Category: Formulation and Quality
Purpose: Omeprazole (OM), typically used for gastric patients, is a proton pump inhibitor: it controls the stomach acid effectively by controlling the proton pump. However, within a long term taking of OM, it can cause side effect of calcium indigestion. To improve the side effect of OM, seaweed was used. The seaweed is abundant in calcium and nutrients like vitamin, and other minerals. Among the minerals, the magnesium can be used to assist the absorption of calcium. For these reasons, hyperfine-seaweed can be a source of nutrients to support OM therapy. And, OM is mainly absorbed in the upper gastrointestinal tract or small intestine. In this property, the oral thin film (OTF) was used. The OTF have property of fast-dissolving. The OTF allow the rapid and efficeint dissolution in acid condition.
Methods: To obtain the seaweed calcium (SC) from seaweed, cryo-milling was used. Briefly, seaweed was lyophilized fully and grinded. After grinding, the seaweed was finely pulverized. After that, SD was fabricated with OM and SC by rotary evaporation method. The solvent was ethyl acetate, and OM and SC was dissolved in ratio of 2: 1. OTF was fabricated by 4 kinds of formulation. For each BAT, we choose a different binding agent. Kollidon VA64, commonly used as a wedge type binder due to its moderate particle size, low humidification, and high binding and water solubility, was added in BAT 1. PVP K-30, a highly safe viscosity control agent that acts as a binder and is mainly used as an additive in the preparation of a sustained release agent, was added in BAT 2. HPMC, regulates the drug elution time according to its viscosity, was added and different molecular weights of HPMC in both BAT 3 (HPMC 4K) and 4 (HPMC 100K). After addition of all ingredients, OTF was fabricated by heating press (Dae Heung Science, Korea). Obtained samples were observed by Scanning Electron Microscopy (SEM). To quantify calcium and other elements, field emission scanning electron microscopy (FE-SEM). All samples molecular structure were analyzed by Fourier transform infrared spectroscopy (FT-IR). X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis were performed to confilm whether granules were formed normally. Thermal properies were analyzed by thermal gravimetric analysis (TGA). Hydrophobicity was evaluated by contact angle. Dissolution test was performed in artificial gastric juice. After that, HPLC analysis was performed to confirm the loading efficiency and quantify the dissolved OM after dissolution.
Results: In SEM observation, The OM particles have size ranging from 1 to 30 μm with an irregular conformation. The SC micrography show the grain results. BAT 1-4 show the morphology of prior to the compression: bigger particles are present in all the samples, indicating the presence of the disintegrating agent. In EDS analysis, all formulations showed high amounts of C, N and O elements. The calcium content of seaweed could be roughly estimated in 1.8%. As the other ingredients were added, the calcium content decreased to minimum of 0.2% (BAT 1 and BAT 3). The XRD analysis show the appearance of broaden peak of SD and it indicated the granule of OM and SC was formed normally. DSC show the endothermic peak of OM at 157 C° and SD at 148 C°. In dissolution test, BAT 3 show the remarkable solubility of 89.7 ± 2.07 % at 120 minutes. These results are considered to be due to the kind of polymer and molecular weight. In HPLC analysis, the loading efficiency of OM in SD was 77 ± 1%, and BAT 1 - 4 show 72 ± 1% of loading efficiency. Also, two clear peaks were shown, and the rate of each isomer was approximately 70:30 (S-omeprazole: R-omeprazole) from SD.
Conclusion: One of side effect of OM is the calcium deficiency that can occur with pharmacological action. This occurs due OM mechanism that inhibit the production of acid causing a decrease in calcium solubility and consequently in its absorption. The fabricated SD composed by OM and SC showed lower crystallinity than OM. This indicates that the crystalinity of OM is lower through amorphous using rotary evaporation with SC.The chemical structure of OM did not change as can be deduced from the FT-IR analysis. The melting point was changed in the DSC that the granules which is formed were melted on the surface of the OM and also affected the OM. In wettability and dissolution test, BAT 3 show superior result. Dissolution test and HPLC analysis was performed to conform that what was happed to OM and check the drug efficiency. SD show 77 ± 1% of drug and all BAT show 72 ± 1% of drug efficiency. BAT 3 show the superior dissolution rate in dissolution test. These results suggest that OTF of BAT 3 with HPMC 4K is the best solution to relieve the calcium deficiency side effects of OM therapy.
Jin Woo Kim– Jeon Ju, Cholla-bukto, Republic of Korea
Won Kyung Kim– Jeon Ju, Cholla-bukto, Republic of Korea
Jeong Eun Song– Jeon Ju, Cholla-bukto, Republic of Korea
Gilson Khang– Jeon Ju, Cholla-bukto, Republic of Korea
Jinwoo Kim– Student, Jeon Buk National Univ., Jeon Ju, jeon ju, Korea, Republic Of