An Overview Of The Nexium Drug Biology Essay

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Nexium is the brand name given by AstraZeneca for esomeprazole-a drug that acts as proton pump inhibitor.15 Proton pump inhibitors are the drugs that are used in the treatment of various gastro enteral related diseases. A proton pump is present in the stomach which triggers the secretion of acid. The over secretion of this acid can lead to many disorders like gastro esophageal reflux disease (GERD), peptic ulcer disease, Zollinger-Ellison's syndrome, heart burn and erosive esophagitis.3 To avoid these diseases that occur by the over secretion of this acid, proton pump inhibitors are used. Nexium is a potent proton pump inhibitor and has been manufactured since 200115. The active ingredient of the drug is esomeprazole which is the S isomer of omeprazole. Omeprazole is present as two different enantiomeric forms, S and R form. The S isomer is very active as a proton pump inhibitor (PPI) and is used extensively as an active ingredient of Nexium.2 Detailed study of Nexium is as below.

Description- Physical & Chemical

Nexium is chemically esomeprazole and the drug is usually present in a highly crystalline state. The drug is taken orally as delayed release capsules. They may be white to slightly yellow in colour. They are very sensitive to pHand rapidly decompose under acidic conditions and remain stable in an alkaline medium. These capsules have an enteric coating which provides protection under acidic conditions of the stomach. The active ingredient in the drug is chemically Bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1yl)magnesium trihydrate. Its empirical formula is (C17 H18 N3 O3 S)2 .Mg . x 3 H2O and the drug comprises a molecular weight of 767.2. Based on these physic-chemical properties, Nexium is most preferably used as delayed release capsules1. Other forms of Nexium include suspensions12 and also sachet formulations5 were prepared. But Nexium, only in the form of pills is extensively marketed and is more commonly referred to as "the purple pill"17

. Mg x 3H2O

Esomeprazole1

History & discovery

Need for treatment: The origination of Nexium did not take place immediately when a treatment for gastric acid secretion was needed. For many years scientists were worried about the treatment of gastric disorders using surgeries because treatment of those resulted in many adverse effects after treatment.2

Omeprazole discovery: To avoid these adverse effects, scientists started their research for drugs that can be administered for the treatment of excess acid secretion. In that process in the 1970s a drug called Cimetidine was discovered which could efficiently inhibit the over secretion of acid by acting as a potent H2 receptor antagonist. Also at the same time in 1960s AstraZeneca also started the search and by the year 1988 came up with a drug that was very potent in inhibition of acid secretion. This drug was named as Losec (in Europe and Prilosec in US in 1990) and Omeprazole, the active ingredient of the drug was a potent proton pump inhibitor with effects quite superior to that of H2 receptor antagonists.2

Nexium (esomeprazole) discovery: Many companies tried to develop a drug based on the Omeprazole structure which would be superior to Omeprazole in function but failed to do so. Astra was in continuous research for finding a drug which was better than Omeprazole and only in 1990 the drug Esomeprazole ( S isomer of Omeprazole) was discovered which is nothing but one of the isomer of the racemate mixture of Omeprazole. Esomeprazole had better bioavailability as well as an increased plasma concentration when compared and also showed better therapeutic effects because of that reason.2 It was launched as Nexium in the market in 2000. A comparison of the effect of Omeprazole as racemate and of its R and S isomers is given below:2

Figure 1: The comparison of plasma concentration of omeprazole and its isomers is given.2

Figure 2: The inhibitory effect of the three forms on gastric acid secretion.2

The first grapHshows by comparison the plasma concentrations of equal doses of R omeprazole, esomeprazole and omeprazole clearly showing that esomeprazole has highest plasma concentration (figure 1)2.

In the second graph, the inhibitory actions of the three drugs is shown by comparison (figure 2)2.

First hit obtained and improvisation: HÓ“ssle- a company within Astra in 1960s started the search for a potent acid inhibitory drug. In 1972 by taking the reference of a drug CMN 131 produced by company Servier, Astra produced another drug making structural modifications in CMN 131 and formed a new drug Benzimidazole H 124/26 in 1973 which showed good potency.

Unfortunately the drug had already been patented by another company and hence metabolization of the drug leading to formation of the metabolite H 83/ 69 which was the sulphoxide compound of drug with better potency was patented by Astra and was called Timoprazole. Timoprazole showed many adverse effects on the thyroid and thymus function and this lead to discovery of another compound which did not show such effects and was called Picoprazole. These substituted Benzimidazoles were indeed needed to be optimized to give lot better results. Research was being carried out and it was assumed that Timoprazole might have properties of proton pump inhibition in the parietal cells of stomach. Hence in view of optimizing the effects of Timoprazole and also to remove the adverse effects, 5 methoxy substitution on the pyridine moiety of Timoprazole was done, resulting in the formation of the most potent drug at that time- omeprazole. Omeprazole undergoes hepatic metabolism and due to the difference in metabolism in different persons, there occurred inter individual variability in the actions of omeprazole. Hence in 1984, Astra started its research to find another drug which has even better bioavailability in people to avoid problems. Lot of research was carried out and this lead to the formation of 4 final compounds which under pre- clinical tests were better than omeprazole. When all aspects of the compounds were tested properly, only one compound was shown to be having better effects and that was esomeprazole which was one of the mirror images of the racemate omeprazole and this has been marketed since 2001.2

Pharmacology

Mechanism of action:

The mechanism of action of most PPIs is similar. The stomach is a muscular organ in the body which can change its shape according to the food present inside. The stomach is lined by a wide number of cells, which of three types- parietal cells, chief cells and mucus secreting cells. These cells are present on the gastric glands lining the stomach. The parietal cells in the gastric glands are mainly responsible for the secretion of acid ( proton) from the H+/K+ adenosine triphosphate, an enzyme which is nothing but the acid pump or otherwise called as the proton pump. The secretion of H+ from this pump in the stomach can bring about a decrease in the pH(increased acidity) to less than 1. The proton pump inhibitors can be present as two states, the active and dormant state. Proton pump inhibitors act on the active sites of the proton pump and attach to

the sulfhydryl group of the enzyme, inactivating it and hence inhibits the secretion of proton and thus, acidity is decreased27. In this way, the diseases that may occur due to the over secretion of acid in the stomach can be treated and avoided.3

The action of PPIs which are continuous-release dosage forms occurs such that the release of the drug from the dosage form into the gastric layer is of two types, the first release and the second release. The first released portion of the drug acts directly on the gastric mucosa and the second released portion is mainly targeted to keep the plasma concentration levels of the drug. The normal plasma concentration of the drug after exceeding 100 ng/ml produces a therapeutic response. A good therapeutical efficiency of the drug is found when the plasma concentration of the drug crosses 250 ng/ml. ideally, a high therapeutic efficiency of the drug is found when the plasma concentration reaches to 600 ng/ml. at this concentration, the drug shows very good therapeutic efficiency3.

Another type of dosage forms are the fast release dosage forms. For drugs that are needed to act fast, the enteric coating protecting the drug is removed. In this case an immediate effect of the drug is noticed. Also sustained treatment of the drug occurs. Usually the peak plasma concentration as in the case of continuous release dosage forms are achieved in 1-3 hs but in the fast release forms, the plasma concentration in reached within 30 to 90 minutes and the effect is sustained for a period of 5 hs. Thus, a suppression of acidity in the stomach occurs for a long period of time and hence efficacy of drug is produced. It is believed that with non-enteric coated dosage forms an increased bioavailability of the drug is possible because of high concentration at the local site of attachment as well as due to the sustained release of the drug for long period. However, continuous release formulations are more preferred.3

However, the mechanism of action of PPIs in no matter what dosage form or the dose is basically the same, wherein the drug attaches to the adenosine triphosphate enzyme and brings about the deactivation by attacking the sulfhydryl group of the moiety and hence inhibits the proton release thereby suppressing the acidity in stomach4. The exact site of action of PPIs by which it shows inhibitory effect is illustrated in figure 1 below2:

Figure 3: The exact site of action of PPIs ie; on proton pump.2

Pharmacokinetics:

Nexium is used for treatment of gastro enteral diseases and the pharmacokinetics of the drug seem to show certain variations in different age groups of people suffering from gastro enteral disease24. The AUC values, Cmax , Tmax , T1/2 and bioavailabiliy show differences in different conditions of dosage, dosage forms, age groups, special populations etc. the ADME of the drug also varies for different age groups1. The Tmax ranges from 1.2 h to 3.5 h in people from Sweden and America24. A comparative study of the pharmacokinetics of the drug in different dosage forms and conditions has been studied. The absorption, distribution, metabolism and excretion form the major part in describing the pharmacokinetics of the drug which is illustrated as below:

A summary of the ADME of Nexium tablets is given below1:

ABSORPTION

DISTRIBUTION

METABOLISM

EXCRETION

Drug is taken orally.

Tmaxreaches in 1.6 h (approx.).

Bioavailability when taken once (40 mg) is 64% and when taken regularly is 90%.

AUC is increased with dose and during fasting.

Apparent volume of distribution:16 L

97% plasma binding and constant for 2-20 μ mol / L

Takes place in the liver with CYP 450 enzyme.

Isoenzymes responsible mainly are CYP2C19 and CYP3A4

Former forms hydroxyl and desmethyl metabolites and latter forms sulphone metabolites.

CYP2C19 has major activity and people lacking it are called poor metabolizers (Asians and Caucasians)

Excretion is maximum through urine (80%) and remaining through faeces as metabolites.

Drug excretion unchanged is 1% or less than 1%

Pharmacokinetics of esomeprazole sachet formulations:

Importance & working: This type of formulation was mainly done for people who have difficulty in swallowing. This formulation contains granules of the drug which are reconstituted after suspending in either water or other juice and can then be administered orally. This formulation is compared with other forms based on pharmacokinetics and the explanation is given by Nina Bladh, Eva Johnson in that respect. The sachet formulation was equivalent almost to the capsule and the tablet formulations5.

Stability assessment: The drug was suspended in the liquid and was left to suspend for 30 minutes. The assessment was then done for different strengths and at different temperatures. Also chemical stability was recorded for different vehicles for suspension like apple sauce, orange juice, apple juice etc. the suspension was then assessed for the presence of degraded materials and was recorded using gradient reverse phase liquid chromatography with detection at 302 nm. Also assessment of the reconstitution was done and for this the time taken for reconstitution was known when the drug particles get completely dispersed in the vehicle without suspending at the bottom of the vessel. This was visually observed for 30 second and the process repeated every minute. The esomeprazole released was determined later by liquid chromatography. The time for reconstitution was 9 to 10 minutes.5

The absorption of the drug was from the oral route and more than 92% of the drug was delivered efficiently. The pharmacokinetic parameters like AUC, Tmax and Cmax were compared with the tablets and capsules and the average values for T1/2 and Tmax were found as 1.1 and 2 h respectively. On comparison of the tablet and capsule with sachet the graph obtained is below (figure 4):5

Figure 4: The comparison of tablet, capsule and packet formulation of esomeprazole for plasma concentration.5

Pharmacokinetic considerations in special cases:

In children (ages 1 to 11): For younger children, test for a lower dose of 10 mg and older children a dose of 20 mg was given. The pharmacokinetic properties were such that the peak plasma concentration Cmax for older children (20 mg dose) was found to be double of that found in 10 mg ie; 3.73 and 1.77 μmol/L respectively and the values of Tmax and T1/2 were found to be almost the same with values given as 0.73 h and 1.75 h (10 mg) and 0.88 h and 1.79 h (20 mg) as studied by J. Zhao 6

The AUC and C max values, when compared with adults is found to be lesser by 25% and 18% respectively. However, there is no need for a dose adjustment1. The use in children has been approved by the FDA.20

In adolescents (ages 12 to 17): The pharmacokinetic parameter AUC showed a value for single doses as well as for repeated doses for 8 days. Two doses of 20 mg and 40 mg were checked and the value of AUC for single administration of drug and repeated administration of both doses were found to be 1.58 and 5.57 μmol .h/L (single) and 3.65 and 13.86 μmol. h/L (repeated). Similarly, the value of Cmax for single and repeated administration and for both doses was found to be 0.67 and 2.78μmol/L (single) and 1.45 and 5.13μmol/L (multiple). The T max value did not change with dose (2h) but there was a 1.5 times increase in the dose for repeated dose administration.7 The properties were found to be more or less similar to as in adults with GERD1.

Male/female (sex): The peak plasma concentrations and AUC are higher in females when compared to males. But the difference is very low and thus, not dose changes for gender are required1.

For Liver problems: It was noticed that in people having low or moderate liver dysfunction, not many changes in the pharmacokinetics when compared with adults are found. But in the case of severe liver problems, there was found 2 to 3 times increase in the value of AUC. For this reason, to adjust doses in the case of severe hepatic insufficiency the dose should not exceed 20 mg per day1.

In Kidney failure: It is true that only 1 or less than 1 % of the drug is removed as waste through urine. Hence, there will not be much of a difference with any renal insufficiency in the pharmacokinetics of such when compared to normal individuals and thus, no dose adjustment is necessary1.

In fasting conditions: The bioavailability shows increased values when esomeprazole is taken under fasting conditions than when taken 15 minutes before a meal25.

Pharmacokinetics during combination therapy: Combination of the drug with other anti-microbials like Clarithromycin and Amoxocyllin causes an increase in the AUC and Cmax values by 70% and 18% respectively, when compared with when the drug is taken alone1.

Pharmacodynamics:

There are various effects of the drug when it is administered in the body. The main action of the drug is its anti-secretory activity. It acts by decreasing the acidity in the stomach. It was tested in many individuals for its action by 20 mg and 40 mg doses and was seen that the pH value was increased to more than 4 for many hours and the mean value in 24 h period was found as 4.1 and 4.9 respectively. It is seen that the drug under continuous therapy results in the ECL cell hyperplasia and this was found to increase under study with the increase in the doses. The drug also has its effects on the serum gastrin levels. The effect is related to the dose which keeps increasing when therapy is taken for 3 months and returns back to normal after 4 weeks of discontinuation of the therapy. When 20 mg and 40 mg doses of Nexium are given orally for 4 weeks, endocrine effects on the thyroid function are seen. The drug when taken with anti-microbials like clarithromycin and Amoxicillin are shown to produce eradication of H. Pylori infections.1

Clinical effects of nexium

Nexium is used effectively in the treatment of GERD8,9, erosive esophagitis10, reflux esophagitis23 , severe heart burn11, reducing the risk of NSAID related ulcers1 and in eradication of H. pylori infection when used in combination with other anti-microbial drugs1. Zollinger-Ellison syndrome, treatment of active duodenal ulcers,(esomeprazole enteric capsule as well as esomeprazole magnesium),22 peptic ulcer diseases also are treated by using nexium4.

It has been studied that for treatment of GERD by Nexium, an increase in the intragastric pH to greater than 4 has been seen for a higher percentage of time when compared with other PPIs available26.

Esomeprazole is found to be very effective in the treatment of erosive esophagitis when compared to Lansoprazole. Nexium (40mg) is found to give beneficial results within 4 to 8 weeks of administration by declining or maintaining the effect of erosive esophagitis. Maintenance of remission is also found very effective with the use of 20 mg of Nexium once daily than with Lansoprazole 15 mg drug. Also, esomeprazole is found be a very cost effective drug and has benefits in that respect too. Also maintenance of healing erosive esophagitis for long term is seen. Healing of erosive esophagitis requires a 4 to 8 week treatment and disease is persistent, another 4 week treatment can be considered. Maintenance of healing of erosive esophagitis is persistent for about 6 months with nexium10.

In severe heart burn, Esomeprazole is found to be very effective in treatment. This on comparison with other PPIs is found to give a lot better relief from heart burn in patients suffering and is also found that the patient compliance is high for the use of esomeprazole for patients suffering from heart burn11. Heart burn and erosive esophagitis are symptoms that occur due to GERD and by the use of Nexium in treating GERD the incidence of erosive esophagitis and heart burn too is reduced and thus, later problems like adenocarcinoma is not prevalent?.

In reducing the risk of duodenal ulcers in patients treated with NSAIDs, esomeprazole is highly efficient. Nexium 20 mg or 40 mg is used in patients who are under long term treatment with NSAID and it is found that the occurrence of any ulcer is reduced in such a case. Patients aged more than 60 are at the risk of developing these ulcers and Nexium is used for prevention1.

Nexium is also useful in the eradication of H. pylori infection. It is used in combination with anti-microbial drugs and thus useful in the eradication of that infection. Clarithromycin and amoxicillin are the drugs used in combination therapy. The eradication of this infection reduces the risk of forming ulcers and its recurrence1.

Ill effects

Any drug that is useful in the treatment of a particular disorder is known to show a minimum number of side effects in the body. Side effects of the drug are the effects other than the desired effects. The effects other than the anti-secretory effects that occur due to Nexium are due to many reasons, one being the increase in the gastric pH. As a result of sudden increase in the pH there are many effects on the solubility as well as on the ionization of substances and hence, changes in absorption. The normal absorption of calcium is disturbed and thus chances of hip fracture increased. Changes in protein hydrolysis is found due to increased ph. A condition called Hypergastrinemia is caused due to hyper secretion of gastrin stimulated by high pH. Another consequence in the bacterial growth formation that occurs mainly due to optimizing the pH for growth of the micro organisms. This may result in many infections in the upper gastro intestinal tract and can also lead to cancer.4

Another set of side effects that occur are due to the direct action on the proton pump inhibition. These side effects are due to action on other cells in the lumen which are non gastric. There may be alteration in the renal cell volume, serious changes in the gene expression. It has been studied to produce apoptosis in some.

Some other general side effects are, effects on the contractility of certain arteries such that relaxation is induced. Mobilization of certain cells like the neutrophils and leucocytes is affected. Inhibiting some useful enzymes is another undesired effect. Interstitial nephritis, hyponatremia ,seizures (due to calcium deficiency). A surprising discovery made by James M. Mullin et.al. was the increase in the incidence of trans epithelial permeability by around 300% in people using esomeprazole for treating GERD.4

However, a classification for the types of side effects of nexium can be given as:

Common ill effects: head ache, nausea, vomitings, abdominal pain, dryness in the mouth, flatulence, constipation.12

Rare ill effects: chest and back pain, edema in face and certain body parts, fatigue, hypertension, tachycardia, goiter, dyspepsia, dysphagia, esophageal disease, anemia, leucopenia, thrombocytopenia, hepatic dysfunction, hyperuricemia, hyponatremia, arthritis, anorexia, hernia, depression, increased appetite, insomnia, acne, dermatitis, skin rash, urticaria, otitis media, cystitis, poly urea.12

It has been studied that esomeprazole has a negative impact on the lives of children upon treatment for GERD. A negative effect on their emotional state, activity and food and drinks was observed.21

Manufacturing of nexium

A number of forms of Nexium(amorphous, crystalline etc) are available. For this reason it is always necessary to search for the most suitable manufacturing processes in preparing the compound so that it is cost effective as well as its characteristics remain potent. Preparing the crystalline form of esomeprazole magnesium tri hydrate is the best option. This is because all the crystalline solids have unique X ray diffraction values and hence on forming, the compound can be easily identified and characterized.13

The best method researched for the production of esomeprazole magnesium is the use of the racemate mixture of omeprazole( contains S and R forms). Omeprazole is made to resolve by reacting with a resolution agent like S-(-)-binol. The binol and a weak base are made to dissolve in omeprazole using a water compatible organic solvent and water as a mixture for dissolution. Temperature conditions of 30° to 70° are maintained. This results in the formation of an inclusion complex of esomeprazole and binol as shown below. When the temperature is brought down to -5°, crystallization of the complex occurs. Removal of the binol moiety is then taken place by filtration or extraction processes. 0.5 to 0.7 mole equivalents of binol can be used in this process. Usage of weak base like methylamine, ammonium hydroxide, ethylamine, dimethylamine, triethylamine, trimethylamine and mixtures in mole equivalents of 0.1 to 0.5 based on omeprazole is done to prevent blackening of the inclusion complex and hence no need of decolorizing agent as a further step in the process is required. Water compatible organic solvents used are methanol, ethanol, propanol, butanol or acetone since these have no toxic effects. The mixture of the water compatible organic solvents and the water is taken in an approximate ratio of 98:2 to 40:60. More water can be added if necessary. The inclusion complex crystals after crystallization can be obtained either from conventional filtration or drying methods. The whitish or whitish yellow crystals obtained show high optical purity of about 95% and purification may be further increased by the use of recrystallization process. The next important step involves the removal of the S-(-)-binol moiety and for this reason, either filtration to obtain highly pure esomeprazole or extraction process for the formation the corresponding salt of esomeprazole is carried out. This step can be performed efficiently at room temperature. Different procedures for extraction can be carried out. In one procedure, the inclusion complex is suspended in water and a base like sodium or potassium hydroxide is added in 1 to 1.2 mole equivalents. By filtration the binol moiety can be successfully isolated and for removal of esomeprazole crystals from the filtrate by acidification using acetic acid and then extraction with an organic solvent. After this if sodium or potassium hydroxide is added to the concentrated extract, sodium or potassium salt of esomeprazole is obtained and for obtaining crystals of magnesium salt of esomeprazole, aqueous magnesium chloride is added to the filtrate containing sodium or potassium salts of esomeprazole. Thus the formation of esomeprazole magnesium of high optical purity is done.

The S-(-)-binol moiety formed also can be used again in the same process and hence there will not be much wastage of material which is highly advantageous for industrial synthesis.14

Another process involves the suspension of the inclusion complex in an alchohol like methanol or ethanol, strontium hydroxide is the base used resulting in the formation of strontium salt of esomeprazole which is then filtered and the same process as above is followed. 0.5 to 0.6 mole equivalents of esomeprazole is required in this step. Organic solvents used for the extraction process are either ethyl acetate, methyl acetate, chloroform or a mixture of these solvents. Some of the reasons why this method is very useful for industrial scale up are14:

This process results in the production of a highly pure esomeprazole with good yield.

The solvents, reagents and other chemicals used are non toxic and hence cannot be hazardous even when used in large scale process.

The S-(-)-binol moiety after isolation can be reused after purification through recrystallization.

There is no chance of any coloration and hence a further step for decolorizing is not required.

The need for the formation of inclusion complex does not require very high amounts of the binol moiety and is hence cost effective.

Based on the above advantages, the process described is found to be most efficient for the industrial scale up in preparing esomeprazole.

As per the patent created by Toplak Casar15 a productive method for the preparation of esomeprazole in a highly stable form is described. Esomeprazole magnesium obtained is added to a non solvent. The non solvent is a solvent in which esomeprazole magnesium cannot be dissolved. The non solvent selected has to be wetted with the use of an aqueous component which may be either water alone or a mixture of water and water soluble organic solvents like alcohols, ketones or dipolar aprotic solvents like DMF or DMSO. It is believed that the stability of a drug is usually affected because of the presence of some residual solvents, hence this process mainly aims at stabilizing by reducing the amount of left over solvents and also this process has shown to bring about certain rearrangements in the structure of the drug when it comes in contact with the wetted non solvent which brings about an increase in the stability15.

Asymmetric oxidation is another efficient method for scale up of nexium. A 100% yield can be obtained after crystallization from two steps. The reaction is as follows:2

Step 1 - asymmetric oxidation (Ti- mediated) to form esomeprazole.

Step 2- reaction with magnesium carbonate to form 100% esomeprazole magnesium.

Marketting of Nexium

The introduction of Nexium in the market took place in 2001 and AstraZeneca is the company responsible for its manufacture and marketing.15 To overcome the diseases related to the gastric system, AstraZeneca came up with the use of PPIs. One of the PPIs which have potent properties discovered by AstraZeneca was omeprazole2. Omeprazole is an active ingredient of the drug Prilosec which was a high marketed drug and brought about good turn over in the company. The patent of Prilosec was going to expire in 2001. AstraZeneca was very worried about the near expiry of patent for Prilosec as this would bring about the manufacture of the compound by other generic companies and sale of the drug at a very low price which would cause a major loss to AstraZeneca. In order to cover the losses that would occur due to expiry of the patent and also competition of other generic companies, the company had created a drug which is only slightly modified from Prilosec so that the drug could be marketed for the same reason, to use as a PPI. Thus, the S isomer of omeprazole was discovered to have better pharmacokinetic properties than omeprazole itself, the magnesium salt of esomeprazole was then checked to have potent properties. Nexium had then been created and then

emerged in the market to become a very extensively used OTC drug and brought about a huge turn over in the company and is still doing so16,28.

AstraZeneca took quite a daring step in the marketing of Nexium. The cost of marketing was then about $500 million, this meant that failure of the drug could bring the company down. The ad commercial of nexium as described by Charles W. Schmidt is "steeped in mystery and intrigue"17.the promotional image is given as figure 5 below28. This had attracted the attention of viewers successfully and publicity of Nexium as "the purple pill" was successfully carried out.(figure 6)28

Figure 5: The image of a running man used for promotion of drug Nexium in the market28.

Figure 6: Nexium marketed as the "purple pill"28

The appearance of a drug to be marketed plays a very important role as emphasized by Charles w. Schmidt. He has emphasized that in this very competitive market, colour of the drug plays a very important role. Purple in AstraZeneca's view is "attractive yet dignified"17. This caught the attention of a large number of people and Nexium is now a highly successfully marketed product in the pharmaceutical industry17.

The profit caused by Nexium has largely exceeded that caused from Prilosec which is also manufactured from the same company. According to chief science and health correspondent, Robert Bazell19 the cost of Prilosec is $30 per month while that of Nexium has come to $200 which has sales six times better than Prilosec although it works with the same function. Robert Bazell also says that according to the industry more than 7 million Americans administer Nexium for their problems. It is all because of the clever marketing strategy that Nexium has become so successful in the pharmaceutical market. A large amount of money was invested on the drug according to "medical marketing and media"18, $16 million for a month and according to various sources the cost of marketing the drug is about $500 million to $1 billion per year and this investment had paid off very well since Nexium has been getting good sales in the market with profits of around $3.5 billion18 per year at present and is the second largest with that respect in the market.19

Conclusion:

The success of Nexium is thus mainly contributed by various factors. The increased potency of the drug when compared to the parent compound. The increased therapeutic efficiency, increase in the bioavailability and other pharmacokinetics. Sutable process for the manufacture and synthesis, suitability for administration in all groups ,and last but not the least, good appearance of the drug- which has attracted a large population and made AstraZeneca very highly profited in the market.

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