Hydrochloride Card Atenolol Oral Disintegrating Tablets Pre-clinical Studies

Carteolol hydrochloride, a non-selectiveβ-receptor blocker with intrinsic sympathomimetic activity, is the onlyβ-receptor blocker for the treatment on cardiac neurosis listed in world. In domestic, there is only eye drop on sale for the treatment on glaucoma, compared with a single dosage form and indication. On the study of cardiac neurosis in-depth, we collaborated with the Institute of Modern Drugs'Applications of ChongqingBeibei on carteolol hydrochloride. Up to now, we have developed many kinds of dosage form of carteolol hydrochloride, including orally disintegrating tablets, pellets, pellet-tablets, coated pellets, pellet-capsules, pellet-suspension agents and so on, and applied for two patents (CN101690720, CN101690718). Carteolol hydrochloride ODTs in this article belong to the third class in our country's new drugs registration and the author made a study on the part of its preclinical according to, the "chemical registration requirements of the classification and reporting information" of "Drug Registration"of State Food and Drug Administration's document of No.28,2007, for the destination of accumulation of data of carteolol hydrochloride ODTs'clinical trials and registration.Prescription Process. By single-factor test, we determined the types of materials: mannitol, MCC as fillers, polyvinylpyrrolidone (PVPP) as a disintegrating agent, citric acid/NaHCO3 as effervescent agents, ethanol as a wetting agent or adhesive, aspartame as a flavoring agent. Then, using orthogonal test to optimize the amount of materials, each tablet contains:5mg of carteolol hydrochloride,30mg of MCC,3mg of PVPP, 10mg of citric acid/NaHCO3 (1.2:1),53mg of mannitol,3mg of aspartame and lmg of magnesium stearate. The influence sequence of each factor one by one in order was: PVPP> ethanol's concentration> MCC> citric acid/NaHCO3 and the best prescription is by wet granulation. The evaluation of quality of carteolol hydrochloride ODTs was:the hardness in the extent of 22N～23N, vitro and in vivo disintegration time within 30s, tasting cool, sweet sour and no sense of gravel, the weight differences and content uniformity all in the limits.Quality Standards. We established a RP-HPLC method for dissolution, content and related substances determination in carteolol hydrochloride ODTs. The RP-HPLC method performed on:column was UltimateXB C18 column (4.6mm×250mm,5μm), mobile phase was 0.2% potassium dihydrogen phosphate-acetonitrile (85:15) (dissolution) and 0.17% Na2HPO4 solution (adjusted to pH3.0±0.05 with 1mol·L-1 phosphoric acid)-acetonitrile(85:15)(content and related substances), detection wavelength were 252nm and 251nm, flow rate was 1mL·min-1, column temperature was 30℃, injection volume was 20μL. Under these conditions, solvent, impurities, related substances and degraded substances were completely separated from carteolol hydrochloride, the number of theoretical plates was not less than 3000, peak separation was greater than 1.5. The RP-HPLC method was simple, rapid, accurate, sensitive and suitable for the determination of the content and related substances. At the same time, we made a preliminary study on carteolol hydrochloride ODTs' characters, identification, inspection and so on. The results were:identification was responsive, disintegration time, dissolution and related substances under the orally disintegrating tablets requirements. At last we established the protocol of carteolol hydrochloride ODTs'quality standards.General pharmacology. We contrived a low, medium and high dose by 1/20,1/10, 1/5 of carteolol hydrochloride ODTs'LD50 and made determinations on the relationgship of the three dosage between locomotor activity, coordination function and hypnosis function of subthreshold dose of Pentobarbital of mice and blood pressure, heart rate and respiratory frequency of rats. The results were:the low, medium and high doses of carteolol hydrochloride ODTs had no significant effects on locomotor activity and coordination(P> 0.05), no significant coordination functions with subthreshold dose of Pentobarbital(P> 0.05), no significant effect on blood pressure, heart rate and respiratory frequency (P> 0.05).Pharmacokinetics and bioavailability. By using self-built RP-HPLC method, we determined the rabbits' Carteolol hydrochloride plasma concentration from different time after administration of carteolol hydrochloride ODTs and conventional tablets, to discover the pharmacokinetic characteristics of carteolol hydrochloride ODTs in rabbits and compare the relative bioavailability of carteolol hydrochloride ODTs and conventional tablets. The results were:the Tmax was 0.5h, Cmax was 1.805ug·L-1 of carteolol hydrochloride ODTs and Tmax was 1h, Cmax was 1.278ug·L-1 of carteolol hydrochloride tablets, the relative bioavailability was 107.51%.The Tmax and Cmax of carteolol hydrochloride ODTs were significantly earlier than conventional tablets (P <0.05). The results showed that carteolol hydrochloride ODTs reached the design requirements.