CN103553996A - Anticholinergic pharmaceutical composition - Google Patents

Anticholinergic pharmaceutical composition Download PDF

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CN103553996A
CN103553996A CN201310571655.XA CN201310571655A CN103553996A CN 103553996 A CN103553996 A CN 103553996A CN 201310571655 A CN201310571655 A CN 201310571655A CN 103553996 A CN103553996 A CN 103553996A
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impurity
glycopyrronium bromide
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bulk drug
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CN103553996B (en
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李兴惠
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Hunan Dongting Pharmaceutical Co Ltd
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李兴惠
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

The invention relates to an anticholinergic pharmaceutical composition. Specifically, the invention relates to a medicament capable of being used in pharmacy, wherein the,medicament comprises a compound expressed by the following formula. The invention further provides a preparation of the medicament, and the medicament and the preparation are used as an anticholinergic medicament and can be clinically used for anesthesia, peptic ulcer, salivation, etc. The raw material medicament or preparation has the function of inhibiting gastric secretion and regulating gastrointestinal peristalsis; the raw material medicament or preparation has relatively strong salivary secretion resistance than atropine while having no central anticholinergic activity. The anticholinergic pharmaceutical composition is generally used for clinically treating such symptoms as gastric and duodenal ulcer, chronic gastritis and excessive secretion of gastric acid.

Description

Anticholinergic drug compositions
Technical field
The invention belongs to medical technical field, relate to a kind of pharmaceutical composition as cholilytic drug, particularly relate to a kind of pharmaceutical composition that comprises Glycopyrronium Bromide as cholilytic drug.
Background technology
Glycopyrronium Bromide; its English Glycopyrronium Bromide by name or Glycopyrrolate; its typical chinesization formal name used at school is: oxygen base (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxyl-2-phenyl acetyl)]-1; 1-dimethyl pyrrolidine bromide; typical English chemistry is by name: (3RS)-3-[(2SR)-(2-Cyclopentyl-2-hydroxy-2-phenylacetyl) oxy]-1; 1-dimethylpyrrolidinium bromide, its molecular formula is C 19h 28brNO 3, molecular weight is 398.3, its typical chemical structural formula is:
Figure BDA0000414809050000011
; as medicinal Glycopyrronium Bromide, be (3R)-3-[(2S)-(2-cyclopentyl-2-hydroxyl-2-phenyl acetyl) oxygen base]-1; 1-dimethyl pyrrolidine bromide and (3S)-3-[(2R)-(2-cyclopentyl-2-hydroxyl-2-phenyl acetyl) oxygen base]-1, one group of enantiomorph of 1-dimethyl pyrrolidine bromide.
Glycopyrronium Bromide is white or the crystalline powder of white almost, and soluble in water, methyl alcohol, ethanol are almost insoluble in trichloromethane or ether.
CN101133021A (Chinese Patent Application No. 200680006901.5, Suo Sai, Granted publication CN101133021B) discloses crystallization and the purification process of Glycopyrronium Bromide.Comprise the grand amine alkali of lattice with monobromethane reacting in solvent, wherein described solvent is selected so that diastereomer R in the diastereomer of described product, S and S, the ratio of R is with respect to diastereomer R, R and S, the ratio of S is preponderated.And by the separated desired diastereomer of one or more crystallization control steps.From this patent documentation, at the later stage of preparation, the grand amine alkali of lattice (can referred to as GP alkali or GP alkali impurity) is reacted with monobromethane in suitable solvent, obtain Glycopyrronium Bromide, elementary operation process is:
What the present invention relates to is as medicinal Glycopyrronium Bromide, when describing together with its enantiomeric impurity and being convenient to distinguish, the present invention also can be described as 3R2S/3S2R Glycopyrronium Bromide as medicinal Glycopyrronium Bromide, and its a pair of enantiomeric impurity existing in addition can be described as 3S2R/3S2S impurity or 3S2R/3S2S Glycopyrronium Bromide or other similar appellation, as CN101133021B specification sheets [0032] section described, that the present invention relates to is the R as medicinal substance, S/S, R Glycopyrronium Bromide, and with relative be that two configurations are respectively R, R and S, the impurity of S, they in the present invention can be referred to as R, R/S, S impurity or be called erythro isomer or be called R, R/S, S Glycopyrronium Bromide.Described R; R/S; S impurity or be called erythro isomer: oxygen base (3RS)-3-[(2RS)-(2-cyclopentyl-2-hydroxyl-2-phenyl acetyl)]-1; 1-dimethyl pyrrolidine bromide; English name (3RS)-3-[(2RS)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl) oxy]-1; 1-dimethylpyrrolidinium bromide, chemical structural formula is:
Figure BDA0000414809050000021
Except R, R/S, outside S impurity, according to the preparation method of above-mentioned CN101133021A and other document, as also having micro-GP alkali impurity by remnants in medicinal Glycopyrronium Bromide.
For example, CN103159659A (Chinese Patent Application No. 201110426038.1, Shenyang medicine section) preparation method of muscarinic receptor antagonist Glycopyrronium Bromide is disclosed, it is characterized in that: benzoylformic acid makes α-cyclopentyl methyl mandelate through grignard reaction, esterification, then through transesterify, quaterisation, make Glycopyrronium Bromide with N-methylpyrrolidin-3-alcohol.
And for example, CN102627595A (Chinese Patent Application No. 201210069208.X, Xu Kui) preparation method of Glycopyrronium Bromide is disclosed, more particularly, relate to enrichment high purity (3R, 2 ' S) and in (3S, 2 ' R) Glycopyrronium Bromide and synthetic method, relate to the preparation method of new intermediate.It is believed that this invention overcome prior art exist yield low, pollute the defects such as large, the preparation method of the Glycopyrronium Bromide of the preparation formula that a kind of yield is high, environmental pollution is little, purifying is easy (I) is provided, and Glycopyrronium Bromide fusing point prepared by the method is 195 ℃～198 ℃.
As a kind of anticholinergic, can be used for clinically anesthesia, peptide ulceration, salivation disease etc.Glycopyrronium Bromide is quaternary amines anticholinergic drug, has the gastric secretion of inhibition and regulates gastrointestinal peristalsis effect; This product also has the anti-salivation effect stronger than coromegine, but does not have central cholinolytic active.Be generally used for clinically the diseases such as gastric and duodenal ulcer, chronic gastritis, gastroxia.Curative effect and propantheline are similar or surpass.Quiet notes or intramuscular injection can be used for preanesthetic medication, to suppress glandular secretion, act on sustainable approximately 7 hours.Consumption usage: oral, each 1～2mg, 3～4 times on the 1st, takes after meal and before sleeping; The each 1mg of maintenance dose, every day 2 times; 1 maximum dose is 4mg, and maximum dose on the 1st is 12mg; Preanesthetic medication, quiet notes or intramuscular injection 0.2～0.4mg.Spendable formulation has its tablet (0.5mg/ sheet, 1mg/ sheet), oral liquid, injection liquid (0.2mg/mL) etc. clinically.
The safe, effective, controlled of streat drug is that industry is very paid close attention to.Even if be successfully applied to clinically, those skilled in the art are still expected for Glycopyrronium Bromide for example pharmaceutical preparation of a kind of medicament production with Good Pharmacy performance are provided.
Summary of the invention
The inventor has been found that, use specific treatment process can effectively reduce R in Glycopyrronium Bromide simultaneously, R/S, the content of S impurity and GP alkali impurity, and show that have the medicinal Glycopyrronium Bromide of low impurity and the formulation example of preparation thereof shows beat all pharmaceutical properties for example stability and/or for example security of biological property as its injection liquid.Therefore the present invention finds and is able to and completes.
For this reason, first aspect present invention provides a kind of preparation method of bulk drug of hyoscine, and the activeconstituents of this bulk drug is Glycopyrronium Bromide, and the method comprises with an organic solvent carries out refining step to the bulk drug that comprises Glycopyrronium Bromide.
In the present invention, term Glycopyrronium Bromide is following formula I compound:
Figure BDA0000414809050000031
(formula I)
And enantiomorph.
In the methods of the invention, in above-mentioned " bulk drug that comprises Glycopyrronium Bromide is carried out to refining step ", it can be rough bulk drug or crude product for described term " bulk drug that comprises Glycopyrronium Bromide ", it can be for example the bulk drug preparing according to art methods, although the bulk drug that art methods prepares equally can be for formulation example as the preparation of injection liquid, but by the inventive method, the bulk drug of the prior art is further processed, so that it and the preparation that is prepared into by it are given better performance, better stability for example, better security.
It can be used as for example bulk drug of pharmaceutical preparation production use of pharmaceutical composition " bulk drug of hyoscine " of the present invention or " bulk drug ", so it also can be regarded as formula I compound and enantiomorph is the bulk drug of Glycopyrronium Bromide.Well-known, as the bulk drug of the hyoscine of useful in preparing drug formulations, they comprise formula I compound and enantiomorph thereof as main ingredient, can also comprise the trace impurity of limit up to specification.
According to the method for first aspect present invention, it comprises that the bulk drug to comprising Glycopyrronium Bromide carries out recrystallization to reach the step of refining object.
According to the method for first aspect present invention, described recrystallization is that bulk drug is dissolved in the first solvent, then in this solution, adds the second solvent, so that Glycopyrronium Bromide is settled out crystallization from solvent.
According to the method for first aspect present invention, described the first solvent is selected from: water, methyl alcohol, ethanol, 1-octanol, phenylcarbinol, methyl-sulphoxide, methylene dichloride, ethyl acetate and combination thereof.In one embodiment, described the first solvent is selected from: ethanol, 1-octanol, methyl-sulphoxide, methylene dichloride, ethyl acetate and combination thereof.In one embodiment, the mixture that described the first solvent is ethanol and ethyl acetate.In one embodiment, described the first solvent is the mixture of ethanol and ethyl acetate volume ratio 100:7～20, preferably the mixture of ethanol and ethyl acetate volume ratio 100:10～16.In the present invention, if not otherwise indicated, the ethanol of mentioning is dehydrated alcohol.
According to the method for first aspect present invention, described the second solvent is selected from: ether, methyl ethyl ether, t-butyl methyl ether, normal heptane, normal hexane, Skellysolve A and combination thereof.In one embodiment, described the second solvent is selected from: ether, methyl ethyl ether, t-butyl methyl ether and combination thereof.In one embodiment, described the second solvent is methyl ethyl ether.
According to the method for first aspect present invention, the volume ratio of described the first solvent and the second solvent is 1:7～25, for example 1:10～20, for example 1:10～15.
According to the method for first aspect present invention, wherein said recrystallization is to carry out according to those skilled in the art's general operation method, particularly comparatively high temps for example more than 40 ° until in the temperature range below solvent refluxing temperature (for example, at the temperature of 55～60 ℃) solute is dissolved in solvent, then for example within the scope of 0～10 °, make at a lower temperature material crystallization, then leach crystallization, dry, to obtain bulk drug of the present invention.Can carry out repeatedly recrystallization as required.
According to the method for first aspect present invention, when bulk drug is dissolved in the first solvent, those skilled in the art understand that now solvent for use amount is more low better conventionally, as long as normally reach the volume of a little higher than meltage, for example reach the solvent volume of 2～4 times of meltages, to create conditions for follow-up crystallization and aftertreatment.Therefore needn't do special stipulation to this first solvent load in the present invention.But in order to obtain good separating effect, in one embodiment of the invention, the ratio that can make bulk drug for example, be dissolved in the first solvent with the concentration of 0.1～0.5g/ml (0.1～0.2g/ml) is processed.
Have been found that and use crystallization method of the present invention can effectively remove erythro isomer impurity and GP alkali impurity simultaneously.
In the present invention, erythro isomer refers to the compound with following formula Ix
Figure BDA0000414809050000041
(formula Ix)
And enantiomorph.It is optionally present in bulk drug of the present invention or preparation as impurity.It also can be described as impurity Ix or Ix impurity or Ix or other similar appellation (for the mixture of formula Ix compound and enantiomorph thereof) in the present invention.
In the present invention, the grand amine alkali of lattice (can referred to as GP alkali or GP alkali impurity) refers to the compound with following formula Iy
Figure BDA0000414809050000042
(formula Iy), it is optionally present in bulk drug of the present invention or preparation as impurity.It also can be described as impurity Iy or Iy impurity or Iy or other similar appellation in the present invention.
In the present invention, with following formula Iz compound
Figure BDA0000414809050000043
(formula Iz), it is optionally present in bulk drug of the present invention or preparation as impurity.It also can be described as impurity Iz or Iz impurity or Iz or other similar appellation in the present invention.
According to the method for first aspect present invention, its prepared bulk drug comprises the Glycopyrronium Bromide as main ingredient, and the optional erythro isomer as impurity, erythro isomer for Glycopyrronium Bromide content lower than 0.5% (for example, lower than 0.4%, for example, lower than 0.3%).
In bulk drug of the present invention (the formula I compound and the enantiomorph thereof that wherein comprise as activeconstituents are Glycopyrronium Bromide), the content of erythro isomer impurity is the weight percent amount with respect to Glycopyrronium Bromide in itself, that is: for certain a collection of bulk drug of the present invention or for example material of preparation of its pharmaceutical composition of making as raw material of take, while calculating the content of impurity erythro isomer wherein, can calculate with following formula:
Impurity erythro isomer content (%)=(in this material in this material of the quality ÷ of impurity erythro isomer the quality of Glycopyrronium Bromide) * 100%
According to above definition, above-mentioned material can be both to take the bulk drug that formula I compound and enantiomorph thereof be chief component, can also be take formula I compound and enantiomorph thereof as activeconstituents and be added with the pharmaceutical composition of other pharmaceutical excipient, for example pharmaceutical preparation, for example injection liquid.Thus, the calculating of impurity erythro isomer content not can because of other composition for example the existence of pharmaceutical excipient be affected.Other impurity the present invention relates to for example during the calculating of impurity Iy and impurity Iz and other impurity, is also processed in the same manner.Below [HPLC-A] and [HPLC-B] although to measure and calculate in erythro isomer, impurity Iy, impurity Iz and the content of other impurity phase for Glycopyrronium Bromide be to calculate by the concentration ratio of the two in need testing solution, due to preparation during need testing solution the extension rate of impurity and Glycopyrronium Bromide identical or can determine, therefore this concentration ratio is compared with being identical more in itself with the mass ratio in above formula.
In the present invention, the method for mensuration impurity Ix content can have many, for example, according to well known to a person skilled in the art the measuring method that mode is definite.A kind of typical method is high performance liquid chromatography.In addition, can obtain highly purified for example chromatographic purity and reach more than 98% impurity reference substance (impurity Ix for example by preparative high performance liquid chromatography is separated, and for example impurity Iy mentioned below and impurity Iz), take this impurity reference substance is contrast, measures the relative content of those impurity in the bulk drug that the present invention comprises formula I compound and enantiomorph thereof and the pharmaceutical preparation being prepared by them by the known feasible method of those skilled in the art.The impurity the present invention relates to comprises impurity Ix, impurity Iy and impurity Iz etc., and they are all that prior art is known or can prepare by art methods, and can buy from commercial channels, and for example Ke Cong Sigma-Aldrich company orders and obtains.In the present invention, α-cyclopentyl amygdalic acid of the article No. 706396 of buying as impurity IzShi Cong Sigma-Aldrich company, purity is more than 98%, as chemical test of the present invention or biological test, use, it is chromatographic purity 99.1% in the present invention [HPLC-B] method, and in this chromatography with respect to the relative retention time of 3R2S/3S2R Glycopyrronium Bromide of the present invention in 2.67～2.69 scopes.
A kind of typical high performance liquid chromatography is high performance liquid chromatography A (can be called for short [HPLC-A] in the present invention) hereinafter described, its can be used for measuring various impurity in the various materials of the present invention (comprising bulk drug and preparation) particularly impurity Ix in this material with respect to the amount of Glycopyrronium Bromide.Certainly, it will be appreciated by those skilled in the art that analytical procedure easily improves, the method for the various impurity in any available and the various materials of potential mensuration the present invention all can be used for the present invention; In view of the content of the various impurity in the various materials of the present invention can be because improving of analytical procedure changes, so the measuring method of the foreign matter content in the various materials of the present invention or relative content can be not particularly limited.Certainly, in the present invention, if not otherwise indicated, particularly the content of impurity Ix or the method for relative content are all to adopt [HPLC-A] described herein to measure in various materials (comprising bulk drug and preparation) various impurity.
A kind of typical high performance liquid chromatography is high performance liquid chromatography B (can be called for short [HPLC-B] in the present invention) hereinafter described, its can be used for measuring various impurity in the various materials of the present invention (comprising bulk drug and preparation) particularly impurity Iy and/or impurity Iz in this material with respect to the amount of Glycopyrronium Bromide.Certainly, it will be appreciated by those skilled in the art that analytical procedure easily improves, the method for the various impurity in any available and the various materials of potential mensuration the present invention all can be used for the present invention; In view of the content of the various impurity in the various materials of the present invention can be because improving of analytical procedure changes, so the measuring method of the foreign matter content in the various materials of the present invention or relative content can be not particularly limited.Certainly, in the present invention, if not otherwise indicated, particularly impurity Iy and/or the content of impurity Iz or the method for relative content are all to adopt [HPLC-B] described herein to measure in various materials (comprising bulk drug and preparation) various impurity.
Have been found that for comprising the bulk drug of the present invention that Glycopyrronium Bromide is formula I compound and enantiomorph thereof or the pharmaceutical preparation of being made by them, along with the prolongation of storage time, impurity Iz content demonstrates the trend gradually increasing.Particularly in the situation that impurity Iy content is higher, for example with respect to the impurity Iy content of Glycopyrronium Bromide meter higher than 0.15% (particularly higher than 0.20%, particularly higher than 0.25%, particularly higher than 0.30%, particularly higher than 0.50%) time, the pharmaceutical preparation that shows bulk drug of the present invention or made by them is along with the prolongation of storage time, and impurity Iz content demonstrates the trend gradually increasing.In the present invention, have been surprisingly found that, the bulk drug of the present invention that comprises formula I compound and enantiomorph thereof by purifying, after the impurity Iy that comes from technique that makes wherein to comprise is reduced to a certain degree, particularly make Iy content (with respect to Glycopyrronium Bromide meter) lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iy content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.500% scope (for example, in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope, for example, in 0.003%～0.250% scope, for example, in 0.003%～0.200% scope, for example, in 0.003%～0.150% scope, for example, in 0.003%～0.130% scope) time, these bulk drugs or pharmaceutical preparation gather way and are significantly suppressed at long-time storage rear impurity Iz content, this is completely beat all.
Although the various chemical substances that the present invention relates to, for example formula I compound and enantiomorph thereof, impurity Ix, impurity Iy, impurity Iz, their chemical structure is known and can with commercial sources, directly obtains from the market, but as well known to those skilled in the art, these impurity can also be come qualitative or be characterized by the high performance liquid chromatography of regulation, for example the high performance liquid chromatography by regulation operates, by measuring the retention behavior of impurity in this regulation high performance liquid chromatography, (be relative retention time, RRT) determine this impurity.Particularly, the present invention has been found that, in [HPLC-A] of the present invention system, for formula I compound, the relative retention time of impurity Ix is (RRT about 0.89 conventionally) in 0.86～0.92 scope, thereby the present invention also can be called RRT0.89 impurity, impurity RRT0.89 or RRT0.89 by this impurity Ix.
And in [HPLC-B] of the present invention system, for formula I compound, the relative retention time of impurity Iy is (RRT about 1.14 conventionally) in 1.10～1.18 scopes, thereby the present invention also can be called RRT1.14 impurity, impurity RRT1.14 or RRT1.14 by this impurity Iy.
In addition, in [HPLC-B] of the present invention system, for formula I compound, the relative retention time of impurity Iz is (RRT about 2.68 conventionally) in 2.63～2.73 scopes, thereby the present invention also can be called RRT2.68 impurity, impurity RRT2.68 or RRT2.68 by this impurity Iz.
Therefore, in the present invention hereinafter, while mentioning RRT0.89 impurity, all refer to that, in [HPLC-A] system, for the retention time of formula I compound, relative retention time occurs impurity in 0.86～0.92 scope, this impurity is impurity Ix; Similarly, in the present invention, while mentioning RRT1.14 impurity, all refer to that, in [HPLC-B] system, for the retention time of formula I compound, relative retention time occurs impurity in 1.10～1.18 scopes, this impurity is impurity Iy; Similarly, in the present invention, while mentioning RRT2.68 impurity, all refer to that, in [HPLC-B] system, for the retention time of formula I compound, relative retention time occurs impurity in 2.63～2.73 scopes, this impurity is impurity Iz.
The implication of relative retention time is being known in the art, for example, the relative retention time of impurity Ix (being abbreviated as RRT) refers in color atlas, the retention time of impurity Ix chromatographic peak is divided by the value of the retention time gained of formula I compound chromatographic peak, it is the RRT=impurity Ix retention time ÷ formula I compound retention time of Ix, and the relative retention time of Glycopyrronium Bromide itself is 1 or 1.00, this algorithm is well known to a person skilled in the art.
According to the method for first aspect present invention, in its prepared bulk drug of the present invention that comprises Glycopyrronium Bromide, Ix impurity phase for Glycopyrronium Bromide content lower than 0.5% (for example, lower than 0.4%, for example, lower than 0.3%).This content can be used high effective liquid chromatography for measuring and calculate, and particularly uses [HPLC-A] to measure and calculate.
In the present invention, the measuring method of [HPLC-A] is as follows:
(i) solution:
The biphosphate sodium water solution of buffered soln: 2.8g/L, is adjusted to pH value 6.50 ± 0.05 with 10% sodium hydroxide solution;
Moving phase: methyl alcohol: acetonitrile: volume of buffer solution is than the mixed solution of 50:10:40;
System suitability solution: with the solution of moving phase preparation, wherein the concentration containing erythro isomer reference substance and Glycopyrronium Bromide reference substance is respectively 40 μ g/mL;
Standardized solution A: precision takes the about 50mg of Glycopyrronium Bromide reference substance, is placed in 100ml measuring bottle, dissolves and is diluted to scale by moving phase, shakes up, and makes the standardized solution A that concentration is about 500 μ g/mL;
[as well known to those skilled in the art, the above-mentioned Glycopyrronium Bromide reference substance " about 50mg " that takes, in actually operating, need to modify with " approximately ", when reason is precision weighing solid materials, for example use ten thousand/balance, conventionally be difficult to directly claim to obtain 50.00mg, but usually can depart to some extent, for example depart from this numerical value ± 2%, for example precision weighing is to 50.40mg, depart from 0.8%, but this concentration making below that departs from continues to depart from and is extended in final numerical evaluation, and in final numerical evaluation, consider that this weighing departs from, thereby finally on this deviation theory, can not cause miscalculation, thereby the statement of " approximately " allows herein, this is also in the Chinese Pharmacopoeia of various version when carrying out precision weighing, to be all the material that takes " approximately " certain amount conventionally.In addition, in one embodiment, the present invention relates to for modify numerical value that " approximately " of a numerical value be defined as allowing departing from its modification ± 2%, for example above-mentioned " precision takes the about 50mg of Glycopyrronium Bromide reference substance " also can be expressed as " precision takes Glycopyrronium Bromide reference substance 50mg ± 1mg " or other similar statement.In other similar statement linguistic context of the present invention, also there is similar meaning]
Standardized solution B: precision measures the above standardized solution A of 1ml, is placed in 100ml measuring bottle, is diluted to scale by moving phase, shakes up, and makes the standardized solution B that concentration is about 5 μ g/mL;
Need testing solution: precision takes the trial-product that is about 50mg containing Glycopyrronium Bromide, be placed in 100ml measuring bottle, by moving phase, dissolve and be diluted to scale, shake up, filter if desired, make and containing Glycopyrronium Bromide concentration, be about the need testing solution of 500 μ g/mL (wherein said trial-product can be the various samples that comprise Glycopyrronium Bromide, it can be for example Glycopyrronium Bromide crude product, bulk drug, highly finished product and the preparation of being made by them, according to concrete mensuration, need to determine, when measure be preparation time, be converted to the Glycopyrronium Bromide comprising in said preparation appropriate to be mixed with respective concentration---these operative techniquies are well known to a person skilled in the art),
(ii) chromatographic system:
Chromatographic run carries out according to two contained high performance liquid chromatography of appendix V D of Chinese Pharmacopoeia version in 2010, and chromatographic condition is as follows:
Detector: UV-detector, detects wavelength UV222nm;
Chromatographic column: beta-cyclodextrin bonded silica gel post, filler granularity 5 μ m, column internal diameter 4.0mm, column length 25cm; [note: the filler of above-mentioned beta-cyclodextrin bonded silica gel post is a kind of beta-cyclodextrin bonding porous silica gel, this type of chromatographic column can easily be buied from the market, it can be for example the Chiradex brand product purchased from Merck KGaA company, can be the YMC CHIRAL CD BR β brand product purchased from YMC company, etc.Below in concrete test, use GaiYMC company product]
Column temperature: 30 ℃;
Flow velocity: 1mL/min;
Sample size: 10 μ L;
System suitability: the resolution in system suitability solution color atlas between erythro isomer and Glycopyrronium Bromide is not less than 1.2, in standardized solution B color atlas, ask the tail factor to be no more than 2.0, in standardized solution B color atlas, relative standard deviation is no more than 6.0%, by system suitability solution color atlas and standardized solution B, determines the retention time of erythro isomer and Glycopyrronium Bromide and the relative retention time of the two;
(iii) measure:
Respectively need testing solution, standardized solution A, standardized solution B injection liquid chromatography are measured, read the peak area of Glycopyrronium Bromide in three color atlass of gained, and the peak area (when this chromatographic peak exists) of erythro isomer in need testing solution color atlas, and their retention time;
According to need testing solution color atlas and standardized solution A color atlas, press external standard method with the concentration of Glycopyrronium Bromide in calculated by peak area need testing solution, (unit is μ g/mL to be designated as Ci; The calculating formula that well-known external standard method is calculated Ci is: Glycopyrronium Bromide concentration in Ci=(in need testing solution color atlas in main peak area ÷ standardized solution A color atlas main peak area) * standardized solution A; Unit is μ g/mL, the interference such as this Glycopyrronium Bromide concentration despumation, auxiliary material, moisture, for bulk drug, this concentration may approach with dosing concentration, but for the more crude product such as impurity and/or moisture and the pharmaceutical composition that added auxiliary material, for example for pharmaceutical preparation, this concentration can reflect the concentration of Glycopyrronium Bromide in solution exactly);
Be calculated as follows the concentration of erythro isomer in need testing solution (when it exists), be designated as Cx (unit is μ g/mL):
Figure BDA0000414809050000071
Be calculated as follows in sample erythro isomer content for Glycopyrronium Bromide (be percentage composition, %):
Erythro isomer content (%)=(Cx ÷ Ci) * 100%.
Above in [HPLC-A], take the relative retention time of Glycopyrronium Bromide as 1 or be 1.00, the relative retention time of erythro isomer in 0.86～0.92 scope, below in concrete measurement result all within the scope of this, be particularly about 0.89.
According to the method for first aspect present invention, in its prepared bulk drug of the present invention that comprises Glycopyrronium Bromide, Iy impurity phase for Glycopyrronium Bromide content lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iy foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.500% scope (for example, in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope, for example, in 0.003%～0.250% scope, for example, in 0.003%～0.200% scope, for example, in 0.003%～0.150% scope, for example, in 0.003%～0.130% scope).This content can be used high effective liquid chromatography for measuring and calculate, and particularly uses [HPLC-B] to measure and calculate.
According to the method for first aspect present invention, in its prepared bulk drug of the present invention that comprises Glycopyrronium Bromide, Iz impurity phase for Glycopyrronium Bromide content lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iz foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.002%～0.500% scope (for example, in 0.002%～0.400% scope, for example, in 0.002%～0.300% scope, for example, in 0.002%～0.250% scope, for example, in 0.002%～0.200% scope, for example, in 0.002%～0.150% scope, for example, in 0.002%～0.130% scope).This content can be used high effective liquid chromatography for measuring and calculate, and particularly uses [HPLC-B] to measure and calculate.
In the present invention, the measuring method of [HPLC-B] is as follows:
(i) solution:
Buffered soln: the 1-sodium hexanesulfonate monohydrate of the anhydrous sodium sulphate of 1.0g and 200mg is dissolved in 650mL water, to the 1N sulfuric acid that adds 3.0mL in this solution, mixes, obtain;
Diluting soln: the 1-sodium hexanesulfonate monohydrate of the anhydrous sodium sulphate of 1.0g, 6.8g potassium primary phosphate and 200mg is dissolved in 650mL water, to the 1N sulfuric acid, the methyl alcohol of 150mL and the acetonitrile of 200mL that add 3.0mL in this solution, mixing, is 2.8 with phosphorus acid for adjusting pH value, obtains;
Solution A: acetonitrile: methyl alcohol: volume of buffer solution is than the mixed solution of 20:15:65;
Solution B: acetonitrile: methyl alcohol: volume of buffer solution is than the mixed solution of 50:15:35;
Standardized solution A: precision takes the about 100mg of Glycopyrronium Bromide reference substance, is placed in 100ml measuring bottle, dissolves and is diluted to scale with diluting soln, if desired through supersound process to impel dissolving, shake up, make the solution that concentration is about 1000 μ g/mL, be standardized solution A;
Standardized solution B: precision takes impurity Iy reference substance and each about 15mg of impurity Iz reference substance respectively, be placed in 100ml measuring bottle, the above standardized solution A that another precision measures 15ml is placed in same measuring bottle, add diluting soln and be diluted to scale, if desired through supersound process to impel dissolving, shaking up, obtain being all about containing Glycopyrronium Bromide, impurity Iy, impurity Iz three concentration the solution of 150 μ g/mL, is standardized solution B;
Standardized solution C: the above standardized solution B that precision measures 1ml is placed in 100ml measuring bottle, adds diluting soln and is diluted to scale, shakes up, makes the solution that is all about 1.5 μ g/mL containing Glycopyrronium Bromide, impurity Iy, impurity Iz three concentration, is standardized solution C;
Standardized solution D: precision takes the about 15mg of impurity Iy reference substance, is placed in 100ml measuring bottle, adds diluting soln and is diluted to scale, if desired through supersound process to impel dissolving, shake up, obtain the solution that impure Iy concentration is about 150 μ g/mL, be standardized solution Dy; Another precision takes the about 15mg of impurity Iz reference substance, is placed in 100ml measuring bottle, add diluting soln and be diluted to scale, if desired through supersound process to impel dissolving, shake up, obtain the solution that impure Iz concentration is about 150 μ g/mL, be standardized solution Dz;
Need testing solution: precision takes the trial-product that is about 100mg containing Glycopyrronium Bromide, be placed in 100ml measuring bottle, with diluting soln, dissolve and be diluted to scale, if desired through supersound process to impel dissolving, shake up, filter if desired, make and containing Glycopyrronium Bromide concentration, be about the need testing solution of 1000 μ g/mL (wherein said trial-product can be the various samples that comprise Glycopyrronium Bromide, it can be for example Glycopyrronium Bromide crude product, bulk drug, highly finished product and the preparation of being made by them, according to concrete mensuration, need to determine, when measure be preparation time, be converted to the Glycopyrronium Bromide comprising in said preparation appropriate to be mixed with respective concentration---these operative techniquies are well known to a person skilled in the art),
(ii) chromatographic system:
Chromatographic run carries out according to two contained high performance liquid chromatography of appendix V D of Chinese Pharmacopoeia version in 2010, and chromatographic condition is as follows:
Detector: UV-detector, detects wavelength UV222nm;
Chromatographic column: octadecylsilane chemically bonded silica post, filler granularity 5 μ m, column internal diameter 4.6mm, column length 15cm; [noting: this is the very conventional chromatographic column in a kind of this area]
Gradient elution program:
Time (min) Solution A (%) Solution B (%)
0 100 0
10 100 0
25 10 90
35 10 90
37 100 0
43 100 0
Column temperature: 40 ℃;
Flow velocity: 1mL/min;
Sample size: 50 μ L;
System suitability: the resolution in standardized solution C color atlas between impurity Iy and Glycopyrronium Bromide is not less than 2.0, the holder tail factor at Glycopyrronium Bromide peak is no more than 2.0, and the relative standard deviation of each chromatographic peak is no more than 6.0%; By the color atlas main peak retention time of standardized solution Dy and standardized solution Dz, determine the retention time of impurity Iy and impurity Iz under this chromatographic condition, and determine impurity Iy, impurity Iz, the retention time of Glycopyrronium Bromide and three's relative retention time by standardized solution B color atlas;
(iii) measure:
Respectively need testing solution, standardized solution A, standardized solution C injection liquid chromatography are measured, read the peak area of Glycopyrronium Bromide in three color atlass of gained, the peak area (when these chromatographic peaks exist) of impurity Iy and impurity Iz and other optional impurity existing in need testing solution color atlas, the peak area of impurity Iy and impurity Iz in standardized solution C color atlas, and their retention time;
According to need testing solution color atlas and standardized solution A color atlas, press external standard method with the concentration of Glycopyrronium Bromide in calculated by peak area need testing solution, (unit is μ g/mL to be designated as Ci; The calculating formula that well-known external standard method is calculated Ci is: Glycopyrronium Bromide concentration in Ci=(in need testing solution color atlas in main peak area ÷ standardized solution A color atlas main peak area) * standardized solution A; The interference such as this Glycopyrronium Bromide concentration despumation, auxiliary material, moisture, for bulk drug, this concentration may approach with dosing concentration, but for the more crude product such as impurity and/or moisture and the pharmaceutical composition that added auxiliary material, for example for pharmaceutical preparation, this concentration can reflect the concentration of Glycopyrronium Bromide in solution exactly);
The concentration that is calculated as follows impurity Iy in need testing solution or impurity Iz, is designated as respectively Cy or Cz (unit is μ g/mL, when it exists):
Figure BDA0000414809050000101
Figure BDA0000414809050000102
The concentration that is calculated as follows optional other the single impurity existing in need testing solution, (unit is μ g/mL to be designated as Cn; When there is a plurality of other impurity, these other impurity calculate respectively separately):
Be calculated as follows in sample for Glycopyrronium Bromide impurity Iy or impurity Iz or other single foreign matter content (be percentage composition, %):
Impurity Iy content (%)=(Cy ÷ Ci) * 100%,
Impurity Iz content (%)=(Cz ÷ Ci) * 100%,
Other single foreign matter content (%)=(Cn ÷ Ci) * 100%.
Above in [HPLC-B], take the relative retention time of Glycopyrronium Bromide as 1 or be 1.00, the relative retention time of impurity Iy in 1.10～1.18 scopes (below in concrete measurement result all within the scope of this, particularly be about 1.14), the relative retention time of impurity Iz (below in concrete measurement result all within the scope of this, be particularly about 2.68) in 2.63～2.73 scopes.
In [HPLC-A] of the present invention or [HPLC-B] testing method, preparation sample solution sample used, it can be the bulk drug of the present invention that comprises formula I compound and enantiomorph thereof, can be also the pharmaceutical preparation that comprises auxiliary material.The latter in this way, the amount that comprises contained formula I compound in the amount of formula I compound and enantiomorph thereof and bulk drug and enantiomorph thereof in the material that takes or measure is suitable.
According to the method for first aspect present invention, its prepared bulk drug of the present invention that comprises Glycopyrronium Bromide is measured according to the present invention [HPLC-A], wherein relative retention time (also can be described as in the present invention RRT0.89 impurity or is called RRT0.89 at the impurity at 0.86～0.92 place, it is essentially impurity Ix) for Glycopyrronium Bromide content lower than 0.5% (for example, lower than 0.4%, for example, lower than 0.3%).
According to the method for first aspect present invention, its prepared bulk drug of the present invention that comprises Glycopyrronium Bromide is measured according to the present invention [HPLC-B], wherein relative retention time (also can be described as in the present invention RRT1.14 impurity or is called RRT1.14 at the impurity at 1.10～1.18 places, it is essentially impurity Iy) for Glycopyrronium Bromide content lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iy content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.500% scope (for example, in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope, for example, in 0.003%～0.250% scope, for example, in 0.003%～0.200% scope, for example, in 0.003%～0.150% scope, for example, in 0.003%～0.130% scope).
According to the method for first aspect present invention, its prepared bulk drug of the present invention that comprises Glycopyrronium Bromide is measured according to the present invention [HPLC-B], wherein relative retention time (also can be described as in the present invention RRT2.68 impurity or is called RRT2.68 at the impurity at 2.63～2.73 places, it is essentially impurity Iz) for Glycopyrronium Bromide content lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iz content (with respect to Glycopyrronium Bromide meter) in 0.002%～0.500% scope (for example, in 0.002%～0.400% scope, for example, in 0.002%～0.300% scope, for example, in 0.002%～0.250% scope, for example, in 0.002%～0.200% scope, for example, in 0.002%～0.150% scope, for example, in 0.002%～0.130% scope).
The present invention finds, impurity Iy content is controlled at lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iy content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.500% scope (for example, in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope, for example, in 0.003%～0.250% scope, for example, in 0.003%～0.200% scope, for example, in 0.003%～0.150% scope, for example, in 0.003%～0.130% scope) time, can be so that impurity Iz have significant increase in bulk drug of the present invention and the pharmaceutical composition for preparing thereof along with the prolongation of storage time.There is in the present invention the discovery of biological significance to be, impurity Iz is that a kind of toxicity is particularly to the obvious material stronger than Glycopyrronium Bromide of the medium lethal dose of Mouse and rat, and impurity Iz has the undesirable action that causes that neutrophil leucocyte reduces, particularly in medical compounds of the present invention and the pharmaceutical composition for preparing thereof impurity Iz with respect to the content of formula I compound lower than 2.0% (for example, lower than 1.5%, for example, lower than 1.0%, for example, lower than 0.75%, for example, lower than 0.50%, for example, lower than 0.40%) time, this bulk drug or its pharmaceutical composition preparing can not cause that obvious neutrophil leucocyte reduces to animal subject, but in this bulk drug or its pharmaceutical composition preparing impurity Iz relative content higher than 0.40% (particularly higher than 0.50%, particularly higher than 0.75%, particularly higher than 1.0%, particularly higher than 1.5%, particularly higher than 2.0%) time, this bulk drug or its pharmaceutical composition preparing still can cause that the obvious neutrophil leucocyte of animal subject reduces this side effect.Therefore, according to the method for first aspect present invention, in its prepared bulk drug of the present invention that comprises Glycopyrronium Bromide, the pharmaceutical composition of particularly being made by this bulk drug is for example in pharmaceutical preparation, impurity Iz with respect to the content of formula I compound lower than 2.000% (for example, lower than 1.500%, for example, lower than 1.000%, for example, lower than 0.750%, for example, lower than 0.500%, for example, lower than 0.400%).
According to the method for first aspect present invention, its prepared bulk drug of the present invention that comprises Glycopyrronium Bromide is placed 6 months in 40 ℃ of condition lower seals, lucifuge, calculate the content disposed with this understanding after 6 months when certain impurity phase was for 0 month and increase percentage ratio, wherein according to [HPLC-B], measure the foreign matter content of relative retention time at 2.63～2.73 places and increase percentage ratio lower than 200%, for example, lower than 150%, for example, lower than 100%, for example, lower than 75%, for example, lower than 50%, for example, lower than 40%.This test method in the present invention can be referred to as investigating 40 ℃-June.Described term " foreign matter content increase percentage ratio " is to calculate according to following formula:
Figure BDA0000414809050000111
In above calculating formula, 0 month content of impurity or impurity content in June refer to this impurity relative content with respect to Glycopyrronium Bromide in material.
Further, second aspect present invention provides a kind of bulk drug of hyoscine, and the activeconstituents of this bulk drug is Glycopyrronium Bromide.
Or further, second aspect present invention provides a kind of bulk drug of hyoscine, the activeconstituents of this bulk drug is with following formula I compound:
Figure BDA0000414809050000112
(formula I)
And enantiomorph.
That is, in the present invention, Glycopyrronium Bromide refers to the mixture of above formula I compound and enantiomer thereof racemic mixture for example.
According to the bulk drug of second aspect present invention, comprising formula I compound and the enantiomorph thereof as main ingredient, and the optional Ix impurity as impurity.
According to the bulk drug of second aspect present invention, wherein Ix impurity phase for Glycopyrronium Bromide content lower than 0.5% (for example, lower than 0.4%, for example, lower than 0.3%).
According to the bulk drug of second aspect present invention, comprising formula I compound and the enantiomorph thereof as main ingredient, and the optional Iy impurity as impurity.
According to the bulk drug of second aspect present invention, wherein Iy impurity phase for Glycopyrronium Bromide content lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iy foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.500% scope (for example, in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope, for example, in 0.003%～0.250% scope, for example, in 0.003%～0.200% scope, for example, in 0.003%～0.150% scope, for example, in 0.003%～0.130% scope).
According to the bulk drug of second aspect present invention, comprising formula I compound and the enantiomorph thereof as main ingredient, and the optional Iz impurity as impurity.
According to the bulk drug of second aspect present invention, wherein Iz impurity phase for Glycopyrronium Bromide content lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iz foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.002%～0.500% scope (for example, in 0.002%～0.400% scope, for example, in 0.002%～0.300% scope, for example, in 0.002%～0.250% scope, for example, in 0.002%～0.200% scope, for example, in 0.002%～0.150% scope, for example, in 0.002%～0.130% scope).
According to the bulk drug of second aspect present invention, it is measured according to the present invention [HPLC-A], wherein relative retention time (also can be described as in the present invention RRT0.89 impurity or is called RRT0.89 at the impurity at 0.86～0.92 place, it is essentially impurity Ix) for Glycopyrronium Bromide content lower than 0.5% (for example, lower than 0.4%, for example, lower than 0.3%).
According to the bulk drug of second aspect present invention, it is measured according to the present invention [HPLC-B], wherein relative retention time (also can be described as in the present invention RRT1.14 impurity or is called RRT1.14 at the impurity at 1.10～1.18 places, it is essentially impurity Iy) for Glycopyrronium Bromide content lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iy content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.500% scope (for example, in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope, for example, in 0.003%～0.250% scope, for example, in 0.003%～0.200% scope, for example, in 0.003%～0.150% scope, for example, in 0.003%～0.130% scope).
According to the bulk drug of second aspect present invention, it is measured according to the present invention [HPLC-B], wherein relative retention time (also can be described as in the present invention RRT2.68 impurity or is called RRT2.68 at the impurity at 2.63～2.73 places, it is essentially impurity Iz) for Glycopyrronium Bromide content lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%), for example Iz content (with respect to Glycopyrronium Bromide meter) in 0.002%～0.500% scope (for example, in 0.002%～0.400% scope, for example, in 0.002%～0.300% scope, for example, in 0.002%～0.250% scope, for example, in 0.002%～0.200% scope, for example, in 0.002%～0.150% scope, for example, in 0.002%～0.130% scope).
According to the bulk drug of second aspect present invention, it is placed 6 months in 40 ℃ of condition lower seals, lucifuge, calculate the content disposed with this understanding after 6 months when certain impurity phase was for 0 month and increase percentage ratio, wherein according to [HPLC-B], measure the foreign matter content of relative retention time at 2.63～2.73 places and increase percentage ratio lower than 200%, for example, lower than 150%, for example, lower than 100%, for example, lower than 75%, for example, lower than 50%, for example, lower than 40%.
According to the bulk drug of second aspect present invention, it is to obtain to reach refining object by the bulk drug that comprises formula I compound and enantiomorph thereof being carried out to recrystallization.
According to the bulk drug of second aspect present invention, described recrystallization is that bulk drug is dissolved in the first solvent, then in this solution, adds the second solvent, so that Glycopyrronium Bromide is settled out crystallization from solvent.
According to the bulk drug of second aspect present invention, wherein said the first solvent is selected from: water, methyl alcohol, ethanol, 1-octanol, phenylcarbinol, methyl-sulphoxide, methylene dichloride, ethyl acetate and combination thereof.In one embodiment, described the first solvent is selected from: ethanol, 1-octanol, methyl-sulphoxide, methylene dichloride, ethyl acetate and combination thereof.In one embodiment, the mixture that described the first solvent is ethanol and ethyl acetate.In one embodiment, described the first solvent is the mixture of ethanol and ethyl acetate volume ratio 100:7～20, preferably the mixture of ethanol and ethyl acetate volume ratio 100:10～16.In the present invention, if not otherwise indicated, the ethanol of mentioning is dehydrated alcohol.
According to the bulk drug of second aspect present invention, described the second solvent is selected from: ether, methyl ethyl ether, t-butyl methyl ether, normal heptane, normal hexane, Skellysolve A and combination thereof.In one embodiment, described the second solvent is selected from: ether, methyl ethyl ether, t-butyl methyl ether and combination thereof.In one embodiment, described the second solvent is methyl ethyl ether.
According to the bulk drug of second aspect present invention, the volume ratio of wherein said the first solvent and the second solvent is 1:7～25, for example 1:10～20, for example 1:10～15.
Further, third aspect present invention provides a kind of pharmaceutical composition (for example pharmaceutical preparation), wherein comprises the bulk drug described in second aspect present invention any one, and optional pharmaceutically acceptable carrier or auxiliary material.In one embodiment, pharmaceutical composition of the present invention is to use the bulk drug described in second aspect present invention any one for example, to prepare through pharmaceutical composition (pharmaceutical preparation) preparation technology.
According to the pharmaceutical composition of third aspect present invention, it is oral preparations or injection formulations.
According to the pharmaceutical composition of third aspect present invention, it is tablet, capsule, granule, injection (comprising injection liquid and lyophilize powder injection), suspensoid, pill.
According to the pharmaceutical composition of third aspect present invention, it is injection liquid.
According to the pharmaceutical composition of third aspect present invention, it is injection liquid, in the every 1ml of this injection liquid, comprises: the Glycopyrronium Bromide of 0.1～0.5mg, acid-base modifier and add to the water for injection of full dose.
According to the pharmaceutical composition of third aspect present invention, it is injection liquid, in the every 1ml of this injection liquid, comprises: the Glycopyrronium Bromide of 0.1～0.5mg, acid-base modifier in right amount with the pH value that regulates injection liquid in 2.0～3.0 scopes and add to the water for injection of full dose.In one embodiment, described acid-base modifier is hydrochloric acid and/or sodium hydroxide, can also be to well known to a person skilled in the art other acid-base modifier.
According to the pharmaceutical composition of third aspect present invention, it is injection liquid, the Glycopyrronium Bromide that comprises 0.15～0.25mg in the every 1ml of this injection liquid.In one embodiment, the Glycopyrronium Bromide that comprises 0.2mg in the every 1ml of this injection liquid.
According to the pharmaceutical composition of third aspect present invention, it is injection liquid, wherein also optionally comprises phenylcarbinol.In one embodiment, the phenylcarbinol concentration in this injection liquid is 0.5～1.5mg/ml, and for example phenylcarbinol concentration is 0.7～1.2mg/ml, and for example phenylcarbinol concentration is 0.8～1.0mg/ml, and for example phenylcarbinol concentration is 0.9mg/ml.
According to the pharmaceutical composition of third aspect present invention, it is lyophilize powder injection, in this powder injection, comprises: the freeze-dried excipient of the Glycopyrronium Bromide of 0.2 weight part, 20～400 weight parts.
According to the pharmaceutical composition of third aspect present invention, it is lyophilize powder injection, in this powder injection, comprises: when appropriate so that this powder injection of the freeze-dried excipient of the Glycopyrronium Bromide of 0.2 weight part, 20～400 weight parts, optional pH adjusting agent is diluted to Glycopyrronium Bromide concentration and is 0.2mg/ml with water for injection, the pH value of solution is in 2.0～3.0 scopes.
According to the pharmaceutical composition of third aspect present invention, it is lyophilize powder injection, in this powder injection, comprises: when appropriate so that this powder injection of the freeze-dried excipient of the Glycopyrronium Bromide of 0.2 weight part, 50～250 weight parts, optional pH adjusting agent is diluted to Glycopyrronium Bromide concentration and is 0.2mg/ml with water for injection, the pH value of solution is in 2.0～3.0 scopes.
In one embodiment, described freeze-dried excipient can be selected from N.F,USP MANNITOL, lactose, maltose, sucrose, sodium-chlor etc.
According to the pharmaceutical composition of third aspect present invention, comprising the Glycopyrronium Bromide as active ingredient, and the optional Ix impurity as impurity.
According to the pharmaceutical composition of third aspect present invention, wherein Ix impurity phase for Glycopyrronium Bromide content lower than 1.0% (for example, lower than 0.75%, for example, lower than 0.5%, for example, lower than 0.4%).
According to the pharmaceutical composition of third aspect present invention, comprising the Glycopyrronium Bromide as active ingredient, and the optional Iy impurity as impurity.
According to the pharmaceutical composition of third aspect present invention, wherein Iy impurity phase for Glycopyrronium Bromide content for example, lower than 0.75% (lower than 0.50%, lower than 0.4%, lower than 0.3%), for example Iy foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.750% scope (for example in 0.003%～0.500% scope, for example in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope).
According to the pharmaceutical composition of third aspect present invention, comprising the Glycopyrronium Bromide as active ingredient, and the optional Iz impurity as impurity.
According to the pharmaceutical composition of third aspect present invention, wherein Iz impurity phase for Glycopyrronium Bromide content for example, lower than 1.00% (lower than 0.75%, lower than 0.50%, lower than 0.4%), for example Iz foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.002%～1.000% scope (for example in 0.002%～0.750% scope, for example in 0.002%～0.500% scope, for example, in 0.002%～0.400% scope).
According to the pharmaceutical composition of third aspect present invention, it is measured according to the present invention [HPLC-A], wherein relative retention time (also can be described as in the present invention RRT0.89 impurity or is called RRT0.89 at the impurity at 0.86～0.92 place, it is essentially impurity Ix) for Glycopyrronium Bromide content lower than 1.0% (for example, lower than 0.75%, for example, lower than 0.5%, for example, lower than 0.4%).
According to the pharmaceutical composition of third aspect present invention, it is measured according to the present invention [HPLC-B], wherein relative retention time (also can be described as in the present invention RRT1.14 impurity or is called RRT1.14 at the impurity at 1.10～1.18 places, it is essentially impurity Iy) for Glycopyrronium Bromide content lower than 0.75% (for example, lower than 0.50%, lower than 0.4%, lower than 0.3%), for example Iy foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.750% scope (for example, in 0.003%～0.500% scope, for example, in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope).
According to the pharmaceutical composition of third aspect present invention, it is measured according to the present invention [HPLC-B], wherein relative retention time (also can be described as in the present invention RRT2.68 impurity or is called RRT2.68 at the impurity at 2.63～2.73 places, it is essentially impurity Iz) for Glycopyrronium Bromide content lower than 1.00% (for example, lower than 0.75%, lower than 0.50%, lower than 0.4%), for example Iz foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.002%～1.000% scope (for example, in 0.002%～0.750% scope, for example, in 0.002%～0.500% scope, for example, in 0.002%～0.400% scope).
According to the pharmaceutical composition of third aspect present invention, it is placed 4 months in 40 ℃ of condition lower seals, lucifuge, calculate the content disposed with this understanding after 4 months when certain impurity phase was for 0 month and increase percentage ratio, wherein the foreign matter content of relative retention time at 2.63～2.73 places increases percentage ratio lower than 200%, for example, lower than 150%, for example, lower than 100%, for example, lower than 75%, for example, lower than 50%, for example, lower than 40%.This test method in the present invention can be referred to as investigating 40 ℃-April.
Further, fourth aspect present invention provides the purposes of pharmaceutical composition described in bulk drug described in method prepares described in first aspect present invention bulk drug, second aspect or the third aspect, for the preparation of narcotic or for the preparation for the treatment of and or the medicine of prevention peptide ulceration.
According to either side of the present invention, in wherein said medicinal raw material medicine, the content of Glycopyrronium Bromide is greater than 99.0%, for example, be greater than 99.5%.This content can be measured according to the method under two 814 pages Glycopyrronium Bromides of version Chinese Pharmacopoeia [assay] item in 2010.
According to either side of the present invention, the chromatographic purity that wherein said medicinal raw material medicine is measured according to the present invention [HPLC-A] is in 98.00%～99.99% scope, for example, in 98.50%～99.99% scope, for example, in 99.00%～99.99% scope.Term " chromatographic purity " is trial-product color atlas to be carried out to the result of area normalization method calculating, deduction solvent, auxiliary material isochromatic spectrum peak and the result that obtains, and it is different from content mentioned above.
According to either side of the present invention, the chromatographic purity that wherein said medicinal raw material medicine is measured according to the present invention [HPLC-B] is in 98.00%～99.99% scope, for example, in 98.50%～99.99% scope, for example, in 99.00%～99.99% scope.
Arbitrary embodiment of either side of the present invention, can combine with other arbitrary embodiment of either side, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characterictic goes for this technical characterictic in other embodiment, as long as they there will not be contradiction.
In the present invention, the implication of " % " can be determined according to concrete environment for use, and particularly it has implication as described in " metering " in two notes on the use of version Chinese Pharmacopoeia in 2010 lower the 28 (4) money.
In the present invention, while mentioning separately, " ethanol " refers to dehydrated alcohol.
In the present invention, each carbon atom of Glycopyrronium Bromide can number indicate as follows:
Figure 201310571655X100002DEST_PATH_IMAGE002
be that Glycopyrronium Bromide represents 3R2S Glycopyrronium Bromide and 3S2R Glycopyrronium Bromide.
Also have document for example to indicate in the following manner the numbering of each carbon atom in CN102627595A:
Figure 201310571655X100002DEST_PATH_IMAGE003
be that Glycopyrronium Bromide represents 3R2 ' S Glycopyrronium Bromide and 3S2 ' R Glycopyrronium Bromide.
In addition, Glycopyrronium Bromide can also called after: oxygen base bromination (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxyl-2-phenyl acetyl)]-1,1-dimethyl pyrrolidine.
In the present invention, although the inventor has known the particular chemical of RRT0.89, RRT1.14, tri-specific impurities of RRT2.68, but these impurity also can, by carrying out qualitative sign in its [HPLC-A] at specific, concrete of the present invention and [HPLC-B], particularly use the RRT parameter presenting under specific HPLC condition to characterize.As well known to those skilled in the art, can completely independently use RRT to characterize and needn't consider its particular chemical completely, reason is that RRT is the parameter of a substantially constant under regulation HPLC condition, and RRT characterizes with structural characterization and can be separate or use in combination with one another.And this characterizing method is pharmaceutical field, bulk drug or preparation quality standard are allowed, possess industrial applicability completely.
In the present invention, if not otherwise indicated, in determining various materials (such as various as bulk drug, pharmaceutical composition such as pharmaceutical preparation etc. for pharmaceutical preparation) during the content of Glycopyrronium Bromide or other impurity, and while determining the chromatographic purity in these materials, can all adopt the method for [HPLC-A] mentioned above and [HPLC-B] to measure.
" pharmaceutically acceptable carrier " using in pharmaceutical composition of the present invention can be the carrier of any routine in field of pharmaceutical preparations.The selection of specific support will be depended on administering mode or disease type and the state that is used for the treatment of particular patient.For the preparation method of the suitable drug composition of specific administration pattern completely in pharmaceutical field technician's ken.For example, can be used as thinner, carrier, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and the lubricant etc. that pharmaceutically acceptable carrier comprises pharmaceutical field routine.If desired, can also in pharmaceutical composition, add flavouring agent, preservative and sweetener etc.
Pharmaceutical composition of the present invention can be made the various ways such as tablet, pulvis, granule, capsule, oral liquid, paste, creme, injectable emulsion (aseptic powder needle for injection).The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
Neutrophil leucocyte (Neutrophil or Neutrophil granulocyte, can be abbreviated as NG in the present invention) is a kind of of blood leucocyte, is also topmost a kind of white corpuscle in mammalian.Neutrophil leucocyte plays a very important role in the non-specific cell immunity system of blood, it resists microbial pathogen in body, particularly, at the First Line of suppurative bacterium invasion, when inflammation occurs, they are attracted inflammation part by chemotaxis material.Because they are to borrow glycolysis-to obtain energy, therefore under the anaerobic conditions of swelling thrombosis, still can survive, they form cell toxicant here and have the cytolemma that destroys bacterium and near tissue.Because neutrophil leucocyte contains a large amount of lysosomal enzymes, therefore can decompose engulfing into intracellular bacterium and fragment of tissue, like this, the bacterium of invasion is enclosed in a part, and eliminates, and prevents that pathogenic micro-organism from spreading in vivo.When neutrophil leucocyte itself disintegrates, disengage each lysosomal enzymes and can dissolve surrounding tissue and form abscess.The cytolemma of neutrophil leucocyte can discharge a kind of unsaturated fatty acids---arachidonic acid, under the effect of enzyme, by it, further generate again one group of paracrine hormone substance, as thromboxane and prostaglandin(PG) etc., this class material is to regulating external caliber and permeability to have obvious effect, can also cause inflammation and react and pain, and affect blood coagulation.Thus, the performance that in blood of human body, neutrophil leucocyte reduces for the normal physiological function of human body is disadvantageous.
The existing Glycopyrronium Bromide medicament of list marketing (such as tablet, oral liquid, injection liquid etc.), it can be used for treating peptide ulceration and the anesthesia when performing the operation etc. as a kind of anticholinergic drug.The invention provides a kind of new Glycopyrronium Bromide bulk drug, it has good feature aspect stability, and demonstrate good biological safety, so material medicine of the present invention can be used for treating peptide ulceration equally and for surgery anesthesia and have low rate of side effects.
Embodiment
By the following examples, can conduct further description the present invention, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the working method that the object of the invention used, the present invention still does to describe in detail as far as possible at this.
What while measuring below the RRT0.89 content of each material, use is that [HPLC-A] method is measured, and what measure that RRT1.14 content and RRT2.68 content uses is that [HPLC-B] method is measured.
embodiment 1: prepare Glycopyrronium Bromide bulk drug
Step (1), synthetic compound of formula i and enantiomorph thereof:
According to the method in US2956062A, hydroxycyclopent base methyl mandelate (MCPM) is reacted with N-methylpyrrolidin-3-alcohol (NMP) and obtain the grand amine alkali of lattice (GP alkali), then according to CN101133021B specification sheets [0015]-[0017] section institute support method, the grand amine alkali of lattice being reacted then with monobromethane carries out recrystallizing and refining to products therefrom, obtains Glycopyrronium Bromide.
RRT0.89 content=4.63%, RRT1.14 content=1.78%, RRT2.68 content=1.14%.
Step (2), recrystallizing and refining:
At the temperature of 55～60 ℃, step (1) products therefrom 1.5g is dissolved in to dehydrated alcohol-ethyl acetate mixed solvent (100:12, v/v) in 10ml, slowly drip wherein methyl ethyl ether 120ml, 4～5 ° of standing abundant precipitations (approximately 24 hours) that make, leach precipitation, with methyl ethyl ether, wash, vacuum-drying, obtains (recrystallization yield 90.2%).
RRT0.89 content=0.77%, RRT1.14 content=0.39%, RRT2.68 content=0.23%.After measured, its MS m/z:318 (M-Br -), 1h NMR is identical with the contained Glycopyrronium Bromide of CN103159659A specification sheets final stage.
This recrystallization purifying, RRT0.89 content reduces i.e. (4.63-0.77) ÷ 4.63 * 100% of 83%[, it is applicable equally hereinafter that this content reduces percentage ratio method of calculation], RRT1.14 content reduces by 78%, RRT2.68 content reduction by 80%.
Step (3), recrystallizing and refining again:
At the temperature of 55～60 ℃, step (2) products therefrom 1.0g is dissolved in to dehydrated alcohol-ethyl acetate mixed solvent (100:10, v/v) in 10ml, slowly drip wherein methyl ethyl ether 100ml, 8～10 ° of standing abundant precipitations (approximately 36 hours) that make, leach precipitation, with methyl ethyl ether, wash, vacuum-drying, obtains (recrystallization yield 94.1%).
RRT0.89 content=0.12%, RRT1.14 content=0.08%, RRT2.68 content=0.05%.This recrystallization purifying, RRT0.89 content reduces by 84%, RRT1.14 content and reduces by 79%, RRT2.68 content reduction by 78%.
Step (4), recrystallizing and refining again:
At the temperature of 55～60 ℃, step (3) products therefrom 0.5g is dissolved in to dehydrated alcohol-ethyl acetate mixed solvent (100:16, v/v) in 2.5ml, slowly drip wherein methyl ethyl ether 37.5ml, 0～2 ° of standing abundant precipitation (approximately 18 hours) that makes, leach precipitation, with methyl ethyl ether, wash, vacuum-drying, obtains (recrystallization yield 91.6%).
RRT0.89 content=0.021%, RRT1.14 content=0.018%, RRT2.68 content=0.011%.This recrystallization purifying, RRT0.89 content reduces by 83%, RRT1.14 content and reduces by 78%, RRT2.68 content reduction by 78%.
Step (5), recrystallizing and refining again:
Step (4) products therefrom is shone to step (4) method recrystallizing and refining again, after vacuum-drying, make to measure weight loss on drying at 105 ℃ and be less than 0.1%, method under Chinese Pharmacopoeia two 814 pages Glycopyrronium Bromides of version [assay] item in 2010 is measured, dry product Glycopyrronium Bromide (C19H28BrNO3) content is 99.97%, RRT0.89 content=0.004%, RRT1.14=0.003%, RRT2.68=0.002%.
When above each batch of sample tested, in [HPLC-A] method, the relative retention time of RRT0.89 impurity is all in 0.88～0.91 scope, and Glycopyrronium Bromide retention time is all about 11.3～11.7min; In [HPLC-B] method, the relative retention time of RRT1.14 impurity is all in 1.12～1.16 scopes, and the relative retention time of RRT2.68 impurity is all in 2.65～2.71 scopes, and Glycopyrronium Bromide retention time is all about 8.2～8.6min.
Above step (2) to step (5) products therefrom, particularly step (3) to step (5) products therefrom all can be used as Glycopyrronium Bromide bulk drug of the present invention, for example, for the preparation of pharmaceutical preparation, use.Step (5) products therefrom also can be used as Glycopyrronium Bromide reference substance in addition, as test, uses.
embodiment 2: prepare Glycopyrronium Bromide bulk drug
Step (1), synthetic compound of formula i and enantiomorph thereof:
Method according to CN103159659A specification sheets embodiment part is that specification sheets [0010] section to [0013] section 4 row institute support methods prepare Glycopyrronium Bromide crude product.RRT0.89 content=4.76%, RRT1.14 content=1.61%, RRT2.68 content=1.21%.
Step (2), recrystallizing and refining:
Get above step (1) products therefrom and carry out recrystallization (recrystallization yield 89.7%) according to the embodiment of the present invention 1 step (2) method.
RRT0.89 content=0.83%, RRT1.14 content=0.34%, RRT2.68 content=0.20%.This recrystallization purifying, RRT0.89 content reduces by 82%, RRT1.14 content and reduces by 79%, RRT2.68 content reduction by 83%.
Step (3), recrystallizing and refining again:
Get above step (2) products therefrom and carry out recrystallization (recrystallization yield 93.5%) according to the embodiment of the present invention 1 step (3) method.
RRT0.89 content=0.17%, RRT1.14 content=0.06%, RRT2.68 content=0.04%.This recrystallization purifying, RRT0.89 content reduces by 80%, RRT1.14 content and reduces by 82%, RRT2.68 content reduction by 80%.
Step (4), recrystallizing and refining again:
Get above step (3) products therefrom and carry out recrystallization (recrystallization yield 91.2%) according to the embodiment of the present invention 1 step (4) method.
RRT0.89 content=0.023%, RRT1.14 content=0.010%, RRT2.68 content=0.007%.This recrystallization purifying, RRT0.89 content reduces by 86%, RRT1.14 content and reduces by 83%, RRT2.68 content reduction by 82%.After measured, its MS m/z:318 (M-Br -), 1h NMR is identical with the contained Glycopyrronium Bromide of CN103159659A specification sheets final stage.
When above each batch of sample tested, in [HPLC-A] method, the relative retention time of RRT0.89 impurity is all in 0.86～0.92 scope, in [HPLC-B] method, the relative retention time of RRT1.14 impurity is all in 1.10～1.18 scopes, and the relative retention time of RRT2.68 impurity is all in 2.63～2.73 scopes.
Above step (2) to step (4) products therefrom, particularly step (3) to step (4) products therefrom all can be used as Glycopyrronium Bromide bulk drug of the present invention, for example, for the preparation of pharmaceutical preparation, use.
embodiment 3: prepare Glycopyrronium Bromide bulk drug
Step (1), synthetic compound of formula i and enantiomorph thereof:
Method according to CN102627595A specification sheets embodiment part is that specification sheets [0043] section to [0046] section institute support method prepares Glycopyrronium Bromide.RRT0.89 content=4.13%, RRT1.14 content=1.36%, RRT2.68 content=1.03%.
Step (2), recrystallizing and refining:
Get above step (1) products therefrom and carry out recrystallization (recrystallization yield 92.4%) according to the embodiment of the present invention 1 step (2) method.
RRT0.89 content=0.70%, RRT1.14 content=0.24%, RRT2.68 content=0.16%.This recrystallization purifying, RRT0.89 content reduces by 83%, RRT1.14 content and reduces by 82%, RRT2.68 content reduction by 84%.
Step (3), recrystallizing and refining again:
Get above step (2) products therefrom and carry out recrystallization (recrystallization yield 92.0%) according to the embodiment of the present invention 1 step (3) method.
RRT0.89 content=0.12%, RRT1.14 content=0.048%, RRT2.68 content=0.027%.This recrystallization purifying, RRT0.89 content reduces by 83%, RRT1.14 content and reduces by 80%, RRT2.68 content reduction by 83%.
Step (4), recrystallizing and refining again:
Get above step (3) products therefrom and carry out recrystallization (recrystallization yield 93.1%) according to the embodiment of the present invention 1 step (4) method.
RRT0.89 content=0.021%, RRT1.14 content=0.009%, RRT2.68 content=0.005%.This recrystallization purifying, RRT0.89 content reduces by 85%, RRT1.14 content and reduces by 81%, RRT2.68 content reduction by 81%.After measured, its MS m/z:318 (M-Br -), 1h NMR is identical with the contained Glycopyrronium Bromide of CN103159659A specification sheets final stage.
When above each batch of sample tested, in [HPLC-A] method, the relative retention time of RRT0.89 impurity is all in 0.86～0.92 scope, in [HPLC-B] method, the relative retention time of RRT1.14 impurity is all in 1.10～1.18 scopes, and the relative retention time of RRT2.68 impurity is all in 2.63～2.73 scopes.
Above step (2) to step (4) products therefrom, particularly step (3) to step (4) products therefrom all can be used as Glycopyrronium Bromide bulk drug of the present invention, for example, for the preparation of pharmaceutical preparation, use.
comparing embodiment 1: with reference to the operation of embodiment 1 step (3) herein, different is only by the first solvent is wherein that dehydrated alcohol-ethyl acetate mixed solvent replaces with ethanol and water, methyl alcohol, 1-octanol, phenylcarbinol, ethyl acetate with the mixed solution of volume ratio (100:10), makes 5 batches of products.Calculate these 5 batches of products RRT0.89, RRT1.14, RRT2.68 three's content after this recrystallization purifying and reduce degree, the content of result RRT0.89 reduces all in 31.3～57.4% scopes, the content of RRT1.14 reduces all in 27.8～55.6% scopes, the content reduction of RRT2.68 is all in 33.6～53.8% scopes, and during more than use dehydrated alcohol-ethyl acetate mixed solvent of the present invention, content reduction at least 75% is low.
comparing embodiment 2: with reference to the operation of embodiment 1 step (3) herein, different is only by the first solvent is wherein that dehydrated alcohol-ethyl acetate mixed solvent 100:10 volume ratio changes 100:0,100:5,100:20 or 100:30 into, makes 4 batches of products.Calculate these 4 batches of products and reduce degree through this recrystallization purifying rear impurity content, the content of result RRT0.89 reduces all in 24.1～52.3% scopes, the content reduction of RRT1.14 is all in 17.4～58.6% scopes, and the content of RRT2.68 reduces all in 21.3～42.3% scopes.
comparing embodiment 3: with reference to the operation of embodiment 1 step (3) herein, different is only by the second solvent is wherein that normal hexane replaces with ether, t-butyl methyl ether, normal heptane, normal hexane, makes 4 batches of products.Calculate these 4 batches of products and reduce degree through this recrystallization purifying rear impurity content, the content reduction of result RRT0.89 all reduces all lower than 38% lower than the content of 41%, RRT2.68 lower than the content reduction of 48%, RRT1.14.
comparing embodiment 4: get the product of the embodiment of the present invention 1 step (2) and the product of embodiment 2 steps (2), according to the method for CN101133021B specification sheets [0021] section, carry out recrystallization respectively, make 2 batches of products.Calculate these 2 batches of products and reduce degree through this recrystallization purifying rear impurity content, the content reduction of result RRT0.89 all reduces all lower than 55% lower than the content of 41%, RRT2.68 lower than the content reduction of 52%, RRT1.14.
comparing embodiment 5: according to CN101133021B specification sheets [0014] to [0021] section institute support method, prepare a collection of Glycopyrronium Bromide product (can be designated as #021B in the present invention).
#021B measures according to the present invention [HPLC-A] and [HPLC-B], RRT0.89 content=0.312%, RRT1.14 content=0.193%, RRT2.68 content=0.176%.
By #021B and the present invention, above embodiment 3 steps (3) and step (4) products therefrom three adopt the contained HPLC method of CN101133021B specification sheets [0022] to [0034] section to detect, result is for the impurity at RRT0.95 place, in #021B sample, be 0.14%, in in embodiment 3 steps (3) sample, be in 0.06%, embodiment, 3 steps (4) sample to be 0.011%.Even if suppose that this RRT0.95 and RRT0.89 of the present invention are same substances, show that the HPLC method sensitivity of CN101133021B is low, may there is test leakage.
preparation example 1: preparation RRT0.89 impurity (impurity Ix)
According to CN103012231A specification sheets [0049] to [0052] phase method, prepare respectively 3S, 2 ' S-Glycopyrronium Bromide and 3R, 2 ' R-Glycopyrronium Bromide, respectively through acetonitrile recrystallization make they in the present invention [HPLC-A] method chromatographic purity all more than 98.5%, the two in this chromatography with respect to the relative retention time of 3R2S/3S2R Glycopyrronium Bromide of the present invention all in 0.88～0.91 scope.By this, the two mixes with 1:1 weight ratio, obtains RRT0.89 impurity, and the erythro isomer of Glycopyrronium Bromide of the present invention (impurity Ix), can be used as chemical test of the present invention or biological test and use.
preparation example 2: preparation RRT1.14 impurity (being GP alkali, impurity Iy)
The method of recording according to US2956062A is prepared the grand amine alkali of lattice, through acetone recrystallization, be purified in the present invention [HPLC-B] method chromatographic purity more than 98.5%, its in this chromatography with respect to the relative retention time of 3R2S/3S2R Glycopyrronium Bromide of the present invention in 1.13～1.15 scopes, obtaining RRT1.14 impurity (impurity Iy), can be that chemical test or biological test are used do the present invention.
test example 1: the performance test of bulk drug of the present invention
The physicochemical data of the Glycopyrronium Bromide material of test implementation example 1 step (2)～step (5), embodiment 2 steps (2)～step (4), embodiment 3 steps (2)～step (4), comparing embodiment 1～4 each batch of gained, result is as follows:
(1) appearance character: be white crystalline powder.
(2) fusing point: all, within the scope of 192～196 ℃, molten distance is all no more than 2 ℃.
(3) according to two 814 pages every detection methods of contained Glycopyrronium Bromide of Chinese Pharmacopoeia version in 2010, measure, the Glycopyrronium Bromide sample of these batches of result all meets this standard code.
test example 2: the study on the stability of bulk drug
Get the Glycopyrronium Bromide material of above embodiment 1 step (1)～step (5), embodiment 2 steps (1)～step (4), embodiment 3 steps (1)～step (4) each batch of gained, #021B sample, and with certain proportion, mixed (with a little anhydrous alcohol solution with preparation example 1 gained impurity Ix, preparation example 2 gained impurity Iy and/or commercially available gained impurity Iz by embodiment 1 step (5) gained Glycopyrronium Bromide, vacuum-drying immediately, so that they fully mix, is measured wherein Ix, Iy and/or Iz with respect to the content of Glycopyrronium Bromide) make assembly thing.
By the sealing of these materials, in 40 ℃ of condition lower seals, lucifuge, place 6 months, calculate and dispose with this understanding certain impurity phase after 6 months the content 0 month time increases percentage ratio for this impurity.
Found that, in various content situations, with respect to it, the content 0 month time increases percentage ratio all lower than 36% in the time of 6 months for impurity Ix and impurity Iy.For example the impurity Ix in embodiment 1 step (1) sample was 4.63% in the time of 0 month, was 5.97% when June, and it is 29%[algorithm: (5.97%-4.63%)/4.63% * 100%=29% that impurity Ix content increases percentage ratio, lower same].The impurity Iy in embodiment 1 step (2) sample was for example 0.39% in the time of 0 month again, was 0.51% when June, and it is 31% that impurity Iy content increases percentage ratio.
But for impurity Iz, at high-temperature treatment, the content after 6 months increases percentage ratio and but shows relevant with impurity Iy content in sample for it: when impurity Iy content is lower than 0.130% time, impurity Iz content increases percentage ratio all lower than 33%; But when impurity Iy content is greater than 0.150%, impurity Iz content increases percentage ratio demonstration and is increased to more than 90%, and in sample, the higher impurity of impurity Iy content Iz content increase percentage ratio is larger.The impurity Iy=0.39% in embodiment 1 step (2) sample for example, this sample June rear impurity Iz by original 0.23%, be increased to 0.75%, impurity Iz content increases percentage ratio and reaches 226%; And impurity Iy=0.08% in embodiment 1 step (3) sample, this sample June rear impurity Iz by original 0.05%, be increased to 0.062%, it is only 24% that impurity Iz content increases percentage ratio.#021B is 129% at the content increase percentage ratio of 6 months rear impurity Iz of high-temperature treatment.Concrete outcome is in Table 1.
Table 1:
No. Sample (source or assembly thing) Feature (0 month Ix, Iy, Iz% content) June, Iz increased percentage ratio
1 Ex1S(1) Ix=4.63，Iy=1.78，Iz=1.14 >500%
2 Ex1S(2) Ix=0.77，Iy=0.39，Iz=0.23 226%
3 Ex1S(3) Ix=0.12，Iy=0.08，Iz=0.05 24%
4 Ex1S(4) Ix=0.021、Iy=0.018、Iz=0.011 21%
5 Ex2S(1) Ix=4.76、Iy=1.61、Iz=1.21 >500%
[0254]?
6 Ex2S(2) Ix=0.83、Iy=0.34、Iz=0.20 213%
7 Ex2S(3) Ix=0.17、Iy=0.06、Iz=0.04 26%
8 Ex2S(4) Ix=0.023、Iy=0.010、Iz=0.007 19%
9 Ex3S(1) Ix=4.13、Iy=1.36、Iz=1.03 >400%
10 Ex3S(2) Ix=0.70、Iy=0.24、Iz=0.16 151%
11 Ex3S(3) Ix=0.12、Iy=0.048、Iz=0.027 19%
12 Ex3S(4) Ix=0.021、Iy=0.009、Iz=0.005 24%
More than in table, secondary series Ex1S (1) represents the embodiment of the present invention 1 step (1) products therefrom, this product is as sample, and wherein each impurity phase is listed in the 3rd row " feature (Ix, Iy, Iz% content) " for the content of Glycopyrronium Bromide, and other statement all has similar meaning.
Table 2:
No. Sample (source or assembly thing) Feature (0 month Ix, Iy, Iz% content) June, Iz increased percentage ratio
1 Ex1S(5) Ix=0.004，Iy=0.003、Iz=0.002 17%
2 Ex1S(5)+Iy Ix=0.004，Iy=0.010、Iz=0.002 13%
3 Ex1S(5)+Iy Ix=0.004，Iy=0.025、Iz=0.002 23%
4 Ex1S(5)+Iy Ix=0.004，Iy=0.050、Iz=0.002 26%
5 Ex1S(5)+Iy Ix=0.004，Iy=0.075、Iz=0.002 19%
6 Ex1S(5)+Iy Ix=0.004，Iy=0.100、Iz=0.002 32%
7 Ex1S(5)+Iy Ix=0.004，Iy=0.130、Iz=0.002 29%
8 Ex1S(5)+Iy Ix=0.004，Iy=0.150、Iz=0.002 93%
9 Ex1S(5)+Iy Ix=0.004，Iy=0.175、Iz=0.002 115%
10 Ex1S(5)+Iy Ix=0.004，Iy=0.200、Iz=0.002 117%
11 Ex1S(5)+Iy Ix=0.004，Iy=0.250、Iz=0.002 156%
12 Ex1S(5)+Iy Ix=0.004，Iy=0.300、Iz=0.002 194%
13 Ex1S(5)+Iy Ix=0.004，Iy=0.500、Iz=0.002 258%
14 Ex1S(5)+Iy Ix=0.004，Iy=0.750、Iz=0.002 >300%
15 Ex1S(5)+Iy Ix=0.004，Iy=1.000、Iz=0.002 >400%
16 Ex1S(5)+Iy Ix=0.004，Iy=1.500、Iz=0.002 >500%
17 Ex1S(5)+Iy Ix=0.004，Iy=2.000、Iz=0.002 >500%
More than in table, secondary series Ex1S (5)+Iy represents that the embodiment of the present invention 1 step (5) products therefrom and preparation example 2 gained impurity Iy carry out assembly, in assembly thing, each impurity phase is listed in the 3rd row " feature (Ix, Iy, Iz% content) " for the content of Glycopyrronium Bromide, and other statement all has similar meaning.
Table 3:
No. Sample (source or assembly thing) Feature (0 month Ix, Iy, Iz% content) June, Iz increased percentage ratio
1 Ex1S(4)+Iy Ix=0.021、Iy=0.030、Iz=0.011 25%
2 Ex1S(4)+Iy Ix=0.021、Iy=0.050、Iz=0.011 18%
[0261]?
3 Ex1S(4)+Iy Ix=0.021、Iy=0.075、Iz=0.011 25%
4 Ex1S(4)+Iy Ix=0.021、Iy=0.100、Iz=0.011 32%
5 Ex1S(4)+Iy Ix=0.021、Iy=0.130、Iz=0.011 30%
6 Ex1S(4)+Iy Ix=0.021、Iy=0.150、Iz=0.011 97%
7 Ex1S(4)+Iy Ix=0.021、Iy=0.200、Iz=0.011 121%
8 Ex1S(4)+Iy Ix=0.021、Iy=0.300、Iz=0.011 181%
9 Ex1S(4)+Iy Ix=0.021、Iy=0.500、Iz=0.011 266%
10 Ex1S(4)+Iy Ix=0.021、Iy=0.750、Iz=0.011 >300%
11 Ex1S(4)+Iy Ix=0.021、Iy=1.000、Iz=0.011 >400%
Table 4:
No. Sample (source or assembly thing) Feature (0 month Ix, Iy, Iz% content) June, Iz increased percentage ratio
1 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.030、Iz=0.200 27%
2 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.050、Iz=0.200 21%
3 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.075、Iz=0.200 24%
4 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.100、Iz=0.200 28%
5 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.130、Iz=0.200 31%
6 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.150、Iz=0.200 103%
7 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.200、Iz=0.200 132%
8 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.300、Iz=0.200 197%
9 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.500、Iz=0.200 271%
10 Ex2S(4)+Iy+Iz Ix=0.023、Iy=0.750、Iz=0.200 >300%
11 Ex2S(4)+Iy+Iz Ix=0.023、Iy=1.000、Iz=0.200 >400%
More than in table, secondary series Ex2S (4)+Iy+Iz represents that the embodiment of the present invention 2 steps (4) products therefrom and preparation example 2 gained impurity Iy and commercially available impurity Iz carry out assembly, in assembly thing, each impurity phase is listed in the 3rd row " feature (Ix, Iy, Iz% content) " for the content of Glycopyrronium Bromide, and other statement all has similar meaning.In table, result is visible, even if the impurity Iz increasing in right amount in sample body measures to 0.200%, it is still relevant with the impurity Iy in sample that its content increases trend.
In addition, with reference to the assembly thing of above table 4, different is in each sample, to add appropriate impurity Ix in composition, for the amount of Glycopyrronium Bromide, to reach 0.5% to it again.Obtain 11 assembly things and carry out equally 40 ℃ of disposal in 6 months, with respect to it, the content 0 month time increases percentage ratio all lower than 33% in the time of 6 months for result impurity Ix and impurity Iy.But in the time of 6 months, with respect to it, the content 0 month time increases the assembly thing result basic identical (being all no more than 5 percentage points) of corresponding impurity Iy content in percentage ratio and table 4 to impurity Iz, for example, be 136% with the Iz increase percentage ratio of the corresponding assembly thing of sample of table 4 numbering 7.
After tested, the sample that wherein impurity Ix content is minimum is 0.004% to the Glycopyrronium Bromide that can be used as bulk drug that these are prepared above, and the sample that impurity Iy content is minimum is 0.003%, and the sample that impurity Iz content is minimum is 0.002%.Obviously, with regard to bulk drug of the present invention, wherein impurity Iy for Glycopyrronium Bromide content lower than 0.50% (for example, lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%) be useful, for example Iy content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.500% scope (for example, in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope, for example, in 0.003%～0.250% scope, for example, in 0.003%～0.200% scope, for example, in 0.003%～0.150% scope, for example, in 0.003%～0.130% scope) be useful.After tested the above-mentioned Glycopyrronium Bromide that can be used as bulk drug for their impurity Iy for Glycopyrronium Bromide content lower than 0.13% sample, their impurity Ix for Glycopyrronium Bromide content all lower than 0.3%, their impurity Iz for Glycopyrronium Bromide content all lower than 0.13%.---for can be used as Glycopyrronium Bromide bulk drug of the present invention, as one embodiment of the invention, in Glycopyrronium Bromide bulk drug of the present invention, impurity Ix for Glycopyrronium Bromide content for example, lower than 0.3% (being 0.004%～0.300%), impurity Iy for Glycopyrronium Bromide content in 0.003%～0.130% scope, content is in 0.002%～0.130% scope for Glycopyrronium Bromide for impurity Iz, and the Glycopyrronium Bromide bulk drug with these features is that the present invention is preferred.
composition example 1:
Use the embodiment of the present invention 1 step (4) gained Glycopyrronium Bromide as bulk drug, by following formulated injection liquid, (with 1ml amount, list formula, but during actual dosing, batch quantity is 1000ml): Glycopyrronium Bromide 0.2mg, it is 2.5 that 1N hydrochloric acid and/or 1N sodium hydroxide regulate the final pH value of injection liquid in right amount, and water for injection adds to 1ml in right amount.
Injection liquid compound method routinely, prepares injection liquid.When dosing, optionally in injection liquid, add appropriate impurity Iy, obtain having the injection liquid of different impurities Iy content.
These injection liquid sealings by fusing, in 1ml Brown Glass Brown glass bottles and jars only, by the sealing of these injection liquids, are placed 4 months in 40 ℃ of condition lower seals, lucifuge, calculated and dispose with this understanding certain impurity phase after 4 months the content 0 month time increases percentage ratio for this impurity.
Found that, in various content situations, with respect to it, the content 0 month time increases percentage ratio all lower than 51% in the time of 6 months for impurity Ix and impurity Iy.For embodiment 1 step (4), be for example the injection liquid that raw material does not add impurity Iy, impurity Ix was 0.024% in the time of 0 month, was 0.031% when June, and it is 29% that impurity Ix content increases percentage ratio; Impurity Iy was 0.021% in the time of 0 month, was 0.028% when June, and it is 33% that impurity Iy content increases percentage ratio.
But for impurity Iz, at high-temperature treatment, the content after 4 months increases percentage ratio and but shows relevant with impurity Iy content in sample for it: when impurity Iy content is lower than 0.300% time, impurity Iz content increases percentage ratio all lower than 45%; But when impurity Iy content is greater than 0.300%, impurity Iz content increases percentage ratio demonstration and is increased to more than 90%, and in sample, the higher impurity of impurity Iy content Iz content increase percentage ratio is larger.Concrete outcome is in Table 5.
Table 5:
No. Injection liquid (the main batching of interpolation) Feature (0 month Ix, Iy, Iz% content) April, Iz increased percentage ratio
1 Ex1S(4) Ix=0.024、Iy=0.021、Iz=0.014 25%
2 Ex1S(4)+Iy Ix=0.025、Iy=0.050、Iz=0.013 18%
3 Ex1S(4)+Iy Ix=0.024、Iy=0.100、Iz=0.014 25%
4 Ex1S(4)+Iy Ix=0.024、Iy=0.150、Iz=0.015 32%
5 Ex1S(4)+Iy Ix=0.023、Iy=0.200、Iz=0.015 30%
6 Ex1S(4)+Iy Ix=0.026、Iy=0.250、Iz=0.014 37%
7 Ex1S(4)+Iy Ix=0.025、Iy=0.300、Iz=0.014 39%
8 Ex1S(4)+Iy Ix=0.024、Iy=0.350、Iz=0.015 97%
9 Ex1S(4)+Iy Ix=0.024、Iy=0.400、Iz=0.014 173%
[0275]?
10 Ex1S(4)+Iy Ix=0.025、Iy=0.500、Iz=0.014 288%
11 Ex1S(4)+Iy Ix=0.024、Iy=0.750、Iz=0.015 >300%
12 Ex1S(4)+Iy Ix=0.025、Iy=1.000、Iz=0.014 >400%
13 Ex1S(4)+Iy Ix=0.023、Iy=1.500、Iz=0.015 >500%
composition example 2:
Reference group compound example 1 is carried out, and different is only in injection liquid, to supplement the phenylcarbinol that increases 9mg/ml concentration.Same according to the method in composition example 1, carry out disposing 40 ℃ of April test, with respect to it, the content 0 month time increases percentage ratio all lower than 47% in the time of 4 months for result impurity Ix and impurity Iy.But in the time of 4 months, with respect to it, the content 0 month time increases the assembly thing result basic identical (being all no more than 7 percentage points) of corresponding impurity Iy content in percentage ratio and table 5 to impurity Iz, for example, be 168% with the Iz increase percentage ratio of the corresponding injection liquid of sample of table 5 numbering 9.
composition example 3:
Reference group compound example 1 is carried out, and different is only to change embodiment 1 step (4) the gained Glycopyrronium Bromide bulk drug using into embodiment 3 steps (3) gained Glycopyrronium Bromide bulk drug when throwing.Same according to the method in composition example 1, carry out disposing 40 ℃ of April test, with respect to it, the content 0 month time increases percentage ratio all lower than 53% in the time of 4 months for result impurity Ix and impurity Iy.But in the time of 4 months, with respect to it, the content 0 month time increases the assembly thing result basic identical (being all no more than 5 percentage points) of corresponding impurity Iy content in percentage ratio and table 5 to impurity Iz, for example, be 38% with the Iz increase percentage ratio of the corresponding injection liquid of sample of table 5 numbering 7.
composition example 4:
Bulk drug: use above embodiment 1 step (5) product, preparation example 1 impurity in products Ix, preparation example 1 impurity in products Iy and commercially available gained impurity Iz, they are mixed, obtain having the bulk drug of following foreign matter content: bulk drug 1:RRT0.89=0.005%, RRT1.14=0.003%, RRT2.68=0.002%; Bulk drug 2:RRT0.89=0.500%, RRT1.14=0.300%, RRT2.68=0.400%; Bulk drug 3:RRT0.89=0.250%, RRT1.14=0.150%, RRT2.68=0.200%; Bulk drug 4:RRT0.89=0.450%, RRT1.14=0.185%, RRT2.68=0.330%; Bulk drug 5:RRT0.89=0.224%, RRT1.14=0.125%, RRT2.68=0.255%.
Reference group compound example 1 is carried out, different is only to change embodiment 1 step (4) the gained Glycopyrronium Bromide bulk drug using into above bulk drug 1, bulk drug 2, bulk drug 3, bulk drug 4, bulk drug 5 when throwing, obtaining 5 batches of compositions, is Glycopyrronium Bromide injection liquid.These Glycopyrronium Bromide injection liquids are carried out disposing in 40 ℃ of April test according to the method in composition example 1 equally, and with respect to it, the content 0 month time increases percentage ratio all lower than 48% in the time of 4 months for result impurity Ix, impurity Iy, impurity Iz three.
Reference group compound example 2 is carried out, different is only to change embodiment 1 step (4) the gained Glycopyrronium Bromide bulk drug using into above bulk drug 1, bulk drug 2, bulk drug 3, bulk drug 4, bulk drug 5 when throwing, obtaining 5 batches of compositions, is Glycopyrronium Bromide injection liquid.These Glycopyrronium Bromide injection liquids are carried out disposing in 40 ℃ of April test according to the method in composition example 1 equally, and with respect to it, the content 0 month time increases percentage ratio all lower than 45% in the time of 4 months for result impurity Ix, impurity Iy, impurity Iz three.
After tested, what wherein impurity Iy content was minimum is 0.003% to these compositions above, and what impurity Iz content was minimum is 0.002%.Obviously, with regard to the present composition, wherein impurity Iy for Glycopyrronium Bromide content (for example lower than 0.50%, lower than 0.4%, lower than 0.3%) is useful lower than 0.75%, for example Iy foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.750% scope (for example in 0.003%～0.500% scope, for example in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope) be useful.
These are prepared above can be used as preparation particularly injection liquid Glycopyrronium Bromide composition after tested, the sample that wherein impurity Ix content is minimum is 0.005%, the sample that impurity Iy content is minimum is 0.003%, the sample that impurity Iz content is minimum is 0.002%.Obviously, with regard to the present composition, wherein impurity Iy for Glycopyrronium Bromide content (for example lower than 0.50%, lower than 0.4%, lower than 0.3%) is useful lower than 0.75%, for example Iy foreign matter content (with respect to Glycopyrronium Bromide meter) in 0.003%～0.750% scope (for example in 0.003%～0.500% scope, for example in 0.003%～0.400% scope, for example, in 0.003%～0.300% scope) be useful.After tested above-mentioned can be used as preparation particularly injection liquid Glycopyrronium Bromide composition for their impurity Iy for Glycopyrronium Bromide content lower than 0.300% sample, their impurity Ix for Glycopyrronium Bromide content all lower than 0.5%, their impurity Iz for Glycopyrronium Bromide content all lower than 0.400%.---for can be used as Glycopyrronium Bromide composition of the present invention, as one embodiment of the invention, in Glycopyrronium Bromide composition of the present invention, impurity Ix for Glycopyrronium Bromide content in 0.005%～0.500% scope, impurity Iy for Glycopyrronium Bromide content in 0.003%～0.300% scope, content is in 0.002%～0.400% scope for Glycopyrronium Bromide for impurity Iz, and the Glycopyrronium Bromide composition with these features is that the present invention is preferred.
test example 3: biological test
This test example is investigated the impact of related substances on the neutrophil leucocyte in mouse blood.
(1) animal: BALB/c mouse, female 6～8 week age.
(2) reagent: use the embodiment of the present invention 1 step (5) gained Glycopyrronium Bromide reference substance, preparation example 1 gained impurity Ix, preparation example 2 gained impurity Iy, commercially available impurity Iz, their mixed thing to test, use 0.9% physiological saline to be mixed with the sterile solution of suitable concentration.
(3) grouping: mouse random packet, 10 every group; Concrete group is as follows: a) control group: injection and the isopyknic physiological saline of each administration group; B) Glycopyrronium Bromide group: embodiment 1 step (5) gained Glycopyrronium Bromide reference substance; C) impurity Ix group; D) impurity Iy group; E) impurity Iz group; F) Glycopyrronium Bromide/impurity Iz group (containing 0.230% Iz and the Glycopyrronium Bromide of surplus) that is mixed; G) Glycopyrronium Bromide/impurity Iz group (containing 0.400% Iz and the Glycopyrronium Bromide of surplus) that is mixed; H) Glycopyrronium Bromide/impurity Iz group (containing 0.750% Iz and the Glycopyrronium Bromide of surplus) that is mixed; I) Glycopyrronium Bromide/impurity Iz group (containing 1.50% Iz and the Glycopyrronium Bromide of surplus) that is mixed; J) Glycopyrronium Bromide/impurity Iz group (containing 5.0% Iz and the Glycopyrronium Bromide of surplus) that is mixed; K) Glycopyrronium Bromide/impurity Iz group (containing 10.0% Iz and the Glycopyrronium Bromide of surplus) that is mixed; L) Glycopyrronium Bromide/impurity Iz group (containing 25.0% Iz and the Glycopyrronium Bromide of surplus) that is mixed; M) Glycopyrronium Bromide/impurity Iz group (containing 50.0% Iz and the Glycopyrronium Bromide of surplus) that is mixed.
(4) dosage, administration, method: each animal is at least raised 48 hours before administration, in the time of-24 hours, 0 hour, eye socket is got blood, cell counting (using the routine blood test automatic analyser that U.S. Coulter company produces to measure) centering granulocyte count routinely, calculating every treated animal counts average at the neutrophil leucocyte of each time point (this average can be abbreviated as PNG below, this average of 0 hour can be abbreviated as PNG0), for every treated animal, within-24 hours, the PNG with 0 hour two time point differs and is no more than 3%.Respectively at 0 hour, 24 hours, 48 hours, through abdominal injection, give respectively to organize reagent 3 times, give total compound amount (with Glycopyrronium Bromide, impurity Ix, impurity Iy, impurity Iz or its summation meter) 50 μ mol/kg the weight of animals at every turn, for example, for m) Glycopyrronium Bromide/impurity Iz group that is mixed, the dosage of the summation meter 50 μ mol/kg the weight of animals of Iz and Glycopyrronium Bromide.At the 54th hour (after being last administration 6 hours) each animal eye socket, get blood, cell counting centering granulocyte count, calculates the neutrophil leucocyte of every treated animal in the time of the 54th hour and counts average (this average is abbreviated as PNG56) routinely.
(5) result is calculated: the neutrophil leucocyte relative number that is calculated as follows every treated animal:
Neutrophil leucocyte relative number (%)=(PNG56 ÷ PNG0) * 100%
The changing conditions of neutrophil leucocyte in above neutrophil leucocyte relative number reflection peripheral blood, this parameter more shows that close to 100% the neutrophil leucocyte in blood changes less, this parameter is lower than 100% time, numerical value is lower shows that neutrophil leucocyte minimizing is more, and this parameter shows while being greater than 100% that neutrophil leucocyte increases.The results are shown in Table 6.
Table 6:
Group Neutrophil leucocyte relative number Group Neutrophil leucocyte relative number
A) control group 102.5% H) Glycopyrronium Bromide/impurity Iz group that is mixed 57.5%
B) Glycopyrronium Bromide group 99.4% I) Glycopyrronium Bromide/impurity Iz group that is mixed 38.6%
C) impurity Ix group 103.3% J) Glycopyrronium Bromide/impurity Iz group that is mixed 23.1%
D) impurity Iy group 101.7% K) Glycopyrronium Bromide/impurity Iz group that is mixed 15.3%
E) impurity Iz group; 1.55% L) Glycopyrronium Bromide/impurity Iz group that is mixed 7.9%
F) Glycopyrronium Bromide/impurity Iz group that is mixed 99.5% M) Glycopyrronium Bromide/impurity Iz group that is mixed 2.1%
G) Glycopyrronium Bromide/impurity Iz group that is mixed 94.7% ? ?
For e) group, the 4530/μ L of neutrophil count during by the 0th hour, the 70/μ L while being reduced to the 54th hour.For Iz content lower than 0.4% assembly thing, this does not change neutrophil leucocyte base in blood, but when Iz content is more than or equal to 0.75%, the neutrophil leucocyte number in blood sharply reduces, this for experimenter maintain normal body function particularly normal immunologic function be totally unfavorable.
test example 4: biological test
Document (B.V.Franko et al. according to people such as B.V.Franko, Toxicol.Appl.Pharmacol.17,361 (1970)) method of recording in, measure the gained Glycopyrronium Bromide of the embodiment of the present invention 1 step (4) and medium lethal dose (the LD50 value of impurity Iz, mouse, i.p. administration, 72hr), to investigate the acute toxicity of related substances to mouse.The LD50=136mg/kg of result Glycopyrronium Bromide, the LD50=17mg/kg of impurity Iz, shows that the security of impurity Iz is poor more than Glycopyrronium Bromide.
industrial applicability
Glycopyrronium Bromide bulk drug provided by the invention or preparation, as a kind of anticholinergic, can be used for anesthesia, peptide ulceration, salivation etc. clinically.This bulk drug or preparation have the gastric secretion of inhibition and regulate gastrointestinal peristalsis effect; There is the anti-salivation effect stronger than coromegine, but do not have central cholinolytic active.Be generally used for clinically the diseases such as gastric and duodenal ulcer, chronic gastritis, gastroxia.

Claims (10)

1. a bulk drug for hyoscine, the activeconstituents of this bulk drug is with following formula I compound:
(formula I)
And enantiomorph.
2. according to the bulk drug of claim 1, comprising formula I compound and the enantiomorph thereof as main ingredient, and the optional Ix impurity as impurity; Further, wherein Ix impurity phase for Glycopyrronium Bromide content lower than 0.5% (for example, lower than 0.4%, for example, lower than 0.3%); Further, wherein said Ix impurity refers to the compound with following formula Ix
Figure FDA0000414809040000012
(formula Ix)
And enantiomorph.
3. according to the bulk drug of claim 1, comprising formula I compound and the enantiomorph thereof as main ingredient, and the optional Iy impurity as impurity; Further, wherein Iy impurity phase for Glycopyrronium Bromide content for example, lower than 0.50% (lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%); Further, wherein said Iy impurity refers to the compound with following formula Iy
Figure FDA0000414809040000013
(formula Iy).
4. according to the bulk drug of claim 1, comprising formula I compound and the enantiomorph thereof as main ingredient, and the optional Iz impurity as impurity; Further, wherein Iz impurity phase for Glycopyrronium Bromide content for example, lower than 0.50% (lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%); Further, wherein said Iz impurity refers to the compound with following formula Iz
Figure FDA0000414809040000021
(formula Iz).
5. according to the bulk drug of claim 1-4 any one, it is characterized in that:
It is measured according to the present invention [HPLC-A], wherein relative retention time the impurity phase at 0.86～0.92 place for Glycopyrronium Bromide content lower than 0.5% (for example, lower than 0.4%, for example, lower than 0.3%);
It is measured according to the present invention [HPLC-B], wherein relative retention time the impurity phase at 1.10～1.18 places for Glycopyrronium Bromide content for example, lower than 0.50% (lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%);
It is measured according to the present invention [HPLC-B], wherein relative retention time the impurity phase at 2.63～2.73 places for Glycopyrronium Bromide content for example, lower than 0.50% (lower than 0.30%, lower than 0.25%, lower than 0.20%, lower than 0.15%, lower than 0.13%); And/or
It is placed 6 months in 40 ℃ of condition lower seals, lucifuge, calculate the content disposed with this understanding after 6 months when certain impurity phase was for 0 month and increase percentage ratio, wherein according to [HPLC-B], measure the foreign matter content of relative retention time at 2.63～2.73 places and increase percentage ratio lower than 200%, for example, lower than 150%, for example, lower than 100%, for example, lower than 75%, for example, lower than 50%, for example, lower than 40%.
6. a pharmaceutical composition, wherein comprises the bulk drug described in claim 1-5 any one, and optional pharmaceutically acceptable carrier or auxiliary material; Further, it is oral preparations or injection formulations; Further, it is tablet, capsule, granule, injection (comprising injection liquid and lyophilize powder injection), suspensoid, pill; Further, it is injection liquid, in the every 1ml of this injection liquid, comprises: the Glycopyrronium Bromide of 0.1～0.5mg, acid-base modifier in right amount with the pH value that regulates injection liquid in 2.0～3.0 scopes and add to the water for injection of full dose; Further, it is injection liquid, wherein also optionally comprises phenylcarbinol; Further, the phenylcarbinol concentration in this injection liquid is 0.5～1.5mg/ml, and for example phenylcarbinol concentration is 0.7～1.2mg/ml, and for example phenylcarbinol concentration is 0.8～1.0mg/ml, and for example phenylcarbinol concentration is 0.9mg/ml; Further, it is lyophilize powder injection, in this powder injection, comprises: the freeze-dried excipient of the Glycopyrronium Bromide of 0.2 weight part, 20～400 weight parts; Further, it is lyophilize powder injection, in this powder injection, comprises: when appropriate so that this powder injection of the freeze-dried excipient of the Glycopyrronium Bromide of 0.2 weight part, 20～400 weight parts, optional pH adjusting agent is diluted to Glycopyrronium Bromide concentration and is 0.2mg/ml with water for injection, the pH value of solution is in 2.0～3.0 scopes.
7. according to the pharmaceutical composition of claim 6, comprising the Glycopyrronium Bromide as active ingredient, and the optional Ix impurity as impurity; Further, wherein Ix impurity phase for Glycopyrronium Bromide content lower than 1.0% (for example, lower than 0.75%, for example, lower than 0.5%, for example, lower than 0.4%).
8. according to the pharmaceutical composition of claim 6, comprising the Glycopyrronium Bromide as active ingredient, and the optional Iy impurity as impurity; Further, wherein Iy impurity phase for Glycopyrronium Bromide content for example, lower than 0.75% (lower than 0.50%, lower than 0.4%, lower than 0.3%).
9. according to the pharmaceutical composition of claim 6, comprising the Glycopyrronium Bromide as active ingredient, and the optional Iz impurity as impurity; Further, wherein Iz impurity phase for Glycopyrronium Bromide content for example, lower than 1.00% (lower than 0.75%, lower than 0.50%, lower than 0.4%).
10. according to the pharmaceutical composition of claim 6-9 any one, it is characterized in that:
It is measured according to the present invention [HPLC-A], wherein relative retention time the impurity phase at 0.86～0.92 place for Glycopyrronium Bromide content lower than 1.0% (for example, lower than 0.75%, for example, lower than 0.5%, for example, lower than 0.4%);
It is measured according to the present invention [HPLC-B], wherein relative retention time the impurity phase at 1.10～1.18 places for Glycopyrronium Bromide content for example, lower than 0.75% (lower than 0.50%, lower than 0.4%, lower than 0.3%);
It is measured according to the present invention [HPLC-B], wherein relative retention time the impurity phase at 2.63～2.73 places for Glycopyrronium Bromide content for example, lower than 1.00% (lower than 0.75%, lower than 0.50%, lower than 0.4%); And/or
It is placed 4 months in 40 ℃ of condition lower seals, lucifuge, calculate the content disposed with this understanding after 4 months when certain impurity phase was for 0 month and increase percentage ratio, wherein the foreign matter content of relative retention time at 2.63～2.73 places increases percentage ratio lower than 200%, for example, lower than 150%, for example, lower than 100%, for example, lower than 75%, for example, lower than 50%, for example, lower than 40%.
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