1. 國防醫學院六十二年班第一名畢業,母校畢業典禮時,曾上台三次領取三個獎項.
2. 英國倫敦大學藥學研究所碩士班傑出畢業生
3. 美國普渡大學工業及物理藥學博士學位.
4. 服務榮民製藥廠期間獲頒優等公務人員獎.
5. 服務外商溫莎藥廠期間獲頒優秀經理獎.
6. 擔任美國奧克拉荷馬大學藥學院助理教授三年.
7. 擔任美國伊利諾州立大學芝加哥分校藥學院兼任副教授逾十年.
8. 共有五十多篇有關藥學研究論文,在歐美重要期刊或雜誌發表.
9. 親撰編寫美國大學製藥工程相關教科書有五章節,教育後進.
10.獲美國製藥技術專利兩件,另有五件正待審核中.
11. 從1995迄今,逾十餘年以上,每年均利用個人假期,返台回母校或台灣重要藥學機構演講或參與研討,其能對歐美先進之製藥技術或先進理念融入教材或研討內容,對教育國內藥學後進,確實盡心盡力.
12. 李祿超博士,為人謙和,腳踏實地.從踏進母校伊始,不論在學校學習研究或服務於製藥界,每一階段均能全力以赴,絕不苟且.其長年投入藥學研究及教育後進，誨人不倦，培育人才，不遺餘力，備受推崇及肯定。其從事醫藥學學術研究聲譽卓著，其著作論文對世界藥學製造研究發展亦有貢獻。
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Prodrugs for IV Delivery of Poorly Water Soluble Drugs – Recent Developments
Luk Chiu Li, Ph.D.
Introduction
A prodrug is a drug molecule covalently bound to a pharmacologically inactive moiety (the promoiety) with the aim to overcome various physicochemical, biopharmaceutical and/or pharmacokinetic limitations of the parent drug so that the therapeutic effect of the drug would be realized. A prodrug must undergo a chemical or biochemical transformation to the parent drug within the body at a reasonable rate, prior to exerting a pharmacological effect. When the prodrug approach is applied to a poorly soluble drug for IV delivery, solubility enhancement becomes the key objective. Ideally, a prodrug for IV administration should possess adequate solubility to be formulated into a solution, acceptable solution stability to provide an appropriate product shelf life, and the ability to rapidly convert to the pharmacologically active parent drug. In addition, the promoieties must also prove to be nontoxic. Water-soluble prodrugs of steroids such as sodium hemisuccinate esters and sodium phosphate esters represent the successful examples for the use of prodrugs of poorly soluble drugs for IV administration (Hemenway et al., 2007). Some recent developments in prodrug design strategies are reviewed below.
Phosphate prodrugs
The synthesis of phosphate esters is the most commonly used approach in enhancing the aqueous solubility of poorly soluble drugs. Phosphate esters are highly ionizable and exhibit significantly higher aqueous solubility than the parent drug. Their stability in both solid state and in aqueous solution allows development of stable injectable dosage forms. Furthermore, phosphate esters are rapidly cleaved in vivo by alkaline phosphatases to release the parent drug and the non-toxic inorganic phosphate. While the preparation of phosphate prodrugs have been mainly involved the formation of phosphate ester with the drug alcohol groups, N-phosphono type prodrugs have also been synthesized for solubility enhancement. A N-phosphono prodrug was prepared with a poorly soluble new cephalosporin derivative (Figure 1) (Ishikawa et al., 2003). The prodrug was shown to rapidly convert to the parent drug following IV administration to rats and monkeys. In vivo activity was shown to be superior to that of vancomycin in systemic bacterial infection in mice (Ishikawa et al., 2003).
Figure 1. A N-Phosphon prodrug of a cephalosporin derivative
Phosphomonoxymethyl prodrugs
The development of phsophonooxymethyl (PMO) prodrugs involves the attachment of the phosphate group to the parent drug through a methoxy spacer. Fosphenytoin, a disodium phosphate ester of 3-(hydroxymethyl)phenyotin is a good example for the use of a PMO prodrug as a water soluble injectable form of phenyotin, commercially marketed as CerebyxÒ (Figure 2) (DeToledo and Ramsay, 2000 and Fischer et al., 2003). The phosphate group of fosphenytoin is first enzymatically cleaved to give 3-(hydroxymethyl)phenyotin, which spontaneously hydrolyzes to form formaldehyde and phenytoin.
Phosphomonoxymethyl prodrugs
The development of phsophonooxymethyl (PMO) prodrugs involves the attachment of the phosphate group to the parent drug through a methoxy spacer. Fosphenytoin, a disodium phosphate ester of 3-(hydroxymethyl)phenyotin is a good example for the use of a PMO prodrug as a water soluble injectable form of phenyotin, commercially marketed as CerebyxÒ (Figure 2) (DeToledo and Ramsay, 2000 and Fischer et al., 2003). The phosphate group of fosphenytoin is first enzymatically cleaved to give 3-(hydroxymethyl)phenyotin, which spontaneously hydrolyzes to form formaldehyde and phenytoin.
Figure 2. Fosphenytoin (CerebyxÒ)
The PMO prodrug approach was recently utilized to develop a water-soluble phosphonooxymethyl ester prodrug of propofol, an IV sedative-hypnotic agent widely used for anesthesia and sedation. Owing to its low aqueous solubility, propofol is currently formulated as an injectable emulsion (DiprivanÒ), which was not an ideal product because of poor physical stability, risk of bacterial contamination, potential for emulsion-induced embolism, and pain at site of injection. In the first human clinical trial (Fechner et al., 2003), the phosphonooxymethyl ester prodrug (Figure 3) (AquavanÒ) was well tolerated with no signs of pain on injection. However, the PK parameters of the propofol produced from the prodrug were different from those reported for the lipid emulsion formulation; both the time to achieve peak concentration and the time for elimination were longer.
Figure 3. A phosphonooxymethyl ester prodrug of propofol (AquavanÒ)
The synthesis and biological evaluation of a POM prodrug of ravuconazole (Figure 4), a potent broad-spectrum antifungal agent were reported (Ueda et al., 2003). The prodrug was rapidly converted to the parent drug in vivo following IV administration to various animal models and showed efficacy comparable to that achieved by oral administration of the parent drug against fungal infection in mice. PMO prodrug of camptothecin (Figure 5) was also prepared; the POM promoiety is attached to the alcohol group adjacent to the ketone of the lactone ring. Following IV injection to rats, the biconversion of the prodrug results predominantly in the generation of the open ring form of the parent drug; however equilibrium between the lactone and carboxylate was found to be rapidly established (Hanson, 2002, 2003).
Figure 4. A Phosphonooxymerthyl prodrug of ravuconazole
Figure 5. The pH equilibrium between the lactone and the carboxylate forms of POM produrg of
camptothecin
Amino acid prodrugs
Numerous examples can be found in the literature on the use of amino acids and amine-containing derivatives as water-soluble prodrugs for IV delivery (Hemenway et al., 2007). Using this approach, the synthesis of water-soluble prodrugs of camptothecin and its derivative has been reported. The glycinate ester and longer chained amine-containing acid esters of camptothecin were investigated for their use in liposomal formulations (Hanson et al. 2003). Although these prodrugs could undergo rapid conversion to the parent drugs at physiological pH, new degradation products were generated by the glycine derivative and a slowdown in conversion rate was noted for derivatives with increased length of alkyl chain between amine and the ester group. Irinotecan is a water-soluble prodrug of a camptothecin derivative (SN-38) (Figure 6), consisting of a cyclic tertiary amine as the solubilizing promoiety linked by a carbamate ester to the phenol group of the parent drug (Mathijssen et al. 2002). Irinotecan (CamptosarÒ) has shown a broad spectrum of activity in solid tumor and was approved for the treatment of advanced cancer of the large intestine and rectum.
Figure 6. Irintoecan (CamptosarÒ)
d-g-Tocopheryl N,N-dimethylglycinate hydrochloride was synthesized as the water-soluble prodrug of d-g-Tocopherol which is one of the major forms of natural tocopherols (vitamin E) (Takata et als., 2002). The hydrolysis of the prodrug was mainly catalyzed by esterases in liver mirosome. The liver availability of d-g-Tocopherol after the administration of the water-soluble prodrug was two times higher than that achieved by administration of the parent drug.
Polymer prodrugs
Water-soluble polymers have been investigated for their use in preparing prodrugs (conjugates) of poorly soluble anticancer drugs. Polymer bound prodrugs are not only water-soluble but also capable of tumor targeting via the enhanced permeability and retention (EPR) effect (Maeda, 2001). N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer has been extensively explored for the formation of polymer drug conjugates (Vicent, 2007). The HPMA-doxorubicin (Dox) (Figure 7) was the first synthetic polymer conjugates to enter phase I clinical trial (Vasey et al., 1999). Doxorubicin is linked to the HPMA copolymer via a tetrapepitde chain comprised of Gly-Phe-Leu-Glycin; the doxorubicin content was 7 to 9 % by weight. The peptidyl linkages are stable in plasma but will be cleaved by lysosomal thiol-dependant proteases followed endocytic capture of the conjugate (Ducan, 2005). Since the development of HPMA-Dox, more HPMA copolymer conjugates of other anticancer drugs such as paclitaxel, camptothecin, and carboplatin platinate have also progressed to clinical testing (Ducan, 2005). Results from the phase I clinical trials of HPMA conjugates of paclitaxel and camptothecin have been disappointing as the conjugates displayed toxicities little or no better than the free drug. It is believed that the toxicities are attributed to the rapid release of the free drug into the systemic circulation, possibly due to the weak ester linkage (Sinh et al. 2006). HPMA copolymer conjugates have also been synthesized to contain targeting ligands such as peptides, sugars, and antibodies with the aim of further promoting increased tumor targeting by receptor-mediated delivery (Ducan, 2006).
Figure 7. HPMA-doxorubicin conjugate
PEG-camptothecin prodrugs formed with various spacer groups have been extensively studied. A PEG-camptothecin prodrug called pegamotecan has been evaluated in clinical trials and show good response from patients and low incidence of toxicities (Rowinsky et al., 2003; Scott et al., 2004). Poly(L-glutamic acid)-Gly-camptothecin is another water-soluble prodrug of camptothecin. Poly-(L-glutamic acid) is a biodegradable peptide homo-polymer with carboxylic acid side chains carrying multiple anionic charges and the parent drug binds to the polymer at multiple sites (Bhatt et al., 2003). The percent of the parent drug in the polymer conjugate can be as high as 50% by weight (Singer et al., 2001). Prolonged plasma residence time and enhanced anti-tumor activity in mice were observed for prodrugs formed with poly(L-glutamic acid) with a higher molecular weight (Singer et al., 2000; Bhatt et al., 2003).
Poly(L-glutamic acid) paclitaxel conjugates have also been investigated for their use as prodrugs. XytotaxÒ (Figure 8) is a poly(L-glutamic acid) paclitaxel conjugate formed with the composition of one paclitaxel molecule per 10.4 glumatic acid monomers (Singer et al., 2003). This prodrug remains inactive while circulating in the bloodstream, which is also less toxic compared to the parent drug. Once in the tumor tissue, the prodrug is taken up by the tumor cell and the parent drug is release as a result of cleavage of the polymer backbone by lysosmal enzymes, principally cathepsin B inside the lysomes (Singer et al., 2003). Results from clinical trials with this prodrug have shown greater efficacy than paclitaxel in a number of human cancer models (Auzenne et al., 2002, Singer et al., 2003).
Figure 8. Poly(L-glutamic acid) paclitaxel conjugate (XytotaxÒ)
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