Studies On Nicotinic Acid Sustained-Release Pellets

Niacin (Nicotinic acid, NiAc) belongs to the hydrophilic vitamin B complex. A high dose of Niacin(2-6g/day) shows hypolipidemic activity and is widely used for treatment of hyperlipidemia. However, use of NiAc often cause adverse effects such as intense cutaneous flush and gastrointestinal disturbance,so sustained release capsule was devised to be administered to relieve the adverse effects.Ultraviolet spectrophotometry (UV) was developed for in vitro assay of drug content and release of pellets, High-performance liquid chromatography(HPLC) was developed to determine the permeated NiAc through ethylcellulose free film. The ion-pair reversed-phase HPLC detection was applied to quantify the drug plasma concentration of Beagle dogs.Free film with different pore formers of aqueous ethylcellulose dispersion Surelease^? E 7-19010 was prepared by spraying method. Vertical diffusion cells were employed as the permeation apparatus. Results show: The pore formers could accelerate the permeation of nicotinic acid. The permeation of the free film with 10% HPMC decreased with the increase of concentration of Ca²⁺ in the release media, while increased with 10% mannitol. When the concentration of Ca²⁺ was more than 0.1%, nicotinic acid was hardly permeated across the free film with 10% PVP.Extrusion-spheronisation and centrifugal granulation were involved to prepare nicotinic acid pellets with high content. The effects of process varibles and formulation varibles on pellets preparation were investigated. The content of NiAc pellets made by these two methods was respectively 89.6% and 94.3%.Niacin pellets were coated with Surelease^? E-7-19010 containing 5% and 10% mannitol in the centrifugal granulator. The infulence of release medium on the release profile of NiAc sustained release pellets was performed-Results show.Pore formers could increase the release of NiAc pellets, Ca²⁺concentration in the release medium had no significant effect, the release was quicker at pH1,and had no difference at pH3,5,7. The release kinetics belonged to first order.The serum concentration in Beagle dogs was tested after a single oral administration of commercial tablets and self-made sustained release pellets (18-24 mesh cut). The pharmacokinctics parameters and the relative bioavailability were measured. The pharmacokinetics parameters of NiAc in sustained release tablets analyzed by non-compartment model theory were T_max 3.33 h, C_max 19.03μg·mL^-1, MRT 4.65 h, The pharmacokinetics parameters of NiAc in sustained release pellets were T_max 3.17 h, C_max 18.04μg·mL^-1, MRT 4.47 h, Fr98.19% respectively and bioequivalent with the control sustained release tablets, after feed with grapefruit (GF)juice the parameters were T_max 3.5h, C_max 26.59μg·mL^-1, MRT 5.20 h. GF could affect the pharmacokinetics greatly.