Proprietary Drug Research Articles

Human Cytochrome P450 Biocatalysts for the Facile Synthesis of Metabolites

Characterizing the human P450 metabolism of potential drug candidates requires considerable effort, due to the instability and poor activity levels of commercially available human cytochrome enzymes. The investigator can choose from many sources: pooled human liver microsomes, recombinant microsomes, or purified recombinant P450s. These forms have their limitations -- poor stability, troublesome reconstitution, and high cost. Using these formulations to generate milligram levels of P450 metabolites would be inefficient and prohibitively expensive. To address these limitations, we have developed Human Cytochrome Biocatalysts that can produce preparatively useful levels of metabolite. Each freeze-dried biocatalyst product incorporates both the P450 and human P450 reductase into a fully functional catalytic system. The corresponding dry Reaction Buffer Mix contains NADPH cofactor, a cofactor recycling system, and stabilizers that improve both the activity and stability of the cytochrome during the reaction. To run a reaction, simply reconstitute with water and add the drug to be metabolized. In most cases, metabolite yields approaching 100% are possible. Using testosterone hydroxylation as a test case, Human Cytochrome Biocatalyst 3A4 converted greater than 70% of the 100 mg testosterone starting material into 40 mg 6β-hydroxytestosterone (34 mg isolated yield following extraction and flash chromatography) and 40 mg other hydroxylated metabolites. A proprietary drug candidate with unknown P450 metabolism was successfully screened against the Human Cytochrome Biocatalysts. Three metabolites were identified, and the reactions were scaled up to deliver at least 100 μg of each metabolite, purified by preparative HPLC, for structure determination by NMR.

Direct Design of Pharmaceutical Antisolvent Crystallization through Concentration Control

Recent advances in in situ measurement technology and automation of batch crystallizers have enabled the development of batch crystallization recipes in which the desired supersaturation profile is followed by feedback control. This paper describes a new approach for following supersaturation setpoints for antisolvent crystallizations that is easy to implement for the tried crystallization. Simulations and application to a proprietary drug compound demonstrate how this combination of automation and in process measurements enables the rapid development of batch crystallization processes in the pharmaceutical industry.

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Advantages of atmospheric pressure photoionization mass spectrometry in support of drug discovery

The performance of the atmospheric pressure photoionization (APPI) technique was evaluated against five sets of standards and drug-like compounds and compared to atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI). The APPI technique was first used to analyze a set of 86 drug standards with diverse structures and polarities with a 100% detection rate. More detailed studies were then performed for another three sets of both drug standards and proprietary drug candidates. All 60 test compounds in these three sets were detected by APPI with an overall higher ionization efficiency than either APCI or ESI. Most of the non-polar compounds in these three sets were not ionized by APCI or ESI. Analysis of a final set of 201 Wyeth proprietary drug candidates by APPI, APCI and ESI provided an additional comparison of the ionization techniques. The detection rates in positive ion mode were 94% for APPI, 84% for APCI, and 84% for ESI. Combining positive and negative ion mode detection, APPI detected 98% of the compounds, while APCI and ESI detected 91%, respectively. This analysis shows that APPI is a valuable tool for day-to-day usage in a pharmaceutical company setting because it is able to successfully ionize more compounds, with greater structural diversity, than the other two ionization techniques. Consequently, APPI could be considered a more universal ionization method, and therefore has great potential in high-throughput drug discovery especially for open access liquid chromatography/mass spectrometry (LC/MS) applications.

Safety advisory group gets mixed marks from members

The FDA Drug Safety and Risk Management Advisory Committee is expected in February to meet for only the sixth time since the agency changed the group’s name in mid-2002 from the Drug Abuse Advisory Committee and recruited members from an unconnected subcommittee. At the time of the name change, FDA declared that the committee’s function was to advise the agency about risk-management plans, active surveillance methods, trademark studies, methods for risk-management communication, and related issues. Of the 13 advisory committee members, 4 are registered pharmacists: Michael R. Cohen, president of the Institute for Safe Medication Practices; Stephanie Y. Crawford, an associate professor at the University of Illinois at Chicago College of Pharmacy; Eleanor Gomez-Fein, patient care coordinator for trauma and critical care services at Jackson Memorial Hospital in Miami, Florida; and Henri R. Manasse Jr., executive vice president of ASHP. The five meetings convened by FDA so far have elicited advice on consumer medication information, look-alike and sound-alike proprietary drug names, the labeling of low-density polyethylene (LDPE) plastic containers, and the risk-management programs for alosetron, isotretinoin, and the yet-to-be-marketed oral formulation of tazarotene, a teratogenic treatment for psoriasis.

West Pharmaceutical Services, Inc.

Mergent's Dividend AchieversVolume 2, Issue 2 p. 306-306 U.S. Company Report West Pharmaceutical Services, Inc.† First published: 22 April 2005 https://doi.org/10.1002/div.2477 † Contact: : Donald E. Morel Jr. — Chmn., Pres., C.E.O. Address: : 101 Gordon Drive, P.O. Box 645, Lionville, PA 9341-0645 Web Site: : www.westpharma.com AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Rubber Products (MIC: 11.6 SIC: 069 NAIC: 26299) West Pharmaceutical Services provides closure systems and components, primarily for use with parenterally administered drugs, and conducts research and development of proprietary drug formulation and delivery technology for nasal and targeted oral delivery of drugs. Operations are divided into two segments. The pharmaceutical systems segment designs, manufactures and sells stoppers, closures, medical device components and assemblies made from elastomers, metals and plastics and provides contract laboratory services for testing drug packaging. The drug delivery systems segment identifies and develops products using Co.'s proprietary drug delivery technology. Volume2, Issue2Spring 2005Pages 306-306 RelatedInformation

Identification of Fmoc‐β‐Ala‐OH and Fmoc‐β‐Ala‐amino acid‐OH as new impurities in Fmoc‐protected amino acid derivatives*

During the manufacture of a proprietary peptide drug substance a new impurity appeared unexpectedly. Investigation of its chemical structure established the impurity as a beta-Ala insertion mutant of the mother peptide. The source of the beta-Ala was identified as contamination of the Fmoc-Ala-OH raw material with Fmoc-beta-Ala-Ala-OH. Further studies also demonstrated the presence of beta-Ala in other Fmoc-amino acids, particularly in Fmoc-Arg(Pbf)-OH. In this case, it was due to the presence of both Fmoc-beta-Ala-OH and Fmoc-beta-Ala-Arg(Pbf)-OH. It is concluded that beta-Ala contamination of Fmoc-amino acid derivatives is a general and hitherto unrecognized problem to suppliers of Fmoc-amino acid derivatives. The beta-Ala is often present as Fmoc-beta-Ala-OH and/or as a dipeptide, Fmoc-beta-Ala-amino acid-OH. In collaboration with the suppliers, new specifications were introduced, recognizing the presence of beta-Ala-related impurities in the raw materials and limiting them to acceptable levels. The implementation of these measures has essentially eliminated beta-Ala contamination as a problem in the manufacture of the drug substance.

Valuation and design of pharmaceutical R&D licensing deals

AbstractIn today's intensely competitive business environment, pharmaceutical companies are augmenting their product pipelines by both developing drugs on their own and in‐licensing proprietary compounds or drug discovery–related technologies from smaller biotechnology companies. In this work, the OptFolio model of pharmaceutical R&D portfolio management is extended to evaluate partnership opportunities as real options and determine the optimal timing and investment policy for proposed alliances in the face of technological and market uncertainties and budgetary restrictions. Licensing deals are modeled within a decision tree as a series of continuation/abandonment options for the pharmaceutical company, deciding at each stage of R&D whether to make a predetermined milestone payment to continue the alliance or terminate the alliance because of unfavorable market conditions and/or internal resource limitations. Results indicate that early stage alliances become more valuable as market uncertainty and the ability of pharmaceutical companies to enhance the value of the licensed drug increase because of the ability to control downside risk by the abandonment option. © 2004 American Institute of Chemical Engineers AIChE J, 51: 198–209, 2005

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Formulation substitution: A frequently overlooked variable in cardiovascular drug management

The excellent articles in this issue ofProgressin Cardiovascular Diseases have reviewed in detail several of the major categories of pharmacotherapeutic agents used in the modern treatment of cardiovascular disorders. Among other components of these reviews has been practical information concerning the selection of an agent among a class of drugs— how drugs in a category may differ from one another and how these differences may come into play in their practical application to patients. This article, in contrast, considers how the existence of varying formulations of a single agent, in the form of an innovator proprietary compound and its generic congeners, may also require consideration in the drug selection process. When the period of patent protection of a successful proprietary drug expires, it has be

Production and Storage of High-Density Chemical Microarrays

Chemical microarrays are applied by Graffinity as part of a proprietary drug discovery platform. Following you will find an overview of the Graffinity automated systems and processes for array production including: Production of Chemical Microarrays; Spotting of tagged compound; Endcapping of active ‘‘anchor’’-modules; Storage of chemical microarrays; Current system set-up. A specific focus is related to the results of the use of an automated storage device—the Kendro Cytomat 6002. Next to an optimized environmental control also the time and therefore cost saving issues are mentioned here.

Insulin inhalation: NN 1998.

Aradigm Corporation has developed an inhaled form of insulin using its proprietary AERx drug delivery system. The system uses liquid insulin that is converted into an aerosol containing very small particles (1-3 micro in diameter), and an electronic device suitable for either the rapid transfer of molecules of insulin into the bloodstream or localised delivery within the lung. The AERx insulin Diabetes Management System (iDMS), AERx iDMS, instructs the user on breathing technique to achieve the best results. Aradigm Corporation and Novo Nordisk have signed an agreement to jointly develop a pulmonary delivery system for insulin [AERx iDMS, NN 1998]. Under the terms of the agreement, Novo Nordisk has exclusive rights for worldwide marketing of any products resulting from the development programme. Aradigm Corporation will initially manufacture the product covered by the agreement, and in return will receive a share of the overall gross profits from Novo Nordisk's sales. Novo Nordisk will cover all development costs incurred by Aradigm Corporation while both parties will co-fund final development of the AERx device. Both companies will explore the possibilities of the AERx platform to deliver other compounds for the regulation of blood glucose levels. Additionally, the agreement gives Novo Nordisk an option to develop the technology for delivery of agents outside the diabetes area. In April 2001, Aradigm Corporation received a milestone payment from Novo Nordisk related to the completion of certain clinical and product development stages of the AERx drug delivery system. Profil, a CRO in Germany, is cooperating with Aradigm and Novo Nordisk in the development of inhaled insulin. Aradigm and Novo Nordisk initiated a pivotal phase III study with inhaled insulin formulation in September 2002. This 24-month, 300-patient trial is evaluating inhaled insulin in comparison with insulin aspart. Both medications will be given three times daily before meals in addition to basal insulin administered once or twice daily. In 2003, the US FDA adopted new GMP guidelines requiring sterile production of inhalation products and their devices. Novo Nordisk, therefore, will need to repeat phase III studies following device optimisation. These studies may begin at the end of 2004 and will include efficacy studies for 6-12 months and safety studies for up to 2 years (Lehman Brothers, Equity research, 7 August 2003). A phase IIb, 12-week clinical trial in 107 patients with type 2 diabetes was completed in the US. This trial was designed to compare the safety and efficacy of pulmonary insulin delivered via AERx iDMS, with intensified treatment with subcutaneous insulin administered at mealtimes. The results of the study positively compared pulmonary insulin with intensified subcutaneous insulin. Aradigm Corporation has a total of 85 patents pertaining to its proprietary AERx drug delivery system. Among those granted patents, 18 patents cover pulmonary insulin formulation including the method of patient breathing technique during pulmonary delivery of insulin. This patent guides patients on how to breathe in certain defined ways to achieve an effective amount and reproducibility of blood levels of insulin.

The Xyrem risk management program.

Sodium oxybate, also known as gamma-hydroxybutyric acid (GHB), was discovered in 1960 and has been described both as a therapeutic agent with high medical value and, more recently, a substance of abuse. The naturally occurring form of this drug is found in various body tissues but has been studied most extensively in the CNS where its possible function as a neurotransmitter continues to be studied. Sodium oxybate has been approved in different countries for such varied uses as general anaesthesia, the treatment of alcohol withdrawal and addiction, and, most recently, cataplexy associated with narcolepsy. During the 1980s, easy access to GHB-containing products led to various unapproved uses, including weight loss, bodybuilding and the treatment of sleeplessness, sometimes with serious long-term effects. The availability of these unapproved and unregulated forms of the drug led to GHB and its analogues being popularised as substances of abuse and subsequent notoriety as agents used in drug-facilitated sexual assault, or 'date rape', eventually leading to the prohibition of GHB sales in the US. Legal efforts to control the sale and distribution of GHB and its analogues nearly prevented the clinical development of sodium oxybate for narcolepsy in the US. However, following extensive discussions with a variety of interested parties, a satisfactory solution was devised, including legislative action and the development of the Xyrem Risk Management Program. Amendments to the US Controlled Substances Act made GHB a schedule I drug, but also contained provisions that allow US FDA-approved products to be placed under schedule III. This unique, bifurcated schedule for sodium oxybate/GHB allowed the clinical development of sodium oxybate to proceed and, in July 2002, it was approved by the FDA as an orphan drug for the treatment of cataplexy in patients with narcolepsy as Xyrem(sodium oxybate) oral solution. To promote the safe use of sodium oxybate, as well as alleviate concerns over possible diversion and abuse following product approval, a proprietary restricted drug distribution system was created, called the Xyrem Success Program. Components of the programme include a centralised distribution and dispensing system, a physician and patient registry, compulsory educational materials for patients and physicians, a specially trained pharmacy staff, a method for tracking prescription shipments, and an initial post-marketing surveillance programme. The system has created a unique opportunity to provide both physician and patient education and ongoing patient counselling, promoting greater drug safety and enhanced patient compliance.

A multiple in silico program approach for the prediction of mutagenicity from chemical structure

We have conducted an evaluation of three of the most widely used commercial toxicity prediction programs, Toxicity Prediction by Komputer Assisted Technology (TOPKAT), Deductive Estimation of Risk from Existing Knowledge (DEREK) for Windows (DfW) and CASETOX. The three programs were evaluated for their ability to predict Ames test mutagenicity using 520 proprietary drug candidate (Test set 1) and 94 commercial (Test set 2) compounds. The study demonstrates that these three commercially available programs are useful, with limitations in their ability to predict mutagenicity over a wide range of chemical space, i.e. global predictivity. Individually, each of the programs performed at an acceptable level for overall accuracy, i.e. the ability to predict the correct outcome. However, analysis of the predictions indicates that the overall accuracy figure is heavily weighted by the ability of the programs to correctly predict non-mutagens, whereas none of the programs individually performed well in the prediction of novel mutagenic structures, i.e. Ames positive compounds. The performance of these programs’ in predicting Ames positive mutagens appeared to be independent of the chemical utility of the compound, i.e. industrial, agricultural or pharmaceutical. The combination of program predictions provided some improvement in overall accuracy, sensitivity and specificity.

Dielectric properties of residual water in amorphous lyophilized mixtures of sugar and drug

Dielectric relaxation spectroscopy was used to investigate the properties of residual water in lyophilized formulations of a proprietary tri-phosphate drug containing a sugar (trehalose, lactose or sucrose) or dextran. The dielectric properties of each formulation were determined in the frequency range (0.1 Hz–0.1 MHz) and temperature range (30°C–Tg). The temperature dependence of the relaxation times for all samples showed Arrhenuis behaviour, from which the activation energy was derived. Proton hopping through the hydrogen-bonded network (clusters) of water molecules was suggested as the principle mode of charge transport. Significant differences in dielectric relaxation kinetics and activation energy were observed for the different formulations, which were found to correlate with the amount of monophosphate degradation product.

Morphine Liposomal--SkyePharma: C 0401, D 0401, morphine--DepoFoam, SKY 0401.

The SkyePharma PLC subsidiary SkyePharma Inc. (formerly DepoTech) is developing a sustained-release formulation of morphine sulphate [DepoMorphine, C 0401, D 0401, SKY 0401] using its DepoFoam proprietary drug delivery technology. It is intended for epidural administration in the treatment of acute postoperative pain. DepoFoam consists of microscopic spherical particles with internal aqueous chambers separated by lipid membranes containing the encapsulated drug. DepoFoam particles are synthetic replicas of natural lipids that are biodegradable and biocompatible. DepoFoam can be administered subcutaneously, intramuscularly and intrathecally. In December 2002, SkyePharma and Endo Pharmaceuticals signed a development and commercialisation agreement providing Endo Pharmaceuticals with exclusive marketing and distribution rights in the US and Canada for Depomorphine and another product, Propofol IDD-D trade mark, with options for other development products. Under the terms of the agreement, SkyePharma will receive an upfront payment and may receive further milestone payments. Skye-Pharma will also receive a share of each product's sales revenue. SkyePharma is responsible for clinical development towards the US FDA approval and for product manufacture and associated costs. Following the approval, SkyePharma will as act as a supplier, while Endo will market each product in the US and Canada. SkyePharma has received 30 million US dollars from Paul Capital Partners, a US private equity group, to develop DepoMorphine. This capital will enable SkyePharma to fund phase III clinical trials without raising extra funds. Paul Capital will have rights to 15% of any revenues from DepoMorphine until 2014, and also receive some royalties on three other SkyePharma products. However, if DepoMorphine fails in clinical trials or is declined for registration, Paul Capital will not be compensated for the investment. SkyePharma expect to conclude a European license by the end of 2003, and are also in discussions with potential Japanese licensees. In July 2003, SkyePharma submitted an NDA to the US FDA for DepoMorphine in the treatment of moderate to severe postoperative pain. The FDA accepted the filing in September, triggering a milestone payment to Skye-Pharma. Positive results from two phase III trials in 750 patients after hip surgery and lower abdominal surgery released in June 2003 report that DepoMorphine is effective in providing sustained dose-related analgesia. DepoMorphine demonstrated sustained dose-related analgesia and achieved its primary endpoint and also statistical significance on several secondary endpoints such as patient perception of pain intensity and adequacy of pain relief. The Financial Times in January 2001 reported that analysts have forecast DepoMorphine to reach peak sales of more than 200 million US dollars. In April 2001, the Wall Street Journal quoted the CEO of SkyePharma predicting that DepoMorphine has the potential to reach combined annual sales, in the US and Europe, of approximately 350 million US dollars.

Oxymorphone ??? Endo/Penwest

Penwest Pharmaceuticals and Endo Pharmaceuticals are jointly developing an oral, controlled-release opioid analgesic oxymorphone [EN 3202] using Penwest's TIMERx proprietary drug delivery technology. The product is being developed for twice-a-day dosing in patients with moderate to severe pain. TIMERx is a controlled-release technology based on an agglomerated hydrophilic matrix, which consists of the polysaccharides locust bean gum and xanthan gum. The technology provides a full spectrum of controlled-release profiles lasting >/=4 h. In February 2003, the US FDA has announced that it accepted the NDA for oxymorphone extended-release tablets, oxymorphone ER, for the treatment of moderate to severe pain in patients requiring continuous opioid therapy for an extended period of time. Late in 2002, the Oxymorphone formulation successfully completed a phase III clinical trial in patients with osteoarthritis pain. Another randomised, double-blind, placebo-controlled trial was completed in 127 patients with moderate to severe pain resulting from surgery in the knee. Results demonstrated that patients receiving EN 3202 treatment had significantly superior pain relief compared with placebo recipients. An immediate-release formulation of oxymorphone (EN 3203) has also been accepted by the US FDA.

Foreign exchange risk and firm value: an analysis of US pharmaceutical firms

Reviews previous research on the impact of changes in exchange rates on firm value and develops hypotheses on the effect of exchange rate exposure on US pharmaceutical firms 1990‐1999. Tests them using data from 523 firms (21 producing proprietary drugs and 32 generic) splite into two sub‐periods (1990‐1994 and 1995‐1999) and explains the methodology. Finds that the proprietary drug producers were negatively affected by the rising US dollar value during the first sub‐period, but positively affected in the second; and that both generic and proprietary companies suffered a one‐month lagged negative effect. Considers the underlying reasons for this and consistency with other research; and calls for more research on the lagged relationship between stock returns and exchange rate risk.

Unknown residual solvents identification in drug products by headspace solid phase microextraction gas chromatography-mass spectrometry

A sensitive headspace SPME method for the extraction of residual solvents from pharmaceutical products has been developed and optimized. It was found that minimizing sample and headspace volume has a beneficial effect on extraction efficiency. At the same time the method reproducibility was seriously affected by reducing sample and headspace volume. The added air volume was not found to have any significant influence on method sensitivity. The method showed reproducibilities of less than 10% and detection limits as low as 1 ppb for benzene and dichloromethane. The headspace SPME method is around 1000 times more sensitive than static headspace. The optimized parameters were headspace volume 1.5 mL, sample volume 10 μL, and extraction time 30 min. The method was successfully applied to the identification of unknown residual solvents in three different proprietary active drug substances and was successfully applied to the confirmation of the presence of benzene in a proprietary drug substance.

Expanding the linear dynamic range in quantitative high performance liquid chromatography/tandem mass spectrometry by the use of multiple product ions.

A strategy for expanding the linear working range in bioanalysis using quantitative high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) is presented. The strategy involves monitoring multiple product ions. Herein we demonstrate the strategy on a rat plasma assay for a proprietary experimental drug where the linear range is expanded from 2 to 4 orders of magnitude. A primary sensitive ion was monitored to obtain a high sensitivity range calibration curve (0.400 to 100 ng/mL) while a less sensitive secondary ion was monitored to obtain a low sensitivity range calibration curve (90.0 to 4000 ng/mL). Each calibration curve gave acceptable linearity (r >0.990). Quality control samples at low, mid and high levels within each calibration curve demonstrated acceptable precision and accuracy (within 20% for all levels). The technique was successfully applied to rat pre-clinical sample analysis.