| Insomnia has become one of the widespread sufferings because of the increased mental pressure,which is probably the most common clinical symptom other than pain.Long-term lack of sleep results in attention-deficit and fatigue.It also affects physical and psychological health and quality of life,more severely,contributing to depression.There are three main kinds of clinical manifestations:Firstly,difficult to fall asleep,more common among young people;secondly,light sleep and dreamed a lot,mostly caused by fatigue;Thirdly,early awakening,not difficult to fall into sleep at night,but wake up in the early morning and unable to fall asleep again,which is common for the elderly.Hypnotics are generally taken nearly at bedtime to ensure a sufficient concentration and efficacy of the drug.Different types of insomnia should select corresponding drugs.Having difficulty in falling asleep,usually will choose short half-life(0.5?3h)drugs,such as Secobarbital,Clonazepam,etc;having light sleep can use drugs of longer half-life(6?8 h),such as Estazolam,Zopiclone,etc;for early waking type,you need to take long half-life(12?15 h)drugs,such as Nitrazepam.The long-term usage of hypnotics will cause adverse reactions,drug resistance or addictive;especially for long half-life drug,it has a greater risk in drug safety.The early awakening type of insomnia,is characterized by waking up before the regular sleep period,most about two to four A.M.,and can not fall asleep again.According to the survey,15%of adults and 50%of the elderly patients suffer from this insomnia.But there is still no drugs available for early awakening,whether in China or abroad.Therefore,the ideal drugs for early waking Insomnia are still missing.Gastrodin,the main active constituent of Gastrodia elata Blume(called"Tianma" in Chinese),a famous traditional Chinese herbal medicine,is widely used in the clinical treatment for headaches,insomnia,neurasthenia and other syndromes.Because of its high elimination rate,Gastrodin was favored by the majority of the patients,of which the domestic market shares ranked fourth in that of sedative hypnotics.Its annual sales growth was over 50%.Acetagastrodin derived from gastrodin by acetylation reaction,which was similar to gastrodin in treatment for insomnia,neurasthenia,vascular headache and nervous headache,etc.It reported that the sedation index of acetagastrodin is 1.7 times than that of gastrodin and its treatment of neurasthenia and vascular headache was much better.Because of their similarities,like clinical effects,rapid absorption and fewer adverse reactions,they were selected to be developed into a new drug delivery system for early waking type of insomnia,aiming to perform a automatic pulse release after a few hours.Now the available forms of gastrodin and acetagastrodin are tablets,capsules,injections and granules.Drugs of short biological half-life can be developed into the chronopharmaceutical delivery system,which has good application and market prospects.The purpose of this study was to develop the chronopharmaceutical delivery system.Prior to that,the physiochemical properties and the intestinal absorption characteristics of gastrodin and acetagastrodin were studied.We designed two types of the chronopharmaceutical delivery systems.One is time-dependent,coated with water-insoluble material;the other is pH-dependent,coated with enteric polymer.A certain release time lag is achieved by balancing the amount of the disintegrating agent and coating thickness when water molecule penetrated the film.The pH-dependent delivery system does not release in the stomach,but releases rapidly after getting into the intestine.We also evaluated the qualities of the two kinds of preparations.The methodologies and results are presented in the following sections.1.Physicochemical properties and intestinal absorption of gastrodinThis study determined the stability and partition coefficient of gastrodin.The results demonstrated that gastrodin was a highly water-soluble phenolic glucoside with poor liposolubility and great stability.Its saturation solubility was approximately 0.45 g · mL-1 and the log P value determined in n-octanol/water system was-1.99,which was absorbed sufficiently and rapidly in the intestine.In situ intestinal perfusion studies validated that the absorption of gastrodin(50 and 200 ?g · mL-1)in the four intestinal segments was significantly different and the Peff values in the duodenum,jejunum and ileum were higher than 1.0,which indicated that gastrodin could be well absorbed in the intestine.The absorption rate of gastrodin in the colon was far lower than that in the other intestinal segments and the Peff at high concentration(200 ?g·mL-1)was the same as that at low concentration(50 ?g·mL-1).When gastrodin was administered in combination with glucose,the permeability coefficient reduced to 1/9 of the original,which implied that the glucose obviously inhibited the intestinal absorption of gastrodin.2.Physicochemical properties and intestinal absorption of acetagastrodinThe physicochemical properties of acetagastrodin were studied,including the equilibrium solubility,oil/water partition coefficient and its stability interrelated to pH value.Moreover,its intestinal absorption characteristics was also investigated.The results showed that the equilibrium solubility in water was about 300 ?g·mL-1,almost not affected by pH value,and the partition coefficient LogP value was about1.1 under acidic and neutral conditions.Acetagastrodin presented high liposolubility and very slight solubility in water.It would degradate in strong acidic and alkaline conditions and remains stable in the vicinity of pH 5.0.Acetagastrodin showed better absorption in duodenum and colon than that in jejunum and ileum and the average effective permeability coefficient was about 0.9.As results showed,gastrodin presented strong stability,high water-solubility and good intestinal absorption.However,Acetagastrodin was very slightly soluble in water and can be easily absorbed by the body,but unstable in strong acidic and alkaline conditions.Preliminary study found that acetagastrodin was absorbed by passive diffusion and no prototype existed.Acetagastrodin would quickly take off acetyl through the phase I metabolism and penetrated the intestinal mucosa after oral administration,which resulted to its high intestinal permeability rate,but slightly lower than that of gastrodin and gastrodigenin.The absorption mechanism of acetagastrodin varied from that of gadtrodin and not transported by carrier,similar to gastrodigenin with water and lipid amphiphilic.The metabolites were substances removed with different numbers of acetyl and their isomers,which presented a complex and dynamic metabolic process.From the perspective of new formulation,gastrodin was considered to be more preferable for the development of chronopharmaceutical delivery system.3.The chronopharmacokinetic study of gastrodinAccording to previous studies,gastrodin was well absorbed via some glucose transporters and inhibited by high level of glucose.Therefore,it is necessary to clarify the chronopharmacokinetics of gastrodin to provide a basis for its rational application and the design of chronopharmaceutical delivery system.The effect of food(glucose)on gastrodin pharmacokinetics was measured.18 healthy male Wistar rats were randomly divided into three groups,orally administered with 200 mg·kg-1 gastrodin,and then respectively co-administered with glucose to make a analog eating,at a single dose of 2 g per kilogram,30 min before or after administration of gastrodin.When administered with glucose after 30 min,the pharmacokinetics parameter of gastrodin,Cmax?was 293.26 ± 20.06 ?g·mL-1,the highest of the three groups and Tmax was 24.00±5.48 min.When co-administered with glucose,Cmax,of gastrodin was decreased to only 177.67 ± 11.39?g· mL-1 and Tmax was delayed to 53.33 ± 5.16 min,which was consistent to the finding.The Cmax of gastrodin,When pre-administered with glucose,was also decreased to 187.71 ±57.90?g·mL-1 and the Tmax was also delayed.Tmax,Cmax,MRT of the three groups were significantly different.However,the AUC showed no significant difference.Due to elevated glucose levels,Tmax increased and Cmax decreased to 1/2,the absorption rate of gastrodin significantly delayed.Gastrodin capsules or ordinary tablets can achieve higher blood concentration before eating and foods containing glucose would obviously delay the absorption of gastrodin.We also investigated the effect of different administration time on the pharmacokinetics of gastrodin under fasting or eating conditions.48 healthy male Wistar rats were randomly divided into fasting and feeding groups of six rats each at 4 circadian stages,orally administered with 200 mg kg-1 gastrodin at four local clock times:00:00,6:00,12:00,18:00.After 30 min administered with gastrodin in the feeding group,glucose was administered.The pharmacokinetic parameters were calculated according to non-compartmental model.At the fasting group,the AUC was maximal at 12:00(11994.28 ? 2190.62,?g min ml-1),varied to the administration time of gastrodin accordingly(p<0.05).The maximal and the minimal Cmax values were obtained when administered at 00:00 and 18:00,respectively.Whereas,Tmax,k showed no significant difference.The pharmacokinetics parameters of gastrodin,following glucose administration,Cmax?Tmax?AUC remained stable for all treated groups.The AUC was maximal when administered at 12:00.It indicated that Cmax?AUC?MRT for the fasting group followed a circadian rhythm.Whereas,there was no significant difference of the parameters for the feeding group.The present study discovered the importance of gastrodin administration time because of the pharmacokinetics variables that related to eating.Viewed from these confirmation,administration before meals is desirable for ordinary tablets.When taking before bedtime,3-4 h apart from meals,the glucose level decayed and would not influence the pharmacokinetic process of gastrodin.Thus,a circadian rhythm of gastrodin did not impact its chronopharmaceutical delivery system.4.Optimize the time-dependent chronopharmaceutical delivery system of gastrodinOn the basis of the pre-formulation studies,we prepared the time-dependent chronopharmaceutical delivery system of gastrodin.We screened four kinds of disintegrants,cCMC-Na,CMS-Na,PVPP,L-HPC.It appeared that,cCMC-Na had greater advantage of disintegrating ability and was then selected as the disintegrant.In addition,we investigated the relation of several host factors,the proportion of diluent,the core weight,increased weight of the isolation layer and the controlled release layer,to the release time lag.Using the method of the response surface methodology(RSM),we got the optimized prescription(1000 pieces).The prescription of tablet core was that,gastrodin 25 g,lactose 35 g,microcrystalline cellulose 35 g,cCMC-Na 1 g,silica powder 1 g,magnesium stearate 1 g and the coating layers was that,the isolated layer Opadry 5%,the controlled layer surelease 8%.The optimized prescription was verified and we successfully prepared the time-dependent chronopharmaceutical delivery system of gastrodin.5.Evaluation of the time-dependent chronopharmaceutical delivery system of gastrodinWe investigated the stability of the formulation and found that the release time lag will significantly shorten at the condition of high humidity and high temperature;the light did not affect its stability.Furthermore,its release mechanism was studied.The greater the osmotic pressure was,the slower the release rate was.When water molecule penetrated into the tablet,the drug tended to release rapidly and the coating film split and no changes of coating film was found during the release.6.Optimize the pH-dependent chronopharmaceutical delivery system of gastrodinThe pH-dependent chronopharmaceutical delivery system of gastrodin was prepared with the globally famous enteric polymer(Eudragit L100-55),a kind of the fully formulated coating system,which provided a consistent,reproducible enteric feature.On the basis of single factor test,we selected three critical factors:the ratio of lactose and microcrystalline cellulose,the dosage of disintegrating agents PVPP and the weight gain of enteric layer to optimize the prescription by orthogonal optimization tests.We obtained the optimal formulation:lactose:micro microcrystalline cellulose 2:1.PVPP in an amount of 15 g/1000 tablets,enteric layer weight gain 8%.The pH-dependent chronopharmaceutical delivery system of gastrodin delayed for 2 or 3 h to release with excellent reproducibility,which was easy to industrialize.7.Evaluation of the pH-dependent chronopharmaceutical delivery system of gastrodinThe pH-dependent chronopharmaceutical delivery system of gastrodin was not influenced by high humidity,high temperature and strong light.It was only related to pH value and released when pH ? 5.0.The formulation showed excellent uniformity and reproducibility and was proper for industry production.In summary,this paper firstly studied the physical and chemical properties of gastrodin and acetagastrodin and their intestinal absorption characteristics.By comparation,we chose gastrodin for the development of chronopharmaceutical delivery system.The effects of food and different administration time on gastrodin pharmacokinetics were investigated.A circadian rhythm of gastrodin did not impact the chronopharmaceutical delivery system.We developed and prepared two types of chronopharmaceutical delivery system of gastrodin referring to early awaking insomnia,which release rapidly after 2?4h. |
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