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Biomedical subjects

G Di Colo

Publications and source records attributed to G Di Colo.

At least 19 recordsLinked to original sources
PubMed2006

A new hydrogel for the extended and complete prednisolone release in the GI tract.

The issue of incomplete release of poorly soluble drugs from sustained-release oral formulations is addressed using prednisolone (PDS) as the model drug and a novel highly swelling hydrogel as the rate-controlling material. The hydrogel was formed by heating N-carboxymethylchitosan (CMC) to 80 degrees C for 24 h. Swelling, alkalimetry, FTIR, DSC, and solid-state NMR studies showed that the treatment produced physical crosslinking, i.e., polymer chain entanglement. A controlled-release system was prepared by coating an inert compacted support of ethylcellulose (50 mg; diameter, 6 mm) with a CMC layer containing dispersed PDS powder (10-50 microm). The system was heated to crosslink the CMC coating, then drug release to simulated GI fluids was studied in vitro. The drug release pattern and term were modulated via the layer mass (LM) (10 or 14 mg cm(-2)) and/or the drug-polymer wt ratio (D/P) (1:5 or 2:5). The rate parameter, K, and the time exponent, n, of the Peppas equation were: K=26.6+/-0.3 h(-n), n = 0.78+/-0.02 (LM, 10 mg cm(-2); D/P, 1:5); K = 24.7+/-0.7 h(-n), n = 0.56+/-0.02 (LM, 14 mg cm(-2); D/P, 1:5); K = 20.7+/-0.3 h(-n), n = 0.76+/-0.01 (LM, 10 mg cm(-2); D/P, 2:5). Hydrogel swelling was faster than drug release. This was controlled, in a first stage, by drug dissolution-diffusion in the swollen gel, and subsequently, by diffusion. The drug release rate was unaffected by the GI pH variations, and slightly affected by the environmental hydrodynamics. The system promises an extended and complete release of poorly soluble drugs in the GI tract.

Chitosan↗
PubMed2005

Matrices for site-specific controlled-delivery of 5-fluorouracil to descending colon.

Colon-specific controlled-delivery 5-fluorouracil (5-FU) matrices for the treatment of colorectal carcinoma were prepared and evaluated. Matrices are destined to be introduced into enteric-coated capsules and thereby carried to and liberated in the ileum. There, drug release should be prevented until matrices reach descending colon where release should occur. Matrices (50 mg, diameter 0.6 mm) were prepared by compression of powders or of granules prepared by melt granulation. The ingredients comprised 30-70% w/w 5-FU, glyceryl palmitostearate as rate-controlling material and 5% w/w Aerosil as glidant. Drug release was measured by the rotating basket method. The matrix containing 60% w/w drug, prepared by compression of powders, was appropriate to make the planned system, in virtue of its fairly high drug load and its nearly constant and reasonable release rate. This matrix was spray-coated with Eudragit S100 (EUD). Subsequently, an external layer of chitosan hydrochloride (CH-HCl) was applied by a dipping-drying technique. When transit of coated matrix through ileum (phosphate buffer (PB) pH 7.4), ascending colon (PB pH 6 containing rat cecal contents) and descending colon (PB pH 7.4) was simulated in vitro, the pH 4.7 of the CH-HCl gel layer and the pH 6 of the ascending colon prevented dissolution of the protective EUD film until descending colon was reached, then controlled release started. The present small matrices can enter size no. 00 capsules. Considering that each capsule contains 10 matrices, the maximal dose is 300 mg.

Animals↗
PubMed2004

Effect of chitosan and of N-carboxymethylchitosan on intraocular penetration of topically applied ofloxacin.

The effects of chitosan hydrochloride (Ch-HCl) and of N-carboxymethylchitosan (CMCh), formulated in ophthalmic solutions, on the ocular pharmacokinetics of ofloxacin were studied in rabbits. The carboxymethylation of a chitosan of high molecular mass (1460 kDa) and deacetylation degree (89.9%) introduced 0.84 N-carboxymethyl groups per repeating unit. Aqueous solutions containing 1% (w/v) of either polymer showed a pseudoplastic rheologic behaviour, and, when instilled in rabbit eyes, produced no irritation. The kinetics of drug disappearance from tear fluid and the profiles of drug concentration in the aqueous humour versus time were determined and interpreted in the light of a pharmacokinetic model and of drug-polymer binding. Ch-HCl significantly enhanced intraocular drug penetration with respect to an isoviscous drug solution containing poly(vinyl alcohol) and to commercial ofloxacin eyedrops. This effect, which resulted in about 190% increase of the peak concentration in the aqueous, was ascribed to an increased corneal permeability. The polyanionic CMCh failed to enhance intraocular drug penetration. It nevertheless increased precorneal drug retention in virtue of its viscosity and of ofloxacin binding. Consequently, the residence time at concentrations higher than the MIC90 and the bioavailability of the antibiotic in the aqueous were increased by about 150 and 240%, respectively, with respect to the reference vehicle.

Animals↗
PubMed2002

Effect of chitosan on in vitro release and ocular delivery of ofloxacin from erodible inserts based on poly(ethylene oxide).

The effects of chitosan hydrochloride (CH-HCl) on in vitro release of ofloxacin (OFX) from mucoadhesive erodible ocular inserts and on the relevant ocular pharmacokinetics have been studied both to contribute evidence of the ability of CH-HCl to enhance transcorneal penetration of drugs and to increase the therapeutic efficacy of topically applied OFX. Circular inserts of 6 mm in diameter, 0.8-0.9 mm in thickness and 20 mg in weight, medicated with 0.3 mg drug, were prepared by powder compression. The addition of 10, 20 or 30% medicated CH-HCl microparticles, obtained by spray-drying, to formulations based on poly(ethylene oxide) of MW 900 kDa (PEO 900) or 2000 kDa (PEO 2000) produced changes in the insert microstructure which accelerated both insert erosion and OFX release from inserts. The effect was stronger with higher CH-HCl fractions. Of the CH-HCl-containing formulations based on either PEO 900 or PEO 2000, PEO 900-CH-HCl (9:1 w/w) was more suitable for a prolonged OFX release. Following insertion in the lower conjunctival sac of the rabbit's eye, such an insert produced no substantial increase of AUC(eff) (AUC in the aqueous humour for concentrations >MIC(90%)) with respect to inserts based on plain PEO; however, it produced a concentration peak in the aqueous significantly higher than that produced by any of the CH-HCl-free PEO inserts, and well higher than the MIC(90%) for the more resistant ocular pathogens (7 microg/ml vs. 4 microg/ml). It has been argued that the increase was due to the ability of CH-HCl to enhance the transcorneal permeability of the drug.

Animals↗
PubMed2002

In vitro evaluation of a system for pH-controlled peroral delivery of metformin.

Oral absorption of the antihyperglycaemic agent metformin (MF x HCl) is confined to the upper part of the intestine, therefore controlled-release oral formulations of this drug should ensure a complete release during transit from stomach to jejunum. Compressed matrix tablets based on pH-sensitive poly(ethylene oxide) (PEO)-Eudragit L100 (EUD L) compounds have shown in vitro a compliance with the above requirement. The polymer compounds were prepared by a coevaporation process. The release pattern of MF x HCl from matrices depended on the PEO-EUD L ratio in the coevaporate. The 1:1 (w/w) ratio was unable to control MF x HCl release in simulated gastric fluid (SGF, pH 1.2), because the matrix material was excessively hydrophilic. Nevertheless, the release rate in SGF could be modulated by increasing the EUD L fraction in the coevaporate. With a PEO (M(w), 400 kDa)-EUD L (1:2, w/w) ratio the percent dose released in 2 h to SGF, where the coevaporate was insoluble, was around 23 or 50% with 10 or 20% loading dose. The release was then completed within the successive 2 h of elution with simulated jejunal fluid (SJF, pH 6.8) where EUD L and the coevaporate gradually dissolved. Release in SGF was controlled by matrix swelling and/or drug diffusion in matrix, whereas matrix dissolution controlled release in SJF. The unique release-controlling properties of the polymer compounds were due to PEO-EUD L macromolecular interactions. Matrices show promise of a gradual and complete release of MF x HCl from stomach to jejunum, unaffected by gastric pH fluctuations. This mode of administration might allow the use of lower therapeutic doses compared to existing immediate- or sustained-release products, thus minimising side effects.

Administration, Oral↗
PubMed2002

A study of release mechanisms of different ophthalmic drugs from erodible ocular inserts based on poly(ethylene oxide).

When topical controlled delivery of ophthalmic drugs is realised via erodible inserts, drug bioavailability is maximised, if release is controlled exclusively by insert erosion, since parallel mechanisms which increase the release rate, also increases the dose fraction cleared from the precorneal area by tear fluid draining. The respective contributions of diffusion and erosion to the release mechanism of different drugs, namely, prednisolone (PDS), oxytetracycline hydrochloride (OTH) and gentamicin sulfate (GTS), from erodible ocular inserts based on poly(ethylene oxide) (PEO) of molecular weight 400 or 900kDa was determined by an in vitro technique adequate to predict the release mechanism in vivo. PDS and OTH were released with erosion-controlled kinetics. With therapeutic doses of these drugs in the inserts (0.3mg, 1.5%), the possibility of a purely erosive mechanism was shown to rely upon drug-PEO molecular interactions, which limit drug diffusion in the swollen matrix. This was the case with OTH, for which strong interactions with PEO were measured, whereas some contribution from the parallel diffusive mechanism was evidenced for PDS, which showed weaker interactions with polymer. Such a contribution disappeared when the PDS concentration in the insert was increased to 6%, which suggested that the erosive mechanism is favoured by a drug concentration in the hydrated insert substantially higher than solubility. On the other hand, the release of about 50% GTS dose was controlled by diffusion, due to the high water solubility of this drug, accompanied by weak drug-PEO interactions. In this case the residence time of drug in the precorneal area is expected to be significantly shorter than that of the PEO carrier.

Benzocaine↗
PubMed2001

Relevance of polymer molecular weight to the in vitro/in vivo performances of ocular inserts based on poly(ethylene oxide).

A previous study of the present authors on gel-forming erodible inserts, based on high molecular weight (MW, 400 kDa) poly(ethylene oxide) (PEO), for ocular controlled delivery of ofloxacin (OFX) has been extended to investigate the effects of PEO MW, in the 200-2000 kDa range, on insert properties relevant to therapeutic efficacy. Mucoadhesion has shown a dependence on MW, with a maximum for PEO 400. The in vitro drug release from inserts based on PEO 200, PEO 400 and PEO 900 was mainly controlled by insert erosion, whereas with PEO 2000 it was mainly diffusion-controlled in a first phase, followed by an erosion-controlled phase. The erosion time scale depended directly on MW. Immediately after application in the lower conjunctival sac of the rabbit eye, the inserts based on PEO of whichever MW formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. PEO 2000 was unsuitable as an insert material, since the resulting gel spilled from the eye, due to excessive swelling. The gel residence time in the precorneal area, the drug permanence time in the aqueous humor at concentrations > MIC and the time to reach the maximal drug concentration in the aqueous humor (C(max)) depended directly on MW, indicating that transcorneal absorption was governed by gel erosion. All inserts increased Cmax and AUCeff (AUC for concentrations > MIC) with respect to the commercial eyedrops. The increases caused by PEO 400 and PEO 900 were similar (3.78- and 3.16-fold, respectively, for Cmax; 11.06- and 12.37-fold, respectively, for AUCeff), whereas smaller increases were produced by PEO 200. The PEO 400 and PEO 900 inserts have shown a potential for a topical treatment of endophthalmitis.

Animals↗
PubMed2001

Gel-forming erodible inserts for ocular controlled delivery of ofloxacin.

A new application of high molecular weight (400 kDa) linear poly(ethylene oxide) (PEO) in gel-forming erodible inserts for ocular controlled delivery of ofloxacin (OFX) has been tested in vitro and in vivo. Inserts of 6 mm diameter, 20 mg weight, medicated with 0.3 mg OFX, were prepared by powder compression. The in vitro drug release from inserts was mainly controlled by insert erosion. The erosion time scale was varied by compounding PEO with Eudragit L100 (EUD) 17% neutralized (EUDNa17) or 71% neutralized (EUDNa71). The insert erosion rate depended on the strength of interpolymer interactions in the compounds, and on the hydrophilic-hydrophobic balance of compounds. Immediately after application in the lower conjunctival sac of the rabbit eyes, the inserts based on plain PEO, PEO-EUDNa17 or PEO-EUDNa71 formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. The gel residence time in the precorneal area was in the order PEO-EUDNa71 < PEO < PEO-EUDNa17. Compared to commercial OFX eyedrops, drug absorption into the aqueous humor was retarded by the PEO-EUDNa71 inserts, and both retarded and prolonged by the PEO-EUDNa17 inserts, while C(max) (maximal concentration in the aqueous) and AUC(eff) (AUC in the aqueous for concentrations > MIC) were barely altered by either insert type. On the other hand, C(max), AUC(eff) and t(eff) (permanence time in the aqueous at concentrations > MIC) were strikingly increased by plain PEO inserts with respect to commercial eyedrops (5.25 +/- 0.56 vs. 1.39 +/- 0.05 microg ml(-1); 693.6 vs. 62.7 microg ml(-1) min; and 290 vs. 148 min, respectively). Bioavailability increase has been ascribed to PEO mucoadhesion and/or increased tear fluid viscosity.

Animals↗
PubMed2000

Polyoxyethylene-poly(methacrylic acid-co-methyl methacrylate) compounds for site-specific peroral delivery.

pH-sensitive interpolymer interactions between high molecular weight polyoxyethylene (POE) and poly(methacrylic acid-co-methyl methacrylate) (Eudragit (EUD) L100 or S100) are evidenced and exploited to prepare, from either POE-EUD coevaporates or POE+EUD physical mixtures, both in the 1:1 wt. ratio, compressed matrix tablets, potentially able to deliver the model drug, prednisolone, to sites in the GI tract characterized by specific pHs, such as the jejunum or the ileum. With these devices, drug release is inhibited at pHs lower than the threshold of EUD ionization, whereas at pHs exceeding such a threshold, the matrix undergoes a gradual erosion, which controls the release. A post-compression exposure of tablets to the vapors of appropriate solvents realizes the necessary compaction of matrices, in fact, a high compression force (3 ton) is insufficient, per se, to prevent matrix disintegration in the dissolution medium, whereas such a disintegration is prevented by the treatment with solvent vapors, even with a low compression force (0.3 ton). With the POE+EUD physical mixtures, the exposure to solvent vapors promotes the formation of a layer of POE-EUD complex at the interfaces of the POE and EUD particles in matrix, which inhibits release at pHs lower than that designed for delivery. Both POE and EUD concur to determine the properties of the POE-EUD complex relevant to drug release, indeed, EUD ionization, which elicits matrix erosion and drug release, is favored by the hydrophilic POE. In fact, matrices based on plain EUD exhibit a comparatively low release rate, more suited to an extended delivery to the colon than to a specific delivery to the ileum. Details of the release mechanism are discussed.

Administration, Oral↗
PubMed1999

Silicone microspheres for pH-controlled gastrointestinal drug delivery.

Silicone microspheres containing pH-sensitive hydrogels are prepared, characterized and evaluated for their potential pH-controlled gastrointestinal (GI) drug delivery. The pH-sensitive hydrogels are semi-interpenetrating polymer networks (semi-IPN(s)) made of varying proportions of poly(methacrylic acid-co-methylmethacrylate) (Eudragit (EUD) L100 or EUD S100) and crosslinked polyethylene glycol 8000 (P8000C). Up to 35 wt% hydrogel particles of mean volume diameters from 89 to 123 microm, medicated with 15 wt% prednisolone (PDN), are encapsulated, with 100% efficiency, into morphologically acceptable silicone microspheres in the 500-1000 microm size range, by a modified emulsion vulcanization method. Microspheres are eluted for 9 h with isotonic fluids at pH values increasing from 1.2 to 7.4, to simulate transit across the GI regions. PDN release depends on dissolution medium pH and on hydrogel composition, which determines hydrogel pH-sensitivity. With the P8000C-EUD L100 (1:2) semi-IPN, the release shows a marked peak at pH 6.8. The P8000C-EUD S100 (1:2) semi-IPN causes a gastroprotection and an almost uniform distribution of released drug between media at pH 6.8 and 7.4. With the P8000C-EUD S100 (1:1) semi-IPN, the dose fraction released to gastric fluid increases to match the values for the media at pH 6.8 and 7.4. With the pH-insensitive, highly swelling, P8000C, the largest dose fraction is released to the gastric medium and release is of Fickian type. With semi-IPNs, release depends weakly on the buffer molarity of the dissolution medium, a reduction from 0.13 to 0.032 of which renders the release rate to the media at pH 6.8 and 7. 4 more uniform.

Digestive System↗
PubMed1998

Effect of vehicles on yohimbine permeation across excised hairless mouse skin.

Turchi et al. [Turchi, P., Canale, D., Ducci, M., Nannipieri, E., Serafini, M. F., Menchini Fabris, G.F. (1992). The transdermal route in the treatment of male sexual impotence: preliminary data on the use of yohimbine. Int. J. Impotence Res. 4, 45-50.] showed that the application on penile skin of an oil-in-water cream (cream I.G) containing yohimbine (YO) was successful in the treatment of male sexual impotence. The components of the cream were stearyl alcohol, isopropyl lanolate, white petrolatum, liquid petrolatum, sodium lauryl sulphate (NaLS), propylene glycol (PG) and water. In the present study, a number of creams were derived from the cream I.G by adding, eliminating or replacing one or more constituents, and the effects of such changes on YO permeation through excised hairless mouse skin were investigated. From the data emerged the possibility of improving YO permeation even through slight changes in I.G composition. The stratum corneum-vehicle interactions were investigated by analyzing samples of isolated hairless mouse stratum corneum by DSC.

Animals↗
PubMed1998

Silicone rubber/hydrogel composite ophthalmic inserts: preparation and preliminary in vitro/in vivo evaluation.

The present report describes the development and in vitro/in vivo testing of rod-shaped mucoadhesive ophthalmic inserts fitting the upper or lower conjunctival fornix. Cylindrical devices (diameter 0.9 mm, length 6-12 mm, weight 3-8 mg) all containing 0.8 mg oxytetracycline HCl (OXT) were prepared from appropriate mixtures of silicone elastomer, OXT and sodium chloride as release modifier. A stable polyacrylic acid (PAA) or polymethacrylic acid (PMA) interpenetrating polymer network (IPN; 30 or 46% w/w) was grafted onto the inserts' surface by treatment with a mixture of acrylic (or methacrylic) acid and ethylene glycol dimethacrylate in xylene at 100 degrees C. Mucoadhesion studies in vitro showed that the mucoadhesive properties increased significantly with increasing thickness of the IPN layer. The inserts were tested for drug release in vitro, and for drug release and retention in rabbit eyes. The presence of IPN, as well as of NaCl, in general increased the drug release rate. The PMA-grafted devices released OXT at lower rates when compared with the PAA-grafted ones. A nearly zero-order release rate for about 1 week was observed in vitro for some types of inserts. When tested in rabbits, some IPN-grafted inserts maintained in the lacrimal fluid a OXT concentration of 20-30 microg/ml for several days: the in vitro minimum inhibitory concentration values (MIC 90%) of OXT against micro-organisms responsible of common ocular infections range from 0.8 to 2.0 microg/ml, while MIC 90% values in the range 14-50 microg/ml have been indicated for Pseudomonas aeruginosa. The ocular retention of IPN-grafted samples was significantly higher with respect to ungrafted ones. The presently described mucoadhesive silicone inserts might prove efficient therapeutic systems for chemotherapy of ocular bacterial infections, such as trachoma.

Animals↗
PubMed1992

Controlled drug release from implantable matrices based on hydrophobic polymers.

Reports on the controlled release of drugs, including macromolecular drugs, from silicone elastomers and ethylene-vinyl acetate copolymers, based on the formation of channels and cracks in the polymer, are reviewed. Aqueous interconnected pores are produced by osmotically active additives or by using loads of water-soluble drugs exceeding the percolation threshold. The release is generally proportional to the square root of time (t1/2). Nevertheless, pseudo-zero-order release kinetics can be obtained by adequately controlling the formulation variables. The factors controlling the release pattern and rate are discussed. In vivo applications of these types of systems are also considered.

Absorption↗
PubMed1983

Effect of different water-soluble additives on water sorption into silicone rubber.

The ability of ethylene glycol; glycerin; polyethylene glycols 200, 400, and 6000; polysorbate 80; and lactose dispersed in silicone rubber, to promote water sorption into the polymer was investigated in water and in isotonic (pH 7.4) phosphate buffer. Polyethylene glycols 200 and 400, lactose, and, especially, glycerin were effective water carriers. Marked differences in the kinetics of rubber swelling were observed, depending on the carrier. The swelling patterns relative to ethylene glycol, glycerin, and polyethylene glycol 200 showed a maximum due to significant leaching of these additives from the polymer. Steady swelling degrees were afforded by polyethylene glycols 400 and 6000 and by polysorbate 80. The interdependent processes of polymer imbibition and carrier release were speeded up without altering their kinetic patterns by increasing the initial surface-volume ratio of the devices. A proportionality resulted between maximal swelling and initial carrier concentration, although the swelling patterns were substantially unaffected by this variable.

Adsorption↗