Cyclodextrins in transdermal and rectal delivery

doi:10.1016/S0169-409X(98)00056-8

Advanced Drug Delivery Reviews

Volume 36, Issue 1, 1 March 1999, Pages 81-99

https://doi.org/10.1016/S0169-409X(98)00056-8 Get rights and content

Abstract

Transdermal and rectal routes of drugs are very important as a useful supplement of oral routes and the direct exposing method of drugs when the systemic and local effects are required. The widespread use of parent cyclodextrins (CDs) and chemically modified CD derivatives (CD derivatives) for in-vitro and in-vivo dermal and rectal drug delivery have been evaluated. In addition, the application of hydrophilic CD derivatives to cosmetics have been progressing. In this article, the current status of parent CDs and CD derivatives in the transdermal and rectal delivery of conventional low molecular weight agents are reviewed.

Introduction

Transdermal drug delivery systems have been gaining increasing popularity. Several drugs have been successfully delivered by this route for both local and systemic action. However, the transdermal drug transport is greatly limited by the particular permeation characteristics of the stratum corneum and is frequently insufficient for medical uses, so that many attempts of improving topical absorption have been performed. Enhancement of drug delivery through the skin may have four possible outcomes: (1) improvement in the release of drug from the transdermal pharmaceutical preparation bases, (2) enhancement in the flux of drug through the skin or the retention of drugs in the skin, (3) increase in topical or localized skin delivery or tissue targeting of drugs, and (4) a combination of (1), (2) and (3). In practice, the chemical and physical modifications to fulfill these criteria have been applied: the former is to use surfactants, permeation enhancers, ion pairs or liposomes and the latter is to use of iontophoresis, electopolation, sonophoresis or gene gun.

Rectal drug delivery systems is so pivotal when the patients have difficulty swallowing, nausea and/or vomiting, and are infants or children. However, the rectal route also has some potential disadvantages: (1) many drugs are poorly or erratically absorbed across the rectal mucosa, (2) a limiting absorbing surface area, (3) dissolution problems due to the small fluid content of the rectum, (4) drug metabolism in microorganisms and rectal mucosa. To overcome these problems, a number of studies have been examined using surfactants, absorption enhancers, mixed micelle and polymers, etc.

Cyclodextrins (CDs), cyclic oligosaccharides consisting of several glucopyranose units, are host molecules which form inclusion compounds. So far, the usefulness of three parent CDs (α-CD, β-CD and γ-CD) in the transdermal and rectal drug delivery has been reported with respect to the stabilization, improvement in release and bioavailability and alleviation of local irritation. Recently, various kinds of chemically modified CD derivatives have been prepared to extend the physicochemical properties and inclusion capacity of parent CDs. The hydroxyl groups of parent CDs were used as a starting point for chemical modifications of the molecule. Generally, the CD derivatives can be divided into three groups; hydrophilic, hydrophobic and ionizable derivatives. The hydrophilic derivatives included methylated CDs such as 2,6-dimethyl-β-CD (DM-β-CD) and 2,3,6,-trimethyl-β-CD (TM-β-CD), hydroxyalkylated CDs such as 2-hydroxypropyl-β-CD (HP-β-CD) and branched CDs such as maltosyl-β-CD (G₂-β-CD), which can augment the aqueous solubility and dissolution rate of poorly water-soluble drugs. The hydrophobic CDs include ethylated CDs such as 2,6-diethyl-β-CD (DE-β-CD), which can retard the dissolution rate of water-soluble drugs. In addition, the ionizable CDs include O-carboxymethyl-β-CD (CM-β-CD), O-carboxymethyl-O-ethyl-β-CD (CME-β-CD), β-CD sulfate and sulfobutylether β-CD (SBE-β-CD), which can realize the improvement in inclusion capacity, the modification of dissolution rate and the alleviation of local irritation of drugs, etc, while the hydrophobic CDs may modulate the release of drugs from the vehicles. Thus, we focused on the multifunctional effects of CDs on the transdermal and rectal delivery of drugs in this chapter.

Section snippets

Cyclodextrins in dermal drug delivery

CDs have been applied to optimizing the dermal delivery of drugs intended for a local and systemic use. The representative examples of parent CDs and CD derivatives are shown in Table 1, Table 2, respectively. Thus, parent CDs and the hydrophilic CD derivatives improve the solubility and stability of lipophilic drugs in the dermal preparations such as an aqueous solution and the water-contained ointments. In addition, CDs, especially hydrophilic CD derivatives, may affect the permeability of

Cyclodextrins in cosmetics

Cosmetics are generally placed at room temperature and are daily used by healthy people over long periods, so that the high standards of safety and stability must be ensured. Cosmetics are composed of oleaginous raw materials (oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, and silicones etc.), humectants, polymers, ultraviolet absorbents, antioxidants, sequestering agents, coloring materials (pigments, lakes and dyes), and fragrance materials, etc. The penetration of

Cyclodextrins in rectal drug delivery

CDs have been also applied to optimizing the rectal delivery of drugs intended for a systemic use. The representative examples of parent CDs and CD derivatives are summarized in Table 6. Many reports have indicated findings that the effects of CDs on the rectal delivery of drugs markedly depends on vehicle type (hydrophilic or oleaginous), physicochemical properties of the complexes, and an existence of tertiary excipients such as viscous polymer, etc. The enhancing effects of CDs on rectal

Conclusion

The effects of CDs on the release, topical bioavailability and pharmacological effects of drugs when applied to the skin and into the rectum are considerably influenced by vehicle type and the interactions of CD-drug-vehicle-biological membrane or CD-drug-vehicle-biological membrane-other additives such as permeation enhancers and polysaccharides. Therefore, we should consider the mechanism for the effects of CDs on the dermal and rectal delivery of drugs in order to design superior topical

Acknowledgements

We are indebted to Professor K. Uekama of the Faculty of Pharmaceutical Sciences, Kumamoto University, for his helpful discussion.

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Citation Excerpt :
Therefore, the drug dissolution at the interface of the oily base and the rectal fluids will improve. At the same time, the reverse diffusion of the drug into the vehicle is hindered [69,122,144]. As with ointments, the success of a formulation depends on the vehicle (aqueous or oleaginous), the physicochemical features of the CD in use, the drug, the CD/drug IC, and their interactions with the other components of the preparation.
We herein disclose how global cyclodextrin-based pharmaceutical technologies have evolved since the early 80s through a 1998 patents dataset retrieved from Derwent Innovation Index. We used text-mining techniques based on the patents semantic content to extract the knowledge contained therein, to analyze technologies related to the principal attributes of CDs: solubility, stability, and taste-masking enhancement. The majority of CDs pharmaceutical technologies are directed toward parenteral aqueous solutions. The development of oral and ocular formulations is rapidly growing, while technologies for nasal and pulmonary routes are emerging and seem to be promising. Formulations for topical, transdermal, vaginal, and rectal routes do not account for a high number of patents, but they may be hiding a great potential, representing opportunity research areas. Certainly, the progress in materials sciences, supramolecular chemistry, and nanotechnology, will influence the trend of that, apparently neglected, research. The bottom line, CDs pharmaceutical technologies are still increasing, and this trend is expected to continue in the coming years.
Patent monitoring allows the identification of relevant technologies and trends to prioritize research, development, and investment in both, academia and industry. We expect the scope of this approach to be applied in the pharmaceutical field beyond CDs technological applications.

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Cyclodextrins in transdermal and rectal delivery

Abstract

Introduction

Section snippets

Cyclodextrins in dermal drug delivery

Cyclodextrins in cosmetics

Cyclodextrins in rectal drug delivery

Conclusion

Acknowledgements

J. Pharm. Sci.

Int. J. Pharm.

Eur. J. Pharm. Sci.

Eur. J. Pharm. Sci.

J. Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.

Eur. J. Pharm. Sci.

Int. J. Pharm.

Eur. J. Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

Food Chem. Toxicol.

Int. J. Pharm.

J. Pharm. Sci.

J. Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.

J. Pharm. Sci.

Cyclodextrins in drug carrier systems.

CRC Crit. Rev. Ther. Drug Carrier Syst.

Improved transdermal delivery of prostaglandin E1 through hairless mouse skin: combined use of carboxymethyl-ethyl-β-cyclodextrin and penetration enhancers

J. Pharm. Pharmacol.

Stabilization of prostaglandin E1 in fatty alcohol propylene glycol ointment by acidic cyclodextrin derivatives, O-carboxymethyl-O-ethyl-β-cyclodextrin

Chem. Pharm. Bull.

Enhancement of the antiinflammatory effect of ethyl 4-biphenyl acetate in ointment by β-cyclodextrin derivatives: Increased absorption and localized activation of the prodrug in rats

Pharm. Res.

Release of ketoprofen from dermal bases in the presence of cyclodextrins:effect of the affinity constant determined in semisolid vehicles

Arch. Pharm.

Evaluation of chloramphenicol-β-cyclodextrin inclusion complex

Eur. J. Pharm. Biopharm.

Evaluation of few ciprofloxacin (CIP) and norfloxacin (NOR) formulations

Drug. Dev. Ind. Pharm.

Effects of β- and γ-cyclodextrins on release of betamethasone from ointment bases

Chem. Pharm. Bull.

Improvement in the percutaneous absorption of beclomethasone dipropionate by γ-cyclodextrin complexation

J. Pharm. Pharmacol.

Improvement in percutaneous absorption of prednisolone by β- and γ-cyclodextrin complexations

Chem. Pharm. Bull.

Effects of β- and dimethyl-β-cyclodextrins on release and percutaneous absorption behaviors of prednisolone from some ointment bases

Yakugaku Zasshi

Improved drug delivery through the skin by hydrophilic β-cyclodextrins. Enhancement of anti-inflammatory effect of 4-biphenylylacetic acid in rats

Drug Invest.

Possible enhancing mechanism of the cutaneous permeation of 4-biphenylylacetic acid by β-cyclodextrin derivatives in hydrophilic ointment

Chem. Pharm. Bull.

Drug carriers for transdermal preparations of flurbiprofen

Drug Dev. Ind. Pharm.

Formulation and evaluation of oral and transdermal preparations of flurbiprofen and piroxicam incorporated with different carriers

Drug. Dev. Ind. Pharm.

Physical chemical analysis of percutaneous absorption process from creams and ointments

J. Soc. Cosmet. Chem.

The influence of 2-hydroxypropyl-β-cyclodextrin on diffusion rates and transdermal delivery of hydrocortisone

Drug Dev. Ind. Pharm.

A study of the percutaneous absorption-enhancing effects of cyclodextrin derivatives in rats

J. Pharm. Pharmacol.

The effect of polyvinylpyrrolidone on cyclodextrin complexation of hydrocortisone and its diffusion through hairless mouse skin

Int. J. Pharm.

Effect of diethyl-β-cyclodextrin on the release of nitroglycerin from formulations

Drug Des. Deliv.

Improved transdermal delivery of prostaglandin E₁ through hairless mouse skin: combined use of carboxymethyl-ethyl-β-cyclodextrin and penetration enhancers

Stabilization of prostaglandin E₁ in fatty alcohol propylene glycol ointment by acidic cyclodextrin derivatives, O-carboxymethyl-O-ethyl-β-cyclodextrin