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Biodegradable microspheres of curcumin for treatment of inflammation.

Curcumin, a natural constituent of Curcuma longa (turmeric, CAS 458-37-7) was formulated as prolonged release biodegradable microspheres for treatment of inflammation. Natural biodegradable polymers, namely, bovine serum albumin and chitosan were used to encapsulate curcumin to form a depot forming drug delivery system. Microspheres were prepared by emulsion-solvent evaporation method coupled with chemical cross-linking of the natural polymers. Curcumin could be encapsulated into the biodegradable carriers upto an extent of 79.49 and 39.66% respectively with albumin and chitosan. Different drug:polymer ratios did not affect the mean particle size or particle size distribution significantly. However, the concentration of the crosslinking agent had remarkable influence on the drug release. In-vitro release studies indicated a biphasic drug release pattern, characterized by a typical burst-effect followed by a slow release which continued for several days. Evaluation of antinflammatory activity using Freund's adjuvant induced arthritic model in Wistar rats revealed significant difference between both the formulations, albumin microspheres and chitosan micropheres as well as against control. It was evident from the present study that the curcumin biodegradable microspheres could be successfully employed as prolonged release drug delivery system for better therapeutic management of inflammation as compared to oral or subcutaneous route.

Absorbable Implants↗

Delivery of neurotrophin-3 to the cochlea using alginate beads.

OBJECTIVE: The aim of this study was to design a novel cochlear neurotrophin (NT) delivery system for the rescue of auditory neurons after ototoxicity-induced deafening. BACKGROUND: NT-3 is a trophic growth factor that promotes the survival of the auditory nerve and may have a potential therapeutic role in slowing neuron loss in progressive deafness, especially as an adjunct to the current cochlear implant. Beads made from alginate are biodegradable, slow release substances that can be placed at the round window or inside the cochlea. This study investigated the loading properties, release kinetics, and implantation potential of alginate beads loaded with NT-3. METHODS: Alginate beads were prepared using an ionic gelation technique and postloaded with NT-3. Release of NT-3 was measured using enzyme-linked immunosorbent assay over 5 days. Alginate beads were implanted into deafened guinea pigs for 28 days, after which survival of auditory neurons was assessed. RESULTS: Enzyme-linked immunosorbent assay studies demonstrated a 98% to 99% loading of NT-3 with a slow, partial release over 5 days in Ringer's solution. Furthermore, the addition of heparin to the delivery system modulated NT-3 release to a steadier pattern. Implantation of alginate-heparin beads in guinea pig cochleae produced minimal local tissue reaction. NT-3 loaded beads implanted at both the round window and within the scala tympani of the basal turn provided auditory neurons significant protection from degradation and apoptosis compared with unloaded beads or untreated cochleae. CONCLUSIONS: This study demonstrates alginate beads to be a safe, biodegradable and effective delivery system for NT-3 to the cochlea.

Alginates↗

Biodegradable polyanhydride devices of cefazolin sodium, bupivacaine, and taxol for local drug delivery: preparation, and kinetics and mechanism of in vitro release.

The overall objective was to design and evaluate biodegradable implants for local drug delivery in clinical conditions and/or diseases described below, which are currently treated with systemic administration of drugs. Local delivery of cefazolin is desired in conditions such as osteomyelitis, soft-tissue infection and for prevention of post-surgical infections. Similarly, implanting a biodegradable device loaded with taxol in the cavity created by tumor resection will provide high local concentrations of taxol killing the malignant cells which may have survived the surgery, thus preventing metastasis and regrowth of the tumor and also prevent the systemic side effects of taxol. Prolonged reversible nerve blockade required in a number of clinical situations involving acute or chronic pain such as post-surgical pain following herniorrhaphy and thoracotomy can be achieved with local delivery of bupivacaine. Therefore, disk-shaped implants of polyanhydride, P(FAD-SA, 50:50 w/w), loaded with 10% w/w of cefazolin sodium, taxol and bupivacaine were prepared and evaluated for content uniformity and in vitro release characteristics for the above mentioned local drug delivery applications. All of cefazolin sodium was released in 14 days while 90% bupivacaine was released in 35 days. In striking contrast, taxol was released very slowly, and only 15% taxol was released in 77 days. The overall release appeared to be following first order kinetics, and the initial linear profile was fitted to zero order kinetics to obtain release parameters. Since cefazolin is highly water soluble and bupivacaine is moderately water soluble, compared to taxol which is extremely lipophilic, the aqueous solubility of the incorporated drug appeared to influence in release characteristics. Very good correlation was observed between release parameters (Ao, ko) and the solubility and intrinsic dissolution rate (IDR) of drugs suggesting that the hydrophilic/hydrophobic nature of the drug influences its release from polyanhydride devices. Since polyanhydrides are believed to undergo pure surface erosion, release of the incorporated drug should be independent of its physicochemical properties, however the results presented in this study suggest otherwise. Therefore, P(FAD-SA, 50:50 w/w) may not be undergoing surface erosion, and the diffusion and dissolution properties of the drug in addition to erosion characteristics of the polyanhydride appear to play a role in drug release. Implants prepared and evaluated in this study released cefazolin, bupivacaine and taxol for a prolonged duration of time; however, depending upon the desired duration of release, an appropriate polyanhydride will have to be selected. For example, taxol was released so slowly that a more hydrophilic polyanhydride may have to be selected to release all the drug in a shorter period of time to be of any therapeutic use. Cefazolin implants released the drug for a sufficient duration for osteomyelitis and soft-tissue infection but the release was more prolonged than required for prevention of post-surgical wound infection.

Anesthetics, Local↗

The use of bioerodible polymers and daunorubicin in glaucoma filtration surgery.

PURPOSE: Glaucoma filtering surgery usually fails from postoperative fibroblast proliferation, collagen deposition, and subsequent sclerostomy or bleb scarring. Daunorubicin inhibits fibroblast proliferation in vivo and in vitro. The authors studied the effect of a sustained subconjunctival release of daunorubicin by way of a bioerodible polymer on the success of glaucoma filtration surgery in a rabbit model. METHODS: Daunorubicin was incorporated into the copolymer by compression molding. The resultant implant measured 3.0 mm in diameter, 1.0 mm in thickness, and 8.0 mg in weight. A posterior lip sclerectomy was performed in both eyes of 23 rabbits by the same surgeon. One eye was randomized to receive the disc with daunorubicin, whereas the fellow eye received a blank disk as a control. The appropriate polymer disk then was placed on the scleral surface immediately posterior to the sclerostomy site and the conjunctiva was closed. Intraocular pressures and slit-lamp biomicroscopy were recorded preoperatively, then every other day after surgery for 31 days. Intraocular pressure, bleb survival, and complications were evaluated. RESULTS: The decrease in intraocular pressure from baseline was significantly greater in the daunorubicin eyes than in the control eyes during postoperative days 5 through 25. Bleb survival was significantly longer in the daunorubicin eyes than in the control eyes (bleb failure in 91% of control eyes versus 22% of treatment eyes by day 13). There were no statistically significant differences between the daunorubicin-treated and control eyes regarding corneal clouding, lens clarity, cataract formation, or conjunctival injection. However, conjunctival erosions occurred in four daunorubicin-treated eyes. Histopathologic examination was performed 2 weeks after surgery on the eyes of three randomly selected rabbits. CONCLUSION: Daunorubicin in a bioerodible delivery system may potentially be a useful adjunct to glaucoma filtering surgery and requires further evaluation.

Animals↗

Site-specific administration of antisense oligonucleotides using biodegradable polymer microspheres provides sustained delivery and improved subcellular biodistribution in the neostriatum of the rat brain.

Antisense oligonucleotides (ODNs) are being increasingly used in the central nervous system as biological tools, as drug-target validation agents and as potential therapeutic agents. Although the local delivery of naked ODNs to the brain can result in the desired biological effects, the duration of efficacy is relatively short lived due to the combined effects of rapid ODN degradation and elimination half-lives in vivo. In this study, we have examined the use of biodegradable polymer microspheres as a site-specific delivery system for targeting ODNs to the neostriatum of the rat brain. Model phosphorothioate backbone-modified ODNs were entrapped within poly(D,L-lactide-co-glycolide) (PLAGA) microspheres using a double emulsion-deposition method and the formulations characterised in terms of particle size, surface morphology, percent encapsulation efficiency, ODN loading and in vitro release profiles. For in vivo evaluation, PLAGA microspheres containing fluorescently-labelled ODNs were stereo-taxically administered to the neostriatum of the rat brain and biodistribution of ODNs monitored after 48 h. Administration of free fluorescently-labelled ODNs to the neostriatum resulted in a punctate cellular distribution of ODNs after 24 h with little or no ODN remaining in the neostriatum after 48 h. In comparison, fluorescently-labelled ODNs delivered using polymer microspheres were intensely visible in cells after 48 h post-administration and the fluorescence appeared to be diffuse covering both cytosolic and nuclear regions. Dual-label immunohistochemical analyses suggested that ODNs were mainly distributed to neuronal cells. These data indicate that site-specific administration of ODNs using biodegradable polymer microspheres will not only provide sustained delivery of nucleic acids but can also improve the cellular distribution of ODNs to brain cells. Sustained or controlled-release biodegradable polymer formulations, therefore, represent an attractive strategy for improved local delivery of ODNs to the CNS.

Animals↗

The use of locally delivered chlorhexidine in the treatment of periodontitis. Clinical results.

Since the advent of a nondegradable controlled local delivery of antibiotics in 1979, several second generation systems have been developed. Second generation systems have attempted to improve on the early system. Chlorhexidine has been used effectively for over 30 years as an antiseptic. In the early 1970s, chlorhexidine gluconate was incorporated at 0.2% into mouthrinses in Europe and in 1986 it was incorporated at 0.12% in a mouthrinse in the United States. Since these mouthrinses were effective in reducing the supragingival flora, had a high safety margin, and had no reported bacterial resistance, chlorhexidine offered a therapeutic advantage for a local delivery system. This system was developed and studied. This report will discuss this new biodegradable system containing chlorhexidine gluconate as the active agent (PerioChip). Pharmacokinetics of the system and a review of the multicenter studies in Europe and the United States are discussed. In these randomized clinical trials the chlorhexidine chip has been shown to enhance the effects of scaling and root planing. Chlorhexidine chip in conjunction with scaling and root planing, when compared to scaling and root planing alone, has shown significant improvement in probing pocket depth reduction, probing attachment level and bleeding on probing. This delivery system, in combination with scaling and root planing, has also resulted in significantly more probing depth reductions of 2 mm or more. The system is safe and efficacious. Placement of the chip is usually done in less than 1 min, it requires no retention system, biodegrades, and does not require a follow-up dental appointment.

Administration, Topical↗

Novel polymer-grafted starch microparticles for mucosal delivery of vaccines.

Recent studies have demonstrated that systemic and mucosal administration of soluble antigens in biodegradable microparticles can potentiate antigen-specific humoral and cellular immune responses. However, current microparticle formulations are not adequate for all vaccine antigens, necessitating the further development of microparticle carrier systems. In this study, we developed a novel microparticle fabrication technique in which human serum albumin (HSA) was entrapped in starch microparticles grafted with 3-(triethoxysilyl)-propyl-terminated polydimethylsiloxane (TS-PDMS), a biocompatible silicone polymer. The immunogenicity of HSA was preserved during the microparticle fabrication process. Following intraperitoneal immunization of mice, TS-PDMS-grafted microparticles (MP) dramatically enhanced serum IgG responses compared with ungrafted MP and soluble HSA alone (P < 0.001). When delivered orally, both TS-PDMS-grafted and ungrafted microparticles elicited HSA-specific IgA responses in gut secretions, in contrast to orally administered soluble antigen. Indeed, TS-PDMS-grafted microparticles stimulated significantly stronger serum IgG (P < 0.005) and IgA (P < 0.001) responses compared with those elicited by ungrafted microparticles. These findings indicate that TS-PDMS-grafted starch microparticles have potential as systemic and mucosal vaccine delivery vehicles.

Administration, Oral↗

Advancing the field of drug delivery: taking aim at cancer.

Drug delivery systems for cancer therapeutics have now been used by millions of patients and have resulted in the creation of new therapies as well as significantly improving existing ones. Here we discuss a number of the drug delivery systems that have been approved by regulatory authorities and that are currently in clinical use, such as controlled delivery of cancer therapeutics, local chemotherapy, polymer drug conjugates, liposomal systems, and transdermal drug delivery patches. The next generation of "smart" drug delivery approaches such as controlled release microchips are discussed as are some of the future challenges and directions in this field.

Absorbable Implants↗

Indocyanine green-loaded biodegradable nanoparticles: preparation, physicochemical characterization and in vitro release.

PURPOSE: The objective of this study is to develop indocyanine green (ICG)-loaded biodegradable nanoparticles by using biodegradable polymer, poly(DL-lactic-co-glycolic acid) (PLGA). METHOD: PLGA nanoparticles entrapping ICG were prepared by a modified spontaneous emulsification solvent diffusion method. To optimize the nanoparticle formulation, the influence of formulation parameters such as types of ICG, amount of ICG and the polymer were investigated. The ICG entrapment in nanoparticles, nanoparticle size and zeta potential were determined. The surface characterization was performed by atomic force microscopy (AFM) and the release of ICG from nanoparticles was determined. RESULTS: All PLGA nanoparticle formulations were found to have the mean diameter within the range of 300-410 nm with polydispersity index (PI) within the range of 0.01-0.06. Indocyanine green showed more efficient entrapment as compared to indocyanine green sodium iodide salt. All indocyanine green-loaded nanoparticle formulations were found to have almost similar ICG content of nanoparticles and showed increase in ICG entrapment with increase in the amount of polymer. The ICG entrapment reached 74% when ICG: PLGA weight ratio in the formulation reached 1:800. AFM images indicated that the nanoparticles were almost spherical in shape and had numerous pores on their surfaces. The release pattern consisted of two phases, with initial exponential phase releasing about 78% of ICG (within 8 h) followed by a slow phase releasing about 2% of ICG (within next 16 h). CONCLUSIONS: ICG-loaded PLGA nanoparticles were prepared and the formulation was optimized. The increase in amount of polymer in formulation leads to higher ICG entrapment. Nanoparticles formed were spherical and had porous surfaces and exhibited the characteristic release pattern of a monolithic matrix based system.

Biodegradation, Environmental↗

In vivo pain relief effectiveness of an analgesic-anesthetic carrying biodegradable controlled release rod systems.

Pain is the most common and feared symptom for patients, especially those with cancer. Treatment of chronic pain with conventional ways of medication usually fails with increasing severity of the pain. New approaches enabling the prolonged provision of pain relievers are required. We designed a controlled release system of pain relievers, mainly for opioids (morphine, M, codeine, C, and hydromorphone, HM), and a local anesthetic (bupivacaine, BP) in the form of poly(L-lactide-co-glycolide) (PLGA) rods. The efficacy of these rods implanted alone or in combination in relieving chronic pain in rats caused by the ligation of the sciatic nerve of their right hind limbs was studied. The two most common tests for measuring analgesia, i.e. tail-flick tests, that show analgesia at sites other than the site of injury, were used to study the degree of systemic distribution of the drugs and paw-withdrawal tests were used to study the analgesia at the site of injury. Alleviation of this chronic and severe neuropathic pain could be obtained for about 3-4 days when rods for two drugs, 'dual drug' (analgesic-anesthetic), were used. This duration is decreased by half (2 days) with the single-drug rods. Also the dual-drug rods, though at half the dose of each single drug application, enhanced the degree of analgesia of the first day. These in vivo results are also consistent with the previous in vitro results as in the case with codeine which had a higher first-day analgesia than morphine, despite a lower potency due to the faster in vitro release rate. Similarly, slower release of hydromorphone from PLGA (85:15) rods resulted in less systemic analgesia than the more rapidly eroding PLGA (50:50) rods of the same drug.

Analgesics, Opioid↗

Noninvasive in vivo monitoring of drug release and polymer erosion from biodegradable polymers by EPR spectroscopy and NMR imaging.

Biodegradable polymers have attracted much attention as implantable drug delivery systems. Uncertainty in extrapolating in vitro results to in vivo systems due to the difficulties of appropriate characterization in vivo, however, is a significant issue in the development of these systems. To circumvent this limitation, noninvasive magnetic resonance techniques, electron paramagnetic resonance (EPR) and magnetic resonance imaging (MRI), were applied to characterize drug release and polymer degradation in vitro and in vivo. MRI makes it possible to monitor water content, tablet shape, and response of the biological system such as edema and encapsulation. The results of the MRI experiments give the first direct proof in vivo of postulated mechanisms of polymer erosion. Using nitroxide radicals as model drug releasing compounds, information on the mechanism of drug release and microviscosity inside the implant can be obtained by means of 1.2 GHz EPR spectroscopy. To be able to attribute nitroxide mobility to a particular layer of the implant, sandwich-like tablets were manufactured, taking advantage of the distinct spectral features of nitroxides containing different isotopes of nitrogen (15N vs 14N). The use of both noninvasive methods to monitor processes in vivo leads to new insights in understanding the mechanisms of drug release and polymer degradation.

Biodegradation, Environmental↗

An insulin delivery system from oxidized cellulose.

Cellulose oxidized with periodate (OC) has been shown to be a biocompatible, biodegradable matrix suitable for immobilization and sustained release of drugs. In the present work, insulin was immobilized on the OC-matrix and the release profile in vivo and in vitro was examined. The hormone is bound to the matrix by Schiff's bond formation and is released by hydrolysis of this bond as well by degradation of the OC-matrix. The release can be sustained over longer periods by reducing the Schiff's base with NaBH4. The insulin depots could be conveniently injected as suspensions and are able to maintain glucose levels in diabetized rabbits at normal values over several days.

Animals↗

Biodegradable polymersomes as a basis for artificial cells: encapsulation, release and targeting.

The encapsulation of biofunctional compounds, release properties and targetability of polymersomes of amphiphilic block-copolymers based on poly(ethylene glycol) (PEG) and biodegradable polyesters or polycarbonate are described. Carboxyfluorescein (CF), as a model for hydrophilic biofunctional compounds, could be readily incorporated in the polymersomes by adding the compound to the aqueous phase during polymersome preparation. The release of encapsulated material from the polymersomes can be adjusted by changing the copolymer composition, especially the molecular weight and type of hydrophobic block of the copolymer. The presence of plasma proteins other than albumin suppressed the release of CF. CF release in PBS both at room temperature and at 60 degrees C followed first order kinetics, confirming that the CF containing polymersome system is a membrane controlled reservoir system. These biodegradable polymersomes have the potential to be targeted to specific sites in the body as shown by the specific interaction of anti-human serum albumin immobilized polymersomes with a human serum albumin coated sensor surface.

Biodegradation, Environmental↗

Stability of poly(D,L-lactide-co-glycolide) and leuprolide acetate in in-situ forming drug delivery systems.

In-situ forming drug delivery systems are prepared by dissolving a drug and a biodegradable polymer (poly(D,L-lactide-co-glycolide), PLGA) in a biocompatible organic solvent (In-situ implant, ISI) or further emulsified into an external phase (oil or aqueous solution), resulting in oil-in-oil or oil-in-water emulsions (In-situ forming microparticles, ISM). The chemical stability of PLGA and the drug is a major concern. In this study, the stability of PLGA and leuprolide acetate in the in-situ forming systems and lyophilized sponges was investigated. The degradation of PLGA increased with increasing storage temperature and water content in the biocompatible solvents. A faster degradation occurred in polar protic solvents (2-pyrrolidone, PEG 400, triethyl citrate) than in polar aprotic solvents (N-methyl-2-pyrrolidone, DMSO, triacetin, ethyl acetate). The presence of leuprolide acetate significantly accelerated PLGA degradation, especially in solution state. PLGA was stable in oily suspensions at 4 degrees C and degraded only slightly faster than solid powder at 25 degrees C. No interaction between the oils and the PLGA was observed as indicated by an unchanged T(g) of approx. 47 degrees C. PLGA underwent a slight degradation at 4 degrees C after 150 days in water and saturated sodium chloride solution. The degradation was slower in saturated sodium chloride solution than in water at 25 degrees C. Residual acetic acid in lyophilized sponges facilitated the PLGA degradation in contrast to dioxane. Leuprolide acetate did not affect the PLGA stability negatively. However, lidocaine significantly enhanced the polymer degradation in the sponges. Finally, leuprolide acetate was chemically stable in the sponges, the oils and the polymer solutions in suspension state, but unstable (aggregation) when dissolved in the polymer solutions and stored at 25 degrees C and 40 degrees C.

Chromatography, Gel↗

[Recent trends in drug delivery systems using biomaterials].

Since the concept of sustained release of biologically active agents was established in 1970's, the sustained release has been examined by controlling the diffusion of drugs through polymeric matrices and/or the degradation of these polymers. Recently, drug release in proportion to internal or external stimuli has been getting important, which can be achieved by using stimuli-responsive polymeric materials. Majority of these polymers have been designed as to achieve their functions by changes in temperature, pH, glucose concentration, and the release of ribosomal enzymes. Especially, among those materials, biodegradable polymers have much potential for applications as implantable carriers for drug delivery system (DDS). In an auto feed-back drug delivery, several physiological changes in a living body can be utilized as the signal inducing polymer degradation and subsequent drug release. A hydrogel composed of hydrophilic biomaterials has been focused because of their high responsibility to the stimulus. In this paper, currently investigated DDS using hydrogels are reviewed with their strategies.

Biocompatible Materials↗

[Preparation of 5-fluorouracil encapsulated in amphiphilic polysaccharide nano-micelles and its killing effect on hepatocarcinoma cell line HepG2].

BACKGROUND & OBJECTIVE: Biodegradable colloidal nano-micelles is a novel targeting drug delivery and controlled release system, which could prolong the biological half-life and lighten the toxicity of chemotherapeutant, meanwhile, present fine biocompatibility. This study was to prepare the biodegradable 5-fluorouracil (5-FU)/DEX-g-PLA nano-micelles, and investigate their killing effect on hepatocarcinoma cell line HepG2 in vitro and in vivo. METHODS: 5-FU/DEX-g-PLA nano-micelles were prepared by 'self-assembly'. Its morphology was observed by transmission electron microscopy. The encapsulating efficiency of 5-FU was determined by ultraviolet spectrophotometry. The in vivo releasing of 5-FU from nano-micelles was investigated by high-performance liquid chromatography (HPLC). The inhibitory effect of 5-FU/DEX-g-PLA on HepG2 cells in vitro was measured by MTT assay. RESULTS: 5-FU/DEX-g-PLA nano-micelles were round or elliptical; the diameter was about 50 nm. The encapsulating efficiency was about 9.3%. The concentration of 5-FU released from 5-FU/DEX-g-PLA nano-micelles was sustained for longer time than that of the naked drug. The in vitro inhibition rate of cell growth was similar in 5-FU/DEX-g-PLA group and naked 5-FU group (58.8% vs. 58.0%, P>0.05); the in vivo inhibition rate of tumor growth was significantly higher in 5-FU/DEX-g-PLA group than in naked 5-FU group (73.1% vs. 57.5%, P<0.05). CONCLUSION: 5-FU/DEX-g-PLA nano-micelles can effectively inhibit the growth of HepG2 cells.

Animals↗

[Dendritic systems for drug delivery applications].

Dendrimers are synthetic, highly branched and nanometer-sized macromolecules that offer potential application to various fields. They have uniform size and molecular weight, wide internal cavity and modifiable surface functionality that made them very attractive for biological and drug delivery applications. Commercially available PAMAM (polyamidoamine) dendrimers are most frequently used for construction of delivery system by modification of surface amino groups. One of the examples is anticancer drug-PAMAM conjugate with folic acid (FA) for targeting. DNA linked FA-PAMAM and FITC-PAMAM conjugates have been recently developed. Polyester dendrimers are expected to be biodegradable and less toxic to cells. An example is shown. Lastly, construction of a delivery system using caged compounds for photochemical release of drug is described.

Biocompatible Materials↗

Innovations in avoiding particle clearance from blood by Kupffer cells: cause for reflection.

Therapeutic applications of drug carrier systems following intravenous administration have been limited because of the pronounced tendency of these carriers to localize primarily in Kupffer cells. Recently, attempts have been made to design colloids and drug carrier systems that can be disguised as "self" and remain unrecognizable, at least to a certain extent, by the hepatic macrophages. This review is designed to provide a critical view on fundamentals, current progress, limitations, and future prospects of such engineered colloids and drug carrier systems for intravenous route of administration.

Binding Sites↗