Effective in-vivo utilization of lipid-based nanoparticles as drug carrier for carvedilol phosphatejphp_1270 774..779 Subhashis Chakraborty, Dali Shukla, Parameswara Rao Vuddanda, Brahmeshwar Mishra and Sanjay Singh Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi, India Abstract Objectives Lipid nanoparticles as carrier for oral drug administration improve gastrointes- tinal solubility of poorly soluble drugs and thus enhance bioavailability. However, basic drugs may undergo rapid dissolution from such solid dispersions in the stomach and precipitate in the intestine due to their higher solubility in acidic medium. Therefore, the objective of this work was to study the enhancement in bioavailability of carvedilol phos- phate (basic drug) by providing an alkaline gastric environment to drug-loaded solid lipid nanoparticles. Methods An alkaline gastric environment in rats was created and maintained with oral administration of an antacid suspension 5 min before and 30 min post dosing. Key findings The formulation administered orally exhibited enhanced bioavailability (~27%) when compared with drug suspension and sustained release behaviour when com- pared with formulation under ideal gastric conditions. The enhanced bioavailability is due to the presence of lipid nanoparticles as drug carrier while the sustained-release characteristic may be attributed to the presence of antacid, which resulted in elevation of gastric pH and reduced the drug’s solubility. Conclusions It may be concluded that although lipid nanoparticles can be instrumental in improving bioavailability, additional sustained release may be achieved by targeting intes- tinal release of basic drugs from lipid vehicles, which is possible by incorporating them into suitable enteric-coated formulations. Keywords alkaline gastric environment; basic drug; bioavailability; lipid nanoparticles; sustained release Introduction Lipid-based nanoparticles for oral drug administration are specifically used to target the uptake of drugs by the lymphatic system, which prevents their first-pass metabolism and thus helps to improve bioavailability. [1] Lymphatic uptake of drugs administered orally through nanoparticulate drug delivery systems follows two routes of transportation: the first being the transcellular transport through the enterocyte and the other being phagocytosis of drugs by M cells of Peyer’s patches lining the intestinal mucosa. Biodegradable nanoparticles, such as lipid nanoparticles, are also naturally taken up by these lymphoid tissues in Peyer’s patches based on the size of the particles. It has been observed that particles in the size range of 0.3–1.0 mm are preferably absorbed by Peyer’s patches over those of 3.0 mm particle size. [2] The basic mechanism by which lipid-based solid dispersions improve bioavailability of lipophilic drugs is by preventing their precipitation in the aqueous media of gastrointestinal tract. [3] Therefore, the functionality of lipids can be effectively utilized if the drug remains associated with, or entrapped within, the carrier and is gradually released during its gas- trointestinal transit such that the drug concentration is within the saturation solubility of the intestinal fluid. As a rule of thumb, the solubility of a typical basic drug is relatively higher in acidic medium. This would result in the rapid dissolution and dissociation of the drug from the solid dispersion well before its gastric transit, finally causing its precipitation in the alkaline condition of the intestine. It is proposed that under the present circumstances an alkaline environment may be advantageous in harvesting maximum benefit of the lipid as a carrier by decreasing its solubility in the gastric environment. In one of our previous studies, carvedilol phosphate (non-selective b-adrenergic blocking agent) was found to exhibit a Research Paper JPP 2011, 63: 774–779 © 2011 The Authors JPP © 2011 Royal Pharmaceutical Society Received October 12, 2010 Accepted February 21, 2011 DOI 10.1111/j.2042-7158.2011.01270.x ISSN 0022-3573 Correspondence: Sanjay Singh, Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi 221005, India. E-mail: drsanjaysingh@rediffmail.com 774 Downloaded from https://academic.oup.com/jpp/article/63/6/774/6135529 by guest on 13 July 2022