CN106539791B - A kind of valsartan amlodipine piece and preparation method thereof - Google Patents
A kind of valsartan amlodipine piece and preparation method thereof Download PDFInfo
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- CN106539791B CN106539791B CN201610912219.8A CN201610912219A CN106539791B CN 106539791 B CN106539791 B CN 106539791B CN 201610912219 A CN201610912219 A CN 201610912219A CN 106539791 B CN106539791 B CN 106539791B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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Abstract
The invention discloses a kind of preparation methods of valsartan amlodipine piece, comprising steps of portion of Lactose is first sufficiently mixed with Valsartan and Amlodipine Besylate Tablet, hydrogenated oil and fat, the Macrogol 6000 of recipe quantity by (1)；(2) it is put into through remaining lactose in the hot melt granulator of 40~45 DEG C of heat preservations, above-mentioned mixed powder is then added；(3) starting hot melt granulator, when material temperature reaches 45~52 DEG C of set temperature, discharging；(4) material for making grain is shared equally in baking pan, cooled to room temperature；(5) by the material cooled down pelletizing machine whole grain, while magnesium stearate is added, total mix；(6) tabletting to get.The method of the present invention enhances the stability of raw material, avoids water to stability influence, reduces the influence of auxiliary material, improve pill flow, so that product quality is more stable；And preparation process it is scientific and reasonable, it is simple and easy to operate, effectively reduce production cost and labor intensity.
Description
Technical field
The invention belongs to field of medicine preparations, and in particular to a kind of valsartan amlodipine piece and preparation method thereof.
Background technique
Valsartan is a kind of Angiotensin Ⅱ receptor antagonist (II antagonist of Angiotensin-) of non-peptides,
The physiological effect that AngII can be blocked to mediate, blocks relevant angiotensin I receptor (AT1), makes vascular smooth muscle relaxation, blood
Enlargement of pipe；Renal blood perfusion amount is improved, water, sodium excretion are increased, reduces blood volume, and declines blood pressure.Due to angiotensins
The main function of converting enzyme inhibitor (ACEI) is realized by way of inhibition angiotensin II, therefore angiotensins
II receptor antagonist (Ang1I-AT1RA) should have curative effect similar with ACEI.In theory, angiotensin-ii-receptor is short of money
Compared with ACEI, advantage is anti-agent: the adverse reaction that 1. do not cough；2. blood catecholamine levels can be reduced；3. can keep away
Exempt from high-renin mass formed by blood stasis or angiotensins caused by prolonged application ACEI to increase.
Amlodipine Besylate Tablet is dihydropyridine type calcium antagonists (calcium ion antagonist or slow channel blocking agent).Cardiac muscle and
The contraction of smooth muscle enters cell by specific ion channel dependent on extracellular calcium.This product selective depression calcium ion
Cross-film enters smooth muscle cell and cardiac muscle cell, is greater than cardiac muscle to the effect of smooth muscle.The interaction of itself and calcium channel determines
Gradual rate in it and acceptor site association and dissociation, therefore pharmacological action gradually generates.This product is peripheral arterial expansion
Agent directly acts on vascular smooth muscle, peripheral vascular resistance is reduced, to reduce blood pressure.
It is reported according to china association of pharmaceutical commerce, cardiovascular disease medication in 2000 has accounted for the 12.46% of medical fee total amount,
Wherein drug for hypertension accounts for the cardiovascular drugs market share 35.92%, accounts for 5% or so of hospital administration total amount, wherein ARB
The market share of drug for hypertension 3/5 is occupied with CCB class drug.Compound amlodipine and valsartan piece be it is first by ARB and
CCB class drug is incorporated in the preparation in same tablet, the more superior therapeutic effect obtained therefrom, and slighter poison is secondary to be made
With, more convenient and fast application method by be this product great market capacity guarantee.
A variety of the relevant technologies are in the past few years disclosed, are studied from different perspectives, to solve valsartan amlodipine drug
Some technical problems in the presence of composition preparation process.As CN101485657 and CN102091069 uses roll-in method first will
Valsartan is prepared into compact, then with Amlodipine and the direct compressing dry granulation of other auxiliary materials and filling capsule, when solving tabletting
The technical problems such as powder fluidity is bad and capsule content uniformity is unqualified；CN101926798 prepares valsartan amlodipine
At dispersible tablet, quick-acting instant features are assigned, are suitble to swallow difficult person's use；CN101836981 uses solid dispersion technology system
Standby valsartan amlodipine composition, the dissolution that can significantly promote drug and drug overcome benzene sulphur in the absorption of gastrointestinal tract
The defect that sour Amlodipine In Vitro Dissolution is poor, bioavilability is low；CN101647797 utilizes microcrystalline cellulose, cross-linked carboxymethyl
Sodium cellulosate, silica and magnesium stearate are major auxiliary burden, and direct tablet compressing technology is used under the adding proportion of optimization, are obtained
The high-dissolution and high stability of Valsartan and Amlodipine；CN101862328 is poly- using microcrystalline cellulose pH102, crosslinking
Vinylpyrrolidone, hydroxypropyl methyl cellulose and magnesium stearate are auxiliary material, are prepared into capsule under suitable adding proportion, obtain
Obtain good dissolution rate and stability；Prepared composition discrete piece after CN101843615A individually pelletizes Valsartan and Amlodipine,
Good medicine stability, disintegration and dissolution rate and high bioavilability can be obtained under the formulation and technology of optimization.
Solves the problems such as bad stability existing for the composition, disintegration and dissolution are slow, and oral administration biaavailability is low and at high cost；
CN102028686 is filler and silica for lubricant by disintegrating agent, microcrystalline cellulose of Crospovidone, by high dose figured silk fabrics
Sha Tan and Amlodipine composition are prepared into capsule, solve the problems, such as to be not easy disintegration and dissolution by injectivity optimizing；
CN101987098 is auxiliary material using microcrystalline cellulose 102, croscarmellose sodium and magnesium stearate, using dry granulation
Technique prepares valsartan amlodipine piece, overcomes heating degradation problem caused by Amlodipine, obtains good fluidity, molten
Out-degree is good, the unconspicuous good result of tablet weight variation；For another example patent CN104367574A, which is disclosed, a kind of contains Valsartan and benzene
The pharmaceutical composition and preparation method thereof of sulfonic acid Amlodipine, the pharmaceutical composition are prepared using technique of direct powder compression, with
Solve medicine disintegration and the technical problems that dissolve out that undesirable, tablet weight variation is big, bioavilability is low etc.；And patent
A kind of Valsartan/amlodipine besylate compound preparation of CN105232551A and preparation method thereof, by raw material sorting, successively
It is formulated, mix, softwood processed, granulation, drying, whole grain, total mix, the processing steps such as finished product are made, suitable for one kind is applied alone
Patient of the drug therapy without can control blood pressure, good effect, medication is convenient, greatly improves patient medication compliance.
We experimentally found that, there is unstable quality, shelf-life in the preparation prepared by above-mentioned existing method
It is short, the problems such as dissolution rate is not high.In addition, it has been found that conventionally, as the change of Valsartan and Amlodipine raw material
Learn unstable, Valsartan is degraded seriously under conditions of high temperature and humidity exists simultaneously, and Amlodipine easily causes high moist lability
The stability problem of tablet, traditional preparation methods have many restrictions for the selection of auxiliary material and dosage, also do not allow in production easily-controllable
Quality processed is not suitable for industrialized production.
Summary of the invention
The present invention is to solve the above problem in the prior art, proposes the Valsartan ammonia that a kind of stability is good, dissolution rate is high
Flordipine piece and preparation method thereof.
Preparation method of the invention pelletizes to Valsartan and Amlodipine raw material and auxiliary material using hot melt granulation technique,
Tabletting is carried out again, enhances the stability of raw material, is avoided water to stability influence, is reduced the influence of auxiliary material, improve tabletting
Mobility, product quality are more stable；Compared to dry granulation process, pill flow is significantly improved, and entire granulating process labor
It is dynamic to pay less.
Granulation technique is heated in preparation method of the present invention to fill using hydrogenated oil and fat, polyethylene glycol and the lactose of specific proportions
Agent and emulsifier, so that only to need 45~52 DEG C i.e. plastic for hot melt granulation, and traditional hot melt pelleting temperature is above the temperature,
Generally 55~100 DEG C, such as 80~90 DEG C of hot melting temperature of valsartan amlodipine piece；The present invention for it is above-mentioned in the prior art
Valsartan amlodipine piece be respectively adopted hot melt granulating process the study found that 60 DEG C or more of temperature to Valsartan and ammonia chlorine
There are larger impacts for flat stability, and therefore, general hot melt granulation technique does not take into account that so low hot melting temperature granulation.
And the application uses the raw material proportioning of specific proportions, under the premise of improving valsartan amlodipine tablet stability, so that figured silk fabrics is husky
Smooth amlodipine is carried out at a lower temperature using hot melt granulation technique, reduces the labour of energy consumption and entire granulating process
Intensity improves production efficiency.
To achieve the above object, the invention adopts the following technical scheme:
The first aspect of the invention is to provide a kind of preparation method of valsartan amlodipine piece, specifically includes following step
It is rapid:
(1) portion of Lactose is first filled with Valsartan and Amlodipine Besylate Tablet, hydrogenated oil and fat, the Macrogol 6000 of recipe quantity
Divide mixing, mixed powder is made；
(2) it is put into through remaining lactose in the hot melt granulator of 40~45 DEG C of heat preservations, the mixed of above-mentioned steps (1) is then added
Close powder；
(3) starting hot melt granulator, and using temperature digital display instrument measure material temperature, when material temperature reach set temperature 45~
At 52 DEG C, discharging；
(4) material that step (3) makes grain is shared equally in baking pan, cooled to room temperature；
(5) by the material cooled down pelletizing machine whole grain, while magnesium stearate is added, total mix 3~8 minutes；
(6) valsartan amlodipine piece is made in tabletting.
Further, 10000 valsartan amlodipine pieces of every preparation, each raw material dosage proportion are as follows:
Further, 10000 valsartan amlodipine pieces of every preparation, each raw material dosage proportion are as follows:
Further, portion of Lactose described in the step (1) accounts for the 30~50% of whole lactose.
Further, the holding temperature of hot melt granulator is 52~54 DEG C in the step (2).
Further, set temperature is 48~51 DEG C in the step (3).
Further, in the step (5) pelletizing machine use 2.0mm sieve.
Further, tabletting uses circle stamping in the step (6).
It further, further include the surface of 0.003~0.005kg in the raw material of every 10000 valsartan amlodipine pieces
Hardness modification agent, the surface hardness modifier are the oxide or chloride of barium, and preferable particle size is the chlorination of 50~150nm
Barium.
The second aspect of the invention is to provide a kind of valsartan amlodipine piece as using above method preparation.
The third aspect of the invention is to provide a kind of application of Valsartan ammonia chlorine in the drug of preparation treatment hypertension.
The present invention by adopting the above technical scheme, compared with prior art, has the following technical effect that
The preparation method of valsartan amlodipine piece of the present invention, by being substituted in production process using hot melt granulation technique
Common dry granulation process or wet granulation technology, then tabletting is carried out, the stability of raw material is enhanced, avoids water to stability
It influences, reduces the influence of auxiliary material, improve pill flow, keep product quality more stable；Compared to dry granulation process, pressure
Piece mobility significantly improves, and effectively reduces production cost and labor intensity in entire granulating process；It is verified through production, this
The preparation process of invention has the characteristics that scientific and reasonable, simple and easy to operate, lower production costs.
Specific embodiment
The present invention is described in more detail below by specific embodiment, for a better understanding of the present invention,
But following embodiments are not intended to limit the scope of the invention.
The preparation of 1 valsartan amlodipine piece of embodiment
(1) by 0.3kg lactose elder generation and 0.5kg Valsartan and 0.04kg Amlodipine Besylate Tablet, 0.1kg hydrogenated oil and fat, 0.10
Macrogol 6000 is sufficiently mixed, and mixed powder is made；
(2) it puts into the hot melt granulator of 40 DEG C of heat preservations, is then added above-mentioned steps (1) through remaining 0.6kg lactose
Mixed powder；
(3) starting hot melt granulator, and material temperature is measured using temperature digital display instrument, when material temperature reaches 52 DEG C of set temperature
When, discharging；
(4) material that step (3) makes grain is shared equally in baking pan, cooled to room temperature；
(5) by the material cooled down pelletizing machine whole grain, while magnesium stearate is added, total mix 5 minutes；
(6) valsartan amlodipine piece J150801 is made in tabletting.
The preparation of 2 valsartan amlodipine piece of embodiment
(1) by 0.75kg lactose first with 1.0kg Valsartan and 0.08kg Amlodipine Besylate Tablet, 0.25kg hydrogenated oil and fat,
0.20 Macrogol 6000 is sufficiently mixed, and mixed powder is made；
(2) it puts into the hot melt granulator of 45 DEG C of heat preservations, is then added above-mentioned steps (1) through remaining 0.75kg lactose
Mixed powder；
(3) starting hot melt granulator, and material temperature is measured using temperature digital display instrument, when material temperature reaches 48 DEG C of set temperature
When, discharging；
(4) material that step (3) makes grain is shared equally in baking pan, cooled to room temperature；
(5) by the material cooled down pelletizing machine whole grain, while magnesium stearate is added, total mix 5 minutes；
(6) valsartan amlodipine piece J150802 is made in tabletting.
The preparation of 3 valsartan amlodipine piece of embodiment
(1) by 0.5kg lactose first with 0.8kg Valsartan and 0.0693kg Amlodipine Besylate Tablet, 0.18kg hydrogenated oil and fat,
0.15 Macrogol 6000 is sufficiently mixed, and mixed powder is made；
(2) it puts into the hot melt granulator of 43 DEG C of heat preservations, is then added above-mentioned steps (1) through remaining 0.75kg lactose
Mixed powder；
(3) starting hot melt granulator, and material temperature is measured using temperature digital display instrument, when material temperature reaches 45 DEG C of set temperature
When, discharging；
(4) material that step (3) makes grain is shared equally in baking pan, cooled to room temperature；
(5) by the material cooled down pelletizing machine whole grain, while magnesium stearate is added, total mix 8 minutes；
(6) valsartan amlodipine piece J150803 is made in tabletting.
The preparation of 4~6 valsartan amlodipine piece of comparative example
Respectively unlike above-described embodiment 1~3, valsartan amlodipine is respectively prepared using the secondary tabletting of dry method
Piece, i.e., dry-pressing after respectively mixing the supplementary material of Examples 1 to 3, admixes magnesium stearate tabletting again after crushing, comparative example is made
150501,150502 and 150503.
The preparation of 7~9 valsartan amlodipine piece of comparative example
Respectively unlike above-described embodiment 1~3, respectively wet granulation prepares valsartan amlodipine piece,
2.25%HPMC is adhesive, and K12 is cosolvent, and lactose is filler high-speed mixing granulating machine mixing granulation, and wet granular is dry
After admix magnesium stearate tabletting again, be made comparative example 150601,150602,150603.
Study on the stability data
According to Chinese Pharmacopoeia 2,015 2 and " technological guidance's principle of chemicals impurity research ": valsartan content 95~
105%, amlodipine content 95~105%, dissolution rate >=75%, uniformity of dosage units A+1.8S≤15, Flordipine impurity D≤
0.5%, single miscellaneous maximum≤0.2%, always miscellaneous≤2%.
Respectively to above-described embodiment J150801, J150802, J150803, comparative example 150501,150502,150503, with
And comparative example 150601,150602,150603 carries out Detection of Stability respectively, specific detection data is as shown in table 1 below:
1 valsartan amlodipine tablet stability experimental data of table summarizes
The stability experiment data analysis of each embodiment and comparative example measured by above-mentioned table 1 is it is found that the present invention uses
Hot melt granulation technique pelletizes to Valsartan and Amlodipine raw material and auxiliary material, then carries out tabletting, compared to usually used two
Kind valsartan amlodipine piece preparation method method, can effectively control valsartan amlodipine compared to wet granulation
The related substance index of piece keeps the stability of product within the effect phase, improves pill flow compared to dry granulation；Effectively keep away
Boiled water reduces the influence of auxiliary material to stability influence, improves pill flow, and product quality is more stable；Compared to secondary
Tabletting granulation, there is no a flowability problems when tabletting, and entire granulating process labour payment is few.
Specific embodiments of the present invention are described in detail above, but it is merely an example, the present invention is simultaneously unlimited
It is formed on particular embodiments described above.To those skilled in the art, any couple of present invention carries out equivalent modifications and
Substitution is also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by equal transformation and
Modification, all should be contained within the scope of the invention.
Claims (9)
1. a kind of preparation method of valsartan amlodipine piece, which comprises the following steps:
(1) Valsartan and Amlodipine Besylate Tablet, hydrogenated oil and fat, Macrogol 6000 of portion of Lactose and recipe quantity is sufficiently mixed
It closes, mixed powder is made；
(2) remaining lactose is put into the hot melt granulator of 40~45 DEG C of heat preservations, the mixing of above-mentioned steps (1) is then added
Powder；
(3) starting hot melt granulator, and material temperature is measured using temperature digital display instrument, when material temperature reaches 45~52 DEG C of set temperature
When, discharging；
(4) material that step (3) makes grain is shared equally in baking pan, cooled to room temperature；
(5) by the material cooled down pelletizing machine whole grain, while magnesium stearate is added, total mix 3~8 minutes；
(6) valsartan amlodipine piece is made in tabletting；
Wherein, every 10000, each raw material dosage proportion are as follows:
2. the preparation method of valsartan amlodipine piece according to claim 1, which is characterized in that every 10000, each original
Expect consumption proportion are as follows:
3. the preparation method of valsartan amlodipine piece according to claim 1, which is characterized in that in the step (1)
The portion of Lactose accounts for the 30~50% of whole lactose.
4. the preparation method of valsartan amlodipine piece according to claim 1, which is characterized in that in the step (2)
The holding temperature for heating granulator is 42~44 DEG C.
5. the preparation method of valsartan amlodipine piece according to claim 1, which is characterized in that in the step (3)
Set temperature is 48~51 DEG C.
6. the preparation method of valsartan amlodipine piece according to claim 1, which is characterized in that in the step (5)
Pelletizing machine uses the sieve of 2.0mm.
7. the preparation method of valsartan amlodipine piece according to claim 1, which is characterized in that in the step (6)
Tabletting is using circle stamping.
8. such as the valsartan amlodipine piece of any one of claim 1-7 the method preparation.
9. application of the valsartan amlodipine piece as claimed in claim 8 in the drug of preparation treatment hypertension.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102988181A (en) * | 2012-12-31 | 2013-03-27 | 广州白云山天心制药股份有限公司 | Granulating method and application for oral solid preparation |
| EP2676660A1 (en) * | 2012-06-22 | 2013-12-25 | Sanovel Ilac Sanayi ve Ticaret A.S. | Compositions preventing hypertension comprising soluplus |
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- 2016-10-19 CN CN201610912219.8A patent/CN106539791B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2676660A1 (en) * | 2012-06-22 | 2013-12-25 | Sanovel Ilac Sanayi ve Ticaret A.S. | Compositions preventing hypertension comprising soluplus |
| CN102988181A (en) * | 2012-12-31 | 2013-03-27 | 广州白云山天心制药股份有限公司 | Granulating method and application for oral solid preparation |
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