CN1939298A - Schuqindin sulfate solid and target preparation and their making method - Google Patents
Schuqindin sulfate solid and target preparation and their making method Download PDFInfo
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- CN1939298A CN1939298A CN 200510030150 CN200510030150A CN1939298A CN 1939298 A CN1939298 A CN 1939298A CN 200510030150 CN200510030150 CN 200510030150 CN 200510030150 A CN200510030150 A CN 200510030150A CN 1939298 A CN1939298 A CN 1939298A
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Abstract
A series of Shuxinding sulfate medicines for preventing and treating arrhythmia includes the solid medicine in the form of tablet, capsule, pill or particle with high stability and biologic utilization rate, and the target medicine in the form of microball, millimicro ball, liposome, or microemulsion with high target performance and low toxic by-effect.
Description
Technical field
The invention belongs to the medicine preparation field, specifically relate to the solid preparation A and the targeting preparation B that contain anti-arrhythmia active component Schuqindin sulfate, and their preparation method.
Technical background
Schuqindin sulfate (Sulcardine sulfate); chemistry 4-methoxyl group-N-(3 by name; 5-pair-(1-pyrrolidinomethyl)-4-hydroxybenzyl) benzsulfamide sulfate; be as lead compound with natural product derivant with antiarrhythmic effect; behind the synthetic a large amount of analog of structural modification, the new construction type compound (China Patent No. ZL99124236.X) that therefrom filters out with very strong antiarrhythmic activity.It directly acts on sodium channel, calcium channel and the potassium channel of myocardial cell membrane, by the maximum depolarization speed of the action potential that slows down, improves threshold of excitation, conduction velocity slows down, change action potential duration and effective refractory period, effective refractory period is prolonged relatively, can be used for treating the arrhythmia of turning back; By the inhibition of relaxing period depolarization, can be used for treating the self-disciplining arrhythmia.Show from the result of study of pharmacy and laboratory animal pharmacodynamic study: Schuqindin sulfate is a safety, efficient, quality controllable, the antiarrhythmic drug with DEVELOPMENT PROSPECT.
Because Schuqindin sulfate is a class original new drug, at present bibliographical information is not seen in the research of its preparation.The various preparation researches that the present invention did have been filled up the blank of Schuqindin sulfate formulation art.
Summary of the invention
The objective of the invention is to the Schuqindin sulfate solid preparation A and the targeting preparation B thereof that develop a kind of stable in properties and can adopt the prior art suitability for industrialized production.
Another object of the present invention has provided the preparation method of Schuqindin sulfate solid preparation A and targeting preparation B thereof.Schuqindin sulfate solid preparation A of the present invention can be ordinary preparation, and its constituent (in weight fraction) is:
1 part of Schuqindin sulfate,
Adjuvant 0.1-100 part
Schuqindin sulfate chemical name wherein: 4-methoxyl group-N-[3,5-is two-(1-pyrrolidinomethyl)-4-hydroxybenzyl] benzsulfamide sulfate (Sulcardine Sulfate), chemical structural formula is:
Molecular weight: 611.75, molecular formula: C
24H
41N
3O
11S
2
Known synthetic route of this chemical compound and technological reaction condition are:
Schuqindin sulfate preparation technology reaction condition gentleness, stable yield, with low cost, be fit to suitability for industrialized production.
The ordinary preparation adjuvant of solid preparation A of the present invention is selected from starch, lactose, microcrystalline Cellulose, dextrin, Icing Sugar, glucose, mannitol, calcium sulfate, calcium hydrogen phosphate, water, ethanol, starch slurry, dextrin, mucialga of arabic gummy, syrup, gelatine size, polyvinylpyrrolidone, Polyethylene Glycol, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, alginic acid, Explotab, stearic acid, calcium stearate, magnesium stearate, hydrogenated vegetable oil, sodium benzoate, sodium laurylsulfate, Polyethylene Glycol (PEG6000, PEG8000), magnesium laurylsulfate, Pulvis Talci, micropowder silica gel etc.
Schuqindin sulfate ordinary preparation of the present invention can be prepared by following distinct methods:
Method one: take by weighing Schuqindin sulfate, various adjuvant by recipe quantity, porphyrize behind the mix homogeneously, prepares soft material in right amount with binding agent respectively, granulates or pill, and drying promptly gets granule or piller, also this granule can be pressed into tablet or fill capsule.
Method two: take by weighing the good adjuvant of Schuqindin sulfate and various flowability, compressibility such as hydrogen phosphate dihydrate dicalcium, calcium phosphate, calcium sulfate, Lactis Anhydrous, spray-dried lactose, pregelatinized Starch, compressibility Icing Sugar, mannitol, microcrystalline Cellulose etc. by recipe quantity, progressively increase behind the method mix homogeneously by equivalent, directly pressed powder or fill capsule.
In addition, also the granule of making, plain sheet, piller sugar coating or film-coat can be made Schuqindin sulfate ordinary coating preparation.
Schuqindin sulfate solid preparation A of the present invention can further make the sustained-release preparation of taking convenience, and said preparation can be matrix type or film coating type.Wherein the adjuvant of matrix type sustained-release preparation is selected from ethyl cellulose Ec, polyacrylic resin class Eudragit, Polyethylene Glycol PEG, polyethylene, polypropylene, polrvinyl chloride, polysiloxanes, polyvinylpyrrolidone PVC, cholesterol, cupreol, the Palmic acid glyceride, the cholesterol stearate, stearic acid, butyl stearate, Brazil wax, Oleum Ricini wax, paraffin, Cera Flava, hydrogenated vegetable oil, synthetic wax, octadecanol, methylcellulose MC, hydroxypropyl emthylcellulose HPMC, hydroxypropyl cellulose HPC, Carbopol, PVAC polyvinylalcohol, chitin, sodium alginate, chitosan, polylactic acid-based, carbomer, carboxymethyl cellulose, hydroxypropyl cellulose HPC; Thin film coating material is selected from the optional autohemagglutination crylic acid resin of coating material Eudragit, ethyl cellulose, Cellulose Acetate Phthalate, single two cellulose acetate, Cera Flava etc.
Schuqindin sulfate matrix type sustained-release preparation of the present invention can be prepared by following distinct methods:
Method one: it is evenly mixed that the principal agent of recipe quantity and various controlled slowly releasing adjuncts and common solid preparation adjuvant are crossed the 80-100 mesh sieve; add adhesive and make soft material in right amount; granulate with the 20-24 mesh sieve; put under the 50-60 ℃ of condition dry 2-4 hour; with 18-24 mesh sieve granulate mixing; promptly get granule, also this granule can be pressed into tablet or fill capsule.
Method two: take by weighing Schuqindin sulfate and various controlled slowly releasing adjuncts and common solid preparation adjuvant mix homogeneously by recipe quantity, directly pressed powder or fill capsule.
Method three: by recipe quantity take by weighing Schuqindin sulfate and various controlled slowly releasing adjuncts and common solid preparation adjuvant mixed evenly after, make piller after making soft material in right amount with adhesive.
Schuqindin sulfate film coating type sustained-release preparation of the present invention, its preparation method add plasticizer with slow controlled release thin film coating material and carry out coating for after making ordinary preparation according to a conventional method, get final product.The wherein slow optional autohemagglutination crylic acid resin of controlled release thin film coating material Eudragit, ethyl cellulose, Cellulose Acetate Phthalate, single two cellulose acetate, Cera Flava etc.Plasticizer can be selected from propylene glycol, glycerol, Polyethylene Glycol, triacetin, acetyl monoglyceride, phthalate, antiplastering aid Pulvis Talci, titanium dioxide, aluminum color lake, silicon dioxide, aluminium stearate etc.
The constituent content (in weight portion) of Schuqindin sulfate targeting preparation B of the present invention is,
1 part of Schuqindin sulfate,
Carrier material 0.5-500 part.
The carrier material here is optional from albumin, the human albumin, bovine serum albumin, Fibrinogen, zein, gelatin, natural gum, Colophonium, paraffin, polylactic acid, polyacrylic acid, poly-hydroxyl fourth fat, poly-epsilon-caprolactone, poly-hydroxypentanoic acid fat, poly-third hands over fat, poly-glycolide/third is handed over resin copolymer, poe, polyanhydride, polypeptide, poly phosphazene and modification thereof, starch, paracyanogen base acrylate, ethyl cellulose, polyamide, polystyrene, polyvinyl alcohol, glucosan, dextran, dextrin, polyacrylamide, the polyacrylamide dextran, polyacrylamide starch, polycarbonate, poly-glutaraldehyde, chitosan, polyglycolic acid, polyvinyl acetate, polyvidone, starch, protein, agarose, ethyl cellulose, the polypropylene glucosan, phospholipid, lecithin, soybean phospholipid, the derivant of phospholipid etc.
Schuqindin sulfate targeting preparation B of the present invention adopts following method preparation:
Method one: solvent evaporated method, carrier material is dissolved in organic solvent after, solution is injected in the aqueous solution of certain density surfactant under different rotating speeds stirs, treat the organic solvent volatilization after, make microsphere, nanoparticle, microcapsule, Emulsion etc.
Method two: the emulsifying method that is heating and curing: the Schuqindin sulfate and the carrier material protein solution of recipe quantity are emulsified into w/o type emulsion with edible oil (Oleum Gossypii semen), this emulsion is instilled in the oil of high temperature (130-180 ℃), stir, solidify, washing promptly gets microsphere, millimicro ball.
Method three: coacervation, add proper amount of surfactant (as tween) in the gelatin solution, add dehydrant then, add coupling agent again microsphere is solidified, promptly get microsphere, millimicro ball.Wherein dehydrant can be sodium sulfate concentrated solution or 95% ethanol; Connecting agent can be formaldehyde or glutaraldehyde.
Method four: the thin-film ultrasonic emulsion process, carrier material is dissolved in organic solvent, evaporation is removed organic solvent and is formed thin film, adds the aqueous solution that contains emulsifying agent, and ultrasonic or newborn even dispersion just can obtain nanoparticle, microemulsion etc.
Method five: the even method of high pressure breast, with the carrier material heating and melting, again fused solution is added to the water that is dissolved with surfactant, high-speed stirred forms colostrum, the high pressure homogenize, quenching can obtain nanoparticle.
Method six: after one of derivant of phospholipid, lecithin, soybean phospholipid, phospholipid or their mixture and cholesterol etc. be dissolved in organic solvent, be prepared into liposome by the conventional technology of preparing of liposome.
Organic solvent described in the above-mentioned Schuqindin sulfate targeting preparation B preparation method can be selected from dichloromethane, chloroform, ethanol, methanol, acetone, isopropyl alcohol, ethyl acetate, ether or their mixture; Surfactant can be phospholipid, cholate, deoxycholate, short chain alcohol, poloxamer, polysorbate, polyoxyethylene aliphatic alcohol ether polyoxyethylene fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Polyethylene Glycol and composition thereof.Wherein, phospholipid is selected from phosphatidylcholine, the phosphatidylinositols Phosphatidylserine, phosphatidyl glycerol, phosphatidic acid, two Laurel phosphatidyl cholines, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, distearyl phosphatidyl glycerol, two palmityl phosphatidyls, two palmityl phosphatidic acid, dioleoyl phospholipid phatidylcholine, DOPE, soybean phospholipid, lecithin, lecithin and composition thereof; Cholate is selected from sodium cholate, sodium glycocholate, sodium taurocholate and composition thereof; Dexycholate is selected from NaTDC, deoxidation sodium taurocholate and composition thereof; Short chain alcohol is selected from butanols, glycerol, isopropyl alcohol, ethanol; The preferred poloxamer 108,188,182,407,908 of poloxamer; The preferred tween 80 of polysorbate, 85,65,60,40,20; The preferred Brij 78,35,30 of polyoxyethylene aliphatic alcohol ether; The preferred Myrj 53,59 of polyoxyethylene fatty acid ester; Polyoxyethylene castor oil is selected from cromophor EL series; Polyoxyethylene hydrogenated Oleum Ricini cromophor RH series.
Adopt the Schuqindin sulfate preparation B of the inventive method preparation, the experiment proved that to have rapid release or advantages such as slow controlled release, targeting, the action time of energy prolong drug, the toxic and side effects of reduction medicine improves bioavailability of medicament and therapeutic effect.And, the mature preparation process of said preparation, constant product quality is convenient to suitability for industrialized production.
Description of drawings
Fig. 1 is the body weight change of Schuqindin sulfate long term toxicity.
Beneficial effect
This invention can improve the anti-arrhythmia cordis effect of Schuqindin sulfate, prolongs action time, reduces toxic and side effect, improves the bioavilability of Schuqindin sulfate. And the preparation method is versatile and flexible, all adopts conventional process equipment, but industrially scalable, high efficiency production, and it is stable that product quality keeps.
The specific embodiment
Embodiment 1:
The preparation of Schuqindin sulfate sheet
Take by weighing Schuqindin sulfate 200g by recipe quantity, microcrystalline Cellulose 20g, porphyrize is crossed 80 mesh sieves respectively, progressively increase behind the method mix homogeneously by equivalent, prepare soft material in right amount with starch slurry (5%), granulate, put under 60 ℃ of conditions dry 3 hours with 24 mesh sieves, behind 24 mesh sieve granulate, add magnesium stearate 0.66g, behind the mixing, tabletting.
2. dissolution determination
Get 6 of Schuqindin sulfate sheets, adopt the oar method to carry out the dissolution method experiment.Add distilled water 900mL in the stripping rotor, bath temperature (37 ± 0.5) ℃, rotating speed 50r/min.Operation in accordance with the law, regularly (1,5,10,15,20,30,45min) sampling 6ml (mending distilled water 6mL at once) through 0.8 μ m membrane filtration, discards coarse filtration liquid immediately.Essence is got in subsequent filtrate 3mL to the 10mL volumetric flask, and the adding distil water standardize solution shakes up.According to spectrophotography, be blank with the distilled water, measure trap at the 240nm place, calculate cumulative leaching rate (Q) and the average cumulative leaching rate (Q) of tablet at each time point.
The dissolution test data show: the accumulation stripping quantity of Schuqindin sulfate sheet in the time of 45 minutes reaches 90%.
Embodiment 2:
Schuqindin sulfate sheet influence factor 3 experiments among the embodiment 1
Determine that according to 2000 editions two appendix of Chinese Pharmacopoeia (XIX C) pharmaceutical preparation stability high spot reviews repertory the investigation project of Schuqindin sulfate tablet stability experiment is: character, content, related substance and dissolution.
1 illumination experiment
Get each 3 lot number of Schuqindin sulfate sheet tablet, reveal and put (light intensity is 4500Lx) under the daylight lamp, irradiation 10d, in placing 0,5, the 10d sampling is investigated mensuration to projects such as character, related substance, content, dissolutions respectively.
2 hot tests
Get each 3 lot number of Schuqindin sulfate sheet tablet, place 10d for xeothermic 60 ℃ in airtight vessel, in placing 0,5, the 10d sampling is investigated mensuration to projects such as character, related substance, content, dissolutions respectively.
The experiment of 3 high humiditys
Get each 3 lot number of Schuqindin sulfate sheet tablet, in the constant humidity hermetic container, under relative humidity 90% ± 5% condition, placed 10 days,, respectively projects such as character, related substance, content, dissolution are investigated mensuration in sampling in the 5th, 10 day at 25 ℃.
Table 1
| Lot number | Storage requirement | Time (my god) | Character | Related substance | Content (%) | Dissolution |
| 030901 030902 030903 | The hot and humid illumination of the hot and humid illumination of illumination is hot and humid | 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 | White tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets | 0.6 0.66 0.7 0.6 0.64 0.68 0.6 0.68 0.74 0.58 0.64 0.7 0.61 0.63 0.67 0.62 0.68 0.74 0.6 0.66 0.7 0.62 0.66 0.69 0.61 0.67 0.74 | 99.81 99.45 99.1 99.81 99.54 99.2 99.81 99.74 99.41 99.89 99.49 99.01 99.85 99.56 99.24 99.86 99.76 99.44 99.83 99.35 99.11 99.61 99.64 99.2 99.71 99.64 99.46 | 91.2 91.4 90.5 91.2 90.5 89.2 91.2 90.4 89.7 91.31 91.42 90.56 91.29 90.58 89.21 91.24 90.42 89.75 91.23 91.34 90.15 91.26 90.5 89.2 91.45 90.54 89.71 |
Influence factor's result of the test shows: the Schuqindin sulfate sheet is through high light, high temperature and high wet test, and its character does not change, and related substance slightly increases, and assay and dissolution slightly reduce, but changes all not obvious.
Schuqindin sulfate sheet accelerated tests and long-term experiment among the embodiment 1
1 accelerated tests
Get each 3 lot number of Schuqindin sulfate tablet, at 40 ℃, RH75% placed 6 months, in 1,2, and 3.Sampling is investigated character, related substance, content, dissolution respectively in the time of 6 months.
2 long-term experiments
Get each 3 lot number of Schuqindin sulfate tablet, at 25 ℃, RH60% placed 12 months, and sampling is investigated character, related substance, content, dissolution respectively in the time of 0,3,6,9,12 month.
Table 2
| Storage requirement | Time (my god) | Character | Related substance | Content (%) | Dissolution |
| 40℃RH75％ 25 | 0 1 2 3 0 3 6 9 12 | White tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets white tablets | 0.6 0.67 0.7 0.75 0.57 0.64 0.68 0.74 0.77 | 99.81 99.68 99.1 98.81 99.82 99.61 100.1 99.38 99.51 | 90.5 90.2 89.86 88.45 92.3 91.57 90.63 89.54 88.78 |
Accelerated tests and long-term experiment show that the Schuqindin sulfate tablet stability is good.
Embodiment 4: the preparation of Schuqindin sulfate slow releasing tablet
Every consumption
Prescription: Schuqindin sulfate 100mg
Hydroxypropyl emthylcellulose K4M 50mg
Starch 40mg
3%HPMC (50% ethanol) is an amount of
Magnesium stearate 10mg
Preparation technology: take by weighing Schuqindin sulfate by recipe quantity and cross 100 mesh sieves, then with adjuvants such as hydroxypropyl emthylcellulose, starch by the equivalent method mix homogeneously that progressively increases, add 3%HPMC (50% ethanol) and make soft material in right amount, crossing 20 mesh sieves granulates, in 60 ℃ of oven dry, the heavily about 200mg of tabletting, sheet, tablet hardness is at 5-7kg.
Embodiment 5:
The mensuration of Schuqindin sulfate slow releasing tablet release among the embodiment 4
Adopt the device of dissolution determination oar method, rotating speed 50r/min, release medium is a water, in accordance with the law operation.At each time point (0.5,1,2,3,4,6,8,12 hours) 5mL that takes a sample respectively, and additional isothermal release medium 5mL, sample liquid is used 0.8 μ m micro-pore-film filtration immediately.The accurate subsequent filtrate 3mL that draws places the 10mL measuring bottle, uses the distilled water standardize solution.Measure trap A in 240nm wavelength place, calculate cumulative release percentage rate (X).The results are shown in Table 3.
Table 3
| | 1 | 2 | 3 | 4 | 5 | 6 | 8 | 10 | 12 |
| 123456 average release RSD | 9.45 6.2 5.73 6.48 8.61 6.31 7.13 0.21 | 21.85 16.11 14.1 19.23 18.9 19.61 18.3 0.15 | 33.93 31.45 25.72 27.65 26.57 28.08 28.9 0.11 | 46.95 46.02 40.13 41.27 39.81 39.62 42.3 0.08 | 60.23 58.26 54.39 50.72 51.14 54.66 54.9 0.07 | 70.69 69.32 65.85 59.61 60.29 61.84 64.6 0.07 | 83.53 84.31 82.9 78.58 79.75 78.13 81.2 0.03 | 93.28 95.39 91.73 87.62 90.49 88.47 91.16 0.03 | 98.11 99.61 92.63 93.43 98.94 96.26 96.5 0.03 |
The result shows that the sustainable release of this product 12 hours has slow release effect.
The Schuqindin sulfate microsphere
Take by weighing PLGA 200mg and be dissolved in the 1ml dichloromethane, make organic facies; Other gets in the 100ml solution that Schuqindin sulfate 100mg is scattered in 1% sodium alginate and 0.2% tween 20 (m/m), makes water; Under the 500r/min stirring condition, organic facies is injected into aqueous phase stirs 30min, under constantly stirring this mixed solution is moved in the water-bath, 45 ℃ are stirred the 4h volatilization and remove dichloromethane, the buchner funnel sucking filtration separates microsphere, distilled water wash, 30 ℃ of vacuum dryings get the Powdered microsphere of white flowability.Microsphere is ball-shaped. size evenly, the microsphere rubbish directly is normal distribution, accounts for 83.3% at the microsphere of 55～135 μ m particle size range, its envelop rate and drug loading are respectively 86.78% and 26.92%.
The pharmacodynamic study of Schuqindin sulfate microsphere among the embodiment 6
Adopt dog left anterior descending coronary artery second phase ligation method to bring out the arrhythmia model, observe Schuqindin sulfate microsphere gastric infusion the ARR therapeutical effect of dog.Performed the operation back 24 hours, each is organized dog and gives Schuqindin sulfate microsphere 20,30 respectively, 60mg/kg and quinidine 60mg/kg, the electrocardiogram of the clear-headed dog of continuous record, heart rate and ARR variation in 4 hours after the observation administration.The results are shown in Table 4.
Table 4
| Preparation | Arrhythmia ratio | |||
| Dosage (mg/kg) | Before the administration | After the | After the | |
| Schuqindin sulfate microsphere quinidine sulfate sheet | 20 30 60 60 | 0.78 0.78 0.8 0.79 | 0.47 0.41 0.1 0.15 | 0.499 0.45 0.11 0.38 |
The result shows that the Schuqindin sulfate microsphere has tangible anti-arrhythmia effect.
The preparation of Schuqindin sulfate millimicro ball
Organic facies: 0.25g monomer α-Qing Jibingxisuanzhengdingzhi BCA, sad two caprins of 1.89g are dissolved in and constitute organic facies in the 25mL ethanol (anhydrous).Water: 0.1g Schuqindin sulfate, 1g F68 and 0.5g glucosan T-70 are dispersed in the phosphate buffer solution of pH=6 and constitute continuous phase.Room temperature slowly is added to the aqueous phase of continuous stirring, injection speed 0.2mL/min, mixing speed 1000r/min with silica gel tube and syringe with organic facies.Syringe needle will disperse organic facies as far as possible near stirring-head as far as possible, keeps 3h.Get the colloid solution that milky is suspended with Tyndall phenomenon, the room temperature rotary evaporation in vacuo is concentrated into about 20mL, and (9～15Lm) sintered filter funnels filter, and get Schuqindin sulfate-PBCA nanocapsule (52Fu2PBCA) colloid concentrated solution with G4.
The physicochemical property research of Schuqindin sulfate millimicro ball among the embodiment 8
1. configuration of surface and particle size determination
It is an amount of to get Schuqindin sulfate millimicro ball suspension colloid concentrated solution respectively, the hypervelocity low-temperature centrifugation, and precipitation separation adds a little distilled water and disperses, and scanning electron microscopic observation, takes the photograph sheet, measures the average diameter of 300 nanocapsules.
The result shows: nanocapsule form rule is elliposoidal, smooth surface, and the actual mean diameter that records is 232 ± 17nm (n=300).
2 envelop rates and drug loading are measured
Get Schuqindin sulfate millimicro spherocolloid concentrated solution hypervelocity low-temperature centrifugation, precipitation separation.Measure the supernatant A value in the 240nm place with the ultraviolet light spectrophotometer, use the standard curve standard measure.
Be calculated as follows the drug loading and the envelop rate of nanocapsule:
Envelop rate=[(Wa-Ws)/Wa] * 100%
Drug loading=[(Wa-Ws)/W
Always] * 100%
Wherein, Wa is initial dosage; Ws: be content of dispersion in the supernatant; W
AlwaysBe the nanocapsule gross mass.The results are shown in Table 5.
Table 5
| Sample | Envelop rate (%) | Drug loading (%) |
| 1 2 3 | 87.43±0.32 87.56±0.24 87.53±0.28 | 25.02±0.21 26.86±0.32 25.74±0.25 |
The pharmacodynamic experiment of Schuqindin sulfate millimicro ball among the embodiment 8
Cavia porcellus (10 every group) is irritated stomach respectively and gives Schuqindin sulfate millimicro spherocolloid solution, dosage gives Schuqindin sulfate 25,50 and 100mg for the per kilogram Cavia porcellus, and administration is after 2.5 hours, the vein constant speed is injected ouabain, measures the ouabain dosage of induction room premature beat respectively.
Table 6
| Preparation | Dosage (mg/kg) | Bring out ventricular premature contraction dosage (μ g/kg) |
| Schuqindin sulfate millimicro ball blank group quinidine sulfate sheet | 25 50 100 - 50 | 156±9 176±16 187±14 134±8 182 15 |
From table 6 explanation, Schuqindin sulfate millimicro ball has the effect of anti-ventricular premature contraction preferably.
The preparation of Schuqindin sulfate liposome
Accurately take by weighing 120mg lecithin and 30mg cholesterol, be dissolved in the 10ml absolute ether, under the 1000r/min stirring condition with slow being injected in the 40ml water (40 ℃) that contains the 100mg Schuqindin sulfate at the uniform velocity of the class lipoprotein solution of gained, after injection finishes, continue 40 ℃ of constant temperature and be stirred to ether and eliminate fully, obtain milky Schuqindin sulfate liposome turbid liquor.
The liposome of getting among the embodiment 11 carries out morphologic observation, particle diameter and measure of spread thereof.
It is an amount of to get liposome, and add water for injection and dilute in right amount, the phosphotungstic acid dyeing with 1%, transmission electron microscope is observed particle shape down.
It is an amount of to get the liposome suspension, adds the suitable quantity of water dilution, measures size and the distribution and the Zeta potential of liposome with the Zetamaster photon correlation spectrometer.
Observe the spheroidal particle that polyene taxol liposome is even rule under the Electronic Speculum, do not have and assemble sticking connection.
The polyene taxol liposome particle size distribution that experiment records is even, and mean diameter is 120nm, and polydispersity index is 0.158, and the zeta current potential is-26.4mv.
Treating excess syndrome is executed the mensuration that Schuqindin sulfate liposome in 11 carries out envelop rate.
Envelop rate is according to determined by ultraviolet spectrophotometry, and liposome solutions separates the not Schuqindin sulfate of parcel through dialysis, measures free sulfuric acid Shu Xin pyridine content with ultraviolet spectrophotometer.By following formula computational envelope rate.
Envelop rate (%)=(adding dose one free drug amount in the liposome)/add dose
To record envelop rate be 87.45% to formula according to this.
Schuqindin sulfate long term toxicity test among the embodiment 11
The SD rat is divided into 4 groups at random, 22 every group (male and female half and half), by rat 200,400,1000mg/kg dosage gastric infusion.Dissect 12 rats and dissect after 30 days convalescent periods and respectively organize 10 rats in each group of administration 3 months, pentobarbital 30mg/kg is by body weight anesthesia femoral artery sacrificed by exsanguination.And make blood biochemical and measure.Rat is dissected and does the pathology inspection.
Observation index:
1. mortality rate: if any dying or dead, the record death toll.
The result shows: each group there is no rats death.
2. general symptom: between administration phase and withdrawal time, observe rat sign, outward appearance behavior, activity and feces shape and color, and fur is next to the shin or sparse perpendicular diffusing after observing administration.The abnormal secretion thing of eye, nose etc.Observe one by one and record every day.
The result is: other bloodstain of nasal cavity and the thin red circle of forelimb ankle appear in initial phase 200 of administration, each 1 rat of 400mg/kg group, 1000mg/kg group rat has that 7 rats (31.3%) go out to lose face, the corners of the mouth, nasal cavity color secretions and the red circle of forelimb ankle, transference cure after 2～3 days.Show relevant with drug dose.
3. body weight: claim weekly 2 times, claim weekly 1 time after 2 months.
Find out that by Fig. 1 the administration group is similar to the matched group body weight gain, do not have significant difference between group.
4. histological examination: each is organized, and rat is cored, lung, liver,spleen,kidney, brain, hypophysis cerebri, thyroid, adrenal gland, thymus, epididymis, prostate/uterus and testis/ovary, mammary gland, trachea, salivary gland, esophagus, stomach, duodenum, ileum, colon, pancreas, eyeball and optic nerve, breastbone (containing bone marrow) etc. are organized and are fixed in 10% neutral formalin solution immediately, conventional embedding, section, dyeing.
The result is: 400, the 1000mg/kg group respectively has in 2,7 rat hepatocytes the rufous granule is arranged.Convalescent period, each group was not seen significant change.
Claims (14)
1. a Schuqindin sulfate oral solid formulation A and targeting preparation B who contains following structure,
It is characterized in that preparation A comprises Schuqindin sulfate and adjuvant, with respect to 1 part of Schuqindin sulfate, contain adjuvant 0.1-100 part in weight portion; Preparation B comprises Schuqindin sulfate and carrier material, with respect to 1 part of Schuqindin sulfate, contains carrier material 0.5-500 part in weight portion.
2. Schuqindin sulfate solid preparation A according to claim 1 is characterized in that being ordinary preparation and sustained-release preparation.
3. Schuqindin sulfate solid preparation A according to claim 2, the adjuvant that it is characterized in that ordinary preparation is selected from starch, lactose, microcrystalline Cellulose, dextrin, Icing Sugar, glucose, mannitol, calcium sulfate, calcium hydrogen phosphate, water, ethanol, starch slurry, dextrin, mucialga of arabic gummy, syrup, gelatine size, polyvinylpyrrolidone, Polyethylene Glycol, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, alginic acid, Explotab, stearic acid, calcium stearate, magnesium stearate, hydrogenated vegetable oil, Polyethylene Glycol (PEG6000, PEG8000), sodium benzoate, sodium laurylsulfate, magnesium laurylsulfate, Pulvis Talci, micropowder silica gel.
4. Schuqindin sulfate solid preparation A according to claim 2 is characterized in that ordinary preparation adopts traditional method to be prepared into tablet, capsule, granule, piller, the ordinary coating preparation.
5. Schuqindin sulfate sustained-release preparation according to claim 2 is characterized in that being matrix type sustained-release preparation or film coating type sustained-release preparation.
6. the preparation method of Schuqindin sulfate matrix type sustained-release preparation as claimed in claim 5 is prepared by following different methods:
1) principal agent of recipe quantity and various controlled slowly releasing adjuncts and common solid preparation adjuvant are crossed 80-100 mesh sieve mix homogeneously, adhesive is made soft material in right amount, granulate with the 20-24 mesh sieve, put under the 50-60 ℃ of condition dry 2-4 hour, with 18-24 mesh sieve granulate mixing, promptly get granule, also this granule can be pressed into tablet or fill capsule;
2) take by weighing Schuqindin sulfate and various controlled slowly releasing adjuncts and common solid preparation adjuvant mix homogeneously by recipe quantity, directly pressed powder or fill capsule;
3) take by weighing Schuqindin sulfate and various slow controlled release dressing and common solid preparation dressing mix homogeneously by recipe quantity after, make piller after preparing soft material in right amount with binding agent.
7. the preparation method of Schuqindin sulfate matrix type sustained-release preparation according to claim 6, it is characterized in that controlled slowly releasing adjuncts can be selected from: ethyl cellulose Ec, polyacrylic resin class Eudragit, Polyethylene Glycol PEG, polyethylene, polypropylene, polrvinyl chloride, polysiloxanes, polyvinylpyrrolidone PVC, cholesterol, cupreol, the Palmic acid glyceride, the cholesterol stearate, stearic acid, butyl stearate, Brazil wax, Oleum Ricini wax, paraffin, Cera Flava, hydrogenated vegetable oil, synthetic wax, octadecanol, methylcellulose MC, hydroxypropyl emthylcellulose HPMC, hydroxypropyl cellulose HPC, Carbopol, PVAC polyvinylalcohol, chitin, sodium alginate, chitosan, polylactic acid-based, carbomer, carboxymethyl cellulose, hydroxypropyl cellulose HPC.
8. the preparation method of Schuqindin sulfate film coating type sustained-release preparation according to claim 5 after it is characterized in that Schuqindin sulfate made ordinary preparation according to conventional method, is got slow controlled release thin film coating material and is added plasticizer and carry out coating and can make.
9. the preparation method of Schuqindin sulfate film coating type sustained-release preparation according to claim 8 is characterized in that the slow optional autohemagglutination crylic acid resin of controlled release thin film coating material Eudragit, ethyl cellulose, Cellulose Acetate Phthalate, single two cellulose acetate, Cera Flava.
10. the preparation method of Schuqindin sulfate film coating type sustained-release preparation according to claim 8, it is characterized in that plasticizer can be selected from propylene glycol, glycerol, Polyethylene Glycol, triacetin, acetyl monoglyceride, phthalate, antiplastering aid Pulvis Talci, titanium dioxide, aluminum color lake, silicon dioxide, aluminium stearate.
11. Schuqindin sulfate targeting preparation B according to claim 1, it is characterized in that carrier material is optional from albumin, the human albumin, bovine serum albumin, Fibrinogen, zein, gelatin, natural gum, Colophonium, paraffin, polylactic acid, polyacrylic acid, poly-hydroxyl fourth fat, poly-epsilon-caprolactone, poly-hydroxypentanoic acid fat, poly-third hands over fat, poly-glycolide/third is handed over resin copolymer, poe, polyanhydride, polypeptide, poly phosphazene and modification thereof, starch, paracyanogen base acrylate, ethyl cellulose, polyamide, polystyrene, polyvinyl alcohol, glucosan, dextran, dextrin, polyacrylamide, the polyacrylamide dextran, polyacrylamide starch, polycarbonate, poly-glutaraldehyde, chitosan, polyglycolic acid, polyvinyl acetate, polyvidone, starch, protein, agarose, ethyl cellulose, the polypropylene glucosan, phospholipid, lecithin, soybean phospholipid, the derivant of phospholipid.
12. the preparation method of Schuqindin sulfate targeting preparation B according to claim 1 is characterized in that adopting following distinct methods preparation:
1) solvent evaporated method, carrier material is dissolved in organic solvent after, solution is injected in the aqueous solution of certain density surfactant under different rotating speeds stirs, treat the organic solvent volatilization after, make microsphere, nanoparticle, microcapsule, Emulsion.
2) the emulsifying method that is heating and curing is emulsified into w/o type emulsion with the Schuqindin sulfate and the carrier material protein solution of recipe quantity with edible oil, this emulsion is instilled in 130-180 ℃ the oil, stir, solidify, washing promptly gets microsphere, millimicro ball, and wherein edible oil can be selected Oleum Gossypii semen for use.
3) coacervation adds proper amount of surfactant (as tween) in the gelatin solution, add dehydrant then, adding coupling agent again solidifies microsphere, promptly get microsphere, millimicro ball, wherein dehydrant can be sodium sulfate concentrated solution or 95% ethanol, and coupling agent can be formaldehyde or glutaraldehyde.
4) the thin-film ultrasonic emulsion process is dissolved in organic solvent with carrier material, and evaporation is removed organic solvent and formed thin film, adds the aqueous solution that contains emulsifying agent, and ultrasonic or newborn even dispersion just can obtain nanoparticle, microemulsion.
5) the even method of high pressure breast with the carrier material heating and melting, is added to fused solution the water that is dissolved with surfactant again, and high-speed stirred forms colostrum, the high pressure homogenize, and quenching can obtain nanoparticle.
6) one of derivant of phospholipid, lecithin, soybean phospholipid, phospholipid or their mixture and cholesterol etc. are dissolved in organic solvent after, be prepared into liposome by the conventional technology of preparing of liposome.
13. the preparation method of Schuqindin sulfate targeting preparation B according to claim 12 is characterized in that organic solvent is selected from dichloromethane, chloroform, ethanol, methanol, acetone, isopropyl alcohol, ethyl acetate, ether or their mixture.
14. the preparation method of Schuqindin sulfate targeting preparation B according to claim 12 is characterized in that surfactant can be phospholipid, cholate, deoxycholate, short chain alcohol, poloxamer, polysorbate, polyoxyethylene aliphatic alcohol ether polyoxyethylene fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Polyethylene Glycol and composition thereof; Wherein phospholipid is selected from phosphatidylcholine, the phosphatidylinositols Phosphatidylserine, phosphatidyl glycerol, phosphatidic acid, two Laurel phosphatidyl cholines, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, the distearyl phosphatidyl glycerol, two palmityl phosphatidyls, two palmityl phosphatidic acid, dioleoyl phospholipid phatidylcholine, DOPE, soybean phospholipid, lecithin, lecithin and composition thereof; Cholate is selected from sodium cholate, sodium glycocholate, sodium taurocholate and composition thereof; Dexycholate is selected from NaTDC, deoxidation sodium taurocholate and composition thereof; Short chain alcohol is selected from butanols, glycerol, isopropyl alcohol, ethanol; The preferred poloxamer 108,188,182,407,908 of poloxamer; The preferred tween 80 of polysorbate, 85,65,60,40,20; The preferred Brij 78,35,30 of polyoxyethylene aliphatic alcohol ether; The preferred Myrj 53,59 of polyoxyethylene fatty acid ester; Polyoxyethylene castor oil is selected from cromophor EL series; Polyoxyethylene hydrogenated Oleum Ricini cromophorRH series.
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| CN112076172A (en) * | 2020-10-20 | 2020-12-15 | 扬州中宝药业股份有限公司 | Sulcardine sulfate tablet and preparation method thereof |
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| US11813245B2 (en) | 2020-06-12 | 2023-11-14 | Huyabio International, Llc | Sulcardine administration for treatment of acute atrial fibrillation |
| CN112076172B (en) * | 2020-10-20 | 2022-04-15 | 扬州中宝药业股份有限公司 | Sulcardine sulfate tablet and preparation method thereof |
| CN112076172A (en) * | 2020-10-20 | 2020-12-15 | 扬州中宝药业股份有限公司 | Sulcardine sulfate tablet and preparation method thereof |
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