Formulation Design of Self-Microemulsifying Drug Delivery Systems for Improved Oral Bioavailability of Celecoxib

Abstract

Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide, is a specific cyclooxygenase-2 (COX-2) inhibitor with no inhibition of cyclooxygenase-1 at therapeutic doses. It is being used successfully for the treatment of rheumatoid arthritis, osteoarthritis, acute pain, familial adenomatous polyposis and primary dysmenorrhea. 1,2) Celecoxib also demonstrated significant chemopreventive activity in colon carcinogenesis, ultraviolet B radiation (UVB) induced skin cancer and breast cancer. [3][4][5] Celecoxib is weakly acidic (pK a is 11.1) and hydrophobic (Log P is 3.5) and its low aqueous solubility (3-7 mg/ml) contributes to high variability in absorption after oral administration. 6)The molecule exists in three polymorphic forms and its solid-state interconversion between the forms at ordinary temperatures has not been observed. It is isolated as agglomerates of long needle-shaped crystals, which exhibit cohesiveness, low bulk density and compressibility, and poor flow properties that impart complications in it's processing into solid dosage forms.7) According to biopharmaceutical classification system, celecoxib is classified as a low solubility and high permeability drug. 6) Therefore, the particle size of celecoxib influences the content uniformity, dissolution and bioavailability of the product. The t max of celecoxib is about three hours after oral administration. Rapid onset of action is necessary to provide fast pain relief in the treatment of acute pain. Therefore, it is necessary to enhance the aqueous solubility and dissolution rate of celecoxib to obtain faster onset of action, to minimize the variability in absorption and improve its overall oral bioavailability. This can be achieved by formulating the drug in lipid-based systems.Among the lipid-based systems, self-microemulsifying drug delivery system (SMEDDS) is a promising technology to improve the rate and extent of the absorption of poorly water-soluble drugs. [8][9][10][11][12][13][14][15] The clinical usefulness of the SMEDDS is evident from the commercially available formulations containing cyclosporin A, ritonavir and Saquinavir. 16,17) SMEDDS are comprised of mixture of drug, oil, surfactant(s) and/or co-solvents which form fine oil in water and/or water in oil microemulsions upon dilution with aqueous medium or in vivo administration. SMEDDS enhances the bioavailability of poorly water-soluble drugs through solubilization in the excipient matrix or interface and dispersion in the gastrointestinal tract. Relatively small size of the dispersed oil droplets in nanometer range and very high surface area to volume ratio are advantages of the microemulsion. These characteristics result in faster drug release from microemulsion in a reproducible manner, which can be designed further to make the release characteristics independent of the gastro intestinal physiology and the fed/fasted state of the patient. 8,[18][19][20] In this study, we have developed an optimized formulation using a self-microemulsifying system in...

Nanoemulsion: A suitable nanodelivery system of clove oil for anesthetizing Nile tilapia

“…Besides no side effect of ethanol, CLN can cause faster induction of fish anesthesia. Nanoformulations can enhance the water miscibility of insoluble drugs (25,26). Due to the extremely small size with large interfacial area of internal oil droplets surrounding with the suitable surfactant in CLN, the miscibility of clove oil in aqueous systems can be enhanced.…”

Development of a Solid Supersaturatable Self-Emulsifying Drug Delivery System of Docetaxel with Improved Dissolution and Bioavailability

“…Water soluble carriers such as mannitol, lactose and dextran 40 were used as solid carriers of the DTX-S-sSEDDS 1 , while commonly used excipients such as pregelatinized starch, dextrin, microcrystalline cellulose, micropowder silica gel, mannitol, lactose and, and dextran 40 were chosen as solid physical adsorbents of the DTX-SsSEDDS 3 . The multiples of adsorbent, repose angle, and reconstituted emulsions properties are compared in Table 3.…”

“…Drug exposure may be enhanced by the increased solubilization in the gastrointestinal tract and enhanced accumulation in Peyer's patch for lymphatic transport of the drug. [1][2][3][4] Surfactants in the formulations such as cremophor play an important role in improving the bioavailability of the drug by improving dissolution and intestinal epithelial permeability. 31,32) However, to avoid GI side-effects caused by high surfactant levels in conventional SEDDS formulations, the supersaturatable self-emulsifying drug delivery system (sSEDDS) of DTX was designed.…”

“…SEDDS/ SMEDDSs may offer a new strategy for enhancing the oral bioavailability of poorly water soluble and lipophilic drugs. [1][2][3][4] However, recent studies suggest that there are some shortcomings in the stability and safety of SEDDS/ SMEDDSs. First of all, SEDDS/SMEDDSs are normally in liquid or semi-solid form and are encapsulated in soft gelatin capsules with high manufacturing costs.…”

“…[1][2][3][4] The objectives of the present study were therefore: (1) to develop a new solid supersaturatable SEDDS (DTX-S-sSEDDS) by combining the technology of S-SEDDS with sSEDDS to improve the solubility, dissolution and oral bioavailability of docetaxel, and (2) to determine whether the new S-sSEDDSs may have any advantages in solubility, dissolution, bioavailability, stability and safety compared with the conventional liquid SEDDSs. Table 1.…”