EXECUTIVE INTERVIEW - Ligand: Effective Drug Delivery Solutions With Captisol

Ligand owned, Captisol® is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Captisol was invented and initially developed by scientists in the laboratories of Dr. Valentino Stella at the University of Kansas’ Higuchi Biosciences Center for specific use in drug development and formulation. Captisol has enabled six FDA-approved products, including Onyx Pharmaceuticals’ Kyprolis®, Baxter International’s Nexterone®, and Pfizer’s Vfend® I.V. There are currently more than 30 Captisol-enabled products in development, including Lundbeck’s I.V. Carbamazepine, Merck’s I.V. posaconazole, and Rib-X’s delafloxacin intravenous program. Ligand’s Senior Director of Technical Operations and Quality Assurance, Vincent D. Antle, PhD, and James D. Pipkin, PhD, Senior Director, New Product Development recently spoke with Drug Development & Delivery about how the company works closely with pharmaceutical and biotechnology companies offering drug delivery solutions that significantly improve stability, solubility, bioavailability, safety, and dosing of APIs.

Q: For our readers who may be unfamiliar with your delivery technology, can you please review Captisol?

A: Captisol is a unique reproducible mixture of polyanionic β-cyclodextrin derivatives in which a sodium sulfonate salt is tethered to the lipophilic cyclodextrin cavity by a butyl ether group, or sulfobutylether (SBE). The sulfobutyl ether (SBE) substituent is introduced at the 2, 3, and 6 positions in one or more of the glucopyranose units in the cyclodextrin structure. The introduction of SBE substituents onto the β-cyclodextrin can produce preparations with different overall average degrees of substitution due to the proportion of multiple species present with different degrees of substitution, theoretically from 1 to 21 sites for substitution. Captisol, with on average 7 such SBE substituents per β-cyclodextrin, introduced by way of a reproducible patent-protected process, was chosen as the cyclodextrin preparation with the most desirable safety profile and drug association properties.

Q: What are the applications of Captisol in drug delivery?

A: Captisol may be applied in drug delivery in many ways. The primary applications are to enhance solubility and stability. Solubility increases of tens of thousand are possible, and when combined with pH and selected salts, solubility increases of hundreds of thousands have been observed.

Stability outcomes may not always be predictable, but when they are observed they can range from protecting from precipitation or photolytic degradation to significantly improving hydrolytic stability and taking a refrigerated drug product to room temperature storage or increasing the time for 10% loss from a few weeks to a few years.

Efficacy and safety can be affected. Enhanced solubility and stability translate into enhancement of efficacy via increased dissolution rate or solubility in the lower GI, leading to greater and faster absorption, bioavailability, and more rapid onset of action. These effects mean that dosing regimens can be optimized to intensify dosing via higher available concentrations or longer infusions.

Greater bioavailability also means a lesser dose may provide the same efficacy and thus there is the potential to reduce the body’s total exposure to a drug and maximize benefit to risk. Ligand has used Captisol to reformulate existing products that contain solvents with undesirable sideeffects and thereby unburden those products. One example is amiodarone, available for injection as a concentrate in polysorbate 80 with benzyl alcohol that requires dilution prior to administration. A marketed Captisol reformulated product, Nexterone, in a ready-to-use bag enables this product to be used in the emergency, life-saving setting, without the cardio side effects from the original vehicle and permit accurate dosing without foaming and drugloss to plastic.

Captisol has been applied in all routes of administration including parenteral routes, oral, ophthalmic, nasal, inhalation, and dermal topical routes.

Q: Does Captisol have utility in the formulation of oral dosage forms?

A: Yes. From the beginning, Captisol hasbeen studied for oral delivery. Hundreds of articles and patents citing use have been published. The Type V Drug Master File for Captisol on file with the FDA contains oral preclinical data out to 1 year and has supported IND Safety submissions and clinical trials. Captisol has been used in dozens of clinical trials, where it was associated with a drug product administered by the oral route.

Although no oral products are yet on the market with Captisol, several orally administered Captisol‐enabled® products are in active development. Many customers have or are running clinical trials with oral products. Use of Captisol in orally administered products has been shown toimprove solubility and availability of basic compounds in the lower gastrointestinal tract, provide taste-masking, and eliminate variability in bioavailability due to food effects.

Q: How has Captisol been utilized in GLP toxicology studies? What role does it play in formulation development within toxicology?

A: Being a proven solubilizing and stabilizing technology designed to overcome various formulation challenges and having a proven safety record, Captisol has enabled increased systemic exposure for toxicology studies of investigative compounds and has been shown to beneficially interact with a large range of compounds. Captisol and the investigative compound may form a complex that results in greatly enhanced aqueous solubility and allows high exposures within animal dosing constraints. The formulations are suitable for both parenteral and non-parenteral routes of administration. It has also been extensively characterized in acute and chronic GLP toxicology studies. A large database characterizing Captisol effects in numerous species has been assembled and updated annually.

Captisol has an excellent clinical safety record and is currently being used as an excipient in multiple FDA-approved prescription drugs (eg, Nexterone®, Abilify®, Kyprolis®, Geodon®, and VFend®). Captisol-enabled products have been approved in more than 50 countries, and formulations in early development can lead to a seamless transition from non-clinical safety to clinical trials.

Q: What is the safety profile of Captisol as it pertains to human risk?

A: Captisol was designed for improved safety over the parent underivatized β- cyclodextrin and to extend and enhance beneficial properties while removing deleterious renal effects ascribed to native β-cyclodextrin. For Captisol, there were minor reversible histological changes observed in high-dose animal studies, but there were no significant hematological changes, ie, red blood cell damage and alteration in serum lipids, as ascribed to hydroxypropyl β-cyclodextrin.

No adverse effects were observed in human studies. Because it is renally eliminated, accumulation has been observed in some renal impaired subjects, but without any evidence of renal functional loss. In animal models, the use of Captisol has been reported to protect against renal damage due to renal toxic agents, such as methotrexate and iodinated radiopaque contrast agents. Captisol is used across a variety of therapeutic classes: CNS, cardiovascular, anti-infectives, and oncology.

Q: How has Captisol been used in ophthalmic drug delivery? What is its effect on the stability and solubility for ocular drug delivery?

A: Preclinical safety data on Captisol administered topically to the eye sufficient to enable clinical studies are included in the Type V Drug Master File on file at the FDA. Included are ophthalmic exposure studies in rabbits up to 6 months and in dogs up to 1 year. In addition, ophthalmic use of Captisol in humans studied up to 6 months has been reported. Cytotoxicity of Captisol was judged similar to that of hydroxypropyl β-cyclodextrin in an immortalized human corneal epithelial cell line. Allergan has reported Captisol as a retinal compatible material. Captisol was reported to reduce irritation of topically administered pilocarpine prodrug.

Investigators reported success in formulating lipophilic water-insoluble drugs as aqueous eye drop solutions by using cyclodextrin complexation. They further explain that the ocular barrier to topical drug delivery into the eye consists of the aqueous tear film and lipophilic epithelium, and most drugs permeate this barrier via passive diffusion.

Cyclodextrins enhance permeation of lipophilic drugs through the aqueous tear film to the epithelial surface, increasing drug availability immediate to the lipophilic membrane surface. As in other settings, it is important to recognize when cyclodextrins are appropriate and to use an appropriate amount.

In addition, Captisol may be added to other platforms, including drug-eluting PLGA fibers, eg, SBECD ciprofloxacin. It may also be used as an additive to solubilize drugs in intraocular implants and can stabilize active agent retention in liposomes. Supersaturated Captisol-based solutions of pazopanib at many thousandsfold, its native solubility have been described as an eye drop dosage form.

Q: What are some of the considerations in the methods to enhancing the complexation efficiency?

A: It is sometimes desirable to find ways to extend the benefit derived from cyclodextrins without adding more cyclodextrin or minimize the cyclodextrin content in a product. Sometimes this is due to sheer bulk, cost, or physic- chemical constraints, such as viscosity, osmolality, or volumetric size.

Many methods have been reported to enhance complexation efficiency. As previously described in the case of ziprasidone, salt formation resulted in significant improvement. Heat and ionization played important roles in formulating amiodarone as well as the drug’s own aggregation or self surfactant-like property.

Captisol, by virtue of carrying a negative charge, electrostatically attracts positively charged drugs. Hence, in addition to the host-guest mode of interaction, Captisol interacts more favorably with ionized basic compounds (a large proportion of drugs fall into this category) than neutral cyclodextrins, such as either the native cyclodextrins, alkyl or hydroxypropyl substituted cyclodextrins.

Q: What are some of the problems associated with delivery that Captisol has solved?

A: Captisol has been used to address numerous delivery issues. It has enabled parenteral dosage forms where none existed prior. Reformulation in which Captisol replaces co-solvent systems also removes their associated side effects, including phlebitis or injection site irritation, and protects against precipitation upon dilution and allows compatibility with alternative packaging to allow direct injection of concentrate or provide ready-to-use diluted presentation.

Enabling an injection where none existed or converting a suspension to solution has allowed rapid onset of activity as well as increased availability and efficacy or equal efficacy at a reduced dose.

Captisol incorporated into an oral dosage form was shown to minimize bioavailability variability due to food effects and provide taste-masked oral solution. It has also enabled a combination of actives and enabled a cold-chain product to now be used at room temperature.

Q: What is the range of binding affinity of Captisol in formulations?

A: The substituent (sulfobutylether) that defines Captisol is negatively charged throughout the physiological pH range. In general, complexation with Captisol outperforms that with just β-cyclodextrin and in almost all cases, leads to only soluble complexes. For neutral molecules and ionized acids (negatively charged species), it is not preordained which cyclodextrin, hydroxypropyl or sulfobutyl ether, provides greater affinity. On the other hand, positively charged drugs tend to demonstrate greater affinity for Captisol.

In general, complexation stability constants for the equilibrium range from a few hundred (102) to several 100,000 (105) M-1. It is very rare, but there have been complexation constants reported into the several million (106) M-1 for synthetic ozonide anti-malarials with an adamantine structure.

More importantly, what does high affinity mean? In some cases, solubility has been enhanced 50,000- or more than 100,000-fold or stability significantly improved from days or months to years. Even interactions characterized by stability constants less than 100 M-1 can produce desirable solubility and stability benefits.

Q: Where and by whom is Captisol manufactured and to what standard is it manufactured?

A: The modified β-cyclodextrin, sold under the name Captisol has successfully enabled six FDA-approved parenteral products along with numerous other parenteral products in late-stage development. Categorized as a functional excipient, Captisol is supported by Type IV and Type V (over 60 volumes) Drug Master Files in the US and a Type III DMF with Health Canada. It is manufactured under cGMP through an exclusive contract with Hovione FarmaCiencia SA on a multiple metric ton scale. For more than a decade now, Captisol has been commercially available and manufactured via patented processes and now incorporates additional patented processes that have improved its purity and morphology. In 2012, a USP NF monograph was approved for Captisol, Betadex Sulfobutyl Ether Sodium, which further defined microbial and endotoxin limits as well and Captisol substitution distribution or fingerprint.