CN102885763A - Novel mupirocin ointment pharmaceutical composition - Google Patents
Novel mupirocin ointment pharmaceutical composition Download PDFInfo
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- CN102885763A CN102885763A CN2012104224267A CN201210422426A CN102885763A CN 102885763 A CN102885763 A CN 102885763A CN 2012104224267 A CN2012104224267 A CN 2012104224267A CN 201210422426 A CN201210422426 A CN 201210422426A CN 102885763 A CN102885763 A CN 102885763A
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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, (Pseudomonas fluorescens) isolates by pseudomonas fluorescens, be a kind of more satisfactory skin surface antibiotic preparation, (Bactroban) introduced to the market as trade name take " Mupirocin Ointment " by GlaxoSmithKline PLC in 1985.U.S. FDA was ratified this medicine and is used in U.S.'s listing in 1987, China was approval Sino-U.S.'s SmithKline pharmaceutical manufacturing in 1993 and sell this medicine.Mupirocin is mainly used in the bacterial skin infections disease of preventing and treating gram-positive cocci to cause, primary cutaneous such as impetigo, furuncle and phyma, folliculitis infects, and reaches 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 the anti-bacteria body.Particularly, mupirocin acts on the binding site of the interior isoleucine of bacterial body-tRNA synzyme and isoleucine, thereby synthesizing of hindered aminoacid also consumed intracellular tRNA, and the building-up process of the synthetic and protein of RNA is ended.
The chemistry of mupirocin is called 9-[[(2E)-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] the oxygen base] n-nonanoic acid, molecular formula is C
26H
44O
9, molecular weight is 500.6, chemical structural formula is:
At present, in the 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 are mupirocin, and ointment base is PEG400 (mean molecule quantity is 400, and is 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 expectation has the good pharmacy characteristics 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, being mixed with the particularly preparation of clinical use of product, and give the good pharmacy characteristics that this new preparation has at least one aspect.The inventor is surprised to find the effect that the mupirocin ointment medicament compositions with prescription of the present invention has obtained desirable, the present invention is based on this and is accomplished.
Aspect first, provide a kind of ointment medicament compositions of the present invention, wherein comprised: mupirocin shown in the 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 mupirocin or the acceptable salt of its pharmacy, molecular weight is that 200 ~ 600 Polyethylene Glycol, molecular weight are 2000 ~ 6000 Polyethylene Glycol and aminoacid.
According to the ointment medicament compositions of first aspect present invention, the acceptable salt of the 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 the 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 the pharmacy of wherein said mupirocin is the dihydrate of the mupirocin calcium salt shown in the following formula:
According to the ointment medicament compositions of first aspect present invention, wherein said molecular weight is that 200 ~ 600 Polyethylene Glycol is that molecular weight is the Polyethylene Glycol of 200-400.For example described molecular weight is that 200 ~ 600 Polyethylene Glycol is that molecular weight is 200,300,400 Polyethylene Glycol or its combination.
According to the ointment medicament compositions of first aspect present invention, wherein said molecular weight is that 200 ~ 600 Polyethylene Glycol is that molecular weight is 400 Polyethylene Glycol.
According to the ointment medicament compositions of first aspect present invention, wherein said molecular weight is that 2000 ~ 6000 Polyethylene Glycol is that molecular weight is the Polyethylene Glycol of 2000-4000.For example described molecular weight is that 2000 ~ 4000 Polyethylene Glycol 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, wherein said molecular weight is that 2000 ~ 6000 Polyethylene Glycol 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 per 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 optional acceptable adjuvant of pharmacy: 0 ~ 5g, and
Molecular weight is 200 ~ 600 Polyethylene Glycol: an amount of, add to 100g.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 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 optional acceptable adjuvant of pharmacy: 0 ~ 2g, and
Molecular weight is 200 ~ 600 Polyethylene Glycol: an amount of, add to 100g.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 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 optional acceptable adjuvant of pharmacy: 0 ~ 2g, and
Molecular weight is 200 ~ 400 Polyethylene Glycol: an amount of, add to 100g.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 1.5g,
PEG4000：18g，
Arginine: 1g,
PEG400: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 2g,
PEG3350：19g，
Arginine: 2g,
PEG400: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 2.5g,
PEG3350：20g，
Arginine: 3g,
PEG300: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 3g,
PEG3000：10g，
PEG4000：5g，
Arginine: 4g,
PEG600: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 1g,
PEG2000：25g，
Arginine: 0.5g,
PEG200: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 2g,
PEG6000：15g，
Arginine: 1.5g,
PEG200: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 2g,
PEG4000：15g，
Lysine: 3.5g,
Borneolum Syntheticum: 0.5g,
PEG400：30g，
PEG300: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin calcium: 2.5g,
PEG3350：20g，
Arginine: 2.5g,
Oleum menthae: 1.5g,
PEG20000：0.5g，
PEG200: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin calcium: 3g,
PEG2000：25g，
Lysine: 3.5g,
PEG400: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 2.5g,
PEG4000：15g，
Arginine: 1g,
Lysine: 1g,
Herba Menthae: 0.2g,
PEG200: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 1.5g,
PEG4000：18g，
Lysine: 1g,
PEG400: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 2g,
PEG3350：19g，
Lysine: 2g,
PEG400: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, comprise in its per 100 grams:
Mupirocin: 2.5g,
PEG3350：20g，
Lysine: 3g,
PEG300: an amount of, add to 100 grams.
According to the ointment medicament compositions of first aspect present invention, the wherein said optional acceptable adjuvant of pharmacy is such as but not limited to warming regulator (such as Borneolum Syntheticum, Mentholum, Oleum menthae), antiseptic (such as benzyl alcohol), thickening agent (such as carbomer, molecular weight greater than 6000 Polyethylene Glycol) etc.
Second aspect present invention provides the method for preparing the described ointment medicament compositions of first aspect present invention, and it may further comprise the steps:
(1) making aminoacid and the optional acceptable adjuvant of pharmacy be dissolved in an amount of molecular weight is in 200 ~ 600 the 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) be that 2000 ~ 6000 Polyethylene Glycol is heated to melting with molecular weight, then it under agitation joined in step (2) the gained material, stir;
(4) add molecular weight be 200 ~ 600 Polyethylene Glycol to full dose, mix homogeneously, and get final product.
According to the method for second aspect present invention, wherein in the step (1) molecular weight be the addition of 200 ~ 600 Polyethylene Glycol can be this component roughly consumption 50 ~ 95%.Respective components fully dissolve or the prerequisite of mixing under, in step (1), suitably add less molecular weight and be 200 ~ 600 aqueous Polyethylene Glycol and help step (1) easier evenly to step (3) dosing, and can in less liquid dispensing container, operate before the mixed technique at the end of execution in step (4).Because aminoacid of the present invention, mupirocin or the acceptable salt of its pharmacy and the optional dissolubility of the acceptable adjuvant of pharmacy in aqueous Polyethylene Glycol are better, therefore it is favourable using the aqueous Polyethylene Glycol of " in right amount " in advance in the step (1), and this " in right amount " is that those skilled in the art are according to easily control or the adjustment of existing knowledge and experience.In addition, for example hereinafter among the embodiment during consumption of the aqueous Polyethylene Glycol of statement, the amount that " an amount of, as to add to 100 grams " expression adds can not done accurately to determine, as long as the end product total amount reaches 100 grams of respective specified.
Method according to second aspect present invention, wherein in the step (3), after the solid polyethylene glycol melting, when joining in step (2) the gained material, if necessary, step (2) gained material can be warming to 40 ~ 50 ° of C in advance, so that the mixing of materials of solid polyethylene glycol and front is even.
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.The below is further described with characteristics to various aspects of the present invention.
All documents that the present invention quotes from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when 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 explain, the term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
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 obtain or obtain according to existing literature method from the market purchase.Some technical information of mupirocin or the acceptable salt of its pharmacy have been recorded such as European Pharmacopoeia, Japanese Pharmacopoeia etc.
In the present invention, use two PEGlike coatings, a class is that aqueous low-molecular-weight Polyethylene Glycol, particularly molecular weight is 200 ~ 600 Polyethylene Glycol; 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 better patient's compliance is arranged.
In the present invention, when mentioning the molecular weight of Polyethylene Glycol, it has the implication of well known to a person skilled in the art, and usually described molecular weight is the mean molecule quantity of Polyethylene Glycol, for example uses molecular weight and is 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 for example molecular weight is that 400 Polyethylene Glycol can be expressed as PEG400.
In the present composition, when mentioning the amount of mupirocin or the acceptable salt of its pharmacy, all in the mupirocin free acid.For example when directly adding in the compositions with mupirocin, directly in the amount of mupirocin; And when adding fashionable with the acceptable salt of the pharmacy of mupirocin, its addition is converted to the amount meter that is equivalent to mupirocin, in the time of for example will preparing 100 grams, 2% mupirocin calcium ointment, as feeding intake with following formula calcium salt dihydrate, then theoretical inventory should be 2.15 grams, and this 2.15 gram is equivalent to 2 gram mupirocin free acids:
In the present invention, when mentioning mupirocin calcium, such as not in addition explanation, refer to have the dihydrate of the calcium salt of mupirocin shown in the following formula.
Mupirocin ointment provided by the invention is applicable to the treatment of the primary infections such as skin infection that gram-positive cocci causes such as pyoderma, folliculitis, furuncle and phyma; Can play effect antibiotic and that prevent protopathy to increase the weight of to eczema, dermatitis, erosion, ulcer secondary infection, be conducive to the protopathy treatment; Suppurate very effective to reducing the skin surgery post-operative wound.Suitable is that ointment of the present invention adopts the local application mode, can be by cooled product being seated in the foldable metal or plastic tube.
In addition, ointment of the present invention can also contain for example antiseptic and help the solvent of drug osmotic and the emollient in the ointment of suitable conventional additives.
Can also contain other conventional carriers in the described ointment.
If necessary, in any suitable step of described method, can raw material components is levigate.
If necessary, in described method, also can comprise suitable sterilization steps.
The present invention is not bound by any theory, and unexpectedly finds to have the made ointment pharmaceutical composition of aminoacid that the present invention's prescription particularly has specific ratios of the present invention and has such as but not limited to aspects such as stability and have good pharmaceutical property.
The specific embodiment
Further specify the present invention below by specific embodiment/experimental example, still, should be understood to, these embodiment and experimental example are only used for the usefulness that specifically describes 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 the test.Although for realizing that the employed many materials of the object of the invention and operational approach are well known in the art, 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 do not specify, material therefor of the present invention and operational approach are well known in the art.
I, Preparation Example part (the preparation present composition)
Embodiment 1: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 1.5g,
PEG4000：18g，
Arginine: 1g,
PEG400: an amount of, add to 100 grams.
Method for making: carry out according to following general step.
(1) make aminoacid (in back embodiment or the reference examples if present, add simultaneously the acceptable adjuvant of other pharmacy this moment) be dissolved in an amount of (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 with high molecular is heated to melting, then it is under agitation joined in step (2) the gained material (approximately 40 ° of C), stirs;
(4) add low-molecular-weight aqueous Polyethylene Glycol to full dose, mix homogeneously lets cool to room temperature, namely gets ointment medicament compositions of the present invention.
Above-mentioned composition can be divided to install to the ointment packets dress with in the aluminum pipe, every pipe 2g, 5g, 10g or 20g are ointment.
Embodiment 2: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 2g,
PEG3350：19g，
Arginine: 2g,
PEG400: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.The aqueous Polyethylene Glycol addition of low-molecular-weight is 50% of prescription expectation consumption in the step (1).
Embodiment 3: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 2.5g,
PEG3350：20g，
Arginine: 3g,
PEG300: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.The aqueous Polyethylene Glycol addition of low-molecular-weight is 95% of prescription expectation consumption in the step (1).
Embodiment 4: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 3g,
PEG3000：10g，
PEG4000：5g，
Arginine: 4g,
PEG600: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out, and mixes as high molecular weight polyethylene glycol with PEG3000 and PEG4000 and uses.
Embodiment 5: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 1g,
PEG2000：25g，
Arginine: 0.5g,
PEG200: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.Solid polyethylene glycol with high molecular in the step (3) is heated to melting, then it is under agitation joined in step (2) the gained material under the room temperature state.
Embodiment 6: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 2g,
PEG6000：15g，
Arginine: 1.5g,
PEG200: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.Solid polyethylene glycol with high molecular in the step (3) is heated to melting, then it is under agitation joined in step (2) the gained material (50 ° of C).
Embodiment 7: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 2g,
PEG4000：15g，
Lysine: 3.5g,
Borneolum Syntheticum: 0.5g,
PEG400：30g，
PEG300: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.Mix as low molecular poly with PEG300 and PEG400 and to use, with the PEG400 of recipe quantity and approximately 30 gram PEG300 in step (1), use.
Embodiment 8: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin calcium: 2.5g,
PEG3350：20g，
Arginine: 2.5g,
Oleum menthae: 1.5g,
PEG20000：0.5g，
PEG200: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.PEG20000 joins in the prescription with the PEG3350 melting.
Embodiment 9: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin calcium: 3g,
PEG2000：25g，
Lysine: 3.5g,
PEG400: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.
Embodiment 10: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 2.5g,
PEG4000：15g，
Arginine: 1g,
Lysine: 1g,
Herba Menthae: 0.2g,
PEG200: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.Use the combination of arginine and lysine as aminoacid.
Embodiment 11: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 1.5g,
PEG4000：18g，
Lysine: 1g,
PEG400: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.
Embodiment 12: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 2g,
PEG3350：19g，
Lysine: 2g,
PEG400: an amount of, add to 100 grams.
Method for making: the method for reference example 1 is carried out.
Embodiment 13: preparation comprises the ointment compositions (with the preparation of 100 gram amounts) of mupirocin
Prescription:
Mupirocin: 2.5g,
PEG3350：20g，
Lysine: 3g,
PEG300: an amount of, 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 preparation mupirocin
Prescription:
Preparation method: citric acid is dissolved in the PEG400, adds again Macrogol 4000, in 60 ℃ water-bath, be heated to melting, add again mupirocin, make the mupirocin dissolving 60 ℃ stirred in water bath, evenly mix, be cooled to room temperature, namely get mupirocin ointment.
Reference examples 2: the ointment compositions of preparation mupirocin
Prescription:
Preparation method: tartaric acid is dissolved in the PEG400, adds again Macrogol 4000, in 55 ℃ water-bath, be heated to melting, add again mupirocin, make the mupirocin dissolving 55 ℃ stirred in water bath, evenly mix, be cooled to room temperature, namely get mupirocin ointment.
Reference examples 3: the ointment compositions of preparation mupirocin
Prescription:
Preparation method: lactic acid dissolution in PEG400, is added Macrogol 4000 again, in 60 ℃ water-bath, be heated to melting, add again mupirocin, make the mupirocin dissolving 60 ℃ stirred in water bath, evenly mix, be cooled to room temperature, namely get mupirocin ointment.
Reference examples 4: the ointment compositions of preparation mupirocin
Except not adding in prescription the aminoacid, other composition is identical with embodiment 2 with method for making.
Reference examples 5: the ointment compositions of preparation mupirocin
Except not adding in prescription the aminoacid, other composition is identical with embodiment 9 with method for making.
Reference examples 6: the ointment compositions of preparation mupirocin
Aminoacid in will filling a prescription is used instead the citric acid, and other composition is identical with embodiment 1 with method for making.
Reference examples 7: the ointment compositions of preparation mupirocin
Aminoacid in will filling a prescription is used instead the citric acid, and other composition is identical with embodiment 2 with method for making.
Reference examples 8: the ointment compositions of preparation mupirocin
Aminoacid in will filling a prescription is used instead the citric acid, and other composition is identical with embodiment 3 with method for making.
III, test example part
The mass analysis method of test example 1, compositions
Put down in writing multiple method of mupirocin being carried out Quality Evaluation Analysis in the prior art, 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 the mupirocin raw material and comprise their preparations.
The mupirocin raw material related substance detection method of for example putting down in writing among the EP5.4 is as follows:
Related substance detects, and carries out according to high performance liquid chromatography.
Test solution: will contain the substance dissolves to be checked of the 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), and be diluted to 10ml with identical mixed solvent again.
Reference solution (a): the test solution of 1.0ml is diluted to 50.0ml with mixed solvent (methanol mixes with 13.6g/l sodium acetate solution equal-volume, is adjusted to pH4.0 with acetic acid).
Reference solution (b): with hydrochloric acid 10ml reference solution (a) is adjusted to pH2.0, places again 20h.
Reference solution (c): 25mg mupirocin lithium (CRS) is dissolved in mixed solvent (methanol mixes with 13.6g/l sodium acetate solution equal-volume, is adjusted to pH4.0 with acetic acid), is diluted to 200.0ml with identical mixed solvent again.
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).The 2nd peak and the peak-to-peak separating degree of mupirocin should be greater than 7 in two major impurity peaks in the reference solution (b).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 the 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 0.05 times of little peak than 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 putting down in writing among the BP2009 is as follows:
Determination of related substances:
(1) preparation of need testing solution and contrast solution: precision takes by weighing this product an amount of (approximately being equivalent to mupirocin 25mg), puts in the 50mL volumetric flask, and to add 0.1mol/L and pH be 6.3 phosphate buffer dissolving and be settled to scale, as need testing solution; Precision measures need testing solution 1mL, puts in the 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: be filler (the rustless steel pre-column that adds C8) with octyl silane group silica gel; Take oxolane: 7.7g/L ammonium acetate (regulating pH value to 5.7 with glacial acetic acid) is (28:72) as mobile phase; The detection wavelength is 240nm, and mupirocin peak and its relative retention time are that the separating degree at 0.73 peak (mupirocin impurity C) must not be less than 3.5;
(3) measure: precision measures need testing solution and each 20uL of contrast solution, and the 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; The total impurities peak area and must not be greater than 20 times (20%) of contrast solution main peak area; Ignore less than the peak of contrast solution main peak area 0.1 times (0.1%) in the need testing solution chromatogram.
The mensuration of mupirocin content:
(1) chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Take acetonitrile: 0.05mol/L and pH as 6.3 phosphate buffers (28:72) as mobile phase; The detection wavelength is 230nm.Mupirocin peak and its relative retention time are that the separating degree at 0.75 peak (mupirocin impurity C) must not be less than 1.5;
(2) measure: precision takes by weighing this product an amount of (approximately being equivalent to mupirocin 12.5mg), puts in the 50mL volumetric flask, adds the mobile phase dissolving and is diluted to scale, shakes up, and filters, and precision measures filtrate 20uL injection liquid chromatography, the record chromatogram; Other gets the mupirocin reference substance, measures with method.With calculated by peak area, namely get mupirocin content by external standard method.
For the present invention, the related substances and assay method is carried out with reference to the method among the BP2009 in the present composition, particularly when carrying out present composition related substance, carry out according to the chromatographic condition among the BP2009 and requirement, making chromatographic condition be adjusted to mupirocin peak and its relative retention time is that the separating degree at 0.73 peak (mupirocin impurity C) must not be less than 3.5; Then use the method among the 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 among the 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 the aluminum matter ointment tube, place 40 ° of C thermostats to place 60 days.Mensuration with respect to certain sample without for the high-temperature treatment, the variation multiple of the variation multiple of impurity C and total impurities in this sample.
Above-mentioned impurity C " variation multiple " refer to, for the sample of certain prescription, it is without 40 ° of C high-temperature treatments but place 8-10 ° of C refrigerator to place 60 days, and the impurity C percent of this moment is X1; This sample is X2 through 60 days rear impurity C of 40 ° of C high-temperature treatments percent, and then with the variation multiple of impurity C=X2 ÷ X1, this changes multiple more close to 1, represents that then the impurity variable quantity is less; When impurity C increased, this multiple was just greater than 1.Similarly, can calculate the variation multiple of total impurities.The prescription of different arginine additions and impurity thereof change multiple and see the following form 1.Result's demonstration, amino acid whose amount only is to demonstrate good result in a certain amount of scope, 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 lysine or histidine, carrying out the test of " investigation of aminoacid consumption ", the result is presented at when using lysine, the result when using arginine near (each corresponding instance result differs and is no more than 10%); Yet regrettably, histidine impurity C in the scope of 0 ~ 15g consumption changes multiple and total impurities changes times number average greater than 2.5.
The investigation of test example 3, the present composition
Will be above each embodiment sample of " I, Preparation Example part " preparation and each reference examples sample of " II, reference examples part " preparation, its sealing is loaded in the aluminum matter ointment tube, place 75 ° of C thermostats to place 20 days.Reference test example 2 described methods are measured with respect to certain sample without for the high-temperature treatment variation multiple of the variation multiple of impurity C and total impurities in this sample.
The result shows, the variation times number average of various embodiments of the present invention sample impurity C is between 1.18 ~ 1.45, and for example the variation multiple of embodiment 2,3,5,9 impurity C is respectively 1.29,1.18,1.41 and 1.37; And the variation times number average of each reference examples sample impurity C is between 2.96 ~ 7.02, and for example the variation multiple of reference examples 2,3,5,7 impurity C is respectively 5.84,4.28,4.73 and 6.35.
In addition, the variation times number average of various embodiments of the present invention sample total impurities is between 1.23 ~ 1.52, and for example the variation multiple of embodiment 1,2,4,7 total impurities is respectively 1.38,1.45,1.33 and 1.28; And the variation times number average of each reference examples sample total impurities is between 3.42 ~ 7.95, and for example the variation multiple of reference examples 3,4,6 total impurities 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 from any aspect but not be determinate.Scope of the present invention should be by additional claim explanation, and the intention of any and claim and the variation of scope equivalence also should be within the scope of the present invention.
Claims (10)
1. ointment medicament compositions wherein comprises: mupirocin shown in the following formula or the acceptable salt of its pharmacy, Polyethylene Glycol and aminoacid,
2. according to claim 1 ointment medicament compositions, it comprises mupirocin or the acceptable salt of its pharmacy, molecular weight is that 200 ~ 600 Polyethylene Glycol, molecular weight are 2000 ~ 6000 Polyethylene Glycol and aminoacid.
3. according to claim 1 to 2 ointment medicament compositions, the acceptable salt of the pharmacy of wherein said mupirocin is calcium salt or its solvate of mupirocin.
4. according to claim 1 to 3 ointment medicament compositions, the acceptable salt of the pharmacy of wherein said mupirocin is the dihydrate of the mupirocin calcium salt shown in the following formula:
5. according to claim 1 to 4 ointment medicament compositions, wherein said molecular weight is that 200 ~ 600 Polyethylene Glycol is that molecular weight is the Polyethylene Glycol of 200-400.
6. according to claim 1 to 5 ointment medicament compositions, wherein said molecular weight is that 2000 ~ 6000 Polyethylene Glycol is that molecular weight is the Polyethylene Glycol of 2000-4000.
7. according to claim 1 to 6 ointment medicament compositions, wherein said aminoacid is selected from lysine, arginine, histidine or its combination.
8. according to claim 1 to 7 ointment medicament compositions, wherein also comprise the acceptable adjuvant of optional pharmacy, for example warming regulator, antiseptic, thickening agent.
9. according to claim 1 to 8 ointment medicament compositions, comprise in its per 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 optional acceptable adjuvant of pharmacy: 0 ~ 5g, and
Molecular weight is 200 ~ 600 Polyethylene Glycol: an amount of, add to 100g;
Perhaps 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 optional acceptable adjuvant of pharmacy: 0 ~ 2g, and
Molecular weight is 200 ~ 600 Polyethylene Glycol: an amount of, add to 100g;
Perhaps comprise:
Mupirocin or the acceptable salt of its pharmacy: 1 ~ 3g,
Molecular weight is 2000 ~ 4000 Polyethylene Glycol: 15 ~ 25g,
Aminoacid: 1 ~ 3g,
The optional acceptable adjuvant of pharmacy: 0 ~ 2g, and
Molecular weight is 200 ~ 400 Polyethylene Glycol: an amount of, add to 100g;
Perhaps comprise:
Mupirocin: 1.5g,
PEG4000：18g，
Arginine: 1g,
PEG400: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 2g,
PEG3350：19g，
Arginine: 2g,
PEG400: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 2.5g,
PEG3350：20g，
Arginine: 3g,
PEG300: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 3g,
PEG3000：10g，
PEG4000：5g，
Arginine: 4g,
PEG600: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 1g,
PEG2000：25g，
Arginine: 0.5g,
PEG200: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 2g,
PEG6000：15g，
Arginine: 1.5g,
PEG200: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 2g,
PEG4000：15g，
Lysine: 3.5g,
Borneolum Syntheticum: 0.5g,
PEG400：30g，
PEG300: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin calcium: 2.5g,
PEG3350：20g，
Arginine: 2.5g,
Oleum menthae: 1.5g,
PEG20000：0.5g，
PEG200: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin calcium: 3g,
PEG2000：25g，
Lysine: 3.5g,
PEG400: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 2.5g,
PEG4000：15g，
Arginine: 1g,
Lysine: 1g,
Herba Menthae: 0.2g,
PEG200: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 1.5g,
PEG4000：18g，
Lysine: 1g,
PEG400: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 2g,
PEG3350：19g，
Lysine: 2g,
PEG400: an amount of, add to 100 grams;
Perhaps comprise:
Mupirocin: 2.5g,
PEG3350：20g，
Lysine: 3g,
PEG300: an amount of, add to 100 grams.
10. prepare the method for the described ointment medicament compositions of claim 1-9, it may further comprise the steps:
(1) making aminoacid and the optional acceptable adjuvant of pharmacy be dissolved in an amount of molecular weight is in 200 ~ 600 the 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) be that 2000 ~ 6000 Polyethylene Glycol is heated to melting with molecular weight, then it under agitation joined in step (2) the gained material, stir;
(4) add molecular weight be 200 ~ 600 Polyethylene Glycol to full dose, mix homogeneously, and get final product.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412000A (en) * | 2015-11-23 | 2016-03-23 | 安徽新和成皖南药业有限公司 | Preparation method for mupirocin ointment |
| CN110772479A (en) * | 2019-11-20 | 2020-02-11 | 湖北人福成田药业有限公司 | Mupirocin ointment and preparation method thereof |
| WO2020141482A1 (en) * | 2019-01-04 | 2020-07-09 | Glenmark Specialty S.A. | Pharmaceutical compositions comprising mupirocin |
| WO2021120268A1 (en) * | 2019-12-17 | 2021-06-24 | 福元药业有限公司 | Mupirocine ointment and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060003969A1 (en) * | 2004-07-02 | 2006-01-05 | Manandhar Madhusudan P | Compositions and methods for treating pathological infections |
| CN102335122A (en) * | 2011-06-21 | 2012-02-01 | 北京协和药厂 | Mupirocin ointment and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060003969A1 (en) * | 2004-07-02 | 2006-01-05 | Manandhar Madhusudan P | Compositions and methods for treating pathological infections |
| CN102335122A (en) * | 2011-06-21 | 2012-02-01 | 北京协和药厂 | Mupirocin ointment and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412000A (en) * | 2015-11-23 | 2016-03-23 | 安徽新和成皖南药业有限公司 | Preparation method for mupirocin ointment |
| WO2020141482A1 (en) * | 2019-01-04 | 2020-07-09 | Glenmark Specialty S.A. | Pharmaceutical compositions comprising mupirocin |
| CN110772479A (en) * | 2019-11-20 | 2020-02-11 | 湖北人福成田药业有限公司 | Mupirocin ointment and preparation method thereof |
| WO2021120268A1 (en) * | 2019-12-17 | 2021-06-24 | 福元药业有限公司 | Mupirocine ointment and preparation method therefor |
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