CN1252992A - Carboprost methyl ester preparation absorbable through oral mucosa and preparation method thereof - Google Patents
Carboprost methyl ester preparation absorbable through oral mucosa and preparation method thereof Download PDFInfo
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- CN1252992A CN1252992A CN 99113376 CN99113376A CN1252992A CN 1252992 A CN1252992 A CN 1252992A CN 99113376 CN99113376 CN 99113376 CN 99113376 A CN99113376 A CN 99113376A CN 1252992 A CN1252992 A CN 1252992A
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- preparation
- tablet
- binding agent
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- carboprost methylate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 59
- QQCOAAFKJZXJFP-XAYIDPIISA-N 15-methyl-15R-PGF2alpha methyl ester Chemical compound CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(=O)OC QQCOAAFKJZXJFP-XAYIDPIISA-N 0.000 title claims abstract description 53
- 210000002200 mouth mucosa Anatomy 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 38
- 239000008187 granular material Substances 0.000 claims abstract description 33
- 239000000843 powder Substances 0.000 claims abstract description 26
- 239000000314 lubricant Substances 0.000 claims abstract description 20
- 238000005516 engineering process Methods 0.000 claims abstract description 19
- 239000000945 filler Substances 0.000 claims abstract description 14
- 238000010521 absorption reaction Methods 0.000 claims abstract description 12
- 239000002250 absorbent Substances 0.000 claims abstract description 10
- 230000002745 absorbent Effects 0.000 claims abstract description 10
- 239000000853 adhesive Substances 0.000 claims abstract description 7
- 230000001070 adhesive effect Effects 0.000 claims abstract description 7
- 239000002245 particle Substances 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 239000011230 binding agent Substances 0.000 claims description 36
- 239000003826 tablet Substances 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 28
- 229920002472 Starch Polymers 0.000 claims description 25
- 239000008107 starch Substances 0.000 claims description 25
- 235000019698 starch Nutrition 0.000 claims description 25
- 239000003795 chemical substances by application Substances 0.000 claims description 19
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- 229930006000 Sucrose Natural products 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- 239000008101 lactose Substances 0.000 claims description 15
- 239000003381 stabilizer Substances 0.000 claims description 15
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 14
- 235000010603 pastilles Nutrition 0.000 claims description 11
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 9
- 238000005303 weighing Methods 0.000 claims description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 239000008188 pellet Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 239000006189 buccal tablet Substances 0.000 claims description 4
- 229940046011 buccal tablet Drugs 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000003623 enhancer Substances 0.000 claims description 4
- 239000007779 soft material Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- HVUMOYIDDBPOLL-UHFFFAOYSA-N 2-(3,4-Dihydroxyoxolan-2-yl)-2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)C1OCC(O)C1O HVUMOYIDDBPOLL-UHFFFAOYSA-N 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 239000006190 sub-lingual tablet Substances 0.000 claims description 3
- 229940098466 sublingual tablet Drugs 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims 2
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- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 11
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 11
- 238000012360 testing method Methods 0.000 description 7
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- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 208000018525 Postpartum Hemorrhage Diseases 0.000 description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 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 2
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 2
- 101800000989 Oxytocin Proteins 0.000 description 2
- 102100031951 Oxytocin-neurophysin 1 Human genes 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- -1 Stepanol MG Chemical compound 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
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- 238000005259 measurement Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 2
- 229960001723 oxytocin Drugs 0.000 description 2
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- 229920000136 polysorbate Polymers 0.000 description 2
- 239000000473 propyl gallate Substances 0.000 description 2
- 235000010388 propyl gallate Nutrition 0.000 description 2
- 229940075579 propyl gallate Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- KNENSDLFTGIERH-UHFFFAOYSA-N 2,2,4,4-tetramethyl-3-phenylpentan-3-ol Chemical compound CC(C)(C)C(O)(C(C)(C)C)C1=CC=CC=C1 KNENSDLFTGIERH-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
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- 229920000858 Cyclodextrin Polymers 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- WVVSZNPYNCNODU-CJBNDPTMSA-N Ergometrine Natural products C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-CJBNDPTMSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
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- WVVSZNPYNCNODU-XTQGRXLLSA-N Lysergic acid propanolamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-XTQGRXLLSA-N 0.000 description 1
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Abstract
A carboprost methyl ester preparation for oral mucosa absorption is prepared from tablet, granule, micropill and powder through preparing, and proportionally mixing. The method is characterized in that the medicine is dissolved in the adhesive, added into the treated filler and granulated according to the conventional technology or the boiling granulation technology, or the medicine is dissolved and adsorbed on the absorbent, then mixed with the prefabricated blank particles, added with the disintegrant and the lubricant, mixed evenly and tabletted to prepare the preparation, which contains 0.1-2.0 mg of active ingredient per tablet per bag. The preparation has stable quality, safe action, remarkable therapeutic effect, and simple application.
Description
The present invention relates to A61K 9/00 class, but be used to prevent and treat carboprost methylate preparation of postpartum hemorrhage oral transmucosal absorption and preparation method thereof.
Carboprost methylate is in 1975, the prostaglandins medicine of being succeeded in developing by institute of Materia Medica,Chinese Academy of Medical Sciences.Its structural formula is:
Molecular formula: C
22H
38O
5Molecular weight: 382.54
Chemical name is racemization-(5Z.9 α .11 α .13E.15S)-9.11.15-trihydroxy-15-U-32921E-5,13-diene-1-acid methyl ester, and this product was a kind new medicine in 1987 by the Ministry of Public Health approval, and product forms is a suppository, and commodity are called methyl carboprost suppositories.Be widely used in drug induced abortion, induced labor and the control official slowness postpartum hemorrhage that contracts at present clinically.Practice has proved that carboprost methylate suppository has than oxytocin, official's effect of contracting that ergometrine is stronger.But no matter the methyl carboprost suppositories agent is to adopt postpartum vaginal administration or rectally mode, and using all has inconvenience, and especially vagina administration easily causes puerpera's secondary infection.Therefore, administration needs medical personnel to operate under aseptic condition.Because of limited by medical condition, influenced this medicine promoting the use of in vast rural area or less medical institutions.In addition, methyl carboprost suppositories is relatively more responsive to external influence factors such as light, wet, heat, and character is not really stable.Therefore, it is preserved needs at cryopreservation below-20 ℃.Still applying unit is all very inconvenient to producing, transporting for this, and its social benefit is subjected to very big influence.Therefore, need to explore, search out a kind of medication and reliable quality pharmaceutical dosage form of easy, safe and effective carboprost methylate.
As everyone knows, but the mouth mucosa drug administration oral transmucosal absorb, flow directly into heart by superior vena cava and enter the body circulation and arrive target tissue or target organ, target cell, can avoid medicine to pass through " first pass effect " of liver, drug absorption is good, and is rapid-action.
But the purpose of this invention is to provide carboprost methylate preparation of a kind of oral transmucosal absorption and preparation method thereof.This method technology is simple, easy to operate, and its product has stability preferably, not only overcome suppository and preserved difficulty, awkward shortcoming, and drug effect is remarkable, has strengthened the contraction to uterine smooth muscle, can obviously reduce puerpera's postpartum hemorrhage amount.
But the carboprost methylate preparation that oral transmucosal absorbs, except that containing the active component carboprost methylate, also contain a large amount of filleies, binding agent, auxiliary elements such as disintegrating agent is characterized in that each set of dispense ratio is: % by weight percentage: effective active composition 0.1-2.0 filler 65-95 binding agent 0.5-3.0 disintegrating agent 3.0-25 lubricant 0.5-4.0 stabilizing agent 0-3.0 Percutaneous absorption enhancer 0-3.0 absorbent 0-25
The preparation of preparation: filler through pulverize, sieve, weighing handles, it is characterized in that the active component carboprost methylate is dissolved in the binding agent for preparing in advance according to the above ratio, this pastille binding agent is joined in the filler of preparing burden by the used prescription of each technology, adopt routine techniques ethanol legal system wet granular, drying under reduced pressure; Also can adopt fluidized granulating technology or prepare blank granule earlier, again active component is adsorbed onto on the absorbent; Behind the granulate, adding disintegrating agent, lubricant, mix homogeneously again. tabletting then promptly obtains containing effective composition 0.1-2.0mg/ sheet, the tablet of bag, granule, pellet, powder.
Preparation method of the present invention has following characteristics:
The present invention adopts active component is dissolved in the ready made binding agent, can make medicine be molecularity evenly spreads in the adjuvant, make to make product not only to contain effective composition even, and avoid of the harm of the extremely strong drug dust of valuable crude drug loss and physiologically active aborning the operating personnel.This method makes constant product quality, can preserve at normal temperatures, and be convenient to storage, transportation and the use of large tracts of land clinical expansion.It is disintegrating agent that said preparation has adopted carboxymethyl starch sodium DST, and disintegrate is fast, release is fast, makes preparation of the present invention reach the clinical instructions for use of quick release.Particularly under equal curative effect, reduce dosage, reduced poison and paid effect, reduced patient's medical expense, the good social benefit is arranged.
Accompanying drawing 1: the conventional Ethanol Method granulation preparation technology flow chart of carboprost methylate preparation;
Accompanying drawing 2: the boiling granulating preparation technology flow chart of carboprost methylate preparation;
Accompanying drawing 3: the prefabricated blank granule preparing process flow chart of carboprost methylate preparation;
Embodiment 1:
But the carboprost methylate preparation that oral transmucosal absorbs except that containing the active component carboprost methylate, also contains auxiliary elements such as a large amount of filleies, binding agent, disintegrating agent, lubricant, it is characterized in that each set of dispense ratio is: (% by weight percentage)
The prescription of granule or tablet a:
Granule tablet % effective active composition carboprost methylate 1.5g 1.5g 1.97% filler lactose 33.33g 33.33g
Sucrose 33.33g 33.33g 87.71%
Binding agent PVP 0.38g 0.38g 0.5%
Stabilizing agent BHT 1.0g 1.0g 1.32%
Lubricant MS---0.38g 0.5%
Disintegrating agent DST---6.08g 8.0%
Prepare adhesive means 1 in advance: measure 28ml ethanol, add 1.0g BHT, stir and make dissolving, add 0.38gPVP again, stir and make the dissolving back add the 1.5g carboprost methylate, abundant stirring and dissolving and being uniformly dispersed, binding agent 1.The granule method for making: with lactose, sucrose pulverize separately, sieve after, respectively take by weighing 33.33g, mix homogeneously, add binding agent 1 and make soft material, by 16 mesh sieves, system wet granular, put in 40 ℃ of vacuum drying ovens, decompression (0.1MPa) is in dry, dried granule is by behind the 16 mesh sieve granulate, be distributed into granule, 1000 bags contain carboprost methylate 1.5mg/ bag.The method for making of tablet a: above-mentioned technology is identical, it is characterized in that adding 6.08gDST and 0.38g magnesium stearate MS behind the granulate, and mix homogeneously, tabletting is made 1000, contains effective composition 1.5mg/ sheet.Tablet comprises Sublingual tablet, buccal tablet and buccal tablet, can make different content, difform dosage form according to agents area.
Embodiment 2:
Adopt the pellet of boiling prepared or the prescription of tablet b:
Pellet tablet % effective active composition carboprost methylate 1.0g 1.0g 0.66% filler lactose 70g 70g
Sucrose 70g 70g 92.78% binding agent, stabilizing agent PVP 2.4g 2.4g 1.59% disintegrating agent DST 6.0g 3.98% lubricant MS 1.5g 0.99%
Prepare adhesive means 2 in advance: measure 30ml ethanol, adding 2.4gPVP stirs and makes dissolving, adds the 1.0g carboprost methylate again, and fully stirring makes dissolving and is uniformly dispersed, and gets binding agent 2.Adopt fluidized granulating technology: with lactose, sucrose pulverize separately, sieve after, respectively take by weighing 70g, place in the fluidized granulating machine staving, open hot blast, do and mixed 3 minutes; Again binding agent 2 is sprayed on the Icing Sugar, carries out fluidized granulating.Dried granule is distributed into pellet behind granulate, 1000 bags contain carboprost methylate 1mg/ bag.The method for making of tablet b: identical with aforementioned technology, it is characterized in that adding disintegrating agent DST 6g and lubricant MS1.5g again behind the granulate, mix homogeneously, tabletting are made tablet b1000 sheet, 1.0mg/ sheet effective ingredient.
Embodiment 3
The prescription of powder 1 or tablet c:
Powder tablet % effective active composition carboprost methylate 0.12g 0.12g 0.11% filler lactose 38g 38g
Sucrose 38g 38g 67.86% binding agent, stabilizing agent PVP 3.4g 3.4g 3.0% absorbent, disintegrating agent dried starch 28g 28g 25% lubricant MS 4.48g 4.48g 4.0%
The preparation method of preparation powder 1: the method a. that prepare the pastille dried starch gets 4ml ethanol, adds 0.12g carboprost methylate stirring and dissolving, evenly is sprayed on the 28g dried starch, makes even absorption, treat ethanol wave be dissipated to the greatest extent after, must the pastille dried starch; After in addition lactose, sucrose being pulverized, sieved, respectively take by weighing 38g, add stabilizing agent PVP, lubricant MS and above-mentioned pastille again in starch, mix homogeneously is made powder 1120 bags, contains carboprost methylate 0.6mg/ bag.
Prepare adhesive means 3 in advance: measure the 10.0ml aquae destillata, add 3.4gPVP stir make dissolve binding agent 3.Prefabricated blank is done the preparation method of particulate tablet c: with lactose, sucrose pulverize separately, sieve after, respectively take by weighing 38g, mix homogeneously is characterized in that adding binding agent 3, makes soft material; By 16 mesh sieve system wet granulars, after 60-80 ℃ of drying, by the 16 mesh sieve granulate white spirit granule of having leisure; Add the pastille dried starch that makes among the powder 1a, add 4.48g lubricant MS again, mix homogeneously, tabletting make tablet c400 sheet, contain effective composition 0.3mg/ sheet.
Embodiment 4:
The prescription of powder 2 or tablet d:
Powder tablet % medicine effective active composition carboprost methylate 0.5g 0.5g 0.47% filler lactose 42.5g 42.5g
Sucrose 42.5g 42.5g 80.19% binding agent PVP 1.0g 1.0g 0.94% stabilizing agent citric acid--2.0g
BHT--1.0g 2.83% Percutaneous absorption enhancer Tween 80--0.5g
Sorbester p18--2.6g 2.93% adsorbent, disintegrating agent dried starch 10.0g 10.0g 9.43% lubricant MS 3.4g 3.4g 3.2%
The method for making of powder 2: by the preparation method preparation that powder 1 was prepared burden, pressed to above-mentioned prescription, get powder 2 500 bags, contain carboprost methylate 1mg/ bag.
Prepare adhesive means 4 in advance: get 1g stabilizing agent BHT, add the 0.5g Tween 80, stir and make dissolving, add the 0.125g sorbester p18 again, stirring makes dispersion, and other gets distilled water 5ml, adds 1.0g stabilizing agent PVP and 2g citric acid, stirring makes dissolving, and two liquid are mixed, stir binding agent 4.The method for making of tablet d is except that using binding agent 4, and all the other methods are identical with the method for making of tablet c, make 1000 in tablet, contain effective composition 0.5mg/ sheet.Embodiment 5: the prescription of powder 3 or tablet e:
Powder tablet % effective active composition carboprost methylate 0.5g 0.5g 0.47% filler lactose 45g 45g
Sucrose 45g 45g 85.31% binding agent PVP 1.0g 1.0g 0.95% stabilizing agent citric acid--2.0g
BHT 1.0g 1.0g 2.84% absorbent, disintegrating agent dried starch 10g 10g 9.48% lubricant MS 1.0g 1.0g 0.95%
The preparation method of powder 3: the method b for preparing the pastille dried starch: get 4ml ethanol, add the 1gBHT stirring and make dissolving, add the 0.5g carboprost methylate again, after the stirring and dissolving, evenly be sprayed onto on the 10g dried starch, other technology is identical with powder 1 method for making, makes powder 3 500 bags, contains carboprost methylate 1mg/ bag.
Prepare adhesive means 5 in advance: get the 6.5ml distilled water and add 1g PVP and 2g citric acid, stir and make dissolving, get binding agent 5.The method for making of tablet e: except that adopting binding agent 5, it is identical with example 3 that all the other make blank dried granule method; Add the pastille dried starch that powder 3 makes, add lubricant MS1.0g again, mix homogeneously, tabletting makes 1000 of tablet e, contains carboprost methylate 0.5mg/ sheet.
Various adjuvants in the above-mentioned technology can be replaced with similar material commonly used.
1, Chang Yong filler can be: except that lactose, also can adopt other saccharide, polyalcohols, cellulose family, starch based, get wherein one or more.
2, Chang Yong binding agent can be: polyvidone (PVP), starch slurry, syrups, rubber cement class, cellulose family, get wherein one or more.
3, Chang Yong disintegrating agent can be: one or more in carboxymethyl starch sodium (DST), low-substituted hydroxypropyl cellulose (LS-PHC), carboxymethylcellulose calcium (CMC-Ca), cross-linking sodium carboxymethyl cellulose, cross-linked pvp, dried starch, the sodium alginate etc.
4, Chang Yong lubricant can be: magnesium stearate, calcium stearate, stearic acid, zinc stearate, Pulvis Talci, Polyethylene Glycol (PEG4000) (PEG6000), in liquid paraffin,light, sodium lauryl sulphate, Stepanol MG, adipic acid, fumaric acid etc. one or more.
5, stabilizing agent: di-tert-butyl hydroxy toluene (BHT), butylated hydroxyarisol (BHA), propyl gallate (PG), vitamin E; Sulfites; Ascorbic acid and derivatives class thereof; Amino acids and organic acid; Metal ion chelation agent, cyclodextrin, PVP, wherein one or more.
6, Percutaneous absorption enhancer: as azone, menthol, urea, thiourea, surfactant: Tweens, spans, sodium lauryl sulphate, sucrose ester etc. one or more.
7, absorbent can be: dried starch, micropowder silica gel, kaolin, Bentonite, light magnesium oxide, Aluminium Hydroxide etc. one or more.
8, solvent can be: the mixed solvent of one or more in ethanol, isopropyl alcohol, ether, dichloromethane, chloroform, carbon tetrachloride, acetone, the n-hexane etc.
The carboprost methylate preparation that the oral transmucosal made from the inventive method is absorbed has carried out medicine stability test and clinical observation.Result of the test shows: this stable and reliable product quality, and the clinical practice determined curative effect, test data is seen attached list.
Subordinate list 1: different factors influence result of the test (content % outward appearance) to the carboprost methylate preparation stability
Annotate: 1. outward appearance no change, white tablets is with " " expression, and slightly flavescence is "+", and the flavescence color is " ++ ";
| Time (my god) | 40 ℃ of 60 ℃ 80 ℃ RH75% RH92.5% 4500 ± 500LX of hot and humid illumination | Room temperature exposes air |
| ?0 ?1 ?3 ?5 ?10 | 100.0-??100.0-???100.0-???100.0-???100.0-???100.0- 100.7-??98.82+???96.64++??100.03-??100.1+???100.5- 100.2+??95.98++??57.84++??100.1+???100.2+???99.83- 100.3+??92.22++??46.57++??100.3+???94.87++??97.09 99.90+??79.05++??18.43++??100.4+???74.38++??93.99- | ??100.0- ??100.2- ??100.2- ??99.9- ??100.1- |
2. the interior data of table are the meansigma methods of 6 measurement results.Subordinate list 2: carboprost methylate tablet stability accelerated test and reserved sample observing result of the test (content % outward appearance)
Annotate: 1. "--" represents outward appearance no change white tablets, the slightly flavescence of "+" expression outward appearance, and (-) do not have determination data;
| Accelerated test | Reserved sample observing | ||
| Time 40 ± 2 ℃ of RH75 ± 5% (moon) | 25±2℃??RH60±5％ | 25±2℃?RH60±10％ | 4℃ |
| ?0???100.0???-- ?1???100.6???+ ?2???96.18???+ ?3???94.31???+ ?6 | 100.0????-- 100.4????-- 99.44????-- 100.1????-- | 100.0???-- (-) (-) 99.90???-- | 100.0- (-) (-) 100.5- |
2. the interior data of table are the meansigma methods of 6 measurement results.
Subordinate list 3: 25 ℃ of carboprost methylate suppositorys and-4 ℃ of reserved sample observing result of the tests
Subordinate list 4: the carboprost methylate different way of administration is to the observation of curative effect of postpartum hemorrhage dosage form dosed administration approach example amount of bleeding in 2 hours puerperal of number third stage of labor time as a result
| Temperature ℃ | ??????????25 | ??-4 |
| Time (my god) | 14????23????35????54 | ??150 |
| Content (%) | 99.7??90.5??88.6??75.8 | ??86.0 |
(mg) (min) (ml) Sublingual tablet 0.5 Sublingual 25 6.68 ± 3.21 139.8 ± 63.4
1.0 Sublingual 50 6.48 ± 7.02 136.6 ± 55.2 suppositorys, 1.0 rectum 150 8.35 ± 3.35 143.2 ± 43.7
1.0 vagina 130 7.60 ± 3.46 146.4 ± 66.0 oxytocin 10IU intramuscular injection 50 12.48 ± 3.44 267.9 ± 69.6
The quiet notes 50 9.84 of 10IU ± 3.92 210.6 ± 61.3
Claims (10)
- But 1, a kind of carboprost methylate preparation of oral transmucosal absorption, dosage form comprises buccal tablet, Sublingual tablet, buccal tablet, granule, pellet, it is characterized in that raw material components % by weight percentage:Effective active composition carboprost methylate 0.1-2.0Filler lactose, sucrose 65-95Binding agent PVP 0.5-3.0Disintegrating agent DST 3.0-25Lubricant MS 0.5-4.0Stabilizing agent citric acid, BHT 0-3.0Percutaneous absorption enhancer Tween 80, sorbester p18 0-3.0Absorbent dried starch 0-25
- 2, preparation according to claim 1 is characterized in that the proportioning of each used in Different Preparation prescription is as follows, precentagewise meter %:Prescription (1) (2) (3) (4) (5)Active component 1.97 0.66 0.11 0.47 0.47Filler 87.71 92.78 67.86 80.19 85.31Binding agent 0.5 1.59 3.0 0.94 0.95Disintegrating agent 8.0 3.98------Lubricant 0.5 0.99 4.0 3.20 0.95Stabilizing agent 1.32----2.83 2.84Penetration enhancer------2.92--Absorbent (disintegrating agent)----25.0 9.43 9.48
- But the preparation method of the carboprost methylate preparation that 3 oral transmucosals absorb, filler is through pulverizing, the processing of sieving; It is characterized in that the active component carboprost methylate is dissolved in the binding agent for preparing in advance according to the above ratio, this binding agent is joined in the filler of preparing burden by the used prescription of each technology, adopt routine techniques ethanol legal system wet granular, drying under reduced pressure; Also can adopt fluidized granulating technology or prepare blank granule earlier, again active component is adsorbed onto on the absorbent; Behind the granulate, add disintegrating agent, lubricant, mix homogeneously again, tabletting then promptly obtains containing the preparation of effective composition, 0.1-2.0mg/ sheet, bag.
- 4, the preparation method of preparation according to claim 3, it is characterized in that the used binding agent of each preparation technology all needs to prepare in advance, raw materials used proportioning by each prescription in the right 2, the preparation binding agent is used following method respectively: prepare adhesive means 1 in advance: measure 28ml ethanol, add 1.0g BHT, stir and make dissolving, add 0.38gPVP again, stirring makes dissolving back add the 1.5g carboprost methylate, abundant stirring and dissolving and being uniformly dispersed, binding agent 1; Method 2: measure 30ml ethanol, adding 2.4gPVP stirs and makes dissolving, adds the 1.0g carboprost methylate again, and fully stirring makes dissolving and is uniformly dispersed, and gets binding agent 2; Method 3: measure the 10.0ml aquae destillata, add 3.4gPVP stir make dissolve binding agent 3; Method 4: get 1g stabilizing agent BHT, add the 0.5g Tween 80, stir and make dissolving, add the 0.125g sorbester p18 again, stirring makes dispersion, and other gets distilled water 5ml, adds 1.0g stabilizing agent PVP and 2g citric acid, stirring makes dissolving, and two liquid are mixed, stir binding agent 4; Method 5: get distilled water 6.5ml and add 1gPVP and 2g citric acid, stir and make dissolving, get binding agent 5.
- 5, the preparation method of preparation according to claim 3 is characterized in that the preparation method or the tablet a method for making of granule; The granule method for making: with lactose, sucrose pulverize separately, sieve after, respectively take by weighing 33.33g, mix homogeneously, add above-mentioned binding agent and make soft material, by 16 mesh sieves, the system wet granular, put in 40 ℃ of vacuum drying ovens, the decompression (0.1MPa) drying, dried granule is by behind the 16 mesh sieve granulate, be distributed into granule, 1000 bags contain carboprost methylate 1.5mg/ bag; Tablet a method for making: by 1 batching of the prescription in the right 2, above-mentioned technology is identical, adds 6.08gDST and 0.38g magnesium stearate MS behind the granulate, mix homogeneously, and tabletting is made 1000 of tablet a, contains effective composition 1.5mg/ sheet.
- 6, the preparation method of preparation according to claim 3 is characterized in that adopting fluidized granulating technology system micropill or tablet b: with lactose, sucrose pulverize separately, sieve after, respectively take by weighing 70g, place in the fluidized granulating machine staving, open hot blast, do and mixed 3 minutes; Binding agent 2 is sprayed on the Icing Sugar again, carries out fluidized granulating, dried granule is distributed into pellet behind granulate, and 1000 bags contain carboprost methylate 1mg/ bag; Tablet b method for making: by 2 batchings of prescription in the right 2, above-mentioned technology is identical, adds disintegrating agent DST 6g and lubricant MS1.5g behind the granulate again, and mix homogeneously, tabletting are made 1000 of tablet b, contain effective composition 1.0mg/ sheet.
- 7, the preparation method of preparation according to claim 3 is characterized in that preparing the prefabricated blank of tablet c in particulate method: with lactose, sucrose pulverize separately, sieve after, respectively take by weighing 38g, mix homogeneously is characterized in that adding binding agent 3, makes soft material; By 16 mesh sieve system wet granulars, place 60-80 ℃ of drying after, dried particles is by the 16 mesh sieve granulate white spirit granule of having leisure; In addition the 0.12g carboprost methylate is dissolved in the 4ml ethanol, evenly is sprayed on the absorbent 10g dried starch, make even absorption, treat ethanol wave disperse after, join in the blank dried granule, add 4.48g lubricant MS again, mix homogeneously, tabletting get 400 of tablet c, contain effective composition 0.3mg/ sheet.
- 8, the preparation method of preparation according to claim 7 is characterized in that preparing the method for tablet d, e: respectively by 4,5 batchings of the prescription in the right 2; Preparation method is identical with right 7 methods, makes 1000 of tablet d respectively, contains effective composition 0.5mg/ sheet.
- 9, the preparation method of preparation according to claim 3, it is characterized in that preparing the preparation method of powder 1: the method a for preparing the pastille dried starch: get 4ml ethanol, add 0.12g carboprost methylate stirring and dissolving, evenly be sprayed on the 28g dried starch, make even absorption, treat ethanol wave be dissipated to the greatest extent after, the pastille dried starch; After in addition lactose, sucrose being pulverized, are sieved, respectively take by weighing 38g, go into stabilizing agent PVP, lubricant MS and above-mentioned pastille dried starch for another example, mix homogeneously, make powder 1120 bags, contain carboprost methylate 0.6ml/ bag, the method for making of powder 2: by prescription 4 batchings of right 2, the preparation method preparation of pressing above-mentioned powder 1, get powder 2 500 bags, contain carboprost methylate 1mg/ bag.
- 10, the preparation method of preparation according to claim 3, the preparation method that it is characterized in that powder 3: by prescription 5 batchings of right 2, the method b for preparing the pastille dried starch: get 4ml ethanol, add the 1gBHT stirring and make dissolving, add the 0.5g carboprost methylate again, after the stirring and dissolving, evenly be sprayed onto on the 10g dried starch, other technology is identical with powder 1 method for making, makes powder 3 500 bags, contains carboprost methylate 1mg/ bag.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99113376 CN1116877C (en) | 1999-10-28 | 1999-10-28 | Carprostenol preparation capable of being absorbed through oral mucosa and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99113376 CN1116877C (en) | 1999-10-28 | 1999-10-28 | Carprostenol preparation capable of being absorbed through oral mucosa and preparation method thereof |
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| Publication Number | Publication Date |
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| CN1252992A true CN1252992A (en) | 2000-05-17 |
| CN1116877C CN1116877C (en) | 2003-08-06 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1299765C (en) * | 2004-10-29 | 2007-02-14 | 卢建军 | Thymosin peptide oral tablet and its preparation method |
| CN104936580A (en) * | 2012-12-31 | 2015-09-23 | Fng研究有限公司 | new microparticle dosage form |
-
1999
- 1999-10-28 CN CN 99113376 patent/CN1116877C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1299765C (en) * | 2004-10-29 | 2007-02-14 | 卢建军 | Thymosin peptide oral tablet and its preparation method |
| CN104936580A (en) * | 2012-12-31 | 2015-09-23 | Fng研究有限公司 | new microparticle dosage form |
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| CN1116877C (en) | 2003-08-06 |
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