History of Solutol HS15

In the 1990s, the use of then novel excipients, polyoxyl 35 castor oil NF (Cremophor EL, BASF) and polyoxyl 40 hydrogenated castor oil NF (Cremophor RH 40, BASF) for solubilization and consequent bioavailability of poorly soluble active pharmaceutical ingredients (APIs) for improved efficacy, enabled drug development for cancer (e.g., BMS' Taxol [paclitaxel]) and AIDS (e.g., Abbott's Norvir, Kaletra). However, Cremophor produced slightly elevated histamine levels in dog studies. To help overcome this challenge, a new product was developed in 1992 whereby castor oil was replaced with 12- hydroxystearic acid and reacted with polyethylene glycol 30 resulting in a new excipient called Solutol HS15 (polyglycol mono- and di-esters of 12-hydroxystearic acid with about 30% polyethylene glycol, BASF). Solutol HS15 has been shown to be safe in various animal toxicity models with reduced histamine levels compared with Cremophor. Solutol HS15 has been approved in Canada and Argentina in marketed injectable-drug products. In the US, a drug master file for Solutol HS15 was filed with FDA in January 1992. However, it has not been used in any commercial product and thus is not listed in the FDA IIG. In the US, Solutol HS15 is therefore still classified as a novel excipient.

Solutol as a compound-enabling excipient. The drug-development group at Wyeth, now part of Pfizer, found Solutol HS15 to be an excellent solubilizerfor liquid-filled capsules for a series of NMEs with a new mechanism of action (10). Wyeth also found that Solutol HS15, in combination with other solubilizers, provided excellent solubility for their poorly soluble NME candidates with water solubility below high-performance liquid chromatography (HPLC) detection limits of 20 ng/mL. This developmental drug by itself is not orally bioavailable and the oral potency was affected using solution formulation containing phospholipids. Preclinical studies utilize a phospholipids formulation, which affords a slower absorption profile with delayed Cmax (maximum plasma concentration). A great bioavailability improvement with a fast absorption rate was seen with the formulation containing Solutol HS15 compared with other formulations during formulation screening studies in animals. Wyeth used the Solutol HS15 formulation in its first-in-human formulation and subsequently completed two Phase I clinical studies on one API—an ascending single dose study (SAD) conducted in healthy subjects and an ascending multiple dose study (MAD) conducted in healthy subjects. In a Phase II proof-of-concept (POC) study with 6 weeks dosing, an endoscopic examination (7 days gastrointestinal safety study) was performed after 5 capsules of the placebo and active were dosed. No adverse events were reported in the 12 patients dosed. Overall, the adverse-event profile showed that a single oral dose of up to 10 capsules of the Wyeth formulation containing 150 mg Solutol HS15/Capsule is generally safe and well tolerated.

IPEC–Americas has explored for years better ways to enable novel excipients to enter the market. After extensive internal discussions with the manufacturers and user members of IPEC–Americas, and with FDA, IPEC–Americas presented a proposal in August 2005 for an independent evaluation of novel excipients and FDA review following an independent expert evaluation. FDA agreed to review the first excipient-safety evaluation performed by a panel of experts for consistency with FDA safety-evaluation procedures. Between 2005 and 2007, the IPEC Safety Committee convened a panel which developed the IPEC Novel Excipient Safety Evaluation Procedure, as previously mentioned, and solicited the first submission for a novel excipient for the expert evaluation and review by FDA (10).

FDA review

Solutol HS15 is presented as the first case study to illustrate an excipient supplier (BASF)/user (Wyeth) collaborative effort to facilitate a safety review by FDA under the IPEC safety evaluation program. In 2007, the IPEC–Americas Safety Committee Chair approached Wyeth R&D who then contracted BASF to consider Solutol HS15 solubilizer for review by FDA.

With promising results from Phase I and II human clinical trials of a solid oral dosage formulation containing Solutol HS15 described above, Wyeth was considering ways to obtain an FDA safety review of of Solutol HS15 before embarking on a large-scale Phase III human clinical trial. In that context, Wyeth decided to provide Phase I and II Solutol HS15 related information to the agency as a part of the IPEC safety evaluation program. With Wyeth's encouragement, BASF's management volunteered to submit Solutol HS15 to the IPEC Novel Excipient Safety Evaluation Procedure.

As defined in the IPEC Novel Excipient Safety Evaluation Procedure, BASF entered into a confidentiality agreement with Aclairo Pharmaceutical Development Group (PDG) to develop an independent expert safety evaluation of Solutol HS15, led by Robert Osterberg, PhD, a distinguished scientist in pharmacology/toxicology. BASF submitted a package of information about Solutol HS15 to PDG containing the following safety and chemistry information: technical data containing a summary of chemistry, manufacturing, and controls (CMC); the company's safety expert report on Solutol HS15; reports of all acute, subchronic, reproductive, and genotoxicity studies; a safety evaluation assessment report that had been conducted by EMA; a safety expert report of a related BASF solubilizer excipient (Cremophor); the FDA IIG information regarding use of Cremophor in 15 FDA-approved drugs; and a list of other excipients with related chemistries derived from the FDA IIG. The package also included a cover letter requesting that PDG evaluate the information submitted and provide an independent safety evaluation for Solutol HS15 to BASF.

Under a separate confidentiality agreement with PDG, Wyeth submitted Phase I and Phase II human clinical trial solid oral-drug information relevant to Solutol HS15. PDG conducted an independent safety assessment using three distinguished toxicologists and issued its evaluation.

BASF then submitted a package to the IPEC–Americas Safety Committee Chair including: a cover letter requesting review and consideration for submission to FDA under the IPEC Novel Excipient Safety Evaluation Procedure, the PDG documents, and the same documents originally submitted to PDG as noted above. IPEC forwarded BASF's submission to FDA, and the agency sent its review letter back to the IPEC safety committee chair who then informed BASF, Wyeth, and PDG of the agency's findings (11–13).