Cyclodextrins: application in different routes of drug administration

The objective of this review article is to explain the use of cyclodextrin in the different routes of drug administration. The article gives the chemistry of cyclodextrins and addresses the issue of the mechanism of drug release from cyclodextrin complexes. Dilution, competitive displacement, protein binding, change in ionic strength and temperature and drug uptake by tissues are the different release mechanisms of the drug from the drug-cyclodextrin complex discussed here. Use and its limitations in the different drug delivery systems like nasal, ophthalmic, transdermal and rectal drug delivery are explained. The application of the cyclodextrins in the oral drug delivery is detailed in this review. Many studies have shown that cyclodextrins are useful additives in the different routes of drug administration because of increased aqueous solubility, stability, bioavailability and reduced drug irritation.     

Cyclosporine A delivery to the eye: a pharmaceutical challenge.

Systemic administration of cyclosporine A (CsA) is commonly used in the treatment of local ophthalmic conditions involving cytokines, such as corneal graft rejection, autoimmune uveitis and dry eye syndrome. Local administration is expected to avoid the various side effects associated with systemic delivery. However, the currently available systems using oils to deliver CsA topically are poorly tolerated and provide a low bioavailability. These difficulties may be overcome through formulations aimed at improving CsA water solubility (e.g. cyclodextrins), or those designed to facilitate tissue drug penetration using penetration enhancers. The use of colloidal carriers (micelles, emulsions, liposomes and nanoparticles) as well as the approach using hydrosoluble prodrugs of CsA have shown promising results. Solid devices such as shields and particles of collagen have been investigated to enhance retention time on the eye surface. Some of these topical formulations have shown efficacy in the treatment of extraocular diseases but were inefficient at reaching intraocular targets. Microspheres, implants and liposomes have been developed to be directly administered subconjunctivally or intravitreally in order to enhance CsA concentration in the vitreous. Although progress has been made, there is still room for improvement in CsA ocular application, as none of these formulations is ideal.     

Topical Ocular Delivery of NSAIDs

In ocular tissue, arachidonic acid is metabolized by cyclooxygenase to prostaglandins which are the most important lipid derived mediators of inflammation. Presently nonsteroidal anti-inflammatory drugs (NSAIDs) which are cyclooxygenase (COX) inhibitors are being used for the treatment of inflammatory disorders. NSAIDs used in ophthalmology, topically, are salicylic-, indole acetic-, aryl acetic-, aryl propionic- and enolic acid derivatives. NSAIDs are weak acids with pKa mostly between 3.5 and 4.5, and are poorly soluble in water. Aqueous ophthalmic solutions of NSAIDs have been made using sodium, potassium, tromethamine and lysine salts or complexing with cyclodextrins/solubilizer. Ocular penetration of NSAID demands an acidic ophthalmic solution where cyclodextrin could prevent precipitation of drug and minimize its ocular irritation potential. The incompatibility of NSAID with benzalkonium chloride is avoided by using polysorbate 80, cyclodextrins or tromethamine. Lysine salts and alpha-tocopheryl polyethylene glycol succinate disrupt corneal integrity, and their use requires caution. Thus a nonirritating ophthalmic solution of NSAID could be formulated by dissolving an appropriate water-soluble salt, in the presence of cyclodextrin or tromethamine (if needed) in mildly acidified purified water (if stability permits) with or without benzalkonium chloride and polyvinyl alcohol. Amide prodrugs met with mixed success due to incomplete intraocular hydrolysis. Suspension and ocular inserts appear irritating to the inflamed eye. Oil drop may be a suitable option for insoluble drugs and ointment may be used for sustained effect. Recent studies showed that the use of colloidal nanoparticle formulations and the potent COX 2 inhibitor bromfenac may enhance NSAID efficacy in eye preparations.     

Cyclodextrins in nasal drug delivery

Nasal drug delivery is an attractive approach for the systemic delivery of high potency drugs with a low oral bioavailability due to extensive gastrointestinal breakdown and high hepatic first-pass effect. For lipophilic drugs nasal delivery is possible if they can be dissolved in the dosage form. Peptide and protein drugs often have a low nasal bioavailability because of their large size and hydrophilicity, resulting in poor transport properties across the nasal mucosa. Cyclodextrins are used to improve the nasal absorption of these drugs by increasing their aqueous solubility and/or by enhancing their nasal absorption. With several cyclodextrins very efficient nasal drug absorption has been reported, but also large interspecies differences have been found. Studies concerning the safety of cyclodextrins in nasal drug formulations demonstrate the non-toxicity of the cyclodextrins and also clinical data show no adverse effects. Therefore, some cyclodextrins can be expected to become effective and safe excipients in nasal drug delivery.     

Role of cyclodextrins in ophthalmics

Cyclodextrins are oligosaccharides having outer hydrophilic surface and central hydrophobic cavity. These agents form inclusion complexes with poorly water-soluble drugs; hence they show an important implication for use in ophthalmics because of their applications in solubilising and stabilising the ocular drugs. Most of the drugs being used in ophthalmics were not tailor-made for the eye and considering the poor bioavailability of <1% from the corneal surface, presentation of the drug in a soluble form and at high concentration is important. Provision of a high drug concentration at the corneal surface increases the percent drug permeation indicating the usefulness of cyclodextrins as penetration enhancers. A decrease in irritation potential of some drugs upon incorporation of cyclodextrins is also reported. Polymer-cyclodextrin multicomponent systems further extend the role of cyclodextrins in improving the solubility and bioavilability of ocular drugs. Large hydrophilic cyclodextrins like hydroxypropyl-beta-cyclodextrin and sulphobutylether-beta-cyclodextrin are safe for the use in aqueous eye drop solutions especially since they do not cross the lipophilic cornea. Various aspects about the applications of cyclodextrins in ophthalmics, the formulation considerations and expected toxicity of cyclodextrins (especially if high concentration is used) is discussed in this review. Strategies like use of polymers to reduce the effective concentration of cyclodextrin required without compromising solubility are also included. Further the concept of incorporating the drug-cyclodextrin complexes into liposomes or niosomes for a better targeting of the drug at appropriate tissue destination is discussed as a possible future option.     

Cyclodextrins

Although cyclodextrins (CDs) have been studied for over 100 years and can be found in at least 35 pharmaceutical products, they are still regarded as novel pharmaceutical excipients. CDs are oligosaccharides that possess biological properties that are similar to their linear counterparts, but some of their physicochemical properties differ. CDs are able to form water-soluble inclusion complexes with many poorly soluble lipophilic drugs. Thus, CDs are used to enhance the aqueous solubility of drugs and to improve drug bioavailability after, for example, oral administration. Through CD complexation, poorly soluble drugs can be formulated as aqueous parenteral solutions, nasal sprays and eye drop solutions. These oligosaccharides are being recognized as non-toxic and pharmacologically inactive excipients for both drug and food products. Recently, it has been observed that CDs and CD complexes in particular self-assemble to form nanoparticles and that, under certain conditions, these nanoparticles can self-assemble to form microparticles. These properties have changed the way we perform CD research and have given rise to new CD formulation opportunities. Here, the pharmaceutical applications of CDs are reviewed with an emphasis on their solubilizing properties, their tendency to self-assemble to form aggregates, CD ternary complexes, and their metabolism and pharmacokinetics.     

Development of eye drops containing antihypertensive drugs: formulation of aqueous irbesartan/γCD eye drops

Abstract

Aqueous nanoparticulated eye drop formulations based on γ-cyclodextrin (γCD) complexes were developed and tested in vitro. Three antihypertensive drugs, i.e. enalapril maleate, irbesartan and verapamil HCl, that have been shown to possess IOP-lowering activity were selected for this study. All three drugs displayed B_s-type phase-solubility diagrams in aqueous γCD solutions and had relatively low affinity for γCD. Irbesartan was selected for further formulation development. The drug was relatively stable at pH 4.5 but somewhat less stable at physiologic pH. However, presence of γCD in the aqueous media enhanced the chemical stability of irbesartan. Aqueous γCD-based eye drop formulations containing 1% and 2% (w/v) irbesartan were prepared and the effect of pH on the particles size distribution and drug release investigated. Only ～2% of the drug was in solution in the pH 4.5 formulations but up to 45% in the pH 7 formulations. The pH 7 formulations, where larger fraction of the drug was in solution, displayed somewhat greater drug permeation flux but much lower drug permeation coefficients than the pH 4.5 formulations. Dynamic light scattering studies indicated the faster permeation was due to formation of smaller particles in presence tyloxapol.     

Topical drug delivery to the posterior segment of the eye: anatomical and physiological considerations

Drug delivery to the posterior segment of the eye is important for potentially treating various disorders in retina, choroid, vitreous humor and optic nerve. Due to anatomic membrane barriers and the lacrimal drainage it can be quite challenging to obtain therapeutic drug concentrations in the posterior parts of the eye after topical drug administration. Since the membrane barriers cannot be altered with non-invasive methods invasive methods such as direct drug injection into the vitreous humor and subconjunctival, subtenons capsule or suprascleral injections are gaining popularity. However, invasive methods can cause discomfort for the patient and can also lead to complications that are even more serious than the disease being treated. Alternatively, novel ophthalmic formulations can be developed that specifically target topical drug delivery to the posterior segment of the eye. Anatomical and physiological barriers in the eye are reviewed as well as the theoretical model of passive drug diffusion from the eye surface into the eye. It is shown that enhanced drug delivery through conjunctiva/sclera to retina can be obtained by formulating lipophilic drugs as hydrophilic drug/cyclodextrin complex solutions. Optimization of the delivery system by formulating the drug as a low-viscosity aqueous drug/cyclodextrin complex suspension results in sustained high concentrations of dissolved drug in the tear fluid which further increases the targeted drug delivery to the posterior segment.     

Determination of permeability coefficients of ophthalmic drugs through different layers of porcine, rabbit and bovine eyes

To treat ophthalmic diseases like glaucoma or inflammatory disorders topically applied ophthalmic formulations such as eye drops are usually used. In addition, novel ophthalmic implants releasing drug substances locally into different parts of the eye are available today. In the work presented here, the permeability coefficients of selected drugs (ciprofloxacin hydrochloride, lidocaine hydrochloride, timolol maleate) for ophthalmic tissues were determined using side-by-side diffusion chambers (so-called Ussing chambers). Sclera, conjunctiva, cornea, choroidea-retina-complex and a complex of conjunctiva-sclera-choroidea-retina were excised from fresh porcine, rabbit and bovine eyes. In the porcine eye tissues the highest P(app) values were obtained for conjunctiva with the exception of lidocaine. Therefore, it can be estimated that a certain amount of drug diffuses or is transported through conjunctiva after application. The P(app) values for sclera were also higher than those for cornea and even more, the surface area of sclera which is available for drug absorption is much larger than that of cornea when applying an implant. The obtained permeability coefficients for sclera and conjunctiva indicate that the administration of periocular implants can be an alternative to topically applied formulations. The complexes of the tissues were a significantly (p<0.01) stronger barrier to the investigated substances than the separated tissues. Distinct differences in permeability coefficients between the investigated animal tissues were observed. Overall the highest P(app) values for all mounted tissues were obtained with the rabbit, followed by porcine and bovine eyes. Because of these distinct interspecies differences one must be very careful when selecting the proper animal model for the permeability experiments.     

Interactions between cyclodextrins and pilocarpine — As an example of a hydrophilic drug

Investigations of interactions between cyclodextrins (CyDs) and pilocarpine (P) were carried out by means of several common methods. Subjects of interest were aqueous solutions and solid dispersions of the drug and various cyclodextrins. The solid dispersions were prepared by spray-drying and by lyophilization of the aqueous solutions. These products and the equivalent physical mixtures were compared by scanning electron microscopy (SEM), differential thermal analysis (DTA), powder X-ray diffractometry (XRD) and Fourier transformation infrared (FTIR) spectroscopy. Methods for investigations of the aqueous solutions were ¹H-NMR, ¹³C-NMR, correlation, rotating frame Overhauser effect and nuclear Overhauser effect spectroscopy, reversed phase high performance liquid chromatography (HPLC), UV-spectroscopy and conductometry. The results obtained may be interpreted as an inclusion of pilocarpine in cyclodextrins. In vitro and in vivo studies yielded results of a modified release and a slightly higher bioavailability of pilocarpine in the presence of the tested cyclodextrins. Therefore we assume that the use of cyclodextrins in ophthalmic preparations could be advantageous not only for lipophilic drugs but also for hydrophilic drugs.     

Biopharmaceutical considerations in topical ocular drug delivery

1. Despite the accessibility of the front of the eye, efficient delivery of drug to treat various ocular disorders is a challenge to the formulation scientist. The majority of ophthalmic medications are formulated as eye drops. Due to anatomical constraints, the volume that can be administered is limited to approximately 30 microL. This, together with the efficient clearance system that exists in the front of the eye, makes it difficult to maintain an effective pre-ocular drug concentration for a desired length of time. Various formulation strategies have been used to increase pre-ocular retention of eye drops. The most successful of these has been the inclusion of viscosity enhancing polymers, particularly those able to interact with the mucous layer on the eye surface or those that can undergo a transition from a solution to a gel under the conditions of the pre-ocular area. 2. When the target site is intra-ocular, drug must be absorbed from the pre-ocular region into the eye. The main route for absorption is across the cornea. However, absorption of drug across the cornea is inefficient due to its impermeable nature and small surface area. Thus, the intra-ocular bioavailability of topically administered medications is typically less than 10%. 3. Corneal permeability favours moderately lipophilic compounds. These compounds often have a low aqueous solubility. Problems in ocular drug delivery and formulation are compounded for poorly soluble drugs that must be formulated as suspensions. 4. Reformulation of ophthalmic suspensions as solutions has many advantages. This may be achieved by complexation using cyclodextrins. Solubilization using cyclodextrins can overcome many of the formulation problems. However, it is unclear as to their potential for improving ocular bioavailability, which is seemingly drug dependent and may be influenced by both the physicochemical properties of the drug and the complex formed.     

Measuring drug-induced eye irritation: a simple new clinical assay

Thirty-six normal subjects received a drop in either eye of two of four ophthalmic solutions, balanced saline (S), carteolol, 1% (C1), carteolol, 2% (C2), or timolol, 0.5% (T), in a double-blind, randomized trial in a balanced incomplete block design. Subjects reported immediately, at three, and again at ten minutes after administration whether one eye felt more irritated and marked an analog scale of irritation. An observer also made ratings at three minutes based on responses to stereotyped questions. Significant differences in irritation between timolol and each of the other drugs and placebo were shown by analog scale scores immediately after instillation of the solutions. Maximum likelihood estimates were calculated based on statements of subject preference, and a significant preference was demonstrated. Observer ratings also demonstrated a treatment effect. This simple clinical assay system provides a new, valid method for estimating irritation induced by ophthalmic solutions.     

Effect of hydroxypropyl-beta-cyclodextrin on the solubility, stability and in-vitro release of ciprofloxacin for ocular drug delivery

Eye drops in the form of an aqueous solution with a lower viscosity are preferred for local administrations in ophthalmology. In ophthalmic formulations, cyclodextrins (CDs) are frequently used in recent years in order to increase water solubility, stability and bioavailability of an active substance and decrease an irritation to the eye. The scope of the present study was to investigate the influence of hydroxypropyl-beta-cyclodextrin (HPCD) on the solubility, stability and in vitro release of ciprofloxacin (CIP). According to the phase solubility studies, A(L) type solubility curve was obtained. HPCD improved the solubility of CIP 3 times at pH 5.5 and 2 times at pH 7.4. The two month stability studies indicated that CIP was more stable at pH 5.5 than at pH 7.4 and the stability of CIP was significantly increased by HPCD. The stability constant of the HPCD:CIP complex was increased further by a-ddition of 0.1% (w/v) polymer (HPMC and PVP) to the aqueous medium including HPCD. Stability constant of solutions prepared in an ultrasonic water bath was higher than solutions prepared by heating in an autoclave. The results indicated that the CIP:HPCD complex increased in vitro release of CIP and the addition of polymer promoted this increase even more.     

Intravenous administration of poorly soluble new drug entities in early drug discovery: the potential impact of formulation on pharmacokinetic parameters

Currently, in early drug discovery, compounds that are formulated for first-animal experiments are increasingly characterized as being lipophilic and poorly water-soluble. Typical examples of intravenous formulations for these compounds include aqueous solutions at non-physiologically high or low pH, co-solvent solutions, solutions in cyclodextrins (CDs), surfactant-based solutions, mixed micellar solutions, parenteral fat emulsions or nano- and microsuspensions. Experiments designed to determine the intrinsic pharmacokinetic behavior of a new drug entity (NDE) are complicated as, depending upon the formulation, disposition in the organism can be affected. This may be due to slow or incomplete dissolution of injected particles, precipitation in the bloodstream, delayed release from the dosing vehicle, competition between compound and formulation ingredients for transport and metabolism mechanisms, or altered binding to blood components. The most important determinant for the successful development of a 'non-interfering' dosing vehicle is the required dose. Provided the analytical technique used to determine drug concentration in the body is sensitive enough to allow compound administration at low doses, screening formulations at comparatively low concentrations may be feasible. In this way, formulation approaches that may potentially impact the pharmacokinetic behavior of the compound of interest can be avoided.     

Age-related differences in ophthalmic drug disposition I. Effect of size on the intraocular tissue distribution of pilocarpine in albino rabbits

It has previously been documented that substantially different aqueous humour drug levels are observed in rabbits of different ages when the same dose of pilocarpine is instilled into the eye. Also, it has been shown that the aqueous humour volume ratio for rabbits of different ages can be used to predict aqueous humour levels of pilocarpine attained after topical dosing. In the present study, concentrations of pilocarpine in the cornea, aqueous humour, iris-ciliary body, lens, and vitreous humour were determined in both 20-day old and 60-day old rabbits following the topical administration of identical doses of drug. For tissues other than the aqueous humour and iris-ciliary body, consideration of only tissue size differences between rabbits of different ages will not suffice to explain the observed differences in pilocarpine concentration. Any attempt to develop rational age-related dosage modifications for ophthalmic drugs must include a consideration of functional and developmental differences as well as size effects.     

Ophthalmic Econazole Hydrogels for the Treatment of Fungal Keratitis

Econazole is a feasible alternative treatment in the management of fungal keratitis. Nevertheless, its low water solubility is considered the main limitation to the incorporation into ophthalmic formulations. In this work, econazole nitrate is solubilized by using cyclodextrins to achieve an optimum therapeutic concentration. Phase solubility diagrams suggest α-cyclodextrin as the most effective cyclodextrin and later the inclusion complex formed with this one was characterized in solution by 1D, 2D-NMR, and molecular modeling. Econazole-α-cyclodextrin inclusion complex was included in 2 types of ocular hydrogels: a natural polysaccharides ion-sensitive hydrogel and a hyaluronic acid hydrogel. Both of them show no ocular irritation in the hen's egg test on chorioallantoic membrane assay and a controlled econazole release over time. Permeability studies suggest that hydrogels do not modify the econazole nitrate permeability through bovine cornea in comparison with an econazole-α-cyclodextrin inclusion complex solution. Finally, ocular biopermanence studies performed using positron emission tomography show these hydrogels present a high retention time on the eye. Results suggest the developed formulations have a high potential as vehicles for the econazole topical ocular administration as fungal keratitis treatment.     

Cyclodextrins in drug delivery

Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are approximately 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.     

Cyclodextrins in drug delivery

Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are ~ 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.     

Comparison of the stability, efficacy, and adverse effect profile of the innovator 0.005% latanoprost ophthalmic solution and a novel cyclodextrin-containing formulation

Recently, a new latanoprost ophthalmic solution containing cyclodextrins was developed. The purpose of the present work was to compare the stability, clinical efficacy, and adverse effect profile of this formulation with the innovator product. The innovator formulation was stable at 4 degrees C but exhibited degradation at higher temperatures, whereas the cyclodextrin-containing formulation was stable at temperatures up to 40 degrees C. Formulations were assayed in a randomized double-blind clinical study in patients with primary open-angle glaucoma and/or ocular hypertension. Both latanoprost ophthalmic solutions produced comparable reduction of intraocular pressure. Conjunctival hyperemia was observed in 11.9% and 11.3% of the patients treated with the innovator and the cyclodextrin-containing formulations, respectively. There were no significant differences between the 2 ophthalmic solutions in efficacy or in the measured adverse effect. It is concluded that these 2 latanoprost ophthalmic solutions yield comparable efficacy and adverse effect outcomes. The cyclodextrin-containing formulation, however, has an improved stability.     

Hydrogels in ophthalmic applications

More and more people worldwide are affected by severe eye diseases eventually leading to visual impairment or blindness. In most cases, the treatment involves the application of ophthalmic dosage forms such as eye drops, suspensions or ointments. Unfortunately, some of the therapeutic approaches have major shortcomings, especially in the treatment of the posterior segment of the eye, where many vision-threatening diseases originate. Therefore, research focuses on the development of new materials (e.g., for vitreous substitution) and more advanced drug delivery systems. Hydrogels are an extremely versatile class of materials with many potential applications in ophthalmology. They found widespread application as soft contact lenses, foldable intraocular lenses, in situ gelling formulations for ophthalmic drug delivery and ocular adhesives for wound repair; their use as vitreous substitutes and intravitreal drug delivery systems is currently under investigation. In this article, we review the different applications of hydrogels in ophthalmology with special emphasis placed on the used polymers and their suitability as ocular drug delivery systems.