Study On Oral Chronopharmacological Drug Delivery System Of Sinomenine Hydrochloride

With the development of Pharmacology and Therapeutics, the body's physiological function and some diseases showed significant rhythm changes, such as rheumatoid arthritis, asthma and cardiovascular disease. The patients of Rheumatoid arthritis fell pain and stiff in the morning, commonly known as "morning stiffness". The zero-order and first-order drug delivery system can not meet the clinical needs. Oral chronopharmacological drug delivery system becomes interesting with the development of time rhythm and therapeutics. Sinomenine extracted from traditional Chinese medicine of sinomenium acutum, which mainly used for treatment of rheumatism and rheumatoid arthritis and has little side effects. Sinomenine hydrochloride was selected as the model drug in this study. The two kinds of sinomenine hydrochloride stomach-stayed pulse release tablets and delayed-onset sustained-release tablets were prepared by dry-coated technique. The first is used for prevention and treatment of "morning stiffness". The second is used for prevention and treatment of "morning stiffness" and continued pain or stiffness in the day. Two kinds are treated in accordance with the physical and therapeutics, which reduce the drug concentration at night and reach the best plasma when the disease attacks to achieve the purpose of time treatment.Sinomenine hydrochloride stomach-stayed pulse release tablets were prepared in the first part of this study. It contains outer shell and core tablets. The core tablets contain an active ingredient and disintegration agent, the outer shell composed of hydrophilic matrix material. The types of core tablets disintegration were chosen according to the expanding rate and lag-time. CMS-Na was selected as the disintegration. The effects of the amount of core disintegration, the ratio and amount of tablet coating matrix materials(HPMC K15M: carrageenan), the amount of lactose and NaCO3, the preparation of coating materials and the pressure in vitro drug release of the tablets were studied. Study the effects of ionic strength, rotation speeds and pH in vitro drug release. The lag-time was prolonged with the increase of the ratio of HPMC/carrrageenan and the amount of matrix material in coating layer, and shortened with the increase of core expansion ratio and rotation speed. The pressure and preparation method of coating materials have no influence on lag-time. The lag-time was prolonged with the increase of pH and ionic strength of dissolution media. Selected the best formulation: CMS-Na as the core disintegration, each contains 25mg; the ratio and amount of coating matrix materials (HPMC: carrageenan) is 4:1 and 45%, the amount of NaHCO3 and lactose content is15%and 20%; Preparation with dry press-coated technique and pressure keep(6±1)kg. Coating layer erosion and core tablet expansion were involved in the mechanism of drug release. The tablets have typical pulse release after a lag time. A suitable lag-time can be achieved by adjusting formulation of coating layer to meet the requirement of chronotherapy.The second part of this study is sinomenine hydrochloride delayed-onset sustained-release tablets. It contains outer shell and core tablets. The core tablets and outer shell is composed of hydrophilic matrix material. The effects of the type (HPMC K15M,HPMC K4M, xanthan gum and carrageenan)and amount of core matrix materials, the type and amount of coating matrix materials, the preparation of coating materials and the pressure in vitro drug release were studied. The type and the amount of the core and the coating matrix materials play an important role on lag time and drug release. With an increase in matrix materials amount and viscosity, the lag time was prolonged and drug release was decreased. With an increase in pressure, the lag time was prolonged, when pressure increased to(7±1)kg, it has little influence on lag time and drug release. The preparation of coating materials has little influence on lag time and drug release. The influence factors included the ratio of HPMC in core tablet and the ratio of HPMC in coating shell. The evaluation parameters included lag-time and release rate. Experiments were done with the central composite design. Selected the best formulation: HPMC as core and out shell matrix materials, the amount is 15% and 36%, preparation with dry press-coated technique and pressure keep(7±1)kg. The lag time of the tablets prepared under the optimum condition was about 5.5h, then drug release slowly within 5～15h which conform to zero-order drug delivery system and was controlled by bulk erosion mechanism. Sinomenine hydrochloride delayed-onset sustained-release tablets release slowly after lag time. The prescription of coating materials and core tablets play an important role on lag time and drug release.