CN109394720A - A kind of composition and preparation method thereof of 3-N-butylphthalide derivative - Google Patents
A kind of composition and preparation method thereof of 3-N-butylphthalide derivative Download PDFInfo
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- CN109394720A CN109394720A CN201811115350.7A CN201811115350A CN109394720A CN 109394720 A CN109394720 A CN 109394720A CN 201811115350 A CN201811115350 A CN 201811115350A CN 109394720 A CN109394720 A CN 109394720A
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- Prior art keywords
- coating
- composition
- derivative
- butylphthalide
- preparation
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical class C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 title claims abstract description 20
- 238000000576 coating method Methods 0.000 claims abstract description 118
- 239000011248 coating agent Substances 0.000 claims abstract description 112
- 239000000843 powder Substances 0.000 claims abstract description 34
- 238000004090 dissolution Methods 0.000 claims abstract description 20
- 239000008187 granular material Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012153 distilled water Substances 0.000 claims abstract description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 7
- 239000011247 coating layer Substances 0.000 claims abstract description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000463 material Substances 0.000 claims description 15
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 11
- 239000001103 potassium chloride Substances 0.000 claims description 11
- 235000011164 potassium chloride Nutrition 0.000 claims description 11
- 239000005711 Benzoic acid Substances 0.000 claims description 9
- 235000010233 benzoic acid Nutrition 0.000 claims description 9
- 229910021645 metal ion Inorganic materials 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 5
- 150000001455 metallic ions Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- -1 3- n-butylbenzene Phthalide derivative Chemical class 0.000 claims description 3
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000002700 tablet coating Substances 0.000 claims 1
- 238000009492 tablet coating Methods 0.000 claims 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 26
- 239000000243 solution Substances 0.000 description 18
- 239000002245 particle Substances 0.000 description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 13
- 235000019359 magnesium stearate Nutrition 0.000 description 13
- 239000008108 microcrystalline cellulose Substances 0.000 description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 12
- 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 12
- 239000002775 capsule Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 241000700159 Rattus Species 0.000 description 6
- 239000000470 constituent Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000002075 main ingredient Substances 0.000 description 6
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 6
- 239000004300 potassium benzoate Substances 0.000 description 6
- 229940103091 potassium benzoate Drugs 0.000 description 6
- 235000010235 potassium benzoate Nutrition 0.000 description 6
- 230000004584 weight gain Effects 0.000 description 6
- 235000019786 weight gain Nutrition 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 229940050390 benzoate Drugs 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 239000011122 softwood Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000007688 edging Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- NGSWKAQJJWESNS-UHFFFAOYSA-N 4-coumaric acid Chemical compound OC(=O)C=CC1=CC=C(O)C=C1 NGSWKAQJJWESNS-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 206010058156 Reperfusion arrhythmia Diseases 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- NGSWKAQJJWESNS-ZZXKWVIFSA-M 4-Hydroxycinnamate Natural products OC1=CC=C(\C=C\C([O-])=O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-M 0.000 description 1
- DFYRUELUNQRZTB-UHFFFAOYSA-N Acetovanillone Natural products COC1=CC(C(C)=O)=CC=C1O DFYRUELUNQRZTB-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of composition and preparation method thereof of 3-N-butylphthalide derivative, the composition contains 3-N-butylphthalide derivative, moistureproof coating layer and other pharmaceutic adjuvants.Wherein, moistureproof coating layer contains AMB type Opadry, the present invention also provides a kind of preparation methods of the composition of above-mentioned 3-N-butylphthalide derivative, it is characterized in that being coated using powder coating, granule coating or tablet, it needs that AMB type Opadry coating powder is dissolved in distilled water before being coated, forms uniform coating solution after completely dissolution.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of composition of 3-N-butylphthalide derivative and its preparation
Method.
Background technique
Acute ischemic cerebral apoplexy and coronary heart disease, myocardial infarction etc. are all to be led due to arteriosclerosis until forming thrombus
The disease of ischemia injury is caused, this kind of disease brings great pain or even threat to life to patient.Such drug is always at present
It is hot spot and the forward position of drug development research.
Chinese patent CN1382682A discloses 2- (Alpha-hydroxy amyl) benzoate and its preparation method and application, relates to
And the salt of monovalent metallic ion, bivalent metal ion and organic base, specifically disclose potassium, sodium, calcium, magnesium, zinc, aniline, benzylamine,
The salt of morpholine, diethylamine.And sylvite is disclosed to the shadow of local rats with cerebral ischemia cerebral infarct size, rat platelet aggregation
It rings, the protective effect to isolated rat heart ischemia-reperfusion arrhythmia cordis, it was demonstrated that beneficial work of the sylvite in above-mentioned experiment
With.Which disclose above-mentioned active constituents to be used in institute by modes such as oral, intravenous injections in the form of compositions
Need patient, such as tablet, granule, capsule, injection solution, water or oleaginous suspension is made etc., and in embodiment
It discloses tablet, capsule and intravenous injection, be injected intravenously freeze-dried prescription and preparation method.
Chinese patent CN1523003A, disclose 2- (Alpha-hydroxy amyl) benzoate N, N- dibenzyl ethylenediamine salt and its
Preparation method and purposes, in the influence to local rats with cerebral ischemia cerebral infarct size, rat platelet aggregation, to the isolated rat heart
Excellent effect is embodied in terms of the protective effect of dirty ischemia-reperfusion arrhythmia cordis.Above-mentioned active constituent is also disclosed to be made
The prescription and preparation method of tablet, capsule and granule.
Chinese patent CN1560018A discloses 2- (the positive pentanone base of α -) benzoate and its preparation method and application.Also
Above-mentioned active constituent is disclosed tablet, capsule, granule is made and is injected intravenously freeze-dried prescription and preparation method.
Chinese patent CN101402565A discloses halogenated 2- (Alpha-hydroxy amyl) benzoate and preparation method thereof and uses
On the way.Above-mentioned active constituent is also disclosed tablet, capsule and intravenous injection is made, is injected intravenously freeze-dried prescription and preparation
Method.
Compound disclosed in foregoing invention is all 3-N-butylphthalide (the trade name En Bipu of its soft capsule)
P-Coumaric acid pharmacologically has the property similar with 3-N-butylphthalide.It is important to note, however, that removing
It is 2- (Alpha-hydroxy amyl) benzoate N, N- dibenzyl second that CN1523003A, which explicitly points out active constituent used in its composition,
Diamine salts, in remaining invention even without clear active constituent why, and foregoing invention is not to disclosed reactive compound
Composition make further research, such as oral tablet, granule or capsule, stability, ifs vitro disintegration or
Dissolution what state, and these pharmaceutical properties, directly have decided on whether to be prepared into reactive compound suitable for clinic
The preparation used.
Summary of the invention
The present invention provides a kind of composition of 3-N-butylphthalide derivative, contains 3-N-butylphthalide derivative, moisture-proof
Coatings and other pharmaceutic adjuvants.
Wherein, the moistureproof coating layer contains AMB type Opadry, i.e. Opadry AMB.
Wherein, the 3-N-butylphthalide derivative is selected from one or more of following compounds:
Wherein, R1Represent H or halogen atom, M be monovalent metallic ion,
Bivalent metal ion, trivalent metal ion or organic base, wherein n=1-3, or
Wherein, M is monovalent metallic ion, bivalent metal ion or organic
Base, wherein n=1 or n=2.
Preferably, the 3-N-butylphthalide derivative is 2- (Alpha-hydroxy amyl) benzoic acid sylvite.
Wherein, other described pharmaceutic adjuvants are selected from one or more of diluent, adhesive, disintegrating agent and lubricant.
The present invention also provides a kind of preparation methods of the composition of above-mentioned 3-N-butylphthalide derivative, it is characterised in that adopts
It is coated with powder coating, granule coating or tablet.
Wherein, it needs that AMB type Opadry coating powder is dissolved in distilled water before being coated, is formed after completely dissolution uniform
Coating solution.
The invention discloses a kind of 2- (Alpha-hydroxy amyl) Potassium Benzoate preparation, by 2- (Alpha-hydroxy amyl) Potassium Benzoate,
Pharmaceutic adjuvant and moistureproof coating layer composition.2- (Alpha-hydroxy amyl) Potassium Benzoate can be made in powder, particle or with pharmaceutic adjuvant
It is coated again with moistureproof coating material after label.
Adoptable coating material includes Opadry AMB, Utech E PO, Utech E100 ethyl cellulose, single tristearin
Acid glyceride, hydrogenated vegetable oil etc..Using Opadry AMB, achieved for the coating of 2- (Alpha-hydroxy amyl) Potassium Benzoate imaginary
Less than good effect.
Wherein coating material and particle or powder quality ratio are 5:100-60:100, and the mass ratio of coating material and label is
1:100-10:100。
Coating solution configuration: weighing a certain amount of Opadry AMB coating powder and be added in distilled water, stirs 45min, makes it
Sufficiently dissolution, obtains uniform coating solution.
Coating:
Powder or granule coating: powder or granule coating are coated using fluidized bed top spray, by 2- (Alpha-hydroxy amyl) Potassium Benzoate
Powder or particle are put into fluidized bed, and making nozzle and storeroom distance is 10-11cm, and being passed through compressed air makes particle suspend, control
Inlet air temperature processed is constant, is preheated to 40 DEG C, starts spray coating.It is 0.18~0.22bar that aspiration pressure is controlled in coating process,
Temperature of charge maintains 30-40 DEG C, after coating, in 40 DEG C of fluidized drying 5min.Coating weight gain control is in 5-40%, discharging
Dry 2h, coated granule are mixed with other auxiliary materials in 40 DEG C of baking ovens afterwards, tabletted or direct encapsulating capsule.
Coating pan coating: the label of 2- (Alpha-hydroxy amyl) Potassium Benzoate and the preparation of other pharmaceutic adjuvants is placed in coating pan
In, start seed-coating machine, setting speed, temperature start to preheat.Pot body 6~10rpm of revolving speed, 30~40 DEG C of piece bed tempertaure, when edging
Between 3~10min, enter the wind 500~700rpm of wind speed, 2600~2800rpm of wind speed, 0.05~0.1Mpa of atomizing pressure, piece
35~42 DEG C of bed tempertaure, coating weight gain reaches 1%~5%, stops whitewashing, continues dry 0.5h, shuts down.
Other auxiliary materials include starch, Icing Sugar, sodium carboxymethylcellulose, microcrystalline cellulose, superfine silica gel powder, magnesium stearate, cream
One or more of sugar mixture.
The present invention overcomes 2- (Alpha-hydroxy amyl) benzoic acid sylvite draw it is moist strong, to the defect of moist lability.
Detailed description of the invention
Fig. 1: Opadry AMB coating powder powder coating (embodiment 1), granule coating (embodiment 4), label coating (are implemented
Example 7) dissolution curve comparison.
Fig. 2: general thin coating powder-Opadry II is coated (embodiment 10), granule coating (embodiment 13), label coating
The comparison of (embodiment 16) dissolution curve.
Fig. 3: two kinds of different function coating material dissolution curve comparisons.
Specific embodiment
The purpose of embodiments described below be in order to better illustrate the present invention, but should not to the scope of the present invention constitute limit
It is fixed.
Embodiment 1-3 powder bag garment piece (1000 preparation units)
| Ingredient | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| 2- (Alpha-hydroxy amyl) benzoic acid sylvite | 200g | 200g | 200g |
| Opadry AMB | 20g | 40g | 80g |
| Microcrystalline cellulose | 50g | 50g | 50g |
| Hydroxypropyl methylcellulose | 8g | 8g | 8g |
| Magnesium stearate | 2g | 2g | 2g |
Preparation process is as follows.
Coating solution configuration: the Opadry AMB coating powder of recipe quantity is added in distilled water under stirring, admittedly contain
Amount about 10%, stirs 45min, dissolves it sufficiently, obtain uniform coating solution, spare.
Coating: main ingredient is placed in fluidized bed, is coated using fluidized bed top spray, and making nozzle and storeroom distance is 10-
11cm, being passed through compressed air makes material suspended, preheating 5min, increases air air quantity and starts hydrojet coating, coating process controls object
Material temperature degree, after coating, dry 5-10min.Coating weight gain is controlled in 10-40%, and detailed coating parameter is as shown in the table:
| Major parameter | Preheating | Hydrojet | It is dry | It is cooling |
| Temperature of charge (DEG C) | 40 | 30~40 | 40~50 | <40 |
| Intake (m3/h) | 40-50 | 50~70 | 50 | 50 |
| Atomizing pressure (bar) | 1 | 2 | --- | --- |
| Hydrojet speed (g/min/kg) | --- | 5~10 | --- | --- |
Particle after coating is uniformly mixed with microcrystalline cellulose, hydroxypropyl methylcellulose and magnesium stearate, tabletting or filling capsule.
Embodiment 4-6 granule coating piece (1000 preparation units)
| Ingredient | Embodiment 4 | Embodiment 5 | Embodiment 6 |
| 2- (Alpha-hydroxy amyl) benzoic acid sylvite | 200g | 200g | 200g |
| Opadry AMB | 20g | 40g | 80g |
| Microcrystalline cellulose | 50g | 50g | 50g |
| Hydroxypropyl methylcellulose | 8g | 8g | 8g |
| Magnesium stearate | 2g | 2g | 2g |
Preparation process is as follows.
Particle preparation: main ingredient, microcrystalline cellulose and hydroxypropyl methylcellulose are uniformly mixed, with 95% ethyl alcohol softwood,
The granulation of 32 meshes, drying, 30 mesh sieves.
Coating solution configuration: the Opadry AMB coating powder of recipe quantity is added in distilled water under stirring, admittedly contain
Amount about 10%, stirs 45min, dissolves it sufficiently, obtain uniform coating solution, spare.
Coating: above-mentioned particle is placed in fluidized bed, is coated using fluidized bed top spray, is made nozzle and storeroom distance
10-11cm, being passed through compressed air makes material suspended, preheating 5min, increases air air quantity and starts hydrojet coating, coating process control
Temperature of charge, after coating, dry 5-10min.Coating weight gain is controlled in 10-40%, and detailed coating parameter is as shown in the table:
| Major parameter | Preheating | Hydrojet | It is dry | It is cooling |
| Temperature of charge (DEG C) | 40 | 30~40 | 40~50 | <40 |
| Intake (m3/h) | 40-50 | 50~70 | 50 | 50 |
| Atomizing pressure (bar) | 1 | 2 | --- | --- |
| Hydrojet speed (g/min/kg) | --- | 5~10 | --- | --- |
Particle after coating is uniformly mixed with magnesium stearate, tabletting or encapsulating capsule.
Embodiment 7-9 label is coated (1000 preparation units)
| Ingredient | Embodiment 7 | Embodiment 8 | Embodiment 9 |
| 2- (Alpha-hydroxy amyl) benzoic acid sylvite | 200g | 200g | 200g |
| Microcrystalline cellulose | 50g | 50g | 50g |
| Hydroxypropyl methylcellulose | 8g | 8g | 8g |
| Magnesium stearate | 2g | 2g | 2g |
| Opadry AMB | 2.6g | 7.2g | 13g |
Preparation process is as follows.
Label preparation: main ingredient, microcrystalline cellulose and hydroxypropyl methylcellulose are uniformly mixed, with 95% ethyl alcohol softwood,
Above-mentioned particle is uniformly mixed, tabletting, hardness 50-120N by the granulation of 32 meshes, drying, 30 mesh sieves with magnesium stearate.
Coating solution configuration: the Opadry AMB coating powder of recipe quantity is added in distilled water under stirring, admittedly contain
Amount about 10%, stirs 45min, dissolves it sufficiently, obtain uniform coating solution, spare.
Coating operations: label is placed in coating pan, starts seed-coating machine, and preheating is coated using above-mentioned coating solution, is sprayed
Continue dry 0.5h after liquid, shuts down.Detailed coating parameter is as shown in the table.
| Major parameter | Numberical range |
| Pot revolving speed (rpm) | 6-10 |
| The edging time (min) | 3-5 |
| It enters the wind wind speed (rpm) | 500~700 |
| Wind speed (rpm) | 2600~2800 |
| Piece bed tempertaure (DEG C) | 35-45 |
| Atomizing pressure (bar) | 0.05~0.1 |
Embodiment 10-12 powder coating-ordinary coating powder (1000 preparation units)
| Ingredient | Embodiment 10 | Embodiment 11 | Embodiment 12 |
| 2- (Alpha-hydroxy amyl) benzoic acid sylvite | 200g | 200g | 200g |
| Opadry II | 20g | 40g | 80g |
| Microcrystalline cellulose | 50g | 50g | 50g |
| Hydroxypropyl methylcellulose | 8g | 8g | 8g |
| Magnesium stearate | 2g | 2g | 2g |
Preparation process is as follows.
Coating solution configuration: II coating powder of Opadry of recipe quantity is added in distilled water under stirring, solid content
About 10%, 45min is stirred, it is dissolved sufficiently, obtains uniform coating solution, it is spare.
Coating: main ingredient is placed in fluidized bed, is coated using fluidized bed top spray, and making nozzle and storeroom distance is 10-
11cm, being passed through compressed air makes material suspended, preheating 5min, increases air air quantity and starts hydrojet coating, coating process controls object
Material temperature degree, after coating, dry 5-10min.Coating weight gain is controlled in 10-40%, and detailed coating parameter is as shown in the table:
| Major parameter | Preheating | Hydrojet | It is dry | It is cooling |
| Temperature of charge (DEG C) | 40 | 30~40 | 40~50 | <40 |
| Intake (m3/h) | 40-50 | 50~70 | 50 | 50 |
| Atomizing pressure (bar) | 1 | 2 | --- | --- |
| Hydrojet speed (g/min/kg) | --- | 5~10 | --- | --- |
Particle after coating is uniformly mixed with microcrystalline cellulose, hydroxypropyl methylcellulose and magnesium stearate, tabletting or filling capsule.
Embodiment 13-15 granule coating-ordinary coating powder (1000 preparation units)
| Ingredient | Embodiment 13 | Embodiment 14 | Embodiment 15 |
| 2- (Alpha-hydroxy amyl) benzoic acid sylvite | 200g | 200g | 200g |
| Opadry II | 20g | 40g | 80g |
| Microcrystalline cellulose | 50g | 50g | 50g |
| Hydroxypropyl methylcellulose | 8g | 8g | 8g |
| Magnesium stearate | 2g | 2g | 2g |
Preparation process is as follows.
Particle preparation: main ingredient, microcrystalline cellulose and hydroxypropyl methylcellulose are uniformly mixed, with 95% ethyl alcohol softwood,
The granulation of 32 meshes, drying, 30 mesh sieves.
Coating solution configuration: II coating powder of Opadry of recipe quantity is added in distilled water under stirring, solid content
About 10%, 45min is stirred, it is dissolved sufficiently, obtains uniform coating solution, it is spare.
Coating: above-mentioned particle is placed in fluidized bed, is coated using fluidized bed top spray, is made nozzle and storeroom distance
10-11cm, being passed through compressed air makes material suspended, preheating 5min, increases air air quantity and starts hydrojet coating, coating process control
Temperature of charge, after coating, dry 5-10min.Coating weight gain is controlled in 10-40%, and detailed coating parameter is as shown in the table:
| Major parameter | Preheating | Hydrojet | It is dry | It is cooling |
| Temperature of charge (DEG C) | 40 | 30~40 | 40~50 | <40 |
| Intake (m3/h) | 40-50 | 50~70 | 50 | 50 |
| Atomizing pressure (bar) | 1 | 2 | --- | --- |
| Hydrojet speed (g/min/kg) | --- | 5~10 | --- | --- |
Particle after coating is uniformly mixed with magnesium stearate, tabletting or encapsulating capsule.
Embodiment 16-18 label coating-ordinary coating powder (1000 preparation units)
| Ingredient | Embodiment 16 | Embodiment 17 | Embodiment 18 |
| 2- (Alpha-hydroxy amyl) benzoic acid sylvite | 200g | 200g | 200g |
| Microcrystalline cellulose | 50g | 50g | 50g |
| Hydroxypropyl methylcellulose | 8g | 8g | 8g |
| Magnesium stearate | 2g | 2g | 2g |
| Opadry II | 2.6g | 7.2g | 13g |
Preparation process is as follows.
Label preparation: main ingredient, microcrystalline cellulose and hydroxypropyl methylcellulose are uniformly mixed, with 95% ethyl alcohol softwood,
Above-mentioned particle is uniformly mixed, tabletting, hardness 50-120N by the granulation of 32 meshes, drying, 30 mesh sieves with magnesium stearate.
Coating solution configuration: II coating powder of Opadry of recipe quantity is added in distilled water under stirring, solid content
About 10%, 45min is stirred, it is dissolved sufficiently, obtains uniform coating solution, it is spare.
Coating operations: label is placed in coating pan, starts seed-coating machine, and preheating is coated using above-mentioned coating solution, is sprayed
Continue dry 0.5h after liquid, shuts down.Detailed coating parameter is as shown in the table.
| Major parameter | Numberical range |
| Pot revolving speed (rpm) | 6-10 |
| The edging time (min) | 3-5 |
| It enters the wind wind speed (rpm) | 500~700 |
| Wind speed (rpm) | 2600~2800 |
| Piece bed tempertaure (DEG C) | 35-45 |
| Atomizing pressure (bar) | 0.05~0.1 |
19 dissolution rate of embodiment compares
Tablet prepared by above-described embodiment 1-18 is taken, according to dissolution method (Chinese Pharmacopoeia two XC thirds of version in 2010
Method), using 900mL water as dissolution medium, revolving speed is 100 revs/min, measures dissolution rate.
Opadry AMB coating powder powder coating (embodiment 1), granule coating (embodiment 4), label coating (embodiment 7)
Dissolution curve comparison, as a result as shown in attached drawing Fig. 1.From powder coating, granule coating, label coating pair known to dissolution curve result
Dissolution rate has no significant effect.
General thin coating powder-Opadry II is coated (embodiment 10), granule coating (embodiment 13), label coating (in fact
Apply example 16) dissolution curve comparison, as a result as shown in attached drawing Fig. 2.From powder coating, granule coating, piece known to dissolution curve result
Core coating has no significant effect dissolution rate.
Two kinds of different function coating material dissolution curve comparisons, as a result as shown in attached drawing Fig. 3.It was found from dissolution curve result
Moistureproof coating powder has no significant effect drug dissolution compared with common Opadry film coating powder.
20 stability of embodiment compares
The sample prepared in above-described embodiment 1,4,7,10,13,16 is investigated under the conditions of humidity 75%RH respectively, as a result
It is as shown in the table:
| Sample | (%) is increased weight in 75% moisture absorption of super-humid conditions 10 days |
| Embodiment 1 | 2.8 |
| Embodiment 4 | 2.9 |
| Embodiment 7 | 3.1 |
| Embodiment 10 | 4.9 |
| Embodiment 13 | 5.0 |
| Embodiment 16 | 4.8 |
The result shows that the dampproof effect of Opadry AMB moistureproof coating powder is good compared with general thin coating powder effect, help to improve
The stability of drug and guarantee long-time stability dissolution are qualified.
Claims (7)
1. a kind of composition of 3-N-butylphthalide derivative, containing 3-N-butylphthalide derivative, moistureproof coating layer and other
Pharmaceutic adjuvant.
2. the composition of 3-N-butylphthalide derivative as described in claim 1, it is characterised in that the moistureproof coating layer contains
There is AMB type Opadry.
3. the composition of 3-N-butylphthalide derivative as claimed in claim 1 or 2, it is characterised in that the 3- n-butylbenzene
Phthalide derivative is selected from one or more of following compounds:
Wherein, R1Represent H or halogen atom, M be monovalent metallic ion,
Bivalent metal ion, trivalent metal ion or organic base, wherein n=1-3, or
Wherein, M is monovalent metallic ion, bivalent metal ion or organic
Base, wherein n=1 or n=2.
4. the composition of 3-N-butylphthalide derivative as claimed in claim 3, it is characterised in that the 3-N-butylphthalide
Derivative is 2- (Alpha-hydroxy amyl) benzoic acid sylvite.
5. the composition of 3-N-butylphthalide derivative as claimed in claim 1 or 2, it is characterised in that described other are medicinal auxiliary
Material is selected from one or more of diluent, adhesive, disintegrating agent and lubricant.
6. the preparation method of the composition of 3-N-butylphthalide derivative as claimed in claim 1 or 2, it is characterised in that use
Powder coating, granule coating or tablet coating.
7. the preparation method of the composition of 3-N-butylphthalide derivative as claimed in claim 6, it is characterised in that carrying out
AMB type Opadry coating powder is dissolved in distilled water before coating, forms uniform coating solution after completely dissolution.
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| CN1382682A (en) * | 2002-05-09 | 2002-12-04 | 中国医学科学院药物研究所 | 2-(alpha-hydroxypentyl) benzoate and its preparing process and usage |
| CN1813762A (en) * | 2005-12-12 | 2006-08-09 | 天津红日药业股份有限公司 | Fasudic hydrochloride oral formulation |
| EP1787638A1 (en) * | 2004-08-27 | 2007-05-23 | Shijiazhuang Pharma Group Zhongqi Pharmaceutical Technology (Shijianzhuang) Co., Ltd. | Butylbenzene phthalein self-emulsifying drug delivery system, its preparation method and application |
| CN101491506A (en) * | 2009-02-19 | 2009-07-29 | 杭州华东医药集团生物工程研究所有限公司 | Acarbose chewing tablets |
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| EP1833466A1 (en) * | 2004-12-28 | 2007-09-19 | Ranbaxy Laboratories Limited | Methods for the preparation of stable pharmaceutical solid dosage forms of atorvastatin and amlodipine |
| CN102525997B (en) * | 2012-03-21 | 2013-07-17 | 齐鲁制药有限公司 | Moisture-proof coating citicoline sodium capsule and preparation method thereof |
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2012
- 2012-11-21 CN CN201210474199.2A patent/CN103830200A/en active Pending
- 2012-11-21 CN CN201811115350.7A patent/CN109394720A/en active Pending
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| CN1382682A (en) * | 2002-05-09 | 2002-12-04 | 中国医学科学院药物研究所 | 2-(alpha-hydroxypentyl) benzoate and its preparing process and usage |
| EP1787638A1 (en) * | 2004-08-27 | 2007-05-23 | Shijiazhuang Pharma Group Zhongqi Pharmaceutical Technology (Shijianzhuang) Co., Ltd. | Butylbenzene phthalein self-emulsifying drug delivery system, its preparation method and application |
| CN1813762A (en) * | 2005-12-12 | 2006-08-09 | 天津红日药业股份有限公司 | Fasudic hydrochloride oral formulation |
| CN101491506A (en) * | 2009-02-19 | 2009-07-29 | 杭州华东医药集团生物工程研究所有限公司 | Acarbose chewing tablets |
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