Design And In Vivo Evaluation Of Manidipine By Self-Nanoemulsifying Drug Delivery Systems

The current research is aimed at developing liquid self-nanoemulsifying drug delivery system (liquid-SNEDDS) of Manidipine for enhanced solubility and oral bioavailability. The Manidipine SNEDDS are formulated with excipients comprising of Capmul MCM (oil phase), Transcutol P (surfactant) Lutrol L 300 as co-surfactant. The prepared fifteen formulations of Manidipine SNEDDS analysed for emulsification time, percentage transmittance, particle size, in vitro drug release, and stability studies. In vivo pharmacokinetic studies of the optimized formulation were carried out in Wistar rats in comparison with control (pure drug). The morphology of Manidipine SNEDDS indicates spherical shape with uniform particle distribution. The percentage drug release from optimized formulation F14 is 98.24 ± 5.14%. The particle size F14 formulation was 22.4 nm and Z-Average 23.3 nm. The PDI and zeta potential of Manidipine SNEDDS optimized formulation (F14) were 0.313 and-5.1mV respectively. From in vivo bioavailability data the optimized formulation exhibited a significantly greater Cmax and Tmax of the SNEDDS was found to be 3.42 ± 0.46ng/ml & 2.00 ± 0.05 h respectively. AUC0-∞ infinity for formulation was significantly higher (11.25 ± 3.45 ng.h/ml) than pure drug (7.45 ± 2.24ng. h/ml). Hence a potential SNEDDS formulation of Manidipine developed with enhanced solubility and bioavailability.

Chiral Separation of Manidipine Enantiomers and the Pharmacodynamics of the Hydrochlorides / 中国药学杂志

OBJECTIVE: To investigate the chiral separation of the manidipine enantiomers by the proposed synthetic route, and the blood pressure effect of the hydrochlorides. METHODS: Based on the solubility differences of the salts which are the reaction products of the manidipine enantiomers and the different chiral resolution agents[(+)-Di-p-toluoyl-D-tartaric acid/(-)-Di-p-toluoyl-L-tartaric acid] in the specific solvents, the S and R manidipine enantiomers were obtained respectively, which is called the chemical salting out crystal method. The changes of systolic pressure, diastolic pressure, and mean arterial pressure of spontaneously hypertensive rats(SHR) before and after manidipine hydrochloride medications administration were monitored through implantable physiological signal remote sensing pressure monitoring system (data science international, DSI). RESULTS: The chiral separation process is simple, maneuverability is strong and the ee values and purity of the S and R enantiomorphism isomers are both higher in the synthetic route; in the SHR model, the antihypertensive effect was equivalent between manidipine hydrochloride group and S-manidipine hydrochloride group; R-manidipine hydrochloride did not have the antihypertensive effect. CONCLUSION: The chiral resolution of manidipine enantiomers has certain scientific value, which can improve the efficacy and safety of drug, and which is of great significance to develop manidipine single enantiomeric new drugs.

Cosistency Evaluation of Dissolubility of Manidipine Hydrochloride Tablet Generic and Original Preparation / 中国药房

OBJECTIVE:To establish a method for the dissolubility determination of Manidipine Hydrochloride tablet and eval-uate the quality consistency of generic and original preparation. METHODS:HPLC was performed on the column of Waters Sym-metry C18 column with mobile phase of potassium phosphate monobasic solution (potassium phosphate monobasic 6.8 g was well-mixed with water 1 000 ml,and pH was adjusted to 4.6 by potassium hydroxide solution)-acetonitrile (49∶51,V/V) at flow rate of 1.0 ml/min,detection wavelength was 228 nm,column temperature was 25℃,and the injection volume was 20μl. The dis-solution mediums were 0.1 mol/L hydrochloric acid solution,acetic acid-sodium acetate buffer solution(pH 4.0)and phosphate buf-fer solution [pH 6.8,adding into 0.5% sodium dodecyl sulfonate(SDS)],volume of dissolution medium was 900 ml and rotating rate was 50 r/min,and the dissolubility of Manidipine hydrochloride tablet generic and original preparation was investigated and the similarity of dissolution profile was evaluated by calculating similar factor (f2). RESULTS:The linear range of manidipine hydro-chloride was 0.625-20 μg/ml;RSDs of instrument precision and stability tests were lower than 2.0%;recoveries of 3 dissolution mediums were 92.86%-102.97%(RSD=1.9%,1.8% and 2.7%,n=9),respectively. The dissolubility of 3 batches of Manidipine hydrochloride tablet generic and original preparations was higher than 85% in 0.1 mol/L hydrochloric acid solution in 15 min;f2 was >50 in acetic acid-sodium acetate buffer solution (pH 4.0) and phosphate buffer solution (pH 6.8,adding into 0.5% SDS). CONCLUSIONS:The method is suitable for the dissolubility determination of Manidipine hydrochloride tablet;meanwhile,the dis-solution profile in vitro of Manidipine hydrochloride tablet generic and original preparations has similarities,so the quality consis-tency is good.

Antihypertensive Effects and Safety of Manidipine in Patients with Essential Hypertension

BACKGROUND: Calcium antagonists are highly effective agents for lowering high blood pressure and play a very important role in the treatment of Patient with ischemic heart disease and various other cardiovascular disorder. Manidipine, a dihydropyridine-type ccalcium channel blocker, is a potent relaxant of the arteriolar smooth muscle. We studied ths new calcium channel blocker to evaluated the efficacy and safety in patients with essectial hypertension. METHODS: Twenty patients(ten women and ten men;range of age, 30-66 years old)with mild-to-moderate essential hypertension were enrolled in this study. After a placebo run-in phase of two weeks duration, 5mg-20mg manidipine once daily orally was administered for eight weeks. RESULTS: 1) At the end of 8 weeks of manidipine therapy, systolic and diastolic blood pressure were significantly reduced from 160.1+/-11.8/105.5+/-5.1mmHG in sitting, 160.1+/-12.1/104.5+/-5.4mmHG in supine, 157.1+/-17.0/104.1+/-5.3mmHg in standing to 128.4+/-10.1/85.2+/-5.7mmHg in sitting, 129.1+/-10.2/84.2+/-5.9mmHg in supine, 128.1+/-12.8/86.7+/-5.9mmHg in standing(p<0.01). 2) The pulse rate did dnot change significantly. 3) The reduction of mean systolic and diastolic blood pressur at the end of 8 weeks were 31.5+/-14.5/20.3+/-7.4mmHg in sitting. 4) There was no serious side effect except mild symptom, mild headache(6 casem 30%) and facial flushing(1 case, 5%). CONCLUSION: These results indicate that manidipine is an effective and safe antihypertensive agent in the treatment of mild and moderate essential hypertension.

Manidipine Monotherapy in Patients with Mild to Moderate Essential Hypertension

A clinical trial was done to evaluate the antihypertensive efficacy and side effects of manidipine, a new calcium antagonist, in 30 patients with mild to moderate essential hypertension. 1) The study patients consisted of 19 men and 11 women, and the mean age was 51.8 years. 2) Blood pressure dropped significantly in 2 weeks and in 4 weeks, and well maintained throughout the study period. The mean-pressure drop was 26.2/14.9mmHg after 10 weeks. 3) Heart rate did not change significantly with manidipine therpy. 4) Optimal dose for effective pressure-drop was between 10 and 20 mg in 86% of patients. Overall good antihypertensive effect was achieved in 83% of patients. 5) All of the laboratory parameters including blood chemistry, glucose, lipid and electrolytes did not change, but serum calcium increased from 9.2% mg/dl (p=0.001) in 10 weeks. 6) Side effects were mild in nature(palpitation in 3, dry mouth in 1, weakness in 1 and impotence in 1 patient). In conclusion, manidipine monotherapy with 10 to 20 mg once a day regimen is effective and well tolerated in the patients with mild to moderate essential hypertension.

Hypotensive Efficacy and Safety of Manidipine on the Patient with Essential Hypertension

Thirty patient with essential hypertension were administered Manidipine, a new calcium antagonist, 10~20mg once daily to evaluate the hypotensive efficacy and safety for 8 weeks. And the followings were the result. 1) Patients were consists of 14 male, 16 female, aged 53 in average and classified as mild in 21 and moderate in 9 patients. 2) Optimum intial dose was 10mg and 10 to 20mg were the doses recommended. 3) Blood pressure dropped after 8 weeks 24/13mmHg in average, rewarding 80% effectiveness and normalized in 87%. 4) Most frequent side reaction was facial flushing in 5 patiens followed by palpitation and dizziness, all of which did not disturb the continuation of medication. 5) Most of routine laboratory parameter were normal and unchanged between before and after the trial. 6) Overall rating of usefulness was 77%. In conclusion, Manidipine 10 to 20mg once daily regimen is well tolerated and effective in the treatment of mild to moderate essential hypertension.