CN1228051C - Medicinal composition for treating cardiovascular disease - Google Patents
Medicinal composition for treating cardiovascular disease Download PDFInfo
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- CN1228051C CN1228051C CN 03148367 CN03148367A CN1228051C CN 1228051 C CN1228051 C CN 1228051C CN 03148367 CN03148367 CN 03148367 CN 03148367 A CN03148367 A CN 03148367A CN 1228051 C CN1228051 C CN 1228051C
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Abstract
The present invention provides a medicine composition for treating cardiovascular and cerebrovascular diseases, which comprises active components of ginkalide and sanchinoside. The present invention also discloses various preparations prepared from the medicine composition.
Description
Technical field
The present invention relates to be used for the treatment of the pharmaceutical composition of cardiovascular and cerebrovascular disease, specifically relating to comprise bilobalide and Radix Notoginseng total arasaponins is the novel medicament compositions of active component.
Background technology
Semen Ginkgo and extract thereof have significant curative effect (Chen Weizhou etc., Chinese Journal of New Drugs and Clinical Remedies, 1999,18 (5): 315 in the treatment of cardiovascular and cerebrovascular disease; Guo sea equality, Tianjin pharmacy, 2001,13 (3): 62-64).Studies show that, Semen Ginkgo extrac can with other active substance couplings, and present certain synergism (yellow grandness etc., Chinese patent medicine, 2002,24 (9): 686-688; Zhang Shuiyuan, Colleges Of Traditional Chinese Medicine Of Fujian's journal, 2001,11 (3): 10-12).In recent years, Semen Ginkgo extrac associating Radix Notoginseng extract has caused people's attention (Qu Hanyin, traditional Chinese medical science research, 2001,14 (5): 24-25 in the application aspect the treatment cardiovascular and cerebrovascular disease; Chen Xiaohong, Hubei Journal of Traditional Chinese Medicine, 2002,24 (5): 27).
Main active substances in the Semen Ginkgo extrac (EGb) is ginkgetin glycosides (Ginkgo Flavone Glycosides) and bilobalide (Ginkgolides), and the main active of Radix Notoginseng extract be Radix Notoginseng total arasaponins (PanaxNotoginoside, PNS).In some disclosed technical literatures (for example, CN1240654A, CN1129118A or CN1262103A), though related to the scheme that comprises this two classes extract and other active component simultaneously, but the integration regulating action rule at the complexity of many target spots compound preparation is not made clear and definite instruction, does not therefore contain the product of this two classes extract in the market simultaneously.In clinical practice, normally use the preparation that contains the said extracted thing respectively.
Self physicochemical property of above-mentioned condition and this two classes extract has substantial connection.Ginkgo leaf extract preparation mainly adopts EGb761 standard (DE2117429A), wherein also comprises organic acid, alkyl phenol and complicated chemical compositions such as alkyl phenolic acid, steroidal compounds and trace element.In addition, water-soluble, bilobalide (biobalide) decomposition easily in aqueous solution that bilobalide itself is difficult to, the preparation of this equal administrable preparation and quality control have brought certain difficult problem.For this reason, formulation specialist proposes some solutions, for example, adds specific solvent (CN1298738A) in injection, perhaps prepares bilobalide sodium salt (CN1315175A) etc.Yet all there is the certain mass problem in conventional bilobalide preparation, and for example poor solubility, stability are not good, solvent zest and color and luster easily change etc.
As for Radix Notoginseng extract, its effective ingredient Radix Notoginseng total arasaponins has and draws moist and easily make the capsule deliquescing of making moist influence the disintegrate effect, the dissolving of its peroral dosage form in aqueous medium is slower, and easily be clamminess, lump at course of dissolution, dissolving is relatively more difficult again, be difficult in the treatment of cardiovascular and cerebrovascular disease and obtain desirable effectiveness, therefore mainly be to use its injection (for example XUESAITONG) clinically, but also there is certain stability problem (easily freeze in for example variable color, crystalline deposit and winter etc.) in injection.Formulation specialist has also been carried out certain improvement to this, for example be made into soft capsule (CN1228960A) or injectable powder (CN1157720A) etc.
Above-mentioned physicochemical property difference in view of two class extracts, for those of ordinary skills, when Semen Ginkgo extrac and Radix Notoginseng extract coupling, other quality problems of its compound preparation are difficult to especially expect, and also do not find the clearly instruction of relevant solution in prior arts.In addition, at the optimal proportion threshold of the two coupling in the different syndromes of treatment cardiovascular and cerebrovascular disease, and problem such as final stability of formulation under the special ratios, prior art is also failed to producing and use the foundation that science is provided.
Therefore, be starved of above-mentioned two kinds of extracts are made and have good stability and deliquescent pharmaceutical composition, it can improve the clinical efficacy and/or the effectiveness of described medicine, and makes above-mentioned shortcoming minimize or be suppressed.
Summary of the invention
An object of the present invention is to provide pharmaceutical composition evident in efficacy, that side effect is low.Described compositions comprises the treatment effective amount of actives---Semen Ginkgo extrac and Radix Notoginseng extract.In the following description, described " Semen Ginkgo extrac " is meant the bilobalide by the international standard preparation, and " Radix Notoginseng extract " is meant Radix Notoginseng total arasaponins.Those skilled in the art can easily determine absorption of active ingredient according to practical situation, for example account for the 1-85% of compositions gross weight, are preferably 20-65%.
Another object of the present invention provides aforementioned pharmaceutical compositions and is used for the treatment of application in the medicine of cardiovascular and cerebrovascular disease in preparation.Bilobalide and Radix Notoginseng total arasaponins have similar pharmacological action (but mechanism may be different), for example all can improve myocardial ischemia, ischemic brain injury is had protective effect, anticoagulant, enhancing erythrocyte deformability, suppresses erythrocytic gathering, blood viscosity lowering, change hemorheology and has function such as blood fat reducing.It should be noted that bilobalide has the effect of height specificity anti-platelet activating factor (PAF), it also has the effect of tangible raise immunity in addition; And PNS has obvious antiarrhythmic effect as slow calcium channel blocker optionally.It can reduce the blood pressure that increases but less to the normal arterial pressure influence, and it is twin to alleviate arteriolar convulsion, and this may can alleviate Ca in the cell with it
2+Overload is relevant.In addition, PNS can make accumulative platelet that depolymerisation is arranged, and therefore also has thrombolytic effect.Above-mentioned mechanism provides strong physiology and pharmacological basis for two kinds of obtained synergism of active component in the pharmaceutical composition of the present invention.Guiding test confirms that the effectiveness of pharmaceutical composition of the present invention significantly is better than the single medicine.Simultaneously, we also are surprised to find, the two different proportioning (for example 1: 10-15: 1) and the relation between the effect be non-linear, for example, in the scope that with the bilobalide is main effect (for example rheology, anticoagulant and viscosity, improve aspects such as myocardial ischemia), drug effect does not always show stronger situation along with the increase of bilobalide, infer that this may exist multi-target effect relevant with the two.Through further investigation, we have determined that further the part by weight of bilobalide and Radix Notoginseng total arasaponins is 1: 10-10: 1, be preferably 1: 5-10: 1, more preferably 1: 1-8: and 1, most preferably be 2: 1-5: 1.
On the one hand, the invention provides pharmaceutical composition with good stability and bioavailability, described pharmaceutical composition can be made into any dosage form for oral administration, the dosage form of being convenient to use when for example granule, tablet, capsule, dry gels, drop pill and micropill etc. are kept treatment.
In the process of preparation drug particles, to add the dissolving that organic solvent, cosolvent or surfactant promote medicine usually.Yet, instruct the pharmaceutical excipient that is suitable for the while solubilising and stablizes this two active component in the prior art.In the process of preparation granule of the present invention, suitable surfactant or medicinal macromolecule include but not limited to: Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, tween 80, tween 20,1,2-propylene glycol, glycerol, polyvinylpyrrolidone, carbomer, lecithin, aminoacid (for example hydrochlorate of arginine, histidine and lysine) or their mixture, be preferably tween 80,1,2-propylene glycol, glycerol, polyvinylpyrrolidone, carbomer or their mixture.Also can be made into the granule that constitutes by phosphatide complexes or cyclodextrin clathrate.The above-mentioned granule that makes also can further be made tablet, capsule, micropill.
In the process of preparation tablet, can adopt conventional preparation technique and pharmaceutic adjuvant.In addition, because the physicochemical property of two kinds of active component is obviously different, therefore be easy to occur active component and disperse inhomogeneous, especially isolating phenomenon in final preparation, this is disadvantageous for the even tablet of preparation, also is unfavorable for the oral administration biaavailability that obtains to suit simultaneously.The inventor finds, adds specific adjuvant in initial mixture, when improving drug particle, has improved the mixing uniformity of active component significantly, has reduced the separation of active component.Described adjuvant includes but not limited to: microcrystalline Cellulose, micropowder silica gel, magnesium stearate, calcium stearate, calcium carbonate, starch, Stepanol MG, Macrogol 4000 and polyethylene glycol 6000.Advantageously, described tablet also can further be done Cotton seeds.
In order to reduce the medication number of times and to improve the bioavailability of preparation, the present invention also provides sustained-release preparation.Except containing blocker, sustained-release preparation of the present invention also contains the pharmaceutical excipient that improves the bilobalide solubility property, for example lecithin, Polyethylene Glycol (for example PEG4000 or PEG6000), polyvinylpyrrolidone, low substituted hydroxy-propyl methylcellulose, poloxamer, beta-schardinger dextrin-, tween 80, sodium lauryl sulphate, pH regulator agent (for example phosphate, amino acid salts, citrate or tartrate etc.).Described blocker includes but not limited to: hydroxypropyl emthylcellulose, ethyl cellulose, carbopol, sodium carboxymethyl cellulose, hydroxypropyl cellulose or sodium alginate etc.
In one embodiment, pharmaceutical composition of the present invention has been made tablet formulation.Advantageously, in order to ensure the evenly disintegrate promptly in suitable time of two kinds of active component, can adopt specific disintegrating agent, for example: carboxymethyl starch sodium, polyvinylpolypyrrolidone, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or their mixed system.Being suitable for diluent of the present invention comprises: pregelatinized Starch, microcrystalline Cellulose, lactose, hyprolose, mannitol or their mixed system.Advantageously, also can add surfactant (for example tween 80, sodium lauryl sulphate, sodium dioctyl sulfosuccinate, poloxamer) in the dispersible tablet of the present invention, to promote disintegration.In addition, also can add fluidizer (for example microcrystalline Cellulose, micropowder silica gel), it can improve the flowability of granule and powder on the one hand, also is beneficial to moisture on the other hand and infiltrates tablet, promotes the disintegrate of tablet and the stripping of medicine.
In another embodiment, pharmaceutical composition of the present invention has been made the oral dry gels that is beneficial to old people and dysphagia patients.This dry gels need not heating in use, mixes to form medicated porridge sample gel with quantitative aqueous solution.Used gellant should guarantee to add water under 40 ℃, the situation of preferred room temperature and form gel rapidly being lower than.Described gellant includes but not limited to: pregelatinized Starch, sodium starch phosphate, carbopol, carrageenin, pectin, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, microcrystalline Cellulose etc., preferably adopt the mixture of pregelatinized Starch or sodium carboxymethyl cellulose and microcrystalline Cellulose.Randomly, also comprise pharmaceutic adjuvants such as binding agent, wetting agent, surfactant in the described dry gels
In the process of preparation capsule, especially soft capsule, take into account two kinds of dissolubilities that active component is different, suspension medium or solvent can be selected liquid polyethylene glycol, tween 80, liquid paraffin oil, vegetable oil (for example soybean oil, Oleum Arachidis hypogaeae semen, olive oil, Oleum Camelliae etc.) or their mixed system for use.Advantageously, also can add surfactant (for example lecithin) or Cera Flava, they can make PNS be suspended in wherein on the one hand, also can stablize bilobalide in addition.In one embodiment, extract is mixed with cyclodextrin, optional freeze in after, be suspended in (oiliness) substrate and make soft capsule.Described cyclodextrin is preferably beta-schardinger dextrin-, hydroxypropyl more preferably.Advantageously, in order further to improve the dissolubility of Semen Ginkgo extrac, can in granule, add Polysorbate surfactant (for example tween 80), polyethylene glycols (for example PEG400) with characteristic of solubilizing, and the polyalcohols (for example xylitol, inositol, lactose, glycerol or propylene glycol) or their mixed system that can promote the active component gastrointestinal absorption.
In another aspect of this invention, also described pharmaceutical composition can be made injection type, this comprises injection, infusion solutions and lyophilized injectable powder.Harmful effect for fear of solvent, do not adopt medicinal organic solvent in the preparation of the present invention as far as possible, therefore in this case, to solve the stability and the solubility problem of injection emphatically, being suitable for pharmaceutical excipient of the present invention includes but not limited to: tween 20, tween 80, Polyethylene Glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyvinylpyrrolidone, poloxamer, 1, the 2-propylene glycol, glycerol, hydroxypropyl, low molecular dextran, aminoacid (arginine for example, the hydrochlorate of histidine and lysine) or their mixed systems of forming.Be preferably polyvinylpyrrolidone, poloxamer, hydroxypropyl, tween 80 or their mixed system.The inventor is surprised to find, in the process of preparation lyophilized injectable powder, in pharmaceutical composition, add above-mentioned pharmaceutical excipient, also can solve active component and in process of reconstruction, dissolve inadequate problem, can promote active component to dissolve and be reconstructed into settled solution rapidly.
Advantageously, also can choose medicinal stabilizing agent of adding and/or pH regulator agent in the injection wantonly, with further dissolubility and the stability of improving active component.Described stabilizing agent comprises but is not limited to: L-cysteine, nicotiamide, poloxamer or their mixture.Described pH regulator agent includes but not limited to: various phosphate buffers, hydrochloric acid, sodium hydroxide or their mixture.Advantageously, also can add medicinal freeze-dried excipient in the lyophilized injectable powder of the present invention.Preferably, described excipient is selected from mannitol, sorbitol, sodium chloride, glucose, fructose, sucrose, xylitol, lactose, aminoacid or their mixture, is preferably mannitol.
Pharmacodynamic experiment
Test drug: compound lyophilized powder of the present invention; Gingko injection (German Weil-McLain relax pharmaceutical factory); Radix Notoginseng injection (Kunming Medicine Stock Co., Ltd).
Said medicine is provided with a plurality of dosage groups with the double distilled water dissolved dilution by 1: 0.5 spacing.
1. to the diastole effect of rabbit myocardium vessel ring
By super (the Chinese Pharmacological circular .1997 such as the good method that waits of dragon; 13:308-311), the thoracic aorta of Japanese white big ear rabbit (body weight 2.5-3.5kg) is handled.Select the complete vascular ring of endothelium, add the medicine of various dose, observe medicine to norepinephrine (NE) preshrinking after the maximum diastole effect and the EC of vascular ring
50Value.With the blood vessel maximum collapse is 100%, calculates the diastole degree of medicine to blood vessel.
Table 1 is the result show, preparation of the present invention has the diastole effect of dose dependent to the complete myocardium vessel ring of endothelium.Preparation of the present invention is enhanced its vasodilatory effect by synergism.
Table 1 medicine is to the diastole effect (n=8) of myocardium vessel ring
| Group | EC 50(mg/mL) | Maximum diastole effect (%) |
| Semen Ginkgo notoginseng (1: 1) compound recipe (2: 1) compound recipe (4: 1) compound recipe (8: 1) | 1.28±0.16 2.68±0.19 1.03±0.19 b 0.80±0.07 ab 0.84±0.11 ab 0.97±0.107 ab | 0.52±0.09 0.37±0.12 0.61±0.18 b 0.72±0.12 ab 0.64±0.09 ab 0.66±0.07 ab |
Annotate:
aCompare p＜0.05 with the Semen Ginkgo group,
bCompare p＜0.05 with the Radix Notoginseng group
2. the protective effect that rat myocardial ischemia and reperfusion is damaged
Get SD rat (body weight 280 ± 38), through the ligation left anterior descending coronary artery (LAD, 10min), again perfusion (30min) handle (chief editor such as Xu Shuyun. pharmacological experimental methodology (the 3rd edition). People's Health Publisher .2001:1052).Sham operated rats wherein: coronary artery LAD wears a silk thread in the place, but not ligation; The damage matched group: ligation coronary artery LAD, cause myocardial ischemia reperfusion injury.Lumbar injection is subjected to reagent thing 1g/kg when damage.
Time point mutually after pouring into 30min again, the sacrificed by decapitation rat is got blood and separation of serum, measures creatine phosphokinase (CPK) and lactic acid dehydrogenase (LDH) activity, malonaldehyde (MDA) content, superoxide dismutase (SOD) content.Take out heart rapidly and measure myocardial infarction district area (IS) after getting blood.Infarct size percentage rate=myocardial infarction area area/myocardium the gross area * %.The result is as shown in table 2.
Preparation of the present invention can make myocardial enzymes behind the myocardial ischemia-reperfusion, SOD and IS significantly reduce, and its protective effect to myocardial ischemia reperfusion injury significantly is better than Semen Ginkgo or the Radix Notoginseng group of using separately.
Table 2 medicine is to the influence (n=8) of rat myocardial ischemia and reperfusion damage
| Group | LDH (mmol/L·s) | CPK (mmol/L·s) | MDA (nmol/L) | SOD (mg/g) | IS (％) |
| Sham operated rats model group Semen Ginkgo, (1: 1), (2: 1), (4: 1), (8: 1) | 0.79±0.12 2.53±0.41 1.68±0.09 * 1.92±0.25 * 1.25±0.17 * 0.95±0.09 * 1.14±0.18 * 1.46±0.52 * | 3.62±0.52 8.25±0.95 6.01±0.51 * 6.58±0.63 * 5.72±0.46 * 4.27±0.38 ** 5.13±0.86 * 5.56±0.47 * | 0.35±0.05 0.97±0.15 0.61±0.07 * 0.72±0.10 0.63±0.09 * 0.41±0.07 ** 0.49±0.08 ** 0.57±0.11 * | 52.7±7.4 30.3±5.3 41.4±5.5 * 37.6±4.8 * 40.8±4.2 * 49.5±6.7 ** 46.8±5.0 * 43.5±3.9 * | 3.56±0.48 15.58±0.92 10.7±0.36 * 12.2±0.57 7.37±0.41 ** 6.94±0.65 ** 8.32±0.34 * 9.5±0.66 * |
Annotate:
*Compare with model group, p＜0.05,
*Compare p＜0.01 with model group
3. to the influence of normal rabbits platelet aggregation
Got new zealand rabbit (body weight 2.5-3.5kg) auricular vein drug administration by injection 5 days, the common carotid artery blood-letting, preparation platelet rich plasma (PRP) and platelet poor plasma (PPP) are induced with ADP, adopt the turbidimetry for Determination platelet aggregation rate, calculate platelet aggregation inhibition rate according to the following equation:
Assemble suppression ratio (%)=(maximum agglutination rate
Matched group-maximum agglutination rate
The administration group)/maximum agglutination rate
Matched group* 100%
Table 3 medicine is to the influence (n=8) of normal plasma in rabbit platelet aggregation
| Group | Dosage (gkg -1) | Aggregation rate (%) | Assemble suppression ratio (%) |
| Distilled water, (matched group) Semen Ginkgo notoginseng, (1: 1) compound recipe, (2: 1) compound recipe, (4: 1) compound recipe, (8: 1) | 0.5 0.5 0.5 0.5 0.5 0.5 0.5 | 57.8±12.37 48.31±9.54 * 52.6±8.65 42.5±12.72 * 35.6±8.91 ** 40.7±9.53 * 45.3±10.38 * | 16.4 9.0 26.5 38.4 27.9 21.6 |
Annotate:
*Compare p＜0.05 with matched group,
*Compare p＜0.05 with the Semen Ginkgo group
4. the influence of and specific immune function non-specific to normal mouse
(Xu Shuyun according to a conventional method, pharmacological experimental methodology. the People's Health Publisher, 1991.286-288.) carrying out the reticuloendothelial system phagocytic function test, kunming mouse (body weight 18-22kg) is all by the continuous ip administration of the dosage of 0.5g/kg 10 days (matched group gives with the volume normal saline).
According to a conventional method (Li Yikui, herbal pharmacology experimental technique. Science and Technology of Shanghai publishing house, 1991.155-160) carry out the test of hemolysin content, calculate HC50 and survey the OD value.
Table 4 medicine is to effect of immunologic function (n=10)
| Group | Clean up index (K) (OD/min) (* 10 -2) | Half hemolysis value (HC50) | Thymus index (0.1mg/g body weight) | Index and spleen index (0.1mg/g body weight) |
| Matched group Semen Ginkgo compound recipe (1: 1) compound recipe (2: 1) compound recipe (4: 1) compound recipe (8: 1) | 3.26±0.31 3.76±0.43 4.17±0.36 4.28±0.54 4.65±0.87 * 4.23±0.47 * 4.05±0.76 | 254.32±28.07 267.24±31.28 272.55±24.31 295.37±32.35 * 302.11±28.54 ** 286.61±27.69 * 283.91±21.54 * | 26.83±2.35 29.98±2.82 30.88±3.64 32.52±2.16 * 39.24±4.05 ** 35.21±2.58 * 31.15±3.12 | 62.43±7.25 65.21±3.54 63.52±6.14 74.15±4.25 * 77.26±3.41 * 73.74±5.67 * 69.25±4.27 |
Annotate:
*Compare p＜0.05 with matched group,
*Compare p＜0.01 with matched group
Example of formulations
Embodiment 1: tablet
| Prescription 1 | Prescription 2 | Prescription 3 | |||
| Bilobalide Radix Notoginseng total arasaponins microcrystalline Cellulose carboxymethyl starch sodium micropowder silica gel magnesium stearate | 160mg 80mg 140.5mg 15mg 1.5mg 3mg | Bilobalide Radix Notoginseng total arasaponins ethyl cellulose micro crystal cellulose milk sugar | 80mg 40mg 180mg 85mg 15mg | Ginkgolides arasaponin HPMC E50 HPMC K4M Tween 80 lactose dolomol 95% ethanol | 135mg 65mg 45mg 40mg 40mg 70mg 5mg is an amount of |
Process example: get active component, microcrystalline Cellulose, carboxymethyl starch sodium and micropowder silica gel, place V-type blender mixing 15-25 minute, granulate sieves.Add magnesium stearate, abundant mixing, tabletting.The gained tablet is coating further.
Embodiment 2: dispersible tablet
| Prescription 1 | Prescription 2 | ||
| Bilobalide Radix Notoginseng total arasaponins carboxymethyl starch sodium low-substituted hydroxypropyl cellulose lactose sweeting agent | 20mg 10mg 68mg 100mg 160mg 40mg | Bilobalide Radix Notoginseng total arasaponins cross-linked pvp micro crystal cellulose milk sugar micropowder silica gel 95% ethanol | 45mg 25mg 40mg 100mg 180mg 10mg is an amount of |
Process example: get above-mentioned supplementary material and cross 100 mesh sieves respectively, place the blender mix homogeneously then, granulate and drying tabletting behind the granulate.Direct compression behind the also desirable supplementary material mix homogeneously.
Embodiment 3: drop pill
| Prescription 1 | |
| Bilobalide Radix Notoginseng total arasaponins polyethylene glycol 6000 poloxamer stearic acid | 65m 35mg 200mg 30mg 70mg |
Process example: get the PEG6000 heating and melting, add Radix Notoginseng total arasaponins, poloxamer and stearic acid, treat complete fusion after, stir and add bilobalide down.Mixture splashed in the liquid paraffin condensed fluid become ball.
Embodiment 4: oral dry gels
| Prescription 1 | Prescription 2 | ||
| Ginkgolides arasaponin pregelatinized starch lactose sweet mellow wine granulation binders: hydroxypropyl methylcellulose absolute ethyl alcohol water | 55mg 25mg 220mg 20mg 10mg 7mg 55mg 8mg | Ginkgolides arasaponin carrageenan locust bean gum low-substituted hydroxypropyl cellulose lactose sweet mellow wine hydroxypropyl cellulose | 40mg 20mg 5mg 10mg 100mg 90mg 125mg 10mg |
Process example: get active component, lactose and the pregelatinized Starch of scheduled volume, place granulator.Stirred 10 minutes in about 100rpm, stirred 10 minutes with 200rpm again.Continue to stir and to add adhesive composition down, then be stirred to and be completed into.Collect and dried particles, obtain dry gels of the present invention.
Embodiment 5: soft capsule
| Prescription 1 | Prescription 2 | ||
| Bilobalide Radix Notoginseng total arasaponins PEG400 Cera Flava | 40mg 20mg 250mg 8mg | Bilobalide Radix Notoginseng total arasaponins soybean oil soybean lecithin | 80mg 40mg 300mg 10mg |
Process example: Cera Flava is dissolved in the Polyethylene Glycol, stirs and to add Radix Notoginseng total arasaponins down, be heated to dissolving, add bilobalide after being cooled to room temperature, inject colloid mill and grind evenly, the gained suspension is placed.Get above-mentioned medicinal liquid and rubber solution, pelleting is drying to obtain.
Embodiment 6: injection
| Prescription 1 | Prescription 2 (infusion solutionses) | ||
| Bilobalide Radix Notoginseng total arasaponins L-lysine nicotiamide Na 2HPO 4Water for injection | 6g 3g 3.5g 3.5g 11g 1000ml | Bilobalide Radix Notoginseng total arasaponins NaOH liquid sodium chloride water for injection | 1.2g an amount of 9.0g 1000ml of 0.6g |
Process example: bilobalide is added to contains Na
2HPO
4Water for injection in, stir dissolving fully.Add Radix Notoginseng total arasaponins, L-lysine and nicotiamide, stirring and dissolving is regulated PH and is about 6.8-7.8, removes by filter insoluble matter then.Add proper amount of active carbon, stirring and adsorbing 30 minutes, carbon removal, fine straining, embedding, sterilization, promptly.
Embodiment 7: injectable powder
| Prescription 1 | Prescription 2 | ||
| Bilobalide Radix Notoginseng total arasaponins arginine monohydrochloride xylitol water for injection | 10g 5g 20g 20g 1000ml | Bilobalide Radix Notoginseng total arasaponins hydroxypropyl mannitol water for injection | 20g 10g 95g 50g 1000ml |
Process example: get bilobalide and be added in the water for injection that contains arginine monohydrochloride, heating for dissolving adds Radix Notoginseng total arasaponins, xylitol, fully stirs and makes dissolving, regulates PH, is cooled to the room temperature after-filtration and removes insoluble matter.Add proper amount of active carbon, stirring and adsorbing 30 minutes, carbon removal, filtration, aseptic subpackaged in cillin bottle, deliver to lyophilization in the freeze drying box, tamponade adds aluminium lid in case.
Claims (9)
1, bilobalide and Radix Notoginseng total arasaponins are used for the treatment of application in the medicine of cardiovascular and cerebrovascular disease in preparation, and wherein the part by weight of active component bilobalide and Radix Notoginseng total arasaponins is 1: 10-10: 1.
2, application as claimed in claim 1, wherein the part by weight of bilobalide and Radix Notoginseng total arasaponins is 1: 5-8: 1.
3, application as claimed in claim 1, wherein the part by weight of bilobalide and Radix Notoginseng total arasaponins is 1: 1-5: 1.
4, a kind of compound medicament composition comprises bilobalide, Radix Notoginseng total arasaponins and pharmaceutical excipient, and wherein the part by weight of bilobalide and Radix Notoginseng total arasaponins is 1: 10-10: 1.
5, compound medicament composition as claimed in claim 4, wherein the part by weight of bilobalide and Radix Notoginseng total arasaponins is 1: 5-8: 1.
6, compound medicament composition as claimed in claim 4, wherein the part by weight of bilobalide and Radix Notoginseng total arasaponins is 1: 1-5: 1.
7, as the compound medicament composition of one of claim 4-6, described pharmaceutical excipient is selected from least a following material: lecithin, Polyethylene Glycol, Polysorbate surfactant, polyvinylpyrrolidone, low substituted hydroxy-propyl methylcellulose, poloxamer, carbomer, beta-schardinger dextrin-, sodium lauryl sulphate, pH regulator agent, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyhydric alcohol, low molecular dextran, aminoacid.
8, compound medicament composition as claimed in claim 7 is for being selected from the peroral dosage form of granule, conventional tablet, slow releasing tablet, dispersible tablet, capsule, micropill, oral dry gels or drop pill.
9, compound medicament composition as claimed in claim 7 is for being selected from the dosage form of injection, infusion solutions or lyophilized injectable powder.
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| CN101744786B (en) * | 2008-12-17 | 2012-11-14 | 南京星银药业集团有限公司 | Prescription of felodipine sustained-release tablets and preparation method |
| CN101708204B (en) * | 2009-11-30 | 2012-04-25 | 浙江省中医药研究院 | Medicinal composition for treating cardio-cerebrovascular diseases |
| CN110420192B (en) * | 2018-04-26 | 2022-01-28 | 鲁南制药集团股份有限公司 | Isosorbide mononitrate sustained-release tablet and preparation method thereof |
| US20230338448A1 (en) * | 2020-05-15 | 2023-10-26 | Nguyen Anh VAN | Organic sol-gel nano-composition from panax notoginseng, rutin, ginkgo biloba effective in enhancing cerebral and cardiovascular protection and method of producing thereof |
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2003
- 2003-06-30 CN CN 03148367 patent/CN1228051C/en not_active Expired - Fee Related
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Assignee: HAINAN GRTANG TRADITIONAL CHINESE MEDICINE PHARMACEUTICAL CO., LTD. Assignor: Wang Fulan Contract record no.: 2010990000966 Denomination of invention: Medicinal composition for treating cardiovascular disease Granted publication date: 20051123 License type: Exclusive License Open date: 20041208 Record date: 20101209 |
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