Preparation Of Ambroxol Hydrochloride Osmotic Pump Tablet And Capsule

Objectives: Ambroxol hydrochloride belong to chemical characteristic of Ambroxol, which can reduce viscosity of sputum and also take a positive effect in aspect of respiratory system. It is well known that ambroxol hydrochloride is generally applied in treatment of asthma. At present, there are lots of conventional dosage forms, few sustained preparation and not find preparation of osmotic pump mechanism on market. Therefore, this study go in for developing preparations of ambroxol hydrochloride which adopt the mechanism of osmotic pump, which contain bilayer-core osmotic pump tablet and osmotic pump capsule. The preparation of osmotic pump mechanism possess multi-advantage, such as improving result of treatment, reducing fluctuation of drug's concentration in plasma, decreasing influence of negative effect and obviating harmful effect in gastrointestinal tract.Methods: Ambroxol hydrochloride was employed as model drug. There were two process for two preparations both of self-made tablet and self-made capsule, which can be briefed as follow. A process for preparation of self- made tablets be stated as follow. The granules of drug layer and push layer were prepared separately by wet granulation method with absolute alcohol as the solvent. The resultant granules were compressed into core tablet using a single-punch tabletting machine. Then core tablet were coated by using a conventional pan-coating process, ethyl cellulose in 95% acetone containing PEG1000 was prepared as coating solution. Finally an orifice was produced by micro drilling machine on drug layer. The other process for preparation of self-made capsules be stated as follow. The granules of mixture containing drug were prepared by wet granulation method. The resultant granules were filled in capsule, then capsules were coating by using a conventional pan-coating process. Finally an orifice was produced by micro drilling machine on top of capsule and anther on bottom.According to preliminary test and scientific literatures, the temperature of coating, rotary speed of coating pot and pressure of spraying were determined. The hardness and diameter of tablet, type and amount of osmotic agent, thickness of coating membrane were investigated and evaluated by similarity factor (?2). The orthogonal experiment was designed to optimize formula in which the amount of osmotic agents, suspending agents, PEG 1000 and thickness of coating membrane were taken as four influential factors and three different levels were selected to part, each of them was selected refer to the L9(34) orthogonal design table. According to accumulative release percentage at 2h, 6h, 12h to select optimal formula with an index of comprehensive evaluation.On the basis of self-made tablet, the central composite design-response surface methodology was employed to optimize formula of self-made capsule in which the amount of osmotic agents, PEG 1000 and thickness of coating membrane were taken as three influential factors and three different levels , each of them was selected refer to the central composite design table. According to accumulative release percentage at 2h, 6h, 12h to select optimal formula with an index of comprehensive evaluation.Concentration of ambroxol hydrochloride was determined by HPLC . Separation was achieved by using a Kromasil column (C18, 4.6 mm×250 mm, 5μm). The wavelength of detection was set at 244 nm. The mobile phase consisted of acetonitrile- 0.01mol/L ammonium dihydrogen phosphate aqueous solution(50:50, v/v). The flow rate was 1.0 ml/min, and the injection volume was 20μl. All chromatographic separations were performed at 30℃.The chemical and physical stabilities of optimal formula both of self- made tablet and self-made capsule were investigated under following circumstances: high temperature ,high humidity, strong illumination and accelerated condition (40℃/ RH 75% for 6 months). In the end of the research period, both formulas of self-made tablet and self-made capsule were observed for change in physical appearance, drug content and drug release characteristics.Pharmacokinetics study in vivo: latin square cross-over designs (3×3)of three preparations and three periods were employed to arrange experiment of animal. Beagle dogs were selected as subjects of study, which were divided into three groups in random. One group was given market capsules and another was given self-made tablets and last group was given self-made capsule. Plasma samples were gained at different times. Cross-over experiments were taken after one weeks. HPLC with Ultraviolet detector was adopted in detecting concentration of drug in plasma. Then pharmacokinetics parameters were caculated by compartmental model analysis method.Results: Both optimal formula and technology of self-made tablet and self-capsule were selected by simple factor tests, orthogonal designs and central composite design-response surface methodology.(1)The preparing technologies of core tablet were as follows: hardness of tablet, 6 kg/mm2; diameter of tablet, 9 mm; weight of tablet, 317 mg; content of drug,75 mg. The conditions of coating were as follows: temperature, 37℃; rotation rate of pot, 45 rpm; spray pressure, 0.15 kg/cm2. Optimal formulas of table were as follows: the type of osmotic agent, glucose; amount of osmotic agent, 30 mg; amount of suspending agent, 80mg; PEG 1000 in the cellulose acetate, 9% (g/g); coating membrane in core tablet, 9% (g/g). Coating materials in the coating solution: 3.0% (w/v).(2) The preparing technologies of capsule were as follows: weight of capsule, 165 mg; content of drug, 37.5 mg. The conditions of coating were as follows: temperature, 35℃; pan-rotating rate, 45 rpm; spray pressure, 0.15 kg/cm2. Optimal formulas of capsule were as follows: the type of osmotic agent, glucose; amount of osmotic agent, 50.5 mg; amount of suspending agent,40 mg; PEG1000 in the cellulose acetate, 11.71% (g/g); coating membrane in core capsule, 4.21% (g/g). Coating materials in the coating solution: 3.0% (w/v).The results of UV method to determine the release of ambroxol hydrochloride in vitro: the recovery was 99.92%, the within-day precision was 0.93%. Regression equation was A= 0.0075C+0.0035 (r= 0.9999). The linearity range of ambroxol hydrochloride was 10 ~ 135μg/ml. Regression equation of ambroxol hydrochloride release in vitro be fitted(r= 0.9921, self-table;r=0.9944,self-capsule).The results of HPLC method to determine the content of ambroxol hydrochloride: the recoveries were 98.59 ~ 100.13%, the within-day precision was 0.79 ~ 1.12%, the between-day precision was 1.19 ~ 1.29%. Regression equation was A= 27.037C+10.514 (r= 0.9923). The linearity range of ambroxol hydrochloride was 15μg/ml ~ 150μg/ml.Stability experiment: the result of high humidity test exhibited that 10 days after both of self-made tablets and self-made capsules being put in humidity (RH 92.5%), the weight quickly increased. But in humidity (RH 75%), the weight slowly increased. There was no change in physical appearance, drug content and drug release characteristics after being placed in high humidity (RH 75%), high temperature (60℃) and strong illumination (4500±500 Lx) for 10 days. The result of accelerated test indicated that the information were not strikingly different from before.Pharmacokinetic research: we took the experiment according to HPLC condition. The main pharmacokinetics parameters were respectively as following: AUC0→∞,Tmax(h), and Cmax(ng/ml) of self-made tablet were 7799±1.8, 7.466±0.28 and 414.70±0.18, respectively. AUC0→∞, Tmax (h) and Cmax (ng/ml) of self-made capsule were 7581±0.40, 6.87±0.30 and 479.33±0.81, respectively. AUC0→∞,Tmax(h), and Cmax(ng/ml) of market sustained capsule were 7390±0.32, 3.912±0.41 and517.97±0.35 ,respectively.Compared with market sustained capsule, Tmax(h) and AUC0→∞of self- made tablet were similar, but Cmax (ng/ml) was decreased.Compared with market sustained capsule, Tmax (h), AUC0→∞, Cmax (ng/ml) of self-made tablet were similar.Conclusions: Ambroxol hydrochloride self-made tablets and capsule both had better features of controlled release property in vitro. Their qualities were independent on temperature, humidity and illumination. Their methods of assay and dissolution were established, which provided a guideline with quality control. The experiment in vivo indicated that both self-made tablet and capsule possessed characteristic of bioequivalence, compared with market capsule.