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H Bundgaard

Publications and source records attributed to H Bundgaard.

At least 73 records · Page 4Linked to original sources
PubMed1991

Macromolecular prodrugs. IXX. Kinetics of hydrolysis of benzyl dextran carbonate ester conjugates in aqueous buffer solutions and human plasma.

Benzyl carbonate esters of dextran with varying degrees of substitution have been synthesized. The kinetics of the hydrolytic cleavage of the carbonate ester bond in aqueous solution within the pH range 0.44-10.46 (37 degrees C) has been investigated. The degradation reactions followed pseudo-first-order kinetics and a rate expression encompassing hydrogen ion-, hydroxide ion- and water-catalyzed hydrolysis of the dextran conjugates was derived. No influence of the degree of substitution on the reaction rates was observed. In alkaline solution a slightly enhanced lability of trifluorethyl benzyl carbonate ester compared to the benzyl dextran carbonate esters was observed, indicating a lack of any significant intramolecular catalytic effect in the hydrolysis of the dextran esters. Almost identical rates of liberation of benzyl alcohol were found in 80% human plasma and aqueous buffer of pH 7.4, indicating the lack of enzyme-mediated cleavage of the dextran carbonate ester bond.

Buffers↗
PubMed1991

Chewing gum and lozenges as delivery systems for noscapine.

Chewing gum and lozenges were evaluated as delivery systems for noscapine with the aim of developing improved antitussive preparations. The formulations studied were prepared with both the water-soluble hydrochloride salt of noscapine and with the poorly soluble embonate salt and noscapine free base. The release characteristics of the preparations were evaluated both in vitro and in vivo, and their taste properties examined. Only the formulations containing noscapine base were without any appreciable taste. Chewing gum containing this compound showed, however, a low level of drug release both in vitro and in vivo and is therefore not a suitable dosage form. Only a lozenge formulation containing noscapine base fulfilled the requirements of taste acceptability and adequate release properties.

Chewing Gum↗
PubMed1991

Synthesis, enzymatic hydrolysis and physico-chemical properties of N-substituted 4-(aminomethyl)benzoate diester prodrugs of ganciclovir.

Various N-substituted 4-(aminomethyl)benzoate diesters of ganciclovir were synthesized and evaluated as prodrug forms with the aim of improving the delivery characteristics of ganciclovir. The esters were hydrolyzed enzymatically by human plasma to the parent drug, the hydrolysis proceeding through formation of the corresponding monoester. The nature of the amino substituents had a marked influence on the rate of enzymatic hydrolysis, the most enzymatically labile ester being the 4-(morpholinomethyl)benzoate derivative. All esters were more lipophilic than ganciclovir in terms of octanol-pH 7.4 buffer partition coefficients. These properties combined with good aqueous solubility and high chemical stability in weakly acidic solutions make the N-substituted 4-(aminomethyl)benzoate diesters a promising prodrug type for ganciclovir to enhance its delivery characteristics for e.g. parenteral administration.

Drug Stability↗
PubMed1991

Kinetics of the acid-catalyzed hydrolysis of acyclovir and an ester prodrug in aqueous solution.

The kinetics of hydrolysis of acyclovir was studied in 0.01-0.5 M hydrochloric acid solutions (pH 0.5-2.2) at 80 degrees C. The hydrolytic cleavage of the 9-C-N bond in acyclovir to give guanine was found to proceed almost quantitatively (greater than 90%) as evidenced by HPLC analysis. The rate of hydrolysis was subject to apparent specific acid catalysis, the specific hydrogen ion catalytic rate constant being 4.9 x 10(-2) M-1 min-1 at 80 degrees C and mu = 0.5. The possible significance of acid-catalyzed hydrolysis for the stability of acyclovir during its transit through the stomach after peroral administration was found to be negligible. A novel 4-(morpholinomethyl)benzoate ester prodrug of acyclovir was found to be three times more stable in acidic solutions than acyclovir itself despite the ester group being an additional site of degradation. The dominating degradation reaction of the ester was found to be cleavage of the 9-C-N bond. The higher stability of the ester was ascribed to the greater electron-withdrawing effect of the ester group relative to the hydroxyl group which decreases the tendency of the 9-C-N bond to be ruptured by an A-1 mechanism.

Acyclovir↗
PubMed1991

Hydrolysis kinetics of 1,3-benzoxazine-2,4-dione (a potential salicylamide prodrug) and various N-substituted derivatives.

The kinetics and mechanism of hydrolysis of 1,3-benzoxazine-2,4-dione and its N-methyl and N-benzoyl derivatives were studied in aqueous solution to provide basic information on the reactivity of the benzoxazinedione structure and to assess the potential of unsubstituted 1,3-benzoxazine-2,4-dione as a prodrug for salicylamide. The compounds were found to hydrolyze quantitatively to the parent salicylamide. The pH-rate profiles obtained at pH 1-11 were accounted for by a spontaneous or water-catalyzed reaction which predominated at pH 1-4 and a hydroxide ion-catalyzed reaction. The rates of hydrolysis were catalyzed slightly in the presence of human plasma and rat liver homogenate, the exception being the N-benzoyl derivative which was hydrolyzed very fast in plasma solutions to N-benzoylsalicylamide. The aqueous solubility and lipophilicity characteristics of 1,3-benzoxazine-2,4-dione were determined. The results obtained suggest that the latter may function as a prodrug for salicylamide with the potential of depressing the extensive first-pass metabolism of salicylamide following oral or rectal administration.

Animals↗
PubMed1991

Prodrugs of cimetidine with increased lipophilicity: N-acyloxymethyl and N-alkoxycarbonyl derivatives.

Bioreversible derivatization of cimetidine to afford more lipophilic prodrugs was performed by N-acyloxymethylation of its imidazole group as well as by N-acylation with various chloroformates. Both the N-acyloxymethyl and N-alkoxycarbonyl derivatives were readily hydrolyzed to cimetidine in human plasma and in rat liver homogenate. The pH-rate profiles for the hydrolysis of the derivatives were derived at 60 degrees C. The derivatives were all more lipophilic than the parent drug as determined by partition experiments in octanol-aqueous buffer systems. In vitro studies using the modified Ussing-chamber technique showed that some derivatives possessed increased permeability coefficients for the transport across the rat jejunum relative to cimetidine. The results obtained suggest that these derivatives may be useful to improve the biomembrane transport characteristics of the hydrophilic cimetidine.

Animals↗
PubMed1991

Ketobemidone prodrugs for buccal delivery.

Various carboxylic acid and carbonate esters of the opioid analgesic ketobemidone were prepared and assessed as potential prodrugs with the aim of obtaining a ketobemidone formulation suitable for buccal or sublingual absorption. The chemical stability, enzymatic hydrolysis and lipophilicity characteristics of the esters were studied using HPLC assay procedures. All esters were rapidly hydrolyzed in human plasma, the half-lives ranging between 0.03 and 1.8 min. A marked enzymatic hydrolysis took place in whole human saliva, the half-lives of hydrolysis being in the range 3-295 min. All esters were more lipophilic than the parent ketobemidone, as determined by octanol-buffer partition experiments and by reversed-phase column chromatography. The relatively high resistance of the sterically hindered 3,3-dimethylbutyryl ester to undergo hydrolysis in saliva combined with its facile plasma-enzyme catalyzed conversion and high lipophilicity makes this ester the most promising prodrug candidate for buccal delivery.

Administration, Buccal↗
PubMed1990

Kinetics and pattern of degradation of thyrotropin-releasing hormone (TRH) in human plasma.

The kinetics and mechanism of degradation of the tripeptide TRH (pGlu-His-Pro-NH2) and its various primary and secondary degradation products (TRH-OH, His-Pro-NH2, and His-Pro) have been determined in human plasma at 37 degrees C. The rates of degradation of both TRH and TRH-OH (pGlu-His-Pro) showed mixed zero-order and first-order kinetics. At low substrate concentrations first-order kinetics occurred, with TRH and TRH-OH degradation half-lives of 9.4 and 27 min, respectively. The initial step in the plasma-catalyzed degradation of TRH is due to hydrolysis of the pGlu-His bond by the TRH-specific pyroglutamyl aminopeptidase serum enzyme, resulting in the exclusive formation of histidyl-proline amide (His-Pro-NH2). Using specific HPLC methods the major degradation route (67%) of this dipeptide in human plasma was hydrolysis of the peptide bond to yield His and Pro-NH2, whereas deamidation to yield His-Pro accounted for 29% of the total degradation. A minor pathway (less than or equal to 4%) was spontaneous cyclization to yield cyclo(His-Pro). Both His-Pro-NH2 and His-Pro degraded by first-order kinetics and faster than TRH, with half-lives of 5.3 and 2.2 min, respectively, in 80% plasma.

Chromatography, High Pressure Liquid↗
PubMed1990

Prodrugs of peptides. 6. Bioreversible derivatives of thyrotropin-releasing hormone (TRH) with increased lipophilicity and resistance to cleavage by the TRH-specific serum enzyme.

Bioreversible derivatization of TRH (pGlu-His-Pro-NH2) to protect the tripeptide against rapid enzymatic inactivation in the systemic circulation and to improve the lipophilicity of this highly hydrophilic peptide was performed by N-acylation of the imidazole group of the histidine residue with various chloroformates. Whereas TRH was rapidly hydrolyzed at its pGlu-His bond in human plasma by a TRH-specific pyroglutamyl aminopeptidase serum enzyme, the N-alkoxycarbonyl derivatives were resistant to cleavage by the enzyme. On the other hand, these derivatives are readily bioreversible as the parent TRH is formed quantitatively from the derivatives by spontaneous hydrolysis or by plasma esterase-catalyzed hydrolysis. In addition to protecting the parent TRH against rapid inactivation in the circulation and hence potentially prolonging the duration of action of TRH in vivo, the N-alkoxycarbonyl prodrug derivatives were much more lipophilic than TRH as assessed by octanol-buffer partitioning. This property may enhance prodrug penetration of the blood-brain barrier and various other biomembranes compared to the parent peptide.

Drug Stability↗
PubMed1990

Kinetics and mechanism of the facile cyclization of histidyl-prolineamide to cyclo (His-Pro) in aqueous solution and the competitive influence of human plasma.

A crucial point in the biosynthesis of cyclo (His-Pro), an endogenous and biologically active cyclic dipeptide, is the spontaneous cyclization of its precursor L-histidyl-L-prolineamide (His-ProNH2). In this study the kinetics and mechanism of the cyclization process has been investigated. His-ProNH2 was found to be converted quantitatively to cyclo(His-Pro) in aqueous solution at pH 2-10 and 37 degrees C, the rate of cyclization being maximal at pH 6-7. Buffer substances such as phosphate (pH 6-7.4) were found to catalyse the cyclization. The bell-shaped pH-rate profile observed was accounted for by assuming spontaneous and specific acid- and base-catalysed reactions of the His-ProNH2 species in which the imidazole group is protonated and the primary amino group unprotonated. The much more rapid rate of cyclization of His-ProNH2 (t1/2 of 140 min at pH 6-7 and 37 degrees C) relative to other proline-containing di- and tripeptides studied was suggested to be due to an intramolecular general acid catalytic effect by the protonated imidazole group. In the presence of human plasma enzymatic hydrolysis of His-ProNH2 competed with the cyclization and predominated greatly at 80% plasma concentration.

Buffers↗
PubMed1990

Hydrolysis and rearrangement of phthalamic acid derivatives and assessment of their potential as prodrug forms for amines.

Although it is well-known that N-substituted phthalamic acid derivatives are readily hydrolyzed in acidic aqueous solution due to intramolecular catalysis by the neighbouring carboxy group, sparse information is available on the degradation behaviour in neutral solutions. A recent publication [5] has claimed that N-(3-bromopropyl)phthalamic acid is very easily hydrolyzed in mildly alkaline solutions by an intramolecular catalytic effect of the ionized carboxy group. In this study, the degradation behaviour of N-(2-bromoethyl)phthalamic acid (I), N-(3-bromopropyl)phthalamic acid (II) and various other N-alkyl and N-aryl substituted phthalamic acid derivatives were examined with the primary aim of assessing their degradation rate at physiological pH. Whereas the compounds I and II were indeed found to be easily degraded in neutral aqueous solutions, the degradation was not due to hydrolysis of the amide bond as previously claimed but rather to an intramolecular displacement reaction of the bromo group by the amide moiety, as evidenced by HPLC analysis of the rection products. The other phthalamic acid derivatives studies showed a very high stability in neutral and alkaline solution. It is concluded that phthalamic acid derivatives are too stable chemically and enzymatically to be considered as prodrug forms for primary or secondary amines.

Amines↗
PubMed1989

Prodrugs of peptides. IV: Bioreversible derivatization of the pyroglutamyl group by N-acylation and N-aminomethylation to effect protection against pyroglutamyl aminopeptidase.

Various N-acyl derivatives and N-Mannich bases of the model compound L-pyroglutamyl benzylamide were synthesized to assess their suitability as prodrug forms for the N-terminal pyroglutamyl residue occurring in several peptides, with the aim of improving peptide delivery characteristics. Whereas pyroglutamyl benzylamide was rapidly hydrolyzed by pyroglutamyl aminopeptidase, the N-acyl derivatives and N-Mannich bases (N-aminomethyl derivatives) were totally resistant to cleavage by the enzyme. On the other hand, these derivatives are readily bioreversible, the conversion to the parent pyroglutamyl amide taking place either by spontaneous hydrolysis at physiological pH, as demonstrated for the N-Mannich bases, or by plasma enzymes, as shown for the N-acyl derivatives. The results suggest that by appropriate N-acylation or N-aminomethylation it may be feasible to protect pyroglutamyl-containing peptides against cleavage by pyroglutamyl aminopeptidase and to obtain a release of the parent peptide in the organism, hence improving the delivery characteristics of such peptides.

Acylation↗
PubMed1989

Evaluation of glycolamide esters and various other esters of aspirin as true aspirin prodrugs.

A series of glycolamide, glycolate, (acyloxy)methyl, alkyl, and aryl esters of acetylsalicylic acid (aspirin) were synthesized and evaluated as potential prodrug forms of aspirin. N,N-Disubstituted glycolamide esters were found to be rapidly hydrolyzed in human plasma, resulting in the formation of aspirin as well as the corresponding salicylate esters. These in turn hydrolyzed rapidly to salicylic acid. The largest amount of aspirin formed from the esters were 50 and 55% in case of the N,N-dimethyl- and N,N-diethylglycolamide esters, respectively. Similar results were obtained in blood with the N,N-dimethyl- and N,N-diethylglycolamide esters. Unsubstituted and monosubstituted glycolamide esters as well as most other esters previously suggested to be aspirin prodrugs were shown to hydrolyze exclusively to the corresponding salicylic acid esters. Lipophilicity parameters and water solubilities of the esters were determined, and structural factors favoring ester prodrug hydrolysis at the expense of deacetylation to yield salicylate ester are discussed. The properties of some N,N-disubstituted glycolamide esters of aspirin are highlighted with respect to their use as potential aspirin prodrugs.

Aspirin↗
PubMed1989

Prodrug forms for the sulfonamide group. IV. Kinetics of hydrolysis of N-sulfonyl pseudourea derivatives.

Two N-sulfonyl pseudourea derivatives, ethyl N-(p-tolylsulfonyl)-1-pyrrolidinecarboximidate and 3-butyl-2-ethyl-1-p-tolylsulfonylpseudourea, were prepared and evaluated as potential prodrug forms for the primary sulfonamide group in the model p-toluenesulfonamide. The stability characteristics of the compounds were examined in aqueous solution at various pH values as well as in the presence of human plasma and rat liver homogenate. The degradation of the derivatives was specific acid and base catalyzed, the maximal stability occurring at pH around 5. The products arising from the degradation included N-ethoxycarbonyl p-toluenesulfonamide, an N-sulfonylurea as well as the parent p-toluenesulfonamide. Human plasma did not significantly catalyze the hydrolysis and although some catalysis was observed in the presence of liver homogenate it is concluded that N-sulfonyl pseudoureas are too stable to be considered as a potentially useful prodrug form for the primary sulfonamide group.

Hydrolysis↗
PubMed1989

Kinetics of hydrolysis of indomethacin and indomethacin ester prodrugs in aqueous solution.

The kinetics of hydrolysis of indomethacin and a glycolamide ester of the drug was studied to assess the possibility of designing a water-soluble and solution-stable prodrug of indomethacin suitable for parenteral or ocular administration. The pH-rate profiles for these compounds were obtained at 60 degrees C and were accounted for by specific acid and base catalytic reactions as well as by a water-catalyzed hydrolysis. From temperature-accelerated studies, pH-rate profiles at 25 degrees C were predicted. Indomethacin and its ester showed maximal stability at pH 4.9 and 4.7, respectively, the shelf lives at these pH values and 25 degrees C being 2.0 years for indomethacin but only 43 days for the ester. The ester degrades both at its ester group and at the indole amide group of the indomethacin moiety, and shows a very pronounced water-catalyzed hydrolysis which accounts for the limited stability. It is concluded that the design of an indomethacin ester prodrug with a stability allowing formulation of a ready-to-use aqueous solution may be difficult.

Chromatography, High Pressure Liquid↗