymer-lipid conjugates for the development of long-circulating liposomes with effective drug-targeting capacity.
The objective of this study was to develop biodegradable polypeptide-lipid conjugates for the design of polymer-coated long-circulating liposomes (LCL). Lipid conjugates of poly(hydroxyalkyl L-asparagine/L-glutamine) were synthesized and incorporated into 0.15 microm dipalmitoyl phosphatidylcholine (DPPC)-cholesterol liposomes. Circulation times and biodistribution were assessed in rats using a radioactive lipid marker. Evaluation of the therapeutic activity of prednisolone phosphate loaded in 0.1 microm PHEA-DPPC-cholesterol liposomes in a rat experimental arthritis model was performed to demonstrate the drug-targeting potential of the polymer-coated liposomes. Coating of liposomes with poly(hydroxyethyl L-asparagine) (PHEA) and poly(hydroxyethyl L-glutamine) (PHEG) extended the circulation half-life to a similar extent as poly(ethylene glycol) (PEG), which is normally used for the preparation of LCL. Glutamine polymers with a hydroxypropyl or a hydroxybutyl group instead of hydroxyethyl group also yield prolonged circulation, however, not to the same extent as PHEA/G. The pharmacokinetic properties of PHEA-liposomes were independent of the lipid dose even at very low lipid doses of around 50 nmol per rat. PLP was successfully entrapped in PHEA-liposomes. These liposomes were shown to be stable in the circulation and equally effective in rat experimental arthritis as PLP encapsulated in PEG-liposomes. PHEA and PHEG are attractive alternative polymers for the design of LCL: their performance is similar to that of PEG-liposomes but they have the advantage of being biodegradable.
1,2-Dipalmitoylphosphatidylcholine↗
Water-soluble degradable hyperbranched polyesters: novel candidates for drug delivery?
A novel approach to hyperbranched polymers is presented in this work. Hyperbranched polyesters with a large amount of terminal hydroxyl groups are prepared by a one-pot synthesis from commercially available AB-type and CD(n)-type monomers (n >/= 2). In this paper, Michael addition of diethanolamine (CD(2)) or N-methyl-d-glucamine (CD(5)) to methyl acrylate (AB) generates dominantly AD(n)-type intermediates. Further self-condensation of intermediates at higher temperature and in the presence of catalyst gives hyperbranched polyesters. Because of the tertiary amino groups in the backbone and the hydroxyl groups in the linear and terminal units, the resulting hyperbranched polyester is highly soluble in water. Furthermore, the hyperbranched polymer is degradable because of its ester units. So, the water-soluble hyperbranched polyesters might be applied as a novel material for drug delivery.
Biodegradation, Environmental↗
Biodegradable microparticles with an entrapped branched octameric peptide as a controlled-release HIV-1 vaccine.
Polyactide-co-glycolide microparticles, with an entrapped branched octameric peptide from human immunodeficiency virus (HIV-1), were prepared by a solvent evaporation method. The microparticles were characterized for size distribution, antigen loading level, and integrity. Mice in one group were each immunized with a single dose of a controlled-release microparticle formulation containing 300 micrograms of peptide and the serum IgG responses to the antigen were compared with those of mice from a second group that were immunized at 0, 4, and 26 weeks with 100-microgram doses of the same peptide immunogen adsorbed to alum. The controlled-release microparticles induced an antibody response comparable to that from the alum-immunized group. The subcutaneous and the intramuscular routes of administration were compared in additional groups of mice for the microparticles, and both routes induced similar responses. A suspending vehicle for the microparticles was also evaluated and did not affect the immunogenicity of the controlled-release formulation containing both small and large microparticles, although the immunogenicity of smaller microparticles immunized alone was affected.
AIDS Vaccines↗
Chemistry: dendrimers set to self-destruct.
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Antineoplastic Agents↗
Self-immolative dendrimer biodegradability by multi-enzymatic triggering.
New self-immolative dendritic molecules have been designed and synthesized. The dendrons are built with a multi-enzymatic triggering mechanism, which initiates their biodegradation through a self-immolative chain fragmentation to release a reporter group from the focal point. The dendritic backbone is constructed from polycarbamate linkages, which are stable to hydrolysis and enhance the dendrons' solubility in water. The degradation can readily take place under physiological conditions on enzymatic triggering.
Biocompatible Materials↗