CN102961389A - Composition containing glucosamine as well as preparation method and detection method thereof - Google Patents
Composition containing glucosamine as well as preparation method and detection method thereof Download PDFInfo
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- CN102961389A CN102961389A CN2012104927084A CN201210492708A CN102961389A CN 102961389 A CN102961389 A CN 102961389A CN 2012104927084 A CN2012104927084 A CN 2012104927084A CN 201210492708 A CN201210492708 A CN 201210492708A CN 102961389 A CN102961389 A CN 102961389A
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Abstract
The invention relates to a composition containing glucosamine. The active ingredients of the composition are glucosamine or pharmaceutically acceptable salt thereof and lidocaine or pharmaceutically acceptable salt thereof, and the composition provided by the invention can be prepared into an injection, preferably a parenteral solution, more preferably a small-volume injection. The parenteral solution further comprises an antioxidant, a pH regulator and an alkaline solvent. The composition containing glucosamine provided by the invention can be used for overcoming the defects that freeze-drying preparation of glucosamine is long in freeze-drying time, high in energy consumption and not beneficial to production in the prior art and free-dying preparations in the same batch are different in the shape and solubility. Control on the stability of the parenteral solution and related substances is realized, and the side effect caused by degradation products is reduced, so that the safety and stability requirements of the parenteral solution are met. Therefore, the glucosamine parenteral solution provided by the invention can meet industrial production and can be safely and reliably applied to the field of medicine.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, mainly be specifically related to contain preparation method and the application thereof of glucosamine compositions.
Background technology
Glycosaminoglycan is a kind of natural saccharide that derives from chitin; be the Main Ingredients and Appearance in the cartilage matrix; by changing its side-chain structure; easilier in articular cartilage be combined with water; the maintenance articular cavity lubricates the effect with compensator or trimmer pressure; impaired chondrocyte is had certain protective effect, can synthetic use, existing commonly used have glucosamine, glucosamine hydrochloride, glucosamine sulfate sodium chloride double salt or potassium chloride double salt etc.Glucosamine is one of least unit that forms poly-glucosamine, and it and alduronic acid have formed poly-glucosamine, comprise chondroitin sulfate, keratan sulfate, dermatan sulfate and hyaluronic acid.
Glycosaminoglycan is a kind of natural saccharide that derives from chitin; be the Main Ingredients and Appearance in the cartilage matrix; by changing its side-chain structure; easilier in articular cartilage be combined with water; the maintenance articular cavity lubricates the effect with compensator or trimmer pressure; impaired chondrocyte is had certain protective effect, can synthetic use, existing commonly used have glucosamine, glucosamine hydrochloride, glucosamine sulfate sodium chloride double salt or potassium chloride double salt etc.Glucosamine is one of least unit that forms poly-glucosamine, and it and alduronic acid have formed poly-glucosamine, comprise chondroitin sulfate, keratan sulfate, dermatan sulfate and hyaluronic acid.
Anti-inflammatory drug only can improve the symptom of osteoarthritis, and glycosaminoglycan also can be controlled the symptom development, is conducive to the reparation of cartilage.Preparation at U.S.'s glycosaminoglycan and chondroitin sulfate has been added in the food, has very high safe reliability.Oral such medicine can reach therapeutic purposes, the patient of, pulmonary disease poor with blood circulation diseases, hepatic and renal function for some, diabetes, has equally safety, for the preparation of taking metallic elements such as adding magnesium, zinc, selenium, should note producing behind these electrolytic etching of metal to cardiovascular inhibitory action.Oral dose reached 1500mg and can reach therapeutic effect every day, patient for obesity or Long-term Oral diuretic also wants boost to 2000～2500mg, just can reach therapeutic effect after confirming in the experiment to take for 4～6 weeks, therefore should adhere to taking at least 1 month.Side reaction behind the long-term taking is less, and is also gentle.
Glucosamine lyophilizing and injection formulation and production method thereof are disclosed among the CN201010270516, but also there are following defective in this lyophilized formulations and production method: because lyophilized formulations is after preparation technology amplifies production, the temperature of freeze dryer on diverse location, vacuum is different, cause there are differences with a collection of medicine formation ice crystal form and rate of drying, and determined by the slowest goods of dry rate drying time, thereby, the freeze-drying time of the lyophilized formulations of glucosamine is long at present, power consumption is high, be unfavorable for actual production, and there is larger difference in same batch lyophilized formulations in form and solubility; Wherein injection formulation easily produces furfural class product, the 2-Acetamido-2-deoxy-D-glucoses and 2 such as catabolite 5 hydroxymethyl furfural at heat sterilization and at storage process in addition, the 6-dimethylaniline, and these degradation materials not only affect the curative effect of medicine, and correspondingly bring various toxic and side effects, affected safety and the effectiveness of injection.
Summary of the invention
The defective that exists for the related preparations such as compositions of present glucosamine, the invention provides a kind of compositions of stable processing technique, and a kind of glucosamine injection of stable processing technique further is provided, and further provide a kind of stable processing technique, curative effect high, safe aminoglucose injection.
Technical scheme of the present invention is as follows:
The compositions that contains glucosamine of the present invention, its active component is glucosamine or its pharmaceutically acceptable salt and lignocaine or its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt of glucosamine is selected from sodium chloride double salt or the potassium chloride double salt of the sodium chloride double salt of glucosamine hydrochloride, glucosamine sulfate, glucosamine hydrochloride or potassium chloride double salt, glucosamine sulfate, wherein the pharmaceutically acceptable salt of lignocaine is selected from lidocaine hydrochloride, sulphuric acid lignocaine, acetic acid lignocaine, but is not limited only to this.
Above-mentioned composition comprises antioxidant, pH adjusting agent and alkaline solvent; Described antioxidant is one or more the mixing in sodium sulfite, sodium pyrosulfite, the ascorbic acid, preferred sodium sulfite, and described alkaline solvent is diethanolamine, triethanolamine or ethylenediamine, preferred diethanolamine; Affiliated pH adjusting agent is selected from hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid etc., but is not limited only to this;
Above-mentioned composition is prepared into injection, and described injection is selected from injection, preferred small-volume injection.
The invention provides a kind of compositions that contains glucosamine, its active component is glucosamine or its pharmaceutically acceptable salt and lignocaine or its pharmaceutically acceptable salt; The pharmaceutically acceptable salt of described glucosamine is selected from the double salt of glucosamine; The pharmaceutically acceptable salt of described glucosamine is selected from sodium chloride double salt or the potassium chloride double salt of the sodium chloride double salt of glucosamine hydrochloride, glucosamine sulfate, glucosamine hydrochloride or potassium chloride double salt, glucosamine sulfate.
Further, the invention provides a kind of compositions that contains glucosamine, the pharmaceutically acceptable salt of wherein said lignocaine is selected from lidocaine hydrochloride, sulphuric acid lignocaine, acetic acid lignocaine.
Further, the invention provides a kind of compositions that contains glucosamine, wherein said compositions is prepared into injection, and described injection is selected from injection, preferred injection with small volume.Described injection comprises antioxidant, pH adjusting agent and alkaline solvent.
Further, the invention provides a kind of injection, described injection is comprised of aminoglucose injection and special solvent, faces the time spent aminoglucose injection and special solvent pairing are used;
Described aminoglucose injection is comprised of the component of following weight proportion:
Glucosamine or its pharmaceutically acceptable salt 100-600 part,
Lignocaine or its pharmaceutically acceptable salt 5-20 part,
PH adjusting agent is an amount of;
Described special solvent is the 0.5-10 milliliter, and it consists of alkaline solvent and water for injection, and described alkaline solvent is diethanolamine, triethanolamine or ethylenediamine, preferred diethanolamine; The described aminoglucose injection brown ampoule of packing into, the described special solvent colourless ampoule of packing into.
The present invention also provides a kind of method for preparing above-mentioned injection, it may further comprise the steps: wherein, get 80% water yield and be mixed with the 0.001mol/L hydrochloric acid solution, add glucosamine or its pharmaceutically acceptable salt and 50-60 ℃ of lower the stirring it is dissolved fully, add again 0.02% active carbon, at the 70-80 ℃ of lower 15～30min that stirs, after taking off charcoal, add again 0.01% active carbon and lignocaine or its pharmaceutically acceptable salt of recipe quantity in the solution, at the 40-50 ℃ of lower 10～15min that stirs, take off charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to capacity when being cooled to 15-25 ℃, then pH is transferred to 4.5-4.8, according to the 2ml embedding, at last at 121 ℃ of lower sterilization 15-20min.
Further, the present invention also provides a kind of method for preparing above-mentioned injection, may further comprise the steps: wherein, get 80% water yield and be mixed with the 0.001mol/L hydrochloric acid solution, add glucosamine sulfate sodium chloride double salt and 55 ℃ of lower stirrings it is dissolved fully, add again 0.02% active carbon, at 75 ℃ of lower 20min that stir, take off charcoal after, add again 0.01% active carbon and the lidocaine hydrochloride of recipe quantity in the solution, at 45 ℃ of lower 10min that stir, take off charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to capacity when being cooled to 20 ℃, then pH is transferred to 4.6, according to the 2ml embedding, at last at 121 ℃ of lower sterilization 17min.
The present invention also provides a kind of above-mentioned detection method of content that contains the compositions of glucosamine, comprises following assay method:
1), the content assaying method of glucosamine
Chromatographic condition: chromatographic column: Hypersil ODS post, column temperature: room temperature, detect wavelength: 340nm, mobile phase: with aqueous sodium acetate solution: methanol=900:100 is as mobile phase, described aqueous sodium acetate solution makes as follows: the 6.80g sodium acetate trihydrate, and add 700 ml water and make dissolving, transfer pH to 5.9 with acetic acid, add water to 1000ml, shake up;
The preparation of contrast liquid: it is an amount of that precision takes by weighing the glucosamine hydrochloride reference substance, adds the solution that water is made 1mg/ml, product solution in contrast,
The preparation of test liquid: it is an amount of that precision is measured this product, puts in the measuring bottle, and thin up shakes up to scale, as test liquid,
Derivatization reagent takes by weighing the 50mg o-phthalaldehyde(OPA) and puts in the 14ml polypropylene test tube, adds the 1.25ml absolute methanol and makes dissolving, adds 3-mercaptopropionic acid 50 μ l and 0.2M borate buffer solution 11.2ml again, and slowly mixing is put the dark place and placed 30 minutes,
Derivatization method: the borate buffer solution 400 μ l that get 0.2mol/L, put in the bottle, add 100 μ l derivatization reagents and 100 μ l contrast liquid or test liquid, mix, derivatization is sample introduction after 1 minute, with the sign content of the calculated by peak area aminoguanidine hydrochloride sugar of β-isomer;
2), the assay of lignocaine, chromatographic condition: be filler with octadecylsilane chemically bonded silica; With phosphate buffer: acetonitrile=50:50, and to transfer pH to 8.0 with phosphoric acid be mobile phase; The detection wavelength is 254nm, column temperature is 30 ℃, flow velocity is 1.0 ml/min, number of theoretical plate calculates by the lignocaine peak and is not less than 2000, and it is an amount of that precision is measured this product, puts in the measuring bottle, adding 2 mol/L NaOH solution transfers pH to neutral, add mobile phase and be diluted to scale, shake up, precision is measured 20 μ l injection liquid chromatographies; Other gets the lidocaine hydrochloride reference substance, and is accurately weighed, puts in the measuring bottle, is diluted to scale with mobile phase, shakes up, and measures with method.
The present invention also provides a kind of above-mentioned detection method of content that contains the compositions related substance of glucosamine, comprises following assay method:
1), the assay of 5 hydroxymethyl furfural
Chromatographic condition: chromatographic column Alltima C8 post; 30 ℃ of column temperatures detect wavelength 284nm, sample size 20 μ l; Take methanol: water=5:95 as mobile phase,
The preparation of test liquid: it is an amount of that precision is measured this product, puts in the measuring bottle, adds mobile phase and be diluted to scale, shakes up, as test liquid;
The preparation of contrast liquid: it is an amount of that precision takes by weighing 5 hydroxymethyl furfural, adds mobile phase and quantitatively be diluted to scale, as the 5 hydroxymethyl furfural contrast solution;
Get test liquid and each 20 μ l injection liquid chromatography of contrast liquid, the record chromatogram is to 3.0 times of 5 hydroxymethyl furfural peak retention time, the chromatographic peak consistent with 5 hydroxymethyl furfural peak retention time in the chromatogram of need testing solution, its peak area must not be greater than contrast solution main peak area 0.1%, other single impurity peak area must not be greater than contrast solution main peak area 0.1%, the total impurities peak area and must not be greater than 10 times of contrast solution main peak area;
2), the assay of N-acetyl-D glucosamine
Chromatographic column: Shodex Suger SH1011 chromatographic column, column temperature: 50 ℃, detect wavelength: 202nm, mobile phase is 0.006 mol/L H2SO4 solution;
The preparation of test liquid: it is an amount of that precision is measured this product, puts in the measuring bottle, adds mobile phase and make in right amount dissolving and be diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution;
The preparation of contrast liquid: it is an amount of that other gets N-acetyl-D glucosamine, adds mobile phase and make in right amount dissolving and be diluted to scale;
Draw respectively each 20 μ l injection liquid chromatography of contrast solution and need testing solution, the record chromatogram, by external standard method with calculated by peak area, in the need testing solution chromatogram if any N-acetyl-D glucosamine, must not be greater than N-acetyl-D glucosamine peak area 0.1%;
3), 2, the content assaying method of 6-dimethylaniline:
Chromatographic condition: be filler with octadecylsilane chemically bonded silica; With phosphate buffer: acetonitrile=50:50, and to transfer pH to 8.0 with phosphoric acid be mobile phase; The detection wavelength is 254nm, and column temperature is 30 ℃, and flow velocity is 1.0 ml/min,
The preparation of test liquid: it is an amount of that precision is measured this product, puts in the measuring bottle, transfers pH to add mobile phase to the neutrality with 2mol/L NaOH solution and be diluted to scale, shake up, as test liquid;
The preparation of contrast liquid: other gets 2,6-dimethylaniline reference substance, and is accurately weighed, adds mobile phase and reference substance solution is made in dilution;
In the chromatogram of need testing solution with 2,6-dimethylaniline retention time consistent chromatographic peak, its peak area must not be greater than 0.04% of reference substance solution main peak area.
The present invention brings useful technique effect to comprise by the temperature of active carbon in the injection preparation, the pH of solution are regulated and control, realized the control to injection stability and related substances, reduce the side effect that degradation material brings, thereby reached the requirement of injection safety, stability.
The present invention overcomes that the freeze-drying time of lyophilized formulations of prior art glucosamine is long, power consumption is high, is unfavorable for producing, and there is the defective of larger difference in same batch lyophilized formulations at form and solubility.Therefore, aminoglucose injection provided by the present invention can satisfy suitability for industrialized production, and can be applied to safely, reliably field of medicaments.
Specific embodiments:
The defective that exists for overcoming existing glucosamine compound injection, the discovery of the present invention by a large amount of experiment accidents is by the best of breed to the parameter of temperature, pH value, addition sequence and sterilization process, obtain unexpected technique effect, and confirmed the technique effect that it is unexpected by following examples and experimental example:
Embodiment 1 glucosamine sulfate injection (in glucosamine sulfate 0.4g)
Process for preparation: get 80% water yield and be mixed with the 0.001mol/L hydrochloric acid solution, add glucosamine sulfate sodium chloride double salt and 55 ℃ of lower stirrings it is dissolved fully, add again 0.02% active carbon, at 75 ℃ of lower 20min that stir, after taking off charcoal, add again 0.01% active carbon and the lidocaine hydrochloride of recipe quantity in the solution, at 45 ℃ of lower 10min that stir, take off charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to capacity when being cooled to 20 ℃, then pH is transferred to 4.6, according to the 2ml embedding, at last at 121 ℃ of lower sterilization 17min.
Other prepares special solvent, and is as follows: diethanolamine 20g adds 1000ml water for injection, makes 1000.Process for preparation: the alkaline conditioner diethanolamine that takes by weighing above-mentioned recipe quantity adds water to capacity, stirs, and adds 0.05% active carbon, stirs 15～30min, takes off charcoal, through the extremely clarification of 0.45 μ m, 0.22 μ m filtering with microporous membrane; According to the 1ml embedding, sterilized 15 minutes for 121 ℃.
Embodiment 2 glucosamine sulfate injection (in glucosamine sulfate 0.4g)
Process for preparation: get 80% water yield and be mixed with the 0.001mol/L hydrochloric acid solution, adding the stirring of glucosamine sulfate sodium chloride double salt dissolves it fully, add again 0.02% active carbon, stir 20min under the room temperature, after taking off charcoal, add again 0.01% active carbon and the lidocaine hydrochloride of recipe quantity in the solution, stir at normal temperatures 10min, take off charcoal, to clarification, medicinal liquid adds water to capacity when being cooled to 20 ℃, then pH is transferred to 4.6 through 0.45 μ m, 0.22 μ m filtering with microporous membrane, according to the 2ml embedding, at last at 121 ℃ of lower sterilization 17min.
Special solvent is with the method preparation of embodiment 1.
Experimental example 1: because the reaction mechanism mechanism of reaction of 5 hydroxymethyl furfural, think that this process is comprised of a series of elementary reactions such as protonated, dehydration and deprotonations, wherein protonated relatively easy, and the deprotonation reaction energy barrier is higher, is that the rate determining step of conversion process is rapid.Therefore, the variation of temperature is larger on the decomposition impact of glucosamine than the variation of pH value.According to the preparation method of the embodiment 4 in the CN201010270516 patent application, get respectively 80% water yield and be mixed with hydrochloric acid solution, after the active component dissolving added the water capacity, pH reached respectively 5.5,5.0,4.7,4.4,4.2,4.0,3.5,3.0,2.0,1.0, at last at 121 ℃ of lower sterilization 17min.Comparing embodiment 1 pH before sterilization reaches respectively 5.5,5.0,4.7,4.6,4.4,4.2,4.0,3.5 simultaneously, at last at 121 ℃ of lower sterilization 17min.
Adopt respectively the trap of the above-mentioned sterilization of the determined by ultraviolet spectrophotometry front and back of conventional determining 5 hydroxymethyl furfural, table 3,4 results show that lower pH value can suppress the generation of 5 hydroxymethyl furfural, but the 5 hydroxymethyl furfural of injection increases by 500 abovely before and after sterilization, changes not obvious; And the 5 hydroxymethyl furfural of the glucosamine sulfate injection of this specific embodiments embodiment 1 obviously reduces, has significant difference (P＜0.05) (annotate: 5 hydroxymethyl furfural is the catabolite of glucose injection in preparation process, and human body striped muscle and internal organs are all had infringement).
Trap before and after the embodiment 4 different pH sterilizations in the table 3 CN201010270516 patent application
Trap before and after the different pH sterilizations of table 4 the present invention
Above result shows that preparation technology of the present invention can significantly reduce the main component degraded.Dissolve under the condition that this may adopt first with the present invention and heat, pH value is lower, medicine fully is dissolved in the water with molecule or ionic species, low temperature takes off charcoal again, and then improves pH value and reduce fluid temperature, again final high temperature sterilization.Because glucosamine sulfate is degraded into 5 hydroxymethyl furfural easily with the form of molecule or ion usually under the condition of water, the present invention has selected the pH value of particular range and has reduced fluid temperature before sterilization, under this specific condition, the medicine major part has formed between molecule, the particular state of the particulate matter aggregation between ion and the crystalline deposit, thereby reduced molecule, the form that ion exists, suppressed the generation of 5 hydroxymethyl furfural, simultaneously in the process of high temperature sterilize heating, the particulate matter aggregation is transformed into again molecule gradually under heating condition, ion, pH value also can decrease after the sterilization, finally makes medicine be in the dissolved state of stable and uniform.
Experimental example 2: because iron salt, the zinc salt content of active carbon are higher, when introducing active carbon, introduced a large amount of easily metal ions of accelerated oxidation variable color, thereby taking rational activated carbon process is the key that reduces metal ion.Respectively comparing embodiment 1,2 glucosamine sulfate injection and Comparative Examples 1(are according to the glucosamine sulfate injection of embodiment 4 preparations in the CN201010270516 patent application) place the hermetic container of 40 ℃ ± 2 ℃ of temperature, placed 6 months, and investigated its stability respectively at l, 2,3, sampling in June.The results are shown in Table 4.
Table 4 accelerates experiment
Adopt the iron ion content after the sterilization among the potassium thiocyanate colorimetric method for determining embodiment 1,2, and under 480nm, measure absorbance, embodiment 1,2 respectively gets 6 samples and measures with method, and wherein the meansigma methods of embodiment 1 absorbance is that the meansigma methods of 0.05, embodiment, 2 absorbances is 0.15.
Above result shows that the present invention adopts the absorbability that heats the effective enhanced activity charcoal of repeatedly activated carbon adsorption energy, while heating for dissolving glucosamine sulfate sodium chloride double salt, it is existed with molecule or ionic species, strengthened the complexing power of iron ion and glucosamine sulfate, and thereby the tiny microgranule of formation is adsorbed by active carbon under acid condition, the minimizing of iron ion also makes medicine more stable, reduces the speed of oxidation stain.
Experimental example 3: because sterilization is an important step of infusion preparation, in the sterilizing works of the large production of reality, can find diverse location in the sterilizing cabinet, has different temperatures, pressure, such as levels, there is certain difference between four angles and the central authorities, the glucosamine sulfate injection that the glucosamine sulfate injection of difference comparing embodiment 1 and Comparative Examples 1(prepare according to the embodiment 4 in CN201010 270516 patent applications) the content difference of glucosamine sulfate after the sterilization, in sterilizing cabinet, arrange 4 layers at injection, be decided to be from the bottom to top h1, h2, h3, h4, four angles of every layer are decided to be the S point, every layer of center is decided to be the M point, respectively to 3 batches of injection 1 bottle of different position draw samples, calculate meansigma methods and the standard variance of content of the glucosamine sulfate of same batch of each point sampling.
The stability of table 4 glucosamine sulfate injection sterilization process
Above result shows that the preparation technology of injection of the present invention is practical, is easy to for actual production, and technique has better stability and repeatability.Because the special process before the present invention sterilizes makes medicinal liquid form specific uniform solution, even still can keep the stable uniform of active medicine content under different temperatures.
The parameter that more than experimental results show that temperature of the present invention, pH value, addition sequence and sterilization process has realized best of breed, has obtained unexpected technique effect.
The detection method of content of ejection preparation of the present invention and related substance inspection method:
1, the assay of glucosamine
Experimental technique: adopt pre-column derivatization-HPLC method.
The reagent preparation:
(1) the 0.2mol/L borate buffer solution takes by weighing the 7.63g sodium borate, adds 80ml water and makes dissolving, transfers pH to 9.5 with dilute hydrochloric acid, adds water to 100ml, shakes up.(store under room temperature condition, if any crystallization, heating makes dissolving.）
(2) derivatization reagent takes by weighing the 50mg o-phthalaldehyde(OPA) and puts in the 14ml polypropylene test tube, adds the 1.25ml absolute methanol and makes dissolving, adds 3-mercaptopropionic acid 50 μ l and 0.2M borate buffer solution 11.2ml again, and slowly mixing is put the dark place and placed 30 minutes.(added 3-mercaptopropionic acid 10 μ l to keep reagent concentration in per two days, and in the dark place room temperature preservation, used in two weeks)
Chromatographic condition:
Mobile phase: with aqueous sodium acetate solution (the 6.80g sodium acetate trihydrate adds 700 ml water and makes dissolving, transfers pH to 5.9 with acetic acid, adds water to 1000ml, shakes up)-methanol (900:100) as mobile phase.
Chromatographic column: Hypersil ODS post (4.6mm * 5cm)
Column temperature: room temperature detects wavelength: 340nm
Flow velocity: 1.0ml/min sample size: 20 μ l
The preparation of contrast liquid: it is an amount of that precision takes by weighing the glucosamine hydrochloride reference substance, adds the solution that water is made 1mg/ml, in contrast product solution.
The preparation of test liquid: precision is measured this product an amount of (being equivalent to glucosamine hydrochloride 20mg), puts in the 20ml measuring bottle, and thin up shakes up to scale, as test liquid.
Derivatization method: get the borate buffer solution 400 μ l of 0.2mol/L, put in the bottle, add 100 μ l derivatization reagents and 100 μ l contrast liquid or test liquid, mix, derivatization is sample introduction after 1 minute.The record chromatogram.β-isomer is 1.6～1.7 with the ratio of the retention time of alpha-isomer.The appearance time of β-isomer is about 4 minutes, with the sign content of the calculated by peak area aminoguanidine hydrochloride sugar of β-isomer.
2, the assay of lignocaine
Chromatographic condition and system suitability experiment
Be filler with octadecylsilane chemically bonded silica; Transferring PH to 8.0 with phosphate buffer (get 1mol/L NaH2PO4 1.3 ml and 0.5 mol/L Na2HPO4 32.5ml, put in the 1000ml measuring bottle, thin up shakes up to scale)-acetonitrile (50:50) with phosphoric acid is mobile phase; The detection wavelength is 254nm, and column temperature is 30 ℃, and flow velocity is 1.0 ml/min, and number of theoretical plate calculates by the lignocaine peak and is not less than 2000.
Precision is measured this product an amount of (being equivalent to approximately lidocaine hydrochloride 20mg), puts in the 10ml measuring bottle, adds 2 mol/L NaOH solution and transfers PH to neutral, adds mobile phase and is diluted to scale, shakes up, and precision is measured 20 μ l injection liquid chromatographies, the record chromatogram; Other gets the about 20mg of lidocaine hydrochloride reference substance, and is accurately weighed, puts in the 10ml measuring bottle, is diluted to scale with mobile phase, shakes up, and measures with method.
Related substance checks
1,5 hydroxymethyl furfural and related substances thereof
Chromatographic condition: Shimadzu LC-10AT pump; Shimadzu SPD-10A UV-detector
Chromatographic column Alltima C8(250 * 4.6mm, 5 μ m) column temperature is 30 ℃
Detect wavelength 284nm sample size 20 μ l
Mobile phase methanol: water=5:95
Precision is measured this product an amount of (being equivalent to approximately glucosamine sulfate 400mg), puts in the 100 ml measuring bottles, adds mobile phase and is diluted to scale, shakes up, as test liquid; It is an amount of that precision takes by weighing 5 hydroxymethyl furfural, adds the quantitative dilution of mobile phase and make the solution that concentration is 400 μ g/ml.Get this solution 1ml, put in the 100ml measuring bottle, add mobile phase to scale, shake up, as the 5 hydroxymethyl furfural contrast solution.Get test liquid and each 20 μ l injection liquid chromatography of contrast liquid, the record chromatogram is to 3.0 times of 5 hydroxymethyl furfural peak retention time, in the chromatogram of need testing solution if any the chromatographic peak consistent with 5 hydroxymethyl furfural peak retention time, its peak area must not be greater than contrast solution main peak area (0.1%), other single impurity peak area must not be greater than contrast solution main peak area (0.1%), the total impurities peak area and must not be greater than 10 times (1.0%) of contrast solution main peak area.
2, N-acetyl-D glucosamine (NAG)
Chromatographic column: Shodex Suger SH1011 chromatographic column (300mm * 8mm)
Column temperature: 50 ℃ are detected wavelength: 202nm mobile phase: 0.006 mol/L H2SO4 solution
Flow velocity: 1.0ml/min sample size: 20 μ l
Precision is measured this product an amount of (being equivalent to approximately glucosamine sulfate 200mg), puts in the 10ml measuring bottle, adds mobile phase and makes in right amount dissolving and be diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution.It is an amount of that other gets NAG, add mobile phase dissolving and quantitatively dilution make the solution solution (0.1%) in contrast that contains approximately NAG 20 μ g among every 1ml.Draw respectively each 20 μ l injection liquid chromatography of contrast solution and need testing solution, the record chromatogram, by external standard method with calculated by peak area, in the need testing solution chromatogram if any N-acetyl-D glucosamine, should be greater than N-acetyl-D glucosamine peak area (0.1%).
2, the HPLC method is measured the related substance of lignocaine in this product
Chromatographic condition is with reference to content assaying method under the lidocaine hydrochloride item.
Precision is measured this product an amount of (being equivalent to approximately lidocaine hydrochloride 20mg), puts in the 10ml measuring bottle, adds mobile phase with 2mol/L NaOH solution accent PH to the neutrality and is diluted to scale, shake up, as test liquid, other gets 2,6-dimethylaniline reference substance, accurately weighed, add mobile phase and the solution that is about 0.8 μ g among every 1ml is made in dilution, product solution is got contrast liquid 20 μ l injection liquid chromatographies in contrast, regulate instrumental sensitivity, make the peak height at main constituent peak be about 10 ~ 30% of full scale; Precision is measured test liquid 20 μ l again, the injection liquid chromatography, and if any the chromatographic peak consistent with 2,6-dimethylaniline retention time, its peak area must not be greater than reference substance solution main peak area (0.04%) in the chromatogram of need testing solution.
Claims (11)
1. a compositions that contains glucosamine is characterized in that, its active component is glucosamine or its pharmaceutically acceptable salt and lignocaine or its pharmaceutically acceptable salt.
2. compositions according to claim 1 is characterized in that, the pharmaceutically acceptable salt of glucosamine is selected from the double salt of glucosamine.
3. compositions according to claim 1, it is characterized in that the pharmaceutically acceptable salt of glucosamine is selected from sodium chloride double salt or the potassium chloride double salt of the sodium chloride double salt of glucosamine hydrochloride, glucosamine sulfate, glucosamine hydrochloride or potassium chloride double salt, glucosamine sulfate.
4. compositions according to claim 1 is characterized in that, the pharmaceutically acceptable salt of lignocaine is selected from lidocaine hydrochloride, sulphuric acid lignocaine, acetic acid lignocaine.
5. compositions according to claim 1 is characterized in that, described compositions is prepared into injection, and described injection is selected from injection, preferred small-volume injection.
6. injection according to claim 5 is characterized in that, described injection comprises antioxidant, pH adjusting agent and alkaline solvent.
7. injection according to claim 6 is characterized in that, this injection is comprised of aminoglucose injection and special solvent, faces the time spent aminoglucose injection and the pairing of special solvent liquid are used;
Described aminoglucose injection is comprised of the component of following weight proportion:
Glucosamine or its pharmaceutically acceptable salt 100-600 part,
Lignocaine or its pharmaceutically acceptable salt 5-20 part,
PH adjusting agent is an amount of;
Described special solvent is the 0.5-10 milliliter, and it consists of alkaline solvent and water for injection, and described alkaline solvent is diethanolamine, triethanolamine or ethylenediamine, preferred diethanolamine;
The described aminoglucose injection brown ampoule of packing into, the described special solvent colourless ampoule of packing into.
8. method for preparing the described injection of above claim 7, it is characterized in that, may further comprise the steps: wherein, get 80% water yield and be mixed with the 0.001mol/L hydrochloric acid solution, add glucosamine or its pharmaceutically acceptable salt and 50-60 ℃ of lower the stirring it is dissolved fully, add again 0.02% active carbon, at the 70-80 ℃ of lower 15～30min that stirs, after taking off charcoal, add again 0.01% active carbon and lignocaine or its pharmaceutically acceptable salt of recipe quantity in the solution, at the 40-50 ℃ of lower 10～15min that stirs, take off charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to capacity when being cooled to 15-25 ℃, then pH is transferred to 4.5-4.8, according to the 2ml embedding, at last at 121 ℃ of lower sterilization 15-20min.
9. method for preparing the described injection of above claim 8, it is characterized in that, may further comprise the steps: wherein, get 80% water yield and be mixed with the 0.001mol/L hydrochloric acid solution, add glucosamine sulfate sodium chloride double salt and 55 ℃ of lower stirrings it is dissolved fully, add again 0.02% active carbon, at 75 ℃ of lower 20min that stir, after taking off charcoal, add again 0.01% active carbon and the lidocaine hydrochloride of recipe quantity in the solution, at 45 ℃ of lower 10min that stir, take off charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to capacity when being cooled to 20 ℃, then pH is transferred to 4.6, according to the 2ml embedding, at last at 121 ℃ of lower sterilization 17min.
10. the described detection method of content that contains the compositions of glucosamine of any one according to claim 1-9 is characterized in that: comprise following assay method:
1) content assaying method of glucosamine
Chromatographic condition: chromatographic column: Hypersil ODS post, column temperature: room temperature, detect wavelength: 340nm, mobile phase: with aqueous sodium acetate solution: methanol=900:100 is as mobile phase, described aqueous sodium acetate solution makes as follows: the 6.80g sodium acetate trihydrate, and add 700 ml water and make dissolving, transfer pH to 5.9 with acetic acid, add water to 1000ml, shake up;
The preparation of contrast liquid: it is an amount of that precision takes by weighing the glucosamine hydrochloride reference substance, adds the solution that water is made 1mg/ml, in contrast product solution;
The preparation of test liquid: it is an amount of that precision is measured this product, puts in the measuring bottle, and thin up shakes up to scale, as test liquid,
Derivatization reagent takes by weighing the 50mg o-phthalaldehyde(OPA) and puts in the 14ml polypropylene test tube, adds the 1.25ml absolute methanol and makes dissolving, adds 3-mercaptopropionic acid 50 μ l and 0.2M borate buffer solution 11.2ml again, and slowly mixing is put the dark place and placed 30 minutes,
Derivatization method: the borate buffer solution 400 μ l that get 0.2mol/L, put in the bottle, add 100 μ l derivatization reagents and 100 μ l contrast liquid or test liquid, mix, derivatization is sample introduction after 1 minute, with the sign content of the calculated by peak area aminoguanidine hydrochloride sugar of β-isomer;
2) assay of lignocaine, chromatographic condition: be filler with octadecylsilane chemically bonded silica; With phosphate buffer: acetonitrile=50:50, and to transfer pH to 8.0 with phosphoric acid be mobile phase; The detection wavelength is 254nm, column temperature is 30 ℃, flow velocity is 1.0 ml/min, number of theoretical plate calculates by the lignocaine peak and is not less than 2000, and it is an amount of that precision is measured this product, puts in the measuring bottle, adding 2 mol/L NaOH solution transfers pH to neutral, add mobile phase and be diluted to scale, shake up, precision is measured 20 μ l injection liquid chromatographies; Other gets the lidocaine hydrochloride reference substance, and is accurately weighed, puts in the measuring bottle, is diluted to scale with mobile phase, shakes up, and measures with method.
11. the described detection method of content that contains the compositions related substance of glucosamine of any one according to claim 1-9 is characterized in that: comprise following assay method:
1) assay of 5 hydroxymethyl furfural
Chromatographic condition: chromatographic column Alltima C8 post; 30 ℃ of column temperatures detect wavelength 284nm, sample size 20 μ l; Take methanol: water=5:95 as mobile phase,
The preparation of test liquid: it is an amount of that precision is measured this product, puts in the measuring bottle, adds mobile phase and be diluted to scale, shakes up, as test liquid;
The preparation of contrast liquid: it is an amount of that precision takes by weighing 5 hydroxymethyl furfural, adds mobile phase and quantitatively be diluted to scale, as the 5 hydroxymethyl furfural contrast solution;
Get test liquid and each 20 μ l injection liquid chromatography of contrast liquid, the record chromatogram is to 3.0 times of 5 hydroxymethyl furfural peak retention time, the chromatographic peak consistent with 5 hydroxymethyl furfural peak retention time in the chromatogram of need testing solution, its peak area must not be greater than contrast solution main peak area 0.1%, other single impurity peak area must not be greater than contrast solution main peak area 0.1%, the total impurities peak area and must not be greater than 10 times of contrast solution main peak area;
2) assay of N-acetyl-D glucosamine
Chromatographic column: Shodex Suger SH1011 chromatographic column, column temperature: 50 ℃, detect wavelength: 202nm, mobile phase is 0.006 mol/L H2SO4 solution;
The preparation of test liquid: it is an amount of that precision is measured this product, puts in the measuring bottle, adds mobile phase and make in right amount dissolving and be diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution;
The preparation of contrast liquid: it is an amount of that other gets N-acetyl-D glucosamine, adds mobile phase and make in right amount dissolving and be diluted to scale;
Draw respectively each 20 μ l injection liquid chromatography of contrast solution and need testing solution, the record chromatogram, by external standard method with calculated by peak area, in the need testing solution chromatogram if any N-acetyl-D glucosamine, must not be greater than N-acetyl-D glucosamine peak area 0.1%;
3) 2, the content assaying method of 6-dimethylaniline:
Chromatographic condition: be filler with octadecylsilane chemically bonded silica; With phosphate buffer: acetonitrile=50:50, and to transfer pH to 8.0 with phosphoric acid be mobile phase; The detection wavelength is 254nm, and column temperature is 30 ℃, and flow velocity is 1.0 ml/min,
The preparation of test liquid: it is an amount of that precision is measured this product, puts in the measuring bottle, transfers pH to add mobile phase to the neutrality with 2mol/L NaOH solution and be diluted to scale, shake up, as test liquid;
The preparation of contrast liquid: other gets 2,6-dimethylaniline reference substance, and is accurately weighed, adds mobile phase and reference substance solution is made in dilution;
In the chromatogram of need testing solution with 2,6-dimethylaniline retention time consistent chromatographic peak, its peak area must not be greater than 0.04% of reference substance solution main peak area.
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Cited By (7)
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| CN103421060A (en) * | 2013-05-06 | 2013-12-04 | 华中农业大学 | Post-column derivatization preparation method and application of aminoglycosides compound |
| CN104739849A (en) * | 2015-04-03 | 2015-07-01 | 俞嘉林 | Injection containing glucosamine sulfate and preparation method thereof as well as application thereof in medicine for treatment of osteoarthritis |
| CN104880530A (en) * | 2015-05-14 | 2015-09-02 | 东北农业大学 | Method for analyzing glucosamine content in whey protein glycosylation product by reverse-phase high performance liquid chromatography (RP-HPLC) |
| CN104931602A (en) * | 2015-05-12 | 2015-09-23 | 广西壮族自治区梧州食品药品检验所 | Method for determining content of glucose and sodium chloride in sodium chloride and dextrose injection |
| CN109481398A (en) * | 2018-12-18 | 2019-03-19 | 江西润泽药业有限公司 | Aminoglucose injection and its preparation method and application |
| CN113122219A (en) * | 2021-04-20 | 2021-07-16 | 大庆佳源信德实业有限公司 | Alkaline liquid gel breaker for oil field fracturing |
| CN116589912A (en) * | 2023-05-16 | 2023-08-15 | 福建海贝乐新材料科技有限公司 | Antibacterial paint for baby houses and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103421060A (en) * | 2013-05-06 | 2013-12-04 | 华中农业大学 | Post-column derivatization preparation method and application of aminoglycosides compound |
| CN104739849A (en) * | 2015-04-03 | 2015-07-01 | 俞嘉林 | Injection containing glucosamine sulfate and preparation method thereof as well as application thereof in medicine for treatment of osteoarthritis |
| CN104931602A (en) * | 2015-05-12 | 2015-09-23 | 广西壮族自治区梧州食品药品检验所 | Method for determining content of glucose and sodium chloride in sodium chloride and dextrose injection |
| CN104880530A (en) * | 2015-05-14 | 2015-09-02 | 东北农业大学 | Method for analyzing glucosamine content in whey protein glycosylation product by reverse-phase high performance liquid chromatography (RP-HPLC) |
| CN109481398A (en) * | 2018-12-18 | 2019-03-19 | 江西润泽药业有限公司 | Aminoglucose injection and its preparation method and application |
| CN113122219A (en) * | 2021-04-20 | 2021-07-16 | 大庆佳源信德实业有限公司 | Alkaline liquid gel breaker for oil field fracturing |
| CN116589912A (en) * | 2023-05-16 | 2023-08-15 | 福建海贝乐新材料科技有限公司 | Antibacterial paint for baby houses and preparation method thereof |
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