| Compound Danshen prescription was composed of Salvia miltiorrhiza,Radix Notoginseng and Borneol.It has the effect of activating blood circulation and removing blood stasis,regulating qi and relieving pain.It is used for chest obstruction caused by qi stagnation and blood stasis,chest tightness,prickly pain in precordial area and angina pectoris in coronary heart disease.It is reported that Salvia miltiorrhiza,Radix Notoginseng and their compatibility have therapeutic and protective effects on cerebral vessels.The purpose of this paper is to develop a Compound Danshen drug delivery system with brain targeting.At present,the most widely used is Compound Danshen dropping pills,Compound Danshen tablets and Compound Danshen capsules.Oral administration of drugs is slow in absorption,and its efficacy is easily affected by gastrointestinal function and gastrointestinal contents and has first-pass effect,but nasal administration can solve these problems.Nanosystem can promote the dissolution and permeation of drugs in nasal mucosa,improve the transmission from nasal cavity to brain,and improve the bioavailability and specificity of drugs.In situ gel is a kind of semisolid preparation which can be given in liquid state.Due to the change of physical and chemical parameters such as temperature,pH or ionic strength,the phase transition occurs immediately at the drug delivery site and is transformed into non-chemically crosslinked semisolid preparation.It has the advantages of convenient application,easy preparation,long residence time and slow controlled release.The pharmacokinetic parameters can reflect the dose-time rule and tissue distribution of drugs in vivo.OBJECTIVE:In this paper,the nasal drug delivery system,pharmacokinetics and brain targeting in rats of Compound Danshen nanoemulsion in situ gel were developed.METHODS:1.A high performance liquid chromatography?HPLC?method for the determination of Danshensu in vivo and in vitro was established.2.By investigating solubility,screening excipients,constructing pseudo-ternary phase diagram,optimizing and designing the optimum formulation of Compound Danshen nanoemulsion,the particle size,potential,transmittance,pH,stability and content of Compound Danshen were detected and determined.3.The formulation and properties of in situ gel were designed and optimized.4.Compound Danshen nanoemulsion in situ gel and Compound Danshen in situ gel were given by intranasal administration,and Compound Danshen drop pills were given by intragastric administration,keep the same dosage of Danshensu.After different times of administration,plasma,heart,liver,spleen,lung,kidney and brain tissues were taken respectively which were pretreated with protein precipitation method.The treated samples were detected by HPLC method and distribution of drugs in each tissue at each time was obtained.Then the pharmacokinetic parameters were obtained by DAS 3.0 software and the target parameters were calculated.RESULTS:1.The HPLC method of Danshensu in vivo and in vitro were accurate and reliable,and the results were reliable.2.The optimal formulation of Compound Danshen nanoemulsion is Capryol 90:CremophorELP:1,2-propanediol:water=2:9:9:180.TheCompoundDanshen nanoemulsion is a brown transparent system that experiment is confirmed to be O/W nanoemulsion.The particle size was 16.79±0.17 nm,PDI was 0.147±0.029,Zeta potential was-1.99±0.59 mV,pH was5.32.The Compound Danshen nanoemulsion had good mechanical stability,temperature stability and long-term stability.The content of Danshensu in Compound Danshen nanoemulsion is 8.64±2.00 mg·mL-11 determined by HPLC.3.The optimal formulation of Compound Danshen nanoemulsion in situ gel was selected as Capryol 90:Cremophor ELP:1,2-propanediol:Poloxamer 407:Poloxamer188:water=4:18:18:72:27:360.The particle size was 20.55±0.26 nm,PDI was0.200±0.121,Zeta potential was-1.02±0.04 mV.Its morphology,distribution and size were observed by TEM,and the pH value was 5.31.The expansion coefficient was about 3%,Compound Danshen nanoemulsion in situ gel was brown transparent and fluidity was better at 4?.The viscosity and fluidity of Compound Danshen nanoemulsion in situ gel were increased at 37?.It was proved to be safe by the observation of nasal mucosa section,and the content of Danshensu in Compound Danshen nanoemulsion in situ gel was determined by HPLC was 7.19±0.275mg·mL-1with good mechanical stability and good stability at low temperature.4.The drug concentration in plasma and tissue of nasal nanoemulsion insitu gel was higher than that in nasal in situ gel,and the drug concentration in the brain was higher than that in stomach dripping pill,and the time of action was longer.DAS 3.0software showed that Danshensu was a two-compartment model in all tissues.The peak time of Danshensu in brain tissue were 1.33 h,0.83 h,11.53 h respectively,the peak concentration were 0.91?g·mL-1,0.59?g·mL-1,0.10?g·mL-1 respectively,The area under the curve were 6.73?g·mL-1·h,4.44?g·mL-1·h,0.92?g·mL-1·h and mean residence time were 7.45 h,7.83 h,6.69 h respectively.The uptake rate that nanoemulsion in situ gel opposite in situ gel was 1.52,uptake rate that nanoemulsion in situ gel opposite dropping pills was 7.31.The target effciency of nanoemulsion in situ gel,in situ gel and dropping pills were 19.57%,17.32%,2.60%in the brain respectively.The brain targeting efficiency of nanoemulsion in situ gel was 13.01%and dropping pill was 653.00%.CONCLUSIONS:1.The preparation method of Compound Danshen nanoemulsion was simple,reliable,stable,safe and non-irritating.2.After nasal administration,the pharmacokinetic results showed that the pharmacokinetic parameters of Compound Danshen nanoemulsion were superior to those of common in situ gel,and that the drug had obvious brain targeting properties compared with Compound Danshen dropping pills.The rate and degree of absorption was better than that of oral drops.3.It lays a foundation for the further study of the protective and therapeutic effects of compound Danshen nano-emulsion on cerebrovascular vessels,provides a reference for the study of new dosage forms and new ways of administration of compound salvia miltiorrhiza,and provides a basis for rational drug use and drug delivery scheme design.INNOVATION:1.The best prescription of Compound Danshen nanoemulsion in situ gel was obtained,which was safe,stable and suitable for nasal administration..2.The pharmacokinetic parameters and tissue distribution parameters of Compound Danshen nanoemulsion in situ gel in rats were obtained by nasal administration.In particular,the brain targeting parameters of salvia miltiorrhiza in situ gel were compared with those of marketable dropping pills.It was proved that the in situ gel of compound salvia miltiorrhiza was brain targeted. |
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