CN102871955B - Ointment medicament composition containing mupirocin - Google Patents
Ointment medicament composition containing mupirocin Download PDFInfo
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- CN102871955B CN102871955B CN2012104205995A CN201210420599A CN102871955B CN 102871955 B CN102871955 B CN 102871955B CN 2012104205995 A CN2012104205995 A CN 2012104205995A CN 201210420599 A CN201210420599 A CN 201210420599A CN 102871955 B CN102871955 B CN 102871955B
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Abstract
The invention relates to an ointment medicament composition containing mupirocin, and particularly relates to an ointment medicament composition. The ointment medicament composition comprises mupirocin or pharmaceutically acceptable salt thereof, polyethylene glycol and inorganic acid, wherein mupirocin or pharmaceutically acceptable salt thereof are shown in the specification. The polyethylene glycol described by the invention comprises polyethylene glycol the molecular weight of which is 200-600 and polyethylene glycol the molecular weight of which is 2000-6000. The ointment medicament composition disclosed by the invention has good pharmaceutical characteristics.
Description
Technical field
The present invention relates to the new ointment medicament compositions that comprises mupirocin, and the preparation method of said 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, in 1985, by GlaxoSmithKline PLC, take " Mupirocin Ointment ", (Bactroban) introduced to the market as trade name.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 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 expects to have 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, to be mixed with the particularly preparation of clinical use of product, and give this new preparation and have the good pharmacy characteristics of at least one aspect.The inventor is surprised to find the mupirocin ointment medicament compositions with formula of the present invention and has obtained the effect of 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 following formula or the acceptable salt of its pharmacy, Polyethylene Glycol and mineral acid,
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 mineral acid.
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 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 mineral acid is boric acid.
, according to the ointment medicament compositions of first aspect present invention, wherein also comprise the acceptable adjuvant of optional pharmacy.It is the adjuvant that is different from above-mentioned Polyethylene Glycol and boric acid.
, 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,
Mineral acid: 0.01 ~ 2g,
The optional acceptable adjuvant of 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,
Mineral acid: 0.1 ~ 1g,
The optional acceptable adjuvant of 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,
Mineral acid: 0.1 ~ 1g,
The optional acceptable adjuvant of 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
Boric acid: 0.25g
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
Boric acid: 0.5g
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
PEG3350： 20g
Boric acid: 0.75g
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： 15g
Boric acid: 1g
PEG600: appropriate, add to 100 grams.
, according to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
, according to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin: 2g
PEG6000： 15g
Boric acid: 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
PEG4000： 15g
Boric acid: 0.6g
Borneolum Syntheticum: 0.5g
PEG300: appropriate, add to 100 grams.
, according to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
, according to the ointment medicament compositions of first aspect present invention, comprise in its every 100 grams:
Mupirocin calcium: 3g
PEG2000： 25g
Boric acid: 0.6g
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
Boric acid: 0.2g
Herba Menthae: 0.2g
PEG200: appropriate, 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 comprises the following steps:
(1) making mineral acid and the optional acceptable adjuvant of pharmacy be dissolved in appropriate molecular weight is in 200 ~ 600 Polyethylene Glycol, to obtain mixture;
(2) add mupirocin or the acceptable salt of its pharmacy, stirring and dissolving in the mixture of step (1);
(3) be that 2000 ~ 6000 Polyethylene Glycol is heated to melting with molecular weight, then it under agitation joined in step (2) gained material, stir;
(4) add molecular weight be 200 ~ 600 Polyethylene Glycol to full dose, mix homogeneously, obtain.
According to the method for second aspect present invention, wherein in 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 that mixes under, suitably adding less molecular weight in step (1) is that 200 ~ 600 aqueous Polyethylene Glycol helps step (1) easier evenly to step (3) dosing, and at the end of execution step (4), can operate in less liquid dispensing container before mixed technique.Due to mineral acid 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 better, therefore it is favourable using the aqueous Polyethylene Glycol of " in right amount " in advance in step (1), and this " in right amount " is that those skilled in the art easily control or adjust according to existing knowledge and experience.In addition, for example hereinafter in embodiment during the consumption of the aqueous Polyethylene Glycol of statement, the amount that " appropriate, 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 step (3), after the 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 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.Below be 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 when the expressed implication of these documents and the present invention are inconsistent, with statement of the present invention, be as the criterion.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, 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 buy acquisition from market or according to existing literature method, obtain.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, while 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, while mentioning the amount of mupirocin or the acceptable salt of its pharmacy, all in the mupirocin free acid.For example when directly with mupirocin, adding in compositions, directly in the amount of mupirocin; And when with the acceptable salt of the pharmacy of mupirocin, adding fashionable, its addition is converted to the amount meter that is equivalent to mupirocin, in the time of for example will preparing 100 gram 2% mupirocin calcium ointment, as with following formula calcium salt dihydrate, feeding intake, theoretical inventory should be 2.15 grams, and this 2.15 gram is equivalent to 2 gram mupirocin free acids:
In the present invention, while mentioning mupirocin calcium, if not otherwise indicated, refer to have the dihydrate of the calcium salt of mupirocin shown in 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.More suitable is that ointment of the present invention adopts the 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 help the solvent of drug osmotic and the emollient in ointment of suitable conventional additives.
Can also contain other conventional carriers in described ointment.
If necessary, in any suitable step of described method, can raw material components is levigate.
If necessary, 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 mineral acid that the present invention formula particularly has a 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
Further illustrate the present invention below by specific embodiment/experimental example, still, should be understood to, these embodiment and experimental example are only used for the use 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 test.Although for to realize that many materials and operational approach that the object of the invention is used 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
Embodiment 1: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
Method for making: according to following general step, carry out.
(1) make boric acid (in back embodiment or reference examples if present, add simultaneously the acceptable adjuvant of other pharmacy this moment) be dissolved in appropriate (being about prescription estimate consumption 70%) low-molecular-weight aqueous Polyethylene Glycol in, obtain mixture;
(2) add active component in the mixture of step (1), 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, let cool to room temperature, obtains ointment medicament compositions of the present invention.
Above-mentioned composition can be divided and install to the ointment packets dress with in aluminum pipe, every pipe 2g, 5g, 10g or 20g, be ointment.
Embodiment 2: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
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: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
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: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
Method for making: the method for reference example 1 is carried out.
Embodiment 5: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
Method for making: the method for reference example 1 is carried out.Use PEG200 and PEG400 combination as low-molecular-weight PEG, wherein the PEG400 of recipe quantity adds in step (1).Step is heated to melting with 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: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
Method for making: the method for reference example 1 is carried out.Step is heated to melting with 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: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
Method for making: the method for reference example 1 is carried out.
Embodiment 8: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
Method for making: the method for reference example 1 is carried out.Use PEG3350 and PEG4000 as high molecular weight PEGs.PEG20000 melting together with PEG3350 and PEG4000 joins in prescription.
Embodiment 9: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
Method for making: the method for reference example 1 is carried out.
Embodiment 10: preparation comprises the ointment compositions (with 100 gram amount preparations) of mupirocin
Formula:
Method for making: the method for reference example 1 is carried out.
II, reference examples part
Reference examples 1: the ointment compositions for 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 for 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 for preparing mupirocin
Formula:
Preparation method: lactic acid dissolution in PEG400, then is added 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 for preparing mupirocin
Except not adding in formula boric acid, other composition and method for making are identical with embodiment 2.
Reference examples 5: the ointment compositions for preparing mupirocin
Except not adding in formula boric acid, other composition and method for making are identical with embodiment 9.
Reference examples 6: the ointment compositions for preparing mupirocin
Boric acid in filling a prescription is used instead citric acid, and other composition and method for making are identical with embodiment 1.
Reference examples 7: the ointment compositions for preparing mupirocin
Boric acid in filling a prescription is used instead citric acid, and other composition and method for making are identical with embodiment 2.
Reference examples 8: the ointment compositions for preparing mupirocin
Boric acid in filling a prescription is used instead citric acid, and other composition and method for making are identical with embodiment 3.
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 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 in EP5.4 is as follows:
Related substance detects, and according to high performance liquid chromatography, carries out.
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, with acetic acid, is adjusted to pH4.0), then with identical mixed solvent, be diluted to 10ml.
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, with acetic acid, is adjusted to pH4.0).
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 mixed solvent (methanol mixes with 13.6g/l sodium acetate solution equal-volume, with acetic acid, is adjusted to pH4.0), then with identical mixed solvent, is diluted to 200.0ml.
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.
Inject 20 μ l reference solutions (b) in instrument.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.Inject 20 μ l reference solutions (c) in instrument.Record chromatogram subject to the foregoing, the retention time of impurity C is approximately 0.75 for mupirocin.Inject 20 μ l test solutions and 20 μ l reference solutions (a) in instrument.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 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 putting down in writing in BP2009 is as follows:
Determination of related substances:
(1) preparation of need testing solution and contrast solution: precision takes this product appropriate (approximately being equivalent to mupirocin 25mg), puts in the 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 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: with octyl silane group silica gel, be filler (the rustless steel pre-column that adds C8); Take oxolane: 7.7g/L ammonium acetate (with glacial acetic acid, regulating pH value to 5.7) 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, record 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: with octadecylsilane chemically bonded silica, be filler; 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 this product appropriate (approximately being equivalent to mupirocin 12.5mg), puts in the 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 the mupirocin reference substance, be measured in the same method., with calculated by peak area, obtain mupirocin content by external standard method.
For the present invention, in the present composition, the related substances and assay method is carried out with reference to the method in BP2009, particularly when carrying out present composition related substance, carry out according to the chromatographic condition in 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 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.
The investigation of test example 2, boric acid consumption
The method of reference example 1, the ointment compositions basic recipe of every 100g is: mupirocin 2g, PEG4000 are that 18g, boric acid amount suitably change, PEG400 adds to 100g.Wherein in different formulations, the addition of boric acid is respectively (in the ointment compositions of every 100g): 0g, 0.01g, 0.025g, 0.05g, 0.075g, 0.1g, 0.2g, 0.3g, 0.5g, 0.6g, 0.8g, 1.0g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 5g.Obtain 19 ointment compositions.
These 19 ointment compositions sealings are loaded in aluminum matter ointment tube, are placed in 45 ° of C thermostats and placed 50 days.Mensuration with respect to certain sample without for 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 formula, it is without 45 ° of C high-temperature treatments but be placed in 4-8 ° of C refrigerator and placed 50 days, and the impurity C percent of this moment is X1; This sample is X2 through 50 days rear impurity C percent of 45 ° of C high-temperature treatments, and with the variation of impurity C multiple=X2 ÷ X1, this changes multiple more close to 1, represents that 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 formula of different boric acid additions and impurity thereof change multiple and see the following form 1.Result shows, the amount of mineral acid is only to demonstrate good result in a certain amount of scope, and the excessive or too small equal nothing of addition is in the stability of product quality.
Table 1:
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 aluminum matter ointment tube, be placed in 80 ° of C thermostats and placed 15 days.The described method of reference test example 2, measure with respect to certain sample without for high-temperature treatment the variation multiple of the variation multiple of impurity C and total impurities in this sample.
Result shows, the variation multiple of various embodiments of the present invention sample impurity C is all between 1.13 ~ 1.46, and for example the variation multiple of embodiment 1,2,4,7 impurity C is respectively 1.21,1.38,1.13 and 1.31; And the variation multiple of each reference examples sample impurity C is all between 2.73 ~ 6.62, and for example the variation multiple of reference examples 1,4,6,7 impurity C is respectively 3.24,5.28,2.73 and 4.31.
In addition, the variation multiple of various embodiments of the present invention sample total impurities is all between 1.25 ~ 1.50, and for example the variation multiple of embodiment 2,3,5,6 total impurities is respectively 1.33,1.50,1.43 and 1.31; And the variation multiple of each reference examples sample total impurities is all between 3.03 ~ 8.55, and for example the variation multiple of reference examples 2,5,7 total impurities is respectively 3.75,6.77 and 4.54.
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 (18)
1. ointment medicament compositions wherein comprises: mupirocin shown in following formula or the acceptable salt of its pharmacy, molecular weight are that 200～600 Polyethylene Glycol, molecular weight are 2000～6000 Polyethylene Glycol and boric acid,
Wherein, comprise in every 100 grams of this ointment medicament compositions:
Mupirocin or the acceptable salt of its pharmacy: 1～3g,
Molecular weight is 2000～6000 Polyethylene Glycol: 15～25g,
Boric acid: 0.1～1g,
The optional acceptable adjuvant of pharmacy: 0～2g, and
Molecular weight is 200～600 Polyethylene Glycol: appropriate, add to 100g.
2. according to claim 1 ointment medicament compositions, the acceptable salt of the pharmacy of wherein said mupirocin is the calcium salt of mupirocin.
3. according to claim 1 ointment medicament compositions, the acceptable salt of the pharmacy of wherein said mupirocin is the dihydrate of the mupirocin calcium salt shown in following formula:
4. according to claim 1 ointment medicament compositions, wherein said molecular weight are that 200～600 Polyethylene Glycol is that molecular weight is the Polyethylene Glycol of 200-400.
5. according to claim 1 ointment medicament compositions, wherein said molecular weight are that 2000～6000 Polyethylene Glycol is that molecular weight is the Polyethylene Glycol of 2000-4000.
6. according to claim 1 ointment medicament compositions, the acceptable adjuvant of wherein said pharmacy is selected from: warming regulator, antiseptic, thickening agent.
7. according to claim 1 ointment medicament compositions comprises in its every 100 grams:
Mupirocin or the acceptable salt of its pharmacy: 1～3g,
Molecular weight is 2000～4000 Polyethylene Glycol: 15～25g,
Boric acid: 0.1～1g,
The optional acceptable adjuvant of pharmacy: 0～2g, and
Molecular weight is 200～400 Polyethylene Glycol: appropriate, add to 100g.
8. according to claim 1 ointment medicament compositions comprises in its every 100 grams:
9. according to claim 1 ointment medicament compositions comprises in its every 100 grams:
10. according to claim 1 ointment medicament compositions comprises in its every 100 grams:
11. ointment medicament compositions according to claim 1 comprises in its every 100 grams:
12. ointment medicament compositions according to claim 1 comprises in its every 100 grams:
13. ointment medicament compositions according to claim 1 comprises in its every 100 grams:
14. ointment medicament compositions according to claim 1 comprises in its every 100 grams:
15. ointment medicament compositions according to claim 1 comprises in its every 100 grams:
16. ointment medicament compositions according to claim 1 comprises in its every 100 grams:
17. ointment medicament compositions according to claim 1 comprises in its every 100 grams:
18. prepare the method for the described ointment medicament compositions of claim 1-17 any one, it comprises the following steps:
(1) making boric acid and the optional acceptable adjuvant of pharmacy be dissolved in appropriate molecular weight is in 200～600 Polyethylene Glycol, to obtain mixture;
(2) add mupirocin or the acceptable salt of its pharmacy, stirring and dissolving in the mixture of step (1);
(3) be that 2000～6000 Polyethylene Glycol is heated to melting with molecular weight, then it under agitation joined in step (2) gained material, stir;
(4) add molecular weight be 200～600 Polyethylene Glycol to full dose, mix homogeneously, obtain.
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| 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 |
| CN111220721A (en) * | 2019-12-06 | 2020-06-02 | 湖北人福成田药业有限公司 | Mupirocin ointment impurity qualitative positioning and testing method and application |
| CN110787128A (en) * | 2019-12-17 | 2020-02-14 | 福元药业有限公司 | Mupirocin ointment and preparation method thereof |
| CN114053210B (en) * | 2021-10-26 | 2023-09-29 | 海南全星制药有限公司 | Mopirocin ointment and preparation method thereof |
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| CN102335122A (en) * | 2011-06-21 | 2012-02-01 | 北京协和药厂 | Mupirocin ointment and preparation method thereof |
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