CN102178665A - Composite preparation containing renin inhibitor and angiotensin II receptor antagonist - Google Patents
Composite preparation containing renin inhibitor and angiotensin II receptor antagonist Download PDFInfo
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- CN102178665A CN102178665A CN201110073450XA CN201110073450A CN102178665A CN 102178665 A CN102178665 A CN 102178665A CN 201110073450X A CN201110073450X A CN 201110073450XA CN 201110073450 A CN201110073450 A CN 201110073450A CN 102178665 A CN102178665 A CN 102178665A
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- aliskiren
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- candesartan cilexetil
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Abstract
The invention relates to a composite preparation containing a renin inhibitor and an angiotensin II receptor antagonist, and a preparation method thereof. The composite preparation is used for treating hypertension. The composite preparation comprises a renin inhibitor aliskiren or pharmaceutical salts thereof as active ingredients in a proper carrier, and an angiotensin II receptor antagonist candesartan or pharmaceutical esters thereof. The weight ratio of aliskiren hemifumarate (in the terms of aliskiren) to candesartan cilexetil is 1:1-230:1. The composite preparation comprises polyvinylpyrrolidone and polyethylene glycol.
Description
Technical field
The present invention relates to a kind of compound preparation of pharmaceutical composition, it is included in renin inhibitor aliskiren or its pharmaceutically useful salt and angiotensin ii receptor antagonist Candesartan or its pharmaceutically acceptable ester as active component in the suitable carrier.Concretely, the present invention relates to comprise aliskiren hemifumarate and Candesartan ester composition, its compound preparation, formulation preparation method and use described compound preparation treatment hypertension.
Background technology
Candesartan Cilexetil is a kind of angiotensin ii receptor antagonist that is used for the treatment of hypertension and medical indications thereof and develops.Candesartan (Candesartan) has following structure:
Aliskiren (aliskiren) is a kind of renin inhibitor, is to use with the form of hemifumarate.The aliskiren chemical name is 2 (S) with following structure, 4 (S), 5 (S), 7 (S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-two (1-Methylethyl)-4-hydroxyl-5-amino-8-[4-methoxyl group-3-(3-methoxyl group-propoxyl group) phenyl]-caprylamide.
Aliskiren has high-hygroscopicity, the medicine crystal conversion be amorphous after, amorphously show relatively poor stability.In addition, the aliskiren of high dose or its officinal salt (every contains free alkali 300mg) need high drug load, so that reach reasonable tablet size (these are recorded in CN200880108860.X).
Because single hypertension therapy is difficult up to standard in a short time, Most patients need be taken the target that two or more antihypertensive drug just can reach blood pressure lowering.Single medicine is prone to drug resistance, and because the bigger probability that toxicity occurs of dosage is also bigger.Therefore, a kind of new treatment pattern is applied to clinical gradually, and the compound hypertension medicine preparation is internationally recognized a kind of orientation treatment.Because the compound antihypertensive drug prescription is followed the principle that different mechanism of action medicines carries out proportioning usually, therefore show as the advantage that increases curative effect or reduce side effect, obtained controlling of blood pressure effect preferably.The existing multiple compound preparation report that contains candesartan Cilexetil of at present existing document, the report that the compound preparation of multiple aliskiren is also arranged simultaneously, compound preparation as compound preparation, aliskiren hemifumarate and the Amlodipine Besylate Tablet of compound preparation, aliskiren hemifumarate and the hydrochlorothiazide of compound preparation, candesartan Cilexetil and the Amlodipine Besylate Tablet of candesartan Cilexetil and hydrochlorothiazide all goes on the market, but do not see the report of aliskiren and candesartan Cilexetil compound preparation and preparation method thereof, the mechanism of action of aliskiren and Candesartan is considered as good fit.
The purpose of this invention is to provide compositions, its compound preparation of aliskiren or its pharmaceutically useful salt and Candesartan or its ester and preparation method thereof.
Another object of the present invention is to use described compound preparation treatment hypertension.
Summary of the invention
The present invention relates to compound preparation of aliskiren or its pharmaceutically useful salt and Candesartan or its pharmaceutically acceptable ester and preparation method thereof.
Because aliskiren hemifumarate and candesartan Cilexetil are all unmanageable chemical compound, aliskiren has higher hygroscopicity, equal tool polymorphic of two medicines and impalpable structure, and preparation granules flowability, bulk density, formulation preparation, preparation stability etc. are all produced negative effect.For overcoming above technical problem, the purpose of this invention is to provide a kind of aliskiren and Candesartan compound preparation and preparation method thereof, and (be polyvidone, PVP), Polyethylene Glycol (PEG) increases the stability of aliskiren (or its salt), Candesartan (or its ester) by adding a certain proportion of polyvinylpyrrolidone.
The aliskiren of the present invention excellent or preferred aliskiren hemifumarate of its pharmaceutically useful salt (aliskiren hemifumarate), Candesartan or the preferred candesartan Cilexetil of its ester (Candesartan Cilexetil).
Aliskiren hemifumarate in the preparation of the present invention (in aliskiren) is 1: 1～230: 1 with the ratio of candesartan Cilexetil weight.
More preferably, described aliskiren hemifumarate (in aliskiren) is 3: 1～150: 1 with the ratio of candesartan Cilexetil weight.
As mentioned above, the aliskiren hemifumarate preferred 50～450mg of content (in aliskiren), more preferably 100～300mg in unit formulation in the compound preparation; Preferred 2～the 30mg of candesartan Cilexetil content in unit formulation, more preferably 2～20mg.
The present invention adopts polyvidone to increase the stability of aliskiren crystal formation and chemical compound; Adopt Polyethylene Glycol to increase the stability of candesartan Cilexetil crystal formation and chemical compound.Described polyvidone is selected from one or more among PVP k17, PVP k25, PVP k30, the PVP k90, is preferably one or both mixing among PVP k30, the PVP k90.Described Polyethylene Glycol is selected from one or more in PEG400～20000, is preferably among PEG1000, PEG2000, PEG4000, the PEG6000 one or more.
Aliskiren hemifumarate in the compound preparation (in aliskiren) is 1: 1～1: 100 with the mass ratio of polyvidone, preferred aliskiren hemifumarate (in aliskiren) is 1: 2～1: 50 with the mass ratio of polyvidone, and polyvidone can increase the stability of aliskiren in described proportion.
The mass ratio of candesartan Cilexetil and Polyethylene Glycol is 0.05: 1～20: 1 in the compound preparation, and the mass ratio of preferred candesartan Cilexetil and Polyethylene Glycol is 0.1: 1～8: 1, and Polyethylene Glycol can increase the stability of candesartan Cilexetil in described proportion.
Preferred dosage form of the present invention is tablet or capsule.
The present invention is prepared in the process of tablet, can will adopt wet granulation technology to granulate behind aliskiren (or its salt), Candesartan (or its ester) and the adjuvant mix homogeneously, mixing behind dry back adding lubricant, the fluidizer, tabletting.Preferably, two active component can be granulated respectively with behind the adjuvant mix homogeneously, then two kinds of granules be mixed and adding lubricant and fluidizer, tabletting behind two kinds of granule mix homogeneously.More preferably, two active component can be granulated respectively with behind the adjuvant mix homogeneously, two kinds of granules are added lubricant, fluidizer respectively and with two kinds of granules mix homogeneously respectively, two kinds of granules are pressed into double-layer tablet.
The present invention is prepared in the capsule process, can will granulate behind two active component and the adjuvant mix homogeneously, then granule is added lubricant and fluidizer, incapsulates behind the mix homogeneously.More preferably, can with two active component respectively with the adjuvant mix homogeneously after, granulate respectively, then two kinds of granules are mixed and add lubricant and fluidizer, incapsulate behind the mix homogeneously.
The present invention can or be filled into capsule with direct compression behind aliskiren (or its salt), Candesartan (or its ester) and the adjuvant mix homogeneously.
The preparation of granules adhesive therefor is selected from hydroxypropyl emthylcellulose, polyvidone, the Polyethylene Glycol one or more mixture.
Used hydroxypropyl emthylcellulose viscosity is 5cps～4000cps in the binding agent, is preferably 5cps～100cps, is more preferably 5cps～50cps.
Used Polyethylene Glycol (PEG) is selected from PEG400～20000 in the binding agent, is preferably among PEG1000, PEG2000, PEG4000, the PEG6000 one or more.
Polyvidone in the binding agent (PVP) is selected from PVP k17, PVP k25, PVP k30, PVP k90, is preferably among PVP k30, the PVP k90 one or both.
The concentration of the mixture of one or more in the binder solution in hydroxypropyl emthylcellulose, polyvidone, the Polyethylene Glycol is 1%～20% (weight ratio), and solvent is the mixture of water or second alcohol and water.
The specific embodiment
Embodiment 1
With adjuvant in aliskiren hemifumarate and the table 1 (not comprising magnesium stearate, micropowder silica gel) mix homogeneously, granulate 50 ℃ of dryings as binder solution with 50% ethanol water that contains 3% (w/w) hydroxypropyl emthylcellulose (50cps).Add magnesium stearate, micropowder silica gel in the table 1, mix homogeneously is as granule A.
Adjuvant in candesartan Cilexetil and the table 2 (not comprising magnesium stearate) mix homogeneously is granulated 50 ℃ of dryings as binder solution with 70% ethanol water that contains 10% (w/w) PEG6000.Add the magnesium stearate in the table 2, mix homogeneously is as granule B.
Granule A, granule B are pressed into bilayer tablet.
Table 1 aliskiren granule
Table 2 candesartan Cilexetil granule
Embodiment 2
With adjuvant in aliskiren hemifumarate and the table 3 (not comprising magnesium stearate, micropowder silica gel) mix homogeneously, granulate 60 ℃ of dryings as binder solution with 70% ethanol water that contains 5% (w/w) PVP k90.Add magnesium stearate, micropowder silica gel in the table 3, mix homogeneously is as granule A.
Adjuvant in candesartan Cilexetil and the table 4 (not comprising magnesium stearate) mix homogeneously is granulated 50 ℃ of dryings as binder solution with 50% ethanol water that contains 6% (w/w) PEG6000.Add the magnesium stearate in the table 4, mix homogeneously is as granule B.
With tabletting behind granule A, the granule B mix homogeneously.
Table 3 aliskiren granule
Table 4 candesartan Cilexetil granule
Embodiment 3
With adjuvant in aliskiren hemifumarate, candesartan Cilexetil and the table 5 (not comprising magnesium stearate, micropowder silica gel) mix homogeneously, granulate 50 ℃ of dryings as binder solution with 70% ethanol water that contains 5% (w/w) hydroxypropyl emthylcellulose (5cps).Add magnesium stearate, micropowder silica gel in the table 5, tabletting behind the mix homogeneously.
Table 5 prescription
Embodiment 4
With tabletting behind the adjuvant mix homogeneously in aliskiren hemifumarate, candesartan Cilexetil and the table 6.
Table 6 prescription
Embodiment 5
With adjuvant in aliskiren hemifumarate and the table 7 (not comprising magnesium stearate, micropowder silica gel) mix homogeneously, granulate 60 ℃ of dryings as binder solution with 30% ethanol water that contains 10% (w/w) hydroxypropyl emthylcellulose (5cps).Add magnesium stearate, micropowder silica gel in the table 7, mix homogeneously is as granule A.
Adjuvant in candesartan Cilexetil and the table 8 (not comprising magnesium stearate) mix homogeneously is granulated 50 ℃ of dryings as binder solution with 70% ethanol water that contains 15% (w/w) PEG6000.Add the magnesium stearate in the table 8, mix homogeneously is as granule B.
With tabletting behind granule A, the granule B mix homogeneously.
Table 7 aliskiren granule
Table 8 candesartan Cilexetil granule
Embodiment 6
With adjuvant in aliskiren hemifumarate and the table 9 (not comprising magnesium stearate) mix homogeneously, granulate 60 ℃ of dryings as binder solution with 30% aqueous solution that contains 5% (w/w) hydroxypropyl emthylcellulose (5cps).Add magnesium stearate, micropowder silica gel in the table 9, mix homogeneously is as granule A.
Adjuvant in candesartan Cilexetil and the table 10 (not comprising magnesium stearate) mix homogeneously is granulated 50 ℃ of dryings as binder solution with 70% ethanol water that contains 20% (w/w) PEG1000.Add the magnesium stearate in the table 10, mix homogeneously is as granule B.
Granule A, granule B are pressed into bilayer tablet.
Table 9 aliskiren granule
Table 10 candesartan Cilexetil granule
Embodiment 7
With adjuvant in aliskiren hemifumarate and the table 11 (not comprising magnesium stearate, micropowder silica gel) mix homogeneously, granulate 60 ℃ of dryings as binder solution with 30% ethanol water that contains 15% (w/w) hydroxypropyl emthylcellulose (5cps).Add magnesium stearate, micropowder silica gel in the table 11, mix homogeneously is as granule A.
Adjuvant in candesartan Cilexetil and the table 12 (not comprising magnesium stearate) mix homogeneously is granulated 50 ℃ of dryings as binder solution with 70% ethanol water that contains 4% (w/w) PEG4000,3% (w/w) hydroxypropyl emthylcellulose (5cps).Add the magnesium stearate in the table 12, mix homogeneously is as granule B.With tabletting behind granule A, the granule B mix homogeneously.
Table 11 aliskiren granule
Table 12 candesartan Cilexetil granule
Embodiment 8
With adjuvant in aliskiren hemifumarate and the table 13 (not comprising magnesium stearate, micropowder silica gel) mix homogeneously, granulate 50 ℃ of dryings as binder solution with 50% ethanol water that contains 15% (w/w) PVP K30.Add magnesium stearate, micropowder silica gel in the table 13, mix homogeneously is as granule A.
Adjuvant in candesartan Cilexetil and the table 14 (not comprising magnesium stearate) mix homogeneously is granulated 50 ℃ of dryings as binder solution with 70% ethanol water that contains 8% (w/w) PEG4000.Add the magnesium stearate in the table 14, mix homogeneously is as granule B.
To be filled into capsule behind granule A, the granule B mix homogeneously.
Table 13 aliskiren granule
Table 14 candesartan Cilexetil granule
Following result describes the quality of product
The interpretation of result of table 15 embodiment 5
The tablet dissolution result of table 16 embodiment 5
Claims (15)
1. a pharmaceutical composition is characterized in that, comprises following active component:
But a) Li Jilun or its officinal salt;
B) Candesartan or its pharmaceutically acceptable ester.
2. pharmaceutical composition according to claim 1, it is characterized in that, the preferred aliskiren hemifumarate of described aliskiren officinal salt (aliskiren hemifumarate), the preferred candesartan Cilexetil of the pharmaceutically acceptable ester of Candesartan (Candesartan Cilexetil).
3. pharmaceutical composition according to claim 2 is characterized in that, aliskiren hemifumarate (in aliskiren) is 1: 1～230: 1 with the ratio of candesartan Cilexetil weight.
4. pharmaceutical composition according to claim 3 is characterized in that, aliskiren hemifumarate (in aliskiren) is 3: 1～150: 1 with the ratio of candesartan Cilexetil weight.
5. according to the described pharmaceutical composition of claim 1～4, it is characterized in that aliskiren hemifumarate is the preferred 50～450mg of content (in aliskiren) in unit formulation, more preferably 100～300mg; Preferred 2～the 30mg of candesartan Cilexetil content in unit formulation, more preferably 2～20mg.
6. according to the described pharmaceutical composition of claim 1～5, it is characterized in that dosage form is tablet or capsule.
7. pharmaceutical composition according to claim 6 is characterized in that, contains polyvinylpyrrolidone, Polyethylene Glycol.
8. pharmaceutical composition according to claim 7, it is characterized in that, polyvinylpyrrolidone is selected from one or more the mixing among PVP k17, PVP k25, PVP k30, the PVP k90, is preferably the mixing of any one or two kinds among PVP k30, the PVP k90; Polyethylene Glycol is selected from one or more in PEG400～20000, is preferably one or more the mixing among PEG1000, PEG2000, PEG4000, the PEG6000.
9. pharmaceutical composition according to claim 7, it is characterized in that, aliskiren hemifumarate (in aliskiren) is 1: 1～1: 100 with the mass ratio of polyvinylpyrrolidone, preferably, aliskiren hemifumarate (in aliskiren) is 1: 2～1: 50 with the mass ratio of polyvinylpyrrolidone.
10. pharmaceutical composition according to claim 7 is characterized in that, the mass ratio of candesartan Cilexetil and Polyethylene Glycol is 0.05: 1～20: 1, and preferably, the mass ratio of candesartan Cilexetil and Polyethylene Glycol is 0.1: 1～8: 1.
11. according to the described pharmaceutical composition of claim 6～10, it is characterized in that, be prepared in the particulate process, binding agent is one or more a mixture in hydroxypropyl emthylcellulose, polyvinylpyrrolidone, the Polyethylene Glycol, and its weight accounts for 1%～20% of binder solution gross weight.
12. pharmaceutical composition according to claim 11 is characterized in that, is prepared in the particulate process, used hydroxypropyl emthylcellulose viscosity is 5cps～4000cps in the binding agent, is preferably 5cps～100cps, is more preferably 5cps～50cps; Used Polyethylene Glycol is selected from PEG400～20000 in the binding agent, is preferably one or more the mixture among PEG1000, PEG2000, PEG4000, the PEG6000; Polyvinylpyrrolidone is selected from one or more the mixture among PVP k17, PVP k25, PVP k30, the PVP k90 in the binding agent, is preferably one or more the mixture among PVP k30, the PVP k90.
13. pharmaceutical composition according to claim 11 is characterized in that, the binder solution that is prepared in the particulate process is the aqueous solution of binding agent or the ethanol water of binding agent.
14., it is characterized in that external stripping is characterized as according to the described pharmaceutical composition of claim 6～13: 30 minutes stripping quantities of aliskiren hemifumarate greater than 60%, 45 minute stripping quantity greater than 80%; 15 minutes stripping quantities of candesartan Cilexetil greater than 50%, 30 minute stripping quantity greater than 80%.
15. according to the described pharmaceutical composition of claim 1～14, it is characterized in that, be used for the treatment of hypertension.
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| CN201110073450XA CN102178665A (en) | 2011-03-25 | 2011-03-25 | Composite preparation containing renin inhibitor and angiotensin II receptor antagonist |
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| CN201110073450XA CN102178665A (en) | 2011-03-25 | 2011-03-25 | Composite preparation containing renin inhibitor and angiotensin II receptor antagonist |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101990428A (en) * | 2008-04-10 | 2011-03-23 | 韩兀生物制药株式会社 | Pharmaceutical formulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101990428A (en) * | 2008-04-10 | 2011-03-23 | 韩兀生物制药株式会社 | Pharmaceutical formulation |
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Application publication date: 20110914 |