Archive for May, 2010
Ambit Biosciences and Astellas Enter Strategic Partnership to Research, Develop and Commercialize FLT3 Kinase Inhibitors in Multiple Indications
Last Updated on Wednesday, 5 May 2010 11:46 Written by Editor Wednesday, 5 May 2010 11:46
Ambit to Receive a US$40 Million Upfront Cash Payment; Up to US$350 Million in Pre-Commercialization Milestones, Double-Digit Royalties with Option to Co-promote and Share Profits in U.S.
SAN DIEGO and TOKYO, December 18 – Ambit Biosciences Corporation and Astellas Pharma Inc. today announced
that they have entered into a worldwide agreement to jointly develop and
commercialize FLT3 kinase inhibitors in oncology and non-oncology
indications. This partnership includes AC220, Ambit’s lead clinical-stage
investigational drug that entered into a Phase 2 clinical trial earlier this
month in relapsed/refractory acute myeloid leukemia (AML), and other
undisclosed FLT3 kinase inhibitors. AC220 is a novel, orally available,
potent and highly selective small molecule that was specifically designed as
a second generation FMS-like tyrosine kinase-3 (FLT3) inhibitor using Ambit’s
proprietary drug discovery engine, KINOMEscan(TM).
The companies will collaborate to develop AC220 for AML and other
indications. The parties will also collaborate on a research and development
program for a series of novel FLT3 inhibitors for a variety of oncology and
non-oncology indications. The companies will share equally in the
responsibilities and expenses for the development of AC220 and any additional
products in the U.S. and Europe, while Astellas will have sole responsibility
to fund development in all other territories. Under the terms of the
agreement, Ambit will receive an up-front cash payment of US$40 million and
will be eligible to receive pre-commercialization payments of up to US$350
million.
Astellas will have sole responsibility for funding and implementing the
commercialization of all products, and Ambit will be entitled to
post-approval milestone payments upon the achievement of certain sales
thresholds, as well as tiered double-digit royalties on net sales. In the
U.S., Ambit will also have the option to co-promote AC220 and other products
under a profit sharing arrangement where Astellas and Ambit share equally in
profits and losses generated from U.S. sales.
“We are pleased to have entered into a great partnership with Ambit,”
stated Masafumi Nogimori, president and chief executive officer of Astellas.
“We believe that AC220, as the most selective and advanced FLT3 kinase
inhibitor, has the potential to provide a new treatment option for AML where
high unmet medical needs exist. Astellas is strongly committed to focus on
oncology and this partnership is a significant milestone to establish our
franchise in oncology.”
“With their strategic commitment to the development and commercialization
of innovative oncology products, Astellas is an ideal partner for Ambit,”
said Scott Salka, Chief Executive Officer of Ambit Biosciences. “This
collaboration establishes a comprehensive and global leadership position in
the discovery and development of FLT3 kinase inhibitors, and we look forward
to working closely with Astellas to explore the clinical utility of AC220 in
AML and other indications.”
About AC220
AC220, Ambit’s lead product candidate, is being developed in
collaboration with Astellas Pharma Inc. and is a novel, potent, highly
selective, orally bioavailable second-generation FLT3 inhibitor. AC220 is
currently under evaluation in a Phase 2 clinical trial designed to support
potential registration of AC220 as monotherapy treatment in adult and elderly
patients with relapsed/refractory AML that have the internal tandem
duplication (ITD) mutation in the FLT3 kinase. AML is one of the most common
types of blood cancers in adults, and the FLT3 kinase is mutated and
constitutively activated in 25-40 percent of such patients. FLT3 ITD
mutations predict poor prognosis and decreased response to existing
treatments, including chemotherapy and hematopoietic stem cell transplant.
Ambit leveraged KINOMEscan(TM), the company’s proprietary, high-throughput
method for screening small molecule compounds against a large number of human
kinases, to advance AC220 from initial chemistry to clinical candidate
selection for IND-enabling studies in only 18 months.
About Acute Myeloid Leukemia (AML)
Acute myeloid leukemia is a form of blood cancer. According to the
American Cancer Society, approximately 13,000 new cases of AML will be
diagnosed in the United States in 2008. The median age of a patient with AML
is about 67 years. Standard treatment for patients 60 years or older with AML
includes systemic combination chemotherapy. The median survival for patients
receiving induction chemotherapy, which is associated with high mortality, is
6-11 months, with shorter survival for patients over the age of 60 years. The
five-year survival rate for AML is less than 15 percent. According to a
report from Decision Resources, the U.S. AML market is expected to more than
double by 2015.
About Ambit Biosciences
Ambit Biosciences is a privately-held biopharmaceutical company engaged
in the discovery and development of small molecule kinase inhibitors for the
treatment of cancer, inflammatory disease, and other indications. Ambit
employs a novel and proprietary kinase profiling technology, KINOMEscan(TM),
to screen compounds against 442 human kinases.
Ambit’s lead compound, AC220, is in clinical development for the
treatment of AML and other indications. Ambit has initiated a Phase 2 pivotal
trial in patients with relapsed or refractory AML and plans to commence
several other clinical studies with AC220 in 2010. Ambit’s clinical pipeline
also includes AC480, an oral pan-HER inhibitor that was in-licensed from BMS.
Ambit is conducting Phase 2 studies with AC480 in patients with solid tumor
cancers. Additionally, Ambit has an advancing pool of preclinical candidates
targeting BRAF (in collaboration with Cephalon), JAK2, Aurora, and CSF1R.
Through its KINOMEscan Division, Ambit markets its technology as a profiling
service. For more information, visit www.ambitbio.com.
About Astellas
Astellas Pharma Inc., located in Tokyo, Japan, is a pharmaceutical
company dedicated to improving the health of people around the world through
the provision of innovative and reliable pharmaceuticals. Astellas has
approximately 15,000 employees worldwide. The organization is committed to
becoming a global category leader in urology, immunology & infectious
diseases, neuroscience, DM complications & metabolic diseases and oncology.
For more information on Astellas Pharma Inc., please visit our website at
www.astellas.com/en.
Contact: -------- Ambit Biosciences: Astellas Pharma: ------------------ ---------------- M. Scott Salka Corporate Communications +1-858-334-2101 +81-(0)3-3244-3201 www.astellas.com/en/ Christopher Morl (business development) +1-858-334-2134 Scott Lerman (media) The Ruth Group +1-646-536-7013 slerman@theruthgroup.com Sara Pellegrino (investors) The Ruth Group +1-646-536-7002 spellegrino@theruthgroup.com
Source: blog.taragana.com
Posted under Drug Development, Oncology Research, Press Releases | Comments Off
We’re winning the war on cancer
Last Updated on Wednesday, 5 May 2010 11:38 Written by Editor Wednesday, 5 May 2010 11:38
What does yesterday’s exciting news of the complete DNA sequencing of two different cancers mean? It is a fantastic feat that promises great improvements in our ability to cure cancer by 2020, but it comes with a hefty price tag.
The numbers are stark. One in three of us will get cancer, and 1.5 million Britons alive today have either had it or have been treated for it. Globally, 10 million people will get cancer this year and this will reach 20 million by 2020.
The most promising advances on the horizon come from our rapidly increasing understanding of the cog molecules that make cancer cells tick. That’s what yesterday’s excitement was about. Imagine that your car breaks down. The difference between you and the roadside repair man is that he knows what goes on under the bonnet, while you can’t even open it.
So we can now compare the exact DNA sequences of five different cancers from real people. Painstaking analysis of these and other data will allow us to work out what went wrong. Eventually this will have a considerable impact on prevention, screening, diagnosis and treatment, and will herald a new golden age of drug discovery.
In the past 20 years, a huge amount of fine detail of the basic biological processes that become disturbed in cancer has been amassed, and the pace is quickening.
We now know the key elements of how signals for growth bind to cells and how messages can get corrupted, leading to uncontrolled growth or failure to die. These are fertile areas to look for rationally based, anti-cancer drugs. This approach has already led to a record number of new compounds in trials, currently estimated to be about 700.
Over the next few years, there will be a marked shift in the type of agents used in the systemic treatment of cancer. They will be precisely targeted to the defined abnormalities found in individual patients.
Because we know the precise targets of these new agents, there will be a revolution in cancer therapy. Instead of defining drugs for different types of cancer empirically and relatively ineffectively, we will identify a series of molecular lesions in tumour samples. Future patients will receive drugs that target these lesions directly.
The human genome project provides a vast repository of comparative information about normal and malignant cells. The new therapies will be more selective, less toxic and be given for prolonged periods of time, in some cases for the rest of the patient’s life. This will lead to a radical overhaul of how we provide cancer care.
Personalised medicine, based on a set of novel molecular diagnostics, will allow us to give the right medicine to the right patient at the right time. Small black boxes into which patients put a blood sample will guide treatment and monitor its effectiveness. Tiny, implantable chips sending radio signals to a home computer will permit continuous monitoring.
Individual cancer risk assessment will lead to tailored prevention messages and a specific screening programme to pick up early cancer, with far-reaching public health consequences. Preventive drugs will be developed to reduce the risk of further genetic deterioration.
But in this bright future, the funding of cancer care will become a significant problem. Already we have seen inequity in access to the drugs Sutent for kidney cancer and Avastin for colon cancer.
For the moment, these drugs are only palliative, adding just a few months to life. But the emerging compounds are likely to be far more successful, and their long-term administration considerably more expensive.
As consumerism increases in medicine, patients will become more informed and assertive, seeking out new therapies and bypassing traditional referral pathways.
New financial structures will arise, with the pharmaceutical, insurance and health care sectors combining to enable future patients to choose the levels of care they wish to pay for, through insurance or directly.
By 2025, chemotherapy is likely to replace other treatments for many cancers. Cancer will become a chronic, controllable illness, like diabetes today. People living with cancer will receive care in attractive, hotel-like environments rather than hospitals, run by competing private-sector providers. Global franchises will use the web to disseminate treatment plans and control their quality.
This transition will bring new ethical dilemmas. The future will be decided by the interaction of four complex factors: technological success, society’s willingness to pay, future health care delivery systems and the financial mechanisms that underpin them.
Cure will still be sought, but it will not be the only satisfactory outcome. Patients will be closely monitored after treatment, but the fear that cancer will definitely kill, still prevalent today, will be replaced by an acceptance that many forms of cancer are a consequence of old age.
Fast-tracking the diagnosis makes good sense. Cancer masquerades as many other less serious illnesses, so even the most experienced GP can’t pick out who actually has the disease. The NHS is often a slow and cumbersome system in which to get the necessary tests. Many cancers have already spread by the time they are eventually diagnosed.
We are still the poor man of Europe in comparative studies of access to diagnostics, despite Gordon Brown’s recent announcement that nobody will have to wait more than seven days for tests. Unfortunately this is aspirational propaganda.
Predicting the future is fraught with difficulties. Who could have imagined in the 1980s the impact of mobile phones, the internet and low-cost airlines on global communication? Medicine will be overtaken by similarly unexpected step changes in innovation.
For these reasons, economic analysis of the impact of developments in cancer care is difficult. The greatest benefit will be achieved simply by assuring that the best care possible is on offer to the most patients. This would be irrespective of their socio-economic circumstances and of any scientific developments.
But this dream is simply unrealistic. Technologies are developing fast, particularly in imaging and the exploitation of the human genome. Well-informed patients, with adequate funds, will ensure that they have rapid access to the newest and the best – anywhere in the world.
More patients will benefit from better diagnosis and newer treatments, with greater emphasis on quality of life. But innovation will inevitably bring more inequality to health. The outcome of the same quality of care differs today between socio-economic groups and will continue to do so.
It is the job of governments to ensure health equity for all their constituents. Living long and dying fast will become the mantra of this century. Profound challenges lie ahead.
Professor Karol Sikora is medical director of CancerPartnersUK and Dean of the University of Buckingham Medical School.
source: telegraph.co.uk
Posted under Cancer Research, Oncology Research, Press Releases | Comments Off
Findings By Scripps Research Scientists Brighten Prospects Of Stem Cell Therapy For Range Of Diseases
Last Updated on Wednesday, 5 May 2010 10:44 Written by Editor Wednesday, 5 May 2010 10:44
A team led by scientists from The Scripps Research Institute has developed a method that dramatically improves the efficiency of creating stem cells from human adult tissue, without the use of embryonic cells. The research makes great strides in addressing a major practical challenge in the development of stem-cell-based medicine.
The findings were published in an advance, online issue of the journal Nature Methods on October 18, 2009.
The new technique, which uses three small drug-like chemicals, is 200 times more efficient and twice as fast as conventional methods for transforming adult human cells into stem cells (in this case called “induced pluripotent stem cells†or “iPS cellsâ€).
“Both in terms of speed and efficiency, we achieved major improvements over conventional conditions,†said Scripps Research Associate Professor Sheng Ding, Ph.D., who led the study. “This is the first example in human cells of how reprogramming speed can be accelerated. I believe that the field will quickly adopt this method, accelerating iPS cell research significantly.â€
In addition to its significant practical advantages, the development of the technique deepens the understanding of the biology behind the transformation of adult human cells into stem cells.
Tackling Major Challenges
The hope of most researchers in the field is that one day it will be possible to use stem cells – which possess the ability to develop into many other distinct cell types, such as nerve, heart, or lung cells – to repair damaged tissue from any number of diseases, from Type 1 diabetes to Parkinson’s disease, as well as from injuries. The creation of iPS cells from adult cells sidesteps ethical concerns associated with the use of embryonic stem cells, and allows the generation of stem cells matched to a patient’s own immune system, avoiding the problem of tissue rejection.
The creation of human iPS cells was first announced in December 2007 by two labs, one in Japan and another in Wisconsin. In both cases, the teams used viruses to insert multiple copies of four genes (eg. c-Myc, Oct4, Sox2, Klf4) into the genome of skin cells. These four genes then produced transcription factors turning on and off other genes, and pushing the cell to “dedifferentiate†into stem cells.
While the work was a major breakthrough, it left two major challenges for the field to solve before iPS cell therapy could be considered of any potential practical use. The first involved safety, since the technique relied on potentially harmful genetic manipulation, and worse yet, the insertion of two known cancer-causing genes (c-Myc and Oct4). The second problem was the length and inefficiency of the iPS cell process, which had a success rate of roughly one in 10,000 cells and took about four weeks from start to finish.
Ding and colleagues essentially solved the first problem, the reliance on genetic manipulation, earlier this year in a paper published in Cell Stem Cell (Volume 4, Issue 5, May 8, 2009). In the paper, the researchers demonstrated that they could use purified proteins to transform adult cells all the way back to the most primitive embryonic-like cells, avoiding the problems associated with inserting genes.
In the current paper, the team makes major strides in solving the second problem, efficiency.
A Focus on Natural Processes
In developing the improved method, Ding drew on his knowledge of biology. He decided he would focus his efforts on manipulating a naturally occurring process in cells, in particular in a type of adult cell called fibroblasts, which give rise to connective tissue.
This naturally occurring process – called MET (mesenchymal to ephithelial cell transition) – pushes fibroblasts closer to a stem-cell-like state. If he could manipulate such a fundamental process to encourage MET and the formation of stem cells, Ding reasoned, such a method would be both safer and more direct than hijacking other aspects of biology, for example those directly involved in cancer.
“People have studied this mechanism for 10 to 20 years,†said Ding. “It is a fundamental mechanism.â€
Ding and colleagues tested a number of drug-like molecules, looking for those that inhibited the TGFb (transforming growth factor beta) and the MEK (mitogen-activated protein kinase) pathways, which are known to be involved in the MET process. The researchers identified the most active compounds, then looked at their effects on stem cell creation when used singly and in combination.
The researchers found two chemicals – ALK5 inhibitor SB43142 and MEK inhibitor PD0325901 – used in combination were highly effective in promoting the transformation of fibroblasts into stem cells.
“This method is the first in human cells that is mechanism-specific for the reprogramming process,†said Ding.
And the two-chemical technique bested the efficiency of the classic genetic method by 100 times.
Efficient, Fast, Safe
But the researchers thought they might be able to do even better.
Attempting to increase the efficiency of the process even further, the team decided to enlist another natural pathway, the cell survival pathway. After screening a library of compounds targeting this pathway, the team focused on a novel compound called Thiazovivin.
The researchers found that a technique using Thiazovivin in combination with the two previously selected chemicals, SB43142 and PD0325901, beat the efficiency of the classic method by 200 times.
In addition, while the classic method required four weeks to complete, the new method took two weeks.
In addition to its virtues of speed and efficiency, Ding emphasizes that the safety profile of the new method is highly promising. Not only is the method based on natural biological processes, he said, but also the type of molecules used have all been tested in humans. – Scripps Research Institute
Posted under Press Releases, Stem Cell Research | Comments Off
SCYNEXIS, Inc. Receives Milestone Payment From Collaboration With Merck & Co., Inc.
Last Updated on Wednesday, 5 May 2010 10:43 Written by Editor Wednesday, 5 May 2010 10:43
RESEARCH TRIANGLE PARK, NC — 12/17/09 — Drug discovery and development company SCYNEXIS, Inc. announced today that it has achieved a third milestone in its collaboration with Merck & Co., Inc. to develop novel antifungal agents. This latest milestone payment was triggered following the initiation of clinical development for a compound derived from the program.SCYNEXIS and Merck initiated the antifungal agent discovery and development program in 2002. SCYNEXIS contributed medicinal chemistry, computational chemistry, bioanalytical and ADMET support to this program. Merck is responsible for development once compounds are accepted as pre-clinical candidates. Under the terms of the collaboration, SCYNEXIS is eligible to receive additional milestone payments and up to double-digit percentage royalties on worldwide sales of any product resulting from the program.
“SCYNEXIS is pleased to reach this important clinical milestone in collaboration with our valued partner, Merck,” noted Yves Ribeill, Ph.D., President and Chief Executive Officer of SCYNEXIS. “This is the eleventh time in SCYNEXIS’ ten year history that a compound originating from our discovery platform has advanced into the clinic — an accomplishment we believe speaks strongly to the strength of our capabilities.”
About SCYNEXIS
SCYNEXIS is a premier drug discovery and development company headquartered in Research Triangle Park, N.C. SCYNEXIS’ mission is to be the leader in delivering effective and innovative drug pipeline solutions to its pharmaceutical partners.
SCYNEXIS research teams integrate medicinal chemistry, advanced biological screening, ADMET-PK, bioanalysis and analytical chemistry, process chemistry, cGMP API manufacturing, and use powerful, proprietary technologies such as the HEOS® Software Suite and MEDCHEM-FACTORY® to advance molecules to candidate selection. The fully integrated research and development teams at SCYNEXIS have been tailored to be especially effective in moving customer projects from the discovery phase to the clinic. www.scynexis.com
For further information, please contact:
SCYNEXIS, Inc.
Terry Marquardt
Executive Director, Market Development & Communications
Email Contact
Tel: +1-919-544-8603
SCYNEXIS Media Contacts:
Rick Rountree
Rick Rountree Communications, Inc.
Email Contact
Tel. +1 919-878-1144
Sarah Cavanaugh
MacDougall Biomedical Communications
Email Contact
Tel. +1 781-235-3060
Source: earthtimes.org
Posted under Press Releases, Research Projects | Comments Off
Colon Cancer – Does Wheat Bran Reduce the Risk?
Last Updated on Wednesday, 5 May 2010 10:40 Written by Editor Wednesday, 5 May 2010 10:40
K-State, Wichita State collaborative research studies wheat bran from different wheat varieties, effect on suppressing colon cancer
MANHATTAN — We’ve heard the conflicting information: Wheat bran can reduce the risk of colon cancer in humans; wheat bran does not reduce the risk in humans.
But which one is true?
Both, sort of.
In the mid-1990s, grain science nutritionists at Kansas State University discovered that bran from one variety of wheat actually suppressed cancer in laboratory tests, while bran from another wheat variety did not.
According to Ronald Madl, director of bioprocessing and industrial value added programs with K- State’s department of grain science and industry, the confusion set in because the resulting medical literature really did not appreciate the genetic diversity in wheat — that not all wheat bran is the same.
“As a consequence, medical literature that followed the initial work sometimes said that wheat bran did suppress cancer,†Madl said. “Other medical literature said it did not suppress cancer.â€
In a cooperative effort that picked up where that previous research left off, Madl and other researchers from K-State — including Carol Klopfenstein, professor emeritus of grain science and industry, Delores Takemoto, professor of biochemistry, and Weiqun Wang, assistant professor of human nutrition — joined with John Carter, associate professor of physical therapy at Wichita State, and discovered the diversity of phytochemicals in wheat bran. They tested about 120 varieties, all with different levels of antioxidants, from very high to very low. Further studies showed wheat bran with a higher antioxidant content demonstrated a potential to suppress cancer cells.
Madl said in subsequent testing on human cancer cells, the bran from high antioxidant wheat varieties either actually killed some of the cancer cells or stopped their growth; the medium and low antioxidant varieties had less of or no effect — the cancer cells kept growing like normal.
Further testing has shown that wheat high in antioxidants demonstrated a significant suppression in both size and number of tumors, while intermediate levels of wheat antioxidants experienced an intermediate level of cancer activity.
“Since then, we have been trying to move this research to the next stage, understanding which particular compounds are responsible for this benefit,†Madl said. “Antioxidant activity is expressed by a lot of chemical compounds, but that doesn’t mean that all antioxidants express that same beneficial, biological effect. Now, we’re trying to determine which antioxidants are actually responsible for cancer suppression.â€
Madl said K-State wheat breeders would like to enhance the levels of antioxidants in wheat.
“The long-term opportunity is that we could produce new wheat varieties with higher levels of antioxidants, and then carry out research to show that these varieties can reduce cancer risk,†he said.
Madl said that once researchers have determined the wheat bran varieties with enhanced levels of antioxidants, clinical studies could be considered for humans to demonstrate if wheat bran could reduce the risk of colon cancer.
Madl said K-State research is currently focused on testing methodology. Development of more rapid screening methods for antioxidants in wheat could make the screening process for wheat breeders, as well as making the wheat selection process for food processors, quicker and more feasible.
Reproduced with permission.
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Source: hongjushe.com
Posted under Cancer Research, Press Releases | Comments Off
Kidney cancer research grant a NZ first
Last Updated on Wednesday, 5 May 2010 10:39 Written by Editor Wednesday, 5 May 2010 10:39
Media Release
Wednesday 16 December 2009
The Auckland Cancer Society Research Centre at The University of Auckland
Kidney cancer research grant a NZ first
University of Auckland chemist Associate Professor Michael Hay has become the first New Zealand scientist to receive a grant from a leading international charity for funding cancer research.
Dr Hay and his team at the University’s Auckland Cancer Society Research Centre will use the ₤137,000 ($NZ 290,000) grant from the UK-based Association for International Cancer Research (AICR) to identify molecular targets in kidney cancer tumours that will help them design more effective anticancer drugs.
This research will expand on Dr Hay and his colleague Dr Jack Flanagan’s recent work designing new drugs for kidney cancer using computers, a project funded by the Maurice Wilkins Centre for Molecular Biodiscovery. Both Dr Hay and Dr Flanagan are associate investigators at the centre.
Dr Hay says although not one of the most common cancers, kidney cancers often don’t respond to standard chemotherapy and radiotherapy, and that advanced kidney cancer has an extremely poor prognosis.
“Cancer is caused by changes to either the structure or activity of key genes that control how cells function. In many kidney cancers, a gene called the von Hippel Lindau gene is switched off. Without this gene, a relatively benign tumour can turn into a more aggressive, invasive tumour.â€
Dr Hay and colleagues at Stanford University have recently discovered two new classes of molecules that can selectively kill kidney cancer cells that have this particular gene turned off, either by getting the cells to “eat themselves†or by cutting off their food supply. However, the exact interactions between these molecules and their protein targets are not yet known.
“With this grant we’ll use advanced 3D computer modelling techniques to help us identify these targets, and show how potential drugs for treating kidney cancers might interact with their target molecules,†says Dr Hay.
Dr Flanagan says this new method of targeted drug discovery, called “virtual screeningâ€, selects potential drug leads suited to a specific target molecule from millions of compounds. “It’s basically a way to find the needle in the haystack.â€
AICR Scientific Advisor Dr Mark Matfield says the charity supports only the very best applications, which it hopes will ultimately lead to powerful new treatments for cancer. “This is the first time we have given a grant to a scientist in New Zealand, and we believe this innovative work could produce significant results.â€
The project is supported by the Auckland Cancer Society Research Centre and the Maurice Wilkins Centre. It involves collaboration with the Department of Radiation Biology at the Stanford University School of Medicine in the US and is due to begin in April 2010.
Source: scoop.co.nz
Posted under Grants and Awards, Press Releases | Comments Off
Cellular Dynamics Announces Commercial Launch of iCell(TM) Cardiomyocytes for Drug Candidate Toxicity Screening
Last Updated on Wednesday, 5 May 2010 10:36 Written by Editor Wednesday, 5 May 2010 10:36
Human iCell Cardiomyocytes Provide Alternative to Non-human, Tumor-derived, and Cadaveric Cellular Model Systems to Better Predict Cardiac Toxicity
MADISON, Wis., Dec. 16 /PRNewswire/ — Cellular Dynamics International (CDI) today announced the commercial launch of iCell(TM) Cardiomyocytes for use in testing of new drug candidates by the pharmaceutical industry. These human heart cells are designed to aid drug discovery and improve the predictability of drug compound efficacy and toxicity screens, weeding out ineffective and potentially toxic compounds early in the pharmaceutical pipeline process before significant time and resources have been invested.
iCell Cardiomyocytes are derived from induced pluripotent stem (iPS) cells, spontaneously beat in vitro and exhibit the electrophysiological and biochemical properties of normal human heart cells. Thus, iCell Cardiomyocytes provide significant advances over non-human cell models, which may exhibit a different response than human tissue; tumor-derived cell models, which are genetically different than normal cells; and cadaveric cells, which exhibit batch-to-batch variability, de-differentiate under in vitro conditions, and exhibit non-cardiomyocyte behaviour.
iCell Cardiomyocytes are the first product ever developed from iPS cells, discovered by CDI senior research fellow Junying Yu, Ph.D., then a postdoctoral research associate in the University of Wisconsin-Madison laboratory of James Thomson, V.M.D., Ph.D., in 2007. iCell Cardiomyocytes are produced in-house by CDI from a master cell bank of iPS cells expanded from a single clonal population reprogrammed from fully mature human cells using Dr. Thomson’s patented technology. Based on strong intellectual property and exclusively licensed patents from several universities, CDI has developed a proprietary process to industrialize iCell Cardiomyocytes production so that the cardiomyocytes are manufactured at the high quantity, quality and purity required by pharmaceutical companies. CDI has successfully engaged in pre-launch validation testing with several pharmaceutical customers.
“Drug toxicity testing is an important part of early-stage drug development, said Chris Parker, chief commercial officer of CDI. “The problem our pharmaceutical customers face today is that current cell models to test drugs are inadequate, because they are either non-human, cadaveric, or tumor-derived cells. They miss toxicities that might have manifested themselves in a human cell model. With the launch of iCell Cardiomyocytes, we hope to improve the efficiency and effectiveness of preclinical research studies, so that our pharmaceutical customers are more assured of the safety and efficacy of their drug candidates and a better return on their research investment.”
Robert Palay, chief executive officer of CDI, continued, “Launching iCell Cardiomyocytes to the pharmaceutical industry is an important step for Cellular Dynamics. We have shown that we can manufacture and provide validated human iPS cell-derived terminally differentiated cardiomyocytes in the quantity and quality needed by our customers. We look forward to growing this product with our pharmaceutical customers and developing line extensions of iCell Cardiomyocytes, including panels with multiple iPS starting materials, as well as launching other iPS cell-derived iCell products.”
James Thomson, chief scientific officer of CDI, said, “Rapid application of stem cell technology has been a goal both of my laboratory at the University of Wisconsin and CDI. Utilizing human iPS cells for new drug toxicity testing should improve the drug discovery process in a timeframe that has an effect on human healthcare now, not 10 years from now. Ultimately applications of stem cell technology in drug discovery will provide great utility and enable movement toward a long-term goal of cellular-based therapeutics and personalized medicine.”
About Cellular Dynamics International, Inc.
Cellular Dynamics International, Inc. (CDI) is a leading developer of next-generation stem cell technologies for drug development and personalized medicine applications. CDI harnesses the power of pluripotent stem cells and their ability to differentiate into any cell type for world-class drug development tools. In addition, it is the leader in iPS technology, the production of pluripotent stem cell lines from adult tissue. CDI was founded in 2004 by James Thomson, a pioneer in human embryonic stem cell research at the University of Wisconsin-Madison, and Tactics II Ventures, a Wisconsin-based venture capital fund. CDI’s facilities are located in Madison, Wisconsin. See www.cellulardynamics.com.
SOURCE Cellular Dynamics International (CDI)
Posted under Drug Development, Drug-Like Compounds, Press Releases | Comments Off
Arno Therapeutics Announces Poster Presentation at ASH Annual Meeting Demonstrating Anti-Leukemic Stem Cell Activity of AR-42
Last Updated on Wednesday, 5 May 2010 10:28 Written by Editor Wednesday, 5 May 2010 10:28
PARSIPPANY, N.J. – (Business Wire) Arno Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on oncology therapeutics, today announced the presentation of a poster at the annual American Society of Hematology (ASH) meeting that describes the preclinical activity of Arno’s drug candidate AR-42 against leukemia stem cells (LSCs). AR-42 is a broad spectrum inhibitor of both histone and non-histone deacetylation proteins that demonstrated potent activity against Acute Myeloid Leukemia (AML) stem cells. The poster, entitled “Identification of the Histone Deacetylase Inhibitor (HDACi), AR-42, as a Novel Anti-Leukemia Stem Cell Agent in Acute Myeloid Leukemia (AML)†was presented at the 51st ASH Annual Meeting and Exposition held December 5-8, 2009 in New Orleans, LA. LSCs are believed to be able to initiate and perpetuate AML while displaying resistance to standard chemotherapies. The ability to target these cells with therapeutic compounds may help improve patient outcomes. The poster’s findings show that AR-42 preferentially targets LSCs compared to normal healthy cells. The research also suggests that AR-42 is active through a mechanism that differentiates it from other compounds with preclinical anti-LSC activity.
“The ability to target cancer stem cells presents an opportunity to change the way that we treat patients, particularly those stricken with diseases that are currently difficult to cure,†stated Monica Guzman, Ph.D., a co-author of the poster with AR-42 at Weill Cornell Medical College. “Patients with AML are prone to recurrent disease, even if therapies are initially effective. Current evidence suggests that the survival of LSCs after treatment may ultimately contribute to the persistence of this disease and its poor clinical prognosis. Inhibiting LSCs may help treat and prevent recurrence of AML in patients.â€
“We identified AR-42 by screening a large number of gene expression profiles from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) for potential anti-LSC agents. We were very excited to see our hypothesis confirmed both in vivo and in vitro, and we look forward to discovering if the same promising activity will be seen in the clinical setting,†said co-author Duane Hassane, Ph.D. of Weill Cornell Medical College.
“Arno is very excited about the results from these recent studies and feels that this data helps to support our belief that AR-42 has the potential to emerge as a meaningful addition to the landscape of cancer therapies,†stated David Tanen, President of Arno.
About AR-42
AR-42 (formerly known as “HDAC-42â€) is an orally available, broad spectrum inhibitor of both histone and non-histone deacetylation proteins (“pan-DACâ€), which may both be important in cancer progression. Histone deacetylase (“HDACâ€) inhibitors are a growing class of compounds that target histone deactylase, a molecule involved in determining which genes are expressed in a particular cell. In preclinical studies, AR-42 has shown activity against a broad spectrum of deacetylation targets and increased potency compared to vorinostat (“SAHA,†or Zolinza®), the first HDAC inhibitor to obtain FDA approval. Arno currently plans to commence an investigator-initiated Phase I/IIa study with AR-42 in collaboration with an academic institution in the first half of 2010.
About Arno Therapeutics
Arno Therapeutics, Inc. is a clinical-stage biopharmaceutical company that develops and commercializes innovative products for the treatment of cancer patients. Arno’s lead clinical compound, AR-12 (formerly known as “OSU-03012â€), is a potentially first-in-class, orally available, targeted anti-cancer agent that inhibits PDK-1, a protein in the PI3K/Akt pathway, and also causes cell death through the induction of endoplasmic reticulum stress. Arno is developing two additional drug candidates, AR-67 and AR-42. AR-67 is a novel, third-generation camptothecin analogue that inhibits topoisomerase I activity. AR-67 has demonstrated activity and an excellent safety profile in clinical studies as well as improved pharmacokinetic properties when compared to approved second-generation products Hycamtin® (topotecan) and Camptosar® (irinotecan). Arno is conducting a Phase II study of AR-67 in patients with Myelodysplastic Syndrome (MDS) who have failed prior therapies and anticipates commencing a Phase II study in patients with glioblastoma multiforme (GBM), a highly aggressive form of brain cancer by the end of this year.
For more information on Arno please visit www.arnothera.com.
Forward Looking Statements
This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, included in this press release regarding the timing, progress and anticipated results of the clinical development, regulatory processes, potential clinical trial initiations, potential IND and NDA filings, as well as our strategy, future operations, outlook, milestones, the success of Arno’s product development, future financial position, future financial results, plans and objectives of management, are forward-looking statements. We may not actually achieve these plans, intentions or expectations and Arno cautions investors not to place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. Various important factors could cause actual results or events to differ materially from the forward-looking statements that we make. Such factors include, among others, risks that the results of clinical trials will not support our claims or beliefs concerning the effectiveness of our product candidates, our ability to finance the development of our product candidates, regulatory risks, and our reliance on third party researchers and other collaborators. Arno is providing this information as of the date of this presentation and does not undertake any obligation to update any forward-looking statements as a result of new information, future events or otherwise.
Arno Therapeutics, Inc.
Brian Lenz, CPA, 862-703-7175
Chief Financial Officer
bl@arnothera.com
source: earthtimes.org
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Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis — state of the art
Last Updated on Wednesday, 5 May 2010 10:25 Written by Editor Wednesday, 5 May 2010 10:25
Fibrosis represents a major global disease burden, yet a potent antifibrotic compound is still not in sight. Part of the explanation for this situation is the difficulties that both academic laboratories and research and development departments in the pharmaceutical industry have been facing in re-enacting the fibrotic process in vitro for screening procedures prior to animal testing.
Effective in vitro characterization of antifibrotic compounds has been hampered by cell culture settings that are lacking crucial cofactors or are not holistic representations of the biosynthetic and depositional pathway leading to the formation of an insoluble pericellular collagen matrix. In order to appreciate the task which in vitro screening of antifibrotics is up against, we will first review the fibrotic process by categorizing it into events that are upstream of collagen biosynthesis and the actual biosynthetic and depositional cascade of collagen I.
We point out oversights such as the omission of vitamin C, a vital cofactor for the production of stable procollagen molecules, as well as the little known in vitro tardy procollagen processing by collagen C-proteinase/BMP-1, another reason for minimal collagen deposition in cell culture. We review current methods of cell culture and collagen quantitation vis-a-vis the high content options and requirements for normalization against cell number for meaningful data retrieval.
Only when collagen has formed a fibrillar matrix that becomes cross-linked, invested with ligands, and can be remodelled and resorbed, the complete picture of fibrogenesis can be reflected in vitro. We show here how this can be achieved.
A well thought-out in vitro fibrogenesis system represents the missing link between brute force chemical library screens and rational animal experimentation, thus providing both cost-effectiveness and streamlined procedures towards the development of better antifibrotic drugs.
Author: Clarice ChenMichael Raghunath
Credits/Source: Fibrogenesis &Tissue Repair 2009, 2:7
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Formulation strategies for improving drug solubility using solid dispersions
Last Updated on Wednesday, 5 May 2010 10:23 Written by Editor Wednesday, 5 May 2010 10:23
Abstract:
The solubility behavior of drugs remains one of the most challenging aspects in formulation development. Solid dispersions have been employed to enhance the dissolution rates of poorly water – soluble drugs. This article reports various solubility enhancement strategies in solid dispersion. The approaches described are fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electro static spinning method and super critical fluid technology. The paper also highlights the potential applications and limitations of these approaches in solid dispersions.
Keywords: micronization, lyophilization, melt agglomeration, extruding, amorphous state, bioavailability, solubility, dissolution
Introduction:
Drug substances are seldom administered alone, but rather as part of a formulation in combination with one or more non-medicinal agents that serve varied and specialized pharmaceutical function. The proper design and formulation of a dosage form requires consideration of the physical, chemical and biological characteristics of all the drug substances and pharmaceutical ingredients to be used in fabricating the product. An important physical-chemical property of a drug substance is solubility, especially aqueous system solubility. Solubility is a predetermined and rate limiting step for absorption. Drugs must have to enter in to the systemic circulation to exert a therapeutic effect1. In recent technologies, innovation of combinatorial chemistry and high throughput screening can effectively discover the seeds of new drugs which exhibit good pharmacological activities however 35-40 % of these new drugs discovered by those technologies suffer from poor aqueous solubility2-3. Consideration of the modifed Noyes-Whitney equation 4, 5 provide some hints regarding how the dissolution rate of very poorly soluble compounds improved to minimize the limitations to oral bioavailability:
dC /dt = AD(Cs – C) / h
where dC/dt is the rate of dissolution, A is the surface are available for dissolution, D is the diffusion coefficient of the compound, Cs is the solubility of the compound in the dissolution medium, C is the concentration of drug in the medium at time t and h is the thickness of the diffusion boundary layer adjacent to the surface of the dissolving compound. To increase the dissolution rate from equation the following approaches are available.
a) To increases the surface area available for dissolution by:
b)Decreasing the particle size of drug.
c)Optimizing the wetting characteristics of compound surface.
d)To decrease the boundary layer thickness
e)Ensure sink condition for dissolution
f)Improve apparent solubility of drug under physiologically relevant conditions. Drug administered in fed state is a way to improve the dissolution rate6. The solubility/dissolution behavior of a drug is key determinant to its oral bioavailability, the latest frequency being the rate-limiting step to absorption of drugs from the gastrointestinal tract7-8. Consequently poor solubility results in low bioavailability, increase in the dosage, large inters and intra-subject variation and large variations in blood drug concentrations under fed versus fasted conditions. Improvement of oral bioavailability of poor water-soluble drugs remains one of the most challenging aspects of drug development. The techniques/ approaches that have commonly been used to overcome drawbacks associated with poorly water-soluble drugs, in general includes micronization, salt formation, use of surfactant and use of pro- drug 7-8 however all these techniques have certain limitations.  Micronization has several disadvantages, the main one being the limited opportunity to control important characters of the final particle such as size, shape, morphology, surface properties and electrostatic charges. In addition micronization is a high-energy process, which causes disruptions in the drug s crystal lattice, resulting in the presence of disordered or amorphous regions in the final product. The amorphous regions are thermodynamically unstable and are therefore susceptible to recrystallization upon storage, particularly in hot and humid conditions9, 10, 11 . All poorly water-soluble drugs are not suitable for improving their solubility by salt formation. The dissolution rate of a particular salt is usually different form that of parent compound. However sodium and potassium salts of weak acids dissolve more rapidly than the free salts. Potential disadvantages of salt forms include high reactivity with atmospheric carbon dioxide and water resulting in precipitation of poorly water-soluble drug, epigastric distress due to high alkalinity. Use of co-solvents or surfactants to improve dissolution rate pose problems, such as patient compliance and commercialization. Even though particle size reduction increases the dissolution rate, the formed fine powders showing poor wettability and flow properties. Solid dispersion technique has come into existence to eliminate all these problems 12-13. Solid dispersion (SD) technique has been widely used to improve the dissolution rate, solubility and oral absorption of poorly water-soluble drugs14-15. In solid dispersion the drugs are dispersed in a biologically inert matrix for the intention of enhancing oral bioavailability. Chiou and Riegelman defined these systems as the dispersion of one or more active ingredient in an inert carrier matrix at solid state prepared by the melting (fusion), solvent or melting-solvent method.16 However, the most attractive option for increasing the release rate is improvement of the solubility through formulation approaches.
Table 1 summarizes the various approaches that can be taken to improve the solubility or to increase the available surface area for dissolution. Review articles have already been published on the use of polymorphs 17, the amorphous form of the drug 18 and complexation 19, 20.
Solubility enhancement strategies in solid dispersions:
Various strategies investigated by several investigators include fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electro static spinning method and super critical fluid technology.
Fusion method:
The fusion process is technically the less difficult method of preparing dispersions provided the drug and carrier are miscible in the molten state. This process employs melting of the mixture of the drug and carrier in metallic vessel heated in an oil bath, immediately after fusion, the sample are poured onto a metallic plate which is kept at ice bath. A modification of the process involves
Spray congealing from a modified spray drier onto cold metal surface. Decomposition should be avoided and is affected by fusion time and rate of cooling21-22. Another modification of the above method, wherein SD(s) of troglitazone- polyvinyl pyrrolidone (PVP) k 30 have been prepared by closed melting point method. This method involves controlled mixing of water content to physical mixtures of troglitazone PVP k30 by storing at various equilibrium relative humidity levels (adsorption method) or by adding water directly (charging method) and then mixer is heated. This method is reported to produce SD with 0% apparent crystallinity23. On the other hand, the fusion process does not require an organic solvent but since the melting of sparingly water-soluble drug and water-soluble polymer entails a cooling step and solid pulverizing step, a time consuming multiple stage operation is required. To overcome this problem Nakano et al 24 have described a method conceptualizing the formation of a SD as the solid-to-solid interaction between a sparingly water soluble drug, nilvadipine and water soluble polymer which, unlike conventional production method, comprises mixing a sparingly water soluble drug and water soluble polymer together under no more than the usual agitation force with heating within the temperature region not melting them, instead of heating the system to the extent that the two materials are melted , the sparingly water soluble drug can be made amorphous to have never been achieved by any dry process heretofore known.
Solvent evaporation method:
The solvent-based process uses organic solvent to dissolve and intimately disperse the drug and carrier molecule. Large volumes of solvents are generally required which can give rise to toxicological problems 25-26. Many investigators studied SD of meloxicam, naproxen27-28, rofecoxib29, felodipine30, atenolol 31, and nimesulide32 using solvent evaporation technique. These findings suggest that the above-mentioned technique can be employed successfully for improvement and stability of solid dispersions of poor water drugs. Suhagic et al. 33 prepared SD of etoricoxib using PEG and PVP as a carriers by solvent evaporation method where carriers along with drug were dissolved in 2-propanol to get a clear solution followed by solvent evaporation and finally dispersion was collected. The prepared SD(s) exhibited improved dissolution attributed to decreased crystallinity, improved wetting and improved bioavailability.
Lyophillization technique:
Freeze-drying involves transfer of heat and mass to and from the product under preparation34. Lyophillization has been thought of a molecular mixing technique where the drug and carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion. Betageri et al. 35, Topalogh et al. 36, Badry et al. 37 and Fathy et al.38 have successfully investigated the potential applications of lyophilization in manufacturing of SD(s). Drooge et al39 suggested spray freeze-drying as a potential alternative to the above-mentioned process to produces 9- tetrahydrocannabino containing inulinbased solid dispersions with improved incorporation of – tetrahydrocannabino in inulin.
Melt agglomeration process:
This technique has been used to prepare SD where the binder acts as a carrier. Binder (carrier), drug and excipients are heated to temperature above the melting point of the binder (melt- in procedure) or by spraying a dispersion of drug in molten binder on the heated excipient (spray-on procedure) by using a high shear mixer40. The rotary processor might be preferable to the high melt agglomeration because it is easier to control the temperature and because a higher binder content can be incorporated in the agglomerates41. Larger particles results in densification of agglomerates while fine particle cause complete adhesion to the mass to bowl shortly after melting attributed to distribution and coalescence of the fine particles41-43.
Extruding method:
The extruding method was originally designed as an extraction / casting method for polymer alloys in plastic industry, is now used to process cereals and functionalize food materials, such as tissue products from animal proteins44. Hot melt extrusion approach represent the advantageous mean of preparation of SD(s) by using the twin screw hot melt extruder where only thermo stable components are relevant45. The extruder consists of a hooper, barrel, a die, a kneading screw and heaters. The physical mixture is introduced into the hopper that is forwarded by feed screw and finally is extruded from the die44. The effect of screw revolution speed and water content on the preparation of SD(s) should be investigated, since these parameters have profound impact on the quality of SD(s). Nakamichi et al 46, studied that presence of kneading paddle element of screw results in super saturation on dissolution testing while slow revolution rate of screw and addition of the suitable amount of water increased rate of dissolution although no super saturation occurred. In addition, high screw speed high feed rate processes in comparison with low screw speed low feed rate processes caused an increase in extrudate radius and porosity and decrease in mechanical strength and drug release rate from the matrix attributed to the expansion promoted under certain extrusion conditions47. To reduce the melt viscosity in the extrudate and to be able to decrease temperature settings, a plasticizer can be added to the formulation. Typically, conventional plasticizer such as triacetin or polyethylene glycol is used in concentration range of 5-30 % weight of the extrudate that lowers the processing temperature. Carbon dioxide can act as temporary plasticizer. During extrusion carbon dioxide is transformed in gaseous phase. As a consequence carbon dioxide escapes from extrudate and does not appear in final product48. The role of methylparaben49 and sorbitol50 has also been investigated as plasticizer in preparation of SD(s) in extrusion method. This method has already been used successfully to prepare SD(s) of i traconazole and hydroxypropylmethylecellulose (HPMC) 51, indomethacin/lacidipine/nefidipine/ piroxicam/ tobutamide and polyvinylpyrrolidone (PVP) 52, itraconazole53 and HPMC 2910/ Eudragit e 100 or a mixture of Eudragit E 100-PVP vinyl acetate 64 to improve solubility and dissolution rate of poor water soluble drugs.
Spray drying:
The manufacture of milk powder was one of the first applications of spray drying when the method was developed in 1920. Today, spray drying finds great utility in pharmaceutical industry because of the rapid drying and specific characteristics such as particle size and shape of the final product. In addition, it is simple and cost effective, as it is 30-50 times less expensive than freeze-drying. It is an established method that is initiated by atomizing suspensions or solutions into fine droplets followed by a drying process, resulting solid particles. The process allows production of fine, dust free powder as well as agglomerated one to precise specifications. The operating conditions and dryer design depends upon the drying characteristics of the product and require powder specifications 54-56. Rankell et al. prepared SD(s) of loperamide with PEG 6000 by this technique wherein solutions containing different concentrations of PEG 6000 and constant amount of loperamide were spray dried. After spray drying, the dispersions were dried at 400C under vacuum until constant weight. Solvent used was dichloromethane. The prepared SD(s) exhibited higher dissolution rates than that of pure crystalline loperamide57. Chouhan et al 58 studied the suitability of this technique for preparation of SD(s) of glibenclamide polyglcolized glycerides. This study revealed the improvement in solubility and dissolution rates, also improvement in the therapeutics efficacy of amorphous glibenclamide in SD(s) was observed. Some other investigators 59-60 also reported improvement in solubility and dissolution rate. The frequent use of the organic solvent in spray drying pose problems such as residues in products, environmental pollution and operational safety as well as corporate problems such as capital investment. Tanno et al61described a process for producing the SD(s) of poorly water-soluble drugs using water-soluble polymer dispersion and/ or water-soluble polymer solution and the plasticizer solution by using 4-nozzle spray gun. The spray drying technique is a useful method to obtain spherical particle and narrow distribution. The role of porous materials such as calcium silicate, controlled pore glass and porous cellulose is appreciated to formulate solid dosages forms because they confer special characteristics such as decrease of melting point and a decrease in the crystallinity of drug entrapped in pores. In addition, porous materials control polymorphs and stabilizes meta-stable crystals in SD(s) under sever storage conditions. Moreover, porous silica has been reported to improve solubility and dissolution rates of indomethacin and tolbutamide 62-63.
The use of surfactant:
The utility of the surfactant systems in solubilization is well known. Surfactant reduces hydrophobicity of drug by reducing interfacial or surface tension because of these unique property surfactants have attracted the attention of investigators for preparation of solid dispersions64- 65. Recently a new class of surfactant known as Gelucires are introduced which identify by melting points and HLB values. Gelucire is a widely use in the formulation of semi solid dispersions. Gelucire is a saturated polyglycolized glyceride consisting of mono-, di- and triglycerides and of mono- and di- fatty acid esters of polyethylene glycol (PEG) derived from natural vegetable fatty acids and having amphiphilic character. Gelucires with low HLB can be employed to decrease the dissolution rate of drugs and higher HLB ones for fast release. Gelucire 44/14 and gelucire 50/13 are two examples of this synthetic group where 44 and 50 represent melting point, while 14 and 313 represent HLB values of gelucire respectively 66-67. Solid dispersions of antiviral agent uc-781-polyethylene glycol 6000- gelucire 44/14 and UC-781- PEG 6000-gelucire 44/14- PVP k 30 were studied. Improvement in solubility, dissolution and stability was observed 68-69. Labrasol, of same chemical nature as gelucire, is a clear liquid surfactant with a HLB of 14. Solid dispersions of piroxicam with labrasol have also resulted in improved solubility and dissolution when compared with pure drug 66-67. The amphiphilic poly (ethylene oxide)-poly (propylene oxide)- poly (ethylene oxide) (PEO-PPO-PEO) block polymers, known as poloxamer or pluronics represent another class of surfactants. These are available in various molecular weights and PEO/PPO ratios, and hence offer a large variety of physico-chemical properties 70. These block polymers are extensively used in the pharmaceutical industry as defoaming agents, gelling agents, detergents, dispersing agents, emulsifying agents and solubilizing agents71. When used in relatively high quantities, poloxamer imparts sustained-release properties to solid dosage forms, by forming a lipid matrix72. Solid dispersions using pluronic F-68 (a type of poloxamer) as a carrier were studied for improving the dissolution and bioavailability of ABT-963, a poorly water- soluble compound. Results showed that the solid dispersion substantially increased the in vitro-dissolution rate of ABT-963. A significant increase of oral bioavailability compared with conventional capsule formulation was also reported73. The presence of water and polar water-miscible solvent, a partially water-miscible solvent, a non- ionic surfactant, an anionic surfactant and cationic surfactant affect domain of the PEO-PPO-PEO block copolymer selfassembly74. Therefore, organic solvents and surfactants should be used with great care for preparation solid dispersion while using in combination with poloxamer. Inutec SPI, a derivative of inulin prepared by the reaction between isocyanates and the polyfructose backbone in the presence of a basic catalyst such as a tertiary amine or lewis acid, has also been evaluated as carrier in formulation of solid dispersions for a poorly water- soluble drug. Inutec SPI has low viscosity and stability effect on emulsion and suspension. Dissolution properties of SD(s) made up of itraconazole and Inutec SPI were improved in comparison to pure itraconazole or physical mixtures with Inutec SPI4. Hemant et al 75 and Sheen et al 76 studied that polysorbate 80, a commonly used surfactant, results in improvement of dissolution and bioavailability of poorly watersoluble drug attributed to solubilization effect of surface active agent. Polysorbate 80 also ensues complete release of drug in metastable finely dispersed state having large surface area.
Super critical fluid (scf) technology:
This technology has been introduced in the late 1980s and early 1990s, and experimental proofs of concept are abundant in the scientific literature for a plethora of model compounds from very different areas such as drugs and pharmaceutical compounds, polymers and biopolymers, explosives and energy materials, superconductors and catalyst precursors dyes and biomolecules such as proteins and peptides. Since the first experiences of Hannay et al in 1879, a number of techniques have been developed and patented in the field of SCF-assisted particle design. These methods use. SCFs either as solvent: rapid expansion from supercritical solution (RESS) or anti-solvent: gas antisolvent (GAS), supercritical antisolvent (SAS), solution enhanced dispersion by supercritical fluids (SEDS) and/or dispersing fluid: GAS, SEDS, particles from gas-saturated solution (PGSS). Conventional methods, i.e. Spray drying, solvent evaporation and hot melt method often result in low yield, high residual solvent content or thermal degradation of the active substance79. Solution enhanced dispersion by supercritical fluids (SEDS), aerosol solvent extraction system (ASES), supercritical anti-solvent (SAS), gas anti-solvent (GAS) and precipitation with a compressed fluid anti-solvent (PCA) are process of micronization. The SAS process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing cocurrently80. The use of supercritical carbon dioxide is advantageous as it is much easier to remove from the polymeric materials when the process is complete, even though a small amount of carbon dioxide remains trapped inside the polymer; it poses no danger to the patient. In addition the ability of carbon dioxide to plasticize and swell polymers can also be exploited and the process can be carried out near room temperature81. Supercritical fluids used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. The reason for this depression is the solubility of the lighter component (dense gas) in the forming phase (heavier component) 82. Wong et al compared the SD(s) of felodipine prepared by conventional solvent evaporation (CSE) and supercritical antisolvent precipitation (SAS) methods. The particle sizes of the SD(s) from CSE process increased at 1h after dispersed in distilled water. However the particle sizes of the SD(s) from SAS process were maintained for 6 h due to the increased solubility of felodipine. Moreover, SD(s) form the SAS process showed a high dissolution rate of over 90% within 2 h showing the potential applications of SCE technology in preparation of SD(s) 83.
Summary And Future Potential:
The solubility of drugs in aqueous media is a key factor highly influencing their dissolution rate and bioavailability following oral administration resulting in low bioavailability. Solubility enhancement of these drugs remains one of the most challenging aspects of drug development. A variety of devices have been developed over the years to enhance the drug solubility and dissolution of the drugs. The solid dispersion method is one of the effective approaches to achieve the goal of solubility enhancement of poorly water-soluble drugs. Various techniques, described in this review, are successfully used for the preparation of SD(s) in the bench and lab scale and can be used at industrial scale also. Solid dispersions came into limelight in pharmaceutical development due to the increasing number of drug candidates which are poorly soluble and the substantial improvements in the manufacturing methods for solid dispersions that have been made in the last few years. Although there are some hurdles like scale up and manufacturing cost to overcome, there lies a great promise that solid dispersion technology will hasten the drug release profile of poorly water soluble drugs.
Acknowledgements:
I am very much thankful to my research guide and co- guide, Dr.N.M.Patel and Dr.M.M.Patel respectively for their constant encouragement and help to write this review.
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Table 1: Approaches to improve the solubility or to increase the available surface area for dissolution
| I. Physical modifications |
| Particle size |
| Micronization |
| Nanosuspensions |
| Modifications of the crystal habit |
| Polymorphs |
| Pseudopolymorphs (including solvates) |
| Complexation/solubilization |
| Use of surfactants |
| Use of cyclodextrines |
| Drug dispersion in carriers |
| Eutectic mixtures |
| Solid dispersions (non-molecular) |
| Solid solutions |
| II. Chemical modification |
| Soluble prodrugs |
| Salts |
Table 2:Methods for the characterization of solid dispersions
| Dissolution testing |
| Thermoanalytical methods: differential thermoanalysis and hot stage |
| Microscopy |
| Calorimetric analysis of the solution or melting enthalpy for calculation of |
| Entropy change |
| X-Ray diffraction |
| Spectroscopic methods, e.g. IR spectroscopy |
| Microscopic methods including polarization microscopy and scanning |
| Electron microscopy |
Table 3: Marketed formulation of solid dispersion
|
Drug Name |
Brand Name |
Company name |
|
Nelfinavir mesylate |
Viracept® |
Agouron Pharmaceuticals |
|
Ritonavir |
Norvir® |
Abbott Laboratories |
|
Amprenavir |
agenerase |
Glaxosmithkline |
|
Calcitriol |
Rocaltrol |
Roche |
|
Cyclosporine |
A/I neoral |
Novaritis |
|
Indomethacin |
Indomethacin |
Eisai Co |
About Authors:
Rajnikant C.Patel , Saiyad Masnoon, Madhabhai M. Patel, and Natvarlal M. Patel
Rajnikant C.Patel currently working as a lecturer and pursuing part time Ph.D. in the Department of Pharmaceutics at Kalol Institute of Pharmacy, Kalol- 38 27 21
Saiyad Masnoon studying in third year B.pharm at Kalol Institute of Pharmacy, Kalol- 38 27 21
Dr. Madhabhai M. Patel is a Principal in Kalol Institute of Pharmacy, Kalol- 38 27 21
Dr. Natvarlal M. Patel is a Principal in Shri B.M.Shah College of Pharmaceutical Education and Research, Modasa
Source: pharmainfo.net
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Study Findings Could Point the Way to New Drugs for a Deadly Leukemia
Last Updated on Wednesday, 5 May 2010 10:19 Written by Editor Wednesday, 5 May 2010 10:19
The study will help researchers in their search for what could be the first highly effective drug for MLL. Such a drug would work by disabling a protein that turns normal blood cells into cancer cells.
Researchers from Loyola University Chicago Stritch School of Medicine and the University of Virginia reported results online Dec. 13 in the journal Nature Structural & Molecular Biology.
“This hopefully will lead to an effective therapeutic approach for patients who generally do not do well with current treatments,” said second senior author Nancy Zeleznik-Le, Ph.D., a professor in the Department of Medicine at Loyola Stritch.
Acute MLL accounts for about 80 percent of infant leukemias. While survival rates for most types of childhood leukemia are high, only about one-third of patients with MLL live longer than five years. Existing drugs have limited effectiveness and often cause toxic side effects.
MLL is caused by a critical gene that regulates hundreds of other genes in blood cells. The problem occurs when this regulatory gene breaks in half and another gene attaches to it, creating a fusion gene. It’s this fusion gene that turns a normal cell into a proliferating cancer cell.
This fusion gene codes for a MLL fusion protein. The MLL fusion protein in turn binds to hundreds of other genes. Consequently, these genes are permanently turned on. So instead of aging and dying like a normal cell, the cell turns cancerous, continually growing and dividing into new cancer cells.
The finding will be a big help in the effort to develop a drug that prevents the MLL fusion protein from binding to other genes, Zeleznik-Le said. The National Institutes of Health has begun screening compounds that might prevent such binding. Zeleznik-Le said researchers likely will be ready to test potential drug compounds on laboratory animals within a year.
The study’s first authors are Laurie Risner, a doctoral student at Loyola Stritch and Tomasz Cierpicki, PhD, a post-doctoral researcher at the University of Virginia. Other authors are John Bushweller, PhD, Monika Omonkowska, PhD and David Shultis, PhD of the University of Virginia. Bushweller is first senior author.
Based in the western suburbs of Chicago, Loyola University Health System is a quaternary care system with a 61-acre main medical center campus, the 36-acre Gottlieb Memorial Hospital campus and 25 primary and specialty care facilities in Cook, Will and DuPage counties. The medical center campus is conveniently located in Maywood, 13 miles west of the Chicago Loop and 8 miles east of Oak Brook, Ill. The heart of the medical center campus, Loyola University Hospital, is a 561-licensed-bed facility. It houses a Level 1 Trauma Center, a Burn Center and the Ronald McDonald® Children’s Hospital of Loyola University Medical Center. Also on campus are the Cardinal Bernardin Cancer Center, Loyola Outpatient Center, Center for Heart & Vascular Medicine and Loyola Oral Health Center as well as the LUC Stritch School of Medicine, the LUC Marcella Niehoff School of Nursing and the Loyola Center for Fitness. Loyola’s Gottlieb Memorial Hospital campus in Melrose Park includes the 264-bed community hospital, the Gottlieb Center for Fitness and the Marjorie G. Weinberg Cancer Care Center.
Source: healthcanal.com
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Conference Proceedings Preview – 2nd Annual Ocular Diseases and Drug Discovery
Last Updated on Tuesday, 4 May 2010 12:05 Written by Editor Tuesday, 4 May 2010 12:05
The conference proceedings preview is composed of speaker biographies and abstracts, along with selected PowerPoint presentations. Registered attendees receive a CD with the full version of the proceedings on May 27, 2010. In addition, registered attendees will receive an updated online version two weeks after the conference.
To view the preview, please click on the following link:
http://www.gtcbio.com/Ocular_Preview/main.htm
Click here to register! Register two, the third goes free.
CONFERENCE HIGHLIGHTS
Keynote Presentation – Megan McLaughlin, Discovery Medicine, Ophthiris DPU, GlaxoSmithKline
Pazopanib Eye Drops for Neovascular AMD
Keynote Presentation – Stephen Tsang, Edward S. Harkness Eye Institute, Columbia University
Transplantation of Reprogrammed Embryonic Stem Cells Improves Visual Function in a Mouse Model for Retinitis Pigmentosa
Conference Sessions:
I:Â Â Â Age-Related Macular Degeneration
II:Â Â Recent Drug Developments & Mechanisms in Ocular Diseases
III:Â Â Ocular Diseases
IV:Â Future of Ocular Diseases Therapeutics
V:Â Â Novel Drug Delivery Methods
For a full agenda visit: http://gtcbio.com/userAgenda.aspx?id=148
Register 2, the 3rd person goes free! Click here to register.
Distinguished Presenters:
+ Megan M. McLaughlin – Keynote Speaker, Ophthiris Discovery Performance Unit, GlaxoSmithKline + Stephen Tsang, M.D., Ph.D. – Keynote Speaker, Edward S. Harkness Eye Institute, Columbia University + Barbara Marie Wirostko, M.D. – Featured Speaker, Senior Medical Director, Team Lead Ophthalmology, Pfizer + Charles S. Tressler, M.D. – Featured Speaker, Senior Director, Global Medical, Pfizer + Richard L. Beckman, M.D., Senior Vice President, Development, Lux Biosciences + Robert M. Burk, Ph.D., Senior Research Investigator, Allergan + Bo Chen, Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School + Daniel C. Chung, DO, MA, Instructor of Ophthalmology, University of Pennsylvania School of Medicine + Robert J. Collier, Ph.D., Associate Director, Retina Drug Discovery, Alcon Research + Valeriu Damian, Manager, GlaxoSmithKline + Darlene A. Dartt, Scepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School + Philip D. Gregory, Ph.D., Chief Scientific Officer, Sangamo BioSciences + Avner Ingerman, M.D., M.Sc, Senior Vice President, General Manager, ORA Clinical R&D + Konrad Kauper, Director, Tissue Engineering, Neurotech + Ivan B. Lobov, Ph.D., Staff Scientist, Ophthalmology Therapeutics, Regeneron + Karen Meerovitch, Ph.D., Senior Director, Mimetogen Pharmaceuticals + Takahiro Ogawa, Ph.D., Senior Vice President, Research and Development, Senju USA + George W. Ousler III, Director of Dry Eye, ORA Clinical Research and Development + Michael A. Patane, Ph.D., Chief Scientific Officer, EyeGate Pharmaceuticals + Przemyslaw Mike Sapieha, Ph.D., Assistant Professor, Ophthalmology, University of Montreal + Abraham Scaria, Ph.D., Senior Scientific Director, Genzyme + David Sherris, Ph.D., President and Chief Executive Officer, Paloma Pharmaceuticals + Craig Struble, Ph.D., Associate Technical Director, Drug Metabolism, Covance + Jennifer Sun, M.D., MPH, Beetham Eye Institute, Joslin Diabetes Center + Corinne G. Wong, Ph.D., Principal, Chief Scientific Officer, SCLERA + Wai T. Wong, M.D., Ph.D., Chief, Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, NIH + David F. Woodward, Ph.D., Senior Director, Allergan
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