CN105030721B - A kind of Orally-administered solid composition containing body of Pramipexole dihydrochloride - Google Patents
A kind of Orally-administered solid composition containing body of Pramipexole dihydrochloride Download PDFInfo
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- CN105030721B CN105030721B CN201510542417.5A CN201510542417A CN105030721B CN 105030721 B CN105030721 B CN 105030721B CN 201510542417 A CN201510542417 A CN 201510542417A CN 105030721 B CN105030721 B CN 105030721B
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- Prior art keywords
- pramipexole dihydrochloride
- tablet
- osmotic
- coating agent
- pramipexole
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- 229960002652 pramipexole dihydrochloride Drugs 0.000 title claims abstract description 97
- VQMNWIMYFHHFMC-UHFFFAOYSA-N tert-butyl 4-hydroxyindole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=CC2=C1O VQMNWIMYFHHFMC-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 239000008247 solid mixture Substances 0.000 title claims description 9
- 239000007962 solid dispersion Substances 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 239000011248 coating agent Substances 0.000 claims description 60
- 230000003204 osmotic effect Effects 0.000 claims description 55
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 42
- 238000000576 coating method Methods 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- 239000008213 purified water Substances 0.000 claims description 22
- 239000011780 sodium chloride Substances 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 16
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 16
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 16
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 10
- 229920003081 Povidone K 30 Polymers 0.000 claims description 10
- 229920002301 cellulose acetate Polymers 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 10
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 10
- 239000000314 lubricant Substances 0.000 claims description 9
- 230000004584 weight gain Effects 0.000 claims description 9
- 235000019786 weight gain Nutrition 0.000 claims description 9
- 238000005550 wet granulation Methods 0.000 claims description 9
- 235000020985 whole grains Nutrition 0.000 claims description 9
- 239000005030 aluminium foil Substances 0.000 claims description 7
- 239000000853 adhesive Substances 0.000 claims description 6
- 230000001070 adhesive effect Effects 0.000 claims description 6
- 239000002075 main ingredient Substances 0.000 claims description 5
- 239000003826 tablet Substances 0.000 abstract description 62
- 239000003814 drug Substances 0.000 abstract description 23
- 238000013270 controlled release Methods 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 11
- 239000000126 substance Substances 0.000 abstract description 11
- 230000007547 defect Effects 0.000 abstract description 5
- 239000003405 delayed action preparation Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000007939 sustained release tablet Substances 0.000 abstract description 5
- 238000009501 film coating Methods 0.000 abstract description 4
- 239000007888 film coating Substances 0.000 abstract description 4
- 238000009472 formulation Methods 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 description 14
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 14
- 229960003089 pramipexole Drugs 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 6
- 229960003638 dopamine Drugs 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- 101100087414 Arabidopsis thaliana RH20 gene Proteins 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 102000015554 Dopamine receptor Human genes 0.000 description 3
- 108050004812 Dopamine receptor Proteins 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 229960001631 carbomer Drugs 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000005253 cladding Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000819 hypertonic solution Substances 0.000 description 1
- 229940021223 hypertonic solution Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 229940101972 mirapex Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The defects of present invention is overcomes body of Pramipexole dihydrochloride conventional tablet and sustained-release tablet non-constant velocity to release the drug, body of Pramipexole dihydrochloride controlled release preparation is researched and developed, in order to overcome bulk pharmaceutical chemicals body of Pramipexole dihydrochloride, content is low in the formulation at the same time, bulk pharmaceutical chemicals are first prepared into solid dispersions by the defects of being not easy to be uniformly mixed.Finally consider from moisture-proof angle, after semi-transparent film coating, coat general thin clothing.Gained body of Pramipexole dihydrochloride controlled release piece preparation method is simple, customary preparation methods production can be used with easy industrialization, production efficiency is high, stability is good, the remarkable advantage such as quality controllable.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of Orally-administered solid composition containing body of Pramipexole dihydrochloride and
Preparation method and use.
Background technology
Parkinson's (Parkinson ' s disease, PD) are a kind of common nervous system degeneration diseases, and the elderly is more
See, average age of onset is 60 years old or so, and the young Parkinson's of less than 40 years old onset are more rare.China over-65s crowd PD
Illness rate be about 1.7%.Most of Parkinsonian is Sporadic cases, and the only patient less than 10% has family history.
The most important pathological change of Parkinson's is that the denaturation of substantia nigra of midbrain dopamine (dopamine, DA) serotonergic neuron is dead, thus
And striatum DA level conspicuousness is caused to reduce and cause a disease.Cause the definite cause of disease of this pathological change still unclear at present, lose
Biography factor, environmental factor, age ageing, oxidative stress etc. may participate in the denaturation death process of PD dopaminergic neurons.
Body of Pramipexole dihydrochloride is a kind of non-ergot analog derivative, acts on DA-2 acceptors highly selectively, in early days can be single
Treatment Parkinson's solely can be shared with dopamine using treatment Parkinson's, late period.Body of Pramipexole dihydrochloride is by Germany
Boehringer Ingelheim companies develop, FDA approvals body of Pramipexole dihydrochloride listing on May 10th, 1997, trade name
Mirapex, is sold jointly in the U.S. by Boehringer Ingelheim companies and Pharmacia companies.It is FDA in 20 generation
Record the nineties in first approval for Parkinson medicine, the medicine at present the whole world more than 50 country use, and in
Listed in China within 2007.Body of Pramipexole dihydrochloride structural formula is as follows：
Body of Pramipexole dihydrochloride is a kind of dopamine-receptor stimulant, and being combined with height with dopamine release subfamily selects
Property and specificity, and there is complete intrinsic activity, there is selective affinity to D3 acceptors therein.Body of Pramipexole dihydrochloride passes through emerging
The put forth energy dopamine receptor of corpus straitum mitigates the dyskinesia of disturbances in patients with Parkinson disease.Animal experiment shows that body of Pramipexole dihydrochloride suppresses more
The synthesis of bar amine, release and renewal.
The mechanism of action of the uneasy comprehensive sign of leg of body of Pramipexole dihydrochloride treatment is not yet clear and definite.The prompting of Neuropharmacology evidence may
It is related with dopaminergic system.
What this product listed earliest is to take the ordinary preparation of 3 times day, and since patient takes medicine difficult, compliance is poor.It is in addition, continuous
It is the basic demand for treating parkinsonism so as to long-term reversal symptom to stimulate dopamine receptor.Therefore, it is external to have listed that day takes again
The common sustained release preparation of 1 time.
Since body of Pramipexole dihydrochloride ordinary tablet and sustained release preparation are non-constant speed release medicines, the release of medicine and absorption rate also by
To the influence of the factors such as gastro-intestinal Fluid in patient body, therefore its blood concentration still has larger fluctuation, it is difficult to controls and it is anticipated that with one
Fixed uncertainty, its useful effect duration and side effect size also vary with each individual, and individual difference is big, have uncontrollable
Property.
Osmotic pump type controlled release preparation is a kind of system characterized by zero-order release kinetics using osmotic pressure as drug release power
Agent technology.
Elementary osmotic pump (elementary osmotic pump, EOP) is the first generation product of osmotic pump controlled release tablet,
It is the basis of all kinds osmotic pump tablet.The structure of the osmotic pump tablet is high for water soluble drug (solubility 5%~10%) and tool
The penetration enhancer of osmotic pressure or other auxiliary materials are pressed into a solid label, and one layer of rate controlling semipermeable membrane of outsourcing, then uses laser
One or more small delivery aperture is opened on label coating membrane, the moisture of oral rear intestines and stomach enters piece by pellicle
Core, makes medicine be dissolved into saturated solution or suspension, has the dissolving of hyperosmosis auxiliary material in addition, so the solution in kind tablet film
For hypertonic solution, osmotic pressure is up to 4053~5066kPa, and osmotic pressure is only 760kPa in vivo.Due to having big inside and outside film
Permeable pressure head, drug solution are then persistently pumped out by small delivery aperture, its discharge is equal with penetrating into the water in film, until
The medicine of label is molten most.
When medicine is not completely dissolved in label, rate of releasing drug is carried out by constant speed, when label drug concentration is gradually less than full
And concentration, rate of releasing drug also gradually decrease down zero.The infiltration rate for controlling water is the rate of release of controllable medicine, and water oozes
Enter speed depending on the transparent performance of film and the osmotic pressure of label.The medicine for having 60~80% or more in general EOP products is
Discharged with constant rate of speed, and often have the time lag of 30~60min before Zero order release.Such a osmotic pump tablet in label because containing
Improve the salt or sugar of osmotic pressure, after punching can moisture absorption, therefore Chang Kai crosses outside the osmotic pump tablet of release hole that to wrap film moisture-proof.
Chinese patent 201110060788.1 provides a kind of body of Pramipexole dihydrochloride osmotic pump type controlled release tablets, including medicated layer
With boosting layer.Medicated layer is made of medicine, rush osmo active substance and other auxiliary materials；Boosting layer is by hydrophilic expanded polymer, rush
Osmo active substance and other auxiliary materials and coloring agent form, then using ethyl cellulose-povidone as pellicle outside double-layer tablets
It is coated, and an aperture is made a call in medicated layer laser, alternatively carries out film coating.
, it is necessary to suppress bilayer tablet, conventional tablet equipment can not be met the requirements osmotic pump tablet complex process described in this patent.
The content of the invention
In view of the above-mentioned defects in the prior art, inventor obtains a kind of prescription and technique is simple, stablize by further investigation
The more preferable Orally-administered solid composition containing body of Pramipexole dihydrochloride of property and reappearance.And provide preparation process and be prepared into single chamber
Osmotic tablet.After being taken orally so as to fulfill body of Pramipexole dihydrochloride, medicine is with zero order kinetics constant release, so as to avoid existing city
The non-constant velocity drug release of body of Pramipexole dihydrochloride ordinary tablet and sustained release tablets is sold, reduces medicine blood concentration fluctuation.
The preparation method of the pharmaceutical composition, method is simple, stablizes, and is easy to industrialized production.
Composition of the present invention is using body of Pramipexole dihydrochloride as main ingredient component, by water-soluble solid dispersant, pellicle bag
Clothing agent, osmotic pressure accelerating agent, penetration-assisting agent, filler, adhesive, lubricant, general thin coating agent composition, can pass through following step
Suddenly it is further prepared into osmotic pump tablet：
1) take body of Pramipexole dihydrochloride, water-soluble solid dispersant, is dissolved in purified water successively, it is dry must contain hydrochloric acid it is general
The slow-release solid dispersion of clarke rope；
2) step 1) obtained solid dispersion is taken, with osmotic pressure accelerating agent, filler, penetration-assisting agent, is uniformly mixed, and adds viscous
Mixture, wet granulation, dry, whole grain, obtains tabletting intermediate；
3) tabletting intermediate obtained by step 2) is taken, adds lubricant, is uniformly mixed, tabletting, obtains body of Pramipexole dihydrochloride plain piece；
4) body of Pramipexole dihydrochloride plain piece obtained by taking step 3), is coated with pellicle coating agent, and the one of coating tablet
Side perforating, obtains body of Pramipexole dihydrochloride osmotic tablet；
5) body of Pramipexole dihydrochloride osmotic tablet obtained by taking step 4), is coated with general thin coating agent, obtains finished product；
It is characterized in that, the water-soluble solid dispersant is PVP K30, the pellicle coating agent is
The mixture of cellulose acetate and polyethylene glycol 400, mass ratio preferably 7:1.
Osmotic pumps coated tablet as described above, every containing body of Pramipexole dihydrochloride (in terms of Pramipexole) 0.5mg~
2.0mg, wherein osmotic pressure accelerating agent are selected from sodium chloride, fructose, the preferably one or more of mannitol, sodium chloride；Penetration-assisting agent selects
From polyethylene oxide, carbomer, the one or more in hydroxypropyl methylcellulose, preferably polyethylene oxide；The preferred crystallite of filler
Cellulose, the preferred purified water of adhesive；The preferred magnesium stearate of lubricant.
Coated tablet prescription is as follows described in this patent：
。
The further preferred prescription of coated tablet described in this patent is as follows：
。
Preparation process is as follows：
1) body of Pramipexole dihydrochloride is taken, PVP K30, is dissolved in purified water successively, dry to contain hydrochloric acid
The slow-release solid dispersion of Pramipexole；
2) step 1) obtained solid dispersion is taken, with sodium chloride, microcrystalline cellulose, polyethylene oxide, is uniformly mixed, and adds
Purified Water q. s, wet granulation, dry, whole grain, obtains tabletting intermediate；
3) tabletting intermediate obtained by step 2) is taken, adds magnesium stearate, is uniformly mixed, tabletting, obtains body of Pramipexole dihydrochloride element
Piece；
4) with cellulose acetate, polyethylene glycol 400 in mass ratio 7:1 is dissolved in acetone, prepares pellicle coating agent, right
Body of Pramipexole dihydrochloride plain piece obtained by step 3) is coated, coating weight gain 10%-15%, and in a side perforating of coating tablet, hole
Footpath about 0.4mm, obtains body of Pramipexole dihydrochloride osmotic tablet；
5) body of Pramipexole dihydrochloride osmotic tablet obtained by taking step 4), is coated with general thin coating agent, and coating increases
Weight 4%-6%；
6) coating tablet obtained by taking step 5), is packed with PVC/ aluminium foils, obtains finished product.
The defects of present invention is overcomes body of Pramipexole dihydrochloride conventional tablet and sustained-release tablet non-constant velocity to release the drug, research and development
Body of Pramipexole dihydrochloride controlled release preparation, while in order to overcome bulk pharmaceutical chemicals body of Pramipexole dihydrochloride, content is low in the formulation, and it is equal to be not easy mixing
Bulk pharmaceutical chemicals are first prepared into solid dispersions by the defects of even.Finally consider from moisture-proof angle, after semi-transparent film coating, cladding
General thin clothing.
Gained body of Pramipexole dihydrochloride controlled release piece preparation method is simple, and customary preparation methods production can be used to have easy industry
Change, production efficiency is high, stability is good, the remarkable advantage such as quality controllable.Patent Shen of the present invention is further illustrated by testing as follows
Please.Experiment one：Auxiliary material compatibility test
By body of Pramipexole dihydrochloride bulk pharmaceutical chemicals；Body of Pramipexole dihydrochloride bulk pharmaceutical chemicals respectively with solid dispersion polyvinylpyrrolidone
K30, osmotic pressure accelerating agent sodium chloride, fructose, mannitol, penetration-assisting agent polyethylene oxide, carbomer, hydroxypropyl methylcellulose, filling
Agent microcrystalline cellulose, lactose monohydrate, according to weight ratio 1:5, it is uniformly mixed, body of Pramipexole dihydrochloride bulk pharmaceutical chemicals and lubricant stearic acid
Magnesium is by weight 20:1, be uniformly mixed, put respectively in culture dish stand into<The thin layer of 5mm thickness.Sample number into spectrum is respectively A, B, C, D,
E, F, G, H, I, J, K.
Above-mentioned sample is put 60 DEG C respectively, RH20% ± 5%；Relative humidity RH90 ± 5%；Illumination 4500Lx ± 500Lx,
RH20% ± 5%；Place 10 days under intense light conditions, sampled in the 5th day and the 10th day, detect body of Pramipexole dihydrochloride content and related
Material.It is as shown in the table to detect data.
1 body of Pramipexole dihydrochloride bulk pharmaceutical chemicals of table and auxiliary material compatibility experiments result (60 DEG C, RH20% ± 5%) to be selected
。
2 body of Pramipexole dihydrochloride bulk pharmaceutical chemicals of table and auxiliary material compatibility experiments result (RH90 ± 5%) to be selected
。
Selected auxiliary material and bulk pharmaceutical chemicals body of Pramipexole dihydrochloride are can be seen that in high temperature from above experimental result, high humidity, under the conditions of
Storage, compared with body of Pramipexole dihydrochloride bulk pharmaceutical chemicals, no significant change.That is body of Pramipexole dihydrochloride and solid dispersion polyvinyl pyrrole
Alkanone K30, osmotic pressure accelerating agent sodium chloride, fructose, mannitol, penetration-assisting agent polyethylene oxide, carbomer, hydroxypropyl methylcellulose,
Filler microcrystalline cellulose, lactose monohydrate is good with magnesium stearate lubricant compatibility, can be with above-mentioned auxiliary material in solid states
Under be grouped compound, and be further prepared into solid pharmaceutical preparation, but equally find out from experimental result, sodium chloride, polyethylene oxide
Better than other auxiliary materials to be selected, therefore it is preferred that sodium chloride is examined at the same time as osmotic pressure accelerating agent, preferably polyethylene oxide as penetration-assisting agent
Consider tablet shaping, preferably microcrystalline cellulose is filler.
Experiment two：Prescription screening is tested
The dosage of each auxiliary material in prescription has further been screened by testing as follows.
Table 2：Formulation study situation (1000 inventorys)
。
Preparation process is as follows：
1) PVP K30 is taken, body of Pramipexole dihydrochloride, is dissolved in purified water successively, dry to contain hydrochloric acid
The slow-release solid dispersion of Pramipexole；
2) step 1) obtained solid dispersion is taken, with sodium chloride, microcrystalline cellulose, polyethylene oxide, is uniformly mixed, and adds
Purified Water q. s, wet granulation, dry, whole grain, obtains tabletting intermediate；
3) tabletting intermediate obtained by step 2) is taken, adds magnesium stearate, is uniformly mixed, tabletting, obtains body of Pramipexole dihydrochloride element
Piece；
4) with cellulose acetate polyethylene glycol 400 in mass ratio 7:1 is dissolved in acetone, prepares pellicle coating agent, right
Body of Pramipexole dihydrochloride plain piece obtained by step 3) is coated, coating weight gain 10%-15%, and in a side perforating of coating tablet, hole
Footpath about 0.4mm, obtains body of Pramipexole dihydrochloride osmotic tablet.
The selection result：
1. 1,3,5,7 formability of prescription is good, Dissolution behaviours are good；
2. prescription 2,4 is since sodium chloride dosage is more, since sodium chloride density is larger in tableting processes, material is layered
Phenomenon, causes final gained plain piece content uneven；
3. prescription 6,8 have adjusted the dosage of penetration-assisting agent polyethylene oxide, cause the final osmotic pump tablet dissolution of dissolution
Property is bad.
Experiment three：Controlled release tablet dissolution is tested
By above-mentioned prescription 1, prescription 3, prescription 5, simultaneously film coating prepares body of Pramipexole dihydrochloride controlled release tablet sample to prescription 7 respectively
Product, and measure its dissolved corrosion.Body of Pramipexole dihydrochloride plain piece prescription is as follows：
。
Preparation process is as follows：
1) body of Pramipexole dihydrochloride is taken, PVP K30, is dissolved in purified water successively, dry to contain hydrochloric acid
The slow-release solid dispersion of Pramipexole；
2) step 1) obtained solid dispersion is taken, with sodium chloride, microcrystalline cellulose, polyethylene oxide, is uniformly mixed, and adds
Purified Water q. s, wet granulation, dry, whole grain, obtains tabletting intermediate；
3) tabletting intermediate obtained by step 2) is taken, adds magnesium stearate, is uniformly mixed, tabletting, obtains body of Pramipexole dihydrochloride element
Piece；
4) with cellulose acetate polyethylene glycol 400 in mass ratio 7:1 is dissolved in acetone, prepares pellicle coating agent, right
Body of Pramipexole dihydrochloride plain piece obtained by step 3) is coated, coating weight gain 10%-15%, and in a side perforating of coating tablet, hole
Footpath about 0.4mm, obtains body of Pramipexole dihydrochloride osmotic tablet；
5) body of Pramipexole dihydrochloride osmotic tablet obtained by taking step 4), is coated with general thin coating agent, and coating increases
Weight 4%-6%；
6) coating tablet obtained by taking step 5), is packed with PVC/ aluminium foils, obtains finished product.
Controlled release tablet sample prepared by aforementioned four prescription, numbering A, B, C, D, puts 500ml respectively, and 0.05M phosphate delays
In fliud flushing, with basket method measure, rotating speed 100rpm, measure 1 it is small when, 2 it is small when, 4 it is small when, 6 it is small when, 9 it is small when, 12 it is small when, 16 it is small when,
20 it is small when and 24 it is small when dissolution rate.
The different prescription Pramipexole controlled release tablet Dissolution of Tablet of 5 four, table investigate (%, n=5)
| Sample | 1 it is small when | 2 it is small when | 4 it is small when | 6 it is small when | 9 it is small when | 12 it is small when | 16 it is small when | 20 it is small when | 24 it is small when |
| A | 5.81 | 13.86 | 23.43 | 37.21 | 52.89 | 72.37 | 97.24 | 98.75 | 99.29 |
| B | 4.39 | 14.99 | 25.16 | 38.34 | 52.76 | 70.48 | 99.57 | 98.26 | 99.47 |
| C | 5.37 | 13.84 | 27.11 | 39.75 | 51.18 | 68.45 | 99.01 | 98.83 | 99.31 |
| D | 6.71 | 15.80 | 25.58 | 38.21 | 50.17 | 66.19 | 97.39 | 99.60 | 99.28 |
It was found from above-mentioned data, with the Pramipexole Dospan of 4 kinds of different prescriptions preparations, continue at the uniform velocity to release in 24
Put, achieveed the purpose that sustained release drugs.
Experiment four：Accelerated stability experiment in 6 months
Pramipexole Dospan obtained by Example 1-4 (embodiment 1-4, containing packaging) and 1.5mg specification imports respectively
Numbering A-E puts 40 DEG C ± 2 DEG C to five groups of samples of product body of Pramipexole dihydrochloride sustained release tablets (Sen Fuluo, containing packaging) respectively respectively, 75% ±
Stored 6 months under the conditions of 5%RH, respectively at 0 month, in January, 2 months, in March, in June, be measured by sampling relevant nature, obtain corresponding data,
It is as shown in the table.
6 embodiment 1-4 of table is compared with import marketed tablet sample stability
。
It is general according to prescription described in embodiment 1-4 of the present invention and the hydrochloric acid prepared by technique it can be seen from upper table data
Clarke rope Dospan, at 40 DEG C ± 2 DEG C, under 75% ± 5%RH acceleration environments, after storage in 6 months, its content, related material
It is varied from, but content, more than 99.2%, maximum list impurity is less than 0.08%, and total impurities is below 0.5%, dissolution rate
It is qualified；Correspond, commercially available pramipexole hydrochloride tablet is after accelerating storage in 6 months, maximum single miscellaneous although its content
Matter and total impurities are compared with embodiment 1-4 without significant difference.
Based on as above analyzing, according to prescription described in embodiment 1-4 of the present invention and the body of Pramipexole dihydrochloride prepared by technique
Under acceleration conditions, the data after storing 6 months show that its stability is suitable with commercially available sustained-release tablet to Dospan, but from
Its dissolved corrosion can be seen that its dissolution rate and be effectively controlled, so that the present invention has prominent substantive distinguishing features
And marked improvement, and there is practicality.
Embodiment
Beneficial effects of the present invention are further illustrated by following experiment.But it is not limited to following embodiments, this area
Technical staff made on the basis of the present invention, equivalent substitute or the conversion of substantive content of the present invention are not departed from, also at this
Within the protection domain of invention.
Embodiment 10.5mg specification body of Pramipexole dihydrochloride controlled release tablets prepare (unit：g)
Prescription：
| Supplementary material | Specification 1 |
| Label forms： | |
| Body of Pramipexole dihydrochloride (in terms of Pramipexole) | 0.5g |
| PVP K30 | 5.0g |
| Sodium chloride | 50.0g |
| Polyethylene oxide | 10.0g |
| Microcrystalline cellulose | 33.5 |
| Purified water | In right amount |
| Magnesium stearate | 1.0g |
| It is made altogether | 1000 |
| Pellicle coating agent forms： | |
| Cellulose acetate | In right amount |
| Polyethylene glycol 400 | In right amount |
| General thin clothing | In right amount |
Preparation process is as follows：
1) body of Pramipexole dihydrochloride is taken, PVP K30, is dissolved in purified water successively, dry to contain hydrochloric acid
The slow-release solid dispersion of Pramipexole；
2) step 1) obtained solid dispersion is taken, with sodium chloride, microcrystalline cellulose, polyethylene oxide, is uniformly mixed, and adds
Purified Water q. s, wet granulation, dry, whole grain, obtains tabletting intermediate；
3) tabletting intermediate obtained by step 2) is taken, adds magnesium stearate, is uniformly mixed, tabletting, obtains body of Pramipexole dihydrochloride element
Piece；
4) with cellulose acetate polyethylene glycol 400 in mass ratio 7:1 is dissolved in acetone, prepares pellicle coating agent, right
Body of Pramipexole dihydrochloride plain piece obtained by step 3) is coated, coating weight gain 10%-15%, and in a side perforating of coating tablet, hole
Footpath about 0.4mm, obtains body of Pramipexole dihydrochloride osmotic tablet；
5) body of Pramipexole dihydrochloride osmotic tablet obtained by taking step 4), is coated with general thin coating agent, and coating increases
Weight 4%-6%；
6) coating tablet obtained by taking step 5), is packed with PVC/ aluminium foils, obtains finished product.
Embodiment 21.0mg specification body of Pramipexole dihydrochloride controlled release tablets prepare (unit：g)
Prescription：
。
Preparation process is as follows：
1) body of Pramipexole dihydrochloride is taken, PVP K30, is dissolved in purified water successively, dry to contain hydrochloric acid
The slow-release solid dispersion of Pramipexole；
2) step 1) obtained solid dispersion is taken, with sodium chloride, microcrystalline cellulose, polyethylene oxide, is uniformly mixed, and adds
Purified Water q. s, wet granulation, dry, whole grain, obtains tabletting intermediate；
3) tabletting intermediate obtained by step 2) is taken, adds magnesium stearate, is uniformly mixed, tabletting, obtains body of Pramipexole dihydrochloride element
Piece；
4) with cellulose acetate polyethylene glycol 400 in mass ratio 7:1 is dissolved in acetone, prepares pellicle coating agent, right
Body of Pramipexole dihydrochloride plain piece obtained by step 3) is coated, coating weight gain 10%-15%, and in a side perforating of coating tablet, hole
Footpath about 0.4mm, obtains body of Pramipexole dihydrochloride osmotic tablet；
5) body of Pramipexole dihydrochloride osmotic tablet obtained by taking step 4), is coated with general thin coating agent, and coating increases
Weight 4%-6%；
6) coating tablet obtained by taking step 5), is packed with PVC/ aluminium foils, obtains finished product.
Embodiment 31.5mg specification body of Pramipexole dihydrochloride controlled release tablets prepare (unit：g)
Prescription：
。
Preparation process is as follows：
1) body of Pramipexole dihydrochloride is taken, PVP K30, is dissolved in purified water successively, dry to contain hydrochloric acid
The slow-release solid dispersion of Pramipexole；
2) step 1) obtained solid dispersion is taken, with sodium chloride, microcrystalline cellulose, polyethylene oxide, is uniformly mixed, and adds
Purified Water q. s, wet granulation, dry, whole grain, obtains tabletting intermediate；
3) tabletting intermediate obtained by step 2) is taken, adds magnesium stearate, is uniformly mixed, tabletting, obtains body of Pramipexole dihydrochloride element
Piece；
4) with cellulose acetate polyethylene glycol 400 in mass ratio 7:1 is dissolved in acetone, prepares pellicle coating agent, right
Body of Pramipexole dihydrochloride plain piece obtained by step 3) is coated, coating weight gain 10%-15%, and in a side perforating of coating tablet, hole
Footpath about 0.4mm, obtains body of Pramipexole dihydrochloride osmotic tablet；
5) body of Pramipexole dihydrochloride osmotic tablet obtained by taking step 4), is coated with general thin coating agent, and coating increases
Weight 4%-6%；
6) coating tablet obtained by taking step 5), is packed with PVC/ aluminium foils, obtains finished product.
Embodiment 42.0mg specification body of Pramipexole dihydrochloride controlled release tablets prepare (unit：g)
Prescription：
。
Preparation process is as follows：
1) body of Pramipexole dihydrochloride is taken, PVP K30, is dissolved in purified water successively, dry to contain hydrochloric acid
The slow-release solid dispersion of Pramipexole；
2) step 1) obtained solid dispersion is taken, with sodium chloride, microcrystalline cellulose, polyethylene oxide, is uniformly mixed, and adds
Purified Water q. s, wet granulation, dry, whole grain, obtains tabletting intermediate；
3) tabletting intermediate obtained by step 2) is taken, adds magnesium stearate, is uniformly mixed, tabletting, obtains body of Pramipexole dihydrochloride element
Piece；
4) with cellulose acetate polyethylene glycol 400 in mass ratio 7:1 is dissolved in acetone, prepares pellicle coating agent, right
Body of Pramipexole dihydrochloride plain piece obtained by step 3) is coated, coating weight gain 10%-15%, and in a side perforating of coating tablet, hole
Footpath about 0.4mm, obtains body of Pramipexole dihydrochloride osmotic tablet；
5) body of Pramipexole dihydrochloride osmotic tablet obtained by taking step 4), is coated with general thin coating agent, and coating increases
Weight 4%-6%；
6) coating tablet obtained by taking step 5), is packed with PVC/ aluminium foils, obtains finished product.
Claims (5)
- A kind of 1. Orally-administered solid composition containing body of Pramipexole dihydrochloride, using body of Pramipexole dihydrochloride as main ingredient component, by water solubility Solid dispersion, pellicle coating agent, osmotic pressure accelerating agent sodium chloride, penetration-assisting agent polyethylene oxide, filler microcrystalline cellulose, Adhesive purified water, magnesium stearate lubricant, general thin coating agent composition, osmotic pumps are further prepared into by following steps Dospan, it is characterised in that the osmotic pumps coated tablet prescription is as follows：。
- A kind of 2. Orally-administered solid composition containing body of Pramipexole dihydrochloride, using body of Pramipexole dihydrochloride as main ingredient component, by water solubility Solid dispersion, pellicle coating agent, osmotic pressure accelerating agent sodium chloride, penetration-assisting agent polyethylene oxide, filler microcrystalline cellulose, Adhesive purified water, magnesium stearate lubricant, general thin coating agent composition, osmotic pumps are further prepared into by following steps Dospan, it is characterised in that the osmotic pumps coated tablet prescription is as follows：。
- A kind of 3. Orally-administered solid composition containing body of Pramipexole dihydrochloride, using body of Pramipexole dihydrochloride as main ingredient component, by water solubility Solid dispersion, pellicle coating agent, osmotic pressure accelerating agent sodium chloride, penetration-assisting agent polyethylene oxide, filler microcrystalline cellulose, Adhesive purified water, magnesium stearate lubricant, general thin coating agent composition, osmotic pumps are further prepared into by following steps Dospan, it is characterised in that the osmotic pumps coated tablet prescription is as follows：。
- A kind of 4. Orally-administered solid composition containing body of Pramipexole dihydrochloride, using body of Pramipexole dihydrochloride as main ingredient component, by water solubility Solid dispersion, pellicle coating agent, osmotic pressure accelerating agent sodium chloride, penetration-assisting agent polyethylene oxide, filler microcrystalline cellulose, Adhesive purified water, magnesium stearate lubricant, general thin coating agent composition, osmotic pumps are further prepared into by following steps Dospan, it is characterised in that the osmotic pumps coated tablet prescription is as follows：。
- 5. the Orally-administered solid composition containing body of Pramipexole dihydrochloride as described in claim 1-4 is any, it is characterised in that described to ooze Pump coated tablet preparation process is as follows thoroughly：1) body of Pramipexole dihydrochloride is taken, PVP K30, is dissolved in purified water successively, dry to contain hydrochloric acid pula The slow-release solid dispersion of gram rope；2) step 1) obtained solid dispersion is taken, with sodium chloride, microcrystalline cellulose, polyethylene oxide, is uniformly mixed, and adds purifying Appropriate amount of water, wet granulation, dry, whole grain, obtains tabletting intermediate；3) tabletting intermediate obtained by step 2) is taken, adds magnesium stearate, is uniformly mixed, tabletting, obtains body of Pramipexole dihydrochloride plain piece；4) with cellulose acetate, polyethylene glycol 400 in mass ratio 7:1 is dissolved in acetone, pellicle coating agent is prepared, to step 3) gained body of Pramipexole dihydrochloride plain piece is coated, coating weight gain 10%-15%, and in a side perforating of coating tablet, aperture is about 0.4mm, obtains body of Pramipexole dihydrochloride osmotic tablet；5) body of Pramipexole dihydrochloride osmotic tablet obtained by taking step 4), is coated, coating weight gain with general thin coating agent 4%-6%；6) coating tablet obtained by taking step 5), is packed with PVC/ aluminium foils, obtains finished product.
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| US20040266794A1 (en) * | 2003-03-21 | 2004-12-30 | Boehringer Ingelheim International Gmbh | Pramipexole for the reduction of excessive food intake for children |
| CN100464740C (en) * | 2006-06-30 | 2009-03-04 | 清华大学 | Osmotic pump controlled release tablet of hydroxycamptothecin solid dispersion and preparation method thereof |
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| CN101721386B (en) * | 2008-10-31 | 2012-06-27 | 北京天衡药物研究院 | Novel two-chamber osmotic pump controlled-release tablet and preparation method thereof |
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