CN103083367B - Losartan ginkgo leaf compound preparation and preparation method thereof - Google Patents
Losartan ginkgo leaf compound preparation and preparation method thereof Download PDFInfo
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- CN103083367B CN103083367B CN201110338115.8A CN201110338115A CN103083367B CN 103083367 B CN103083367 B CN 103083367B CN 201110338115 A CN201110338115 A CN 201110338115A CN 103083367 B CN103083367 B CN 103083367B
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- losartan
- ginkgo leaf
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Abstract
The invention provides a losartan ginkgo leaf compound preparation. According to the invention, a ginkgo leaf extract is used in combination with losartan, such that losartan metabolism can be accelerated, and plasma concentration of losartan active metabolite EXP3174 can be increased. Therefore, adverse reactions brought by losartan can be reduced, and better antihypertensive effect can be provided.
Description
Technical field
The present invention relates to one and treat hypertensive compound preparation, particularly relate to a kind of compound preparation of Integrated TCM and the preparation method of described compound preparation.
Background technology
Hypertension is the modal cardiovascular disease in the world, and be also the great public health problem in global range, often cause the complication of the internal organs such as the heart, brain, kidney, the health of the mankind in serious harm.Therefore the severe complications such as along with the development of China's aged tendency of population, Hypertension incidence rises year by year, its cardiovascular and cerebrovascular disease have constituted a serious threat to our people's health has extremely important meaning to the timely treatment of hypertension.
Current clinical conventional antihypertensive drug comprises diuretic, adrenoceptor blocker, angiotensin-convertion enzyme inhibitor, angiotensin II receptor blockers and calcium ion antagonist, Chinese patent medicine etc.Angiotensin II receptor blockers can stop the combination of Angiotensin II and ATI receptor, can play effect to hypertension in various degree.
Losartan (losartan,, Losartan, losartan smooth also known as network sand, 2-Butyl-4-chloro-1-[[2 '-(1H-tetrazol-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-1H-imidazole-5-methanol) be first for clinical non-peptide class angiotensin II receptor blockers, the vasoconstriction that AT1 hypotype in energy competitive antagonism angiotensin-ii receptor causes, reach reduction Peripheral resistance and treat hypertensive object, be mainly used in essential hypertension.The main feature of this medicine comprises:
1) unique mechanism of action: this medicine is a kind of Orally active angiotensin ii receptor antagonist of non-peptide class, can to heavens for AII moving part (i.e. aii receptor) and effectively play hindrance function.Vasoconstriction is the main cause causing hyperpietic's blood pressure to rise, and vasoconstriction is caused by AII is combined with aii receptor.Unique sum of losartan (losartan) is only to be combined with aii receptor, and can not adhere to or other hormone of impedance, ion pipeline or receptor.
2) superior toleration: because the mechanism of action of this medicine is special, therefore there is not the side effect that other most of antihypertensive is common.These side effect comprise the edema that calcium channel blocker causes, the dry cough that ACE inhibitor causes, and the heart beating change that agent causes is squeezed in the resistance of B-mode epinephrine, and the hyperlipoidemia that B-mode epinephrine impedance agent and diuretic cause.Its accurate mechanism of action of height, can control blood pressure and can not affect the running of other Cardiovascular regulation system, thus can reduce side effect.Clinical trial also shows, the patient that one of percentage or more is taken medicine, and only incidence of side effects is dizzy higher than placebo group.Compare with the patient taking other antihyperalgesic, the patient's that midway is withdrawn is less.
3) effectiveness extends: after the blood plasma level of losartan (losartan) disappears, still can play effect to systolic blood pressure and AII level for a long time, reason is the active metabolite that losartan can form that a kind of half-life is about 6.5 hours, thus strengthens its biological agent.
But single medicine treatment hypertension is more difficult up to standard in a short time, and Most patients needs to take two or more antihypertensive drug, and single medicine more easily occurs drug resistance, occurs that the probability of toxicity is also larger because dosage is larger.Take the untoward reaction that losartan often occurs to comprise: slight and of short duration dizziness, metering dependency postural hypotension, rare erythra, urticaria, vasodilation (comprising: face, lip and/or swollem tongue), diarrhoea, migraine etc.
Summary of the invention
The invention provides the compound preparation of a kind of losartan and Folium Ginkgo, effectively can control blood pressure, and reduce the generation of untoward reaction.
Losartan ginkgo leaf compound of the present invention, active component comprises:
A) losartan;
B) Folium Ginkgo extract or the Folium Ginkgo containing commensurability described extract.
The weight ratio of described losartan and Folium Ginkgo is preferably 10 ~ 400:20 ~ 600, is more preferably 10 ~ 400:20 ~ 500, most preferably is 10 ~ 400:20 ~ 480.
Losartan ginkgo leaf compound of the present invention can be conventionally be prepared into peroral dosage form, as any one dosage form in capsule, tablet, granule, powder, pill, oral administration solution, slow releasing agent or controlled release agent.
In the case, losartan ginkgo leaf compound of the present invention can also comprise pharmacopedics can excipient substance, as correctives, excipient, disintegrating agent, diluent, binding agent, lubricant, solvent etc.
Present invention also offers a kind of preparation method of above-mentioned losartan ginkgo leaf compound, step comprises:
Step 1, mixes active component losartan by equal increments method with Folium Ginkgo extract;
Step 2, mixes the mixture of excipient substance with the active component prepared in step 1 according to equal increments method;
Step 3, the solution adding binding agent makes soft material, and drying is prepared into granule, and to control water content be 2 ~ 3%;
Step 4, dried granule mixes with magnesium stearate, makes solid dosage forms.
In above-mentioned preparation method, described binder solution is preferably the alcoholic solution of PVPk-30.
In above-mentioned preparation method, in described binder solution, binder wt percentage ratio is preferably 5%.
In above-mentioned preparation method, baking temperature described in step 3 is preferably 40 DEG C.
In foregoing of the present invention, Folium Ginkgo extract can be extract from Folium Ginkgo medical material, also can be the mixture of the effective ingredient such as the direct composition containing ginkgo total flavones from market purchase and bilobalide, wherein, Ginkgo total flavones content >10%, Ginkgo total lactones content >2%.
Folium Ginkgo uses by the present invention together with losartan, verify through zoopery, can promote that losartan metabolism in vivo generates active metabolite EXP3174, improve the blood drug level of EXP3174, by the pharmacological action of EXP3174 to Angiotensin II, thus produce better antihypertensive effect, the generation of losartan untoward reaction can be reduced simultaneously.
Chinese medicine and western medicine drug combination of the present invention, the mechanism giving full play to medicine complementary action increases curative effect, up to standard fast, is conducive to reducing untoward reaction, keeps longer action time.Compound preparation of the present invention has instant effect, side effect is little, and concentration raises, the feature of protection cardiovascular function.
Accompanying drawing explanation
Fig. 1 is the EXP3174 mean blood plasma concentration-time changing curve (n=6) after rat uses losartan ginkgo leaf compound of the present invention and alone losartan;
Fig. 2 is the losartan mean blood plasma concentration-time changing curve (n=6) after rat uses losartan ginkgo leaf compound of the present invention and alone losartan.
Detailed description of the invention
The invention provides a kind of losartan ginkgo leaf compound, and provide a kind of preparation method of described compound preparation, losartan ginkgo leaf compound active component of the present invention comprises: A) losartan; B) Folium Ginkgo extract or the Folium Ginkgo containing commensurability described extract, pharmacopedics can also be comprised and can use adjuvant, comprise correctives, excipient, disintegrating agent, diluent, binding agent, lubricant, solvent etc., as microcrystalline Cellulose or cellulose derivative, Polyethylene Glycol, ethanol, mannitol, water, carboxymethyl starch sodium, lactose, starch or pregelatinized Starch, dextrin, polyvidone, magnesium stearate etc.
Losartan ginkgo leaf compound of the present invention can adopt traditional handicraft to be prepared into various peroral dosage form, as capsule, tablet, granule, powder, pill, oral administration solution, slow releasing agent or controlled release agent, the present invention preferably adopts and is prepared into solid dosage forms with the following method:
Step 1, mixes active component losartan by equal increments method with Folium Ginkgo extract;
Step 2, mixes the mixture of excipient substance with the active component prepared in step 1 according to equal increments method;
Step 3, the solution adding binding agent makes soft material, and drying is prepared into granule, and to control water content be 2 ~ 3%;
Step 4, dried granule mixes with magnesium stearate, makes solid dosage forms.
Wherein, in described Folium Ginkgo extract, Ginkgo total flavones content >10%, Ginkgo total lactones content >2%.
Below by specific embodiment to losartan ginkgo leaf compound of the present invention, and preparation method thereof be described in detail and describe, to make better to understand the present invention, but following embodiment does not limit the scope of the invention.
embodiment 1
Be that 1:5 gets crude drug losartan and Folium Ginkgo extract according to weight ratio, after crossing 100 mesh sieves respectively, press equal increments method mix homogeneously, for subsequent use.
Microcrystalline Cellulose, carboxymethyl starch are received, lactose, starch respectively at after 70 DEG C of dryings, cross 100 mesh sieves, mixing; Adjuvant is mixed homogeneously by equal increments method with mixed crude drug.
The PVP K-30 dissolve with ethanol solution adding 5% concentration makes soft material in right amount, and 24 mesh sieves are granulated, 40 DEG C of dryings, controls the water content 2 ~ 3% of granule, crosses 20 mesh sieve granulate.
Mixed with magnesium stearate by dried granule, tabletting after assay, makes tablet, wherein losartan content 10mg, Folium Ginkgo extract content 50mg in every sheet medicine.
embodiment 2
Be that 1:4 gets crude drug losartan and Folium Ginkgo extract according to weight ratio, after crossing 100 mesh sieves respectively, press equal increments method mix homogeneously, for subsequent use.
Microcrystalline Cellulose, carboxymethyl starch are received, lactose, starch respectively at after 70 DEG C of dryings, cross 100 mesh sieves, mixing; Adjuvant is mixed homogeneously by equal increments method with mixed crude drug.
The PVP K-30 dissolve with ethanol solution adding 5% concentration makes soft material in right amount, and 24 mesh sieves are granulated, 40 DEG C of dryings, controls the water content 2 ~ 3% of granule, crosses 20 mesh sieve granulate.
Mixed with magnesium stearate by dried granule, tabletting after assay, makes tablet, wherein losartan content 25mg, Folium Ginkgo extract content 100mg in every sheet medicine.
embodiment 3
Be that 1:1 gets crude drug losartan and Folium Ginkgo extract according to weight ratio, after crossing 100 mesh sieves respectively, press equal increments method mix homogeneously, for subsequent use.
Microcrystalline Cellulose, carboxymethyl starch are received, lactose, starch respectively at after 70 DEG C of dryings, cross 100 mesh sieves, mixing; Adjuvant is mixed homogeneously by equal increments method with mixed crude drug.
The PVP K-30 dissolve with ethanol solution adding 5% concentration makes soft material in right amount, and 24 mesh sieves are granulated, 40 DEG C of dryings, controls the water content 2 ~ 3% of granule, crosses 20 mesh sieve granulate.
Mixed with magnesium stearate by dried granule, tabletting after assay, makes tablet, wherein losartan content 50mg, Folium Ginkgo extract content 50mg in every sheet medicine.
embodiment 4
Be that 1:2 gets crude drug losartan and Folium Ginkgo extract according to weight ratio, after crossing 100 mesh sieves respectively, press equal increments method mix homogeneously, for subsequent use.
Microcrystalline Cellulose, carboxymethyl starch are received, lactose, starch respectively at after 70 DEG C of dryings, cross 100 mesh sieves, mixing; Adjuvant is mixed homogeneously by equal increments method with mixed crude drug.
The PVP K-30 dissolve with ethanol solution adding 5% concentration makes soft material in right amount, and 24 mesh sieves are granulated, 40 DEG C of dryings, controls the water content 2 ~ 3% of granule, crosses 20 mesh sieve granulate.
Mixed with magnesium stearate by dried granule, tabletting after assay, makes tablet, wherein losartan content 50mg, Folium Ginkgo extract content 100mg in every sheet medicine.
embodiment 5
Be that 1:1 gets crude drug losartan and Folium Ginkgo extract according to weight ratio, after crossing 100 mesh sieves respectively, press equal increments method mix homogeneously, for subsequent use.
Microcrystalline Cellulose, carboxymethyl starch are received, lactose, starch respectively at after 70 DEG C of dryings, cross 100 mesh sieves, mixing; Adjuvant is mixed homogeneously by equal increments method with mixed crude drug.
The PVP K-30 dissolve with ethanol solution adding 5% concentration makes soft material in right amount, and 24 mesh sieves are granulated, 40 DEG C of dryings, controls the water content 2 ~ 3% of granule, crosses 20 mesh sieve granulate.
Mixed with magnesium stearate by dried granule, tabletting after assay, makes tablet, wherein losartan content 100mg, Folium Ginkgo extract content 100mg in every sheet medicine.
embodiment 6
Be that 1:2 gets crude drug losartan and Folium Ginkgo extract according to weight ratio, after crossing 100 mesh sieves respectively, press equal increments method mix homogeneously, for subsequent use.
Microcrystalline Cellulose, carboxymethyl starch are received, lactose, starch respectively at after 70 DEG C of dryings, cross 100 mesh sieves, mixing; Adjuvant is mixed homogeneously by equal increments method with mixed crude drug.
The PVP K-30 dissolve with ethanol solution adding 5% concentration makes soft material in right amount, and 24 mesh sieves are granulated, 40 DEG C of dryings, controls the water content 2 ~ 3% of granule, crosses 20 mesh sieve granulate.
Mixed with magnesium stearate by dried granule, tabletting after assay, makes tablet, wherein losartan content 100mg, Folium Ginkgo extract content 200mg in every sheet medicine.
embodiment 7
Be that 1:1.4 gets crude drug losartan and Folium Ginkgo extract according to weight ratio, after crossing 100 mesh sieves respectively, press equal increments method mix homogeneously, for subsequent use.
Microcrystalline Cellulose, carboxymethyl starch are received, lactose, starch respectively at after 70 DEG C of dryings, cross 100 mesh sieves, mixing; Adjuvant is mixed homogeneously by equal increments method with mixed crude drug.
The PVP K-30 dissolve with ethanol solution adding 5% concentration makes soft material in right amount, and 24 mesh sieves are granulated, 40 DEG C of dryings, controls the water content 2 ~ 3% of granule, crosses 20 mesh sieve granulate.
Mixed with magnesium stearate by dried granule, tabletting after assay, makes tablet, wherein losartan content 200mg, Folium Ginkgo extract content 480mg in every sheet medicine.
embodiment 8
Be that 1:1.2 gets crude drug losartan and Folium Ginkgo extract according to weight ratio, after crossing 100 mesh sieves respectively, press equal increments method mix homogeneously, for subsequent use.
Microcrystalline Cellulose, carboxymethyl starch are received, lactose, starch respectively at after 70 DEG C of dryings, cross 100 mesh sieves, mixing; Adjuvant is mixed homogeneously by equal increments method with mixed crude drug.
The PVP K-30 dissolve with ethanol solution adding 5% concentration makes soft material in right amount, and 24 mesh sieves are granulated, 40 DEG C of dryings, controls the water content 2 ~ 3% of granule, crosses 20 mesh sieve granulate.
Mixed with magnesium stearate by dried granule, tabletting after assay, makes tablet, wherein losartan content 400mg, Folium Ginkgo extract content 480mg in every sheet medicine.
Get the losartan ginkgo leaf compound prepared in above-described embodiment and carry out zoopery (compound preparation group), and compare with alone losartan matched group (alone medicine group).
When feeding to rat filling, losartan ginkgo leaf compound of the present invention is filled with the amount of feeding and is taken Folium Ginkgo extract 100mg/kg according to per kilogram of body weight, and alone medicine group is identical with the amount that compound preparation group rat takes losartan, takes 14 days continuously.
Table 1 gives the alone losartan of rat (alone medicine group) and uses losartan ginkgo leaf compound of the present invention (compound preparation group) EXP3174 and losartan pharmacokinetic parameter result (n=6) afterwards.
Table 1, EXP3174 and losartan pharmacokinetic parameter result (n=6)
In table 1, * representative p<0.05, * * compared with alone medicine group represents p<0.01 compared with alone medicine group.
Fig. 1 gives EXP3174 blood concentration-time change curve after alone medicine group and the medication of compound preparation group rat, and Fig. 2 gives losartan blood concentration-time change curve after alone medicine group and the medication of compound preparation group rat.
Although in table 1, losartan pharmacokinetic parameter does not have statistical significance, as can be seen from Figure 2, after the medication of compound preparation group rat, losartan metabolism is obviously accelerated.
Can be found out by table 1 and Fig. 1, Folium Ginkgo extract can the metabolism of appreciable impact losartan activity in vivo metabolite EXP3174, makes EXP3174's
t maxremarkable shortening (P<0.05),
c max, AUC
0-8and AUC
0-∞remarkable increase (P<0.01), Cl significantly shortens (P<0.01).
Both losartan and EXP3174 can be combined, resist the pharmacological action of Angiotensin II with AT1 receptor-selective, thus produce hypotensive effect.The research display affinity power of EXP3174 to angiotensin-ii receptor is 10 times of losartan, reaches 2 times and 5 ~ 8 times that peak concentration (Cmax) and area under the drug-time curve (AUC) are respectively losartan; And comparatively losartan is long the EXP3174 half-life in vivo; Therefore, compound preparation of the present invention by affecting the metabolism of EXP3174, thus can produce antihypertensive effect better.
Above-mentioned zoopery shows, losartan ginkgo leaf compound of the present invention, the metabolism of losartan can be accelerated, improve the blood drug level of losartan active metabolite EXP3174, therefore, Folium Ginkgo extract and losartan drug combination clinically, can reduce the untoward reaction that losartan brings, and plays better antihypertensive effect.
Be described in detail specific embodiments of the invention above, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, equalization conversion done without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.
Claims (9)
1. a losartan ginkgo leaf compound, is characterized in that, active component is:
A) losartan;
B) Folium Ginkgo extract;
Wherein, described losartan and Folium Ginkgo extract weight ratio are 10 ~ 400:20 ~ 500.
2. losartan ginkgo leaf compound according to claim 1, is characterized in that, described losartan and Folium Ginkgo extract weight ratio are 10 ~ 400:20 ~ 480.
3. losartan ginkgo leaf compound according to claim 1, is characterized in that, described compound preparation also comprises excipient substance.
4. losartan ginkgo leaf compound according to claim 3, is characterized in that, described excipient substance comprise in correctives, excipient, disintegrating agent, diluent, binding agent, lubricant, solvent any one.
5. losartan ginkgo leaf compound according to claim 1, is characterized in that, described compound preparation is peroral dosage form.
6. prepare a method for losartan ginkgo leaf compound as claimed in claim 1, it is characterized in that, step comprises:
Step 1, mixes active component losartan by equal increments method with Folium Ginkgo extract;
Step 2, mixes the mixture of excipient substance with the active component prepared in step 1 according to equal increments method;
Step 3, the solution adding binding agent makes soft material, and drying is prepared into granule, and to control water content be 2 ~ 3%;
Step 4, dried granule mixes with magnesium stearate, makes solid dosage forms.
7. method according to claim 6, is characterized in that, described binder solution is the alcoholic solution of PVPk-30.
8. method according to claim 7, is characterized in that, in described binder solution, binder wt percentage ratio is 5%.
9. method according to claim 6, is characterized in that, baking temperature described in step 3 is 40 DEG C.
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Citations (2)
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| CN101683526A (en) * | 2008-05-29 | 2010-03-31 | 北京奥萨医药研究中心有限公司 | Pharmaceutical composition containing angiotensin II receptor antagonist, B vitamins and gingo biloba extract |
| CN102065847A (en) * | 2008-04-29 | 2011-05-18 | 韩诺生物制约株式会社 | Pharmaceutical formulation containing angiotensin-II receptor blocker |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102065847A (en) * | 2008-04-29 | 2011-05-18 | 韩诺生物制约株式会社 | Pharmaceutical formulation containing angiotensin-II receptor blocker |
| CN101683526A (en) * | 2008-05-29 | 2010-03-31 | 北京奥萨医药研究中心有限公司 | Pharmaceutical composition containing angiotensin II receptor antagonist, B vitamins and gingo biloba extract |
Non-Patent Citations (2)
| Title |
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| 氯沙坦联合银杏达莫治疗早期糖尿病肾病疗效观察;王晓文等;《现代中西医结合杂志》;20101101;第19卷(第31期);第3393－3394页 * |
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