CN100548297C - A kind of slow-release micro-pill that contains toraesmide active ingredient and preparation method thereof - Google Patents
A kind of slow-release micro-pill that contains toraesmide active ingredient and preparation method thereof Download PDFInfo
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- CN100548297C CN100548297C CNB2005100148141A CN200510014814A CN100548297C CN 100548297 C CN100548297 C CN 100548297C CN B2005100148141 A CNB2005100148141 A CN B2005100148141A CN 200510014814 A CN200510014814 A CN 200510014814A CN 100548297 C CN100548297 C CN 100548297C
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Abstract
The invention discloses a kind of slow-release micro-pill that contains toraesmide active ingredient, form by pastille micropill and controlled release layer, its preparation method comprises: celphere is wrapped obtained the pastille micropill after micropill is made by torasemide or adjuvant and medicament mixed, after blocker, porogen, plasticizer or antiplastering aid be made into coating solution, in coating pan or fluid bed, be sprayed at the skin of pastille micropill, make slow-release micro-pill.The slow-release micro-pill of the present invention's preparation can effectively be controlled medicine and discharge in the regular hour, keeps effective blood drug concentration stably, does not have the prominent phenomenon of releasing and takes place.
Description
Technical field
The invention belongs to the technical field of medicament slow release preparation, relate to a kind of slow-release micro-pill that contains toraesmide active ingredient and preparation method thereof in particular.
Background technology
Show that according to relevant investigation China's painstaking effort tubing medication is sold and is only second to classes of anti-infective medication and the medication of gastrointestinal tract class, occupy the third-largest class medication, and China hypertensive patient accounts for about 50% of cardiovascular case.Hypertension is the pathogenetic main hazard factor of coronary disease.Long-term hypertension can increase the heart burden, when causing heart failure, also can concurrent renal failure, and increase the weight of hypertension conversely again, form vicious cycle.Hypertension still can not be cured fully, but strict controlling blood pressure notes selecting for use the antihypertensive drug of protection target organ can reduce cardiovascular and cerebrovascular disease danger, reduces the generation of organ complication such as the heart, brain, kidney, blood vessel, thereby reduces general mortality rate.The Drug therapy principle of the hypertension of WHO proposition recently is as follows:
(1) use effective lowest dose level during any medicine begin treatment, reducing side effect, as single Drug therapy effectively but controlling of blood pressure is undesirable, as long as patient's well-tolerated then should increase drug dose.
(2) use 24 hours every days 1 time effective durative action preparations as far as possible reach round-the-clock treatment.Its advantage is good, the steady blood pressure lowering of patient dependence, to reducing the cardiovascular danger incident and protecting the more fugitive preparation of target organ damage good.
(3) the choose reasonable drug combination makes side effect minimum to reach the highest pressure reduction effect, if a curative effect of medication difference maybe can not tolerate, generally would rather add at present with the 2nd low dose of non-similar medicine, rather than increase the drug dose of the 1st beginning, make the 1st, 2 medicine all in the low dosage scope, then good effect and side effect is less.The ideal bp level should be below the 138/83mmHg.
Estimate the index of medicine antihypertensive effect: 1. paddy p-ratio (T: PR), the ratio of the blood pressure reduction value (peak) that the blood pressure depreciation (paddy) before it refers to the last dosage effect of depressor end, next dosage use eventually and medicine peak recorded as the time spent, be intended to avoid do time spent blood pressure excessive descent at the peak, do the time spent in paddy and still can keep most of peak effect, make blood pressure in 24 hours, maintain maintenance level.(2.SI Smoothnesess index), i.e. the standard deviation of blood pressure reduction value of SI=24 hourly average blood pressure lowering value/per hour.
Torasemide's chemistry is by name: between 1-isopropyl-3-[(4--toluidino-3-pyridine radicals) sulfonyl] urea, be long-acting medullary loop diuretic of new generation, have diuresis, hypotensive effect, be used for the treatment of diseases such as hypertension, heart failure, renal failure and hepatic ascites.Torasemide acts on ascending thick limb of Henle's loop, and possible mechanism comprises the following aspects: suppress aldosterone and receptors bind in medullary substance portion and the cortex, reduce the activity of aldosterone, the effect that reduces row's potassium, increases row's sodium is arranged.Torasemide not only alleviates the retention of body inner salt and water, increases its diuretic effect, also makes its row's potassium effect obviously be weaker than other potent medullary loop diuretic.These characteristics have the important clinical effect during with illness such as the hepatic ascites of hypokalemia, heart failures in treatment.Torasemide promptly reached maximum plasma concentration in oral 1 hour, and bioavailability is 76 ~ 92%, and plasma protein binding rate is 97%～99%, and distribution volume is 0.2 liter/kilogram.Torasemide transforms through liver metabolism, and only 20% original shape medicine is through homaluria, and removing the half-life is 2.2～5 hours, the half-life is not had obvious influence in continuous use 8-21 days.The chronic renal failure patients, the kidney clearance rate of torasemide reduces, but the blood plasma total body clearance is unaffected.Torasemide is effective to various types of hypertension models, can produce antihypertensive function under the diuresis threshold dose.Clinical research shows that torasemide can make light moderate hypertension patient mean arterial pressure reduce by 24 ~ 29 millimetress of mercury for 2.5 ~ 10 milligrams.The independent using dosage of torasemide is generally 2.5 ~ 5 milligrams/time, and every day 1 time, 71 ~ 95% patients' diastolic pressure can be controlled in below 90 millimetress of mercury, for the unconspicuous patient's doubling dosage of effect, can make patient's diastolic pressure of 70 ~ 80% be controlled at desired value.
What gone on the market at present, has torasemide's tablet, capsule, an injection etc.Oral formulations has: torasemide of Jiangsu Suzhong Haixin Pharmaceutical Co., Ltd. sheet etc.
At present, torasemide is oral to be used for the treatment of the hypertensive ordinary preparation that has only, 2.5-10 single oral administration clinically, and the fluctuation of ordinary preparation blood drug level is big, the paddy p-ratio of blood pressure (T: PR) big.Torasemide is 2.2～5 hours the removing half-life in blood, and is still effective when keeping paddy concentration, must improve dosage, and long-term prescription may bring bigger side effect.According to the Therapeutic Principle of WHO, the blood pressure lowering treatment needs long-term prescription, steadily blood pressure lowering, and exploitation torasemide slow releasing preparation has extremely important meaning.
Summary of the invention
An object of the present invention is overcoming the shortcoming and defect of above-mentioned prior art, a kind of slow-release micro-pill that contains toraesmide active ingredient of novelty is provided, this slow-release micro-pill can evenly discharge in vivo, keeps effective blood drug concentration under less dosage, can satisfy steady blood pressure lowering treatment needs.Another purpose of the present invention provides the preparation method of this slow-release micro-pill.
The objective of the invention is to be achieved by the following technical programs:
A kind of slow-release micro-pill that contains toraesmide active ingredient is made up of pastille micropill and slow release layer, calculates pastille micropill: slow release layer=0.5-50: 0.1-10, preferred 10: 0.3-3.0 by weight proportion; The pastille micropill can be to wrap immediate release drug or medicine and adjuvant by blank micropill to be mixed and made into micropill, and wherein, the weight ratio of blank micropill and medicine is 10-100: 1-20; The weight ratio of medicine and adjuvant is 1: 10-100.
Specifically comprise of the present invention containing in the pill core:
The fillibility adjuvant of a, pastille micropill of the present invention is lactose, starch, microcrystalline Cellulose etc.; Binding agent is sucrose, methylcellulose, hypromellose, polyvinylpyrrolidone; Lubricant is magnesium stearate, stearic acid, colloidal silica, Pulvis Talci;
B, slow control layer of the present invention comprise: blocker; Porogen; Plasticizer; Antiplastering aid or the like pharmaceutic adjuvant.Blocker wherein is acrylic resin, ethyl cellulose or river wax; Porogen is lactose, hypromellose, polyvinylpyrrolidone or Pulvis Talci; Plasticizer is triethyl citrate, diethyl phthalate, polyethylene glycol 6000, tributyl citrate or dibutyl sebacate; Antiplastering aid is Pulvis Talci, magnesium stearate or glyceryl monostearate.
Described slow release layer blocker acrylic resin is any one or a few the mixture in Youteqi S-100, RS30D, RL30D, RS100, RL100, E-100 or NE30D, NE30D aqueous dispersion or RS30D and the RL30D aqueous dispersion etc.; Described slow release layer blocker ethyl cellulose is ethyl cellulose powder or Aquacoat.
In the slow-release micro-pill of the present invention, the weight ratio of blocker, porogen, plasticizer, antiplastering aid is 10-100: 0.1-100: 0.1-100: 0.1-100, preferred 10-100: 0.1-20: 0.1-20: 0.1-20.
A kind of preparation method that contains the toraesmide active ingredient slow-release micro-pill comprises the pastille micropill is placed fluid bed or coating pan, wraps slow release layer, is drying to obtain.Promptly as required the pastille micropill is wrapped the slow release layer of different proportion, made the micropill of different release properties, be mixed into slow-release micro-pill according to concrete needs again.
Pastille micropill for example: slow release layer 0.5-50: 0.1-10, preferred 10: 0.3-3.0, make slow-release micro-pill according to concrete needs skin again, the scope that its weightening finish is needed is preferably at 3%-30%.
Concrete preparation method comprises the following steps:
(1) preparation of pastille micropill:
A. with fillibility adjuvant mix homogeneously; add binding agent; play female also pill-rolling to required order with comminutor (or coating pan) and count 15-30 order (pill-rolling limit, limit adds lubricant); oven dry; make the blank micropill of smooth ball, blank micropill is placed fluid bed (or coating pan), make the temperature of micropill be controlled at 25-50 ℃; with water or water and alcohol mixeding liquid, the skin that is coated on the ball celphere is made the pastille micropill with torasemide and polymeric membrane clothing material.
B. fillibility adjuvant and medicament mixed is even, add binding agent, play female also pill-rolling to required order with comminutor (or coating pan) and count 15-30 order (pill-rolling limit, limit adds lubricant), oven dry makes smooth ball-shaped pastille micropill.
(2) coating of slow release layer
The pastille micropill is placed fluid bed (or coating pan), make the temperature of micropill be controlled at 20-50 ℃, blocker, porogen, plasticizer, antiplastering aid are mixed with solution or suspension with water or water and alcohol mixeding liquid, the skin that is sprayed at the pastille micropill is made slow-release micro-pill, the scope that its weightening finish is needed is preferably at 3%-30% (percentage by weight).In can incapsulating after the slow-release micro-pill drying or directly packed, make slow releasing preparation.
The slow-release material that torasemide's slow-release micro-pill of the present invention's preparation is adopted is hydrophobic macromolecular material, and is insoluble in water, but the energy swelling forms the duct in coating membrane.And the porogen that adds in slow release layer mostly is highly osmotic substance or water-soluble material, by water-soluble expand or dissolving after, on coating membrane, also formed the duct, because the water passing hole channel enters medicated layer, formed permeable pressure head inside and outside the release membranes, the medicine passing hole channel of coating inboard is discharged.Select different slow-release materials, regulate to mix the rate of release that the coating thickness of the different proportion of slow-release material and controlling slow release film can be regulated slow-release micro-pill.
Be used for that the present invention prepares active component torasemide of torasemide's slow-release micro-pill and pharmaceutical carrier preferably selects to make 100% composition by following proportioning.
A. pastille micropill composition
The 0.5-10% of torasemide
Filler 20-90%
Binding agent 1-25%
Lubricant 1-10%
B. slow release layer composition
Blocker 0.5-15%
Porogen 0.1-5%
Plasticizer 0.1-5%
Antiplastering aid 0.2-10%
The slow-release micro-pill of the present invention's preparation is compared with ordinary preparation has following characteristics:
(1) the slow-release micro-pill uniformly dispersing is in gastrointestinal tract, the too high and situation in stimulating gastrointestinal road of local blood concentration can not occur for the high medicine of drug effect.The prominent generation of releasing phenomenon that slow-release micro-pill has avoided ordinary preparation to exist has increased safety, has improved therapeutic effect.
(2) surface area different according to the ball core adjusted the size of drug loading, to reach required drug release rate; Also can reach required dissolution rate by mixed proportion and the spraying consumption of adjusting polymer; Perhaps can be mixed, to reach required release with the pastille micropill of different rates of release.In the design of formulation and technology, has flexible and changeable advantage.
(3) because the flowability of spheroidal micropill better, in the process of coating medicine and polymer, can obtain higher productive rate and repeatability, be easy to industrialization.
Description of drawings:
Fig. 1 torasemide slow-release micro-pill release curve;
The time front of blood concentration of Fig. 2 torasemide slow-release micro-pill, wherein 1 is torasemide's capsule, and 2 is the sample of embodiment 3, and 3 is the sample of embodiment 5.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment.Embodiment only is indicative content, means that never it limits the scope of the invention by any way.
The preparation of embodiment 1, pastille micropill
Lactose (or microcrystalline Cellulose), starch mix homogeneously with recipe quantity; the binding agent that adds the preparation of sucrose or hypromellose; play female also pill-rolling to required order with comminutor (or coating pan) and count 15-30 order (pill-rolling limit, limit adds lubricant and fluidizer); best 18-25 order is sifted out in oven dry.
Preparation method:
Torasemide, hypromellose (or polyvinylpyrrolidone), Pulvis Talci described in the prescription are joined respectively in water or 70% ethanol, stir and made into uniform mixed liquor in 20 minutes.In fluid bed (or coating pan), the temperature that keeps micropill is 40 ℃-60 ℃ a condition, and the blank micropill skin that this mixed liquor evenly is sprayed at the step gained makes the pastille micropill.
The preparation of embodiment 2, pastille micropill
Preparation method
Lactose (or microcrystalline Cellulose), starch and the medicament mixed of recipe quantity is even; the binding agent that adds sucrose and Polyethylene Glycol or (hypromellose and Polyethylene Glycol) preparation; play female also pill-rolling to required order with comminutor (or coating pan) and count 15-30 order (pill-rolling limit, limit adds lubricant and fluidizer); sift out best 18-25 order; oven dry, promptly.
The preparation of embodiment 3, slow-release micro-pill
Prescription
The pastille micropill 150g of embodiment 1
Acrylic resin NE30D 20g
Pulvis Talci 5g
Water 150ml
Preparation method:
The micropill of embodiment 1 gained is put into fluid bed (or coating pan), make the temperature of micropill remain on 25 ℃.With adding triethyl citrate and Pulvis Talci in the acrylic resin NE30D aqueous dispersion, stir, with the flow velocity of 5ml/min, the skin that is sprayed at the pastille micropill is made slow-release micro-pill.
The preparation of embodiment 4, slow-release micro-pill
Prescription
The pastille micropill 150g of embodiment 1
Acrylic resin RS30D 20g
Acrylic resin RL30D 10g
Triethyl citrate 3.5g
Pulvis Talci 5g
Water 150ml
Preparation method
The micropill of embodiment 1 gained is put into fluid bed (or coating pan), make the temperature of micropill remain on 25 ℃-28 ℃.With adding triethyl citrate and Pulvis Talci in the aqueous dispersion, stir, with the flow velocity of 5ml/min, the skin that is sprayed at the pastille micropill is made slow-release micro-pill.
The preparation of embodiment 5, slow-release micro-pill
Prescription
The pastille micropill 150g of embodiment 2
Acrylic resin RS100 15g
Acrylic resin RL100 1.5g
Triethyl citrate 3.8g
Pulvis Talci 11.3g
90% ethanol 250ml
Preparation method
The micropill of embodiment 2 gained is put into fluid bed (or coating pan), make the temperature of micropill remain on 35 ℃-40 ℃.Acrylic resin is dissolved in the ethanol, adds triethyl citrate and Pulvis Talci again, stir, with the flow velocity of 5ml/min, the skin that is sprayed at the pastille micropill is made slow-release micro-pill.
The preparation of embodiment 6, slow-release micro-pill
Prescription
The pastille micropill 150g of embodiment 1
Ethyl cellulose 10g
Hydroxypropyl methylcellulose 2g
0.1% diethyl phthalate 5g
75% ethanol 100ml
Preparation method
The micropill of embodiment 1 gained is put into fluid bed (or coating pan), make the temperature of micropill remain on 35 ℃-45 ℃.The mixture of ethyl cellulose and hypromellose is dissolved in 75% ethanol, adds 0.1% diethyl phthalate again, stir, with 5ml/ minute flow velocity, the skin that is sprayed at the pastille micropill was made slow-release micro-pill.
The preparation of embodiment 7, slow-release micro-pill
The pastille micropill 150g of embodiment 2
Aquacoat 15g
Pulvis Talci 10g
Water 100ml
Preparation method
The pastille micropill of embodiment 2 gained is put into fluid bed (or coating pan), make the temperature of micropill remain on 28-30 ℃.Aquacoat is water-soluble, add Pulvis Talci again, stir, with the flow velocity of 5ml/min, the skin that is sprayed at the pastille micropill is made slow-release micro-pill.
Determination of plasma concentration in embodiment 8, release and the body
Of the present inventionly contain that toraesmide active ingredient slow-release micro-pill and torasemide's ordinary tablet have carried out in the body, the comparative experiments of external biological availability, experimental result is as follows:
A. release in vitro degree
Drug release determination condition: instrument: ZRS-4 medicament dissolution instrument, solvent: water 250ml, rotating speed: 50 rev/mins.
Assay method adopts UV-VIS spectrophotometry: detect wavelength 286nm.
The rapid release sample was respectively at 5,10,15,30,45,60 minutes sampling and measuring dissolutions, and the slow release sample was respectively at 1,2,4,8,12,16,24 hour sampling and measuring release
Measurement result is as follows:
By above fruit as can be known, select different slow-release materials, adopt different condition coatings, prepared micropill can both play slow releasing function in 24 hours, and release result is even, the not prominent phenomenon of releasing.Its result meets the guideline of version pharmacopeia in 2005 about slow releasing preparation.
B. blood drug level in the body
Condition determination: HPLC; Immobile phase: C
18Post, 4.6 * 100mm, 5 μ Ball-type packings; Mobile phase: methanol: acetonitrile: water: triethylamine: phosphoric acid=45: 20: 35: 1: 0.2, flow velocity: 1.0ml/min.Detect: UV detects λ=286nm; Sample size: 50 μ l.
Behind the oral different samples of beasle dog (2 animals of each sample), take a blood sample in different time, separation of serum, 0.5ml serum, and the extracting solution of adding 2ml (dichloromethane: normal hexane=3: 1), behind the shake well, separate 1.5ml lower floor organic facies, nitrogen dries up, and 100 μ l redissolve, and 50 μ l sample introductions are measured.Measurement result is seen accompanying drawing 2.
Claims (2)
1, a kind of slow-release micro-pill that contains toraesmide active ingredient is characterized in that selecting to make 100% composition by following proportioning:
A. pastille micropill composition
The 0.5-10% of torasemide
Filler 20-90%
Binding agent 1-25%
Lubricant 1-10%
B. slow release layer composition
Blocker 0.5-15%
Porogen 0.1-5%
Plasticizer 0.1-5%
Antiplastering aid 0.2-10%
Wherein filler is lactose, starch or microcrystalline Cellulose; Binding agent is sucrose, methylcellulose, hypromellose or polyvinylpyrrolidone; Lubricant is magnesium stearate, stearic acid, colloidal silica or Pulvis Talci;
Blocker wherein is that acroleic acid resin is any one or a few the mixture in Youteqi S-100, RS30D, RL30D, RS100, RL100, E-100 or NE30D, NE30D aqueous dispersion or RS30D and the RL30D aqueous dispersion; Or ethyl cellulose powder, Aquacoat or river wax; Porogen is lactose, hypromellose, polyvinylpyrrolidone or Pulvis Talci; Plasticizer is triethyl citrate, diethyl phthalate, polyethylene glycol 6000, tributyl citrate or dibutyl sebacate; Antiplastering aid is Pulvis Talci, magnesium stearate or glyceryl monostearate.
2, slow-release micro-pill according to claim 1, wherein release in vitro is characterized as release in 1～3 hour release in 0～30%, 3～6 hours release in 20～60%, 6～8 hours release in 50～90%, 12 hours more than 70%; The release of torasemide can be provided after the administration in 24 hours, and the body giving drugs into nose is 3～8 hours for the average peak reaching time of blood concentration of kinetics.
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| CNB2005100148141A CN100548297C (en) | 2005-08-22 | 2005-08-22 | A kind of slow-release micro-pill that contains toraesmide active ingredient and preparation method thereof |
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| CNB2005100148141A CN100548297C (en) | 2005-08-22 | 2005-08-22 | A kind of slow-release micro-pill that contains toraesmide active ingredient and preparation method thereof |
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| CN100548297C true CN100548297C (en) | 2009-10-14 |
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| CN101884619B (en) * | 2009-05-15 | 2012-07-04 | 天津药物研究院 | Zolpidem tartrate controlled-release pellet and preparation method thereof |
| CN102125610A (en) * | 2011-03-12 | 2011-07-20 | 江西本草天工科技有限责任公司 | Xiaojin sustained-release pellets and composition thereof |
| WO2015050570A1 (en) | 2013-10-06 | 2015-04-09 | Shah Salim | Controlled-release formulations comprising torsemide |
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