CN1582910A - Calcium phenol sulfonate dispersive tablets and their preparation - Google Patents
Calcium phenol sulfonate dispersive tablets and their preparation Download PDFInfo
- Publication number
- CN1582910A CN1582910A CN 200410042865 CN200410042865A CN1582910A CN 1582910 A CN1582910 A CN 1582910A CN 200410042865 CN200410042865 CN 200410042865 CN 200410042865 A CN200410042865 A CN 200410042865A CN 1582910 A CN1582910 A CN 1582910A
- Authority
- CN
- China
- Prior art keywords
- parts
- agent
- disintegrating agent
- dispersible tablet
- calcium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 8
- JVEDXKIOAFPPPG-UHFFFAOYSA-L calcium;4-hydroxybenzenesulfonate Chemical compound [Ca+2].OC1=CC=C(S([O-])(=O)=O)C=C1.OC1=CC=C(S([O-])(=O)=O)C=C1 JVEDXKIOAFPPPG-UHFFFAOYSA-L 0.000 title 1
- QGNBTYAQAPLTMX-UHFFFAOYSA-L calcium dobesilate Chemical compound [Ca+2].OC1=CC=C(O)C(S([O-])(=O)=O)=C1.OC1=CC=C(O)C(S([O-])(=O)=O)=C1 QGNBTYAQAPLTMX-UHFFFAOYSA-L 0.000 claims abstract description 44
- 229960005438 calcium dobesilate Drugs 0.000 claims abstract description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000000741 silica gel Substances 0.000 claims abstract description 16
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 9
- 239000007919 dispersible tablet Substances 0.000 claims description 44
- 239000003795 chemical substances by application Substances 0.000 claims description 41
- 239000008187 granular material Substances 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 25
- 239000011575 calcium Substances 0.000 claims description 25
- 229910052791 calcium Inorganic materials 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 23
- WHOZNOZYMBRCBL-OUKQBFOZSA-N (2E)-2-Tetradecenal Chemical compound CCCCCCCCCCC\C=C\C=O WHOZNOZYMBRCBL-OUKQBFOZSA-N 0.000 claims description 20
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 20
- 229940044654 phenolsulfonic acid Drugs 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 18
- 239000003826 tablet Substances 0.000 claims description 18
- 229920002472 Starch Polymers 0.000 claims description 16
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 16
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 16
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 16
- 239000008107 starch Substances 0.000 claims description 16
- 235000019698 starch Nutrition 0.000 claims description 16
- 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 claims description 14
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- 230000001476 alcoholic effect Effects 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- 239000000080 wetting agent Substances 0.000 claims description 13
- 239000002671 adjuvant Substances 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 12
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 12
- 239000000314 lubricant Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 8
- 239000007779 soft material Substances 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 7
- 239000000499 gel Substances 0.000 claims description 5
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 4
- 239000000853 adhesive Substances 0.000 claims description 4
- 230000001070 adhesive effect Effects 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 2
- -1 hydroxypropyl Chemical group 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002002 slurry Substances 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 235000021419 vinegar Nutrition 0.000 claims description 2
- 239000000052 vinegar Substances 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims 1
- 229920000053 polysorbate 80 Polymers 0.000 claims 1
- 239000007884 disintegrant Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 239000000843 powder Substances 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000000857 drug effect Effects 0.000 description 4
- 230000004089 microcirculation Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000007938 effervescent tablet Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000005336 cracking Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 241000167880 Hirundinidae Species 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical class OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- 206010038491 Renal papillary necrosis Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- ZQNPDAVSHFGLIQ-UHFFFAOYSA-N calcium;hydrate Chemical compound O.[Ca] ZQNPDAVSHFGLIQ-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000013409 condiments Nutrition 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000007948 fast release tablet Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000004137 mechanical activation Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
A dispersing tablet of calcium dobesilate is prepared from calcium dobesilate, disintegrant and silica gel through proportional mixing and granulating twice.
Description
Technical field
The present invention relates to the improvement pharmaceutical dosage form of calcium dobesilate, relate in particular to phenolsulfonic acid calcium dispersible tablet and preparation method thereof, it compares rapid-action with common calcium dobesilate, and the rapid release effect is obvious, and curative effect is conclusive.
Background technology
Calcium dobesilate (Calcium dobesilate), white or off-white powder, soluble in water, chemical name 2,5-dihydroxy benzenes sulfonic acid calcium monohydrate, molecular formula is C
12H
10CaO
10S
2H
2O, molecular weight are 436.42.
Calcium dobesilate is the microcirculation improving agent or the blood vessel protective agent of nineteen seventies listing; be applicable to the multiple disease that prevention and treatment blood capillary circulatory disturbance cause clinically; be specially adapted to the heart, brain, kidney disease that diabetic renal papillary necrosis (it is sick to be called for short the sugar net) microcirculation disturbance causes; for example myocardial infarction, angina pectoris, thrombus sequela, atherosclerosis of renal glomerulus etc., and blood is sticking and microthrombus etc.
Calcium dobesilate in the market mostly is common capsule and tablet, adopts phenolsulfonic acid calcium powder and pharmaceutic adjuvant (starch, a spot of Icing Sugar and dextrin) to form through encapsulated or tabletting.Capsule and tablet are one of most widely used oral dosage forms of field of medicaments, and it has takes and store and transport convenient and the stable advantage of medicine, but are often fully absorbed because of problems such as disintegrate make the medicine stripping slowly influence medicine.In addition, the escalated dose of having to when the needs quick acting is first once taken medicine more for a long time, often makes troubles for the patient of old man, child and dysphagia.Require every day three times (grain) in the clinical treatment at present, each a slice (grain) (500mg dosage).The result of clinical practice shows, there are the shortcoming of above-mentioned rate of release aspect really in calcium dobesilate and calcium hydrophenyl sulfonate capsule, those microcirculation disturbance patient, the patient who especially tormented by sugared net disease or glaucoma, its treatment generally at first needs rapid-action, after medicine discharges rapidly and is absorbed by the body, keep by the medicine of suitable dosage again, so people expect to solve the rapid release problem of calcium dobesilate.Yet as the ripe medicine with good clinical effectiveness and safety, the rapid release problem of calcium dobesilate is unresolved all the time.
What have the rapid release function comprises dosage forms such as dispersible tablet, effervescent tablet.The characteristics of dispersible tablet (being advantage) are that tablet is met behind the water in the short as far as possible time (generally in 3 minutes) disintegrate and become very granule and form uniform suspension, therefore, compare with general tablet, dispersible tablet has good dispersing state, and disintegration time is short, the medicine stripping is rapid, absorb soon bioavailability height, characteristics such as taking convenience, can swallow, chew to contain and suck, especially be fit to old, young and the patient of difficulty that swallows.With effervescent tablet relatively, dispersible tablet does not need effervescent (as carbonate and solid organic acid) and water soluble adjuvant, does not need the gentle relative temperature in control room, and instructions of taking various (effervescent tablet can only water in dissolving back oral).In addition, the dispersible tablet production technology is identical with common non-coated tablet, and no specific (special) requirements does not need vacuum lyophilization and extra package, and production cost is low.Therefore advantage is conspicuous.
British Pharmacopoeia has been worked out the quality standard general rule to dispersible tablet, promptly dispersible tablet be can be in water homodisperse non-coated tablet; It also should disintegrate within 3 minutes in 19～21 ℃ of water except that the quality standard that should meet non-coated tablet; Put into 100ml water for 2 and be stirred to the screen cloth that the homogeneous dispersion that disperses the back to form fully can pass through 710 μ m apertures.Since dispersible tablet can be in 19 ℃～21 ℃ water disintegrate fully in 3 minutes, thereby improved the dissolution of medicine greatly.
The insider also is being devoted to that actively the improvement of calcium dobesilate dosage form is the research of fast-release tablet, but does not get along with all the time.On the basis of guide's Journal of Sex Research, the inventor has made following indefiniteness and has inferred:
With the dispersible tablet is example, and its drug dissolution is relevant with used pharmaceutic adjuvant, particle grain size size, and the cooperation of adjuvant assistant is managed, particle diameter is more little, and the medicine stripping is fast more, and at different medicines, the relation of the two also has very big-difference.So, though may knowing, those skilled in the art how common drug is developed to tablet formulation, but for calcium dobesilate, its uncertain factor is a lot of and be difficult to prediction, for example comprises that the granularity of crude drug is determined, the selection of adjuvant (for example filler, disintegrating agent) etc.Discover that if the selection of adjuvant and mismatch, the dissolution rate of medicine may fall flat.For example design its dispersible tablet prescription discovery to contain this product 250mg: the calcium dobesilate powder flowbility is better, but compressibility extreme difference, and sticking very easily during tabletting, so consider to add an amount of filler, binding agent, lubricant so that this product molding, add an amount of disintegrating agent so that its quick disintegrate, dispersion, but disintegrate is incomplete yet 2 minutes the time in disintegrate experiment for the dispersible tablet of making like this, will remain sheet and break into two with one's hands, and label is still dried.Infer that this may be because calcium dobesilate is very easily water-soluble, and the principal agent amount is higher relatively in the prescription, the effect of disintegrating agent is difficult to performance during disintegrate, promptly be difficult to make the slice, thin piece disintegrate by capillarity and expansion, just can make the slice, thin piece disintegrate complete but lean on calcium dobesilate to dissolve gradually, so disintegrate is over time limit.So, want to solve the problem of disintegration, must screen a kind of adjuvant that can promote disintegrate.Yet,, do not find the clearly instruction of relevant solution in the prior art at the obstacle that for example disintegration, overtime grade was difficult to go beyond that its practical operation exists.
Summary of the invention
The present invention gropes through a large amount of tests, is developed into the phenolsulfonic acid calcium dispersible tablet, has solved the shortcoming that the conventional dosage forms onset is slow, bioavailability is low, has improved its clinical value aspect the multiple disease of preventing and treating blood capillary circulatory disturbance to cause.
On the one hand, the invention provides a kind of pharmaceutical composition of phenolsulfonic acid calcium dispersible tablet, contain calcium dobesilate and suitable pharmaceutic adjuvant in the said composition, its mechanism is to utilize conventional calcium dobesilate raw material to cooperate the good and adjuvant that possess short molten effect of molten aqueous to prepare onset phenolsulfonic acid calcium dispersible tablet rapidly.
Pharmaceutic adjuvant in the present composition includes but not limited to (calcium dobesilate is by 100 parts of calculating):
A. disintegrating agent:
Microcrystalline Cellulose: consumption is 10～40 parts;
Polyvinylpolypyrrolidone: consumption is 3～40 parts;
Carboxymethyl starch sodium: consumption is 3～15 parts;
Low-substituted hydroxypropyl cellulose: consumption is 2～16 parts;
Or cross-linking sodium carboxymethyl cellulose: consumption is 2～16 parts.
Preferred polyvinylpolypyrrolidone and carboxymethyl starch sodium coupling, totally 2～60 parts.
B. short disintegrating agent:
Micropowder silica gel: consumption is 1.6～45 parts;
Sodium lauryl sulphate (SLS): consumption is 0.1～2 part;
Tween 1: consumption is 1～4 part;
Or sulfo-succinic acid two hot vinegar sodium: consumption is 0.1～2 part.
3～25 parts of preferred micropowder silica gels, more preferably 8～25 parts.
C. fluidizer:
Starch: consumption is 8～30 parts;
Or Pulvis Talci: consumption is 2～20 parts.
The preferably talc powder, itself and short disintegrating agent micropowder silica gel coupling can be played the fluidizer effect simultaneously.
D. binding agent
Polyvinylpyrrolidone alcoholic solution, concentration range are 1～15%, and consumption is 2～20 parts;
Copolyvidone alcoholic solution, concentration range are 1%～15%, and consumption is 2～20 parts;
Starch slurry, consumption are 2～20 parts;
Or the hydroxypropyl emthylcellulose aqueous solution, consumption is 2～20 parts.
Preferred adhesive is 10% polyvinylpyrrolidone alcoholic solution, 10 parts of consumptions.
E. wetting agent
Concentration is not less than 70% alcoholic solution, is preferably 95% ethanol, and consumption is 2～20 parts, most preferably 8～10 parts.
F. lubricant:
Stearic acid: consumption is 0.2～2.5 part;
Polyethylene Glycol: consumption is 0.2～2.5 part (Polyethylene Glycol of multi-purpose solid);
Magnesium stearate: consumption is 0.2～2.5 part;
Or Pulvis Talci: consumption is 2～20 parts.
Preferred magnesium stearate and Pulvis Talci coupling, wherein magnesium stearate is 0.9～1 part, 8～10 parts of Pulvis Talci.
In the above-mentioned composition, most preferably comprise 100 parts of calcium dobesilates, 38 parts of disintegrating agents, 20 parts of short disintegrating agents, 10 parts of binding agents, 8 parts of wetting agent, 8.9 parts of lubricants.
In one embodiment, disintegrating agent comprises polyvinylpolypyrrolidone, and consumption is 3～40 parts, and carboxymethyl starch sodium, consumption are 3～15 parts, and short disintegrating agent is micropowder silica gel, and consumption is 1.6～45 parts; Fluidizer comprises micropowder silica gel, and consumption is 1.6～45 parts, and Pulvis Talci, consumption are 2～20 parts; Binding agent is that its concentration range of polyvinylpyrrolidone alcoholic solution is 1～15% (g/g), and consumption is 2～20 parts; Wetting agent is that concentration is not less than 70% alcoholic solution, and consumption is 2～20 parts; Lubricant comprises magnesium stearate, and consumption is 0.2～2.5 part, and amount of talc is 2～20 parts.
In a preferred embodiment, 100 parts of calcium dobesilates, 10～40 parts of polyvinylpolypyrrolidone, 5～10 parts of carboxymethyl starch sodium, 10～30 parts of micropowder silica gels, 5～15 parts of 10% polyvinylpyrrolidone alcoholic solution, 5～15 parts of 95% ethanol, 0.3～1.5 part of magnesium stearate, 5～10 parts of Pulvis Talci.
In another preferred embodiment, 100 parts of calcium dobesilates, 30 parts of polyvinylpolypyrrolidone, 8 parts of carboxymethyl starch sodium, 20 parts of micropowder silica gels, 10 parts of 10% polyvinylpyrrolidone alcoholic solution, 8 parts of 95% ethanol, 0.9 part of magnesium stearate, 8 parts of Pulvis Talci.
The present invention finds through a large amount of tests, selects suitable pharmaceutic adjuvant, especially selects to promote disintegrating agent (being called short disintegrating agent among the present invention), and film-making, the dispersible tablet that the effect that can obtain medical treatment significantly improves are carried out in combination then.In the general scientific research micropowder silica gel is used as fluidizer, consumption general the highest be no more than sheet heavy 1%, we find, in prescription of the present invention, the consumption of micropowder silica gel is increased to more than 8%, this adjuvant has good promotion disintegrating property, reach at 10% o'clock, the disintegrating property of this tablet takes place significantly to change, and is analyzed as follows: select micropowder silica gel as short disintegrate, be because of the specific surface area of micropowder silica gel big, hydrophilic is strong, can increase the wettability of tablet, strengthen capillarity, make moisture impel its disintegrate to the sheet heart by rapid permeability.
On the other hand, the present invention also provides the preparation method of phenolsulfonic acid calcium dispersible tablet.The starting point of dispersible tablet prescription design is to make the granule that disintegrate one-tenth is very little in the short as far as possible time (less than 3min) behind the tablet chance water and form uniform suspension.Advantageously, in conjunction with the characteristics of principal agent calcium dobesilate, technology of the present invention takes principal agent to granulate earlier, granulates the last and blended method of other adjuvants again with disintegrating agent.
Specifically, this method comprises: phenolsulfonic acid calcium raw material drug elder generation and suitable amount of adhesive mixing, and the system soft material is crossed the sieve series wet granular, must do granule after the drying, and then after being mixed in proportion with adjuvant, add wetting agent, the system soft material, cross the sieve series wet granular, must do granule after the drying, granulate adds the moderate lubrication agent and makes tablet.
General pelletization, especially once granulate, be applied in the dispersible tablet of the present invention, the disintegrate effect is bad, analysis may be because principal agent (being calcium dobesilate) consumption is big in this tablet, and this granules of main drug is thin, and it has wrapped up the disintegrating agent that is added, make disintegrating agent can not fully absorb water, expand, be difficult to bring into play the disintegration that disintegrating agent should have.And secondary is granulated and have been disperseed the distribution of principal agent and disintegrating agent, makes itself and the contact surface increase of water, and the effect of in addition urging disintegrating agent makes it rapid disintegrate, reaches the rapid release effect.
Just disintegrate is complete in the time of 1 minute for the dispersible tablet that the present invention makes, and the granule after the disintegrate all can pass through 24 sieves, and the slice, thin piece outward appearance is bright and clean, non-cracking, be full of cracks and crushing phenomenon.
As a kind of selection, the calcium dobesilate raw material powder that uses in the dispersible tablet of the present invention also can keep smaller particle size to satisfy the requirement of dissolution as far as possible, is to rely on superfine powder to reach the purpose of rapid release with this dispersible tablet of making.
Therefore, in another embodiment of the present invention, also can adopt any known or feasible superfine powder technology of preparing to realize the micronization of calcium dobesilate, and then make phenolsulfonic acid calcium dispersible tablet with instant effect.Preferably, the particle diameter of 90% above micro powder granule is less than 10 microns, and more preferably no more than 6 microns, for example, mechanical activation comminution (ultrafine crusher, super micron mill, fluid energy mill) or ultrasonic grinding etc. are then with adjuvant mixing film-making.The employed pharmaceutic adjuvant of this micronized method should satisfy the requirement of conventional pharmacopedics, the different situations of looking raw material, and processing such as can sieve earlier before film-making makes granularity in claimed range.Except that the micronization processes of medicine was had relatively high expectations, dispersible tablet preparation technology and tablet were basic identical, can adopt medicine and hydrophilicity condiment to grind altogether or adopted fluid bed one step pelletize or the method for Topo vacuum granulation mechanism grain.Different with the hydrotropy adjuvant according to concrete micronized degree, required equipment and technological process are than routine operation also difference to some extent, and described these all belong to techniques well known, repeat no more.
The phenolsulfonic acid calcium dispersible tablet sees the following form with the comparative result of the calcium dobesilate that has gone on the market.
| The phenolsulfonic acid calcium dispersible tablet | Calcium dobesilate | |
| Specification | 0.25g | 0.5g |
| Outward appearance | The off-white color sheet, unilateral bright clean | The off-white color sheet, unilateral coarse |
| Disintegration | Just disintegrate is complete in the time of 1 minute, and the granule after the disintegrate all can be by 24 sieves. | Disintegrate in 15 minutes |
| Friability | 0.3%, the sheet of non-cracking, be full of cracks and pulverizing | Greater than 1.0%, and the slice, thin piece fragmentation is arranged |
Calcium dobesilate commodity sharp doubly think of by name, manufacturer is a Nanjing Chang'ao Pharmaceutical Co., Ltd.
The detection method of friability in the above-mentioned experiment: it is some to get slice, thin piece, make its gross weight be about 6.5g, blow away the powder that comes off with hair-dryer, precision is weighed, and puts in the drum, rotate 100 times, take out, remove powder with method, precision is weighed, subtract weight loss and must not cross 1%, and the sheet that must not detect fracture, be full of cracks and pulverize.
The mensuration of disintegration, measure in the water that condition 900ml is 37 ℃:
Dispersible tablet: get 2 of test samples, put jolting in the 100ml water, in 20 ℃ ± 1 ℃ water, all disintegrate was also by No. 2 sieves in 3 minutes, and the while is passed through the screen cloth in 710 μ m apertures at the appointed time.
Ordinary tablet: get it filled 6, put respectively in the glass tubing of hanging basket, start disintegration tester and check that each sheet did not all have disintegrate in 3 minutes.
Dispersible tablet of the present invention meets the quality standard of the dispersible tablet of pharmacopeia regulation after testing fully.
Pharmacodynamic experiment:
The dissolution experiment
The common calcium dobesilate sample that the long Australia of three batches of phenolsulfonic acid calcium dispersible tablets of the present invention (lot number is respectively 031215,031216,031217) and Nanjing is produced passes through the basket method, carried out the dissolution investigation, pressed Chinese Pharmacopoeia version dissolution detection method second method in 2000 and detect.
Testing result: the stripping in 5 minutes of phenolsulfonic acid calcium dispersible tablet reaches 95%, and the stripping in 15 minutes of calcium dobesilate ordinary tablet reaches 95%.
Drug effect contrast experiment
Get the big ear rabbit of (2.0 ± 0.5) kg, male and female half and half are carried out phenolsulfonic acid calcium dispersible tablet and ordinary tablet (domestic and imported) drug effect contrast experiment.The result shows: the phenolsulfonic acid calcium dispersible tablet can significantly reduce the rabbit platelet aggregation rate, can significantly reduce the viscosity of rabbit platelet adhesion rate and blood plasma and serum, has the tangible microcirculation of mouse auricle effect that improves, above drug effect result all is better than homemade conventional tablet, and stomach discomfort, feel sick, heartburn, untoward reaction such as appetite descends, weak, headache, dizziness, skin allergy are lighter.
Conclusion: all more common calcium dobesilate of the disintegration time of phenolsulfonic acid calcium dispersible tablet, dissolving out capability increases, and is rapid-action, can effectively control and keep drug effect more than 4 hours.
Calcium dobesilate belongs to the ease of solubility chemical compound, the inventor is combined into calcium dobesilate raw material and pharmaceutic adjuvant (disintegrating agent, short disintegrating agent, filler and cosolvent etc.) through a large amount of test discoveries the pharmaceutical composition of new phenolsulfonic acid calcium dispersible tablet, can reduce the onset time of calcium dobesilate to greatest extent, reach the rapid release effect, compare with common calcium dobesilate, the medicine dissolution rate is fast, and the rapid release effect is remarkable.Should, the present invention is to the once breakthrough of calcium dobesilate in dosage form is improved.
The specific embodiment
Further set forth the present invention below in conjunction with specific embodiments, but not as limitation of the present invention.
Embodiment 1:
Calcium dobesilate 250g (calculating) with anhydride
Polyvinylpolypyrrolidone 75g
Micropowder silica gel 50g
Carboxymethyl starch sodium 20g
Pulvis Talci 20g
10%PVPk
29/32Alcoholic solution 25g
95% ethanol 20g
Magnesium stearate 2.2g
Make 1000
Preparation technology:
Calcium dobesilate is crossed 80 mesh sieves, and is standby.
Press recipe quantity weighing calcium dobesilate, with 10%PVP
K29/32Alcoholic solution is a binding agent system soft material, 24 eye mesh screen system wet granulars, 40 ℃ dry must do granule, 24 eye mesh screen granulate, granule A.
The polyvinylpolypyrrolidone mixing of granule A and 50g is a wetting agent with 95% ethanol, and the system soft material is crossed 24 eye mesh screens and granulated, 40 ℃ of oven dry, and 24 eye mesh screen granulate get granule B.
Get carboxymethyl starch sodium and the 25g polyvinylpolypyrrolidone and the granule B mixing of recipe quantity, add micropowder silica gel, Pulvis Talci, the magnesium stearate mix homogeneously of recipe quantity again.After check intermediate content is qualified, determine that sheet is heavy, tabletting, packing gets final product.
Embodiment 2:
Calcium dobesilate 250g (by dry product)
Sodium lauryl sulphate 2.5g
Low-substituted hydroxypropyl cellulose 15g
Polyvinylpolypyrrolidone 60g
Micropowder silica gel 50g
Pulvis Talci 22.6g
10%PVPk
29/32Alcoholic solution 25g
95% ethanol 20g
Preparation technology:
Calcium dobesilate is crossed 80 mesh sieves, and is standby.
Press recipe quantity weighing calcium dobesilate, with 10%PVP
K29/32Alcoholic solution is a binding agent system soft material, 24 eye mesh screen system wet granulars, 40 ℃ dry must do granule, 24 eye mesh screen granulate, granule A.
The polyvinylpolypyrrolidone mixing of granule A and 40g is a wetting agent with 95% ethanol, and the system soft material is crossed 24 eye mesh screens and granulated, 40 ℃ of oven dry, and 24 eye mesh screen granulate get granule B.
Get recipe quantity low-substituted hydroxypropyl cellulose and 20g polyvinylpolypyrrolidone and granule B mixing, add micropowder silica gel, Pulvis Talci, the mix homogeneously of recipe quantity again.After check intermediate content is qualified, determine that sheet is heavy, tabletting, packing gets final product.
More than described the preferred embodiment for the present invention, so it is not in order to limit the present invention.Those skilled in the art can not depart from the improvement of category of the present invention and spirit to embodiment disclosed herein.
Claims (9)
1, phenolsulfonic acid calcium dispersible tablet, contain the calcium dobesilate and the pharmaceutic adjuvant for the treatment of effective dose, it is characterized in that described pharmaceutic adjuvant comprises disintegrating agent and short disintegrating agent, wherein disintegrating agent is selected from least a of microcrystalline Cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose; Should short disintegrating agent be selected from least a in micropowder silica gel, sodium lauryl sulphate, Tween 80 and the sulfo-succinic acid two hot vinegar sodium.
2, the described dispersible tablet of claim 1, wherein by 100 parts of calcium dobesilates, described disintegrating agent consumption is 2～60 parts, the consumption of described short disintegrating agent is 0.1～45 part.
3, the described dispersible tablet of claim 2, wherein pharmaceutic adjuvant also comprises binding agent, wetting agent, at least a in the lubricant, described binding agent is selected from polyvinylpyrrolidone ethanol, starch slurry, at least a in hydroxypropyl emthylcellulose aqueous solution and the copolyvidone alcoholic solution, wetting agent comprises ethanol, lubricant is selected from stearic acid, magnesium stearate, Pulvis Talci, Polyethylene Glycol, at least a in the Stepanol MG, press 100 parts of calculating of calcium dobesilate, described adhesive consumption is 2～25 parts, described wetting agent consumption is 5～20 parts, and lubricant is 0.2～20 part.
4, the described dispersible tablet of claim 3, wherein disintegrating agent is polyvinylpolypyrrolidone and/or carboxymethyl starch sodium, and short disintegrating agent is micropowder silica gel, and binding agent is a polyvinylpyrrolidone ethanol; Wetting agent is that concentration is not less than 70% ethanol; Lubricant is magnesium stearate and/or Pulvis Talci, also contains the fluidizer Pulvis Talci.
5, the described dispersible tablet of claim 4, wherein disintegrating agent and short disintegrating agent are polyvinylpolypyrrolidone, carboxymethyl starch sodium and micropowder silica gel coupling; Fluidizer is a Pulvis Talci; Binding agent is a polyvinylpyrrolidone ethanol; Wetting agent is to be not less than 70% alcoholic solution; Lubricant comprises magnesium stearate and Pulvis Talci.
6, the described dispersible tablet of claim 5 is pressed 100 parts of calculating of calcium dobesilate, and wherein disintegrating agent comprises 3～40 parts of polyvinylpolypyrrolidone, 3～15 parts of carboxymethyl starch sodium, and short disintegrating agent is 1.6～45 parts of micropowder silica gels; Fluidizer comprises 2～20 parts of Pulvis Talci; Binding agent is that concentration range is 2～20 parts of the polyvinylpyrrolidone alcoholic solution of 1～15% (g/g); Wetting agent is that concentration is not less than 2～20 parts of 70% alcoholic solution; Lubricant is 0.2～2.5 part of magnesium stearate, 2～17 parts of Pulvis Talci.
7, the described dispersible tablet of claim 6, wherein calcium dobesilate is 100 parts, 30 parts of polyvinylpolypyrrolidone, 8 parts of carboxymethyl starch sodium, 20 parts of micropowder silica gels, 10 parts of 10% polyvinylpyrrolidone alcoholic solution, 8 parts of 95% ethanol, 0.9 part of magnesium stearate, 8 parts of Pulvis Talci.
8, preparation is characterized in that as the method for claim 1-6 dispersible tablet as described in each, the phenolsulfonic acid calcium raw material drug earlier with binding agent system granule, and then with residue adjuvant be mixed in proportion system granule, tabletting at last.
9, the described method of claim 8 comprises: phenolsulfonic acid calcium raw material drug elder generation and suitable amount of adhesive mixing, system soft material, cross the sieve series wet granular, must do granule after the drying, after being mixed in proportion with the disintegrating agent that surpasses 1/2 amount then, add wetting agent, the system soft material, cross the sieve series wet granular, must do granule, granulate after the drying, again with the disintegrating agent of surplus and short collapse the agent mixing after, add the moderate lubrication agent and make tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410042865 CN1259042C (en) | 2004-05-28 | 2004-05-28 | Calcium phenol sulfonate dispersive tablets and their preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410042865 CN1259042C (en) | 2004-05-28 | 2004-05-28 | Calcium phenol sulfonate dispersive tablets and their preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1582910A true CN1582910A (en) | 2005-02-23 |
| CN1259042C CN1259042C (en) | 2006-06-14 |
Family
ID=34601686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410042865 Expired - Lifetime CN1259042C (en) | 2004-05-28 | 2004-05-28 | Calcium phenol sulfonate dispersive tablets and their preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1259042C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100377705C (en) * | 2005-11-03 | 2008-04-02 | 上海朝晖药业有限公司 | Calcium hydrophenyl sulfonate capsule and its prepn process |
| CN104644587A (en) * | 2015-03-20 | 2015-05-27 | 王雪雁 | Preparation method of medicine composition for treating cardiovascular disease |
| CN108272763A (en) * | 2018-03-29 | 2018-07-13 | 海南林恒制药股份有限公司 | A kind of Calcium Dobsilate and preparation method thereof |
-
2004
- 2004-05-28 CN CN 200410042865 patent/CN1259042C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100377705C (en) * | 2005-11-03 | 2008-04-02 | 上海朝晖药业有限公司 | Calcium hydrophenyl sulfonate capsule and its prepn process |
| CN104644587A (en) * | 2015-03-20 | 2015-05-27 | 王雪雁 | Preparation method of medicine composition for treating cardiovascular disease |
| CN108272763A (en) * | 2018-03-29 | 2018-07-13 | 海南林恒制药股份有限公司 | A kind of Calcium Dobsilate and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1259042C (en) | 2006-06-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1805738A (en) | Extended-release tablets of metformin | |
| KR20120117985A (en) | Dry-coated orally disintegrating tablet | |
| CN1823091A (en) | Functional starch powder | |
| JP3534130B2 (en) | Pharmaceutical composition | |
| KR20040005986A (en) | Solid Pharmaceutical Formulations Comprising Modafinil | |
| CN101612135A (en) | A kind of levetiracetam composition and method of making the same that is used for direct compression | |
| CN104042580B (en) | A kind of valsartan dispersible tablet and preparation method thereof | |
| CN1613442A (en) | Disintegrants for deodoring effectively and their preparation | |
| CN104706640B (en) | A kind of Pharmaceutical composition and its preparation technology containing Irbesartan | |
| TWI316406B (en) | Novel pharmaceutical formulations of modafinil | |
| CN103610677A (en) | Repaglinide troche and preparation method thereof | |
| CN102526748B (en) | Oral tablet containing Valsartan, Hydrochioro and Amlodipine Besylate Tablet | |
| CN103263395A (en) | Telmisartan tablet preparation and preparation method thereof | |
| CN1259042C (en) | Calcium phenol sulfonate dispersive tablets and their preparation | |
| CN1903208A (en) | Adefovir dipivoxil oral disintegration tablets medicine prepn., and prepn. method therefor | |
| CN1864679A (en) | A composite bergenin dispersible tablet and preparation method thereof | |
| JP4774739B2 (en) | Kampo extract-containing tablet composition and method for producing the same | |
| CN102198107B (en) | Lacidipine dispersible tablets and preparation method thereof | |
| CN1443535A (en) | Tegasevod maleate oral preparation and its preparation process-for curing intestinal irritability syndrome | |
| CN101711753B (en) | Preparation method of lansoprazole solid preparation | |
| CN114129524A (en) | Paracetamol tablet and preparation method thereof | |
| CN1297263C (en) | Calcium gluconate oral disintegrating tablet and its preparation process | |
| CN1634014A (en) | Sodium ferulate oral disintegrating tablet and its preparation process | |
| CN1528273A (en) | Analgesic tramadol hydrochloride oral disintegrating tablet and preparing method thereof | |
| CN1296045C (en) | Oral disintegration tablet of dihydroergotoxine and its derivatives and its preparing process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: JIANGSU WANGAO PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: XU XINSHENG; WEN YANQIU Effective date: 20060804 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20060804 Address after: 226100 Haimen Road, 688, economic and Technological Development Zone, Haimen, Jiangsu Patentee after: JIANGSU WANGAO PHARMACEUTICAL CO.,LTD. Address before: Four Beijing 100012 Chaoyang District City Beiyuan No. five hospital (Beijing Institute of geology research building) Co-patentee before: Wen Yanqiu Patentee before: Xu Xinsheng |
|
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 226100 Haimen Road, 688, economic and Technological Development Zone, Haimen, Jiangsu Patentee after: Jiangsu Wangao Pharmaceutical Co.,Ltd. Address before: 226100 Haimen Road, 688, economic and Technological Development Zone, Haimen, Jiangsu Patentee before: JIANGSU WANGAO PHARMACEUTICAL CO.,LTD. |
|
| CX01 | Expiry of patent term |
Granted publication date: 20060614 |