Development and in-vitro evaluation of peroral and buccoadhesive formulations for biologically active crude oil extracted from Ligusticum chuanxiong, a traditional Chinese medicine.

摘要

Rhizoma chuanxiong (CX), the dried rhizome of Ligusticum Chuangxiong Hort. (Umbelliferae), has been extensively used in mainland China as a traditional herbal medicine for treating cardio-/cerebrovascular diseases and gynecological disorders. However, the active components in CX, which are predominantly essential oils, generally exhibit poor stability (mostly photo-oxidation), high volatility, low aqueous solubility, and extensive gut/hepatic metabolism, all of which can significantly reduce their oral bioavailability and therapeutic efficacy. The present project has investigated the feasibility of utilizing three formulation approaches to circumvent the aforementioned problems associated with the peroral delivery of CX (as crude oil mixture or individual components).;The first approach involved inclusion of CX oil in beta-cyclodextrin (beta-CD) as solid granules using a coprecipitation method optimized with the aid of an orthogonal study design. The resulting CX oil granules were colorless and odorless with a median particle size of 11.38mum; were stable to heat, light and moisture, and readily soluble in simulated gastric and intestinal fluids. The granules were largely amorphous, as evidenced by an absence of the melting endotherm for beta-CD in the formulation could be largely explicated by the complexation behavior and hydration properties of the two polymers blended in different weight percentages, as substantiated by turbidity measurement, viscosity determination and FTIR analysis of the pure polymer mixtures as well as swelling measurement of the formulated tablets. The sustained release behavior of 3-BDPH from the tablet was dependent on the relative proportion of the two polymers present, and could be similarly explained by the changes in hydration and complexation behavior of the polymers during the penetration of aqueous fluid into the tablet matrix.;differential scanning calorimetric profile and the generation of much less intense and broader peaks in the powder X-ray diffraction pattern compared to beta-CD. FTIR analysis revealed significant physical interactions between CX oil and beta-CD in the granules, possibly due to complexation. Results from phase solubility measurements and proton nuclear magnetic resonance ( 1H-NMR) analysis of pure 3-butylidenephthalide (3-BDPH), a representative CX component, lend some support for the formation of a 1:1 stoichiometric inclusion complex between 3-BDPH and beta-CD.;The second approach involved incorporation of CX oil into surfactant micelles and liquid crystals as a self-emulsifying drug delivery system (SEDDS). An optimal formulation was developed through a judicial choice of excipients (lipids and surfactants/cosurfactant) and their proper combination in the correct proportions, as determined by the spontaneity of the emulsification process and the change in emulsion droplet size. The formulation was readily dispersible in water upon mild agitation, free from unpleasant odor, and stable in soft gelatin capsules for a storage period of at least 12 months under ambient condition. The optimal utilization of the lipid and surfactant blends in defined proportions in the formulation was further substantiated by interfacial tension determination and equilibrium phase analysis.;The third approach involved formulation of 3-BDPH (or crude CX oil) into a sustained-release buccoadhesive tablet, based on a systematic evaluation of the adhesive properties of two polymers (Carbopol 974P and hydroxypropyl methylcellulose K4M) used in the formulation. The adhesive properties of the formulation could be largely explicated by the complexation behavior and hydration properties of the two polymers blended in different weight percentages, as substantiated by turbidity measurement, viscosity determination and FTIR analysis of the pure polymer mixtures as well as swelling measurement of the formulated tablets. The sustained release behavior of 3-BDPH from the tablet was dependent on the relative proportion of the two polymers present, and could be similarly explained by the changes in hydration and complexation behavior of the polymers during the penetration of aqueous fluid into the tablet matrix.