CN102885763B - Mupirocin ointment pharmaceutical composition - Google Patents
Mupirocin ointment pharmaceutical composition Download PDFInfo
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- CN102885763B CN102885763B CN201210422426.7A CN201210422426A CN102885763B CN 102885763 B CN102885763 B CN 102885763B CN 201210422426 A CN201210422426 A CN 201210422426A CN 102885763 B CN102885763 B CN 102885763B
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Abstract
The invention relates to a novel mupirocin ointment pharmaceutical composition, particularly to an ointment pharmaceutical composition. The ointment pharmaceutical composition comprises mupirocin shown in the following formula in the specification or pharmaceutically acceptable salt thereof, polyethylene glycol and amino acid, wherein polyethylene glycol comprises polyethylene glycol with a molecular weight of 200-600 and polyethylene glycol with a molecular weight of 2000-6000. The ointment pharmaceutical composition provided by the invention has excellent pharmaceutical characteristics.
Description
Technical field
The present invention relates to a kind of mupirocin ointment pharmaceutical composition of novelty, and the preparation method of this pharmaceutical composition.
Background technology
Mupirocin (Mupirocin) has another name called Mupirocin, by pseudomonas fluorescens (Pseudomonas fluorescens), isolated, be a kind of more satisfactory skin surface antibiotic preparation, in 1985, by GlaxoSmithKline PLC, take " Mupirocin Ointment " (Bactroban) as trade name is introduced to the market.U.S. FDA is used in the approval Gai Yao U.S. in 1987 listing, and China was approval Sino-U.S.'s SmithKline pharmaceutical manufacturing in 1993 and sell this medicine.Mupirocin is mainly used in prevention and treats the bacterial skin infections disease that gram-positive cocci causes, primary cutaneous such as impetigo, furuncle and phyma, folliculitis infects, and the Secondary cases skin infection diseases such as eczema concurrent infection, ulcer concurrent infection, wound concurrent infection.The dominant mechanism of mupirocin antibacterial action is the protein synthesis in anti-bacteria body.Particularly, mupirocin acts on the binding site of isoleucine-tRNA synzyme in bacterial body and isoleucine, thereby hindered aminoacid is synthetic, has also consumed intracellular tRNA, and the building-up process of the synthetic and protein of RNA is ended.
The chemistry 9-[[(2E by name of mupirocin)-4-[(2S, 3R, 4R, 5S)-5-[(2S, 3S; 4S, 5S)-2,3-epoxy-5-hydroxy-4-methyl hexyl]-3,4-dihydroxy-3; 4,5,6-tetrahydrochysene-2H-pyrans-2-yl]-3-methyl but-2-ene acyl group] oxygen base] n-nonanoic acid, molecular formula is C
26h
44o
9, molecular weight is 500.6, chemical structural formula is:
At present, in clinical practice, the main preparation of mupirocin has two kinds of mupirocin calcium cream (take mupirocin calcium as active component) and mupirocin ointments (take mupirocin as active component).The mupirocin ointment of existing Sino-America Tianjin Shike Pharmaceutical Co., Ltd. production and selling, its active component is mupirocin, ointment base is PEG400 (mean molecule quantity is 400, lower same) and PEG3350.
However, the product preparation of clinical use particularly of the new method preparation of mupirocin is still expected to have in this area, and this new preparation expects to have the good pharmacy feature of at least one aspect.
Summary of the invention
The object of the present invention is to provide a kind of method of new preparation mupirocin, to be mixed with the particularly preparation of clinical use of product, and give the good pharmacy feature that this new preparation has at least one aspect.The inventor is surprised to find the effect that the mupirocin ointment medicament compositions with formula of the present invention has obtained desirable, the present invention is based on this and is accomplished.
Of the present invention, aspect first, provide a kind of ointment medicament compositions, wherein comprised: mupirocin shown in following formula or the acceptable salt of its pharmacy, Polyethylene Glycol and aminoacid,
According to the ointment medicament compositions of first aspect present invention, it comprises the Polyethylene Glycol that mupirocin or the acceptable salt of its pharmacy, molecular weight are 200 ~ 600, Polyethylene Glycol and the aminoacid that molecular weight is 2000 ~ 6000.
According to the ointment medicament compositions of first aspect present invention, the acceptable salt of pharmacy of wherein said mupirocin is calcium salt or its solvate of mupirocin.
According to the ointment medicament compositions of first aspect present invention, the acceptable salt of pharmacy of wherein said mupirocin is calcium salt or its hydrate of mupirocin.
According to the ointment medicament compositions of first aspect present invention, the acceptable salt of pharmacy of wherein said mupirocin is the dihydrate of the mupirocin calcium salt shown in following formula:
According to the ointment medicament compositions of first aspect present invention, the Polyethylene Glycol that wherein said molecular weight is 200 ~ 600 is that molecular weight is the Polyethylene Glycol of 200-400.The Polyethylene Glycol that for example described molecular weight is 200 ~ 600 is that molecular weight is 200,300,400 Polyethylene Glycol or its combination.
According to the ointment medicament compositions of first aspect present invention, the Polyethylene Glycol that wherein said molecular weight is 200 ~ 600 is that molecular weight is 400 Polyethylene Glycol.
According to the ointment medicament compositions of first aspect present invention, the Polyethylene Glycol that wherein said molecular weight is 2000 ~ 6000 is that molecular weight is the Polyethylene Glycol of 2000-4000.The Polyethylene Glycol that for example described molecular weight is 2000 ~ 4000 is that molecular weight is 2000,3000,3350,4000 Polyethylene Glycol or its combination.
According to the ointment medicament compositions of first aspect present invention, the Polyethylene Glycol that wherein said molecular weight is 2000 ~ 6000 is that molecular weight is 3350 Polyethylene Glycol.
According to the ointment medicament compositions of first aspect present invention, wherein said aminoacid is selected from lysine, arginine, histidine or its combination.In one embodiment, described aminoacid is selected from lysine, arginine or its combination.
According to the ointment medicament compositions of first aspect present invention, wherein also comprise the acceptable adjuvant of optional pharmacy.It is to be different from above-mentioned Polyethylene Glycol and amino acid whose adjuvant.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin or the acceptable salt of its pharmacy: 0.5 ~ 5g,
Molecular weight is 2000 ~ 6000 Polyethylene Glycol: 10 ~ 30g,
Aminoacid: 0.5 ~ 10g,
The acceptable adjuvant of optional pharmacy: 0 ~ 5g, and
Molecular weight is 200 ~ 600 Polyethylene Glycol: appropriate, add to 100g.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin or the acceptable salt of its pharmacy: 1 ~ 3g,
Molecular weight is 2000 ~ 6000 Polyethylene Glycol: 15 ~ 25g,
Aminoacid: 0.5 ~ 4g,
The acceptable adjuvant of optional pharmacy: 0 ~ 2g, and
Molecular weight is 200 ~ 600 Polyethylene Glycol: appropriate, add to 100g.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin or the acceptable salt of its pharmacy: 1 ~ 3g,
Molecular weight is 2000 ~ 4000 Polyethylene Glycol: 15 ~ 25g,
Aminoacid: 1 ~ 3g,
The acceptable adjuvant of optional pharmacy: 0 ~ 2g, and
Molecular weight is 200 ~ 400 Polyethylene Glycol: appropriate, add to 100g.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 1.5g,
PEG4000：18g，
Arginine: 1g,
PEG400: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 2g,
PEG3350：19g，
Arginine: 2g,
PEG400: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 2.5g,
PEG3350：20g，
Arginine: 3g,
PEG300: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 3g,
PEG3000：10g，
PEG4000：5g，
Arginine: 4g,
PEG600: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 1g,
PEG2000：25g，
Arginine: 0.5g,
PEG200: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 2g,
PEG6000：15g，
Arginine: 1.5g,
PEG200: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 2g,
PEG4000：15g，
Lysine: 3.5g,
Borneolum Syntheticum: 0.5g,
PEG400：30g，
PEG300: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin calcium: 2.5g,
PEG3350：20g，
Arginine: 2.5g,
Oleum menthae: 1.5g,
PEG20000：0.5g，
PEG200: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin calcium: 3g,
PEG2000：25g，
Lysine: 3.5g,
PEG400: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 2.5g,
PEG4000：15g，
Arginine: 1g,
Lysine: 1g,
Herba Menthae: 0.2g,
PEG200: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 1.5g,
PEG4000：18g，
Lysine: 1g,
PEG400: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 2g,
PEG3350：19g，
Lysine: 2g,
PEG400: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 2.5g,
PEG3350：20g，
Lysine: 3g,
PEG300: appropriate, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, the acceptable adjuvant of wherein said optional pharmacy is such as but not limited to warming regulator (such as Borneolum Syntheticum, Mentholum, Oleum menthae), antiseptic (such as benzyl alcohol), thickening agent (Polyethylene Glycol that is greater than 6000 such as carbomer, molecular weight) etc.
Second aspect present invention provides the method for preparing ointment medicament compositions described in first aspect present invention, and it comprises the following steps:
(1) making aminoacid and the optional acceptable adjuvant of pharmacy be dissolved in appropriate molecular weight is, in 200 ~ 600 Polyethylene Glycol, to obtain mixture;
(2) in the mixture of step (1), add mupirocin or the acceptable salt of its pharmacy, stirring and dissolving;
(3) Polyethylene Glycol that is 2000 ~ 6000 by molecular weight is heated to melting, then it is under agitation joined in step (2) gained material, stirs;
(4) add molecular weight be 200 ~ 600 Polyethylene Glycol to full dose, mix homogeneously, obtains.
According to the method for second aspect present invention, the addition of the Polyethylene Glycol that wherein molecular weight is 200 ~ 600 in step (1) can be this component roughly consumption 50 ~ 95%.Respective components fully dissolve or the prerequisite that mixes under, in step (1), suitably add less molecular weight be 200 ~ 600 aqueous Polyethylene Glycol contribute to step (1) to step (3) dosing more easily evenly, and can in less liquid dispensing container, operate before mixed technique at the end of execution step (4).Due to aminoacid of the present invention, mupirocin or the acceptable salt of its pharmacy and the optional acceptable adjuvant of the pharmacy dissolubility in aqueous Polyethylene Glycol better, therefore it is favourable in step (1), using the aqueous Polyethylene Glycol of " in right amount " in advance, and this " in right amount " is that those skilled in the art easily control or adjust according to existing knowledge and experience.In addition, when for example below explaining the consumption of aqueous Polyethylene Glycol in embodiment, " appropriate, to add to 100 grams " represents that the amount adding can not do accurately to determine, as long as end product total amount reaches 100 grams of respective specified.
According to the method for second aspect present invention, wherein in step (3), by after solid polyethylene glycol melting, while joining in step (2) gained material, if necessary, step (2) gained material can be warming to 40 ~ 50 ° of C in advance, so that solid polyethylene glycol is even with mixing of materials above.
Arbitrary embodiment of applicable equally other the arbitrary embodiment of arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has or other either side, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
In the present invention, active component mupirocin or the acceptable salt of its pharmacy are well known to a person skilled in the art, and can from market, buy acquisition or obtain according to existing literature method.Some technical information of mupirocin or the acceptable salt of its pharmacy such as European Pharmacopoeia, Japanese Pharmacopoeia etc., have been recorded.
In the present invention, use two PEGlike coatings, a class is the Polyethylene Glycol that aqueous low-molecular-weight Polyethylene Glycol, particularly molecular weight is 200 ~ 600; Another kind of is that the Polyethylene Glycol of the high molecular of solid, particularly molecular weight are 2000 ~ 6000 Polyethylene Glycol.Two PEGlike coatings are used in combination can be for ointment compositions of the present invention provides good physical property, coating performance for example, and because they are water-soluble high-molecular material and easily eccysis, than the ointment in oleaginous base have better patient's compliance.
In the present invention, while mentioning the molecular weight of Polyethylene Glycol, it has the implication of well known to a person skilled in the art, and typically described molecular weight is the mean molecule quantity of Polyethylene Glycol, for example, use molecular weight and be 400 Polyethylene Glycol and refer to that mean molecule quantity is 400 Polyethylene Glycol.
In the present invention, Polyethylene Glycol can represent with PEG, and the Polyethylene Glycol that for example molecular weight is 400 can be expressed as PEG400.
In the present composition, while mentioning the amount of mupirocin or the acceptable salt of its pharmacy, all in mupirocin free acid.For example, when directly adding in compositions with mupirocin, directly in the amount of mupirocin; And the acceptable salt of pharmacy of working as with mupirocin adds fashionable, its addition is converted to the amount meter that is equivalent to mupirocin, for example, in the time of will preparing 100 gram of 2% mupirocin calcium ointment, as fed intake with following formula calcium salt dihydrate, theoretical inventory should be 2.15 grams, and these 2.15 grams are equivalent to 2 grams of mupirocin free acids:
In the present invention, while mentioning mupirocin calcium, if not otherwise indicated, refer to the dihydrate of the calcium salt with mupirocin shown in above formula.
Mupirocin ointment provided by the invention is applicable to skin infection that gram-positive cocci causes as the treatment of the primary infections such as pyoderma, folliculitis, furuncle and phyma; To eczema, dermatitis, erosion, ulcer secondary infection, can play effect antibacterial and that prevent protopathy to increase the weight of, be conducive to protopathy treatment; To reducing skin surgery post-operative wound, suppurate very effective.More suitable, ointment of the present invention adopts local application mode, can be by cooled product being seated in foldable metal or plastic tube.
In addition, ointment of the present invention can also contain for example antiseptic and contribute to the solvent of drug osmotic and the emollient in ointment of suitable conventional additives.
In described ointment, can also contain other conventional carriers.
If needed, in any suitable step of described method, can raw material components is levigate.
If need, also can comprise suitable sterilization steps in described method.
The present invention is not bound by any theory, and have been surprisingly found that having the made ointment pharmaceutical composition of aminoacid that the present invention formula particularly has specific ratios of the present invention has such as but not limited to aspects such as stability and have good pharmaceutical property.
The specific embodiment
Below by specific embodiment/experimental example, further illustrate the present invention, still, should be understood to, these embodiment and experimental example are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form 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 operational approach that the object of the invention used, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and operational approach are well known in the art.
i, Preparation Example part (preparing the present composition)
embodiment 1: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 1.5g,
PEG4000：18g，
Arginine: 1g,
PEG400: appropriate, add to 100 grams.
Method for making: carry out according to following general step.
(1) make aminoacid (below in embodiment or reference examples if present, now add the acceptable adjuvant of other pharmacy simultaneously) be dissolved in appropriate (being about prescription estimate consumption 70%) low-molecular-weight aqueous Polyethylene Glycol in, obtain mixture;
(2) in the mixture of step (1), add active component, stirring and dissolving;
(3) solid polyethylene glycol of high molecular is heated to melting, then it is under agitation joined in step (2) gained material (approximately 40 ° of C), stir;
(4) add low-molecular-weight aqueous Polyethylene Glycol to full dose, mix homogeneously, lets cool to room temperature, obtains ointment medicament compositions of the present invention.
Above-mentioned composition can be divided and install to ointment packets dress with in aluminum pipe, every pipe 2g, 5g, 10g or 20g, be ointment.
embodiment 2: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 2g,
PEG3350：19g，
Arginine: 2g,
PEG400: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.In step (1), the aqueous Polyethylene Glycol addition of low-molecular-weight is 50% of prescription expectation consumption.
embodiment 3: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 2.5g,
PEG3350：20g，
Arginine: 3g,
PEG300: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.In step (1), the aqueous Polyethylene Glycol addition of low-molecular-weight is 95% of prescription expectation consumption.
embodiment 4: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 3g,
PEG3000：10g，
PEG4000：5g，
Arginine: 4g,
PEG600: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out, usings PEG3000 and PEG4000 as high molecular weight polyethylene glycol mixing use.
embodiment 5: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 1g,
PEG2000：25g，
Arginine: 0.5g,
PEG200: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.Step is heated to melting by the solid polyethylene glycol of high molecular in (3), then it is under agitation joined in step (2) the gained material under room temperature state.
embodiment 6: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 2g,
PEG6000：15g，
Arginine: 1.5g,
PEG200: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.Step is heated to melting by the solid polyethylene glycol of high molecular in (3), then it is under agitation joined in step (2) gained material (50 ° of C).
embodiment 7: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 2g,
PEG4000：15g，
Lysine: 3.5g,
Borneolum Syntheticum: 0.5g,
PEG400：30g，
PEG300: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.Using PEG300 and PEG400 as low molecular poly mixing use, the PEG400 of recipe quantity and approximately 30 grams of PEG300 are used in step (1).
embodiment 8: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin calcium: 2.5g,
PEG3350：20g，
Arginine: 2.5g,
Oleum menthae: 1.5g,
PEG20000：0.5g，
PEG200: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.PEG20000 melting together with PEG3350 joins in prescription.
embodiment 9: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin calcium: 3g,
PEG2000：25g，
Lysine: 3.5g,
PEG400: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.
embodiment 10: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 2.5g,
PEG4000：15g，
Arginine: 1g,
Lysine: 1g,
Herba Menthae: 0.2g,
PEG200: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.Use arginine and lysine combination as aminoacid.
embodiment 11: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 1.5g,
PEG4000：18g，
Lysine: 1g,
PEG400: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.
embodiment 12: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 2g,
PEG3350：19g，
Lysine: 2g,
PEG400: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.
embodiment 13: the ointment compositions that preparation comprises mupirocin (with 100 grams of amount preparations)
Formula:
Mupirocin: 2.5g,
PEG3350：20g，
Lysine: 3g,
PEG300: appropriate, add to 100 grams.
Method for making: the method for reference example 1 is carried out.
iI, reference examples part
reference examples 1: the ointment compositions of preparing mupirocin
Formula:
Preparation method: citric acid is dissolved in PEG400, then adds Macrogol 4000, be heated to melting in the water-bath of 60 ℃, add again mupirocin, the stirred in water bath of 60 ℃, mupirocin is dissolved, evenly mix, be cooled to room temperature, obtain mupirocin ointment.
reference examples 2: the ointment compositions of preparing mupirocin
Formula:
Preparation method: tartaric acid is dissolved in PEG400, then adds Macrogol 4000, be heated to melting in the water-bath of 55 ℃, add again mupirocin, the stirred in water bath of 55 ℃, mupirocin is dissolved, evenly mix, be cooled to room temperature, obtain mupirocin ointment.
reference examples 3: the ointment compositions of preparing mupirocin
Formula:
Preparation method: lactic acid dissolution, in PEG400, then is added to Macrogol 4000, be heated to melting in the water-bath of 60 ℃, add again mupirocin, the stirred in water bath of 60 ℃, mupirocin is dissolved, evenly mix, be cooled to room temperature, obtain mupirocin ointment.
reference examples 4: the ointment compositions of preparing mupirocin
Except not adding in formula aminoacid, other composition and method for making are identical with embodiment 2.
reference examples 5: the ointment compositions of preparing mupirocin
Except not adding in formula aminoacid, other composition and method for making are identical with embodiment 9.
reference examples 6: the ointment compositions of preparing mupirocin
Except the aminoacid in formula is used instead citric acid, other composition and method for making are identical with embodiment 1.
reference examples 7: the ointment compositions of preparing mupirocin
Except the aminoacid in formula is used instead citric acid, other composition and method for making are identical with embodiment 2.
reference examples 8: the ointment compositions of preparing mupirocin
Except the aminoacid in formula is used instead citric acid, other composition and method for making are identical with embodiment 3.
iII, test example part
the mass analysis method of test example 1, compositions
In prior art, recorded multiple method of mupirocin being carried out to Quality Evaluation Analysis, European Pharmacopoeia 5.4 editions (EP5.4) and British Pharmacopoeias 2009 editions (EP2009) for example, these analytical methods all can be used for the Quality Evaluation Analysis that carries out mupirocin raw material and comprise their preparations.
The mupirocin raw material related substance detection method of for example recording in EP5.4 is as follows:
Related substance detects, and according to high performance liquid chromatography, carries out.
Test solution: by containing the substance dissolves to be checked of 50.0mg active component of having an appointment in mixed solvent (methanol mixes with 13.6g/l sodium acetate solution equal-volume, is adjusted to pH4.0 with acetic acid), then be diluted to 10ml with identical mixed solvent.
Reference solution (a): the mixed solvent for test solution of 1.0ml (methanol mixes with 13.6g/l sodium acetate solution equal-volume, is adjusted to pH4.0 with acetic acid) is diluted to 50.0ml.
Reference solution (b): with hydrochloric acid, 10ml reference solution (a) is adjusted to pH2.0, then places 20h.
Reference solution (c): 25mg mupirocin lithium (CRS) is dissolved in to mixed solvent (methanol mixes with 13.6g/l sodium acetate solution equal-volume, is adjusted to pH4.0 with acetic acid), then is diluted to 200.0ml with identical mixed solvent.
Use following equipment to carry out chromatographic run:
-chromatographic column: 0.25m is long, internal diameter 4.6mm, and implant is chromatographic grade octyl silane group silica gel (5 μ m),
-mobile phase: 20 volume water, 30 volume oxolanes and 50 volume 10.5g/l are mobile phase with the mixture that acetic acid is adjusted to the ammonium acetate solution of pH5.7 in advance, and flow velocity is 1ml/min,
-detector, ultraviolet spectrophotometer, wavelength 240nm.
In instrument, inject 20 μ l reference solutions (b).In reference solution (b), in two major impurity peaks, the 2nd peak and the peak-to-peak separating degree of mupirocin should be greater than 7.In instrument, inject 20 μ l reference solutions (c).Record chromatogram subject to the foregoing, the retention time of impurity C is approximately 0.75 for mupirocin.In instrument, inject 20 μ l test solutions and 20 μ l reference solutions (a).Continuous record test solution chromatogram is to 3.5 times of mupirocin retention time.In the chromatogram of test solution: the peak area of impurity C is not more than 2 times (4%) of main peak area in reference solution (a) chromatogram; The area at other any peak except main peak and impurity C peak is not more than half (1%) of main peak area in reference solution (a) chromatogram; Whole peak area sums except main peak are not more than 3 times (6%) of main peak area in reference solution (a) chromatogram.Ignore than 0.05 times of little peak of main peak area in reference solution (a) chromatogram.
Assay also can carry out with reference to said method.
The mupirocin raw material related substance detection method of for example recording in BP2009 is as follows:
Determination of related substances:
(1) preparation of need testing solution and contrast solution: precision takes this product appropriate (being approximately equivalent to mupirocin 25mg), puts in 50mL volumetric flask, adds 0.1mol/L and pH and is 6.3 phosphate buffer and dissolve and be settled to scale, as need testing solution; Precision measures need testing solution 1mL, puts in 100mL volumetric flask, adds 0.1mol/L and pH and is 6.3 phosphate buffer and be diluted to scale, in contrast solution;
(2) chromatographic condition and system suitability: with octyl silane group silica gel, be filler (the rustless steel pre-column that adds C8); Take oxolane: 7.7g/L ammonium acetate (regulating pH value to 5.7 with glacial acetic acid) is (28:72) mobile phase; Detection wavelength is 240nm, and the separating degree of the peak that retention time is 0.73 corresponding thereto, mupirocin peak (mupirocin impurity C) must not be less than 3.5;
(3) measure: precision measures need testing solution and each 20uL of contrast solution, injection liquid chromatography, records chromatogram respectively.In the chromatogram of need testing solution, impurity C peak area must not be greater than 4 times (4%) of contrast solution main peak area; Impurity D (relative retention time 0.6) peak area must not be greater than 5 times (5%) of contrast solution main peak area; Impurity E (relative retention time 0.64) peak area must not be greater than 10 times (10%) of contrast solution main peak area; Other single impurity peak area must not be greater than 1.5 times (1.5%) of contrast solution main peak area; 20 times (20%) total impurities peak area and that must not be greater than contrast solution main peak area; Ignore in the peak that is less than contrast solution main peak area 0.1 times (0.1%) in need testing solution chromatogram.
The mensuration of mupirocin content:
(1) chromatographic condition and system suitability: with octadecylsilane chemically bonded silica, be filler; Take acetonitrile: 0.05mol/L and pH as 6.3 phosphate buffers (28:72) be mobile phase; Detection wavelength is 230nm.The separating degree at the peak that retention time is 0.75 corresponding thereto, mupirocin peak (mupirocin impurity C) must not be less than 1.5;
(2) measure: precision takes this product appropriate (being approximately equivalent to mupirocin 12.5mg), puts in 50mL volumetric flask, adds mobile phase and dissolves and be diluted to scale, shakes up, and filters, and precision measures filtrate 20uL injection liquid chromatography, records chromatogram; Separately get mupirocin reference substance, be measured in the same method.By external standard method, with calculated by peak area, obtain mupirocin content.
For the present invention, in the present composition, related substances and assay method is carried out with reference to the method in BP2009, particularly when carrying out present composition related substance, according to the chromatographic condition in BP2009 and requirement, carry out, the separating degree that makes chromatographic condition be adjusted to the peak that retention time is 0.73 corresponding thereto, mupirocin peak (mupirocin impurity C) must not be less than 3.5; Then use the method in BP2009, measure the test solution of the present composition, thereby can calculate the amount of some single impurity or the amount of total impurities.During the content of the active component in measuring the present composition, also adopt with reference to the method in BP2009 and carry out.
test example 2, aminoacid consumption are investigated
The method of reference example 1, the ointment compositions basic recipe of every 100g is: mupirocin 2g, PEG4000 are that 18g, arginine amount suitably change, PEG400 adds to 100g.Wherein, in different formulations, arginic addition is respectively (in the ointment compositions of every 100g): 0g, 0.05g, 0.1g, 0.25g, 0.5g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2.0g, 2.5g, 3.0g, 3.5g, 4g, 4.5g, 5g, 6g, 7.5g, 10g.Obtain 20 ointment compositions.
These 20 ointment compositions sealings are loaded in aluminum matter ointment tube, are placed in 40 ° of C thermostats and place 60 days.Mensuration with respect to certain sample without for high-temperature treatment, the variation multiple of impurity C and the variation multiple of total impurities in this sample.
Above-mentioned impurity C " variation multiple " refer to, for the sample of certain formula, it is without 40 ° of C high-temperature treatments but be placed in 8-10 ° of C refrigerator and place 60 days, and impurity C percent is now X1; This sample is X2 through 60 days rear impurity C percent of 40 ° of C high-temperature treatments, and by variation multiple=X2 ÷ X1 of impurity C, this changes multiple more close to 1, represents that impurity variable quantity is less; When impurity C increases, this multiple is just greater than 1.Similarly, can calculate the variation multiple of total impurities.The formula of different arginine additions and impurity thereof change multiple and see the following form 1.Result shows, amino acid whose amount is only in a certain amount of scope, to demonstrate good result, and the excessive or too small equal nothing of addition is in the stability of product quality.
Table 1:
With reference to above method, different is that arginine is wherein replaced with to lysine or histidine, to carry out the test of " investigation of aminoacid consumption ", result is presented at while using lysine, approaches (each corresponding instance result differs and is no more than 10%) when result and use arginine; Yet regrettably, histidine impurity C in the scope of 0 ~ 15g consumption changes multiple and total impurities and changes multiple and be all greater than 2.5.
the investigation of test example 3, the present composition
Each reference examples sample prepared by each embodiment sample that by above prepared by " I, Preparation Example part " and " II, reference examples part ", is loaded on its sealing in aluminum matter ointment tube, is placed in 75 ° of C thermostats and places 20 days.Method described in reference test example 2, measures with respect to certain sample without for high-temperature treatment the variation multiple of impurity C and the variation multiple of total impurities in this sample.
Result demonstration, the variation multiple of various embodiments of the present invention sample impurity C is all between 1.18 ~ 1.45, and for example the variation multiple of the impurity C of embodiment 2,3,5,9 is respectively 1.29,1.18,1.41 and 1.37; And the variation multiple of each reference examples sample impurity C is all between 2.96 ~ 7.02, for example the variation multiple of the impurity C of reference examples 2,3,5,7 is respectively 5.84,4.28,4.73 and 6.35.
In addition, the variation multiple of various embodiments of the present invention sample total impurities is all between 1.23 ~ 1.52, and for example the variation multiple of the total impurities of embodiment 1,2,4,7 is respectively 1.38,1.45,1.33 and 1.28; And the variation multiple of each reference examples sample total impurities is all between 3.42 ~ 7.95, for example the variation multiple of the total impurities of reference examples 3,4,6 is respectively 5.13,4.67 and 6.11.
Above-described embodiment just illustrates of the present invention, and the present invention also can implement with other ad hoc fashion or other particular form, and does not depart from main idea of the present invention or substitutive characteristics.Therefore, the embodiment of description all should be considered as illustrative but not determinate from the viewpoint of any.Scope of the present invention should illustrate by the claim of adding, and any and the intention of claim and the variation of scope equivalence also should be within the scope of the present invention.
Claims (11)
1. an ointment medicament compositions, wherein comprises: mupirocin shown in following formula or the acceptable salt of its pharmacy, Polyethylene Glycol and aminoacid,
2. according to the ointment medicament compositions of claim 1, it comprises the Polyethylene Glycol that mupirocin or the acceptable salt of its pharmacy, molecular weight are 200～600, Polyethylene Glycol and the aminoacid that molecular weight is 2000～6000.
3. according to the ointment medicament compositions of claim 1, the acceptable salt of pharmacy of wherein said mupirocin is calcium salt or its hydrate of mupirocin.
4. according to the ointment medicament compositions of claim 1, the acceptable salt of pharmacy of wherein said mupirocin is the dihydrate of the mupirocin calcium salt shown in following formula:
5. according to the ointment medicament compositions of claim 1, the Polyethylene Glycol that wherein said molecular weight is 200～600 is that molecular weight is 200～400 Polyethylene Glycol.
6. according to the ointment medicament compositions of claim 1, the Polyethylene Glycol that wherein said molecular weight is 2000～6000 is that molecular weight is 2000～4000 Polyethylene Glycol.
7. according to the ointment medicament compositions of claim 1, wherein said aminoacid is selected from lysine, arginine, histidine or its combination.
8. according to the ointment medicament compositions of claim 1, wherein also comprise the acceptable adjuvant of optional pharmacy.
9. ointment medicament compositions according to Claim 8, the acceptable adjuvant of wherein said pharmacy is selected from warming regulator, antiseptic, thickening agent.
10. according to the ointment medicament compositions of claim 1 to 9 any one, comprise in its every 100 grams:
Mupirocin or the acceptable salt of its pharmacy: 0.5～5g,
Molecular weight is 2000～6000 Polyethylene Glycol: 10～30g,
Aminoacid: 0.5～10g,
The acceptable adjuvant of optional pharmacy: 0～5g, and
Molecular weight is 200～600 Polyethylene Glycol: appropriate, add to 100g;
Or comprise:
Mupirocin or the acceptable salt of its pharmacy: 1～3g,
Molecular weight is 2000～6000 Polyethylene Glycol: 15～25g,
Aminoacid: 0.5～4g,
The acceptable adjuvant of optional pharmacy: 0～2g, and
Molecular weight is 200～600 Polyethylene Glycol: appropriate, add to 100g;
Or comprise:
Mupirocin or the acceptable salt of its pharmacy: 1～3g,
Molecular weight is 2000～4000 Polyethylene Glycol: 15～25g,
Aminoacid: 1～3g,
The acceptable adjuvant of optional pharmacy: 0～2g, and
Molecular weight is 200～400 Polyethylene Glycol: appropriate, add to 100g;
Or comprise:
Or comprise:
Or comprise:
Or comprise:
Or comprise:
Or comprise:
Or comprise:
Or comprise:
Or comprise:
Or comprise:
Or comprise:
Or comprise:
Or comprise:
11. prepare the method for ointment medicament compositions described in claim 1-10 any one, and it comprises the following steps:
(1) making aminoacid and the optional acceptable adjuvant of pharmacy be dissolved in appropriate molecular weight is, in 200～600 Polyethylene Glycol, to obtain mixture;
(2) in the mixture of step (1), add mupirocin or the acceptable salt of its pharmacy, stirring and dissolving;
(3) Polyethylene Glycol that is 2000～6000 by molecular weight is heated to melting, then it is under agitation joined in step (2) gained material, stirs;
(4) add molecular weight be 200～600 Polyethylene Glycol to full dose, mix homogeneously, obtains.
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