CN102961389B - 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
- Publication number
- CN102961389B CN102961389B CN201210492708.4A CN201210492708A CN102961389B CN 102961389 B CN102961389 B CN 102961389B CN 201210492708 A CN201210492708 A CN 201210492708A CN 102961389 B CN102961389 B CN 102961389B
- Authority
- CN
- China
- Prior art keywords
- injection
- glucosamine
- solution
- stir
- glucosamine sulfate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention discloses a composition containing glucosamine sulfate double salt. The active ingredients of the composition are glucosamine sulfate double salt and lidocaine hydrochloride, and the injection is preferably as a small-volume injection. The injection further comprises an antioxidant, a pH regulator and an alkaline solvent. The injection 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, be mainly specifically related to the injection and the wherein detection of composition that contain glucosamine sulfate double salt.
background technology
Glycosaminoglycan is the natural saccharide of one that derives from chitin; for the Main Ingredients and Appearance in cartilage matrix; by changing its side-chain structure; in articular cartilage, be more easily combined with water; maintenance articular cavity lubricates the effect with compensator or trimmer pressure; impaired chondrocyte is had to certain protective effect, can synthetic application, existing conventional have glucosamine, glucosamine hydrochloride, glucosamine sulfate sodium chloride double salt or potassium chloride double salt etc.Glucosamine is one of least unit of composition poly-glucosamine, and it and alduronic acid have formed poly-glucosamine, comprise chondroitin sulfate, keratan sulfate, dermatan sulfate and hyaluronic acid.
Glycosaminoglycan is the natural saccharide of one that derives from chitin; for the Main Ingredients and Appearance in cartilage matrix; by changing its side-chain structure; in articular cartilage, be more easily combined with water; maintenance articular cavity lubricates the effect with compensator or trimmer pressure; impaired chondrocyte is had to certain protective effect, can synthetic application, existing conventional have glucosamine, glucosamine hydrochloride, glucosamine sulfate sodium chloride double salt or potassium chloride double salt etc.Glucosamine is one of least unit of composition 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 symptom development, is conducive to the reparation of cartilage.Preparation at U.S.'s glycosaminoglycan and chondroitin sulfate has been added in 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, there is equally safety, for the preparation of taking metallic elements such as adding magnesium, zinc, selenium, should note producing after 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, in experiment, confirm to take after 4～6 weeks just to reach therapeutic effect, therefore should adhere to taking at least 1 month.Side reaction after long-term taking is less, also gentleer.
Glucosamine lyophilizing and injection formulation and production method thereof are disclosed in CN201010270516, but also there is following defect 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 difference, cause there are differences with a collection of medicine formation ice crystal form and rate of drying, and determined drying time by the slowest goods of dry rate, thereby, the freeze-drying time of the lyophilized formulations of glucosamine is long at present, consume energy high, be unfavorable for actual production, and there is larger difference in form and solubility in the lyophilized formulations of same batch, injection formulation wherein easily produces bran aldehyde 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, 6-dimethylaniline, and these degradation materials not only affect the curative effect of medicine, and correspondingly bring various toxic and side effects, affect safety and the effectiveness of injection.
Summary of the invention
The defect existing for related preparations such as the compositionss of current glucosamine, the invention provides a kind of compositions of stable processing technique, and a kind of glucosamine injection of stable processing technique is further 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, ascorbic acid, preferably sodium sulfite, and described alkaline solvent is diethanolamine, triethanolamine or ethylenediamine, preferably 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, preferably 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, preferably 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 made up of aminoglucose injection and special solvent, faces the used time by aminoglucose injection and special solvent pairing use;
Described aminoglucose injection is made up 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 appropriate;
Described special solvent is 0.5-10 milliliter, and it consists of alkaline solvent and water for injection, and described alkaline solvent is diethanolamine, triethanolamine or ethylenediamine, preferably diethanolamine; Described aminoglucose injection packs brown ampoule into, and described special solvent packs colourless ampoule into.
The present invention also provides a kind of method of preparing above-mentioned injection, it comprises the following steps: wherein, get 80% water yield and be mixed with 0.001mol/L hydrochloric acid solution, add glucosamine or its pharmaceutically acceptable salt and stir it is dissolved completely at 50-60 DEG C, add again 0.02% active carbon, at 70-80 DEG C, stir 15～30min, after de-charcoal, again toward adding 0.01% active carbon and lignocaine or its pharmaceutically acceptable salt of recipe quantity in solution, at 40-50 DEG C, stir 10～15min, de-charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to enough in the time being cooled to 15-25 DEG C, then pH is adjusted to 4.5-4.8, according to 2ml embedding, finally sterilizing 15-20min at 121 DEG C.
Further, the present invention also provides a kind of method of preparing above-mentioned injection, comprise the following steps: wherein, get 80% water yield and be mixed with 0.001mol/L hydrochloric acid solution, add glucosamine sulfate sodium chloride double salt and stir it is dissolved completely at 55 DEG C, add again 0.02% active carbon, at 75 DEG C, stir 20min, after de-charcoal, again toward adding 0.01% active carbon and the lidocaine hydrochloride of recipe quantity in solution, at 45 DEG C, stir 10min, de-charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to enough in the time being cooled to 20 DEG C, then pH is adjusted to 4.6, according to 2ml embedding, finally sterilizing 17min at 121 DEG C.
The present invention also provides a kind of detection method of content of the above-mentioned compositions that contains 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: using aqueous sodium acetate solution: methanol=900:100 is as mobile phase, described aqueous sodium acetate solution makes as follows: 6.80g sodium acetate trihydrate, adds 700 ml water to make to dissolve, with acetic acid tune pH to 5.9, add water to 1000ml, shake up;
The preparation of contrast liquid: it is appropriate that precision takes glucosamine hydrochloride reference substance, adds water and makes the solution of 1mg/ml, product solution in contrast,
The preparation of test liquid: it is appropriate that precision measures this product, puts in measuring bottle, is diluted with water to scale, shake up, and as test liquid,
Derivatization reagent takes 50mg o-phthalaldehyde(OPA) and puts in 14ml polypropylene test tube, adds 1.25ml absolute methanol to make to dissolve, then adds 3-mercaptopropionic acid 50 μ l and 0.2M borate buffer solution 11.2ml, slowly mixes, and put dark place and place 30 minutes,
Derivatization method: the borate buffer solution 400 μ l that get 0.2mol/L, put in a 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: with octadecylsilane chemically bonded silica be filler; With phosphate buffer: acetonitrile=50:50, and with phosphoric acid adjust pH to 8.0 be mobile phase; Detection wavelength is 254nm, column temperature is 30 DEG C, flow velocity is 1.0 ml/min, number of theoretical plate calculates and is not less than 2000 by lignocaine peak, and it is appropriate that precision measures this product, puts in measuring bottle, adding 2 mol/L NaOH solution adjusts pH to neutral, add mobile phase and be diluted to scale, shake up, precision measures 20 μ l injection liquid chromatographies; Separately get lidocaine hydrochloride reference substance, accurately weighed, put in measuring bottle, be diluted to scale by mobile phase, shake up, be measured in the same method.
The present invention also provides a kind of detection method of content of the above-mentioned compositions related substance that contains glucosamine, comprises following assay method:
1), the assay of 5 hydroxymethyl furfural
Chromatographic condition: chromatographic column Alltima C8 post; 30 DEG C of column temperatures, detect wavelength 284nm, sample size 20 μ l; Taking methanol: water=5:95 as mobile phase,
The preparation of test liquid: it is appropriate that precision measures this product, puts in measuring bottle, adds mobile phase and is diluted to scale, shakes up, as test liquid;
The preparation of contrast liquid: it is appropriate that precision takes 5 hydroxymethyl furfural, adds mobile phase and be quantitatively diluted to scale, as 5 hydroxymethyl furfural contrast solution;
Get test liquid and the each 20 μ l injection liquid chromatographies of contrast liquid, record 3.0 times to 5 hydroxymethyl furfural peak retention time of chromatogram, 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%, 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 DEG C, detect wavelength: 202nm, mobile phase is 0.006 mol/L H2SO4 solution;
The preparation of test liquid: it is appropriate that precision measures this product, puts in measuring bottle, adds mobile phase and makes in right amount to dissolve and be diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution;
The preparation of contrast liquid: separately get N-acetyl-D glucosamine appropriate, add mobile phase and make in right amount to dissolve and be diluted to scale;
Draw respectively the each 20 μ l injection liquid chromatographies of contrast solution and need testing solution, record chromatogram, with calculated by peak area, in need testing solution chromatogram, if any N-acetyl-D glucosamine, must not be greater than N-acetyl-D glucosamine peak area 0.1% by external standard method;
3), 2, the content assaying method of 6-dimethylaniline:
Chromatographic condition: with octadecylsilane chemically bonded silica be filler; With phosphate buffer: acetonitrile=50:50, and with phosphoric acid adjust pH to 8.0 be mobile phase; Detection wavelength is 254nm, and column temperature is 30 DEG C, and flow velocity is 1.0 ml/min,
The preparation of test liquid: it is appropriate that precision measures this product, puts in measuring bottle, adjusts pH to be diluted to scale to adding mobile phase after neutrality with 2mol/L NaOH solution, shakes up, as test liquid;
The preparation of contrast liquid: separately get 2,6-dimethylaniline reference substance, accurately weighed, add mobile phase and dilute and make reference substance solution;
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 pH of the temperature to active carbon in injection preparation, solution, realize 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 overcome the freeze-drying time of lyophilized formulations of prior art glucosamine long, consume energy high, be unfavorable for producing, and there is the defect of larger difference in the lyophilized formulations of same batch at form and solubility.Therefore, aminoglucose injection provided by the present invention can meet suitability for industrialized production, and can be applied to safely, reliably field of medicaments.
Specific embodiments:
The defect existing for overcoming existing glucosamine compound injection, the present invention passes through the best of breed of the parameter to temperature, pH value, addition sequence and sterilization process by the discovery of a large amount of experiment accidents, obtain unexpected technique effect, and confirmed by following examples and experimental example the technique effect that it is unexpected:
Embodiment 1 glucosamine sulfate injection (in glucosamine sulfate 0.4g)
Process for preparation: get 80% water yield and be mixed with 0.001mol/L hydrochloric acid solution, add glucosamine sulfate sodium chloride double salt and stir it is dissolved completely at 55 DEG C, add again 0.02% active carbon, at 75 DEG C, stir 20min, after de-charcoal, again toward adding 0.01% active carbon and the lidocaine hydrochloride of recipe quantity in solution, at 45 DEG C, stir 10min, de-charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to enough in the time being cooled to 20 DEG C, then pH is adjusted to 4.6, according to 2ml embedding, finally sterilizing 17min at 121 DEG C.
Another preparation special solvent, as follows: diethanolamine 20g adds 1000ml water for injection, make 1000.Process for preparation: the alkaline conditioner diethanolamine that takes above-mentioned recipe quantity adds water to enough, stirs, and adds 0.05% active carbon, stirs 15～30min, de-charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane to clarification; According to 1ml embedding, 121 DEG C of sterilizings 15 minutes.
Embodiment 2 glucosamine sulfate injection (in glucosamine sulfate 0.4g)
Process for preparation: get 80% water yield and be mixed with 0.001mol/L hydrochloric acid solution, adding glucosamine sulfate sodium chloride double salt to stir dissolves it completely, add again 0.02% active carbon, under room temperature, stir 20min, after de-charcoal, again toward adding 0.01% active carbon and the lidocaine hydrochloride of recipe quantity in solution, stir at normal temperatures 10min, de-charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane, to clarification, medicinal liquid adds water to enough in the time being cooled to 20 DEG C, then pH is adjusted to 4.6, according to 2ml embedding, finally sterilizing 17min at 121 DEG C.
Special solvent is with the method preparation of embodiment 1.
Experimental example 1: due to the reaction mechanism mechanism of reaction of 5 hydroxymethyl furfural, think that this process is made up of a series of elementary reactions such as protonated, dehydration and deprotonations, wherein protonated relatively easy, and 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 CN201010270516 patent application, get respectively 80% water yield and be mixed with hydrochloric acid solution, active component dissolve add water enough after, pH reaches respectively 5.5,5.0,4.7,4.4,4.2,4.0,3.5,3.0,2.0,1.0, finally sterilizing 17min at 121 DEG C.Comparing embodiment 1 pH before sterilizing reaches respectively 5.5,5.0,4.7,4.6,4.4,4.2,4.0,3.5, finally sterilizing 17min at 121 DEG C simultaneously.
Adopt respectively the trap of the above-mentioned sterilizing 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 it is above to increase by 500 at the 5 hydroxymethyl furfural of sterilizing front and back injection, changes not obvious; And the 5 hydroxymethyl furfural of the glucosamine sulfate injection of this specific embodiments embodiment 1 obviously reduces, there is significant difference (P<0.05) (note: 5 hydroxymethyl furfural is the catabolite of glucose injection in preparation process, and human body striped muscle and internal organs are all had to infringement).
Trap before and after the different pH sterilizings of embodiment 4 in table 3 CN201010270516 patent application
Trap before and after the different pH sterilizings of table 4 the present invention
Above result shows, preparation technology of the present invention can significantly reduce main component degraded.Under the condition that this may first adopt with the present invention and heat, pH value is lower, dissolve, medicine is fully dissolved in water with molecule or ionic species, the more de-charcoal of low temperature, and then improve pH value and reduce fluid temperature, then final high temperature sterilizing.Because glucosamine sulfate is easily degraded into 5 hydroxymethyl furfural with the form of molecule or ion conventionally under the condition of water, the present invention has selected the pH value of particular range and has reduced fluid temperature before sterilizing, under this specific condition, medicine major part has formed between molecule, the particular state of the particulate matter aggregation between ion and crystalline deposit, thereby reduce molecule, the form that ion exists, suppress the generation of 5 hydroxymethyl furfural, simultaneously in the process of high temperature sterilize heating, particulate matter aggregation is transformed into gradually again molecule under heating condition, ion, after sterilizing, pH value also can decrease, finally make the dissolved state of medicine in stable and uniform.
Experimental example 2: because iron salt, the zinc salt content of active carbon are higher, introduced a large amount of easily metal ions of accelerated oxidation variable color in introducing active carbon, thereby taking rational activated carbon process is the key that reduces metal ion.The glucosamine sulfate injection that the glucosamine sulfate injection of comparing embodiment 1,2 and comparative example 1(are prepared according to the embodiment 4 in CN201010270516 patent application respectively) be placed in the hermetic container of 40 DEG C ± 2 DEG C of temperature, place 6 months, investigate 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 sterilizing in potassium thiocyanate colorimetric method for determining embodiment 1,2, and measure absorbance under 480nm, embodiment 1,2 respectively gets 6 samples and is measured in the same 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, heating for dissolving glucosamine sulfate sodium chloride double salt simultaneously, it is existed with molecule or ionic species, strengthen the complexing power of iron ion and glucosamine sulfate, thereby and under acid condition, form tiny microgranule and adsorbed by active carbon, the minimizing of iron ion also makes medicine more stable, reduces the speed of oxidation stain.
Experimental example 3: because sterilizing is an important step of infusion preparation, in the sterilizing works of the large production of reality, can find diverse location in sterilizing cabinet, there is different temperatures, pressure, as levels, between four angles and central authorities, there is certain difference, the glucosamine sulfate injection that the glucosamine sulfate injection of comparing embodiment 1 and comparative example 1(are prepared according to the embodiment 4 in CN201010 270516 patent applications respectively) the content difference of glucosamine sulfate after sterilizing, 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 S point, Mei Ceng center is decided to be M point, respectively to 3 batches of injection 1 bottle of different position draw samples, calculate meansigma methods and the standard variance of the 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, 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 making medicinal liquid, the special process before sterilizing of the present invention forms specific uniform solution, even if 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.
Reagent preparation:
(1) 0.2mol/L borate buffer solution takes 7.63g sodium borate, adds 80ml water and makes to dissolve, and adjusts pH to 9.5 with dilute hydrochloric acid, adds water to 100ml, shakes up.(under room temperature condition, store, if any crystallization, heating makes to dissolve.）
(2) derivatization reagent takes 50mg o-phthalaldehyde(OPA) and puts in 14ml polypropylene test tube, adds 1.25ml absolute methanol to make to dissolve, then adds 3-mercaptopropionic acid 50 μ l and 0.2M borate buffer solution 11.2ml, slowly mixes, and puts dark place and places 30 minutes.(within every two days, add 3-mercaptopropionic acid 10 μ l to keep reagent concentration, in dark place room temperature preservation, two weeks interior uses)
Chromatographic condition:
Mobile phase: with aqueous sodium acetate solution (6.80g sodium acetate trihydrate, adds 700 ml water to make to dissolve, and adjusts pH to 5.9 with acetic acid, add 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 appropriate that precision takes glucosamine hydrochloride reference substance, adds water and make the solution of 1mg/ml, in contrast product solution.
The preparation of test liquid: precision measures this product appropriate (being equivalent to glucosamine hydrochloride 20mg), puts in 20ml measuring bottle, is diluted with water to scale, shakes up, as test liquid.
Derivatization method: get the borate buffer solution 400 μ l of 0.2mol/L, put in a bottle, add 100 μ l derivatization reagents and 100 μ l contrast liquid or test liquid, mix, derivatization is sample introduction after 1 minute.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
With octadecylsilane chemically bonded silica be filler; Adjusting PH to 8.0 with phosphate buffer (get 1mol/L NaH2PO4 1.3 ml and 0.5 mol/L Na2HPO4 32.5ml, put in 1000ml measuring bottle, be diluted with water to scale, shake up)-acetonitrile (50:50) phosphoric acid is mobile phase; Detection wavelength is 254nm, and column temperature is 30 DEG C, and flow velocity is 1.0 ml/min, and number of theoretical plate calculates and is not less than 2000 by lignocaine peak.
Precision measures this product appropriate (being approximately equivalent to lidocaine hydrochloride 20mg), puts in 10ml measuring bottle, adds 2 mol/L NaOH solution and adjusts PH to neutral, adds mobile phase and is diluted to scale, shakes up, and precision measures 20 μ l injection liquid chromatographies, records chromatogram; Separately get the about 20mg of lidocaine hydrochloride reference substance, accurately weighed, put in 10ml measuring bottle, be diluted to scale by mobile phase, shake up, be measured in the same 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, m) 30 DEG C of column temperatures of 5 μ
Detect wavelength 284nm sample size 20 μ l
Mobile phase methanol: water=5:95
Precision measures this product appropriate (being approximately equivalent to glucosamine sulfate 400mg), puts in 100 ml measuring bottles, adds mobile phase and is diluted to scale, shakes up, as test liquid; It is appropriate that precision takes 5 hydroxymethyl furfural, adds mobile phase and quantitatively dilute and make the solution that concentration is 400 μ g/ml.Get this solution 1ml, put in 100ml measuring bottle, add mobile phase to scale, shake up, as 5 hydroxymethyl furfural contrast solution.Get test liquid and the each 20 μ l injection liquid chromatographies of contrast liquid, record 3.0 times to 5 hydroxymethyl furfural peak retention time of chromatogram, 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%), 10 times (1.0%) total impurities peak area and that must not be greater than contrast solution main peak area.
2, N-acetyl-D glucosamine (NAG)
Chromatographic column: Shodex Suger SH1011 chromatographic column (300mm × 8mm)
Column temperature: 50 DEG C are detected wavelength: 202nm mobile phase: 0.006 mol/L H2SO4 solution
Flow velocity: 1.0ml/min sample size: 20 μ l
Precision measures this product appropriate (being approximately equivalent to glucosamine sulfate 200mg), puts in 10ml measuring bottle, adds mobile phase and makes in right amount to dissolve and be diluted to scale, shakes up, and filters, and gets subsequent filtrate as need testing solution.Separately get NAG appropriate, add mobile phase dissolving and quantitatively dilute and make the solution solution (0.1%) in contrast that approximately contains NAG 20 μ g in every 1ml.Draw respectively the each 20 μ l injection liquid chromatographies of contrast solution and need testing solution, record chromatogram, with calculated by peak area, in need testing solution chromatogram, if any N-acetyl-D glucosamine, should be greater than N-acetyl-D glucosamine peak area (0.1%) by external standard method.
2, HPLC method is measured the related substance of lignocaine in this product
Chromatographic condition is with reference to content assaying method under lidocaine hydrochloride item.
Precision measures this product appropriate (being approximately equivalent to lidocaine hydrochloride 20mg), puts in 10ml measuring bottle, is diluted to scale with 2mol/L NaOH solution tune PH to adding mobile phase after neutrality, shake up, as test liquid, separately get 2,6-dimethylaniline reference substance, accurately weighed, add mobile phase and dilute and make the solution that is about 0.8 μ g in every 1ml, product solution in contrast, gets contrast liquid 20 μ l injection liquid chromatographies, regulate instrumental sensitivity, make the peak height at main constituent peak be about 10 ~ 30% of full scale; Precision measures test liquid 20 μ l again, injection liquid chromatography, and in the chromatogram of need testing solution, 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%).
Claims (2)
1. an injection that contains glucosamine sulfate sodium chloride double salt and lidocaine hydrochloride, is characterized in that, described injection is made up of injection and special solvent, faces the used time injection and special solvent liquid are matched to use wherein:
1), described injection is made up of the component of following weight proportion, makes 1000:
Glucosamine sulfate sodium chloride double salt, in glucosamine sulfate 400g,
Lidocaine hydrochloride 10g,
Hydrochloric acid is appropriate;
Inject water 2000ml
2), described special solvent is 0.5-10 milliliter, it consists of alkaline solvent and water for injection, described alkaline solvent is diethanolamine, triethanolamine or ethylenediamine;
3), described aminoglucose injection packs brown ampoule into, described special solvent packs colourless ampoule into;
4), the preparation method of described injection comprises the following steps:
Wherein, get 80% water yield and be mixed with 0.001mol/L hydrochloric acid solution, add glucosamine sulfate sodium chloride, and stir it is dissolved completely at 50-60 DEG C, add again 0.02% active carbon, at 70-80 DEG C, stir 15～30min, after de-charcoal, again toward adding 0.01% active carbon and the lidocaine hydrochloride of recipe quantity in solution, at 40-50 DEG C, stir 10～15min, de-charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to enough in the time being cooled to 15-25 DEG C, then pH is adjusted to 4.5-4.8, according to 2ml embedding, finally sterilizing 15-20min at 121 DEG C.
2. injection according to claim 1, is characterized in that, the preparation method of described injection comprises the following steps:
Wherein, get 80% water yield and be mixed with 0.001mol/L hydrochloric acid solution, add glucosamine sulfate sodium chloride double salt and stir it is dissolved completely at 55 DEG C, add again 0.02% active carbon, at 75 DEG C, stir 20min, after de-charcoal, again toward adding 0.01% active carbon and the lidocaine hydrochloride of recipe quantity in solution, at 45 DEG C, stir 10min, de-charcoal, through 0.45 μ m, 0.22 μ m filtering with microporous membrane is to clarification, medicinal liquid adds water to enough in the time being cooled to 20 DEG C, then pH is adjusted to 4.6, according to 2ml embedding, finally sterilizing 17min at 121 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210492708.4A CN102961389B (en) | 2012-11-27 | 2012-11-27 | Composition containing glucosamine as well as preparation method and detection method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210492708.4A CN102961389B (en) | 2012-11-27 | 2012-11-27 | Composition containing glucosamine as well as preparation method and detection method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102961389A CN102961389A (en) | 2013-03-13 |
| CN102961389B true CN102961389B (en) | 2014-07-16 |
Family
ID=47792008
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210492708.4A Active CN102961389B (en) | 2012-11-27 | 2012-11-27 | Composition containing glucosamine as well as preparation method and detection method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102961389B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103421060A (en) * | 2013-05-06 | 2013-12-04 | 华中农业大学 | Post-column derivatization preparation method and application of aminoglycosides compound |
| CN104739849B (en) * | 2015-04-03 | 2016-06-08 | 俞嘉林 | Injection containing glucosamine sulfate and preparation method thereof and the application in preparation treatment medicine for treating arthritis of this injection |
| CN104931602B (en) * | 2015-05-12 | 2017-02-01 | 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 |
| CN104880530B (en) * | 2015-05-14 | 2016-11-30 | 东北农业大学 | A kind of method of glucosamine content in rp-hplc analysis lactalbumin glycation product |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4006224A (en) * | 1975-09-29 | 1977-02-01 | Lescarden Ltd. | Method and agent for treating inflammatory disorders of the gastrointestinal tract |
| US4642340A (en) * | 1981-04-30 | 1987-02-10 | Rotta Research Laboratorium S.P.A. | Stable compounds of glucosamine sulphate |
| CN101947234A (en) * | 2010-09-02 | 2011-01-19 | 南京威尔曼药物研究所 | Preparation method for preparation containing glucosamine and application thereof |
-
2012
- 2012-11-27 CN CN201210492708.4A patent/CN102961389B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4006224A (en) * | 1975-09-29 | 1977-02-01 | Lescarden Ltd. | Method and agent for treating inflammatory disorders of the gastrointestinal tract |
| US4642340A (en) * | 1981-04-30 | 1987-02-10 | Rotta Research Laboratorium S.P.A. | Stable compounds of glucosamine sulphate |
| CN101947234A (en) * | 2010-09-02 | 2011-01-19 | 南京威尔曼药物研究所 | Preparation method for preparation containing glucosamine and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| 初立梅 等.反相高效液相色谱法测定硫酸氨基葡萄糖泡腾片中硫酸氨基葡萄糖的含量.《儿科药学杂志》.2012,第18卷(第3期),40－42. |
| 反相高效液相色谱法测定硫酸氨基葡萄糖泡腾片中硫酸氨基葡萄糖的含量;初立梅 等;《儿科药学杂志》;20120331;第18卷(第3期);40－42 * |
| 周婷婷 等.高效液相色谱法测定老陈醋中的5-羟甲基糠醛.《食品工业科技》.2012,第33卷(第8期),83－85. |
| 高效液相色谱法测定老陈醋中的5-羟甲基糠醛;周婷婷 等;《食品工业科技》;20120831;第33卷(第8期);83－85 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102961389A (en) | 2013-03-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102961389B (en) | Composition containing glucosamine as well as preparation method and detection method thereof | |
| CN101411710B (en) | Pemetrexed disodium freeze-dried injection and preparation method thereof | |
| CN101584670B (en) | Decitabine freeze-dried powder injection | |
| CN103076214A (en) | Preparation method of glycosylated hemoglobin quality control | |
| CN111529493A (en) | Amoxicillin soluble powder easy to dissolve in water and high in stability and preparation method thereof | |
| CN108938654B (en) | Pulsatillae saponin B4 injection preparation | |
| CN111122724B (en) | Method for analyzing acarbose and related substances | |
| CN103804397B (en) | Cefoxitin sodium compound and preparation method thereof | |
| CN104558064A (en) | Preparation method of iron sucrose | |
| CN102525963A (en) | Netilmicin sulfate lyophiled powder injection and preparation method thereof | |
| CN102379886A (en) | Scutellarin clinical preparation and preparation method thereof | |
| CN1679563A (en) | Freeze-dried powder injection of pantoprazole sodium and its preparation | |
| CN101904862B (en) | Water-soluble vitamin composition freeze-drying preparation for injection | |
| CN102617643B (en) | Riboflavin sodium phosphate compound | |
| CN101993503B (en) | Method for preparing powdered sodium hyaluronate | |
| CN104434803A (en) | Artesunate and L-lysine composition for injection and preparation method therof | |
| CN102949337B (en) | Gemcitabine hydrochloride injection and preparation method thereof | |
| CN105287404A (en) | Preparation method of nicorandil freeze-drying preparation with good stability | |
| CN113730344B (en) | Naproxen preparation for injection and application thereof | |
| CN1813713A (en) | Solution type potassium sodium dehydroandroan drographolide succinate injection and its preparing method | |
| CN103271880A (en) | Cefodizime sodium injection and preparation method thereof | |
| CN103271878A (en) | Ceftezole sodium agent and preparation method thereof | |
| CN104721153B (en) | Injection aminomethylbenzoic acid freeze-drying powder-injection pharmaceutical composition | |
| CN103159710B (en) | Antiviral decalin derivate | |
| CN103110656B (en) | Water-soluble vitamin freeze-dried preparation for injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CB03 | Change of inventor or designer information |
Inventor after: Ren Jinshan Inventor after: Yu Jialin Inventor after: Yu Mohan Inventor after: Quan Xiaodan Inventor after: Cong Yan Inventor after: Zhang Jin Inventor after: Zou Aifeng Inventor after: Wu Jingjing Inventor before: Ren Jinshan Inventor before: Yu Jialin Inventor before: Quan Xiaodan Inventor before: Cong Yan Inventor before: Zhang Jin Inventor before: Zou Aifeng Inventor before: Wu Jingjing |
|
| COR | Change of bibliographic data |