CN105796519A - Pramipexole dihydrochloride sustained-release tablet and preparation method thereof - Google Patents
Pramipexole dihydrochloride sustained-release tablet and preparation method thereof Download PDFInfo
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- CN105796519A CN105796519A CN201410842464.7A CN201410842464A CN105796519A CN 105796519 A CN105796519 A CN 105796519A CN 201410842464 A CN201410842464 A CN 201410842464A CN 105796519 A CN105796519 A CN 105796519A
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Abstract
The invention discloses a pramipexole dihydrochloride sustained-release tablet and a preparation method thereof. The sustained-release tablet is prepared from a treatment effective amount of pramipexole dihydrochloride, at least one low-viscosity neutral water-swelling polymer, at least one high-viscosity neutral water-swelling polymer, at least one anionic water-swelling polymer and other medicinal excipients, wherein the mass contents of the low-viscosity and high-viscosity neutral water-swelling polymers in the sustained-release tablet are both 5 to 90%, and the particle size D90 of the pramipexole dihydrochloride raw material is 20 to 150 [mu]m. Compared with the prior art, the particle size of the pramipexole dihydrochloride raw material is controlled so as to allow the content uniformity of the tablet to be good; through selection of proper adjuvant, the sustained-release tablet can rapidly reach effective plasma concentration in the human body and realizes slow release in a medium with a pH value of 6.8, achieving the effect of complete release within 24 h; product stability is improved by using a direct tableting process; moreover, the preparation method is simple, easily practicable, suitable for industrial production and high in application value.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, be specially body of Pramipexole dihydrochloride slow releasing tablet and preparation method thereof.
Background technology
Body of Pramipexole dihydrochloride chemical name is: hydration two hydrochloric acid (S)-2-amino-4,5,6,7-tetrahydrochysene-6-propylamine-benzothiazole, body of Pramipexole dihydrochloride molecular formula is C10H17N3S·2HCl·H2O, molecular weight is 302.26, for treating the S&S of idiopathic parkinsonism.For Parkinsonian, body of Pramipexole dihydrochloride, as non-Ergota class dopamine-receptor stimulant, stimulating dopamine receptor in high selectivity ground, thus improving patients symptomatic, being an advantage over the medicine of new generation of Ergota analog derivative.1997, pramipexole immediate release (IR) tablet was granted at U.S. head, listed respectively at European Union, Switzerland, Canada and South America and East Bloc and Asia subsequently, for Parkinsonian first-line treatment.Body of Pramipexole dihydrochloride is white or off-white color crystalline powder, is absent from polymorphic；Soluble in water and methanol, dissolubility is higher than 20mg/ml；Slightly soluble in 96% ethanol, dissolubility is about 18mg/ml.In buffer within the scope of pH value 1-7.5, dissolubility is above 10mg/ml.Body of Pramipexole dihydrochloride belongs to Biopharmaceutics Classification I class, namely high-dissolvability, high osmosis medicine, and solid-state stability is higher, degrades hardly, but under solution state, room temperature is placed, and less stable can produce a lot of impurity.Clinical research shows that body of Pramipexole dihydrochloride fast-release tablet can be used for treating Early Parkinson's disease or advanced Parkinson symptom million and symptom with levodopa combination.IR sheet must take 3 times every day.Abroad show about the body of Pramipexole dihydrochloride slow releasing tablet Parkinsonian multiple center trial for the treatment of, randomized controlled, 3 groups of parallel clinical researchs, for early stage disturbances in patients with Parkinson disease, when giving levodopa treatment, give body of Pramipexole dihydrochloride slow releasing tablet, dosage was increased to 3mg/ days by 0.375mg/ days, and when treating 18 weeks, the UPDRS scoring for the treatment of group is for-8.1, placebo group is-5.1, and the two has significant difference.When treating 33 weeks, the UPDRS scoring for the treatment of group is for-8.6, and placebo group is-3.8, and in research process, it does not have because of the Different therapeutical effect that age or sex cause.For advanced Parkinson patients, the motor fluctuation having at least 2h every day is in "Off" state, gives body of Pramipexole dihydrochloride slow releasing tablet while giving levodopa treatment, and initial dose is 0.375mg, and in 7 weeks, increase to 4.5mg gradually according to curative effect and toleration, then continue medication 26 weeks.The dosage of levodopa can be reduced when Dopaminergic Drugs untoward reaction occurs.When treating 18 weeks, the UPDRS scoring for the treatment of group is for-11.0, and placebo group is-6.1, and the adjustment of the "Off" state for the treatment of group is changed to-2.1h, and placebo group is-1.4h.When 33 weeks, the UPDRS for the treatment of group is-11.1, and placebo group is-6.8.From pharmacokinetics regard, pramipexole IR sheet after oral administration, absorbs completely rapidly.Its absolute bioavailability is more than 90%, and maximal plasma concentration occurs in 1 to 3 hour.Feed can affect the absorption of body of Pramipexole dihydrochloride.Body of Pramipexole dihydrochloride demonstrates linear kinetics, and the change of blood plasma level is relatively small in the patient.Its elimination half-life is 8 hours in adolescence, is 12 hours in old people.Body of Pramipexole dihydrochloride conventional tablet, needs to take 3 times every day, and for handicapped, the disturbances in patients with Parkinson disease medication compliance of trick or body tremor is extremely disadvantageous, and required medical and nursing work and expense are also more higher.Body of Pramipexole dihydrochloride slow releasing tablet can ensure that long-term slow releasing in 24 hours, daily once, can effectively reduce administration frequency, improve patient medication compliance；Meanwhile, slow releasing preparation is ordinary preparation relatively, can reduce the fluctuation of blood medicine, advantageously reduce the toxic and side effects of medicine, improve Drug safety and effectiveness.
Prior art describes many methods preparing body of Pramipexole dihydrochloride slow releasing tablet:
Patent WO2004/010997 describes the prolongation release of pharmaceutical compositions of a kind of oral tablet form, it comprises the pramipexole water soluble salt being dispersed in substrate, described substrate comprises hydrophilic polymer and pregelatinized Starch, and the tensile strength of described starch is at least 0.15kN.cm-2, it is preferable that at least 0.175kN.cm-2, more preferably at 0.2kN.cm-2.According to preferred scheme, it provides the pharmaceutical composition of oral tablet form, this tablet contains the kernel being dispersed in substrate, described kernel comprises the pramipexoledihydrochloride monohydrae that content is about 0.375,0.75,1.5,3.5 or 4.5mg, described substrate comprises (a) HPMC type 2208, content is about the 35% to 50% of tablet weight, and (b) pregelatinized Starch, and the tensile strength in the solid compositions of 0.8 is at least 0.15kNcm-2, account for about the 45% to 65% of tablet weight；Described kernel is substantially enclosed within the coating accounting for tablet weight about 2% to 7%, and described coating comprises hydrophobic fibre element and insoluble component and HPMC hole-forming component.This patent prescription is without pH dependency, it is impossible to arrives more than effective blood drug concentration faster after reaching commercialized product administration, then maintains effective blood drug concentration slowly.
Patent CN101005830B describes the pramipexole of a kind of oral delivery form and extends release tablet compositions, it comprises the pramipexole being dispersed in substrate or its officinal salt, described substrate comprises the water-swellable polymer of at least two non-pregelatinized starch, and one of which is anionic polymer, preferred acrylate copolymer, being more preferably carbomer, content accounts for the 1% to 10% of tablet total weight amount；The water-swellable polymer of another kind of non-pre-paying starch based is neutral polymer, it is preferable that hydroxypropyl cellulose, more preferably hypromellose, content accounts for the 25% to 65% of tablet total weight amount.This patent is Yuan Yan producer patent, described slow releasing tablet, and in the simulated gastric fluid of pH1.2, in 24 hours slow releasing, final burst size is higher than 90%；And 24 hours burst sizes are about 80% in pH4.5 and pH6.8 buffer, it is impossible to discharge completely.And the vitro release that pH6.8 buffer is intestinal juice pH environment in analogue body measures medium, as the main portions Duodeno-small intestinal of drug absorption, as medicine can not discharge completely, bioavailability will reduce.There is defective risk in slow releasing tablet uniformity of dosage units and the release standard deviation (RSD) prepared by this patented method simultaneously.
Patent CN102406626B discloses compositing formula and the preparation method of a kind of Pramipexole hydrochloride slow release tablet, body of Pramipexole dihydrochloride proportion is 0.1%～1.5%, ethyl cellulose amount ranges is 30.0～45.0%, and hydroxypropyl methyl cellulose is 30.0～50.0%；Technique adopts direct powder compression.There is the defect identical with CN1671381 in this Formulation and technical scheme.On the one hand because technique of direct powder compression is guarantee that the slow-release auxiliary material consumption relatively wet granulation technology needed for 24 hours slow release is high, increase R&D costs, body of Pramipexole dihydrochloride prescription ratio in slow releasing tablet is 0.1%～1.5% on the other hand, belong to low dosage low content medicine, there is defective risk in direct powder compression uniformity of dosage units and release standard deviation (RSD), can cause every batch sample mass discrepancy because of the differences between batches of the physical propertys such as supplementary material granularity, mobility, bulk density.
Patent application CN103520128A discloses the slow releasing tablet of a kind of pramipexole, it is characterised in that: this slow releasing tablet is by pramipexole or its officinal salt, two or more water-swellable neutral polymers and other excipient composition；This slow releasing tablet is without pH dependency, it is impossible to arrives more than effective blood drug concentration faster after reaching commercialized product administration, then maintains effective blood drug concentration slowly.
Summary of the invention
It is an object of the invention to, it is provided that a kind of content uniformly, good stability, in pH6.8 medium, 24h discharges body of Pramipexole dihydrochloride slow releasing tablet and preparation method thereof completely, its be applicable to every day oral administration once.
The present invention adopts the following technical scheme that a kind of body of Pramipexole dihydrochloride slow releasing tablet, is made up of the body of Pramipexole dihydrochloride of therapeutically effective amount, at least one low viscosity neutral water swelling polymer, at least one high viscosity neutral water swelling polymer, at least one anionic water swelling polymer and other pharmaceutical excipient；Low viscosity neutral water swelling polymer, high viscosity neutral water swelling polymer mass content in slow releasing tablet are 5%-90%；The particle diameter D90 of described body of Pramipexole dihydrochloride raw material is 20 μm-150 μm；Described low viscosity refers to the viscosity < 1000mPa.s of mass concentration 2% aqueous solutions of polymers, and described high viscosity refers to the viscosity > 1000mPa.s of mass concentration 2% aqueous solutions of polymers.
In aforementioned body of Pramipexole dihydrochloride slow releasing tablet, described low viscosity neutral water swelling polymer, high viscosity neutral water swelling polymer are selected from one or more in the copolymer of methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl methyl cellulose, galactomannan, tragacanth, agar, guar gum, levan, poly(ethylene oxide), poly(propylene oxide), oxirane and expoxy propane.
In aforementioned body of Pramipexole dihydrochloride slow releasing tablet, described anionic water swelling polymer is one or more in carbomer, acrylate copolymer, methacrylate polymer, methacrylic acid copolymer, alginate, carrageenin, arabic gum, xanthan gum, chitosan, sodium carboxymethyl cellulose, carboxymethylcellulose calcium.
In aforementioned body of Pramipexole dihydrochloride slow releasing tablet, other described pharmaceutical excipient includes disintegrating agent, filler, fluidizer, lubricant.
In aforementioned body of Pramipexole dihydrochloride slow releasing tablet, described disintegrating agent is one or more in low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, dried starch.
In aforementioned body of Pramipexole dihydrochloride slow releasing tablet, described filler is one or more in starch, Icing Sugar, dextrin, microcrystalline Cellulose, mannitol, xylitol, sorbitol, lactose calcium sulfate, calcium hydrogen phosphate, medicinal calcium carbonate.
In aforementioned body of Pramipexole dihydrochloride slow releasing tablet, described fluidizer is silicon dioxide.
In aforementioned body of Pramipexole dihydrochloride slow releasing tablet, described lubricant is one or more in magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, Pulvis Talci.
The preparation method of above-described body of Pramipexole dihydrochloride slow releasing tablet is: adopts direct compression process, comprises the following steps:
(1) weigh body of Pramipexole dihydrochloride, grind so that it is particle diameter D90 is between 20 μm-150 μm；Body of Pramipexole dihydrochloride after grinding is progressively increased with anionic water swelling polymer and other pharmaceutical excipient equivalent of part and mixes, obtain premix；
(2) premix is mixed homogeneously through multidirectional mixer with all the other adjuvants, obtain intermediate；
(3) intermediate tabletting in tablet machine, to obtain final product.
Preparation method is more specifically: comprise the following steps:
(1) weigh body of Pramipexole dihydrochloride, grind so that it is particle diameter D90 is between 20 μm-150 μm；100 mesh sieves that body of Pramipexole dihydrochloride after grinding and anionic water swelling polymer equivalent progressively increased mix 3 times, obtain premix A；80 mesh sieves that premix A and filler equivalent progressively increased mix 3 times, obtain premix B；
(2) by premix B and low viscosity neutral water swelling polymer, high viscosity neutral water swelling polymer and disintegrating agent through multidirectional mixer mixing 20min, mixture C is obtained；Again by mixture C and fluidizer, lubricant through multidirectional mixer mixing 2min, obtain intermediate；
(3) intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting, Stress control, at 1500lbs, to obtain final product.
In order to ensure the effect of the present invention, applicant is through experimental study, each influence factor of having investigated in body of Pramipexole dihydrochloride slow releasing tablet preparation process, specific as follows:
Test example one:
For research slow releasing tablet preparation process under the high temperature conditions on the impact having related substance, prepared slow releasing tablet A and slow releasing tablet B by wet granule compression tablet and direct compression, put in the baking oven of 60 DEG C simultaneously, investigate the 5th, the 10th day dissolution result.
1, the preparation of slow releasing tablet A
1.1 pastille solution preparations: for weighing more accurately, dissolving and divided dose, solution is made into 3 times of batches, divides 3 parts after weighing, add the amount of 1 part.Namely weigh 0.5625g crude drug, add in 27g water and dissolve, decile three parts.
1.2 silicon dioxide weighing recipe quantity are placed in mortar, add recipe quantity containing drug solns, when dry, add HPMCK4M, equivalent is progressively increased mixing three times of sieving.Add HPC-EF, Carbomer971 p equivalent progressively increases mixing three times of sieving.
1.3 always mix: add the magnesium stearate of recipe quantity, mix 2min.
1.4 tablettings: with φ 9.0mm, shallow arc, without carving characters punch die tabletting；Tablet weight controls at 250 ± 2mg, and Stress control is at 1500lbs.
2, the preparation of slow releasing tablet B
| Supplementary material | Every content (mg) | Percentage composition (%) | Test consumption (g) |
| Body of Pramipexole dihydrochloride | 0.375 | 0.15 | 0.1875 |
| HPMCK4M | 40 | 15.98 | 20 |
| HPC-EF | 162 | 64.7 | 81 |
| Carbomer971 p | 7.5 | 3.00 | 3.75 |
| Mannitol | 36 | 14.38 | 18 |
| Silicon dioxide | 2 | 0.80 | 1 |
| Magnesium stearate | 2.5 | 1.00 | 1.25 |
| Gross weight | 250.375 |
2.1 body of Pramipexole dihydrochloride and Carbomer971 p equivalent progressively increased 100 mesh sieves mix 3 times, obtain A；
2.2A and mannitol equivalent progressively increased 80 mesh sieves mix 3 times, obtain B；
2.3B and HPMCK4M equivalent progressively increased 80 mesh sieves mix 3 times, obtain C；
2.4C and HPC-EF equivalent progressively increased 60 mesh sieves mix 3 times, obtain D；
2.5D and all the other adjuvants (silicon dioxide, magnesium stearate) manual mixing 2min (plastic bag), obtains intermediate.
2.6 tablettings: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting；Tablet weight controls at 250 ± 2mg, and Stress control is at 1500lbs.
3, both the above slow releasing tablet is put in the baking oven of 60 DEG C simultaneously, investigate and have related substance result in the 0th, 5,10 days.
Relevant substance detecting method is as follows:
Lucifuge operates.Take test formulation fine powder appropriate (being approximately equivalent to body of Pramipexole dihydrochloride 0.75mg), put in 10ml measuring bottle, add acetonitrile 2ml, shake up gently and make sample fully dispersed, the pH2.0 phosphate buffer adding 10% sodium chloride is appropriate, shake up, be diluted to scale after ultrasonic 20 minutes, shake up, it is centrifugal that (rotating speed is 13000 revs/min, time is 15 minutes), precision pipettes supernatant 2.0ml, puts in 10ml measuring bottle, it is diluted to scale with pH2.0 phosphate buffer, shake up, filter with the filter membrane of 0.45 μm, take subsequent filtrate as need testing solution；Weigh corn starch, hypromellose and carbomer each in right amount, put in 10ml measuring bottle, add acetonitrile 2ml, shake up gently and make sample fully dispersed, the pH2.0 phosphate buffer adding 10% sodium chloride is appropriate, shake up, be diluted to scale after ultrasonic 20 minutes, shake up, it is centrifugal that (rotating speed is 13000 revs/min, time is 15 minutes), precision pipettes supernatant 2.0ml, puts in 10ml measuring bottle, it is diluted to scale with pH2.0 phosphate buffer, shake up, filter with the filter membrane of 0.45 μm, take subsequent filtrate as adjuvant solution；Another precision respectively weighs body of Pramipexole dihydrochloride reference substance, impurity J reference substance, impurity K reference substance about 15mg each with impurity L reference substance, put in 100ml measuring bottle, the pH2.0 phosphate buffer 20ml adding acetonitrile-10% sodium chloride makes dissolving, it is diluted to scale with pH2.0 phosphate buffer, shake up, precision measures in right amount, the solution of each about 0.15 μ g of hydrochloric pramipexole reference substance in every 1ml, impurity J reference substance, impurity K reference substance and impurity L reference substance is made, as reference substance solution with pH2.0 phosphate buffer.Weigh impurity G reference substance, impurity I1 reference substance, impurity I2 reference substance, body of Pramipexole dihydrochloride reference substance respectively each in right amount, the pH2.0 phosphate buffer adding acetonitrile-10% sodium chloride makes dissolving in right amount, the solution of each about 0.15 μ g of impure G in every 1ml, impurity I1, impurity I2 and body of Pramipexole dihydrochloride, 0.15 μ g, 0.15 μ g and 15 μ g is made, as system suitability solution with the dilution of pH2.0 phosphate buffer.It is filler with octadecylsilane chemically bonded silica, as suitable in intersilODS-3V chromatographic column (150mm × 4.6mm × 5 μm) or performance；With phosphate buffer pH3.0 (taking 9.1g potassium dihydrogen phosphate and 5.0g1-perfluorooctane sulfonate, the 1000ml that adds water dissolves, and adjusts pH3.0 with phosphoric acid), for mobile phase A, acetonitrile is Mobile phase B, and according to the form below carries out gradient elution；Detection wavelength is 240nm, 262nm and 326nm；Column temperature is 40 DEG C.Precision measures system suitability solution 100 μ l and injects chromatograph of liquid, records chromatogram.Separating degree between impurity I1 and impurity I2 is not less than 2.0, is not less than 1.3 between impurity G and impurity I2, and the separating degree between impurity G and body of Pramipexole dihydrochloride is not less than 2.0.Precision measures each 100 μ l of need testing solution, reference substance solution and adjuvant solution again, is injected separately into chromatograph of liquid, records chromatogram.In the chromatogram of 262nm wavelength record, need testing solution as aobvious with impurity G, the chromatographic peak of the identical retention time of impurity I1, impurity I2 or other impurity peaks, with body of Pramipexole dihydrochloride for reference substance by external standard method with each impurity content of calculated by peak area, all must not persalt pramipexole labelled amount 0.4%；If aobvious relative retention time is the chromatographic peak of 0.96, with body of Pramipexole dihydrochloride for reference substance by external standard method with its content of calculated by peak area, must not persalt pramipexole labelled amount 1.0%.In the chromatogram of 326nm wavelength record, such as the chromatographic peak of aobvious retention time identical with impurity J, by external standard method with its content of calculated by peak area, must not persalt pramipexole labelled amount 0.4%；Such as other impurity peaks aobvious, be multiplied by 1.1547 calculating impurity contents by external standard method with peak area for reference substance with impurity J, all must not persalt pramipexole labelled amount 0.4%.In the chromatogram of 240nm wavelength record, such as the chromatographic peak of aobvious retention time identical with impurity K, impurity L, by external standard method with calculated by peak area impurity content, all must not persalt pramipexole labelled amount 0.4%.Such as other impurity peaks aobvious, with body of Pramipexole dihydrochloride for reference substance by external standard method with calculated by peak area, all must not persalt pramipexole labelled amount 0.4%.Total impurities must not persalt pramipexole labelled amount 2.0%.(adjuvant peak and solvent peak are disregarded；If a certain unknown impuritie occurs in the chromatogram of more than 1 wavelength record, then calculate obtained maximum contaminant content meter at each wavelength place with this impurity).
60 DEG C of stability result of 0 day high temperature:
60 DEG C of stability result of 5th day high temperature:
60 DEG C of stability result of 10th day high temperature:
Result: substantially can be seen that slow releasing tablet A and slow releasing tablet B detected when 0 day and have related substance not to be clearly distinguished from, but slow releasing tablet A's has related substance apparently higher than slow releasing tablet B after high temperature 60 DEG C 5 days, 10 days, thus may indicate that the stability of medicine is better than by the technique of direct compression and former grind wet granule compression tablet technique.
Test example two:
For studying the impact on mixing homogeneity of the slow releasing tablet preparation process Raw particle diameter, prepare slow releasing tablet C, slow releasing tablet D, slow releasing tablet E by the raw material of different-grain diameter and adjuvant direct compression, investigate the uniformity of dosage units after tabletting.
1, the preparation of slow releasing tablet C
| Supplementary material | Every content (mg) | Percentage composition (%) | Test consumption (g) |
| Body of Pramipexole dihydrochloride | 0.375 | 0.15 | 3.75 |
| HPMCK4M | 40 | 15.98 | 400 |
| HPC-EF | 162 | 64.7 | 1620 |
| Carbomer971 p | 7.5 | 3.00 | 75 |
| Mannitol | 36 | 14.38 | 360 |
| Silicon dioxide | 2 | 0.80 | 20 |
| Magnesium stearate | 2.5 | 1.00 | 25 |
| Gross weight | 250.375 |
1.1 by body of Pramipexole dihydrochloride raw mill, crosses 100 mesh sieves, takes raw material on screen cloth, and surveying particle diameter D (90) is 150 μm, and body of Pramipexole dihydrochloride and Carbomer971 p equivalent 100 mesh sieves that progressively increased mix 3 times, obtain A；
1.2A and mannitol equivalent progressively increased 80 mesh sieves mix 3 times, obtain B；
1.3B and HPMCK4M, HPC-EF, through multidirectional mixer mixing 20min, obtain C；C and silicon dioxide, magnesium stearate, through multidirectional mixer mixing 2min, obtain intermediate.
1.4 tablettings: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting；Tablet weight controls at 250 ± 2mg, and Stress control is at 1500lbs.
2, the preparation of slow releasing tablet D
| Supplementary material | Every content (mg) | Percentage composition (%) | Test consumption (g) |
| Body of Pramipexole dihydrochloride | 0.375 | 0.15 | 3.75 |
| HPMCK4M | 40 | 15.98 | 400 |
| HPC-EF | 162 | 64.7 | 1620 |
| Carbomer971 p | 7.5 | 3.00 | 75 |
| Mannitol | 36 | 14.38 | 360 |
| Silicon dioxide | 2 | 0.80 | 20 |
| Magnesium stearate | 2.5 | 1.00 | 25 |
| Gross weight | 250.375 |
2.1 by body of Pramipexole dihydrochloride raw mill, crosses 250 mesh sieves, takes raw material on screen cloth, and surveying particle diameter D (90) is 63 μm, and body of Pramipexole dihydrochloride and Carbomer971 p equivalent 100 mesh sieves that progressively increased mix 3 times, obtain A；
2.2A and mannitol equivalent progressively increased 80 mesh sieves mix 3 times, obtain B；
2.3B and HPMCK4M, HPC-EF, through multidirectional mixer mixing 20min, obtain C；C and silicon dioxide, magnesium stearate, through multidirectional mixer mixing 2min, obtain intermediate.
2.4 tablettings: intermediate φ 9.0mm, shallow arc, punch die tabletting, tablet weight control at 250 ± 2mg without carving characters, Stress control is at 1500lbs.
3, the preparation of slow releasing tablet E
| Supplementary material | Every content (mg) | Percentage composition (%) | Test consumption (g) |
| Body of Pramipexole dihydrochloride | 0.375 | 0.15 | 3.75 |
| HPMC K4M | 40 | 15.98 | 400 |
| HPC-EF | 162 | 64.7 | 1620 |
| Carbomer971 p | 7.5 | 3.00 | 75 |
| Mannitol | 36 | 14.38 | 360 |
| Silicon dioxide | 2 | 0.80 | 20 |
| Magnesium stearate | 2.5 | 1.00 | 25 |
| Gross weight | 250.375 |
3.1 by after body of Pramipexole dihydrochloride raw material micronization, and surveying particle diameter D (90) is 20 μm, and body of Pramipexole dihydrochloride and Carbomer971 p equivalent 100 mesh sieves that progressively increased mix 3 times, obtain A；
3.2A and mannitol equivalent progressively increased 80 mesh sieves mix 3 times, obtain B；
3.3B and HPMCK4M, HPC-EF, through multidirectional mixer mixing 20min, obtain C；C and silicon dioxide, magnesium stearate, through multidirectional mixer mixing 2min, obtain intermediate.
3.4 tablettings: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting；Tablet weight controls at 250 ± 2mg, and Stress control is at 1500lbs.
4, by slow releasing tablet C, slow releasing tablet D, slow releasing tablet E measure uniformity of dosage units result as follows:
Result: substantially can be seen that slow releasing tablet C and the slow releasing tablet E uniformity of dosage units compared with slow releasing tablet D is poor, illustrates that raw material particle size mixing homogeneity between 20 μm to 150 μm is relatively better.
Test example three:
For studying anionic water swelling polymer and the high and low viscosity neutral water swelling polymer synergy impact on release, only it is prepared from slow releasing tablet F with anionic water swelling polymer and high viscosity neutral water swelling polymer；It is prepared from slow releasing tablet G with anionic water swelling polymer, high viscosity neutral water swelling polymer and low viscosity neutral water swelling polymer；Separately take former slow releasing tablet (i.e. CN101005830B) of grinding, investigate these three slow releasing tablet release behavior in different pH medium.
1, the preparation of slow releasing tablet F
| Supplementary material | Every content (mg) | Percentage composition (%) | Test consumption (g) |
| Body of Pramipexole dihydrochloride | 0.375 | 0.15 | 3.75 |
| HPMCK4M | 202 | 80.68 | 2020 |
| Carbomer971 p | 7.5 | 3.00 | 75 |
| Mannitol | 36 | 14.38 | 360 |
| Silicon dioxide | 2 | 0.80 | 20 |
| Magnesium stearate | 2.5 | 1.00 | 25 |
| Gross weight | 250.375 |
1.1 by body of Pramipexole dihydrochloride raw mill, crosses 250 mesh sieves, takes raw material on screen cloth, and surveying particle diameter D (90) is 63 μm, and body of Pramipexole dihydrochloride and Carbomer971 p equivalent 100 mesh sieves that progressively increased mix 3 times, obtain A；
1.2A and mannitol equivalent progressively increased 80 mesh sieves mix 3 times, obtain B；
1.3B and HPMCK4M, through multidirectional mixer mixing 20min, obtains C；C and silicon dioxide, magnesium stearate, through multidirectional mixer mixing 2min, obtain intermediate.
1.4 tablettings: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting；Tablet weight controls at 250 ± 2mg, and Stress control is at 1500lbs.
2, the preparation of slow releasing tablet G
| Supplementary material | Every content (mg) | Percentage composition (%) | Test consumption (g) |
| Body of Pramipexole dihydrochloride | 0.375 | 0.15 | 3.75 |
| HPMCK4M | 40 | 15.98 | 400 |
| HPC-EF | 162 | 64.7 | 1620 |
| Carbomer971 p | 7.5 | 3.00 | 75 |
| Mannitol | 36 | 14.38 | 360 |
| Silicon dioxide | 2 | 0.80 | 20 |
| Magnesium stearate | 2.5 | 1.00 | 25 |
| Gross weight | 250.375 |
1.1 by body of Pramipexole dihydrochloride raw mill, crosses 250 mesh sieves, takes raw material on screen cloth, and surveying particle diameter D (90) is 63 μm, and body of Pramipexole dihydrochloride and Carbomer971 p equivalent 100 mesh sieves that progressively increased mix 3 times, obtain A；
1.2A and mannitol equivalent progressively increased 80 mesh sieves mix 3 times, obtain B；
1.3B and HPMCK4M, HPC-EF, through multidirectional mixer mixing 20min, obtain C；C and silicon dioxide, magnesium stearate, through multidirectional mixer mixing 2min, obtain intermediate.
1.4, tabletting: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting；Tablet weight controls at 250 ± 2mg, and Stress control is at 1500lbs.
Take slow releasing tablet F, G and former grind slow releasing tablet, according to drug release determination method (Chinese Pharmacopoeia two annex XD the first methods of version in 2010), adopt dissolution method (Chinese Pharmacopoeia two annex XC the first methods of version in 2010) device, with pH1.2 hydrochloric acid-sodium chloride solution, pH6.8 0.05mol/L phosphate buffer 500ml for dissolution medium, rotating speed is 100 turns per minute, operate in accordance with the law, through 1,2,4,6,9,12,16,20,24 hours, take solution appropriate, filter, take continuous worry liquid as need testing solution；It is appropriate that another precision weighs body of Pramipexole dihydrochloride reference substance, makes in every 1ml the solution containing about 0.75 μ g (0.375mg) as reference substance solution with dissolution medium.It is measured, calculates the stripping quantity of every.Result is as follows:
Average stripping quantity in pH1.2 hydrochloric acid-sodium chloride solution
| Time (h) | 1 | 2 | 4 | 6 | 9 | 12 |
| Slow releasing tablet F (%) | 18.5 | 30.6 | 40.9 | 57.9 | 67.8 | 76.5 |
| Slow releasing tablet G (%) | 22.1 | 37.9 | 54.9 | 63.8 | 79.1 | 89.6 |
| Former grind slow releasing tablet (%) | 24.1 | 39.9 | 55.0 | 66.2 | 78.1 | 86.6 |
Average stripping quantity in the 0.05mol/L phosphate buffer of pH6.8
| Time (h) | 1 | 2 | 4 | 6 | 9 | 12 | 16 | 20 | 24 |
| Slow releasing tablet F (%) | 10.6 | 18.4 | 25.4 | 35.5 | 42.9 | 52.9 | 62.1 | 68.5 | 73.3 |
| Slow releasing tablet G (%) | 14.3 | 22.8 | 31.6 | 41.3 | 53.8 | 67.8 | 79.3 | 83.6 | 86.9 |
| Former grind slow releasing tablet (%) | 14.6 | 22.4 | 33.4 | 42.5 | 52.9 | 62.9 | 72.1 | 78.5 | 80.3 |
Result: substantially can be seen that slow releasing tablet G and former can grind that slow releasing tablet is the same quickly to be discharged in pH1.2 hydrochloric acid-sodium chloride solution, simultaneously can be complete in 24h release in the 0.05mol/L phosphate buffer of pH6.8.
Conclusion: the slow releasing tablet simultaneously prepared with anionic water swelling polymer, high viscosity neutral water swelling polymer and low viscosity neutral water swelling polymer both can reach effective blood drug concentration faster in human body, again can in pH6.8 medium slow releasing be finally reached the effect discharged completely.
Compared with prior art, the present invention is by controlling body of Pramipexole dihydrochloride raw material particle size D (90) between 20 μm-150 μm, make the particle diameter difference between raw material and adjuvant less, mix more uniform, make tableting processes more smooth simultaneously, not easily it is layered, thus effectively controlling the uniformity of dosage units of product；Slow releasing tablet is made to discharge faster in pH1.2 medium by anionic water swelling polymer so that slow releasing tablet can reach effective blood drug concentration faster in human body；Make slow releasing tablet discharge in pH6.8 medium slowly by anionic water swelling polymer and high viscosity neutral water swelling polymer, reach the effect of 24h slow releasing；Slow releasing tablet is made to form substantial amounts of duct thus reaching the effect discharged completely in the later stage of release because low viscosity neutral water swelling polymer is dissolved in the water by low viscosity neutral water swelling polymer；And avoid the contact of raw material and water by direct compression technique thus reach can the effect of storage steady in a long-term.It addition, production technology of the present invention is simple, it is suitable for industrialized production, has higher using value.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further illustrated:
Embodiments of the invention 1: the preparation of body of Pramipexole dihydrochloride slow releasing tablet:
According to the form below, practical amount weighs various supplementary material (HPMC and hydroxypropyl methyl cellulose, wherein K4M model is full-bodied, and K100 model is low viscous):
| Supplementary material | Every weight (mg) | Percentage composition (%) | Practical amount (g) |
| Body of Pramipexole dihydrochloride | 0.375 | 0.15 | 3.75 |
| HPMCK4M | 40 | 15.98 | 400 |
| HPMCK100 | 162 | 64.7 | 1620 |
| Carbomer971 p | 7.5 | 3.00 | 75 |
| Mannitol | 36 | 14.38 | 360 |
| Silicon dioxide | 2 | 0.80 | 20 |
| Magnesium stearate | 2.5 | 1.00 | 25 |
| Amount to | 250.375 | 100 | 2503.75 |
Concrete preparation process is:
(1) being ground by body of Pramipexole dihydrochloride raw material, cross 300 mesh sieves, take raw material on screen cloth, recording particle diameter D (90) is 50 μm；100 mesh sieves that body of Pramipexole dihydrochloride after grinding and Carbomer971 p equivalent progressively increased mix 3 times, obtain premix A；80 mesh sieves that premix A and mannitol equivalent progressively increased mix 3 times, obtain premix B；
(2) by premix B and HPMCK4M, HPMCK100 through multidirectional mixer mixing 20min, mixture C is obtained；Again by mixture C and silicon dioxide and magnesium stearate through multidirectional mixer mixing 2min, obtain intermediate；
(3) tabletting: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting, Stress control is at 1500lbs, and tablet weight controls at 250 ± 2mg, obtains the body of Pramipexole dihydrochloride slow releasing tablet that specification is 0.25g.
Embodiment 2: the preparation of body of Pramipexole dihydrochloride slow releasing tablet:
According to the form below, practical amount weighs various supplementary material (wherein K4M model is full-bodied, and E5 model is low viscous):
| Supplementary material | Every weight (mg) | Percentage composition (%) | Practical amount (g) |
| Body of Pramipexole dihydrochloride | 0.375 | 0.15 | 3.75 |
| HPMCK4M | 40 | 15.98 | 400 |
| HPMCE5 | 162 | 64.7 | 1620 |
| Carbomer971 p | 7.5 | 3.00 | 75 |
| Mannitol | 36 | 14.38 | 360 |
| Silicon dioxide | 2 | 0.80 | 20 |
| Magnesium stearate | 2.5 | 1.00 | 25 |
| Amount to | 250.375 | 100 | 2503.75 |
Concrete preparation process is:
(1) being ground by body of Pramipexole dihydrochloride raw material, cross 250 mesh sieves, take raw material on screen cloth, recording particle diameter D (90) is 63 μm；100 mesh sieves that body of Pramipexole dihydrochloride after grinding and Carbomer971 p equivalent progressively increased mix 3 times, obtain A；80 mesh sieves that A and mannitol equivalent progressively increased mix 3 times, obtain B；
(2) by B and HPMCK4M, HPMCE5 through multidirectional mixer mixing 20min, C is obtained；Again by C and silicon dioxide and magnesium stearate through multidirectional mixer mixing 2min, obtain intermediate；
(3) tabletting: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting, Stress control is at 1500lbs, and tablet weight controls at 250 ± 2mg, obtains the body of Pramipexole dihydrochloride slow releasing tablet that specification is 0.25g.
Embodiment 3: the preparation of body of Pramipexole dihydrochloride slow releasing tablet:
According to the form below, practical amount weighs various supplementary material:
| Supplementary material | Every weight (mg) | Percentage composition (%) | Practical amount (g) |
| Body of Pramipexole dihydrochloride | 0.375 | 0.15 | 3.75 |
| HPMCK4M (highly viscous) | 40 | 15.98 | 400 |
| HPMCK100 (low viscous) | 162 | 64.7 | 1620 |
| Carbomer971 p | 7.5 | 3.00 | 75 |
| Starch | 36 | 14.38 | 360 |
| Silicon dioxide | 2 | 0.80 | 20 |
| Magnesium stearate | 2.5 | 1.00 | 25 |
| Amount to | 250.375 | 100 | 2503.75 |
Concrete preparation process is:
(1) being ground by body of Pramipexole dihydrochloride raw material, cross 400 mesh sieves, take raw material on screen cloth, recording particle diameter D (90) is 38 μm；100 mesh sieves that body of Pramipexole dihydrochloride after grinding and Carbomer971 p equivalent progressively increased mix 3 times, obtain A；80 mesh sieves that A and starch equivalent progressively increased mix 3 times, obtain B；
(2) by B and HPMCK4M, HPMCK100 through multidirectional mixer mixing 20min, C is obtained；Again by C and silicon dioxide and magnesium stearate through multidirectional mixer mixing 2min, obtain intermediate；
(3) tabletting: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting, Stress control is at 1500lbs, and tablet weight controls at 250 ± 2mg, obtains the body of Pramipexole dihydrochloride slow releasing tablet that specification is 0.25g.
Embodiment 4: the preparation of body of Pramipexole dihydrochloride slow releasing tablet:
According to the form below, practical amount weighs various supplementary material (HEC and hydroxyethyl cellulose, HPC and hydroxypropyl cellulose, crosslinking CMC-Na and cross-linking sodium carboxymethyl cellulose):
| Supplementary material | Every weight (mg) | Percentage composition (%) | Practical amount (g) |
| Body of Pramipexole dihydrochloride | 5 | 2 | 50 |
| HEC (highly viscous) | 62.5 | 25 | 625 |
| HPC-EF (low viscous) | 127.5 | 51 | 1275 |
| Methacrylate polymer | 25 | 10 | 250 |
| Crosslinking CMC-Na | 10 | 4 | 100 |
| Microcrystalline Cellulose | 16.5 | 6.6 | 165 |
| Silicon dioxide | 1.5 | 0.6 | 15 |
| Calcium stearate | 2 | 0.8 | 20 |
| Amount to | 250 | 100 | 2500 |
Concrete preparation process is:
(1) being ground by body of Pramipexole dihydrochloride raw material, cross 150 mesh sieves, take raw material on screen cloth, recording particle diameter D (90) is 100 μm；100 mesh sieves that body of Pramipexole dihydrochloride after grinding and methacrylate polymer equivalent progressively increased mix 3 times, obtain A；80 mesh sieves that A and microcrystalline Cellulose equivalent progressively increased mix 3 times, obtain B；
(2) by B and HEC, HPC-EF and crosslinking CMC-Na through multidirectional mixer mixing 20min, obtain C；Again by C and silicon dioxide and calcium stearate through multidirectional mixer mixing 2min, obtain intermediate；
(3) tabletting: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting, Stress control is at 1500lbs, and tablet weight controls at 250 ± 2mg, obtains the body of Pramipexole dihydrochloride slow releasing tablet that specification is 0.25g.
Embodiment 5: the preparation of body of Pramipexole dihydrochloride slow releasing tablet:
According to the form below, practical amount weighs various supplementary material (HEMC and hydroxyethylmethyl-cellulose):
| Supplementary material | Every weight (mg) | Percentage composition (%) | Practical amount (g) |
| Body of Pramipexole dihydrochloride | 10 | 4 | 100 |
| HEMC (highly viscous) | 165 | 66 | 1650 |
| Tragacanth (low viscous) | 37.5 | 15 | 375 |
| Alginate | 12.5 | 5 | 125 |
| Polyvinylpolypyrrolidone | 7.5 | 3 | 75 |
| Xylitol | 12.5 | 5 | 125 |
| Silicon dioxide | 2.5 | 1 | 25 |
| Stearic acid | 2.5 | 1 | 25 |
| Amount to | 250 | 100 | 2500 |
Concrete preparation process is:
(1) being ground by body of Pramipexole dihydrochloride raw material, cross 200 mesh sieves, take raw material on screen cloth, recording particle diameter D (90) is 75 μm；100 mesh sieves that body of Pramipexole dihydrochloride after grinding and alginate equivalent progressively increased mix 3 times, obtain A；80 mesh sieves that A and xylitol equivalent progressively increased mix 3 times, obtain B；
(2) by B and HEMC, tragacanth and polyvinylpolypyrrolidone through multidirectional mixer mixing 20min, C is obtained；Again by C and silicon dioxide and stearic acid through multidirectional mixer mixing 2min, obtain intermediate；
(3) tabletting: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting, Stress control is at 1500lbs, and tablet weight controls at 250 ± 2mg, obtains the body of Pramipexole dihydrochloride slow releasing tablet that specification is 0.25g.
Embodiment 6: the preparation of body of Pramipexole dihydrochloride slow releasing tablet:
According to the form below, practical amount weighs various supplementary material (L-HPC and low-substituted hydroxypropyl cellulose):
| Supplementary material | Every weight (mg) | Percentage composition (%) | Practical amount (g) |
| Body of Pramipexole dihydrochloride | 0.125 | 0.05 | 1.25 |
| Poly(ethylene oxide) (highly viscous) | 12.5 | 5 | 125 |
| Agar (low viscous) | 225 | 90 | 2250 |
| Arabic gum | 2.5 | 1 | 25 |
| L-HPC | 2.5 | 1 | 25 |
| Calcium hydrogen phosphate | 5 | 2 | 50 |
| Silicon dioxide | 1 | 0.4 | 10 |
| Hydrogenated vegetable oil | 1.375 | 0.55 | 13.75 |
| Amount to | 250 | 100 | 2500 |
Concrete preparation process is:
(1) being ground by body of Pramipexole dihydrochloride raw material, cross 180 mesh sieves, take raw material on screen cloth, recording particle diameter D (90) is 85 μm；100 mesh sieves that body of Pramipexole dihydrochloride after grinding and arabic gum equivalent progressively increased mix 3 times, obtain A；80 mesh sieves that A and calcium hydrogen phosphate equivalent progressively increased mix 3 times, obtain B；
(2) by B and poly(ethylene oxide), agar and L-HPC through multidirectional mixer mixing 20min, C is obtained；Again by C and silicon dioxide and hydrogenated vegetable oil through multidirectional mixer mixing 2min, obtain intermediate；
(3) tabletting: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting, Stress control is at 1500lbs, and tablet weight controls at 250 ± 2mg, obtains the body of Pramipexole dihydrochloride slow releasing tablet that specification is 0.25g.
Embodiment 7: the preparation of body of Pramipexole dihydrochloride slow releasing tablet:
According to the form below, practical amount weighs various supplementary material (CMC and sodium carboxymethyl cellulose, crosslinking CMS-Na and crosslinked carboxymethyl fecula sodium):
| Supplementary material | Every weight (mg) | Percentage composition (%) | Practical amount (g) |
| Body of Pramipexole dihydrochloride | 0.25 | 0.1 | 2.5 |
| Levan (highly viscous) | 225 | 90 | 2250 |
| Poly(propylene oxide) (low viscous) | 12.5 | 5 | 125 |
| CMC | 2.5 | 1 | 25 |
| Crosslinking CMS-Na | 2.5 | 1 | 25 |
| Dextrin | 5 | 2 | 50 |
| Silicon dioxide | 1 | 0.4 | 10 |
| Pulvis Talci | 1.25 | 0.5 | 12.5 |
| Amount to | 250 | 100 | 2500 |
Concrete preparation process is:
(1) being ground by body of Pramipexole dihydrochloride raw material, cross 120 mesh sieves, take raw material on screen cloth, recording particle diameter D (90) is 125 μm；100 mesh sieves that body of Pramipexole dihydrochloride after grinding and CMC equivalent progressively increased mix 3 times, obtain A；80 mesh sieves that A and dextrin equivalent progressively increased mix 3 times, obtain B；
(2) by B and levan, poly(propylene oxide) and crosslinking CMS-Na through multidirectional mixer mixing 20min, C is obtained；Again by C and silicon dioxide and Pulvis Talci through multidirectional mixer mixing 2min, obtain intermediate；
(3) tabletting: intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting, Stress control is at 1500lbs, and tablet weight controls at 250 ± 2mg, obtains the body of Pramipexole dihydrochloride slow releasing tablet that specification is 0.25g.
Claims (10)
1. a body of Pramipexole dihydrochloride slow releasing tablet, it is characterised in that: this slow releasing tablet is made up of the body of Pramipexole dihydrochloride of therapeutically effective amount, at least one low viscosity neutral water swelling polymer, at least one high viscosity neutral water swelling polymer, at least one anionic water swelling polymer and other pharmaceutical excipient；Low viscosity neutral water swelling polymer, high viscosity neutral water swelling polymer mass content in slow releasing tablet are 5%-90%；The particle diameter D90 of described body of Pramipexole dihydrochloride raw material is 20 μm-150 μm；Described low viscosity refers to the viscosity < 1000mPa.s of mass concentration 2% aqueous solutions of polymers, and described high viscosity refers to the viscosity > 1000mPa.s of mass concentration 2% aqueous solutions of polymers.
2. body of Pramipexole dihydrochloride slow releasing tablet according to claim 1, it is characterised in that: described low viscosity neutral water swelling polymer, high viscosity neutral water swelling polymer are selected from one or more in the copolymer of methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl methyl cellulose, galactomannan, tragacanth, agar, guar gum, levan, poly(ethylene oxide), poly(propylene oxide), oxirane and expoxy propane.
3. body of Pramipexole dihydrochloride slow releasing tablet according to claim 1, it is characterised in that: described anionic water swelling polymer is one or more in carbomer, acrylate copolymer, methacrylate polymer, methacrylic acid copolymer, alginate, carrageenin, arabic gum, xanthan gum, chitosan, sodium carboxymethyl cellulose, carboxymethylcellulose calcium.
4. the body of Pramipexole dihydrochloride slow releasing tablet according to claim 1,2 or 3, it is characterised in that: other described pharmaceutical excipient includes disintegrating agent, filler, fluidizer, lubricant.
5. body of Pramipexole dihydrochloride slow releasing tablet according to claim 4, it is characterised in that: described disintegrating agent is one or more in low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, dried starch.
6. body of Pramipexole dihydrochloride slow releasing tablet according to claim 4, it is characterised in that: described filler is one or more in starch, Icing Sugar, dextrin, microcrystalline Cellulose, mannitol, xylitol, sorbitol, lactose calcium sulfate, calcium hydrogen phosphate, medicinal calcium carbonate.
7. body of Pramipexole dihydrochloride slow releasing tablet according to claim 4, it is characterised in that: described fluidizer is silicon dioxide.
8. body of Pramipexole dihydrochloride slow releasing tablet according to claim 4, it is characterised in that: described lubricant is one or more in magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, Pulvis Talci.
9. the preparation method of the body of Pramipexole dihydrochloride slow releasing tablet as described in any one of claim 1-8, it is characterised in that: adopt direct compression process, comprise the following steps:
(1) weigh body of Pramipexole dihydrochloride, grind so that it is particle diameter D90 is between 20 μm-150 μm；Body of Pramipexole dihydrochloride after grinding is progressively increased with anionic water swelling polymer and other pharmaceutical excipient equivalent of part and mixes, obtain premix；
(2) premix is mixed homogeneously through multidirectional mixer with all the other adjuvants, obtain intermediate；
(3) intermediate tabletting in tablet machine, to obtain final product.
10. the preparation method of body of Pramipexole dihydrochloride slow releasing tablet according to claim 9, it is characterised in that: comprise the following steps:
(1) weigh body of Pramipexole dihydrochloride, grind so that it is particle diameter D90 is between 20 μm-150 μm；100 mesh sieves that body of Pramipexole dihydrochloride after grinding and anionic water swelling polymer equivalent progressively increased mix 3 times, obtain premix A；80 mesh sieves that premix A and filler equivalent progressively increased mix 3 times, obtain premix B；
(2) by premix B and low viscosity neutral water swelling polymer, high viscosity neutral water swelling polymer and disintegrating agent through multidirectional mixer mixing 20min, mixture C is obtained；Again by mixture C and fluidizer, lubricant through multidirectional mixer mixing 2min, obtain intermediate；
(3) intermediate φ 9.0mm, shallow arc, without carving characters punch die tabletting, Stress control, at 1500lbs, to obtain final product.
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| CN106619514A (en) * | 2017-02-27 | 2017-05-10 | 佛山市弘泰药物研发有限公司 | Pramipexole dihydrochloride self-microemulsion preparation and preparing method thereof |
| CN107951853A (en) * | 2016-10-17 | 2018-04-24 | 四川海思科制药有限公司 | A kind of body of Pramipexole dihydrochloride sustained release pharmaceutical composition and preparation method thereof |
| CN108014342A (en) * | 2016-11-04 | 2018-05-11 | 广州共禾医药科技有限公司 | A kind of preparation method of cellulose ether sustained-release preparation quality analysis test solution |
| CN113820427A (en) * | 2021-10-09 | 2021-12-21 | 南通联亚药业有限公司 | Method for determining pramipexole dihydrochloride content in pramipexole dihydrochloride sustained-release tablets |
| CN114939112A (en) * | 2017-12-28 | 2022-08-26 | 北京北大维信生物科技有限公司 | Pramipexole sustained-release pharmaceutical composition, preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107951853A (en) * | 2016-10-17 | 2018-04-24 | 四川海思科制药有限公司 | A kind of body of Pramipexole dihydrochloride sustained release pharmaceutical composition and preparation method thereof |
| CN107951853B (en) * | 2016-10-17 | 2022-04-08 | 海思科制药(眉山)有限公司 | Pramipexole dihydrochloride sustained-release pharmaceutical composition and preparation method thereof |
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| CN114939112A (en) * | 2017-12-28 | 2022-08-26 | 北京北大维信生物科技有限公司 | Pramipexole sustained-release pharmaceutical composition, preparation method and application thereof |
| CN114939112B (en) * | 2017-12-28 | 2024-03-01 | 北京北大维信生物科技有限公司 | Pramipexole sustained-release pharmaceutical composition, preparation method and application thereof |
| CN113820427A (en) * | 2021-10-09 | 2021-12-21 | 南通联亚药业有限公司 | Method for determining pramipexole dihydrochloride content in pramipexole dihydrochloride sustained-release tablets |
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