Phatsawee Jansook

Cyclodextrins: structure, physicochemical properties and pharmaceutical applications

Since their discovery over 100 years ago cyclodextrins (CDs) have been the subject of numerous scientific publications. In 2016 alone CDs were the subject of over 2200 research articles published in peer-reviewed journals and mentioned in over 2300 patents and patent applications, many of which were on pharmaceutical applications. Natural CDs and their derivatives are used as enabling pharmaceutical excipients that enhance aqueous solubility of poorly soluble drugs, increase drug permeability through biological membranes and improve drug bioavailability. Unlike conventional penetration enhancers, their hydrophilic structure and high molecular weight prevents them from penetrate into lipophilic membranes leaving biological membranes intact. The natural CDs and some of their derivatives have monographs in pharmacopeias and are also commonly used as food additives and in toiletry products. CDs form inclusion complexes with lipophilic moieties of hydrophobic drugs. Furthermore, CDs are able to form non-inclusion complexes and self-assembled aggregates; small and large complex aggregates with micellar-like structures that can enhance drug solubility. Excipients commonly used in pharmaceutical formulations may have additive or inhibiting effect on the CD solubilization. Here various methods used to investigate CD aggregate formation are reviewed as well as techniques that are used to increase the solubilizing effects of CDs; methods that enhance the apparent intrinsic solubility of drugs and/or the complexation efficacy and decrease the amount of CD needed to develop CD-containing pharmaceutical formulations. It will be explained how too much or too little CD can hamper drug bioavailability, and the role of CDs in solid dosage forms and parenteral formulations, and examples given on how CDs can enhance drug delivery after ocular, nasal and pulmonary administration.

Development of a cyclodextrin-based aqueous cyclosporin A eye drop formulations

Cyclosporin A (CyA) is a lipophilic, cyclic polypeptide drug with anti-inflammatory properties. It is used in topical treatment of dry eyes and is now commercially available in oil based surfactant containing eye drops. Surfactants can irritate the eye surface causing burning, itching and irritation of the conjunctiva, and oil-based drops can result in blurred vision. Thus, the aim of this study was to develop surfactant free aqueous 0.05% (w/v) CyA eye drops where the drug is present in an aqueous vehicle containing CyA/cyclodextrin (CyA/CD) nanoparticles. The effects of the natural α-, β- and γ-cyclodextrins (αCD, βCD and γCD), as well as of the water soluble hydroxypropyl derivatives of γCD and αCD (HPγCD, HPαCD) and randomly methylated βCD (RMβCD), were determined in pure water. αCD had the best solubilizing effect increasing the solubility of CyA above 0.05% upon addition of only 5% (w/v) αCD. γCD did not have as good solubilizing effect but was tested further due to its superior ability to form nanoparticles and its favorable toxicological profile. Seven eye drop formulations were prepared and tested. All contained 0.05% (w/v) CyA in addition to polyvinyl alcohol, benzalkonium chloride, disodium edetate and various amounts of CD (αCD, γCD and mixtures thereof). When the formulation contained only αCD most of the drug was dissolved but some small aggregates were formed with hydrodynamic diameter of about 6 and 155 nm. When the formulation contained only γCD negligible CyA/CD complexation occurred with most of the drug present as solid CyA particles. When the formulation contained a mixture of αCD and γCD, where αCD concentration was at least 3% (w/v), the entire drug content was dissolved in the media under formation of relatively large (100-2000 nm) CyA/CD nanoparticles. αCD solubilized the drug while γCD enhanced nanoparticle formation. The effect of polyvinyl alcohol, benzalkonium chloride and disodium edetate on the nanoparticle formation was also investigated and shown to have positive effect on the aggregate formation.

Effect of γ-cyclodextrin on solubilization and complexation of irbesartan: influence of pH and excipients.

In effort to prepare an eye drop formulation of irbesartan, the effect of γ-cyclodextrin complexation on irbesartan solubilization in aqueous solutions was investigated. The optimum cyclodextrin concentration for formation of irbesartan/cyclodextrin inclusion complex was found to be 10% (w/v) and the solubility of ionized irbesartan/γ-cyclodextrin complex (at pH 7.2) was shown to be three fold greater than that of the unionized complex (at pH 4.3). The irbesartan flux through semipermeable membranes increased with increasing γ-cyclodextrin concentration at both pH values. However, the ionized complex displayed decrease in the drug permeation coefficient with increasing cyclodextrin concentration. The effect of four pharmaceutical excipients on the cyclodextrin solubilization was investigated. EDTA, hydroxypropyl methylcellulose, and tyloxapol increased complexation efficiency of γ-cyclodextrin while benzalkonium chloride had negligible effect. The largest solubilization was observed in the eye drop vehicle that contained all four excipients in addition to γ-cyclodextrin. Dynamic light scattering measurements disclosed that excipients had impact on size of complex aggregates and consequently on the drug flux through the semipermeable membranes. Complex of irbesartan/γ-cyclodextrin was characterized by FT-IR, (1)H NMR, XRPD, and TEM techniques.

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 Bs-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.

Cyclodextrin–poloxamer aggregates as nanocarriers in eye drop formulations: dexamethasone and amphotericin B

Abstract In this present study cyclodextrin (CD)–poloxamer aggregates were characterized and developed as ophthalmic drug carriers. The combined effect of γCD/2-hydroxypropyl-γCD (HPγCD) mixtures and poloxamer on solubilization and permeability of two model drugs, dexamethasone (Dex) and amphotericin B (AmB), was investigated. The CD–poloxamer interaction and complex aggregation were examined by 1H nuclear magnetic resonance (1H-NMR), their solubilizing ability by high-performance liquid chromatography, and their particle size determined by dynamic light scattering and transmission electron microscopy. Formulations containing either 1.5% w/v Dex or 0.15% w/v AmB in eye drop suspensions containing various γCD/HPγCD ratios and poloxamer 407 (P407) were prepared. The solubility of the drugs, surface tension and hemolytic effect of the eye drops and drug permeation from selected formulations were determined. The 1H-NMR study showed that P407 formed inclusion complex with CDs by inserting its poly(propylene oxide) segment into the CD cavity. P407 and γCD interacted with each other to form nanosized aggregates, and the observed concentration of dissolved γCD and P407 progressively decreased with increasing γCD and P407 concentrations. Including a high proportion of HPγCD improved the drug solubilization and reduced the hemolytic effect. The surface tension of the formulations decreased with increasing P407 concentration. Furthermore, increasing P407 content in the formulations enhanced formation of complex aggregates with consequent slower drug release. It was concluded that the drug/γCD/HPγCD complex was stabilized by P407 through formation of multi-component aggregates. Thus, CD–poloxamer aggregates are self-assembled nanocarriers from which drug delivery characteristics can be adjusted by changing the γCD/HPγCD/P407 ratios.

Cyclodextrin-based telmisartan ophthalmic suspension: Formulation development for water-insoluble drugs

In this study, cyclodextrin-based aqueous eye drop suspension of the water insoluble drug telmisartan was developed. Formation of a drug/γ-cyclodextrin complex was enabled by preventing formation of a poorly water-soluble zwitterion using a volatile base that was removed upon drying of the complex powder. Hydroxypropyl methylcellulose was shown to have the overall best effect, stabilizing the complexes without hampering the drug release from the formulation. Two strategies for preparing cyclodextrin-based aqueous eye drop suspensions of telmisartan were investigated, one where hydroxypropyl methylcellulose was added to the medium during preparation of the drug/γ-cyclodextrin complex powder (ternary complex) and the other where hydroxypropyl methylcellulose was added to the complex powder after preparation of the complex (binary complex). The complexation was characterized by DSC, FT-IR and (1)H NMR and the eye drop suspensions formed were examined regarding their stability and in vitro mucoadhesion property. The ternary complex exhibited inferior mucoadhesive property compared to the binary complex. However, the ternary complex was more stable as no notable change in particle size and particle size distribution was observed during storage at 4°C over 6 months (p<0.05) with the mean particle size determined between 2.0 and 2.5μm.

Evaluation of γ-cyclodextrin effect on permeation of lipophilic drugs: application of cellophane/fused octanol membrane

Abstract According to the Biopharmaceutics Classification System, oral bioavailability of drugs is determined by their aqueous solubility and the ability of the dissolved drug molecules to permeate lipophilic biological membranes. Similarly topical bioavailability of ophthalmic drugs is determined by their solubility in the aqueous tear fluid and their ability to permeate the lipophilic cornea. Enabling pharmaceutical excipients such as cyclodextrins can have profound effect on the drug bioavailability. However, to fully appreciate such enabling excipients, the relationship between their effects and the physicochemical properties of the permeating drug needs to be known. In this study, the permeation enhancing effect of γ-cyclodextrin (γCD) on saturated drug solutions containing hydrocortisone (HC), irbesartan (IBS), or telmisartan (TEL) was evaluated using cellophane and fused cellulose-octanol membranes in a conventional Franz diffusion cell system. The flux (J), the flux ratio (JR) and the apparent permeability coefficients (Papp) demonstrate that γCD increases drug permeability. However, its efficacy depends on the drug properties. Addition of γCD increased Papp of HC (unionized) and IBS (partially ionized) through the dual membrane but decreased the Papp of TEL (fully ionized) that displays low complexation efficacy. The dual cellophane-octanol membrane system was simple to use and gave reproducible results.

Amphotericin B-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLCs): effect of drug loading and biopharmaceutical characterizations

Abstract The aim of this study was to further investigate the effect of drug loading, drug entrapment efficiency, the drug release profiles and biopharmaceutical point of views of amphotericin B (AmB) lipid formulations, that is, degree of aggregation by UV-spectroscopy, in vitro hemolytic and antifungal activities. The optimum drug loading was 2.5% by weight corresponded to lipid fraction in formulation. Increasing of the drug entrapment was achieved by blending small amount of phospholipid in solid lipid nanoparticle (SLN) dispersions. All AmB lipid dispersions were less aggregated species and hemolytic response than Fungizone® indicating that lipid nanoparticles could reduce its toxicity. The sustained release profiles of AmB formulations depended on its aggregated form and entrapment efficiency. Too high AmB loaded (5% w/w) showed a biphasic drug release profile probably due to some amounts of drug deposited on the nanosphere surface including in continuous phase which promptly released. For in vitro antifungal testing, all AmB lipid formulations were equal and more effective than both AmB itself and Fungizone®. These observations suggested that AmB loaded SLNs, nanostructured lipid carriers and modified SLNs by blending lecithin could enhance AmB solubility, prolong release characteristics, reduce toxicity and improve antifungal activity.