The Experts below are selected from a list of 123 Experts worldwide ranked by ideXlab platform
Abraham J Domb - One of the best experts on this subject based on the ideXlab platform.
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biocompatibility of a Polymeric Implant for the treatment of osteomyelitis
Journal of Biomaterials Science-polymer Edition, 2009Co-Authors: Yaron S Brin, Jacob Golenser, Abraham Nyska, Abraham J Domb, Boaz Mizrahi, Meir NyskaAbstract:We evaluated the biocompatibility of an injectable gelling Polymeric device for the controlled release of gentamicin sulfate in the treatment of invasive bacterial infections in bone of male Wister rats. The biodegradable delivery carrier, poly(sebacic-co-ricinoleic-ester-anhydride), designated as p(SA:RA), was injected, with and without gentamicin, into the tibial canal. Rats were killed 3 weeks later. The tibiae were processed histologically, leaving the injectable polymer in situ. The local tissue reaction to the polymer with or without antibiotic consisted mainly of mild reactive fibroplasia/fibrosis and mild to moderate increased reactive bone formation. At this stage, no evidence for any active inflammatory response to the polymer was seen. Thus, the injection of p(SA:RA) was well tolerated and did not induce any signs of a progressive inflammatory reaction.
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synthesis and characterization of Polymeric Implant for kyphoplasty
Journal of Biomedical Materials Research Part B, 2008Co-Authors: Boaz Mizrahi, Ronen Shavit, Abraham J DombAbstract:Copolymers of methyl methacrylate (MMA) and lauryl methacrylate (LMA) were prepared to obtain injectable ductile materials to be used in restoring vertebra height in kyphoplasty. Copolymers with Mw in the range of 130,000 and polydispersity of 1.8 were obtained. Several aspects of the effect of adding LMA monomers were examined including intrinsic viscosity, thermal properties, mechanical properties, and the ability to be injected under high pressure. By increasing the amount of LMA, the ductility of the polymer was increased, accompanied by a decrease in Young's modulus and strength. The copolymer with monomers ratio (MMA:LMA) 1:1 v/v possessed the most suitable mechanical properties and injectability, which may have potential clinical use in orthopedics. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 2008
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gentamicin extended release from an injectable Polymeric Implant
Journal of Controlled Release, 2007Co-Authors: Michal Y Krasko, Jacob Golenser, Abraham Nyska, Meir Nyska, Yaron S Brin, Abraham J DombAbstract:Abstract Gentamicin sulfate, a potent antibiotic agent, is currently used for treatment of osteomyelitis mainly by intravenous injection with a long-term indwelling catheter, local Implant of antibiotic containing polymethylmethacrylate beads or calcium phosphate (bone cements). Searching for more effective treatments, this study was designed to evaluate biodegradable injectable gelling Polymeric devices for the controlled release of gentamicin sulfate in the treatment of invasive bacterial infections. Gentamicin sulfate was incorporated in poly(sebacic-co-ricinoleic-ester-anhydride P(SA-RA)) paste at 10–20% w/w and its release in buffer solution was monitored. The in vitro activity of the formulations was determined against Staphylococcus aureus . A constant release of active gentamicin for over 28 days was found. The stability of the formulation was determined under different storage conditions. The formulations were stable to sterilization by γ-irradiation and long term storage under freezing. The toxicity of the polymer and the formulations with gentamicin was examined by subcutaneous injection to rats. Four weeks after Implantation, histopathological examination of the tissues surrounding the Implant showed no inflammation. A preliminary study revealed positive effect of gentamicin containing P(SA-RA) on established osteomyelitis in a rat model. In conclusion this study suggests that poly(sebacic-co-ricinoleic-ester-anhydride) 3:7 loaded with 10%–20% gentamicin sulfate, might be used as an injectable biodegradable device for in situ treatment of osteomyelitis induced by S. aureus .
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excretion of a radiolabelled anticancer biodegradable Polymeric Implant from the rabbit brain
Biomaterials, 1995Co-Authors: Abraham J Domb, M Rock, C Perkin, G Yipchuck, B Broxup, J G VillemureAbstract:The elimination of a clinically used anticancer biodegradable polymer Implant (Gliadel™) in the rabbit brain was studied. The Implant is composed of N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU) (1.6 wt%) dispersed in a copolyanhydride matrix of 1,3-bis(p-carboxyphenoxypropane) (CPP) and sebacic acid (SA) in a 20:80 molar ratio. Four groups of rabbits were Implanted with wafers loaded with BCNU, one in a 14C-SA-labelled polymer, another in a 14C-CPP-labelled polymer and two groups with 14C-BCNU in a non-labelled polymer, one for BCNU disposition study and one for residual drug study. In the rabbits Implanted with the 14C-SA-labelled polymer, approximately 10% of the radioactivity was found in the urine and 2% in the faeces, and about 10% remained in the device 7d after Implantation. In contrast, only 4% of the radioactivity of the 14C-CPP-labelled polymer was found in urine and faeces during this period. However, a drastic increase in the CPP excretion was found after 9d, and at 21 d, 64% of the Implanted 14C-CPP was found in the urine and faeces, and 29% was still in the recovered wafers. Approximately 50% of the BCNU in the wafers was released in 3d, and over 95% was released after 6 d in the rabbit brain. This study demonstrates that BCNU-loaded polyanhydride is biodegradable and is excreted from the body primarily through the renal system. The water-soluble components SA and BCNU were rapidly excreted, while the insoluble CPP was gradually eliminated after a lag time of 9 d.
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metabolic disposition and elimination studies of a radiolabelled biodegradable Polymeric Implant in the rat brain
Biomaterials, 1994Co-Authors: Abraham J Domb, M Rock, C Perkin, B Broxup, J Schwartz, G Yipchuk, J G VillemureAbstract:Abstract The metabolic disposition and elimination process of the anhydride co-polymer poly[1,3-bis( p -carboxyphenoxypropane): sebacic acid] 20:80 [P(CPP:SA)20:80] Implanted in the rat brain was studied. Two polymers were prepared, one with [ 14C ]SA and unlabelled CPP, and the other co-polymer with [ 14 C]CPP and unlabelled SA. With these two polymers we were able to study the metabolic disposition of each monomer after polymer degradation. Polymer wafers loaded with AJ,AJ-bis(2-chloroethyl)-JV-nitrosourea or without the drug were Implanted in the rat brain. For the rats Implanted with the [ 14 C]SA-labelled polymer, approximately 40% of the radioactivity was found in the expired CO 2 , 10% in the urine, about 2% in the faeces and about 10% remained in the device 7d after Implantation. On the other hand, only 4% of the [ 14 C]CPP monomer was eliminated by urine and faeces during this period. The drug-loaded polymer degraded faster than the blank polymer. This study supports the theory that the polymer is a biodegradable material that can be used for the direct and specific delivery of drugs into a targeted organ and can provide continued release of drugs over a period of time. Biomaterials (1994) 15 , (9) 681–688
Ramesh C. Gupta - One of the best experts on this subject based on the ideXlab platform.
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Controlled Delivery of Chemopreventive Agents by Polymeric Implants
Methods of Molecular Biology, 2020Co-Authors: Farrukh Aqil, Ramesh C. GuptaAbstract:The clinical development of cancer chemopreventive agents has been hampered by poor oral bioavailability issue. Several compounds have low aqueous solubility and undergo extensive first pass metabolism following oral dosing. To overcome this limitation, we developed Polymeric Implants from biodegradable ε-polycaprolactone (PCL) that can deliver both lipophilic as well as hydrophilic compounds. Implants furnish controlled release of compounds for long duration and provide dose-dependent release. The rate of release in vitro correlated well with the in vivo release. The Polymeric Implant technology thus overcomes the oral bioavailability issues, lowers the total required dose and minimizes or eliminates toxicity generally associated with high doses.
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Polymeric Implants for the Delivery of Green Tea Polyphenols
Journal of Pharmaceutical Sciences, 2014Co-Authors: Jeyaprakash Jeyabalan, Farrukh Aqil, Ramesh C. Gupta, Srivani Ravoori, Manicka V. VadhanamAbstract:ABSTRACT Polymeric Implants (millirods) have been tested for local delivery of chemotherapeutic agents in cancer treatment. Modeling of drug release profiles is critical as it may provide theoretical insights on rational Implant design. In this study, a biodegradable poly ( e -caprolactone) (PCL) Polymeric Implant delivery system was tested to deliver green tea polyphenols (GTPs), both in vitro and in vivo . Factors including polymer compositions, supplements, drug loads, and surface area of Implants were investigated. Our data showed that GTPs were released from PCL Implants continuously for long durations, and drug load was the main determining factor of GTPs release. Furthermore, rates of in vitro release and in vivo release in the rat model followed similar kinetics for up to 16 months. A mathematical model was deduced and discussed. GTP Implants have the potential to be used systemically and locally at the tumor site as an alternative strategy.
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Abstract 2883: Enhanced anti-tumor activity and bioavailability of chemopreventives by coated Polymeric Implants
Cancer Research, 2012Co-Authors: Samir-yitzhak Gadre, Farrukh Aqil, Jeyaprakash Jeyabalan, Hina Kausar, Ramjee Sharma, Inder Pal Singh, Ramesh C. GuptaAbstract:Poor oral bioavailability limits the use of many chemopreventives in the prevention and treatment of cancer. We previously reported a novel concept in which polycaprolactone (PCL) Implants embedded with test agents provide sustained delivery for long duration (months to >1year), reduce effective dose substantially and increase bioavailability. While tested successfully for various agents, this formulation results in an initial burst release and does not apply to heat-labile compounds. Furthermore, it takes 2 or more years for the Polymeric Implant to biodegrade. To overcome these limitations, we hypothesized that formulation of low mol wt Polymeric Implants will provide more sustained and higher release compared with higher mol. wt polymers; the low mol. wt polymers are also expected to biodegrade in weeks to months. To test part of this hypothesis, we used three different mol wt PCL polymers and two co-polymers, poly(D, L-lactide-co-glycolide) (PLGA). The method involves i) preparation of blank PCL Implants (1.4 mm dia), and ii) coating of 30-40 layers by dipping blank Implants, with intermittent drying, in 10-20% of different mol wt PCL solutions in dichloromethane containing 10% curcumin in tetrahydrofuran. The curcumin Implants when tested for in vitro release showed that i) the burst release effect and the amount released varied with mol wt of the polymer. Implants prepared with PCL of 3,600 mol wt (PCL-3.6K) did not show any burst release phenomenon. Instead, these Implants took nearly 7 days to render maximum daily release and thereafter the rate of release declined gradually over a period of two weeks. Implants prepared from higher mol wt polymers (PCL-31K and PCL-112K) were accompanied with some initial burst release and the rate of release declined gradually. Cumulative release measured over two weeks was found to be inversely proportional to the mol wt of PCL: PCL-3.6K (30%) > PCL-31K (24%) > PCL-112K (21%). On the other hand, the co-polymers, PLGA (50:50) and PLGA (75:25) showed only 1% and 0.5% total release, respectively. To determine if the Implant delivery reduced the effective dose in a tumor model, nude mice were inoculated with human lung cancer (A549) cells and then treated with coated Implants of withaferin A, a potent triterpenoid isolated from the traditional Ayurvedic herb “Ashwagandha”. Withaferin A given via the coated Implants significantly inhibited (>50%) human lung cancer (A549) xenograft, while it was ineffective when the same dose was administered i.p. Together, our data suggest that coated Implants of low mol wt PCL can accommodate heat-labile compounds, enhance bioavailability, furnish more sustained and higher cumulative release, and elicits anti-tumor activity. Our ultimate goal is to use low mol Polymeric Implants that will biodegrade in few months and provide continuous release of the drug. (Supported from CA-118114, KLCRP and Duggan Endowment). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2883. doi:1538-7445.AM2012-2883
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Enhanced activity of punicalagin delivered via Polymeric Implants against benzo[a]pyrene-induced DNA adducts
Mutation Research, 2012Co-Authors: Farrukh Aqil, Manicka V. Vadhanam, Ramesh C. GuptaAbstract:Abstract We investigated the effect of punicalagin (PC) on benzo[ a ]pyrene (BP)-induced DNA adducts in vitro and in vivo . Incubation of BP (1 μM) with rat liver microsomes, appropriate co-factors and DNA in the presence of vehicle or punicalagin (1–40 μM) showed dose-dependent inhibition of the resultant DNA adducts, with essentially complete (97%) inhibition at 40 μM. However, PC failed to inhibit anti -BPDE-induced DNA adducts when tested in an in vitro non-microsomal system, suggesting that the inhibition of the microsomal BP–DNA adducts occurred due to inhibition of P450 1A1 by PC. To determine its efficacy in vivo , female S/D rats were administered punicalagin via the diet (1500 ppm; ∼19 mg/day/animal) or subcutaneous Polymeric Implants (two 2-cm, 200 mg with 20% drug load; 40 mg PC/Implant) and then treated with continuous low-dose of BP by a subcutaneous Polymeric Implant (2 cm, 200 mg with 10% load; 20 mg BP/Implant) and euthanized after 10 days. Analysis of the lung DNA by 32 P-postlabeling showed significant (60%; p = 0.029) inhibition of DNA adducts by PC administered via the Implants; the dietary route showed modest (34%) but statistically insignificant inhibition. Furthermore, total PC administered by Implants was approximately 38-fold lower compared with the dietary route. Analysis of the lung microsomes showed significant inhibition of cytochrome P450 1A1 activity and induction of glutathione. Release of PC from the Implants was found to be biphasic starting with a burst release, followed by a gradual decline. Ultra performance liquid chromatography analysis showed no detectable PC in the plasma but its hydrolyzed product, ellagic acid was readily detected. The plasma concentration of ellagic acid was over two orders of magnitude higher (589 ± 78 ng/mL) in the Implant group compared with diet (4.36 ± 0.83 ng/mL). Together, our data show that delivery of PC by Implants can reduce its effective dose substantially, and that the inhibition of DNA adducts in vivo occurred presumably due to the conversion of PC to ellagic acid.
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Enhanced activity of punicalagin delivered via Polymeric Implants against benzo[a]pyrene-induced DNA adducts.
Mutation research, 2012Co-Authors: Farrukh Aqil, Manicka V. Vadhanam, Ramesh C. GuptaAbstract:We investigated the effect of punicalagin (PC) on benzo[a]pyrene (BP)-induced DNA adducts in vitro and in vivo. Incubation of BP (1 μM) with rat liver microsomes, appropriate co-factors and DNA in the presence of vehicle or punicalagin (1-40 μM) showed dose-dependent inhibition of the resultant DNA adducts, with essentially complete (97%) inhibition at 40 μM. However, PC failed to inhibit anti-BPDE-induced DNA adducts when tested in an in vitro non-microsomal system, suggesting that the inhibition of the microsomal BP-DNA adducts occurred due to inhibition of P450 1A1 by PC. To determine its efficacy in vivo, female S/D rats were administered punicalagin via the diet (1500 ppm; approximately 19 mg/day/animal) or subcutaneous Polymeric Implants (two 2-cm, 200mg with 20% drug load; 40 mg PC/Implant) and then treated with continuous low-dose of BP by a subcutaneous Polymeric Implant (2 cm, 200mg with 10% load; 20mg BP/Implant) and euthanized after 10 days. Analysis of the lung DNA by (32)P-postlabeling showed significant (60%; p=0.029) inhibition of DNA adducts by PC administered via the Implants; the dietary route showed modest (34%) but statistically insignificant inhibition. Furthermore, total PC administered by Implants was approximately 38-fold lower compared with the dietary route. Analysis of the lung microsomes showed significant inhibition of cytochrome P450 1A1 activity and induction of glutathione. Release of PC from the Implants was found to be biphasic starting with a burst release, followed by a gradual decline. Ultra performance liquid chromatography analysis showed no detectable PC in the plasma but its hydrolyzed product, ellagic acid was readily detected. The plasma concentration of ellagic acid was over two orders of magnitude higher (589 ± 78 ng/mL) in the Implant group compared with diet (4.36 ± 0.83 ng/mL). Together, our data show that delivery of PC by Implants can reduce its effective dose substantially, and that the inhibition of DNA adducts in vivo occurred presumably due to the conversion of PC to ellagic acid.
J G Villemure - One of the best experts on this subject based on the ideXlab platform.
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excretion of a radiolabelled anticancer biodegradable Polymeric Implant from the rabbit brain
Biomaterials, 1995Co-Authors: Abraham J Domb, M Rock, C Perkin, G Yipchuck, B Broxup, J G VillemureAbstract:The elimination of a clinically used anticancer biodegradable polymer Implant (Gliadel™) in the rabbit brain was studied. The Implant is composed of N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU) (1.6 wt%) dispersed in a copolyanhydride matrix of 1,3-bis(p-carboxyphenoxypropane) (CPP) and sebacic acid (SA) in a 20:80 molar ratio. Four groups of rabbits were Implanted with wafers loaded with BCNU, one in a 14C-SA-labelled polymer, another in a 14C-CPP-labelled polymer and two groups with 14C-BCNU in a non-labelled polymer, one for BCNU disposition study and one for residual drug study. In the rabbits Implanted with the 14C-SA-labelled polymer, approximately 10% of the radioactivity was found in the urine and 2% in the faeces, and about 10% remained in the device 7d after Implantation. In contrast, only 4% of the radioactivity of the 14C-CPP-labelled polymer was found in urine and faeces during this period. However, a drastic increase in the CPP excretion was found after 9d, and at 21 d, 64% of the Implanted 14C-CPP was found in the urine and faeces, and 29% was still in the recovered wafers. Approximately 50% of the BCNU in the wafers was released in 3d, and over 95% was released after 6 d in the rabbit brain. This study demonstrates that BCNU-loaded polyanhydride is biodegradable and is excreted from the body primarily through the renal system. The water-soluble components SA and BCNU were rapidly excreted, while the insoluble CPP was gradually eliminated after a lag time of 9 d.
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metabolic disposition and elimination studies of a radiolabelled biodegradable Polymeric Implant in the rat brain
Biomaterials, 1994Co-Authors: Abraham J Domb, M Rock, C Perkin, B Broxup, J Schwartz, G Yipchuk, J G VillemureAbstract:Abstract The metabolic disposition and elimination process of the anhydride co-polymer poly[1,3-bis( p -carboxyphenoxypropane): sebacic acid] 20:80 [P(CPP:SA)20:80] Implanted in the rat brain was studied. Two polymers were prepared, one with [ 14C ]SA and unlabelled CPP, and the other co-polymer with [ 14 C]CPP and unlabelled SA. With these two polymers we were able to study the metabolic disposition of each monomer after polymer degradation. Polymer wafers loaded with AJ,AJ-bis(2-chloroethyl)-JV-nitrosourea or without the drug were Implanted in the rat brain. For the rats Implanted with the [ 14 C]SA-labelled polymer, approximately 40% of the radioactivity was found in the expired CO 2 , 10% in the urine, about 2% in the faeces and about 10% remained in the device 7d after Implantation. On the other hand, only 4% of the [ 14 C]CPP monomer was eliminated by urine and faeces during this period. The drug-loaded polymer degraded faster than the blank polymer. This study supports the theory that the polymer is a biodegradable material that can be used for the direct and specific delivery of drugs into a targeted organ and can provide continued release of drugs over a period of time. Biomaterials (1994) 15 , (9) 681–688
Joseph Kost - One of the best experts on this subject based on the ideXlab platform.
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characterization of a Polymeric plga injectable Implant delivery system for the controlled release of proteins
Journal of Biomedical Materials Research, 2000Co-Authors: Rom Eliaz, Joseph KostAbstract:Physico-chemical properties of injectable Polymeric Implant systems, based on the principle that a water-insoluble polymer dissolved in a biocompatible solvent will precipitate upon contact with water, were studied and utilized to predict the release of proteins from these systems. Polylactide-co-glycolide copolymer (PLGA) and glycofurol were chosen since they both have pharmaceutical precedence. Changes in polymer composition, its weight percent in solution, molecular weight, and protein loading level were assessed to provide formulations with the desired release rates and duration of release. © 2000 John Wiley & Sons, Inc. J Biomed Mater Res, 50, 388–396, 2000.
A T Bennett - One of the best experts on this subject based on the ideXlab platform.
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physico chemical characterization of a Polymeric injectable Implant delivery system
Journal of Controlled Release, 1995Co-Authors: M L Shively, B A Coonts, W D Renner, J L Southard, A T BennettAbstract:Physico-chemical properties of an injectable Polymeric Implant system were evaluated and utilized to predict and understand the in vivo release of a model drug. The injectable Implant system is based on the principle that a water insoluble polymer, dissolved in a biocompatible solvent, will precipitate upon contact with water. The solubility parameter of poly(dl-lactide) and dl-lactide-co-glycolide copolymers were experimentally determined by evaluating the solubility of these polymers in hydrogen bonding solvents having solubility parameters ranging from 8.9 to 14.8 (cal/cm3)12. The appropriate Flory-Huggins interaction parameters were then calculated at 25 and 37°C. Analysis of ternary phase diagrams indicated that the quantity of water needed to initiate precipitation, as well as the precipitation threshold, increased with increasing temperature in agreement with theoretical calculations. Rats were subcutaneously administered formulations comprised of polymer concentrations above and below the precipitation threshold, i.e., 40% w/w polymer. Formulations with polymer concentrations below the precipitation threshold exhibited approximately twice the initial release compared to formulations having a polymer content above the precipitation threshold. A key factor affecting the initial release of a model drug from formulations was the polymer content of the formulation with respect to the precipitation threshold. The reported method of analysis may be utilized to screen polymers and biocompatible solvents for use in these injectable Implant systems.