German scientists use oxygen and light to synthesise anti-malaria drug

German researchers have discovered a process to make the most effective anti-malaria drug cheaper and easier to produce in large quantities.

Scientists at the Max Planck Institute of Colloids and Interfaces in Potsdam and the Freie Universität Berlin have developed a simple process for the synthesis of artemisinin, which pharmaceutical companies could only obtain from plants up to now.

The chemists use a waste product from current artemisinin production as their starting substance, which can also be produced biotechnologically in yeast, and convert it into the active ingredient using a simple yet ingenious method.

Peter Seeberger, director at the Max Planck Institute of Colloids and Interfaces in Potsdam and Professor of Chemistry at the Freie Universität Berlin and his colleague François Lévesque, said they used artemisinic acid, a substance produced as a by-product from the isolation of artemisinin from sweet wormwood, which is produced in volumes 10 times greater than the active ingredient itself. Moreover, artemisinic acid can easily be produced in genetically modified yeast as it has a simpler structure.

‘We convert the artemisinic acid into artemisinin in a single step,’ said Seeberger. ‘And we have developed a simple apparatus for this process, which enables the production of large volumes of the substance under very controlled conditions.’

The only reaction sequence known up to now required several steps, following each of which the intermediate products had to be isolated – a method that was too expensive to offer as a viable alternative to the production of the drug from plants.

The simplification of artemisinin synthesis meant the chemists had to depart from the paths typically taken by industry up to now. The effect of the molecule, which not only targets malaria but possibly also other infections and even breast cancer, is due to, among other things, a very reactive chemical group formed by two neighbouring oxygen atoms – referred to as an endoperoxide.

Seeberger and Lévesque used photochemistry to incorporate this structural element into the artemisinic acid. Ultraviolet light converts oxygen into a form that can react with molecules to form peroxides.

‘Photochemistry is a simple and cost-effective method. However, the pharmaceutical industry has not used it to date because it was so difficult to control and implement on a large scale,’ explains Seeberger. In the large reaction vessels with which industrial manufacturers work, flashes of light do not penetrate deeply enough from outside and the reactive form of oxygen is not produced in sufficient volumes.

The scientists say they have resolved this problem by channelling the reaction mixture containing all of the ingredients through a thin tube that they have wrapped around a UV lamp. In this structure, the light penetrates the entire reaction medium and triggers the chemical conversion process with optimum efficiency.

‘The fact that we do not carry out the synthesis as a one-pot reaction in a single vessel, but in a continuous-flow reactor enables us to define the reaction conditions down to the last detail,’ explained Seeberger.

‘We assume that 800 of our simple photoreactors would suffice to cover the global requirement for artemisinin.’

The scientists estimates that the synthesis process could be ready for technical use in about six months.

Indian scientists show insoluble drugs can be taken orally in nano crystal form

Taking a big leap in how oral medicines are administered, Indian scientists have shown that producing nanoscopic crystals of a pharmaceutical product can allow the medication to be absorbed by the gut even if the drug is not soluble in water.

The study suggests that more than half of the medicinal drugs being developed by the pharmaceutical industry dissolve only very weakly in water, if at all.

This is a major problem for administering such drugs as it means they are not effective if taken by mouth.

The industry has developed many approaches to addressing this problem, such as adding a small quantity of an organic solvent, such as ethanol, to the mixture, coupling the drug with a charged ion to increase bioavailability and in more recent times using water-soluble "carriers", such as the ring-shaped cyclodextrin.

A much more effective approach would be to somehow make the drug soluble without resorting to such additives.

Scientists have, over the last decade or so, discovered that producing microscopic crystals of a pharmaceutical product can make it soluble in water even if the bulk compound is not.

The tiny particle size, means a much greater surface area to volume ratio giving access to more water molecules that can surround the particles, which is the essence of dissolving a compound.

This effect can then allow the particles to be carried across the lining of the gut wall where they would previously simply move past with no interaction.

The effect can be explained in terms of the physical chemistry and mathematics known to nineteenth century scientist Lord Kelvin, Herbert Freundlich, and Wilhelm Ostwald.

Now, R. Ravichandran of the Regional Institute of Education (NCERT), in Bhopal, India, has demonstrated that gymnemic acids derived from the herb Gymnema sylvestre , can be made more readily bioavailable by forming the active compounds as nanoscopic crystals, nanocrystals.

The compounds have medicinal activity in a range of diseases, in particular diabetes mellitus, with the native herb having been used in traditional medicine for several centuries.

Ravichandran's detailed examination of the physical and chemical properties of nanocrystals of gymnemic acids could provide important clues as to how to transfer the medical benefits of the herb to a regulated pharmaceutical product for further investigation and with a more strict profile in treating disease.

The study has been published in the International Journal of Nanoparticles.

Milk negates healing power of antibiotics, reveals PU study

Seven-year research was conducted by University Institute of Pharmaceutical Sciences; study also finds antacids and multivitamin-mineral combinations render ciprofloxacin, gatifloxacin ineffective

A research conducted by the University Institute of Pharmaceutical Sciences, Panjab University, has revealed that antibiotics, if taken with dairy products, tend to lose effectiveness to less than 50 per cent, and in some cases, are rendered ineffective completely. The study holds much significance in the Indian context, for it is quite common among people here to take antibiotics with milk.

The study, conducted by a team comprising a couple of PhD and M Pharma scholars under the guidance of Dr Bhupinder Singh Bhoop, professor and Dean-Alumni, Panjab University, has already been presented at the International Conference held at NIPER (National Institute of Pharmaceutical Education and Research), Mohali, last year.

It has also been published in one of the popular journals on pharmaceutical sciences — Clinical Pharmacokinetics. The research has been recently published by the Panjab University, too.

It took the team almost seven years to complete the study on the intake of two commonly used antibiotics— ciprofloxacin and gatifloxacin. The results showed a drastic decline in their effect —between 31 and 66 per cent (with a mean of 52 per cent); in some cases, milk totally nullified the effect of these antibiotics.

“The antibiotics are partially or even absolutely ineffective if they are consumed with dairy products, especially milk. The study was conducted on 12 male volunteers,” said Dr Bhoop.

The research further revealed that the concurrent intake of even antacids with these drugs should be avoided, as these, too, might thwart the attainment of optimal therapeutic effect of these drugs.

In a nutshell, serious and significant clinical consequences of antibiotic interaction were discerned. The scientific reason for this phenomenon deduced from the study is that reduction in the plasma levels of these antibiotics may turn out to be sub-therapeutic for many pathogens (disease causing organisms) against which these drugs are intended to be used to combat various infective disorders. This may lead to treatment failure when these drugs are co-administered with antacids, dairy products and/or multivitamin-mineral combinations containing iron, calcium, and the like.

“This is true for many drugs that they should not be taken with certain food items and I am not surprised if ciprofloxacin has shown such results. The reason could be that certain drugs compete for absorption with food items after their intake; they get attached to certain food items and are flushed out without getting absorbed. Also, certain medicines are absorbed at higher pH levels. Thus, the food items can interfere with medicines including antibiotics,” said Dr Subhash Verma, who has held the post of MD at the Department of Medicine, PGIMER, for over 30 years.

One of the recommendations of the study is that these drugs should be taken at least two hours before or six hours after the intake of these items, including milk products, antacids or multivitamin-mineral combinations.

“Surprisingly, some doctors do not advise the patients on the possible consequences of taking these antimicrobials with other drugs and dairy products. Looking into the significance of the outcome of these drug interaction studies, it is highly desirable to propagate rational awareness among physicians, pharmacists, chemists, pharmaceutical manufacturers, educators, medical salesmen and even the general public on the potential risks of concurrent therapy using these drugs. Labeling instructions and insert information should also be modified accordingly. This will help a great deal in circumventing any treatment failures occurring as a consequence,” said Dr Bhoop.

Dr Surjit Singh, another senior doctor in the department of medicine, PGIMER, echoed Dr Verma’s views. “It is possible that the absorption of antibiotics is inhibited by the intake of food items, including milk. It is also true that such is the prevalence of the habit among the society that 99.9 per cent of people usually take medicines with milk or meals. I have been advocating all my life that certain medicines can be safely taken without milk and even on an empty stomach, but to no avail. As most of the doctors do not advise patients on the intake of medicines, the practice continues to be widespread,” he said.

Scientists Discover 16 Active Pharmaceutical Substances in Doñana National Park

The unfiltered pharmaceutical compounds present in Doñana National Park’s waterways pose eco-toxicological risks to aquatic organisms.

Wastewater treatment facilities were not designed with the pharmaceutical industry in mind, which may explain why they are increasingly incapable of filtering out the cacophony of drugs we now consume. After finding 16 different pharmaceutical substances in the waterways that flow through the Doñana National Park, scientists recommended that the surrounding wastewater facilities incorporate a tertiary treatment system in order to more effectively cleanse the water that is subsequently dumped into the Guadiamar River, Partido stream, and La Rocina stream.

According to Wildlife Extra, scientists from the University of Seville discovered the following pharmaceuticals in the Doñana National Park:

Five anti-inflammatory drugs (diclofenac, ibuprofen, ketoprofen, naproxen and salicylic acid)

A nervous system stimulant (caffeine)

Two antibiotics (sulfametoxazol and trimethoprim)

Two lipid regulators (clofibric acid and gemfibrozil)

An anti-epilepsy drug (carbamazepine)

A beta blocker (propranolol), and

Four hormones (three natural: oestrone, 17β-oestradiol and oestriol; and one artificial: 17α-ethynyloestradiol)

Ibuprofen is the most prevalent of all pharmaceutical compounds found in Doñana: 140kg of it is consumed and metabolized by human beings, and then discharged through their urine and faeces.

This discharge is then piped to the wastewater treatment plant, where only 60% of the substances are effectively removed before that water then travels to the river and streams.

Scientists warn that this contaminated water poses eco-toxicological risks to aquatic organisms, including Hydra attenueta. In a separate experiment, they discovered that exposure to such chemicals altered the genes in the liver and brain of Atlantic Salmon.

While not mentioned in this particular report, constructed wetlands – comprised of bulrushes and papyrus and other wetland organisms – have proven to be significantly more effective at filtering out substances that conventional wastewater treatment centers are unable to process. In the meantime, scientists have recommended the addition of a third treatment step that incorporates either oxidation or membrane systems to improve the quality of water discharged “24 hours a day, 365 days a year.”

“Now, the scientists will transfer these results to native species living in the water systems of Doñana in order to “better understand the way these compounds influence genetic expression,” Esteban Alonso, lead author of the study and a researcher at the Department of Analytical Chemistry at the US, tells SINC.

Freeman Technology to Sponsor Course on Blending and Flow of Pharmaceutical Powders

Freeman Technology, in partnership with Gericke and Glatt Air Techniques, is sponsoring a new three-day course presented by Mixing Consultants, Inc. on the subject of 'Blending and Flow of Pharmaceutical Powders'. The course will be run in the US and in Europe, beginning in Pearl River, New York on 27-29 October and then at Graz University of Technology in Austria from 9-11 December 2009. Each will feature high-level presentations given by academic experts from Rutgers University and by industry specialists, including Tim Freeman, Director of Operations for Freeman Technology.

Prompted by the success of a similar event held in Puerto Rico in May this year, Tim Freeman will once again join Professor Fernando Muzzio of Rutgers University, together with pharmaceutical manufacturing leaders from Glatt Air Techniques and Gericke. Designed for those working in product and process design, manufacturing, scale-up, technology transfer, and control, the course program begins with an introduction from the regulatory perspective. It then moves through the topics of: mixing of free-flowing materials; automation for powder blending; mixing of cohesive materials; lubrication; and continuous mixing techniques and process design. The final day then takes a further look into regulatory issues before moving on to powder flow measurements in relation to pharmaceutical development and manufacturing.

Freeman's knowledge of powder flow is based on a strong foundation of experience and technical know-how. The company's FT4 powder tester is capable of rapid measurements of shear, bulk and dynamic properties using only small amounts of sample material and a range of methodologies. Knowledge of why some formulations are 'easy' to manufacture while others are not is the basis of effective processing enabling optimum formulation development within plant performance specifications.

Top-Five Global Pharmaceutical Company Names NewCardio as its Provider of Automated Thorough QT Solution

SANTA CLARA, Calif., - NewCardio, Inc., (OTC Bulletin Board: NWCI) a cardiac diagnostic and services company, today announced that a top-five pharmaceutical company has named NewCardio's QTinno(TM) software suite, NewCardio's first commercial product, as the technology that will be used in all of its fully automated Thorough QT (TQT) studies.

The pharmaceutical company evaluated several automated cardiac safety solutions before choosing QTinno(TM) as its automated solution moving forward. As part of this evaluation, a blinded TQT dataset was provided for processing by the automated solutions. The automated results were then un-blinded by the pharmaceutical company and compared to the original core lab results. The pharmaceutical company determined that NewCardio's solution demonstrated the highest consistency and lowest variability in relation to the original core lab results. After reviewing NewCardio's underlying platform technology, the pharmaceutical company determined that QTinno(TM) was the solution it will utilize to begin replacing the semi-automated methodology currently utilized by its preferred ECG core labs. At recent industry conferences, a number of pharmaceutical companies have expressed a strong desire to transition to fully automated methods in an effort to reduce human error, minimize intrinsic variability and increase efficiency.

Going forward, all TQT study requests for proposals (RFPs) issued by the pharmaceutical company that will require a fully automated component will require the use of NewCardio's QTinno(TM) by its preferred ECG core labs. It is anticipated that this pharmaceutical company will conduct its first clinical trial using fully automated readings by the end of the year and will increasingly utilize fully automated results in its TQT studies.

"NewCardio is excited to work with a major pharmaceutical company and we believe this is the clearest signal yet of the impending transition to fully automated cardiac testing in drug development as sponsors look for ways to improve quality while simultaneously reducing expenses," said Vincent Renz, NewCardio's President and Chief Operating Officer. "This global pharmaceutical leader is an early adopter, and this announcement demonstrates their commitment to quality, safety and the use of new technologies to drive innovation."

NewCardio's innovative 3D ECG platform technology dramatically improves the accuracy and significantly increases the diagnostic value of the standard 12-lead electrocardiogram (ECG). NewCardio's lead product is QTinno(TM), a software suite that provides an automated, comprehensive analysis of QT intervals and other ECG-based cardiac safety for the pharmaceutical industry and drug regulators. The Company believes that its QTinno(TM), software-based, analytical technology is the industry's first solution for the reliable automated analysis of ECGs used to determine cardiac toxicity during drug development.

Cleveland Clinic takes equity stake in Pa. pharmaceutical company

The Cleveland Clinic has acquired an equity stake in FTA Therapeutics LLC, which develops clinical stage pharmaceutical products.

Terms of the deal with the Pennsylvania firm were not disclosed. The Clinic will help FTA develop products using a silver dihydrogen citrate antimicrobial agent made by Pure Bioscience of San Diego.

“FTA will commence the first of several multi-centered studies later this year for various indications for (the antimicrobial agent), including wound care and acne,” said Michael Krall, president and CEO of Pure Bioscience.

FTA and Pure began working together a year ago to use the antimicrobial agent to develop products for the dermatology, wound care and medical biofilm control industries.

As a result of FTA's new partnership with the Clinic, the FTA board of directors now includes three Clinic doctors. Dr. Wilma Fowler Bergfeld is co-director of dermatopathology, the departments of dermatology and pathology, and a staff pathologist at the Clinic.

Dr. Frank Papay, who is co-founder and medical director of FTA, also is chairman of the Clinic's Dermatology and Plastic Surgery Institute, and section head of the Craniofacial Surgery/Department of Plastic Surgery. Dr. Allison Vidimos is chairwoman of the Clinic's Department of Dermatology.

Skura Corporation’s SFX Suite™ Closed Loop Marketing Software Featured in Pharmaceutical Commerce Article

Skura Corporation and its SFX Suite™ software was featured in a recent article in Pharmaceutical Commerce. Touted as “a better way to sell,” closed loop marketing has not been used by marketers to its fullest potential. However, in these changing times, when companies are reducing their sales forces and physicians are limiting their face-time with representatives, closed loop marketing can help maximize the customer interaction.

The Skura product has the ability to provide customized e-detailing messages. Physician feedback on marketing messages delivered by the sales force can be analyzed and subsequent messages adjusted for improved results on the next detailing visit. Predictive modeling technology is the key component used at the analysis stage to guide brand managers on what messages will have the best results.

Says Jeff Wessinger, President of Skura, “You take the results of what has been captured from a tablet pc or a clickstream on a website and run it through advanced algorithms to determine what’s working and what’s not with specific customers.” The next time the rep interacts with the customer, the software “suggests the assets that will work best in priority order….”

Gasket Standardization: A New Tool for Cost Reduction in API Pharmaceutical Processes

The API pharmaceutical market has been increasingly buffeted by winds of global change. Even as new and innovative drugs have been developed and brought to market successfully, manufacturing operations have been increasingly challenged by the need to be more competitive and productive.

The trend has been to move to more efficient operations and lower costs, while at the same time increasing process reliability and the throughput of high purity products. Furthermore, manufacturing operations are shifting to the most desirable locations to meet the increased demands of cost controls and efficiency. Older, lower-volume facilities are being consolidated with larger, higher-volume sites that require ever-tighter process effectiveness. For API pharma manufacturers, this means finding new methods to economize and streamline all production processes. This has led the way to adopting new technologies and more simplified procurement processes, leading in turn to "standardization" as a tool to meet these challenges. And in fact, manufacturing and maintenance simplification, as well as inventory reduction, are achievable goals with standardization.

As process optimization trickles down from the most expensive items, it is reaching into all corners of processing plants that handle chemicals and other aggressive media. For example, there is already a definite trend in the chemical process industry towards the standardization of materials. We believe this will take place in the API pharmaceutical sector as well. Higher-cost items such as pumps and piping systems have seen the rapid advance of standardization. Now the trend is moving to standardization of smaller process components such as mechanical seals, bearings, O-rings, gaskets – and even nuts and bolts. Each of these categories has their own unique standardization challenges.

Gasket Standardization

Gasket standardization is one of the challenges now being addressed by chemical plants and processing units. From recent market research conducted by W. L. Gore & Associates, Inc. among leading North American chemical processors, it was found that approximately 75% of the companies interviewed have a gasket standardization effort in place. In most cases, the processors have standardized on a specific gasketing material for each of the three main piping categories – steel, glass-lined and FRP – while also allowing for some exceptions in the case of abnormal application requirements. Among the gasketing experts interviewed, 80% feel that gasket standardization is a top-level or highly important activity.

What does gasket standardization mean in terms of an "ideal world" to these experts? It means essentially one thing: a single gasket that can be used anywhere and is suitable for practically all applications. Unfortunately, ideal situations rarely exist. Thus, the focus has been to reduce the number of materials rather than to standardize on a single gasket material.

Several gasket materials available today may be categorized as suited for only one pipe class (e.g., for FRP, for glass lined steel, or for steel piping). Now, technology developed by Gore is capable of overcoming this challenge. The GORE™ Universal Pipe Gasket is compatible with steel, glass-lined, and FRP piping. It has been adopted successfully by many CPI chemical companies over the past five years.

The strategic benefits of this type of standardization are significant. Today, cost-effectiveness is integral to the strategic plans of all plants in the chemical and pharma processing industries. Gasket standardization can unlock the long-term strategic value that plants are seeking. Not only will the lowest procurement cost to seal a flange be achieved, but also the total "lifetime cost" of sealing will be optimized, producing continuous annual cost savings.

Gasket simplification of the type envisioned here would facilitate system-wide standardization across piping classes – metal, plastic and glass-lined – while increasing reliability and safety. A Pressure Vessel Research Council (PVRC) study showed that the average plant experienced 180 leaks per year, with 2% being serious enough to cause a process shutdown or worse. Knowing that the primary causes of leaks are improper installation of gaskets and use of the wrong gasket for the service, it's not difficult to conclude that installation effectiveness would be positively impacted with a standard gasket. In the final analysis, gasket standardization is a "win" for every function that is now involved with gasket selection, acquisition and use.

The Right Material

Approximately 95% of all process piping systems operate at less than 450°F and 1,000 psi internal pressure. To enable standardization, the gasketing material must withstand as close to 100% of these operating parameters as possible. This gasket material must achieve a bolt load retention that emulates graphite. It must also have the tightest sealing and lowest emissions, as well as the greatest safety against blowout. In other words, it should be the most reliable gasket. It must work effectively and deliver this performance across all three piping classes -- glass-lined, FRP and steel pipes. It must also support the full range of 0-14 pH service and low stress-to-seal systems.

There are additional, unique benefits available to API pharmaceutical companies with the standardization of gasket materials. The needs of this industry go beyond CPI in that the final products must maintain high purity and are subject to regulatory controls. Every component in the process system that comes into contact with the process fluid must meet the highest purity standards – and many need full traceability to the source of the material as well. The GORE™ Universal Pipe Gasket is the only 100% ePTFE non-contaminating (USPC VI Tested) gasket which can replace all non-metallic gaskets used in applications below 600°F, can effectively seal all types of process piping, and is fully traceable to the source.

Such technology enables API pharmaceutical companies to achieve all the cost reduction benefits of standardization to one gasket material while increasing process reliability, safety and purity.

Cost Considerations

In addition to performance qualifications, the standardization process offers economic advantages as well. Cost reduction is a primary driver of standardization, so obviously a gasket material must be cost-competitive if it is has any hope of becoming a standardization "flag bearer." It is important to look at the complete picture when analyzing the cost impact of standardization.

The initial cost of the gasket is one consideration, but additional cost savings are achieved when the correct gasket is always at hand. Maintenance requires less time, thus lowering labor costs. Fewer errors are made, resulting in fewer interruptions to production. Finally, inventory requirements are reduced.

API pharmaceutical companies can realize many benefits by standardizing on a single gasket material for all processes below 600°F that utilize non-metallic gaskets. In doing so, be sure to choose a gasket material that has passed USPC VI qualification testing and is traceable to the source, while also delivering the reliable sealing performance upon which every processing plant must rely.