CN103479643A - Preparation method of compound preparation for treating high blood pressure - Google Patents
Preparation method of compound preparation for treating high blood pressure Download PDFInfo
- Publication number
- CN103479643A CN103479643A CN201310467192.2A CN201310467192A CN103479643A CN 103479643 A CN103479643 A CN 103479643A CN 201310467192 A CN201310467192 A CN 201310467192A CN 103479643 A CN103479643 A CN 103479643A
- Authority
- CN
- China
- Prior art keywords
- amlodipine
- valsartan
- hydrochlorothiazide
- adjuvant
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a compound preparation for treating high blood pressure. The compound preparation is prepared by making valsartan and/or amlodipine and/or hydrochlorothiazide into nanometer or micrometer powder with an average particle size of 100 nanometers-60 micrometers by means of air flow crushing or grinding. According to an adopted solid dispersion technique, valsartan and/or amlodipine and/or hydrochlorothiazide and at least one pharmaceutic adjuvant are made into a solid dispersion, which is obtained by carrying out spray drying or grinding on the drugs and the adjuvant. The drugs are dispersed in the adjuvant in a nanometer or micrometer state. The prepared valsartan, amlodipine and hydrochlorothiazide micropowder or the solid dispersion material can be individually encapsuled or mixed with a pharmaceutically acceptable adjuvant and then encapsuled, or can be made into particles by a preparation technology and then encapsuled.
Description
Technical field
The invention belongs to technical field of medicine, relate to the preparation method that is used for the treatment of the hypertension compound capsule; Particularly adopt nanotechnology, micronization technology or solid dispersion technology to prepare the capsule of valsartan, amlodipine and hydrochlorothiazide.
Background technology
Valsartan is a kind of novel non-peptide class, orally active Angiotensin II (AT) receptor antagonist, contestable ground antagonism AT, the physiological effect of mediation, blood vessel dilating, improve ventricle and vascular remodeling, suppress aldosterone, thereby reduce blood pressure, be applicable to light, Moderate Essential Hypertension.Valsartan is atomic molten it is affected the to a great extent medicine absorption of main absorption site in vivo in slant acidity, so valsartan only has the approximately absolute oral administration biaavailability of 25% (wide region is 10 ~ 35%).
Amlodipine benzenesulphonate is dihydropyridine type calcium antagonists, and selectivity suppresses the calcium ion cross-film and enters smooth muscle cell and myocardial cell, and the effect of smooth muscle is greater than to cardiac muscle.It is decided by with the interaction of calcium channel the gradual speed that it and acceptor site are combined and dissociate, and this product is the peripheral arterial expander, directly acts on vascular smooth muscle, reduces peripheral vascular resistance, thereby reduces blood pressure.Amlodipine benzenesulphonate is slightly soluble in water, and only has 64 ~ 90% absolute bioavailability.
Hydrochlorothiazide is the diuretic that acts on tubular distal of extensive use clinically, and mechanism of action mainly suppresses the heavily absorption to sodium chloride of distal tubule leading portion and proximal tubule (acting on lighter), thereby increases the Na of distal tubule and collecting tubule
+-K
+exchange, K
+secretion increasing.Except the effect of diuresis row sodium, also have the outer mechanism of action of kidney to participate in blood pressure lowering.Be applicable to edema and hypertensive treatment, can effectively control moderate hypertension, adverse reaction rate is low.Hydrochlorothiazide is slightly soluble in water, and only has 60 ~ 80% oral administration biaavailability.
Result of complicated biopharmaceutics character as these, the dosage of oral routine, nearly half (absolute bioavailability of amlodipine benzenesulphonate 64 ~ 90% is wherein arranged, hydrochlorothiazide only has 60 ~ 80% oral administration biaavailability) even most medicines (valsartan only has approximately 25% absolute oral administration biaavailability) can not absorb for human body, thereby cause the accumulation of drug toxicity and the waste of drug resource, therefore exploitation improves valsartan, in the dissolution in vitro of amlodipine and hydrochlorothiazide and oral body, the preparation method of bioavailability and preparation have the challenge domestic animal, also be very important.
The nanotechnology adopted, micronization technology refer to by comminution by gas stream or grind nanometer or the micron powder of valsartan and/or amlodipine and/or hydrochlorothiazide being made to mean diameter 100nm ~ 60 μ m; The solid dispersion technology adopted is that valsartan and/or amlodipine and/or hydrochlorothiazide and at least one pharmaceutic adjuvant are made to solid dispersion, solid dispersion is that medicine and adjuvant are obtained by spray drying method or polishing, and medicine is dispersed in adjuvant with nanometer or micron state.By the valsartan of above-mentioned preparation, amlodipine and hydrochlorothiazide micropowder or solid dispersion material can be separately or with incapsulate after the acceptable adjuvant of pharmacy mixes or by incapsulating after the preparation technique granulation.
At present, U.S. FDA approval Novartis Co.,Ltd amlodipine+valsartan+hydrochlorothiazide tablet commodity compound tablet (amlodipine+valsartan+hydrochlorothiazide, Exforge HCT) listing treatment hypertension, this for two types of antihypertensive drug therapeutic alliances of those application after the poor effect patient a kind of important new selection is provided.The consumption of this compound tablet that following table is the FDA approval:
| Numbering | Amlodipine mg | Hydrochlorothiazide mg | Valsartan |
| 1 | 5 | 12.5 | 160 |
| 2 | 5 | 25 | 160 |
| 3 | 10 | 12.5 | 160 |
| 4 | 10 | 25 | 160 |
| 5 | 10 | 25 | 320 |
Existing patent of invention (CN101478956A) discloses a kind of amlodipine+valsartan+hydrochlorothiazide Compound Tablet agent, but this dosage form comes with some shortcomings, in preparation process substantially: through the valsartan in three kinds of raw materials is mixed with adjuvant, be pressed into sheet through roller mill, through grinding, sieving, (actual be exactly to wave grinding through oscillating granulator and so on to cross the larger sieve in aperture simultaneously again, in order to make mobility granule preferably) make the granule that mobility meets the tabletting requirement, with amlodipine and/or hydrochlorothiazide and magnesium stearate, mix again, tabletting (sometimes as required must coating) forms.
In this patent preparation process, do not relate to any to playing the amlodipine of therapeutical effect, valsartan, hydrochlorothiazide carries out describing or research for the method that improves bioavailability in dissolution in vitro and oral body, technique needs through twice mixing and tabletting repeatedly again, technique does not adopt the novel formulation technology, technical process is comparatively loaded down with trivial details, double-deck, three-layer tablet is had relatively high expectations to equipment, in preparation, yield rate is relatively low, the phenomenons such as the sheet that occurs giving up is more, thereby the alkaline magnesium stearate lubricant especially added for tabletting in the prescription can react with Amlodipine Besylate Tablet and affect its stability and dissolution determination result.
In addition, patent of invention (CN 201668750U) discloses equally a kind of capsule body 1 and loads amlodipine 2, valsartan sheet 3 and the hydrochlorothiazide tablet 4 in capsule body 1, this utility model is convenient to quality control, can be when product inspection, tablet directly takes out from capsule, and three tablets can be tested by standard separately.But the method need to prepare three kinds of microplates, in then incapsulating, production process is various; Thereby can reacting with Amlodipine Besylate Tablet, the alkaline magnesium stearate lubricant added for tabletting in prescription affects its stability and dissolution determination result.。
In a word, existing product does not all solve amlodipine benzenesulphonate, the hydrochlorothiazide oral administration biaavailability is lower, especially the very low problem of valsartan oral administration biaavailability.
Summary of the invention
Some shortcomings based on existing preparation, the present invention adopts nanotechnology, micronization technology or solid dispersion technology to prepare the capsule of valsartan, amlodipine and hydrochlorothiazide.
Therefore, the purpose of this invention is to provide a kind of capsule preparation method thereof that contains valsartan, amlodipine and hydrochlorothiazide, improve dissolution in vitro and the interior bioavailability of body of valsartan, amlodipine and hydrochlorothiazide, in order to improve the toxic and side effects of the curative effect of medicine, the taking dose that reduces medicine, reduction medicine.
The invention discloses for achieving the above object a kind of preparation method that is used for the treatment of the hypertension compound capsule, it is characterized in that being undertaken by following step:
(1) adopt nanotechnology, micronization technology or solid dispersion technology to prepare the capsule of valsartan, amlodipine and hydrochlorothiazide.
(2) nanotechnology, the micronization technology adopted refers to by comminution by gas stream or grinds nanometer or the micron powder of valsartan and/or amlodipine and/or hydrochlorothiazide being made to mean diameter 100nm ~ 60 μ m;
(3) solid dispersion technology adopted is that valsartan and/or amlodipine and/or hydrochlorothiazide and at least one pharmaceutic adjuvant are made to solid dispersion, solid dispersion is that medicine and adjuvant are obtained by spray drying method or polishing, and medicine is dispersed in adjuvant with nanometer or micron state.
(4) can be separately by the valsartan of above-mentioned preparation, amlodipine and hydrochlorothiazide micropowder or solid dispersion material or with incapsulate after the acceptable adjuvant of pharmacy mixes or by incapsulating after the preparation technique granulation.
Preparation method of the present invention, wherein valsartan is 50 ~ 700 mg, amlodipine is 2.0 ~ 25mg, hydrochlorothiazide 5.0 ~ 60mg.
Preparation method of the present invention, the nanotechnology of employing, micronization technology refer to by comminution by gas stream or grind nanometer or the micron powder of valsartan and/or amlodipine and/or hydrochlorothiazide being made to mean diameter 100nm ~ 60 μ m; Comminution by gas stream institute use equipment mainly refers to jet mill or claims fluid energy mill, grinds institute's use equipment and mainly refer to ball mill etc.
Can select one or more in following water solublity pharmaceutic adjuvant in described solid dispersion technology: be the sugar alcohols such as mannitol, Sorbitol, lactose; Or be selected from the Polyethylene Glycol that mean molecule quantity is 1000-10000; Or be selected from the water-soluble polymer classes such as polyvidone, the surfactants such as poloxamer; Also can select one or more in the medicinal adjuvant of following water-insoluble in solid dispersion technology: the celluloses such as microcrystalline Cellulose, hydroxypropyl cellulose, the inorganic salts such as dicalcium phosphate, calcium phosphate, the starch based such as starch, pregelatinized Starch.
Of the present inventionly by spray drying method, prepare the solid dispersion method, the steps include:
(a) preparation contains solution or the micropowder suspension of valsartan and/or amlodipine and/or hydrochlorothiazide, and contains at least one water soluble adjuvant or water-insoluble adjuvant;
(b) by spray drying by the described solution of step (a) make containing in valsartan, amlodipine, hydrochlorothiazide any, powder or the granular solids dispersion of two or three medicine.Wherein the prepared solution of step (a) or suspension are that any one or several in valsartan, amlodipine, hydrochlorothiazide are dissolved fully or are suspended in suitable solvent, then it is mixed with the solution that contains at least one adjuvant.
Solution manufacturing method of the present invention is: by any one or several dissolvings in the valsartan of 10 weight portions, amlodipine, hydrochlorothiazide or be suspended in the solvent more than 8 weight portions, it is mixed to spray drying and get final product with the water of at least one adjuvant (water solublity or water-insoluble adjuvant) or organic solution or suspension more than containing 0.5 weight portion.Described solvent is water or organic solvent: the above any one or several mixed solvent such as ethanol, methanol, isopropyl alcohol, the tert-butyl alcohol, acetone, oxolane.
Of the present inventionly by polishing, prepare the solid dispersion method, the steps include: any one or several and at least one adjuvant (water solublity or water-insoluble adjuvant) more than 3 weight portions in the valsartan of 10 weight portions, amlodipine, hydrochlorothiazide is mixed homogeneously, make solid dispersion through ball mill grinding to desirable degree, obtain.The present invention relates to amlodipine free base provides with the form of amlodipine benzenesulphonate.
In the present invention relates to capsule the amount of valsartan used preferably approximately 50 mg to approximately 700 mg, preferably 160 mg or 320mg; The amount of amlodipine used is about 2.0mg to about 20mg, and preferably 5mg or 10mg; The amount of hydrochlorothiazide used preferably about 6.25mg to about 50mg, and preferably 12.5mg or 25mg.
The present invention can adopt nanotechnology, micronization technology or solid dispersion technology by valsartan, amlodipine and hydrochlorothiazide respectively or combination be prepared into micropowder or solid dispersion, directly make capsule after mixing, or, by after the mixed material granulation, make capsule.
The present invention relates to adopt nanotechnology, micronization technology or solid dispersion technology that valsartan, amlodipine and hydrochlorothiazide are prepared into to micropowder or solid dispersion powder, be selected from diluent, fluidizer combination with pharmaceutically acceptable additive again, mix homogeneously, make capsule.
The present invention relates to adopt nanotechnology, micronization technology or solid dispersion technology valsartan, amlodipine and hydrochlorothiazide to be prepared on the basis of micropowder or solid dispersion powder, further they and pharmaceutically acceptable additive are selected to diluent, binding agent, disintegrating agent etc. and mix, be prepared into the granule of suitable size by dry method or wet granulation technique; Granule is mixed in proportion, adds appropriate fluidizer, mix homogeneously, load capsule and become capsule.
The ultra-micro powder of the valsartan the present invention relates to, amlodipine and hydrochlorothiazide can be ground into the powder of particle diameter at 100nm ~ 60 μ m by jet mill or ball mill etc.
Adopt nanotechnology, micronization technology or solid dispersion technology that valsartan, amlodipine and hydrochlorothiazide respectively or after combination is prepared into ultra-micro powder or solid dispersion powder, can be adopted to the dry granulation granulation.First by valsartan, amlodipine and hydrochlorothiazide respectively or combination be prepared into micropowder or the solid dispersion powder is mixed homogeneously with suitable disintegrating agent, diluent, adhesive and coloring agent, the employing dry granulation technology is granulated, granulate, obtain granule, for filled capsules.Suitable diluent is including but not limited to microcrystalline Cellulose, pregelatinized Starch, mannitol, sucrose or other sugar or sugar derivatives, the low hydroxy propyl cellulose replaced, dicalcium phosphate and its combination, diluent can account for Capsule content weight approximately 0% to approximately 80%, preferably approximately 32% use to about 50% amount.Suitable disintegrating agent is including but not limited to crospovidone, sodium starch glycollate, L-hydroxy propyl cellulose, cross-linked carboxymethyl cellulose sodium and its combination, disintegrating agent can account for Capsule content weight approximately 0.5% to approximately 30%, preferably approximately 5% use to about 14% amount.
After adopting nanotechnology, micronization technology or solid dispersion technology that valsartan, amlodipine and hydrochlorothiazide are prepared into to micropowder or solid dispersion powder, can adopt the wet granulation granulation.First by valsartan, amlodipine and hydrochlorothiazide respectively or combination be prepared into ultra-micro powder or solid dispersion powder, with suitable disintegrating agent, diluent, adhesive, mix homogeneously again, adopt wet granulation technique to prepare dry granule, for filled capsules.Suitable diluent is including but not limited to microcrystalline Cellulose, mannitol, sucrose or other sugar or sugar derivatives, the low hydroxy propyl cellulose replaced, dicalcium phosphate, lactose and its combination, diluent can account for Capsule content weight approximately 0% to approximately 80%, preferably approximately 32% use to about 50% amount.Suitable disintegrating agent is including but not limited to crospovidone, carboxymethyl starch sodium, L-hydroxy propyl cellulose, cross-linked carboxymethyl cellulose sodium and its combination, disintegrating agent can with Capsule content weight approximately 0% to approximately 30%, preferably approximately 5% use to about 14% amount.Suitable binding agent is including but not limited to polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, pregelatinized Starch, 0 ~ 10% starch slurry and its combination.When binding agent is 1 ~ 10% starch slurry, consumption prepares in right amount soft material and gets final product; When polyvinyl pyrrolidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, pregelatinized Starch etc., binding agent can account for Capsule content weight 0.5% to approximately 40%, preferably approximately 10% amount is used, and selects the ethanol water of water or variable concentrations to prepare soft material.
Preparation method high spot reviews of the present invention following factor:
1, formulation factors (for example, whether adjuvant is influential to principal agent);
2, whether technological level is advanced, and whether preparation method is simple and easy to do, especially the application of new agent technology;
3, the impact of poorly soluble diameter of aspirin particle on dissolution;
4, adopt new agent technology to reduce the impact of diameter of aspirin particle on bioavailability in the medicine body;
Determine adjuvant according to above Factor Selection; The key issue that finally definite preparation method solves:
(1) adopt the new agent technologies such as nanotechnology, micronization technology or solid dispersion technology to reduce diameter of aspirin particle and make it reach nanometer or micron order, improve medicine dissolution and raising medicine bioavailability in vivo in vitro.
(2) at emphasis, screened on the medicine method of pulverizing and the granularity basis of having investigated the medicine pulverizing, drug of choice as diluent, has finally determined that the present invention adopts the preparation method of nanotechnology, the preferred valsartan of micronization technology, amlodipine and hydrochlorothiazide Compound capsule: valsartan, amlodipine and hydrochlorothiazide are crushed to the powder that particle diameter is 100nm ~ 60 μ m with jet mill or ball mill respectively with adjuvant commonly used.Valsartan, hydrochlorothiazide and the amlodipine benzenesulphonate powder (or with pharmaceutic adjuvant) of getting recipe quantity are mixed homogeneously, and incapsulate, and obtain.
(3) on the basis of emphasis screening of medicaments solvent and solid dispersion carrier, finally determined that the present invention adopts another preferred valsartan of solid dispersion technology, the preparation method of the compound capsule of amlodipine and hydrochlorothiazide is as follows: by valsartan, hydrochlorothiazide, amlodipine is dissolved in dehydrated alcohol, appropriate mannitol is dissolved in to water, the heating Osmitrol is to approximately 75 ℃, under agitation it is joined in above-mentioned organic solution, gained solution is placed in approximately under 75 ℃ of conditions, spray-dried machine spray drying, finally make dry valsartan, the solid dispersion powder of hydrochlorothiazide and amlodipine, mix homogeneously, incapsulate, obtain.
The preparation method of a preferred treatment hypertension compound capsule of the present invention is as follows:
Adopt nanotechnology, micronization technology or solid dispersion technology by valsartan, amlodipine and hydrochlorothiazide respectively or combination be prepared into micropowder or solid dispersion, by after the mixed material granulation, make capsule after mixing.
Another preparation method of preferably treating the hypertension compound capsule of the present invention is as follows:
Adopt nanotechnology, micronization technology or solid dispersion technology that valsartan, amlodipine and hydrochlorothiazide are prepared into to micropowder or solid dispersion powder, they and pharmaceutically acceptable additive are selected to diluent, binding agent, disintegrating agent etc. and mix, be prepared into the granule of suitable size by dry method or wet granulation technique; Granule is mixed in proportion, adds appropriate fluidizer, mix homogeneously, load capsule and become capsule.
The present invention another preferably to treat the preparation method of hypertension compound capsule as follows:
Adopt nanotechnology, micronization technology or solid dispersion technology by valsartan, amlodipine and hydrochlorothiazide respectively or combination be prepared into micropowder or solid dispersion, directly make capsule after mixing.
The present invention another preferably to treat the preparation method of hypertension compound capsule as follows:
Adopt nanotechnology, micronization technology or solid dispersion technology that valsartan, amlodipine and hydrochlorothiazide are prepared into to micropowder or solid dispersion powder, be selected from diluent, fluidizer combination with pharmaceutically acceptable additive again, mix homogeneously, make capsule.
Disclosed by the inventionly be used for the treatment of the preparation method of hypertension compound capsule and the difference of existing formulation preparation method is:
(1) preparation method of existing patent is and adopts the preparation method of conventional tablet to prepare tablet (monolayer tablet or multilayer tablet), or adopts the preparation method of conventional tablet to be prepared into respectively containing encapsulated again after the tablet of three kinds of different pharmaceuticals.Therefore, all do not solve the existing product amlodipine benzenesulphonate, the hydrochlorothiazide oral administration biaavailability is lower, especially the very low problem of valsartan oral administration biaavailability.
(2) the present invention adopts the new agent technologies such as nanotechnology, micronization technology or solid dispersion technology to prepare the capsule of valsartan, amlodipine and hydrochlorothiazide.By the valsartan of above-mentioned preparation, amlodipine and hydrochlorothiazide micropowder or solid dispersion material can be separately or with incapsulate after the acceptable adjuvant of pharmacy mixes or by incapsulating after the preparation technique granulation.I.e. difference is:
1. the present invention is capsule truly; Prescription is (without alkaline magnesium stearate lubricant, thereby can not react with Amlodipine Besylate Tablet and affect its stability and dissolution determination result) technique simple possible rationally; And existing patent is tablet or tablet capsule, write out a prescription unreasonable (thereby the alkaline magnesium stearate lubricant added for tabletting in prescription can react with Amlodipine Besylate Tablet affect its stability and dissolution determination result), technique is loaded down with trivial details, complexity.
2. the present invention adopts the new agent technologies such as nanotechnology, micronization technology or solid dispersion technology to prepare capsule 's content and then prepare capsule, encapsulated again after the preparation method of existing patent is the preparation method that adopts conventional tablet and prepares tablet or make tablet.
3. the invention solves amlodipine benzenesulphonate, hydrochlorothiazide, the low problem of valsartan oral administration biaavailability.Existing patent does not all solve the existing product amlodipine benzenesulphonate, the hydrochlorothiazide oral administration biaavailability is lower, especially the very low problem of valsartan oral administration biaavailability.
The accompanying drawing explanation:
Fig. 1 is the average time front of blood concentration that the oral marketed tablet of beasle dog and prescription 4 are made compound valsartans, hydrochlorothiazide, amlodipine capsule by oneself.
The specific embodiment
Below in conjunction with specific embodiment, the present invention will be further described, and following each embodiment is not only limitation of the present invention for the present invention is described.The present invention's various raw materials used, preparation all have commercially available.
In the following prescription 1 of use, listed component prepares the capsule of valsartan, amlodipine and hydrochlorothiazide.
Valsartan 160g
Hydrochlorothiazide 12.5g
Amlodipine benzenesulphonate 5g(amlodipine meter)
1000 capsules
Use respectively pulverizer (as: jet mill) or ball mill to be crushed to the powder that particle diameter is 100nm ~ 60 μ m sizes valsartan, amlodipine and hydrochlorothiazide.Get valsartan, hydrochlorothiazide and the amlodipine benzenesulphonate powder mix homogeneously of recipe quantity, incapsulate, obtain.
In the following prescription 2 of use, listed component prepares the capsule of valsartan, amlodipine and hydrochlorothiazide.
Valsartan 160g
Hydrochlorothiazide 12.5 g
Amlodipine benzenesulphonate 5g(amlodipine meter)
Microcrystalline Cellulose 10g
Silica sol 3g
1000 capsules
Use respectively pulverizer (as: jet mill) or ball mill to be crushed to the powder that particle diameter is 100nm ~ 60 μ m valsartan, amlodipine and hydrochlorothiazide.Valsartan, hydrochlorothiazide and the amlodipine benzenesulphonate powder of getting recipe quantity are mixed homogeneously with adjuvant.Incapsulate, obtain.
Embodiment 3
In the following prescription 3 of use, listed component prepares the capsule of valsartan, amlodipine and hydrochlorothiazide.
Prescription 3
Valsartan 160 g
Hydrochlorothiazide 12.5 g
Amlodipine benzenesulphonate 5g(amlodipine meter)
10% starch slurry is appropriate
Polyvinylpolypyrrolidone 40g
1000 capsules
Use respectively pulverizer (as: jet mill) or ball mill to be crushed to the powder that particle diameter is 100nm ~ 60 μ m valsartan, amlodipine and hydrochlorothiazide.Valsartan, hydrochlorothiazide and the amlodipine benzenesulphonate powder of getting recipe quantity are mixed homogeneously with adjuvant, through wet granulation, after obtaining dried particles.Incapsulate to obtain capsule.
In the following prescription 4 of use, listed component prepares the capsule of valsartan, amlodipine and hydrochlorothiazide.
Valsartan 160g
Hydrochlorothiazide 12.5g
Amlodipine benzenesulphonate 5g(amlodipine meter)
Microcrystalline Cellulose 30g
Polyvinylpolypyrrolidone 20g
1000 capsules
Use respectively pulverizer (as: jet mill) or ball mill to be crushed to the powder that particle diameter is 100nm ~ 125 μ m valsartan, amlodipine and hydrochlorothiazide.Valsartan, hydrochlorothiazide and the amlodipine benzenesulphonate powder of getting recipe quantity are mixed homogeneously with adjuvant, after the dry granulation granulation, incapsulate to obtain capsule.
Embodiment 5
In the following prescription 5 of use, listed component prepares the capsule of valsartan, amlodipine and hydrochlorothiazide.
Prescription 5
Valsartan 160g
Hydrochlorothiazide 12.5 g
Amlodipine benzenesulphonate 5g(amlodipine meter)
Mannitol 50g
Microcrystalline Cellulose 20g
Polyvinylpolypyrrolidone 5g
1000 capsules
Valsartan is dissolved in the 1200ml dehydrated alcohol, under agitation 50g mannitol is dissolved in to the water of 500ml, heating Osmitrol to 75 ℃, then under agitation, it is joined in above-mentioned organic solution, gained solution is placed in and is not less than under 75 ℃ of conditions, use the spray dryer spray drying, finally make dry valsartan solid dispersion powder.
Use respectively pulverizer (as: jet mill) or ball mill to be crushed to the powder that particle diameter is 100nm ~ 60 μ m the amlodipine of recipe quantity and hydrochlorothiazide; with valsartan solid dispersion powder, microcrystalline Cellulose, polyvinylpolypyrrolidone, mix homogeneously; make dry granule through dry granulating machine, incapsulate into capsule.
In the following prescription 6 of use, listed component prepares the capsule of valsartan, amlodipine and hydrochlorothiazide.
Valsartan 160 g
Hydrochlorothiazide 12.5 g
Amlodipine benzenesulphonate 5g(amlodipine meter)
Microcrystalline Cellulose 100 g
5% starch slurry is appropriate
1000 capsules
Valsartan, hydrochlorothiazide are dissolved in 800ml ethanol, under agitation will cellulose be suspended in 75 ℃ of water of 600ml, under agitation, it is mixed with above-mentioned organic solution, gained solution is placed in and is not less than under 75 ℃ of conditions, use the spray dryer spray drying, finally make dry valsartan, hydrochlorothiazide solid dispersion powder.
Valsartan, hydrochlorothiazide solid dispersion powder are mixed homogeneously with amlodipine benzenesulphonate superfine powder, the microcrystalline Cellulose of recipe quantity, set high in fast stirring granulating machine, take 5% starch slurry as binding agent; wet granular processed, drying, granulate; the dry granule obtained, incapsulate, and obtains.
In the following prescription 7 of use, listed component prepares the capsule of valsartan, amlodipine and hydrochlorothiazide.
Valsartan 160 g
Hydrochlorothiazide 12.5 g
Amlodipine benzenesulphonate 5g(amlodipine meter)
Mannitol 50 g
Silica sol 3 g
1000 capsules
Valsartan, hydrochlorothiazide, amlodipine are dissolved in the 1200ml dehydrated alcohol, under agitation 50g mannitol is dissolved in to the water of 500ml, heating Osmitrol to 75 ℃, then under agitation, it is joined in above-mentioned organic solution, gained solution is placed in and is not less than under 75 ℃ of conditions, use the spray dryer spray drying, finally make the solid dispersion granule of dry valsartan, hydrochlorothiazide and amlodipine, the solid dispersion granule is mixed homogeneously with silica sol, incapsulate, obtain.
Following table 1 prescription 1 ~ 7 is the self-control compound valsartan, hydrochlorothiazide, amlodipine capsule (preparation method is shown in embodiment 1 ~ 7) and commercially available compound valsartan, hydrochlorothiazide, the comparison (n=6) of the stripping data of valsartan in the amlodipine tablet, dissolution method adopts following method to carry out (for ease of comparing, commercially available compound valsartan, hydrochlorothiazide, amlodipine tablet dissolution determination is also used and is measured the self-control compound valsartan, hydrochlorothiazide, two appendix X C first methods of Chinese Pharmacopoeia version in 2010 that the amlodipine capsule dissolution method is identical are that the basket method is carried out).
dissolution determination method:
Get this product, according to dissolution method (two appendix X C first methods of Chinese Pharmacopoeia version in 2010) (basket method), phosphate buffer (pH 6.8) 1000ml of take is dissolution medium, rotating speed is per minute 100 to turn, operation, in the time of 30 minutes, get solution 10ml in accordance with the law, filter, get subsequent filtrate as need testing solution; Another precision takes Amlodipine Besylate Tablet reference substance 6.93mg, valsartan reference substance 160mg and hydrochlorothiazide reference substance 12.5mg, put in the 100ml measuring bottle, add ultrasonic the making of acetonitrile 10ml and dissolve, with dissolution medium, be diluted to scale, shake up, precision measures 5ml, puts in the 50ml measuring bottle, with dissolution medium, is diluted to scale, shake up, in contrast product solution.According to the chromatographic condition under the assay item, calculate respectively the stripping quantity of every with peak area by external standard method.The limit of amlodipine, valsartan and hydrochlorothiazide is 80% of labelled amount, should be up to specification.
content assaying method:
According to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), measure.
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler, and the acetonitrile-water-phosphoric acid (10:90:0.05) of take is mobile phase A, and acetonitrile-water-phosphoric acid (90:10:0.05) is Mobile phase B, and according to the form below carries out gradient elution; Flow velocity is 1.0ml/min; The detection wavelength is 225nm.Measure the system suitability solution 20 μ l under the related substance item, the injection liquid chromatography, record chromatogram, and the separating degree at hydrochlorothiazide peak and impurity I peak should be greater than 3.0.
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 20 | 20 | 80 |
| 22 | 90 | 10 |
| 30 | 90 | 10 |
algoscopy: get the content under the content uniformity item, mix, porphyrize, precision takes in right amount (approximately being equivalent to valsartan 160mg), puts in the 100ml measuring bottle, adds 50% acetonitrile appropriate, within ultrasonic 15 minutes, make amlodipine, valsartan and hydrochlorothiazide dissolve,, shake up to scale by 50% dilution in acetonitrile, filter, precision measures subsequent filtrate 5ml, put in the 50ml measuring bottle, by 50% dilution in acetonitrile to scale, shake up, as need testing solution; Precision measures need testing solution 20 μ l, and the injection liquid chromatography, record chromatogram; Separately get Amlodipine Besylate Tablet, valsartan and hydrochlorothiazide reference substance appropriate, accurately weighed, add 50% acetonitrile dissolving and quantitatively dilute and make every 1ml approximately containing amlodipine 5 μ g, the solution of valsartan 160 μ g and hydrochlorothiazide 12.5 μ g, be measured in the same method.By external standard method, with calculated by peak area, obtain.
Conclusion:
(1) above-mentioned various preparation method all can obtain desirable capsule preparations product.
(2) in technique, granulation (dry method or wet granulation) can make mobility increase (be convenient to the fill capsule, reduce content uniformity), content smaller volume (available more small size capsule fill, be convenient to the patient and swallow).
(3) for measuring commercially available compound valsartan, hydrochlorothiazide, amlodipine tablet and making the dissolution method of compound valsartan, hydrochlorothiazide, amlodipine capsule by oneself and the method that announce content assaying method source Chinese Pharmacopoeia Commission website, through methodological study, said method is practical.
Table 1 prescription 1 ~ 7 is the comparison (n=6) of the stripping data of valsartan in self-control compound valsartan, hydrochlorothiazide, amlodipine capsule and commercially available compound valsartan, hydrochlorothiazide, amlodipine tablet
The average blood drug level (n=3) of valsartan in self-control compound valsartan, hydrochlorothiazide, amlodipine capsule and the commercially available compound valsartan of table 2 prescription 4, hydrochlorothiazide, amlodipine tablet
Conclusion:
(1), under the same terms, the self-control capsule is than the average blood drug level in commercial preparation high (approximately nearly 1 times);
(2), under the same terms, the self-control capsule is more much bigger than commercial preparation AUC;
(3) under the same terms, the oral self-control compound valsartan of beasle dog, hydrochlorothiazide, amlodipine capsule and marketed tablet, the former valsartan oral administration biaavailability is higher.
Claims (8)
1. a preparation method that is used for the treatment of the hypertension compound capsule is characterized in that being undertaken by following step:
(1) adopt nanotechnology, micronization technology or solid dispersion technology to prepare the capsule of valsartan, amlodipine and hydrochlorothiazide; Wherein valsartan is 50 ~ 700 mg, and amlodipine is 2.0 ~ 25mg, hydrochlorothiazide 5.0 ~ 60mg;
(2) nanotechnology, the micronization technology adopted refers to by comminution by gas stream or grinds nanometer or the micron powder of valsartan and/or amlodipine and/or hydrochlorothiazide being made to mean diameter 100nm ~ 60 μ m;
(3) solid dispersion technology adopted is that valsartan and/or amlodipine and/or hydrochlorothiazide and at least one pharmaceutic adjuvant are made to solid dispersion, solid dispersion is that medicine and adjuvant are obtained by spray drying method or polishing, and medicine is dispersed in adjuvant with nanometer or micron state;
(4) can be separately by the valsartan of above-mentioned preparation, amlodipine and hydrochlorothiazide micropowder or solid dispersion material or with incapsulate after the acceptable adjuvant of pharmacy mixes or by incapsulating after the preparation technique granulation.
2. preparation method claimed in claim 1, the nanotechnology of employing, micronization technology refer to by comminution by gas stream or grind nanometer or the micron powder of valsartan and/or amlodipine and/or hydrochlorothiazide being made to mean diameter 100nm ~ 60 μ m; Comminution by gas stream institute use equipment mainly refers to jet mill or claims fluid energy mill, grinds institute's use equipment and mainly refer to ball mill etc.
3. preparation method claimed in claim 1, wherein can select one or more in following water solublity pharmaceutic adjuvant: be the sugar alcohols such as mannitol, Sorbitol, lactose in solid dispersion technology; Or be selected from the Polyethylene Glycol that mean molecule quantity is 1000-10000; Or be selected from the water-soluble polymer classes such as polyvidone, the surfactants such as poloxamer; Also can select one or more in the medicinal adjuvant of following water-insoluble in solid dispersion technology: the celluloses such as microcrystalline Cellulose, hydroxypropyl cellulose, the inorganic salts such as dicalcium phosphate, calcium phosphate, the starch based such as starch, pregelatinized Starch.
4. claimed in claim 1ly by spray drying method, prepare the solid dispersion method, the steps include:
(a) preparation contains solution or the micropowder suspension of valsartan and/or amlodipine and/or hydrochlorothiazide, and contains at least one water soluble adjuvant or water-insoluble adjuvant;
(b) by spray drying by the described solution of step (a) make containing in valsartan, amlodipine, hydrochlorothiazide any, powder or the granular solids dispersion of two or three medicine.
5. preparation method claimed in claim 4, it is characterized in that, the solution that step (a) is prepared or suspension are that any one or several in valsartan, amlodipine, hydrochlorothiazide are dissolved fully or are suspended in suitable solvent, then it is mixed with the solution that contains at least one adjuvant.
6. preparation method claimed in claim 5, described solution manufacturing method is: by any one or several dissolvings in the valsartan of 10 weight portions, amlodipine, hydrochlorothiazide or be suspended in the solvent more than 8 weight portions, it is mixed with the water of at least one adjuvant (water solublity or water-insoluble adjuvant) or organic solution or suspension more than containing 0.5 weight portion. above-mentioned solution or suspension is spray-dried and get final product.
7. the described preparation method of claim 4 ~ 6, described solvent is water or organic solvent: the above any one or several mixed solvent such as ethanol, methanol, isopropyl alcohol, the tert-butyl alcohol, acetone, oxolane.
8. claimed in claim 1ly by polishing, prepare the solid dispersion method, the steps include: any one or several and at least one adjuvant (water solublity or water-insoluble adjuvant) more than 3 weight portions in the valsartan of 10 weight portions, amlodipine, hydrochlorothiazide is mixed homogeneously, make solid dispersion through ball mill grinding to desirable degree, obtain.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310467192.2A CN103479643A (en) | 2013-10-10 | 2013-10-10 | Preparation method of compound preparation for treating high blood pressure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310467192.2A CN103479643A (en) | 2013-10-10 | 2013-10-10 | Preparation method of compound preparation for treating high blood pressure |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103479643A true CN103479643A (en) | 2014-01-01 |
Family
ID=49820465
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310467192.2A Pending CN103479643A (en) | 2013-10-10 | 2013-10-10 | Preparation method of compound preparation for treating high blood pressure |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103479643A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104274468A (en) * | 2014-10-11 | 2015-01-14 | 江西施美制药有限公司 | Valsartan/hydrochlorothiazide pharmaceutical composition and preparation method thereof |
| CN104324037A (en) * | 2014-11-12 | 2015-02-04 | 孙丽华 | Valsartan and hydrochlorothiazide-containing tablet and preparation method thereof |
| CN110123778A (en) * | 2019-06-18 | 2019-08-16 | 南京致中生物科技有限公司 | A kind of valsartan capsule and preparation method thereof |
| CN111603449A (en) * | 2019-02-22 | 2020-09-01 | 鲁南制药集团股份有限公司 | Levamlodipine besylate tablet and preparation method thereof |
| CN112641743A (en) * | 2020-12-23 | 2021-04-13 | 上海耀大生物科技有限公司 | Compound preparation for treating hypertension and preparation process thereof |
| CN113041250A (en) * | 2021-04-06 | 2021-06-29 | 上海耀大生物科技有限公司 | Valsartan and hydrochlorothiazide compound preparation and preparation process thereof |
| CN114642644A (en) * | 2020-12-17 | 2022-06-21 | 鲁南制药集团股份有限公司 | Valsartan tablet and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559042A (en) * | 2008-04-16 | 2009-10-21 | 北京万全阳光医药科技有限公司 | Compound double-layer tablet containing telmisartan and hydrochlorothiazide |
| CN101836981A (en) * | 2009-12-01 | 2010-09-22 | 严洁 | Compound valsartan benzenesulfonic acid amlodipine medicament composition and new preparation method thereof |
| CN102008482A (en) * | 2009-07-11 | 2011-04-13 | 邬林祥 | Compound preparation containing valsartan for treating hypertension |
| CN102357078A (en) * | 2011-10-17 | 2012-02-22 | 苏州大学 | Valsartan solid dispersion and preparation method thereof |
| CN102526748A (en) * | 2011-12-27 | 2012-07-04 | 浙江华海药业股份有限公司 | Oral tablet containing valsartan, hydrochlorothiazide and amlodipine besylate |
-
2013
- 2013-10-10 CN CN201310467192.2A patent/CN103479643A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559042A (en) * | 2008-04-16 | 2009-10-21 | 北京万全阳光医药科技有限公司 | Compound double-layer tablet containing telmisartan and hydrochlorothiazide |
| CN102008482A (en) * | 2009-07-11 | 2011-04-13 | 邬林祥 | Compound preparation containing valsartan for treating hypertension |
| CN101836981A (en) * | 2009-12-01 | 2010-09-22 | 严洁 | Compound valsartan benzenesulfonic acid amlodipine medicament composition and new preparation method thereof |
| CN102357078A (en) * | 2011-10-17 | 2012-02-22 | 苏州大学 | Valsartan solid dispersion and preparation method thereof |
| CN102526748A (en) * | 2011-12-27 | 2012-07-04 | 浙江华海药业股份有限公司 | Oral tablet containing valsartan, hydrochlorothiazide and amlodipine besylate |
Non-Patent Citations (1)
| Title |
|---|
| 田燕等: "《药剂学》", 30 September 2011 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104274468A (en) * | 2014-10-11 | 2015-01-14 | 江西施美制药有限公司 | Valsartan/hydrochlorothiazide pharmaceutical composition and preparation method thereof |
| CN104324037A (en) * | 2014-11-12 | 2015-02-04 | 孙丽华 | Valsartan and hydrochlorothiazide-containing tablet and preparation method thereof |
| CN111603449A (en) * | 2019-02-22 | 2020-09-01 | 鲁南制药集团股份有限公司 | Levamlodipine besylate tablet and preparation method thereof |
| CN111603449B (en) * | 2019-02-22 | 2022-12-27 | 鲁南制药集团股份有限公司 | Levamlodipine besylate tablet and preparation method thereof |
| CN110123778A (en) * | 2019-06-18 | 2019-08-16 | 南京致中生物科技有限公司 | A kind of valsartan capsule and preparation method thereof |
| CN114642644A (en) * | 2020-12-17 | 2022-06-21 | 鲁南制药集团股份有限公司 | Valsartan tablet and preparation method thereof |
| CN112641743A (en) * | 2020-12-23 | 2021-04-13 | 上海耀大生物科技有限公司 | Compound preparation for treating hypertension and preparation process thereof |
| CN113041250A (en) * | 2021-04-06 | 2021-06-29 | 上海耀大生物科技有限公司 | Valsartan and hydrochlorothiazide compound preparation and preparation process thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103479643A (en) | Preparation method of compound preparation for treating high blood pressure | |
| JP6577980B2 (en) | Apixaban preparation | |
| SA517390473B1 (en) | Solid dosage forms of palbociclib | |
| CN102266307B (en) | Valsartan capsules and preparation method thereof | |
| CN104173313A (en) | Rivaroxaban troche pharmaceutical composition | |
| CN1377270A (en) | B-carboline drug products | |
| CN105188676A (en) | Solid compositions comprising a glucokinase activator and methods of making and using the same | |
| US20150238616A1 (en) | Solid preparation comprising enteric solid dispersion | |
| CN103156860A (en) | Olanzapine composition and preparation method thereof | |
| CN105640913A (en) | Olmesartan medoxomil tablet and preparation method thereof | |
| US20100034885A1 (en) | Formulations containing glimepiride and/or its salts | |
| CN114302712A (en) | Acipimox multi-unit sustained-release pellet tablet and preparation method thereof | |
| CN106511348A (en) | Huperzine-A framework particles, orally disintegrating tablets and preparation methods thereof | |
| CN103007286B (en) | General smooth solid composite medicament is cut down in a kind of holder | |
| CN110638768B (en) | Preparation method of medicine for treating male erectile dysfunction | |
| CN102885774B (en) | Prasugrel composition and preparation method thereof | |
| CN104826120B (en) | The preparation of Bosentan | |
| CN104415034A (en) | Imidafenacin pharmaceutical composition and preparation method thereof | |
| CN102488667A (en) | Glimepiride tablet and preparation method thereof | |
| CN104274444B (en) | Oral double pellet pharmaceutical compositions of dabigatran etcxilate or its salt | |
| CN104138365B (en) | A kind of telmisartan capsules agent and preparation method thereof | |
| CN103768068B (en) | A kind of Bosentan pharmaceutical composition | |
| CN103655571A (en) | Lopinavir and ritonavir compound high-uniformity nano co-dispersion body and preparation method thereof | |
| JPH0776516A (en) | Production of slightly soluble medicine-containing preparation | |
| CN106913538A (en) | A kind of Abiraterone acetate sublingual tablets and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140101 |