CN102107007B - Sterides anti-progestogen composition and preparation method thereof - Google Patents
Sterides anti-progestogen composition and preparation method thereof Download PDFInfo
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- CN102107007B CN102107007B CN2011100306600A CN201110030660A CN102107007B CN 102107007 B CN102107007 B CN 102107007B CN 2011100306600 A CN2011100306600 A CN 2011100306600A CN 201110030660 A CN201110030660 A CN 201110030660A CN 102107007 B CN102107007 B CN 102107007B
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- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 claims description 49
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- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 claims description 32
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Abstract
The invention provides a sterides anti-progestogen composition which comprises immediate-release pellets and sustained-release adhesive pellets, wherein the immediate-release pellet contains anti-progestogen, dispersing agent, disintegrating agent, filler and binder; and the sustained-release adhesive pellet contains the immediate-release pellet, sustained-release agent, adhesive agent, foaming agent and porogen. The anti-progestogen composition provided by the invention can promote absorption of sterides anti-progestogen medicine and improve bioavailability and curative effect.
Description
Technical field
The invention of these article relates to a kind of steroidal onapristone compositions and comprises the preparation of said composition, and said composition and pharmaceutical preparation comprise fast release micropill and slow release sticks micropill.Anti-progesterone drug preparation of the present invention can make gestation fully absorb at gastric, has improved bioavailability, has reduced untoward reaction.
Background technology
Gestation can combine with progesterone receptor, has termination of early pregnancy, anti-implantation, induces effects such as menstruation and promotion cervix maturation.Successfully developed at present and go on the market mifepristone, the excellent Li Pusi ketone of acetic acid (CDB-2914) arranged, symipristone (cymipristone), CDB-4124 etc. are still under study for action in addition.The excellent Li Pusi ketone of mifepristone and acetic acid all can be used as emergency contraception and uses, and numerous women are benefited.Symipristone developing at present with misoprostol unite be used for the miscarriage, make the women avoid the hardship of artificial abortion.
Wherein, in year surplus the mifepristone listing has had 20, clinical research is also quite a lot of.Discover that the individual variation of mifepristone is very big, carry out human bioavailability research like the sample that adopts the mifepristone preparation preparation, the AUC standard deviation value is greater than 30%.AUC individual variation huge also caused the significant difference of clinical effectiveness.
Clinical trial shows that the mifepristone oral administration biaavailability is about 70%; There is 30% medicine not to be absorbed approximately; The inventor is through discover in a large number; Mainly contain following 2 reasons: 1) dissolubility of mifepristone o'clock has higher dissolubility in pH＜3, but when pH increases to 3, significantly reduces, and particularly 4 do not dissolve when above basically.After mifepristone is oral, have the part medicine as yet not stomach just dissociate by fast evacuation to intestinal because the pH value higher (＞4) of intestinal, the mifepristone that gets into intestinal can not dissolve, thereby can not be absorbed by the body.2) the part mifepristone dissolves at gastric fully, because of the still unabsorbed mifepristone of fast evacuation part directly is emptied to intestinal, because the intestinal pH value significantly raises, causes dissolved mifepristone after getting into intestinal, to be separated out once more, thereby can not be absorbed by the body.
Also there is same problem in steroidal gestations such as CDB-2914, symipristone, CDB-4124.Dissolve and absorb dependency in order to solve gestation to pH, the problem that bioavailability is low, domestic scholars provides following solution at present:
CN 1311000A discloses a kind of mifepristone capsule and preparation method thereof, it is characterized in that mifepristone is present in the pharmaceutical preparation with the solution form, and when medicine got into stomach release, after the soft gelatin capsule dissolving, mifepristone discharged rapidly.But the limited absorbability of stomach can't absorb dissolved mifepristone fully at short notice, and absorption portion can not separated out once more and can't absorb because of dissolubility is low after getting into intestinal, and bioavailability improves few.
CN1846703A discloses a kind of vagina administration mifepristone preparation and method for preparing, and its characteristics are that the mifepristone transvaginal absorbs, and can avoid the first pass effect of liver, improve bioavailability of medicament.But also there is the shortcoming of the difference that vagina absorbs between medication inconvenience and individuality in it.
Clinical research shows that also the bioavailability of vagina administration mifepristone is starkly lower than the bioavailability of oral administration.(Pharmacokinetics?of?Mifepristone?following?intragastric?or?Vaginal?Administration?in?Rats?by?High?Performance?Liguid?Chromatography)。
CN200780048031.2 discloses a kind of method and formulation of gestation, and its characteristics are that the non-aqueous solution with gestation is sprayed onto on the carrier matrix carefully and prepare.The purpose of this invention is to improve the bioavailability of gestation, but from description, can not find any data about the raising bioavailability, therefore can't judge whether to have realized this purpose.
Do not find other scheme as yet about the raising bioavailability of other gestations such as raising mifepristone, CDB-2914, symipristone and CDB-4124.
Above-mentioned all patents all conducting a research around same main body, promptly improve the dissolution of medicine, thereby improve the absorption of medicine, improve bioavailability.Yet above-mentioned patent is not all recognized the gestation dissolubility to the dependent problem of pH, can not solve gestation and get into behind the intestinal because of dissolubility reduces the problem of separating out again because of gastric emptying, so bioavailability does not significantly improve.
Summary of the invention
The present invention seeks in order to solve the gestation that exists in the prior art owing to dissolve and absorb dependency pH; Cause the low problem of bioavailability; A kind of new onapristone compositions is provided, and this pharmaceutical composition comprises that fast release micropill and slow release stick micropill two parts.After human body was taken, only the slow micropill of speed rapid release under one's belt reached onset concentration immediately, and slow release sticks micropill and is attached on gastric and slowly discharges, and increases gestation in the holdup time of stomach, makes most of gestation discharge fully and absorb at stomach.While gestation compositions provided by the invention; Also improved the dissolubility of gestation greatly at higher pH value (3-5); Even therefore there is the gestation of part molecularity to get into intestinal; Can not separate out once more yet, thereby gestation is fully absorbed, improve bioavailability and reduce untoward reaction because of dissolubility reduces.
Therefore, one of the object of the invention provides a kind of onapristone compositions, and it comprises that fast release micropill and slow release stick micropill two parts, and wherein both weight ratios are preferably 0.29-2.21: 1, wherein comprise in the fast release micropill gestation, dispersant,
Disintegrating agent, filler and binding agent; Slow release sticks and comprises described fast release micropill, slow releasing agent, binder, foaming agent and porogen in the micropill.
Preferably; A kind of onapristone compositions provided by the invention; It comprises that weight ratio is 0.29-2.21: 1 fast release micropill and slow release stick micropill two parts, wherein comprise gestation, dispersant, disintegrating agent, filler and binding agent that weight ratio is 4-50: 0-67: 0-33: 4-90: 0.5-5 in the fast release micropill; Slow release sticks and comprises weight ratio in the micropill is the described fast release micropill of 70-95: 4-16: 1-10: 0-5: 0-5, slow releasing agent, binder, foaming agent and porogen.
In the onapristone compositions that the invention described above provides, comprise gestation, dispersant, disintegrating agent, filler and binding agent that weight ratio is 4-50: 0-67: 0-33: 4-90: 0.5-5 in the fast release micropill; More preferred weight ratio is 10-30: 10-40: 5-10: 10-50: 0.5-2, and most preferred weight ratio is 20-25: 25-30: 5-10: 35-40: 0.5-2:.
In the onapristone compositions that the invention described above provides; Slow release sticks and comprises weight ratio in the micropill is the said fast release micropill of 70-95: 4-16: 1-10: 0-2: 0-2, slow releasing agent, binder, foaming agent and porogen; More preferred weight ratio is 80-90: 6-12: 4-8: 0-2: 0-2, and most preferred weight ratio is 80-90: 6-12: 4-8: 0: 0.
The gestation that is suitable among the present invention is preferably the chemical compound with structure general formula:
Wherein
R
1Be to be selected from following group :-N (CH
3)
2,-NHCH
3,-NC4H
8,-NC
5H
10Or-NC
4H8
O
R
2Be selected from hydrogen, halogen, alkyl, acyl group, hydroxyl, alkoxyl, acyloxy, the alkyl carbonate base encircles penta propiono oxygen base, S-alkyl, SCN, S-acyl group or OC (O) R
6, R wherein
6Be to be selected from alkyl, alkoxy ester or alkoxyl;
R
3Be selected from alkyl-alkoxyl or acyloxy; R4 is selected from hydrogen or alkyl;
X is selected from=O and=N-OR
5, R wherein
5Be selected from hydrogen or alkyl.
Being suitable for the most preferred gestation of the present invention is mifepristone, symipristone, CDB-2914, CDB-4124 etc.
In the onapristone compositions of the present invention, the dispersant that is suitable in the said fast release micropill is selected from: CELUCIRE 35/10,37/02,44/14,50/13, WL2514CS, LABRASOL, PEG8000, PEG6000, PEG4000, poloxamer, hydroxypropyl emthylcellulose (HPMC), hydrogenated vegetable Oleum Ricini one or more; Most preferably PEG8000, PEG6000, PEG4000.
In the onapristone compositions of the present invention; The disintegrating agent that is suitable in the said fast release micropill is selected from one or more in carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose (L-HPC), the cross-linking sodium carboxymethyl cellulose, more preferably carboxymethyl starch sodium and/or cross-linking sodium carboxymethyl cellulose.
In the onapristone compositions of the present invention, be suitable for filler in the said fast release micropill and be selected from: one or more mixing in microcrystalline Cellulose, lactose, starch, Icing Sugar, the dextrin, more preferably microcrystalline Cellulose.
In the onapristone compositions of the present invention, suitable adhesive is selected from one or more mixing of low-viscosity hydroxypropylmethylc,llulose, hydroxypropyl cellulose, polyvinylpyrrolidone in the said fast release micropill.
In the onapristone compositions of the present invention; Said slow release sticks slow releasing agent in the micropill and is selected from polyacrylic resin, ethyl cellulose, cellulose acetate-phthalate (CAP), the phthalic acid hypromellose (HPMCP) one or more, preferably polyacrylic resin.
In the onapristone compositions of the present invention, said slow release sticks porogen in the micropill and is selected from one or more of water soluble adjuvants such as lactose, Icing Sugar, PEG, preferably Icing Sugar.
In the onapristone compositions of the present invention, said slow release sticks that foaming agent is selected from carbonate in the micropill, comprises but is not limited in sodium carbonate, sodium bicarbonate, the calcium carbonate one or more.Sodium carbonate preferably.
In the onapristone compositions of the present invention; Said slow release sticks that binder is selected from hydroxypropyl emthylcellulose, hyprolose in the micropill; In carbomer, polyvidone, polypropylene acid resin, gelatin, xanthan gum, the sodium carboxymethyl cellulose one or more, preferred hydroxypropyl emthylcellulose and/or carbomer.
In the onapristone compositions of the present invention; Except fast release micropill and slow release stick the micropill, also can add other molding adjuvant such as lubricant, filler, disintegrating agent: comprise stearic acid, magnesium stearate, Pulvis Talci, micropowder silica gel, pregelatinized Starch, lactose, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose (L-HPC), cross-linking sodium carboxymethyl cellulose etc.
Onapristone compositions of the present invention, to stick the diameter of the ball of micropill be 0.2mm～2mm for fast release micropill and slow release in more preferred scheme.
It is the gestation of 300nm～500 μ m that gestation of the present invention is preferably through micronized particle diameter, specifically can comprise mifepristone, symipristone, CDB-2914, CDB-4124 etc.
The weight ratio that onapristone compositions of the present invention, the fast release micropill of individualism and slow release stick the fast release micropill that exists in the micropill is 3: 7-7: 3.
Another object of the present invention provides a kind of anti-progesterone drug preparation of compositions method of the present invention; It comprises the preparation of fast release micropill and the preparation that slow release sticks micropill; The wherein preparation of fast release micropill; Method one: gestation, disintegrating agent are joined in the dispersant of heating and melting, behind the mix homogeneously, spray cooling is granulated; Dried particles mixes with filler, binding agent, adds entry or organic solvent such as ethanol water system soft material again, extrudes, and places round as a ball pot round as a ball, and discharging is drying to obtain fast release micropill; Method two: gestation is joined in the dispersant of heating and melting, behind the mix homogeneously, spray cooling is granulated; Dried particles mixes with disintegrating agent, filler, binding agent, adds entry or organic solvent such as ethanol water system soft material again, extrudes, and places round as a ball pot round as a ball, and discharging is drying to obtain fast release micropill; Method three: gestation joined be dispersed in water or organic solvent such as the alcoholic acid dispersant, behind the mix homogeneously, spray-drying process; Dried particles is mixed with filler, disintegrating agent, binding agent; Add entry or ethanol water system soft material again, extrude, place round as a ball pot round as a ball; Discharging is drying to obtain fast release micropill; Wherein said slow release sticks the micropill preparation:
5) get slow releasing agent, foaming agent, porogen is water-soluble or organic solvent such as ethanol in preparation sustained release coating liquid,
6) get and add water preparation after binder is scattered in organic solvent such as the ethanol and stick coating solution,
7) get fast release micropill as the ball core, be drying to obtain slow-release micro-pill at the outer bag of ball core sustained release coating liquid,
8) wrap again at the slow-release micro-pill skin and stick coating solution, be drying to obtain slow release and stick micropill,
Fast release micropill and slow release are sticked the micropill proportional mixing promptly get onapristone compositions of the present invention.
The present invention also provides capsule or the tablet with the said anti-progesterone drug preparation of compositions of invention.Contain the gestation promotor composition capsular the time in preparation, can the gestation compositions directly be incapsulated shell by specification and promptly get.
When preparation contains the gestation composition tablet, can get gestation compositions and a certain amount of molding adjuvant such as lubricant, filler and disintegrating agent and mix, tabletting promptly gets.Lubricant wherein commonly used includes but not limited to be magnesium stearate, stearic acid, Pulvis Talci, micropowder silica gel; Filler commonly used includes but not limited to adjuvants such as starch, lactose starch, mannitol, microcrystalline Cellulose; Disintegrating agent commonly used includes but not limited to that carboxymethyl starch is received, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone etc.
The compositions of gestation provided by the invention; Wherein fast release micropill can rapid release; Guarantee that medicine can reach onset concentration fast; And slow release sticks micropill through slowly release, thereby prolongs gestation in the holdup time of gastric, and most of gestation is fully absorbed at the gastric of low pH value.Gestation compositions provided by the invention and preparation have improved the dissolubility of gestation when higher pH value (＞3) simultaneously; Therefore the gestation that can avoid getting into intestinal is separated out once more; The gestation that gets into intestinal also can fully be absorbed, improve bioavailability.In addition,, the higher crowd of part stomach inner pH value also can fully be absorbed, thereby reduce individual variation owing to improved the dissolubility under the higher pH value.The present invention is sticked the ratio of micropill through control fast release micropill and slow release and is sticked micropill and realize the control to drug releasing rate through selecting for use specific accessories to prepare fast release micropill and slow release.
With the tablet or the capsule of gestation compositions provided by the invention or preparation, compare with existing gestation preparation and to have following characteristics:
(1) gestation compositions provided by the invention; Contain a certain proportion of fast release micropill and slow release and stick micropill; Can control medicine part rapid release and absorption, a part slowly discharges and absorbs, thereby guarantees that medicine is after reaching drug effect concentration fast; Can keep stable blood drug level the long period, avoid the too high side effect that brings of local drug concentration perhaps to reduce the absorption of medicine.
(2) gestation compositions provided by the invention, its blood drug level is more steady with respect to existing gestation preparation.
(3) gestation compositions provided by the invention can improve the bioavailability that has the gestation preparation now.
(4) gestation compositions provided by the invention can reduce individual variation.
Gestation compositions of the present invention or contain said composition preparation the day using dosage be 5-50mg.
Description of drawings
Fig. 1. sample 1-6 mifepristone preparation and the comparative study of common mifepristone sheet dissolution curve.
Embodiment
Below in conjunction with specific embodiment the present invention is elaborated, embodiment provided by the present invention understands technical scheme provided by the present invention in order to help, and can not limit protection scope of the present invention; The multitude of different ways that the present invention can be defined by the claims and cover is implemented.
Embodiment 1:
(1) preparation of fast release micropill:
To get micronized particle diameter be 2 μ m gestation mifepristone 40g, join among the dispersant polyethylene glycol 6000 32g of heating and melting, and behind the mix homogeneously, spray cooling is granulated; Dried particles mixes with disintegrating agent carboxymethyl base Starch Sodium and each 18g of cross-linking sodium carboxymethyl cellulose, filler lactose 72g, binding agent low substituted hydroxy-propyl methylcellulose 8g; Add organic solvent ethanol water system soft material again; Extruding orifice plate with 0.5mm extrudes; Place round as a ball pot round as a ball rapidly, discharging is drying to obtain fast release micropill 188g.
(2) slow release sticks the preparation of micropill:
Get slow releasing agent polyacrylic acid resin 4g, be dissolved in and be prepared into sustained release coating liquid in the organic solvent ethanol.Get fast release micropill 120g that step 1 makes as the ball core, at the outer bag of ball core one deck sustained release coating liquid, slow-release micro-pill.Other gets and adds water after binder HPMCK100M and each 3g of carbomer 974P are scattered in the organic solvent ethanol and prepare and stick coating solution.Get slow-release micro-pill, wrap one deck again at the slow-release micro-pill skin and stick coating solution, be drying to obtain slow release and stick micropill 130.6g.
(3) get fast release micropill 60g, slow release sticks micropill 130.6g and mixes, and incapsulates in the shell by containing gestation mifepristone 25mg/ grain, promptly gets sample 1.
Embodiment 2:
1) preparation of fast release micropill:
Get among the dispersant poloxamer 40g that gestation mifepristone 20g, disintegrating agent carboxymethyl base Starch Sodium and each 10g of cross-linking sodium carboxymethyl cellulose join heating and melting, behind the mix homogeneously, spray cooling is granulated; Dried particles mixes with filler microcrystalline Cellulose 380g, the low HPMC30g that replaces of binding agent, adds a certain amount of water system soft material again, extrudes orifice plate with 0.4mm and extrudes, and places round as a ball pot round as a ball rapidly, and discharging is drying to obtain fast release micropill 490g.
2) slow release sticks the preparation of micropill:
Get and add water after slow releasing agent cellulose acetate-phthalate 40g, foaming agent sodium bicarbonate 10g, porogen Icing Sugar 20g are scattered in the organic solvent ethanol and prepare sustained release coating liquid.Other gets binder polyvidone 20g, is dissolved in preparing in the organic solvent ethanol sticking coating solution.Get fast release micropill 300g that step 1 makes as the ball core, at the outer bag of ball core one deck sustained release coating liquid, slow-release micro-pill.Get slow-release micro-pill, wrap one deck again at the slow-release micro-pill skin and stick coating solution, be drying to obtain slow release and stick micropill.
3) get fast release micropill 180g, slow release sticks micropill 390g and mixes, and adds filler lactose starch 500g, lubricant stearic acid 5g and disintegrating agent crospolyvinylpyrrolidone 50g, by containing gestation mifepristone 25mg/ sheet tabletting, promptly gets sample 2.
Embodiment 3:
Method for preparing is with embodiment 1, mifepristone 60g, and wherein dispersant replaces with Polyethylene Glycol 800012g; Disintegrating agent replaces with crospolyvinylpyrrolidone 6g, and filler replaces with Icing Sugar 90g, and binding agent replaces with PVP K3033g; Slow releasing agent replaces with ethylcellulose dispersion 9g; Foaming agent replaces with calcium carbonate 0.3g, and porogen replaces with Polyethylene Glycol 0.6g, and binder replaces with xanthan gum 9g.
Get fast release micropill 81g, slow release sticks micropill 129g and mixes, and incapsulates in the shell by containing gestation mifepristone 25mg/ grain, promptly gets sample 3.
Embodiment 4:
Method for preparing is with embodiment 1, and wherein gestation replaces with mifepristone 10g, and dispersant replaces with Polyethylene Glycol 8000140g; Disintegrating agent replaces with carboxymethyl starch and receives 20g, and filler replaces with dextrin 80g, and binding agent replaces with low-viscosity hydroxypropylcelluloand 5g; Slow releasing agent replaces with phthalic acid hypromellose 20g; Foaming agent replaces with sodium carbonate 6g, and porogen replaces with Icing Sugar 5g, and binder replaces with polyacrylic resin 15g.
Get fast release micropill 120g, slow release sticks micropill 166g and mixes, and incapsulates in the shell by containing gestation mifepristone 25mg/ grain, promptly gets sample 4.
Embodiment 5:
Method for preparing is with embodiment 1, and wherein gestation replaces with mifepristone 100g, and dispersant replaces with hydrogenated vegetable Oleum Ricini 10g; Disintegrating agent replaces with cross-linking sodium carboxymethyl cellulose 10g, and filler replaces with Icing Sugar 60g, and binding agent replaces with PVP K3020g; Slow releasing agent replaces with ethyl cellulose 20g; Foaming agent replaces with sodium bicarbonate 4g, and porogen replaces with lactose 4g, and binder replaces with carbomer 974P 1g.
Get fast release micropill 100g, slow release sticks micropill 99g and mixes, and incapsulates in the shell by containing gestation mifepristone 25mg/ grain, promptly gets sample 5.
Embodiment 6:
Method for preparing is with embodiment 1, and wherein gestation replaces with mifepristone 10g, and dispersant replaces with Macrogol 4000 10g; Disintegrating agent replaces with crospolyvinylpyrrolidone 10g, and filler replaces with dextrin 220g, and binding agent replaces with low-viscosity hydroxypropylmethylc,llulose 10g; Slow releasing agent replaces with polyacrylic resin 5g; Foaming agent does not add, and porogen does not add, and binder replaces with hydroxypropyl emthylcellulose 8g.
Get fast release micropill 150g, slow release sticks micropill 113.2g and mixes, and incapsulates in the shell by containing gestation mifepristone 25mg/ grain, promptly gets sample 6.
Embodiment 7:
Method for preparing is with embodiment 1, and wherein gestation replaces with CDB-412480g, and dispersant replaces with Polyethylene Glycol 800072g; Disintegrating agent replaces with crospolyvinylpyrrolidone 40g, and filler replaces with microcrystalline Cellulose 32g, and binding agent replaces with PVPK304g; Slow releasing agent replaces with phthalic acid hypromellose 32; Foaming agent replaces with calcium carbonate 10g, and porogen replaces with Macrogol 4000 8g, and binder replaces with sodium carboxymethyl cellulose 16g.
Get fast release micropill 140g, slow release sticks micropill 168g and mixes, and incapsulates in the shell by containing the CDB-412425mg/ grain, promptly gets sample 7.
Embodiment 8:
Method for preparing is with embodiment 1, and wherein gestation replaces with CDB-291460g, and dispersant replaces with polyethylene glycol 6000 160g; Disintegrating agent replaces with crospolyvinylpyrrolidone 20g, and filler replaces with lactose 20g, and binding agent does not add; Slow releasing agent replaces with O-phthalic cellulose acetate 8; Foaming agent does not add, and porogen replaces with Icing Sugar 1g, and binder replaces with polyvidone 1g.
Get fast release micropill 180g, slow release sticks micropill 88g and mixes, and incapsulates in the shell by containing the CDB-291425mg/ grain, promptly gets sample 8.
Embodiment 9:
Method for preparing is with embodiment 1, and wherein gestation replaces with symipristone 30g, and dispersant replaces with polyethylene glycol 6000 60g; Disintegrating agent replaces with cross-linking sodium carboxymethyl cellulose 50g, and filler replaces with microcrystalline Cellulose 60g, and binding agent replaces with low-viscosity hydroxypropylmethylc,llulose 4g; Slow releasing agent replaces with polyacrylic resin 10g; Foaming agent does not add, and porogen does not add, and binder replaces with carbomer 8g.
Get fast release micropill 130g, slow release sticks micropill 88g and mixes, and incapsulates in the shell by containing symipristone 25mg/ grain, promptly gets sample 9.
Embodiment 10:
Method for preparing is with embodiment 1, and wherein gestation replaces with CDB-412430g, and dispersant replaces with Polyethylene Glycol 800020g; Disintegrating agent replaces with crospolyvinylpyrrolidone 20g; Filler replaces with dextrin 80g, and binding agent replaces with low-substituted hydroxypropyl cellulose 7g, and slow releasing agent replaces with polyacrylic resin 9g; Foaming agent and porogen do not add, and binder replaces with polyvidone 4g.
Get fast release micropill 90g, slow release sticks micropill 58g and mixes, and incapsulates in the shell by containing the CDB-412425mg/ grain, promptly gets sample 10.
Experimental result:
Since at present in the gestation only mifepristone listing is arranged at home, so we select the gestation compositions that contains mifepristone provided by the invention or its preparation contrast experiment that be correlated with, commercially available mifepristone sheet (the 25mg/ sheet contrasts 1) is selected in contrast for use
1, pharmacy test
1.1 dissolution determination experiment
(1) embodiment 1-6 sample and the dissolution curve comparative study that contrasts 1.
Method: measure according to 2010 editions mifepristone sheets of Chinese Pharmacopoeia assay method.It is dissolution medium that former method adopts 0.1mol/L hydrochloric acid solution 900ml, and adopting the phosphate buffer 900ml of PH4.0 in this test is dissolution medium, and all the other conditions are with former assay method.
Adopt above-mentioned dissolution determination method that embodiment 1 to 6 sample is carried out the dissolution comparative study, experimental result shows that sample dissolution curve ratio provided by the present invention is consistent.The result of dissolution curve comparative study can draw as drawing a conclusion: compare with contrast 1; Mifepristone preparation provided by the invention can prolong dissolution time; But final total dissolution all about 90%, is significantly higher than contrast 1, explains that this technology can improve the dissolution of mifepristone.The result sees Fig. 1.
1.2 solubility experiment
PH value through regulator solution; Investigate embodiment sample 1-6 and contrast the variation of 1 mifepristone dissolubility with PH, be used to simulate mifepristone and be emptied to the change that dissolubility takes place along with the variation of internal milieu behind the intestinal by stomach, the result shows when P H≤1; The dissolubility of sample 1-6 is 100% with the dissolubility of contrast 1; But when PH was increased to 3.0,4.0 and 5.0, the dissolubility of sample 1-6 was significantly higher than contrast 1, even therefore have the part gestation to be emptied to intestinal; Sample 1-6 also can be good at absorbing, and contrasts 1 because the dissolubility reduction can not absorb.
Embodiment sample 1-6 and contrast 1 dissolubility (%) research
2, pharmacodynamic experiment
1.1 the antiearly pregnancy effect of mifepristone capsule (contrast) is measured
Get pregnant rat and contrast 1, every day 1 time, totally 3 times in pregnant 7-9 days according to the form below dosage filling stomaches.Gestation was observed embryo's situation on the 14th day, and measuring half has quantity (ED
50) result sees the following form:
Can know the ED of contrast 1 from last table
50Be 63.238 μ g/kg.
1.2 (method is with 1.1) are compared in the antiearly pregnancy effect of (63ug/kg) under the same dose of embodiment sample 1-6 and commercially available mifepristone sheet (contrast 1)
The mifepristone antiearly pregnancy effect of same dose
| Sample | The animal (n) of becoming pregnant | The inhibition (n) of becoming pregnant | The suppression ratio of becoming pregnant |
| 1 | 20 | 14 | 70％ |
| 2 | 20 | 13 | 65％ |
| 3 | 20 | 10 | 50％ |
| 4 | 20 | 12 | 60％ |
| 5 | 20 | 12 | 60％ |
| 6 | 20 | 10 | 50％ |
| Contrast 1 | 20 | 9 | 45.5％ |
The above results is illustrated under the identical dosage, and the suppression ratio of becoming pregnant of embodiment of the invention sample all is higher than contrast, has improved effective percentage.
1.3 (method is with 1.1) are measured in the antiearly pregnancy effect of embodiment of the invention 1-6 product
Can know that from last table the median effective dose of sample provided by the present invention (ED50) comparison significantly reduces according to 1, has improved effective percentage.
In conjunction with more than; Gestation compositions provided by the present invention; The gestation product (as contrasting 1) of existing relatively listing; Through implementation part immediate release section slow release, improve gestation dissolubility and release degree when higher pH value (3-5) simultaneously, finally play and improve bioavailability and efficient effect.
Claims (16)
1. onapristone compositions; It comprises that weight ratio is 0.29-2.21: 1 fast release micropill and slow release stick micropill two parts, wherein comprise gestation, dispersant, disintegrating agent, filler and binding agent that weight ratio is 4-50: 0-67: 0-33: 4-90: 0.5-5 in the fast release micropill; Slow release sticks and comprises weight ratio in the micropill is the described fast release micropill of 70-95: 4-16: 1-10: 0-5: 0-5, slow releasing agent, binder, foaming agent and porogen,
Wherein:
Gestation is mifepristone, symipristone, CDB-2914 or CDB-4124;
Dispersant is one or more in CELUCIRE 35/10,37/02,44/14,50/13, WL2514CS, LABRASOL, PEG8000, PEG6000, PEG4000, poloxamer, hydroxypropyl emthylcellulose, the hydrogenated vegetable Oleum Ricini;
Disintegrating agent is one or more in carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, the cross-linking sodium carboxymethyl cellulose;
Filler is one or more mixing in microcrystalline Cellulose, lactose, starch, Icing Sugar, the dextrin;
Binding agent is one or more mixing in low-viscosity hydroxypropylmethylc,llulose, hydroxypropyl cellulose, the polyvinylpyrrolidone;
Slow releasing agent is one or more in polyacrylic resin, ethyl cellulose, cellulose acetate-phthalate, the phthalic acid hypromellose;
Binder is hydroxypropyl emthylcellulose, hyprolose, one or more in carbomer, polyvidone, polyacrylic resin, gelatin, xanthan gum, the sodium carboxymethyl cellulose;
Porogen is one or more among lactose, Icing Sugar, the PEG;
Foaming agent is one or more in sodium carbonate, sodium bicarbonate, the calcium carbonate.
2. onapristone compositions as claimed in claim 1 wherein comprises gestation, dispersant, disintegrating agent, filler and binding agent that weight ratio is 10-30: 10-40: 5-10: 10-50: 0.5-2 in the fast release micropill; Slow release sticks and comprises weight ratio in the micropill is the described fast release micropill of 80-90: 6-12: 4-8: 0-2: 0-2, slow releasing agent, binder, foaming agent and porogen.
3. onapristone compositions as claimed in claim 2 wherein comprises gestation, dispersant, disintegrating agent, filler and binding agent that weight ratio is 20-25: 25-30: 5-10: 35-40: 0.5-2 in the fast release micropill; Slow release sticks and comprises weight ratio in the micropill is 80-90: 6-12: 4-8: 0: 0 described fast release micropill, slow releasing agent, binder, foaming agent and porogen.
4. onapristone compositions as claimed in claim 3 is characterized in that the dispersant described in the fast release micropill is selected from: PEG8000, PEG6000, PEG4000.
5. onapristone compositions as claimed in claim 4 is characterized in that the disintegrating agent described in the fast release micropill is carboxymethyl starch sodium and/or cross-linking sodium carboxymethyl cellulose.
6. onapristone compositions as claimed in claim 5 is characterized in that the filler described in the fast release micropill is a microcrystalline Cellulose.
7. onapristone compositions as claimed in claim 6 is characterized in that it is polyacrylic resin that slow release sticks the slow releasing agent described in the micropill.
8. onapristone compositions as claimed in claim 7 is characterized in that it is Icing Sugar that slow release sticks the porogen described in the micropill.
9. onapristone compositions as claimed in claim 8 is characterized in that it is sodium carbonate that slow release sticks the foaming agent described in the micropill.
10. onapristone compositions as claimed in claim 9 is characterized in that it is hydroxypropyl emthylcellulose and/or carbomer that slow release sticks the binder described in the micropill.
11. onapristone compositions as claimed in claim 10 is characterized in that the diameter that fast release micropill and slow release stick the ball of micropill is 0.2mm～2mm.
12. onapristone compositions as claimed in claim 11 is characterized in that the fast release micropill of individualism in this pharmaceutical composition and the weight ratio that slow release sticks the fast release micropill that exists in the micropill are 3: 7-7: 3.
13. onapristone compositions as claimed in claim 12, it is capsule or tablet.
14. one kind like any described anti-progesterone drug preparation of compositions of the claim method of claim 1-13; It comprises the preparation of fast release micropill and the preparation that slow release sticks micropill; The wherein preparation of fast release micropill; Method one: gestation, disintegrating agent are joined in the dispersant of heating and melting, behind the mix homogeneously, spray cooling is granulated; Dried particles mixes with filler, binding agent, adds entry or ethanol water system soft material again, extrudes, and places round as a ball pot round as a ball, and discharging is drying to obtain fast release micropill; Method two: gestation is joined in the dispersant of heating and melting, behind the mix homogeneously, spray cooling is granulated; Dried particles mixes with disintegrating agent, filler, binding agent, adds entry or ethanol water system soft material again, extrudes, and places round as a ball pot round as a ball, and discharging is drying to obtain fast release micropill; Method three: gestation joined be dispersed in water or the alcoholic acid dispersant, behind the mix homogeneously, spray-drying process; Dried particles is mixed with filler, disintegrating agent, binding agent; Add entry or ethanol water system soft material again, extrude, place round as a ball pot round as a ball; Discharging is drying to obtain fast release micropill; Wherein said slow release sticks the micropill preparation:
1) get slow releasing agent, foaming agent, porogen is water-soluble or ethanol in preparation sustained release coating liquid,
2) get and add water preparation after binder is scattered in the ethanol and stick coating solution,
3) get fast release micropill as the ball core, be drying to obtain slow-release micro-pill at the outer bag of ball core sustained release coating liquid,
4) wrap again at the slow-release micro-pill skin and stick coating solution, be drying to obtain slow release and stick micropill,
Fast release micropill and slow release are sticked the micropill proportional mixing promptly get onapristone compositions of the present invention.
15. anti-progesterone drug preparation of compositions method as claimed in claim 14 is sticked micropill with fast release micropill and slow release and is mixed by weight proportion and incapsulate shell and promptly get capsule.
16. anti-progesterone drug preparation of compositions method as claimed in claim 14, with the fast release micropill of certain weight ratio and slow release sticks micropill and lubricant, filler, disintegrating agent mix, tabletting promptly gets tablet.
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|---|---|---|---|
| CN2011100306600A CN102107007B (en) | 2011-01-28 | 2011-01-28 | Sterides anti-progestogen composition and preparation method thereof |
| PCT/CN2011/083853 WO2012083801A1 (en) | 2010-12-20 | 2011-12-12 | Streoidal anti-progesterone composition, preparation method therefor, and use thereof |
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| CN2011100306600A CN102107007B (en) | 2011-01-28 | 2011-01-28 | Sterides anti-progestogen composition and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1408356A (en) * | 2002-09-05 | 2003-04-09 | 上海医药工业研究院 | Composition of mifepristone semi-solid skeleton preparation |
| EP1987820A1 (en) * | 2007-05-04 | 2008-11-05 | Christian Fiala, Ph. D. | Slow release misoprostol for obstetric and/or gynaecological applications |
| CN101455671A (en) * | 2009-01-08 | 2009-06-17 | 湖北葛店人福药业有限责任公司 | Mifepristone medicinal preparation and preparation method thereof |
-
2011
- 2011-01-28 CN CN2011100306600A patent/CN102107007B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1408356A (en) * | 2002-09-05 | 2003-04-09 | 上海医药工业研究院 | Composition of mifepristone semi-solid skeleton preparation |
| EP1987820A1 (en) * | 2007-05-04 | 2008-11-05 | Christian Fiala, Ph. D. | Slow release misoprostol for obstetric and/or gynaecological applications |
| CN101455671A (en) * | 2009-01-08 | 2009-06-17 | 湖北葛店人福药业有限责任公司 | Mifepristone medicinal preparation and preparation method thereof |
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