Macromolecular prodrugs XI. Synthesis and characterization of polymer-estradiol conjugate

Estradiol-3-benzoate (EB), an ester derivative of the main oestrogen hormone estradiol, was chemically modified and bound to poly(alpha,beta-(N-2-hydroxyethyl-DL-aspartamide))-poly(alpha,beta-(N-2-aminoethyl-DL-aspartamide)) copolymer (PAHA). EB was first converted to estradiol-3-benzoate-17-(benzotriazole-1-carboxylate), which readily reacted with amino groups in PAHA affording the polymer-drug conjugate PAHA-EB. In PAHA-EB estradiol moiety was covalently bound to the polymeric carrier by carbamate linkage, through non-toxic ethylenediamine spacer. The synthesized compound is a potential hydrosoluble estradiol prodrug.     

Macromolecular prodrugs V. Polymer-broxuridine conjugates

Broxuridine (BrdU) was covalently bound to α,β-poly[(2-hydroxyethyl)-dl-aspartamide](PHEA) and α,β-poly[(2-aminoethyl)-DL-aspartamide]-α,β-poly[(2-hydroxyethyl)-DL-aspartamide](PAHA). BrdU was first chemically modified to 3′-O-acetyl-5′-O-chloroformyl-5-bromo-2′-deoxyuridine (AcCBrdU) and 3′-O-acetyl-5′-O-phosphooxydichloride-5-bromo-2′-deoxyuridine (AcPBrdU). These compounds were bound to PHEA by carbonate and phosphodiester linkages, respectively. 5-Bromo-2′-deoxyuridine 5′-monophosphate (PBrdU) was linked to PAHA by an amide type bond. Neuroepithelial cells were used as a model system to assess the suitability of the conjugated BrdU for cell proliferation. Parallel experiments were performed with unconjugated BrdU and the extent of incorporation into DNA was determined by immunocytochemistry using an BrdU antibody. The results from these studies suggest that conjugated BrdU can be used as an alternative to currently used means of BrdU delivery.     

Macromolecular prodrugs. IX. Synthesis of polymer-fenoprofen conjugates

Synthesis of several polymer-fenoprofen conjugates is described. Fenoprofen was first chemically modified into benzotriazolide 2 and amino acid amide derivatives: glycine fenoprofenamide (3a) and beta-alanine fenoprofenamide (3b) and their benzotriazolides 6a and 6b. Compounds 2 and 6 readily reacted with polyhydroxy aspartamide-type polymers, i.e. poly[alpha,beta-(N-2-hydroxyethyl-DL-aspartamide)] (PHEA) and poly[alpha,beta-(N-3-hydroxypropyl-DL-aspartamide)] (PHPA) forming conjugates 5, 8a,b and 9a,b, respectively. Conjugate 11 was obtained by partial aminolysis of poly-DL-(2,5-dioxo-1,3-pyrrolidinediyl) (PSI) with 2-aminoethyl fenoprofenamide (3c), followed by total aminolysis with 2-hydroxyethylamine. The synthesised polymer-drug conjugates differed in type of covalent bounding, type and/or length of spacer and drug-loading.     

Macromolecular prodrugs. VIII. Synthesis of polymer-gemfibrozil conjugates

Gemfibrozil is covalently linked to two similar polymers: poly[alpha,beta-(N-2-hydroxyethyl-DL-aspartamide)] and poly[alpha,beta-(N-3-hydroxypropyl-DL-aspartamide)]. The synthesised polymer drug conjugates differ in average molecular mass, type of covalent bonding, length of spacer, drug-loading and solubility.     

非诺洛芬钙亲水凝胶缓释骨架片释药机理影响因素考察

研究了非诺洛芬钙亲水凝胶缓释骨架片释放机制的影响因素。通过对骨架材料的种类、型号及用量、填充剂的性质及用量、压片压力、制剂工艺等各因素对药物释放机制的影响考察发现 :骨架材料的种类及用量、填充剂的性质及用量和压片力对释药机制影响较大 ,其余因素影响较弱。     

N-(Acyloxyalkoxycarbonyl) derivatives as potential prodrugs of amines. II. esterase-catalysed release of parent amines from model prodrugs

N-(Acetoxyethoxycarbonyl) derivatives of primary amines released a major fraction of the parent amine in the desired free form in plasma but a significant fraction of the undesired N-acetylated parent amine was also produced. The fraction of the parent amines released from the carbamate derivatives of the primary amines was greater in human plasma than in pH 7.4 buffer. In human plasma, the N-(acetoxyethoxycarbonyl) derivative of a secondary amine released the parent amine in a quantitative manner at a rate higher than that observed in pH 7.4 buffer. Experimental results suggested that the observed catalysis of the release of the parent amines from N-(acetoxyethoxycarbonyl) derivatives of primary and secondary amines was due to participation by plasma esterases. The data suggested that N-(acetoxyethoxycarbonyl) derivatives are well suited for use as prodrugs of secondary amines. Their utility as prodrugs of primary amines is more problematic and cannot be predicted prior to in-vivo studies for the individual compound.     

Kinetics of antibiotics release from ceramic implants

Presented study describes kinetics of antibiotics release: cefazolin, gentamicin, netilmicin and vancomycin, from two types of ceramic implants: corundum and apatite cement prepared for osteosurgery. The experiments was based on our experimental model developed previously, in which the extraction of antibiotics from implants to polyurethane sponge was made for 3 days. The concentrations of antibiotics in the sponges were determined by spectrophotometric and biological methods. Among all ceramic materials tested, corundum implants with netilmicin and cement implants with gentamicin proved to be most efficacious regarding antibiotics release within 3 days of extraction to polyurethane sponge (yield of the release was 50% and 80% respectively). The lowest release was obtained in the case of cefazolin from cement disks (yield about 0.02%). The kinetics and effectiveness of antibiotics release from the ceramic implants tested depended on ceramic carrier and kind of the drug.     

Macromolecular prodrugs based on synthetic polyaminoacids: drug delivery and drug targeting in antitumor therapy

In the last twenty years a depth study on potential pharmaceutical applications of synthetic polymers at proteinlike structure as carrier for macromolecular prodrug production has been performed in academia and in industry. In particular α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), α,β-polyaspartylhydrazide (PAHy), poly(glutamic acid) (PGA), poly(aspartic acid) (PAA) and polylysine (PLL) have been extensively studied in this field. In the present review, the use of PHEA, PAHy, PGA as starting materials to prepare macromolecular prodrugs is reported and drug delivery and targeting aspects have been considered.     

Dyphylline prodrugs: plasma hydrolysis and dyphylline release in rabbits

Ester hydrolysis of prodrugs of dyphylline [7-(2,3-dihydroxypropyl)theophylline] followed first-order kinetics in both human and rabbit plasma. Rate constants were estimated by linear regression analysis of initial conversion rates, determined at different initial prodrug concentrations. Release of dyphylline from different prodrugs was 1.3 to 13 times faster in rabbit plasma than human plasma. However, relative rates of drug release (lability order) followed the same patterns in rabbit and human plasma. Dyphylline concentrations in rabbit plasma were extended slightly following intravenous administration of dyphylline 2',3'-dipivaloate. Oral dosing of the prodrug in rabbits greatly sustained plasma dyphylline concentrations.     

Investigation into drug release from colon-specific azoreductase-activated steroid prodrugs using in-vitro models

Objectives The aim of this study was to investigate drug release from a double steroid prodrug, OPN501, which incorporates a phenylpropionate linker, and its phenylacetate analogue. The prodrugs, which were designed to deliver prednisolone to the colon for the treatment of inflammatory bowel disease, are based on a novel design that requires sequential azoreductase activity and cyclization of an amino ester to trigger drug release. We sought to explain the divergent effects of the two compounds in anti‐inflammatory models and to justify the selection of OPN‐501 for clinical development. Methods The compounds were incubated in mouse colonic contents (10%) fermented in brain heart infusion under anaerobic conditions. The disappearance of the prodrugs and release of prednisolone was monitored by HPLC. We then developed a method for assessment of prodrug activation using suspensions of Clostridium perfringens, an anaerobe from the human colon. The cyclization of the compounds was studied in various media, assessing the influence of pH and bulk solvent polarity on cyclization rate using HPLC and NMR. Key findings The prodrugs were activated via multiple pathways releasing prednisolone in mouse colonic ferment. The compounds released prednisolone by reduction–cyclization in C perfringens suspension. The active OPN‐501 generated a stoichiometric amount of prednisolone following azoreductase activation, whereas its analogue did not. The pH rate profile for the cyclization of the amino intermediates of the two compounds revealed significant differences in rate at pH values relevant to the inflamed colon, which explain in part the different amounts of drug produced. Conclusions The steroid prodrug OPN‐501 has optimal drug release characteristics for colon targeting because of a kinetic advantage of a six‐membered ring formation in the aminolysis reactions of anilides. The results are relevant to the development of OPN‐501 but also to cyclization strategies in prodrug design especially for colon targeting.     

Kinetics of drug release from polylactic acid-hydrocortisone microcapsules

Polylactic acid microcapsules of similar particle size distribution containing various drug loadings of hydrocortisone were prepared. The microcapsules, which contained randomly dispensed drug particles, showed a dissolution pattern which consists of a fast first-stage and a slow second-stage drug release. Our studies showed that the kinetics of drug release from the microcapsules can be adequately described by a spherical matrix model based on a flux mechanism involving the diffusion of dissolved drug at the penetrating front of the dissolution medium. Drug loading played an important role in the control of drug release rate. An empirical relationship between drug loading and drug diffusibility through the polymeric matrix was developed and showed that the rate of drug release increased exponentially with the increase in drug loading. The microcapsules were further shown to exhibit increased rate of drug release in dissolution medium containing either cetylpyridium chloride or aerosol OT. The effect of the surfactants was attributed to surface tension lowering and improved wetting of the microcapsule particles.     

In vitro enantioselective glucuronidation of fenoprofen.

The diastereomeric glucuronic acid conjugates are major metabolites of the nonsteroidal anti-inflammatory drug fenoprofen (FEN). Glucuronidation of FEN enantiomers was investigated with liver microsomal preparations from different species (sheep, rabbit, rat and human). The formed R- and S-FEN conjugates can be separated and quantitated directly on a C18 reversed-phase HPLC column using a mixture of acetonitrile and tetrabutylammonium sulfate buffer, pH 2.5, as mobile phase. Applying this analytical procedure, it is possible to characterize enantioselective glucuronidation of FEN. For in vitro procedures, rates of glucuronide formation are substrate (FEN) and cosubstrate (UDP glucuronic acid, UDPGA) dependent with initial rates of glucuronide formation being higher for R- than for S-FEN. The R/S ratio of the formed products was independent of UDPGA (2.5-15 mmol/l) and substrate concentrations greater than or equal to 0.4 mmol/l. Enantioselective cleavage of the formed FEN conjugates by alkaline hydrolysis and hydrolytic enzymes (R greater than S-glucuronide) can be controlled during in vitro studies by pH adjustment and the addition of enzyme inhibitors.     

Linear pharmacokinetics of orally administered fenoprofen calcium.

The bioavailability of fenoprofen from three different fenoprofen calcium capsule formulations containing the equivalent of 60, 165, and 300 mg of fenoprofen was determined in two studies. In the first study, 12 subjects received one capsule of each formulation according to a three-period crossover design. The second study required each of 13 subjects to receive 300 mg of fenoprofen equivalent of the 60- and 300-mg capsules and 330 mg of the 165-mg capsule. The initial study provided information on the linearity of fenoprofen pharmacokinetics, and the second study established that the three capsule formulations were bioequivalent. The bioavailability parameters Cmax, tmax, and AUC0--12 hr for the drug in plasma were consistent with a linear pharmacokinetic model, as were the amounts of fenoprofen and hydroxyfenoprofen excreted in the urine. These data show linearity of kinetics for fenoprofen in plasma throughout the 60--300-mg dosage range after a single dose. Physical measurements of each capsule formulation drug content, weight variation, and dissolution showed the products to be uniform and readily soluble.     

Renal selective N-acetyl-L-gamma-glutamyl prodrugs: studies on the selectivity of some model prodrugs.

1. In this study, a number of structurally different N-acetyl-L-gamma-glutamyl prodrugs were investigated with respect to selective uptake by the kidney in male Wistar rats. 2. All prodrugs were tested in vitro in rat kidney slices and kidney homogenate to study their uptake and conversion. It was found that the prodrugs of para-nitroaniline (agPNA), aminophenyl acetic acid (agAFA), sulphamethoxazole (agSM), sulphadimethoxine (agSDM), propranolol (agPP) and metoprolol (agMP) were accumulated by a probenecid-sensitive carrier. The prodrug of 4'-aminoantipyrine (agAAP) was not accumulated by a probenecid- or buthionine sulphoximine-sensitive carrier. Unlike all other prodrugs, agAAP and agMP were not, or only a very limited extent converted to the parent compound in vitro. 3. agPNA, agAFA and agPP were also investigated in vivo. The tissue distribution of the prodrugs and the parent drugs was established, as was their urinary excretion and pharmacokinetic behaviour. agPNA and agAFA showed selective uptake by the kidney, in contrast to agPP which accumulated in the liver. The distribution of the parent compounds following prodrug administration was as follows: agPNA was found in kidney and plasma: agAFA in kidney only; agPP in liver only. 4. The factors which determine the selectivity of N-acetyl-L-gamma-glutamyl prodrugs are discussed. The main factors are: the transport into the kidney, the conversion rate, the residence time of the prodrug in the kidney and the presence or absence of competition for uptake and conversation by other tissues, e.g. the liver.(ABSTRACT TRUNCATED AT 250 WORDS)     

Macromolecular therapeutic systems based on polyurethanes. Kinetic laws of the release of dioxidine

Pharmaceutical Chemistry Journal -     

Characterization of calcium fenoprofen 2. Dissolution from formulated tablets and compressed rotating discs

Calcium fenoprofen samples previously studied in powder form have been made into formulated tablets and into pure compressed discs. The wide variation in dissolution rate noted for powders is not noted in the early stages of tablet dissolution, all samples giving about the same rate in spite of variation in the disintegration rate. It is possible that smaller particles have been compressed or agglommerated to larger ones, or have been rendered hydrophobic by magnesium stearate. In later stages there is some intersample variation, apparently linked to larger particles in the parent active ingredient. Intrinsic dissolution rates from compressed discs cannot be influenced by any excipients as these are not present, or by particle size considerations as the area of the discs is constant. Rates differ only slightly after compression, and this is thought to be due to only partial retention of energetic differences following compression.     

Kinetics and mechanisms of activation of alpha-amino acid ester prodrugs of camptothecins

The alpha-amino acid ester prodrugs of the antitumor agent camptothecin and a more potent, lipophilic silatecan analogue, DB-67, have been shown by NMR spectroscopy and quantitative kinetic analyses to undergo quantitative conversion to their pharmacologically active lactones via a nonenzymatic mechanism that at pH 7.4 is favored over direct hydrolysis. The alternate pathway involves the reversible intramolecular nucleophilic amine attack at the camptothecin E-ring carbonyl to generate a lactam (I) followed by a second intramolecular reaction to produce a bicyclic hemiortho ester (I'). The intermediates were isolated and shown to exist in an apparent equilibrium dominated by the hemiortho ester in DMSO using NMR spectroscopy. The conversion of prodrugs of camptothecin or DB-67 containing either alpha-NH(2) or alpha-NHCH(3) and their corresponding hemiortho esters were monitored versus time in aqueous buffer (pH 3.0 and 7.4) at 37 degrees C, and the kinetic data were fit to a model based on the proposed mechanism. The results indicated that while the prodrugs are relatively stable at pH 3, facile lactone release occurs from both the prodrugs and their corresponding hemiortho ester intermediates under physiological conditions (pH 7.4). The glycinate esters and their hemiortho esters were found to be more cytotoxic than the N-methylglycinates or their corresponding hemiortho ester intermediates in vitro using a human breast cancer cell line (MDA-MB-435S), consistent with their more rapid conversion to active lactone. The pH dependence of the nonenzymatic pathway for conversion of these alpha-amino acid ester prodrugs suggests that they may be useful for tumor-targeting via liposomes, as they can be stabilized in an acidic environment in the core of liposomes and readily convert to the active lactone following their intratumoral release.