CN1823762A - Chuanxiong lactone kind component soft capsule for treating cardiovascular and cerebrovascular diseases - Google Patents
Chuanxiong lactone kind component soft capsule for treating cardiovascular and cerebrovascular diseases Download PDFInfo
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Abstract
A soft capsule of cnidium lactone for treating cardiovascular and cerebrovascular diseases is prepared from the active cnidium lactone type components, dispersing medium, plasticizer, disintegrant, coloring agent, optical mask and others.
Description
(1) technical field:
The present invention relates to the lactone soft capsule, particularly a kind of soft capsule of chuanxiong lactone kind component treatment cardiovascular and cerebrovascular disease.
(2) background technology:
Capsule generally can be divided into hard capsule, soft capsule and enteric coated capsule, pro ore.Hard capsule means and a certain amount of medicine added adjuvant is made uniform powder or grain packing is made in Capsules, or the medicine direct packaging is made in hollow glue is assisted.Soft capsule means a certain amount of medicinal liquid is sealed in spherical or the oval-shaped soft capsule material, available dropping preparation method or pressing preparation.Also claiming elastic capsule, is to be made by gelatinum pro capsulae, glycerol or suitable medicinal materials.Enteric coated capsule means that hard capsule or soft capsule handle or process with other proper method through pharmaceutical polymers, and its softgel shell is insoluble to gastric juice, but can be in intestinal juice disintegrate and release of active ingredients.Soft capsule medicine, health food are used the natural curative effect composition that extracts more from animals and plants, its purity height, healthy nutritive value are big, and carry and taking convenience.It is good that the advantage of soft capsule preparation is to have bioavailability, sealing, safety, and medicament is stable, and dosage is accurate, and good looking appearance carries and characteristics such as easy to use.
Soft capsule preparation the earliest has vitamin A, D soft gelatin capsule, invented rotation punch die encapsulation machine from 1933, output is improved greatly, cost declines to a great extent, and European and American countries adopts one after another, and constantly plant equipment is made improvements, make capsule can not only load liquid, pasty state software medicine, develop into again and can load group's powder, volume grain etc., kind and output constantly increase.Soft capsule preparation is because the soft capsule product have fundamentally been broken through traditional ampere bottle, tablet, pill, unguentum, be direct splendid attire content packaged form, so it has some special advantages, also more and more be subjected to the favor of consumer, domestic and abroad market prospect is wide, and development potentiality is huge.Just because of above advantage, so in recent years, Alaska deep sea fish oil, lecithin, the two balls of zinc calcium are impacting continental market, and these nutriments are all made the form of the soft capsule preparation that outward appearance is beautiful, mouthfeel is good, obtain the favor of numerous consumers.External very popular soft capsule medicine health food, nearly more than 2000 kinds, China every year will be from the soft capsule of more than 200,000,000 dollar of external import.Soft capsule becomes the packing new trend.The popular packing in international market is based on soft capsule, not only has been easy to carry but also health.In the world the R and D of soft capsule are paid much attention in recent years, soft capsule preparation is also in continuous development.The whole world has nearly ten thousand of revolving die formula soft capsule makers, 7,000,000 hundred million of annual productions at present.The U.S. is maximum in the world soft capsule manufacturer, is provided with nearly 20 tame subsidiaries in tens countries, and sales volume accounts for 70% of soft capsule market, the whole world.The company that also has Germany and Britain that sales volume is bigger.About 400,000,000 dollars of present global soft capsule sales volume, wherein the large percentage that accounts for of tonic nutriment reaches more than 70% the most for a long time, and vast market is arranged in developed country.
Owing to soft capsule preparation is the dosage form that a kind of relative difficult is produced, technical equipment requires high, and is strongly professional, and the pharmaceutical factory of therefore being engaged in the production soft capsule preparation is less.External this product is all born by professional soft capsule factory, and pharmaceutical factory or other factory all commence business with the consigned processing form, and its formulation and technology and patent are all maintained secrecy, so soft capsule preparation production is affected.China begins to produce soft capsule in the sixties, and behind the soft capsule preparation production equipment, poor product quality is before the damp production not before the seventies.Late nineteen seventies; China begins to introduce and digests external advanced revolving die machine, equipment, production capacity and technical merit large increase; at present China has had surplus the soft capsule maker 70; account for 10% of the world, half is wherein arranged from state's imports such as the U.S., Japan, Britain, Italy and Australia.There is more than 40 house in manufacturer, and more than 70 hundred million of annual productions account for the world 10%, but of less types, have only 40 surplus, account for the world about 1%.Kind is also relatively more dull, and main production kind has MAITONG JIAONANG, vitamin E soft gelatin capsule, Radix Oenotherae erythrosepalae soft gelatin capsule, Capsulae Duoxikang etc., and each factory's duplication of production.In addition, at face shaping, different purposes kinds, also there are many gaps with the developmental research of aspects such as technology preparation in product quality with comparing abroad.
Rhizoma Chuanxiong is a Umbelliferae herbaceos perennial Ligusticum wallichii Franch rhizome.Mainly originate in ground such as Sichuan, Hebei, the Inner Mongol, Gansu.Rhizoma Chuanxiong is one of clinical the most frequently used Chinese medicine, but this medicine blood-activating and qi-promoting walk the table wind that becomes and open the stasis of blood in going into, the property of medicine is celebrated with versatility.Rhizoma Chuanxiong is coronary artery dilating significantly, increases arteria coronaria capacity and blood supply of cardiac muscle amount, and the myocardial oxygen delivery amount is increased, and reduces myocardial oxygen consumption, for alleviation coronary heart disease, angina pectoris better curative effect is arranged.Rhizoma Chuanxiong has inhibitory action to multiple Gram-negative intestinal.The contained alkaloid of Rhizoma Chuanxiong, ferulic acid, ligustrazine and cnidium lactone all have the smooth muscle spasmolysis effect.Cnidium lactone can be removed the tracheal smooth muscle spasm that acetylcholine histamine causes, stops the formation of immune complex, and inflammation is had inhibitory action, and it is evident in efficacy to be used for status asthmaticus.We from the Rhizoma Chuanxiong crude drug isolation identification several lactone chemical constituents, wherein chuanxiong lactone kind component accounts for 1.6% of Rhizoma Chuanxiong crude drug, is the main component of Rhizoma Chuanxiong.
Adopt isolated heart constant voltage perfusion method, perfusion rate with 0.5 ml/min, concentration is respectively the cnidium lactone A of 0.0125 mg/ml, 0.025 mg/ml and 0.05 mg/ml and K-H perfusate perfusion rat heart 10 minutes simultaneously, stopped whole-heartedly then to irritate 30 minutes, irritated again 60 minutes.The result shows, the chuanxiong lactone kind component pretreatment can improve coronary flow and the myocardial contraction that heart ischemia is irritated the phase again, reduce that quiver in the chamber and the incidence rate of chamber speed, make the lactic acid dehydrogenase (LDH) of myocardium homogenate, malonaldehyde (MDA) content reduce superoxide dismutase (SOD) increased activity.Confirm chuanxiong lactone kind component (4; 5-dihydro-3-cyclobutenyl benzene peptide) to the protective effect of isolated rat heart ischemical reperfusion injury; can increase coronary flow and myocardial contraction; not only reduce ARR incidence rate; and postpone ARR time of origin, shorten persistent period and recovery time.Release to LDH, MDA and SOD improves significantly.Dwindle by the ischemia pretreatment is mainly shown the protective effect of heart that myocardial infarct size, ischemia resisting pour into arrhythmia again, improve myocardial contraction, the release of diastolic function and biochemical substances etc.Therefore, chuanxiong lactone kind component provides new approaches to the measure of seeking more effective control ischemical reperfusion injury that proves of the protective effect of ischemia pretreatment and heart.
(3) summary of the invention:
The objective of the invention is to design a kind of soft capsule of chuanxiong lactone kind component treatment cardiovascular and cerebrovascular disease, damage has protective effect to heart ischemia reperfusion for it, can increase coronary flow and myocardial contraction, reduce ARR incidence rate, postpone ARR time of origin, shorten persistent period and recovery time; Said preparation can also effectively see through the human body blood brain barrier, and through cerebral infarction focus dwindles that infarction size, ischemia resisting pour into again, microcirculation improvement, neuroprotective cell function and the release etc. of regulating biochemical substances.
Technical scheme of the present invention: a kind of soft capsule of chuanxiong lactone kind component treatment cardiovascular and cerebrovascular disease, it is characterized in that soft capsule comprises that the principal agent chuanxiong lactone kind component reaches the accessory drugs that comprises plasticizer, disintegrating agent, coloring agent, opacifier and other related component based on disperse medium, the ratio of said principal agent and accessory drugs is 0.01%-80%: 99.99%-20%.
Said principal agent chuanxiong lactone kind component mainly from the Rhizoma Chuanxiong medical material; It is lactone compound that the zoopery proof enters Rhizoma Chuanxiong chemical constituents maximum in the animal brain.The Rhizoma Chuanxiong crude drug has been carried out extracting processing, and water extract obtains chemical constituent after extracting.Adopt the analysis of high performance liquid chromatogram-mass spectrometry method (HPLC-MS) to find, can identify (seeing accompanying drawing 1, accompanying drawing 2, accompanying drawing 3) to the lactone chemical constituent of the principal character peak correspondence of finger printing with HPLC-MS.
The preferred proportion of above-mentioned said principal agent chuanxiong lactone kind component (4,5-dihydro-3-cyclobutenyl benzene and isomer) in soft capsule is 0.05%-50%, and more preferably ratio is 0.1%-40%.
Above-mentioned said in accessory drugs be main disperse medium to account for soft capsule weight be 20%-99.99%, preferably about 50%-99.95%, more preferably from about 60%-99.9%.
Said disperse medium is a dispersant, can make principal agent be evenly distributed in substrate inside, guarantees the accurate and preparation stability of its content, thereby guarantees the safety and effectiveness of medicine.
Above-mentioned said disperse medium includes but not limited to polyethylene glycols (PEG400-20000) and PVP, and PEG 400-20000 has induration to softgel shell, adds or does not add 5%～10% glycerol or propylene glycol, improves the water sorption of Polyethylene Glycol to the glue shell; Medicine dissolution is made the soft capsule administration in PEG, play good diluting effect, encystation behind the solution is made in dilution behind the principal agent, has guaranteed the accuracy of its content.
The polyethylene glycols that above-mentioned said disperse medium is got (PEG400-20000) and each vegetable oil, include but not limited to olive oil, Oleum Camelliae, oil with hydrogenated soybean, short chain vegetable oil, the PEG-40 castor oil hydrogenated, the PEG-60 castor oil hydrogenated, the PEG-35 Oleum Ricini, NPE-14, mineral oil and the combination between them.10%～80% oily wax mixture commonly used, general prescription is: 2 parts of oil with hydrogenated soybean, 1 part of montanic acid ester type waxes,, 5 parts of short chain vegetable oil (33～38 ℃ of fusing points).Many thixotropings of oil mass value is low, good fluidity, but be easy to seepage; Oil mass is few, good stability, but mobile poor, be difficult for pelleting.Oils can increase the dissolubility of steroid drugs, and low viscous oils can increase the flowability of capsule 's content.
The composition plasticizer that can have in the above-mentioned said accessory drugs accounts for the about 0.01%-85% of soft capsule weight, preferably about 0.05%-60%, more preferably from about 0.1%-40%; Said plasticizer includes but not limited to glycerol, polyhydric alcohol, xylitol, sorbitol, hydrogenated corn syrup and the combination between them.
Said plasticizer is meant the material that can make polymeric material increase plasticity, and they are boiling point height, more difficult evaporable liquid or low-melting solid normally.The purpose that adds plasticizer is to increase the plasticity of soft capsule, guarantees the good stretchability of soft capsule goods; Long-term its hardness that keeps makes it not yielding.The composition of plasticizer is very big to the influence of liquid in the soft capsule " microviscosity ", can influence the migration of material.
It is 0.01%-50% that the composition disintegrating agent that can have in the above-mentioned said accessory drugs accounts for soft capsule weight, is preferably 0.05%-30%, more preferably 0.1%-20%; The various disintegrating agents that add or do not add include but not limited to the carboxymethyl cellulose (CMC) of cellulose family, low degree of substitution hydroxypropyl cellulose, the degree of cross linking, crosslinked polyvinylpyrrolidone (PVP) and starch based such as carboxymethyl starch sodium, Sodium Hydroxymethyl Stalcs (DST), amylum pregelatinisatum, PEG400-20000, cyclodextrin, sorbitol, citric acid, sorbitol anhydride and the combination between them.
Said disintegrating agent is meant that in softgel shell a small amount of use can improve the material of the dissolution rate of soft capsule.
The composition colorant comprises soft capsule weight 0.001%-10% that can have in the above-mentioned said accessory drugs, preferably about 0.002%-5%, more preferably from about 0.005%-2%; Coloring agent includes but not limited to curcumin, various pharmaceutical grade dyestuff and the combination between them.
Said coloring agent is meant, in the oral soft capsule, needs to add in softgel shell or does not add an amount of coloring agent and pass through to suppress light, makes the content stable components.In addition, also be based on the consideration that is easy to distinguish kind or gives the gratified sense of patient's spirit sometimes.
The composition opacifier that can have in the above-mentioned said accessory drugs accounts for soft capsule weight 0.0001%-15%, preferably about 0.0002%-10%, more preferably from about 0.0005%-5%; Include but not limited to red, Huang and brown iron oxide, titanium dioxide and the combination between them.
Said opacifier is meant, adds opacifier and makes softgel shell opaque, reduces one of radioparent method of soft capsule shell.
Can there be other related component of composition to comprise wetting agent, suspending agent, flavoring agent, antioxidant, antiseptic in the above-mentioned said accessory drugs; Wetting agent generally is a surfactant, as polyoxyethylene ether list oleic acid sorbitol ester ( tween series 20,40,60,80), and single oleic acid sorbitan ester ( span series 20,40,60,80) etc.; Suspending agent can be selected for use can increase the solid matter that disperses media viscosity, as Cera Flava, aluminum monostearate, ethyl cellulose etc.; Flavoring agent can be chosen wantonly; Antioxidant can be selected dimension E, dimension C etc. for use; Antiseptic methyl parahydroxybenzoate commonly used and propyl p-hydroxybenzoate; It is 0%-15% that said other related component accounts for soft capsule weight, preferred 0%-10%, more preferably from about 0%-5%.
Surfactants such as said polyglycerin ester as wetting agent, sucrose ester are made soft capsule to reach purpose efficiently.The adding of suspending agent can improve the dispersity of principal agent in disperse medium.The adding of antioxidant, soft capsule excess moisture or deposit in the bigger environment of humidity can be quickened the oxidation of gelatin, makes that cyst wall is aging to be accelerated, and causes disintegration time to prolong, and therefore must add proper quantity of antioxidant sometimes.The adding of flavoring agent, flavoring agent such as sucrose can increase sweet taste, but chewing, and regulate hardness.The adding of antiseptic, methyl parahydroxybenzoate commonly used and propyl p-hydroxybenzoate.
The manufacturing of the soft capsule of said chuanxiong lactone kind component treatment cardiovascular and cerebrovascular disease is a conventional manufacture method of utilizing the conventional manufacturing equipment and the soft capsule of soft capsule.
It adopts the production equipment preparation of the relevant soft capsule in present technique field:
Encapsulating machine
The key technical indexes:
1. encapsulated content species: liquid, ointment, tablet, powder and combination mutually
2. roll the mould size: Φ 103 * 180mm (is different from 6 inches and rolls mould Φ 103 * 152mm)
3. roll the mould rotating speed: the 0-6rpm infinitely variable speeds
4. fluid single plunger quantity delivered: 0-2ml (the special order of 0-3ml)
5. finished capsule product loading amount precision: liquid ± 2% other ± 5%
Soft capsule washing machine
Ten thousand/hour of cleansing power: 4-5
Cleanout fluid kind: organic solvent cleanout fluid consumptions such as anhydrous alcohol, 80 liters
Cleanout fluid is changed at interval: 4-6 hour
Plant capacity: 2kW 380V/50Hz
Drying machine
The key technical indexes:
(1) rotating cage size: Φ 450 * 600mm;
(2) rotating cage rotating speed: 15rpm;
(3) power of motor: 4 * 0.1kW;
(4) fan delivery: 55m^3/min;
(5) fan pressure: 300Pa;
(6) power of fan: 2 * 0.4kW;
Other equipment
Soft capsule rolls mould, vacuum stirring bucket, insulation storage bucket.
The soft capsule quality standard of the lactone component for treating cardiovascular and cerebrovascular disease among the present invention is as follows:
1. soft capsule meets following pertinent regulations at production and storage period among the present invention.
1.1 small dose drug is released the capsule 's content mix homogeneously with suitable diluent weighing apparatus.
1.2 the soft capsule surface is clean and tidy, no bonding, distortion or fracture phenomena, no foreign odor.
1.3 sealed storage.
2. the loading amount difference limit of content uniformity soft capsule meets following provisions.
| Par | The content uniformity limit |
| 0.30g below | ±10％ |
| 0.30 or more than the 0.30g | ±7.5％ |
3. inspection technique
Get 20 of test samples, after weight decided in accurate respectively title, inclining content, and accurate the title decided softgel shell weight, obtains tolerant loading amount of every intragranular and average loading amount.Every loading amount is compared with average loading amount, exceeds no more than 2 of the capsule of difference limit, and 1 times of 1 overrun must not be arranged.
4. disintegration
Get 6 of test samples, the method under photo agent item disintegration, each all disintegrate and in 30 minutes by screen cloth (except the softgel shell fragment)
5. note
5.1 simulated gastric fluid is got dilute hydrochloric acid 16.4ml, adds about 800ml of water and pepsin 10g, after shaking up, adds the water weighing apparatus and releases to 100ml, promptly.
5.2 simulated intestinal fluid is got potassium dihydrogen phosphate 6.8g, adds water 500ml and makes dissolving, regulates pH value to 6.8 with 0.4% sodium hydroxide solution and gets pancreatin 10g in addition, amount of water makes dissolving, after two liquid are mixed, thin up to 1000ml promptly.
Superiority of the present invention is: 1, can effectively see through blood brain barrier, through focus, dwindle that infarction size, ischemia resisting pour into again, microcirculation improvement, protect the release of cell function and adjusting biochemical substances etc., developed the medicine of the another soft capsule dosage form of lactone component for treating cardiovascular and cerebrovascular disease; 2, product appearance novel form, rich color are tempting, easily swallow, and to the attractive and novel sense of consumer, can effectively prevent personation; 3, product one-shot forming the secondary capsule in use can not occur and pollute, and packing is smart little, and its net content can be designed to ampoule, has guaranteed that consumer uses the cleanliness factor of product at every turn; 4, safe to carry, be used the instant packed thing of this series products, the people that go out are separately carried according to consumption becomes possibility; 5, soft capsule is difficult for brokenly, safe to carry, when being suitable for the daily house of consumer and using, is more suitable for people and is being away on a vacation, is using when tourism and field work; 6, be the exploitation new results of Chinese medicine west system, have vast business development prospect.
(4) description of drawings:
Fig. 1: the Rhizoma Chuanxiong crude drug has been carried out extracting processing, and extract obtains chemical constituent after extracting.1-ferulic acid, 2-6 chuanxiong lactone kind component (Fig.1 Chromatograms of waterextract from Chuanxiong 1-ferulic acid, 2-Senkyunolide I, 3-Senkyunolide H, 4-IsomSenkyunolide 5-butylidene-phthalide, 6-Ligustilide).
Fig. 2: adopt high performance liquid chromatogram-mass spectrometry method (HPLC-MS) that its main fragment ion peak is analyzed, analyze the Rhizoma Chuanxiong extraction phase with HPLC-MS, the chemical constituent of main chromatographic peak 3 correspondences has identical molecular ion peak [M+H] among the total ion current figure
+(m/z 225), molecule easily loses a part water, forms fragment ion 207 (Fig.2 MS spectra of peaks 3 inbenzene extracts chromatogram).
Fig. 3: adopt high performance liquid chromatogram-mass spectrometry method (HPLC-MS) that its main fragment ion peak is analyzed, illustrate the characteristic peak of chuanxiong lactone kind component (ligustilide) finger printing, molecular ion peak [M+H]
+(m/z 225) (Fig.3 Mass spectrum of compoundcollected at peak 6).
Fig. 4: detect wavelength at 270nm, the blank serum behind the rat administration 2hr, the HPLC chromatogram of administration serum respectively as Fig. 4 (a, b); Wherein: ultraviolet detection wavelength: 270nm, all the other chromatographic conditions are identical, ferulic acid, 2-5 chuanxiong lactone kind component;
4 (a) do not have the retention time of chuanxiong lactone kind component chromatographic peak at blank serum, and corresponding with Rhizoma Chuanxiong standard finger-print composition retention time, 4-(a) is blank serum rat blood serum chromatogram;
The chuanxiong lactone kind component chromatographic peak appears in 4 (b) administration serum; 4-(b) for the 2hr that takes medicine after experimental rat serum chromatogram.
Fig. 5: detect wavelength at 270nm, after the blank brain homogenate behind the rat administration 2hr, the administration HPLC chromatogram of brain homogenate respectively as Fig. 5 (a, b); Wherein: 2,3,5 chuanxiong lactone kind components
5 (a) do not have the retention time of chuanxiong lactone kind component chromatographic peak at blank brain homogenate, and corresponding with Rhizoma Chuanxiong standard finger-print composition retention time, 5-(a) is blank brain homogenate chromatogram;
The chuanxiong lactone kind component chromatographic peak appears in brain homogenate after 5 (b) administration, 5-(b) for the 2hr that takes medicine after experimental rat brain homogenate chromatogram.
Fig. 6: detect wavelength at 320nm, the blank serum behind the rat administration 2hr, the HPLC chromatogram of administration serum respectively as Fig. 6 (a, b); Wherein: ultraviolet detection wavelength: 320nm, the same 1-ferulic acid of all the other conditions, 5-degradation product;
6 (a) do not have the retention time of chuanxiong lactone kind component chromatographic peak at blank serum, and corresponding with Rhizoma Chuanxiong standard finger-print composition retention time, 6-(a) is blank serum rat blood serum chromatogram;
The chuanxiong lactone kind component chromatographic peak appears in 6 (b) administration serum, 6-(b) for the 2hr that takes medicine after experimental rat serum chromatogram.
Fig. 7: detect wavelength at 320nm, after the blank brain homogenate behind the rat administration 2hr, the administration HPLC chromatogram of brain homogenate respectively as Fig. 7 (a, b); Wherein: 1-ferulic acid, 5-chuanxiong lactone kind component;
7 (a) do not have the retention time of chuanxiong lactone kind component chromatographic peak at blank brain homogenate, and corresponding with Rhizoma Chuanxiong standard finger-print composition retention time, 7-(a) is blank brain homogenate chromatogram;
The chuanxiong lactone kind component chromatographic peak appears in brain homogenate after 7 (b) administration, 7-(b) for the 2hr that takes medicine after experimental rat brain homogenate chromatogram.
Fig. 8: after testing the time Changing Pattern animals administer of chuanxiong lactone kind component in administration front and back animal serum and the brain homogenate, getting different time points (0.5,1,2,4,6,8h) serum and brain homogenate analyzes, the HPLC chromatographic peak retention time of chuanxiong lactone kind component is drawn the working curve of chuanxiong lactone kind component concentration changes with time in laboratory animal serum and the brain homogenate;
8-(a) is chuanxiong lactone kind component peak area (concentration) time changing curve in the back serum of taking medicine;
8-(b) is chuanxiong lactone kind component peak area (concentration) time changing curve in the brain homogenate.
(5) specific embodiment:
Embodiment 1: the chuanxiong lactone kind component soft capsule
The following example illustrates specific embodiments of the present invention, and each component of soft capsule preparation is mixed, and changes glue, batching → soft capsule pellet press → fluid bed soft capsule predryer → ultrasound wave soft capsule cleaning machine
The full-automatic dry machine of ground feeding machine → crawler type → semi-automatic apsule and tablet is inspected machine → plastic-aluminum inner packing and outer package.
| Content | Prescription | Proportioning (Wt%) |
| Oil with hydrogenated soybean, short chain vegetable oil | 60.0 | |
| The PEG-400/ propylene glycol | 32.0 | |
| Ethyl cellulose | 2.0 | |
| Two imidazolidinyl urea/methyl parahydroxybenzoate | 1.0 | |
| Principal agent | Chuanxiong | 5 |
Embodiment 2: the chuanxiong lactone kind component soft capsule
Each component of soft capsule preparation is mixed, and changes glue, batching → soft capsule pellet press → fluid bed soft capsule predryer → ultrasound wave soft capsule cleaning machine
The full-automatic dry machine of ground feeding machine → crawler type → semi-automatic apsule and tablet is inspected machine → plastic-aluminum inner packing and outer package
| Content | Prescription | Proportioning (Wt%) |
| Olive oil, short chain vegetable oil | 65.0 | |
| The PEG-400/ isopropyl palmitate | 27.0 | |
| Vitamin E | 2.0 | |
| Propyl p-hydroxybenzoate | 1.0 | |
| Principal agent | Chuanxiong |
5 |
Embodiment 3: biological screening method research chuanxiong lactone kind component sees through blood brain barrier, reaches the time service curve of therapeutic effect
1. chromatographic condition is selected
HPLC: chromatographic column Nova-Pak
C18 (3.9 * 150mm); Mobile phase: methanol-water-acetic acid (35: 65: 0.5, V/V/V); Flow velocity 0.8mL/min; Ultraviolet detection wavelength: 270nm, 320nm; Sample size: 20 μ L.
MS: Atmosphere Pressure Chemical Ionization (APCI) (APCI); Sweep spacing: 1.00s; Mass range: m/z 100-300; AP+ detects.
2. experimental result
Serum, brain homogenate and blank serum after 270nm detects rat oral gavage 2hr, the HPLC chromatogram of blank brains are respectively as shown in Figure 4 and Figure 5.The retention time corresponding with Rhizoma Chuanxiong standard finger-print composition retention time (seeing accompanying drawing 4, accompanying drawing 5) of chuanxiong lactone kind component chromatographic peak in serum and brain homogenate.
When detecting with 320nm, the HPLC chromatogram of the serum behind the rat oral gavage 2hr, brain homogenate and blank serum, blank brains is respectively as Fig. 6, and is shown in Figure 7.As seen, taking medicine afterwards, ferulic acid (FA) has also entered in the brain homogenate.Enter FA serum and the brain homogenate as can be seen and variation has taken place the relative amount of chromatographic peak 5 from Fig. 6 (b) and Fig. 7 (b).In serum, FA is higher than peak 5 (degradation product) widely, and this is consistent with situation in the medical material; And in brain homogenate, peak 5 proves that significantly more than FA the brain barrier is to have necessarily optionally to the ingredient that enters in the brain.From structure peak 5 fat-soluble bigger as can be known, be easier to pass the brain barrier than FA.This result and human drug absorption's universal law is (sees accompanying drawing 6, accompanying drawing 7: i.e. the time Changing Pattern of chuanxiong lactone kind component in laboratory animal serum and the brain homogenate) that coincide.
By analyzing, get the HPLC chromatographic peak area of chuanxiong lactone kind component correspondence in different time points (0.5,1,2,4,6,8h) serum and the brain homogenate behind the animals administer, draw the working curve (seeing accompanying drawing 8) of chuanxiong lactone kind component concentration changes with time in laboratory animal serum and the brain homogenate.
By the biological screening method, prove that the chuanxiong lactone kind component absorption enters into animal blood, and the selective permeation blood brain barrier, effective ingredient enters animal brain and reaches therapeutic effect.
Claims (12)
1, a kind of soft capsule of chuanxiong lactone kind component treatment cardiovascular and cerebrovascular disease, it is characterized in that soft capsule comprises that the principal agent chuanxiong lactone kind component reaches the accessory drugs that comprises plasticizer, disintegrating agent, coloring agent, opacifier and other related component based on disperse medium, the ratio of said principal agent and accessory drugs is 0.01%-80%: 99.99%-20%.
2, treat the soft capsule of cardiovascular and cerebrovascular disease according to the said a kind of chuanxiong lactone kind component of claim 1, it is characterized in that said principal agent chuanxiong lactone kind component (4,5-dihydro-3-cyclobutenyl benzene and isomer) preferred proportion in soft capsule is 0.05%-50%, and more preferably ratio is 0.1%-40%.
3, treat the soft capsule of cardiovascular and cerebrovascular disease according to the said a kind of chuanxiong lactone kind component of claim 1, it is characterized in that said is that to account for soft capsule weight be 20%-99.99% to main disperse medium in accessory drugs, preferred about 50%-99.95%, more preferably from about 60%-99.9%.
4, treat the soft capsule of cardiovascular and cerebrovascular disease according to the said a kind of chuanxiong lactone kind component of claim 3, it is characterized in that said disperse medium includes but not limited to polyethylene glycols (PEG400-20000) and PVP, PEG 400-20000 has induration to softgel shell, add or do not add 5%～10% glycerol or propylene glycol, improve the water sorption of Polyethylene Glycol the glue shell.
5, soft capsule according to the said a kind of chuanxiong lactone kind component treatment cardiovascular and cerebrovascular disease of claim 4, it is characterized in that polyethylene glycols (PEG400-20000) and each vegetable oil that said disperse medium is got, include but not limited to olive oil, Oleum Camelliae, oil with hydrogenated soybean, the short chain vegetable oil, the PEG-40 castor oil hydrogenated, the PEG-60 castor oil hydrogenated, the PEG-35 Oleum Ricini, NPE-14, mineral oil and the combination between them, 10%～80% oily wax mixture commonly used, general prescription is: 2 parts of oil with hydrogenated soybean, 1 part of montanic acid ester type waxes, 5 parts of short chain vegetable oil (33～38 ℃ of fusing points).
6, treat the soft capsule of cardiovascular and cerebrovascular disease according to the said a kind of chuanxiong lactone kind component of claim 1, it is characterized in that the composition plasticizer that can have in the said accessory drugs accounts for the about 0.01%-85% of soft capsule weight, preferred about 0.05%-60%, more preferably from about 0.1%-40%; Said plasticizer includes but not limited to glycerol, polyhydric alcohol, xylitol, sorbitol, hydrogenated corn syrup and the combination between them.
7, treat the soft capsule of cardiovascular and cerebrovascular disease according to the said a kind of chuanxiong lactone kind component of claim 1, it is characterized in that it is 0.01%-50% that the composition disintegrating agent that can have in the said accessory drugs accounts for soft capsule weight, be preferably 0.05%-30%, more preferably 0.1%-20%; The various disintegrating agents that add or do not add include but not limited to the carboxymethyl cellulose (CMC) of cellulose family, low degree of substitution hydroxypropyl cellulose, the degree of cross linking, crosslinked polyvinylpyrrolidone (PVP) and starch based such as carboxymethyl starch sodium, Sodium Hydroxymethyl Stalcs (DST), amylum pregelatinisatum, PEG400-20000, cyclodextrin, sorbitol, citric acid, sorbitol anhydride and the combination between them.
8, treat the soft capsule of cardiovascular and cerebrovascular disease according to the said a kind of chuanxiong lactone kind component of claim 1, it is characterized in that the composition colorant comprises soft capsule weight 0.001%-10% that can have in the said accessory drugs, preferred about 0.002%-5%, more preferably from about 0.005%-2%; Coloring agent includes but not limited to curcumin, various pharmaceutical grade dyestuff and the combination between them.
9, treat the soft capsule of cardiovascular and cerebrovascular disease according to the said a kind of chuanxiong lactone kind component of claim 1, it is characterized in that the composition opacifier that can have in the said accessory drugs accounts for soft capsule weight 0.0001%-15%, preferred about 0.0002%-10%, more preferably from about 0.0005%-5%; Include but not limited to red, Huang and brown iron oxide, titanium dioxide and the combination between them.
10, according to the soft capsule of the said a kind of chuanxiong lactone kind component treatment cardiovascular and cerebrovascular disease of claim 1, it is characterized in that to have in the said accessory drugs other related component of composition to comprise wetting agent, suspending agent, flavoring agent, antioxidant, antiseptic; Wetting agent generally is a surfactant, as polyoxyethylene ether list oleic acid sorbitol ester (tween series 20,40,60,80), and single oleic acid sorbitan ester (span series 20,40,60,80) etc.; Suspending agent can be selected for use can increase the solid matter that disperses media viscosity, as Cera Flava, aluminum monostearate, ethyl cellulose etc.; Flavoring agent can be chosen usefulness wantonly; Antioxidant can be selected dimension E, dimension C etc. for use; Antiseptic methyl parahydroxybenzoate commonly used and propyl p-hydroxybenzoate; It is 0%-15% that said other related component accounts for soft capsule weight, preferred 0%-10%, more preferably from about 0%-5%.
11, treat the soft capsule of cardiovascular and cerebrovascular disease according to the said a kind of chuanxiong lactone kind component of claim 1, it is characterized in that principal agent chuanxiong lactone kind component 5%, accessory drugs oil with hydrogenated soybean, short chain vegetable oil 60.0%, PEG-400/ propylene glycol 32.0%, ethyl cellulose 2.0%, two imidazolidinyl urea/methyl parahydroxybenzoate 1.0%.
12, treat the soft capsule of cardiovascular and cerebrovascular disease according to the said a kind of chuanxiong lactone kind component of claim 1, it is characterized in that principal agent chuanxiong lactone kind component 5%, olive oil, short chain vegetable oil 65.0%, PEG-400/ isopropyl palmitate 27.0%, vitamin E2 .0%, propyl p-hydroxybenzoate 1.0%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510122519 CN1823762A (en) | 2005-12-21 | 2005-12-21 | Chuanxiong lactone kind component soft capsule for treating cardiovascular and cerebrovascular diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510122519 CN1823762A (en) | 2005-12-21 | 2005-12-21 | Chuanxiong lactone kind component soft capsule for treating cardiovascular and cerebrovascular diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1823762A true CN1823762A (en) | 2006-08-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510122519 Pending CN1823762A (en) | 2005-12-21 | 2005-12-21 | Chuanxiong lactone kind component soft capsule for treating cardiovascular and cerebrovascular diseases |
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| CN (1) | CN1823762A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552441A (en) * | 2012-03-12 | 2012-07-11 | 广州康和药业有限公司 | Flaccid anemone rhizome extract soft capsule and preparation method thereof |
| CN106265863A (en) * | 2016-08-30 | 2017-01-04 | 山东百维药业有限公司 | A kind of vitacoenzyme compositions, hard capsule comprising said composition and preparation method thereof |
| CN106266252A (en) * | 2016-08-25 | 2017-01-04 | 赣南医学院 | A kind of lycopene Oleum Camelliae soft capsule and preparation method thereof |
-
2005
- 2005-12-21 CN CN 200510122519 patent/CN1823762A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552441A (en) * | 2012-03-12 | 2012-07-11 | 广州康和药业有限公司 | Flaccid anemone rhizome extract soft capsule and preparation method thereof |
| CN106266252A (en) * | 2016-08-25 | 2017-01-04 | 赣南医学院 | A kind of lycopene Oleum Camelliae soft capsule and preparation method thereof |
| CN106265863A (en) * | 2016-08-30 | 2017-01-04 | 山东百维药业有限公司 | A kind of vitacoenzyme compositions, hard capsule comprising said composition and preparation method thereof |
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