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Forty years ago, disorders associated with gastric acid were a major problem and the options available for treatment were very limited. Gastric acid is a key factor for the digestion and absorption of nutrients. However inappropriate levels of this will lead to diseases. The treatment options available were very limited, one could opt for surgery or take antacids which neutralized the acid, the latter being just a temporary relief. This could have been life threatening had not the treatment discovered.
Astra, a Swedish company was the first to envisage in finding a drug to inhibit acid secretion. After a lot of hiccups, Astra was able to find the breakthrough and in April, 1979 filed the patent of the new drug compound- omeprazole. (Junggren; Ulf K. (Molnlycke 1979). The drug was made but then the administration form was a problem. Omeprazole is a acid labile drug and it took almost five years to settle the formulation form. Finally omeprazole was launched as Losec in Europe and as Prilosec in USA. Prilosec was launched in US in 1989 by signing co-marketing deal with Merck and Co.
Prilosec became one of the largest selling drugs of the world. The sales of Prilosec/losec of nine months for the year 1999 was about $4.4billion.(zeneca 1999).Executives at Astra was aware that marketing exclusivity of Prilosec would come to an end one day. They got two year patent extension under Hatch-Waxman Act, another six month extension was obtained for conducting clinical trials on children. Astra launched the follow-up drug- Nexium in Feb, 2001.(Gladwell 2004). Finally Astra Zeneca launched the Prilosec OTC in association with P & G in June, 2003. (CNN Money 2002)
Programme for inhibiting acid secretions in stomach by Astra
Patent filing of Omeprazole
Patent filing for formulation of Omeprazole
Launch of Prilosec in US
Launch of follow-up drug. Nexium
Patent expiry of omeprazole
Launch of Prilosec OTC
SYNTHESIS AND ENGINEERING
Omeprazole is a sulfoxide and a chiral compound with S-atom being the steriogenic centre. Omeprazole is a racemic mixture of its two single enantiomers- s and r. The synthesis of omeprazole involves mainly three steps:
Formation of Pyridine derivative
Formation of thioether which is by the reaction of 2-chloromethyl pyridine derivative and mercaptobenzimidazolic compound.
Oxidation of the corresponding thioether.
There are a large number of synthetic routes for the manufacture of omeprazole of which some routes are explained below.
Depending on the starting material there are three essential routes for the preparation of pyridine derivative.(CORREIA, ROMÃO et al. 2003)
The first route involves 2, 3, 5- colidine as the starting material. This is then converted to its corresponding nitrous oxide followed by nitration and posterior methoxylation of the 4-position. The product is then acetylated followed by hydrolysis to give the corresponding alcohol and then finally the chlorination to give the desired pyridine derivative. (US patent No 4544750)
The second route has 3, 5- lutidine as the starting material. This is converted to the corresponding nitrous oxide followed by nitration and methoxylation of the 4-position. This is followed by methylation of the nitrous oxide and the introduction of hydroxymethyl radical which gives us the alcohol derivative. This on chlorination gives 2- chloromethyl- 3, 5- dimethyl-4- methoxypyridine.(US patent No 4544750)
In the above two routes there is a chance of decomposition of compounds during the oxidation of the thio-ether in acid conditions.
In the third route the pyridine-N- oxide is prepared with hydrogen peroxide or tert-butyl hydro peroxide as oxidizing agents and an organotrioxorhenium compound as catalyst. This reaction takes less time, gives good yield and N-oxides are obtained at room temperature. The N-oxides are nitrated at 4-position using HNO3 acid fuming and acetic anhydride. This is then chlorinated with a system of POCl3/Et3N which allowed the chlorination of the methyl group and deoxygenation of N-oxide in one step. (International pub no WO 91/18895)
The pyridine derivative obtained is then treated with mercaptobenzimidazolic compound to yield the thioether. The reaction can be speeded by giving ultrasonic radiation. The reaction will be over in 5 minutes and we get the required product.
Final step is the oxidation of the thioether. A wide variety of oxidizing agents can be used and the product quality will vary accordingly. The oxidizing agents that are commonly used are meta chloro peroxy benzoic acid in diethyl chloride at a pH of 8.6 (international pub no WO 91/18895), peroxides like cumene hydro peroxide, tert- butyl hydro peroxide and hydrogen peroxide catalyzed by a rhenium or vanadium compound.(CORREIA, ROMÃO et al. 2003). The use of a titanium complex along with the oxidizing agent helps in the easy separation of omeprazole. (International pub no: wo 99/25711).
A typical synthetic route for the preparation of omeprazole is explained below. (International pub no WO 91/18895)
Oxidation of the pyridines.
A solution of 2, 3, 5- colidine is prepared in DCM. To this 30% hydrogen peroxide is added and stirred for 3 hours after which aq.NaHSO3 is added. The 2 phases are separated and the aq. phase is extracted with DCM. The organic phase is dried with anhydrous Na2SO4 and the solvent is evaporated to give the solid with a yield of 91%.
Nitration of pyridine-N-oxide
A suspension of clay cop in acetic anhydride is stirred at room temperature to get a blue colour. To this a solution of 2, 3, 5- trimethyl N oxide in HNO3 fuming is added. After 2 hours , the mixture is filtered and residue washed with DCM. The organic phase is dried with anhydrous Na2SO4 and the solvent is evaporated to give product with a yield of 85%.
Chlorination of 2-methyl pyridine
1/10 of POCl3 is added to stirred solution of pyridine-N oxide under nitrogen atmosphere. After 1/10 of POCl3 was added simultaneously Et3N in DCM is also added. Both the solutions are added simultaneously and after 15 min of stirring the solution is neutralized with NaHSO3 and extracted with DCM. The organic phases are dried with Na2SO4 and after evaporation 2-chloromethyl-3, 5- dimethyl-4- nitro pyridine is obtained with a yield of 91%.
Reaction for thioether formation
Solution of 5-methoxy-2- mercaptobenzimadazole and NaOH is stirred at room temperature for 10 min. To this the product from the above step is added and ultra sonic radiation is administered for 15 minutes. Reaction mixture is filtered and dried with Na2SO4 and this process is repeated. The thioether is recrystallised in methanol with a yield of 93%.
Oxidation of Thioether
To the solution of thioether, oxone was added at a temperature of 0OC. The reaction mixture is stirred at the temperature of 0 - 5 OC for 2 hours. The 2 phases are separated and the organic phase is dried with Na2SO4 and evaporated. The sulfoxide is precipitated with acetonitrile.
Substitution of Nitro group by methoxide group.
Solution of sulfoxide and catalyst hexadecyltributylphosphonium bromide is added to the solution of sodium methoxide in methanol. The mixture is stirred for 4 hours at reflux temperature and the mixture is evaporated. The solid is washed with DCM, treated with norit and evaporated. The oil obtained is crystallized in acetonitrile giving a yield of 60%.
The manufacture of an active pharmaceutical ingredient like omeprazole involves some amount of chemical reactions. The manufacturing involves many chemical processes and each process has a variety of unit operations involved. The unit operations involved are common for above processes and involve common techniques. Most of the bulk manufacturing of pharmaceutical drugs is done by batch processes.
The main equipment in a batch process is a stirred tank reactor. The reactor can be of any alloy metal like stainless steel or the reactors can be glass lined. Glass lined reactors are not used in those industries where hydrofluoric acid is used as a reagent. In the case of omeprazole, glass lined reactors can be used. The agitator in the reactor will ensure proper mixing of reagents. Based on the energy balance of the particular reaction, jacketed reactors are used which can be used for heating as well as for cooling.(Sambamurthy.K 1998)
The main unit operations that we come across are evaporation, drying, filtration, centrifugation and distillation. Depending upon the type of operation the equipments have to be selected accordingly. Evaporation can be done under reduced pressure or in atmospheric pressure. Similarly filtration can be done using activated charcoal or even by filter paper.
FORMULATION OF OMEPRAZOLE
The launch of omeprazole was delayed by almost 5 years as a formulation suitable for the drug couldn't be engineered. Astra finally settled the problem in 1987 and filed patent. Omeprazole being an acid labile drug has to be protected if it is to reach its active site. The formulation by Astra was a three layered pellet form. The innermost layer was the drug substance with an alkaline stabilizer. The outermost layer comprised of an enteric coating which is mainly an acidic polymer. The middle layer was an inert sub coating which is soluble or rapidly disintegrating in water and it mainly comprised of materials from tablet excepients and polymeric film forming compounds. The technique of three layers was introduced for the reason that acidic residue of enteric coating started degrading with time. (US Pat No 4786505).
Another novel method reduced the three layer to two layer, thereby removing the need for 2 separate functional coating operations and thus decreasing the manufacturing process time as well as the cost. In this, the formulation had a core of inert component usually starch or sugar sphere. The core forming inert component was coated with a formulation comprising of omeprazole, surface acting agent, filler, an alkaline material and a binder. The enteric coating agent comprised of acid resisting material, inert process aid and the solvent. The dried cores are coated with enteric coating agent to give us the final product. Colour imparting agents may also be adde to the enteric coating agent.(Chen, Chou et al. 1999).
Omeprazole belongs to the proton-pump inhibitor (PPI) group of drugs. The PPIs are substituted benzimidazoles that are acid labile which are protected from breaking down in the stomach. They are absorbed in the proximal small intestine and circulate in the blood stream. Finally they are taken up across the basolateral gastric cells which are the active sites of the drug.(Thomson 2000). Basically they are inhibiting the H+ / K+ ATPase enzyme. This enzyme is unique in its site and location. It is located in the secretory canaliculi of the parietal cells and it secretes hydrogen ions in exchange for potassium ions.(Holt and Howden 1991).
The approximate pka value of omeprazole is 4. It is metabolized to a cyclic sulfonamide which attacks the sulfhydryl groups of the enzymes in the canalicular membrane of the gastric cells. Thus they block the production of H+ ions as hydrochloric acid in the stomach. Since PPIs are weakly basic drugs that are unprotonated, they remain uncharged at the neutral pH of the blood. In the acidic environment that is the activated parietal cell, the drug becomes protonated. A sulfeninic acid is produced by the proton transfer from the pyridine nitrogen to the benzimidazoles nitrogen which is a nucleophilic attack. This reaction takes place on the acid face of the enzyme. The acid resulted is in equilibrium with the sulfenamide on the acidic surface of the proton pump. "The reaction pathway of acidic sulfenamide is a permanent cation and a sulfhydryl reagent." (Thomson 2000)
Inhibition of H+ / K+ ATPase enzyme by omeprazole blocks the final pathway for the acid secretion. The rate of inhibition of the acid secretion depends on the rate of acid catalyzed conversion of the drug to the active form. The rate of conversion depends on the pH to a great extent. The chemical activation half life of the drug at pH 1.2 and pH 5.1 were 2.8 minutes and 84 minutes respectively. The acid secretion is blocked until new enzymes are synthesized which might take close to 96 hours.(Holt and Howden 1991; Thomson 2000).
Omeprazole when administered orally is enteric coated as it is unstable in conditions of low pH. There is an indirect correlation between the efficacy of the drug and the plasma concentration. The increase in concentration of the drug in the parietal cell will increase the anti secretory effect and with time it will attain a steady state. Pharmacokinetic characteristics such as bioavailability, speed and extent of action, linearity of pharmacokinetics, protein binding all will have a significant role. The bioavailability of omeprazole is about 37% and the pharmacokinetics is non-linear.(Thomson 2000). The absorption of omeprazole commences in the duodenum, Cmax is achieved by 2hours and it has plasma half life of about 1 hour.(Holt and Howden 1991).
Omeprazole is usually administered in 20mg to 80mg doses and it is given in repeated doses. Omeprazole's pharmacological effect is prolonged so a once daily dosing pattern is preferred and employed. The degree of absorption is faster in the first few days and this may be due to the fact that when more omeprazole is taken less amount of acid will be present in the stomach and therefore less degradation and more absorption. Food intake may slow the rate of absorption but the amount of drug absorbed will be the same.(Holt and Howden 1991). Clinical studies were conducted to emphasize the effectiveness of repeated dosing. There was significant increase in AUC, t1/2 did not change significantly but there was definite increase in the absorption rate constant. By repeated dosing more than the increased availability the enhanced absorption rate was vital.(Howden, Meredith et al. 1984).
30 to 40
Time to peak plasma concentration (hours)
0.5 to 3.5
Plasma elimination half-life (hours)
0.5 to 1.0
Protein binding (%)
Urinary excretion of oral dose (%)
Omeprazole exists as a racemic mixture, of which the s-enantiomer is the one which helps in the inhibition of the gastric acid. The importance of s-enantiomer led to the launch of Nexium- esomeprazole by AstraZeneca which was the follow up drug to Prilosec. The pharmacokinetics of the two optical isomers was studied on a group of people including both single and multiple doses. The Cmax of s-omeprazole was 80% higher when compared to r-omeprazole and the value kept on increasing and reached as high as 150% after repeated dosing. This was the case with AUC and t1/2 also. AUC was five fold greater for s-omeprazole and the t1/2 was 44% longer than r-omeprazole. The slower metabolite rate of s-omeprazole could be the reason for its higher AUC and this was noted from the plasma concentration of the metabolites.(Hassan-Alin, Andersson et al. 2005).
Omeprazole undergoes hepatic first pass metabolism.(Holt and Howden 1991). Study was conducted on rats to find the bioavailability of different routes. The plasma concentrations of the rats were studied after each roué administration. The routes selected were oral, hepatoportal, intraperitoneal, intrarectal and intravenous. The bioavailability calculated was maximum for hepatoportal (88.5%) and minimum for intrarectal (38.5%) with oral administration coming around 40%. (Choi, Lee et al. 1995). However oral administration is preferred due to its ease of manufacture and patient comfort. Those having problem in the intake of hard capsules can sprinkle the granules on a tablespoon of applesauce, yoghurt, or cheese and swallowed immediately without stirring.(BRUCE T. VANDERHOFF and RUNDSARAH M. TAHBOUB 2002).
Omeprazole undergoes hepatic first pass metabolism and the metabolites include 5-hydroxy and sulphone metabolites. 5-hydroxy metabolism is mediated by CYP2C19 and the sulphone metabolism by CYP3A4.(Hassan-Alin, Andersson et al. 2005). The metabolism of the drug depends on the person being a PM or an EM. In case of EMs 80% of the drug is metabolized by the CYP2C19 and in case of PMs, majority is done by the other.CYP3A4 belongs to the CYP3 family and this family is involved in the metabolism of the largest number of medications and most important in drug interactions. CYP3A4 is the isoenzyme most abundantly present in the human body and is involved in the metabolism of 60% of the drugs.(Burton, shaw et al. 2006). CYP2C19 is a polymorphically expressed cytochrome P450 and it is the third member of the human CYP2C subfamily. This enzyme is also very important for the metabolism of a wide variety of therapeutic drugs. In addition it is having inter-individual differences which make it more important to study the role of CYP2C19 in metabolism of drugs before it causes adverse reactions to certain section of the population.(loannides 2008). The pharmacokinetics and pharmacodynamics of omeprazole significantly depend on CYP2C19 genotype status.(Uno, Niioka et al. 2007).
Genotypic and phenotypic studies have to be conducted before administering drugs. In case of omeprazole study was conducted among Thai population and whwn plasma concentration of metabolites and drug was compared to the genotype and phenotype, the number of PMs and allele frequency of defective alleles was significantly lower than the oriental population.(Tassaneeyakul, Tawalee et al. 2002). Similarly a study was conducted among the Japanese population and the frequency PMs is found to be greater than Europeans and Americans.(Uno, Niioka et al. 2007).
TOXICOLOGY AND METABOLISM
Omeprazole is 95% protein bound mainly to albumin and alpha glycoprotein. It undergoes hepato first pass metabolism. It has mainly three metabolites- a sulfide, a sulphone and 2- hydroxy omeprazole. Most of the metabolites are excreted through the urine but about 20% is recovered in faeces from biliary secretions.(Holt and Howden 1991). Metabolism of omeprazole is done by CYP2C19 and CYP3A. Hydroxylation metabolic index is affected by the CYP2C19 genotype and as for sulfoxidation metabolite index intestinal CYP3A4 plays the vital role. Studies have proved that omeprazole belongs to high clearance drugs.(RegÃÂ¥rdh, Gabrielsson et al. 1985).
Doubts were raised whether prolonged use of Prilosec and Nexium could lead to any cardio vascular problems. FDA conducted a comprehensive and scientific review of known safety data of the drugs. FDA released a press release that no evidence was found relating to the use of the drugs and cardiovascular problems.(release 2007). Omeprazole is a PPI which lowers intra gastric acidity thus decreasing the ionization and increasing the absorption of weak acids such as diazepam, aspirin or furosamide. Omeprazole has the opposite effect on weak bases such as tetracycline, chlorpromazine or ketoconazole. Omeprazole reduces the clearance of phenytoin carbamazepine and diazepam which can lead to adverse effects. The most important drug interaction is that of diazepam in which the diazepam clearance is reduced by 25 to 50%. This is due to the competition between the two drugs for CYP2C19.(Thomson 2000). Omeprazole also interacts closely with r-warfarin, as a result blood coagulation has to be closely monitored if these drugs are taken together.(Holt and Howden 1991)
Omeprazole has been found to have a lot of therapeutic uses. It is used for the treatment of Duodenal Ulcer, Gastric Ulcer, Refractory peptic Ulcer, Gastro Esophageal Reflux Disease (GERD), Zollinger Ellison Syndrome and Helicobacter pylori eradication in Patients with Duodenal Ulcer Disease.
FDA gave approval for the use of omeprazole in short term and first line of treatment of duodenal ulcer. During the clinical trials, omeprazole 20mg gave faster healing rates than ranitidine as well as cimetidine. The proportion of healing the duodenal ulcer by taking omeprazole 20 mg for 2weeks is between 24 to 86% and if it is taken for 4 weeks the proportion becomes 64 to 100%.(Holt and Howden 1991)
Omeprazole is used for the treatment of gastric ulcer. Here also it came out superior when compared to ranitidine and cimetidine. 80% of the ulcers was treated after the intake for 4 weeks and the relapse rate is as low as 2%.(Holt and Howden 1991).
Refractory Peptic Ulcer
Refractory peptic ulcers are those ulcers which do not get healed even after treatment with H2- receptor antagonists for at least 8 weeks. When omeprazole was administered healing started within 2 weeks and 88 to 100% got healed after 8 weeks.(Holt and Howden 1991).
Gastro Esophageal Reflux Disease ( GERD )
GERD is the mucosal damage cause by the abnormal reflux of stomach acid to the esophagus. Omeprazole was superior to ranitidine in the treatment of GERD patients who were resistant to H2- receptor antagonists. Maintenance therapy was effective for atleast five years with the use of omeprazole. Treatment was accompanied with an increase in gastric levels in a steady state.(Klinkenberg-Knol, Festen et al. 1994)
Zollinger Ellison Syndrome
Clinical studies of omeprazole on Zollinger Ellison Syndrome patients showed that the gastric secretion was in a controlled rate. No histological changes were observed in the gastric mucosa. The dosage rate varies from 20mg to 160mg.(Holt and Howden 1991)
Helicobacter pylori eradication in Patients with Duodenal Ulcer Disease.
Omeprazole has the ability to suppress H.pylori but it cannot eradicate the organism without the help of other antibiotics. A combination of omeprazole and amoxicillin 500mg eradicates the organism to a great extend. Omeprazole is used for triple therapies along with amoxicillin 500mg and metronidazole 400mg in a 7 day regimen. The clinical studies showed eradication rate of 85%.(Thomson 2000)
FDA panel oks OTC Prilosec, CNN Money, June 21, 2002