CN1589783A - N-[O-(P-trimethyl acetoxyl benzene sulfonamide) benzoyl] glycine mono sodium salt tetrahydrate - Google Patents
N-[O-(P-trimethyl acetoxyl benzene sulfonamide) benzoyl] glycine mono sodium salt tetrahydrate Download PDFInfo
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- CN1589783A CN1589783A CN 03144236 CN03144236A CN1589783A CN 1589783 A CN1589783 A CN 1589783A CN 03144236 CN03144236 CN 03144236 CN 03144236 A CN03144236 A CN 03144236A CN 1589783 A CN1589783 A CN 1589783A
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Abstract
A powder injection contains the tetrahydrated monosodium N-[O-(P-trimethylacetoxyphenylsulfonylamino) benzoyl] aminoacitate and optional medical filler or not. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to be used for the treatment of a kind of elastin laminin enzyme inhibitor injectable powder of acute lung injury, a kind of N-[of containing neighbour that says so more specifically-(right-trimethyl acetoxyl benzenesulfonamide) benzoyl] powder ampoule agent for injection (I) of glycine monosodium salt tetrahydrate and preparation method thereof.
Technical background
N-[neighbour shown in the formula (I)-(right-trimethyl acetoxyl benzenesulfonamide) benzoyl] glycine monosodium salt tetrahydrate (sivelestat sodium) is a kind of NE inhibitor; acute pulmonary lesion when being used for treating systemic inflammatory response syndrome is applied clinically.Suffer from acute pulmonary lesion and generally be in a bad way, mortality rate is up to 40-50%, the intravenous drip of chemical compound shown in the preferred formula (I) clinically.
But compound water-soluble degree of separating is low shown in the formula (I), and at room temperature dissolubility is less than 0.4mg/ml in its water, and therefore preparing its injection is the comparison difficulty, and it is more difficult particularly to prepare the solution that is suitable for used for intravenous injection.In addition, in the chemical constitution of this product, have ester bond, infer in aqueous solution particularly unstablely in alkaline aqueous solution or in the acidic aqueous solution, facile hydrolysis in long term store particularly in preparation injection process forms hydrolyzate.For addressing the above problem, many people study, but are suitable for intravenous stable this product injection for intravenous medicine with preparation.
JP kokai hei 5-194366 (being EP0539223) description discloses the injection lyophilized preparation of this product, with formula (I) chemical compound and sodium chloride, natrium carbonicum calcinatum mixes, use dissolved in distilled water, pack in the 5ml glass tube vial, adopt the normal freeze-drying legal system to be equipped with the injection lyophilized preparation, though the present invention has solved formula (I) compound dissolution and has spent low problem, but in dosing and freezing dry process, a period of time formula (I) chemical compound is present in the alkaline aqueous solution, still be difficult to avoid its hydrolysis, hydrolyzate increases to some extent, and long term store will speed up the decomposition of (I) chemical compound.
The CN1341591A description then discloses the preparation method of another kind of injection lyophilized preparation, formula (I) chemical compound and suitable filler are mixed, be suspended in the water for injection, add a kind of at least a alkali that is selected from tertiary sodium phosphate, sodium hydroxide or potassium hydroxide, regulate pH value and reach 7.0-8.5, form solution, be redistributed in glass tube vial or the ampoule, adopt the normal freeze-drying method to prepare the injection lyophilized preparation.Though this inventive method can prepare the lyophilized preparation that is suitable for injecting, but for good surface appearance is arranged, the filler (mannitol) that in the preparation lyophilized preparation, adds more amount, and this filler for acute lung injury without any therapeutical effect, and because dosing volume big (0.1g needs with the about 5ml of water for injection) before the lyophilizing, freeze cycle is longer, and energy resource consumption is big, causes the preparation cost higher.In order to overcome the shortcoming of above-mentioned preparation method, we have carried out further investigation and have obtained success the intravenous injection of the described chemical compound of formula (I).
Summary of the invention
The objective of the invention is to overcome the shortcoming that above-mentioned injection lyophilized powder exists, a kind of easy brand-new formula (I) medicine powder ampoule agent for injection and its preparation method are provided.
The present invention is achieved by the following scheme.
A kind of N-[neighbour-(right-trimethyl acetoxyl benzenesulfonamide) benzoyl that contains] powder ampoule agent for injection (I) of glycine monosodium salt tetrahydrate, it is characterized in that this injectable powder comprises arbitrary form in following two kinds of forms.
(1) by treatment effective dose formula (I) medicine, at least a medicinal alkaline matter, contain or do not contain medicinal filler and form a kind of aseptic mixture according to a certain ratio, its (I) medicine: alkaline matter: the percentage by weight of filler is 1: 0.01-0.4: an amount of;
(2) by treatment effective dose formula (I) medicine, contain or do not contain medicinal filler and form a kind of sterile solid powder, additional simultaneously an aqueous solution ampoule by a kind of pH7.0-10.5 of Gong injection of alkaline matter preparation.
The alkaline matter that the present invention prepares powder ampoule agent for injection comprises sodium carbonate (or potassium), sodium bicarbonate (or potassium), tertiary sodium phosphate (or potassium), sodium hydroxide (or potassium), their anhydride or contain the water of crystallization thing.Preferred alkali is sodium carbonate or sodium bicarbonate (anhydrous or close water of crystallization), and its consumption is generally the 1.0%-40% (weight) of formula (I) chemical compound.Be preferably 1.0%-30% (weight); Preferred consumption is for after whenever containing 0.1g formula (I) compound injection and dissolving with 5.0ml water for injection with injectable powder, and the pH value of solution is 6.8-10.5; Each formula (I) compound injection that contains 0.1g of preferred consumption with injectable powder with the dissolving of 5.0ml water for injection after, the pH value of solution is 7.2-9.0; Its pH value should be optimum between 7.5 and 8.5 after injectable powder is with the dissolving of 5.0ml pure water.According to the present invention, this injection powder pin neutral and alkali material can adopt dual mode to add.But what need emphasize is because sodium hydroxide and potassium hydroxide have easy water absorption, when formula (I) chemical compound and alkaline matter are mixed and made into the medicated powder injection, should not comprise sodium hydroxide and potassium hydroxide, best natrium carbonicum calcinatum or the sodium bicarbonate of adopting.
In addition, the formula according to the present invention (I) compound injection injectable powder can add one or more additament (filler) that pharmacy is suitable for, and can also not add.But for the convenience of packing and a kind of filler of accurately preferred adding, filler is selected from a kind of of medicinal sodium chloride, glucose, maltose, mannitol, sorbitol or xylitol.Preferred sodium chloride, glucose, mannitol, xylitol a kind of; More preferably sodium chloride or glucose, its consumption is not done particular provisions, but preferred consumption is for after dissolving with 5.0ml water for injection when injectable powder, and the osmotic pressure of solution equates with 0.9% sodium chloride or is close.
Preparation method of the present invention comprises the following steps:
(1) will treat effective dose formula (I) medicine, alkaline matter adds or does not add the filler pulverize separately, sieves, mixes and obtain suitable powder, joins in glass tube vial or the ampoule by aseptic subpackaged standard measure, and capping gets final product, and dissolves with water for injection during application;
(2) will treat effective dose formula (I) medicine, add or do not add filler, pulverize, sieve, mix and obtain suitable powder, join in glass tube vial or the ampoule by aseptic subpackaged standard measure, capping, additional simultaneously an aqueous solution ampoule by a kind of pH7.0-10.5 of Gong injection of alkaline matter preparation, its basic preparation process is that dosing, decolouring, filtration (membrane filtration), quantitative embedding are in ampoule, sterilize behind the sealing by fusing, dissolve above-mentioned powder with this ampoule solution during application.
The physicochemical property of formula (I) chemical compound be studies show that this chemical compound dissolubility in water is very low, its aqueous solubilities＜0.4mg/ml under the room temperature, an and clinical application dose is more than the 100mg.Obviously, be difficult to the injection that preparation is fit to clinical practice,, separate out again when being cooled to room temperature though elevated temperature can make dissolubility improve.Find to add the pH value that alkaline matter or alkali carbonate class or bicarbonate etc. improve solvent under study for action, formula (I) compound dissolution degree improves, and when pH reached 7.5-8.5, its dissolubility can reach more than the 15mg/ml, and at room temperature no longer separated out crystallization.This kind dissolubility can prepare its injection, but finds simultaneously, because there is ester bond in the compound structure, even preparation at room temperature, formula (I) chemical compound also hydrolyzable in alkaline aqueous solution.Hydrolyzate is pressed the inspection of HPLC method, rises to some extent, and, deposits two existing 10% above hydrolysis as room temperature along with period of storage prolongation hydrolysis is more serious.In order to solve this difficulty, not only guaranteed formula (I) chemical compound in water dissolubility but also keep its stability, the present invention's design is with the pressed powder mix homogeneously of formula (I) chemical compound and an amount of above-mentioned alkali, check its stability and test dissolubility with the HPLC method, found that formula (I) chemical compound 100mg and natrium carbonicum calcinatum 15mg mix, with the dissolving of 5.0ml water for injection, dissolving easily, the solution clarification, the pH7.0-8.5 of solution.Adopt (1) 60 ℃ to store for 2 weeks down this solid mixed-powder; (2) deposited under the room temperature 2 months.Check its stability, find (1) though catabolite has rising but still see Table 1 in allowed band; (2) store and almost not have any catabolite and rise and see Table 2, study with other alkaloids and also obtain equifinality.Thereby solved the difficulty of formula (I) compound injection agent preparation, developed easy, unique method of the present invention.
The standard that powder ampoule agent for injection shown in the formula produced according to the present invention (I), formula (I) raw materials of compound must meet is aseptic, apyrogeneity, no foreign body, the clarification of dissolving back promptly meet injection.After adopting injecting drug use raw material conventional method to carry out refinement treatment the general synthetic medicine, just can be used for the present invention after meeting the injection standard.
Specific embodiment
The present invention is described further below in conjunction with specific embodiment, but do not limit the present invention.
Embodiment 1:
Formula (I) chemical compound (four water things) 10.0g
Sodium chloride 7.0g
Anhydrous sodium bicarbonate 1.5g
Preparation method: three kinds of materials are the no fungus that injectable is used, under aseptic dustfree environment, with above-mentioned three kinds of materials grind sieve the suitable powder of granularity, mix homogeneously, pack in the middle of 100 cleaning sterile glass tube vials with mechanical or manual mode branch, cap seal, the time spent dissolves with water for injection.
Embodiment 2:
Formula (I) chemical compound (four water things) 10.0g
Sodium chloride 7.0g
Preparation method: two kinds of materials are the no fungus that injectable is used, and above-mentioned two kinds of materials are ground down in powder pin preparation condition sieve, and mix homogeneously is sub-packed in 100 cleaning sterile glass tube vials, cap seal.Natrium carbonicum calcinatum 1.5g, with water for injection 500ml dissolving, preparation pH8.5 aqueous solution, embedding is in ampoule, and every 5.0ml sterilizes.Dissolve powder in the above-mentioned glass tube vial with this simultaneously.
Subordinate list 1 formula (I) compound injection 60 ℃ of stability test results of solids mixing medicinal powder
Blanking time (my god) appearance luster catabolite % content %
0 white crystalline powder 0.35 100.2
5 white crystalline powders 0.32 100.1
10 white crystalline powders 0.37 99.97
12 white crystalline powders 0.45 99.93
14 white crystalline powders 0.46 99.8
Subordinate list 2 formulas (I) compound injection 2 months stability test results of solids mixing medicinal powder room temperature
Blanking time (my god) appearance luster catabolite % content %
0 white crystalline powder 0.35 100.2
5 white crystalline powders 0.37 100.3
10 white crystalline powders 0.38 100.1
15 white crystalline powders 0.34 100
20 white crystalline powders 0.34 100.1
35 white crystalline powders 0.41 100.3
45 white crystalline powders 0.36 100.2
50 white crystalline powders 0.37 100.1
60 white crystalline powders 0.39 100.1
Claims (7)
1, a kind of N-[neighbour-(right-trimethyl acetoxyl benzenesulfonamide) benzoyl that contains] powder ampoule agent for injection (I) of glycine monosodium salt tetrahydrate, it is characterized in that this injectable powder comprises arbitrary form in following two kinds of forms;
(1) by treatment effective dose formula (I) medicine, at least a medicinal alkaline matter, contain or do not contain medicinal filler and form a kind of aseptic mixture according to a certain ratio, its formula (I) medicine: alkaline matter: the percentage by weight of filler is 1: 0.01-0.4: an amount of;
(2) by treatment effective dose formula (I) medicine, contain or do not contain medicinal filler and form a kind of sterile solid powder, additional simultaneously an aqueous solution ampoule by a kind of pH7.0-10.5 of Gong injection of alkaline matter preparation.
2, powder ampoule agent for injection according to claim 1 is characterized in that the treatment effective dose of formula (I) medicine is 100-400mg, and the alkaline matter consumption is the 1.0%-30% (weight) of formula (I) drug dose; Preferred consumption is 7.0-8.5 for the pH value of solution when formula (I) the medicine injection powder pin with specification 0.1g dissolves with 5.0ml water for injection.
3, powder ampoule agent for injection according to claim 1 and 2, it is characterized in that described alkaline matter comprise sodium carbonate (or potassium), sodium bicarbonate (or potassium), tertiary sodium phosphate (or potassium), sodium hydroxide (or potassium), they anhydride or contain the water of crystallization thing.
4, powder ampoule agent for injection according to claim 1 is characterized in that described filler is the no fungus of the sodium chloride, glucose, maltose, mannitol, sorbitol or the xylitol that are selected from medicinal Gong injection.
5, according to claim 1 or 4 described powder ampoule agent for injection, the addition that it is characterized in that described filler is every powder ampoule agent for injection that contains 0.1g formula (I) medicine, after the dissolving of 5.0ml water for injection, its osmotic pressure should be worked as with the 0.9%NaCl liquid phase or be more approaching.
6, a kind of N-[neighbour-(right-trimethyl acetoxyl benzenesulfonamide) benzoyl that contains] preparation method of powder ampoule agent for injection (I) of glycine monosodium salt tetrahydrate, it is characterized in that comprising the following steps:
(1) will treat effective dose formula (I) medicine, alkaline matter adds or does not add the filler pulverize separately, sieves, mixes and obtain suitable powder, joins in glass tube vial or the ampoule by aseptic subpackaged standard measure, and capping gets final product, and dissolves with water for injection during application;
(2) will treat effective dose formula (I) medicine, and add or do not add filler, and pulverize, sieve, mix and obtain suitable powder, join capping in glass tube vial or the ampoule by aseptic subpackaged standard measure; Additional simultaneously an aqueous solution ampoule by a kind of pH7.0-10.5 of Gong injection of alkaline matter preparation, its basic preparation process is that dosing, decolouring, filtration (membrane filtration), quantitative embedding are in ampoule, sterilize behind the sealing by fusing, dissolve above-mentioned powder with this ampoule solution during application.
7, the preparation method of powder ampoule agent for injection according to claim 6, it is characterized in that described alkaline matter is the sodium carbonate of injection, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydrogen phosphate (or potassium), the sterile solid material of sodium hydroxide (or potassium) comprises anhydride or contains the water of crystallization thing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03144236 CN1589783A (en) | 2003-09-04 | 2003-09-04 | N-[O-(P-trimethyl acetoxyl benzene sulfonamide) benzoyl] glycine mono sodium salt tetrahydrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03144236 CN1589783A (en) | 2003-09-04 | 2003-09-04 | N-[O-(P-trimethyl acetoxyl benzene sulfonamide) benzoyl] glycine mono sodium salt tetrahydrate |
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| Publication Number | Publication Date |
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| CN1589783A true CN1589783A (en) | 2005-03-09 |
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| CN 03144236 Pending CN1589783A (en) | 2003-09-04 | 2003-09-04 | N-[O-(P-trimethyl acetoxyl benzene sulfonamide) benzoyl] glycine mono sodium salt tetrahydrate |
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| CN (1) | CN1589783A (en) |
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