Duodenum Targeting Drug Delivery System - Berberine Bioadhesive Coated Tablets

Hydroxypropyl methylcellulose acetate maleate coated berberine chloride bioadhesive tablets were prepared in this research. Release behaviors and mechanism were investigated deeply. Furthermore, duodenum-specific drug delivery was studies.Duodenal ulcer (DU) is a kind of chronic disease commonly found in digesive system with the symptoms of repeated pain in the superior belly, periodically and regularly. It is believed as a defection occurred in the duodenal mucous membrane, usually followed by bleeding, perforation, and duodenal cancer. Up to now, there is no a single drug which can effectively deal with DU. Therefore, program about triple treatment or quadruple treatment was widely used in DU clinical therapy, which centered by drug eradicating the helicobacter pylori(Hp).The aim of our study is establish a kind of duodenum-specific drug delivery system. Due to the special environmental pH of the ulcer duodenum, we synthesize pH sensitive polymer HPMCAM as a coating agent which dissolve at pH 3.6. On the basis, HPMCAM coated bioadhesive tablets were prepared which include HPMC-K_4M and carbopol-934P as bioadhesive materials. HPMCAM coated bioadhesive tablets can carry the therapeutics directly to the duodenum without drug release in the stomach, allowing the released drug to accumulate at the surface of the pathological ulcer, thereby achieving the function of a duodenum-specific and eradiation therapy for Hp.To obtain pH-sensitive HPMCT (Hydroxypropyl methylcellulose trimellitate) and HPMCAM (Hydroxypropyl methylcellulose acetate maleate) polymers, HPMC (Hydroxypropyl methylcellulose) as a base polymer was modified with trimellitic anhydride or maleic anhydrides at various degree of substitution. The structure of this polymer was characterized by FT-IR and ¹H-NMR. Its pharmaceutical properties such as film forming, dissolution behavior, acidity, pH-sensitive values, water vapor permeability of the free film, tensile strength and Tg were investigated. It proved that HPMCT and HPMCAM have good film forming and can be used as an ideal pharmaceutical coating material. Chang the reaction condition such as ration of reactants,the amount of the catalyst,the amount of solvents or reaction time, we can obtain HPMC derivatives that have slightly different pH sensitive point. The pH-sensitive value of HPMCAM can be controlled within the range 3.2-4.4 by adjusting the maleic anhydrides and acetic anhydrides ratios. However, the pH-sensitive value of HPMCT can be controlled within the range 3.8-4.2.Considering characteristics of berberine hydrochloride and the purpose of our project, we improve formulation and preparing method of tablet core on the basis of some preparing method of formulation. After HPMC-K4M was selected as bioadhesive polymer, the basic formulation of bioadhesive tablet I was formed, including lactose as fillers, PVP-K30 as adhesives. While HPMC-K_4M and carbopol-934P were selected, the basic formulation of bioadhesive tabet II was formed by orthogonal design. The result of adhesive force show that bioadhesive tabet II > bioadhesive tablet I > immediate released tablet. Study on drug release mechanism demonstrated that Weibull model could be used to the best describe the drug release curve of CBT I and Hixson-Crowell equation could be used to CBT II. The release mechanism of CBT I and II were proved to be erosion mechanism and non-Fickian diffusion, respectively.According to the regulations in Chinese Pharmacopoeia(2005), a series of quality evaluation approaches were established for berberine hydrochloride HPMCAM coated bioadhesive tablets and a preliminary study on its stability, comprising influence factors test, accelerated test and long-term test, was also performed. It suggested that berberine hydrochloride HPMCAM coated bioadhesive tablet should be stored in a well-closed container, away from moisture.Distribution of berberine hydrochloride in the luminal contents of GI tract was measured after oral of CBT or equivalent dose of IBT to beagle. The pharmacokinetic parameters of test group and control group were as follows: AUC_0-Tn were 14.723 ug·h·g^-1 and 5.032 ug·h·g^-1 ;C_max were 4.630 ug·mL^-1 and 2.345ug·mL^-1; T_1/2 werel.626h and 1.573h; CLs were 7.407 mg·g/kg/h/μg and 18.569 mg·g/kg/h/μg, the result indicated that CBT could increase concentration of drug in duodenum, delay the time of evacuation in duodenum which is very important for the treatment of DU. Targeting index including Re,TE,RTE and Ce were evaluated, these results indicated that CBT had a good duodenum targeting efficiency in vivo and affect the extent of GI tract distribution.