CN108236609A - A kind of GPR40 anti-depressant medications composition and preparation method thereof - Google Patents
A kind of GPR40 anti-depressant medications composition and preparation method thereof Download PDFInfo
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- CN108236609A CN108236609A CN201711429787.3A CN201711429787A CN108236609A CN 108236609 A CN108236609 A CN 108236609A CN 201711429787 A CN201711429787 A CN 201711429787A CN 108236609 A CN108236609 A CN 108236609A
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Abstract
The present invention relates to a kind of GPR40 anti-depressant medications compositions and preparation method thereof.Specifically, pharmaceutical composition of the present invention contains 2 ((S) 6 ((2', 6' dimethyl 4'(((R) 3 base of tetrahydrofuran) oxygroup) [1,1' biphenyl] 3 bases) methoxyl group) 2,3 Dihydrobenzofuranes, 3 base) acetic acid or its officinal salt and polyvinylpyrrolidone, the characteristics such as the composition, which has, to be dissolved out, and stability is good.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to one kind contains 2- ((S) -6- ((2', 6'- dimethyl -4'-
(((R)-tetrahydrofuran -3- bases) oxygroup)-[1,1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
Or the pharmaceutical composition of its officinal salt.
Background technology
Diabetes are a kind of common Chronic Non-Communicable Diseases, caused by by insulin deficit in human body or resisting.Glycosuria
Disease is generally divided into two kinds of type-1 diabetes mellitus and type-2 diabetes mellitus.Wherein type-2 diabetes mellitus is most commonly seen, accounts for about total sufferer number
90%.Adverse reaction is a difficult problem that many antidiabetic drugs face, and is serious hypoglycemic reaction first, therefore, exploitation has
Completely new mechanism of action and more safely and effectively novel antidiabetic drug has become a vital task urgently to be resolved hurrily.
GPR40 is the g protein coupled receptor found before 10 years, and endogenic ligand is FFAs (free fatty
Acids), under the stimulation of free fatty, it can play the insulin secretion effect of amplification glucose stimulation, be a kind of potential
Treatment diabetes medicament target.The TAK-875 of military field (Takeda) company is first entrance in the current such drug in the whole world
The new drug of clinical end-stage research, secondly the JTT-851 of Tobacco companies, enters clinical 1 phase (Japan) for 2010.TAK-875
It is the oral hypoglycemic agents for treating type-2 diabetes mellitus, is the small molecule agonist of GPR40 selectivity.
WO2008001931 discloses the pharmaceutical composition containing GPR40 agonists TAK-875, and provides two kinds of dosage form pieces
Agent and capsule, the requirements such as dissolution rate, stability during meeting TAK-875 compound patent medicine.
CN104740635A discloses a kind of pharmaceutical composition containing GPR40 agonists and SGL2 inhibitor, to improve
Hypoglycemic effect；WO201401429A then provides the compound medicament composition containing TAK-875 and melbine, provides and is had
There is the drug of better healing diabetes effect.
WO2013014257 discloses compound shown in a kind of formula (I), and the external activity of the compound is 30nM and the positive
Compound TAK-875 is suitable, and the OGTT experiments of diabetic mice show that the hypoglycemic effect of the compound is better than TAK-875,
In the experiment of diabetes monkey, which also has apparent hypoglycemic effect, and hypoglycemic activity is better than TAK-875.In addition, formula (I) institute
Show that big raticide generation and the TAK-875 of compound are suitable, dog medicine generation and monkey medicine generation will be substantially better than TAK-875, toxicity result
It has been shown that, under the dosage of 500mg/kg, which does not have obvious toxic-side effects.
Invention content
The present invention provides one kind and has good stability while dissolve out rapid pharmaceutical composition, and described pharmaceutical composition contains work
Property ingredient 2- ((S) -6- ((2', 6'- dimethyl -4'- (((R)-tetrahydrofuran -3- bases) oxygroup)-[1,1'- biphenyl] -3- bases)
Methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid or officinal salt and polyvinylpyrrolidone.When the pharmaceutical composition
The dosage of polyvinylpyrrolidone accounts for the 0.5~20% of pharmaceutical composition weight in object, which, which has, preferably may be used
Pressure property and mobility, it is described conducive to control drug quality to ensure that (such as tablet) avoids tablet weight variation when preparing solid pharmaceutical preparation
Polyvinylpyrrolidone with being more preferably 2~15%, in embodiments can be 2,3,4,5,6,7,8,9,10,11,12,
13rd, 14,15%.
In embodiments, the content 1~50% of active constituent of the present invention, can be 1,2,3,4,5,6,7,8,9,
10th, 12,15,16,18,20,23,25,27,30,32,35,37,40,45,50%, preferably 3~30%, with pharmaceutical composition
Weight meter；In embodiments, the amount of active constituent of the present invention is at most 200mg, it is preferable that the amount of active constituent is
100mg, 25mg or 5mg.
For pharmaceutical composition of the present invention also containing other pharmaceutic adjuvants, these pharmaceutic adjuvant types are the art people
Well known to member, selected from least one of filler, disintegrant, lubricant.
Filler of the present invention is water-soluble or water-swellable filler, and water-swellable filler is swollen after referring to addition water
Pharmaceutic adjuvant.Water-soluble filler is including but not limited to dextrin, lactose, sucrose, calcium monohydrogen phosphate.Water-swellable filler includes
But it is not limited to pregelatinized starch, gelatinized starch, crystallite (crystallization) cellulose, starch, hydroxypropyl methyl cellulose (HPMC-
K100LV), calcium sulfate, calcium monohydrogen phosphate.These water-soluble or water-swellable additives can be used alone or with two kinds or more
Type is applied in combination, and is preferable in dextrin, lactose, sucrose, starch, pregelatinized starch, calcium monohydrogen phosphate, microcrystalline cellulose
At least one, in preferred embodiments, the filler are lactose and microcrystalline cellulose；Preferably, the use of the filler
Amount account for the 55~95% of pharmaceutical composition weight, more preferably 60~85%, in embodiments can be 60,61,62,63,
64th, 65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85%, with medicine group
Polymer weight.
Further, the weight ratio 2 of lactose and microcrystalline cellulose in filler of the present invention:1~6:1, preferably 3:1
~5:1, can be 3 in embodiments:1、3.1:1、3.2:1、3.3:1、3.5:1、3.7:1、3.9:1、4:1、4.1:1、
4.2:1、4.3:1、4.5:1、4.7:1、5:1。
" in terms of weight of pharmaceutical composition " of the present invention for not comprising coating agent label weight meter calculate activity into
Point or other type pharmaceutic adjuvants usage amount numberical range, for details, reference can be made to embodiment 1.
Disintegrant of the present invention be selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose,
At least one of sodium carboxymethyl starch, starch, pregelatinized starch, alginic acid, it is preferable that the dosage of the disintegrant accounts for drug
The 2~15% of composition weight, specific embodiment can be 2,3,4,5,6,7,8,9,10,11,12,13,14,15%, with
Pharmaceutical composition weight meter.
Lubricant of the present invention is selected from magnesium stearate, stearic acid, palmitic acid, calcium stearate, talcum powder, babassu
At least one of wax, sodium stearyl fumarate；Preferably, the dosage of lubricant of the present invention accounts for pharmaceutical composition weight
0.1~5%, specific embodiment can be 0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9%, 1%, 1.5%,
2%th, 2.5%, 3%, 3.5%, 4%, 4.5,5%, preferably 0.1~2%, in terms of pharmaceutical composition weight.
The present invention also provides a kind of pharmaceutical compositions, contain following ingredient：
1) active constituent 2- ((S) -6- ((2', 6'- dimethyl -4'- (((R)-tetrahydrofuran -3- of 3~30% weight
Base) oxygroup)-[1,1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid or its officinal salt；
2) filler of 60~85% weight；
3) disintegrant of 2~15% weight, the disintegrant is in croscarmellose sodium, sodium carboxymethyl starch
At least one；
4) lubricant of 0.1~2% weight, the lubricant in magnesium stearate, stearic acid, Compritol 888 ATO extremely
Few one kind；
Wherein, the filler is lactose and microcrystalline cellulose, further, the lactose and microcrystalline cellulose weight ratio
It is 3:1~5:1, more preferably 3.3:1 or 4.7:1.
In preferred embodiments, coating agent, plasticizer are also contained in pharmaceutical composition of the present invention, is protected from light agent, color
At least one of element.
Coating agent of the present invention is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, acrylic resin
At least one of.
Plasticizer of the present invention is selected from propylene glycol, castor oil, polyethylene glycol, silicone oil, glycerine, phthalic acid ester or two
At least one of butyl ester；Opacifier of the present invention is titanium dioxide.
Pigment of the present invention is selected from least one of amaranth, carmine cap cylinder, lemon yellow.
The present invention also provides a kind of method for preparing aforementioned pharmaceutical compositions, this method includes：1) by active constituent or its
Officinal salt is mixed with polyvinylpyrrolidone and optionally from least one of filler, disintegrant, lubricant excipient,
It 2) will be from tabletting after the granulating mixture 1) obtained or filling capsule, direct tablet compressing or direct filling capsule.
Further, coating steps are further included described in the preparation method after granulation step, the coating agent is selected from hydroxypropyl
At least one of ylmethyl cellulose, hydroxypropyl cellulose, acrylic resin and polyvinyl alcohol.
Granulation mode of the present invention can be wet granulation and dry granulation, can when selecting wet granulation scheme
To be pelletized using fluidized bed granulation or bulk drug of pretreatment adds with interior.
In the present embodiment, it is as follows using high-shearing granulation processing step：
1) active constituent or its officinal salt or its solvate are added in into filler, disintegrant and are uniformly mixed；
2) it will be made in adhesive or adhesive solvent addition 1 after carrying out wet whole grain after softwood, dry, whole grain；
3) granular substance into step 2 adds in lubricant and mixes；
4) it is the mixture in step 3 is tabletted；
5) it by the tablet in step 4, is coated with the aqueous dispersion or alcohol aqueous dispersion liquid of coating agent, coating weight gain
2-4%, optimal is 3%.
In the present embodiment, it is as follows using fluidized bed granulation processing step：
1) active constituent or its officinal salt or its solvate are added in into filler, disintegrant and are uniformly mixed, is used in combination
Polyvinylpyrrolidone (K30) prepares binder solution；
2) mixture of powders in step 1 is fluidized, then after binder solution is sprayed to powder blending surface, done
It is dry, whole grain；
3) granular substance into step 2 adds in lubricant and mixes；
4) it is the mixture in step 3 is tabletted；
5) it by the tablet in step 4, is coated with the aqueous dispersion or alcohol aqueous dispersion liquid of coating agent, coating weight gain
2-4%, optimal is 3%.
Pharmaceutical composition of the present invention is solid pharmaceutical preparation, preferred tablet or capsule.Solid pharmaceutical preparation can be by extensive
Known preparation method obtains, and the maximum water holding capacity control 3% of final dry particle is hereinafter, then filling capsule or straight after granulation
Connect tabletting.When dosage form is tablet, control tabletting ambient humidity ensures that the water content of final plain piece is less than 3% in tableting processes
(less than 3%).
It, can be by compressing the particle preparation obtained as described above when Pharmaceutical composition of the present invention uses tablet.It can
The pressure of compression is determined in proper range.Moreover, figure of tablet is without specifically limited, preferably lablab shape, disc, circle,
Oval (such as caplet), tear drop shape or polygonal (such as triangle or diamond shape).It can be sprayed by pan coater (pan coater)
The tablet of preparation is coated by the mode for spilling the suspension/solution of coating agent.After the completion of coating, then will by drying process
The moisture of final tablet is controlled within 3%.
HPLC testing conditions of the present invention：
Chromatographic column：C18,4.6mm × 25cm, 5 μm；Detection wavelength：205nm；Mobile phase：0.01mol/L potassium dihydrogen phosphates
Solution-acetonitrile.
Term " compressibility " is characterized with compressibility index or Hausner ratios in the application, the two indexs are characterization powder
The characteristic parameter of last compressibility, compressibility index=(1- tap densities/bulk density) × 100%, Hausner ratios=Song Mi
Degree/tap density.
Term " homogeneity " in the application is carried out according to Content uniformity test.10, tablet is taken, is measured respectively
Every using labelled amount as 100 relative amount X, calculate mean value X, standard deviation S, labelled amount and mean value absolute value of the difference A (|
100-X |)；Chinese Pharmacopoeia provides that, if A+1.80S≤15.0, the uniformity of dosage units of test sample meets regulation；If A+
1.80S ＞ 15.0, then it is against regulation.Term " RSD " in the application is relative standard deviation.
Pharmaceutical composition Determination of Content Uniformity method, known to those skilled in the art in the present invention, takes this product 1
Piece is put in the measuring bottle suitable for size, adds dilution (0.01mol/L potassium dihydrogen phosphates-acetonitrile) in right amount, and ultrasound makes dissolving,
It with diluted to scale, shakes up, filters, take subsequent filtrate diluted, shake up, precision measures 10 μ l injection liquid phase colors
Spectrometer records chromatogram, plans content, should meet regulation.
The composition dissolution of the present invention is very complete, according to 2015 editions four the second methods of general rule dissolution determination of Chinese Pharmacopoeia
(paddle method), with 1.5% lauryl sodium sulfate (SDS) aqueous solution, preferably 1000ml is dissolution medium, and at 37 ± 0.5 DEG C
Under dissolution test carried out to the present composition with the paddle speed of 50rpm, be more than or equal to 90% 15 minutes or 45 minutes dissolution rates.
Specific embodiment
The present invention is further described by following embodiment and experimental example.These embodiments and experimental example are only used for
Bright property purpose, and the range being not intended to restrict the invention.
Examples 1 to 4
By 2- ((S) -6- ((2', 6'- dimethyl -4'- (((R)-tetrahydrofuran -3- bases) oxygroup)-[1,1'- biphenyl] -3-
Base) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (hereinafter referred to as compound A), lactose or mannitol, microcrystalline cellulose
Element, croscarmellose sodium, according to the ratio in table 1, wet granulation is carried out using high-shearing granulation machine, with polyethylene
5% aqueous solution that pyrrolidones K30 is configured to is pelletized for adhesive, and wet whole grain and drying process are carried out to wet softwood,
Then dry particl (moisture is less than 3%) is subjected to dry whole grain, adds in the magnesium stearate of recipe quantity, be uniformly mixed.It is total by what is obtained
Mixed particle is tabletted.
Table 1
When selecting mannitol as filler, pharmaceutical composition shows poor compressibility, and mobility is also poor, so as to
Cause the tablet weight variation when tablet is made larger, be 3%, and when selecting lactose with microcrystalline cellulose, pharmaceutical composition shows
Preferable compressibility and mobility, comply fully with patent medicine quality standard, the especially weight ratio 190 when lactose and microcrystalline cellulose:
57 (about 3.3:1) when, tablet weight variation is less than 2.5% after tablet is made, and can preferably control the tablet weight variation of patent medicine, specific number
According to being shown in Table 2.
Table 2
The dissolution experiment of embodiment 1-4
According to 2015 editions four the second methods of general rule dissolution determination (paddle method) of Chinese Pharmacopoeia, to the tablet of experimental example 1~4 into
Row dissolution determination.Using 1.5% lauryl sodium sulfate (SDS) aqueous solution 1000ml as dissolution medium, and at 37 ± 0.5 DEG C
Under dissolution test carried out with the paddle speed of 50rpm, specific data are shown in Table 3.
Table 3
The result shows that although the prescription of experimental example 3 shows preferable compressibility and mobility, dissolved out endless after its patent medicine
Such as people's will, 45min dissolution rates are only 92.2% under above-mentioned leaching condition, it is impossible to active matter in good release of pharmaceutical compositions
Matter, and experimental example 2 and 4 can reach 99% dissolution in 45min, comparatively fast discharge active material.
Embodiment 2,5 and 6
By 2- ((S) -6- ((2', 6'- dimethyl -4'- (((R)-tetrahydrofuran -3- bases) oxygroup)-[1,1'- biphenyl] -3-
Base) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (hereinafter referred to as compound A), lactose, microcrystalline cellulose, crosslinking carboxylic
Sodium carboxymethylcellulose pyce, according to the ratio in table 4, wet granulation is carried out using high-shearing granulation machine, respectively with polyvinyl pyrrole
Alkanone K30 is configured to 5% aqueous solution, pregelatinized starch is configured to 13% aqueous solution and PVP K30 is prepared
Into 8% aqueous solution as adhesive, wet whole grain and drying process are carried out to wet softwood, then by dry particl (moisture is less than 3%)
Dry whole grain is carried out, the magnesium stearate of recipe quantity is added in, is uniformly mixed.Obtained always mixed particle is tabletted.
Table 4
When hydroxypropyl methylcellulose in prescription, pharmaceutical composition shows poor compressibility, and mobility is also poor, so as to lead
It is 3% to cause the tablet weight variation when tablet is made, and when selecting polyvinylpyrrolidone (trade name K30), pharmaceutical composition exhibition
Now preferable compressibility and mobility, tablet weight variation is respectively 1.2% and 1.5% after tablet is made, and can preferably control patent medicine
Tablet weight variation, preferably control sample quality, specific data are shown in Table 5.
Table 5
The dissolution experiment of embodiment 2,5,6
According to 2015 editions four the second methods of general rule dissolution determination (paddle method) of Chinese Pharmacopoeia, to the tablet of embodiment 2,5,6
Carry out dissolution determination.Using 1.5% lauryl sodium sulfate (SDS) aqueous solution 1000ml as dissolution medium, and 37 ± 0.5
Dissolution test is carried out with the paddle speed of 50rpm at DEG C.The result shows that in embodiment 2,5,6, compound A dissolutions are complete, close
100%, dissolution the results are shown in Table 6.
Table 6
Embodiment 6~8
By 2- ((S) -6- ((2', 6'- dimethyl -4'- (((R)-tetrahydrofuran -3- bases) oxygroup)-[1,1'- biphenyl] -3-
Base) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (hereinafter referred to as compound A), lactose, microcrystalline cellulose, crosslinking carboxylic
Sodium carboxymethylcellulose pyce or crospovidone or sodium carboxymethyl starch according to the ratio in table 7, are carried out using high-shearing granulation machine
Wet granulation is configured to 8% aqueous solution as adhesive using PVP K30 respectively, wet whole grain is carried out to wet softwood
And be dried, dry particl (moisture is less than 3%) is then subjected to dry whole grain, the magnesium stearate of recipe quantity is added in, is uniformly mixed.
Obtained always mixed particle is tabletted.
Table 7
The dissolution experiment of embodiment 6~8
According to 2015 editions four the second methods of general rule dissolution determination (paddle method) of Chinese Pharmacopoeia, to the tablet of embodiment 6~8 into
Row dissolution determination.Using 1.5% lauryl sodium sulfate (SDS) aqueous solution 1000ml as dissolution medium, and at 37 ± 0.5 DEG C
Under dissolution test carried out with the paddle speed of 50rpm.The result shows that in embodiment 6,7,8, compound A dissolutions 45min can dissolve out near
100% or so, but 10min dissolutions are 74.4% in embodiment 8, and 10min dissolutions are molten more than 80% in embodiment 6 and 7
Go out to the results are shown in Table 8.
Table 8
The result shows that although the prescription of embodiment 8 shows preferable compressibility and mobility, dissolved out endless after its patent medicine
Such as people's will, 10min dissolution rates are only 74.4% under above-mentioned leaching condition, and embodiment 6 and 7 but can reach 80% in 10min
Dissolution, comparatively fast discharges active material.
Embodiment 9~11
By 2- ((S) -6- ((2', 6'- dimethyl -4'- (((R)-tetrahydrofuran -3- bases) oxygroup)-[1,1'- biphenyl] -3-
Base) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (hereinafter referred to as compound A), lactose, microcrystalline cellulose, crosslinking carboxylic
Sodium carboxymethylcellulose pyce or crospovidone or sodium carboxymethyl starch according to the ratio in table 9, are carried out using high-shearing granulation machine
Wet granulation is configured to 8% aqueous solution as adhesive using PVP K30, wet whole grain is carried out to wet softwood and is done
Dry particl (moisture is less than 3%) is then carried out dry whole grain, adds in the magnesium stearate of recipe quantity, be uniformly mixed by dry processing.Will
The always mixed particle arrived is tabletted.
Table 9
The dissolution experiment of embodiment 9~11
According to 2015 editions four the second methods of general rule dissolution determination (paddle method) of Chinese Pharmacopoeia, to the tablet of embodiment 9~11
Carry out dissolution determination.Using 1.5% lauryl sodium sulfate (SDS) aqueous solution 1000ml as dissolution medium, and 37 ± 0.5
Dissolution test is carried out with the paddle speed of 50rpm at DEG C.The result shows that in embodiment 9,10,11, compound A dissolutions 45min can be molten
Go out nearly 100% or so, dissolution the results are shown in Table 10.
Table 10
Claims (12)
1. a kind of pharmaceutical composition contains active constituent 2- ((S) -6- ((2', 6'- dimethyl -4'- (((R)-tetrahydrofuran -3-
Base) oxygroup)-[1,1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid or officinal salt and poly- second
Alkene pyrrolidone, the dosage of preferably described polyvinylpyrrolidone account for the 0.5~20% of pharmaceutical composition weight, more preferably 2
~15%.
2. pharmaceutical composition according to claim 1, it is characterised in that the content of the active constituent is preferred for 1~50%
It is 3~30%, in terms of pharmaceutical composition weight.
3. pharmaceutical composition according to claim 1 or 2, it is characterised in that the amount of the active constituent at most 200mg, it is excellent
It is selected as 100mg, 25mg or 5mg.
4. pharmaceutical composition according to claim 1 or 2, it is characterised in that described pharmaceutical composition also containing filler,
At least one of disintegrant, lubricant.
5. pharmaceutical composition according to claim 4, it is characterised in that the filler is selected from dextrin, lactose, sucrose, shallow lake
At least one of powder, pregelatinized starch, calcium monohydrogen phosphate, microcrystalline cellulose, the dosage of preferably described filler account for pharmaceutical composition
The 50~95% of object weight, more preferably 60~85%.
6. pharmaceutical composition according to claim 4, it is characterised in that the disintegrant is selected from cross-linked carboxymethyl fiber
In plain sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, starch, pregelatinized starch, alginic acid extremely
Few one kind, preferably is selected from croscarmellose sodium, crospovidone, and the dosage of the more preferable disintegrant accounts for pharmaceutical composition
The 2~15% of weight.
7. pharmaceutical composition according to claim 4, it is characterised in that the lubricant is selected from magnesium stearate, tristearin
At least one of acid, palmitic acid, calcium stearate, talcum powder, Brazil wax, sodium stearyl fumarate, preferably described lubricant
Dosage account for the 0.1~2% of pharmaceutical composition weight.
8. pharmaceutical composition according to claim 5, it is characterised in that the filler be lactose and microcrystalline cellulose, it is excellent
It is 2 to select the weight ratio of the lactose and microcrystalline cellulose:1~6:1, preferably 3:1~5:1.
9. according to claim 1-8 any one of them pharmaceutical compositions, contain following ingredient：
1) active constituent 2- ((S) -6- ((2', 6'- dimethyl -4'- (((R)-tetrahydrofuran -3- bases) oxygen of 3~30% weight
Base)-[1,1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid or its officinal salt, it is preferably described
The amount of active constituent at most 200mg, more preferably 100mg, 25mg or 5mg；
2) filler of 60~85% weight, the filler are lactose and microcrystalline cellulose, and preferably described lactose is fine with crystallite
The plain weight ratio of dimension is 3:1~5:1；
3) disintegrant of 2~15% weight, the disintegrant in croscarmellose sodium, sodium carboxymethyl starch extremely
Few one kind；
4) lubricant of 0.1~2% weight, the lubricant is at least one in magnesium stearate, stearic acid, Compritol 888 ATO
Kind.
10. pharmaceutical composition according to claims 1 to 9, it is characterised in that also containing coating in described pharmaceutical composition
Agent, plasticizer are protected from light at least one of agent, pigment, and it is fine that preferably described coating agent is selected from hydroxypropyl methyl cellulose, hydroxypropyl
Tie up at least one of element, polyvinyl alcohol, acrylic resin.
11. the method for claim 1~10 any one of them pharmaceutical composition is prepared, including：1) by active constituent or its can
Pharmaceutical salts are mixed with polyvinylpyrrolidone and optionally from least one of filler, disintegrant, lubricant excipient,
It 2) will be from tabletting after the granulating mixture 1) obtained or filling capsule, direct tablet compressing or direct filling capsule.
12. according to the method for claim 11, it is characterised in that coating steps, the packet are further included after the granulation step
Clothing agent is selected from least one of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, acrylic resin.
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| WO2013104257A1 (en) * | 2012-01-12 | 2013-07-18 | 江苏恒瑞医药股份有限公司 | Polycyclic derivatives, preparation method and medical uses thereof |
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