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Drug Delivery Technology Selection

The challenge was to develop an intravenous product capable of delivering 5-gram intravenous doses of a compound with an aqueous solubility of less than 100 ng/mL.  Technologies considered included cosolvents, complexation, prodrugs, and nanoparticle dispersions.  Multiple advantages were seen in aqueous nanoparticle dispersions.  Preliminary composition and process experiments evaluated phospholipid, bile-salt, and synthetic surfactants using Microfluidics high-pressure homogenization.  Subsequent experiments optimized a phospholipid formulation and Microfluidizer operating parameters.  Supplies were manufactured for IND-enabling toxicology studies.  The product is currently in Phase 2 clinical trials. 


Natural Product Surfactants

Certain diterpene glycosides have been found to be effective solubilizers of hydrophobic compounds.  Hightower advised the university tech transfer office on pharmaceutical market opportunities and was then engaged by the commercial spin-off to direct mechanistic investigations of the natural-product surfactants.

Oral Lipid Formulation Assessment

Reviewed data describing solubility and mouse oral bioavailability of hydrophobic new chemical entity in triglycerides and surfactants and recommended advancement of one of the triglyceride solutions.  Found and critically reviewed relevant research elucidating reactivity of core structure of the API, suggesting susceptibility to oxidation which was confirmed by experiments.  Drafted CMC section of pre-IND briefing package.

Multicomponent Dietary Supplement Formulation

Was engaged by a dietary-supplement marketing organization with limited laboratory resources to lead formulation-development activities for a proposed product composed of multiple herbal extracts.  The water solubility of the ingredient phytochemicals ranged from high to very low.  Experiments were conducted using visual observation of the dispersability of candidate formulations in water.  The selected composition included extract solids, medium-chain triglyceride oil to dissolve the hydrophobic components, and lecithin and was filled into soft-gelatin capsules.

Development and Characterization of an Electronic Nicotine Delivery System (ENDS, aka Electronic Cigarette) for Clinical Research

Under contract from the National Institute on Drug Abuse (NIDA) and in collaboration with a design engineering firm developed and characterized a standardized electronic nicotine delivery system (ENDS) for use in electronic cigarette clinical research.  Investigated the influence of hardware design, nicotine-containing liquid (e-liquid) composition, and power-control parameters on the delivery of nicotine and harmful and potentially harmful constituents (HPHCs).  Monitored the stability of the e-liquid in the packaged assembly.  Prepared a drug-device combination product Drug Master File (DMF) in Common Technical Document (CTD) format for reference by investigator-initiated Investigational New Drug (IND) applications.




Qualification of Generic-Product Impurity

Crafted an argument used in a successful qualification of a generic drug product impurity at a level higher than that found in the reference listed drug (RLD) by prediction of the impurity’s inevitable existence as a “significant metabolite” after dosing of the RLD.  This argument was based on analyses of various published nonenzymatic temperature and pH rate data (including those of a structurally related molecule) predicting significant formation of the impurity at body temperature and gastric pH, and on the analyses of various quantitative human metabolic data describing the formation in serum of an analogous metabolite of a structurally related endogenous substance.

Remediation of Medical Device Extractables and Leachables Analytical Methods Deficiency

The manufacturer of an implantable medical device received a deficiency letter in response to their IDE filing: quantitative analytical methods used in ISO-10993 biocompatibility studies were judged to be inadequately sensitive and specific to determine expected polymer degradation products.  Suitably specific and sensitive analytical methods were developed, validated, and applied to extractables and leachables testing demonstrating, to the satisfaction of the FDA, that the flag impurities were not present above the lower limits of detection.

Qualification of a Manufacturing-Process Change for the Polymer Component of an Implantable Medical Device

The manufacturer of an implantable medical device developed more efficient processes for the thermoforming of a polymer component.  New extractables and leachables studies, compliant with ISO-10993, were conducted and reported with a critical review of the thermal degradation chemistry of the polymer and combined with a toxicology opinion in an FDA-accepted argument for an absence of safety issues associated with the manufacturing changes.

Patent Litigation

Was engaged by plaintiff's counsel as a testifying expert witness in three related intravenous formulation patent infringement lawsuits.  Provided counsel and the court with an understanding of relevant physicochemical and biological properties of the formulations at issue.  Opined on issues of claim construction, obviousness, and infringement in nine declarations and three depositions.

Drug Product Licensing Dispute

Was engaged by defendant's counsel as a testifying expert in a drug-product licensing lawsuit in which the licensor sued for breach of contract when the licensee terminated the development of the licensed drug.  Disputed issues included the value of the prior development work performed by the licensor on an oral extended-release formulation of the very water-soluble drug.  Reviewed several years of licensor's records describing significant difficulties in formulation and manufacturing-process development and opined on probability of eventual regulatory success.

Delivery Technology

Selected Examples of Our Work

FDA Responses
Litigation Support
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