Pharmaceutical Industry Essay Example
IMPORTANCE OF ENANTIOMERICALLY PURE COMPOUNDS
An enantiomer is clearly described as one of two stereoisomers. “Enantiomers can be described as mirror images of each other that are not superimposable on each other” (Agranat, 1999). When a reaction occurs and produces a mixture of enantiomers together, the mixture is called a racemic mixture (Agranat, 1999). Enantiomers are in most cases have the same physical and chemical properties other than their differed reaction to polarized light. They rotate the polarized light by equal amounts only in opposite directions. The major difference between enantiomers is observed when reacted with other enantiomers. This difference is predominantly observed in the pharmaceutical field. This is due to the fact that the molecules found in the body are mainly enantiomers. In the production of drugs for example, one enantiomer can produce the required effect on the body while the other enantiomer can remain inactive or can even be a source of life threatening negative effects (Jones, 1993). This occurs when a drug is produced and administered as a racemic mixture. These adverse effects have brought the issue of the administration of chiral drugs as racemic mixtures up for discussion. Meetings involving all the stake holders were held in the late 1980’s and early 1990’s where it was unanimously agreed that there was a great importance to give the chirality of drugs great consideration. New technologies were born so as to develop single enantiomer drugs from their respective racemates (Krstulovic, 1999). The most common process is liquid chromatography. “This process is referred to as the chiral switch” (Agranat, 1999). A chiral switch is the production of a single enantiomer from its racemic mixture that was previously marketed. The result of most chiral switches is a better performing drug with lesser side effects. This has led to the increase of technological advances associated with the chemical synthesis of the drugs as well as the separation of each enantiomer from the racemic mixture (Krstulovic, 1999).
As mentioned above, the pharmaceutical industry is hardest hit by the need to produce enantiomerically pure drugs. Before the heightened technological processes of producing these drugs were discovered, most drugs caused unbearable side effects. These side effects were brought about by the enantiomers that were not taking place in the medical reaction. Chiral switching gave the solution to these bad side effects (Agranat, 1999).
Chiral switching has been carried out on a number of stereoisomers that have previously been observed to have unbearable side effects on patients. For instance, racemic dopa was initially used for the treatment of Parkinson’s disease. “the use of this drug usually displayed side effects such as involuntary body movements, nausea, anorexia and granulocytopenia” (Crossley, 1996). After a chiral switch was done, L-dopa was administered to the Parkinson’s patients. The dose administered was halved. This is because initially, a dose consisted of 50% L-dopa and 50% of its other enantiomer. Only the L-dopa was required for the treatment of the disease. The other enantiomer was responsible for the side effects. During the chiral switch, all the L-dopa was separated from its enantiomer hence the need to administer half the initial dose. The L-dopa registered lesser side effects in all the patients. As a matter of fact, the granulocytopenia was not observed in any patient. There was even improvement noted in some of the patients (Crossley, 1996).
L-dopa (Crossley, 1996).
The above chiral switch clearly shows the advantage of administering L-dopa over the administration of its racemic mixture.
Another drug that has undergone the same kind of chiral switch is esomeprazole. This is a proton pump inhibitor. Esomeprazole consists of the s-enantiomer of the racemic mixture omeprazole. The clinical use of esomeprazole alone has recorded reduced inter-patient variability in regards to response. The s-enantiomer also maintains a PH of above 4 in gastro-oesophageal reflux patients. This was a better response from the patients as compared to when the racemic mixture was administered (Lind, 2000).
Esomeprazole (s-enantiomer) (Lind, 2000).
Cardio-toxicity is a well known problem when it comes to the administration of various anaesthesias. Levobupivacaine, a local anaesthetic had for years displayed cardio-toxicity as one of its major side effects. Research done on the drug showed that the cardio-toxicity was mainly associated with the R-enantiomer (Foster, 2000). Clinical trials using the S-enantiomer alone displayed lesser negative inotropic effect on the patient as compared to the use of the racemic mixture. It was also noted that the use of the S-enantiomer produced the same required clinical results as did the racemic mixture. Therefore, the S-enantiomer resulted in the same clinical results as well as significantly reduced the negative effects of cardio-toxicity (Foster, 2000).
(S)-Levobupivacain (Foster, 2000).
Cisatracurium is another great example of the advantage of using an enantiomerically pure compound. It is a neuromuscular blocker that is obtained from atracurium. Atracurium has four chiral centres and is symmetrical (Eichelbaum, 1994). This fact enables it to exist as a racemic mixture of ten stereoisomers. The single stereoisomer, cisatracurium is observed to be more powerful as compared to the racemic mixture. It also showed reduced histamine properties. After the chiral switch, a lower dose of the single enantiomer is required. Clinical trials showed significant reduction in the production of laudanosine which is a seizure causing metabolite (Eichelbaum, 1994).
Cisatracurium (Eichelbaum, 1994).
As the years progress, the number of new drugs developed each year decreases every year. This can be blamed on the rising cost of research that is required for the development of a new drug. This is a worrying trend as the patents of already developed drugs are due for expiration in the coming five years or so. The patents due for expiration are worth approximately $40 billion. If the trend of reduced developments goes on, the global pharmaceutical market is headed for major looses (Jones, 1993). The introduction of the chiral switch has come at the right time and will contribute in holding together the pharmaceutical market. Even though the cost of chiral switching is relatively high, it cannot be compared to the cost of development of a new product all together. The process of approval of the chiral switch by various bodies is also a tedious task but this is the only way that most pharmaceutical companies are going to maintain relevance in the market without production of new products. When an old product undergoes a chiral switch and is successfully screened, it could qualify for a patent extension. Most pharmaceutical companies are focussing their energies in that direction (Lane & Baker, 1994).
The introduction of chiral switching and the evidence showing its advantages has changed how pharmaceutical products are viewed in general. In the past, most drugs were administered as a racemic mixture. Today, the possibility of a better performing, enantiomerically pure compound is considered. It is true that a large percentage of all drugs that have undergone the chiral switch have emerged better performing with lesser negative side effects. This fact however, does not mean that all drugs should undergo the chiral switch (.Strong, 1997) Careful evaluation of the pharmacokinetics of the enantiomers should be done before the decision of chiral switching is reached. In some selected cases, the separation of enantiomers produced different effects on the patients other than the required of the drug. On top of the pharmacokinetics, the financial benefit of the switch should also be factored in. The separation of two enantiomers is not a cheap venture and it should only be done if the good being achieved has been verified (Strong, 1997).
We can therefore conclude that enantiomerically pure compounds are more suitable for use especially in the pharmaceutical field. Their production also gives the pharmaceutical companies a new financial lease of life.
Agranat, I. (1999). Intellectual property and chirality of drugs. Drug discovery today 4, 330-357.
Campbell D.B. (1990). Selectivity in clinical pharmacokinetics and drug development. Pharmacol Ther, 278-316.
Crossley, R. (1996). Chirality and the biological activity of drugs. Boca Raton, CRC Press, 120-175.
Eichelbaum, M. (1994). Stereochemical aspects of drug action and disposition. Advances in drug research, Vol. 22. London Academic Press, 321-330.
Foster, R.H. (2000). Levobupivacaine: A review of its pharmacology and use as a local anaesthetic. Drugs 59, 99-127.
Jones, J.B. (1993). Applications of biochemical systems in organic chemistry. Wiley inter-science: New York, 278-295.
Krstulovic, A.M. (1999). Chiral Separations by HPLC. Chirality in industry II. New York, Wiley, 457-468.
Lane R.M, Baker G.B. (1994). Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites. Chirality, 347-351.
Lind, T. (2000). Esomeprazole provides improved acid control in gastro-oesophageal reflux disease. Aliment pharmacol. Ther.14, 236-250.
Strong, M. (1997). FDA policy and regulation of stereoisomers: paradigm shift and the future of safer more effective drugs. Food Drug Law J. 54, 271-296.
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