http://www.clinicalleader.com/doc/nice-endorses-lundbeck-s-alcohol-dependency-drug-for-use-in-uk-0001

A structural analog of Naltrexone (N285780) with opiate antagonist activity used in pharmaceutical treatment of alcoholism. Other pharmacological applications of this compound aim to reduce food cravings, drug abuse and pulmonary disease in affected individuals. Used as an opioid-induced tranquilizer on large animals in the veterinary industry. Narcotic antagonist.

Nalmefene

Systematic (IUPAC) name
17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol
Clinical data
Trade names	Selincro
AHFS/Drugs.com	monograph
MedlinePlus	a605043
Legal status	POM (UK)
Routes	Oral, Intravenous
Pharmacokinetic data
Protein binding	45%
Metabolism	hepatic
Half-life	10.8 ± 5.2 hours
Excretion	renal
Identifiers
CAS number	55096-26-9 58895-64-0 (HCl)
ATC code	N07BB05
PubChem	CID 5284594
ChemSpider	4447642
UNII	TOV02TDP9I
ChEMBL	CHEMBL982
Chemical data
Formula	C21H25NO3
Mol. mass	375.9 g/mol (hydrochloride)

Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid receptor antagonist developed in the early 1970s,^[1] and used primarily in the management of alcohol dependence, and also has been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping.

Nalmefene is an opiate derivative similar in both structure and activity to the opiate antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity. As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.

Nalmefene differs from naltrexone by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH₂), which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors, and is known as a “universal antagonist” for its ability to block all three.

In clinical trials using this drug, doses used for treating alcoholism were in the range of 20–80 mg per day, orally.^[2] The doses tested for treating pathological gambling were between 25–100 mg per day.^[3] In both trials, there was little difference in efficacy between the lower and higher dosage regimes, and the lower dose (20 and 25 mg, respectively) was the best tolerated, with similar therapeutic efficacy to the higher doses and less side effects. Nalmefene is thus around twice as potent as naltrexone when used for the treatment of addictions.

Intravenous doses of nalmefene at between 0.5 to 1 milligram have been shown effective at counteracting the respiratory depression produced by opiate overdose,^[4] although this is not the usual application for this drug as naloxone is less expensive.

Doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit in this application. Nalmefene’s longer half-life might however make it useful for treating overdose involving longer acting opioids such as methadone, as it would require less frequent dosing and hence reduce the likelihood of renarcotization as the antagonist wears off.

Nalmefene is extensively metabolised in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.

Lundbeck has licensed the drug from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.^[5] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.^[6] It has not been available on the US market since at least August 2008.^{[citation needed]}

Side effects

• Common: drowsiness, hypertension, tachycardia, dizziness, nausea, vomiting
• Occasional: fever, hypotension, vasodilatation, chills, headache
• Rare: agitation, arrhythmia, bradycardia, confusion, hallucinations, myoclonus, itching^[7]

Properties

• Soluble in water up to 130 mg/mL, soluble in chloroform up to 0.13 mg/mL
• pK_a 7.6
• Distribution half-life: 41 minutes

Nalmefene is a known opioid receptor antagonist which can inhibit pharmacological effects of both administered opioid agonists and endogenous agonists deriving from the opioid system. The clinical usefulness of nalmefene as antagonist comes from its ability to promptly (and selectively) reverse the effects of these opioid agonists, including the frequently observed depressions in the central nervous system and the respiratory system.

Nalmefene has primarily been developed as the hydrochloride salt for use in the management of alcohol dependency, where it has shown good effect in doses of 10 to 40 mg taken when the patient experiences a craving for alcohol (Karhuvaara et al, Alcohol. Clin. Exp. Res., (2007), Vol. 31 No. 7. pp 1179-1187). Additionally, nalmefene has also been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping. In testing the drug in these developmental programs, nalmefene has been used, for example, in the form of parental solution (Revex™).

Nalmefene is an opiate derivative quite similar in structure to the opiate antagonist naltrexone. Advantages of nalmefene compared to naltrexone include longer half- life, greater oral bioavailability and no observed dose-dependent liver toxicity. Nalmefene differs structurally from naltrexone in that the ketone group at the 6- position of naltrexone is replaced by a methylene (CH₂) group, which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors (K and δ receptors) and is known as a “universal antagonist” as a result of its ability to block all three receptor types.

Nalmefene can be produced from naltrexone by the Wittig reaction. The Wittig reaction is a well known method within the art for the synthetic preparation of olefins (Georg Wittig, Ulrich Schόllkopf (1954). “Uber Triphenyl-phosphin- methylene ah olefinbildende Reagenzien I”. Chemische Berichte 87: 1318), and has been widely used in organic synthesis.

The procedure in the Wittig reaction can be divided into two steps. In the first step, a phosphorus ylide is prepared by treating a suitable phosphonium salt with a base. In the second step the ylide is reacted with a substrate containing a carbonyl group to give the desired alkene.

The preparation of nalmefene by the Wittig reaction has previously been disclosed by Hahn and Fishman (J. Med. Chem. 1975, 18, 259-262). In their method, naltrexone is reacted with the ylide methylene triphenylphosphorane, which is prepared by treating methyl triphenylphosphonium bromide with sodium hydride (NaH) in DMSO. An excess of about 60 equivalents of the ylide is employed in the preparation of nalmefene by this procedure.

For industrial application purposes, the method disclosed by Hahn and Fishman has the disadvantage of using a large excess of ylide, such that very large amounts phosphorus by-products have to be removed before nalmefene can be obtained in pure form. Furthermore, the NaH used to prepare the ylide is difficult to handle on an industrial scale as it is highly flammable. The use of NaH in DMSO is also well known by the skilled person to give rise to unwanted runaway reactions. The Wittig reaction procedure described by Hahn and Fishman gives nalmefene in the form of the free base. The free base is finally isolated by chromatography, which may be not ideal for industrial applications.

US 4,535,157 also describes the preparation of nalmefene by use of the Wittig reaction. In the method disclosed therein the preparation of the ylide methylene triphenylphosphorane is carried out by using tetrahydrofuran (THF) as solvent and potassium tert-butoxidc (KO-t-Bu) as base. About 3 equivalents of the ylide are employed in the described procedure.

Although the procedure disclosed in US 4,535,157 avoids the use of NaH and a large amount of ylide, the method still has some drawbacks which limit its applicability on an industrial scale. In particular, the use of THF as solvent in a Wittig reaction is disadvantageous because of the water miscibility of THF. During the aqueous work-up much of the end product (nalmefene) may be lost in the aqueous phases unless multiple re-extractions are performed with a solvent which is not miscible with water.

Furthermore, in the method described in US 4,535,157, multiple purification steps are carried out in order to remove phosphine oxide by-products of the Wittig reaction. These purification steps require huge amounts of solvents, which is both uneconomical and labor extensive requiring when running the reaction on an industrial scale. As in the case of the Wittig reaction procedure described by Hahn and Fishman (see above) the Wittig reaction procedure disclosed in US 4,535,157 also yields nalmefene as the free base, such that an additional step is required to prepare the final pharmaceutical salt form, i.e. the hydrochloride, from the isolated nalmefene base.

US 4,751,307 also describes the preparation of nalmefene by use of the Wittig reaction. Disclosed is a method wherein the synthesis is performed using anisole (methoxybenzene) as solvent and KO-t-Bu as base. About 4 equivalents of the ylide methylene triphenylphosphorane were employed in this reaction. The product was isolated by extraction in water at acidic pHs and then precipitating at basic pHs giving nalmefene as base.

Even though the isolation procedure for nalmefene as free base is simplified, it still has some disadvantages. The inventors of the present invention repeated the method disclosed in US 4,751,307 and found that the removal of phosphine oxide by-products was not efficient. These impurities co-precipitate with the nalmefene during basifϊcation, yielding a product still contaminated with phosphorus byproducts and having, as a consequence, a low chemical purity, as illustrated in example 2 herein.

There is therefore a need within the field to improve the method of producing nalmefene by the Wittig reaction. In particular, there is a need for a method that is readily applicable on a large industrial scale and which avoids the use of water- miscible solvents, such as THF, in the Wittig reaction, and permits easy isolation of nalmefene in a pure form suitable for its transformation to the final pharmaceutical salt form.

………………………………..

http://www.google.com/patents/EP2435439A1?cl=en

present invention the Wittig reaction may be performed by mixing a methyltriphenylphosphonium salt with 2- methyltetrahydrofuran (MTHF) and a suitable base to afford the ylide methylene triphenylphosphorane :

Methyltriphenylphosphonium salt Methylene triphenylphosphorane Yhde

The preformed ylide is subsequently reacted ‘in situ’ with naltrexone to give nalmefene and triphenylphosphine oxide (TPPO):

Naltrexone Yhde    Nalmefene TPPO

Example 1 Methyltriphenylphosphonium bromide (MTPPB, 25.8 Kg) was suspended in 2- methyltetrahydrofuran (MTHF, 56 litres). Keeping the temperature in the range 20-25⁰C, KO-t-Bu (8.8 kg) was charged in portions under inert atmosphere in one hour. The suspension turned yellow and was stirred further for two hours. An anhydrous solution of naltrexone (8.0 Kg) in MTHF (32 litres) was then added over a period of one hour at 20-25⁰C. The suspension was maintained under stirring for a few hours to complete the reaction. The mixture was then treated with a solution of ammonium chloride (4.2 Kg) in water (30.4 litres) and then further diluted with water (30.4 litres). The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water (16 litres). The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (40 litres) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 2 litres) was added over one hour at 20- 25⁰C. The suspension was stirred for at least three hours at the same temperature, and then filtered and washed with dichloromethane (8 litres) and then with acetone (16 litres). The solid was then re-suspended in dichloromethane (32 litres) at 20-25⁰C for a few hours and then filtered and washed with dichloromethane (16 litres), affording 9.20 Kg of nalmefene hydrochloride, corresponding to 7.76 kg of nalmefene hydrochloride (99.7% pure by HPLC). Molar yield 89%.

HPLC Chromatographic conditions

Column: Zorbax Eclipse XDB C-18, 5 μm, 150 x 4.6 mm or equivalent Mobile Phase A: Acetonitrile / Buffer pH = 2.3 10 / 90

Mobile Phase B: Acetonitrile / Buffer pH = 2.3 45 / 55

Buffer: Dissolve 1.1 g of Sodium Octansulfonate in 1 L of water. Adjust the pH to 2.3 with diluted

H₃PO₄. Column Temperature: 35°C

Detector: UV at 230 nm

Flow: 1.2 ml/min

Injection volume: 10 μl

Time of Analysis: 55 minutes

Example 2

The procedure described in US 4,751,307 was repeated, starting from 1Og of naltrexone and yielding 8.5g of nalmefene. The isolated product showed the presence of phosphine oxides by-products above 15% molar as judged by 1HNMR.

Example 3.

Methyltriphenylphosphonium bromide (MTPPB, 112.9g) was suspended in 2- methyltetrahydrofuran (MTHF, 245 ml). Keeping the temperature in the range 20- 25°C, KO-t-Bu (38.7 g) was charged in portions under inert atmosphere in one hour. The suspension was stirred for two hours. An anhydrous solution of naltrexone (35 g) in MTHF (144 ml) was then added over a period of one hour at 20-25⁰C. The suspension was maintained under stirring overnight. The mixture was then treated with a solution of glacial acetic acid (17.7 g) in MTHF. Water was then added and the pH was adjusted to 9-10. The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water. The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (175 ml) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 10. Ig) was added over one hour at 20- 25°C. The suspension was stirred and then filtered and washed with dichloromethane and acetone. The product was dried affording 38.1g of Nalmefene HCl. Example 4

Example 3 was repeated but the Wittig reaction mixture after olefmation completeness was treated with acetone and then with an aqueous solution of ammonium chloride. After phase separation, washings, distillation and dilution with dichloromethane, the product was precipitated as hydrochloride salt using HCl 37%. The solid was filtered and dried affording 37.6 g of Nalmefene HCl.

Example 5 Preparation of Nalmefene HCl dihydrate from Nalmefene HCl Nalmefene HCl (7.67 Kg, purity 99.37%, assay 93.9%) and water (8.6 litres) were charged into a suitable reactor. The suspension was heated up to 80⁰C until the substrate completely dissolved. Vacuum was then applied to remove organic solvents. The resulting solution was filtered through a 0.65 μm cartridge and then diluted with water (2.1 litres) that has been used to rinse the reactor and pipelines. The solution was cooled down to 50⁰C and 7 g of Nalmefene HCl dihydrate seeding material was added. The mixture was cooled to 0-5⁰C over one hour with vigorous stirring and then maintained under stirring for one additional hour. The solid was filtered of and washed with acetone. The wet product was dried at 25°C under vacuum to provide 5.4 Kg of Nalmefene HCl dihydrate (purity 99.89%, KF 8.3% , yield 69%).

………………….

http://www.google.com/patents/EP2316456A1?cl=en

……………………

http://www.google.com/patents/US8598352

References

1.  US patent 3814768, Jack Fishman et al, “6-METHYLENE-6-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS”, published 1971-11-26, issued 1974-06-04
2.  Barbara J. Mason, Fernando R. Salvato, Lauren D. Williams, Eva C. Ritvo, Robert B. Cutler (August 1999). “A Double-blind, Placebo-Controlled Study of Oral Nalmefene for Alcohol Dependence”. Arch Gen Psychiatry 56 (8): 719. doi:10.1001/archpsyc.56.8.719.
3.  Clinical Trial Of Nalmefene In The Treatment Of Pathological Gambling
4.  http://www.fda.gov/cder/foi/label/2000/20459S2lbl.pdf
5.  “Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE1)”.
6.  “Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan”. thepharmaletter. 22 December 2011.
7.  Nalmefene Hydrochloride Drug Information, Professional
8.  Brittain, H.G., et al.: Anal. Profiles Drug Subs. Excip., 24, 351 (1996), Anton, R., et al.: J. Clin. Psychopharmacol., 24, 421 (2004), Bart, G., et al.: Neuropsychopharmacol., 30, 2254 (2005), Wu, X., et al.: Chem. Pharmacol. Bull., 54, 977 (2006),

ICH gets new Members and informs about the ICH Q3D Implementation
The International Conference on Harmonisation (ICH) is the most significant organisation for the harmonisation of requirements with regard to the authorisation and the manufacture of medicinal products. Read more about the current decisions of the ICH Steering Committees.

http://www.gmp-compliance.org/enews_4395_ICH%20gets%20new%20Members%20and%20informs%20about%20the%20ICH%20Q3D%20Implementation_8559,S-AYL_n.html

ICH gets new Members and informs about the ICH Q3D Implementation\

The International Conference on Harmonisation (ICH) is the most significant organisation for the harmonisation of requirements with regard to the authorisation and the manufacture of medicinal products. The ICH wants this function to be extended. For that reason – during the last meeting in Minneapolis, USA – the Steering Committee decided to welcome two new members. Beside the American FDA, the EMA/EU Commission and the Japanese Authority belong to the founding members. Now, the Swiss Authority Swissmedic and the Canadian one (Health Canada) have joined the ICH Board.

Another important notice has been announced after the meeting in Minneapolis. In September 2014, the harmonised Guideline ICH Q3D Elemental Impurities will reach the Step 4 status. The FDA as well as the EMA/EU Commission and the Japanese MHLW will take over the whole document into their respective national regulations. This last – and formal – procedure will be defined as Step 5. No changes will be made in the guidance document when the authorities will make the transfer to the regulatory framework.

The new ICH Q3D and the recently adopted ICH M7 (Genotoxic Impurities) will therefore be addressed at the international Impurities Forum in Berlin.

Source: Press Release of the ICH Meeting in Minneapolis

http://www.gmp-compliance.org/enews_4395_ICH%20gets%20new%20Members%20and%20informs%20about%20the%20ICH%20Q3D%20Implementation_8559,S-AYL_n.html

An analysis of warning letters issued in the past fiscal year essentially shows the same pattern of frequently cited GMP violations. It also shows a noticeable increase in the GMP deficiencies relating to the qualification of suppliers and their certificates of analysis. Find out more

http://www.gmp-compliance.org/enews_4390_Insufficient%20failure%20investigations%2C%20supplier%20qualification%2C%20stability%20testing%20-%20the%20most%20common%20GMP%20violations%20in%20the%20FDA%20warning%20letters_8500,8489,S-QSB_n.html

The analysis of the warning letters issued in the last fiscal year shows no surprise at a first glance: as in recent years the FDA detected an insufficient investigation of unexplained discrepancies and deviations from defined standards and specifications in their inspections. The corresponding paragraph 21 CFR 211.192 requires that the drug maker clarifies the reason for the deviation, takes corrective actions and also creates a complete documentation. In the last 5-year period on average annually about 22 companies received a warning letter listing this GMP deficiency. This fact shows that many quality assurance departments’ understanding of deviations handling, failure investigations and corrective actions is frequently fragmentary.

Quite interesting is the detailed study of the warning letters referring to GMP violations with regard to 211.192. These warning letters take into account the drugs’ dosage forms. In particular manufacturers of oral dosage forms were addressees of warning letters containing citations with regard to 211.192, followed by parenteral drugs manufacturers, companies in the area of blood/blood products and manufacturers of topical drugs. The respective scenarios are quite different. However, main shortcoming is always the inadequate education and documentation in each incident.

A rather unexpected finding in the lineup of the most common GMP violations is the high number of citations with regard to 21 CFR 211.84 “Testing and approval or rejection of components, drug product containers, and closures”. This quote appears so frequently as never before: 16 out of the 32 companies that received a warning letter in the fiscal year 2013 for violations of part 211 had not implemented the provisions of paragraph 211.84 as expected by the FDA investigators. Interestingly, in this case most of these companies (12 of the 16) are manufacturers of topical products (ointments, creams, etc.).

The formulations in the warning letters in this regard are very similar (in some cases identical) and are usually limited to the following standard wording: “Your firm has not established the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals” or “Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or exampled, as appropriate, and released for use by the quality control unit.”

Under the addressees of warning letters with quotations in the area of quality control – 21 CFR 211.166 “Stability Testing” and 21 CFR 211.160 “General Requirements” – there are also many of the companies that were already criticised due to non-compliances with regard to 211.84. This is not surprising as the thematic connection of all three paragraphs has a reference to the function of quality control. These two paragraphs 211.166 and 211.160 – just as 211.192 – have been in the top ten of GMP deficiencies for many fiscal years. Main shortcoming relating to 211.166 is the lack of a written stability test programme. Therefore, the following sentence can be read in almost all warning letters: “Your firm does not have an adequate written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates.”

Information on infringements of 211.160 are more differentiated. Partly some interesting scenarios are described, as, for instance, “inappropriate visual particle inspection” or “switched off audit trail function in the chromatography system”. Here too Topika makers make the majority of addressees – even though not as clear as in the previous paragraphs of part 211. Main shortcoming in the implementation of the guidelines in 211.160 is the lack of scientifically sound and appropriate specifications, standards, test plans and test methods for products, intermediates, components etc.

The analysis of the warning letters of last fiscal year has shown that the FDA increasingly focuses on the subject “supplier qualification” and in this context on critically questioning analysis results and certificates of the suppliers. A detailed examination of the warning letters of the current fiscal year will show whether this trend further continues.

A more detailed analysis of the warning letters of the previous fiscal year will be available in the October issue of the GMP Journal.

http://www.gmp-compliance.org/enews_4390_Insufficient%20failure%20investigations%2C%20supplier%20qualification%2C%20stability%20testing%20-%20the%20most%20common%20GMP%20violations%20in%20the%20FDA%20warning%20letters_8500,8489,S-QSB_n.html

The identification and determination of Impurities is a key challenge in pharmaceutical Quality Control. Method Validation, Analytical techniques, Leachables and Extractables are only a few of the problem areas. In addition Elemental (Metal) Impurities and Genotoxic Impurities have caused various uncertainties and questions in industry as well as in authorities. This is why the ECA Academy has set up a comprehensive Impurities Forum with experts from authorities as well as from companies like Boehringer Ingelheim, Novartis Pharma, Baxter, UCB, AstraZeneca, AbbVie and others. To offer a maximum of flexibility the Impurities Forum can be booked for all 3 days or only special parts of interest e.g. on Metal Impurities and/or Genotoxic Impurities. Find out more about the Impurities Forum programme and the options.

http://www.gmp-compliance.org/eca_seminare_isearch_Impurities%20Forum.html

Italian API Manufacturer Receives FDA Warning Letter for Data Integrity Issues
On July 7th the US FDA issued a Warning Letter to Trifarma S.p.A. for violating Good Manufacturing Standards at their facility in Rozzano, Italy. The company produces APIs and had been inspected early this year.

Read more about this Warning Letter here

http://www.gmp-compliance.org/enews_4400_Italian%20API%20Manufacturer%20Receives%20FDA%20Warning%20Letter%20for%20Data%20Integrity%20Issues_8509,S-WKS_n.html

On July 7th the US FDA issued a Warning Letter to Trifarma S.p.A. for violating Good Manufacturing Standards at their facility in Rozzano, Italy. The company produces APIs and had been inspected early this year. As a result of the inspection and the response of the company to the GMP findings the FDA decided to issue a Warning Letter.

While so far mainly Indian Manufacturers have been blamed by FDA and EU Inspectors for data integrity issues, now also an European API manufacturer has been cited for that problem. According to the Warning Letter the firm deleted all electronic raw data supporting the companies high performance liquid chromatography (HPLC) testing. Moreover, Trifarma failed to retain basic chromatographic information such as injection sequence, instrument method or integration method for the tests.

In a response to the FDA the firm explained that it has been researching backup systems since July 2013 and will have a backup system online by the third quarter of 2014. But FDA is not satisfied with this answer. Some interim actions such as storing backup data on each computer, including the integration method as part of that data are not sufficient. The FDA expects to see backups of the injection sequence, the instrument method and audit trails. According to the FDA the firm does not address how it will ensure that electronic files are not deleted prematurely from local computers.

In addition further basic GMP provisions are not met in the lab. There are no proper controls in place to prevent the unauthorized manipulation of the raw electronic data. All persons in the lab were able to delete and/or adulterate data because all lab employees were granted full privileges to the computer systems. Some equipment in place in the lab such as the HPLC and the GC lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change.

The FDA also expected to see electronic raw data supporting cleaning, method and process validations but the company was not able to provide these data. Another critical deviation referred to the fact that the company did not document any training of production employees on the production operations they perform. The company did change an SOP on how to perform training at the manufacturing site in July 2013 in order to include on-the-job training but Trifarma is not following it’s own procedures.

Interestingly the US FDA has used the information gathered in a previous inspection of another production site of the company to check the compliance in the Rozzano site. Trifarma received a 483 form on similar deficiencies for it’s Ceriano Laghetto plant but did not take the necessary actions to check if similar problems exist also at other manufacturing sites. From this the FDA concluded that there is not robust quality system is in place. The FDA also references the ICH Q7 Guide GMP for APIs and expects form API manufacturers to meet the requirements stated in that Guide.

Source. FDA Warning Letter for Trifarma S.p.A.

What GMP Changes can we still expect for 2014?

Heraclitus once said: “There is nothing permanent except change”. This statement is even true for the rather conservative GMP environment. What can we still expect for 2014? The answer to that question can be found in a work plan of EMA’s GMP/GDP Inspectors Working Group.

What are the coming plans?

• Finalising the changes planned for the Chapters 3 and 5 of the EU GMP Guide
• Finalising the revision of Chapter 8 of the EU GMP guide (with regard to product shortage notifications and specific risk management concepts)
• Agreeing, in consultation with PIC/S, whether guidance is needed on biofilms concerning Annex 1 of the EU GMP Guide
• Finalising the revision of Annex 15 of the EU GMP Guide (comparison with the new EMA process validation guideline and inclusion of necessary changes in the light of ICH Q 8-10)
• Finalising the revision of Annex 16 of the EU GMP Guide
• Finalising the revision of Annex 17 of the EU GMP Guide
• Further measures regarding the EudraGMDP database

The finalisation of the revision of Chapter 6 (Quality Control) of the EU GMP Guide is already completed (April 2014). The revised chapter will apply as of October 2014.

The following topics are also addressed in the work paper:

• Inspections under the centralised system
• Mutual Recognition Agreements (MRAs)
• Harmonisation topics
• Collaboration with the EU Commission (the collaboration should enable by the end of 2014 the publication of the GDP guidelines for APIs and  the risk assessment guidelines to establish GMP for excipients)
• Collaboration with other groups (i.e. Reverse Osmosis for the production of WFI and biological indicators for monitoring and the control of sterilisation are topics addressed together with the EDQM in Strasburg)

Please also see the complete “Work plan for GMP/GDP Inspectors Working Group for 2014“.

http://www.gmp-compliance.org/enews_04349_What-GMP-Changes-can-we-still-expect-for-2014%3F.html

Perrigo Company plc

Perrigo Company plc is a large Irish manufacturer of private label over-the-counter pharmaceuticals.^[2] The company’s shares are traded on the NYSE and the Tel Aviv Stock Exchange; as a result of the merger with Agis Industries the company is a constituent of the TA-25 Index. Perrigo is the only non-Israeli company on the TA-25.

Perrigo Company plc, through its wholly owned subsidiaries, engages in the manufacture and sale of consumer healthcare products, generic prescription drugs, active pharmaceutical ingredients (API), and consumer products primarily in the United States, Australia,Israel, Europe, India and Mexico.

Type	Public
Traded as	NYSE: PRGO TASE: PRGO S&P 500 Component
Industry	Pharmaceutical
Founded	1887
Headquarters	Allegan, Michigan, USA
Key people	Joseph C. Papa, Chairman, President and CEO
Products	OTC, RX, API, Medical Diagnostic, pharmaceuticals
Revenue	$3,540 million (2013)[1]
Operating income	$805 million(2013)
Net income	$ 530 million (2013)
Employees	7,250 (2009)
Website	www.perrigo.com

Address:

Telephone: (269) 673-8451
Toll Free: 800-253-3606
Fax: (269) 673-7535

Website: www.perrigo.com

Public Company
Incorporated: 1892
Employees: 3,983
Sales: $826.0 million (2003)
Stock Exchanges: NASDAQ
Ticker Symbol: PRGO
NAIC: 325412 Pharmaceutical Preparation Manufacturing; 325413 In-Vitro Diagnostic Substance Manufacturing

History

Black and white photo of L.Perrigo Co. Aspirin tablets

The L. Perrigo Company was founded in 1887 in Allegan, Michigan, by Luther and Charles Perrigo, who ran a country general store .^[3] In 1991 Perrigo had an Initial public offering onNASDAQ.

In March 2005 the firm acquired Agis Industries Ltd. (TASE:AGIS), an Israel based generic pharmaceuticals company in an $850 million transaction. Agis was founded in 1983 by Moshe (Mori) Arkin

MOSHE ARKIN

who developed his father’s small drug import business into a multinational generic pharmaceutical company. As a result of the acquisition Arkin owns 9% of Perrigo, and was appointed as Vice Chairman of the company.^[4]

Acquisitions

On 9 January 2008, the firm acquired Galpharm Healthcare, Ltd., a supplier of over-the-counterstore brand pharmaceuticals in the United Kingdom.^[5] On 16 September 2008, the firm acquired J.B. Laboratories.^[6] On 6 October 2008, it acquired Laboratorios Diba S.A., enabling the company to market its products in Mexico.^[7]On 13 November 2008, it acquired Unico Holdings, a manufacturer of store brand pediatric electrolytes, enemas and feminine hygiene products for retail consumers in the U.S.^[8]

On 1 March 2010, the firm acquired Orion Laboratories Pty, Ltd. a supplier of over-the-counter (OTC) store brand pharmaceutical products in Australia and New Zealand.^[9] On 23 March 2010, it acquired PBM Holdings, Inc.,a producer of over-the-counter store brand infant formula and baby foods in the United States, Canada, Mexico and China.^[10]

Perrigo Company is the largest manufacturer of over-the-counter (OTC) pharmaceuticals and nutritional products for store brands in the United States. The company estimates that it holds more than 50 percent of the store brand market. Perrigo produces more than 30 billion pills per year and manufactures about 1,200 products. Most of these are pharmaceuticals–such as analgesics, cough and cold remedies, and gastrointestinal and feminine hygiene products–which account for about four-fifths of the company’s sales. Perrigo ranks as the largest producer of aspirin in the United States. The remaining 20 percent of revenues come from the sale of nutritional products, including vitamins and nutritional supplements and drinks. Perrigo supplies 300 different retailers with these products under the retailer’s own label so that they can be promoted as house brands. These customers include major drugstore chains (CVS, Eckerd, Walgreens), grocery chains (Albertson’s, Kroger, Safeway), mass discounters (Kmart, Target, Wal-Mart), and major wholesalers (McKesson, Supervalu). Perhaps not surprisingly, the largest Perrigo customer by far is retailing giant Wal-Mart, which accounted for 27 percent of net sales for fiscal 2003. The company also markets certain products under its own brand name, Good Sense, although such products account for only a small percentage of sales. Two non-U.S. subsidiaries generate a little more than 9 percent of revenues. Wrafton Laboratories Ltd. supplies store brand products to major grocery and drug retailers in the United Kingdom, while the Mexican firm Química y Farmacia, S.A. de C.V. produces mainly OTC and prescription pharmaceuticals for retail, wholesale, and government customers. Perrigo Company operates 11 manufacturing plants in Michigan, South Carolina, Mexico, and the United Kingdom. Perrigo has enjoyed nearly continuous growth since the end of World War II. This growth can be partly attributed to the mass acceptance of generic and store brand pharmaceutical products.

Early Years

The company was founded by Luther and Charles Perrigo in 1887. The Perrigo brothers had moved to Allegan County, Michigan, a few years earlier from New York. Once in Michigan the brothers established a modest business. Luther Perrigo ran a country general store and apple drying business, while Charles helped with sales. Luther decided to package generic home remedies and sell them to other small country stores like his own. The first packaging plant for these medicines was run out of Charles Perrigo’s home, but Charles soon moved to Ohio, leaving the business entirely to his brother. Luther became president of the firm when it incorporated in 1892. Perrigo remained a family-owned business for 90 years. Five of the company’s seven presidents were descendants of Luther Perrigo, who died in 1902. His son Harry became president at that time, holding the position for the next 49 years.

During the 1920s the company turned to the private label concept in order to build customer loyalty. Stores ordering a certain minimum number could have their own names imprinted on the labels. Products of the era that were the subject of such deals included aspirin, bay rum, epsom salts, sweet oil, and zinc oxide. In the mid-1930s Perrigo gained its first major private label customer, the K & W group, a buying organization that evolved into the People’s Drug Store chain. The second such customer was Sam’s, a major Detroit area drug chain. At the same time the company’s customer base was shifting from small general stores to large regional and national drug chains.

Post-World War II Shift from Packager to Manufacturer

Harry Perrigo turned over the reins to his brother Ray in 1951. It was in the 1950s that the company, while still under the leadership of Ray Perrigo and future President William L. Tripp, Sr., made a crucial decision. Perrigo shifted its focus from that of a repackager of generic drugs to a manufacturer of quality drugs and beauty aids.

William L. Tripp, one of Luther Perrigo’s grandchildren, became president in 1967. During Tripp’s tenure as president the company began to reap the rewards of the change from repackager to manufacturer. The company’s income and the number of Perrigo employees quadrupled. When Tripp died in 1969 his son Bill Tripp, Jr., took over the presidency. During the 1970s Perrigo’s base of customers expanded with the addition of grocery chains and mass merchandisers to the core drugstore chains. By the time of his death in a boating accident in 1980 at the age of 45, Perrigo was the leading private label manufacturer of health and beauty products in the United States. William C. Swaney had been named president of the company two years before the accident, becoming the first leader of the company who was not a member of the Perrigo family.

End of Family Ownership: Early 1980s

Swaney’s presidency lasted from 1978 until 1983. In those five years Perrigo sales tripled and the company became a much larger operation all around. Swaney acquired new companies, set up distribution centers in three states, and expanded and refurbished existing plants. Before leaving as president Swaney oversaw the sale of the company from the Perrigo family to the management. After almost 100 years of family operation the company was sold.

Michael Jandernoa, who had joined the company in 1979 as vice-president for finance, became the seventh president of Perrigo in 1984, while Swaney took over as chairman of the board and CEO. Swaney instituted a style of management at Perrigo that his successor Jandernoa admitted he probably would have tried to block had he been in a position to do so at the time. Yet Jandernoa came to appreciate the open style of administration that Swaney initiated. The company contended that the different disciplines interacted in the decision-making process much more than in traditional American businesses.

Part of the Grow Group, 1986-88

Jandernoa continued the policy of expansion started by Swaney. Perrigo acquired Bell Pharmacal Labs of South Carolina in 1984. Early in the Jandernoa presidency, however, the board of directors began entertaining offers from larger companies that might want to acquire Perrigo itself. In 1986 Perrigo became the largest single company in Grow Group, Inc., a publicly held group of 23 manufacturing companies that bought Perrigo for $45 million. Jandernoa was named CEO of Perrigo; he continued to serve as president. Perrigo represented about a third of Grow Group. As the largest component in a conglomerate with access to funds through the New York Stock Exchange, Perrigo was able to raise new funds for more expansion.

Perrigo celebrated the company’s centenary with two ambitious building projects. It built a $1.5 million plant for the manufacture of effervescent tablets and a $3.5 million graphics art complex to house all of the company’s printing needs. Because Perrigo supplied many different retailers with the same house brand product, their printing facilities were an important part of their production system. The graphics and printing department employed about 290 people and produced almost 70 percent of the company’s labels and 44 percent of their cartons in the early 1990s. The construction of the graphics department, coupled with other expenses, totaled approximately $12.6 million in outlays to the company’s printing and graphics department since the Grow purchase in 1986.

Back to Management Ownership and Then Taken Public: Late 1980s to Early 1990s

After only two years as a part of Grow Group, however, Perrigo was sold back to its management in 1988 in a $106 million deal. That year the company posted sales of $146 million, but by 1994 company sales had ballooned to $669 million. Three years after the sale by Grow to Perrigo management, Jandernoa took the company public. The stock proved popular, though the value fell and rose significantly over time. The market value of the company in July 1994 based on a closing price of $14 a share was $1 billion, for instance. But this price was down from a value of $32 a share in January 1994.

The drop in the value of Perrigo shares was attributed to a drop in sales growth. The company, in fact, had another year of record sales and continued to expand, but stock speculators felt that the market had overreacted to the Perrigo stock offering and had inflated the value beyond its true market worth. Some analysts predicted that the drop in growth was a sign that the national brands would win back bargain-hunting customers in a healthy economy.

Other problems that Perrigo faced in its competition with national brands in the early 1990s concerned finding the right price range for its products. While Perrigo had long wielded its ability to offer lower prices than national brand competitors, sometimes the price difference could be so dramatic–more than 50 percent in some cases–that it could have a reverse effect on the consumer. The consumer weighed the relative cost savings with a judgment on efficacy equivalence. If the price difference was too dramatic, some observers contended, the consumer became suspicious of the Perrigo brand and turned to the national brand. Perrigo therefore developed a system whereby some of the money that it saved from advertising was spent on market research to determine exactly how its products were accepted by the consumer, which products were worth developing, and which had limited potential because of brand allegiance.

One reason for Perrigo’s enormous dominance over the store brand market was its ability to work closely with retailers to promote consumer allegiance to store brands. Beginning in the 1980s Perrigo began a major campaign to help retailers design labels, manage inventory, and develop promotions. Perrigo used its house printing and graphics department to ensure accuracy and reliability in labeling and packaging, permitting rapid new product introductions. Perrigo also enjoyed an advantage over many of its competitors because retail stores had a real incentive to give Perrigo’s product prominence on their shelves. Profit margins for store brand products were considerably greater than for national brands. The store’s public image could be enhanced as well, provided the product sold under their name was satisfactory.

Most of Perrigo’s products were packaged to be readily identifiable with the national brand equivalents. There was a fine line between taking advantage of the competitor’s advertising and carving out a niche that was independently recognized by the consumer. The OTC Market Report disclosed in 1995 that the company was threatened with lawsuits “once or twice a year,” but the vast majority of them were settled in a short period of time. Most of the disputes focused on product dress rather than the actual content of the product. While Perrigo management had become accustomed to lawsuits from competitor companies, in July 1994 Perrigo found itself faced with a lawsuit from closer to home. Its former parent company, Grow Group, filed suit against the company. The Grow Group, valued at less than half of Perrigo, demanded the return of Perrigo stock or a sizable settlement in lieu thereof. Grow claimed that Perrigo management did not act in good faith at the time of the 1988 sale, particularly alleging that they did not reveal a pending agreement to supply products to Wal-Mart, and asked for $2 billion in actual damages and $2 billion in punitive damages. Perrigo contended that the suit was wholly without merit.

One of the company’s strengths was that it faced little legitimate competition. In December 1994 the company purchased Vi-Jon Laboratories, Inc., a leading manufacturer of store brand personal care products, thereby expanding Perrigo’s sales and eliminating a potential competitor at the same time. The purchase price was about $33 million. A similar acquisition occurred earlier, in January 1992, when Cumberland-Swan, Inc., a Tennessee-based maker of store brand personal care products and vitamins, was bought for $35 million.

As the patents on dozens of major prescription drugs began to run out in the mid-1990s, Perrigo began to aggressively go after these lucrative new sources of revenue. Once a prescription drug was reclassified as OTC, the patent holder had two years of exclusivity. At that point generic versions of brand-name OTC products could be produced. An example of this process was Tavist-D, a decongestant and antihistamine that switched from prescription-only to OTC status in 1992. Two years later, Perrigo reached an agreement with the drug’s maker, Sandoz Pharmaceuticals Corp., to begin making a store brand version of Tavist-D in 1995. In subsequent years, Perrigo increasingly turned to such joint ventures to develop new products.

Also in the mid-1990s, Perrigo began looking to the international market for growth, forming subsidiary Perrigo International, Inc. to lead this effort. Among the initially targeted countries were Canada, Japan, Mexico, and Russia.

On 20 January 2011, the firm announced that it would acquire Paddock Laboratories Inc., with the deal expected to close in fiscal 2012.^[11]

In September 2012, Perrigo announced its intention to enter the animal wellness category by acquiring the assets of Sergeant’s Pet Care Products, Inc., a privately held manufacturer of over-the-counter companion animal healthcare products. ^[12]

On 11 February 2013, Perrigo announced the completion of the acquisition of Rosemont Pharmaceuticals Ltd., a specialty and generic prescription pharmaceutical company focused on the manufacturing and marketing of oral liquid formulations. ^[13]On 29 July 2013, the firm announced that it would acquire Élan, a major drugs firm based in Dublin.^[14][15]

Segments

The company operates in three segments; Consumer Healthcare, Rx Pharmaceuticals, and Active Pharmaceutical Ingredients. The Consumer Healthcare segment produces over-the-counter pharmaceutical and nutritional products in the United States, the United Kingdom, and Mexico. This segment offers analgesic, cough/cold/allergy/sinus, gastrointestinal, smoking cessation, first aid, antacids, hemorrhoidal remedies, motion sickness, sleep aid products, feminine hygiene products, vitamin, and nutritional supplementproducts.

The Rx Pharmaceuticals segment produces generic prescription drugs in the United States. This segment provides creams, ointments, lotions, gels, and solutions, as well as nasal sprays, foams, and transdermal devices.

The Active Pharmaceutical Ingredients segment produces pharmaceutical ingredients in Israel with sales to customers worldwide. The company also offers cosmetics, toiletries, detergents, manufactured and imported pharmaceutical products, and medical diagnostic products. The company’s customers include national and regional retail drug, supermarket, wholesalers, and mass merchandise chains.

Management

Joseph C. Papa is the Chief Executive Officer and President.^[16]

Joseph C. Papa Jr.

PATENTS

Awards

101 Best and Brightest Companies to Work For of West Michigan awarded Perrigo overall “Best of the Best” for 2009.^[17]

In 2010 Perrigo was named one of the top 100 Fastest-Growing Companies by Fortune Magazine.^[18]

From its beginnings as a packager of generic home remedies in 1887, Perrigo Company plc, headquartered in Ireland, has grown to become a leading global healthcare supplier. Perrigo develops, manufactures and distributes over-the-counter (OTC) and generic prescription (Rx) pharmaceuticals, nutritional products and active pharmaceutical ingredients (API), and receives royalties from Multiple Sclerosis drug Tysabri®. The Company is the world’s largest manufacturer of OTC healthcare products for the store brand market and an industry leader in pharmaceutical technologies. Perrigo’s mission is to offer uncompromised “Quality Affordable Healthcare Products®,” and it does so across a wide variety of product categories primarily in the United States, United Kingdom, Mexico, Israel and Australia, as well as more than 40 other key markets worldwide, including Canada, China and Latin America.

Perrigo API (formerly known as Chemagis) provides differentiated Active Pharmaceutical Ingredients (APIs) and Finished Dosage Forms (FDFs) for the branded and generic pharmaceutical industries.

• FDF
• Under Development
• Patents

Founded in 1987 in Israel and led by an accomplished team of industry experts, Perrigo API products comply with the highest regulatory requirements of leading health authorities such as FDA, PMDA, TGA, ANVISA and EU authorities. The company’s facility in Israel is FDA-inspected, cGMP-compliant and recognized for environmental stewardship.

Leveraging our strengths in complex chemistry, innovative patent development and in-depth regulatory expertise, Perrigo API provides tailor-made solutions to meet individual client requirements. We offer our customers comprehensive, customized solutions which include IP assets, API and FDF products, dossiers, bundling and P-IV partnerships, some through joint ventures and some independently, and all strengthened by well-designed and mutually beneficial strategic alliances.

Perrigo API offers comprehensive technical and regulatory support across the entire product lifecycle, from project inception to final production. Our state-of-the-art efficiency and control measures applied across the supply, development and manufacturing chain, allow Perrigo API to provide exceptional value and product differentiation to hundreds of customers worldwide. (Learn more about partnership opportunities)

With the ever-changing and increasingly competitive climate in the global API and Pharma industry, Perrigo API has been proactively searching for ways to continually add customer value and improve our leadership position. In 2009, Perrigo API (PAI) was established, following the acquisition of 85% of the holdings of a state-of-the-art API plant near Mumbai. Fully operational as of 2013, PAI supports Perrigo efforts to increase production capacity and competitiveness, while strictly complying with all industry regulations. This strategic move towards diversified capabilities further enhances Perrigo API highly valued operational flexibility, and adds to our company’s competitive edge.

Perrigo API specializes in tailor-made research and process development of Active Pharmaceutical Ingredients (APIs) and Finished Dosage Forms (FDFs), with special emphasis on complex, differentiated APIs and FDFs.

Perrigo API carefully selects APIs and FDFs which provide our customers with a competitive market position by delivering unique IP as part of a total solution. All Perrigo API products comply with the exacting regulatory requirements of leading health authorities, including the FDA, PMDA, TGA, ANVISA and other EU authorities.

Below is a list of APIs and FDFs which are currently under development.

Products under patent are not sold until patent expiration in the relevant country.

API

Perrigo API team is deeply committed to achieving uncompromising quality and reliability at every point in the value chain, from product inception to production, from regulatory affairs to go-to-market activities.

Mr. Yoav Grinberg
General Manager

Mr. Grinberg brings extensive general management experience as well as international marketing and sales experience. Previously MR. Grinberg was responsible for Perrigo API sales and marketing activities worldwide. Before joining Perrigo API in 2010, Mr. Grinberg worked for 20 years in the chemical and plastics industries in various senior general management and sales and marketing positions, based in Israel and Europe. Mr. Grinberg holds an MBA from Tel Aviv University.

Dr. Shireesh Ambhaikar
CEO, Perrigo API India Private Limited (PAI)

Dr. Ambhaikar has held numerous positions of increasing responsibility in manufacturing, project management and general management in the pharmaceutical industry. Prior to joining PAI, Dr. Ambhaikar was head of manufacturing, supply chain and global sourcing at UCB Pharm. Prior to that, he was with Sandoz/Novartis, with responsibilities in both manufacturing and project management. Dr. Ambhaikar holds a PhD degree in Organic Chemistry from Mumbai University.

Mr. Ilan Avni
Director Business Development & Pipeline

Mr. Avni joined Perrigo in 2006 and has held several Business Development positions of increasing responsibility both in the US Rx and API business units with experience in acquisitions, divestures, joint ventures, co development and product licensing. In his previous position, Mr. Avni served as an integration project leader for Perrigo API India. Mr. Avni holds an MBA with dual major in Finance and Marketing from Tel Aviv University and a BSc Pharm from the Hebrew University of Jerusalem.

Dr. Tami Greenberg
Head of Quality Perrigo Israel API

As Head of Quality for Perrigo Israel API, Dr. Greenberg is responsible for all QA/QC operations, regulatory compliance and meeting customers’ technical needs. Prior to joining Perrigo API in 2006, Dr. Greenberg was part of the R&D team in Bromine Compounds and lead different development projects. Dr. Greenberg holds Ph.D. in Material engineering from the Ben-Gurion university of the Negev.

Mrs. Dina Hanuna
API Finance Controller

Mrs. Hanuna joined Perrigo Israel (formerly Agis) in 1991. Prior to joining Perrigo, Mrs. Hanuna held the position of Senior Manager with the CPA firm Jungerman, Gilboa & Co. Mrs. Hanuna has more than 20 years of experience in several roles in the Finance Department at Perrigo Israel, nine years of which have been in senior management roles. Mrs. Hanuna is a Certified Public Accountant (Israel). She holds a BA in Economics and Business Administration from Bar Ilan University as well as a BA in Accounting from Tel Aviv University.

SEE…http://investing.businessweek.com/research/stocks/private/person.asp?personId=8971366&privcapId=881270&previousCapId=881270&previousTitle=Perrigo%20Israel%20Pharmaceuticals%20Limited

Mrs. Ayala Kost
VP of Global Operations Perrigo API

As the Perrigo API executive in charge of Operations, Previously Mrs. Kost was responsible for Quality Assurance and control as well as regulatory compliance and meeting customers’ technical needs. Prior to joining Perrigo API in 2002, Mrs. Kost was U.S. Marketing Director and Pilot Lab Manager at, a leading manufacturer of crop protection chemicals. Prior to that she held the position of Process Engineer at Nepro Negev Projects. Mrs. Kost holds an MBA from Tel Aviv University and a BSc in Chemical Engineering from Ben-Gurion University.

Mrs. Dganit Vered
VP, API Research & Development

Mrs. Vered joined Perrigo in 2012 as VP Research and Development. Mrs. Vered is responsible for all Perrigo API R&D activities worldwide. Prior to joining Perrigo she worked at Intel Corporation for more than 17 years and at total of 21 years in the semiconductors business. While with Intel Mrs. Vered held several senior management positions and performed R&D, Engineering, Operations and Facilities, QA/QC and project management roles. Mrs. Vered holds BSc of Chemical engineering from the Technion.

Dr. Alexander Weisman
CSO

Dr. Weisman has more than 25 years of experience in R&D in Analytical and Organic Chemistry, out of which15 years in the pharmaceutical industry including 10 years in management roles. Dr. Weisman joined Perrigo API in 1998, as manager of Analytical R&D and later nominated as VP R&D. In 2012 Alex became the CSO of the company. Dr. Weisman has more than 15 articles and patents to his credit. He holds a PhD in Biochemistry from Moldova State University.

References

External links

• Perrigo’s Corporate Website

Key Dates:

1887:

Luther and Charles Perrigo begin packaging generic home remedies and selling them at their own and to other general stores.

1892:

Company is incorporated.1920s:Perrigo begins offering private label products.1930s:Customer base begins to shift from general stores to large regional and national drug chains.1950s:Company shifts from a repackager of generic drugs to a manufacturer of quality drugs and beauty aids.

1970s:Grocery chains and mass merchandisers are added to the customer base.

1980:

Perrigo is now the nation’s largest private label manufacturer of health and beauty products.Early 1980s:Perrigo family ownership ends with the sale of the company to management.

1986:

Company is sold to Grow Group, Inc. for $45 million.

1988:

Grow Group sells the company back to management for $106 million.

1991:

Perrigo is taken public.

1997:

Controlling stake in Mexican pharmaceutical firm Química y Farmacia, S.A. de C.V. is acquired.

1998:

Perrigo posts a net loss of $51.6 million thanks to a restructuring of its personal care business.

1999:

The personal care business is divested to focus the company on OTC drugs and nutritional products.

2001:

Perrigo acquires Wrafton Laboratories Ltd., a U.K. maker of store brand pharmaceuticals.

Executive Management

Joseph C. Papa
President, Chief Executive Officer and Chairman

Mr. Papa joined the Company in October 2006 as President and Chief Executive Officer. Mr. Papa was elected as a director in November 2006 and, subsequently, was appointed as Chairman of the Board of Directors in October 2007. Previously, Mr. Papa served from December 2004 to October 2006 as Chairman and Chief Executive Officer of the Pharmaceutical and Technologies Services segment of Cardinal Health, Inc. Prior to that position, he served as President and Chief Operating Officer of Watson Pharmaceuticals, Inc. from November 2001 to November 2004. Additionally, Mr. Papa has held management positions at DuPont Pharmaceuticals, Pharmacia Corporation, G.D. Searle & Company and Novartis AG. Mr. Papa is a director of Smith & Nephew, a developer of advanced orthopedic medical devices.

Judy L. Brown
Executive Vice President and Chief Financial Officer

Ms. Brown was named Executive Vice President and Chief Financial Officer in July 2006. She served as Vice President and Corporate Controller from September 2004 to July 2006. Previously, Ms. Brown held various senior positions in finance and operations at Whirlpool Corporation from 1998 to August 2004. Ms. Brown is a director of Belden Corporation, a NYSE traded company, that designs, manufactures and markets cable, connectivity and networking products in markets including industrial automation, enterprise, transportation, infrastructure and consumer electronics.

Tom Farrington
Senior Vice President and Chief Information Officer

Mr. Farrington was named Senior Vice President and Chief Information Officer in October 2006. He formerly served as Chief Information Officer for F. Dohmen Co. in addition to serving as a division President for JASCORP LLC from March 2003 to October 2006. Prior to that position, Mr. Farrington held various senior positions in information technology and finance at Dell, Inc. from 1999 to 2003.

John T. Hendrickson
Executive Vice President, Global Operations and Supply Chain

Mr. Hendrickson was named Executive Vice President, Global Operations and Supply Chain in March 2007. He served as Executive Vice President and General Manager, Perrigo Consumer Healthcare from August 2003 to March 2007. He served as Executive Vice President of Operations from October 1999 to August 2003.

Scott Jamison
Executive Vice President, General Manager of Nutritionals

Mr. Jamison was named Executive Vice President, General Manager of Nutritionals in January 2011. Before the Company acquired PBM in fiscal 2010, Mr. Jamison had served as PBM’s Executive Vice President and General Counsel since the formation of PBM in 1997 and was a key member of the executive team throughout the evolution and growth of PBM. In addition to his legal responsibilities, Mr. Jamison has held senior leadership responsibilities in operations and sales, as well as in new business and product development.

Todd W. Kingma
Executive Vice President, General Counsel and Secretary

Mr. Kingma was named Executive Vice President in May 2006. He served as Vice President, General Counsel and Secretary from August 2003 to May 2006. Previously, Mr. Kingma held various positions at Pharmacia Corporation from 1991 through August 2003. His last position with Pharmacia Corporation was Vice President and Associate General Counsel, Global Specialty Operations

Sharon Kochan
Executive Vice President and General Manager, International

Mr. Kochan was named Executive Vice President and General Manager, International in August 2012. He served as Executive Vice President, General Manager of Rx Pharmaceuticals from March 2007 to August 2012 and as Senior Vice President of Business Development and Strategy from March 2005 to March 2007. Mr. Kochan was Vice President, Business Development of Agis Industries (1983) Ltd. from July 2001 until the acquisition of Agis by the Company in March 2005.

Jeff Needham
Executive Vice President, General Manager of Consumer Healthcare

Mr. Needham was named Executive Vice President, General Manager of Consumer Healthcare in October 2009. He served as Senior Vice President of Commercial Business Development from March 2005 through October 2009. Previously, he served as Senior Vice President of International from November 2004 to March 2005. He served as Managing Director of Perrigo’s U.K. operations from May 2002 to November 2004 and as Vice President of Marketing from 1993 to 2002.

Jatin Shah
Senior Vice President and Chief Scientific Officer

Dr. Shah was named Senior Vice President and Chief Scientific Officer in June 2005. He served as Vice President of Research and Development for Rx products from February 2004 to June 2005. Previously, Dr. Shah held various senior positions in Research and Development at Mayne Pharma (known previously as Faulding Pharmaceuticals) from June 1996 to January 2004.

Mike Stewart
Senior Vice President, Global Human Resources

Mr. Stewart was named Senior Vice President, Global Human Resources in September 2004. He served as Vice President, Human Resources from July 1993 to September 2004. Mr. Stewart began his employment with the Company in August 1981.

Louis Yu
Executive Vice President, Global Quality and Compliance

Dr. Yu joined the Company in November 2006 as Senior Vice President, Global Quality and Compliance. Previously, Dr. Yu served from October 2005 to October 2006 as Vice President, Quality at CV Therapeutics Inc. Prior to that position, he served as Global Head of Quality & Compliance for Forest Laboratories, Inc. from April 1999 to October 2005. He served as the Vice President, Quality & Compliance for Solvay Pharmaceuticals between October 1996 and March 1999. Currently, he is associated with the University of Wisconsin, serving as Adjunct Professor, Extension Services in Pharmacy, School of Pharmacy.

Douglas Boothe
Executive Vice President and General Manager, Perrigo Pharmaceuticals

Mr. Boothe joined Perrigo in January 2013 as Executive Vice President and General Manager, Perrigo Pharmaceuticals. Previously, Mr. Boothe served as Chief Executive Officer of Actavis Inc. from August 2008 to December 2013 and as Executive Vice President and Chief Operating Officer from 2006 to 2008. Prior to that position, Mr. Boothe held various senior positions in strategic planning and business development for Alpharma Inc., Pharmacia Corporation and Xerox Corporation.

Glenmark Pharmaceuticals to set up a new manufacturing facility in the US

http://timesofindia.indiatimes.com/business/india-business/Glenmark-joins-pharma-companies-setting-up-US-plants/articleshow/38398901.cms

• The facility will be situated in Monroe, North Carolina, USA
• The facility will manufacture oral solids, injectables and topicals over a five year period
Mumbai, India; July 17, 2014: Glenmark Pharmaceuticals Ltd; a research-driven, global, integrated pharmaceutical company plans to set up a new manufacturing facility in the US. The company plans to set up this manufacturing facility at Monroe Corporate Center, North Carolina, USA. The facility will be spread over 100,000 sq. feet (around 15 acre plot) and the company will first begin work on an oral solid unit and thereafter set up manufacturing units for injectables and topicals.

GLEN SALDANHA

CEO GLENMARK

http://www.moneycontrol.com/news/announcements/glenmark-pharmaceuticals-to-setnew-manufacturing-facilityus_1129890.html

Decernotinib

N2-[2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]-N-(2,2,2-trifluoroethyl)-D-isovalinamide

Vertex Pharmaceuticals Inc

In phase 3  for the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis.

DECERNOTINIB

The Janus kinases (JAK) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3, and TYK2. The JAKs play a critical role in cytokine signaling. The down-stream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as psoriasis. Moreover, JAK kinases represent an established therapeutic target for this disease. For example, JAK kinases are an established therapeutic target for treating psoriasis. Stump K. L., et al., Arthritis Res. Ther. (201 1) 13:R68; Fridman J.S., et al., J Immunol. (2010) 184:5298-5307; West K., Curr. Op. Investig. Drugs (2009) 10:491-504; Kremer J. M. et al., Arthritis Rheumatism (2009) 60(7):1895- 1905; Xiong, W. et al., Ther Adv Musculoskelet Dis. (201 1) 3(5): 255-266; Panes, J. et al. 19^th Ann. Eur. Gastroenterology Week (Oct 22-26, 2011) Stockholm, SE, PI 456; and Drugs in R & D “Tofacitinib” (2010) 10(4):271-84.

Compounds described as kinase inhibitors, particularly the JAK family kinases, are disclosed in WO 2005/095400 and WO 2007/084557. Also disclosed in these publications are processes and intermediates for preparing these compounds

Decernotinib ( VX-509 ) is an oral selective JAK3 inhibitor being evaluated for the treatment of rheumatoid arthritis ( RA ). This was a 24-week, randomized, placebo-controlled, double-blind, phase 2 study of four dosing regimens of Decernotinib, administered to patients with RA with inadequate response to Methotrexate ( MTX ).

The aim of the study was to assess the efficacy and safety of four dosing regimens of VX-509 administered to patients with rheumatoid arthritis on stable background Methotrexate therapy.

Patients with active rheumatoid arthritis ( C-reactive protein [ CRP ] greater than ULN, greater than or equal to 6 swollen joints [ of 66 ], and greater than or equal to 6 tender joints [ of 68 ] ) taking stable doses of MTX were randomized 1:1:1:1:1 to receive placebo or one of four dosing regimens of Decernotinib ( 100 mg QD, 150 mg QD, 200 mg QD, or 100 mg BID ) for a duration of 24 weeks.

The primary efficacy endpoints at week 12 were met and have previously been reported; 24-week efficacy and safety results are now reported.

A total of 358 patients were randomized and received greater than or equal to 1 dose of study drug; 81% of patients were female, with a mean age of 53 years.
At baseline, the mean tender joint count was 23.8, the mean swollen joint count was 16.1, and the average disease duration was 7.3 years.

After 24 weeks of treatment the proportion of patients achieving ACR20, ACR50, ACR70, DAS28 ( CRP ) less than 2.6 and DAS28 ( ESR ) less than 2.6 and the decrease from baseline in DAS28 ( CRP ) were statistically significantly greater in each of the Decernotinib dose groups than in the placebo group.

Over 24 weeks, the percentage of patients with any adverse event was higher in the Decernotinib group ( all Decernotinib dose groups combined ) ( 59.9% ) relative to placebo ( 42.3% ) and led to study discontinuation in 9.1% and 8.5% of patients in the Decernotinib and placebo groups, respectively.
The most common adverse reactions in the Decernotinib group were headache ( 8.7% ), hypercholesterolemia ( 5.2% ), and diarrhea ( 4.5% ).
Serious adverse reactions occurred in similar proportions of patients receiving Decernotinib ( 7.3% ) or placebo ( 5.6% ), but there were more serious infections in the Decernotinib group ( 3.5% ) compared with placebo ( 1.4% ).
Through 24 weeks there were two serious adverse effects that resulted in death; one was cardiac failure in the Decernotinib 100 mg BID group ( previously reported ) and one was pancytopenia in a patient with pneumonia in the Decernotinib 200 mg QD group.
Elevations in transaminase levels and decreases in median neutrophil and lymphocyte counts were observed in the Decernotinib groups and were generally mild.

Safety profiles were comparable across groups receiving Decernotinib.

In conclusion, all tested doses of Decernotinib significantly improved signs and symptoms of rheumatoid arthritis versus placebo when administered in combination with stable background Methotrexate therapy for 24 weeks.
Decernotinib was associated with small increases in adverse reactions rates, serious infections, and mostly minor laboratory abnormalities. ( Xagena )

Source: EULAR Meeting – van Vollenhoven R et al, Ann Rheum Dis 2014;73(Suppl2)

see

WO 2007084557

WO 2013006634

WO 2013070606

………………………………………………….

WO2014074471 claiming use of heterocyclic compound (preferably decernotinib) for treating psoriasis. Vertex is developing decernotinib, an oral JAK 3 inhibitor, for the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis. As of July 2014, the drug is Phase 3 trials.

http://www.google.com/patents/WO2014074471A1?cl=en

Table 1:

COMPD 1 IS DECERNOTINIB

Example 1: Analytical Methods Used

[0260] (A) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA (60:40:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230 nm. Run time was 25-26 minutes.

[0261] (B) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA (90: 10:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230 nm.

[0262] (C) HPLC on a Waters XBridge Phenyl column, 4.6 x 150 mm, 3.5 μπι. Mobile phase A was water/1 M ammonium formate, pH 4.0 (99: 1). Mobile phase B was

acetonitrile/water/ 1M ammonium formate, pH 4.0 (90:9:1). Gradient 5 % to 90 % B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min. Detection at UV, 245 nm.

T = 25 °C.

[0263] (D) HPLC on a Waters XBridge Phenyl column, 4.6 x 150 mm, 3.5 μπι. Mobile phase A was water/1 M ammonium formate, pH 4.0 (99: 1). Mobile phase B was

acetonitrile/water/ 1M ammonium formate, pH 4.0 (90:9: 1). Gradient 15% to 90 % B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min. Detection at UV, 220 nm.

T = 35 °C.

[0264] Example 2: Preparation of Compounds of Formula I [0265] General Synthetic Scheme

[0266] The Boc-protected amino acid starting material (1) undergoes amidation in the presence of an activating agent, a coupling reagent, and the acid salt of the amine HNR⁷R¹⁷ to generate the Boc-protected amide intermediate (2). The amide intermediate (2) is

deprotected under acidic conditions and reacted with the halogenated heteroaryl (3) to generate the aminoheteroaryl intermediate (4). Boronated azaindole (5) is coupled with the aminoheteroaryl intermediate (4) under cross-coupling condition to generate the compound of Formula I.

………………………………………………………………………….

Patent

http://www.google.com/patents/US8163917

346

Example 1 Preparation of Compounds of the Invention

General Synthetic Scheme

Step 1

To a stirred solution of Boc-valine (1; R₁ is Me; 3.8 g, 0.02 mol), EDC (4.63 g, 0.024 mol), HOBt (4.0 g, 0.026 mol), DIEA (10.5 mL, 0.06 mol) in 100 mL of DCM is added trifluoroethylamine HCl (2.92 g, 0.022 mol). The reaction mixture is stirred for 16 h. It is concentrated to dryness and redissolved in EtOAc, washed successively with 0.5N HCl, saturated aqueous solution of NaHCO₃ and brine. The organic layer is dried (Na₂SO₄) and concentrated in vacuo to give 5.4 g (98%) of 2 as a white solid.

Step 2

Compound 2 (5.32 g, 0.0197 mol) is deprotected with a 1:1 mixture of DCM/TFA at rt for 45 min. Concentration to dryness gives the intermediate amine that is used directly for the next step. A mixture of 5-fluoro-2,4-dichloropyrimidine (3; R is F; 3.28 g, 0.0197 mol), the crude amine TFA salt (5.25 g, 0.0197 mol) and DIEA (10.27 mL, 0.059 mol) are stirred in isopropanol at rt for 16 h. The reaction mixture is concentrated in vacuo and redissolved in EtOAc, washed successively with 0.5N HCl, saturated aqueous solution of NaHCO₃ and brine. The organic layer is dried (Na₂SO₄) and concentrated in vacuo to give a crude oil that is subjected to chromatography (50% EtOAc/50% hexanes) to yield the desired compound 4.

Step 3

A mixture of 5 (30 mg, 0.075 mmol; prepared according to WO 2005/095400), 4 (23 mg, 0.075 mmol), Pd (Ph₃P)₄ (9 mg, 0.0078 mmol) and sodium carbonate 2M (115 uL, 0.23 mmol) in 1 mL of DME is microwaved at 150° C. for 10 minutes. The reaction mixture is filtered through a short pad of silica gel with 30% EtOAc-70% hexanes as eluent to provide, after concentration to dryness, the crude intermediate that is used directly for the next step.

The crude intermediate is dissolved in 1 mL of dry methanol and 200 uL of sodium methoxide in methanol 25% was added. The reaction mixture is stirred at 60° C. for 1 h and quenched with 6N HCl (154 uL). The mixture is dried under a flow of nitrogen and purified by reverse phase HPLC (10-60 MeCN/water w/0.5% TFA) to provide the desired material of formula 6a.

Compounds of formulae 6b and 6c may be prepared in an analogous manner using the appropriate starting reagents. For instance, a compound of formula 6b may generally be made by substituting Cert-butyl 2-(2,2,2-trifluoroethylcarbamoyl)pyrrolidine-1-carboxylate for compound 1, while a compound of formula 6c may generally be made by substituting tert-butyl 2-(2,2,2-trifluoroethylcarbamoyl)propan-2-ylcarbamate for compound 1.

Example 2 Analytical Results

Tables 4, 5 and 6 below depicts exemplary ¹H-NMR data (NMR) and liquid chromatographic mass spectral data, reported as mass plus proton (M+H), as determined by electrospray, and retention time (RT) for certain compounds of the present invention, wherein compound numbers in Tables 4, 5 and 6 correspond to the compounds depicted in Tables 1, 2 and 3, respectively (empty cells indicate that the test was not performed):

PATENTS

new patent

WO-2014110259

Pixantrone

BBR-2778 , CTK0H5262

• Pixolti
• Pixuvri
• UNII-P0R64C4CR9

An immunosuppressant.

144510-96-3 [RN]

5,8-Bis((2-aminoethyl)amino)-2-aza-anthracene-9,10-dione

6,9-Bis((2-aminoethyl)amino)benz(g)isoquinoline-5,10-dione

5,8-Bis((2-aminoethyl)amino)-2-aza-anthracene-9,10-dione

6,9-Bis((2-aminoethyl)amino)benz(g)isoquinoline-5,10-dione

CTI BioPharma receives Israeli approval for aggressive B-cell non-Hodgkin’s lymphoma therapy

read at

http://www.pharmaceutical-technology.com/news/newscti-biopharma-receives-israeli-approval-aggressive-b-cell-non-hodgkins-lymphoma-therapy-4321986?WT.mc_id=DN_News

Pixantrone
IUPAC name 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
Identifiers
CAS number	144510-96-3
PubChem	134019
ChemSpider	118174
KEGG	D05522
ChEMBL	CHEMBL167731
ATC code	L01DB11
Jmol-3D images	Image 1
SMILES [show]
InChI [show]
Properties
Molecular formula	C17H19N5O2
Molar mass	325.365 g/mol
Appearance	Blue solid
Pharmacology
Routes of administration	Intravenous
Elimination half-life	9.5–17.5 hours
Excretion	Fecal (main route of excretion) and renal (4–9%)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)

Pixantrone dimaleate [USAN]

CAS  144675-97-8

Molecular Formula

On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin’s B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNA-forming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m² administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician’s best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).

Pixantrone (rINN; trade name Pixuvri) is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewertoxic effects on cardiac tissue.^[1] It acts as a topoisomerase II poison and intercalating agent.^[2][3] The code name BBR 2778 refers topixantrone dimaleate, the actual substance commonly used in clinical trials.^[4]

History

Anthracyclines are important chemotherapy agents. However, their use is associated with irreversible and cumulative heart damage. Investigators have attempted to design related drugs that maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines.^[5] Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.^[1]

Random screening at the US National Cancer Institute of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant anti-tumor activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone, which also exhibited marked anti-tumor activity^[5] Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In clinical studies, mitoxantrone was shown to be effective against numerous types of tumors with less toxic side effects than those resulting from doxorubicin therapy. However, mitoxantrone was not totally free of cardiotoxicity. A number of structurally modified analogs of mitoxantrone were synthesized and structure-activity relationship studies made.^[5] BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho^[5] and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center, Monza, and University of Vermont, Burlington.^[4]Other studies have been completed at the University of Texas M. D. Anderson Cancer Center, Houston, the Istituto Nazionale Tumori,Milan, and the University of Padua.^[2][6][4] In the search for novel heteroanalogs of anthracenediones, it was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and US patents are held by the University of Vermont. An additional US patent application was completed in June 1995 by Boehringer Mannheim, Italy.^[5]

Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, and BBR 2778 was developed as Novuspharma’s leading anti-cancer drug, pixantrone.^[7] A patent application for the injectable preparation was filed in May 2003.^[8]

In 2003, Cell Therapeutics, a Seattle biotechnology company, acquired pixantrone through a merger with Novuspharma.^[9]

Clinical trials

Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.^[10] phase III clinical trials of pixantrone have been completed.^[11][12] Pixantrone is being studied as an antineoplastic for different kinds of cancer, including solid tumors and hematological malignancies such as non-Hodgkin lymphomas.

Animal studies demonstrated that pixantrone does not worsen pre-existing heart muscle damage, suggesting that pixantrone may be useful in patients pretreated with anthracyclines. While only minimal cardiac changes are observed in mice given repeated cycles of pixantrone, 2 cycles of traditional anthracyclines doxorubicin or mitoxantrone result in marked or severe heart muscle degeneragion.^[1]

Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin’s lymphoma, had a reduction in severe side effects when compared to patients treated with standard doxorubicin-based therapy. Despite pixantrone patients receiving more treatment cycles, a three-fold reduction in the incidence of severe heart damage was seen as well as clinically significant reductions in infections and thrombocytopenia, and a significant reduction in febrile neutropenia. These findings could have major implications for treating patients with breast cancer, lymphoma, and leukemia, where debilitating cardiac damage from doxorubicin might be prevented.^[13]Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.^[14]

The completed phase II RAPID trial compared the CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to the same regimen, but substituting Doxorubicin with Pixantrone. The objective was to show that Pixantrone was not inferior to Doxorubicin and less toxic to the heart.^[15]

Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated non-Hodgkin lymphomapatients.^[14]

The pivotal phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating patients with relapsed non-Hodgkin’s lymphoma.^[16] The complete response rate in patients treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.^[14]

Administration

It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs.^[8][14]

Regulatory approval

U.S. Food and Drug Administration

The FDA granted fast track designation for pixantrone in patients who had previously been treated two or more times for relapsed or refractory aggressive NHL. Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint. The minutes of the Oncologic Drugs Advisory Committee meeting of March 22, 2010^[17]show that this had not in fact been achieved with statistical significance and this combined with major safety concerns lead to the conclusion that the trial was not sufficient to support approval. In April 2010 the FDA asked for an additional trial.^[18]

European Medicines Agency

On May 5, 2009, Pixantrone became available in Europe on a Named-Patient Basis. A named-patient program is a compassionate use drug supply program under which physicians can legally supply investigational drugs to qualifying patients. Under a named-patient program, investigational drugs can be administered to patients who are suffering from serious illnesses prior to the drug being approved by the European Medicines Evaluation Agency. “Named-patient” distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In Europe, under the named-patient program the drug is most often purchased through the national health system.^[19] In 2012 pixantrone received conditional marketing authorization in the European Union as Monotherapy to Treat Adult Patients with Multiply Relapsed or Refractory Aggressive Non-Hodgkin B-Cell Lymphomas.

Research

Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis.^[20] Pixantrone has a similar mechanism of action as mitoxantrone on the effector function of lymphomonocyte B and T cells in experimental allergic encephalomyelitis but with lower cardiotoxicity. Pixantrone inhibits antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production.^[21] Clinical trials are currently ongoing in Europe.

Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats,^[22] and in vitro cell viability experiments indicated that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer’s disease.^[23]

http://www.chemdrug.com/databases/8_0_mhpyqlxgrykqdwig.html

3,4-Pyridinedicarboxylic acid (I) was converted to the cyclic anhydride (II) upon heating with acetic anhydride. Friedel-Crafts condensation of anhydride (II) with p-difluorobenzene (III) in the presence of AlCl3 gave rise to a mixture of two regioisomeric keto acids, (IV) and (V). Cyclization of this mixture in fuming sulfuric acid at 140 C generated the benzoisoquinoline (VI) (1,2). Subsequent displacement of the fluorine atoms of (VI) with ethylenediamine ( VII) in pyridine provided the target bis (2-aminoethylamino) derivative, which was finally converted to the stable dimaleate salt. Alternatively, ethylenediamine (VII) was protected as the mono-N-Boc derivative (VIII) by treatment with Boc2O. Condensation of the difluoro compound (VI) with the protected ethylenediamine (VIII) furnished (IX). The Boc groups of (IX) were then removed by treatment with trifluoroacetic acid. After adjustment of the pH to 4.2 with KOH, treatment with maleic acid provided BBR-2778.

J Med Chem1994,37, (6): 828

SEE MORE

http://www.chemdrug.com/databases/8_0_mhpyqlxgrykqdwig.html

References

Ruconest

• Ruconest® is the first recombinant human C1 esterase inhibitor (rhC1INH) approved for use in patients with HAE.
• rhC1INH and plasma-derived C1INH have an identical amino acid sequence. ¹⁸

The in vitro inhibitory potency of rhC1INH toward target enzymes is comparable with that of plasma-derived C1INH. ^{1, 6, 19}

Ruconest® is the first recombinant human C1 esterase inhibitor (rhC1INH) developed and approved for the treatment of acute angioedema attacks in HAE patients. Use of a well-controlled transgenic platform for the production of Ruconest® ensures that product supply is virtually unlimited and avoids the risk of transmission of human blood-borne infections.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm405526.htm

fda …..July 17, 2014 approved

Salix Pharmaceuticals and Pharming receive FDA approval for Ruconest
Salix Pharmaceuticals and Pharming have announced US Food and Drug Administration (FDA) approval of Ruconest for treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE).

Salix Pharmaceuticals and Pharming receive FDA approval for Ruconest

read at

http://www.pharmaceutical-technology.com/news/newssalix-pharmaceuticals-pharming-receive-fda-approval-for-ruconest-4322007?WT.mc_id=DN_News

Salix Pharmaceuticals, Ltd.SLXP -1.30% and Pharming Group NV today announced that the Food and Drug Administration has approved RUCONEST® (C1 Esterase Inhibitor [Recombinant]) 50 IU/kg for the treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE). Because of the limited number of patients with laryngeal attacks, effectiveness was not established in HAE patients with laryngeal attacks.

“We are pleased that RUCONEST® provides the HAE community with another FDA-approved option for treating painful and debilitating HAE attacks,” said Anthony Castaldo, President of the Hereditary Angioedema Association (US HAEA), a non-profit patient services and research organization with a membership of over 5,000 HAE patients in the United States.

RUCONEST® is a recombinant C1 esterase inhibitor that can be administered by the patient after receiving training by a healthcare provider. HAE attacks stem from a deficiency of the C1 inhibitor protein in the blood. HAE is a rare inherited genetic condition that is often not properly diagnosed until later in a patient’s life as the symptoms of an attack can mirror someone experiencing an allergic reaction. Severe, painful swelling can occur at any time, which means most people suffering from HAE deal with the constant fear of when their next attack might surface and how that might impair their lives and those around them.

“Results in the pivotal clinical trial demonstrate RUCONEST® is a safe and effective option for the treatment of acute hereditary angioedema attacks,” said Dr. Marc Riedl of the US HAEA Angioedema Center at the University of California – San Diego and primary investigator of the phase III study. “At the US HAEA Angioedema Center, we strive to better the lives of those suffering from hereditary angioedema and part of that is ensuring patients have access to advanced treatments that have been proven to work in clinical trials. RUCONEST is an important addition to those treatment options.”

Sijmen de Vries, CEO of Pharming, said: “The approval of RUCONEST® in the US is a very significant milestone for Pharming. For many years we have strived to make RUCONEST® – the first recombinant replacement therapy for C1Inhibitor deficiency – available to the HAE patient community in the US, because we were aware of the great value and benefit this product adds to patients’ lives. Today we are proud to have achieved this goal in the US.”

“RUCONEST® is a much needed treatment option for patients suffering from acute attacks of hereditary angioedema. Until now, there hasn’t been an FDA approved recombinant C1 esterase inhibitor option to treat symptoms of HAE,” said Carolyn J. Logan, President and Chief Executive Officer of Salix. “The unpredictability of HAE can make patients feel uncertain about when their next attack might strike, which is why it is important to have a medicine that can be administered by the patient that resolves an attack. Salix is proud to make RUCONEST® available.”

The FDA approval of the Biologics License Application (BLA) for RUCONEST® for treatment of acute angioedema attacks in patients with HAE is based on a randomized, double-blind, placebo-controlled, phase III trial (RCT) which included an open-label extension (OLE) phase and is supported by the results of two additional RCTs and two additional OLE studies. The pivotal RCT and OLE studies analyzed the results from 44 subjects who experienced 170 HAE attacks. The primary efficacy endpoint was the time to beginning of symptom relief, assessed using patient-reported responses to two questions about the change in overall severity of their HAE attack symptoms after the start of treatment. These were assessed at regular time points for each of the affected anatomical locations for up to 24 hours. To achieve the primary endpoint, a patient had to have a positive response to both questions along with persistence of improvement at the next assessment time (i.e., the same or better response).

A statistically significant difference in the time to beginning of symptom relief was observed in the intent-to-treat population (n=75) between RUCONEST and placebo (p=0.031, log-rank test); the median time to beginning of symptom relief was 90 minutes for RUCONEST patients (n=44) and 152 minutes for placebo patients (n=31).

RUCONEST® is manufactured by Pharming Group NV in the Netherlands. Salix has licensed exclusive rights from Pharming to commercialize RUCONEST® in North America and market RUCONEST® for the treatment of acute HAE attack symptoms.

Salix currently plans on making RUCONEST® accessible to patients later in 2014.

About RUCONEST ®

RUCONEST® (C1 Esterase Inhibitor [Recombinant]) 50 IU/kgis an injectable medicine that is used to treat acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE). HAE is caused by a deficiency of the C1 esterase inhibitor protein, which is present in blood and helps control inflammation (swelling) and parts of the immune system. A shortage of C1 esterase inhibitor can lead to repeated attacks of swelling, pain in the abdomen, difficulty breathing and other symptoms. RUCONEST® contains C1 esterase inhibitor at 50 IU/kg.

When administered at the onset of HAE attack symptoms at the recommended dose, RUCONEST® works to return a patient’s C1-INH levels to normal range and quickly relieve the symptoms of an HAE attack with a low recurrence of symptoms.

RUCONEST® is the first and only plasma-free, recombinant C1-INH approval from the U.S. Food and Drug Administration (FDA) and was approved in July 2014.

About HAE

RUCONEST has been granted Orphan Drug designation by the FDA for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). With RUCONEST now approved by the FDA, Salix believes this designation should provide seven years of marketing exclusivity in the United States.

Hereditary angioedema (HAE) is a genetic condition occurring between 1 in 10,000 to 1 in 50,000 people. Those with HAE experience episodes of swelling in their extremities, face and abdomen, with potentially life-threatening swelling of the airway. When it occurs in the abdomen, this swelling can be accompanied by bouts of nausea, vomiting and severe pain. Swelling in the face or extremities can be painful, disfiguring, and disabling.

HAE patients have a defect in the gene that controls production of a protein found in the blood vessels, called C1 inhibitor or C1-INH. When a person’s C1-INH levels are low, fluid from blood vessels can leak into nearby connective tissues, causing severe pain and swelling and, in rare cases, death from asphyxiation from airway swelling.

About Pharming Group NV

Pharming Group NV is developing innovative products for the treatment of unmet medical needs. RUCONEST® (conestat alfa) is a recombinant human C1 esterase inhibitor approved for the treatment of angioedema attacks in patients with HAE in the USA, Israel, all 27 EU countries plus Norway, Iceland and Liechtenstein. RUCONEST® is distributed in the EU by Swedish Orphan Biovitrum. RUCONEST® is partnered with Salix Pharmaceuticals Inc. SLXP -1.30% in North America. The product is also being evaluated for various follow-on indications. Pharming has a unique GMP compliant, validated platform for the production of recombinant human proteins that has proven capable of producing industrial volumes of high quality recombinant human protein in a more economical way compared to current cell based technologies. In July 2013, the platform was partnered with Shanghai Institute for Pharmaceutical Industry (SIPI), a Sinopharm Company, for joint global development of new products. Pre- clinical development and manufacturing will take place at SIPI and are funded by SIPI. Pharming and SIPI initially plan to utilize this platform for the development of rhFVIII for the treatment of Haemophilia A. Additional information is available on the Pharming website; www.pharming.com .

About Salix Pharmaceuticals

Salix Pharmaceuticals, Ltd., headquartered in Raleigh, North Carolina, develops and markets prescription pharmaceutical products and medical devices for the prevention and treatment of gastrointestinal diseases. Salix’s strategy is to in-license late-stage or marketed proprietary therapeutic products, complete any required development and regulatory submission of these products, and commercialize them through the Company’s 500-member specialty sales force.

Salix markets XIFAXAN® (rifaximin) tablets 200 mg and 550 mg, MOVIPREP® (PEG 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution, 100 g/7.5 g/2.691 g/1.015 g/5.9 g/4.7 g), OSMOPREP® (sodium phosphate monobasic monohydrate, USP, and sodium phosphate dibasic anhydrous, USP) Tablets, APRISO® (mesalamine) extended-release capsules 0.375 g, UCERIS® (budesonide) extended release tablets, for oral use, GIAZO® (balsalazide disodium) tablets, COLAZAL® (balsalazide disodium) Capsules, GLUMETZA® (metformin hydrochloride extended-release tablets) 500 mg and 1000 mg, ZEGERID® (omeprazole/sodium bicarbonate) Powder for Oral Suspension, ZEGERID® (omeprazole/sodium bicarbonate) Capsules, METOZOLV® ODT (metoclopramide hydrochloride), RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection, FULYZAQ® (crofelemer) delayed-release tablets, SOLESTA®, DEFLUX®, PEPCID® (famotidine) for Oral Suspension, DIURIL® (chlorothiazide) Oral Suspension, AZASAN® (azathioprine) Tablets, USP, 75/100 mg, ANUSOL-HC® 2.5% (Hydrocortisone Cream, USP), ANUSOL-HC® 25 mg Suppository (Hydrocortisone Acetate), PROCTOCORT® Cream (Hydrocortisone Cream, USP) 1% and PROCTOCORT® Suppository (Hydrocortisone Acetate Rectal Suppositories) 30 mg, CYCLOSET® (bromocriptine mesylate) tablets, FENOGLIDE® (fenofibrate) tablets. UCERIS (budesonide) rectal foam, RELSITOR®, encapsulated bowel prep and rifaximin for additional indications are under development.

ピルフェニドン,  吡非尼酮

Esbriet (EU),  Pirespa (ピレスパ, Japan), Pirfenex (India), Etuary(China)

F647, S-7701,  AMR-69, Deskar

CAS Number:53179-13-8

FOR….  idiopathic pulmonary fibrosis (IPF)
REGULATORY….        US (NDA), EU (approved), China (approved), Japan (approved)
Originator:  Marnac, Inc.
Developer:  InterMune, Shionogi
Sales:$70.3 million (2013),$130−$140 million (expected 2014)

InterMune has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for its pirfenidone, an investigational treatment for adult patients with idiopathic pulmonary fibrosis (IPF).

The company had submitted a new drug application to the FDA in May for pirfenidone and noted a target FDA review of six months under the Prescription Drug User Fee Act.

http://www.pharmaceutical-technology.com/news/newsfda-grants-breakthough-therapy-designation-for-intermunes-pirfenidone-4321293

InterMune’s Esbriet (Pirfenidone), an orally active, anti-fibrotic agent that inhibits the synthesis of TGF-beta, is currently seeking approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with idiopathic pulmonary fibrosis (IPF), a progressive and eventually fatal lung disease. On May 27, 2014 Brisbane, California-based InterMune resubmitted its pirfenidone New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in response to a Complete Response Letter (CRL) received in May 2010.

On July 17, 2014, Pirfenidone was awardedbreakthrough therapy designation by the FDA. If the FDA approves it within six months, Pirfenidonecould be sold in the United States in the first quarter of 2015.

InterMune licensed pirfenidone from Marnac, Inc. and its co-licensor, KDL GmbH, in 2002 and in 2007 purchased from Marnac and KDL the rights to sell the compound in the United States, Europe and other territories except in Japan, Taiwan and South Korea where rights to the molecule were licensed by Marnac and KDL to Shionogi & Co. Ltd. of Japan.

Pirfenidone is the only commercially approved drug for the treatment of mild to moderate idiopathic pulmonary fibrosis(IPF) in the world and is now approved in the EU, Norway, Iceland, Canada, Japan, China, India, South Korea, Argentina and Mexico.

 

In Japan it is marketed as Pirespa (ピレスパ) by Shionogi & Co since 2008.

In 2011 it was approved for use in Europe for IPF under the trade nameEsbriet, where the drug is priced in the range of $33,000 to $47,000 per year, depending on the country.

 

In October 2010, the Indian Company Cipla launched it as Pirfenex.

In September 2011, the China Food and Drug Administration  (CFDA) granted Shanghai genomics (上海睿星基因技术有限公司), the wholly owned subsidiary of Japan-based GNI Group Ltd,  with approval of pirfenidone (F647) under the trade name Etuary (艾思瑞) in China. Etuary (pirfenidone, F647) was manufactured by GNI’s affiliate Beijing Continent Pharmaceuticals (北京康蒂尼药业有限公司).

The U.S. Food and Drug Administration (FDA) declined to approve pirfenidone in 2010 because InterMune’s two previous Phase III studies ( known as CAPACITY) of Esbriet brought mixed results, insisting on another Phase III trial after an advisory committee recommended approval of the drug, but by a 9–3 margin.

In February 2014, InterMune said its latest Esbriet the phase III “Ascend” study of 555 IPF patients showed strong and positive results. Pirfenidone improved lung function and slowed the progression of IPF — meeting its primary endpoint of reducing the risk of a meaningful decline in forced vital capacity compared to the placebo group from baseline at week 52.

Pirfenidone is still under investigation for the treatment of IPF in the United States and has not been approved by the FDA.

Esbriet (Pirfenidone) is the only product marketed by InterMune.  Revenue from the drug was about $70.3 million in 2013. The company recorded Esbriet sales of $30.3 million in the first quarter of 2014. Esbriet sales in 2014 are expected in the range of $130−$140 million.

 

 

 

 

Pirfenidone

Systematic (IUPAC) name
5-Methyl-1-phenylpyridin-2-one
Clinical data
Trade names	Esbriet; Pirespa; Etuary
AHFS/Drugs.com	International Drug Names
Licence data	EMA:Link
Legal status	POM (UK)
Routes	Oral
Pharmacokinetic data
Protein binding	50–58%[1]
Metabolism	Hepatic (70–80% CYP1A2-mediated; minor contributions from CYP2C9,CYP2C19, CYP2D6 andCYP2E1)[1]
Half-life	2.4 hours[1]
Excretion	Urine (80%)[1]
Identifiers
ATC code	L04AX05
PubChem	CID 40632
ChemSpider	37115
UNII	D7NLD2JX7U
KEGG	D01583
ChEMBL	CHEMBL1256391
Chemical data
Formula	C12H11NO
Mol. mass	185.22 g/mol

Pirfenidone (INN, BAN) is a drug developed by several companies worldwide, including InterMune Inc., Shionogi Ltd., and GNI Group Ltd., for the treatment of idiopathic pulmonary fibrosis (IPF). In 2008, it was first approved in Japan for the treatment of IPF after clinical trials, under the trade name of Pirespa by Shionogi & Co. In October 2010, the Indian Company Cipla launched it as Pirfenex. In 2011, it was approved for use in Europe for IPF under the trade name Esbriet.^[2] The proposed trade name in the US is also Esbriet. In September 2011, the Chinese State Food and Drug Administration provided GNI Group Ltd with new drug approval of pirfenidone in China,^[3] and later manufacture approval in 2013 under the trade name of Etuary.^[4]

In 2014 it was approved in México under the name KitosCell LP, indicated for pulmonary fibrosis and liver fibrosis.^[5] There is also a topical form created for the treatment of abnormal wound healing processes.^[6]

 

 

Mechanism of action

Pirfenidone has well-established antifibrotic and anti-inflammatory properties in various in vitro systems and animal models offibrosis.^[7] A number of cell-based studies have shown that pirfenidone reduces fibroblast proliferation,^{[8][9][10][11]} inhibits TGF-βstimulated collagen production^{[8][9][12][13][14]} and reduces the production of fibrogenic mediators such as TGF-β.^[10][13] Pirfenidone has also been shown to reduce production of inflammatory mediators such as TNF-α and IL-1β in both cultured cells and isolatedhuman peripheral blood mononuclear cells.^[15][16] These activities are consistent with the broader antifibrotic and anti-inflammatoryactivities observed in animal models of fibrosis.

Preclinical studies

Studies in models of fibrosis

In animal models, pirfenidone displays a systemic antifibrotic activity and has been shown to reduce biochemical and histopathological indices of fibrosis of the lung, liver, heart and kidney.^[7]

Pirfenidone demonstrates a consistent antifibrotic effect in several animal models of pulmonary fibrosis.^{[17][18][19][20][21]} Of these, the bleomycin model is the most widely used model of pulmonary fibrosis. In this model, bleomycin administration results in oxidative stress and acute inflammation, with the subsequent onset of pulmonary fibrosis in a number of animal species including the mouse and hamster.^[7][19] Numerous studies have demonstrated that pirfenidone attenuates bleomycin-induced pulmonary fibrosis.^{[17][18][21][22][23][24]} One study investigated the effect of pirfenidone over a 42-day period after repeated bleomycin administration.^[18] Administration of pirfenidone minimised early lung oedema and pulmonary fibrosis when treatment was initiated concurrently with lung damage. This study evaluated pulmonary protein expression and found pirfenidone treatment normalised expression of pro-inflammatory and fibrogenic proteins. Similar reductions in pulmonary fibrosis were observed when pirfenidone treatment was delayed until pulmonary fibrosis was established and progressing,^[17] i.e. when administered in a therapeutic as opposed to a prophylactic treatment regimen.

The antifibrotic effect of pirfenidone has been further established in animal models of cardiac,^[25][26][27] renal,^[28][29] and hepatic^[8][30][31] fibrosis. In these models, pirfenidone demonstrated a consistent ability to reduce fibrosis and the expression of fibrogenic mediators.

Pharmacokinetics

Pirfenidone is administered orally. Though the presence of food significantly reduces the extent of absorption, the drug is to be taken after food, to reduce the nausea and dizziness associated with the drug. The drug is around 60% bound to plasma proteins, especially to albumin.^[32] Up to 50% of the drug is metabolized by hepatic CYP1A2 enzyme system to yield 5-carboxypirfenidone, the inactive metabolite. Almost 80% of the administered dose is excreted in the urine within 24 hours of intake.^[32]

Clinical trials in Idiopathic Pulmonary Fibrosis (IPF)

The clinical efficacy of pirfenidone has been studied in three Phase III, randomized, double-blind, placebo-controlled studies in patients with IPF.^[33][34]

The first Phase III clinical trial to evaluate the efficacy and safety of pirfenidone for the treatment of patients with IPF was conducted in Japan. This was a multicentre, randomised, double-blind, trial, in which 275 patients with IPF were randomly assigned to receive pirfenidone 1800 mg/day (110 patients), pirfenidone 1200 mg/day (56 patients), or placebo(109 patients), for 52 weeks. Pirfenidone 1800 or 1200 mg/day reduced the mean decline in vital capacity from baseline to week 52 compared with placebo. Progression-free survival was also improved with pirfenidone compared with placebo.^[33]

The CAPACITY (004 & 006) studies were randomized, double-blind, placebo-controlled Phase III trials in eleven countries across Europe, North America, and Australia.^[34] Patients with IPF were randomly assigned to treatment with oral pirfenidone or placebo for a minimum of 72 weeks.^[34] In study 004, pirfenidone reduced decline in forced vital capacity(FVC) (p=0.001). Mean change in FVC at week 72 was –8.0% (SD 16.5) in the pirfenidone 2403 mg/day group and –12.4% (SD 18.5) in the placebo group, a difference of 4.4% (95% CI 0.7 to 9.1). Thirty-five (20%) of 174 versus 60 (35%) of 174 patients, respectively, had an FVC decline of at least 10%. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0.501). Mean change in FVC at week 72 was –9.0% (SD 19.6) in the pirfenidone group and –9.6% (19.1) in the placebo group. The difference between groups in change in predicted FVC at week 72 was not significant (0.6%, 95% CI –3.5 to 4.7).^[34]

In May, 2014, the results of ASCEND studies (Phase III) were published. ASCEND is a randomized, double-blind, placebo-controlled trial that enrolled 555 patients. The results confirmed observations from previous clinical studies that pirfenidone significantly reduced IPF disease progression as measured by change in percent predicted forced vital capacity (FVC) from Baseline to Week 52 (rank ANCOVA p<0.000001). In addition, significant treatment effects were shown on both of the key secondary endpoints of six-minute walk test distance change (p=0.0360) and progression-free survival (p=0.0001). A pre-specified analysis of the pooled population (N=1,247) from the combined ASCEND and CAPACITY studies (taking CAPACITY mortality data through Week 52) showed that the risk of all-cause mortality was reduced by 48% in the pirfenidone group compared to the placebo group (HR=0.52, log rank p=0.0107)^[35] .

A review by the Cochrane Collaboration concluded that pirfenidone appears to improve progression-free survival and, to a lesser effect, pulmonary function in patients with IPF.^[36]Randomised studies comparing non-steroid drugs with placebo or steroids in adult patients with IPF were included. Four placebo-controlled trials of pirfenidone treatment were reviewed, involving a total of 1155 patients. The result of the meta-analysis showed that pirfenidone significantly reduces the risk of disease progression by 30%. In addition, meta-analysis of the two Japanese studies confirmed the beneficial effect of pirfenidone on the change in VC from baseline compared with placebo.^[36]

Indication

In Europe, pirfenidone is indicated for the treatment of mild-to-moderate idiopathic pulmonary fibrosis. It was approved by the European Medicines Agency (EMA) in 2011.^[2] In October 2008, it was approved for use in Japan, in India in 2010, and in China in 2011 (commercial launch in 2014).

In Mexico it has been approved on a gel^[37] form for the treatment of scars and fibrotic tissue ^[38] and has proven to be effective in the treatment of skin ulcers, such as diabetic foot.

Other research done shows that Pirfenidone can be an effective anti-fibrotic treatment ^[39] for chronic liver fibrosis.^[40]

Adverse effects

Gastrointestinal

Pirfenidone is frequently associated with gastrointestinal side effects such as dyspepsia, nausea, gastritis, gastroesophageal reflux disease (GERD) and vomiting.To reduce the severity of these reactions, pirfenidone is to be taken after meals.^[32]

Skin

Pirfenidone is known to cause photosensitivity reactions, rash, pruritus and dry skin. Patients are usually advised to avoid direct exposure to sunlight, including sun lamps, and to use protective clothing and sunscreen agents. Continuing photosensitivity reactions are usually managed by dose adjustment and temporary discontinuation of treatment if required, along with local symptomatic treatment.^[32]

Hepatic dysfunction

Pirfenidone can increase hepatic enzyme levels, especially those of aspartate transaminase (AST), alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT); periodic monitoring of hepatic enzyme levels is required during therapy: once before the initiation of therapy, monthly monitoring until 6 months after initiation of therapy, and 3 monthly thereafter. Extra precaution is required while prescribing the drug in patients with hepatic impairment and in patients who are concomitantly taking a CYP1A2 inhibitor. The drug is contraindicated in patients who have severe hepatic impairment.^[32]

Dizziness and fatigue

Dizziness and fatigue have been reported in patients undergoing pirfenidone treatment. Dizziness typically resolves, although patients should know how they react to pirfenidone before undertaking activities that need mental alertness or coordination. If severe, dose adjustment or treatment discontinuation may be required.^[32]

Weight loss

Weight loss has been reported in patients treated with pirfenidone. Doctors should monitor patients’ weight and encourage increased calorific intake if necessary.^[32]

Interactions

Most drug interactions are mediated by various cytochrome P450 (CYP) enzymes.^[32]

CYP1A2 inhibitors

Since Pirfenidone is metabolised through the CYP1A2 enzyme pathway, any drug which inhibits this enzyme is likely to precipitate the toxicity of pirfenidone: concomitant therapy is to be avoided. Fluvoxamine is contraindicated in patients who are on treatment with pirfenidone. Other inhibitors of CYP1A2 such as ciprofloxacin, amiodarone and propafenoneshould be used with caution.^[32]

Other CYP inhibitors

Some pirfenidone is also metabolized by CYP enzymes other than CYP1A2. Consequently, strong inhibitors of other CYP systems such as fluconazole (CYP2C9), chloramphenicol(CYP2C19), fluoxetine and paroxetine (both CYP2D6) should be used with caution.^[32]

CYP1A2 inducers

Moderate inducers of CYP1A2 such as omeprazole should be used with caution since they might reduce the circulating plasma levels of the drug.^[32]

Cigarette smoking

Cigarette smoking causes increased clearance of pirfenidone by inducing CYP1A2, thereby decreasing exposure to the drug. Patients must be advised to abstain from cigarette smoking while on therapy with pirfenidone.^[32]

Regulatory progress

In May 2010, the U.S. Food and Drug Administration declined to approve the use of pirfenidone for the treatment of idiopathic pulmonary fibrosis, requesting additional clinical trials.^[41] In December 2010 an advisory panel to the European Medicines Agency recommended approval of the drug.^[2] In February 2011, the European Commission (EC) has granted marketing authorisation in all 27 EU member states and China FDA granted approval in September, 2011. Afterwards, a randomised, Phase III trial (the ASCEND study) has been completed in the U.S. in 2014.^[42] Application for the U.S. regulatory approval is expected in 2014.

In Mexico it has been approved in gel for the treatment of chronic wounds and skin injuries and the oral form it is approved for the treatment of Pulmonary Fibrosis and Liver fibrosis.

Pirfenidone is a non-peptide synthetic molecule with a molecular weight of 185.23 daltons. Its chemical elements are expressed as C_I2H_HNO, and its structure is known. The synthesis of pirfenidone has been worked out. Pirfenidone is manufactured and being evaluated clinically as a broad- spectrum anti-fibrotic drug. Pirfenidone has anti-fibrotic properties via: decreased TNF-α expression, decreased PDGF expression, and decreased collagen expression. Several pirfenidone Investigational New Drug Applications (INDs) are currently on file with the U.S. Food and Drug Administration. Phase II human investigations have been initiated or completed for pulmonary fibrosis, renal glomerulosclerosis, and liver cirrhosis. There have been other Phase II studies that used pirfenidone to treat benign prostate hypertrophy, hypertrophic scarring (keloids), and rheumatoid arthritis.

One important use of pirfenidone is known to be providing therapeutic benefits to patients suffering from fibrosis conditions such as Hermansky-Pudlak Syndrome (HPS) associated pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF). Pirfenidone demonstrates a pharmacologic ability to prevent or remove excessive scar tissue found in fibrosis associated with injured tissues including that of lungs, skin, joints, kidneys, prostate glands, and livers. Published and unpublished basic and clinical research suggests that pirfenidone may safely slow or inhibit the progressive enlargement of fibrotic lesions, remove pre-existing fibrotic lesions, and prevent formation of new fibrotic lesions following tissue injuries.

It is understood that one mechanism by which pirfenidone exerts its therapeutic effects is by modulating cytokine actions. Pirfenidone is a potent inhibitor of fibrogenic Attorney Docket: 30481/30033 A cytokines and TNF-α. It is well documented that pirfenidone inhibits excessive biosynthesis or release of various fibrogenic cytokines such as TGF-βl, bFGF, PDGF, and EGF. Zhang S et ah, Australian New Eng. J. OphthaL, 26:S74-S76 (1998). Experimental reports also show that pirfenidone blocks the synthesis and release of excessive amounts of TNF-α from macrophages and other cells. Cain et al., Int. J. Immunopharm. , 20:685-695 (1998).

Pirfenidone has been studied in clinical trials for use in treatment of IPF. Thus, there is a need for a synthetic scheme that provides pirfenidone having sufficient purity as an active pharmaceutical ingredient (API) and involves efficient and economical processes. Prior batches of pirfenidone were shown to have residual solvent traces of ethyl acetate (e.g., about 2 ppm) and butanol.

http://www.google.com/patents/EP2440543A2?cl=en

improved process for preparing pirfenidone. The process involves using a cuprous oxide catalyst to couple 5-methyl-2-pyridone and bromobenzene in an organic solvent. Without intending to be limited by any particular theory, it is believed that the purity of the bromobenzene is important, as amounts of a dibromobenzene impurity in the bromobenzene can lead to dimer-type byproducts, which can complicate the Attorney Docket: 30481/30033 A purification of the resulting pirfenidone.

These dimer-type byproducts cannot be in a product intended as to be marketed as an active pharmaceutical ingredient (API), and they are difficult to remove from the intended pirfenidone product. Thus, the bromobenzene used in the disclosed processes preferably have an amount of dibromobenzene of less than about 0.15% by weight or molar ratio, and more preferably less than about 0.1% by weight or molar ratio or less than 0.05% by weight or molar ratio.

 

 

 

http://www.google.com/patents/US8519140

EXAMPLES

Coupling of Bromobenzene and 5-Methyl-2-pyridone

5-Methyl-2-pyridone (1.0 equivalents), potassium carbonate (1.2 equivalents), copper(I) oxide (0.05 equivalents), bromobenzene (1.8 equivalents, with a purity of at least 98%, preferably at least 99%, or at least 99.8%), and dimethyl formamide (2.0 volume equivalents) were charged into an inert reactor. This mixture was heated to 125° C. for about 18 hours. A sample was collected and analyzed for reaction completion. If reaction completion was not satisfactory, the reaction was maintained at 125° C. for an additional 2 hours. The reaction mixture was then cooled to 25° C. to form a slurry.

The resulting slurry was filtered in a Nutsche filter in order to remove salts. The filter cake was rinsed twice with toluene. The mother liquor and process liquor were collected in Vessel (A). A sodium chloride solution (15%) was charged into the product solution. The pH was adjusted to greater than or equal to 11.5 using a 32% sodium hydroxide solution. The mixture was then agitated. After agitation was stopped, the mixture was allowed to settle for at least 30 minutes to allow the two phases to separate. The organic layer was separated and the aqueous layer was extracted with toluene. The toluene extraction was added to the organic layer. The combined organics were then washed with a 15% sodium chloride solution and agitated for at least 15 minutes. The agitation was stopped and the layers were allowed to settle for at least 30 minutes. The organic layer was separated from the aqueous layer, and then carbon treated by flowing it through Zeta Carbon filters for 2 hours at 20-25° C. The carbon treated solution was then concentrated under vacuum to remove all water and much of the toluene.

Heptanes were then added to the concentrated solution, and it was heated to about 80° C. The solution was slowly cooled to about 0° C. over at least 7 hours. The pirfenidone precipitated out of the solution, was collected by filtration and dried, using a Nutsche filter/drier. The pirfenidone cake was washed twice with a mixture of toluene and heptanes (at 0° C.), then vacuum dried at a temperature of about 42° C. The crude pirfenidone was formed in about 85% yield.

Crystallization of Pirfenidone

Pirfenidone, a 32% hydrochloride solution, and deionized water were charged in an inert reactor. The mixture was heated to about 45° C., then a 32% sodium hydroxide solution was titrated into the mixture until the pH was at least 11. The temperature of the mixture was maintained at about 45° C. during the titration. Upon reaching the pH of at least 11, the mixture was then cooled slowly to 5° C., over the course of at least 2 hours. The pirfenidone crystallized from this cooled solution and was isolated in a Nutsche filter/drier. The pirfenidone cake was washed twice with deionized water (at 5° C.). The pirfenidone was then vacuum dried in the filter/drier at a temperature of about 45° C. The pirfenidone was also milled through a loop mill in order to reduce the particle size to less than 150 μm.

The resulting pirfenidone was then analyzed and the only residual solvents observed were toluene and heptanes at about 10 to 13 ppm. No ethyl acetate or butanol was detected in the pirfenidone. The amount of bis-conjugate in the purified pirfenidone was 0.03% or less. All impurities of the purified pirfenidone were less than about 0.05%.

 

…………………………….

http://www.google.com/patents/CN1218942C?cl=en

 fibrotic diseases such as renal fibrosis and cirrhosis, myocardial fibrosis is a class of serious harm to human life and health of important diseases, as well as people living with global industrialization, changes in diet, the incidence of fibrotic diseases is gradually increased correspondingly, many domestic and foreign scholars fibrosis links from chemical compounds, natural compounds, biologics, gene therapy and other different areas of a large number of anti-fibrotic compounds studied. So far, the pyridone compound has been found that a class of effective antifibrotic compound.

U.S. Patent US3839346, US4052509A discloses a pyridone compound of structural formula are available (O) of the general formula 1 – mono-substituted phenyl-5 – methyl -2 (1H)-pyridone.

Image not available. View PDF Wherein the number of the substituent R is 0 or 1, R represents a nitro substituent species, a chlorine atom, an alkyl group, a methoxy group; such pyridones have anti-inflammatory, antipyretic, lower serum uric acid levels, pain and so on.

In addition, U.S. Patent (US3839346) discloses a process approach is to formula (IV), 5 – methyl -2 (1H)-pyridone as raw materials, and formula (V) monosubstituted phenyl iodide, the reaction and generating (O) type 1 – benzene substituted-5 – methyl -2 (1H) pyridone compound, the reaction process is as follows: Image not available. View PDF Chinese Patent (1086514A) discloses a process for preparing formula (IV) method is based on formula (IV) 1 – nitrile-1 – butene and (VII) formula 1,1 – bis dimethyl ether as amine starting material, the reaction of (VIII) Formula 1 – dimethylamine -2 – methyl-4 – cyano-1 ,3 – butadiene intermediates in acid conditions and then cyclized to generate ( IV ‘) formula and formula (IV) of the desired compound, the reaction process is as follows:Image not available. View PDF Although these methods to some of the previous methods were further improved, but there are still formula (VI) compound is unstable, prone to aggregation, (VII) is not easy to obtain the compound of formula shortcomings.

On the other hand, ORGANIC SYNTHESES Vol.78, 51 discloses the compound (II) Preparation of Compound (IV) method Image not available. View PDF SUMMARY OF THE INVENTION For the above-mentioned disadvantages of the prior art, the present invention is one of the technical solution is to provide a class of anti-fibrosis effect, and organ and has a wide applicability antifibrotic pyridinone compound; technical solution of the present invention The second program is to provide an easy to use on the market too, and the starting material for production of stable molecules antifibrotic pyridone compound process method.

 

……………………………..

 

………………………

Pirfenidone

http://www.chemdrug.com/databases/9_0_buppyobhgedloxck.html

By condensation of 5-methyl-2- (1H) -pyridone (I) with iodobenzene (II) by means of K2CO3 and Copper powder at reflux temperature.

Casta Lv r, J .; Blancafort, P .; Pirfenidone. Drugs Fut 1977, 2, 6,

 US 3839346; ZA 7309472

CA 1049411;. DE 2555411; US ​​3974281

WO2002085858A1 *	Apr 19, 2002	Oct 31, 2002	Asahi Glass Co Ltd	Process for producing purified piperidine derivative
WO2003014087A1 *	Aug 6, 2002	Feb 20, 2003	Asahi Glass Co Ltd	Process for preparation of 5-methyl-1-phenyl-2(1h) -pyridinone
WO2008147170A1 *	May 29, 2008	Dec 4, 2008	Armendariz Borunda Juan Socorr	New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same

US3839346	Dec 18, 1972	Oct 1, 1974	Affiliated Med Res	N-substituted pyridone and general method for preparing pyridones
US5356898	Jan 17, 1992	Oct 18, 1994	Warner-Lambert Company	Antiinflammatory agents, antiallergens, antiulcer agents
US20080319026	Jun 20, 2008	Dec 25, 2008	Auspex Pharmaceuticals, Inc.	Substituted n-aryl pyridinones
US20090131485	Sep 10, 2008	May 21, 2009	Concert Pharmaceuticals, Inc.	Deuterated pirfenidone
CN1386737A	Jun 11, 2002	Dec 25, 2002	中南大学湘雅医学院	Antifibrosis pyridinone medicine and its prepaing process
CN1817862A	Mar 15, 2006	Aug 16, 2006	浙江省医学科学院	Production of pyriphenanthrenone as anti-fibrosis medicine
KR20040022232A				Title not available
MX2007006349A				Title not available
WO2002085858A1	Apr 19, 2002	Oct 31, 2002	Asahi Glass Co Ltd	Process for producing purified piperidine derivative
WO2003014087A1	Aug 6, 2002	Feb 20, 2003	Asahi Glass Co Ltd	Process for preparation of 5-methyl-1-phenyl-2(1h) -pyridinone
WO2008147170A1	May 29, 2008	Dec 4, 2008	Armendariz Borunda Juan Socorr	New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same

Reference
1	*	See also references of WO2010141600A2
2	*	WU ET AL.: “Tissue distribution and plasma binding of a novel antifibrotics drug pirfenidone in rats“, ASIAN JOURNAL OF PHARMADYNAMIS AND PHARMACOKINETICS, vol. 6, no. 4, 2006, pages 351-356, XP002684997,

Hegde et al., “17. Pirfenidone (Idiopathic Pulmonary Fibrosis), Chapter 28 To Market, To Market-2008,” Ann Rep Med Chem, vol. 44 (2009).
2		Hegde et al., “17. Pirfenidone (Idiopathic Pulmonary Fibrosis), Chapter 28 To Market, To Market—2008,” Ann Rep Med Chem, vol. 44 (2009).
3		International Search Report from corresponding International Application No. PCT/US2010/037090, dated Mar. 1, 2011.
4		Ma et al., “Synthesis of pirfenidone,” Zhongguo Yiyao Gongye Zazhi, 37(6):372-373 as summarized in Liu et al., “Synthetic Approaches to the 2008 New Drugs,” Mini-Reviews in Medicinal Chemistry, 9:1655-75 (2009).
5	*	Vogel, A., Practical Organic Chemistry, 3d ed., London, Longman Group, 1974, pp. 44-45 and 122-127.
6		Wu et al., Tissue distribution and plasma binding of a novel antifibrotics drug pifenidone in rats, Asian J. Pharmadynamics and Pharmacokinetics, 6(4):351-6 (2006).
7		Zhang et al., Pirfenidone reduces fibronectin synthesis by cultured human retinal pigment epithelial cells, Aust. N Z J Ophthalmol., 26 Suppl 1:S74-6 (1998).

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2.  “InterMune: Pirfenidone”. InterMune.
3.  “China SFDA Approves F647/pirfenidone for the Treatment of Idiopathic Pulmonary Fibrosis”. Press Release. EvaluatePharma. 2011-09-22.
4.  “GNI Group receives manufacture approval for F647 from China FDA for first idiopathic pulmonary fibrosis drug in China”. Press Release. 2014-01-06.
5.  kitoscelllp.com
6. Jump up^ Coadjuvant treatment with surgery and pirfenidone in sever facial trauma due to dog bite. The journal of Craniofacial Surgery, volume 24, Number 2, March 2013
7. ^ Jump up to:^a b c Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K (June 2011). “Antifibrotic activities of pirfenidone in animal models”. Eur Respir Rev 20 (120): 85–97.doi:10.1183/09059180.00001111. PMID 21632796.
8. ^ Jump up to:^a b c Di Sario A, Bendia E, Svegliati Baroni G, Ridolfi F, Casini A, Ceni E, Saccomanno S, Marzioni M, Trozzi L, Sterpetti P, Taffetani S, Benedetti A (November 2002). “Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production”. J. Hepatol.37 (5): 584–91. doi:10.1016/S0168-8278(02)00245-3. PMID 12399223.
9. ^ Jump up to:^a b Hewitson TD, Kelynack KJ, Tait MG, Martic M, Jones CL, Margolin SB, Becker GJ (2001). “Pirfenidone reduces in vitro rat renal fibroblast activation and mitogenesis”. J. Nephrol. 14 (6): 453–60. PMID 11783601.
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11.  Lee BS, Margolin SB, Nowak RA (January 1998). “Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production”. J. Clin. Endocrinol. Metab. 83 (1): 219–23. doi:10.1210/jc.83.1.219. PMID 9435445.
12.  Ozes ON, Blatt LM (2006). “Development of a high throughput collagen assay using a cellular model of idiopathic pulmonary fibrosis”. Chest 130: 230S.doi:10.1378/chest.130.4_meetingabstracts.230s-a.
13.  Sulfab M (2007). “The effects of pirfenidone and IFN-inducible T-cell alpha chemoattractant (ITAC) on transforming-growth factor-beta 1-mediated synthesis of extracellular matrix proteins in endothelial cells”. Am J Respir Crit Care Med 175: A730.
14.  Nakayama S, Mukae H, Sakamoto N, Kakugawa T, Yoshioka S, Soda H, Oku H, Urata Y, Kondo T, Kubota H, Nagata K, Kohno S (January 2008). “Pirfenidone inhibits the expression of HSP47 in TGF-beta1-stimulated human lung fibroblasts”. Life Sci. 82 (3–4): 210–7. doi:10.1016/j.lfs.2007.11.003. PMID 18093617.
15.  Phillips R, Wang T, Blatt LM, Seiwert S (2005). “Pirfenidone mediates differential effects on lipopolysaccharide-induced cytokine expression in human peripheral mononuclear cells”. Chest 128. doi:10.1378/chest.128.4_meetingabstracts.169s-a.
16.  Grattendick KJ, Nakashima JM, Feng L, Giri SN, Margolin SB (May 2008). “Effects of three anti-TNF-alpha drugs: etanercept, infliximab and pirfenidone on release of TNF-alpha in medium and TNF-alpha associated with the cell in vitro”. Int. Immunopharmacol.8 (5): 679–87. doi:10.1016/j.intimp.2008.01.013. PMID 18387510.
17. ^ Jump up to:^a b c Kakugawa T, Mukae H, Hayashi T, Ishii H, Abe K, Fujii T, Oku H, Miyazaki M, Kadota J, Kohno S (July 2004). “Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis”. Eur. Respir. J. 24 (1): 57–65.doi:10.1183/09031936.04.00120803. PMID 15293605.
18.  Oku H, Shimizu T, Kawabata T, Nagira M, Hikita I, Ueyama A, Matsushima S, Torii M, Arimura A (August 2008). “Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis”. Eur. J. Pharmacol. 590 (1–3): 400–8.doi:10.1016/j.ejphar.2008.06.046. PMID 18598692.
19.  Card JW, Racz WJ, Brien JF, Margolin SB, Massey TE (September 2003). “Differential effects of pirfenidone on acute pulmonary injury and ensuing fibrosis in the hamster model of amiodarone-induced pulmonary toxicity”. Toxicol. Sci. 75 (1): 169–80.doi:10.1093/toxsci/kfg167. PMID 12832656.
20.  Liu H, Drew P, Gaugler AC, Cheng Y, Visner GA (June 2005). “Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway”. Am. J. Transplant. 5 (6): 1256–63.doi:10.1111/j.1600-6143.2005.00876.x. PMID 15888029.
21.  Hirano A, Kanehiro A, Ono K, Ito W, Yoshida A, Okada C, Nakashima H, Tanimoto Y, Kataoka M, Gelfand EW, Tanimoto M (September 2006). “Pirfenidone modulates airway responsiveness, inflammation, and remodeling after repeated challenge”. Am. J. Respir. Cell Mol. Biol. 35 (3): 366–77. doi:10.1165/rcmb.2005-0452OC.PMC 2643289. PMID 16675785.
22.  Iyer SN, Wild JS, Schiedt MJ, Hyde DM, Margolin SB, Giri SN (June 1995). “Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters”. J. Lab. Clin. Med. 125 (6): 779–85. PMID 7539478.
23.  Iyer SN, Margolin SB, Hyde DM, Giri SN (1998). “Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model”.Exp. Lung Res. 24 (1): 119–32. doi:10.3109/01902149809046058. PMID 9457473.
24.  Iyer SN, Gurujeyalakshmi G, Giri SN (April 1999). “Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis”.J. Pharmacol. Exp. Ther. 289 (1): 211–8. PMID 10087006.
25. Jump up^ Lee KW, Everett TH, Rahmutula D, Guerra JM, Wilson E, Ding C, Olgin JE (October 2006). “Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure”. Circulation 114 (16): 1703–12.doi:10.1161/CIRCULATIONAHA.106.624320. PMC 2129103. PMID 17030685.
26.  Nguyen DT, Ding C, Wilson E, Marcus GM, Olgin JE (October 2010). “Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias”. Heart Rhythm 7 (10): 1438–45. doi:10.1016/j.hrthm.2010.04.030.PMID 20433946.
27.  Mirkovic S, Seymour AM, Fenning A, Strachan A, Margolin SB, Taylor SM, Brown L (February 2002). “Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats”. Br. J. Pharmacol. 135 (4): 961–8.doi:10.1038/sj.bjp.0704539. PMC 1573203. PMID 11861324.
28. Jump up^ Shimizu T, Kuroda T, Hata S, Fukagawa M, Margolin SB, Kurokawa K (July 1998). “Pirfenidone improves renal function and fibrosis in the post-obstructed kidney”. Kidney Int. 54 (1): 99–109. doi:10.1046/j.1523-1755.1998.00XXX.x. PMID 9648068.
29. Jump up^ Takakuta K, Fujimori A, Chikanishi T, Tanokura A, Iwatsuki Y, Yamamoto M, Nakajima H, Okada M, Itoh H (March 2010). “Renoprotective properties of pirfenidone in subtotally nephrectomized rats”. Eur. J. Pharmacol. 629 (1–3): 118–24.doi:10.1016/j.ejphar.2009.12.011. PMID 20006961.
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35. Jump up^ http://www.intermune.com/pirfenidone. Missing or empty |title= (help)
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37. Jump up^ http://www.kitoscell.com
38. Jump up^ A controlled clinical trial with pirfenidone in the treatment of pathological skin scarring caused by burns in pediatric patients, annals of plastic surgery, volume 68, number 1, january 2012
39. Jump up^ The multifaceted role of pirfenidone and its novel target. Macias-Barragan et al. Fibrogenesis 6 Tissue Repair 2010, 3:16
40.  Pirfenidone effectively reverses experimental liver fibrosis. Journal of Hepatology, 37 (2002) 797-805
41.  Frieden J (2010-05-10). “FDA Nixes Pirfenidone for Now, Wants New Trial”. MedPage Today.
42. “Efficacy and Safety of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis (IPF)”. NCT01366209. U.S. National Institutes of Health: ClinicalTrials.gov.

MORE MORE…………..

 

Cottin, Vincent; Wijsenbeek, M.; Bonella, F.; Vancheri, C.Slowing progression of idiopathic pulmonary fibrosis with pirfenidone: from clinical trials to real-​life experience.Clinical Investigation (London, United Kingdom) (2014), 4(4), 313-326.

Zhang, Kang.Application of pirfenidone in manuf. of anti-​angiogenic drugs.Faming Zhuanli Shenqing (2014), CN 103800325 A 20140521.

Ma, Zhen; Pan, Youlu; Huang, Wenhai; Yang, Yewei; Wang, Zunyuan; Li, Qin; Zhao, Yin; Zhang, Xinyue; Shen, Zhengrong.Synthesis and biological evaluation of the pirfenidone derivatives as antifibrotic agents.Bioorganic & Medicinal Chemistry Letters (2014), 24(1), 220-223.

Ramachandran Radhakrishnan, Michael Cyr, Sabine M. Pyles.Method for synthesizing pirfenidone.US Patent Number: US8519140 B2 , Also published as:CA2764043A1, CN102482255A, EP2440543A2, EP2440543A4, US20110003863, US20120016133, US20130345430, WO2010141600A2, WO2010141600A3,Publication date: Aug 27, 2013.Priority date:Jun 3, 2009.Original Assignee: Intermune, Inc.

Li, Fa and Wang, Ping,A new method for preparation of pirfenidone, Anhui Huagong, 38(4), 27, 31; 2012

Du, Zhenxin et al,Preparation of pirfenidone, Faming Zhuanli Shenqing, CN102558040, 11 Jul 2012
一种吡非尼酮的制备方法,申请号：CN 201110447487,公开(公告)号：CN102558040 A,

Zhang, Chengzhi and Sommers, Andreas, Substituted n-aryl pyridinones, PCT Int. Appl., WO2012122165, 13 Sep 2012

Hu, Gaoyun et al,1-(Substituted aryl)-5-((substituted arylamino)methyl)pyridin-2(1H)-one useful in the treatment of cancer and its preparation, Faming Zhuanli Shenqing, CN102241625, 16 Nov 2011

Qiang, Jianhua and Shi, Wei,A process for preparing pirfenidone,Faming Zhuanli Shenqing, CN101891676, 24 Nov 2010

Radhakrishnan, Ramachadran et al,Process for preparation of pirfenidone from bromobenzene and 5-methyl-2-pyridone in the presence of cuprous oxide and an organic solvent. PCT Int. Appl., WO2010141600, 09 Dec 2010

Gant, Thomas G. and Sarshar, Sepehr.Preparation of substituted N-aryl pyridinones as fibrotic inhibitors, PCT Int. Appl., WO2008157786, 24 Dec 2008

Magana Castro, Jose Agustin Rogelio et al,New process of synthesis for obtaining 5-methyl-1-phenyl-2-(H)-pyridone, pharmaceutical compositions and use thereof as cytoprotective and dermatological agent in topical applications,PCT Int. Appl., WO2008147170, 04 Dec 2008

Ma, Zhen et al,Synthesis of pirfenidone,Zhongguo Yiyao Gongye Zazhi, 37(6), 372-373; 2006

Ma, Zhen and Wang, Zunyuan,Process for preparation of pirfenidone as antifibrotic agent, Faming Zhuanli Shenqing Gongkai Shuomingshu, CN1817862, 16 Aug 2006

一种抗纤维化药物吡非尼酮的制备方法,申请号：200610049852.5,申请日：2006.03.15,公开(公告)号：CN1817862,

Tao, Lijian et al,Preparation of pyridone derivatives for treatment of fibrosis, Faming Zhuanli Shenqing, CN1386737, 25 Dec 2002

Taniguchi, Tomoko et al, Process for preparation of 5-methyl-1-phenyl-2(1H)-pyridinone by phenylation of 5-methyl-2(1H)-pyridinone with bromobenzene, PCT Int. Appl., WO2003014087, 20 Feb 2003

Talmadge King et al. A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. NEJM May 18, 2014. DOI: 10.1056/NEJMoa1402582.

Raghu G, et al “Treatment of idiopathic pulmonary fibrosis with ambrisentan: A parallel, randomized trial” Ann Intern Med 2013; DOI: 10.7326/0003-4819-158-9-201305070-00003.

Luca Richeldi et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis,N Engl J Med 2014; 370:2071-2082 , May 29, 2014DOI: 10.1056/NEJMoa1402584 (INPULSIS-1 and INPULSIS-2  ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.)

Deoxyribonucleic acid (DNA) synthesis is a process by which copies of nucleic acid strands are made. In nature, DNA synthesis takes place in cells by a mechanism known as DNA replication. Using genetic engineering and enzyme chemistry, scientists have developed man-made methods for synthesizing DNA. The most important of these is poly-merase chain reaction (PCR). First developed in the early 1980s, PCR has become a multi-billion dollar industry with the original patent being sold for $300 million dollars.

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DNA synthesis

GMP News: Final ICH M7 Guideline on Genotoxic Impurities published

http://www.gmp-compliance.org/enews_4416_Final%20ICH%20M7%20Guideline%20on%20Genotoxic%20Impurities%20published_8559,8500,S-QSB_n.html

On on 15 July 2014, the ICH issued the guideline M7 “Assessment and Control of DNA reactive (mutagenic) Impurities in Pharmaceuticals to limit Potential Carcinogenic Risk” as Step 4 document. in In the last step of the ICH process (Step 5) this guideline now has to be implemented in the national regulations in the three ICH regions Europe, United States and Japan. The final M7 Guideline was published exactly 17 months after the release of the draft consensus guideline (Step 2) in February 2013, where it could be commented in a 6-month period.

The guideline comprises information, how impurities in pharmaceutical products relative to their genotoxic potential have to be evaluated with the analysis of structure-activity relationships and how the critical toxicological threshold (threshold of toxicological concern TTC) has to be determined. In the individual chapters, some highly complex issues and scenarios are covered – as, for instance, the question why potentially genotoxic substances with similar molecular structure and probably the same mechanism of action should still not be combined for the calculation of the TTC. Another problem the Guideline tries to clarify is the different values of the TTC, depending on the duration of the use of the medicinal product.

The last section of the document contains a statement of the ICH, that due to its complexity the guideline has to be implemented in the respective national rules and regulations after 18 months only. However, the following exceptions apply to some requests:

• For the implementation of Ames tests the specifications of M7 have to be applied immediately. However, the Ames tests carried out before release of M7 need not be repeated.
• The development programmes having started phase 2b/3 prior to publication of M7 can be continued. The requirements for the execution of two quantitative analyses of structure-activity relations (section 6), for impurity assessment (section 5) and for the documentation (section 9) do not have to be considered, though.

• For a new marketing authorisation application which does not include the phase 2b/3 clinical trials, compliance with the aforementioned points is expected until 36 months after the publication of M7.

Compared to the previous Guideline version (Step 2) it now contains changes, clarifications and precisions in several parts. For a more detailed analysis of the new M7 Guideline please see one of our next newsletters.

The ECA will conduct the Impurities Forum 2014in Berlin, where a complete day will be dedicated to the implementation of Genotoxic Impurities ICH M7. On another day you will cover the implementation of Elemental Impurities ICH Q3D – whose finalisation is scheduled for September. The days can be booked separately or alternatively the entire 3 days of the Impurities Forum.