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[Abstract]

Use of the Combination of Prodrug Design and Salt Optimization - A Strategy to Enhance Aqueous Solubility of Drugs

Anders Bach Nielsen

The fact that many synthesized new chemical entities exhibit poor aqueous solubility and consequently low oral bioavailability due to dissolution rate and limited absorption poses a significant challenge to the pharmaceutical industry. This thesis gives an account on different methods to enhance aqueous solubility with particular focus on the applicability of the prodrug approach to improve water solubility of drug candidates.

The overall aim of the project was to investigate the possibility of enhancing the aqueous solubility of poorly water-soluble compounds by using the combined approach involving prodrug design and salt formation. The strategy was to synthesize biolabile quaternary ammonium derivatives of tertiary amines containing a permanent positive charge and to determine the solubility of different salts of such prodrug derivatives. A further goal was to design adequate quaternary ammonium prodrugs allowing drug regeneration to take place in the GI-tract.

The experimental work revealed that N-alkylation (methyl, ethyl, propyl, and butyl) of the model compound bupivacaine and salt formation (iodide, chloride, mesylate, formate, acetate, glycolate, and tosylate) afforded quaternary ammonium salts possessing pH-independent aqueous solubilities. Some of the salts possessed aqueous solubilities far exceeding that of the parent tertiary amine (up to a factor of 3200 at pH 8). In case of the N-methyl bupivacaine, derivative variation of the counterion had a significant impact on the solubility with the iodide salt being 200 times less soluble than the chloride salt. Likewise, bioreversible quaternary N-acyloxymethyl (butanoyl-, isobutanoyl- and pivaloyloxymethyl) chloride salts of bupivacaine provided a 10,000-fold increase in water solubility as compared to that of the bupivacaine base. Decomposition of the prodrugs was found to follow first-order kinetics and U-shaped pH-rate profiles were obtained. The prodrug derivatives were poor substrates for plasma enzymes. Conversely, they were hydrolyzed rapidly to parent bupivacaine in the presence of pancreatic enzymes. N-acyloxymethylation (acetyl-, propanoyl-, butanoyl-, isobutanoyl- and pivaloyloxymethyl) was also investigated to improve the aqueous solubility of Lu 28-179, a tertiary amine with an intrinsic solubility in the nanomolar range. Solubilities of the prodrugs far exceeded that of the parent amine by a factor of 2-4x106. Enzyme-mediated regeneration of Lu 28-179 was observed in human plasma, simulated intestinal fluid and duodenum juice from pigs and dogs. Despite promising in vitro properties the selected prodrugs were unable to improve the oral bioavailability of Lu 28-179 as compared to that obtained after administration of an orally reference formulation of the parent drug in the dog.

The theoretical part of the thesis has been divided into two sections. The first part deals with the fundamentals of solubility, where thermodynamic terms (lattice energy and hydration energy) have been used to describe solubility of solids. Such theories have been used to enable prediction of aqueous solubility (mainly the general solubility equation (GSE)). Alternative strategies for improving the solubility and dissolution rate of poorly water-soluble drugs are discussed, encompassing reduction of particle size, addition of surfactants and cosolvents, formulation of solid dispersion, complexation with solubilizing agents such as cyclodextrins, and prodrug formation.

The last section gives an account on water-soluble prodrugs intended for various routes of administration with particular attention paid to the feasibility of the approach for the oral route. The rationale for design of water-soluble quaternary prodrugs of tertiary amines is discussed. The main reason for choosing this prodrug type is provision of derivatives endowed with pH independent solubility and increased solubility, as compared to parent amine, especially at high pH values. Drug solubilities above approximately 1 mg/ml are expected (as a rule of thumb) not to cause solubility-limited absorption. Thus, from a practical point of view the prodrug approach (oral administration) appears primarily feasible for drugs (tertiary amines) characterized by pKa values below approximately 8 and intrinsic solubilities below 1 µg/ml. Finally, the fate of water-soluble prodrugs after oral administration is considered and with the present knowledge it is expected that prodrug conversion-time and -place are major determinants in relation to optimization of oral bioavailability of poorly soluble drugs.

Based on the present work it can be concluded that N-acyloxymethyl derivatization of tertiary amines constitutes a promising means to enhance aqueous solubility of poorly soluble drugs.