We have read Ramos Martinez et al.’s interesting review article1, which mistakenly concludes that the introduction of cyclodextrins is not a viable alternative for their use in extemporaneous formulations.

First of all, the authors point to the complexity inherent in selecting cyclodextrins to be incorporated in an extemporaneous formulation. Numerous cyclodextrin-based compounds have been described in the literature, with their own routes of administration, safety profiles and physical compositions, conceived for different kinds of extemporaneous formulations (liquid, semisolid or solid)2. Pharmacists are not mere transcribers of already developed formulas; our role is to find, select and interpret the published scientific knowledge indispensable for preparing new extemporaneous formulations. This is the only way in which scientific advancement and innovation are possible in these areas.

At the same time, it is not true that there is great variability across the different suppliers and batches. There are of course differences regarding the degree of substitution, in the same way as there are differences between polymers or macromolecules with different molecular weights, or with different degrees of crosslinking. Polyethylene glycol 300 does not behave in the same way as polyethylene glycol 50,000, nor does low-molecular weight hyaluronic acid with is proinflammatory effect behave in the same way as high-molecular weight hyaluronic acid with its anti-inflammatory properties. If we opt for a variety with a certain degree of substitution we shall not observe any variety beyond the ones present in any pharmaceutical excipient3.

In addition, the statement on the “high complexity required for preparing inclusion compounds” is not correct. Preparing the majority of inclusion compounds in solution is as easy as dissolving the corresponding cyclodextrin, and then the active ingredient, at the desired concentration. This was shown by the authors of this letter in the research they published on the subject, all of it implemented in galenics and in clinical practice4.

Another striking aspect about the review article discussed here is a comment it makes on the potential change in the bioavailability of the drug as a result of the use of cyclodextrins. However, it is obvious that any hydrosolubilization technique, using either cyclodextrins or other methods used in extemporaneous formulations (pH changes or the use of co-solvents), will result in increased bioavailability. Moreover, the review indicates that cyclodextrins may increase membrane patency, with an ensuing increase in bioavailability. Again, this is not observed only in cyclodextrins: surfactants may also modify the dermal, nasal or ocular patency of many drugs. Moreover, co-solvents such as polyethylene gycols, propylene glycol or even ethanol may also modify the lipid layer of the skin or the mucosae as well as inhibit the Pgp efflux system and the action of cytochromes related with the metabolization of active ingredients in the gut and in the liver. All of them are used in extemporaneous formulations5.

Lastly, the argument that the use of cyclodextrins increases the cost of extemporaneous formulations does not hold together. A case in point is that of a recent development by the authors of this letter with a tacrolimus-based eye drop formulation solubilized with hydroxypropyl-β-cyclodextrin. Addition of cyclodextrin not only resulted in an improvement at galenic level, increasing the compound's tolerability (by making it unnecessary to use irritating excipients) and biopermanence on the ocular surface, but also allowed annual savings of €9,000 as a result of using tacrolimus as an active ingredient instead of the usual intravenous formulation. Given its higher efficiency, this new development has been incorporated to the formulary of the pharmacy department4.

There are many aspects of extemporaneous formulations that require further improvement. However, adopting a negative approach to the aspects currently backed by the largest body of evidence may not be the most appropriate strategy to allow the development of this activity. Rejecting the latest advances in the field of extemporaneous formulations would send us back to the era of alchemy.

For all the reasons above, we cannot agree with the conclusions drawn in the review article discussed.

Beatriz Ramos-Martínez’, Carmela Dávila-Pousa2, Vicente Merino-Bohórquez3, Marta García-Palomo4, M.ª Pilar Flox-Benítez5

• 1

  Pharmacy Department, Hospital Universitario de la Princesa, Madrid. Spain. Galenics Working Group of the Spanish Society of Hospital Pharmacists (former resident).

• 2

  Pharmacy Deportment, Complexo Hospitolorio Universitario de Pontevedra, Pontevedra. Spain. Galenics Working Group of the Spanish Society of Hospital Pharmacists.

• 3

  Pharmacy Department, Hospital Universitario Virgen Macarena, Sevilla. Spain. Galenics Working Group of the Spanish Society of Hospital Pharmacists.

• 4

  Pharmacy Department, Hospital Virgen de la Salud, Toledo. Spain. Galenics Working Group of the Spanish Society of Hospital Pharmacists.

• 5

  Pharmacy Department, Hospital Universitario Santa Cristina, Madrid. Spain. Galenics Working Group of the Spanish Society of Hospital Pharmacists.