Firstly, it must be pointed out that there are natural CDs and modified or substituted CDs. It is essential to understand the differences between them in terms of solubility, stability against hydrolysis and complexation efficiency, as well as the physicochemical and structural characteristics of the drugs with which CDs are meant to be complexed (Table 1)1,2.

Concerning the use of CDs to enhance the solubilization of orally administered drugs, it must be considered that CDs have been shown to increase the bioavailability of the FDA's biopharmaceutics classification system class II drugs, which are poorly water soluble and highly permeable. In contrast, class I (highly water soluble and highly permeable) and class III (high solubility and low permeability) drugs may reduce bioavailability1,4. This interesting aspect should be born in mind when coformulating multiple active substances in one single extemporaneous preparation.

Moreover, it must be remembered that the stability of the resulting inclusion complexes may impact bioavailability both in terms of degree and dynamics. Indeed, when the stability of such complexes is high, the release and dissolution rate of the drug may slow down, which may speed down absorption17. On the other hand, use of low-stability inclusion complexes may speed up the release of the drug in the gastrointestinal tract, leading to its precipitation in the gut. In these cases, although complexation efficiency may be satisfactory, the amount of medication absorbed may be lower, which would therefore decrease its degree of bioavailability28.

As regards the preparation of pediatric extemporaneous formulations, there is the added difficulty that the administration of many of the drugs for which CD complexation is indicated both to optimize bioavailability and to mask their unpleasant organoleptic characteristics (i.e., isavuconazole) needs to be monitored in these patients. Alterations in the dynamics or the degree of bioavailability, caused by highly stable or low-stability inclusion complexes respectively, may result in changes in the plasma levels achieved by drugs that may otherwise be regarded as appropriate29.

As far as ophthalmic administration is concerned, use of CDs may help improve not only the solubility and the stability of certain drugs but also their permeability through the tear film thereby reducing local irritation17. In the specific case of eyedrops, α-CD is considered the CD of choice as it is capable of directly interfering with the lipid membranes of the epithelial layer, increasing their porosity to the administered drug. Some authors have reported that substituted CDs such as HPβCD can also be used in these applications15,16,30,31.

When preparing a topically administered ointment or cream based on a drug that one wishes to complex in order to enhance its solubility and mask its irritating properties, it is vital to, first of all, ensure that no incompatibilities exist between CD and the other excipients. In these types of preparations, CDs are associated with a higher risk of lump and foam formation in the emulsions. If CDs are to be used in the formulation, it is best to use HPβCD as, apart from its surfactant properties, it also increases the drug-skin contact time. Other substituted CDs may also be employed15,32,33.

Although CDs have generally been shown to be highly safe excipients, it is essential to take into consideration that administration of doses above the recommended threshold, and/or for long periods of time, may result in side effects. It is for that reason that it is important to consider not only the advisability of using a given CD in an extemporaneous preparation in terms of pharmaceutical and biopharmaceutic/pharmacokinetic criteria, but also the maximal doses established by the different European regulations for the different CDs authorized for pharmaceutical use (Table 4)15,16.

As regards oral CD administration, it has been shown that only insignificant amounts of CD are absorbed during colonic transit by intestinal bacteria, RMβCD showing the highest absorption rates, with an oral bioavailability rate of 12% in rats, as compared with 0.1-3% for the other CDs. There is, however, evidence from animal studies that high doses of orally administered CDs (> 1,000 mg/kg/day) may result in reversible diarrhea and cecal enlargement2,15,16,34–36.

It has also been shown that the presence of specific components in the formulation or a given concentration of the CD used may enhance absorption of CDs when administered by other routes of administration. Such is the case of the intranasal and the intratracheal routes, for which systemic absorption of CDs is practically negligible. Specifically, administration of drugs containing very high doses of CDs could have an impact on the absorption not only of the complexed drug but also of the CDs themselves13,29–31,37. It has been shown that, following intranasal administration of dipropyl-β-cyclodextrin (not used in pharmaceutical products) at a concentration of 80 mM in rats, as much as 16% of the dose is excreted in the urine. Moreover, in the case of HPβCD it has been shown that the presence of absorption-stimulating agents increases absorption of CD, with urine excretion rates of 45% of the administered dose, as compared with only 3% when HPβCD is administered on its own15,34. Likewise, topical absorption of CDs is practically nonexistent, although when CD is combined with absorption stimulators such as HPE-101 or with occlusive excipients, absorption rates of 12% have been found for β-CD, 43% for RMβCD and 53% for HPβCD, albeit without evidence of any adverse events15,34–36.

The rectal route, for its part, has shown that absorption of CDs may be significant as they may act as drug absorption optimizers and be absorbed accordingly17. Nevertheless, the risk of toxic reactions following rectal absorption is not as high as in the case of parenteral administration, where high doses of CDs may cause severe toxicity at renal and hematological level13–16,34. Intravenous administration of CD-containing pharmaceutical preparations may induce changes in cell morphology as well as hemolysis, possibly due to the complexation of cell membrane components such as cholesterol, phospholipids and proteins. Such hemolytic activity seems to follow the β- > α- > γ-cyclodextrin order38.

From a safety standpoint, the most appropriate natural CD for parenteral administration is γ-CD, which is not associated with significant nephrotoxicity (probably as a result of its rapid enzymatic degradation) and presents with low hemolytic activity. There are however some β-CD derivatives that may be safely used in parenteral administration such as HPβCD and SBEβCD, provided that they are administered in amounts above 15 mg/kg/day and that the length of administration of the extemporaneous preparation containing the CD in question is not too prolonged13–16.

It is important to bear in mind that not all the available CDs may be used in extemporaneous preparations, regardless of their favorable properties and their good safety profile. As established in Royal Decree 175/2001 of 23 February 2001, which sets out the procedures to be followed for compounding and controlling the quality of extemporaneous preparations and officinal formulations, all the raw materials used in extemporaneous preparations must be warranted by a specific monograph in the Royal Spanish Pharmacopeia or, failing that, in the European Pharmacopeia or in some other well-established pharmacopeia39. The Royal Spanish Pharmacopeia currently recognizes natural CDs (α-CD and β-CD) and HPβCD as pharmaceutical grade excipients. Both supplement 8.7 of the European Pharmacopeia and the 2017 edition of the British Pharmacopoeia include monographs for γ-CD and dimethyl-β-cyclodextrin (DMβCD), which is nowadays seldom used. The American Pharmacopeia (USP-40) only recognizes γ-CD as an excipient, although the FDA's inactive ingredients list also includes HPβCD and SBEβCD2. In view of the above, it is not advisable to use CDs not included in any of the mentioned pharmacopeias, even if their use may be referenced in the literature.

Furthermore, it should be mentioned that natural CDs (α-CD, β-CD and γ-CD) are included in the FDA's GRAS List as flavor stabilizers, which means they could be a valid alternative for masking the unpleasant taste of pediatric pharmaceutical formulations2. However it must be remembered that, as their water solubility is lower, they should be formulated as suspensions in these applications12. As mentioned above, when used in solution form, the formulations should be subject to stability studies.

Although their price has declined in the recent past, CDs are still expensive excipients. The relatively high costs associated to the use of CDs in extemporaneous preparations, combined with the need to perform frequent quality control tests as a result of the variability across different manufacturers, and even batches from the same manufacturer, for one same cyclodextrin, and the exhaustive pharmaceutical validations that must be carried out of the formulations prepared, require an increased time investment by the compounding laboratory staff. If we add to this the fact that it is at times necessary to include some extra excipient to the extemporaneous preparation in order to boost its complexation efficiency, it is clear that the cost of the formulation may experience a substantial increase40.

On the other hand, the impossibility to access these components through the usual vendors included in the Spanish Unified Registry of Active Substance Providers (RUESA) constitutes a significant impediment to acquiring these raw materials. The Registry only includes HPβCD, added in 2021. Its indications are parentally-administered drugs and treatment of Niemann-Pick disease, for which it has been designated an “orphan drug”41. This means that if a decision was made to incorporate a different cyclodextrin to a routinely-formulated extemporaneous preparation it would be necessary to resort to non-RUESA approved vendors, which would involve a preliminary risk analysis of the CD synthesis procedure implemented by such vendors and an evaluation of the quality assurance systems they apply, in accordance with Guidelines 2015/C 95/02 of 19th March 2015 on the formal risk evaluation required to ensure the appropriateness of the practices followed to manufacture excipients employed in medicines for human use42.