CN102580056B - Controlled-release injection containing antidiuresis components and preparation method thereof - Google Patents
Controlled-release injection containing antidiuresis components and preparation method thereof Download PDFInfo
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- CN102580056B CN102580056B CN201110427805.0A CN201110427805A CN102580056B CN 102580056 B CN102580056 B CN 102580056B CN 201110427805 A CN201110427805 A CN 201110427805A CN 102580056 B CN102580056 B CN 102580056B
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- desmopressin acetate
- sustained
- release
- carboxymethyl cellulose
- sodium carboxymethyl
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- 239000007924 injection Substances 0.000 title claims abstract description 35
- 238000002347 injection Methods 0.000 title claims abstract description 35
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- 206010030302 Oliguria Diseases 0.000 title abstract 2
- 230000011224 negative regulation of urine volume Effects 0.000 title abstract 2
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Images
Abstract
The invention relates to a controlled-release injection containing antidiuresis components and a preparation method thereof. The controlled-release injection contains main drugs of desmopressin acetate, sustained release auxiliary materials, suspending agent and menstruum. The sustained release auxiliary materials are selected from polylactic acid, polylactic acid-co-glycolic acid, ethylene-vinyl acetate copolymer, polifeprosan and the like, which can be used for slowly releasing medicine into disease local parts in a degrading and absorbing process, so that general toxicity reaction is obviously reduced, and simultaneously, the effective medicine concentration can be maintained on the disease local parts; the suspending agent is selected from sodium carboxymethylcellulose, mannitol and the like, which is used for suspending sustained-release granules or microspheres of biological active ingredients; and the menstruum is common menstruum or special menstruum containing the suspending agent, wherein the common menstruum is selected from distilled water, water for injection, physiological lotion, absolute ethyl alcohol or buffer solution prepared by various salts, and the like. According to the controlled-release injection, the action time of the medicine can be prolonged, the dosage times are reduced, the stability of blood drug concentration in vivo is maintained, and the drug toxic and side effects are reduced.
Description
Technical field:
The present invention relates to formulation art, specifically a kind of slow releasing injection containing diuresis composition and preparation method thereof.
Background technology:
Desmopressin (Desmopressin) is a kind of synthetic analogues of natural hormone arginine vasopressin, has the inhibition activity of urinating of height, is used for the treatment of diseases of urinary system.Natural human arginine vasopressin is 9 peptides, and 1 is connected with cystine linkage and forms loop configuration with 6 cysteine, and 1 and 9 has an amino, and 8 is L-arginine.Desmopressin has the transformation of two places to the structure of natural molecule, the one, remove the amino of 1, the 2nd, with D-Arg, replace the L-arginine of 8, i.e. DDAVP (1-deamino-8-D-arginine vasoprssin, DDAVP).This structure of modification has strengthened the ability of molecule to resistance to enzymic degradation greatly, and antidiuretic activity strengthens, and extend action time, and blood vessel pressurization significantly reduces.Doubly, drug effect can maintain 10-12 hour to the diuresis of the Desmopressin/large 2000-3000 of active odds ratio parent molecule that pressurizes, and parent molecule only has 2-3 hour.In addition, the vassopressin of larger dose can also improve the level of blood coagulation factor VIII, has anastalsis.
The clinical practice of more than 20 year proves, no matter is that its nasal cavity drop, spray or oral tablet have all been obtained good curative effect, and side effect seldom occurs, and unanimously generally acknowledges that Desmopressin is the choice drug for the treatment of central diabetes insipidus.Though existing desmopressin preparation can reach patient's demand, but still need to improve.Tablet conventionally need to be with water delivery service, and the treatment of Desmopressin must limit fluid picked-up, and when absorbing with tablet form, the bioavailability of Desmopressin is approximately equivalent to intravenous 0.1%.Intranasal administration can obtain higher bioavailability, but patient's acceptance is lower.And intranasal administration may have harmful effect to cilium, cause virus and antibacterial more easily to enter mucosa.Injection administration number of times is frequent, inconvenient clinical use and patient's medication.
The present invention is directed to the deficiency of existing preparation, a kind of slow releasing injection that desmopressin acetate is active component of take is provided.This slow releasing injection can prolong drug action time, reduce medication number of times and Drug tolerance, maintain more stably blood drug level in body, reduce poisonous side effect of medicine, improve patient's compliance.
Summary of the invention:
The object of the invention is to prepare a kind of slow releasing injection that desmopressin acetate is active component of take, have can prolong drug action time, reduce medication number of times and Drug tolerance, maintain more stably blood drug level in body, reduce poisonous side effect of medicine, improve patient's the advantages such as compliance.
The present invention has prepared a kind of slow releasing injection containing desmopressin acetate medicine, and it comprises principal agent desmopressin acetate, slow-release auxiliary material, suspending agent and solvent; This slow releasing injection comprises following component:
(A) sustained-release microparticle, consists of the following composition, and is all weight percentage: principal agent desmopressin acetate 0.5-60%, slow-release auxiliary material 40-99.5%, suspending agent 0.0-30%;
(B) solvent, is divided into common solvent or special solvent.
The present invention has prepared a kind of slow releasing injection containing desmopressin acetate medicine, its slow-release auxiliary material is selected from polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA), ethylene vinyl acetate copolymer, polifeprosan, poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol/polylactic acid, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid, polyethylene glycol/polylactic acid copolymer, end carboxyl polylactic acid, PPDO, PTMC, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, albumin glue one or a combination set of, its suspending agent is selected from sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40 and Tween 80 one or a combination set of, its solvent is divided into common solvent or special solvent, and common solvent is selected from the buffer that distilled water, water for injection, physiology rush liquid, dehydrated alcohol or the preparation of various salt, when the suspending agent in sustained-release microparticle is " 0 ", solvent is special solvent, special solvent is the common solvent containing suspending agent, and suspending agent is selected from sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40 and Tween 80 one or a combination set of.
Through a large amount of optimization experiment, the present invention has found that most preferably formula forms.Wherein, the preferred 10%-50% of the percentage by weight of its principal agent desmopressin acetate; The preferred 50%-90%PLA of its slow-release auxiliary material, 50%-90%PLGA (3: 1); Its suspending agent is 1.5% sodium carboxymethyl cellulose, 1.5% sodium carboxymethyl cellulose and 0.1% Tween 80,1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80 preferably.
In addition, the present invention also provides the method for preparation containing desmopressin acetate slow releasing injection, and its step is as follows:
(A) sustained-release microparticle that is " 0 " by suspending agent is directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Or
(B) by suspending agent for the sustained-release microparticle of " 0 " is mixed in special solvent or common solvent, obtain corresponding sustained-release microparticle injection; Or
(C) sustained-release microparticle is mixed in common solvent, then adds suspending agent to mix, obtain corresponding sustained-release microparticle injection; Or
(D) first sustained-release microparticle is mixed in special solvent and makes corresponding suspension, then by ways such as vacuum dryings, remove the moisture in suspension, use again afterwards special solvent or common solvent suspendible, obtain corresponding sustained-release microparticle injection.
Accompanying drawing explanation:
Accompanying drawing 1, accompanying drawing 2, accompanying drawing 3, accompanying drawing 4 is respectively release degree-drug release time curve chart of desmopressin acetate in the slow releasing injection of each embodiment.
The specific embodiment:
The present invention is including but not limited to following examples.
Embodiment 1:
20mg principal agent desmopressin acetate, 80mg PLA, special solvent is the normal saline of 1.5% sodium carboxymethyl cellulose.
Its preparation technology is as follows:
80mg polylactic acid (PLA) is put into container, add 100ml dichloromethane, after dissolving mixes, add 20mg desmopressin acetate, again shake up the dry organic solvent of removing of final vacuum.Dried pastille solid composite freezing and pulverizing is made to the sustained-release microparticle containing 20% desmopressin acetate, then be suspended in 5000ml containing in the normal saline of 1.5% (percentage by weight) sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.
By the present embodiment, make 5000 bottles of desmopressin acetate slow releasing injection, every bottle containing principal agent 4 μ g (1ml/ bottle).By the mensuration of release, its slow release effect and clinical drug safety are investigated.
Precision takes the desmopressin acetate sustained-release microparticle of some parts of embodiment 1 preparation, and every part of 5mg is placed in the cillin bottle of 35 10mL, and every part adds the Na that contains 0.1M
2hPO
4naH with 0.1M
2pO
4the phosphate buffer solution of pH7.4, be placed in 37 ℃ of waters bath with thermostatic control, respectively the 0th, 4, 8, 12, 16, 20, 24, 28, within 32 days, take out, centrifugal, again be dispersed in acetate dichloromethane buffer (1: 1v/v), chromatographic column is C1850 * 2mm, mobile phase is 1: 1 containing 0.1% trifluoracetic acid and containing 1% trifluoroacetic 50% acetonitrile mixed solution, flow velocity 1.0ml/min, at 240nm place, detect, measure remaining dose in microgranule, according to external standard method, calculate accumulative releasing degree, the tablets in vitro measurement result of the desmopressin acetate sustained-release microparticle preparation of embodiment 1 preparation is as shown in table 1:
The tablets in vitro experimental result of the desmopressin acetate sustained release microsphere agents of table 1 embodiment 1 preparation
Take drug release time as abscissa, and accumulative releasing degree is vertical coordinate, draws the desmopressin acetate sustained-release microparticle preparation tablets in vitro curve of embodiment 1 preparation, the results are shown in Figure of description 1.
Embodiment 2:
20mg principal agent desmopressin acetate, 80mg PLA, special solvent is the normal saline of 1.5% sodium carboxymethyl cellulose and 0.1% Tween 80.Its preparation technology is as follows:
80mg polylactic acid (PLA) is put into container, add 100ml dichloromethane, after dissolving mixes, add 20mg desmopressin acetate, again shake up the dry organic solvent of removing of final vacuum.Dried pastille solid composite freezing and pulverizing is made to the sustained-release microparticle containing 20% desmopressin acetate, then be suspended in the normal saline of 5000ml containing 1.5% (percentage by weight) sodium carboxymethyl cellulose and 0.1% Tween 80, make corresponding suspension type slow releasing injection.
By the present embodiment, make 5000 bottles of desmopressin acetate slow releasing injection, every bottle containing principal agent 4 μ g (1ml/ bottle).By the mensuration of release, its slow release effect and clinical drug safety are investigated.
Precision takes the desmopressin acetate sustained-release microparticle of some parts of embodiment 2 preparation, and every part of 5mg is placed in the cillin bottle of 35 10mL, and every part adds the Na that contains 0.1M
2hPO
4naH with 0.1M
2pO
4the phosphate buffer solution of pH7.4, be placed in 37 ℃ of waters bath with thermostatic control, respectively the 0th, 4, 8, 12, 16, 20, 24, 28, within 32 days, take out, centrifugal, again be dispersed in acetate dichloromethane buffer (1: 1v/v), chromatographic column is C1850 * 2mm, mobile phase is 1: 1 containing 0.1% trifluoracetic acid and containing 1% trifluoroacetic 50% acetonitrile mixed solution, flow velocity 1.0ml/min, at 240nm place, detect, measure remaining dose in microgranule, according to external standard method, calculate accumulative releasing degree, the tablets in vitro measurement result of the desmopressin acetate sustained-release microparticle preparation of embodiment 2 preparations is as shown in table 2:
The tablets in vitro experimental result of the desmopressin acetate sustained release microsphere agents of table 2 embodiment 2 preparations
Take drug release time as abscissa, and accumulative releasing degree is vertical coordinate, draws the desmopressin acetate sustained-release microparticle preparation tablets in vitro curve of embodiment 2 preparations, the results are shown in Figure of description 2.
Embodiment 3:
20mg principal agent desmopressin acetate, 80mg PLA, special solvent is the normal saline of 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80.Its preparation technology is as follows:
80mg polylactic acid (PLA) is put into container, add 100ml dichloromethane, after dissolving mixes, add 20mg desmopressin acetate, again shake up the dry organic solvent of removing of final vacuum.Dried pastille solid composite freezing and pulverizing is made to the sustained-release microparticle containing 20% desmopressin acetate, then be suspended in the normal saline of 5000ml containing 1.5% (percentage by weight) sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80, make corresponding suspension type slow releasing injection.
By the present embodiment, make 5000 bottles of desmopressin acetate slow releasing injection, every bottle containing principal agent 4 μ g (1ml/ bottle).By the mensuration of release, its slow release effect and clinical drug safety are investigated.
Precision takes the desmopressin acetate sustained-release microparticle of some parts of embodiment 3 preparation, and every part of 5mg is placed in the cillin bottle of 35 10mL, and every part adds the Na that contains 0.1M
2hPO
4naH with 0.1M
2pO
4the phosphate buffer solution of pH7.4, be placed in 37 ℃ of waters bath with thermostatic control, respectively the 0th, 4, 8, 12, 16, 20, 24, 28, within 32 days, take out, centrifugal, again be dispersed in acetate dichloromethane buffer (1: 1v/v), chromatographic column is C1850 * 2mm, mobile phase is 1: 1 containing 0.1% trifluoracetic acid and containing 1% trifluoroacetic 50% acetonitrile mixed solution, flow velocity 1.0ml/min, at 240nm place, detect, measure remaining dose in microgranule, according to external standard method, calculate accumulative releasing degree, the tablets in vitro measurement result of the desmopressin acetate sustained-release microparticle preparation of embodiment 3 preparations is as shown in table 3:
The tablets in vitro experimental result of the desmopressin acetate sustained release microsphere agents of table 3 embodiment 3 preparations
Take drug release time as abscissa, and accumulative releasing degree is vertical coordinate, draws the desmopressin acetate sustained-release microparticle preparation tablets in vitro curve of embodiment 3 preparations, the results are shown in Figure of description 3.
Embodiment 4:
20mg principal agent desmopressin acetate, 80mg PLGA (3: 1), special solvent is the normal saline of 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80.Its preparation technology is as follows:
80mg Poly(D,L-lactide-co-glycolide (PLGA, 3: 1) is put into container, add 100ml dichloromethane, after dissolving mixes, add 20mg desmopressin acetate, again shake up the dry organic solvent of removing of final vacuum.Dried pastille solid composite freezing and pulverizing is made to the sustained-release microparticle containing 20% desmopressin acetate, then be suspended in the normal saline of 5000ml containing 1.5% (percentage by weight) sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80, make corresponding suspension type slow releasing injection.
By the present embodiment, make 5000 bottles of desmopressin acetate slow releasing injection, every bottle containing principal agent 4 μ g (1ml/ bottle).By the mensuration of release, its slow release effect and clinical drug safety are investigated.
Precision takes the desmopressin acetate sustained-release microparticle of some parts of embodiment 4 preparation, and every part of 5mg is placed in the cillin bottle of 35 10mL, and every part adds the Na that contains 0.1M
2hPO
4naH with 0.1M
2pO
4the phosphate buffer solution of pH7.4, be placed in 37 ℃ of waters bath with thermostatic control, respectively the 0th, 4, 8, 12, 16, 20, 24, 28, within 32 days, take out, centrifugal, again be dispersed in acetate dichloromethane buffer (1: 1v/v), chromatographic column is C1850 * 2mm, mobile phase is 1: 1 containing 0.1% trifluoracetic acid and containing 1% trifluoroacetic 50% acetonitrile mixed solution, flow velocity 1.0ml/min, at 240nm place, detect, measure remaining dose in microgranule, according to external standard method, calculate accumulative releasing degree, the tablets in vitro measurement result of the desmopressin acetate sustained-release microparticle preparation of embodiment 3 preparations is as shown in table 3:
The tablets in vitro experimental result of the desmopressin acetate sustained release microsphere agents of table 4 embodiment 4 preparations
Take drug release time as abscissa, and accumulative releasing degree is vertical coordinate, draws the desmopressin acetate sustained-release microparticle preparation tablets in vitro curve of embodiment 4 preparations, the results are shown in Figure of description 4.
Claims (4)
1. containing a slow releasing injection for diuresis composition, it is characterized in that: contain 20mg desmopressin acetate, 80mg polylactic acid (PLA), special solvent is the normal saline of 1.5% sodium carboxymethyl cellulose; Its preparation technology is as follows: 80mg polylactic acid (PLA) is put into container, add 100ml dichloromethane, after dissolving mixes, add 20mg desmopressin acetate, again shake up the dry organic solvent of removing of final vacuum; Dried pastille solid composite freezing and pulverizing is made to the sustained-release microparticle containing 20% desmopressin acetate, then be suspended in 5000ml containing in the normal saline of 1.5% (percentage by weight) sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.
2. containing a slow releasing injection for diuresis composition, it is characterized in that: contain 20mg desmopressin acetate, 80mg polylactic acid (PLA), special solvent is the normal saline of 1.5% sodium carboxymethyl cellulose and 0.1% Tween 80; Its preparation technology is as follows: 80mg polylactic acid (PLA) is put into container, add 100ml dichloromethane, after dissolving mixes, add 20mg desmopressin acetate, again shake up the dry organic solvent of removing of final vacuum; Dried pastille solid composite freezing and pulverizing is made to the sustained-release microparticle containing 20% desmopressin acetate, then be suspended in the normal saline of 5000ml containing 1.5% (percentage by weight) sodium carboxymethyl cellulose and 0.1% Tween 80, make corresponding suspension type slow releasing injection.
3. containing a slow releasing injection for diuresis composition, it is characterized in that: contain 20mg desmopressin acetate, 80mg polylactic acid (PLA), special solvent is the normal saline of 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80; Its preparation technology is as follows: 80mg polylactic acid (PLA) is put into container, add 100ml dichloromethane, after dissolving mixes, add 20mg desmopressin acetate, again shake up the dry organic solvent of removing of final vacuum; Dried pastille solid composite freezing and pulverizing is made to the sustained-release microparticle containing 20% desmopressin acetate, then be suspended in the normal saline of 5000ml containing 1.5% (percentage by weight) sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80, make corresponding suspension type slow releasing injection.
4. the slow releasing injection containing diuresis composition, it is characterized in that: contain 20mg desmopressin acetate, 80mg Poly(D,L-lactide-co-glycolide, lactic acid and hydroxyacetic acid polymerization ratio are 3:1, and special solvent is the normal saline of 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80; Its preparation technology is as follows: 80mg Poly(D,L-lactide-co-glycolide is put into container, lactic acid and hydroxyacetic acid polymerization ratio are 3:1, add 100ml dichloromethane, after dissolving mixes, add 20mg desmopressin acetate, again shake up the dry organic solvent of removing of final vacuum; Dried pastille solid composite freezing and pulverizing is made to the sustained-release microparticle containing 20% desmopressin acetate, then be suspended in the normal saline of 5000ml containing 1.5% (percentage by weight) sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80, make corresponding suspension type slow releasing injection.
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| CN106667897A (en) * | 2017-02-16 | 2017-05-17 | 辽宁省计划生育科学研究院 | Biodegradable slow/controlled-release drug delivery system and preparation method thereof |
| CN108939136B (en) * | 2018-08-20 | 2020-12-22 | 重庆医科大学附属永川医院 | Dressing for nasal filling hemostasis and preparation method thereof |
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| AU4198793A (en) * | 1992-07-24 | 1994-01-27 | Takeda Chemical Industries Ltd. | Microparticle preparation and production thereof |
| WO1999048519A1 (en) * | 1998-03-20 | 1999-09-30 | Takeda Chemical Industries, Ltd. | Sustained-release preparation of physiologically active polypeptide and production thereof |
| EP1532985B1 (en) * | 2002-06-25 | 2016-10-12 | Takeda Pharmaceutical Company Limited | Process for producing a sustained-release composition |
| WO2007021970A2 (en) * | 2005-08-15 | 2007-02-22 | Praecis Pharmaceuticals, Inc. | Stable pharmaceutical formulations and methods of use thereof |
| CN101372505B (en) * | 2007-08-22 | 2011-03-30 | 深圳翰宇药业股份有限公司 | Method for preparing desmopressin acetate |
| US20110268807A1 (en) * | 2008-08-04 | 2011-11-03 | James Su | Biodegradable Microspheres and Methods of Use Thereof |
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