CN102836155A - Medicinal composition containing pramipexole - Google Patents
Medicinal composition containing pramipexole Download PDFInfo
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- CN102836155A CN102836155A CN2012103157725A CN201210315772A CN102836155A CN 102836155 A CN102836155 A CN 102836155A CN 2012103157725 A CN2012103157725 A CN 2012103157725A CN 201210315772 A CN201210315772 A CN 201210315772A CN 102836155 A CN102836155 A CN 102836155A
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- pramipexole
- mannitol
- corn starch
- pharmaceutical composition
- magnesium stearate
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Abstract
The invention provides a medicinal composition containing pramipexole and a preparation method. The composition provided by the invention is a tablet prepared by dried solid particles containing pramipexole and a pharmaceutically acceptable adjuvant which is not contained in the particles. The tablet is strong in stability and apt to industrial production.
Description
Technical field:
The present invention relates to field of medicaments, be specifically related to a kind of solid composite medicament that contains pramipexole and preparation method thereof, said composition presents high storage stability.
Background technology:
Pramipexole is a kind of known d2 dopamine receptor agonist.It structurally is different from the medicine (for example, bromocriptine (bromocriptine) or pergolide (pergolide)) that is derived from ergotin.It also is unique on the pharmacology, and it has receptor-selective for full agonist and to the dopamine D 2 family of dopamine receptor.Pramipexole is disclosed in the United States Patent (USP) No. 4731374, No. 4843086 and No. 4886812 at first.
Pramipexole dihydrochloride monohydrate (molecular formula C
10H
17N
3S.2HCl.H
2O relative molecular mass 302.26).
Commercially available pramipexole dihydrochloride monohydrate tablet, normal temperature storage is after 18 months, and drug content is reduced to about 95%, thereby has shortened its effect duration greatly, for the circulation and the use of medicine brought inconvenience.
Pramipexole is in when solid-state highly stable, but its easy moisture absorption, however it has heliosensitivity when being in solution state, is unfavorable for preserving.
Chinese patent 200780031523.0 discloses a kind of method for preparing of pramipexole dihydrochloride tablets; This prescription is mainly become to be grouped into by intragranular film-making composition, pramipexole dihydrochloride particulate mixtures and the outer film-making of grain; This method prepares in the process; Preparation does not earlier contain intragranular film-making composition, adds the pramipexole dihydrochloride particulate mixtures again, again with the outer film-making reagent mix of grain after tabletting.This method is before pelletizing press sheet; Moisture to particulate mixtures has strict demand; Require its granular mixed thing to be dried to 1.0% to about 2.5% end point moisture content, could with the outer film-making reagent mix tabletting of grain, and this tablet manufacture at least a portion is in sealing system, to implement; Environment to producing has very high requirement, is unfavorable for commercial production.
The production technology that present commercially available article adopt should be the fluidized bed granulation technology of sealing, and ultimate principle also is a wet granulation technology, and needs the fluidized bed granulation technology of sealing; Be sprayed at pelletize on the adjuvant in the fluid bed; And carry out online drying, perhaps the tabletting process has strict restriction to moisture
The present invention provides a kind of pramipexole pharmaceutical composition, and it is highly stable to consider that pramipexole is in when solid-state, yet it has heliosensitivity when being in solution state, carries out tabletting after will adopting dry granulation, and used adjuvant process need not carried out biological function explore.Used adjuvant is solid-state; Overcome known available hydrate preparation heliosensitivity problem; With respect to Chinese patent 200780031523.0 disclosure technical problem, the present invention does not need to control the moisture before the tabletting is strict separately, and all production processes all do not need in sealing system, to implement especially; The tablet stability of producing is strong, is easy to the big production of industry.
Summary of the invention:
The object of the invention is to provide a kind of good stability, reliable in quality, safe pramipexole pharmaceutical composition.
Compositions of the present invention adds pharmaceutically the acceptable adjuvant by the solid, dry granule of pramipexole and granule and forms.
Concrete, pharmaceutical composition according to the invention is grouped into by following one-tenth:
" pramipexole " is meant pramipexole dihydrochloride and pharmaceutically useful solvate thereof, particularly including the pramipexole dihydrochloride monohydrate.
The amount of pramipexole is the intensity of desired solid preparation and deciding.Preparation intensity can be 0.125mg to 2.5mg, and wherein typical intensity is 0.125mg, 0.25mg, 0.50mg, 1mg, 1.25,1.5mg.
Pharmaceutical composition of the present invention is used for the dried particulate adjuvant of preparation and is preferably corn starch and mannitol, and its granule adds acceptable accessories and is preferably silicon dioxide, magnesium stearate.
The present invention preferably fills a prescription and forms in an embodiment.
Another object of the present invention is to provide the preparation of drug combination method.
Preparation of drug combination technology of the present invention may further comprise the steps:
1) with corn starch, mannitol is crossed 100 mesh sieves respectively, and is subsequent use;
2) pramipexole was pulverized 200 mesh sieves, subsequent use;
3) pramipexole and corn starch are pressed equivalent incremental method mix homogeneously, add the mannitol mix homogeneously;
4) above-mentioned gained material is put be pressed into dry and hard material in the dry granulation machine, and smash and be dried granule through waving granulator;
5) the dried granule of gained is passed through 24 orders and 80 order stainless steel meshs successively, collect 80 eye mesh screen upper sections, be qualified granule;
6) adding adds adjuvant silicon dioxide, magnesium stearate, mix homogeneously in above-mentioned material;
7) this final material thing is pressed into tablet;
8) packing;
Preferably, ambient humidity is controlled at below 50% when granulating.
Further specify beneficial effect of the present invention through following experiment.
Experiment one, prescription screening experiment
1, filler:
Mannitol: be widely used in pharmaceutical preparation and food, in preparation process, it mainly as diluent (10% ~ 90%W/W) is used for tablet formulation because it is non-hygroscopic, can with wet sensitivity active component compatibility.Mannitol can be used for direct compression technology.Mannitol is because of its heat of solution is a negative value, and the sugariness mouthfeel of becoming reconciled is arranged, and uses as the excipient of chewable tablet usually.The good fluidity of mannitol particles, and can partly improve the flowability of unclassified stores.The adjuvant of other participation recipe developments such as microcrystalline Cellulose, lactose, pregelatinized Starch etc. all are oral solid formulation adjuvants commonly used, and stable in properties does not influence product and detects.These article are through experiment, and when finally confirming mannitol 50-60%, the disintegration of tablet time limit is best.
, make up a plurality of prescriptions and screen as filler with mannitol, lactose, microcrystalline Cellulose.Disintegrating agent in order rationally to screen filler, increases corn starch and investigates in selection course, investigates filler and disintegrating agent synergism in tablet simultaneously.
Prescription 1: mannitol, prescription 2: mannitol, lactose; Prescription 3: mannitol, lactose, microcrystalline Cellulose, prescription 4: mannitol, microcrystalline Cellulose, corn starch; Write out a prescription 5 mannitol, corn starch.
Table 1, filler screening experiment
Can know that from experimental result the 5th group effect is best, all is superior to other groups at aspects such as character, hardness and disintegrations,
It is best to explain that mannitol and corn starch are used effect, and physical property indexs such as lid, tomography do not appear taking off in tabletting after the tablet granulation, tablet.
2, disintegrating agent:
Corn starch is the basic adjuvant of oral solid formulation, binding agent, diluent and the disintegrating agent done commonly used.
Low-substituted hydroxypropyl cellulose: low-substituted hydroxypropyl cellulose is nontoxic, non-irritating material.The general working concentration of low-substituted hydroxypropyl cellulose in prescription is 5%～25%.
Carboxymethyl starch sodium: the disintegrating agent as capsule and tablet is widely used in the oral drug preparation, can be used in the tablet of direct compression and wet granulation, and the consumption in tablet is 2%～8% usually.
Table 2, disintegrating agent screening experiment
Use carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose to cooperate corn starch and the disintegrate effect zero difference that uses corn starch separately, therefore, do not increase disintegrating agent in addition, as disintegrating agent, 35-45% content corn starch is best with corn starch.
3, the selection of lubricant and fluidizer:
Lubricant is to add before the tabletting, in order to reduce the adjuvant of granule or tablet frictional force between punch die.Because of it has reduced the friction with punch die, can increase particulate flowability, make and fill well, the Density Distribution of tablet is even, has also guaranteed to release the integrity of tablet.The purpose that adds fluidizer in the tablet is the flowability that promotes the tabletting material, makes it in time " feedstuff ", can make granule permutatation in nib before tabletting.Fluidizer is very important to quick tabletting.
Magnesium stearate: be white powder, fine and smooth loose, there is good tack after granule mixes, to be evenly distributed and should not separates, lubrication is good, has block resistance and unilateral smooth and beautiful appearance, is widely used.Content to magnesium stearate is investigated, through experiment, draw write out a prescription according to these article in magnesium stearate content when being 1-3%; The pramipexole disintegration of tablet degree of preparation meets pharmacopeia regulation, and disintegration is good, and consumption is greater than 3% the time; Tablet produces sliver, and consumption is less than 1% o'clock, the extremely difficult disintegrate of tablet; Influence the performance of curative effect of medication, so the selected magnesium stearate of these article is at 1-3%.
Silicon dioxide: small particle diameter and bigger serface make it have the flowability of expectation; These characteristics can be used for improving the flowability of dry powder in many processes, such as the tabletting process, therefore; In tablet, use, also can be used as the disintegrating agent of tablet mainly as fluidizer.
The selection of table 3, lubricant and fluidizer
| Character | Hardness | Disintegration | Friability |
| White tablets; Unilateral bright and clean; No pit, skin dark stain etc. | 6.18kg | 6 ' 02 "; Collapse unfolded granule and all pass through screen cloth | 0.84% |
4, confirming of binding agent:
Corn starch is used at " dry adhesives " that can be used as direct powder compression as binding agent in these article prescription.And stable in properties, do not have or hygroscopicity little, compressibility is good, the tablet that is pressed into is attractive in appearance, it is more excellent to be used mannitol diluent tabletting effect, tabletting is remarkably productive.According to experimental result, confirm that finally corn starch content is 35-45% in these article.
Prescription is confirmed in the adjuvant; Mannitol is the crucial adjuvant that increases tablet hardness; And mannitol is difficult for moisture absorption, can with wet sensitivity active component prescription compatibility, product can not influence quality index such as product moisture, related substance, content because of moisture absorption at shelf life like this; Corn starch in product mainly as disintegrating agent, can disintegrate fast after making product and water contacting, the filler of holding concurrently simultaneously can be assisted the mannitol extrusion modling behind the last dry granulation machine, increases particulate hardness.Particle size distribution after the granulation and particulate flowability satisfy the production equipment requirement, prevent to occur in the tabletting process tablet top and split, and process abnormality problems such as part occur.Magnesium stearate has ensured smooth tabletting in the tabletting process as lubricant, the fineness of push jack and tablet, if excessive use, problems such as top cover, tomography, sudden and violent face can appear in tablet in the tabletting process.Silicon dioxide is assisted particulate flowability as fluidizer, reduces the weight differential of tablet in the tabletting.
Through above-mentioned a series of prescription screening, finally obtain the most preferred prescription of the present invention:
Experiment two, stable comparative experiments
Find that through testing us the pramipexole preparation of the present invention's preparation can keep the active ingredient of high percentage ratio under high temperature, super-humid conditions.In order further to verify effect of the present invention, we compare medicine of the present invention and present commercially available like product.
Experimental group 1: the embodiment of the invention 1
Experimental group 2: the embodiment of the invention 2
Experimental group 3: the embodiment of the invention 3
Matched group: present commercially available body of Pramipexole dihydrochloride sheet
The content ratio that table 4, commercially available article and the inventive method preparation room temperature keep under 25 ℃, 60% humidity situation:
Table 5, impurity contrast test
Experimental result shows, the pramipexole solid preparation of the present invention's preparation the condition of storage of 25 ℃ and 60% relative humidity down maintenance after 18 months active constituent content still can reach 99.2%., the commercial preparation meansigma methods that stores under the same conditions is merely 95.5% of labelled amount, explains that the body of Pramipexole dihydrochloride sheet of the present invention's preparation is more stable than commercially available tablet, and quality is more reliable.
At this, just list the related experiment data of having lifted embodiment of the invention 1-3, in fact other embodiment of the present invention also can obtain the beneficial effect identical or close with the foregoing description.
The specific embodiment:
Embodiment 1: the pramipexole tablet recipe:
Preparation technology:
1) with corn starch, mannitol is crossed 100 mesh sieves respectively, and is subsequent use;
2) pramipexole was pulverized 200 mesh sieves, subsequent use;
3) pramipexole and corn starch are pressed equivalent incremental method mix homogeneously, add the mannitol mix homogeneously;
4) above-mentioned gained material is put be pressed into dry and hard material in the dry granulation machine, and smash and be dried granule through waving granulator;
5) the dried granule of gained is passed through 24 orders and 80 order stainless steel meshs successively, collect 80 eye mesh screen upper sections, be qualified granule;
6) adding adds adjuvant silicon dioxide, magnesium stearate, mix homogeneously in above-mentioned material;
7) this final material thing is pressed into the tablet with final hardness;
8) packing;
Ambient humidity is controlled at below 50% when 9) granulating.
Embodiment 2: the pramipexole tablet recipe:
Preparation technology:
1) with corn starch, mannitol is crossed 100 mesh sieves respectively, and is subsequent use;
2) pramipexole was pulverized 200 mesh sieves, subsequent use;
3) pramipexole and corn starch are pressed equivalent incremental method mix homogeneously, add the mannitol mix homogeneously;
4) above-mentioned gained material is put be pressed into dry and hard material in the dry granulation machine, and smash and be dried granule through waving granulator;
5) the dried granule of gained is passed through 24 orders and 80 order stainless steel meshs successively, collect 80 eye mesh screen upper sections, be qualified granule;
6) adding adds adjuvant silicon dioxide, magnesium stearate, mix homogeneously in above-mentioned material;
7) this final material thing is pressed into the tablet with final hardness;
8) packing;
Ambient humidity is controlled at below 50% when 9) granulating.
Embodiment 3: the pramipexole tablet recipe:
Preparation technology:
1) with corn starch, mannitol is crossed 100 mesh sieves respectively, and is subsequent use;
2) pramipexole was pulverized 200 mesh sieves, subsequent use;
3) pramipexole and corn starch are pressed equivalent incremental method mix homogeneously, add the mannitol mix homogeneously;
4) above-mentioned gained material is put be pressed into dry and hard material in the dry granulation machine, and smash and be dried granule through waving granulator;
5) the dried granule of gained is passed through 24 orders and 80 order stainless steel meshs successively, collect 80 eye mesh screen upper sections, be qualified granule;
6) adding adds adjuvant silicon dioxide, magnesium stearate, mix homogeneously in above-mentioned material;
7) this final material thing is pressed into the tablet with final hardness;
8) packing;
Ambient humidity is controlled at below 50% when 9) granulating.
Embodiment 4, pramipexole tablet recipe:
Preparation technology:
1) with corn starch, mannitol is crossed 100 mesh sieves respectively, and is subsequent use;
2) pramipexole was pulverized 200 mesh sieves, subsequent use;
3) pramipexole and corn starch are pressed equivalent incremental method mix homogeneously, add the mannitol mix homogeneously;
4) above-mentioned gained material is put be pressed into dry and hard material in the dry granulation machine, and smash and be dried granule through waving granulator;
5) the dried granule of gained is passed through 24 orders and 80 order stainless steel meshs successively, collect 80 eye mesh screen upper sections, be qualified granule;
6) adding adds adjuvant silicon dioxide, magnesium stearate, mix homogeneously in above-mentioned material;
7) this final material thing is pressed into the tablet with final hardness;
8) packing;
Ambient humidity is controlled at below 50% when 9) granulating.
Embodiment 5, pramipexole tablet recipe:
Preparation technology:
1) with corn starch, mannitol is crossed 100 mesh sieves respectively, and is subsequent use;
2) pramipexole was pulverized 200 mesh sieves, subsequent use;
3) pramipexole and corn starch are pressed equivalent incremental method mix homogeneously, add the mannitol mix homogeneously;
4) above-mentioned gained material is put be pressed into dry and hard material in the dry granulation machine, and smash and be dried granule through waving granulator;
5) the dried granule of gained is passed through 24 orders and 80 order stainless steel meshs successively, collect 80 eye mesh screen upper sections, be qualified granule;
6) adding adds adjuvant silicon dioxide, magnesium stearate, mix homogeneously in above-mentioned material;
7) this final material thing is pressed into the tablet with final hardness;
8) packing;
Ambient humidity is controlled at below 50% when 9) granulating.
Embodiment 6, pramipexole tablet recipe:
Preparation technology:
1) with corn starch, mannitol is crossed 100 mesh sieves respectively, and is subsequent use;
2) pramipexole was pulverized 200 mesh sieves, subsequent use;
3) pramipexole and corn starch are pressed equivalent incremental method mix homogeneously, add the mannitol mix homogeneously;
4) above-mentioned gained material is put be pressed into dry and hard material in the dry granulation machine, and smash and be dried granule through waving granulator;
5) the dried granule of gained is passed through 24 orders and 80 order stainless steel meshs successively, collect 80 eye mesh screen upper sections, be qualified granule;
6) adding adds adjuvant silicon dioxide, magnesium stearate, mix homogeneously in above-mentioned material;
7) this final material thing is pressed into the tablet with final hardness;
8) packing;
Ambient humidity is controlled at below 50% when 9) granulating.
The foregoing description only is used to explain Chinese medicine preparation of compositions method of the present invention; Protection scope of the present invention is not so limited; Concrete embodiment only is for indivedual aspect of the present invention is described, method that is equal on the function and component are within the scope of the invention.
Claims (10)
1. a pharmaceutical composition that contains pramipexole is characterized in that, is grouped into by following one-tenth:
。
2. the described pharmaceutical composition of claim 1 is characterized in that, is grouped into by following one-tenth:
。
3. the described pharmaceutical composition of claim 1 is characterized in that, is grouped into by following one-tenth:
。
4. the described pharmaceutical composition of claim 1 is characterized in that, is grouped into by following one-tenth:
。
5. the described pharmaceutical composition of claim 1 is characterized in that, is grouped into by following one-tenth:
。
6. the described pharmaceutical composition of claim 1 is characterized in that, is grouped into by following one-tenth:
。
7. the described pharmaceutical composition of claim 1 is characterized in that, is grouped into by following one-tenth:
8. the arbitrary described pharmaceutical composition of claim 1-7 is a tablet.
9. the described preparation of drug combination method of claim 1 is characterized in that, may further comprise the steps:
1) with corn starch, mannitol is crossed 100 mesh sieves respectively, and is subsequent use;
2) pramipexole was pulverized 200 mesh sieves, subsequent use;
3) pramipexole and corn starch are pressed equivalent incremental method mix homogeneously, add the mannitol mix homogeneously;
4) above-mentioned gained material is put be pressed into dry and hard material in the dry granulation machine, and smash and be dried granule through waving granulator;
5) the dried granule of gained is passed through 24 orders and 80 order stainless steel meshs successively, collect 80 eye mesh screen upper sections, be qualified granule;
6) adding adds adjuvant silicon dioxide, magnesium stearate, mix homogeneously in above-mentioned material;
7) this final material is pressed into tablet;
8) packing.
10. the described method for preparing of claim 9 is characterized in that ambient humidity is controlled at below 50% during granulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103157725A CN102836155A (en) | 2012-08-30 | 2012-08-30 | Medicinal composition containing pramipexole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103157725A CN102836155A (en) | 2012-08-30 | 2012-08-30 | Medicinal composition containing pramipexole |
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| CN102836155A true CN102836155A (en) | 2012-12-26 |
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|---|---|---|---|
| CN2012103157725A Pending CN102836155A (en) | 2012-08-30 | 2012-08-30 | Medicinal composition containing pramipexole |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030036548A1 (en) * | 2001-08-10 | 2003-02-20 | Boehringer Ingelheim Pharma Kg | Method for treating anhedonia using dopamine agonists |
-
2012
- 2012-08-30 CN CN2012103157725A patent/CN102836155A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030036548A1 (en) * | 2001-08-10 | 2003-02-20 | Boehringer Ingelheim Pharma Kg | Method for treating anhedonia using dopamine agonists |
Non-Patent Citations (1)
| Title |
|---|
| 崔福德: "《药剂学》", 29 February 2004, 人民卫生出版社 * |
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Application publication date: 20121226 |