Cyclodextrin in Drug Release

β-CD has been most commonly used in the food, agricultural, and environmental

engineering industries indicating its large range of applications. Excipients have also been used to aid with the delivery and dispersion of the active ingredients. More recently though, β-CD has become of considerable interest in the pharmaceutical

industry for drug delivery and release studies. This is due to CD being easy to handle, its ability to increase the bioavailability and solubility of drugs, decrease drug irritation, stabilise active ingredients, and to reduce drug-drug interactions. CD is also able to decrease the integrity of cell membranes through the inclusion of some cell components leading to the increase in the permeability of some impermeable drugs. CD is stable in acid down to a pH of approximately 3 and thermally stable below 200°C and these properties are readily exploited for drug release. External functionalisation of CDs primary or secondary hydroxy groups can increase its water solubility therefore allowing easier transportation of molecules around the body.23-24

In aqueous solution, the CD cavity is able to weakly hold between three (α-CD) and

nine (γ-CD) water molecules, which can easily be displaced. This cavity is also able to

accommodate aliphatic and aromatic compounds, including drugs. They can bind in differing ratios from 1:1, 2:1, and 1:2 depending upon the CD involved and the size of the guest molecule. This binding is driven by enthalpic and entropic forces controlling the release of water from the cavity increasing the solubility of CD in aqueous medium.23-24

CDs can recognise the size, shape, and chirality of amino acids, however since peptides and proteins are generally quite large, they are not able to fit entirely inside the CD cavity. Therefore, there are only local interactions between the CD and the accessible hydrophobic parts of the peptides/proteins. Such interactions affect the overall three- dimensional structure of the peptide/proteins and hence also affect their biological and chemical properties.23-24

It has been found that non-covalent interactions between peptides and CD derivatives occur in solution forming host-guest complexes. An example of this can be seen in the interaction of the BK peptide with permethylated β-CD which has been studied by mass

spectrometry (MS).23-24 The guest is driven to the CD cavity by its hydrophobic nature, such as the phenyl group of phenylalanine. Studies indicate that BK forms a non- covalently bound complex with the CD in the region where the basic-amino acid residues, such as arginine and phenylalanine are located. This non-covalent interaction is likely to be from an ion-dipole interaction, with no evidence of an inclusion complex formed.23-24

Encapsulation of metals and other small molecules by CD is also possible. These are held in the cavity by the functionalisation of the primary and secondary faces, as well as by hydrophobic and hydrophilic interactions of the CD cavity. Due to this, CD is also able to act as a molecular receptor important for the separation of chiral and/or impure compounds.23-24

1.4.1.1 Drug Bioavailability

CD enhances the bioavailability of drugs by increasing their solubility, dissolution, and/or membrane permeability. For example, CD can aid the drug permeability by direct action on mucosal membranes by interacting with cholesterol increasing the membranes fluidity and induce membrane invagination through a loss of bending resistance and cause cell lysis. CD can also cause the removal of phospholipids, especially phosphatidylcholine and sphingomyelin from the outer half of the membrane bilayer causing an imbalance.23c,25

1.4.1.2 Drug Safety

The ability of CD to increase drug solubility ideally means that less drug is required therefore reducing potential side effects or toxicity by making the drug more effective at lower doses.23c,25

1.4.1.3 Drug Stability

CDs have the ability to increase drug stability against, e.g., dehydration, hydrolysis, and oxidation therefore increasing the drug’s shelf life. This stability has been proposed to be due to CD shielding the drug and particularly the drug’s active site thus insulating the drug from degradation.25 The stabilisation effect is dependent upon the nature of the groups attached to CD, and the nature of the drug.25

1.4.2 Cyclodextrins Application in Drug Delivery

Various types of delivery methods using CD-based drugs have been studied. These include oral, parenteral, ocular, nasal, rectal, and more controlled delivery methods including, e.g., colon-specific delivery.23,25-26 Each method demands specific requirements that focus the selection from such a broad range of drug delivery systems. For example, oral drug delivery requires improvement to the drug’s bioavailability with increased solubility, a better rate and extent of dissolution, and the stability of the drug at the absorption site, such as the stomach or the intestine. Elimination of taste and odour of the drug must also be taken into consideration. For oral delivery to be successful, the time of drug release is important in order to get the maximum effect of the drug, so release in transit is not ideal. CDs enhance the absorption of drugs by oral delivery by increasing the free drug availability at the absorptive surface and their complexation provides better and uniform absorption of desired low-soluble drugs with poor and erratic absorption. However, when considering the type of delivery method, safety, efficacy in terms of complexation, cost, and acceptance in pharmacopeia should be considered.25 Ocular delivery, such as CD in eye drops, has been used to aid solubilisation and chemical stabilisation of drugs, reduction of eye irritation, and enhancement of drug permeability. CD is ideal for this instance as it is non-irritating to

the eyes surface maximising the absorption of the drug.25 Nasal delivery of drugs has optimised the use of CDs due to increasing the aqueous solubility of the drug and/or by enhancing the drug’s permeability. This is also the case with suppository and parenteral drug delivery with the addition of minimising toxicity and increasing drug stability.25

Controlled drug release has been extensively studied with CD based drugs due to their ability to carry or complex drugs. The hydrophilic and hydrophobic nature of CD enables exploitation and transport to differing areas within the body, and therefore differing release times. For example, hydrophilic derivatives improve the aqueous solubility and dissolution rate of poorly soluble drugs, while hydrophobic derivatives retard the dissolution rate of water-soluble drugs from vehicles. Therefore, hydrophilic and hydrophobic combinations are used in immediate and prolonged release type formulations, respectively. pH can also be applied to induce a delayed and specific release time of a drug.25