CN105997994A - Solid oral preparation and preparation method thereof - Google Patents

Solid oral preparation and preparation method thereof Download PDF

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Publication number
CN105997994A
CN105997994A CN201610541076.4A CN201610541076A CN105997994A CN 105997994 A CN105997994 A CN 105997994A CN 201610541076 A CN201610541076 A CN 201610541076A CN 105997994 A CN105997994 A CN 105997994A
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China
Prior art keywords
solid oral
compound
oral forms
preparation
mass parts
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Chinese (zh)
Inventor
许文杰
叶冠豪
植建琼
邓运
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Mai Lifang
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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
    • 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
    • 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
    • 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

Abstract

The invention provides a stable solid oral preparation. The solid oral preparation has the advantage of being high in storage stability due to the fact that the water content is controlled within a specific range. Compared with a preparation in the prior art, the solid oral preparation is more suitable for industrial production and clinic use.

Description

A kind of solid oral forms preparation and preparation method thereof
Technical field
The invention belongs to field of pharmaceutical preparations, particularly to a kind for the treatment of cardiovascular diseases such as heart failure of can be used for Solid oral forms preparation and preparation method thereof.
Background technology
Heart failure (abbreviation heart failure), is owing to any cardiac structure or dysfunction cause ventricular filling or penetrate One group of complex clinical syndrome that blood ability is impaired.Heart failure main clinical manifestation is dyspnea and weak (activity tolerance is limited), and fluid retention (pulmonary venous pleonaemia and periphery edema).Heart failure is various heart disease In the serious and the most last stage, sickness rate is high, is one of current most important cardiovascular disease (" China's heart failure Diagnosis and treatment guidelines 2014 ").
Since two thousand five, popular due to cardiovascular risk factors, the number of the infected of China cardiovascular diseases In the situation continued to increase.According to statistics, China's cardiovascular patient is about 2.9 hundred million people, and wherein heart failure is sick Suffer from and there are about 4,500,000 people (" China cardiovascular diseases report 2013 ").Angiotensin-convertion enzyme inhibitor (ACEI) It is the first kind medicine being proved and reducing patient's case fatality rate, is also that evidence-based medical accumulates most medicines, The choice drug of the treatment heart failure being well recognized as, Enalapril be usually used in the treatment of clinical heart failure ACEI it One.
Compound 1 is a kind of medicine for treating heart failure, and its molecular weight is 957.99.This compound is by changing The supramolecular complex (complex) that compound 2 and compound 3 are combined by non-covalent bond, has blood vessel Angiotensin receptor blocks and neutral endopeptidase suppresses dual function.Clinical trial results shows, controls with Enalapril Treatment group is compared, and compound 1 makes experimenter have dropped 21% because of heart failure admission rate, and decreases heart failure The symptom exhausted and health limit, and are better than Yi Lapu in terms of the mortality rate reducing heart failure patient and admission rate Profit (N Engl J Med, 2014,371 (1): 993-1004).Predict according to authoritative institution, its whole world annual sales amount Peak value is expected to reach 50-100 hundred million dollars.It can be seen that compound 1 is the anti-heart of a kind of great market potential Decline medicine, and product is anticipated will be in the granted listing second half year in 2015.
Due to compound 1 hydrolabil, therefore should avoid being exposed to compound in production process as far as possible Water, therefore preparation process many employings dry process prepares compound 1 preparation.Patent WO2009061713 is public Having opened a kind of solid oral forms preparation containing compound 1, said preparation uses dry process to prepare, and has molten Go out the feature that performance is good, meet clinical administration requirement.But this dry process has only considered the dissolving out capability of preparation, Preparation stability is not the most studied.
And it is true that preparation stability is one of key factor affecting clinical administration, but affect the quality of the pharmaceutical preparations One of and the key factor of clinical application risk, for the preparation that stable effective ingredients is the highest, need to find Be conducive to the quality state of preparation long term storage.Therefore find and be conducive to compound 1 solid oral forms preparation long The quality state that phase stores is the prior art technical issues that need to address.
Summary of the invention
First of the present invention aims to overcome that the deficiencies in the prior art, it is provided that a kind of stable containing chemical combination The solid oral forms preparation of thing 1, this solid oral forms preparation has the advantages that storage stability is high, more existing Preparation disclosed in technology more meets industrialized production and Clinical practice.
The above-mentioned beneficial effect of the present invention is achieved through the following technical solutions:
A kind of solid oral forms preparation containing the compound 1 that is shown below, described solid oral forms preparation bag Containing compound 1, filler, binding agent, disintegrating agent, it is characterised in that the moisture content of described solid oral forms preparation Content range is 2.5%≤w%≤7.0%.
Under normal circumstances, the factor affecting preparation stability is a lot, and common influence factor has the quality of the pharmaceutical preparations, miscellaneous Matter content, moisture content, storage temperature, storage humidity etc., but for specific products, each influence factor is for matter There is difference in the influence degree of amount.
During the quality investigation to compound 1 solid oral forms preparation, we have surprisingly found that, for Compound 1, when water content (w%) 2.5%≤w%≤7.0% in solid oral forms preparation, can substantially carry The storage stability of high described solid oral forms preparation.Concrete, when other conditions reach unanimity, solid port When taking water content 2.5%≤w%≤7.0% in type preparation, during accelerating storage, solid oral forms preparation Impurity 1 increase substantially slowly, long term storage can be realized.Concrete, impurity 1 is probably and causes solid system One of reason of agent toxic and side effects, and can gradually increase during storing, therefore, impurity 1 is compound 1 One of solid oral forms preparation impurity needing priority control.It was found that when moisture content in solid oral forms preparation Content is when particular range, and the rate of rise of impurity 1 substantially eases up, beneficially the raising of preparation stability.More Concrete, the moisture in described solid oral forms preparation can be the most concrete number between 2.5%～7.0% Value, such as 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5% etc..
Preferably, water content (w%) 3.0%≤w%≤6.0% in described solid oral forms preparation；More preferably , water content (w%) 4.0%≤w%≤6.0% in described solid orally ingestible.If no special instructions, originally Invent described water content (w%) to all refer to moisture content and account for the mass percent of solid orally ingestible gross weight.
Described water content can be by former, the water content control of adjuvant, it is also possible to pass through in coating process Drying course controls, it is also possible to by two kinds of method Comprehensive Control.
Present invention firstly discovers that, for compound 1, under where side in office, preparation process, water content is all Affect the key factor of the quality of the pharmaceutical preparations.Concrete, in solid oral forms preparation of the present invention, described filling Agent be microcrystalline Cellulose, lactose, mannitol, starch, pregelatinized Starch, sucrose, dextrin, calcium hydrogen phosphate, One or more in sorbitol are with the mixing of arbitrary proportion.Described filler preferably microcrystalline cellulose, breast Sugar, mannitol, pregelatinized Starch, calcium hydrogen phosphate, sorbitol.When the mass parts of compound 1 is 1, institute The mass parts consumption stating filler is 0.5～2.75 part, due to the regular size of compound 1 be 100mg and 200mg, the use of too much filler makes final preparation tablet weight excessive, reduces the compliance that patient takes, The use of very few filler is then unfavorable for rationally dispersion and the compression molding of effective ingredient, it is preferred that described in fill out The mass parts consumption filling agent is 0.6～2 part, more preferably 0.6～1 part.If no special instructions, chemical combination in the present invention The consumption of thing 1 is all with pure rear calculating of giving money as a gift, i.e. with the quality of effective ingredient after removal slaine and water of crystallization Calculate.
Described binding agent is selected from one or both in polyvidone, high replacement hydroxypropylcellulose, hypromellose Above with the mixing of arbitrary proportion.The use of binding agent is to make described solid oral forms preparation in preparation process In be beneficial to molding.Preferably, described binding agent replaces in hydroxypropylcellulose, hypromellose selected from height Kind or the two or more mixing with arbitrary proportion.When the mass parts of compound 1 is 1, described binding agent Mass parts consumption is 0.02～0.4 part, and the consumption of described binding agent can be any value of 0.02～0.4, such as 0.05, 0.1,0.2,0.3 etc..There is selection in the usage amount of binding agent, the use of too much binding agent makes described solid port Taking that type preparation hardness is excessive and not easy disintegrating, the use of very few binding agent is then unable to reach adhesive effect, unfavorable In compression molding, it addition, the use of very few binding agent also can make preparation disintegrate too fast, it is unfavorable for clinical administration. Preferably, the mass parts consumption of described binding agent is 0.02～0.34 part.
Described disintegrating agent is selected from polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose, low Replace one or more in hydroxypropyl cellulose with the mixing of arbitrary proportion.The use of disintegrating agent is Product is made to realize effective dissolution, to reach therapeutic effect after entering internal rear disintegrate smoothly.Preferably, described Disintegrating agent one or two in polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose With the mixing of arbitrary proportion more than kind.When the mass parts of compound 1 is 1, the mass parts of described disintegrating agent Consumption is 0.02～0.4 part, and the consumption of described disintegrating agent can be any value of 0.02～0.4, such as 0.05,0.1, 0.2,0.3 etc..Too much the use of disintegrating agent makes the described easy moisture absorption of solid oral forms preparation, is prepared as preparation Rear too fast disintegrate is also unfavorable for realizing clinical treatment purpose, and the use of very few disintegrating agent is then it cannot be guaranteed that medicine Discharge completely, be unfavorable for realizing clinical treatment purpose, it is preferred that the mass parts consumption of described disintegrating agent is 0.04～0.35 part.
The described compound 1 visual prescription of solid oral forms preparation needs to contain further fluidizer, described fluidizer One or more in silicon dioxide, the Pulvis Talci of agent are with the mixing of arbitrary proportion.Use fluidizer Purpose is to improve powder flowing performance further.When the mass parts of compound 1 is 1, described fluidizer Mass parts consumption be 0.002～0.05 part.
Compound 1 solid oral forms preparation of the present invention can also need to comprise further lubricant depending on prescription. Described lubricant is selected from magnesium stearate, hydrogenated vegetable oil, polyethylene glycols, stearic acid, Palmic acid, cohune One or more in palmitic acid wax are with the mixing of arbitrary proportion.The purpose of lubricant is to prevent described solid There is sticking in oral type preparation in follow-up punching course, the amount of described lubricant is real with energy well known in the art Existing lubricant effect is as the criterion, it is preferred that the mass parts consumption of described lubricant is 0.01～0.1 part.
Described compound 1 is single crystal form, under described single crystal form preferred X-ray powder diffraction spectrum includes Interval, row lattice plane: 21.2 (s), 17.0 (w), 7.1 (s), 5.2 (w), 4.7 (w), 4.6 (w), 4.2 (w), 3.5 (w) With 3.3 (w).
Compound 1 solid oral forms preparation uses film coating, can use coating material commonly used in the art, It is coated by art for coating commonly used in the art, it is preferred to use Opadry (Opadry), aqueous with 70% Ethanol is solvent coating.
Second object of the present invention is to provide compound 1 solid oral forms preparation process thereof.Describedization Compound 1 solid oral forms preparation can use the dry formulations technique of routine to prepare.Concrete, described chemical combination Thing 1 solid oral forms preparation can use dry granulation process and powder vertical compression technique.
One preferred technical scheme of the present invention: a kind of powder vertical compression prepares compound 1 solid oral forms system The method of agent, described method comprises the steps of:
1) former, adjuvant are crossed 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) step 2 gained mixes powder A addition step 3 gained mix in powder B, and it is mixed to add recipe quantity lubricant Close uniformly, obtain and always mix powder；
5) it is directly compressed into the plain sheet containing compound 1 by always mixing powder；
6) gained element sheet film coating is obtained compound 1 solid oral forms preparation.
The technique of described powder vertical compression defers to general knowledge known in this field, it is preferred that described tablet format be 50mg, 100mg, 200mg, 400mg, the technique of described powder vertical compression tablet hardness need to be controlled 10kgf with Under.
One preferred technical scheme of the present invention: a kind of dry granulation process prepares compound 1 Peroral solid dosage form The method of type preparation, described method comprises the steps of:
1) by former, adjuvant sieving for standby；
2) raw material in prescription and the adjuvant in addition to lubricant are carried out premixing, use dry granulating machine compacting Mixture after premixing, obtains internal phase granule after granulate；
3) internal phase granule is mixed with remaining adjuvant, after mixing, the mixture of gained is carried out tabletting and obtain To the plain sheet containing compound 1；
4) gained element sheet film coating is obtained compound 1 solid oral forms preparation.
Described dry granulation process defers to general knowledge known in this field, it is preferred that described tablet format be 50mg, 100mg, 200mg, 400mg, tablet hardness need to be controlled at below 10kgf by described tablet forming technique.
The water content of described compound 1 solid oral forms preparation can be by combining water content former, adjuvant Close and control, it is also possible to controlled by drying course in coating process, it is also possible to two kinds of water contents of comprehensive use Control method the water content of solid oral forms preparation is controlled.
Third object of the present invention is to provide a kind of compound 1 solid oral forms preparation at the preparation treatment heart Cerebrovascular and the application of relevant disease medicine, described disease is selected from hypertension, acute and chronic heart failure, left ventricle Functional defect, hypertrophic cardiomyopathy, diabetic cardiomyopathy, room mo(u)ld top half and ventricle type arrhythmia, atrial fibrillation, Atrial flutter, harmful vascular remodeling, myocardial infarction and sequela thereof, arteriosclerosis, instability or stable Type angor, Secondary cases aldosteronism, constitutional and secondary pulmonary hypertension, diabetic nephropathy, blood vessel Ball nephritis, scleroderma, glomerular sclerosis, Primary Nephrosis albuminuria, renovascular hypertension, diabetic Retinopathy, migraine, peripheral blood vessel, Raynaud disease, chamber hypertrophy, cognitive disorder, glaucoma and in Wind.Due to by the moisture control of described solid oral forms preparation in the range of specific so that of the present inventionization Impurity in compound 1 solid oral forms preparation, particularly may cause the impurity of poisonous side effect of medicine storing During speedup slow down, it is possible to achieve the long term storage of preparation, and reduce clinical application risk.
Compared with prior art, the present invention has a following technology character and superiority:
1, providing a kind of stable solid oral forms preparation containing compound 1, this solid oral forms preparation contains The water yield is in particular range so that described preparation has disclosed in the feature that storage stability is high, relatively prior art Preparation more meets industrialized production and Clinical practice.
2, providing compound 1 solid oral forms preparation process thereof, by prescription, that technology controlling and process obtains this is steady Qualitative high solid oral forms preparation.
3, provide compound 1 solid oral forms preparation preparation treatment cardiovascular and cerebrovascular vessel and relevant disease medicine should With, described 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, atrial flutter, harmful blood vessel weight Mould, myocardial infarction and sequela, arteriosclerosis, instability or stable type angor, Secondary cases aldosterone mistake Many diseases, constitutional and secondary pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, kidney are little Ball hardening, Primary Nephrosis albuminuria, renovascular hypertension, diabetic retinopathy, migraine, periphery Angiopathy, Raynaud disease, chamber hypertrophy, cognitive disorder, glaucoma and apoplexy.Due to by described Peroral solid dosage form The moisture control of type preparation is in the range of specific so that compound 1 solid oral forms preparation of the present invention In impurity, the impurity of poisonous side effect of medicine speedup during storing particularly may be caused to slow down, Ke Yishi The long term storage of existing preparation, and reduce clinical application risk.
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.
Compound 1 crude drug uses method disclosed in patent WO2007056546 embodiment to prepare.
Embodiment 1
1, use double-cone dryer that adjuvant water content is dried to about 1.0% (80 DEG C)；
2, microcrystalline Cellulose, high replacement hydroxypropylcellulose, polyvinylpolypyrrolidone, silicon dioxide, magnesium stearate are crossed 40 Mesh sieve is standby, carries out weighing according to recipe quantity and gets the raw materials ready；
3, recipe quantity polyvinylpolypyrrolidone, high replacement hydroxypropylcellulose and 1/2 recipe quantity microcrystalline Cellulose mix homogeneously are taken Powder A must be mixed；
4, recipe quantity crude drug (water content 5.0%, Karl_Fischer method), silicon dioxide, 1/2 recipe quantity crystallite fibre are taken Dimension element mix homogeneously must mix powder B；
5, 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；
6, powder vertical compression technique is used to be prepared as the plain sheet that specification is 100mg by always mixing powder, described element sheet hard Degree controls 5～10kgf；
7, using Opadry (Opadry) coating material, using 70% aquiferous ethanol is solvent formulation content 8% Coating Solution gained element sheet is carried out spray coating, control weightening finish between 2%～4%, inlet temperature 40～60 DEG C, drying time 90min.
The water content using Karl_Fischer method detection gained solid oral forms preparation is 4.5%.
Embodiment 2
Use the compound 1 crude drug (Karl_Fischer method) of water content 4.8%, use same as in Example 1 Method prepares compound 1 solid oral forms preparation.
Using Opadry (Opadry) coating material, using 70% aquiferous ethanol is solvent formulation content 8% Coating Solution gained element sheet is carried out spray coating, control weightening finish between 2%～4%, inlet temperature 40～60 DEG C, drying time 60min.
The water content using Karl_Fischer method detection gained solid oral forms preparation is 5.3%.
Embodiment 3
Use the compound 1 crude drug (Karl_Fischer method) of water content 5.1%, use same as in Example 1 Method prepares compound 1 solid oral forms preparation.
Using Opadry (Opadry) coating material, using 70% aquiferous ethanol is solvent formulation content 8% Coating Solution gained element sheet is carried out spray coating, control weightening finish between 2%～4%, inlet temperature 40～60 DEG C, drying time 120min.
The water content using Karl_Fischer method detection gained solid oral forms preparation is 4.1%.
Embodiment 4～6, comparative example 1～2
Use crude drug, prescription and preparation process same as in Example 1, controlled drying time by coating The moisture of gained solid oral forms preparation, obtains the solid oral forms preparation of various moisture contents, as follows:
Embodiment Drying time (min) Moisture content (%)
Embodiment 4 150min 2.9
Embodiment 5 40min 6.2
Embodiment 6 120min 3.7
Comparative example 1 180min 2.1
Comparative example 2 30min 7.7
Embodiment 7
Preparation method:
1, use double-cone dryer that adjuvant water content is dried to about 1.0% (80 DEG C)；
2, crude drug (water content 4.8%, Karl_Fischer method) is crossed 80 mesh sieves, all adjuvants are crossed 40 mesh Sieve, standby；
3, internal phase particulate component in prescription is carried out premixing, after using dry granulating machine compacting premixing Mixture, obtains internal phase granule after granulate；
4, internal phase granule is mixed with magnesium stearate, after mixing, the mixture of gained is carried out tabletting and obtain To element sheet.
5, using Opadry (Opadry) coating material, using 70% aquiferous ethanol is solvent formulation content 8% Coating Solution gained element sheet is carried out spray coating, control weightening finish between 2%～4%, air intake temperature Spend 40～60 DEG C, drying time 60min.
The water content using Karl_Fischer method detection gained solid oral forms preparation is 5.3%.
Embodiment 8
Use the compound 1 crude drug (Karl_Fischer method) of water content 5.2%, use and embodiment 7 phase Same method prepares the plain sheet containing compound 1.
Using Opadry (Opadry) coating material, using 70% aquiferous ethanol is solvent formulation content 8% Coating Solution gained element sheet is carried out spray coating, control weightening finish between 2%～4%, air-out Temperature 40～60 DEG C, drying time 90min.
The water content using Karl_Fischer method detection gained solid oral forms preparation is 4.3%.
Embodiment 9
Use the compound 1 crude drug (Karl_Fischer method) of water content 4.9%, use and embodiment 7 phase Same method prepares the plain sheet containing compound 1.
Using Opadry (Opadry) coating material, using 70% aquiferous ethanol is solvent formulation content 8% Coating Solution gained element sheet is carried out spray coating, control weightening finish between 2%～4%, air intake Temperature 40～60 DEG C, drying time 70min.
The water content using Karl_Fischer method detection gained solid oral forms preparation is 5.0%.
Embodiment 10～12, comparative example 3～4
Use crude drug, prescription and preparation process same as in Example 7, controlled drying time by coating The moisture of gained solid oral forms preparation, obtains the solid oral forms preparation of various moisture contents, as follows:
Embodiment Drying time (min) Moisture content (%)
Embodiment 10 120min 4.2
Embodiment 11 180min 2.7
Embodiment 12 150min 3.2
Comparative example 3 210min 2.0
Comparative example 4 30min 7.8
Embodiment 13
Detection of Stability
By embodiment and comparative example's gained solid oral forms preparation acceleration environment (40 DEG C ± 2 DEG C, RH75% ± 5%) place 60 days under, detect the situation of change of its impurity 1, and study in itself and solid oral forms preparation Relation between impurity 1 content, acquired results is as follows:
As seen from the above table, in Acceleration study, impurity 1 changes of contents of embodiment 1～12 gained preparation is less, Meet the requirement of clinical application correlated quality regulation, it is known that embodiment 1～12 gained preparation stability is higher；Tool Body, when water content controls at 2.5%≤w%≤7.0%, in 60 days, impurity 1 increment is less than 0.1%, when Water content 3.0%≤w%≤6.0%, in 60 days, impurity 1 increment is less than 0.06%, works as water content 3.0%≤w%≤6.0%, in 60 days, impurity 1 increment is less than 0.03%.
And for comparative example 1-4, generally, due to its water content do not control within, be presented as miscellaneous The content of matter 1 is in accelerating the state that rises, and in 60 days, impurity 1 increment is all more than 0.2%, and longer for it The fastest rate of climb is presented during the storage of time；Particularly, for comparative example 1 and 3, Its simultaneous water content during storing rises.
Dissolving out capability detects
Chinese Pharmacopoeia (2010 editions) annex XC dissolution determination method the second method paddle method is used to detect reality respectively Executing the dissolution situation of example 1～12 gained compound 1 solid oral forms preparation, all formulations is in 10 minutes Can realize discharging 70% effective above composition, in 30 minutes, effective ingredient is released in more than 85%, in 45 minutes Effective ingredient is released in more than 90%, meets clinical application requirement.
Embodiment 14
Experiment (Behaviors survey) is investigated in untoward reaction
Laboratory sample:
Test sample: comparative example 2 gained 0 day and compound 1 Peroral solid dosage form processed for 60 days through acceleration Type preparation；Negative controls: use Vehicle controls product deionized water (prepared by laboratory).
Laboratory animal:
ICR mice, SPF level, for Animal Sex and quantity, the jenny: 25, male of test Animal: 25.
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 1 solid oral forms preparation pulverizing, by active compound component 1 Low dose group 1.0mg/kg, middle dosage group 10mg/kg, high dose group 110mg/kg gastric infusion, during administration Between be one week.
Test procedure:
Pole-jump test operates: (diameter is about 0.9cm to the metal bar smooth with a root surface, and length is about 72cm), stand vertically.Before being administered and after administration, the operation of different time points pole-jump test terminates in laggard line space Righting reflex operates: mention mousetail, mice of dishing out after rotating 4 circles, observes the abnormal appearance that mice lands State (side or the back side land), continuously repeats 5 times, and comments according to Irwin ' s behavior rank scores standard Point.Within before being administered and after last administration 0.5,1,2,4,6,24 hours, respectively observe a pole-climbing With aerial righting reflex.After experiment terminates, use excess CO2This test surviving animals used is put to death in anesthesia. 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:
The content of the solid oral forms preparation impurity 1 of 0 day is relatively low, uses compound 1 1.0,10 and 110mg/kg Treated animal puts pole-climbing with aerial righting reflex observed result each observing time compared with Vehicle controls group (0mg/kg) All no significant differences.
And the solid oral forms preparation after 60 days Acceleration study is 3 grades 5 grades, Some Animals is observed different Often performance.
From above-mentioned statistical result, because of water content not in target zone of the present invention, it might therefore impact is solid Body oral type preparation produces other specificity impurity or due to the collaborative restrictive function between medicine, so that Adverse reaction rate substantially increases, but concrete reason is unknown, absolutely proves control solid oral forms preparation moisture content Content is in target zone of the present invention, it is possible to reduce the generation of untoward reaction, it is ensured that the effectiveness of medication and Safety.
Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention are not by above-mentioned reality Execute the restriction of example, the change made under other any spirit without departing from the present invention and principle, modification, Substitute, combine, simplify, all should be the substitute mode of equivalence, within being included in protection scope of the present invention.

Claims (11)

1. the solid oral forms preparation containing the compound 1 that is shown below, described solid oral forms preparation inclusion compound 1, filler, binding agent, disintegrating agent, the water content scope that it is characterized in that described solid oral forms preparation is 2.5%≤w%≤7.0%, preferably 3.0%≤w%≤6.0%, more preferably 4.0%≤w%≤6.0%.
。
Solid oral forms preparation the most according to claim 1, it is characterized in that described filler be one or more in microcrystalline Cellulose, lactose, mannitol, starch, pregelatinized Starch, sucrose, dextrin, calcium hydrogen phosphate, sorbitol with the mixing of arbitrary proportion, when the mass parts of compound 1 is 1, the mass parts consumption of described filler is 0.5～2.75 part, preferably 0.6～2 part.
3. according to the solid oral forms preparation described in claim 1 or 2 any one, it is characterized in that described binding agent selected from polyvidone, high replace in hydroxypropylcellulose, hypromellose one or more with the mixing of arbitrary proportion, when the mass parts of compound 1 is 1, the mass parts consumption of described binding agent is 0.02～0.4 part.
4. according to the solid oral forms preparation described in claim 1-3 any one, it is characterized in that one or more in polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose of described disintegrating agent are with the mixing of arbitrary proportion, when the mass parts of compound 1 is 1, the mass parts consumption of described disintegrating agent is 0.02～0.4 part.
5. according to the solid oral forms preparation described in claim 1-4 any one, it is characterized in that when the mass parts of compound 1 is 1, the mass parts consumption of described filler is 0.6～1 part, the mass parts consumption of described binding agent is 0.02～0.34 part, and the mass parts consumption of described disintegrating agent is 0.04～0.35 part.
6. according to the solid oral forms preparation described in claim 1-5 any one, it is characterized in that described solid oral forms preparation contains fluidizer further, one or more in silicon dioxide, the Pulvis Talci of described fluidizer are with the mixing of arbitrary proportion, when the mass parts of compound 1 is 1, the mass parts consumption of described fluidizer is 0.002～0.05 part.
7. according to the solid oral forms preparation described in claim 1-6 any one, it is characterized in that described compound 1 solid oral forms preparation comprises lubricant further, one or more in magnesium stearate, hydrogenated vegetable oil, polyethylene glycols, stearic acid, Palmic acid, the Brazil wax of described lubricant are with the mixing of arbitrary proportion, when the mass parts of compound 1 is 1, the mass parts consumption of described lubricant is 0.01～0.1 part.
8. according to the solid oral forms preparation described in claim 1-7 any one, it is characterized in that the X-ray powder diffraction spectrum of described compound 1 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) and 3.3 (w).
9. a preparation method for compound 1 solid oral forms preparation as described in claim 1-8 any one, described method comprises the steps of:
1) former, adjuvant are crossed 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) step 2 gained mixes powder A addition step 3 gained mix in powder B, and add recipe quantity mix lubricant uniformly, obtain and always mix powder；
5) it is directly compressed into the plain sheet containing compound 1 by always mixing powder；
6) gained element sheet film coating is obtained compound 1 solid oral forms preparation；
Or, described method comprises the steps of:
1) by former, adjuvant sieving for standby；
2) raw material in prescription and the adjuvant in addition to lubricant are carried out premixing, use the mixture after dry granulating machine compacting premixing, after granulate, obtain internal phase granule；
3) internal phase granule is mixed with remaining adjuvant, after mixing, the mixture of gained is carried out tabletting and obtains the plain sheet containing compound 1；
4) gained element sheet film coating is obtained compound 1 solid oral forms preparation.
The preparation method of compound 1 solid oral forms preparation the most according to claim 9, it is characterised in that described film-coat uses Opadry with 70% aquiferous ethanol for solvent coating.
11. treat cardiovascular and cerebrovascular vessel and the application of relevant disease medicine according to the solid oral forms preparation described in claim 1-8 any one in preparation, described disease is 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, atrial flutter, harmful vascular remodeling, myocardial infarction and sequela thereof, arteriosclerosis, instability or stable type angor, Secondary cases aldosteronism, 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.
CN201610541076.4A 2015-07-11 2016-07-08 Solid oral preparation and preparation method thereof Pending CN105997994A (en)

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