Hannu Taipale

Co-Administration of a Water-Soluble Polymer Increases the Usefulness of Cyclodextrins in Solid Oral Dosage Forms

AbstractPurpose. The aim of this study was to investigate the effect of cyclodextrins (β-CD, HP-β-CD and (SBE)7m-β-CD), and co-administration of a water-soluble polymer (HPMC) and cyclodextrins, on the oral bioavailability of glibenclamide in dogs. Methods. Effects of cyclodextrins on the aqueous solubility of glibenclamide, with and without hydroxypropylmethylcellulose (HPMC), were determined by a phase-solubility method. Solid inclusion complexes were prepared by freeze-drying. Glibenclamide was administered orally and intravenously to beagle dogs. Results. Aqueous solubility of glibenclamide increased as a function of cyclodextrin concentration, showing an AL-type diagram for β-CD and an Ap-type diagrams for both of the β-CD derivatives studied. HPMC enhanced the solubilising effect of cyclodextrins, but did not affect the type of phase-solubility diagram. Orally administered glibenclamide and its physical mixture with HP-β-CD showed poor absolute bioavailability, while orally administered glibenclamide/cyclodextrin-complexes significantly enhanced the absolute bioavailability of glibenclamide. Orally administered glibenclamide/β-CD/HPMC and glibenclamide/(SBE)7m-β-CD/HPMC complexes showed similar absolute bioavailability compared to formulations not containing HPMC, even though 80% (in the case of (SBE)7m-β-CD) or 40% (in the case of β-CD) less cyclodextrin was used. Conclusions. The oral bioavailability of glibenclamide was significantly increased by cyclodextrin complexation. HPMC increased the solubilising effect of cyclodextrins and, therefore, the amount of cyclodextrin needed in the solid dosage form was significantly reduced by their co-administration. In conclusion, the pharmaceutical usefulness of cyclodextrins in oral administration may be substantially improved by co-administration of a water-soluble polymer.

Bisphosphonate prodrugs : synthesis and in vitro evaluation of alkyl and acyloxymethyl esters of etidronic acid as bioreversible prodrugs of etidronate

The synthesis and preliminary evaluation of novel alkyl and acyloxymethyl esters of etidronic acid as etidronate prodrugs is reported. Tetramethyl ester of etidronic acid was found be isomerized at pH 7.4 and P-C-P bridge was rearranged to P-C-O-P. This unwanted process was prevented via acylation of the bridging carbons alcohol group. Acylation showed to be stable if one or more phosphonic OH- groups were substituted. However, when none of the phosphonic OH- groups were substituted, the acylation was chemically hydrolysed and the parent drug was released. This finding was successfully applied in the design of tetrapivaloyloxymethyl ester of acetylated etidronic acid which released etidronic acid via enzymatic (first step) and chemical (second step) hydrolysis in liver homogenate. However, the corresponding tri-substituted pivaloyloxymethyl ester having adequate water-solubility and lipophilicity (logP(app) 0.6 at pH 7.4), is probably the most potential prodrug candidate reported to enhance the oral bioavailability of etidronate.

Synthesis and in vitro evaluation of aminoacyloxyalkyl esters of 2-(6-methoxy-2-naphthyl)propionic acid as novel naproxen prodrugs for dermal drug delivery.

AbstractPurpose. To synthesize and evaluate various novel aminoacyloxyalkyl esters of naproxen (3a-i) and naproxenoxyalkyl diesters of glutamic and aspartic acids (3j-m) as potential dermal prodrugs of naproxen. Methods. The prodrugs 3a-m were synthesized, and their aqueous solubilities, lipophilicities and hydrolysis rates were determined in a buffered solution and in human serum. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. Results. The aminoacyloxyalkyl prodrugs showed higher aqueous solubilities and similar lipid solubilities, in terms of octanol-buffer partition coefficients (log Papp) at pH 5.0, when compared with naproxen. At pH 7.4 the prodrugs were significantly more lipophilic than naproxen. Prodrugs3a-i showed moderate chemical stability in aqueous solutions at pH 5.0 and were rapidly converted to naproxen in human serum (t1/2 = 4−19 min). The selected aminoacyloxyalkyl prodrugs possessed a higher flux across the skin than naproxen, with a maximum enhancement of 3-fold compared to naproxen. Prodrugs 3j-mshowed poor aqueous solubility and permeation across the skin. Conclusions. Combinations of adequate aqueous solubility and lipophilicity of naproxen aminoacyloxyalkyl prodrugs having fast rates of enzymatic hydrolysis resulted in improved dermal delivery of naproxen.

Synthesis and in vitro/in vivo evaluation of novel oral N-alkyl- and N,N-dialkyl-carbamate esters of entacapone.

Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueous solubility at low pH and/or its hydrophilic character at neutral pH. Various novel N-alkyl and N,N-dialkyl carbamate esters of entacapone were synthesized as possible prodrugs of entacapone in order to increase its aqueous solubility at an acidic pH and to increase its lipophilicity at neutral pH. Oral bioavailability of entacapone and selected carbamate esters were investigated in rats. Both N-alkyl and N,N-dialkyl carbamate esters were relatively stable against chemical hydrolysis at pH 7.4 (t1/2 = 14.9-20.7 h), but hydrolyzed rapidly (t1/2 = 0.8-2.7 h) in human serum. However, in contrast to N-alkyl carbamates, N,N-dialkyl carbamates did not release entacapone in in vitro enzymatic hydrolysis (human serum) studies. N-Alkyl carbamates, 2a-c, showed increased aqueous solubility at pH 7.4, of which 2a and 2c also show increased aqueous solubility at pH 5.0, compared to entacapone. In addition to increased aqueous solubility, 2c showed increased lipophilicity at pH 7.4. However, two N-alkyl carbamates of entacapone did not increase the oral bioavailability of the parent drug in rats. Thus, it can be concluded that the relatively low lipophilicity of entacapone is not the cause of its low bioavailability.

Effects of aqueous solubility and dissolution characteristics on oral bioavailability of entacapone

Entacapone is a new catechol‐O‐methyltransferase (COMT) inhibitor used clinically in a triple combination therapy for Parkinsons disease (PD). The bioavailability of entacapone after oral administration is low and subject to large interindividual variation. The purpose of this study was to evaluate aqueous solubility/dissolution profiles of entacapone in vitro, and to evaluate their role in the poor oral bioavailability of entacapone in rats. The effect of the novel pharmaceutical excipient hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) on the aqueous solubility and dissolution of entacapone, and on entacapone bioavailability in rats, was also studied.

Histological and chemical comparison of triterpene and phenolic deterrent contents of juvenile shoots of Betula species

SummaryDefence-related epithelial structures of juvenile stems and their phytochemistry were compared between six woody species of Betula from different geographical areas. The shoots of B. pendula, B. papyrifera, B. platypylla and B. ermanii are covered by resin droplets secreted by multicellular peltate glands. The seedlings of B. papyrifera and B. pubescens are covered with long epithelial hairs. Closer topical examination also revealed smaller glands on B. papyrifera and B. pubescens. The glands of B. ermanii are oval while the other species have a round shape. Phenol-specific histochemical staining indicated phenolic compounds in the cells in active glands of the resinous birches, but not in those of the pubescent birches. The epithelial hairs were strongly positive to the phenol stain. Analysis of the triterpenoids (3α- and 3β-papyriferic acid and pendulic acid) and a phenolic (platyphylloside) deterrent indicated that the morphological differences are accompanied by chemical ones. Pendulic acid was the main triterpene in B. ermanii instead of the 3α-papyriferic acid of the other resinous species. Concentrations of the triterpenes ranged from about 0.3 to 12 mg/g, while the platyphylloside level was around 0.5 mg/g in all of them. Some triterpenes were also detected in B. papyrifera, but none in B. pubescens. The former contained only about 0.05 mg/g of platyphylloside, but B. pubescens contained 4 mg/g of this compound.

Directly acting geno- and cytotoxic agents from a wild mushroom Dermocybe sanguinea.

The wild mushroom, Dermocybe sanguinea, contains several anthraquinone pigments, of which emodin (1,3,8-trihydroxy-6-methylanthraquinone) is quantitatively the most important. In our preliminary tests, Dermocybe sanguinea extracts were genotoxic without metabolic activation. The ethanol extract of Dermocybe sanguinea was fractionated by flash chromatography, and the emodin contents of the fractions were determined by HPLC. Their genotoxicities were assayed using a bacterial repair assay and sister-chromatid exchange analysis. The cytotoxicity of the fractions was assayed with mouse hepatoma cells using growth inhibition as the endpoint. The results of the biological tests were compared with those obtained with pure emodin. It was concluded that, in addition to emodin, Dermocybe sanguinea contains several other geno- and cytotoxic compounds.

Bisphosphonate prodrugs : synthesis and in vitro evaluation of novel partial amides of clodronic acid

Abstract Novel partial amides of clodronic acid were synthesized and evaluated in vitro for their properties as bioreversible prodrugs of clodronate. The hydrolysis studies indicated that these derivatives release the parent drug via chemical hydrolysis. Monoamides were hydrolysed rapidly ( t 1/2 =16–19 min at pH 7.4) to clodronic acid, which suggests that they are useful intermediates in the design of enzymatically labile double prodrugs of clodronate.

Isolation and structure determination of three triterpenes from bark resin of juvenile european white birch

Abstract 3α-O-Malonyl-12β-O-acetyl-25-hydroxy-(20S,24R)-epoxydammarane (papyriferic acid) and two previously unknown dammarane triterpenes w

Synthesis and in-vitro/in-vivo evaluation of orally administered entacapone prodrugs

Entacapone is a new inhibitor of catechol‐O‐methyltransferase (COMT) that is used as an adjunct to l‐dopa therapy in the treatment of Parkinsons disease. The bioavailability of orally administered entacapone is, however, relatively low (29–46%). In this study we have prepared more lipophilic acyl and acyloxyacyl esters, an acyloxy alkyl ether and an alkyloxycarbonyl ester of entacapone, and we have evaluated them as potential prodrugs to enhance the oral bioavailability of entacapone. All the derivatives fulfilled prodrug criteria and released entacapone in human serum in‐vitro. The oral bioavailability of monopivaloyl (1a) and dipivaloyl (1b) esters of entacapone were investigated further in rats. The lipophilicity of 1b was high (log Papp 4.0 at pH 7.4) but its oral bioavailability was low (F = 0.6%), most probably due to its low aqueous solubility. The monopivaloyl ester of entacapone (1a) had a higher lipophilicity (log Papp 0.80) than entacapone (log Papp 0.18) at pH 7.4 while maintaining an aqueous solubility equal to entacapone. However, oral bioavailability was not increased when compared with the parent drug entacapone (F = 7.0% and 10.4%, respectively).