CN106474084A - A kind of body of Pramipexole dihydrochloride slow releasing preparation and preparation method thereof - Google Patents
A kind of body of Pramipexole dihydrochloride slow releasing preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of body of Pramipexole dihydrochloride slow releasing preparation and preparation method thereof, the Pramipexole Dihydrochloride Sustained Release Tablets that the present invention provides are passed through to add non-cellulose class neutrality slow-release material and cross-linking polyethylene pyrrolidone, so that the slow releasing preparation obtaining not only has grinds, with former, the sustained release performance that medicine phases are worked as, and its uniformity of dosage units is good.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, more particularly, to a kind of body of Pramipexole dihydrochloride slow releasing preparation and its system
Preparation Method.
Background technology
Body of Pramipexole dihydrochloride, chemical name is：One hydration two hydrochloric acid (S) -2- amino -4,5,6,7- tetrahydrochysene -6-
Propylamine-benzothiazole, shown in structural formula such as formula (I),
Body of Pramipexole dihydrochloride is a kind of dopamine-receptor stimulant, by excited striatal dopamine receptor
To mitigate the dyskinesia of disturbances in patients with Parkinson disease, for treating the Parkinsonian S＆S of adult idiopathic.
Body of Pramipexole dihydrochloride is as the fiest-tire medication of early stage PD patient, excellent in the dysfunction improving late period PD
In bromocriptine, clinically it is subject to the recognition and acceptance of neurosurgeon and PD patient.Body of Pramipexole dihydrochloride
It is that MDS in 2011 uniquely recommends to treat the depressed effectively medicine of parkinson disease.Body of Pramipexole dihydrochloride is still
The first-line drug for the treatment of RLS, is A class evidence in American-European guide.
Pramipexole Dihydrochloride Sustained Release Tablets are a kind of novel forms developed on the basis of fast-release tablet, the two
Different in the mode of release medicine.Compared with fast-release tablet, slow releasing tablet constantly can discharge medicine,
Thus extending plasma half-life, more meeting physiological statuss, and decreasing daily medicining times and medicine
Piece quantity, increased the facility of patient and nursing staff, improves the compliance of patient.And clinical trial
It is further characterized by, on treatment early stage PD and auxiliary treatment late period PD, pramipexole slow release formulation has
The safety similar to fast dissolving dosage form and toleration.So far, there is no with regard to applying body of Pramipexole dihydrochloride
Slow releasing tablet increases the report of untoward reaction.
Research currently, with respect to Pramipexole Dihydrochloride Sustained Release Tablets is more, such as：1) patent
The pramipexole that CN200580027634.5 describes a kind of oral delivery form extends release tablet combination
Thing, it comprises the body of Pramipexole dihydrochloride being dispersed in substrate, and described substrate comprises at least two non-pregelatinized
The water-swellable polymer of starch, and one of which is anionic polymer, preferably acrylate copolymer,
More preferably Carbomer, content accounts for the 1% to 10% of total weight of tablet；Another kind of non-pre-paying starch based
Water-swellable polymer be neutral polymer, preferably hydroxypropyl cellulose, more preferably Hypromellose,
Content accounts for the 25% to 65% of total weight of tablet.But, this slow releasing tablet is that the dependent release of pH value is special
Property preparation, not only increased the complexity of preparation, also increase simultaneously its discharge in human body absorb
Diversity.2) patent CN201310475466.2 discloses and describes a kind of pula of oral delivery form
Ke Suo extends release tablet compositionss, comprises at least two neutral polymerizations from substrate described unlike former grinding
Thing, a kind of is non-cellulose class neutral polymer, the group of preferably polyethylene ketopyrrolidine and vinylacetate
Compound；Another kind of is cellulose family neutral polymer, preferably Hypromellose, its obtained slow release
Piece release characteristics are not affected by pH value, but the scattered uniformity of the medicine of said preparation is poor, release standard
There is unqualified risk in deviation (RSD), can be because supplementary material granularity, mobility, heap density rationality
The differences between batches of matter etc. and lead to every batch sample mass discrepancy, product uniformity, repeatability are bad.3) special
Sharp CN201210351475.6 describes a kind of preparation of the Pramipexole Dihydrochloride Sustained Release Tablets of the high-load uniformity
Method, the preparation method providing solves the problems, such as that the mixing uniformity of low dosage is poor, but due to its slow release
Mechanism only relies on the hydrogel matrix of Hypromellose, and content be 30%-60% it is impossible to reach with
Former grind consistent sustained release performance.
A kind of therefore it provides Pramipexole Dihydrochloride Sustained Release Tablets not only uniformity of dosage units height, and sustained release performance
It is well the current technical issues that need to address.
Content of the invention
In view of this, the technical problem to be solved is to provide a kind of body of Pramipexole dihydrochloride slow release
Preparation and preparation method thereof, not only sustained release performance is good for the Pramipexole Dihydrochloride Sustained Release Tablets that the present invention provides, and
And the uniformity of dosage units of slow releasing tablet is good.
The invention provides a kind of slow releasing preparation of body of Pramipexole dihydrochloride, including：Body of Pramipexole dihydrochloride, the
One non-cellulose class neutrality slow-release material, the second non-cellulose class neutrality slow-release material and crosslinked polyethylene pyrrole
Pyrrolidone；
Wherein, described first non-cellulose class neutrality slow-release material is vinylacetate, polyvinylpyrrolidine
One or more of ketone, polyvinyl alcohol and polyalkylene oxide；
Described second non-cellulose class neutrality slow-release material be Glyceryl Behenate, glyceryl monostearate,
One or more of hexadecanol, octadecanol and Brazil wax.
Preferably, described first non-cellulose class neutrality slow-release material with the mass ratio of described slow releasing preparation is
(25～70)：100, preferably (30～60)：100.
Preferably, described two non-cellulose class neutrality slow-release materials with the mass ratio of described slow releasing preparation are
(5～40)：100, preferably (10～30)：100.
Preferably, described crospolyvinylpyrrolidone and the mass ratio of described slow releasing preparation are (3～30)：
100, preferably (4～20)：100.
Preferably, described body of Pramipexole dihydrochloride and the mass ratio of described slow releasing preparation are (0.1～3)：100,
It is preferably (0.15～2)：100.
Preferably, described slow releasing preparation also includes excipient.
Preferably, described excipient is one of Microcrystalline Cellulose, micropowder silica gel and magnesium stearate or several
Kind.
Present invention also offers a kind of preparation method of the slow releasing preparation of body of Pramipexole dihydrochloride, including：
1) by body of Pramipexole dihydrochloride solution and crospolyvinylpyrrolidone mixing granulation, obtain containing hydrochloric acid
The granule of pramipexole；
2) by obtain the granule containing body of Pramipexole dihydrochloride, the first non-cellulose class slow-release material, second
Non-cellulose class slow-release material and excipient mixing, obtain body of Pramipexole dihydrochloride slow releasing preparation.
Preferably, described excipient is one of micropowder silica gel, Microcrystalline Cellulose and magnesium stearate or several
Kind.
Preferably, described step 2) it is specially：
Second non-cellulose class neutrality slow-release material is mixed with micropowder silica gel in excipient, obtains containing the
The mixture of two non-cellulose class neutrality slow-release materials；
By the mixture containing the second non-cellulose class neutrality slow-release material, add the first non-cellulose class
Neutral slow-release material and step 1) obtain containing body of Pramipexole dihydrochloride granule mixing, be subsequently adding tax
In shape agent, Microcrystalline Cellulose continues mixing, is eventually adding magnesium stearate mixing in excipient, obtains hydrochloric acid general
Clarke rope slow releasing preparation.
Compared with prior art, the invention provides a kind of body of Pramipexole dihydrochloride slow releasing preparation, the present invention carries
For Pramipexole Dihydrochloride Sustained Release Tablets pass through to add non-cellulose class neutrality slow-release material and crosslinked polyethylene
Base ketopyrrolidine so that the slow releasing preparation that obtains not only has and grinds, with former, the sustained release performance that medicine phases are worked as, and
Its uniformity of dosage units is good, test result indicate that, the slow releasing preparation that the present invention prepares is in different pH value
In solution, sustained release performance is all fine, and uniformity of dosage units A+1.8S is respectively less than 15, as little as 4.2, and content is equal
Evenness is good.
A kind of preparation method of body of Pramipexole dihydrochloride slow releasing preparation that the present invention provides, compared with prior art,
By first the solution of body of Pramipexole dihydrochloride being mixed with cross-linking polyethylene pyrrolidone, then and slow-release material
Mix so that the uniformity of dosage units of the body of Pramipexole dihydrochloride slow releasing preparation preparing is fine with excipient,
And sustained release performance might as well.
Brief description
Fig. 1 is for the Pramipexole Dihydrochloride Sustained Release Tablets described in the embodiment of the present invention 1 under different pH condition
Release profiles；
Fig. 2 is for the Pramipexole Dihydrochloride Sustained Release Tablets described in the embodiment of the present invention 2 under different pH condition
Release profiles；
Fig. 3 is for the Pramipexole Dihydrochloride Sustained Release Tablets described in the embodiment of the present invention 3 under different pH condition
Release profiles；
Fig. 4 is for the Pramipexole Dihydrochloride Sustained Release Tablets described in the embodiment of the present invention 4 under different pH condition
Release profiles.
Specific embodiment
The invention provides a kind of slow releasing preparation of body of Pramipexole dihydrochloride, including：Body of Pramipexole dihydrochloride, the
One non-cellulose class neutrality slow-release material, the second non-cellulose class neutrality slow-release material and crosslinked polyethylene pyrrole
Pyrrolidone.
According to the present invention, described body of Pramipexole dihydrochloride is preferably (0.1～3) with the mass ratio of described slow releasing preparation：
100, more preferably (0.15～2)：100, most preferably (0.3～1.5)：100.
Described first non-cellulose class neutrality slow-release material is preferably vinylacetate, Polyvinylpyrrolidone
One or more of (polyvidone), polyvinyl alcohol and polyalkylene oxide；It is preferably polyvidone and acetic acid second
The mixture of alkene ester, more preferably polyvidone and vinylacetate weight are than for 2:8 mixture；Described first
Non-cellulose class neutrality slow-release material is (25～70) with the mass ratio of described slow releasing preparation：100, more excellent
Elect (30～60) as：100, most preferably (40～55)：100.
Described second non-cellulose class neutrality slow-release material be Glyceryl Behenate, glyceryl monostearate,
One or more of hexadecanol, octadecanol and Brazil wax, more preferably Glyceryl Behenate, list
One or more of tristerin, hexadecanol and octadecanol, most preferably Glyceryl Behenate or
Glyceryl monostearate.Described second non-cellulose class neutrality slow-release material and the quality of described slow releasing preparation
Than for (5～40)：100, more preferably (10～30)：100, most preferably (20～25)：100.
Described crospolyvinylpyrrolidone is preferably (3～30) with the mass ratio of described slow releasing preparation：100,
More preferably (4～20)：100, most preferably (5～10)：100, the most it is preferably (6～8)：100.
According to the present invention, in described slow releasing preparation, also include excipient, the present invention does not have to described excipient
Particular/special requirement, well known to a person skilled in the art can apply to the excipient of slow releasing preparation, preferably
For one or more of Microcrystalline Cellulose, micropowder silica gel and magnesium stearate, more preferably Microcrystalline Cellulose,
Micropowder silica gel and magnesium stearate；Described Microcrystalline Cellulose is preferably with the mass ratio of described slow releasing preparation
(10～60)：100, more preferably (20～50)：100；Described micropowder silica gel and described slow releasing preparation
Mass ratio be preferably (0.1～1)：100, more preferably (0.5～0.8)：100, described magnesium stearate
It is preferably (0.1～1) with the mass ratio of described slow releasing preparation：100, more preferably (0.5～0.8)：100.
The body of Pramipexole dihydrochloride slow releasing preparation that the present invention provides, by adding non-cellulose class neutrality slow release material
Material and cross-linking polyethylene pyrrolidone, wherein, the first non-cellulose class neutrality slow-release material and second
The adding so that the slow releasing preparation that obtains has and grinds what medicine phases were worked as with former of non-cellulose class neutrality slow-release material
Sustained release performance, meanwhile, is neutral slow-release material, and its release is not limited by pH environment；And pass through
Add crosslinked Polyvinylpyrrolidone, be found surprisingly that, the content of the slow releasing preparation being mixed to get is uniform
Degree becomes fine.
Present invention also offers a kind of preparation method of the slow releasing preparation of body of Pramipexole dihydrochloride, including：
1) by body of Pramipexole dihydrochloride solution and crospolyvinylpyrrolidone mixing granulation, obtain containing hydrochloric acid
The granule of pramipexole；
2) granule containing body of Pramipexole dihydrochloride, the first cellulose family slow-release material, the second fibre will be obtained
The plain class slow-release material of dimension and excipient mixing, obtain body of Pramipexole dihydrochloride slow releasing preparation.
According to the present invention, body of Pramipexole dihydrochloride solution is mixed with crospolyvinylpyrrolidone and makes by the present invention
Grain, obtains the granule containing body of Pramipexole dihydrochloride；
Wherein, described body of Pramipexole dihydrochloride solution is preferably the ethanol water of body of Pramipexole dihydrochloride, described
In ethanol water, ethanol and the volume ratio of water are (40～90)：(10～60)；Described ethanol water
Consumption be so that body of Pramipexole dihydrochloride is dissolved；Described body of Pramipexole dihydrochloride and described crosslinked polyethylene pyrrole
The mass ratio of pyrrolidone is (0.1～3)：(3～30), more preferably (0.15～2)：(4～20),
Most preferably (0.15～1.5)：(5～10).
The present invention does not have particular/special requirement to pelletize, well known to a person skilled in the art pelletize, in order that
More preferably, it is general containing hydrochloric acid that the present invention preferably makes that pelletize obtains for the slow releasing preparation uniformity of dosage units for preparing
The mesh number of the granule of clarke rope is more than 20 mesh；Present invention additionally comprises by pelletize obtain containing hydrochloric acid pula gram
The granule of rope is dried, and obtains the pramipexole granule containing hydrochloric acid dried, the present invention is to the mode dried
It is not particularly limited, drying mode well known in the art.
According to the present invention, the present invention will obtain the granule containing body of Pramipexole dihydrochloride, the first cellulose family
Slow-release material, the second cellulose family slow-release material and excipient mixing, obtain body of Pramipexole dihydrochloride slow release
Preparation；
Wherein, described first non-cellulose class neutrality slow-release material is preferably vinylacetate, polyethylene pyrrole
One or more of pyrrolidone, polyvinyl alcohol and polyalkylene oxide, preferably polyvidone and vinylacetate mix
Compound, more preferably polyvidone and vinylacetate weight are than for 2:8 mixture；Described first non-cellulose
Class neutrality slow-release material is (25～70) with the mass ratio of described slow releasing preparation：100, more preferably (30～60)：
100, most preferably (40～55)：100.Described second non-cellulose class neutrality slow-release material is behenic acid
One or more of glyceride, glyceryl monostearate, hexadecanol, octadecanol and Brazil wax,
More preferably one or more of Glyceryl Behenate, glyceryl monostearate, hexadecanol and octadecanol,
Most preferably Glyceryl Behenate or glyceryl monostearate.Described second non-cellulose class neutrality slow release material
Material is (5～40) with the mass ratio of described slow releasing preparation：100, more preferably (10～30)：100,
It is preferably (20～25)：100.Described crospolyvinylpyrrolidone and the mass ratio of described slow releasing preparation
It is preferably (3～30)：100, more preferably (4～20)：100, most preferably (5～10)：100,
The most it is preferably (6～8)：100.Excipient is also included, the present invention is to described tax in described slow releasing preparation
Shape agent does not have particular/special requirement, well known to a person skilled in the art the excipient that can apply to slow releasing preparation is equal
Can, preferably one or more of microcrystalline cellulose, micropowder silica gel and magnesium stearate, more preferably crystallite
Cellulose, micropowder silica gel and magnesium stearate；Described Microcrystalline Cellulose is excellent with the mass ratio of described slow releasing preparation
Elect (10～60) as：100, more preferably (20～50)：100；Described micropowder silica gel and described slow release
The mass ratio of preparation is preferably (0.1～1)：100, more preferably (0.5～0.8)：100, described Hard Fat
Sour magnesium is preferably (0.1～1) with the mass ratio of described slow releasing preparation：100, more preferably (0.5～0.8)：
100.
In the present invention, the present invention does not have particular/special requirement to hybrid mode, well known in the art for medicine system
Mixing in agent preparation process.
Specifically, in order that the mixing of each raw material is more uniform, described step 2) it is preferably：
Second non-cellulose class neutrality slow-release material is mixed with micropowder silica gel in excipient, obtains containing the
The mixture of two non-cellulose class neutrality slow-release materials；
Will be neutral slow to the mixture containing the second non-cellulose class neutrality slow-release material and the first non-cellulose class
Release material and step 1) obtain containing body of Pramipexole dihydrochloride granule mixing, be subsequently adding in excipient
Microcrystalline Cellulose continues mixing, is eventually adding magnesium stearate mixing in excipient, obtains body of Pramipexole dihydrochloride
Slow releasing preparation.
In preparation method of the present invention, the hybrid mode of mixing is used for making for those skilled in the art
Conventional hybrid mode, not particular/special requirement during standby pharmaceutical preparation, the temperature of mixing is room temperature.
The present invention does not have particular/special requirement to the shape of described body of Pramipexole dihydrochloride slow releasing preparation, known in this field
The shape that can prepare of solid sustained-release preparation, can be such as chip base, granule.
A kind of preparation method of body of Pramipexole dihydrochloride slow releasing preparation that the present invention provides, by first general by hydrochloric acid
The solution of clarke rope is mixed with cross-linking polyethylene pyrrolidone, it is to avoid body of Pramipexole dihydrochloride is subsequently mixing
Occur in conjunction mixing uneven problem, meanwhile, by by second non-cellulose class neutrality slow-release material with
In excipient, micropowder silica gel first mixes, more neutral slow-release material, Microcrystalline Cellulose with the first non-cellulose class
And step 1) mixing of the granule containing body of Pramipexole dihydrochloride that obtains, further increased obtain slow
The mixing homogeneity of release formulation.
Technical scheme below in conjunction with the embodiment of the present invention is clearly and completely described it is clear that institute
The embodiment of description is only a part of embodiment of the present invention, rather than whole embodiments.Based on this
Embodiment in bright, those of ordinary skill in the art are obtained under the premise of not making creative work
Every other embodiment, broadly falls into the scope of protection of the invention.
Embodiment 1
1) body of Pramipexole dihydrochloride is dissolved in the ethanol water of 40wt%, obtains body of Pramipexole dihydrochloride molten
Liquid；
2) add cross-linking polyethylene pyrrolidone (Kollidon CL-SF) in body of Pramipexole dihydrochloride solution
For adsorbing the ethanol solution of body of Pramipexole dihydrochloride, stir while adding, obtain soft material, made with 20 mesh sieves
Grain, dries, obtains the granule containing body of Pramipexole dihydrochloride；
3) by micropowder silica gel and Glyceryl Behenate (888ATO) mix homogeneously, adds
Polyvidone and vinyl acetate ester admixture (Kolidon SR) and step 2) prepare contain hydrochloric acid
The granule mixing of pramipexole, is subsequently adding Microcrystalline Cellulose and continues mixing, is eventually adding magnesium stearate and mixes
Close, tabletting, obtain Pramipexole hydrochloride slow release tablet.
Wherein, hydrochloric acid according to embodiment 1 for the consumption of each raw material in the preparation method described in embodiment 1
In pramipexole slow releasing tablet, the content of each raw material adds, each former in described Pramipexole hydrochloride slow release tablet
The content of material is shown in Table 1, and table 1 is each raw material in Pramipexole hydrochloride slow release tablet prepared by the embodiment of the present invention 1
Content.
The content of each raw material in the Pramipexole hydrochloride slow release tablet of table 1 embodiment of the present invention 1 preparation
According to《Chinese Pharmacopoeia》The hydrochloric acid that version dissolution method first method in 2010 is prepared to embodiment 1 is general
Clarke rope slow releasing tablet is measured, and dissolution medium is respectively pH1.2 hydrochloric acid solution, pH4.5 acetate salt buffer
Liquid, pH6.8 phosphate buffer 500ml, water, rotating speed 100rpm, dissolution medium temperature is 37 DEG C ± 0.5 DEG C,
Sampled respectively at 1,2,4,6,9,12,16,20,24 hours, release profiles are as shown in figure 1, Fig. 1
Release profiles under different pH condition for the Pramipexole Dihydrochloride Sustained Release Tablets described in the embodiment of the present invention 1；
It will be seen from figure 1 that Pramipexole Dihydrochloride Sustained Release Tablets all assume 24 hours slow release in 4 kinds of dissolution mediums,
In non-TCP friendly flow, and sustained release performance is good.
According to《Chinese Pharmacopoeia》Two annex XE Content uniformity test regulations of version in 2010, to enforcement
The uniformity of the Pramipexole Dihydrochloride Sustained Release Tablets of example 1 preparation is detected, specifically, prepared by Example 1
Pramipexole Dihydrochloride Sustained Release Tablets 10 be measured, adopt high performance liquid chromatography measure respectively every with mark
The amount of showing is 100 relative amount X, seeks the absolute of its average X and standard deviation S and labelled amount and the difference of average
Value A (A=100-X)；As A+1.80S≤15.0, that is, the uniformity of dosage units of test sample meets regulation；
Result shows, the uniformity of dosage units A+1.80S of the slow releasing tablet of embodiment 1 preparation is 4.2；The uniformity is higher.
Embodiment 2
1) body of Pramipexole dihydrochloride is dissolved in the ethanol water of 80wt%, obtains body of Pramipexole dihydrochloride molten
Liquid；
2) Kollidon CL-SF is added to be used for adsorbing body of Pramipexole dihydrochloride in body of Pramipexole dihydrochloride solution
Ethanol solution, stirs while adding, and obtains soft material, with 20 mesh sieve pelletizes, dries, obtains containing hydrochloric acid
The granule of pramipexole；
3) micropowder silica gel is mixed homogeneously with Glyceryl Behenate, add Kolidon SR and step 2)
The mixing of the granule containing body of Pramipexole dihydrochloride preparing, is subsequently adding Microcrystalline Cellulose and continues mixing,
It is eventually adding magnesium stearate mixing, tabletting, obtain Pramipexole hydrochloride slow release tablet.
Wherein, hydrochloric acid according to embodiment 2 for the consumption of each raw material in the preparation method described in embodiment 2
In pramipexole slow releasing tablet, the content of each raw material adds, each former in described Pramipexole hydrochloride slow release tablet
The content of material is shown in Table 2, and table 2 is each raw material in Pramipexole hydrochloride slow release tablet prepared by the embodiment of the present invention 2
Content.
The content of each raw material in the Pramipexole hydrochloride slow release tablet of table 2 embodiment of the present invention 2 preparation
According to《Chinese Pharmacopoeia》The hydrochloric acid that version dissolution method first method in 2010 is prepared to embodiment 2 is general
Clarke rope slow releasing tablet is measured, and dissolution medium is respectively pH1.2 hydrochloric acid solution, pH4.5 acetate salt buffer
Liquid, pH6.8 phosphate buffer 500ml, water, rotating speed 100rpm, dissolution medium temperature is 37 DEG C ± 0.5 DEG C,
Sampled respectively at 1,2,4,6,9,12,16,20,24 hours, release profiles are as shown in Fig. 2 Fig. 2
Release profiles under different pH condition for the Pramipexole Dihydrochloride Sustained Release Tablets described in the embodiment of the present invention 2；
Figure it is seen that Pramipexole Dihydrochloride Sustained Release Tablets all assume 24 hours slow release in 4 kinds of dissolution mediums,
In non-TCP friendly flow, and sustained release performance is good.
According to《Chinese Pharmacopoeia》Two annex XE Content uniformity test regulations of version in 2010, to enforcement
The uniformity of the Pramipexole Dihydrochloride Sustained Release Tablets of example 2 preparation is detected, specifically, prepared by Example 2
Pramipexole Dihydrochloride Sustained Release Tablets 10 be measured, adopt high performance liquid chromatography measure respectively every with mark
The amount of showing is 100 relative amount X, seeks the absolute of its average X and standard deviation S and labelled amount and the difference of average
Value A (A=100-X)；As A+1.80S≤15.0, that is, the uniformity of dosage units of test sample meets regulation；
Result shows, the uniformity of dosage units A+1.80S of the slow releasing tablet of embodiment 2 preparation is 3.6；The uniformity is higher.
Embodiment 3：
1) body of Pramipexole dihydrochloride is dissolved in the ethanol water of 80wt%, obtains body of Pramipexole dihydrochloride molten
Liquid；
2) Kollidon CL-SF is added to be used for adsorbing body of Pramipexole dihydrochloride in body of Pramipexole dihydrochloride solution
Ethanol solution, stirs while adding, and obtains soft material, with 20 mesh sieve pelletizes, dries, obtains containing hydrochloric acid
The granule of pramipexole；
3) micropowder silica gel is mixed homogeneously with Glyceryl Behenate, add Kolidon SR and step 2)
The mixing of the granule containing body of Pramipexole dihydrochloride preparing, is subsequently adding Microcrystalline Cellulose and continues mixing,
It is eventually adding magnesium stearate mixing, tabletting, obtain Pramipexole hydrochloride slow release tablet.
Wherein, hydrochloric acid according to embodiment 3 for the consumption of each raw material in the preparation method described in embodiment 3
In pramipexole slow releasing tablet, the content of each raw material adds, each former in described Pramipexole hydrochloride slow release tablet
The content of material is shown in Table 3, and table 3 is each raw material in Pramipexole hydrochloride slow release tablet prepared by the embodiment of the present invention 3
Content.
The content of each raw material in the Pramipexole hydrochloride slow release tablet of table 3 embodiment of the present invention 3 preparation
According to《Chinese Pharmacopoeia》The hydrochloric acid that version dissolution method first method in 2010 is prepared to embodiment 3 is general
Clarke rope slow releasing tablet is measured, and dissolution medium is respectively pH1.2 hydrochloric acid solution, pH4.5 acetate salt buffer
Liquid, pH6.8 phosphate buffer 500ml, water, rotating speed 100rpm, dissolution medium temperature is 37 DEG C ± 0.5 DEG C,
Sampled respectively at 1,2,4,6,9,12,16,20,24 hours, release profiles are as shown in figure 3, Fig. 3
Release profiles under different pH condition for the Pramipexole Dihydrochloride Sustained Release Tablets described in the embodiment of the present invention 2；
From figure 3, it can be seen that Pramipexole Dihydrochloride Sustained Release Tablets all assume 24 hours slow release in 4 kinds of dissolution mediums,
In non-TCP friendly flow, and sustained release performance is good.
According to《Chinese Pharmacopoeia》Two annex XE Content uniformity test regulations of version in 2010, to enforcement
The uniformity of the Pramipexole Dihydrochloride Sustained Release Tablets of example 3 preparation is detected, specifically, prepared by Example 3
Pramipexole Dihydrochloride Sustained Release Tablets 10 be measured, adopt high performance liquid chromatography measure respectively every with mark
The amount of showing is 100 relative amount X, seeks the absolute of its average X and standard deviation S and labelled amount and the difference of average
Value A (A=100-X)；As A+1.80S≤15.0, that is, the uniformity of dosage units of test sample meets regulation；
Result shows, the uniformity of dosage units A+1.80S of the slow releasing tablet of embodiment 3 preparation is 3.2；The uniformity is higher.
Embodiment 4
1) body of Pramipexole dihydrochloride is dissolved in the ethanol water of 90wt%, obtains body of Pramipexole dihydrochloride molten
Liquid；
2) Kollidon CL-SF is added to be used for adsorbing body of Pramipexole dihydrochloride in body of Pramipexole dihydrochloride solution
Ethanol solution, stirs while adding, and obtains soft material, with 20 mesh sieve pelletizes, dries, obtains containing hydrochloric acid
The granule of pramipexole；
3) micropowder silica gel is mixed homogeneously with Glyceryl Behenate, add Kolidon SR and step 2)
The mixing of the granule containing body of Pramipexole dihydrochloride preparing, is subsequently adding Microcrystalline Cellulose and continues mixing,
It is eventually adding magnesium stearate mixing, tabletting, obtain Pramipexole hydrochloride slow release tablet.
Wherein, hydrochloric acid according to embodiment 4 for the consumption of each raw material in the preparation method described in embodiment 4
In pramipexole slow releasing tablet, the content of each raw material adds, each former in described Pramipexole hydrochloride slow release tablet
The content of material is shown in Table 4, and table 4 is each raw material in Pramipexole hydrochloride slow release tablet prepared by the embodiment of the present invention 4
Content.
The content of each raw material in the Pramipexole hydrochloride slow release tablet of table 4 embodiment of the present invention 4 preparation
According to《Chinese Pharmacopoeia》The hydrochloric acid that version dissolution method first method in 2010 is prepared to embodiment 4 is general
Clarke rope slow releasing tablet is measured, and dissolution medium is respectively pH1.2 hydrochloric acid solution, pH4.5 acetate salt buffer
Liquid, pH6.8 phosphate buffer 500ml, water, rotating speed 100rpm, dissolution medium temperature is 37 DEG C ± 0.5 DEG C,
Sampled respectively at 1,2,4,6,9,12,16,20,24 hours, release profiles are as shown in figure 4, Fig. 4
Release profiles under different pH condition for the Pramipexole Dihydrochloride Sustained Release Tablets described in the embodiment of the present invention 4；
From fig. 4, it can be seen that Pramipexole Dihydrochloride Sustained Release Tablets all assume 24 hours slow release in 4 kinds of dissolution mediums,
In non-TCP friendly flow, and sustained release performance is good.
According to《Chinese Pharmacopoeia》Two annex XE Content uniformity test regulations of version in 2010, to enforcement
The uniformity of the Pramipexole Dihydrochloride Sustained Release Tablets of example 4 preparation is detected, specifically, prepared by Example 4
Pramipexole Dihydrochloride Sustained Release Tablets 10 be measured, adopt high performance liquid chromatography measure respectively every with mark
The amount of showing is 100 relative amount X, seeks the absolute of its average X and standard deviation S and labelled amount and the difference of average
Value A (A=100-X)；As A+1.80S≤15.0, that is, the uniformity of dosage units of test sample meets regulation；
Result shows, the uniformity of dosage units A+1.80S of the slow releasing tablet of embodiment 4 preparation is 2.8；The uniformity is higher.
The explanation of above example is only intended to help and understands the method for the present invention and its core concept.Should
Point out, for those skilled in the art, under the premise without departing from the principles of the invention,
The present invention can also be carried out with some improvement and modify, these improve and modification also falls into right of the present invention and wants
In the protection domain asked.
Claims (10)
1. a kind of slow releasing preparation of body of Pramipexole dihydrochloride, including：Body of Pramipexole dihydrochloride, the first non-cellulose
Class neutrality slow-release material, the second non-cellulose class neutrality slow-release material and crospolyvinylpyrrolidone；
Wherein, described first non-cellulose class neutrality slow-release material is vinylacetate, polyvinylpyrrolidine
One or more of ketone, polyvinyl alcohol and polyalkylene oxide；
Described second non-cellulose class neutrality slow-release material be Glyceryl Behenate, glyceryl monostearate,
One or more of hexadecanol, octadecanol and Brazil wax.
2. preparation according to claim 1 is it is characterised in that described first non-cellulose class is neutral
Slow-release material is (25～70) with the mass ratio of described slow releasing preparation：100, preferably (30～60)：100.
3. preparation according to claim 1 is it is characterised in that described two non-cellulose classes are neutral slow
The mass ratio releasing material with described slow releasing preparation is (5～40)：100, preferably (10～30)：100.
4. preparation according to claim 1 is it is characterised in that described crospolyvinylpyrrolidone
Mass ratio with described slow releasing preparation is (3～30)：100, preferably (4～20)：100.
5. preparation according to claim 1 it is characterised in that described body of Pramipexole dihydrochloride with described
The mass ratio of slow releasing preparation is (0.1～3)：100, preferably (0.15～2)：100.
6. preparation according to claim 1 is it is characterised in that described slow releasing preparation also includes figuration
Agent.
7. preparation according to claim 6 it is characterised in that described excipient be Microcrystalline Cellulose,
One or more of micropowder silica gel and magnesium stearate.
8. a kind of preparation method of the slow releasing preparation of body of Pramipexole dihydrochloride, including：
1) by body of Pramipexole dihydrochloride solution and crospolyvinylpyrrolidone mixing granulation, obtain containing hydrochloric acid
The granule of pramipexole；
2) by obtain the granule containing body of Pramipexole dihydrochloride, the first non-cellulose class slow-release material, second
Non-cellulose class slow-release material and excipient mixing, obtain body of Pramipexole dihydrochloride slow releasing preparation.
9. preparation method according to claim 8 is it is characterised in that described excipient is micropowder silicon
One or more of glue, Microcrystalline Cellulose and magnesium stearate.
10. preparation method according to claim 9 is it is characterised in that described step 2) it is specially：
Second non-cellulose class neutrality slow-release material is mixed homogeneously with micropowder silica gel in excipient, is contained
There is the mixture of the second non-cellulose class neutrality slow-release material；
By the mixture containing the second non-cellulose class neutrality slow-release material, add the first non-cellulose class
Neutral slow-release material and step 1) obtain containing body of Pramipexole dihydrochloride granule mixing, be subsequently adding tax
In shape agent, Microcrystalline Cellulose continues mixing, is eventually adding magnesium stearate mixing in excipient, obtains hydrochloric acid general
Clarke rope slow releasing preparation.
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