CN102266333B - Brand new medicinal composition containing levamlodipine and atorvastatin calcium and preparation method thereof - Google Patents
Brand new medicinal composition containing levamlodipine and atorvastatin calcium and preparation method thereof Download PDFInfo
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- CN102266333B CN102266333B CN 201110239148 CN201110239148A CN102266333B CN 102266333 B CN102266333 B CN 102266333B CN 201110239148 CN201110239148 CN 201110239148 CN 201110239148 A CN201110239148 A CN 201110239148A CN 102266333 B CN102266333 B CN 102266333B
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- Prior art keywords
- levamlodipine
- levamlodipine besylate
- parts
- crystal
- atorvastatin calcium
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Links
- 229950008554 levamlodipine Drugs 0.000 title claims abstract description 156
- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 title claims abstract description 155
- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 68
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 title claims abstract description 63
- 239000000203 mixture Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
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- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
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- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 7
- 229910017488 Cu K Inorganic materials 0.000 claims abstract description 6
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- 238000000034 method Methods 0.000 claims description 25
- 239000008187 granular material Substances 0.000 claims description 22
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 13
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 13
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a brand new medicinal composition containing levamlodipine and atorvastatin calcium and a preparation method thereof. The medicinal composition comprises the levamlodipine and the atorvastatin calcium serving as active ingredients and medicinal auxiliary materials, including a filling agent, a disintegrating agent and a lubricating agent, wherein the levamlodipine refers to a levamlodipine besylate crystal; and the characteristic peaks of the crystal in an X-ray powder diffraction pattern obtained by measuring through Cu-K alpha rays are displayed when 2 theta is 8.0 degrees, 12.1 degrees, 15.4 degrees, 17.0 degrees, 19.8 degrees, 21.6 degrees, 23.0 degrees, 24.3 degrees, 25.7 degrees, 27.4 degrees, 30.7 degrees and 33.5 degrees. The crystal can be used for improving the solubility of levamlodipine besylate, so that the synergy, accumulation and complementation effects of the levamlodipine besylate and the losartan potassium are enhanced, a high in-vitro dissolution rate is achieved, and the medicinal composition has high bioavailability is high and a more remarkable curative effect.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of breakthrough drug that contains Levamlodipine and Atorvastatin calcium and use composition and method of making the same.
Background technology
Levamlodipine besylate is white or off-white powder, and its chemical name is (s)-(-)-3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate, molecular formula C
20H
25N
2O
5ClC
6H
6O
3S, molecular weight 567.1, structural formula is:
Levamlodipine besylate belongs to long-acting dihydropyridine (DHP) type calcium antagonists; On the amlodipine basis, split out; Its drug effect is 2 times of racemic amlodipine, and Levamlodipine besylate has the effect of protection EH patient renal function, not only depends on the decline of system's blood pressure.Also because the afferent glomerular arteriole of nephrectasia bead lastingly of this medicine; Improve the kidney ischemia, stop the disorder of kidney blood vessel and glomerule 26S Proteasome Structure and Function, alleviate the kidney hypertrophy; Reducing mesenteric tissue catches macromolecular substances; Suppress free radical and form, weaken the somatomedin mitosis reaction, improve the mitochondrial calcium load and reduce the nephron metabolism all useful kidney.Levamlodipine besylate possess onset slowly, long action time, characteristics that the paddy p-ratio is high, the clinical treatment that has been widely used in cardiovascular and cerebrovascular diseases such as hypertension, angina pectoris.Levamlodipine besylate can change the VSMC calcium ion and stride the film transfer, reduces flow of calcium ions, makes cardiac muscle and vascular smooth muscle relaxation; Regulate the picked-up of vascular endothelial cell, smooth muscle cell and macrophage to lipoprotein; Regulate cellular cholesterol for body, reduce the deposition of cholesterol, suppress the short vascular smooth muscle hypertrophy of somatomedin at arterial wall; The mononuclear cell that slows down is invaded profit and platelet aggregation; Increase erythrocyte deformability, blood viscosity lowering delays atherosclerotic formation and development.Levamlodipine besylate mainly acts on all blood vessels; Also can act on coronary artery and renal artery, slow with the acceptor site effect, vasorelaxation action is steady; Conducting system of heart and myocardial contraction all there is not the obvious suppression effect; Can reduce cardiac load, reverse ventricular hypertrophy, and blood glucose, blood fat and serum electrolyte are had no adverse effects.
Atorvastatin calcium, molecular formula: C
66H
68CaF
2N
4O
10, molecular weight: 1253.53..Atorvastatin calcium is 3-hydroxyl 3 methyl glutaryl coenzyme A reductase inhibitor; But competitive inhibition cell inner cholesterol synthesizes the activity of rate-limiting enzyme in the early process and has the effect of the ester of accent; The Atorvastatin calcium expression that can reduce MCP-1 and proinflammatory cytokine generates in addition, significantly reduces human atheromatous plaque macrophage and T cell, reduction oxidized ldl (ox-LDL)-C and collagen level and has antiinflammatory action.Statins can improve endothelial function through many approach; Atorvastatin calcium suppresses OX-LDL and reduces endothelial cell nitric oxide synthase (eNOS) mRNA and protein expression; And can raise the expression of eNOS mRNA, and strengthen the activity of endothelium eNOS, improve the vasodilation function that endothelium relies on rapidly; And have the effect of protecting vascular endothelial function, so Atorvastatin calcium treatment RA patient has multiple benefit.
Blood fat raises and can cause that the whole body small artery hardens, tube wall thickens, and peripheral arterial resistance is increased, and causes elevation of the blood pressure.But vasoactive amines, angiotensin endothelial cell injury and stimulate its contraction all made gap enlargement when blood pressure increased, and lipoprotein is prone to the intravasation wall.Research shows that statins has the assistance hypotensive effect that is independent of outside the cholesterol reducing, and the treatment of associating reducing blood pressure and regulating blood lipid can have efficient recovery hyperpietic arterial elasticity.
European hypertension guide, U.S.'s hypertension guide and Chinese hypertension prevention and control guide all proposed in 2007, and the hypertension more than 2 grades needs therapeutic alliance.Recently research is thought, in order at utmost to obtain the hypertensive curative effect of treatment, require to bring high blood pressure down greatly, and single therapy usually can not reach this purpose, and the dosage increase is prone to untoward reaction.Extensive clinical trial shows the depressor Combined application, and the depressor of promptly uniting two or more can strengthen antihypertensive effect, and the synergism and the complementary action of performance medicine, can reduce dosage, can offset untoward reaction again.In this case, many scholars propose to treat hypertension with the drug combination mode again, and think that there is clear superiority in drug combination when treatment hypertension: (1) mechanism of action different drug hypotensive effect possibly add up, work in coordination with or be complementary; The ill effect that dosage caused more greatly when (2) low dose of associating can reduce single drug; (3) but and medicament passivation counter regulation, limit mutually that another is drug-induced bad compensatory; (4) help taking into account multiple risk factor that the patient exists with and deposit disease; (5) improve patient's compliance and quality of life; Find that simultaneously therapeutic alliance has good toleration, therefore, reasonably the Combined application antihypertensive drug is of crucial importance in hypertensive treatment.
" amlodipine associating Atorvastatin calcium is to the influence of hypertension carotid artery intima middle level thickness " studied the influence of Levamlodipine besylate Combined application Atorvastatin calcium to hyperpietic's carotid artery intima middle level thickness (IMT), and the result shows that the treatment of hyperpietic's Levamlodipine besylate associating Atorvastatin calcium can better delay the Carotid arterial IMT showed progress.
CN102000075A relates to a kind of novel medicament compositions, and it is made up of the amlodipine of the Atorvastatin calcium anhydride of 5～160mg and 0.5～20mg or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable carrier; Wherein said amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine Besylate Tablet, amlodipine maleate, Amlodipine mesylate, L-Aspartic Acid amlodipine, amlodipine camsylate, amlodipine camsylate, hydrochloric acid amlodipine, maleic acid levo amido chloro diping, Levamlodipine besylate etc.; Be used for prevention or treatment cardiovascular and cerebrovascular disease, reduce the sickness rate and/or the mortality rate of cardiovascular and cerebrovascular disease, reduce the untoward reaction of medicine, improve the compliance that the patient takes medicine simultaneously.Embodiment 4 specifically discloses a kind of bilayer tablet that comprises Atorvastatin calcium anhydride and Levamlodipine besylate; Its preparation method is for preparing earlier Atorvastatin calcium anhydride granule and Levamlodipine besylate granule respectively; Repress is processed bilayer tablet, and its complicated process of preparation is too high to equipment requirements; Be difficult to suitability for industrialized production, and the double-layer tablet joint face then is difficult to discharge medicine up and down.
ZL200710007667.4 relates to the compositions of a kind of Atorvastatin calcium and Levamlodipine; Mainly form, guaranteed the stability and the bioavailability of Atorvastatin calcium and Levamlodipine compound recipe by Levamlodipine or its officinal salt, Atorvastatin calcium or its officinal salt, alkaline metal salt, cyclodextrin and derivant thereof.Atorvastatin calcium and Levamlodipine beaylate tablets are specifically disclosed in the embodiment.This tablet is united use alkali metal and beta-schardinger dextrin-, cooperates suitable adjuvant, and each item index and the dissolution of the stability of Atorvastatin calcium and Levamlodipine compositions are good.
CN1857726A discloses a kind of pharmaceutical composition of treating the hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease; Its technical scheme is; With Levamlodipine and officinal salt, HMG-COA reductase inhibitor and officinal salt thereof is but that main component, the carrier that reaches medicament are formed; Each constituent content is Levamlodipine 1.25-20mg, HMG-COA reductase inhibitor 2.5-100mg.Embodiment also specifically discloses a kind of Levamlodipine besylate of beta-schardinger dextrin-and tablet composition of Atorvastatin calcium of comprising.
But the retrieval analysis through to prior art finds that Levamlodipine besylate is insoluble in water, and its dissolubility in water is 0.053mg/mL; It is absorbed in human body slowly; The time that reaches peak concentration (Cmax) after the medication is longer, and the blood drug level aggregate level is low, and particularly the blood drug level at initial stage is very low after the administration; This medicine onset is very slow, and effect slowly; And Atorvastatin calcium can reach the blood drug level peak value in 1-2 hour after administration; Drug effect is rapid-action; Time phase difference when two kinds of medicines reach the blood drug level peak value after the administration at the same time separately is far away, collaborative, accumulation, complementary action are very limited, thereby influences its curative effect.
Summary of the invention
For overcoming above-mentioned defective; The inventor starts with from the Levamlodipine besylate that is insoluble in water; Made a kind of Levamlodipine besylate crystal through a large amount of refining tests, this crystal can improve the dissolubility of Levamlodipine besylate to a certain extent, and more pleasantly surprised finds to adopt the Pharmaceutical composition of this crystal and Atorvastatin calcium can overcome above-mentioned defective well; Make both bring into play synergism better, its curative effect is more remarkable.Therefore, primary and foremost purpose of the present invention just is to provide this brand-new Pharmaceutical composition that contains Levamlodipine besylate crystal and Atorvastatin calcium.
For realizing above-mentioned purpose, the present invention adopts following technical scheme:
A kind of brand-new Pharmaceutical composition that contains Levamlodipine and Atorvastatin calcium; Comprise active constituents of medicine Levamlodipine and Atorvastatin calcium; And pharmaceutic adjuvant filler, disintegrating agent, lubricant, wherein, described Levamlodipine is the Levamlodipine besylate crystal.
According to aforesaid brand-new Pharmaceutical composition; Wherein, described Levamlodipine besylate crystal uses that characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that the Cu-K alpha ray measures.
According to aforesaid brand-new Pharmaceutical composition, wherein, the following method preparation of described Levamlodipine besylate crystal by adopting:
1) Levamlodipine besylate is dissolved in dichloromethane and the ethanol mixed solvent, obtains the dichloromethane/alcoholic solution of Levamlodipine besylate;
2) under ultrasonic field, in the dichloromethane/alcoholic solution of the Levamlodipine besylate of step 1) gained, drip normal heptane, separate out to crystallization;
3) close ultrasonic field, leave standstill growing the grain, filter, filter cake is used dichloromethane, washing with alcohol respectively, and drying obtains described Levamlodipine besylate crystal.
According to aforesaid brand-new Pharmaceutical composition, wherein, the consumption of dichloromethane described in the step 1) and ethanol mixed solvent is 10～20 times of Levamlodipine besylate weight; Dichloromethane and alcoholic acid volume ratio are 5～8: 1 in said dichloromethane and the ethanol mixed solvent.
According to aforesaid brand-new Pharmaceutical composition, wherein, step 2) power of ultrasonic field is 0.4～0.6KW described in.
According to aforesaid brand-new Pharmaceutical composition, wherein, the growing the grain that leaves standstill described in the step 3) is at 20～25 ℃ of following growing the grain 4-8 hours.
According to aforesaid brand-new Pharmaceutical composition; Wherein, Described active constituents of medicine is made up of 2～20 parts Levamlodipine besylate crystal and 5～120 parts Atorvastatin calcium; Preferably form by 2.5～20 parts Levamlodipine besylate crystal and 5～80 parts Atorvastatin calcium; More preferably by 2.5 parts of Levamlodipine besylate crystal and 5 parts of Atorvastatin calciums, perhaps 5 parts of Levamlodipine besylate crystal and 10 parts of Atorvastatin calciums, perhaps 5 parts of Levamlodipine besylate crystal and 20 parts of Atorvastatin calciums; Perhaps 5 parts of Levamlodipine besylate crystal and 40 parts of Atorvastatin calciums; Perhaps 10 parts of Levamlodipine besylate crystal and 10 parts of Atorvastatin calciums, perhaps 20 parts of Levamlodipine besylate crystal and 60 parts of Atorvastatin calciums, wherein the crystalline amount of Levamlodipine besylate is in Levamlodipine.
According to aforesaid brand-new Pharmaceutical composition, wherein, described filler is lactose and microcrystalline Cellulose, and described disintegrating agent is a low-substituted hydroxypropyl cellulose, and said lubricant is magnesium stearate and micropowder silica gel; By weight, in the said Pharmaceutical composition: microcrystalline Cellulose is that 10～50 parts, lactose are that 10～50 parts, low-substituted hydroxypropyl cellulose are that 1～10 part, micropowder silica gel are that 2～8 parts, magnesium stearate are 1～6 part.
Simultaneously, the present invention also provides a kind of method for preparing of said Pharmaceutical composition, and this method for preparing may further comprise the steps:
1) earlier Atorvastatin calcium and adjuvant are crossed 60 mesh sieves respectively, subsequent use;
2) take by weighing the Levamlodipine besylate crystal of recipe quantity and filler, disintegrating agent and the lubricant of 50% recipe quantity respectively, behind equivalent incremental method mix homogeneously, obtain the mix powder of Levamlodipine besylate directly compressible;
3) take by weighing the Atorvastatin calcium of recipe quantity and the filler and the disintegrating agent of 50% recipe quantity more respectively; Behind equivalent incremental method mix homogeneously, behind the 20 mesh sieve dry granulations, granulate obtains dried granule; The lubricant of dried granule and surplus gets the Atorvastatin calcium granule after always mixing;
4) respectively with step 2) mix powder and the Atorvastatin calcium granule of step 3) of Levamlodipine besylate directly compressible place mixer to mix; Detect and carry out tabletting after qualified; Open tablet machine, make Levamlodipine besylate and Atorvastatin calcium Pharmaceutical composition label as active ingredient;
5) film coating.
Below the present invention is made further detailed description:
Levamlodipine besylate is insoluble in water; Its dissolubility in water is 0.053mg/mL, and it is absorbed in human body slowly, and 6～12h reaches the blood drug level peak value after the medication; The blood drug level aggregate level is low; Particularly the blood drug level at initial stage is very low after the administration, and this medicine onset is very slow, and effect slowly; And Atorvastatin calcium can reach the blood drug level peak value in 1-2 hour after administration; Drug effect is rapid-action; Time phase difference when two kinds of medicines reach the blood drug level peak value after the administration at the same time separately is far away, collaborative, accumulation, complementary action are very limited, thereby influences its curative effect.
The inventor starts with from the Levamlodipine besylate that is insoluble in water; Made a kind of Levamlodipine besylate crystal through a large amount of refining tests; This crystal can improve the dissolubility of Levamlodipine besylate to a certain extent; And more pleasantly surprised find to adopt the Pharmaceutical composition of this crystal and Atorvastatin calcium can overcome above-mentioned defective well, and make both bring into play synergism better, its curative effect is more remarkable.Therefore, primary and foremost purpose of the present invention just is to provide this brand-new Pharmaceutical composition that contains Levamlodipine besylate crystal and Atorvastatin calcium.
Specifically; The brand-new Pharmaceutical composition that contains Levamlodipine and Atorvastatin calcium provided by the present invention; Comprise active constituents of medicine Levamlodipine and Atorvastatin calcium; And pharmaceutic adjuvant filler, disintegrating agent and lubricant, wherein, described Levamlodipine is the Levamlodipine besylate crystal.
Characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that Levamlodipine besylate crystal use Cu-K alpha ray of the present invention measures.
Because the crystal formation of medicine is different, may influence its stripping and absorption in vivo, and then influence bioavailability of medicament, clinical efficacy and safety.Polymorph medicine between different crystal forms, its stability of the differentia influence of physicochemical property.Same medicine is because crystal formation is different, and the arrangement mode of drug molecule on lattice is different, causes the difference of intracell intermolecular force, causes the difference of various physicochemical properties between the polymorph medicine different crystal forms.And the physicochemical property of medicine and dissolution and its stability and bioavailability have much relations.The inventor starts with from the crude drug Levamlodipine besylate; It is made with extra care---recrystallization; Carrying out after the lot of test; Obtain a kind of Levamlodipine besylate crystal, shown that from dissolubility test Levamlodipine besylate crystal of the present invention compares with the Levamlodipine besylate of prior art and have better dissolubility, can significantly improve the dissolubility of Levamlodipine besylate.
The following method preparation of Levamlodipine besylate crystal by adopting of the present invention:
1) Levamlodipine besylate is dissolved in dichloromethane and the ethanol mixed solvent, obtains the dichloromethane/alcoholic solution of Levamlodipine besylate;
2) under ultrasonic field, in the dichloromethane/alcoholic solution of the Levamlodipine besylate of step 1) gained, drip normal heptane, separate out to crystallization;
3) close ultrasonic field, leave standstill growing the grain, filter, filter cake is used dichloromethane, washing with alcohol respectively, and drying obtains described Levamlodipine besylate crystal.
The inventor is carrying out after the lot of test, finds at first to adopt dichloromethane and ethanol mixed solvent that it is dissolved, and under ultransonic condition, drips anti-solvent---normal heptane again, has obtained a kind of Levamlodipine besylate crystal of stable crystal form.And further show that through dissolubility test Levamlodipine besylate crystal of the present invention compares with the Levamlodipine besylate of prior art and have better dissolubility, can significantly improve the dissolubility of Levamlodipine besylate.
The crystalline particle diameter in the left-handed ammonia chlorine of benzenesulfonic acid provided by the present invention ground is 80～120 μ m.
In addition, owing in method for preparing of the present invention, introduced ultrasound wave, prepared crystal particle diameter is less; Specific surface area increases; Its solubility property is improved, and in the research of carrying out subsequently that contains this crystalline tablet, finds to adopt the prepared compound preparation of crystal of the present invention owing to contain the less crystal of said particle diameter more pleasantly surprisedly, thereby has accelerated the intravital absorption the people; Improve bioavailability, thereby improved curative effect.
Wherein, the consumption of dichloromethane described in the step 1) and ethanol mixed solvent is 10～20 times of Levamlodipine besylate weight; Dichloromethane and alcoholic acid volume ratio are 5: 1～8: 1 in said dichloromethane and the ethanol mixed solvent.
The power of ultrasonic field step 2) is 0.4～0.6KW.
Leaving standstill described in the step 3) under 20～25 ℃, leaving standstill 4-8 hour.
The present invention also is to provide the method for preparing of said Pharmaceutical composition, and this method may further comprise the steps:
1) earlier Atorvastatin calcium and adjuvant are crossed 60 mesh sieves respectively, subsequent use;
2) take by weighing the Levamlodipine besylate crystal of recipe quantity and filler, disintegrating agent, the lubricant of 50% recipe quantity respectively, behind equivalent incremental method mix homogeneously, obtain the mix powder of Levamlodipine besylate directly compressible;
3) take by weighing the Atorvastatin calcium of recipe quantity and filler, the disintegrating agent of 50% recipe quantity more respectively; Behind equivalent incremental method mix homogeneously, behind the 20 mesh sieve dry granulations, granulate obtains dried granule; The lubricant of dried granule and surplus gets the Atorvastatin calcium granule after always mixing;
4) respectively with step 2) mix powder and the Atorvastatin calcium granule of step 3) of Levamlodipine besylate directly compressible place mixer to mix; Detect and carry out tabletting after qualified; Open tablet machine, make Levamlodipine besylate and Atorvastatin calcium Pharmaceutical composition label as active ingredient;
5) film coating.
Film coating is specially in the step 5):
A, preparation film-coat layer are stirred well to and are even emulsus;
B, get amlodipine hydrate crystal and the Atorvastatin calcium Pharmaceutical composition label as active ingredient, place in the coating pan, coating pan slowly rotates, and heating waits chip temperature to be increased to 45 ℃ simultaneously;
C, the coating solution of atomizing slowly evenly is sprayed at the sheet wicking surface of rolling with spray gun, along with coating pan and label continue to be heated, solvent evaporation, coating material forms the film coating layer at the sheet wicking surface, until the film-coat of formation uniform drying.
Method for preparing of the present invention can be so that abundant mixing of principal agent composition and ability homodisperse make said composition have good stability, have disintegration and dissolution preferably.
Relative with prior art, provided by the inventionly a kind ofly by amlodipine and Atorvastatin calcium as the beneficial effect of Pharmaceutical composition of active ingredient and preparation method thereof be:
(1) prescription is reasonable, and used adjuvant is safe and reliable, has improved patient's drug safety greatly;
(2) obtained label outward appearance is good, has better dissolving out capability simultaneously;
(3) steady quality is difficult for decomposing and goes bad, and also can not jolt because of transportation produces destruction to tablet;
(4) cost is low, and is profitable;
(5) Pharmaceutical composition provided by the present invention contains Levamlodipine besylate crystal of the present invention; This crystal has improved the dissolubility of Levamlodipine besylate; Thereby make the working in coordination with of Levamlodipine besylate and Atorvastatin calcium, add up, complementary action is strong; External stripping is good, and its bioavailability is high, and curative effect is more remarkable.
Description of drawings
Fig. 1 is the crystalline X-ray powder diffraction of a Levamlodipine besylate of the present invention spectrogram.
The specific embodiment
Following embodiment will do to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
The crystalline preparation of [embodiment 1] Levamlodipine besylate
1) Levamlodipine besylate is dissolved in dichloromethane and the ethanol mixed solvent, obtains the dichloromethane/alcoholic solution of Levamlodipine besylate;
2) under ultrasonic field, in the dichloromethane/alcoholic solution of the Levamlodipine besylate of step 1) gained, drip normal heptane, separate out to crystallization;
3) close ultrasonic field, leave standstill, filter, filter cake is used dichloromethane, washing with alcohol respectively, and drying obtains described Levamlodipine besylate crystal.
Characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that the Levamlodipine besylate crystal use Cu-K alpha ray of gained measures, and is as shown in Figure 1.
Below be embodiment 2-9, method for preparing is with embodiment 1, and its concrete technological parameter is seen table 1:
Table 1
Annotate: A is that the consumption of dichloromethane and ethanol mixed solvent is the multiple of Levamlodipine besylate weight;
B is dichloromethane and an alcoholic acid volume ratio in dichloromethane and the ethanol mixed solvent.
The prepared Levamlodipine besylate crystal of embodiment 2-9 used X-ray powder diffraction pattern that the Cu-K alpha ray measures and embodiment's 1 is consistent.
[FORMULATION EXAMPLE 1] Levamlodipine besylate hydrate crystal/atorvastatin calcium tablet
Prescription: specification (Levamlodipine besylate hydrate crystal/Atorvastatin calcium 2.5mg/5mg)
The Levamlodipine besylate crystal
Preparation technology:
1) earlier Atorvastatin calcium and adjuvant are crossed 60 mesh sieves respectively, subsequent use;
2) take by weighing lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate and the micropowder silica gel of the Levamlodipine besylate crystal and 50% recipe quantity of recipe quantity respectively; Behind equivalent incremental method mix homogeneously, obtain the mix powder of Levamlodipine besylate directly compressible;
3) take by weighing the Atorvastatin calcium of recipe quantity and lactose, microcrystalline Cellulose and the low-substituted hydroxypropyl cellulose of 50% recipe quantity more respectively; Behind equivalent incremental method mix homogeneously; Behind the 20 mesh sieve dry granulations; Granulate obtains dried granule, and the magnesium stearate of dried granule and surplus and micropowder silica gel get the Atorvastatin calcium granule after always mixing;
4) respectively with step 2) mix powder and the Atorvastatin calcium granule of step 3) of Levamlodipine besylate directly compressible place mixer to mix; Detect and carry out tabletting after qualified; Open tablet machine, make Levamlodipine besylate and Atorvastatin calcium Pharmaceutical composition label as active ingredient;
5) preparation film-coat layer is stirred well to and is even emulsus; Get Levamlodipine besylate crystal and the Atorvastatin calcium Pharmaceutical composition label as active ingredient, place in the coating pan, coating pan slowly rotates; Heating simultaneously; Be increased to 45 ℃ Deng chip temperature, with spray gun the coating solution of atomizing slowly evenly be sprayed at the sheet wicking surface of rolling, along with coating pan and label continue to be heated; Solvent evaporation; Coating material forms the film coating layer at the sheet wicking surface, and the film-coat until forming uniform drying promptly gets described Levamlodipine besylate hydrate crystal/atorvastatin calcium tablet.
Wherein the Levamlodipine besylate crystal is the prepared Levamlodipine besylate crystal of the embodiment of the invention 1.
Below be FORMULATION EXAMPLE 2-9, its prescription sees shown in the table 2 that preparation technology is with FORMULATION EXAMPLE 1.
Table 2, FORMULATION EXAMPLE 2-9
Annotate: used Levamlodipine besylate corresponds to the prepared Levamlodipine besylate crystal of embodiment 29 respectively in the FORMULATION EXAMPLE 29.
Test Example 1
Solubility test
Test method is with reference to Levamlodipine besylate (Shandong Xinshidai Pharmaceutical Industry Co., Ltd. of " research of Levamlodipine besylate Losartan Potassium controlled release tablet " (Shandong University's master thesis) the 19th page of " mensuration of 4.LB and LP dissolubility in different medium " mensuration prior art; Linyi, China) and the prepared dissolubility of Levamlodipine besylate crystal in water of the embodiment of the invention.
The Levamlodipine besylate dissolubility of table 3, the present invention and prior art relatively
| Dissolubility (mg/mL) | |
| Prior art | 0.053 |
| Embodiment 1 | 21.312 |
| Embodiment 2 | 21.408 |
| Embodiment 3 | 21.413 |
| Embodiment 4 | 21.416 |
| Embodiment 5 | 21.389 |
| Embodiment 6 | 21.397 |
| Embodiment 7 | 21.420 |
| Embodiment 8 | 21.386 |
| Embodiment 9 | 21.421 |
Can find out the Levamlodipine besylate of the crystalline dissolubility of the prepared Levamlodipine besylate of the embodiment of the invention greater than prior art from last table, visible Levamlodipine besylate crystal of the present invention can significantly improve the dissolubility of Levamlodipine besylate.
Test Example 2
Pharmacodynamics test
1, data and method
1.1 object of study
Select hyperpietic's 168 examples, be divided into three groups at random, with the 56 routine patients that take control formulation as matched group, male's 29 examples, women's 27 examples, 66～84 years old age (68.1 ± 4.0) year, hypertension I level 31 examples wherein, II level 25 examples; With the 56 routine patients that take experimental preparation A as experiment A group, male's 30 examples, women's 26 examples, 66～82 years old age (67.1 ± 3.6) year, hypertension I level 29 examples wherein, II27 example; With the 56 routine patients that take experimental preparation B as experiment B group, male's 30 examples, women's 26 examples, 66～82 years old age (67.1 ± 3.6) year, hypertension I level 29 examples wherein, II27 example; Those selected meets hypertension diagnosis and grade scale that Chinese hypertension prevention and control guide in 2005 is formulated, removes patients such as secondary hypertension, serious cardiovascular and cerebrovascular disease, liver, gallbladder, pancreas, kidney, diabetes.Systolic pressure before two groups of patient's age, sex composition ratio, smoking, blood lipid level, hypertension histories and the treatment and diastolic pressure etc. are no difference of science of statistics all, has comparability.All patients all do not take calcium antagonist in nearly 10 weeks.
1.2 method
Experiment A group, experiment B group and matched group are taken experimental preparation A, experimental preparation B and control formulation respectively, and 1 time/d, experimental preparation A, experimental preparation B and control formulation are following:
Experimental preparation A: the Levamlodipine besylate/atorvastatin calcium tablet of FORMULATION EXAMPLE 4 preparations of the present invention;
Experimental preparation B: according to prescription and preparation technology's preparation of FORMULATION EXAMPLE 4 of the present invention, different is that used Levamlodipine besylate is the Levamlodipine besylate (Shandong Xinshidai Pharmaceutical Industry Co., Ltd., Linyi, China) of prior art;
Control formulation: according to the atorvastatin and the Levamlodipine beaylate tablets of ZL200710007667.4 embodiment 3 preparations;
After 4 weeks, do not reach blood pressure lowering therapeutic goal person and reject, 12 totally months course of treatment, during the treatment, avoid using the medicine that other can influence blood pressure and blood fat.Both patients all reach the target blood pressure, all accomplish and treat and follow up a case by regular visits to.
1.3 observation index
Those selected respectively before treatment, treatment is after 12 months, measures blood pressure.Blood pressure adopts standard desktop mercury column sphygomanometer, is defined as systolic pressure and diastolic pressure with Koroto-koff I sound and V sound.During measurement, require the patient at indoor quiet rest 10min, seat is measured the right side brachial arterial pressure, continuous measurement 4 times, and each 5min at interval gets back 3 meansigma methodss and record.
1.4 statistical method
Use SPSS 11.0 softwares and carry out date processing.Measurement data with
Expression, the relatively employing t check of three sample averages, enumeration data relatively adopts x
2Check.There is statistical significance P＜0.05 for difference.
2, result
Blood pressure is relatively seen table 4 before and after two kinds of patient treatments.
Table 4, three groups of patient treatment front and back blood pressure are relatively
Can find out from last table; Compare with matched group; Experiment A group and experiment B group have better antihypertensive effect; And compare with experiment B group, it is more remarkable then to test A group antihypertensive effect, the visible better efficacy that adopts the Levamlodipine besylate/atorvastatin calcium tablet of Levamlodipine besylate crystal preparation of the present invention.
The prepared Levamlodipine besylate of other embodiment of the present invention/atorvastatin calcium tablet has also been carried out above-mentioned test, and the result of its acquisition is similar.
Claims (8)
1. Pharmaceutical composition that contains Levamlodipine and Atorvastatin calcium; Comprise active constituents of medicine Levamlodipine and Atorvastatin calcium; And pharmaceutic adjuvant filler, disintegrating agent and lubricant; It is characterized in that; Described Levamlodipine is the Levamlodipine besylate crystal, and characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that described Levamlodipine besylate crystal use Cu-K alpha ray measures; Described active constituents of medicine is made up of 2 ~ 20 parts Levamlodipine besylate crystal and 5 ~ 120 parts Atorvastatin calcium, and wherein the crystalline amount of Levamlodipine besylate is in Levamlodipine.
2. Pharmaceutical composition according to claim 1 is characterized in that, the following method preparation of described Levamlodipine besylate crystal by adopting:
1) Levamlodipine besylate is dissolved in dichloromethane and the ethanol mixed solvent, obtains the dichloromethane/alcoholic solution of Levamlodipine besylate; Wherein, the consumption of described dichloromethane and ethanol mixed solvent is 10～20 times of Levamlodipine besylate weight; Dichloromethane and alcoholic acid volume ratio are 5～8:1 in said dichloromethane and the ethanol mixed solvent;
2) under ultrasonic field, in the dichloromethane/alcoholic solution of the Levamlodipine besylate of step 1) gained, drip normal heptane, separate out to crystallization;
3) close ultrasonic field, leave standstill growing the grain, filter, filter cake is used dichloromethane, washing with alcohol respectively, and drying obtains described Levamlodipine besylate crystal.
3. Pharmaceutical composition according to claim 2 is characterized in that step 2) described in the power of ultrasonic field be 0.4～0.6KW.
4. Pharmaceutical composition according to claim 2 is characterized in that, the growing the grain that leaves standstill described in the step 3) is at 20～25 ℃ of following growing the grain 4-8 hours.
5. according to any described Pharmaceutical composition of claim 1-4; It is characterized in that; Described active constituents of medicine is made up of 2.5 ~ 20 parts Levamlodipine besylate crystal and 5 ~ 80 parts Atorvastatin calcium, and wherein the crystalline amount of Levamlodipine besylate is in Levamlodipine.
6. Pharmaceutical composition according to claim 5; It is characterized in that; Described active constituents of medicine is by 2.5 parts of Levamlodipine besylate crystal and 5 parts of Atorvastatin calciums; Perhaps 5 parts of Levamlodipine besylate crystal and 10 parts of Atorvastatin calciums; Perhaps 5 parts of Levamlodipine besylate crystal and 20 parts of Atorvastatin calciums, perhaps 5 parts of Levamlodipine besylate crystal and 40 parts of Atorvastatin calciums, perhaps 10 parts of Levamlodipine besylate crystal and 10 parts of Atorvastatin calciums; Perhaps 20 parts of Levamlodipine besylate crystal and 60 parts of Atorvastatin calciums are formed, and wherein the crystalline amount of Levamlodipine besylate is in Levamlodipine.
7. Pharmaceutical composition according to claim 6; It is characterized in that; Described filler is lactose and microcrystalline Cellulose, and described disintegrating agent is a low-substituted hydroxypropyl cellulose, and said lubricant is magnesium stearate and micropowder silica gel; By weight, in the said Pharmaceutical composition: microcrystalline Cellulose is that 10～50 parts, lactose are that 10～50 parts, low-substituted hydroxypropyl cellulose are that 1～10 part, micropowder silica gel are that 2～8 parts, magnesium stearate are 1～6 part.
8. the method for preparing of each described Pharmaceutical composition of claim 1 ~ 7 is characterized in that, said method for preparing may further comprise the steps:
1) earlier Atorvastatin calcium and adjuvant are crossed 60 mesh sieves respectively, subsequent use;
2) take by weighing the Levamlodipine besylate crystal of recipe quantity and filler, disintegrating agent and the lubricant of 50% recipe quantity respectively, behind equivalent incremental method mix homogeneously, obtain the mix powder of Levamlodipine besylate directly compressible;
3) take by weighing the Atorvastatin calcium of recipe quantity and the filler and the disintegrating agent of 50% recipe quantity more respectively; Behind equivalent incremental method mix homogeneously, behind the 20 mesh sieve dry granulations, granulate obtains dried granule; The lubricant of dried granule and surplus gets the Atorvastatin calcium granule after always mixing;
4) respectively with step 2) mix powder and the Atorvastatin calcium granule of step 3) of Levamlodipine besylate directly compressible place mixer to mix; Detect and carry out tabletting after qualified; Open tablet machine, make Levamlodipine besylate and Atorvastatin calcium Pharmaceutical composition label as active ingredient;
5) film coating.
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| CN102846608A (en) * | 2012-09-13 | 2013-01-02 | 北京万全阳光医学技术有限公司 | Pharmaceutical composition containing amlodipine and atorvastatin calcium, and preparation method thereof |
| CN103006652A (en) * | 2013-01-10 | 2013-04-03 | 河南福森药业有限公司 | Pharmaceutical composition capable of reducing blood pressure and blood fat simultaneously and preparation method of pharmaceutical composition |
| CN104983690A (en) * | 2015-08-18 | 2015-10-21 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine atorvastatin calcium composition dry suspension for treating coronary heart disease |
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| CN1238342C (en) * | 2001-03-29 | 2006-01-25 | 韩美药品工业株式会社 | Novel amlodipine camsylate and method for preparing thereof |
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