CN101229132B - Nimodipine pulse sustained release mircopill preparation and preparing method thereof - Google Patents
Nimodipine pulse sustained release mircopill preparation and preparing method thereof Download PDFInfo
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- CN101229132B CN101229132B CN2008100141502A CN200810014150A CN101229132B CN 101229132 B CN101229132 B CN 101229132B CN 2008100141502 A CN2008100141502 A CN 2008100141502A CN 200810014150 A CN200810014150 A CN 200810014150A CN 101229132 B CN101229132 B CN 101229132B
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- Medicinal Preparation (AREA)
Abstract
The invention relates to a pulsed sustained-release pellet comprising nimodipine and a preparation method is also provided. The sustained-release pellet comprises: one of gastric-dissolved and medicines containing sustained-release pellets and enteric-coated and medicines containing sustained-release pellets, or the combination. The preparation method is that: making medicines containing pellets using nimodipine and excipents, coating the medicines containing pellets with the gastric coating or the enteric coating, mixing the sustained-release pellets coated with gastric coating and enteric coating in proportion and putting the sustained-release pellets into capsules or tabletting. The pulsed sustained-release pellet of the invention has a special release behavior and needs to be taken only once per day. The release curve agrees well with the disease circadian rhythm of cerebrovascular disease patients, playing a role of the best prevention and treatment.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to contain the pulse sustained release mircopill preparation its preparation method of nimodipine.
Technical background
Nimodipine (Nimodipine) is a dihydropyridine calcium ion antagonist, and the cerebral tissue receptor is had high selectivity, sees through blood brain barrier easily.By stoping calcium ion to enter in the cell, suppress smooth muscle contraction effectively, reach the purpose of removing vascular smooth muscle, thereby protected brain neuron, stablize its function and promote brain blood perfusion, improve cerebral blood supply, improve anoxybiotic tolerance.Be widely used in cerebrovascular disease and nootropics at present clinically, principal indication is: (1) prevention and treatment subarachnoid hemorrhage, the sick cerebral vasospasm of sending out; (2) prevention vascular headache outbreak; (3) be used for the treatment of ischemic cerebrovascular, ischemic sudden deafness; (4) the light moderate hypertension of constitutional; (5) disease such as migraine.In addition, report that also nimodipine is used for alzheimer disease, nervous system disease has better curative effect.
The nimodipine dosage form of listing has injection, tablet, capsule, soft capsule, dispersible tablet, soft gelatin capsule, slow releasing tablet, slow releasing capsule at present, and injection has very big limitation because using inconvenience.It is short that common oral preparation is taken the back half-life, it is 1.5～2 hours, and need repeatedly medication, medication every day 3～4 times, therefore cause blood concentration fluctuation big, cause untoward reaction such as fluctuation of blood pressure, headache and dizzy, skin irritation, gastrointestinal hemorrhage easily, and incidence rate is higher, be about 11.2%, this brings huge misery and inconvenient to the patient.After after deliberation, the Nimodipine sustained release preparation listing is arranged, yet because the nimodipine physicochemical property is special, almost insoluble in water, therefore the slow releasing preparation of making also needs medication every day 2 times, has untoward reaction such as hotness, erubescence, blood pressure drops, heart rate quickening, dizziness, headache, gastrointestinal upset equally.Also there is not the problem in conjunction with the division of day and night rhythm and pace of moving things of cerebrovascular jointly in existing preparation, does not reach best prevention and therapeutic effect.
Chinese patent file CN1554329 (200310117837.6) discloses sustained-release micro-spheres of a kind of year nimodipine medicament and preparation method thereof, described microsphere is single nuclear structure or nucleocapsid structure, the nuclear material is made up of Nimodipine solid dispersoid and Rhizoma amorphophalli glucomannan-calcium alginate, and the shell material is a chitin-alginic acid calcium polyelectrolyte film.Preparation process is utilized the capillary tube crush method with Nimodipine solid dispersoid and Rhizoma amorphophalli glucomannan-calcium alginate mixing water colloidal sol, is added dropwise to CaCl
2Aqueous solution or chitosan-CaCl
2In the aqueous solution, gained round washing and drying obtains the Rhizoma amorphophalli glucomannan-calcium alginate microsphere or the medicine carrying Rhizoma amorphophalli glucomannan-calcium alginate-chitosan microball of medicine carrying.
Nimodipine is used for the treatment of cerebral vasospasm, cerebral infarction, cerebral hemorrhage, reaches light moderate hypertension etc.Show that according to medical findings clear and definite above-mentioned disease has tangible division of day and night rhythmicity, these diseases are the time occurred frequently in morning.Therefore, nimodipine is developed into medication every day once, increase and at other usual time period drug releases preparation stably, help bringing into play the therapeutical effect of medicine at disease symptoms time occurred frequently drug release, and reducing side effect takes place, make things convenient for patient's medication simultaneously, improve patient's compliance.But because nimodipine dosage every day is bigger than normal, and almost do not allow in water, and the particularity of other physicochemical property, drug releasing rate is difficult to control, is difficult to make medication every day once and the pulse slow-releasing preparation with division of day and night characteristic.
Summary of the invention
The present invention is intended to overcome the deficiencies in the prior art, a kind of Nimodipine pulse sustained release mircopill preparation and preparation method thereof is provided, said preparation medication every day is once, drug release has with the characteristic that matches of morbidity division of day and night rhythmicity, safer, effective, take more convenient.
Technical scheme of the present invention is as follows:
A kind of pulse sustained release mircopill preparation that contains nimodipine is characterized in that comprising: one of stomach dissolution type pastille slow-release micropill, enteric solubility pastille slow-release micropill or combination,
To be (1) contain pill core by what nimodipine and pharmaceutic adjuvant were formed to described stomach dissolution type pastille slow-release micropill, or the pill core that contains that (2) are made up of nimodipine and pharmaceutic adjuvant wraps the gastric solubleness clothing outward again,
Pill core is enteric coated to be made described enteric solubility pastille slow-release micropill containing of forming by nimodipine and pharmaceutic adjuvant.Perhaps get and contain pill core directly as stomach dissolution type pastille slow-release micropill;
Ratio is not particularly limited when above-mentioned gastric solubility pastille slow-release micropill and the combination of enteric solubility pastille slow-release micropill, and arbitrary proportion all can.
Preferably, when above-mentioned gastric solubility pastille slow-release micropill and the combination of enteric solubility pastille slow-release micropill, gastric solubility pastille slow-release micropill and enteric solubility pastille slow-release micropill weight ratio are 1: 3～7: 5.
Above-mentioned by containing in the pill core that nimodipine and pharmaceutic adjuvant are formed, pharmaceutic adjuvant is selected from one or more among starch, lactose, dextrin, microcrystalline Cellulose, methylcellulose, pregelatinized Starch, mannitol, sorbitol, Polyethylene Glycol, polyvidone, acrylic resin, magnesium stearate, Pulvis Talci, sodium lauryl sulphate, tween, the Bo Luoshamu.
Above-mentioned by containing in the pill core that nimodipine and pharmaceutic adjuvant are formed, the percentage by weight of nimodipine is 10～60%wt, and the percentage by weight of further preferred nimodipine is 20～40%wt.
Above-mentioned stomach dissolution type pastille slow-release micropill, used stomach dissolution type coating material is selected from water-soluble film clothing material, specifically is selected from one or more of the amido of hypromellose, methylcellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyvidone, sodium carboxymethyl cellulose, sugar or polyhydric alcohol or para-amino benzoic acid derivant, polyethylene acetal diethylamine acetate, hydroxypropyl two d ritalinic acid cellulose ethers, polyacrylic resin, Opadry, Eudragit (You Teqi or Youteqi) etc.Used stomach dissolution type coating material consumption is to contain 5～20% of pill core weight.Also can add plasticizer in the described coating material, as one or more of glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini, Oleum Cocois, acetoglyceride, phthalate etc.Also can add coloring agent in the described coating material, but as one or more of the various pigments of hyoscine, ferrum oxide, titanium dioxide, organic toner etc.
Above-mentioned enteric solubility pastille slow-release micropill, used enteric solubility coating material are selected from one or more of Lac, cellulose acetate-phthalate, O-phthalic acid methyl cellulose, hypromellose phthalate ester, polyacrylic resin, Opadry, Eudragit (You Teqi or Youteqi) etc.Used enteric solubility coating material consumption is to contain 8～35% of pill core weight.Also can add an amount of plasticizer in the described coating material, consumption is with reference to state of the art, and plasticizer specifically is selected from one or more of glycerol, propylene glycol, Polyethylene Glycol, Oleum Ricini, Oleum Cocois, acetoglyceride, phthalate etc.Also can add coloring agent in the described coating material, but specifically be selected from hyoscine pigment, ferrum oxide, titanium dioxide, organic toner etc. one or more, consumption is with reference to state of the art.
The foregoing preparation method that contains the pulse sustained release mircopill preparation of nimodipine, step is as follows:
1) nimodipine and pharmaceutic adjuvant are made contained pill core;
2) will contain pill core and wrap gastric solubleness clothing or enteric coating respectively, make stomach dissolution type pastille slow-release micropill, enteric solubility pastille slow-release micropill respectively, and perhaps get and contain pill core directly as stomach dissolution type pastille slow-release micropill;
3) stomach dissolution type pastille slow-release micropill, enteric solubility pastille slow-release micropill are packed in the capsule after being mixed in proportion, make the pulse sustained release mircopill capsule; Perhaps
After stomach dissolution type pastille slow-release micropill, enteric solubility pastille slow-release micropill be mixed in proportion, add additive of tablet again and be pressed into tablet.
Above-mentioned steps 1) method that the preparation method that contains pill core can adopt and roll into the ball method, extrudes spheronization, centrifugal fluidization is made or other are suitable, the present invention preferably extrudes spheronization.
Above-mentioned steps 2) contain pill core and wrap gastric solubleness clothing and enteric coating respectively, concrete coating method can adopt pan coating method, fluidized bed coating or other suitable coating methods.
Above-mentioned steps 3) described additive of tablet comprises one or more in binding agent, disintegrating agent, the lubricant.Wherein binding agent can be selected from one or more in cellulose derivative, the polyvidones such as microcrystalline Cellulose, methylcellulose, hypromellose; Disintegrating agent can be selected from one or more in dried starch, sodium carboxymethyl cellulose, sodium alginate, microcrystalline Cellulose, hydroxypropyl cellulose, the polyvinylpolypyrrolidone; Lubricant can be selected from one or more in stearic acid, Pulvis Talci, fatty acid ester, liquid paraffin, the vegetable oil.
The pill core that contains of the present invention is a slow-release micro-pill, will contain the pill core filled capsules or add other adjuvants to be pressed into tablet and can to make the slow releasing preparation of taking every day once.
What be not particularly limited in the above preparation method all can adopt state of the art.
Nimodipine pulse sustained release mircopill preparation of the present invention, its release in vitro curve display, drug release has reached 24 hours slow release effects slowly, fully, and Canis familiaris L. body giving drugs into nose shows that for the dynamic test result drug release has significant pulsed release effect in the scope at the appointed time.Detailed result of the test will further specify in an embodiment.
Key problem in technology of the present invention is: nimodipine and pharmaceutic adjuvant are made contain pill core, will contain pill core and wrap gastric solubleness clothing and enteric coating respectively, the preparation that the ratio of gastric solubleness micropill and enteric coated micropill adjusted can obtain to have different pulse slow-releasing characteristics.In height morbidity or sx time interval, drug release increases, and in the normal time interval, drug release is steady.Said preparation has following distinguishing feature:
1) only needs medication once every day, reduce the medication number of times, make things convenient for patient's medication;
2) slowly discharge stably in the certain hour behind the drug administration, play effective therapeutical effect, blood drug level is steady, reduces side effect and takes place;
3) division of day and night rhythmicity, in morning, the incidence rate of situations such as cerebral vasospasm, cerebral hemorrhage, cerebral infarction, hypertension is the highest, symptom is more obvious, need higher blood drug level just can play effective prevention and therapeutical effect, and pulse sustained release mircopill of the present invention at this moment between in the section drug release increase, blood drug level raises, and just in time can bring into play best prophylactic treatment effect.
Description of drawings
Fig. 1 contains the outer release test of pill core body figure as a result for nimodipine,
Fig. 2 is the slow-release micro-pill extracorporeal releasing test of bag gastric solubility clothing layer figure as a result,
Fig. 3 is the slow-release micro-pill extracorporeal releasing test of bag enteric solubility clothing layer figure as a result,
Fig. 4 is embodiment 4 described Nimodipine pulse sustained release mircopill preparation extracorporeal releasing tests figure as a result,
Fig. 5 is embodiment 5 described Nimodipine pulse sustained release mircopill preparation extracorporeal releasing tests figure as a result,
Fig. 6 is embodiment 6 described Nimodipine pulse sustained release mircopill preparation extracorporeal releasing tests figure as a result,
Fig. 7 is embodiment 7 described Nimodipine pulse sustained release mircopill preparation extracorporeal releasing tests figure as a result,
Fig. 8 is embodiment 8 described Nimodipine pulse sustained release mircopill preparation extracorporeal releasing tests figure as a result,
Fig. 9 is embodiment 9 described Nimodipine pulse sustained release mircopill preparation extracorporeal releasing tests figure as a result,
Figure 10 is embodiment 10 described Nimodipine pulse sustained release mircopill preparation extracorporeal releasing tests figure as a result,
Figure 11 for the different preparations of the oral nimodipine of Beagle dog after average blood drug level-time graph (curve A is the average blood drug level-time graph behind the oral Nimodipine pulse sustained release mircopill capsule 1, curve B is the average blood drug level-time graph behind the oral Nimodipine sustained release sheet)
Figure 12 for the different preparations of the oral nimodipine of Beagle dog after average blood drug level-time graph (curve A is the average blood drug level-time graph behind the oral Nimodipine pulse sustained release mircopill capsule 2, curve B is the average blood drug level-time graph behind the oral Nimodipine sustained release sheet)
Figure 13 is average blood drug level-time graph (curve A is the average blood drug level-time graph behind the oral Nimodipine pulse sustained release mircopill capsule 3, and curve B is the average blood drug level-time graph behind the oral Nimodipine sustained release sheet) behind the different preparations of the oral nimodipine of Beagle dog.
The specific embodiment
The present invention will be further described below in conjunction with drawings and Examples, but be not limited thereto.In following examples except that have special instruction, said ratio is weight ratio or percentage by weight.
Embodiment 1. nimodipine contain pill core, and are composed as follows:
Nimodipine 24g
Lactose 41g
Microcrystalline Cellulose 20g
Bo Luoshamu 4g
Water 30g
Preparation method:
With nimodipine, lactose, microcrystalline Cellulose mix homogeneously, with Bo Luoshamu aqueous solution system soft material, place and extrude on the round as a ball comminutor, extrude, extruding rotating speed is 14Hz; Round as a ball, round as a ball rotating speed is 23Hz 0.5min, 17Hz 2.5min; 60 ℃ of oven dry, promptly.
Extracorporeal releasing test
Adopt " the device of 2005 editions two appendix XC dissolution methods of Chinese Pharmacopoeia, first method, get six parts of Nimodipine sustained release micropills (being equivalent to nimodipine 120mg), containing 30% isopropyl alcohol pH with 1000mL is that 1.0 hydrochloric acid solution is a release medium, rotating speed is that per minute 100 changes, respectively at certain hour sampling 5mL, add the dissolution medium of uniform temp, equal volume simultaneously, institute's sample thief filters immediately, gets subsequent filtrate and measures.After sampling in 4 hours finished, transferring pH with NaOH immediately was 6.8; After sampling in 8 hours finishes, add sodium hydroxide immediately in dissolution fluid, transferring pH is 7.4, takes a sample in different time points successively.Its average release the results are shown in Figure 1.
Conclusion: extracorporeal releasing test is the result show, the nimodipine rate of release is slow, discharges fully, estimates can reach in vivo 1 time slow release effect every day.
The slow-release micro-pill of embodiment 2. bag gastric solubility clothing layers
Containing pill core forms: (by 200 capsules)
Nimodipine 24g
Sodium lauryl sulphate 4g
Lactose 16g
Microcrystalline Cellulose 45g
Water 40g
Coating material:
Eudragit?E?PO 9g
Preparation method:
With nimodipine, sodium lauryl sulphate, lactose, microcrystalline Cellulose mix homogeneously, with aqueous solution system soft material, place and extrude on the round as a ball comminutor, extrude, round as a ball, 60 ℃ of oven dry are carried out coating with Eudragit E PO aqueous dispersion.Must wrap the slow-release micro-pill of gastric solubility clothing layer.
Slow-release micro-pill behind the above-mentioned coating is filled in the capsulae vacuus, and every contains nimodipine 120mg, gets the capsule of slow-release micro-pill.
Extracorporeal releasing test
Get 6 of capsules, test according to the method under the embodiment 1 extracorporeal releasing test item, its release the results are shown in Figure 2.
Conclusion: extracorporeal releasing test is the result show, bag gastric solubleness clothing is to not influence of drug release, and the nimodipine rate of release is slow, discharges fully, estimates can reach in vivo 1 time slow release effect every day.
The slow-release micro-pill of embodiment 3. bag enteric solubility clothing layers
Containing pill core forms: (by 200 capsules)
Nimodipine 24g
Sodium lauryl sulphate 6g
Lactose 37g
Microcrystalline Cellulose 29g
Water 35g
Coating material:
Eudragit?S100 20g
Preparation method:
With nimodipine, sodium lauryl sulphate, lactose, microcrystalline Cellulose mix homogeneously, with aqueous solution system soft material, place and extrude on the round as a ball comminutor, extrude, round as a ball; Oven dry; Carry out coating with Eudragit S100 aqueous dispersion.Must wrap the slow-release micro-pill of enteric solubility clothing layer.
Slow-release micro-pill behind the above-mentioned coating is filled in the capsulae vacuus, and every contains nimodipine 120mg.Get the capsule of slow-release micro-pill.
Extracorporeal releasing test
Measure according to method under the extracorporeal releasing test item among the embodiment 2, its release the results are shown in Figure 3.
Extracorporeal releasing test is the result show, less than 7.4 o'clock, medicine did not almost discharge enteric coated micropill at pH, and in the external purpose that reaches control drug release, medicine began slow release at pH greater than 7.4 o'clock, and the 24h release is complete.
The slow-release micro-pill of embodiment 2 described bag gastric solubility clothing layers and the slow-release micro-pill of embodiment 3 described bag enteric solubility clothing layers are pressed 1: 3 mixing, fill in (every capsules contains nimodipine 120mg) in the capsule, promptly get the Nimodipine pulse sustained release mircopill capsule.
Extracorporeal releasing test
Measure according to method under the extracorporeal releasing test item among the embodiment 2, the results are shown in Figure 4 according to its release.
Extracorporeal releasing test is the result show, less than 7.4 o'clock, drug release was slowly steady at pH, and greater than 7.4 o'clock, a pulse appearred in drug release, and the 24h release is complete, in the external purpose that reaches control drug release at pH.Estimate that medicine in vivo can be to pulsatile effect.
Embodiment 5. contains the pulse sustained release mircopill preparation of nimodipine
The slow-release micro-pill of embodiment 2 described bag gastric solubility clothing layers and the slow-release micro-pill of embodiment 3 described bag enteric solubility clothing layers are pressed 5: 7 mixings, fill in (every capsules contains nimodipine 120mg) in the capsule, promptly get the Nimodipine pulse sustained release mircopill capsule.
Extracorporeal releasing test
Measure according to method under the extracorporeal releasing test item among the embodiment 2, the results are shown in Figure 5 according to its release.
Extracorporeal releasing test is the result show, less than 7.4 o'clock, drug release was slowly steady at pH, and greater than 7.4 o'clock, a pulse appearred in drug release, and the 24h release is complete, in the external purpose that reaches control drug release at pH.Estimate that medicine in vivo can be to pulsatile effect.
The slow-release micro-pill of embodiment 2 described bag gastric solubility clothing layers and the slow-release micro-pill of embodiment 3 described bag enteric solubility clothing layers are pressed 7: 5 mixings, fill in (every capsules contains nimodipine 120mg) in the capsule, promptly get the Nimodipine pulse sustained release mircopill capsule.
Extracorporeal releasing test
Measure according to method under the extracorporeal releasing test item among the embodiment 2, the results are shown in Figure 6 according to its release.
Extracorporeal releasing test is the result show, less than 7.4 o'clock, drug release was slowly steady at pH, and greater than 7.4 o'clock, a pulse appearred in drug release, and the 24h release is complete, in the external purpose that reaches control drug release at pH.Estimate that medicine in vivo can be to pulsatile effect.
Embodiment 7. contains the pulse sustained release mircopill preparation of nimodipine, and it is as follows to form (by 200): contain pill core:
Nimodipine 26g
Polyethylene glycol 1500 8g
Starch 16g
Dextrin 15g
Microcrystalline Cellulose 30g
Water 40g
Magnesium stearate 1.5g
Gastric solubleness clothing material:
Stomach dissolution type Opadry 5.5g
Enteric coating material:
Enteric solubility Opadry 95 9g
Preparation method:
With nimodipine, polyethylene glycol 1500, starch, dextrin, microcrystalline Cellulose mix homogeneously, add water system soft material, place and extrude on the round as a ball comminutor, extrude, round as a ball, 60 ℃ of oven dry must contain pill core.
To contain pill core carries out coating with gastric solubleness clothing material and enteric coating material respectively and gets gastric solubleness slow-release micro-pill and enteric sustained-release pellet.Gastric solubleness slow-release micro-pill and enteric sustained-release pellet is mixed according to 1: 1 ratio, tabletting behind the adding magnesium stearate mixing, every contains nimodipine 130mg, promptly gets the Nimodipine pulse sustained release sheet.
Extracorporeal releasing test
Get 6 of Nimodipine pulse sustained release sheets, test according to the method under the embodiment 1 extracorporeal releasing test item, its release the results are shown in Figure 7.
Extracorporeal releasing test is the result show, less than 7.4 o'clock, drug release was slowly steady at pH, and greater than 7.4 o'clock, a pulse appearred in drug release, and the 24h release is complete, in the external purpose that reaches control drug release at pH.Estimate that medicine in vivo can be to pulsatile effect.
Nimodipine 18g
Mannitol 26g
Microcrystalline Cellulose 30g
Water 40g
Pulvis Talci 2.0g
Gastric solubleness clothing material:
Methylcellulose 8g
Macrogol 4000 2g
Enteric coating material:
Hypromellose phthalate ester 18g
Preparation method:
With nimodipine, mannitol, microcrystalline Cellulose mix homogeneously, add Tween 80 aqueous solution system soft material, place and extrude on the round as a ball comminutor, extrude, round as a ball, 60 ℃ of oven dry must contain pill core.
To contain pill core carries out coating with gastric solubleness clothing material and enteric coating material respectively and gets gastric solubleness slow-release micro-pill and enteric sustained-release pellet.Gastric solubleness slow-release micro-pill and enteric sustained-release pellet is mixed according to 5: 7 ratio, tabletting behind the adding Pulvis Talci mixing, every contains nimodipine 90mg, promptly gets the Nimodipine pulse sustained release sheet.
Extracorporeal releasing test
Get 6 of Nimodipine pulse sustained release sheets, test according to the method under the embodiment 1 extracorporeal releasing test item, its release the results are shown in Figure 8.
Extracorporeal releasing test is the result show, less than 7.4 o'clock, drug release was slowly steady at pH, and greater than 7.4 o'clock, a pulse appearred in drug release, and the 24h release is complete, in the external purpose that reaches control drug release at pH.Estimate that medicine in vivo can be to pulsatile effect.
Embodiment 9. contains the pulse sustained release mircopill preparation of nimodipine, and it is as follows to form (by 200): contain pill core:
Nimodipine 12g
Polyethylene glycol 1500 8g
Sorbitol 17g
Microcrystalline Cellulose 35g
Water 40g
Gastric solubleness clothing material:
Stomach dissolution type polyacrylic resin 12g
Polyethylene glycol 6000 2g
Enteric coating material
Cellulose acetate-phthalate 22g
Oleum Ricini 2g
Preparation method:
With nimodipine, polyethylene glycol 1500, sorbitol, microcrystalline Cellulose mix homogeneously, add water system soft material, place and extrude on the round as a ball comminutor, extrude, round as a ball, 60 ℃ of oven dry must contain pill core.
To contain pill core carries out coating with gastric solubleness clothing material and enteric coating material respectively and gets gastric solubleness slow-release micro-pill and enteric sustained-release pellet.With gastric solubleness slow-release micro-pill and enteric sustained-release pellet ratio mixing according to 11: 13, fill in (every capsules contains nimodipine 60mg) in the capsule, promptly get the Nimodipine pulse sustained release mircopill capsule.
Extracorporeal releasing test
Get 6 of Nimodipine pulse sustained release mircopill capsules, test according to the method under the embodiment 1 extracorporeal releasing test item, its release the results are shown in Figure 9.
Extracorporeal releasing test is the result show, less than 7.4 o'clock, drug release was slowly steady at pH, and greater than 7.4 o'clock, a pulse appearred in drug release, and the 24h release is complete, in the external purpose that reaches control drug release at pH.Estimate that medicine in vivo can be to pulsatile effect.
Nimodipine 36g
Polyethylene glycol 1500 8g
Mannitol 12g
Sorbitol 8g
Microcrystalline Cellulose 30g
20% ethanol water 50g
Enteric coating material:
Lac 5g
Cellulose acetate-phthalate 5g
Diethyl phthalate 1g
Preparation method:
With nimodipine, polyethylene glycol 1500, mannitol, sorbitol, microcrystalline Cellulose mix homogeneously, add water system soft material, place and extrude on the round as a ball comminutor, extrude, round as a ball, 60 ℃ of oven dry must contain pill core.
To contain pill core carries out coating with enteric coating material and gets enteric sustained-release pellet.Get and contain pill core directly as the gastric solubleness slow-release micro-pill, gastric solubleness slow-release micro-pill and enteric sustained-release pellet is mixed according to 1: 1 ratio, fill in (every capsules contains nimodipine 180mg) in the capsule, promptly get the Nimodipine pulse sustained release mircopill capsule.
Extracorporeal releasing test
Get 6 of Nimodipine pulse sustained release mircopill capsules, test according to the method under the embodiment 1 extracorporeal releasing test item, its release the results are shown in Figure 10.
Extracorporeal releasing test is the result show, less than 7.4 o'clock, drug release was slowly steady at pH, and greater than 7.4 o'clock, a pulse appearred in drug release, and the 24h release is complete, in the external purpose that reaches control drug release at pH.Estimate that medicine in vivo can be to pulsatile effect.
The test of embodiment 11. animal pharmacokinetics
8 beagle dogs, body weight 18-22kg.Adopt the Latin square experimental design, 4 cycles 4 preparations 4 intersect the own control experimental designs, by body weight be divided at random 4 groups (R, T1, T2, T3), 2 every group.
R organizes in 8 of mornings and 1 commercially available Nimodipine sustained release sheet of 8 difference orally give in evening (Qilu Pharmaceutical Co., Ltd.'s production, specification: 60mg/ sheet, lot number: 750002KG); 1 embodiment of T1 group orally give, 4 described Nimodipine pulse sustained release mircopill capsules (being called for short Nimodipine pulse sustained release mircopill capsule 1); 1 embodiment of T2 group orally give, 5 described Nimodipine pulse sustained release mircopill capsules (being called for short Nimodipine pulse sustained release mircopill capsule 2), T3 grain embodiment 6 described Nimodipine pulse sustained release mircopill capsules (being called for short Nimodipine pulse sustained release mircopill capsule 3).
Get blank blood before the administration, after the administration respectively at 1,2,3,4,5,6,7,8,9,10,12,13,16,19, the animal forelimb was got blood 2.5ml in 24,30 hours, measured blood drug level.The medicine cleaning phase is 7 days, gets blood every 7 days by the design administration.
Data result is handled and to be shown: T1, T2, the T3 group respectively with R group bioequivalence (F value 95%～110%), three groups of pellet capsule preparations all have pulsatile effect in various degree.Blood drug level-the time graph of different preparations is seen Figure 11～13.
Claims (8)
1. a pulse sustained release mircopill preparation that contains nimodipine is characterized in that comprising the combination of stomach dissolution type pastille slow-release micropill and enteric solubility pastille slow-release micropill, and wherein stomach dissolution type pastille slow-release micropill and enteric solubility pastille slow-release micropill weight ratio are 1: 3～7: 5;
To be (1) contain pill core by what nimodipine and pharmaceutic adjuvant were formed to described stomach dissolution type pastille slow-release micropill, or the pill core that contains that (2) are made up of nimodipine and pharmaceutic adjuvant wraps the gastric solubleness clothing outward again; Wherein, by containing in the pill core that nimodipine and pharmaceutic adjuvant are formed, the percentage by weight of nimodipine is 10～60%;
Pill core is enteric coated to be made described enteric solubility pastille slow-release micropill containing of forming by nimodipine and pharmaceutic adjuvant.
2. the pulse sustained release mircopill preparation that contains nimodipine as claimed in claim 1, it is characterized in that describedly by containing in the pill core that nimodipine and pharmaceutic adjuvant are formed, pharmaceutic adjuvant is selected from one or more in starch, lactose, dextrin, microcrystalline Cellulose, methylcellulose, mannitol, sorbitol, Polyethylene Glycol, polyvidone, acrylic resin, magnesium stearate, Pulvis Talci, sodium lauryl sulphate, tween, the poloxamer.
3. the pulse sustained release mircopill preparation that contains nimodipine as claimed in claim 1 is characterized in that describedly by containing in the pill core that nimodipine and pharmaceutic adjuvant are formed, and the percentage by weight of nimodipine is 20～40%.
4. the pulse sustained release mircopill preparation that contains nimodipine as claimed in claim 1, it is characterized in that described stomach dissolution type pastille slow-release micropill, used stomach dissolution type coating material is selected from one or more among hypromellose, methylcellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyvidone, sodium carboxymethyl cellulose, polyethylene acetal diethylamine acetate, hydroxypropyl two d ritalinic acid cellulose ethers, polyacrylic resin, Opadry, the Eudragit.
5. the pulse sustained release mircopill preparation that contains nimodipine as claimed in claim 1 is characterized in that the used enteric solubility coating material of described enteric solubility pastille slow-release micropill is selected from one or more among Lac, cellulose acetate-phthalate, O-phthalic acid methyl cellulose, hypromellose phthalate ester, polyacrylic resin, Opadry, the Eudragit.
6. the pulse sustained release mircopill preparation that contains nimodipine as claimed in claim 5 is characterized in that used enteric solubility coating material consumption is to contain 8～35% of pill core weight.
7. the described preparation method that contains the pulse sustained release mircopill preparation of nimodipine of claim 1, step is as follows:
1) nimodipine and pharmaceutic adjuvant are made contained pill core; Contain pill core directly as stomach dissolution type pastille slow-release micropill;
2) will contain pill core and wrap gastric solubleness clothing or enteric coating respectively, make stomach dissolution type pastille slow-release micropill, enteric solubility pastille slow-release micropill respectively;
3) stomach dissolution type pastille slow-release micropill, enteric solubility pastille slow-release micropill are packed in the capsule after being mixed in proportion, make the pulse sustained release mircopill capsule; After perhaps stomach dissolution type pastille slow-release micropill, enteric solubility pastille slow-release micropill being mixed in proportion, adding additive of tablet again and be pressed into tablet.
8. the preparation method that contains the pulse sustained release mircopill preparation of nimodipine as claimed in claim 7 is characterized in that preparation method that step 1) contains pill core adopts to extrude spheronization.
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| CN103655506A (en) * | 2012-09-11 | 2014-03-26 | 南京亿华药业有限公司 | Cefaclor sustained release tablet and preparation method thereof |
| CN103768607B (en) * | 2014-02-19 | 2015-07-15 | 东南大学 | Self-assembled multi-pulse drug-release device, and preparation method and application thereof |
| CN105853599A (en) * | 2015-01-19 | 2016-08-17 | 温州医科大学附属第二医院 | Pulsatile release preparation containing Callicarpa nudiflora |
| CN107213138B (en) * | 2017-08-07 | 2020-12-18 | 北京罗诺强施医药技术研发中心有限公司 | Method and pharmaceutical composition for treating hypertension by timed release of drugs |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011395A (en) * | 2007-02-02 | 2007-08-08 | 东南大学 | Sustained release preparation of licardipine hydrochloride and its preparing process |
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| Publication number | Publication date |
|---|---|
| CN101229132A (en) | 2008-07-30 |
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