Increased Shelf-Life of Fosphenytoin: Solubilization of a Degradant, Phenytoin, through Complexation with (SBE)7M-β-CD

Narisawa, Shinji; Stella, Valentino J.

doi:10.1021/js980041h

Cited by 25 publications

(5 citation statements)

References 14 publications

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“…Generally, CDs can enhance the stability or catalyze the degradation of some drug molecules, although there are more examples of the latter than the former. If the reader is interested in a few specific examples, the following articles are suggested: Narisawa and Stella, 1998;Ma et al, 1999;Jarho et al, 2000;Ma et al, 2000;Tonnesen et al, 2002. CDs have also been used to overcome other issues, such as taste masking of bitter materials, lowering drug volatility, controlled release of drugs for oral and parenteral delivery, and so on. The reader is directed to the earlier referenced reviews for specific examples.…”

Section: What Can Cyclodextrins Do and What Can't They Do?mentioning

confidence: 99%

Cyclodextrins

Stella

He²

2008

Toxicol Pathol

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629

415

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β-cyclodextrin (β-CD) and other cyclodextrins (CDs) have utility for solubilizing and stabilizing drugs; however, some are nephrotoxic when administered parenterally. A number of workers have attempted to identify, prepare, and evaluate various CD derivatives with superior inclusion complexation and maximal in vivo safety for various biomedical uses. A systematic study led to SBE-β-CD (Captisol), a polyanionic variably substituted sulfobutyl ether of β-CD, as a non-nephrotoxic derivative and HP-β-CD, a modified CD developed by Janssen. SBE-β-CD and HP-β-CD have undergone extensive safety studies and are currently used in six products approved by the Food and Drug Administration (four for Captisol and two for HP-β-CD). They are also in use in numerous clinical and preclinical studies. This article will focus on the issues that led to the development of these two CDs, their safety, characterization, and applications, and especially their ability to improve drug delivery. SBE-β-CD interacts very well with neutral drugs to facilitate solubility and chemical stability, and because of its polyanionic nature, it interacts particularly well with cationic drugs. Complexes between SBE-β-CD and HP-β-CD and various drugs have been shown to rapidly dissociate after parenteral drug administration, to have no tissue-irritating effects after intramuscular dosing, and to result in superior oral bioavailability of poorly water-soluble drugs. The pharmacokinetics, tissue distribution, and cellular effects of some representative CDs, including SBE-β-CD and HP-β-CD, are reviewed. The safety profiles of CDs are discussed, with emphasis on the biological effects of some CDs on the gastrointestinal tract, kidney, and reproduction and development and the carcinogenic potential of CDs. In addition, human experience with CD derivatives, specifically SBE-β-CD and HP-β-CD, indicates that these two CDs are well tolerated in humans and have no adverse effects on the kidneys or other organs following either oral or intravenous administration.

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Section: What Can Cyclodextrins Do and What Can't They Do?mentioning

confidence: 99%

Cyclodextrins

Stella

He²

2008

Toxicol Pathol

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629

415

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“…Other literature values include 18.1 μ g · mL − 1 at pH 7.4 [54] and 32 μ g · mL − 1 at pH 1.1 and 22 ° C [108] .…”

Section: Phenytoinmentioning

confidence: 99%

Solubility

2012

Absorption and Drug Development

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“…However, the presence of these solvents can in some cases interfere with the determination of the true aqueous solubility. If measurements are done in the presence of simple surfactants [459], bile salts [460], complexing agents such as cyclodextrins [448][449][450]452], or ion-pair forming counterions [451], extensive considerations need to be applied in attempting to extract the true aqueous solubility from the data. Such corrective measures will be described below.…”

Section: Complications May Thwart Reliable Measurement Of Aqueous Solmentioning

confidence: 99%

Physicochemical Profiling (Solubility, Permeability and Charge State)

Avdeef¹

2004

Frontiers in Medicinal Chemistry - Online

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About 30% of drug candidate molecules are rejected due to pharmacokineticrelated failures. When poor pharmaceutical properties are discovered in development, the costs of bringing a potent but poorly absorbable molecule to a product stage by "formulation" can become very high. Fast and reliable in vitro prediction strategies are needed to filter out problematic molecules at the earliest stages of discovery. This review will consider recent developments in physicochemical profiling used to identify candidate molecules with physical properties related to good oral absorption. Poor solubility and poor permeability account for many PK failures. FDA's Biopharmaceutics Classification System (BCS) is an attempt to rationalize the critical components related to oral absorption. The core idea in the BCS is an in vitro transport model, centrally embracing permeability and solubility, with qualifications related to pH and dissolution. The objective of the BCS is to predict in vivo performance of drug products from in vitro measurements of permeability and solubility. In principle, the framework of the BCS could serve the interests of the earliest stages of discovery research. The BCS can be rationalized by considering Fick's first law, applied to membranes. When molecules are introduced on one side of a lipid membrane barrier (e.g., epithelial cell wall) and no such molecules are on the other side, passive diffusion will drive the molecules across the membrane. When certain simplifying assumptions are made, the flux equation in Fick's law reduces simply to a product of permeability and solubility. Many other measurable properties are closely related to permeability and solubility. Permeability (P e) is a kinetic parameter related to lipophilicity (as indicated by the partition and distribution coefficients, log P and log D). Retention (R) of lipophilic molecules by the membrane (which is related to lipophilicity and may predict PK volumes of distribution) influences the characterization of permeability. Furthermore, strong drug interactions with serum proteins can influence permeability. The unstirred water layer on both sides of the membrane barrier can impose limits on permeability. Solubility (S) is a thermodynamic parameter, and is closely related to dissolution, a kinetic parameter. The unstirred water layer on the surfaces of suspended solids imposes limits on dissolution. Bile acids effect both solubility and dissolution, by a micellization effect. For ionizable molecules, pH plays a crucial role. The charge state that a molecule exhibits at a particular pH is characterized by the ionization constant (pK a) of the molecule. Buffers effect pH gradients in the unstirred water layers, which can dramatically affect both permeability and dissolution of ionizable molecules. In this review, we will focus on the emerging instrumental methods for the measurement of the physicochemical parameters P e, S, pKa, R, log P, and log D (and their pH-profiles). These physicochemical profiles can be valuable tools for the medicinal che...

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Increased Shelf-Life of Fosphenytoin: Solubilization of a Degradant, Phenytoin, through Complexation with (SBE)7M-β-CD

Cited by 25 publications

References 14 publications

Cyclodextrins

Cyclodextrins

Solubility

Physicochemical Profiling (Solubility, Permeability and Charge State)

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