Summary of the invention
For overcoming the shortcoming of suspension type triamcinolone acetonide acetate injection in prior art, the invention provides a kind of preparation method of injection of solution-type triamcinolone acetonide acetate, stir to clarify by under environment that triamcinolone acetonide acetate and sulfobutyl ether-beta-cyclodextrin are existed at organic solvent, then evaporate organic solvent, and then add hyaluronic acid sodium aqueous solution and dilution water etc. and be prepared from.The preparation method of the injection of solution-type triamcinolone acetonide acetate provided by the invention, its production technology is simple, and during the injection Clinical practice of preparation, local irritation is less; Particularly when intraarticular injection, medicine easily absorbs, and the granule avoiding suspension type triamcinolone acetonide acetate injection to cause, in the deposition of periostal surface, thus can reduce the damage caused periosteum.
Provided by the invention containing triamcinolone acetonide acetate solution type injection, its production technology is simple, and during Clinical practice, local irritation is less; Particularly when intraarticular injection, medicine easily absorbs, and avoids granule to deposit at periostal surface, thus periosteum injury.
The object of the invention is to, provide a kind of preparation method of injection of solution-type triamcinolone acetonide acetate, described preparation method comprises:
1) join in organic solvent by sulfobutyl ether-beta-cyclodextrin, triamcinolone acetonide acetate, stirring and dissolving, to clarification, evaporates organic solvent;
2) in step 1) in the mixture of gained, add the aqueous solution of hyaluronic acid sodium, be dissolved to clarification, then add dilution water, stir, after sterilizing, be prepared into the injection containing sulfobutyl ether-beta-cyclodextrin inclusion compound.
In one embodiment of the invention, described triamcinolone acetonide acetate and the mol ratio of sulfobutyl ether-beta-cyclodextrin are 1:1 ~ 20, are preferably 1:2 ~ 10; The weight ratio of triamcinolone acetonide acetate and water is 1:10 ~ 40, and be preferably 1:20 ~ 40, the mol ratio of triamcinolone acetonide acetate and hyaluronic acid sodium is 1:1 ~ 10, is preferably 1:1 ~ 5.
In one embodiment of the invention, described organic solvent can be one or more in alcohol, ketone, ether, organic amine or their analog; Be preferably ethanol, acetonitrile, acetone, oxolane, one or more in dimethyl formamide, most preferably be ethanol, acetone and acetonitrile one or more; Described dilution water is water for injection, and the weight ratio of triamcinolone acetonide acetate and water is 1:10 ~ 40.
In one embodiment of the invention, also one or more in pH adjusting agent, osmotic pressure regulator, surfactant, antibacterial are comprised containing pharmaceutically acceptable adjuvant in the injection that prepared by described method.
In one embodiment of the invention, described pH adjusting agent comprises one or more in sodium hydroxide, hydrochloric acid, phosphoric acid, triethylamine, and wherein pH is 4 ~ 7.
In one embodiment of the invention, described osmotic pressure regulator comprises one or more in glycerol, propylene glycol, sodium chloride, potassium chloride, Sorbitol, mannitol.
In one embodiment of the invention, described surfactant comprises tween 80, HCO60, Polyethylene Glycol-stearate, Macrogol 4000, lecithin, one or more in polyoxypropylene and derivant thereof.
In one embodiment of the invention, described antibacterial comprises one or more in thimerosal, Benzalkonii Chloridum, potassium sorbate, p-Hydroxybenzoate, nipagin A, propyl p-hydroxybenzoate.
Detailed description of the invention
" scope " disclosed herein is with the form of lower limit and the upper limit.One or more lower limit can be respectively, and one or more upper limit.Given range is limited by a selected lower limit and a upper limit.Selected lower limit and the upper limit define the border of special scope.All scopes that can carry out by this way limiting comprise and may be combined with, and namely any lower limit can be combined to form a scope with any upper limit.Such as, list the scope of 60-120 and 80-110 for special parameter, be interpreted as that the scope of 60-110 and 80-120 also expects.In addition, if the minimum zone value listed 1 and 2, and if list maximum magnitude value 3,4 and 5, then the scope below can all expect: 1-3,1-4,1-5,2-3,2-4 and 2-5.
In the present invention, unless otherwise indicated, new technical scheme can be mutually combined to form between the content range of each component of compositions and its preferable range.
In the present invention, unless otherwise indicated, " its combination " represents the multicomponent mixture of described each element, such as two kinds, three kinds, four kinds and until the multicomponent mixture of maximum possible.
In the present invention, unless otherwise indicated, all " part " and percent (%) all refer to percetage by weight.
In the present invention, unless otherwise indicated, in all compositionss, the percent sum of each component is 100%.
In the present invention, unless otherwise indicated, the breviary of any real combinings that numerical range " a-b " represents between a to b represents, wherein a and b is real number.Such as numerical range " 0-5 " represents the whole real numbers all listed between " 0-5 " herein, and the breviary of " 0-5 " just these combinations of values represents.
In the present invention, unless otherwise indicated, the breviary of the arbitrary integer combination that integer numerical range " a-b " represents between a to b represents, wherein a and b is integer.Such as integer numerical range " 1-N " represents 1,2 ... N, wherein N is integer.
If do not particularly not pointed out, this description term " one " used refers to " at least one ".
If do not particularly not pointed out, the benchmark of percent of the present invention (comprising percetage by weight) is all the gross weight of described compositions.
In this article, except as otherwise noted, the ratio of each component or weight all refer to dry weight.
In the present invention, if do not illustrated especially, all embodiments mentioned in this article and preferred implementation can be combined to form new technical scheme mutually.
In the present invention, if do not illustrated especially, all technical characteristics mentioned in this article and preferred feature can be combined to form new technical scheme mutually.
In the present invention, if do not illustrated especially, mentioned in this article sequentially can to carry out in steps, also can carry out at random, but preferably order is carried out.Such as, described method comprises step (a) and (b), represents that described method can comprise the step (a) and (b) of sequentially carrying out, also can comprise the step (b) and (a) of sequentially carrying out.Such as, describedly mention described method and also can comprise step (c), represent that step (c) random order can join described method, such as, described method can comprise step (a) and (b) and (c), also step (a), (c) and (b) be can comprise, step (c), (a) and (b) etc. also can be comprised.
In the present invention, if do not illustrated especially, " comprising " mentioned in this article represents open, also can be closed.Such as, described " comprising " can represent other elements that can also comprise and not list, and also can only comprise the element listed.
In the present invention, if do not illustrated especially, the concrete numerical value herein in embodiment and concrete material can with other integrate features describing part herein.Such as, the temperature that description part herein mentions reaction is 10-100 DEG C, and the reaction temperature that embodiment is mentioned is 20 DEG C, so can think the scope having specifically disclosed 10-20 DEG C herein, or the scope of 20-100 DEG C, and other integrate features that this scope can describe part get up to be formed new technical scheme.Again such as, description part herein mentions a compounds alcohol, and the concrete alcohol that embodiment is mentioned is ethanol, and so ethanol can get up formed new technical scheme with other integrate features of description part.
The invention provides a kind of preparation method of injection of solution-type triamcinolone acetonide acetate, described preparation method comprises:
1) join in organic solvent by sulfobutyl ether-beta-cyclodextrin, triamcinolone acetonide acetate, stirring and dissolving, to clarification, evaporates organic solvent;
2) in step 1) in the mixture of gained, add the aqueous solution of hyaluronic acid sodium, be dissolved to clarification, then add dilution water, stir, after sterilizing, be prepared into the injection containing sulfobutyl ether-beta-cyclodextrin inclusion compound.
Method as above, wherein said triamcinolone acetonide acetate and the mol ratio of sulfobutyl ether-beta-cyclodextrin are 1:1 ~ 20, are preferably 1:2 ~ 10; The weight ratio of triamcinolone acetonide acetate and water is 1:10 ~ 40, and be preferably 1:20 ~ 40, the mol ratio of triamcinolone acetonide acetate and hyaluronic acid sodium is 1:1 ~ 10, is preferably 1:1 ~ 5.
Method as above, wherein said organic solvent can be one or more in alcohol, ketone, ether, organic amine or their analog; Be preferably ethanol, acetonitrile, acetone, oxolane, one or more in dimethyl formamide, most preferably be ethanol, acetone and acetonitrile one or more; Described dilution water is water for injection, and the weight ratio of triamcinolone acetonide acetate and water is 1:10 ~ 40.
Method as above, injection prepared by wherein said method contains one or more that pharmaceutically acceptable adjuvant comprises in pH adjusting agent, osmotic pressure regulator, surfactant, antibacterial.
Method as above, wherein said pH adjusting agent comprises one or more in sodium hydroxide, hydrochloric acid, phosphoric acid, triethylamine, and wherein pH is 4 ~ 7.
Method as above, wherein said osmotic pressure regulator comprises one or more in glycerol, propylene glycol, sodium chloride, potassium chloride, Sorbitol, mannitol.
Method as above, wherein said surfactant comprises tween 80, HCO60, Polyethylene Glycol-stearate, Macrogol 4000, lecithin, one or more in polyoxypropylene and derivant thereof.
Method as above, wherein said antibacterial comprises one or more in thimerosal, Benzalkonii Chloridum, potassium sorbate, p-Hydroxybenzoate, nipagin A, propyl p-hydroxybenzoate.
The invention provides a kind of preparation method of injection of solution-type triamcinolone acetonide acetate: join in moisture or water-free organic solvent by sulfobutyl ether-beta-cyclodextrin, triamcinolone acetonide acetate, stirring and dissolving is to clarification, evaporate organic solvent, add the aqueous solution of hyaluronic acid sodium, be dissolved to clarification, add dilution water again, stir, fill.Be prepared into the injection containing sulfobutyl ether-beta-cyclodextrin inclusion compound.
In above-mentioned technique, described triamcinolone acetonide acetate and the mol ratio of sulfobutyl ether-beta-cyclodextrin are 1:1 ~ 20, are preferably 1:2 ~ 10; The weight ratio of triamcinolone acetonide acetate and water is 1:10 ~ 40, and be preferably 1:20 ~ 40, the mol ratio of triamcinolone acetonide acetate and hyaluronic acid sodium is 1:1 ~ 10, is preferably 1:1 ~ 5.
Organic solvent of the present invention can be one or more in alcohol, ketone, ether, organic amine or their analog; Be preferably ethanol, acetonitrile, acetone, oxolane, one or more in dimethyl formamide, most preferably be ethanol, acetone and acetonitrile.So that can sulfobutyl ether-beta-cyclodextrin be dissolved in process for preparation and triamcinolone acetonide is as the criterion.
Dilution water of the present invention is water for injection, and adding dilution water is concentration in order to regulating drug, makes the weight ratio of triamcinolone acetonide or its 21-acetate and water be 1:10 ~ 40.After regulating drug level, drug solution is filled in cillin bottle.
The pharmaceutically acceptable adjuvant contained in injection provided by the present invention can include but not limited to one or more that pH adjusting agent, osmotic pressure regulator, surfactant, antibacterial etc. are applicable in the pharmaceutic adjuvant of drug administration by injection.
PH adjusting agent of the present invention is without any restriction, and can include but not limited to one or more in sodium hydroxide, hydrochloric acid, phosphoric acid, triethylamine, wherein pH is preferably 4 ~ 7.
Containing the injection of triamcinolone acetonide acetate with one or more pharmaceutically acceptable adjuvants, containing hyaluronic acid sodium and Sulfobutyl ether β _ cyclodextrin
Osmotic pressure regulator of the present invention, without any restriction, can include but not limited to one or more in glycerol, propylene glycol, sodium chloride, potassium chloride, Sorbitol, mannitol.
Surfactant of the present invention, without any restriction, can include but not limited to tween 80, HCO60, Polyethylene Glycol-stearate, Macrogol 4000, lecithin, one or more in polyoxypropylene and derivant thereof.
Antibacterial of the present invention, without any restriction, can include but not limited to one or more in thimerosal, Benzalkonii Chloridum, potassium sorbate, p-Hydroxybenzoate, nipagin A, propyl p-hydroxybenzoate.
Triamcinolone acetonide injection of the present invention is suitable for muscle, subcutaneous or intraarticular injection, should meet the requirement that injection product is aseptic, is meeting the explained hereafter of sterile workshop according to sterile working of existing GMP.
embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.Those skilled in the art can make suitable amendment, variation to the present invention, and these amendments and variation are all within the scope of the present invention.
The experimental technique of unreceipted actual conditions in the following example, can adopt the conventional method in this area.
Unless otherwise indicated, otherwise percentage ratio and number calculate by weight.Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
The preparation of comparative example suspension type triamcinolone acetonide acetate injection
50g sodium carboxymethyl cellulose and 0.1g thimerosal swelling are filtered, adds 30g Tween-80, stir 30min, heating in water bath to 90 DEG C, adds 100g triamcinolone acetonide acetate, continues heated and stirred 30min, cooling, add 10L water, namely sterilizing prepares suspension type triamcinolone acetonide acetate injection.
The preparation of embodiment 1 solution-type triamcinolone acetonide acetate injection
Join in the ethanol of 75% ~ 100% of 1L by the sulfobutyl ether-beta-cyclodextrin of 1mol, the triamcinolone acetonide acetate of 1mol, stirring and dissolving is to clarification, and rotary evaporation in vacuo goes out organic solvent; Add the aqueous solution of the 4mol/L hyaluronic acid sodium of 2.5L again, be dissolved to clarification, then add 2250ml sterilized water for injection, stir, after filtration sterilization, be prepared into the injection containing sulfobutyl ether-beta-cyclodextrin inclusion compound.
The preparation of embodiment 2 solution-type triamcinolone acetonide acetate injection
Join in the acetonitrile of 75% ~ 100% of 20L by the sulfobutyl ether-beta-cyclodextrin of 20mol, the triamcinolone acetonide acetate of 1mol, stirring and dissolving is to clarification, and rotary evaporation in vacuo goes out organic solvent; Add the aqueous solution of the 0.1mol/L hyaluronic acid sodium of 10L again, be dissolved to clarification, add 9040ml sterilized water for injection afterwards, stir, regulate PH to 6.The injection containing sulfobutyl ether-beta-cyclodextrin inclusion compound is prepared into after filtration sterilization.
The preparation of embodiment 3 solution-type triamcinolone acetonide acetate injection
Join in the acetone of 8L75% ~ 100% by the sulfobutyl ether-beta-cyclodextrin of 10mol, the triamcinolone acetonide acetate of 1mol, stirring and dissolving is to clarification, and rotary evaporation in vacuo goes out organic solvent; Add the aqueous solution of the 2mol/L hyaluronic acid sodium of 2.5L again, be dissolved to clarification, add 11900ml sterilized water for injection afterwards, stir, regulate PH to 6.The injection containing sulfobutyl ether-beta-cyclodextrin inclusion compound is prepared into after filtration sterilization.
The preparation of embodiment 4 solution-type triamcinolone acetonide acetate injection
Join in the oxolane of 4L75% ~ 100% by the sulfobutyl ether-beta-cyclodextrin of 5mol, the triamcinolone acetonide acetate of 1mol, stirring and dissolving is to clarification, and rotary evaporation in vacuo goes out organic solvent; Add the aqueous solution of the 2mol/L hyaluronic acid sodium of 3L again, be dissolved to clarification, add 7800ml sterilized water for injection afterwards, stir, regulate PH to 6.The injection containing sulfobutyl ether-beta-cyclodextrin inclusion compound is prepared into after filtration sterilization.
The preparation of embodiment 5 solution-type triamcinolone acetonide acetate injection
Join in the dimethyl formamide of 3L75% ~ 100% by the sulfobutyl ether-beta-cyclodextrin of 2mol, the triamcinolone acetonide acetate of 1mol, stirring and dissolving is to clarification, and rotary evaporation in vacuo goes out organic solvent; Add the aqueous solution of the 4mol/L hyaluronic acid sodium of 1L again, be dissolved to clarification, stir, regulate PH to 5.The injection containing sulfobutyl ether-beta-cyclodextrin inclusion compound is prepared into after filtration sterilization.
The preparation of embodiment 6 solution-type triamcinolone acetonide acetate injection
Join in the ethanol of 10L75% ~ 100% by the sulfobutyl ether-beta-cyclodextrin of 10mol, the triamcinolone acetonide acetate of 1mol, stirring and dissolving is to clarification, and rotary evaporation in vacuo goes out organic solvent; Add the aqueous solution of the 0.5mol/L hyaluronic acid sodium of 10L again, be dissolved to clarification, add 9040ml sterilized water for injection afterwards, stir, regulate PH to 6.The injection containing sulfobutyl ether-beta-cyclodextrin inclusion compound is prepared into after filtration sterilization.
Embodiment 7 clarity is tested
Injection and the comparative example injection of Example 1 ~ 6 carry out clarity experiment respectively, and pH detects and patient's pain sensation organoleptic test, and result is as table 1 ~ 3.
Clarity experiment is carried out in accordance with the following methods: the injection of Example 1 ~ 6 and comparative example injection, estimate its clarity, then once observe every 12h, result is as table 1.Experimental result shows, injection of the present invention places 0 ~ 72h, still clarifies, without visible particle; The comparative example injection adopting traditional method to prepare, has visible particle.Place 24h, occur layering; And engender sedimentation.
Table 1. injection clarity
Embodiment 8PH stability experiment
PH test experience is carried out in accordance with the following methods: injection and the comparative example injection of getting Example 2 ~ 6, every 12h or 24h, carry out pH mensuration, result is as shown in table 2.Experimental result shows, injection pH value of the present invention is stablized.
Table 2. injection pH
Embodiment 9 pain sensation organoleptic test
Patient's pain sensation organoleptic test is carried out in accordance with the following methods: injection and the comparative example injection of getting Example 1 ~ 6, carry out clinical practice, result is as shown in table 3.Experimental result shows, injection of the present invention, and the pain sensation sense of patient is not obvious.
Table 3. patient pain sensation organoleptic test
In above embodiment, can refer to traditional method in the injection of embodiment 1 ~ 6, add osmotic pressure regulator (glycerol, propylene glycol, sodium chloride, potassium chloride, Sorbitol, and/or mannitol), surfactant (tween 80, HCO60, Polyethylene Glycol-stearate, Macrogol 4000, lecithin, and/or polyoxypropylene and derivant thereof) and/or antibacterial (thimerosal, Benzalkonii Chloridum, potassium sorbate, p-Hydroxybenzoate, nipagin A, and/or propyl p-hydroxybenzoate) etc. component, in these unlisted specific experiment data.
Sulfobutyl ether-beta-cyclodextrin used in the present invention be succeeded in developing by Cydex company of the U.S. nineties in 20th century anion, highly-water-soluble beta-cyclodextrin derivative.Sulfobutyl ether-beta-cyclodextrin is the product of beta-schardinger dextrin-and Isosorbide-5-Nitrae-butane group lactone generation substitution reaction, and substitution reaction occurs in 2 of beta-schardinger dextrin-glucose unit, on 3,6 carbon hydroxyls.Sulfobutyl ether-beta-cyclodextrin, has the unrivaled advantage of other cyclodextrin derivative: it without association, is discharged with crude urine in vivo fast; Mainly be distributed in extracellular fluid, lower with the combination rate of plasma protein; Hemolytic test finds, when same concentrations, the haemolysis of sulfobutyl ether-beta-cyclodextrin is much smaller than other cyclodextrin derivative.
The foregoing is only preferred embodiment of the present invention, and be not used to limit substantial technological context of the present invention, substantial technological content of the present invention is broadly defined in the right of application, any technology entities that other people complete or method, if with application right define identical, also or a kind of change of equivalence, be all covered by being regarded as among this right.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read foregoing of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.