Prodrug strategies to overcome poor water solubility

Stella, Valentino J.; Nti-Addae, Kwame

doi:10.1016/j.addr.2007.05.013

Cited by 459 publications

(303 citation statements)

References 100 publications

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“…26−30 Cucurbituril (Scheme 1) contains a hydrophobic cavity with two uniform hydrophilic portals composed of carbonyl functional groups. 27,31 Among the CB [n] homologues, the size and shape of CB [6], CB [7] and CB [8] are close to those of α-, β-, and γ-cyclodextrin, respectively. Unlike the poor solubility of CB [6] and CB [8] (below 10 −5 M), CB [7] is aqueous soluble (0.02− 0.03 M).…”

Section: ■ Introductionmentioning

confidence: 96%

“…1,2 Various approaches have been investigated to improve solubility of drugs, including cocrystal, 3,4 salts, 5 prodrugs, 6 solid dispersion, 7 macrocyclic hosts (e.g., cyclodextrins, cucurbiturils), 8,9 etc. Triamterene, 2,4,7-triamino-6-phenylpteridine (Scheme 1) is a mild potassium-sparing diuretic used either alone or in combination with potassium-wasting diuretics such as hydrochlorothiazide.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Recently, cucurbit [n]urils (CB [n], Scheme 1) have attracted much attention due to their wide applications in chemistry, 20 material, 21 biology, 22,23 and medicine science, 24,25 following the discovery of CB [n] homologues (CB [5], CB [6], CB [7], CB [8], CB [5]@CB [10], CB [10] and CB [14]). 26−30 Cucurbituril (Scheme 1) contains a hydrophobic cavity with two uniform hydrophilic portals composed of carbonyl functional groups.…”

Section: ■ Introductionmentioning

confidence: 99%

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The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Chen

Jiang

et al. 2013

Mol. Pharmaceutics

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In recent years, cucurbit [7]uril (CB [7]) has attracted great attention in drug delivery. Though the effect of CB [7] in enhancing the solubility of water insoluble drugs has been validated, the underlying mechanism remains poorly understood, particularly at a molecular level. This study is designed to evaluate a CB [7]-based pharmaceutical formulation to improve solubility and bioavailability of triamterene (a mild potassium-sparing diuretic). Two polymorphs of triamterene@CB [7] were obtained, and their crystal structures were determined by single crystal X-ray diffraction. The CB [7] molecule forms a stable host−guest complex with triamterene (K a = 1.69 ± 0.34 × 10 4 M −1 ) in aqueous solution (pH = 1.0). The results of dissolution study demonstrate that the apparent solubility value of triamterene@CB [7] complex in 0.1 M HCl is 1.6 times as large as that of triamterene, while free triamterene was released from triamterene@CB [7] complex in phosphate buffer of pH 6.8. Pharmacokinetic studies in rats reveal that the AUC 0−∞ value of triamterene@CB [7] complex increases 2.8-fold compared with that of free triamterene, and t 1/2 is prolonged from 1.42 to 2.61 h (P < 0.05) after oral administration. The increased solubility and oral bioavailability are attributed to the formation of a hydrophilic capsule composed of two CB [7] molecules, in which two insoluble triamterene molecules are encapsulated. These results demonstrate that triamterene@CB [7] complex is a stable and effective pharmaceutical formulation. KEYWORDS: cucurbit [7]uril, triamterene, crystal structure, solubility, pharmacokinetics ■ INTRODUCTIONPoor aqueous solubility is a major bottleneck in drug discovery and drug development: more than 40% of drug candidates are poorly water-soluble, and poor aqueous solubility is the main factor to restrict the bioavailability of drugs.1,2 Various approaches have been investigated to improve solubility of drugs, including cocrystal, 3,4 salts, 5 prodrugs, 6 solid dispersion, 7 macrocyclic hosts (e.g., cyclodextrins, cucurbiturils), 8,9 etc. Triamterene, 2,4,7-triamino-6-phenylpteridine (Scheme 1) is a mild potassium-sparing diuretic used either alone or in combination with potassium-wasting diuretics such as hydrochlorothiazide.10,11 It displays low oral bioavailability, and there exists wide intersubject variation because of its poor aqueous solubility (45 mg/L). 12,13 Though triamterene contains three primary amine groups, various methods to obtain soluble salts failed, probably due to its weak basicity. 12 To date, only a few formulations have been proposed to improve the solubility of triamterene, including cyclodextrins 14,15 and solid dispersions. 16,17 However, parenteral administration of β-cyclodextrin results in renal toxicity, 18 and solid dispersions are often physically unstable upon storage at elevated temperature and humidity, 19 and neither of the two triamterene formulations has been applied for clinical therapy. Therefore, the development of new pharmaceutical formulation of triam...

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Section: ■ Introductionmentioning

confidence: 96%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Chen

Jiang

et al. 2013

Mol. Pharmaceutics

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“…To solve this problem, several approaches have emerged to improve API solubility, such as salt formation [2] , crystal engineering [3] , nanosizing [4] , lipid formulation [5] , cyclodextrin complexation [6] and prodrug strategies [7] . Among these, we focused on the mixed micelle systems due to their synergistic properties, such as increased micelle stability and drug loading efficiency, which are superior to those of the individual components [8] .…”

Section: Introductionmentioning

confidence: 99%

Mixed micelles loaded with silybin-polyene phosphatidylcholine complex improve drug solubility

et al. 2010

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Aim: To prepare a novel formulation of phosphatidylcholine (PC)-bile salts (BS)-mixed micelles (MMs) loaded with silybin (SLB)-PC complex for parenteral applications. Methods: SLB-PC-BS-MMs were prepared using the co-precipitation method. Differential scanning calorimetry (DSC) analysis was used to confirm the formation of the complex and several parameters were optimized to obtain a high quality formulation. The water-solubility, drug loading, particle size, zeta potential, morphology and in vivo properties of the SLB-PC-BS-MMs were determined. Results: The solubility of SLB in water was increased from 40.83±1.18 µg/mL to 10.14±0.36 mg/mL with a high drug loading (DL) of 14.43%±0.44% under optimized conditions. The SLB-PC-BS-MMs were observed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed spherical shapes. The particle size and zeta potential, as measured by photon correlation spectroscopy (PCS), were about 30±4.8 nm and -39±5.0 mV, respectively. In vivo studies showed that incorporation of the SLB-PC complex into PC-BS-MMs led to a prolonged circulation time of the drug. Conclusion:This novel formulation appears to be a good candidate for drug substances that exhibit poor solubility for parenteral administration.

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“…In order 60 to overcome these problems, new aqueous-based formulations for PTX, that do not require solubilization by Cremophor EL ® , have been developed (Marupudi et al, 2007;Skwarczynski et al, 2006). The prodrug strategy is a promising way in terms of improving the drug solubility and keeping the pharmacological functions unaltered (Stella and Nti-Addae, 2007). Several reports of water-soluble prodrugs of PTX have been reported that are considered to improve water solubility 65 of the parent drug and to avoid the use of toxic detergents during administration (Vyas and Vittorio, 1995).…”

mentioning

confidence: 99%

Preparation and characterization of novel poly(ethylene glycol) paclitaxel derivatives

Berlier¹,

Stella²,

Schiavon³

et al. 2013

International Journal of Pharmaceutics

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25Paclitaxel has been found to be very effective against several human cancers; one of the major problems with its use is its poor solubility, which makes necessary its solubilization with excipients that can determine allergic reactions often severe. The aim of this study is to develop highly watersoluble and less toxic analogues of paclitaxel. For this purpose we prepared a series of new paclitaxel-poly(ethylene glycol) (PEG) conjugates that were characterized and evaluated for their in 30 vitro stability and cytotoxicity. In particular, in order to modulate the release of paclitaxel from prodrugs, we prepared different compounds introducing PEG in the drug C2' and/or C7 positions via ester or carbamate linkage. The conjugates were obtained in high purity and good yield. The carbamate prodrugs were highly stable in different media, while the compounds obtained linking PEG at C2' position through an ester bond showed lower stability. Finally, the cytotoxic activity of 35 the conjugates was evaluated on two cancer cell lines and the results showed that all the derivatives had a reduced cytotoxicity compared to that of paclitaxel.

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Prodrug strategies to overcome poor water solubility

Cited by 459 publications

References 100 publications

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Mixed micelles loaded with silybin-polyene phosphatidylcholine complex improve drug solubility

Preparation and characterization of novel poly(ethylene glycol) paclitaxel derivatives

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