J.M. Teijón

5-Fluorouracil release from copolymeric hydrogels of itaconic acid monoester. I. Acrylamide-co-monomethyl itaconate.

The aim of this work was to test the application of new copolymeric poly (acrylamide-co-monomethyl itaconate) (A/MMI) hydrogels to 5-fluorouracil (5-FU) release. Three different compositions of copolymers have been studied, 90A:10MMI 75A:25MMI and 60A:40MMI. The equilibrium swelling degree in saline solution was between 76 and 80% depending on the copolymer composition. 5-FU, as the sodium salt, was trapped in the gels by including it in the feed mixture of polymerization. The swelling kinetics of the hydrogels in saline solution were studied at four temperatures, and the diffusion coefficient and the activation energy of the process were obtained. The 5-FU release as a function of temperature and disc load was studied; the diffusion coefficient and the activation energy of the release process were also obtained. The diffusion studies follow Ficks second law.

Chitosan microspheres in PLG films as devices for cytarabine release.

Cytarabine was included in chitosan microspheres and several of these microspheres were embedded in a poly(lactide-co-glycolide) (PLG) film to constitute a comatrix system, to develop a prolonged release form. Chitosan microspheres, in the range of 92+/-65 microm, having good spherical geometry and a smooth surface incorporating cytarabine, were prepared. The cytarabine amount included in chitosan microspheres was 43.7 microg of ara-C per milligram microsphere. The incorporation efficiency of the cytarabine in microspheres was 70.6%. Total cytarabine release from microspheres in vitro was detected at 48 h. Inclusion of cytarabine-loaded microspheres in poly(lactide-co-glycolide) film initiated a slower release of the drug and, in this way, the maximum of cytarabine released (80%) took place in vitro at 94.5 h. Comatrices, with 8.7 mg of cytarabine, signifying a dose of 34.5 microg/kg, were subcutaneously implanted in the back of rats. Maximum plasma cytarabine concentration was 18.5+/-1.5 microg/ml, 48 h after the device implantation and the drug was detected in plasma for 13 days. The histological studies show a slow degradative process. After 6 months of implantation, most of the microspheres of the matrix seemed to be intact, the comatrix appeared surrounded by conjunctive tissue and small blood vessels and nerve packets were detected in the periphery of the implant.

Preparation of bupivacaine-loaded poly(ε-caprolactone) microspheres by spray drying: drug release studies and biocompatibility

Abstract Poly(e-caprolactone) microspheres containining bupivacaine were prepared by the spray-drying process. The average size of drug loaded microspheres was less than 3xa0μm in diameter, and the percentage of entrapment efficiency was 91±3%. In vitro drug release kinetic in phosphate buffer at 37°C showed a hyperbolic profile, with a burst-effect during the first hour. Subcutaneous injection of bupivacaine-loaded microspheres in the back of rats caused an increase in drug concentration in plasma. Maximum bupivacaine concentration in plasma was 237±58xa0ng/ml at 105xa0h, and drug was detected in plasma for 16 days. The half-life time of the drug was increased by more than 125 times with regard to that of the drug administered in a solution by intraperitoneal injection. After 30 days of injection, a mass formed by microspheres surrounded by a thin fibrous capsule was observed. Small blood vessels and multinucleate foreign body giant cells with macrophagic function around microspheres were detected. After 60 days of injection a subcutaneous mass was also observed, which was formed of more degraded dispersed microspheres in conjunctive tissue, which had a normal structure. Thus, bupivacaine-loaded poly(e-caprolactone) microspheres could be considered as a device to be used in the treatment of severe pain that is not responsive to opioids for example in cancer-related syndromes or in intractable herpetic neuralgia.

Cytarabine trapping in poly(2-hydroxyethyl methacrylate) hydrogels: drug delivery studies

The release of cytarabine (ara-c) from poly(2-hydroxyethyl methacrylate) hydrogels cross-linked with different amounts of ethyleneglycol dimethacrylate (EGDMA) has been studied. The drug (range 5-25 mg) was trapped in polymer discs by including it in the feed mixture of polymerization. The drug delivery was followed by HPLC. The release was in accordance with Fickian behaviour. Total release of ara-C was reached after between 3 and 7 days depending on the percentage of EGDMA in the gels. A constant release rate of ara-C from the hydrogels was obtained, the time depending on the degree of cross-linking of the gels: 22 h for gels with 0.5% EGDMA, 32 h for gels with 5% EGDMA and 42 h for gels with 7% EGDMA; the amount of ara-C released being 50%, 80% and 85%, respectively, of the drug load of the gel discs. An increase of the release rate with the disc load was observed for each sort of hydrogel. Neither during the loading of the gels nor right through the drug release was degradation of ara-C observed.

5-Fluorouracil-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(lactide-co-glycolide) polymers: Characterization and drug release

5-Fluorouracil (5-FU), a hydrosoluble anti-neoplastic drug, was encapsulated in microspheres of poly(D,L-lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) polymers using the spray-drying technique, in order to obtain small size microspheres with a significant drug entrapment efficiency. Drug-loaded microspheres included between 47u2009±u200911 and 67u2009±u200912u2009µg 5-FUu2009mg−1 microspheres and the percentage of entrapment efficiency was between 52u2009±u200912 and 74u2009±u200913. Microspheres were of small size (average diameter: 0.9u2009±u20090.4–1.4u2009±u20090.8u2009µm microspheres without drug; 1.1u2009±u20090.5–1.7u2009±u20090.9u2009µm 5-FU-loaded microspheres) and their surface was smooth and slightly porous, some hollows or deformations were observed in microspheres prepared from polymers with larger Tg. A fractionation process of the raw polymer during the formation of microspheres was observed as an increase of the average molecular weight and also of Tg of the polymer of the microspheres. The presence of 5-FU did not modify the Tg values of the microspheres. Significant interactions between the drug and each one of the polymers did not take place and total release of the included drug was observed in all cases. The time needed for the total drug release (28–129u2009h) was in the order PLAu2009>u2009PLGA 75/25u2009>u2009PLGA 50/50. A burst effect (17–20%) was observed during the first hour and then a period of constant release rate (3.52u2009±u20090.82–1.46u2009±u20090.26u2009µg 5-FUu2009h−1 per milligram of microspheres) up to 8 or 13u2009h, depending on the polymer, was obtained.

Transdermal application of bupivacaine-loaded poly(acrylamide(A)-co-monomethyl itaconate) hydrogels

Bupivacaine, an amide local anaesthetic agent of long-acting and intense anaesthesia, was incorporated into poly(acrylamide(A)-co-monomethyl itaconate (MMI)) hydrogels. The swelling behaviour of two gel compositions, without drug, 75A/25MMI and 60A/40MMI, through rabbit ear skin, mounted on a modified Franz diffusion cell, was studied. Both gel compositions reach the equilibrium swelling degree (88.9+/-0.7 wt.% for 75A/25MMI and 92.5+/-0.1 wt.% for 60A/40MMI). The swelling kinetics was in accordance with the second Ficks Law; diffusion coefficients indicate faster swelling for gels with lower amount of monomethyl itaconic acid. The skin flux of bupivacaine solution through rabbit ear skin was 105+/-24 microg/cm(2)/h, the effective permeability coefficient was 26 x 10(-3)+/-9 x 10(-3)cm/h, and 77+/-15% of bupivacaine was permeated. Bupivacaine-loaded gels allow the drug was permeated through the skin. 47+/-4% and 36+/-3% of the drug amount included in 75A/25MMI and 60A/40MMI hydrogels, respectively, was permeated. The skin flux of the drug was between 90+/-5 and 16+/-7 microg/cm(2)/h depending on the amount of bupivacaine included in the gel and the gel composition. Skin flux increases with the drug load of the gels. Furthermore, as more MMI in the gel slower skin flux of the drug due to bupivacaine-gel interactions.

Influence of degree of crosslinking on 5-fluorouracil release from poly(2-hydroxyethyl methacrylate) hydrogels.

Controlled release of 5-fluorouracil (5-FU) from poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels with three different degrees of crosslinking is reported. The swelling kinetic of PHEMA hydrogels in water was studied at different disc thicknesses and temperatures, and the diffusion coefficient and activation energy of the process were obtained. The gels were loaded with 5-FU by immersing them in concentrated aqueous solutions of the drug. The 5-FU release was studied as a function of temperature, disc thickness, disc load and degree of crosslinking of the gels; the diffusion coefficient and activation energy of the release process were also obtained.

Anticancer drug, ara-C, release from pHEMA hydrogels

This study investigates the controlled release of cytarabine (ara-C), an anticancer drug, from a polymeric matrix of lightly cross-linked poly(2-hydroxyethyl methacrylate) (pHEMA). The swelling of pHEMA discs in water was analysed as a function of temperature and thickness of xerogel discs. The fractional swelling was linear in (time)1/2 for short time periods. Drug release kinetics were examined as a function of temperature, initial drug load and thickness of pHEMA discs. The fraction of available drug release was also linear in (time)1/2 during the initial stages. These studies allow for the determination of diffusion coefficients for both the transport of water into the hydrogel and ara-C release from the polymer.

Bupivacaine-loaded comatrix formed by albumin microspheres included in a poly(lactide-co-glycolide) film: in vivo biocompatibility and drug release studies

Bupivacaine-loaded comatrix, formed by bupivacaine-loaded microspheres included in a poly(lactide-co-glycolide) film, was assayed for the controlled release of the drug in vivo. The comatrix, with 66.37 microg of bupivacaine, signifying a dose of 265.5 microg/kg, was subcutaneously implanted in the back of rats. Maximum plasma bupivacaine concentration was 147.6 +/- 5.0 ng/ml 95 h after the device implantation, and the drug was detected in plasma for 17 days. The half-life time of bupivacaine improves by more than 50 times with regard to that of the drug administered in a solution by intraperitoneal injection. After 15 days of implantation the comatrix was included in a thin fibrous capsule and degradation of the microspheres was observed. The histological studies show good biocompatibility of this comatrix. After 50 days the comatrix was degraded and its remains were almost indistinguishable from the surrounding tissue. Small number of microspheres was observed and they were surrounded by conjunctive tissue. Nerve packets and small blood vessels were also observed in the periphery of the implant.

Tamoxifen‐loaded thiolated alginate‐albumin nanoparticles as antitumoral drug delivery systems

Nanoparticles based on disulfide bond reduced bovine serum albumin and thiolated alginate (alginate-cysteine conjugate) have been prepared by coacervation method and have been loaded with tamoxifen (TMX). The TMX load into the nanoparticles was optimized (4-6 μg/mg NP) by freeze-drying the systems before the loading procedure. Maximum TMX release (45-52%) took place between 2 and 25 h. Cytotoxicity of unloaded nanoparticles in MCF-7 and HeLa cells was not observed, although a small decrease in viability took place at very high concentration. Cell uptake of nanoparticles occurred in both cell types and the presence of polysaccharide in the nanoparticle composition allowed a better interaction with cells. The administration of 10 μM TMX by TMX-nanoparticles was effective in both cellular lines, and the effect of the drug-loaded systems on MCF-7 cell cycle showed the efficacy of the TMX-loaded nanoparticles.