Development of a New Bioequivalent Omeprazole Product

Abstract

Background and Objectives: The enteric form of omeprazole is one of the most commonly prescribed medications. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and good-quality medicines. This study comprehensively describes the technologically available development of bioequivalent delayed-release omeprazole.

Materials and Methods: Various regimes and technological parameters were tested on laboratory- and production-scale equipment to establish a technical process where a functional and gastro-protective layer is essential. According to the ICH guidance on stability testing and Kazakhstan local rules, stability studies were conducted under conditions appropriate for climate zone II. The comparison of the rate and extent of absorption with subsequent assessment of the bioequivalence of the generic and reference drugs after a single dose of each drug at a dose of 40 mg was performed.

Results: The quantitative and qualitative composition and technology of producing a new generic enteric form of omeprazole in capsules were developed and implemented at the manufacturing site of solid forms. Dissolution profiles in media with pH 1.2 and 6.8 were proven. During the accelerated six-month and long-term twelve-month studies, the developed formulation in both packaging materials at each control point passed the average weight and mass uniformity test, dissolution test, acid-resistance stage test, buffer stage test, impurity assay, and microbiological purity test and met all the specification criteria. A bioequivalence study in 24 healthy volunteers compared against the innovative drug showed the bioequivalency of the new generic system. The obtained values from the test and reference products were 1321 ± 249.0 ng/mL and 1274 ± 233 ng/mL for C_max, 4521 ± 841 ng·h /mL and 4371 ± 695 ng·h /mL for AUC_0-t, and 4636 ± 814 ng·h /mL and 4502 ± 640 ng·h /mL for AUC_0-∞.

Conclusions: Using affordable technologies, a bioequivalent generic delayed-release formulation of 20 and 40 mg omeprazole has been developed.

Introduction

Peptic ulcer disease (PU) is a chronic, recurrent acid-dependent disease characterized by alternating periods of exacerbation and remission. It is considered the most common disease of the digestive system, affecting 10–15% of the world’s population. The main component of gastric juice is hydrochloric acid. When secreted at levels above normal, it has a pathological effect and is the main factor in the pathogenesis of ulcers. This pathology shows defects (ulcers) in the wall of the stomach and duodenum. In contrast to erosive changes in the mucosa, an ulcer affects the mucous membrane as well as the submucosal layer [1,2,3].

Currently, proton pump inhibitors (PPIs) are the primary drugs used to treat acid-related diseases of the upper gastrointestinal tract due to their highly selective inhibitory effect on the acid-forming function of the stomach. The primary drug from the PPI group is omeprazole, which was synthesized in 1979 after the discovery of a unique enzyme, K+-stimulated ATPase, in parietal cells during experiments on the gastric mucosa [2,4,5]. Omeprazole, as an agent that reduces gastric acid secretion, is prescribed for the treatment of the following diseases: duodenal ulcer; gastric ulcer; NSAID-associated (non-steroidal anti-inflammatory drugs) gastric and duodenal ulcers; reflux esophagitis; symptomatic gastroesophageal reflux disease (GERD), i.e., heartburn and regurgitation; Zollinger–Ellison syndrome (pathological hypersecretory condition); Helicobacter pylori (H. pylori) [3]. In 2022, omeprazole was found to be the second most commonly prescribed chemical substance in England, with the drug listed on approximately 35 million prescriptions [6]. According to the Drug Usage Statistics for 2021 in the USA, omeprazole was ranked as the ninth top drug in the market, with an estimated number of 54.5 million prescriptions [7].

In the Republic of Kazakhstan, drugs for patients with acidity disorders are the eighth most often prescribed according to the ATC (Anatomical Therapeutic Chemical) classification system. Omeprazole is among the top 15 main molecules (active ingredients) of the general prescription market and ranks 13th in terms of importance (Vi-ORTIS data). PPIs account for 75.3% in monetary terms and 89.6% in volume terms of the total market for medicines used to treat acid-related disorders. Omeprazole ranks first among the top ten PPI market leaders in terms of the number of packages sold, accounting for 71.66% of the total PPI market in volume terms, and in monetary terms, it comes to 43.56% of the total PPI market [8].

The enteric form is the most common form of omeprazole oral dosage formulations. Since omeprazole is a pro-drug that accumulates in the acidic space of the parietal cell and is converted into an active state there, it has the characteristics of a weak base, so it remains stable in neutral pH but degrades rapidly in an acidic environment. Therefore, to reach the small intestine where it is absorbed, omeprazole must be protected from gastric acid when administered orally. These characteristics are a challenge for drug developers in the search for optimal delivery of the pharmacologically active substance to the desired site of absorption or activation [8]. Ten products are marketed in Kazakhstan: a powder for suspension for oral administration (India), one lyophilizate for intravenous administration (India), and ten enteric capsules (Belarus, India, Spain, Slovenia, Russia). Only one of these is manufactured in Kazakhstan.

The presented capsules contain enteric-coated micropellets, pellets, granules, and microgranules [8,9].
There have been several inventions aimed at producing enteric-coated pellets of PPIs. These pellets consist of an empty pellet core, a drug-loaded layer, isolating layers I and II, and an enteric-coated layer coated using a fluidized bed coater [10,11,12]. Against this background, the development of an enteric form of omeprazole in Kazakhstan has been of great interest. However, the coating of pellets or granules is a complex process that requires a high level of technology. The technical capacity to produce such products on an industrial scale is not available in all manufacturing locations. This article describes the technologically feasible development of a bioequivalent extended-release generic product containing 20 mg and 40 mg of omeprazole, focusing on an in vivo bioequivalence study.

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Materials

The following materials were used in the study: omeprazole (Hetero Labs, Hyderabad, India) Active Pharmaceutical Ingredient (API), lactose monohydrate Supertab 22AN (Glentnam Life Sciences Ltd., Corsham, UK), sodium lauryl sulfate (RNDr Kulich Pharma s.r.o., Hradec Králové, Czech Republic), disodium hydrogen phosphate dodecahydrate cryst. EMPROVE® (Merck KGaA, Darmstadt, Germany), hydroxypropylmethylcellulose (Tailopur 603), hydroxypropyl cellulose Klucel EF Pharm (Ashland Industries Europe GmbH, Schaffhausen, Switzerland), pellets from microcrystalline cellulose (MCC) Cellets®700 (IPC Process center GmbH & Co.Kg, Dresden, Germany), polyethylene glycol 400 (Applichem GmbH, Darmstadt, Germany), methacrylic acid–ethyl acrylate copolymer Eudragit® L30-D55 (Evonik Nutrition and Care GmbH, Darmstadt, Germany), hard gelatin capsules size 0 (Capsugel, Bornem, Belgium), PlasAcryl® HTP20 (Emerson Resources Ink., Norristown, PA, USA), titanium dioxide (Venator Germany GmbH, Krefeld, Germany), talc (Imerys Talc Italy S.p.A, Porte, Italy). All ingredients were of pharmaceutical production grade as described in the European Pharmacopoeia, and are widely used in preparations for oral use at concentrations not exceeding the recommended limits. Losec®, enteric capsules, 20 mg, AstraZeneca AB, Sweden, was used as the reference drug.

Kumisbek, G.; Vetchý, D.; Kadyrbay, A. Development of a New Bioequivalent Omeprazole Product. Medicina 2024, 60, 427. https://doi.org/10.3390/medicina60030427