Industry puts bets on optically pure drugs

02 January 1992 00:00  [Source: PCE]

Optically pure drugs appear to be fast becoming the chemical industry's hope for the future, if present rates of investment are anything to go by. Janet Dansie talks to Mike Jones of ICI Fine Chemicals about investment tactics and future strategies

In a generally recessionary chemicals industry, time and again the only bright spot in company results has been provided by the pharmaceuticals division.

Optically active compounds are the most heavily invested and researched aspect of pharmaceutical product development, offering the possibility of both increasing the efficacy of a drug and reducing the dosage.

In the second volume of its study Optically Active Chiral Compounds, Technology Catalysts International, based in Virginia, US, says the present world market for optically pure drugs is 'conservatively' estimated to be $18bn, measured at the ex-factory pharmaceutical shipment level.

By the year 2000, the market value is minimally expected to increase to $40bn, equivalent to an average annual growth of 9.3%. At the bulk active shipment level, the corresponding values for 1991 and 2000 are $3bn and $6bn on a global basis. Intermediates currently have a value of $700m, but this will change, as companies continue their backward integration and acquisition of captive suppliers.

There are several factors driving the research and supporting these expectations: there is increased awareness that only one stereoisomer or chiral form has a greater patient benefit:cost ratio than the racemic mixture; there is a flurry of use patents filed worldwide on one isomer of established major racemic drugs; regulatory agencies worldwide have published policies and guidelines which are interpreted differently in practice, leading to faster commercialisation of 'racemic switches', such as S-(+)- ibuprofen (see box), S-(+)- atenolol and S-(+)- terfenadine.

Pharmaceutical companies are employing five strategies to protect branded optically pure drugs and racemates and to sustain growth after patent expiration, says Technology Catalysts. They are developing new dosage forms of optically pure drugs such as diltiazem and naproxen, creating optically pure forms of branded racemates which are going off-patent (racemic switches) and they are testing new dosage forms of racemic switches, such as S-(+)- ibuprofen.

They are also using low-cost asymmetric synthesis, biotransformations or prep HPLC for the inexpensive manufacture of optically pure drugs at a higher level of purity, as protection against generic competition. Finally, they are employing R_x to OTC switches of optically pure drugs such as naproxen, S-(+)- terfenadine and S-(+)- ibuprofen.

Best candidates for racemic switches
Cardiovascular
Acebutolol	Alprenolol	Atenolol
Betaxolol	Bisoprolol	Bopindolol
Bucumolol	Butefolol	Bufuralol
Bunitrolol	Bupranolol	Butofilolol
Carazolol	Carvedilol	Curteolol
Disoppyramidine	Dobutamine	Indenolol
Mepindolol	Metipranolol	Metoprolol
NadololNicardipine	Oxpranolol	Pindolol
Propanolol	Quinidine sulfate	Sotalol
Toliprolol	Verapamil	Xibenolol
Central nervous system
Butaclomol	Butorphanol	Buprenorphine
Codeine	Dihydroergotoxine	Dobutamine
Fluoxetine	Ketamine	Lorazepam
Meclizine	Nalbuphine	Nalmefane
Naloxone	Natrexone	Oxaprotiline
Oxymorphone	Phenylpropanolamine	Physostigmine
Polycloramphetamine	Thioridazine	Toloxaton
Tomoxetine	Vasopressin	Viloxazin
Anti-inflammatory & analgesics
Beclomethasone	Betamethasone	cicloprofen
Corticosteroid	Dihydroxythebiane	Fenbuphen
Fenoprofen	Fluriprofen	Ibuprofen
Indoprofen	Ketoprofen	Minoxiprofen
Norlevorphanol	Oxycodone	Pirpofen
Stanozolol	Steroids	Suprofen
Triamcinolone
Anticancer
Bleomycin	Cytarabine	Doxorubicin
Methotrexate	Mitomycin C
Antibiotics, anti-infectives, anti-virals
Ciprofloxacin	Norfloxacin	Ofloxacin
Hormones, genitourinary
Benyl glutamate	Bromocriptine	Butoconazole
Calcitonin	Estradiol	Fluorogesterone
Gonadorelin	Ketodesogestrel/Estrogen	Norgestrel
Prednisolone	Progestin nitanol	Testosterone
Source: Technology Catalysts

World market for optically-pure pharmaceuticals (Sm ex-factory 1990)
Ampicillin	2050
Amoxicillin	2000
Captopril	1501
Enalapril	1482
Cefaclor	1050
Lovastatin	751
Diltiazem	746
Cefadroxil	690
Naproxen	686
Chloramphenicol	460
Lisinopril	430
Penicillin G	400
Timolol	297
Cefoperazone	270
Penicillin V	180
L-Depanyl	141
Methyldopa	140
Dexfenfluramine	52
Transdermal nicotine	5
Sertraline	3
Total	13 334
Source: Technology Catalysts

Another factor behind the forecast high growth rate is the expanded number of initial public offerings (IPOs such as Celgene and Sepracor) and several acquisitions.

In Volume II of the study, now available, Technology Catalysts estimates that about $40bn of presently marketed racemates could be switched to their pure form, for the purpose of extending or obtaining new patent protection and new therapeutic indications.

Dr Mike Jones of ICI Fine Chemicals says: 'Chirality is not a new issue, single isomer products have been available for many years, L-lactic or D-lactic acid, for example.

###3990###

'However, the increasing molecular complexity of actives, together with the rate of new technology developments and the realisation over the last 10 years that individual optical isomers are indeed different molecules with different pharmacology and pharmacokinetic properties, has led to an explosion of interest in homochirality.

'The real interest now lies in the NCEs in the pharmaceutical development lines, which will gradually come to the marketplace. These are future-based technologies, looking ahead perhaps 10 years to when most pharmaceutical companies will only be producing single isomers.'

The main customer focus is on the chemical innovators involved in original molecule design, says Jones. At present, they are mostly based in the US and Europe, but major growth is taking place in Japan and in 10-20 years' time, the country is likely to be a major source of chiral molecules.

'However, while many companies are offering a wide range of novel chiral products, in reality, most of them are only available in small quantities', Jones continues. 'This is of little interest to the major customers, who require a supplier who can not only produce small quantities of the product in the early development stages, but also supply large tonnage quantities when it reaches maturity.'

'It is really only the major multinationals which have the multi-disciplinary team resources, breadth of technology and assets to develop new complex chiral intermediates up to a fully commercial scale,' says Jones. ICI itself has a substantial investment in R&D, considerable human and financial resources, breadth of experience and range of facilities for the production of chiral intermediates.

From resolution through to chiral synthesis and bio-transformations, ICI Fine Chemicals aims to find novel routes for the cost-effective production of chiral molecules. Using skills in biosciences, classical chemistry and chemical engineering, the company has proven ability to progress from laboratory to full industrial production, shown by its production of S-2-chloropropionic acid on a 2000-tonne scale.

In contrast, many small companies are trying to get into the chiral market to exploit their own novel technology, but lack the resources and facilities to scale up from the benchtop to full commercial production. They also tend to have a narrow field of expertise. A few may be successful, but most will either be bought by one of the majors, or license their technology to those capable of implementing it commercially.

'Most of our major competitors in complex chiral intermediates are the large integrated pharmaceutical companies, producing in-house for their own requirements', says Jones. 'They have the choice, "make or buy", which means that we have to offer them a product which at least equals their own quality standards and is more cost effective.

'ICI differentiates its products to firms making this decision by developing new molecules through its complex custom synthesis service. A package comprises selection, process definition, scale-up and manufacture.'

For the latest chemical news, data and analysis that directly impacts your business sign up for a free trial to ICIS news - the breaking online news service for the global chemical industry.

Get the facts and analysis behind the headlines from our market leading weekly magazine: sign up to a free trial to ICIS Chemical Business.

Printer Friendly