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Captisol is an inactive pharmaceutical ingredient that greatly improves the solubility and stability of an interacting molecule, such as an active agent. Captisol^® is a polyanionic β-cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group, aka sulfobutylether (SBE) group. Cyclodextrins are a group of cyclic oligosaccharides (cyclic oligomers of glucose) produced from starch. These cyclodextrins have a torus-like shape with a hydrophilic outer surface and a less hydrophilic inner surface. Because of this special architecture, cyclodextrins are soluble in water and can simultaneously host lipophilic guest molecules or portions of larger molecules. 

The sulfobutyl ether groups in Captisol impart exceptional solubility and parenteral safety to this modified cyclodextrin.

Cyclodextrins improve solubility and stability by forming water soluble host-guest inclusion complexes whereby the hydrophobic portion of the molecule (guest) will interact with the cavity of the cyclodextrin (host). These complexes are a result of reversible, non-covalent interactions that can include hydrogen bonding, hydrophobic interactions, and Van der Waal’s forces. In addition, to complexation, other interactions may occur with other parts of the cyclodextrin molecule.  The negative charges on sulfobutyl ether groups of Captisol allows for additional ionic interactions such as acid salt formation like with other sulfonic acids.

For many molecules, these interactions can hide hydrophobic functional groups to improve aqueous solubility or they can protect a part of a molecule that is prone to degradation. Many molecules that have poor solubility or stability characteristics have been prepared with Captisol to overcome these properties.

There are moieties that are known to fit well into the beta cyclodextrin cavity. These include groups such as adamantane, aryls such as phenyl, fused aromatic rings, etc. However, there have been many unexpected interactions as well.  Examples include straight and branched chain low MW alcohols and counterions. Ionic interactions with negatively charged sulfobutyl ether groups is another handle with which molecules may interact and therefore be aided by Captisol.  Furthermore, the pKa of the molecule of interest may be manipulated to enhance ionic interactions and overall solubility.

The best way to evaluate whether your molecule’s solubility will be helped by Captisol is to perform a few basic experiments. Click here to see the solubility procedure for Captisol Powder or Captisol 40% Solution.

Other techniques can be employed to determine if your molecule will interact with Captisol. These include NMR, circular dichroism, UV spectroscopy, isothermal calorimetry and many others. To assess whether stability is improved, stress challenge a formulation with Captisol and without Captisol (a control) and analyze for loss of active or growth of impurities.

Complexation and desirable interactions can occur between Captisol and peptides/proteins through the side chains of individual amino acids. The complexation can assist in solubilization, stabilization, particularly in terms of reduced aggregation, and refolding, which can lead to improved bioavailability.

Cyclodextrins can also improve the effectiveness of antisense therapies by assisting in cellular uptake, internalization, nuclease resistance, improved activity, and reduced side effects (References available).

Captisol has been in FDA-approved products since 2002. As of mid-year 2024, there are 15 unique Captisol-enabled products approved by the FDA and one additional unique product approved by the Japanese Ministry of Health (Pmda). Many of the FDA approved drug products have been accepted internationally. Drug Master Files (DMFs) are established in the United States, the Type IV Captisol Chemistry, Manufacturing and Controls (CMC) and Type V Captisol Safety Studies.  Additionally, CMC DMFs are available in Canada, China and Japan and a technical dossier is available to support regulatory submissions where excipient DMFs aren’t established. USP-NF, BP and EP monographs exist for Captisol under the names Betadex Sulfobutyl Ether Sodium and Sulfobutylbetadex sodium respectively. Captisol is a well-established globally accepted excipient. For just one product, VEKLURY® (remdesivir), more than 600 Metric Tons of Captisol supplied to treat greater than 13 million patients in more than 170 countries.

The amount of Captisol that can be given in preclinical studies depends on many factors. These factors include animal  species, route of administration, rate of administration (i.e., slow infusion or bolus for parenteral route), and dosing duration (references available). Captisol has been investigated in more than 175 preclinical safety studies in the Type V DMF. 

Approved products containing Captisol include parenteral and oral routes of administration. NDA submissions of products containing Captisol by other routes of administration are under review. These new products include subcutaneous infusion and ophthalmically administered products. Clinically and preclinically, Captisol has been given by parenteral, oral, ophthalmic, nasal, inhalation and topical routes.

The pH of a solution has the potential to effect complexation of a molecule with Captisol in several ways. If the molecule has one or more ionizable functionalities, altering the pH will affect the extent of ionization of the compound. In general, complexation of molecules with cyclodextrins is strongest when the compounds are uncharged. However, since Captisol is negatively charged at all relevant pH values, the presence of a positive charge on the molecule can assist complexation via charge attraction (ionic interaction).

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