CN106176725A - A kind of pharmaceutical composition improving stability and its production and use - Google Patents
A kind of pharmaceutical composition improving stability and its production and use Download PDFInfo
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- CN106176725A CN106176725A CN201610539648.5A CN201610539648A CN106176725A CN 106176725 A CN106176725 A CN 106176725A CN 201610539648 A CN201610539648 A CN 201610539648A CN 106176725 A CN106176725 A CN 106176725A
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
Abstract
The present invention relates to technical field of medicine, particularly to the pharmaceutical composition of a kind of raising stability containing compound A, the most miscellaneous of described pharmaceutical composition controls≤1.3%, improves stability and the drug safety of pharmaceutical composition.
Description
Technical field
The present invention relates to technical field of medicine, particularly to the medicine of a kind of raising stability containing compound A
Compositions and its production and use.
Background technology
Angiotensin II is to cause vasoconstrictive hormone, can cause hypertension and heart strain.This hormone is thin with target
Specific receptor on cellular surface interacts.Two kinds of receptor subtypes, such as AT1 of Angiotensin II are identified at present
And AT2.In recent years, people have paid huge effort and have identified the material being combined with AT1 receptor.Angiotensin receptor blocker
(ARB, angiotensin-ii antagonist) stops Angiotensin II to be combined with its receptor in blood vessel wall, thus reduces blood
Pressure.Due to the suppression to AT1 receptor, so this type of antagonist can act as hypotensive agent, or it is used for treating the congested heart
Decline and other indication.
Neutral endopeptidase (EC 3.4.24.11；Enkephalinase；Neprilysin；NEP) it is the metal egg containing zinc
White enzyme, it can crack peptide substrates on the aminoterminal of various hydrophobic residue [see Pharmacol Rev, volume 45, page 87
(1993)].The substrate of this enzyme includes but not limited to atrial natriuretic peptide (ANP, also referred to as ANF), brain natriuretic peptide (BNP), methionine
Enkephalin and leucine enkephalin, Kallidin I, neurokinin A, EDN1 and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2.ANP is strong blood vessel
Diastole agent and promote natruresis agent [see J Hypertens, volume 19, page 1923 (2001)].To normal subjects infusion ANP
Cause the reproducible significant increase of natruresis and diuresis, including fractional excretion of sodium, the flow velocity of urine and glomerular filtration rate
Increase [see J Clin Pharmacol, volume 27, page 927 (1987)].But, ANP has shorter circulating half-life,
And the NEP being proved in Renal Cortex film be can degrade this peptide important enzyme [see Peptides, volume 9, page 173
(1988)].So, nep inhibitor (neutral endopeptidase inhibitor, NEPi) will increase the blood plasma level of ANP, thus expects it
Induction can promote natruresis and diuresis.
So, material, such as angiotensin receptor blocker and neutral endopeptidase inhibitor, can be used for controlling high blood
Pressure.Essential hypertension is multigenic disease, cannot control fully by single therapy.2000, in developed country about
333000000 adult, the U.S. about 65,000,000 (adults of 1/3rd) suffer from hypertension [see Lancet, volume 365, page 217
And Hypertension (2005), volume 44, page 398 (2004)].Long-term and uncontrolled hypertensive vascular disease is
The pathologic causing target organ (such as heart and kidney) at last changes.Lasting hypertension also is able to cause the sickness rate of apoplexy
Increase.
The complex of dual function or combination, the supermolecule of two kinds of activating agents particularly with different mechanism of action are combined
Body or the prodrug connected or particularly there is peptide in the referred to as angiotensin receptor antagonist of different mechanism of action and neutrality
The supramolecular complex of two kinds of activating agents of enzyme inhibitor, has been disclosed in the U.S. Patent application submitted on November 9th, 2005
60/735,093；In submission on November 10th, 2005 60/735,541；60/789,332 submitted on April 4th, 2006；With
In 60/822,086 and International Publication WO2007056546A1 that on August 11st, 2006 submits to, it is fully incorporated herein as ginseng
Examine.Described supramolecular complex can be used for treating the patient suffering from various cardiovascular and/or kidney disease.Described one has especially
Active component be supramolecular complex be following formula: compound A,
, also referred to as " supramolecular complex ".
Another prior art WO2009061713A1 discloses the drug regimen comprising described supramolecular complex compound A
The solid oral dosage form of thing, especially tablet can be prepared such as rolling by direct compression method or drawing method.Avoid activity
Composition is exposed to amorphous increase and/or the separation of its component of dual function complex under water, overheated and/or high shearing.So
After, find that through experiment this preparation technology still difficult generation effectively controlling pharmaceutical composition impurity is unfavorable for the safety of drug use
Property control.
Summary of the invention
The technical problem existed in view of prior art, it is an object of the invention to provide a kind of drug regimen improving stability
Thing, described pharmaceutical composition is preferably oral solid formulation, is mixed with excipient by compound A, makes preferably further
The dosage formulation such as tablet or capsule.
The active component (raw material or referred to as crude drug) of pharmaceutical composition of the present invention is following formula: compound A, also referred to as
For " supramolecular complex ", structural formula is as follows:
And more than one pharmaceutically acceptable excipient,
Wherein, the most miscellaneous of described pharmaceutical composition controls≤1.3%, and total miscellaneous finger is relative to the percentage of compound A weight
Content.It is preferably controlled in≤1.0%, more preferably≤0.5%.
Described pharmaceutical composition the most miscellaneous control≤1.3% ,≤1.0% or≤0.5% can be by control further
Excipient processed composition and consumption, and optimize preparation process thereof, or purify active raw materials medicine and combine optimization system
Agent scheme obtains.
Specifically, described excipient (or referred to as adjuvant) refers to pharmaceutically acceptable inert fraction, is used for preparing solid oral dosage form.
Excipient includes the one or two kinds of in binding agent, disintegrating agent, lubricant, fluidizer, stabilizer, filler and diluent etc.
Above mixture.
The example of described pharmaceutically acceptable binding agent includes but not limited to starch；Cellulose and its derivates, such as microcrystalline cellulose
Element, (the lowest substituted hydroxypropylcellulose, hydroxypropyl content is 5 to 16% and Mw to be to hydroxypropylcellulose the most by weight
80 000 to 1 150 000)；Hydroxyethyl cellulose and hydroxypropyl methyl cellulose；Sucrose；Glucose；Corn syrup；Polysaccharide；
And gelatin, most preferably cellulose such as hydroxypropylcellulose, the lowest substituted hydroxypropylcellulose.Binding agent can be with compositions
The concentration of about 1 to about 60% of weight (before optional coating) exists；Such as, 5% to about 40%, particularly 10% to about
40%.
The example of described pharmaceutically acceptable disintegrating agent includes but not limited to starch；Clay；Cellulose；Cross linked polymer: crosslinking
Sodium carboxymethyl cellulose or cross-linking sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose calcium；Soybean polysaccharide；And guar gum, more excellent
Select crospolyvinylpyrrolidone or crospovidone.These disintegrating agents can be with composition weight (before optional coating)
The concentration of about 0% to about 65% exists, preferably from about 1% to about 40% (such as, about 0.05% to about 10%).
The example of described pharmaceutically acceptable filler and pharmaceutically acceptable diluent includes but not limited to Icing Sugar, sompressible sugar, glucose
Bonding agent, dextrin, glucose, lactose, mannitol, microcrystalline Cellulose, sorbitol and sucrose, particularly microcrystalline Cellulose.Fill
Agent can exist with the concentration of about 4% to about 60% of composition weight (before optional coating), and preferably from about 20% to about
40%.
The example of described pharmaceutically acceptable lubricant and pharmaceutically acceptable fluidizer includes but not limited to colloidal silica, three silicic acid
Magnesium, starch, Pulvis Talci, tricalcium orthophosphate, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, magnesium oxide, Polyethylene Glycol, powder
Shape cellulose, Glyceryl Behenate, stearic acid, castor oil hydrogenated, glyceryl monostearate and sodium stearyl fumarate.Fluidizer
Agent can be deposited with composition weight (before optional coating) 0% to 10%, concentration such as up to 2%, the most about 0.1%
?.
Pharmaceutical composition of the present invention is preferably prepared to solid oral dosage form, can be to be the form of tablet, now this solid port
Oral dosage form is wrapped with one layer of coating, is generally sugar, lac or is entirely other film coatings commonly used in the art, such as Opadry
Deng.The various known coating method of application in this area can be used, such as, spray in fluid bed, or application submergence, spraying
Coating method.
Described pharmaceutical composition the most miscellaneous control≤1.3% ,≤1.0% or≤0.5% can also pass through further
Optimize preparation process thereof to realize, preferably compressing dry granulation method, include but not limited to the dry method pressures such as dry granulation tabletting, powder vertical compression
The preparation technology of sheet.
The preparation technology of described dry granulation tabletting is preferably as follows, but can do accommodation according to actual needs.One
Planting the method that compound A pharmaceutical composition prepared by the dry granulation tabletting optimized, described method comprises the steps of:
1), pharmaceutically acceptable excipient is sieved by 40 mesh sieves, obtain mixture；
2), by said mixture and active component put in hopper mixer and mix, cross 40 mesh sieves；
3), shred after tablet machine pressure sheet, cross 40 mesh sieves；
4), with the tablet of the tablet machine described specification of compacting, then coating.
The preparation technology of described powder vertical compression is preferably as follows, but can do accommodation according to actual needs.A kind of excellent
The method that the preparation changed is suitable for powder vertical compression compound A pharmaceutical composition, described method comprises the steps of:
1), by crude drug, adjuvant cross 40 mesh sieves, and carry out weighing by recipe quantity and get the raw materials ready；
2), take recipe quantity binding agent, disintegrating agent and 1/2 recipe quantity filler mix homogeneously and must mix powder a；
3), take recipe quantity crude drug, fluidizer, filler mix homogeneously must mix powder b；
4), by step 2 gained mix powder a addition step 3 gained to mix in powder b, and add recipe quantity mix lubricant uniformly,
Total mixed powder, tabletting, coating.
Described pharmaceutical composition the most miscellaneous control≤1.3% ,≤1.0% or≤0.5% can be further by essence
System, active raw materials medicine as described in recrystallization purifies realizes, and including screening raw material single crystal form, makes to contain less in raw material
There are amorphous other physical aspects such as grade.Described single crystal form preferred X-ray powder diffraction spectrum includes between following lattice plane
Every: 21.2 (s), 17.0 (w), 7.1 (s), 5.2 (w), 4.7 (w), 4.6 (w), 4.2 (w), 3.5 (w) and 3.3 (w).
As it has been described above, by preparation technique knowledge, have and multiple can control the method that pharmaceutical composition is the most miscellaneous, can be above-mentioned
The further derivative and amendment of method adjusts, but for the compound A pharmaceutical composition of the present invention, control the most miscellaneous≤
The purpose of 1.3% is improve the stability of pharmaceutical composition and reduce adverse reaction rate, limits with above-mentioned excipient, makes
Preparation Method and raw material crystal formation do not have directly contact.Therefore, as long as effectively control the most miscellaneous≤1.3% of described pharmaceutical composition
In the range of, should be understood as identical with the spirit of present inventive concept, belong to protection scope of the present invention.
Inventive compound concentration in pharmaceutical composition represents with therapeutically effective amount, and it depends on active component
Absorb, inactivate and excretion rate, and the other factors known to those of ordinary skill in the art.Furthermore, it is necessary to it is to be noted that agent
Value changes always according to the seriousness of wanted relief of symptoms.It should also be appreciated that for any specific receptor, concrete dosage regimen
Should be according to individual needs and enforcement or instruct the professional judgement of people that pharmaceutical composition uses to adjust in time.Therapeutic
Complex maybe can be divided into many smaller doses use at various time intervals by applied once.Thus applicable controlling
Treating effective dose is known to those of ordinary skill in the art.
Preferably (in the present invention, the consumption of active compound component A is all with pure rear calculating of giving money as a gift, i.e. to remove for active component
The Mass Calculation of effective ingredient after slaine and water of crystallization) unit dose can in the range of every day about 1 to about 1000mg, as
40 to 400mg (such as, 50mg, 100mg, 200mg, 400mg).Or can provide less dosage, such as every day 0.5 to
100mg；0.5 to 50mg；Or 0.5 to 20mg.In the present case, have now surprisingly been found that when with dual function complex such as supermolecule
When the form of complex delivers, valsartan component has a bigger exposure, and thus individually dosed with valsartan compared with have higher
Bioavailability.Therefore it is possible for lowering dosage for valsartan component.
Pharmaceutical composition described herein is preferably immediate release oral solid dosage form, after described term " rapid release " refers to be orally ingested
Within a short period of time, such as, in 1 hour, 40 minutes, 30 minutes or 20 minutes, discharge rapidly most therapeutic conjugate,
E.g., from about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80% or about more than 90% therapeutic be combined
Thing.Particularly preferred useful rapid release situation refers to discharge at least in 30 minutes after being orally ingested or be equal to the treatment of about 80%
Property complex.Rapid release performance is by dissolution in vitro measuring.
Term " dissolution " refers to the process that solid matter (herein referring to active component) is scattered in medium with molecular forms.This
The dissolution of the active component of invention drug oral fixed dosage compositions is by liquid/solid interface, temperature and group of solvents
Define in the medication amount of unit interval dissolving under the standard conditions become.Dissolution is by standard well known by persons skilled in the art
Method measures, and sees the consistent method described in Chinese Pharmacopoeia.For the object of the invention, this test is used for measuring single
The dissolution of active component, it uses oar agitating element to carry out with 50rpm (rev/min) according to described in Chinese Pharmacopoeia at pH 6.8
Or use oar agitating element to carry out with 75rpm (rev/min) at pH 4.5.Dissolution medium is preferably buffer, usually phosphoric acid
Salt buffer, especially such as the buffer salt described in embodiment " dissolution test ".
One of preferred version of the present invention delivers the valsartan free acid of therapeutically effective amount or consolidating of its officinal salt for providing
Body peroral dosage form, wherein, when by USP paddle method with about 50rpm in the phosphate buffer of the pH 6.8 of 900mL and 37 ±
During 0.5 DEG C of mensuration, the In Vitro Dissolution characteristic of peroral dosage form is: after 10 minutes, and the most about 10% to average about 100% (with weight
Meter) valsartan free acid or its officinal salt be released, after 20 minutes, the most about 30% to average about 100% (with weight
Meter) valsartan free acid or its officinal salt be released, after 30 minutes, the most about 40% to average about 100% (with weight
Meter) valsartan free acid or its officinal salt be released.
Preferred version of the present invention another be to provide to deliver the valsartan free acid of therapeutically effective amount or consolidating of its officinal salt
Body peroral dosage form, wherein, when by USP paddle method with about 75rpm in the pH4.5 phosphate buffer of 1000mL and 37 ±
During 0.5 DEG C of mensuration, the In Vitro Dissolution characteristic of peroral dosage form is: after 10 minutes, and the most about 20% to average about 100% (with weight
Meter) valsartan free acid or its officinal salt be released, after 20 minutes, the most about 30% to average about 100% (with weight
Meter) valsartan free acid or its officinal salt be released, after 30 minutes, the most about 40% to average about 100% (with weight
Meter) valsartan free acid or its officinal salt be released.
In another preferred embodiment of the present invention, active component exists with the amount of per unit dosage form about 100mg, mouth
The In Vitro Dissolution characteristic of oral dosage form is: after 10 minutes, and the valsartan free acid of the most about 50% is released, after 20 minutes, averagely
The valsartan free acid of about 85% is released, and after 30 minutes, the valsartan free acid of the most about 95% is released.Real at another
Executing in scheme, active component exists with the amount of per unit dosage form about 200mg, and the In Vitro Dissolution characteristic of peroral dosage form is: 10 minutes
After, the valsartan free acid of the most about 50% is released, and after 20 minutes, the valsartan free acid of the most about 85% is released, and 30
After minute, the valsartan free acid of the most about 95% is released.In another embodiment, active component is with per unit dosage form
The amount of about 400mg exists, and the In Vitro Dissolution characteristic of peroral dosage form is: after 10 minutes, the valsartan free acid quilt of the most about 40%
Release, after 20 minutes, the valsartan free acid of the most about 70% is released, and after 30 minutes, the valsartan of the most about 90% dissociates
Acid is released.
The exact dose of the active component that the present invention uses and particular dosage form depend on many factors, such as, to be treated
Disease, the persistent period needed for treatment and the rate of release of activating agent.Such as, amount and the rate of release thereof of required activating agent can base
Measure in known external or vivo techniques, which determine given activity agent concentration and be maintained at for therapeutical effect in blood plasma
The time length of the acceptable level of speech.
Pharmaceutical composition of the present invention may be used for following disease or disease: selected from hypertension, acute and chronic heart failure,
Left ventricular insufficiency, hypertrophic cardiomyopathy, diabetic cardiomyopathy, room mo(u)ld top half and ventricle type arrhythmia, atrial fibrillation, atrium are flutterred
Dynamic, harmful vascular remodeling, myocardial infarction and sequela thereof, arteriosclerosis, instability or stable type angor, Secondary cases aldehyde steroid
Hyperketosis disease, constitutional and secondary pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis,
Primary Nephrosis albuminuria, renovascular hypertension, diabetic retinopathy, migraine, peripheral blood vessel, Raynaud disease,
Chamber hypertrophy, cognitive disorder, glaucoma and apoplexy.
Pharmaceutical composition of the present invention has such advantages as relative to prior art and beneficial effect, including but do not limit
In this:
1, the invention provides a kind of compound A pharmaceutical composition improving stability, described pharmaceutical composition the most miscellaneous
Control≤1.3%, improve the stability of pharmaceutical composition.
In more detail, the most miscellaneous of pharmaceutical composition controls≤1.3%, after 2 months acceleration environments preserve, and medicine
The total miscellaneous changes of contents of compositions is less, all within 0.1%, particularly, for control Light absorbing impurty within 1.0%, and medicine
The total miscellaneous changes of contents of compositions is less, all within 0.05%, for control Light absorbing impurty within 0.5%, and pharmaceutical composition
Total miscellaneous changes of contents is the most unchanged, all within 0.02%.
2, the invention provides a kind of compound A pharmaceutical composition improving stability, described pharmaceutical composition the most miscellaneous
Control≤1.3%, reduce the generation of untoward reaction during pharmaceutical composition uses, be more conducive to ensure the effectiveness of medicine
And safety.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but the embodiment of invention is not limited to this.
Embodiment 1 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) 40 mesh sieve use crossed by microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, silicon dioxide, stearic acid,
Carry out weighing standby according to recipe quantity；
(2) take recipe quantity polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose and 1/2 recipe quantity microcrystalline Cellulose mix homogeneously to obtain
Mixed powder a；
(3) take recipe quantity crude drug, silicon dioxide, 1/2 recipe quantity microcrystalline Cellulose mix homogeneously must mix powder b；
(4) mixed powder a is added in mixed powder b, another add the mixing of recipe quantity stearic acid, obtain and always mix powder and always mix powder.The system of tablet
Standby:
Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder
Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA
Related request.
Embodiment 2 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) microcrystalline Cellulose, polyvinylpolypyrrolidone, polyvidone, silicon dioxide, magnesium stearate cross 40 mesh sieve use, according to prescription
Amount carries out weighing standby；
(2) take recipe quantity polyvinylpolypyrrolidone, polyvidone and 1/2 recipe quantity microcrystalline Cellulose mix homogeneously and must mix powder a；
(3) take recipe quantity crude drug, silicon dioxide, 1/2 recipe quantity microcrystalline Cellulose mix homogeneously must mix powder b；
(4) mixed powder a is added in mixed powder b, another add the mixing of recipe quantity magnesium stearate, obtain and always mix powder and always mix powder.Tablet
Preparation:
Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder
Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA
Related request.
Embodiment 3 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of tablet:
(1) calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, hypromellose, magnesium stearate cross 40 mesh sieve use, according to place
Side's amount carries out weighing and gets the raw materials ready；
(2) taking recipe quantity crude drug, calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, hypromellose use equivalent to pass
Increasing method adds mixing, pelletizes with 75% appropriate amount of ethanol；
(3) it is dried, crosses 40 mesh sieves, add magnesium stearate mix homogeneously, tabletting, coating.
Embodiment 4 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) lactose, cross-linking sodium carboxymethyl cellulose, hydroxypropylcellulose, stearic acid are crossed 40 mesh sieve use, enter according to recipe quantity
Row weighs, mixing；
(2) said mixture and crude drug are put in hopper mixer and mix, cross 40 mesh sieves
(3) shred after tablet machine pressure sheet, cross 40 mesh sieves, the mixed powder of compound A must be contained.
The preparation of tablet:
With tablet machine, above-mentioned mixed powder being pressed into the tablet that specification is 100mg, coating, the Hardness Control of described tablet is 5
～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets the relevant of " Chinese Pharmacopoeia " (2010 editions) second annex IA and want
Ask.
Embodiment 5 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) sucrose, polyvinylpolypyrrolidone, hypromellose, silicon dioxide cross 40 mesh sieve use, weigh according to recipe quantity
Standby；
(2) take recipe quantity polyvinylpolypyrrolidone, hypromellose and 1/2 recipe quantity sucrose mix homogeneously and must mix powder a；
(3) take recipe quantity crude drug, silicon dioxide, 1/2 recipe quantity sucrose mix homogeneously must mix powder b；
(4) mixed powder a is added in mixed powder b, obtain and always mix powder and always mix powder.
The preparation of tablet:
Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder
Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA
Related request.
Embodiment 6 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) calcium hydrogen phosphate, polyvinylpolypyrrolidone, hypromellose, magnesium stearate are crossed 40 mesh sieve use, enter according to recipe quantity
Row weighs, mixing；
(2) said mixture and crude drug are put in hopper mixer and mix, cross 40 mesh sieves
(3) shred after tablet machine pressure sheet, cross 40 mesh sieves, the mixed powder of compound A must be contained.
The preparation of tablet:
With tablet machine, above-mentioned mixed powder being pressed into the tablet that specification is 100mg, coating, the Hardness Control of described tablet is 5
～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets the relevant of " Chinese Pharmacopoeia " (2010 editions) second annex IA and want
Ask.
Embodiment 7 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) mannitol, alginate, hypromellose, silicon dioxide, magnesium stearate cross 40 mesh sieve use, according to recipe quantity
Carry out weighing standby；
(2) take recipe quantity alginate, hypromellose and 1/2 recipe quantity mannitol mix homogeneously and must mix powder a；
(3) take recipe quantity crude drug, silicon dioxide, 1/2 recipe quantity mannitol mix homogeneously must mix powder b；
(4) being added by mixed powder a in mixed powder b, the another recipe quantity magnesium stearate that adds mixes, and obtains and always mixes powder.
The preparation of tablet:
Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder
Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA
Related request.
Embodiment 8 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table
The preparation of total mixed powder:
(1) 40 mesh sieve use crossed by microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, beta-schardinger dextrin-, Pulvis Talci,
Carry out weighing standby according to recipe quantity；
(2) recipe quantity polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, beta-schardinger dextrin-and 1/2 recipe quantity microcrystalline Cellulose are taken
Mix homogeneously must mix powder a；
(3) take recipe quantity crude drug, 1/2 recipe quantity microcrystalline Cellulose mix homogeneously must mix powder b；
(4) being added by mixed powder a in mixed powder b, the another recipe quantity Pulvis Talci that adds mixes, and obtains and always mixes powder.
The preparation of tablet:
Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder
Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA
Related request.
Embodiment 9 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) lactose, crosslinked carboxymethyl fecula sodium, hypromellose, magnesium stearate cross 40 mesh sieve use, enter according to recipe quantity
Row weighing is got the raw materials ready；
(2) take recipe quantity crosslinked carboxymethyl fecula sodium, hypromellose and 1/2 recipe quantity lactose mix homogeneously and must mix powder
a；
(3) take recipe quantity crude drug, 1/2 recipe quantity lactose mix homogeneously must mix powder b；
(4) being added by mixed powder a in mixed powder b, the another recipe quantity magnesium stearate that adds mixes, and obtains and always mixes powder.
The preparation of tablet:
Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder
Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA
Related request.
Embodiment 10 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) starch, cross-linking sodium carboxymethyl cellulose, hydroxypropylcellulose, hydrogenated vegetable oil are crossed 40 mesh sieve use, according to prescription
Amount weighs, mixing；
(2) said mixture and crude drug are put in hopper mixer and mix, cross 40 mesh sieves
(3) shred after tablet machine pressure sheet, cross 40 mesh sieves, the mixed powder of compound A must be contained.
The preparation of tablet:
With tablet machine, above-mentioned mixed powder is pressed into the tablet that specification is 100mg, the Hardness Control of tablet described in coating 5～
10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets the relevant of " Chinese Pharmacopoeia " (2010 editions) second annex IA and want
Ask.
Embodiment 11 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose are crossed 40 mesh sieve use, according to place
Side's amount carries out weighing standby；
(2) recipe quantity cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and 1/2 recipe quantity microcrystalline Cellulose are taken mixed
Close and uniform must mix powder a；
(3) take recipe quantity crude drug, 1/2 recipe quantity microcrystalline Cellulose mix homogeneously must mix powder b；
(4) mixed powder a is added in mixed powder b, obtain and always mix powder.
The preparation of tablet:
Powder vertical compression technique is used to be prepared as the tablet that specification is 100mg, coating, the hardness of described tablet by always mixing powder
Control 5～10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets " Chinese Pharmacopoeia " (2010 editions) second annex IA
Related request.
Embodiment 12 pharmaceutical composition and preparation method thereof
Pharmaceutical composition prescription such as following table:
The preparation of total mixed powder:
(1) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, acrylic resin, magnesium stearate are crossed 40 mesh sieve use, according to
Recipe quantity weighs, mixing；
(2) said mixture and crude drug are put in hopper mixer and mix, cross 40 mesh sieves；
(3) shred after tablet machine pressure sheet, cross 40 mesh sieves, the mixed powder of compound A must be contained.
The preparation of tablet:
With tablet machine, above-mentioned mixed powder is pressed into the tablet that specification is 100mg, the Hardness Control of described tablet 5～
10kgf.The fluctuation of gained tablet tablet weight variation is less, and meets the relevant of " Chinese Pharmacopoeia " (2010 editions) second annex IA and want
Ask.
Note: embodiment 1 12 (in addition to embodiment 2) all uses same batch compound A, total miscellaneous all≤1.3%, embodiment
2 another batch compound A, the most miscellaneous > 1.3%.The total miscellaneous limitation of gained pharmaceutical composition is shown in embodiment 13 list data.
The total miscellaneous limit detection of embodiment 13 is tested
The HPLC method that embodiment 1 12 gained preparation uses Chinese Pharmacopoeia annex record detects the most miscellaneous of pharmaceutical composition
Percentage composition (%), acquired results is as follows:
From the above it is known that embodiment 1 12 (in addition to embodiment 2) all uses same batch compound A, the most miscellaneous
All≤1.3%, but affected by prescription composition and ratio and preparation process, gained art pharmaceutical compositions is limited the quantity >
1.3%.
Embodiment 14 stability experiment
Embodiment 1 12 gained preparation is placed 2 months under acceleration environment (40 DEG C ± 2 DEG C, RH75% ± 5%), adopts
With the total miscellaneous percentage composition (%) of the HPLC method detection pharmaceutical composition that Chinese Pharmacopoeia annex is recorded, acquired results is as follows:
As seen from the above table, after Acceleration study 60 days, embodiment 1,4,5,6,8,9,10 and 11 is by effectively controlling medicine
Total miscellaneous limitation≤1.3% of compositions, after preserving, the total miscellaneous changes of contents of pharmaceutical composition is less, all within 0.1%,
Particularly, for control Light absorbing impurty within 1.0%, the total miscellaneous changes of contents of pharmaceutical composition is less, all within 0.05%,
For control Light absorbing impurty within 0.5%, the total miscellaneous changes of contents of pharmaceutical composition is the most unchanged, all within 0.02%.
And for not controlling Light absorbing impurty pharmaceutical composition within 1.3%, impurity amplification is very fast, more than 0.2%.So, this
Invention pharmaceutical composition is by effectively controlling Light absorbing impurty, and preparation stability is higher, more meets clinical application correlated quality regulation
Requirement.
Experiment (Behaviors survey) is investigated in embodiment 15 untoward reaction
Laboratory sample:
Test sample: compound A pharmaceutical composition (embodiment 1 12)；Negative controls: use Vehicle controls product to go
Ionized water (prepared by laboratory).
Laboratory animal:
ICR mice, SPF level, for Animal Sex and quantity, jenny: 25, the buck: 25 of test.
Body weight and the range of age when buying, jenny: 9.6～13.5g, 3 week old；Buck: 10.0～13.0g, 3
Week old.
Dosage:
Vehicle controls group 0mg/kg, compound A pharmaceutical composition pulverizing, by active compound component A low dose group
1.0mg/kg, middle dosage group 10mg/kg, high dose group 110mg/kg gastric infusion, it is administered one week.
Test procedure:
Pole-jump test operates: with the metal bar (diameter is about 0.9cm, and length is about 72cm) that a root surface is smooth, vertically
Erect.Before being administered and after successive administration one week, the operation of different time points pole-jump test terminates righting reflex in laggard line space and grasps
Make: mention mousetail, mice of dishing out after rotating 4 circles, observe the abnormal attitude (side or the back side land) that mice lands, continuously
It is repeated 5 times, and marks according to Irwin ' s behavior rank scores standard.Before being administered, after successive administration one week 0.5,
1, a pole-climbing and aerial righting reflex within 2,4,6,24 hours, are respectively observed.After experiment terminates, use excess CO2This examination is put to death in anesthesia
Test surviving animals used.Neurological deficit score result all represents with frequency.Above-mentioned data should use SAS 9.1 to carry out statistical analysis.
Standards of grading, Irwin ' s behavior rank scores standard:
0 grade: normal stand
1 grade: 5 times have 1～2 time in lying on one's side
2 grades: 5 times have 3～4 times in lying on one's side
3 grades: 5 times complete in lying on one's side
4 grades: 5 times have 1～2 time in carrying ground
5 grades: 5 times have 3～4 times in carrying ground
6 grades: 5 times complete in carrying ground
7 grades: carry ground and right slow
8 grades: can not right
Result and discussion:
Embodiment 1,4,5,6,8,9,10 and 11 pharmaceutical composition, by effectively control the total miscellaneous limitation of pharmaceutical composition≤
1.3%, use compound A 1.0,10 and 110mg/kg treated animal to put pole-climbing and aerial righting reflex observation knot each observing time
Fruit equal no significant difference (P > 0.05) compared with Vehicle controls group (0mg/kg).
Embodiment 1,4,5,6,8,9,10 and 11 pharmaceutical composition uses compound A 1.0,10 and 110mg/kg treated animal
Put pole-climbing and aerial righting reflex observed result each observing time and use compound A with embodiment 2,3,7 and 12 pharmaceutical composition
1.0,10 comparing with 110mg/kg group, embodiment 1,4,5,6,8,9,10 and 11 pharmaceutical composition is 0 grade 1 grade, and embodiment
2,3,7 and 12 pharmaceutical compositions are 3 grades 5 grades, and Some Animals observes Novel presentation.
From above-mentioned statistical result, tested by untoward reaction, embodiment 1,4,5,6,8,9,10 and 11 medicine
Compositions is by effectively controlling the total miscellaneous limitation of pharmaceutical composition, and pharmaceutical composition adverse reaction rate is the least；And implement
Example 2,3,7 and 12 is because of containing the impurity such as a certain amount of, it might therefore affect pharmaceutical composition produce other specificity impurity or
Due to the collaborative restrictive function between medicine, so that adverse reaction rate substantially increases, but concrete reason is unknown, fully says
Bright control pharmaceutical composition Light absorbing impurty is in the range of medicine of the present invention, it is possible to reduce the generation of untoward reaction, it is ensured that medication
Effectiveness and safety.
Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention are not by above-described embodiment
Limit, the change made under other any spirit without departing from the present invention and principle, modify, substitute, combine, simplify,
All should be the substitute mode of equivalence, within being included in protection scope of the present invention.
Claims (12)
1. improving a pharmaceutical composition for stability, the active component of described pharmaceutical composition is following formula: compound A:
And more than one pharmaceutically acceptable excipient, it is characterised in that wherein, the total miscellaneous control of described pharmaceutical composition
≤ 1.3%.
A kind of pharmaceutical composition improving stability the most according to claim 1, it is characterised in that wherein, described medicine
The the most miscellaneous of compositions controls≤1.0%, and more preferably 0.5%.
A kind of pharmaceutical composition improving stability the most according to claim 1, it is characterised in that described excipient includes
One or more kinds of mixing in binding agent, disintegrating agent, lubricant, fluidizer, stabilizer, filler and diluent
Thing.
A kind of pharmaceutical composition improving stability the most according to claim 3, it is characterised in that described pharmaceutically acceptable bonding
Agent includes: starch, cellulose and its derivates, hydroxypropylcellulose, the most substituted hydroxypropylcellulose, hydroxyethyl cellulose and
Hydroxypropyl methyl cellulose, sucrose, glucose, corn syrup, polysaccharide, and gelatin；Binding agent can with composition weight (
Before optional coating) about 1 to about 60% concentration exist, preferably 5% to about 40%, particularly preferred 10% to about 40%.
A kind of pharmaceutical composition improving stability the most according to claim 3, it is characterised in that described disintegrating agent includes
Starch；Clay；Cellulose；Cross linked polymer: the sodium carboxymethyl cellulose of crosslinking or cross-linking sodium carboxymethyl cellulose, cross-links carboxylic first
Base cellulose calcium；Soybean polysaccharide；And guar gum, more preferably crospolyvinylpyrrolidone or crospovidone；Disintegrating agent can be with
The concentration of about 0% to about 65% of composition weight (before optional coating) exists, and preferably from about 1% to about 40%.
A kind of pharmaceutical composition improving stability the most according to claim 3, it is characterised in that described filler and dilute
Release agent and include Icing Sugar, sompressible sugar, dextrates, dextrin, glucose, lactose, mannitol, microcrystalline Cellulose, sorbitol
And sucrose, particularly microcrystalline Cellulose；Filler can be with about the 4% of composition weight (before optional coating) to about
The concentration of 60% exists, and preferably from about 20% to about 40%.
A kind of pharmaceutical composition improving stability the most according to claim 3, it is characterised in that described lubricant and helping
The example of stream agent includes colloidal silica, magnesium trisilicate, starch, Pulvis Talci, tricalcium orthophosphate, magnesium stearate, aluminium stearate, hard
Fat acid calcium, magnesium carbonate, magnesium oxide, Polyethylene Glycol, Powderd cellulose, Glyceryl Behenate, stearic acid, castor oil hydrogenated, list are hard
Glycerol and sodium stearyl fumarate；Lubricant and fluidizer respectively can be with composition weight (at optional coatings
Before) concentration of 0% to 10% exists, and preferably 0.1% to 2%.
8. the method preparing a kind of pharmaceutical composition improving stability described in claim 1-7 any claim,
It is characterized in that, preferably the preparation technology of compressing dry granulation.
Method the most according to claim 8, it is characterised in that the preparation technology of described compressing dry granulation is dry granulation tabletting
Preparation technology, comprise the steps of:
1), pharmaceutically acceptable excipient is sieved by 40 mesh sieves, obtain mixture；
2), by said mixture and active component put in hopper mixer and mix, cross 40 mesh sieves；
3), shred after tablet machine pressure sheet, cross 40 mesh sieves；
4), with the tablet of the tablet machine described specification of compacting, then coating.
Method the most according to claim 8, it is characterised in that the preparation technology of described compressing dry granulation is powder vertical compression
Preparation technology, comprises the steps of:
1), by crude drug, adjuvant cross 40 mesh sieves, and carry out weighing by recipe quantity and get the raw materials ready；
2), take recipe quantity binding agent, disintegrating agent and 1/2 recipe quantity filler mix homogeneously and must mix powder a；
3), take recipe quantity crude drug, fluidizer, filler mix homogeneously must mix powder b；
4), by step 2 gained mix powder a addition step 3 gained to mix in powder b, and add recipe quantity mix lubricant uniformly, obtain and always mix
Powder, tabletting, coating.
11. according to a kind of pharmaceutical composition improving stability described in claim 1-7 any claim, and its feature exists
In, compound A is single crystal form, and its X-ray powder diffraction spectrum includes that following lattice plane is spaced: 21.2 (s), 17.0
(w), 7.1 (s), 5.2 (w), 4.7 (w), 4.6 (w), 4.2 (w), 3.5 (w), 3.3 (w).
A kind of pharmaceutical composition improving stability described in 12. claim 1-7 any claim is being used as preparation treatment
Cardiovascular and cerebrovascular vessel and the application of relevant disease medicine, described disease is selected from hypertension, acute and chronic heart failure, left ventricular function not
Entirely, hypertrophic cardiomyopathy, diabetic cardiomyopathy, room mo(u)ld top half and ventricle type arrhythmia, atrial fibrillation, atrial flutter, harmful blood
Pipe is reinvented, myocardial infarction and sequela, arteriosclerosis, instability or stable type angor, Secondary cases aldosteronism, former
The property sent out and secondary pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, Primary Nephrosis egg
Albiduria, renovascular hypertension, diabetic retinopathy, migraine, peripheral blood vessel, Raynaud disease, chamber hypertrophy, cognitive barrier
Hinder, glaucoma and apoplexy.
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|---|---|---|---|
| CN201510407699 | 2015-07-11 | ||
| CN2015104076998 | 2015-07-11 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101848700A (en) * | 2007-11-06 | 2010-09-29 | 诺瓦提斯公司 | Dual-acting pharmaceutical compositions based on superstructures of angiotensin receptor antagonist/blocker (arb) and neutral endopeptidase (nep) inhibitor |
| CN102702119A (en) * | 2005-11-09 | 2012-10-03 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an NEP inhibitor |
| CN105748420A (en) * | 2016-03-04 | 2016-07-13 | 山东省药学科学院 | Preparation method of LCZ696 sustained release matrix tablet for treatment of heart failure |
| CN105902506A (en) * | 2016-06-12 | 2016-08-31 | 佛山市腾瑞医药科技有限公司 | Sacubitril/valsartan preparation and application thereof |
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2016
- 2016-07-07 CN CN201610539648.5A patent/CN106176725A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702119A (en) * | 2005-11-09 | 2012-10-03 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an NEP inhibitor |
| CN101848700A (en) * | 2007-11-06 | 2010-09-29 | 诺瓦提斯公司 | Dual-acting pharmaceutical compositions based on superstructures of angiotensin receptor antagonist/blocker (arb) and neutral endopeptidase (nep) inhibitor |
| CN105748420A (en) * | 2016-03-04 | 2016-07-13 | 山东省药学科学院 | Preparation method of LCZ696 sustained release matrix tablet for treatment of heart failure |
| CN105902506A (en) * | 2016-06-12 | 2016-08-31 | 佛山市腾瑞医药科技有限公司 | Sacubitril/valsartan preparation and application thereof |
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Application publication date: 20161207 |