Sanguis Draxonis flavoniod self-emulsifying microemulsion liquid
Technical field
The present invention relates to Sanguis Draxonis flavoniod self-emulsifying microemulsion liquid, particularly, capsule of the Sanguis Draxonis flavoniod self-emulsifying microemulsion liquid that the present invention relates to include and preparation method thereof.
Background technology
Sanguis Draxonis (Dragon ' s Blood), have another name called Sanguis Draxonis, be mainly derived from the resin of Palmae Daemonorops (Dae-monorops) and Liliaceae dracaena (Dracaena) 10 various plants, be traditional rare Chinese medicine, beginning is stated from Tang Materia Medica, in China's medicinal history that has more than 1500 year among the people.Have detumescence, antiinflammatory, pain relieving, stop blooding, invigorate blood circulation, effect such as removing the necrotic tissue and promoting granulation.Compendium of Material Medica claims that it is the panacea of invigorating blood circulation.Be the traditional Chinese medical science promoting blood circulation to remove blood stasis and hemorrhage commonly used.According to textual criticism, the used Sanguis Draxonis of Song Yiqian is based on the resin of Liliaceae dracaena plant woody part, bright, clear since used Sanguis Draxonis then based on the secretions of Palmae Daemonorops plant.Its source relies on import for a long time.For a change Sanguis Draxonis relies on the situation of import over the years, just carry out the prospecting in Sanguis Draxonis medicine source from the beginning of the seventies in Yunnan and Guangxi emphasis, the famous botanist Cai Xitao professor of China at first finds dracaena cambodiana Pierre in the southern regions of the Yunnan Province, thinks that through preliminary study it makes the Sanguis Draxonis Application Prospect." Yunnan Province's drug standard " (1974) have recorded this Sanguis Draxonis, and plant-origin is dracaena cambodiana Pierre Dracaena canbodiana Pierreex Gagnep.." Chinese Plants will " the 14 volume revision dracaena cambodiana Pierre formal name used at school determine that its former plant is a Dracaena cochinchinensis, so the Yunnan Sanguis Draxonis is consistent with the plant-origin of Guangxi Sanguis Draxonis.Domestic Dragon Blood proves that through drug effect, toxicity and clinical research in more than 20 years its every index meets or exceeds present import Sanguis Draxonis, can be used as Sanguis Draxonis fully and uses.
Domestic Dragon Blood (Sanguis Draxonis) derives from dracaena cambodiana Pierre Dracaena canbodianaPierreex Gagnep..Domestic Dragon Blood mainly contains flavonoid, volatile oil, cardiotonic glycoside, anthraquinone, tannin and other phenoloid.
Modern medicine study confirms that Sanguis Draxonis has the body of improvement microcirculation, improves effects such as body's immunity.It can make the blood that is in hypercoagulability circulate again, plays function of promoting blood circulation to disperse blood clots; The blood that is in hypocoagulability is solidified at blood vessel cut place and make stopped bleeding, play anastaltic effect, have dual regulation aspect the Chinese traditional treatment blood disorder.Be mainly used in coronary heart disease, hyperlipidemia, cerebral infarction, peptic ulcer, upper respiratory tract hemorrhage, gastritis, colitis, type ii diabetes, hyperthyroidism etc. clinically.
Sanguis Draxonis is widely used in clinical multiple treatment of diseases as the panacea of invigorating blood circulation, and is evident in efficacy reliable, has no side effect, and is national essential drugs.But have only Sanguis Draxonis powder or Sanguis Draxonis powder capsule at present for clinical use, taking dose is big, thereby has limited its range of application.Water insoluble owing to Sanguis Draxonis simultaneously, absorption difference, bioavailability is not high, and its good drug effect is not fully exerted.
At the shortcoming of the former medicated powder of above-mentioned Sanguis Draxonis, prior art has proposed multiple improving one's methods.
For example CN1265321A discloses a kind of Resina Draconis preparation as one and preparation method thereof, described preparation is mixed and made into the Sanguis Draxonis solid dispersion by the former medicated powder of Sanguis Draxonis and solid dispersion such as cyclodextrin, cellulose, Polyethylene Glycol, poloxamer or Myrij etc., further makes capsule, tablet etc. according to a conventional method.
CN1457835A discloses a kind of Sanguis Draxonis drop pill and preparation method thereof, and described drop pill is added in the substrate of melting such as Polyethylene Glycol, poloxamer, the stearic acid etc. by fine powder of dragons blood and makes.
CN1483432A discloses a kind of Sanguis Draxonis inclusion, and it is made up of fine powder of dragons blood and beta-schardinger dextrin-.
Because the crude drug that uses is the former medicated powder of Sanguis Draxonis, above-mentioned patent application still can not be satisfactory aspect dissolubility, absorbability and the bioavailability of Sanguis Draxonis composition and drug effect performance.
Modern study proves that the contained flavone compound of Sanguis Draxonis is the effective ingredient of Sanguis Draxonis blood circulation promoting and blood stasis dispelling.The present inventor discovers by intensive, with the Sanguis Draxonis flavoniod effective ingredient, adopt the self-emulsifying micro-emulsion technology, be made into liquid capsule, can obviously improve the dissolubility of Sanguis Draxonis flavoniod, significantly improve its bioavailability, give full play to it as invigorating blood circulation the effect of panacea, so and finished the present invention.
Self-emulsifying drug delivery system (Self-emulsifying drug delivery system, SEDDS) be under the no water situation, by active constituents of medicine and emulsifying agent and/or help Emulsion and thermodynamically stable uniform solution that optional solvent and/or dispersant form, generally be sub-packed in soft capsule or the transparent hard capsule (liquid capsule); Oral back is at the gastric juice aqueous phase, spontaneous formation granularity is the Emulsion about 5 microns owing to the existence of gastric peristalsis and emulsifying agent (being often referred to about 37 ℃) under the physiological environment temperature, thereby be distributed in fast in the whole gastrointestinal tract, reduced the stimulation that medicine causes with direct contact of gastrointestinal wall; The distribution of medicine between oil/water is biphase relies on the huge specific surface area of microemulsion and the stripping that improved water-insoluble drug greatly, improves bioavailability of medicament, can also avoid the hydrolysis of water unstable medicine and medicine to the gastrointestinal pessimal stimulation simultaneously.
Lipid-lowering medicine, antithrombotic are the medicines of global sales maximum, only fall the ester medicine and promptly reach 30,000,000,000 dollars the market share.Along with the world population senescence, its market share will enlarge.Simultaneously, currently used medicine mostly is insoluble chemical compound, and bioavailability is low, and the medication period limit for length, and liver and gall are all had side effect, like this as determined curative effect, and safety, the little natural Resina Draconis preparation as one of side effect will have immeasurable market potential.
Summary of the invention
The purpose of this invention is to provide a kind of Sanguis Draxonis flavoniod self-emulsifying microemulsion liquid, it is characterized in that: it contains Sanguis Draxonis flavoniod and emulsifying agent and/or helps Emulsion and optional solvent and/or dispersant.Generally speaking, contain the emulsifying agent of 5-90% Sanguis Draxonis flavoniod, 10-95% by weight and/or help Emulsion and 0-80% solvent and/or dispersant by weight from littleization fluid component; Preferably, contain the emulsifying agent of 5-80% Sanguis Draxonis flavoniod, 10-80% by weight and/or help Emulsion and 5-80% solvent and/or dispersant by weight; More preferably, contain the emulsifying agent of 5-50% Sanguis Draxonis flavoniod, 10-50% by weight and/or help Emulsion and 5-50% solvent and/or dispersant by weight.
Another object of the present invention provides a kind of capsule that includes Sanguis Draxonis flavoniod self-emulsifying microemulsion liquid, it is characterized in that: containing Sanguis Draxonis flavoniod and emulsifying agent and/or helping Emulsion and optional solvent and/or dispersant from littleization fluid component in the capsule.Generally speaking, contain the emulsifying agent of 5-90% Sanguis Draxonis flavoniod, 10-95% by weight and/or help Emulsion and 0-80% solvent and/or dispersant by weight from littleization fluid component; Preferably, contain the emulsifying agent of 5-80% Sanguis Draxonis flavoniod, 10-80% by weight and/or help Emulsion and 5-80% solvent and/or dispersant by weight; More preferably, contain the emulsifying agent of 5-50% Sanguis Draxonis flavoniod, 10-50% by weight and/or help Emulsion and 5-50% solvent and/or dispersant by weight.
Another object of the present invention is that the capsular preparation method that includes Sanguis Draxonis flavoniod self-emulsifying microemulsion liquid also is provided, it is characterized in that: Sanguis Draxonis flavoniod is added emulsifying agent and/or helps Emulsion, when selecting solvent and/or dispersant for use, can earlier Sanguis Draxonis flavoniod be dissolved in solvent and/or dispersant, after the mixing, stir, again by fill, seal and make the capsule that content is a transparent and homogeneous liquid, also claim liquid capsule.According to the difference of selecting cyst material for use, described liquid capsule can also be divided into soft capsule or hard capsule.
Can be used for emulsifying agent of the present invention and/or help Emulsion to include but not limited to: polysorbate, lecithin, soybean lecithin, sodium lauryl sulphate, mono stearate glyceryl ester, polyoxyethylene decanoyl/octanoyl glycerides, polyglycereol dioleate, poloxamer, Brij (Brij), Myrij (Mjri) and sucrose ester etc.; Preferably, polysorbate, lecithin, soybean lecithin, sodium lauryl sulphate, mono stearate glyceryl ester, polyoxyethylene decanoyl/octanoyl glycerides and polyglycereol dioleate.
Can be used for solvent of the present invention and/or dispersant is to be the polyalcohols of liquid under the room temperature, can exemplify for example Liquid Macrogol-600, propylene glycol or glycerol etc.
The preferred embodiment of the invention is to select for use solvent and/or dispersant as one of self emulsifying component.Under the situation of not selecting solvent and/or dispersant for use, emulsifying agent and/or to help Emulsion to select for use under the room temperature be the kind of liquid; The emulsifying agent of perhaps selecting for use and/or help that to have at least a kind of in the Emulsion composition be liquid, mixing the back is the kind of liquid.
In the embodiment preferred, the invention provides a kind of capsule that includes Sanguis Draxonis flavoniod self-emulsifying microemulsion liquid, it is characterized in that: containing the emulsifying agent of 5-50% Sanguis Draxonis flavoniod, 10-50% by weight and/or helping Emulsion and 5-50% solvent and/or dispersant by weight in the capsule from littleization fluid component, wherein, solvent and/or dispersant are the liquid polyhydric alcohols, for example are at least a in Liquid Macrogol-600, propylene glycol or the glycerol etc.
Sanguis Draxonis flavoniod of the present invention is known, perhaps can adopt conventional or known method preparation, referring to for example CN1482124A or CN1481788A.Sanguis Draxonis flavoniod can also adopt conventional mode refining, to improve content of effective in the Sanguis Draxonis flavoniod.Preferably Sanguis Draxonis flavoniod contains lourerin A5-30%, lourerin B 5-40%, and in lourerin A and/or lourerin B, general flavone content is more than 30%, more preferably more than 50%.
Preparation of the present invention can also contain other medicinal adjuvant for example antioxidant such as ascorbic acid, tea polyphenols, tocopherols etc.
Sanguis Draxonis flavoniod self emulsifying liquid of the present invention can adopt usual manner to make various pharmaceutical dosage forms.For example, can be processed into dosage forms such as tablet, capsule, solid dispersion sheet, fast-release tablet, drop pill by adding suitable pharmaceutic adjuvant.Preferred dosage form is that capsule comprises soft capsule and hard capsule.In capsule of the present invention, the capsule-wall material of employing does not have special qualification, can be the material that routine is used to prepare pharmaceutical soft capsule or hard capsule.
After Sanguis Draxonis flavoniod self-emulsifying microemulsion liquid of the present invention is oral, under physiological environment temperature and gentle agitation, can spontaneous emulsification formation granularity be lower than 5 microns Emulsion.
Sanguis Draxonis flavoniod make the microemulsion style as make include capsule after, make it have the advantage of self emulsifying medicinal liquid, for example, oral back is at the gastric juice aqueous phase, spontaneous formation granularity is the Emulsion about 5 microns owing to the existence of gastric peristalsis and emulsifying agent (being often referred to about 37 ℃) under the physiological environment temperature, thereby be distributed in fast in the whole gastrointestinal tract, reduced the stimulation that medicine causes with direct contact of gastrointestinal wall; Distribution between oil/water is biphase relies on the huge specific surface area of microemulsion and the stripping that improved the water-insoluble drug composition greatly, improves bioavailability of medicament, can also avoid the hydrolysis of water unstable medicine and medicine to the gastrointestinal pessimal stimulation simultaneously.Thereby overcome Sanguis Draxonis class medicine (comprising for example Sanguis Draxonis flavone of its extract) owing to water insoluble, absorption difference, bioavailability is not high, the defective that makes its good drug effect be difficult to give full play to.
Sanguis Draxonis flavoniod can improve its stability and bioavailability after making self-emulsifying microemulsion liquid, gives full play to its therapeutical effect as " panacea of invigorating blood circulation ".More be applicable to disease treatments such as coronary heart disease, hyperlipidemia, cerebral infarction, peptic ulcer, upper respiratory tract hemorrhage, gastritis, colitis, type ii diabetes, hyperthyroidism.
The specific embodiment
Embodiment 1
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 5
Liquid Macrogol 20
Polyoxyethylene Sorbitan Monooleate 5
Preparation method: taking polyethylene glycol 300, under 60-70 ℃, add Polyoxyethylene Sorbitan Monooleate, Sanguis Draxonis flavoniod, stir, insulation down fill in transparent hard capsule, seal promptly.
Embodiment 2
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 5
Polyoxyethylene decanoyl/octanoyl glycerides 20
Sodium lauryl sulphate 5
Preparation method: under 60-70 ℃, add polyoxyethylene decanoyl/octanoyl glycerides, sodium lauryl sulphate and Sanguis Draxonis flavoniod, stir, insulation down fill in transparent hard capsule, seal promptly.
Embodiment 3
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 10
Propylene glycol 20
Soybean lecithin 3
Polyoxyethylene Sorbitan Monooleate 12
Preparation method: be similar to embodiment 1.
Embodiment 4
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 10
PEG400 20
Soybean lecithin 3
Polyoxyethylene Sorbitan Monooleate 12
Preparation method: be similar to embodiment 1.
Embodiment 5
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 5
Propylene glycol 20
Lecithin 5
Polyoxyethylene Sorbitan Monooleate 10
Preparation method: be similar to embodiment 1.
Embodiment 6
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 10
Glycerol 20
Mono stearate glyceryl ester 5
Poloxamer 5
Preparation method: be similar to embodiment 1.
Embodiment 7
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 5
Liquid Macrogol 10
Soybean lecithin 5
Polysorbate-60 10
Preparation method: be similar to embodiment 1.
Embodiment 8
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 15
Propylene glycol 20
Polyglycereol dioleate 15
Preparation method: be similar to embodiment 1.
Embodiment 9
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 15
Propylene glycol 20
Lecithin 5
Myrij 10
Preparation method: be similar to embodiment 1.
Embodiment 10
Form from littleization liquid: (g)
Sanguis Draxonis flavoniod 5
Glycerol 20
Brij 15
Preparation method: be similar to embodiment 1.
Experimental example 1: Sanguis Draxonis flavoniod is to hemorheological influence
Experiment grouping and dosage design
Laboratory animal is divided into 6 groups at random:
(1) solvent control group: 10 of laboratory animals.Gavage 0.25%CMC 10ml/kg body weight every day, continuous seven days.
(2) blood stasis model group: 10 of laboratory animals.Gavage 0.25%CMC every day, 10ml/kg body weight, continuous seven days.
(3) positive drug FUFANG DANSHEN PIAN group: 10 of laboratory animals.Gavage compound Salviae Miltiorrhizae 1.0g/kg body weight every day, continuous seven days.
(4) the heavy dose of group of Sanguis Draxonis: 10 of laboratory animals.Gavage Sanguis Draxonis flavoniod 100mg/kg body weight every day, continuous seven days.
(5) dosage group in the Sanguis Draxonis: 10 of laboratory animals.Gavage Sanguis Draxonis flavoniod 50mg/kg body weight every day, continuous seven days.
(6) Sanguis Draxonis small dose group: 10 of laboratory animals.Gavage Sanguis Draxonis flavoniod 25mg/kg body weight every day, continuous seven days.
Experimental procedure: in the 7th day except that the blank group, each organizes the equal subcutaneous injection adrenalin hydrochloride of rat (Adr) 0.08ml/100g, totally twice, two minor tick is 4 hours, and (front and back each at interval 2 hours) were immersed rat in the 1 degree left and right sides frozen water 5 minutes between double injection Adr.Stop eating inferior abdominal aortic blood survey in morning hemorheology index (the full-automatic hemorheology measuring and analysing meter of MDK3200) after the disposal.The results are shown in Table 1:
Table 1 Sanguis Draxonis flavoniod is to the influence of hemorheology of rat (X ± SD)
Group |
Dosage (mg/kg) |
Whole blood contrast viscosity |
The plasma viscosity ratio |
Packed cell volume (%) |
Erythrocyte electrophoretic time |
Height is cut |
Low cutting |
Solvent control group blood stasis model group Sanguis Draxonis flavoniod Sanguis Draxonis flavoniod Sanguis Draxonis flavoniod FUFANG DANSHEN PIAN |
100 50 25 1000 |
4.25±0.07 4.95±0.32## 3.85±0.20*** 4.22±0.22** 4.47±0.36 3.95±0.17*** |
5.05±0.24 7.45±0.22### 5.25±0.73*** 5.85±0.67** 7.35±0.85 5.35±0.26*** |
1.15±0.08 1.65±0.03### 1.55±0.08* 1.53±0.06* 1.75±0.07 1.45±0.07*** |
39.5±1.6 43.1±4.6 31.8±3.2*** 29.1±1.4*** 33.8±2.4** 31.0±3.8** |
28.1±3.16 36.54±4.46# 27.50±2.14** 27.45±2.41*** 35.10±3.64 28.53±2.89** |
Annotate: the experiment of this experimental example uses the Sanguis Draxonis flavoniod material to adopt the self emulsifying liquid of embodiment 1, and dosage wherein refers to the Sanguis Draxonis flavoniod amount.
Compare with the solvent control group: # represents P<0.05, and ## represents P<0.01, and ### represents P<0.001; Compare with the blood stasis model group:
*Expression P<0.05,
*Expression P<0.01,
* *Expression P<0.001.
The result shows: Sanguis Draxonis flavoniod 100mg/kg body weight, 50mg/kg body weight continuous irrigation stomach 7 days, all can obviously reduce the high viscous state of stasis syndrome disease rat blood, whole blood viscosity, plasma viscosity and packed cell volume obviously reduce, shorten erythrocyte electrophoretic time, the effect of 25mg/kg group is not obvious.
Above embodiment is only for the present invention is further illustrated, and scope of the present invention is not subjected to the limitation of illustrated embodiment.