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Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective


How Drugs are Developed and Approved

The mission of FDA’s Center for Drug Evaluation and Research (CDER) is to ensure that drugs marketed in this country are safe and effective. CDER does not test drugs, although the Center’s Office of Testing and Research does conduct limited research in the areas of drug quality, safety, and effectiveness.

CDER is the largest of FDA’s five centers.   It has responsibility for both prescription and nonprescription or over-the-counter (OTC) drugs. For more information on CDER activities, including performance of drug reviews,  post-marketing risk assessment, and other highlights, please see the CDER Update: Improving Public Health Through Human Drugs The other four FDA centers have responsibility for medical and radiological devices, food, and cosmetics, biologics, and veterinary drugs.

Some companies submit a new drug application (NDA) to introduce a new drug product into the U.S. Market.  It is the responsibility of the company seeking to market a drug to test it and submit evidence that it is safe and effective. A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the sponsor’s NDA containing the data and proposed labeling.

The section below entitled From Fish to Pharmacies: The Story of a Drug’s Development, illustrates how a drug sponsor can work with FDA’s regulations and guidance information to bring a new drug to market under the NDA process.

From Fish to Pharmacies:  A Story of Drug Development

Osteoporosis, a crippling disease marked by a wasting away of bone mass, affects as many as 2 million American, 80 percent of them women, at an expense of $13.8 billion a year, according to the National Osteoporosis Foundation.,  The disease may be responsible for 5 million fractures of the hip, wrist and spine in people over 50, the foundation says, and may cause 50,000 deaths. Given the pervasiveness of osteoporosis and its cost to society, experts say it is crucial to have therapy alternatives if, for example, a patient can’t tolerate estrogen, the first-line treatment.

Enter the salmon, which, like humans, produces a hormone called calcitonin that helps regulate calcium and decreases bone loss.  For osteoporosis patients, taking salmon calcitonin, which is 30 times more potent than that secreted by the human thyroid gland, inhibits the activity of specialized bone cells called osteoclasts that absorb bone tissue.  This enables bone to retain more bone mass.

Though the calcitonin in drugs is based chemically on salmon calcitonin, it is now made synthetically in the lab in a form that copies the molecular structure of the fish gland extract.  Synthetic calcitonin offers a simpler, more economical way to create large quantities of the product.

FDA approved the first drug based on salmon calcitonin in an injectable. Since then, two more drugs, one injectable and one administered through a nasal spray were approved.  An oral version of salmon calcitonin is in clinical trials now.  Salmon calcitonin is approved only for postmenopausal women who cannot tolerate estrogen, or for whom estrogen is not an option.

How did the developers of injectable salmon calcitonin journey “from fish to pharmacies?”

After obtaining promising data from laboratory studies, the salmon calcitonin drug developers took the next step and submitted an Investigational New Drug (IND) application to CDER.  The IND Web page explains the need for this application, the kind of information the application should include, and the Federal regulations to follow.

Once the IND application is in effect, the drug sponsor of salmon calcitonin could begin their clinical trials.  After a sponsor submits an IND application, it must wait 30 days before starting a clinical trial to allow FDA time to review the prospective study.  If FDA finds a problem, it can order a  “clinical hold” to delay an investigation, or interrupt a clinical trial if problems occur during the study.

Clinical trials are experiments that use human subjects to see whether a drug is effective, and what side effects it may cause.  The Running Clinical Trials Webpage provides links to the regulations and guidelines that the clinical investigators of salmon calcitonin must have used to conduct a successful study, and to protect their human subjects.

The salmon calcitonin drug sponsor analyzed the clinical trials data and concluded that enough evidence existed on the drug’s safety and effectiveness to meet FDA’s requirements for marketing approval.  The sponsor submitted a New Drug Application (NDA) with full information on manufacturing specifications, stability and bioavailablility data, method of analysis of each of the dosage forms the sponsor intends to market, packaging and labeling for both physician and consumer, and the results of any additional toxicological studies not already submitted in the Investigational New Drug application.  The NDA Web page   provides resources and guidance on preparing the NDA application, and what to expect during the review process.

New drugs, like other new products, are frequently under patent protection during development. The patent protects the salmon calcitonin sponsor’s investment in the drug’s development by giving them the sole right to sell the drug while the patent is in effect.   When the patents or other periods of exclusivity on brand-name drugs expire, manufacturers can apply to the FDA to sell generic versions. TheAbbreviated New Drug Applications (ANDA) for Generic Drug Products Webpageprovides  links to guidances, laws, regulations, policies and procedures, plus other resources to assist in preparing and submitting applications.

Bringing Nonprescription Drug Products to the Market Under an OTC Monograph

OTC drugs can be brought to the market following the NDA process as described above or under an OTC monograph. Each OTC drug monograph is a kind of “recipe book” covering acceptable ingredients, doses, formulations, labeling, and, in some cases, testing parameters. OTC drug monographs are continually updated to add additional ingredients and labeling as needed. Products conforming to a monograph may be marketed without FDA pre-approval. The NDA and monograph processes can be used to introduce new ingredients into the OTC marketplace. For example, OTC drug products previously available only by prescription are first approved through the NDA process and their “switch” to OTC status is approved via the NDA process. OTC ingredients marketed overseas can be introduced into the U.S. market via a monograph under a Time and Extent Application (TEA) as described in 21 CFR 330.14. For a more thorough discussion of how OTC drug products are regulated visit  FDA laws, regulations and guidances that affect small business. Information is also provided on financial assistance and incentives that are available for drug development.

CDER Small Business and Industry Assistance (CDER SBIA)

Drug sponsors which qualify as small businesses can take advantage of special offices and programs designed to help meet their unique needs. The CDER Small Business and Industry Assistance (CDER SBIA) Webpage provides links to FDA laws, regulations and guidances that affect small business. Information is also provided on financial assistance and incentives that are available for drug development.

 

The path a drug travels from a lab to your medicine cabinet is usually long, and every drug takes a unique route. Often, a drug is developed to treat a specific disease. An important use of a drug may also be discovered by accident.

For example, Retrovir (zidovudine, also known as AZT) was first studied as an anti-cancer drug in the 1960s with disappointing results. Twenty years later, researchers discovered the drug could treat AIDS, and Food and Drug Administration approved the drug, manufactured by GlaxoSmithKline, for that purpose in 1987.

Most drugs that undergo preclinical (animal) testing never even make it to human testing and review by the FDA. The drugs that do must undergo the agency’s rigorous evaluation process, which scrutinizes everything about the drug–from the design of clinical trials to the severity of side effects to the conditions under which the drug is manufactured.

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Stages of Drug Development and Review Banner

Animal Testing Icon

Investigational New Drug Application (IND)–The pharmaceutical industry sometimes seeks advice from the FDA prior to submission of an IND.

Sponsors–companies, research institutions, and other organizations that take responsibility for developing a drug. They must show the FDA results of preclinical testing in laboratory animals and what they propose to do for human testing. At this stage, the FDA decides whether it is reasonably safe for the company to move forward with testing the drug in humans.

IND Application Icon

Clinical Trials–Drug studies in humans can begin only after an IND is reviewed by the FDA and a local institutional review board (IRB). The board is a panel of scientists and non-scientists in hospitals and research institutions that oversees clinical research.

IRBs approve the clinical trial protocols, which describe the type of people who may participate in the clinical trial, the schedule of tests and procedures, the medications and dosages to be studied, the length of the study, the study’s objectives, and other details. IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm.

Phase 1 Clinical Trial Icon

Phase 1 studies are usually conducted in healthy volunteers. The goal here is to determine what the drug’s most frequent side effects are and, often, how the drug is metabolized and excreted. The number of subjects typically ranges from 20 to 80.

Phase 2 Clinical Trial Icon
Phase 2 studies begin if Phase 1 studies don’t reveal unacceptable toxicity. While the emphasis in Phase 1 is on safety, the emphasis in Phase 2 is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment–usually an inactive substance (placebo), or a different drug. Safety continues to be evaluated, and short-term side effects are studied. Typically, the number of subjects in Phase 2 studies ranges from a few dozen to about 300.

Phase 3 Clinical Trial Icon

At the end of Phase 2, the FDA and sponsors try to come to an agreement on how large-scale studies in Phase 3 should be done. How often the FDA meets with a sponsor varies, but this is one of two most common meeting points prior to submission of a new drug application. The other most common time is pre-NDA–right before a new drug application is submitted.
Phase 3 studies begin if evidence of effectiveness is shown in Phase 2. These studies gather more information about safety and effectiveness, studying different populations and different dosages and using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people.

Review Meeting Icon

Postmarket requirement and commitment studies are required of or agreed to by a sponsor, and are conducted after the FDA has approved a product for marketing. The FDA uses postmarket requirement and commitment studies to gather additional information about a product’s safety, efficacy, or optimal use.

NDA Application Icon

New Drug Application (NDA)–This is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the United States. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured
Application Reviewed Icon
When an NDA comes in, the FDA has 60 days to decide whether to file it so that it can be reviewed. The FDA can refuse to file an application that is incomplete. For example, some required studies may be missing. In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA’s Center for Drug Evaluation and Research (CDER) expects to review and act on at least 90 percent of NDAs for standard drugs no later than 10 months after the applications are received. The review goal is six months for priority drugs. (See “The Role of User Fees.”)

“It’s the clinical trials that take so long–usually several years,” says Sandra Kweder, M.D., deputy director of the Office of New Drugs in the CDER. “The emphasis on speed for FDA mostly relates to review time and timelines of being able to meet with sponsors during a drug’s development,” she says.

Drug Approval Process Infographic

View larger image and printable PDF version of Drug Approval Process Infographic


Drug Review Steps Simplified

  1. Preclinical (animal) testing.
  2. An investigational new drug application (IND) outlines what the sponsor of a new drug proposes for human testing in clinical trials.
  3. Phase 1 studies (typically involve 20 to 80 people).
  4. Phase 2 studies (typically involve a few dozen to about 300 people).
  5. Phase 3 studies (typically involve several hundred to about 3,000 people).
  6. The pre-NDA period, just before a new drug application (NDA) is submitted. A common time for the FDA and drug sponsors to meet.
  7. Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval.
  8. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed.
  9. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor’s research on the drug’s safety and effectiveness.
  10. The FDA reviews information that goes on a drug’s professional labeling (information on how to use the drug).
  11. The FDA inspects the facilities where the drug will be manufactured as part of the approval process.
  12. FDA reviewers will approve the application or issue a complete response letter.

Supplemental Information About the Drug Approval Process

Reviewing Applications

Though FDA reviewers are involved with a drug’s development throughout the IND stage, the official review time is the length of time it takes to review a new drug application and issue an action letter, an official statement informing a drug sponsor of the agency’s decision.

Once a new drug application is filed, an FDA review team–medical doctors, chemists, statisticians, microbiologists, pharmacologists, and other experts–evaluates whether the studies the sponsor submitted show that the drug is safe and effective for its proposed use. No drug is absolutely safe; all drugs have side effects. “Safe” in this sense means that the benefits of the drug appear to outweigh the known risks.

The review team analyzes study results and looks for possible issues with the application, such as weaknesses of the study design or analyses. Reviewers determine whether they agree with the sponsor’s results and conclusions, or whether they need any additional information to make a decision.

Each reviewer prepares a written evaluation containing conclusions and recommendations about the application. These evaluations are then considered by team leaders, division directors, and office directors, depending on the type of application.

Reviewers receive training that fosters consistency in drug reviews, and good review practices remain a high priority for the agency.

Sometimes, the FDA calls on advisory committees, who provide FDA with independent opinions and recommendations from outside experts on applications to market new drugs, and on FDA policies.  Whether an advisory committee is needed depends on many things.

“Some considerations would be if it’s a drug that has significant questions, if it’s the first in its class, or the first for a given indication,” says Mark Goldberger, M.D., a former director of one of CDER’s drug review offices. “Generally, FDA takes the advice of advisory committees, but not always,” he says. “Their role is just that–to advise.”Accelerated Approval

Traditional approval requires that clinical benefit be shown before approval can be granted. Accelerated approval is given to some new drugs for serious and life-threatening illnesses that lack satisfactory treatments. This allows an NDA to be approved before measures of effectiveness that would usually be required for approval are available.

Instead, less traditional measures called surrogate endpoints are used to evaluate effectiveness. These are laboratory findings or signs that may not be a direct measurement of how a patient feels, functions, or survives, but are considered likely to predict benefit. For example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of time with anti-retroviral drugs.

Gleevec (imatinib mesylate), an oral treatment for patients with a life-threatening form of cancer called chronic myeloid leukemia (CML), received accelerated approval. The drug was also approved under the FDA’s orphan drug program, which gives financial incentives to sponsors for manufacturing drugs that treat rare diseases. Gleevec blocks enzymes that play a role in cancer growth. The approval was based on results of three large Phase 2 studies, which showed the drug could substantially reduce the level of cancerous cells in the bone marrow and blood.

Most drugs to treat HIV have been approved under accelerated approval provisions, with the company required to continue its studies after the drug is on the market to confirm that its effects on virus levels are maintained and that it ultimately benefits the patient. Under accelerated approval rules, if studies don’t confirm the initial results, the FDA can withdraw the approval.

Because premarket review can’t catch all potential problems with a drug, the FDA continues to track approved drugs for adverse events through a postmarketing surveillance program.

Bumps in the Road

If the FDA decides that the benefits of a drug outweigh the known risks, the drug will receive approval and can be marketed in the United States. But if there are problems with an NDA or if more information is necessary to make that determination, the FDA may issue a complete response letter.

Common problems include unexpected safety issues that crop up or failure to demonstrate a drug’s effectiveness. A sponsor may need to conduct additional studies–perhaps studies of more people, different types of people, or for a longer period of time.

Manufacturing issues are also among the reasons that approval may be delayed or denied. Drugs must be manufactured in accordance with standards called good manufacturing practices, and the FDA inspects manufacturing facilities before a drug can be approved. If a facility isn’t ready for inspection, approval can be delayed. Any manufacturing deficiencies found need to be corrected before approval.

“Sometimes a company may make a certain amount of a drug for clinical trials. Then when they go to scale up, they may lose a supplier or end up with quality control issues that result in a product of different chemistry,” says Kweder. “Sponsors have to show us that the product that’s going to be marketed is the same product that they tested.”

John Jenkins, M.D., director of CDER’s Office of New Drugs, says, “It’s often a combination of problems that prevent approval.” Close communication with the FDA early on in a drug’s development reduces the chance that an application will have to go through more than one cycle of review, he says. “But it’s no guarantee.”

The FDA outlines the justification for its decision in a complete response letter to the drug sponsor and CDER gives the sponsor a chance to meet with agency officials to discuss the deficiencies. At that point, the sponsor can ask for a hearing, correct any deficiencies and submit new information, or withdraw the application.

The Role of User Fees

Since PDUFA was passed in 1992, more than 1,000 drugs and biologics have come to the market, including new medicines to treat cancer, AIDS, cardiovascular disease, and life-threatening infections. PDUFA has allowed the Food and Drug Administration to bring access to new drugs as fast or faster than anywhere in the world, while maintaining the same thorough review process.

Under PDUFA, drug companies agree to pay fees that boost FDA resources, and the FDA agrees to time goals for its review of new drug applications. Along with supporting increased staff, drug user fees help the FDA upgrade resources in information technology. The agency has moved toward an electronic submission and review environment, now accepting more electronic applications and archiving review documents electronically.

The goals set by PDUFA apply to the review of original new human drug and biological applications, resubmissions of original applications, and supplements to approved applications. The second phase of PDUFA, known as PDUFA II, was reauthorized in 1997 and extended the user fee program through September 2002. PDUFA III, which extended to Sept. 30, 2007, was reauthorized in June 2002.

PDUFA III allowed the FDA to spend some user fees to increase surveillance of the safety of medicines during their first two years on the market, or three years for potentially dangerous medications. It is during this initial period, when new medicines enter into wide use, that the agency is best able to identify and counter adverse side effects that did not appear during the clinical trials.

On September 27, 2007, President Bush signed into law the Food and Drug Administration Amendments Act of 2007 which includes the reauthorization and expansion of the Prescription Drug User Fee Act. The reauthorization of PDUFA will significantly broaden and upgrade the agency’s drug safety program, and facilitate more efficient development of safe and effective new medications for the American public.

In addition to setting time frames for review of applications, PDUFA sets goals to improve communication and sets goals for specific kinds of meetings between the FDA and drug sponsors. It also outlines how fast the FDA must respond to requests from sponsors. Throughout a drug’s development, the FDA advises sponsors on how to study certain classes of drugs, how to submit data, what kind of data are needed, and how clinical trials should be designed.

The Quality of Clinical Data

The Food and Drug Administration relies on data that sponsors submit to decide whether a drug should be approved. To protect the rights and welfare of people in clinical trials, and to verify the quality and integrity of data submitted, the FDA’s Division of Scientific Investigations (DSI) conducts inspections of clinical investigators’ study sites. DSI also reviews the records of institutional review boards to be sure they are fulfilling their role in patient protection.

“FDA investigators compare information that clinical investigators provided to sponsors on case report forms with information in source documents such as medical records and lab results,” says Carolyn Hommel, a consumer safety officer in DSI.

DSI seeks to determine such things as whether the study was conducted according to the investigational plan, whether all adverse events were recorded, and whether the subjects met the inclusion/exclusion criteria outlined in the study protocol.

At the conclusion of each inspection, FDA investigators prepare a report summarizing any deficiencies. In cases where they observe numerous or serious deviations, such as falsification of data, DSI classifies the inspection as “official action indicated” and sends a warning letter or Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) to the clinical investigator, specifying the deviations that were found.

The NIDPOE begins an administrative process to determine whether the clinical investigator should remain eligible to receive investigational products and conduct clinical studies.

CDER conducts about 300-400 clinical investigator inspections annually. About 3 percent are classified in this “official action indicated” category.

The FDA has established an independent Drug Safety Oversight Board (DSOB) to oversee the management of drug safety issues. The Board meets monthly and has representatives from three FDA Centers and five other federal government agencies. The board’s responsibilities include conducting timely and comprehensive evaluations of emerging drug safety issues, and ensuring that experts–both inside and outside of the FDA–give their perspectives to the agency. The first meeting of the DSOB was held in June 2005.

Once the review is complete, the NDA might be approved or rejected. If the drug is not approved, the applicant is given the reasons why and what information could be provided to make the application acceptable. Sometimes the FDA makes a tentative approval recommendation, requesting that a minor deficiency or labeling issue be corrected before final approval. Once a drug is approved, it can be marketed.

Some approvals contain conditions that must be met after initial marketing, such as conducting additional clinical studies. For example, the FDA might request a postmarketing, or phase 4, study to examine the risks and benefits of the new drug in a different population or to conduct special monitoring in a high-risk population. Alternatively, a phase 4 study might be initiated by the sponsor to assess such issues as the longer term effects of drug exposure, to optimize the dose for marketing, to evaluate the effects in pediatric patients, or to examine the effectiveness of the drug for additional indications. Postmarketing surveillance is important, because even the most well-designed phase 3 studies might not uncover every problem that could become apparent once a product is widely used. Furthermore, the new product might be more widely used by groups that might not have been well studied in the clinical trials, such as elderly patients. A crucial element in this process is that physicians report any untoward complications. The FDA has set up a medical reporting program called Medwatch to track serious adverse events (1-800-FDA-1088). The manufacturer must report adverse drug reactions at quarterly intervals for the first 3 years after approval,  including a special report for any serious and unexpected adverse reactions.

Recent Developments in Drug Approval

The Food and Drug Administration Modernization Act of 1997 (FDAMA) extended the use of user fees and focused on streamlining the drug approval process.  In 1999, the 35 drugs approved by the FDA were reviewed in an average of 12.6 months, slightly more than the 12-month goal set by PDUFA.  This act also increased patient access to experimental drugs and facilitated an accelerated review of important new medications. The law ended the ban on disseminating information to providers about non-FDA-approved uses of medications. A manufacturer can now provide peer-reviewed journal articles about an off-label indication of a product if the company commits to filing a supplemental application to establish the use of the unapproved indication. As part of this process, the company must still conduct its own phase 4 study. As a condition for an accelerated approval, the FDA can require the sponsor to carry out postmarketing studies to confirm a clinical benefit and product safety. Critics contend the 1997 act compromises public safety by lowering the standard of approval.  Within a year after the law was passed, several drugs were removed from the market. Among these medications were mibefradil for hypertension, dexfenfluramine for morbid obesity, the antihistamine terfenadine, and bromfenac sodium for pain.  More recently, additional drugs including troglitazone were removed from the market. Although the increase in recalls might reflect the dramatic increase in drugs approved and launched, others argue that several safety questions were ignored.  Another concern was that many withdrawn drugs were me-too drugs which did not represent a noteworthy advance in therapy. Persons critical of the FDA believe changes in the approval process, such as allowing some new drugs to be approved based on only a single clinical trial, expanded use of accelerated approvals, and the use of surrogate end points, have created a dangerous situation.  Proponents of the changes in the approval process argue that there is no evidence of increased risk from the legislative changes,  and that these changes improve access to cancer patients and those with debilitating disease who were previously denied critical and lifesaving medications.

New drugs are an important part of modern medicine. Just a few decades ago, a disease such as peptic ulcers was a frequent indication for major surgery. The advent of new pharmacologic treatments has dramatically reduced the serious complications of peptic ulcer disease. Likewise, thanks to many new antiviral medications, the outlook for HIV-infected patients has improved dramatically. It is important that physicians understand the process of approving these new medications. Understanding the process can promote innovation, help physicians assess new products, underline the importance of reporting adverse drug events, and provide physicians with the information to educate patients about participating in a clinical trial.

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Drug discovery


In the fields of medicinebiotechnology and pharmacologydrug discovery is the process by which new candidate medications are discovered.

Historically, drugs were discovered through identifying the active ingredient from traditional remedies or by serendipitous discovery. Later chemical libraries of synthetic small moleculesnatural products or extracts were screened in intact cells or whole organisms to identify substances that have a desirable therapeutic effect in a process known as classical pharmacology. Sincesequencing of the human genome which allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease modifying in a process known as reverse pharmacology.

 

Hits from these screens are then tested in cells and then in animals for efficacy. Even more recently, scientists have been able to understand the shape of biological molecules at the atomic level, and to use that knowledge to design (seedrug design) drug candidates.

Modern drug discovery involves the identification of screening hits, medicinal chemistry and optimization of those hits to increase the affinityselectivity (to reduce the potential of side effects), efficacy/potencymetabolic stability (to increase the half-life), and oral bioavailability. Once a compound that fulfills all of these requirements has been identified, it will begin the process of drug development prior to clinical trials. One or more of these steps may, but not necessarily, involve computer-aided drug design.

Despite advances in technology and understanding of biological systems, drug discovery is still a lengthy, “expensive, difficult, and inefficient process” with low rate of new therapeutic discovery.[1]In 2010, the research and development cost of each new molecular entity (NME) was approximately US$1.8 billion.[2] Drug discovery is done by pharmaceutical companies, with research assistance from universities. The “final product” of drug discovery is a patent on the potential drug. The drug requires very expensive Phase I, II and III clinical trials, and most of them fail. Small companies have a critical role, often then selling the rights to larger companies that have the resources to run the clinical trials.

Drug targets

The definition of “target” itself is something argued within the pharmaceutical industry. Generally, the “target” is the naturally existing cellular or molecular structure involved in the pathology of interest that the drug-in-development is meant to act on. However, the distinction between a “new” and “established” target can be made without a full understanding of just what a “target” is. This distinction is typically made by pharmaceutical companies engaged in discovery and development of therapeutics. In an estimate from 2011, 435 human genome products were identified as therapeutic drug targets of FDA-approved drugs.[3]

“Established targets” are those for which there is a good scientific understanding, supported by a lengthy publication history, of both how the target functions in normal physiology and how it is involved in human pathology. This does not imply that the mechanism of action of drugs that are thought to act through a particular established targets is fully understood. Rather, “established” relates directly to the amount of background information available on a target, in particular functional information. The more such information is available, the less investment is (generally) required to develop a therapeutic directed against the target.

The process of gathering such functional information is called “target validation” in pharmaceutical industry parlance. Established targets also include those that the pharmaceutical industry has had experience mounting drug discovery campaigns against in the past; such a history provides information on the chemical feasibility of developing a small molecular therapeutic against the target and can provide licensing opportunities and freedom-to-operate indicators with respect to small-molecule therapeutic candidates.

In general, “new targets” are all those targets that are not “established targets” but which have been or are the subject of drug discovery campaigns. These typically include newly discoveredproteins, or proteins whose function has now become clear as a result of basic scientific research.

The majority of targets currently selected for drug discovery efforts are proteins. Two classes predominate: G-protein-coupled receptors (or GPCRs) and protein kinases.

Screening and design

The process of finding a new drug against a chosen target for a particular disease usually involves high-throughput screening (HTS), wherein large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor (see antagonist and agonist): if the target is a protein kinase, the chemicals will be tested for their ability to inhibit that kinase.

Another important function of HTS is to show how selective the compounds are for the chosen target. The ideal is to find a molecule which will interfere with only the chosen target, but not other, related targets. To this end, other screening runs will be made to see whether the “hits” against the chosen target will interfere with other related targets – this is the process of cross-screening. Cross-screening is important, because the more unrelated targets a compound hits, the more likely that off-target toxicity will occur with that compound once it reaches the clinic.

It is very unlikely that a perfect drug candidate will emerge from these early screening runs. It is more often observed that several compounds are found to have some degree of activity, and if these compounds share common chemical features, one or more pharmacophores can then be developed. At this point, medicinal chemists will attempt to use structure-activity relationships (SAR) to improve certain features of the lead compound:

  • increase activity against the chosen target
  • reduce activity against unrelated targets
  • improve the druglikeness or ADME properties of the molecule.

This process will require several iterative screening runs, during which, it is hoped, the properties of the new molecular entities will improve, and allow the favoured compounds to go forward to in vitro and in vivo testing for activity in the disease model of choice.
Amongst the physico-chemical properties associated with drug absorption include ionization (pKa), and solubility; permeability can be determined by PAMPA and Caco-2. PAMPA is attractive as an early screen due to the low consumption of drug and the low cost compared to tests such as Caco-2, gastrointestinal tract (GIT) and Blood–brain barrier (BBB) with which there is a high correlation.

A range of parameters can be used to assess the quality of a compound, or a series of compounds, as proposed in the Lipinski’s Rule of Five. Such parameters include calculated properties such as cLogP to estimate lipophilicity, molecular weightpolar surface area and measured properties, such as potency, in-vitro measurement of enzymatic clearance etc. Some descriptors such asligand efficiency[4] (LE) and lipophilic efficiency[5][6] (LiPE) combine such parameters to assess druglikeness.

While HTS is a commonly used method for novel drug discovery, it is not the only method. It is often possible to start from a molecule which already has some of the desired properties. Such a molecule might be extracted from a natural product or even be a drug on the market which could be improved upon (so-called “me too” drugs). Other methods, such as virtual high throughput screening, where screening is done using computer-generated models and attempting to “dock” virtual libraries to a target, are also often used.

Another important method for drug discovery is drug design, whereby the biological and physical properties of the target are studied, and a prediction is made of the sorts of chemicals that might (e.g.) fit into an active site. One example is fragment-based lead discovery (FBLD). Novel pharmacophores can emerge very rapidly from these exercises. In general, computer-aided drug design is often but not always used to try to improve the potency and properties of new drug leads.

Once a lead compound series has been established with sufficient target potency and selectivity and favourable drug-like properties, one or two compounds will then be proposed for drug development. The best of these is generally called the lead compound, while the other will be designated as the “backup”.

Historical background

The idea that effect of drug in human body are mediated by specific interactions of the drug molecule with biological macromolecules, (proteins or nucleic acids in most cases) led scientists to the conclusion that individual chemicals are required for the biological activity of the drug. This made for the beginning of the modern era in pharmacology, as pure chemicals, instead of crude extracts, became the standard drugs. Examples of drug compounds isolated from crude preparations are morphine, the active agent in opium, and digoxin, a heart stimulant originating from Digitalis lanata. Organic chemistry also led to the synthesis of many of the cochemicals isolated from biological sources.

Nature as source of drugs

Despite the rise of combinatorial chemistry as an integral part of lead discovery process, natural products still play a major role as starting material for drug discovery.[7] A report was published in 2007,[8] covering years 1981-2006 details the contribution of biologically occurring chemicals in drug development. According to this report, of the 974 small molecule new chemical entities, 63% were natural derived or semisynthetic derivatives of natural products. For certain therapy areas, such as antimicrobials, antineoplastics, antihypertensive and anti-inflammatory drugs, the numbers were higher. In many cases, these products have been used traditionally for many years.

Natural products may be useful as a source of novel chemical structures for modern techniques of development of antibacterial therapies.[9]

Despite the implied potential, only a fraction of Earth’s living species has been tested for bioactivity.

Plant-derived

Prior to Paracelsus, the vast majority of traditionally used crude drugs in Western medicine were plant-derived extracts. This has resulted in a pool of information about the potential of plant species as an important source of starting material for drug discovery. A different set of metabolites is sometimes produced in the different anatomical parts of the plant (e.g. root, leaves and flower), and botanical knowledge is crucial also for the correct identification of bioactive plant materials.

Microbial metabolites

Microbes compete for living space and nutrients. To survive in these conditions, many microbes have developed abilities to prevent competing species from proliferating. Microbes are the main source of antimicrobial drugs. Streptomyces species have been a valuable source of antibiotics. The classical example of an antibiotic discovered as a defense mechanism against another microbe is the discovery of penicillin in bacterial cultures contaminated by Penicillium fungi in 1928.

Marine invertebrates

Marine environments are potential sources for new bioactive agents.[10] Arabinose nucleosides discovered from marine invertebrates in 1950s, demonstrating for the first time that sugar moieties other than ribose and deoxyribose can yield bioactive nucleoside structures. However, it was 2004 when the first marine-derived drug was approved. The cone snail toxin ziconotide, also known as Prialt, was approved by the Food and Drug Administration to treat severe neuropathic pain. Several other marine-derived agents are now in clinical trials for indications such as cancer, anti-inflammatory use and pain. One class of these agents are bryostatin-like compounds,under investigation as anti-cancer therapy.

Chemical diversity of natural products

As above mentioned, combinatorial chemistry was a key technology enabling the efficient generation of large screening libraries for the needs of high-throughput screening. However, now, after two decades of combinatorial chemistry, it has been pointed out that despite the increased efficiency in chemical synthesis, no increase in lead or drug candidates has been reached.[8] This has led to analysis of chemical characteristics of combinatorial chemistry products, compared to existing drugs or natural products. The chemoinformatics concept chemical diversity, depicted as distribution of compounds in the chemical space based on their physicochemical characteristics, is often used to describe the difference between the combinatorial chemistry libraries and natural products. The synthetic, combinatorial library compounds seem to cover only a limited and quite uniform chemical space, whereas existing drugs and particularly natural products, exhibit much greater chemical diversity, distributing more evenly to the chemical space.[7] The most prominent differences between natural products and compounds in combinatorial chemistry libraries is the number of chiral centers (much higher in natural compounds), structure rigidity (higher in natural compounds) and number of aromatic moieties (higher in combinatorial chemistry libraries). Other chemical differences between these two groups include the nature of heteroatoms (O and N enriched in natural products, and S and halogen atoms more often present in synthetic compounds), as well as level of non-aromatic unsaturation (higher in natural products). As both structure rigidity and chirality are both well-established factors in medicinal chemistry known to enhance compounds specificity and efficacy as a drug, it has been suggested that natural products compare favourable to today’s combinatorial chemistry libraries as potential lead molecules.

Natural product drug discovery

Screening

Two main approaches exist for the finding of new bioactive chemical entities from natural sources.

The first is sometimes referred to as random collection and screening of material, but in fact the collection is often far from random in that biological (often botanical) knowledge is used about which families show promise, based on a number of factors, including past screening. This approach is based on the fact that only a small part of earth’s biodiversity has ever been tested for pharmaceutical activity. It is also based on the fact that organisms living in a species-rich environment need to evolve defensive and competitive mechanisms to survive, mechanisms which might usefully be exploited in the development of drugs that can cure diseases affecting humans. A collection of plant, animal and microbial samples from rich ecosystems can potentially give rise to novel biological activities worth exploiting in the drug development process. One example of a successful use of this strategy is the screening for antitumour agents by the National Cancer Institute, started in the 1960s. Paclitaxel was identified from Pacific yew tree Taxus brevifolia. Paclitaxel showed anti-tumour activity by a previously undescribed mechanism (stabilization of microtubules) and is now approved for clinical use for the treatment of lung, breast and ovarian cancer, as well as for Kaposi’s sarcoma. Early in the 21st century, Cabazitaxel (made by Sanofi, a French firm), another relative of taxol has been shown effective against prostate cancer, also because it works by preventing the formation of microtubules, which pull the chromosomes apart in dividing cells (such as cancer cells). Still another examples are: 1. Camptotheca (Camptothecin · Topotecan · Irinotecan · Rubitecan · Belotecan); 2. Podophyllum (Etoposide · Teniposide); 3a. Anthracyclines (Aclarubicin · Daunorubicin · Doxorubicin · Epirubicin · Idarubicin · Amrubicin · Pirarubicin · Valrubicin · Zorubicin); 3b. Anthracenediones (Mitoxantrone · Pixantrone).

Nor do all drugs developed in this manner come from plants. Professor Louise Rollins-Smith of Vanderbilt University‘s Medical Center, for example, has developed from the skin of frogs a compound which blocks AIDS. Professor Rollins-Smith is aware of declining amphibian populations and has said: “We need to protect these species long enough for us to understand their medicinal cabinet.”

The second main approach involves Ethnobotany, the study of the general use of plants in society, and ethnopharmacology, an area inside ethnobotany, which is focused specifically on medicinal uses.

Both of these two main approaches can be used in selecting starting materials for future drugs. Artemisinin, an antimalarial agent from sweet wormtree Artemisia annua, used in Chinese medicine since 200BC is one drug used as part of combination therapy for multiresistant Plasmodium falciparum.

Structural elucidation

The elucidation of the chemical structure is critical to avoid the re-discovery of a chemical agent that is already known for its structure and chemical activity. Mass spectrometry, often used to determine structure, is a method in which individual compounds are identified based on their mass/charge ratio, after ionization. Chemical compounds exist in nature as mixtures, so the combination of liquid chromatography and mass spectrometry (LC-MS) is often used to separate the individual chemicals. Databases of mass spectras for known compounds are available. Nuclear magnetic resonance spectroscopy is another important technique for determining chemical structures of natural products. NMR yields information about individual hydrogen and carbon atoms in the structure, allowing detailed reconstruction of the molecule’s architecture.

Business Insights’ drug discovery research stream critically analyzes the cutting edge technologies and novel approaches shaping the future of drug discovery.

Our analysis spans the entire drug discovery process, from target selection and validation to drug safety testing and clinical trial design, with assessment of both small-molecule and biologic modalities. Our independent experts highlight where the future opportunities lie and which companies are best positioned to take advantage.

The pharmaceutical industry is facing unprecedented pressure from a combination of factors: key product patent expiries, an increasingly demanding regulatory environment, declining R&D productivity, and escalating costs. The urgent need to combat these threats places a premium on scientific innovation, but innovation itself does not guarantee success. Achieving the required increase in drug discovery output will only be achieved by those making investments in the right diseases, biological targets, and therapeutic approaches, and the right technologies to expedite the process.

Typically research and drug discovery are not regulated at all. GLP starts with preclinical development, for example toxicology studies. Clinical trials are regulated by good clinical practice regulations and manufacturing through GMPs. There is a frequent misunderstanding that all laboratory operations are regulated by GLP. This is not true. For example, Quality Control laboratories in manufacturing are regulated by GMPs and not by GLPs. Also Good laboratory Practice regulations are frequently mixed up with good analytical practice. Applying good analytical practices is important but not sufficient, as we will see in this presentation. When small quantities of active ingredients are prepared in a research or development laboratory for use in samples for clinical trials or finished drugs, that activity has be covered by GMP and not by GLP.

Part 11 is FDA’s regulation on electronic records and signatures and applies for electronic records or to computer systems in all FDA regulated areas. For example, it applies for computers that are used in GLP studies.

Characteristic for GLPs is that they are study based where as GMPs are processed based.

Independent from Location and Duration of a Study

GLPs regulate all non-clinical safety studies that support or are intended to support applications for research or marketing permits for products regulated by the FDA, or by similar other national agencies. This includes drugs for human and animal use but also aroma and color additives in food, biological products and medical devices. The duration and location of the study is of no importance. For example GLP applies to short term experiments as well as to long term studies. And if a pharmaceutical company subcontracts part of a study to a university, that university still must comply with the same requirements as the sponsor company. Some laboratories tried to get away from GLP through outsourcing, but I can tell you this does not work.

Facility Management and Other Personnel

Qualification of Personnel

Like all regulations also GLPs have chapters on personnel.

The assumption is that in order to conduct GLP studies with the right quality a couple of things are important:* Number one there should be sufficient people and second, the personnel should be qualified.

The FDA is not specific at all what type of qualification or education people should have. Qualification can come from education, experience or additional trainings, but it should be documented. This also requires a good documentation of the job descriptions, the tasks and responsibilities.

Facility management

Responsibilities of facility management are well defined. They include to designate a study director and also to monitor the progress of the study and if it is not going well to replace the study director.

The management is responsible for many things, basically they should assure that a quality assurance unit is available, test and control articles are characterized, and that sufficient qualified personnel is available for the study.

Because it is obvious that management can not take care personally about all this they have to rely on other functions, for example GLPs require that the QA should give a regular report on the compliance status of the study.

Small Molecule Drugs versus Biomolecular Drugs (Biologics)

Biotechnology has created a broad range of therapies, including vaccines, cell or gene therapies, therapeutic protein hormones, cytokines and tissue growth factors, and monoclonal antibodies.  In this discussion we will focus on the categories of biomolecular drugs that are presently managed by the FDA Center for Drugs Evaluation and Research (CDER): monoclonal antibodies, cytokines, tissue growth factors and therpeutic proteins. Some of the data that we will show includes all biologics.  Modern biomolecular drugs arise through the processes of genetic engineering.

It has been a little over thirty years since human insulin received U.S. approval (1982) as the first genetically engineered biomolecular drug.  Since then biomolecular drugs have become a major force in the bio/pharmaceutical industry.  As seen in Table 1, based on worldwide sales, eight out of the top 20 biopharmaceuticals in 2012 were Biomolecular Drugs. (Ref 1, 2)  In fact seven of the top 10 were biomolecular drugs!

Table 1, Eight of the Top Twenty Biopharmaceuticals Worldwide in 2012 are BiomolecularDrugs (Data from references  US Ranking.  Copaxone ranked 9th in US Sales (Ref 3), and was unranked in worldwide sales.

This may come as a surprise to many in the U.S. where biomolecular drugs have yet to achieve such a prominent stature. In 2012 Humira, Enbrel, Remicade, Neulasta and Rituxan were in the top 10 drugs based on U.S. sales, but the small molecules Nexium, Abilify, Crestor, Advair, and Cymbalta were the top five.  None of the biomolecular drugs were in the top 10 in the U.S. in 2010. (How the rankings of drugs in the U.S. could be so different from the rest of the world is a whole other discussion.) In any event, the rise of biomolecular drugs into the top tier is a recent phenomenon.

Let us compare and contrast these two types of drugs – small molecule and biomolecular drugs, and see how the Industry deals with two seemingly very different types of drugs.

The bio/pharmaceutical industry embraces the discovery and development of both small molecule drugs (also referred to as New Chemical Entities or NCEs) and biomolecular drugs, also called biologics (also referred to as New Biological Entities or NBEs).  Small Molecule and biomolecular drugs can take on different names over the lifetime of drug discovery and development and marketing, as shown in Fig 1 and described in Ref 5.

Figure 1, Small Molecules and Biomolecules can take on different names over the lifetime of drug discovery and development and marketing.  Biosimilars are also referred to as Follow-on Biologics. Phase length is not implied by the size of stage marker. *NME relates to the first approvable drug as opposed to second indications or new formulations.   The application for a generic small molecule is an “Abbreviated New Drug Application” (ANDA) which doesn’t require clinical trials to prove equivalency.  Processes for biosimilars or follow-on biologics are in the discussion stage.

A biotechnology company or a biopharmaceutical company tends to focus on the discovery and development of biomolecular drugs. A bio/pharmaceutical company will have the resources to discover and develop both types of drugs, NCEs and NBEs.

Since the early ‘80s the number of INDs per year from NCEs has leveled off while the INDs from NBEs have increased and helped maintain an increasing number of INDs/year (up to 1993). Trusheim et al. and others have studied the number of new small molecule drug approvals (NMEs) compared to new biologic drug approvals (new BLAs) in the period between 1988-2008, Table 2.

Table 2, Numbers of New Small Molecule Drug Approvals per Year (NMEs) Compared to New Biologic Drug Approvals (new BLAs) 1988-2008.  Biologics here are not restricted to monoclonal antibodies, cytokines, tissue growth factors and therapeutic proteins.  Last line* shows therapeutic proteins and Mabs from Reichert 8  We extended the tally by Reichert beyond 2003 by adding our own count of Mab and therapeutic protein new BLAs from annual FDA reports through 2008.  Mullard and Kneller  recently published counts of NMEs and New BLAs which differ somewhat from Trusheim or Reichert .  We are not in a position to rectify the differences, except to offer a potential explanation – certain small peptide and protein drugs may be considered either biologics or small molecules (Kneller considered such drugs to be biologics).

The analysis by Trusheim et al. was not restricted to monoclonal antibodies, cytokines, tissue growth factors and therapeutic proteins.  They found that from 1988 to 2003 the industry averaged 34 NMEs and new BLAs per year, whereas from 2004-2008 the industry averaged only 21 NMEs and new BLAs per year.  Within those two periods the percentage of new BLAs was quite similar (31% vs 32%).    To add some perspective we include the mabs and therapeutic proteins counted by Reichert.  By the numbers, all biologics are making a substantial contribution to the number of new drugs approved per year.

By 1997 worldwide sales of biologics were over $7 billion dollars.  The global sales of biologics have continued to rise – monoclonal antibodies alone in 2006 totaled $4.7 billion dollars.

A popular misconception is that in the early days most of the new biologics were discovered and developed within biotech companies.  Certainly few of the classically NCE-oriented companies entered the NBE arena – The pharmaceutical companies J&J (Ortho Biotech), Lilly and Roche were early players, getting BLAs approved in the ‘80s, Table 3.

Table 3, Early Biotech and Drug Company Biologics Approvals (without Diagnostics)

But 50% of the BLAs in the 80’s came from drug companies.  In the ‘90s, 52% of the BLAs came from drug companies (data from Table 3).  Thus while  a lot of investment may have gone into biotech startups, it was the previous experience of the drug companies with bringing drugs to market that made them at least equal partners in that aspect of biomolecular R&D.  Still only 17 drug companies and 16 biotech companies got BLAs in the ‘80s and ‘90s which is a small subset of the pharmaceutical industry.  By 1998 the PhRMA determined that more than 140 US-based companies were engaged in biomolecular drug development.  Most likely many more pharmaceutical companies were investing in biotech in that period.  The investment in biologics was enormous and the payout uncertain. As with the discovery and development of any drug it took years before the new biotechs achieved their first BLA, over 14 years on average, Table 4.

Table 4 Early Biotech Approvals – Years Since Founding.

While many of the discoveries of new biologics continue to originate in biotech companies, the clinical development of new biologics are increasingly supported by large pharma which had been NCE-oriented, Table 3.

In recent years most of the large pharma have gained an expertise in biologics through entry into field, and also through acquisitions and are now bio/pharmaceutical companies, Table 5.. The acquisition of Genzyme by Sanofi-Aventis is a most recent example.

Table 5, Notable Acquisitions and Partnerships involving Biologics

A recent collaborative study by Deloitte and Thomson Reuters showed that the twelve top bio/pharmaceutical companies all had biologics in their late stage portfolios, ranging from 21-66% of their portfolios (avg. 39%)

Prior to the ‘80s there were sufficiently few biomolecular drugs that the very term “pharmaceutical” or “drug” was taken to mean small molecule. With the exception of insulin, the few biomolecules approved for human use were administered by a trained health practitioner and were often considered “therapies”. Thus one may see the comparison of “small molecule drugs (or pharmaceuticals) versus large molecule therapies”. Here we will consider a large molecule therapy that is regulated by CDER to be a biomolecular type of drug or pharmaceutical.

The term for first small molecule drug approval, or New Molecular Entity (NME) could in theory be applied to first biologic approval, but because NME has long been associated with small molecules it is not being associated with first biologic approval – which is simply called a new BLA.

On March 23, 2010 President Obama signed into law the Biologics Price Competition and Innovation Act (BPCIA) which provides for biosimilar biologic drug approvals, as part of the omnibus health care bill. As the FDA develops guidelines for biosimilar approvals and begins to review applications for biosimilars, biologics will begin to enter the large generics market in the U.S.

The Processes that Give Rise to Biomolecular Drugs. Human insulin was the first recombinant biopharmaceutical approved in the U.S. in 1982. Prior to that protein products approved for use in humans were extracted from natural sources. It is beyond the scope of this website to delve into the details of the processes that give rise to biomolecular drugs or small molecule drugs. The following are good general references that cover the processes involved in the discovery and development of both small molecule drugs and biomolecular drugs.

Understanding the Differences and Similarities Between Small Molecules and Biologics. Now, more than ever, anyone interested in understanding the bio/pharmaceutical industry will need to understand both the differences and similarities between small molecules and biologics and their discovery and development as drugs.

1. How Do Small Molecule Drugs Differ from Biomolecular Drugs?

One has only to consider the size of biologics to recognize that the technologies that give rise to biomolecular drugs must be considerably different from the classical small molecule drugs. Genentech equates the difference between aspirin (21 atoms) and an antibody (~25,000 atoms) to the difference in weight between a bicycle (~20 lbs) and a business jet (~30,000 lbs).19 We will consider how they differ with respect to distribution, metabolism, serum half-life, typical dosing regimen, toxicity, species reactivity, antigenicity, clearance mechanisms, and drug-drug interactions (especially small molecule/biologic drug interactions).

A project leader who has worked in one field and is now facing the prospect of leading a project in the other field should become familiar with these differences as they will give rise to issues that the project leader may not have faced before.

2. Historical Changes in FDA Biologics Oversite in Response to the Biotech Boom

Prior to the ‘80s biologics were extracted from natural sources and required different regulatory oversight than that of small molecule drugs. Since then, the production of biologics shifted to recombinant proteins, which involved more consistent production processes, and the number of approvals has risen dramatically. We will review how FDA oversight has changed to accommodate the boom in biotechnology.

3. Overall Clinical Success Rates of Biologics versus Small Molecules

Only a few biomolecular drugs were approved in the U.S. per year until 1997, when eight were approved in one year. From that time onward approvals have been over a half dozen per year. There are now sufficient numbers of biomolecular drugs to begin to allow cross-industry comparisons of metrics between small molecule and biomolecular drugs. We compare the various studies over the last twenty years that have been published on overall clinical success rates for both small molecules and biologics from Dimasi and Reichert at the Tufts Center for the Study of Drug Development, Grabowski at Duke University and others. Since these metrics have changed over time we provide era-by-era comparisons, wherever possible.

4. Stage Related Success Rates and Cycle Times for Small Molecules vs Biologics

We also examine the success rates and cycle times for the various stages of clinical development for both small molecules and biologics. Again, since these metrics have changed over time we provide era-by-era comparisons where ever possible.

5. Comparative Cost of R&D for Biologics Versus Small Molecules

The differences in success rates and cycle times noted above have a knock-on effect on the cost of R&D for biomolecules over small molecules.

6. Are Peptide Drugs Small Molecules or Biologics?

This hybrid class of drugs tends to be considered a class of biologics, especially because oral activity is rare amongst peptide drugs. But we show that peptides truly bridge the gap between small molecules and biologics, in terms of physical properties, range of therapy areas and means of production. (The processes employed in producing peptide drugs vary, from the chemical processes used for the smaller peptide drugs to recombinant technologies used for the larger peptide drugs.)

7. Biosimilar and Biobetter Macromolecules versus Generic Small Molecules

Those early biotechnology wonder drugs are now facing patent expiration. The industry has been engaged in an intense debate as to how a generic biomolecular drug, aka biosimilar or follow-on biologic) can be approved and managed by the same regulations that govern generic small molecule drugs. The issues are complex, arising out of the considerable differences between small molecules and biologics.  More recently big biopharma have taken an interest biobetters. A biobetter is a biologic which has a purposefully modified structure from the original that allows it to be afforded patent protection and pricing strategy akin to the original biologic because it is in some way “better” than the original.

8. Discovery and Preclinical Stages – Where the Technologies Differ the Most– Small Molecules vs Biologics

It is in the stages of Discovery and Preclinical Development where the technologies are most different. We outline the differences and similarities between small molecules and biologics in Lead Discovery, Lead Optimization and Preclinical Development.

9. Small Molecule and Biologics Approvals by Therapy Areas

With technological advances in the discovery and development of biologics most therapy areas (80%) are now amenable to either a small molecule or biologic strategy.

10. Managing Small Molecule & Biomolecular Drug R&D in the Same Company

The bio/pharmaceutical company that has the resources to discover and develop both types of drugs will inevitably face the challenge of organizing these activities. We argue that the fact that both small molecules and biologics can be managed with the same milestones and stages argues for treating both strategies in the same portfolio. The savvy portfolio manager will understand the differences and ensure the differences are transparent from a portfolio perspective.

Applications in Drug Discovery and Development

Several phase in drug discovery and development can be supported by metabonomics. In a very early phase, metabonomics can help in selecting drug candidates by monitoring toxicity. On the one hand the protocols of candidate selection studies are very simple, rendering metabonoic analyses very challenging in terms of number of samples. On the other hand rather high doses can result in clear metabonomic effects, which can be used for outruling candidates. In later clinical phases, metabonomics can help in an advanced profiling of a drug candidate. Thereby metabonomics can be added to acute and chronic GLP studies. As these studies are highly controled and as typically several sampling time points are available, detailed mechanistic investations can be performed. These studies also allow looking for bridging biomarker and effects, which can be monitored in clinical phase I studies later on. In clinical studies metabonomics can be used for several purposes, such as monitoring safety biomarkers, for monitoring the efficacy of therapy, for diagnosis and for stratification of patients.

References

  1.  Anson, Blake D.; Ma, Junyi; He, Jia-Qiang (1 May 2009). “Identifying Cardiotoxic Compounds”Genetic Engineering & Biotechnology News. TechNote 29 (9) (Mary Ann Liebert). pp. 34–35.ISSN 1935-472XOCLC 77706455. Archived from the original on 25 July 2009. Retrieved 25 July 2009
  2.  Steven M. Paul, Daniel S. Mytelka, Christopher T. Dunwiddie, Charles C. Persinger, Bernard H. Munos, Stacy R. Lindborg & Aaron L. Schacht (2010). “How to improve R&D productivity: the pharmaceutical industry’s grand challenge”. Nature Reviews Drug Discovery 9 (3): 203–214. doi:10.1038/nrd3078PMID 20168317.
  3.  Rask-Andersen M, Almén MS, Schiöth HB (August 2011). “Trends in the exploitation of novel drug targets.”. Nature Reviews Drug Discovery 8 (10): 549–90. doi:10.1038/nrd3478PMID 21804595.
  4.  Hopkins, A. L., Groom, C. R. and Alexander, A. (2004). “Ligand efficiency: a useful metric for lead selection”. Drug Discovery Today 9 (10): 430–431. doi:10.1016/S1359-6446(04)03069-7.PMID 15109945.
  5.  Ryckmans, T. et al. (2009). “Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis”. Bioorg. Med. Chem. Lett. 19 (15): 4406–4409. doi:10.1016/j.bmcl.2009.05.062PMID 19500981.
  6.  Leeson, P. D. et al. (2007). “The influence of drug-like concepts on decision-making in medicinal chemistry”. Nature Reviews Drug Discovery 6 (11): 881–890. doi:10.1038/nrd2445.PMID 17971784.
  7.  Feher M, Schmidt JM (2003). “Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry”. J Chem Inf Comput Sci 43 (1): 218–27.doi:10.1021/ci0200467PMID 12546556.
  8.  Newman DJ, Cragg GM (March 2007). “Natural products as sources of new drugs over the last 25 years”. J. Nat. Prod. 70 (3): 461–77. doi:10.1021/np068054vPMID 17309302.
  9.  von Nussbaum F, Brands M, Hinzen B, Weigand S, Häbich D (August 2006). “Antibacterial natural products in medicinal chemistry–exodus or revival?”. Angew. Chem. Int. Ed. Engl. 45 (31): 5072–129. doi:10.1002/anie.200600350PMID 16881035. “The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chemistry and target-finding tools from biology (reversed genomics) is one option for their revival.”
  10.  John Faulkner D, Newman DJ, Cragg GM (February 2004). “Investigations of the marine flora and fauna of the Islands of Palau”. Nat Prod Rep 21 (1): 50–76. doi:10.1039/b300664f.PMID 15039835.

  • Gad, Shayne C. (2005). Drug discovery handbook. Hoboken, N.J: Wiley-Interscience/J. Wiley. ISBN 0-471-21384-5.
  • Madsen, Ulf; Krogsgaard-Larsen, Povl; Liljefors, Tommy (2002). Textbook of drug design and discovery. Washington, DC: Taylor & Francis. ISBN 0-415-28288-8.

FDA Issues Draft Guidance on NCE Exclusivity Determinations


Feb 25, 2014
FDA has released draft guidance on the agency’s interpretation of the five-year new chemical entity (NCE) exclusivity provisions as they apply to certain fixed-combination drug products (fixed-combinations).  The guidance document states that FDA, historically, has said that a fixed-combination was ineligible for five-year NCE exclusivity if it contained a previously approved active moiety, even if the product also contained a new active moiety (i.e., an active moiety that FDA had not previously approved).The guidance states that because fixed-combinations have become increasingly prevalent in certain therapeutic areas (e.g., cancer, cardiovascular, and infectious disease) and play an important role in optimizing adherence to dosing regimens, FDA is revising their interpretation of the five-year NCE exclusivity provisions “to further incentivize the development of certain fixed-combination products.” FDA intends to apply the new interpretation prospectively. The guidance, however, does not apply to fixed-combination drug products that were approved prior to adopting the new interpretation.

Source: FDA.gov

see below

The Food and Drug Administration (FDA or the Agency) is issuing this guidance to set forth a change in the Agency’s interpretation of the 5-year new chemical entity (NCE) exclusivity provisions as they apply to certain fixed-combination drug products (fixed-combinations).
Historically, FDA has interpreted these provisions such that a fixed-combination was ineligible for 5-year NCE exclusivity if it contained a previously approved active moiety, even if the  product also contained a new active moiety (i.e., an active moiety that the Agency had not  previously approved).

The Agency recognizes that fixed-combinations have become increasingly prevalent in certain therapeutic areas (including cancer, cardiovascular, and  infectious disease) and that these products play an important role in optimizing adherence to
dosing regimens and improving patient outcomes.

As further discussed below, we are therefore revising our historical interpretation of the 5-year NCE exclusivity provisions to further  incentivize the development of certain fixed-combination products.
If the new interpretation is adopted, FDA intends to apply the new interpretation prospectively.Therefore, this guidance does not apply to fixed-combination drug products that were approvedprior to adopting the new interpretation.

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are  cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required. read at

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM386685.pdf

FDA publishes new Guidance on Validation of Analytical Methods


The FDA has published a new Guidance on the validation of analytical methods which shall replace the 14 years old existing Guideline on the topic. More details about the contents of this highly topical document can be found here.

A new FDA Guidance for Industry entitled “Analytical Procedures and Methods Validation for Drugs and Biologics” was published a few days ago. This Guideline replaces the Guidance for Industry “Analytical Procedures and Methods Validation” from 2000 (this document has never been finalised and has had a draft status 14 years long) and – when finalised – should also replace the “Guidelines for Submitting Samples and Analytical Data for Methods Validation” which came into force in 1987.

Unlike the previous Guideline from 2000, the new document explicitly mentions biologics in its title. The objective of the Guideline is to inform applicants about what data are expected by the FDA in marketing authorisation dossiers. The provisions of the Guideline apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and variation applications regarding these types of application, as well as to Type II Drug Master Files. The Guideline can’t be directly used for investigational new drug applications (INDs) as the scope of data with regard to analytical procedures and methods validation varies with the development phase. Nevertheless, IND applicants should orientate themselves to the provisions of the new Guideline.

When comparing it with the former and now invalid “Methods Validation” Guidance, it is apparent that the Draft Guidance has been kept much shorter. There are no detailed descriptions available: for example the table about recommended validation parameters for different analytical tests has been deleted without substitution. Yet, new chapters have been added, like chapter “VIII. Life cycle management of analytical procedures” and its following chapter on the verification of analytical methods in FDA’s own laboratories (“IX: FDA methods verification”).

The document contains plenty of cross-references to corresponding 21 CFR paragraphs and provides – in the last chapter “X. References” – an extensive list of essential FDA Guidelines which also have to be considered in this context, as well as references to corresponding USP chapters, and technical literature on statistical topics. The fact that many aspects of methods validation are addressed in those referenced Guidelines explains the reason why the new Guidance has become shorter.

The document can be commented within 90 days.

read all at

http://www.gmp-compliance.org/enews_4155_FDA%20publishes%20new%20Guidance%20on%20Validation%20of%20Analytical%20Methods_8267_n.html

 

ANTHONY MELVIN CRASTO

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Tivorbex (indomethacin); Iroko Pharmaceuticals; For the treatment of acute pain,


Indometacin skeletal.svg

Tivorbex (indomethacin); Iroko Pharmaceuticals; For the treatment of acute pain, Approved February of 2014

2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid

cas 53-86-1

PHILADELPHIA—Iroko Pharmaceuticals, LLC, a global specialty pharmaceutical company dedicated to advancing the science of analgesia, today announced that the U.S. Food and Drug Administration (FDA) has approved TIVORBEX™ (indomethacin) capsules, a nonsteroidal anti-inflammatory drug (NSAID), at 20 mg and 40 mg doses for the treatment of mild to moderate acute pain in adults1.

“TIVORBEX is the second NSAID to be approved from Iroko’s lower dose NSAID pipeline that uses proprietary SoluMatrix Fine Particle Technology™.”

TIVORBEX was approved at dosage strengths that are 20 percent lower than the 25 mg and 50 mg indomethacin products currently on the market2. FDA approval of TIVORBEX was supported by data from two Phase 3 multi-center, placebo-controlled trials that demonstrated significant improvement in pain relief in patients with post-surgical acute pain receiving TIVORBEX compared with patients receiving placebo3.

“The FDA approval of TIVORBEX is another significant milestone for Iroko as it validates our strategic approach towards developing a suite of NSAID products that offer pain management at lower doses,” said John Vavricka, President and CEO of Iroko Pharmaceuticals. “TIVORBEX is the second NSAID to be approved from Iroko’s lower dose NSAID pipeline that uses proprietary SoluMatrix Fine Particle Technology™.”  read at

http://www.businesswire.com/news/home/20140224006983/en/Iroko-Pharmaceuticals-Receives-FDA-Approval-TIVORBEX%E2%84%A2#.Uw7ui-PoSuo

Indometacin (INN) or indomethacin (USAN and former BAN) is a non-steroidal anti-inflammatory drug (NSAID) commonly used as a prescriptionmedication to reduce feverpain, stiffness, and swelling. It works by inhibiting the production of prostaglandins, molecules known to cause these symptoms. It is marketed under more than seventy different trade names.[1]

 

Indomethacin was discovered in 1963[8] and it was first approved for use in the U.S. by the Food and Drug Administration in 1965. Its mechanism of action, along with several other NSAIDs that inhibit COX, was described in 1971.[9]

References

  1.  Trade names are listed on DrugBank.ca entry DB00328
  2. Sanders, Lisa (6 January 2012). “Think Like a Doctor: Ice Pick Pain Solved!”The New York Times.
  3.  Garza, I & Schwedt, TJ. “Hemicrania continua.” UpToDate.http://www.uptodate.com/contents/hemicrania-continua. Accessed 8/27/13.
  4.  Smyth JM, Collier PS, Darwish M et al. (September 2004). “Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study”Br J Clin Pharmacol 58 (3): 249–58. doi:10.1111/j.1365-2125.2004.02139.x.PMC 1884560PMID 15327584.
  5.  “INDOMETHACIN”Hazardous Substances Data Bank (HSDB). National Library of Medicine’s TOXNET. Retrieved April 4, 2013.
  6.  Giles W, Bisits A (October 2007). “Preterm labour. The present and future of tocolysis”. Best Pract Res Clin Obstet Gynaecol 21 (5): 857–68. doi:10.1016/j.bpobgyn.2007.03.011.PMID 17459777.
  7.  Akbarpour F, Afrasiabi A, Vaziri N (1985). “Severe hyperkalemia caused by indomethacin and potassium supplementation”. South Med J 78 (6): 756–7. doi:10.1097/00007611-198506000-00039PMID 4002013.
  8.  Hart F, Boardman P (October 1963). “Indomethacin: A New Non-steroid Anti-inflammatory Agent”Br Med J 2 (5363): 965–70. doi:10.1136/bmj.2.5363.965PMC 1873102.PMID 14056924.
  9. Ferreira S, Moncada S, Vane J (Jun 23, 1971). “Indomethacin and aspirin abolish prostaglandin release from the spleen”. Nat New Biol 231 (25): 237–9.doi:10.1038/231237a0PMID 5284362.

IBRUTINIB 依鲁替尼 A Btk protein inhibitor.


Ibrutinib.svg

IBRUTINIB 依鲁替尼

A Btk protein inhibitor.

1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one

1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

CAS number 936563-96-1
Ibrutinib, PCI 32765, PCI32765,  ibrutinibum,  IMBRUVICA,
  • CRA-032765
  • Ibrutinib
  • Imbruvica
  • Pc-32765
  • PCI 32765
  • PCI32765
  • UNII-1X70OSD4VX
Molecular Formula: C25H24N6O2
Molecular Weight: 440.49706

Company: Pharmacyclics
Approval Status: Approved February 2014US FDA:link
Treatment Area: chronic lymphocytic leukemia

Bruton’s tyrosine kinase (Btk) inhibitor

U.S. Patent No: 7,514,444 , 7,718,662
patent validity: December 2026

An orally bioavailable small-molecule inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Ibrutinib binds to and inhibits BTK activity, preventing B-cell activation and B-cell-mediated signaling and inhibiting the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is required for B cell receptor (BCR) signaling, plays a key role in B-cell maturation, and is overexpressed in a number of B-cell malignancies.

Imbruvica (ibrutinib) is an orally available, selective inhibitor of Bruton’s tyrosine kinase (Btk), a gene that is disrupted in the human disease X-linked agammaglobulenemia (XLA). BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.

Imbruvica is specifically approved for chronic lymphocytic leukemia in patients who have received at least one prior therapy.

Imbruvica (Ibrutinib, previously known as PCI-32765) was approved as a “breakthrough therapy” on November 13, 2013 by the US Food and Drug Administration (FDA) for the treatment of mantle cell lymphoma (MCL), a rare and deadly form of blood cancer.

IBRUTINIB

Ibrutinib, a first in class oral Bruton’s tyrosine kinase (Btk) inhibitor, was launched in the U.S. for the treatment of patients with mantle cell lymphoma in 2013, and for the treatment of chronic lymphocytic leukemia in 2014. In the E.U., the product candidate is awaiting registration for both indications. Additional phase III clinical trials are ongoing for the treatment of these indications in combination with bendamustine and rituximab and for the treatment of relapsed or refractory marginal zone lymphoma (MZL). Janssen and Pharmacyclics are conducting phase II clinical trials for the treatment of refractory follicular lymphoma. Early clinical development is also under way at Pharmacyclics for the treatment of recurrent B-cell lymphoma, relapsed/refractory MCL, and relapsed or relapsed and refractory multiple myeloma. The company filed an IND seeking approval to commence clinical evaluation of ibrutinib for the treatment of autoimmune disease. Preclinical studies had been under way for rheumatoid arthritis; however, no recent development has been reported. Ibrutinib is also active against Lyn and LCK tyrosine kinases.

In 2011, a codevelopment agreement was signed between the National Cancer Institute (NCI) and Pharmacyclics for the treatment of hematologic/blood cancer. Also in 2011, a worldwide codevelopment and comarketing agreement was signed by Janssen and Pharmacyclics for the treatment of cancer. In 2012, orphan drug designation was assigned in the U.S. and the E.U. for the treatment of CLL. This designation was also assigned by the FDA in 2012 for the treatment of mantle cell lymphoma. In 2013, several orphan drug designations were assigned in the U.S.; for the treatment of small lymphocytic lymphoma, for the treatment of Waldenstrom’s macroglobulinemia and for the treatment of diffuse large B-cell lymphoma. For this indication, orphan drug designation was assigned also in the E.U. the same year. In 2012, fast track designation was assigned by the FDA for the treatment of CLL. In 2013, breakthrough therapy designations were assigned to the compound in the U.S.: for the treatment (as monotherapy) of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, for the treatment of relapsed or refractory mantle cell lymphoma who have received prior therapy and for the treatment of Waldenstrom’s macroglobulinemia.

Imbruvica is supplied as a capsule for oral administration. The recommended dose is 420 mg taken orally once daily (three 140 mg capsules once daily). Capsules should be taken orally with a glass of water. Do not open, break, or chew the capsules.

The FDA approval of Imbruvica for chronic lymphocytic leukemia was based on an open-label, multi-center trial of 48 previously treated patients. Imbruvica was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The overall response rate (ORR) and duration of response (DOR) were assessed using a modified version of the International Workshop on CLL Criteria by an Independent Review Committee. The ORR was 58.3%, all partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached.

Imbruvica (ibrutinib) is an orally available, selective inhibitor of Bruton’s tyrosine kinase (Btk). Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK’s crole in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion.

Ibrutinib (USAN,[1] also known as PCI-32765 and marketed in the U.S. under the name Imbruvica) is an anticancer drug targeting B-cell malignancies. It was approved by the US FDA in November 2013 for the treatment of mantle cell lymphoma[2] and in February 2014 for the treatment ofchronic lymphocytic leukemia.[3] It is an orally-administered, selective and covalent inhibitor of the enzyme Bruton’s tyrosine kinase (BTK).[4][5][6]Ibrutinib is currently under development by Pharmacyclics, Inc and Johnson & Johnson‘s Janssen Pharmaceutical division for additional B-cell malignancies including diffuse large B-cell lymphoma and multiple myeloma.[7][8][9]

Mechanism

In preclinical studies on chronic lymphocytic leukemia (CLL) cells, ibrutinib has been reported to promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment.[12] In this study, treatment of activated CLL cells with ibrutinib resulted in inhibition of Btk tyrosine phosphorylation and also effectively abrogated downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. Additionally, ibrutinib inhibited proliferation of CLL cells in vitro, effectively blocking survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact.

In early clinical studies, the activity of ibrutinib has been described to include a rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis, suggesting that the drug might have direct effects on cell homing or migration to factors in tissue microenvironments.[13]

Ibrutinib has been reported to reduce CLL cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor.[14][15] Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumour microenvironments.

History

Ibrutinib was first designed and synthesized at Celera Genomics which reported in 2007 a structure-based approach for creating a series of small molecules that inactivate BTK through covalent binding to cysteine-481 near the ATP binding domain of BTK.[4] These small molecules irreversibly inhibited BTK by using a Michael acceptor for binding to the target cysteine. In April 2006, Pharmacyclics acquired Celera’s small molecule BTK inhibitor discovery program, which included a compound, PCI-32765 that was subsequently chosen for further preclinical development based on the discovery of anti-lymphoma properties in vivo.[16] Since 2006, Pharmacyclics’ scientists have advanced the molecule into clinical trials and identified specific clinical indications for the drug. It also has potential effects against autoimmune arthritis.[17] It was approved by the US FDA on November 13, 2013 for the treatment of mantle cell lymphoma.[2] On Feb. 12, 2014, the U.S. Food and Drug Administration expanded the approved use​ of the drug ibrutinib to chronic lymphocytic leukemia (CLL). [18]

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). It is a white to off-white solid with the empirical formula C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water.

The chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[ 3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure:

IMBRUVICATM (ibrutinib) Structural Formula Illustration

IMBRUVICA (ibrutinib) capsules for oral administration are supplied as white opaque capsules that contain 140 mg ibrutinib as the active ingredient. Each capsule also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Each white opaque capsule is marked with “ibr 140 mg” in black ink.

PCI-32765 (ibrutinib) is disclose d in U.S. Patent No. 7,514,444, issued on April 7, 2009, and has the following structur

Figure imgf000002_0001

Ibrutinib is an orally available drug that targets Bruton’s tyrosine kinase (BTK).

Ibrutinib is an irreversible small molecule BTK inhibitor that is in Ph Ib/II of clinical trials in a variety of B-cell malignancies including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (cancer of plasma cells, a type of white blood cell present in bone marrow). At present ibrutinib is administered orally in clinical trials, via the gastrointestinal tract, at high clinical doses (420 mg/day or 840 mg/day) to patients with CLL and SLL to obtain the desired thereapeutic effect. The need for such high doses of ibrutinib may be due to low bioavailability (the oral bioavailability of ibrutinib is reported to be 22.8% in rats) and may be responsible for the adverse side effects associated with the use of ibrutinib such as nausea or emesis, dizziness and diarrhea. Moreover, low bioavailability results in more variable absorption and potential variability of the desired therapeutic response.

As stated above, at present ibrutinib is administered orally, via the gastrointestinal tract, at high clinical doses (420 mg/day or 840 mg/day) to patients to obtain the desired clinical benefit. It is presently disclosed that when ibrutinib is administered intraduodenally versus via the gastrointestinal tract in rats, the oral bioavailability of ibrutinib unexpectedly increased from 21 % to 100% as determined by AUC.

This unexpected increase in oral bioavailability of ibrutinib can translate into a number of desirable practical benefits. The increase in oral bioavailability should enable administration of ibrutinib at a significantly lower therapeutically effective dose than is currently being used. The lower variability associated with this greater bioavailability should lead to a more reliable therapeutic response as well as more predictable drug absorption.

And avoidance of exposure of Ibtrutinib to the stomach and/or use of lower therapeutically effective dose of ibrutinib can reduce or altogether eliminate potential adverse side effects of this drug such as diahrrea, nausea or emesis, and dizziness. U.S. Patent No. 7,514,444, mentioned above, discloses administration of 0.02-5000 mg/kg andl-1500 mg of ibrutinib/per day and in clinical trials 420 or 840 mg/day of ibrutinib is being administered to the patients with CLL and SLL.

There is no reasonable expectation in the art that ibrutinib can be adminstered orally at lower efficacious doses to the patients with CLL and SLL, particularly as evidenced by the 420 or 840 mg/day of ibrutinib being administered in clinical trials to those patients. Moreover, other than for active agents that are unstable in the stomach or at acidic pH delivery of any active agent with low bioavailability further along in the gastrointestinal tract reduces the path length for drug absorption and would be expected to reduce bioavailability. Therefore, it was unexpected to achieve delivery of ibruntinib directly to the small intestine with greater bioavailability.

PC1-32765 (Ibrutinib), chemical name: 1_ [(3R) _3-[4_-3 – (4 – phenoxy-phenyl)-1H-pyrazolo [3,4-d] pyrimidine – 1 – yl] – 1-piperidinyl]-2 – propen-1 – one, and its structural formula is as follows:

Figure CN103121999AD00031

PC1-32765 is an oral medication that inhibits B cell as the main receptor tyrosine kinase signaling and promote cell death process, preventing cell migration and adhesion in malignant B cells.

US20080108636 basic patent has been disclosed a synthetic route:

This synthetic route with 4 – phenoxy-benzoic acid as raw material, after eight-step reaction the final product, the following reaction steps:

Figure CN103121999AD00032

The above method has the following disadvantages:

1, eight single-step reaction, long route, the economy is bad; i1, to use synthetic intermediates 4:00 trimethylsilyl diazomethane (TMSCHN2), this material easy to blow up, the risk coefficient is large, so large-scale production greatly reduces the possibility;

ii1, synthetic intermediates 7:00, set out to use polymer-supported triphenylphosphine, non-industrial raw materials used, the price is expensive, the cost of smell;

iv, the final step of acylation, the selectivity is poor, a large amount of negative product, purification is difficult, amplification reaction is difficult.

In summary, the route material is not common, expensive step, high costs, the reaction dangerous side reactions, purification difficult, limiting the possibility of industrial production of the route.

………………………

WO2013184572A1

Polymorphs

EXAMPLES

[00438] The following ingredients, formulations, processes and procedures for practicing the methods disclosed herein correspond to that described above. Example 1; Preparation of Crystalline Forms of l-((R)-3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-dlpyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (Compound 1)

Form A – Route 1:

[00439] Amorphous Compound 1 (ca. 15 mg) was measured into a vial. Ten volumes (150 μΐ) of solvent [methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, methanol, nitromethane, 10% aqueous acetone, or 10% aqueous isopropyl alcohol] were added to the vial. The vial was sealed and placed in a shaker at 50 °C for one hour. If a slurry was obtained, an additional thirty volumes (total of 600 μΐ) of solvent was added, then the slurry was returned to 50 °C for another hour. If the sample remained as a slurry at this point, no further solvent was added. The solution/slurry was stirred at 50 °C for one hour, then cooled to 0 °C at 0.1 °C/min, then held at 0 °C overnight. If a slurry was obtained, the solids were filtered under vacuum to provide Compound 1 , Form A; the solution was returned to ambient temperature for slow evaporation through a pin-hole to furnish Compound 1, Form A.

 

“Compound 1” or “l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one” or “1 – {(3i?)-3-[4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-JJpyrimidin-l-yl]piperidin-l-yl}prop-2-en-l-one” or “2-Propen- 1 -one, 1- [(3R)-3-[4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-<f]pyrimidin- 1 -yl] – 1 -piperidinyl-” or ibrutinib or any other suitable name refers to the compound with the following structure:

Figure imgf000037_0001

………….

Synthesis

US20080214501

Synthesis of Compound 3—Btk Activity Probe

4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 2) is prepared. Briefly, 4-phenoxybenzoic acid (48 g) is added to thionyl chloride (100 mL) and heated under gentle reflux for 1 hour. Thionyl chloride was removed by distillation, the residual oil was dissolved in toluene and volatile material removed at 80° C./20 mbar. The resulting acid chloride was dissolved in toluene (200 mL) and tetrahydrofuran (35 mL). Malononitrile (14.8 g) was added and the solution and stirred at −10° C. while adding diisopropylethylethylamine (57.9 g) in toluene (150 mL), while maintaining the temperature below 0° C. After 1 hour at 0° C., the mixture was stirred at 20° C. overnight. Amine hydrochloride is removed by filtration and the filtrate evaporated in vacuo. The residue was taken up in ethyl acetate and washed with 1.25 M sulphuric acid, then with brine and dried over sodium sulfate. Evaporation of the solvents gave a semisolid residue which was treated with a portion of ethyl acetate to give 4.1 g of 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a white solid (m.p. 160-162° C.). The filtrate on evaporation gave 56.58 (96%) of 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a grey-brown solid, which was sufficiently pure for further use.

1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20° C., and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3×250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil.

1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (22.5 g) and 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (29.5 g) is suspended in formamide (300 mL) and heated under nitrogen at 180° C. for 4 hours. The reaction mixture is cooled to 30° C. and water (300 mL) is added. The solid is collected, washed well with water, then with methanol and dried in air to give of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 2).

Synthesis of 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl (Intermediate 4); a) triphenylphosphine (TPP), diisopropyl diazodicarboxylate (DIAD), tetrahydrofuran (THF); b) TFA/CH2Cl2.

Figure US20080214501A1-20080904-C00011

To a solution of 1-boc-3-(S)-hydroxypiperidine (3.98 g, 19.8 mmol) and triphenylphosphine (5.19 g, 19.8 mmol) in THF (150 ml) was added DIAD (3.9 ml, 19.8 mmol). The yellow solution was stirred 1 minute then Intermediate 2 (4.0 g, 13.2 mmol) was added and the reaction was heated with a heat gun (3-5 minutes) until the solid had dissolved. After stirring for 1 hour at room temperature, the solvent was removed and the resulting brown oil was subjected to flash chromatography (30% then 50% THF/hexanes) to provide 4.45 g (69%) of Intermediate 3 (trace of triphenylphosphine oxide is present) as a light brown foam.

To a solution of Intermediate 3 (4.4 g, 9.0 mmol) in CH2Cl(20 ml) was added TFA (2.8 ml, 36.2 mmol). After stirring 2 hrs at room temperature, the solvent was removed and the residue was partitioned between ethyl acetate (250 ml) and dilute aq. K2CO3. The organic layer was dried (MgSO4), filtered and concentrated to 70 ml. The resulting solution was stirred and 4.0M HCl in dioxane (4 ml) was added to provide a thick light orange precipitate. The precipitate was collected by filtration and washed with ethyl acetate (50 ml). The material was then partitioned between ethyl acetate (300 ml) and dilute aq. K2CO3. The organic layer was dried (MgSO4), filtered and concentrated to provide 2.78 g (80%) of Intermediate 4 as a light yellow foam.

……………………

SYNTHESIS

US7514444

Compounds described herein may be prepared using the synthetic methods described herein as a single isomer or a mixture of isomers.

A non-limiting example of a synthetic approach towards the preparation of compounds of any of Formula (A), (B), (C) or (D) is shown in Scheme I.

Figure US07514444-20090407-C00033

Halogenation of commercially available 1H-pyrazolo[3,4-d]pyrimidin-4-amine provides an entry into the synthesis of compounds of Formula (A), (B), (C) and/or (D). In one embodiment, 1H-pyrazolo[3,4-d]pyrimidin-4-amine is treated with N-iodosuccinamide to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. Metal catalyzed cross coupling reactions are then carried out on 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. In one embodiment, palladium mediated cross-coupling of a suitably substituted phenyl boronic acid under basic conditions constructs intermediate 2. Intermediate 2 is coupled with N-Boc-3-hydroxypiperidine (as non-limiting example) via Mitsunobu reaction to give the Boc (tert-butyloxycarbonyl) protected intermediate 3. After deprotection with acid, coupling with, but not limited to, an acid chloride, such as, but not limited to, acryloyl chloride, completes the synthesis to give compound 4.

Example 1 Synthesis of Compounds Preparation of 4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 2)

4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 2) is prepared as disclosed in International Patent Publication No. WO 01/019829. Briefly, 4-phenoxybenzoic acid (48 g) is added to thionyl chloride (100 mL) and heated under gentle reflux for 1 hour. Thionyl chloride is removed by distillation, the residual oil dissolved in toluene and volatile material removed at 80° C./20 mbar. The resulting acid chloride is dissolved in toluene (200 mL) and tetrahydrofuran (35 mL). Malononitrile (14.8 g) is added and the solution and stirred at −10° C. while adding diisopropylethylethylamine (57.9 g) in toluene (150 mL), while maintaining the temperature below 0° C. After 1 hour at 0° C., the mixture is stirred at 20° C. overnight. Amine hydrochloride is removed by filtration and the filtrate evaporated in vacuo. The residue is taken up in ethyl acetate and washed with 1.25 M sulphuric acid, then with brine and dried over sodium sulfate. Evaporation of the solvents gives a semisolid residue which is treated with a little ethyl acetate to give 4.1 g of 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a white solid (m.p. 160-162° C.). The filtrate on evaporation gives 56.58 (96%) of 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a grey-brown solid, which is sufficiently pure for further use.

1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20° C., and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3×250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil.

1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (22.5 g) and 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (29.5 g) is suspended in formamide (300 mL) and heated under nitrogen at 180° C. for 4 hours. The reaction mixture is cooled to 30° C. and water (300 mL) is added. The solid is collected, washed well with water, then with methanol and dried in air to give of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine.

Example 1a Synthesis of 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 4)

Figure US07514444-20090407-C00034
    • Synthesis of compound 4; a) polymer-bound triphenylphosphine (TPP), diisopropyl diazodicarboxylate (DIAD), tetrahydrofuran (THF); b) HCl/dioxane; then acryloyl chloride, triethylamine (TEA).

Compounds described herein were synthesized by following the steps outlined in Scheme 1. A detailed illustrative example of the reaction conditions shown in Scheme 1 is described for the synthesis of 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 4).

101 mg of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine and 330 mg of polymer-bound triphenylphosphine(TPP) (polymerlab) were mixed together with 5 mL of tetrahydrofuran (THF). tert-Butyl 3-hydroxypiperidine-1-carboxylate (200 mg; 2.0 equivalents) was added to the mixture followed by the addition of diisopropyl diazodicarboxylate (0.099 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove the resins and the reaction mixture was concentrated and purified by flash chromatography (pentane/ethyl acetate=1/1) to give intermediate 3 (55 mg).

Intermediate 3 (48.3 mg) was treated with 1 mL of 4N HCl in dioxane for 1 hour and then concentrated to dryness. The residue was dissolved in dichloromethane and triethylamine (0.042 mL) was added followed by acryl chloride (0.010 mL). The reaction was stopped after 2 hours. The reaction mixture washed with 5% by weight aqueous citric acid and then with brine. The organic layer was dried with MgSO4, and concentrated. Flash chromatography (with CH2Cl2/MeOH=25/1) gave 22 mg of compound 4 as a white solid. MS (M+1): 441.2; 1H-NMR (400 MHz): 8.26, s, 1H, 7.65, m, 2H, 7.42, m, 2H, 7.1-7.2, m, 5H, 6.7-6.9, m, 1H, 6.1, m, 1H, 5.5-5.7, m, 1H, 4.7, m, 1H, 4.54, m, 0.5H, 4.2, m, 1H, 4.1, m, 0.5H, 3.7, m, 0.5H, 3.2, 1,1H, 3.0, m, 0.5H, 2.3, m, 1H, 2.1, m, 1H, 1.9, m, 1H, 1.6, m, 1H.

Example 1b Synthesis of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13)

Figure US07514444-20090407-C00035

The synthesis of compound 13 was accomplished using a procedure analogous to that described in Example 1a. EM (calc.): 440.2; MS (ESI) m/e (M+1H)+: 441.1, (M−1H): 439.2.

Example 1c Synthesis of 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 14)

Figure US07514444-20090407-C00036

The synthesis of compound 14 was accomplished using a procedure analogous to that described for Example 1a. EM (calc.): 440.2; MS (ESI) m/e (M+1H)+: 441.5, (M−1H)−: 439.2.

……………….

US7718662

Synthesis of Compounds Example 1 Preparation of 4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (2a)

4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 2) is prepared as disclosed in International Patent Publication No. WO 01/019829. Briefly, 4-phenoxybenzoic acid (48 g) is added to thionyl chloride (100 mL) and heated under gentle reflux for 1 hour. Thionyl chloride is removed by distillation, the residual oil dissolved in toluene and volatile material removed at 80° C./20 mbar. The resulting acid chloride is dissolved in toluene (200 mL) and tetrahydrofuran (35 mL). Malononitrile (14.8 g) is added and the solution and stirred at −10° C. while adding diisopropylethylethylamine (57.9 g) in toluene (150 mL), while maintaining the temperature below 0° C. After 1 hour at 0° C., the mixture is stirred at 20° C. overnight. Amine hydrochloride is removed by filtration and the filtrate evaporated in vacuo. The residue is taken up in ethyl acetate and washed with 1.25 M sulphuric acid, then with brine and dried over sodium sulfate. Evaporation of the solvents gives a semisolid residue which is treated with a little ethyl acetate to give 4.1 g of 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a white solid (m.p. 160-162° C.). The filtrate on evaporation gives 56.58 (96%) of 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene as a grey-brown solid, which is sufficiently pure for further use.

1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20° C., and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3×250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil.

1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (22.5 g) and 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.

3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (29.5 g) is suspended in formamide (300 mL) and heated under nitrogen at 180° C. for 4 hours. The reaction mixture is cooled to 30° C. and water (300 mL) is added. The solid is collected, washed well with water, then with methanol and dried in air to give of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine.

Example 1a Synthesis of 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (4)

Figure US07718662-20100518-C00010

Synthesis of compound 4; a) polymer-bound triphenylphosphine (TPP), diisopropyl diazodicarboxylate (DIAD), tetrahydrofuran (THF); b) HCl/dioxane; then acryloyl chloride, triethylamine (TEA)

Compounds described herein were synthesized by following the steps outlined in Scheme III. A detailed illustrative example of the reaction conditions shown in Scheme II is described for the synthesis of 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 4).

101 mg of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine and 330 mg of polymer-bound triphenylphosphine (TPP) (polymerlab) were mixed together with 5 mL of tetrahydrofuran (THF). tert-Butyl 3-hydroxypiperidine-1-carboxylate (200 mg; 2.0 equivalents) was added to the mixture followed by the addition of diisopropyl diazodicarboxylate (0.099 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove the resins and the reaction mixture was concentrated and purified by flash chromatography (pentane/ethyl acetate=1/1) to give intermediate 3a (55 mg).

Intermediate 3a (48.3 mg) was treated with 1 mL of 4N HCl in dioxane for 1 hour and then concentrated to dryness. The residue was dissolved in dichloromethane and triethylamine (0.042 mL) was added followed by acryl chloride (0.010 mL). The reaction was stopped after 2 hours. The reaction mixture was washed with 5% by weight aqueous citric acid and then with brine. The organic layer was dried with MgSO4, and concentrated. Flash chromatography (with CH2Cl2/MeOH=25/1) gave 22 mg of compound 4 as a white solid. MS (M+1): 441.2; 1H-NMR (400 MHz): 8.26, s, 1H, 7.65, m, 2H, 7.42, m, 2H, 7.1-7.2, m, 5H, 6.7-6.9, m, 1H, 6.1, m, 1H, 5.5-5.7, m, 1H, 4.7, m, 1H, 4.54, m, 0.5H, 4.2, m, 1H, 4.1, m, 0.5H, 3.7, m, 0.5H, 3.2, m, 1H, 3.0, m, 0.5H, 2.3, m, 1H, 2.1, m, 1H, 1.9, m, 1H, 1.6, m, 1H.

…………………….

SYNTHESIS

CN 103121999

To solve the above problems, the present invention adopts a technical solution is: to provide a tyrosine kinase inhibitor PC1-32765 synthesis method, the reaction steps are as follows:

Figure CN103121999AD00041

The beneficial effect of the present invention: The invention relates to a tyrosine kinase inhibitor synthesis of PC1-32765, as the B cell to inhibit the tyrosine kinase receptor signaling key, not only can inhibit the formation of blood cells and less side effects and mild reaction conditions, simple operation, easy purification, low cost, environmentally friendly, suitable for large-scale production.

A tyrosine kinase inhibitor PC1-32765 synthesis method comprising the steps of:

1, the compound 10 and the coupling reaction of compound 15 to give compound 6;

2, the compound 6 obtained by reacting compound 16 with compound 11 in the process, we have chosen a more perfect catalyst;

3, compound 11 to give compound 12 by protecting;

4, selective deprotection of Compound 12 Compound 13; 5, Compound 13 for Compound 17 only attack only remaining position to obtain a very pure compound 14;

6, take off the protecting group to obtain PC1-32765

Figure CN103121999AD00051

Wherein the compound can 10,15,16,17 agent or industrial grade reagent compound or the use of methods and techniques related to synthesis.

Example 1 Preparation of Compound 6

Under nitrogen and the 0.1moL 1.5 equivalents of compound 10 Compound 15 and 800mL of dioxane was added to 2L reaction flask, and then 1.5 equivalents of sodium acetate was added and the catalyst PdC12 (PPh3) 2 0.2 equivalents, 50_60 ° C for 5 hours , filtered hot and the filter residue was washed three times with ethanol, the combined filtrate was concentrated to give a solid, rinsed with ethanol to give the pure product 16.2 g, yield 60%

Example 2 Preparation of Compound 6

Under nitrogen and the 0.1moL 1.5 equivalents of compound 10 Compound 15 and 2L 800mL DMF was added to the reaction flask, and then 1.5 equivalents of sodium acetate was added and the catalyst PdCl2 (PhCN) 2 0.2 equivalents, 50_60 ° C for 5 hours, hot filtered, the filter residue was washed three times with ethanol, the combined filtrate was concentrated to give a solid, which was rinsed with ethanol to give pure product 21.5 g, yield 71%.

Example 3 Preparation of Compound 11

The compound 0.1moL 1.2 equivalent of compound 6 and 16, and 2L IOOOmL THF was added to the reaction flask, 1.5 equivalents of cesium carbonate was added, refluxed for 24 hours, after the reaction, most of the solvent was concentrated and the remaining water was poured into a large, precipitated solid was filtered, washed with water to afford compound 36.9 g compound 11, yield 76%, used without further purification.

Example 4 Preparation of Compound 12

The compound will be to 0.1moL 11 and 1.2 equivalent of compound IOOOmL THF trifluoroacetyl chloride and the reaction was added to 2L flask, then triethylamine was added 2.5 ,30-40 0C for 24 hours, after the reaction, the solvent was concentrated, diluted with water, extracted with ethyl acetate, washed with water, saturated sodium chloride each time, and concentrated to obtain the product 50.1 g of ethyl acrylate, 86% yield, used directly in the next reaction.

Example 5 Preparation of Compound 13

The compound 0.1moL 12 and 500mL of methanol and 50mL 6N hydrochloric acid was added to IL reaction flask, stirred at room temperature for 3 hours to complete the reaction quickly, and a solid precipitates, filtered and the solid was washed several times with ethyl acetate, obtain 38.5 g of pure compound 13 in 80% yield.

Example 6 Preparation of Compound 14 ‘

The 0.1moL compound 13 and 1.2 equivalents of acrylic acid chloride was added to 2L of methylene chloride IL reaction flask ,20-40 ° C was added dropwise 1.2 equivalents of triethylamine was added dropwise, at room temperature for 3 hours after the reaction with two chloride extraction and concentrated to give the product 47.7 g, yield 89%. Without further purification.

Example 7 PC1-32765 Preparation

Compound 14 with the 0.1moL 160mL 800mL of methanol and a saturated solution of sodium carbonate small, 50_60 ° C for 5 hours,

After completion of the reaction was diluted with water, concentrated and then extracted with methylene chloride, concentrated to obtain crude product was recrystallized from toluene to give the final product 28.6 g, yield 65%. HPLC purity 98.6%, ee%> 98%.

The present invention relates to a tyrosine kinase inhibitor of the synthesis of PC1-32765, as the B cell to inhibit the tyrosine kinase receptor signaling key, not only can inhibit the formation of blood cells and less side effects, and the reaction conditions gentle, simple operation, easy purification, low cost, environmentally friendly, suitable for large-scale production.

Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase

ChemMedChem

Volume 2, Issue 1, pages 58–61, January 15, 2007

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.200600221/full

http://www.wiley-vch.de/contents/jc_2452/2007/z600221_s.pdf

SYN OF COMPD 4

To 101 mg of a known intermediate 2 [WO 2001019829] and 330 mg polymer-bound Triphenylphosphine (polymerlab) in 5 ml THF, 200 mg (2.0 eq.) of 3-OH N-Boc piperidine was added followed by 0.099 ml diisopropyl diazodicarboxylate. The reaction mixture stirred at room temperature overnight. After filtered off resins, the reaction mixture was concentrated and purified with flash chromatography (pentane/ethyl acetate = 1/1) to give 55 mg of intermediate 3. This compound (48.3 mg) was treated with 1 ml of 4N HCl in dioxane for 1 hour and concentrated to dryness, which was dissolved in dichloromethane and 0.042 ml of triethylamine, followed by 0.010 ml of acryl chloride. The reaction was stopped after 2 hours. The reaction mixture was washed with 5wt% citric acid (aq.) and brine, dried with MgSO4, and concentrated. Flash chromatography with (CH2Cl2/MeOH = 25/1) gave 22 mg of compound 4 as white solids. MS (M+1): 441.2; 1H-NMR (400MHz): 8.26, s, 1H; 7.65, m, 2H; 7.42, m, 2H; 7.1-7.2, m, 5H; 6.7-6.9, m, 1H; 6.1, m, 1H; 5.5-5.7, m, 1H; 4.7, m, 1H; 4.54, m, 0.5H; 4.2, m, 1H; 4.1, m, 0.5H; 3.7, m, 0.5H; 3.2, m, 1H; 3.0, m, 0.5H; 2.3, m, 1H; 2.1, m, 1H; 1.9, m, 1H; 1.6, m, 1H

……………..

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9) Michael L. Wang, MD, et al, Targeting with BTK. Ibrutinib in Refractory or Relapsed Mantle-Cell Lymphoma; N Engl J Med 2013; 369:507-516

8-8-2012
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BRUTON’S TYROSINE KINASE ACTIVITY PROBE AND METHOD OF USING
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FDA Approves Monovisc Injection for Knee Pain


Sodium Hyaluronate

9067-32-7 (sodium salt)

MF: C14H22NNaO11
MW: 403.31

26 feb 2014

Anika Therapeutics Inc. announced it has received marketing approval for Monovisc from the U.S. Food and Drug Administration (FDA). Monovisc is a single injection supplement to synovial fluid of the osteoarthritic joint, used to treat pain and improve joint mobility in patients suffering from osteoarthritis (OA) of the knee.
Monovisc is the first FDA-approved, single-injection product with HA from a non-animal source. It is comprised of a sterile, clear, biocompatible, resorbable, viscoelastic fluid composed of partially cross-linked sodium hyaluronate (NaHA) in phosphate buffered saline.
read all at

http://www.dddmag.com/news/2014/02/fda-approves-monovisc-injection-knee-pain

Sodium hyaluronate is the sodium salt of hyaluronic acid, a glycosaminoglycan found in various connectiveepithelial, and neural tissues. Sodium hyaluronate, a long-chain polymer containing repeating disaccharide units of Na-glucuronate-N-acetylglucosamine, occurs naturally on the corneal endothelium, bound to specific receptors for which it has a high affinity. The polyanionic form, commonly referred to as hyaluronan, is a visco-elasticpolymer normally found in the aqueous and vitreous humour. As a pharmaceutical, the uses of sodium hyaluronate include:

sodium hyaluronate

Sodium hyaluronate for intra-articular injection (brand names: Euflexxa, Hyalgan, Supartz, Gel-One) is used to treat knee pain in patients withosteoarthritis who have not received relief from other treatments. It is very similar to the lubricating fluid that occurs naturally in the articular capsule of the knee joint. Once injected into the joint capsule, it acts as both a shock absorber and a lubricant for the joint.[1]

Sodium hyaluronate for intraocular viscoelastic injection (brand names: Healon, Provisc, Viscoat) is used as a surgical aid in variety of surgical procedures performed on the eyeball including cataract extraction (intra- and extracapsular), intraocular lens implantation, corneal transplant,glaucoma filtration, and retina attachment surgery. In surgical procedures in the anterior segment of eyeball, instillation of sodium hyaluronate serves to maintain a deep anterior chamber during surgery, allowing for efficient manipulation with less trauma to the corneal endothelium and other surrounding tissues. Its viscoelasticity also helps to push back the vitreous face and prevent formation of a postoperative flat chamber. In posterior segment surgery, sodium hyaluronate serves as a surgical aid to gently separate, maneuver, and hold tissues. It creates a clear field of vision, facilitating intra-operative and post-operative inspection of the retina and photocoagulation.[2]

Sodium hyaluronate is used as a viscosupplement, administered through a series of injections into the knee, increasing the viscosity of the synovial fluid, which helps lubricate, cushion and reduce pain in the joint.[3] It is generally used as a last resort before surgery[4] and provides symptomatic relief, by recovering the viscoelasticity of the articular fluid, and by stimulating new production from synovial fluid.[5] Use of sodium hyaluronate may reduce the need for joint replacement.[6] Injections appear to increase in effectiveness over the course of four weeks, reaching a peak at eight weeks and retaining some effectiveness at six months, with greater benefit for osteoarthritis than oral analgesics.[7] It may also be effective when used with other joints.[8]

Sodium hyaluronate may also be used in plastic surgery to reduce wrinkles on the face or as a filler in other parts of the body.[9] It may be used in ophthalmology to assist in the extraction ofcataracts, the implantation of intraocular lensescorneal transplantsglaucoma filtration, retinal attachment and in the treatment of dry eyes.[10]

Sodium hyaluronate is also used to coat the bladder lining in treating interstitial cystitis.

hyaluronan

cas 9004-61-9

Sodium hyaluronate functions as a tissue lubricant and is thought to play an important role in modulating the interactions between adjacent tissues. Sodium hyaluronate is a polysaccharide which is distributed widely in the extracellular matrix of connective tissue in man. It forms a viscoelastic solution in water which makes it suitable for aqueous and vitreous humor in ophthalmic surgery. Mechanical protection for tissues (iris, retina) and cell layers (corneal, endothelium, and epithelium) are provided by the high viscosity of the solution. Elasticity of the solution assists in absorbing mechanical stress and providing a protective buffer for tissues. This viscoelasticity enables maintenance of a deep chamber during surgical manipulation since the solution does not flow out of the open anterior chamber. In facilitating wound healing, it is thought that it acts as a protective transport vehicle, taking peptide growth factors and other structural proteins to a site of action. It is then enzymatically degraded and active proteins are released to promote tissue repair.[11] Sodium hyaluronate is being used intra-articularly to treat osteoarthritis.

Sodium hyaluronate is an ophthalmic agent with viscoelastic properties that is used in joints to supplement synovial fluid.

Sodium hyaluronate is absorbed and diffuses slowly out of the injection site. It is eliminated via the canal of Schlemm.

Sodium hyaluronate hyaluronan started to be in use to treat osteoarthritis of the knee in year 1986 with the product Hyalart/Hyalgan by Fidia of Italy, in intra-articular injections.

Sodium Hyaluronate

Brand names of Sodium hyaluronate in Market include (alphabetically):

  • AMO Vitrax (ocular)
  • AMVISIC Plus (ocular)
  • CYSTISTAR, Healon (ocular)
  • EYEFILL (ocular)
  • HYLO-COMOD (Eye Drop)
  • OLIXIA Pure (Eye Drop)
  • EUFLEXXA, Bio Technology General (Israel)-Meditrina SA (Rx articular), Molecular weight: 2,400,000-3,600,000 Daltons
  • GONILERT/Verisfield (UK) (Rx/articular). Molecular weight:1,800,000-2,000,000 Daltons
  • HYALGAN/HYALART– Fidia (Italy)(Medical Device/Rx articular)
  • MONOVISC– Anika (USA)(MedicalDevice/articular)
  • OSTENIL– TRB Chemedica (Switzerland)(articular injection) [1]
  • RECOSYN– Merckle Recordati (Germany) Recosyn info leaflet
  • SYNOCROM– Croma Pharma (Austria) (articular injection) . Molecular weight:1,600,000 Daltons
  • VISCURE– Cube (UK)(Rx/articular), Molecular weight:1,800,000-2,000,000 Daltons
  • VISMED– TRB Chemedica (Switzerland)(eye drop)[2]
  • YARDEL– Libytec (Impfstoffwerk Dessau-Tornau/Germany,(Rx/articular), Molecular weight:1,800,000-2,000,000 Daltons

Hyaluronic acid (HA) is a glycosaminoglycan which is present in the hyaline cartilage, synovial joint fluid and skin tissues. More particularly, HA is a linear glycosaminoglycan formed by a mixture of chains of different length constituted by the repetition of a regular disaccharide formed by a glucuronic acid unit and a N- acetyl-glucosamine unit linked beta 1-4. Disaccharides are linked beta 1-3 with an average molecular weight up to 6 Md (6×106 Da). Therefore, each chain in said mixture of chains shows the same repetitive sequence of formula (A)

Figure imgf000002_0001

the corresponding cation generally being hydrogen (hyaluronic acid) or sodium (sodium hyaluronate).

In the tissues, the function of hyaluronic acid is mainly to maintain the structural density allowing in the same time the biochemical actions of the natural products in the specific body districts. In fluids like synovia the action of HA is to keep the right viscosity by a lubricant action. To exert these actions, HA needs to be fully biocompatible including a right metabolic balance. Natural HA is continuously degraded and synthesized by the body enzymes. This homeostasis is deviated when pathological situations occur, therefore increases in the HA catabolism can results in wide range of effects from a severe pathology to simple tissue modifications. The application of HA, as sodium hyaluronate, as filler in cosmetic or in viscoelastic replacement in synovitis, requires that the employed HA polymer has enhanced viscoelastic properties. This rheology has to be balanced with an efficient capability to make the production of the injectable product.

The industrial hyaluronic acid is obtained by extraction from animal tissues or by microorganism fermentation and is commonly available as sodium hyaluronate. Concerning molecular weight, it is generally recognized that low molecular weight HA is a mixture of chains having a mean molecular weight below 250 Kd (2.5×105Da). HA is used, generally as sodium hyaluronate, in many applications in cosmetics, ophthalmology, rheumatology and tissues engineering. In particular HA with a mean molecular weight above 1 Md is used as viscosupplement in joint arthrosis or in wrinkle management. The high molecular weight is required to supplement the synovial fluid or to fill skin connective dead spaces thanks to the viscosity of the resulting solution.

Many medicaments based on the above technology are currently available on the market. They have a high biocompatibility but they are subjected to a rather rapid degradation by the body enzymes, in particular by hyaluronidase, with the consequence of a short half-life.

sodium hyaluronate

References

  1.  “Hyaluronate sodium: Indications, Side Effects, Warnings” (Web). Drugs.com. Drugs.com. 5 February 2014. Retrieved 25 February 2014.
  2.  “Healon (Sodium Hyaluronate)” [package insert]. (2002). Kalamazo, Michigan: Pharmacia Corporation. (Web). RxList. (Updated 8 December 2004). RxList, Inc. Retrieved 25 February 2014.
  3.  Puhl, W.; Scharf, P. (1997). “Intra-articular hyaluronan treatment for osteoarthritis”Annals of the rheumatic diseases 56 (7): 441. doi:10.1136/ard.56.7.441PMC 1752402.PMID 9486013edit
  4.  Karlsson, J.; Sjögren, L. S.; Lohmander, L. S. (2002). “Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study”. Rheumatology (Oxford, England) 41 (11): 1240–1248.PMID 12421996edit
  5.  Jubb, R. W.; Piva, S.; Beinat, L.; Dacre, J.; Gishen, P. (2003). “A one-year, randomised, placebo (saline) controlled clinical trial of 500-730 kDa sodium hyaluronate (Hyalgan) on the radiological change in osteoarthritis of the knee”. International journal of clinical practice 57 (6): 467–474. PMID 12918884edit
  6.  Kotz, R.; Kolarz, G. (1999). “Intra-articular hyaluronic acid: Duration of effect and results of repeated treatment cycles”. American journal of orthopedics (Belle Mead, N.J.) 28 (11 Suppl): 5–7. PMID 10587245edit
  7.  Bannuru, R. R.; Natov, N. S.; Dasi, U. R.; Schmid, C. H.; McAlindon, T. E. (2011). “Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis – meta-analysis”. Osteoarthritis and Cartilage 19 (6): 611–619. doi:10.1016/j.joca.2010.09.014.PMID 21443958edit
  8.  Salk, R. S.; Chang, T. J.; d’Costa, W. F.; Soomekh, D. J.; Grogan, K. A. (2006). “Sodium Hyaluronate in the Treatment of Osteoarthritis of the Ankle: A Controlled, Randomized, Double-Blind Pilot Study”. The Journal of Bone and Joint Surgery 88 (2): 295–302.doi:10.2106/JBJS.E.00193PMID 16452740edit
  9. Beasley, K.; Weiss, M.; Weiss, R. (2009). “Hyaluronic Acid Fillers: A Comprehensive Review”.Facial Plastic Surgery 25 (2): 086–094. doi:10.1055/s-0029-1220647PMID 19415575edit
  10.  Shimmura, S.; Ono, M.; Shinozaki, K.; Toda, I.; Takamura, E.; Mashima, Y.; Tsubota, K. (1995).“Sodium hyaluronate eyedrops in the treatment of dry eyes”The British journal of ophthalmology 79 (11): 1007–1011. PMC 505317PMID 8534643edit
  11.  Boucher, W. S.; Letourneau, R.; Huang, M.; Kempuraj, D.; Green, M.; Sant, G. R.; Theoharides, T. C. (2002). “Intravesical sodium hyaluronate inhibits the rat urinary mast cell mediator increase triggered by acute immobilization stress”. The Journal of Urology 167 (1): 380–384.doi:10.1016/S0022-5347(05)65472-9PMID 11743360edit

Scientists discover new drug targets for aggressive breast cancer


Lyra Nara Blog

Singapore scientists discover new drug targets for aggressive breast cancer

The image shows the aggressive growth of TNBC cells. Credit: Genome Institute of Singapore, A*STAR

Scientists at A*STAR’s Genome Institute of Singapore (GIS) led in a study that has identified genes that are potential targets for therapeutic drugs against aggressive breast cancer. These findings were reported in the July 2013 issue of PNAS.

Out of the 1.5 million women diagnosed with breast cancer in the world annually, nearly one in seven of these is classified as triple negative. Patients with triple-negative breast cancer (TNBC) have tumours that are missing three important proteins that are found in other types of breast cancer. The absence of these three proteins make TNBC patients succumb to a higher rate of relapse following treatment and have lower overall survival rates. There is currently no effective therapy for TNBC.

Using integrated genomic approaches, GIS scientists led by Dr. Qiang Yu, in collaboration with local…

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What Does 100% of Your Daily Value of Cholesterol Look Like?


Healthline just published an interesting infograph that gives a visualization of what your daily value of cholesterol looks like.  In the graphic, you can see what 300 mg of cholesterol looks like for 20 high cholesterol foods: http://www.healthline.com/health/high-cholesterol/daily-value

This is a very informative resource as it helps us visualize what their cholesterol intake look like

What Does 100% of Your Daily Value of Cholesterol Look Like?

It’s no secret that eating fatty foods raises your bad cholesterol level, also known as LDL. An elevated LDL clogs up your arteries and makes it difficult for your heart to do its job. Potentially, it could lead to heart disease.

The USDA recommends consuming no more than 300 mg of cholesterol a day. While a deep-fried Twinkie at the county fair is an obvious no-no, other high cholesterol culprits may be sneaking into your diet. Check out what that number looks like in terms of everyday food items.

Warning: you may need to revise your grocery list—and your eating habits!

Image

Fried Chicken:

4 pieces=300mg cholesterol

Image

Croissants:

6 2/3 rolls=300mg cholesterol

Image

Cheddar Cheese:

12 3/4 slices=300mg cholesterol

Image

Prosciutto:

28 slices=300mg cholesterol

Image

Corned Beef:

14 thin slices=300mg cholesterol

Image

Butter:

1 1/5 sticks=300mg cholesterol

read at

http://www.healthline.com/health/high-cholesterol/daily-value

Bhasma : The ancient Indian nanomedicine


Figure 1: Standardization of <i>Bhasma</i>

Bhasma : The ancient Indian nanomedicine

Dilipkumar pal

Department of Pharmaceutical Sciences, Guru Ghasidash Vishwavidyalya (A Central University), Koni, Bilaspur – 495 009, Chhattisgarh 

India

Ayurveda is the science made up of Veda (knowledge) and Ayush (life) i.e. knowledge of life. An Ayurvedic system adopts a holistic approach towards health care by balancing the physical, mental and spiritual functions of the human body. RasaShastra (vedic-chemistry) is one of the parts of Ayurveda, which deals with herbo-mineral/metals/non-metals preparations called Bhasmas. Rasayana (immunomodulation and anti-aging quality) and yogavahi (ability to target drugs to the site) are characteristics of a properly made herbo-mineral/metals/non-metals preparation, which is also nontoxic, gently absorbable, adaptable and digestible in the body

read at http://www.japtr.org/article.asp?issn=2231-4040;year=2014;volume=5;issue=1;spage=4;epage=12;aulast=Pal

Pal D, Sahu CK, Haldar A. Bhasma : The ancient Indian nanomedicine. J Adv Pharm Technol Res [serial online] 2014 [cited 2014 Feb 26];5:4-12. Available from: http://www.japtr.org/text.asp?2014/5/1/4/126980

DOI: 10.4103/2231-4040.126980
more info

Bhasma[1] in Ayurveda has been defined as a substance obtained by calcination.

Use of both bhasma (Residue after incineration – calcined preparation) as well as in pishti (powdered gem or metal) form along with appropriate herbs for treatment of critical ailments is a medicinal preparation in Ayurveda and to some extent Unani (both Indian branches of medical science using natural curative methods. The procedures for preparing these medicines are time-consuming and complicated.

Bhasma is a calcined preparation in which the gem or metal is converted into ash. Gems or metals are purified to remove impurities and treated by triturating and macerating in herbal extracts. The dough so obtained is calcinated to obtain the ashes.[2]^

Bhasma or vibhooti is the sacred ash from the dhuni or fire of a yogi or avadhoota, or from the sacrificial fire or yajna, where special wood, ghee, herbs, grains and other auspicious and purifying items are offered in worship along with mantras. It is believed that bhasma destroys sins (paap), and that it links us with the divine. It is called ‘bhasma’ because it has the power to consume all evils. Any matter, broken up through the process of fire is reduced to its ‘bhasmic’ form, which is infinitely more refined and pure than the original matter, devoid as it is of all impurities niranjan. The grossness of matter obscures the subtle essence inherent within it, just as wood hides fire and milk conceals butter and cheese, but when it is burnt (or churned in the case of milk) only the pure essence remains. Similarly, the great heat of tapasya and the churning of the mind in meditation reveals the underlying subtle spirit or atman.

Vibhuti

In certain circumstances Bhasma, ‘Vibhuti‘ (Sanskrit) and ‘Thiruneeru’ (Tamil) are synonymous.

Bhasmikaran

Bhasmikaran is a process by which a substance which is otherwise bioincompatible is made biocompatible by certain samskaras or processes (Puranik and Dhamankar, 1964e). The objectives of samskara are :- a) elimination of harmful matters from the drug b) modification of undesirable physical properties of the drug c)conversion of some of the characteristics of the drug d) enhancement of the therapeutic action(Puranik and Dhamankar, 1964e). Various steps involved in the preparation of bhasma(or bhasmikaran) are:- 1) Shodhan -Purification, 2) Maran – Powdering, 3) Chalan- Stirring, 4) Dhavan – Washing, 5) Galan- Filtering, 6) Putan- Heating, 7) Mardan- Triturating, 8) Bhavan- Coating with herbal extract, 9) Amrutikaran – Detoxification and 10) Sandharan- Preservation (Puranik and Dhamankar, 1964e). Selection of these steps depends on the specific metal. Sometimes there is an overlapping of the steps e.g. maran is achieved by puttan. Since the present thesis work is on bhasma, Bhasmikaran process is elaborated in details in the following paragraphs.

Steps of bhasmikaran

1. Shodhan: The principle objective of shodhan is to remove unwanted part from the raw material and separate out impurities( Vaiday and Dole 1996b). Metals obtained from ores may contain several impurities, which are removed by subjecting them to Shodhan process. In context of bhasma, shodhan means purifying and making the product suitable for the next step i.e. Maran. Ayurveda classifies shodhan into a) General process and b) Specific process.

General process for shodhan:

“The sheets of metals are heated till red hot and are successively dipped into liquids like oil, buttermilk, cow’s urine etc. The procedure is repeated seven times”.

b. Specific process for shodhan For some metals a specific process is described for shodhan e.g. for purification of Jasad, the molten mass is poured in cow’s milk 21 times (Shastri K,1979b).

2. Maran : Maran literally means killing. As the name suggests in maran process, a change is brought about in the chemical form or state of the metal. This makes it to lose its metallic characteristics and physical nature. In short, after maran, metal can be converted into powder or other form suitable for administration. To convert various metals into a form appropriate for human consumption, several techniques have been employed which ultimately gave birth to concept: “Bhasma prepared by using Rasa i.e. mercury is the best, whereas the one prepared using herbs are of better quality and those prepared using Gandhak (sulfur) are of inferior quality. Thus there are 3 methods given for maran. It is carried out by heating the metal in presence of 1) mercury 2) plants and 3 ) sulfur.

When various maran procedures for different metals were reviewed, it was found that mercury is mainly used. The unique property of mercury to amalgamate with many metals must have been the reason behind its maximum use in the process of Bhasmikaran. Ancient practitioners might have found it as the most suitable chemical and therefore probably have mentioned that bhasmas using mercury are superior. Plants used in maran process may be serving as catalyst in the process or the minerals in the plants may be forming complexes with the metals. However, no such explanation can be obtained for the use of sulfur.

3. Chalan: Process of stirring during heating the metal is chalan. Stirring is carried out either with iron rod or stick made from a specific plant. As we know today, iron serves as catalyst in many chemical reactions. The phytoconstituents of plant stick may be enhancing the therapeutic effect. For example, stick of Neem is used for chalan process of Jasad bhasma, which is used topically for ophthalmic diseases. We can interpret the significance of this process now. Neem is an antiseptic (Puranik and Dhamankar, 1964h). Zinc is antiseptic, astringent and has ulcer healing property (Block et al., 1982b). These effects of both the constituents may impart the final product better therapeutic activity.

4. Dhavan: In this process, several water washes are given to the product obtained in the previous stage. Perhaps this is to remove the excess amounts of agents used in shodhan or maran stage. Such agents may adversely affect the quality of final product. Hence intermediates are washed with water, thereby water soluble constituents are removed (Puranik and Dhamankar, 1964h).

5. Galan: The product is then sifted either through a fine cloth or through sieves of suitable mesh so as to separate residual material larger in size (Puranik and Dhamankar, 1964h).

6. Puttan: The term puttan means ignition. The general term used for heating in the process of Bhasmikaran is Puta. A special earthen pot, Sharav is generally used for the process. It has two parts, each having a shape of soccer. Sharav is used for direct heating of the material. Its shallowness is useful in heating the material faster and uniformly. After keeping the material on the shallow surface, other part is used as a lid, by placing it in an inverted position. This Puttan process can be looked upon as the key step in manufacturing of bhasma. The classification of putta is primarily done on the basic nature of the process and is as under :- (Puranik and Dhamankar, 1964f) 1)Chandraputta 2) Dhanyarashiputta 3) Suryaputta 4)Bhugarbhaputta 5) Agniptuta.

Toxicity

Modern medical science finds that mercury is inherently toxic, and that its toxicity is not due to the presence of impurities. While mercury does have anti-microbial properties, and formerly waswidely used in Western medicine, its toxicity does not warrant the risk of using it as a health product in most circumstances.[3][4] The Centers for Disease Control and Prevention have also reported a number of cases of lead and mercury poisoning associated with rasa shastra containing Ayurvedic medicines.[5]

Literal and symbolic meaning of bhasma

The Sanskrit word bhasma literally means ‘disintegration’. Bha implies bhartsanam (to destroy), while sma implies smaranam (to remember). Bhasma is thus a reminder to us of the ephemeral nature of life. Also, if we wish to unite with God (or the ‘supreme self’) and remember him constantly, our ego or ‘little self’ has first to be disintegrated or burnt to ashes. Bhasma is a symbol of this process. It is also called raksha because it protects one from all fears. When applied to the forehead before sleep, it is said to keep away spirits or ghosts, whether external or those which manifest from the depths of the mind in the form of nightmares.

Bhasma symbolises the burning of our false identification with the mortal body, and freedom from the limitations of the painfully illusive cycle of birth and death. It also reminds us of the perishable quality of the body, which will one day be reduced to mere ashes. As it says in the Bible, “Ashes to ashes; soul to soul” – the body will return to dust but the soul will continue its journey until it unites with God. All the saints and sages beseech us to remember the ephemeral nature of our earthly existence. In the Rubayyat of Omar Khyyam the poet tells us to, “ . . . make the most of what we yet may spend, before we too into the dust descend, dust into dust, and under dust to lie.” Here he calls for us to seek the eternal, not the temporal. Ash or dust, on the other hand, can be said to represent permanency (or the soul itself), because the ash, just like imperishable truth, does not itself decay. The realised soul is said to rise from the ashes (of the individual self) as the mythical phoenix. The Sufis say, “To reach the goal we have to be burned with the fire of love, so that nothing remains but ashes, and from the ashes will resurrect the new being. Only then can there be real creation!”

The power of bhasma

Bhasma is also called ‘vibhooti’, because it gives spiritual power. The Sanskrit word, vibhooti means ‘glory’, as it gives glory to one who applies it, protection (raksha) from ill health and negative forces, and attracts the higher forces of nature. Another meaning of vibhooti is ‘healing power’, and it is widely used as a medicinal treatment in both Ayurveda and Chinese and Tibetan medicine, which are all ancient and profound systems for the rejuvenation of life. Gold, silver, copper, pearls, mica and other precious stones and metals have curative properties which can quite safely and most effectively be taken into the body after being reduced to ash using great heat.

In Indian villages you will find tantric healers called ojhas who say certain mantras over the ash, which the sick person then applies to the body or eats. These healers can take some earth in their hands, hold it up to the sun, repeat some mantras, and the earth turns into the most beautifully scented ash for curative purposes. Vibhooti is also the name given to siddhis (perfections or psychic powers), as it acts as a vehicle for them. Patanjali’s Yoga Sutras devotes an entire chapter to yogic siddhis. Vibhooti also means ‘dominion’, and is the subtle power lying behind creation, from which all things manifest. From vibhooti or bhasma, anything can be created by a tantric and aghora, because the potential of creation lies within it, and he has penetrated the law and controlled the elements.

Maha Yogi Shiva, father of tantra, is usually depicted naked in sadhana, his whole body covered in bhasma. The first verse of the Shiva Panchakshara Stotram gives the following description: Naagendrahaaraaya trilochanaaya, bhasmaangaraagaaya maheshwaraaya. Nityaaya shuddhaaya digambaraaya – ‘Salutations to the mighty three-eyed Shiva, eternal and pure, wearing the king of snakes as his garland, naked and besmeared with sacred ash.’ Some other names given to Lord Shiva are Bhasmashayaaya (abode of bhasma) and Bhasmabhootaaya (covered with bhasma). Covering the body with ash is considered to be an auspicious act for discovering one’s Shiva nature. Shiva is said to be responsible for mahapralaya, the dissolution of the universe at the end of each kalpa. At this time he dances his tandava nritya, the dance of destruction.

The great tantric siddha Avadhoota Dattatreya was referred to as Bhasma Nishta – one who loves bhasma. Bhasma is generally applied on the forehead, while many sadhus also apply it on the arms, chest and stomach. Some ascetics, especially nagas (naked ascetics) rub it all over the body. While applying it, many devotees also consume a pinch. Shaivites use only bhasma from cremated bodies, which is believed to be very powerful. Bhasma has the power of fire. Agni, the inner fire, scorches and reduces all impurities in the body. It is said that one who smears ash on the body is purified as if bathed in fire. This is known as ‘the bath of fire’. After smearing the body with ash, one should reflect on and realise the highest truth.

Tripundra

Sannyasins wear three lines of bhasma on the forehead. These three lines (tripundra), with a red dot of kumkum underneath, between the eyebrows, symbolise Shiva-Shakti (the unity of energy and matter that creates the entire seen and unseen universe). The lower line represents tamoguna (the state of inertia and darkness), the middle line represents rajas (activity and dynamism) and the top line represents sattwa (balance and illumination). The red dot or tika represents the power of shakti through sadhana, which can take the sadhaka beyond the three gunas or qualities to the state of turiya, the fourth dimension of existence. This is the state of trigunatita – beyond the three gunas.

Swami Niranjanananda says, “The three stripes represent the tradition of the paramahamsas. Jignasus are one stripe sannyasins, representing the drive and motivation to overcome the tamasic tendency. Karma sannyasins are given two stripes, representing their drive to overcome the rajasic along with the tamasic tendencies. Poorna sannyasins are given three stripes, which represent their motivation to transcend the three gunas and attain inner sublimation. The red dot represents the spiritual power or energy that gives us the strength to control the three gunas. It is the awakening of that shakti which is the real aim of sannyasa.”

Bhasma and tattwa shuddhi

Consciousness manifests as energy, which then condenses into matter. In the tantric practice of tattwa shuddhi, in order to experience consciousness free from matter, we reverse the process of evolution back through more and more subtle dimensions to its original cause. Bhasma is an integral part of tattwa shuddhi sadhana, as a symbol of purification on the physical, subtle and causal realms of consciousness. The process of disintegration undergone in tattwa shuddhi is the breaking down of conscious awareness. Just as we reduce matter to its bhasmic form, the ‘fire’ of this practice leads us to the realisation of our essential essence. The stages of pratyahara (sense withdrawal) and dharana (concentration) take us through the more subtle states of consciousness, culminating in samadhi, the ultimate experience or ‘Shiva consciousness’. The journey is from gross matter to pure consciousness.

At the end of the practice of tattwa shuddhi, bhasma is applied to the forehead with the repetition of mantras. It is taken on the middle and ring fingers and wiped slowly on the forehead from left to right, repeating the mantra Om Hraum Namah Shivaya. Sannyasins use the index, middle and ring fingers, and repeat the mantra Om Hamsa. The bhasma used in tattwa shuddhi is prepared from gobar or cow dung. The word gobar literally means ‘gift from the cow’; it is also known as go-maya. The cow is a pure and sacred animal, full of auspicious qualities. It is even said to contain all the devas and devatas within it. Not only does gobar have mystical qualities, but it also contains useful hormones with germicidal properties. The word go also means ‘senses’. So bhasma is also symbolic of the disintegration of the senses which keep us trapped and bound in the gross material world. The transformation of gobar to bhasma is parallel to the transformation from the material world to cosmic consciousness that we find in tattwa shuddhi.

Panchagni bhasma

During the Sat Chandi Mahayajna, and on other auspicious occasions at Rikhia Dham, devotees receive the precious prasadam of panchagni bhasma. This is much prized by sadhakas, because as it has the power of Swami Satyananda’s sadhana behind it, it quickly helps to raise the consciousness at the time of mantra japa and other sadhana when applied to the forehead. Just keeping it in the pooja room is auspicious. This bhasma given is from the Maha Kaal Chita Dhuni, where the previously fierce fires of Sri Swamiji’s panchagni tapasya now lie smouldering quietly under ashes in their shanta roopa or peaceful form. Dhuni is the yogi’s fire, which is the witness or sakshi to his sadhana. It is also where he cooks, takes warmth, and chants the name of God. (Maha means ‘great’, kaal is ‘time’ and chita is ‘consciousness’).

This akhanda dhuni, eternal fire, has been burning in Sri Swamiji’s pooja area ever since he first came to Rikhia in 1989 and devotees come daily for its darshan. It was the centre and support of his life during his austerity, and is the very heart of the Rikhia Ashram (next to Sri Swamiji himself). Although Sri Swamiji no longer goes to this area, the fire is still tended daily. The ashes are moved to the side and the burning embers taken out. Balls of dried cow dung mixed with purifying herbs (vanaspati) are then placed inside along with fresh wood. The embers are then replaced, and the whole area is covered over once more with the ashes. From time to time the ash is removed, carefully sieved through fine cloth, and given as prasadam (that which has been blessed by a divine power.

For the panchagni sadhana itself, Sri Swamiji prepared his own bhasma to protect his body from the great heat, according to the formula prescribed in the Devi Bhagavat Purana. This special bhasma is called mahabhasma and is made from pure cow dung cakes, reeds and ghee. It is treated eleven times with many herbs, honey and other ingredients, being re-burnt each time. Bhasma is smeared on the body only during the first few days of the panchagni sadhana, and is applied in the morning. Sri Swamiji’s dog-cum-companion Bholenath, in whom he manifested the spirit of Bhairava, also took part in the tapasya. “Alsatian dogs can’t bear the heat,” commented Sri Swamiji. “I would put bhasma on him in the morning and he would sit with me.”

Tantric siddhas like Maha Yogi Shiva, Avadhoota Dattatreya and Sri Swamiji are extremely rare beings, and a gift to us beyond our understanding. They belong to a great tradition and leave behind for us a great spiritual legacy. The parampara, the line of avadhootas (those who have become immortal), continues, just as the Mahakaal Chita Dhuni continues to smoulder, unseen beneath the symbol of their glory, their bhasma – the sacred ash.

 

Abhrak Bhasma

Strengthens body, ligaments & Saptadhatu, effective in raktapitta, vat diseases and joint pain. Relieves problems related to chronic hyperacidity like stomache, headache etc.

 

Details

The Indian ayurved philosophy is founded on three basic classifications of human body known as doshasand its well-being:

Vat – related to the central nervous system and gastric tract,

Pitta –digestion and metabolism, governs movement of heat in the body and

Kapha – concerned with structure, stability and fluid balance in the body.

Indian herbal medicines are designed for the specific maintenance of these respective doshas or the aspects of the human body.

Abhrak Bhasma or Sahastraputi is an ancient Indian ayurvedic medicine which is trusted worldwide for healing Vat related issues of the human body. It is also found extremely effective for treating heart related issues.

Abhrak is known to have a high penetrative property which spreads in the body at a faster rate and impacts micro tissues quickly.That is why this herbal medicine is supremely effective in cell regeneration. When used as an alterative, it strengthens ligaments. It is known for rapidly increasing the production of T-cell phagocytes, antibacterial components, which are responsible for a strong immune system.

Kesar Herbals has been in the ayurvedic medicine manufacturing business for about 25 years. This company is one of the foremost and trusted ayurvedic medicine suppliers in India.The concept was let entire mankind benefit from the ancient herbal wealth of India.

Composition:

Purified Mica, Magnesium, Iron, Potassium, Calcium and Aluminium.

Major Benefits of Abhrak Bhasma

  • It finds its application in curing diseases like Hepatitis, Tuberculosis, Asthma and Plague.
  • Abhrak Bhasma is also recommended for breathlessness due to chronic Bronchitis, Asthma, and even Chest Congestion. When taken in the initial stage of TB, it can completely cure it.
  • It is beneficial to all the seven dhatus (energy elements) in the body.
  • It rejuvenates the human mind.
  • It improves blood circulation, improves the general tone of tissues and conductivity.
  • It cures erectile dysfunction and impotency in men.
  • Abhrak is hematinic, which means increases the count of red blood cells. This also increases oxygen carrying ability of the cells.
  • It helps in curing jaundice and anemia.
  • It restores damaged tissues and maintains their health.
  • It is highly effective in cases of bone marrow depletion and hepatic dysfunction.
  • It is effective in curing respiratory tract infections.
  • It is beneficial for curing Bells Palsy and dysentery.
  • It is beneficial in curing anemia, pernicious and azoospermia.
  • Also, helps in controlling many types of veneral diseases like EBV, HIV, Lupus bronchitis and pneumonia.
  • It cures breast cancer.
  • It is also known to cure chronic hyperacidity like stomach-ache and vomiting with blood.

 

Suvarna Bhasma

Boosts immunity, Acts as a nervine tonic , Indicated in old age debility, urinal disorders, anemia, Shwas, Helps to improve complexion, Kas & chronic fever etc.

 

Details

Swarna Bhasma is an ancient Indian ayurvedic medicine that enjoys wide popularity and application.Gold has been accepted as most useful ingredient in Indian ayurvedic medicine system. SwarnaBhasma is used for the effective treatment of Gonorrhoea and Syphilis.

Fortified with potent ayurvedic herbs it is effective for maintaining a healthy life-style and relieves stress.Bhasma denotes the metal based medicine prepared from metals after scientific process to harness the hidden richness of raw metals for therapeutic effects. Swarna Bhasmaor Gold Ash is a therapeutic form of gold metal of nano-sized particles that is one of the most treasured ayurvedic medicines in the world.

It has multi-purpose ayurvedic medicine: it can be used as an antacid, haematinic, and alterative. It is highly effective as a cardiac tonic, maintaining the vitality of the human heart. It is a general vitality booster.

Kesar Herbals firmly believes in the power of nature in healing various ailments. Ayurvedic medicines from India are a gift from nature itself, without any side-effects, and hence they are trusted world-wide.Through scientific processes, nature’s best healing powers from herbs are obtained and used for medicinal purposes, helping million people worldwide. Kesar Herbals is involved in consulting, manufacturing and supplying FDA approved ayurvedic medicines for over three decades.

Major Benefits of Swarna Bhasma

  • Swarna Bhasma improves resistance power in human body.
  • It is responsible for boosting immunity and strengthening the human body.
  • It can be used on a regular basis as an alterative and acts as a nerve tonic.
  • Swarna Bhasma is excellent in treating Anemia, and chronic fever.
  • Due to its gold base, it is helpful in improving complexion.
  • Swarna Bhasma eradicates all chronic disorders, when used consistently.
  • It is indicated in chronic fever, cough, Asthma, urinary disorders, sleeplessness and weak digestion.
  • It strengthens weak muscles, debilities associated with old-age.
  • It is excellent for treating Tuberculosis.
  • It increases sexual power.
  • Swarna Bhasma slows down the process of degeneration of tissues thus helps to prevent premature ageing.
  • It helps prevent symptoms of ageing like wrinkles, dullness of skin, dark circles around the eyes, debility, fatigue, etc.
  • Swarna Bhasma strengthens tissues and ligaments of the human body.
  • It is highly effective in maintaining vigor, vitality and stamina.

Hirak Bhasma

effective against immunity disorders, Bone marrow depression and arthritis, increases stamina, vitality and strength

Ayurvedic medicinal science has been at the forefront of solving most diseases and disorders of the human body because of the purity of its ingredients- this forms the core of the ancient Indian healing system. Ayurvedic medicines and herbal products are effective because of the composition or the formulation of herbs. One such effective ayurvedic medicine is the Hirak Bhasma, which contains diamond ash.

According to Ayurveda, diamond ash is very useful in cancers, immunity disorders, Crippling Rheumatoid arthritis, and even bone marrow depression. Hirak Bhasma is known for toning heart muscles and avoiding cardiovascular syndromes and diseases. It is highly effective as a tonic and alterative, which means, it can be used regularly to strengthen immunity, aid stamina and overall vitality or the functionality of the human body.

Hirak Bhasma is made with diamond- the most precious as well as the hardest gemstone known to mankind. In its healing formulation, diamond is known since ages to make the human body stronger. It is also known for sharpening the human mind by strengthening memory power.

The effectiveness of ayurvedic medicines depends on the company. So be careful in selecting the brand for these medicines and products. Kesar Herbals has been in the ayurvedic consulting space and even manufacturing and supplying of ayurvedic medicines and herbal products for over 25 years. The trust and good will it represents in the field of Ayurveda is affirmed by its customers the world over. It is important to ascertain the brand equity of the company before purchasing these medicines.

Composition:

Hirak Bhasma (diamond ash), Kumari Rasa (Aloe Vera Juice), Gulab Jala (Rose Water), Sunthi Kwath (Dry Ginger Dicoction)

Benefits:

  • Hirak Bhasma is known the world over to make the human body stronger and the mind sharper.
  • It is also recommended for the well-being of the human heart.
  • It helps in toning the muscles of the heart.
  • Its regular consumption as a tonic or an alterative, under medical prescription or supervision is known for toning the heart muscles.
  • Hirak Bhasma also increases stamina, vitality and strength.
  • It is highly effective against immunity disorders.
  • It is known for curing Crippling Rheumatoid
  • It is effective against Bone marrow depression and arthritis.
  • Hirak Bhasma is also known to cure one of the most dangerous and lethal diseases known to mankind: cancer. When used in the initial stages, under medical supervision, it can cure cancerous cells.
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