CN100342232C - Method for determining cyclophosphadenosineglucamine content in its high-transfusion preparation - Google Patents
Method for determining cyclophosphadenosineglucamine content in its high-transfusion preparation Download PDFInfo
- Publication number
- CN100342232C CN100342232C CNB200510124456XA CN200510124456A CN100342232C CN 100342232 C CN100342232 C CN 100342232C CN B200510124456X A CNB200510124456X A CN B200510124456XA CN 200510124456 A CN200510124456 A CN 200510124456A CN 100342232 C CN100342232 C CN 100342232C
- Authority
- CN
- China
- Prior art keywords
- meglumine
- solution
- adenosine
- glucose
- cycle phosphate
- 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.)
- Expired - Lifetime
Links
Abstract
The present invention relates to a cyclic AMP glucosamine infusion preparation and a method for testing the content thereof. An isosmotic infusion preparation of cyclic AMP glucosamine contains 54 to 66 mg of cyclic AMP glucoamine as a main medicine and isosmotic media (4.5 to 5.5g of glucose or 0.85 to 0.95g of sodium chloride) in every 100 ml of preparations. The present invention determines the key condition of a pH range for stabilizing the cyclic AMP glucosamine infusion preparation and a preparation method thereof and solves the method for testing the content of the cyclic AMP glucosamine. The present invention is favourable for controlling the production quality of the cyclic AMP glucosamine infusion preparation to establish a proper production method and make the industrial mass production of the cyclic AMP glucosamine infusion preparation possible. The cyclic AMP glucosamine infusion preparation can avoid an intermediate step for extracting liquid medicine by using small needles to perform the infusion of glucose or the sodium chloride so that cross infection and pollution are prevented during medication. Therefore, the medication is safe and convenient. The preparation can be made into various specifications for medical care personnel to select according to specific conditions.
Description
Technical field
The present invention relates to meglumine adenosine cycle phosphate content assaying method in a kind of meglumine adenosine cycle phosphate great transfusion preparation and this great transfusion preparation.
Background technology
Meglumine adenosine cycle phosphate (chemical name, meglumine cyclic adenylate; English name, Meglumine AdenosineCyclophosphate; Be called for short MCA; Former name, the meglumine cyclic adenylate and the Mei Le heart) parenteral solution, be a kind of cardiac drug of non-cardiac glycosides, be mainly used in treatment heart failure, myocarditis, sick sinus syndrome, coronary heart disease, cardiomyopathy, and ARR supplemental treatment.In recent years because of its determined curative effect, act on originally, security performance is good, is widely used clinically.
The meglumine cyclic adenosine injection of using clinically is little liquid drugs injection at present, specification 2ml:30mg; Usual amounts 60～180mg/ day.Strong because of the main ingredient effect, and osmotic pressure is low excessively, can not directly be used for drip-feed, needs with after 5% glucose or the normal saline solution dilution, can intravenous injection, and make troubles not only for clinical use, also may cause soup to infect and pollution.
Totally 224 pieces in the document (on June 30th, 1984～2002) that retrieves according to the data and the Chinese biomedical journal data storehouse (CMCC) of collection over the years.The clinical document statistics of answering of wherein relevant these product shows, all adopts more than 98% with 5% glucose dilution posterior vein and instils.And the technical bottleneck of preparation MCA glucose infusion solutions is: the stable pH of (1) glucose solution is 3.2～5.5.PH easily causes color, 5 hydroxymethyl furfural and clarity defective extremely unstable more than 5.5; And meglumine adenosine cycle phosphate MCA liquid drugs injection stable p H scope is 5.5～7.0.PH easily is decomposed to form adenosine monophosphate and adenosine less than 5.5, thus both stablize required pH scope difference, both simple mixing can not be obtained the stable MCA glucose infusion solutions product with certain shelf-life.(2) glucose for injection itself just contains some uv absorption impurity, and produces new uv absorption impurity and acidic materials in its solution storage.And the legal assay method of existing MCA liquid drugs injection meglumine adenosine cycle phosphate content can't be separated these ultraviolet impurity and adenosine cyclophosphate feature uv absorption, can't accurately measure meglumine adenosine cycle phosphate content in the MCA glucose infusion solutions with current methods like this, the quality of medicine can't be effectively guaranteed and control aborning, need a kind of new meglumine adenosine cycle phosphate content in accurate the mensurations MCA glucose infusion solutions that the production of MCA glucose infusion solutions adapts that is suitable for, control effective detection method of production quality.
Summary of the invention
Technical matters to be solved by this invention is that meglumine adenosine cycle phosphate content assaying method in a kind of meglumine adenosine cycle phosphate great transfusion preparation and this great transfusion preparation will be provided, the grade that can be directly used in the meglumine adenosine cycle phosphate of drip-feed is oozed great transfusion preparation, need not dilute when using this product clinically and dissolve, avoided extracting the intermediate link that soup injects glucose or sodium chloride infusion solutions by little pin, and cross-infection in the soup transfer process and pollution, make more convenient, the safety of medication.Especially rescuing the urgent patient, when racing against time, more showing the convenience of this product use, the advantage of safety.This preparation can be made plurality of specifications according to the consumption requirement, takes the circumstances into consideration to select for use for medical personnel.
Solving the technology of the present invention problem is achieved through the following technical solutions.
The present invention (1) adopts suitable prescription and production technology; (2) through investigating, the key factor that influences preparation stability is the pH value of its storage life, and the present invention has determined to make the pH scope and the best stabilized pH value thereof of preparation stabilization, for producing preparation steady in a long-term, provides reliable foundation; (3) the existing assay method of main ingredient meglumine adenosine cycle phosphate content is the feature uv absorption according to adenosine cyclophosphate.Through test, the present invention has separated all impurity that disturb adenosine cyclophosphate to measure, thereby has set up the content assaying method that is suitable for meglumine adenosine cycle phosphate-glucose injection.The recovery of method is 100.44 ± 1.166, RSD1.16%.Below introduce respectively:
1. the meglumine adenosine cycle phosphate great transfusion preparation is filled a prescription and production method
Meglumine adenosine cycle phosphates of the present invention etc. ooze the transfusion great transfusion preparation and are divided into: meglumine adenosine cycle phosphate glucose injection formulation and meglumine adenosine cycle phosphate chloride injection liquid formulation.
A. fill a prescription:
The meglumine adenosine cycle phosphate glucose injection formulation is characterized in containing in per 100 ml of formulation etc. and oozes medium glucose 4.5-5.5 gram, meglumine adenosine cycle phosphate 54-66 milligram, and 42 milligrams of adding citric acids (or not adding), all the other are water for injection.The pH scope of its preparation stabilization is 3.5～5.5, and best stabilized pH value is 4.75 ± 0.25.Properties of product quite stable of the present invention is investigated by the room temperature shelf stability, and it is qualified to deposit 1 year every index, estimates the term of validity at least two years.
Meglumine adenosine cycle phosphate chloride injection liquid formulation is characterized in containing in per 100 ml of formulation etc. and oozes medium sodium chloride 0.85-0.95 gram, meglumine adenosine cycle phosphate 54-66 milligram, and all the other are water for injection.The pH scope of its preparation stabilization is 5.5～7.0, and its best stabilized pH value is 6.1 ± 0.2.Properties of product quite stable of the present invention is investigated by the room temperature shelf stability, and it is qualified to deposit 1 year every index, estimates the term of validity at least two years.
B. produce the method for meglumine adenosine cycle phosphate great transfusion preparation: it is an amount of to get water for injection, and heated and boiled constantly stirs, and gradation adds glucose, is made into 50 ~ 70% strong solutions (or gradation add sodium chloride, be made into 20 ~ 25% dope).Transfer pH 3.8 ~ 4.0 with 1% hydrochloric acid or 1% sodium hydroxide solution, add an amount of 0.1 ~ 1.0% injection activated charcoal.Under agitation boiled 30 minutes, put and be chilled to 45 ℃ ~ 50 ℃ filtering activated charcoals, press the great transfusion preparation full dose and add meglumine adenosine cycle phosphate, adjust pH 6.0～6.5 (or add citric acid solution 0.1～0.3ml of 1mol/L, again with 1% NaOH accent pH to 5.0) with 1% sodium hydroxide solution.Add the injection water again to aequum.Smart filter is to clarification, and embedding was in 115 ℃ of pressure sterilizings 30 minutes.
The effects the influence of sterilization process to the quality (pH value, color, clarity, 5 hydroxymethyl furfural and drug content) of meglumine adenosine cycle phosphate glucose injection, the results are shown in Table 1.
By table 1. as seen, select to adjust the reagent difference of pH, difference is obvious.With 1%NaOH or HCl, no surge capability on average reduces pH1.25 unit, and sodium bicarbonate reduces by 1.50～1.70 units, along with pH descends, and CO
2Discharging increases, and the sterilization extrusion rate of heating reaches 20%, so do not adopt.And add citric acid the best, and its concentration is 1mmol/L, pH is basicly stable, adds to 3mmol/L and can make pH stable.This test also discloses a key character, and promptly main ingredient meglumine adenosine cycle phosphate in this infusion solutions oozes medium glucose than its grade, and is more stable.
Embodiment 1 meglumine adenosine cycle phosphate glucose injection
Prescription meglumine adenosine cycle phosphate 60mg
Glucose 5g
Water for injection adds to 100ml
By prescription glucose is dropped in the water for injection, make into 50 ~ 60% dope, stir, boil by above-mentioned technology, the activated charcoal that adds strong solution 0.3% (restrain/100 milliliters) through boiling, takes off adding main ingredient 60mg behind the charcoal, add water for injection to 80% of full dose, adjust pH to 6.2 with 1% NaOH, add to the full amount of water for injection, smart filter is to clarification, embedding is in legal containers such as 50ml or 100ml, seal, 115 ℃, pressure sterilizing 30 minutes.At last, by the content of meglumine adenosine cycle phosphate in the method for quantitatively determining detection parenteral solution of meglumine adenosine cycle phosphate in the described meglumine adenosine cycle phosphate glucose injection in back, content is qualified can to dispatch from the factory.
Embodiment 2 meglumine adenosine cycle phosphate glucose injections
Prescription meglumine adenosine cycle phosphate 60mg
Glucose 5g
Citric acid 1mol/L solution 0.2ml
1% NaOH (or hydrochloric acid) an amount of (being used to adjust pH)
Water for injection adds to 100ml
By prescription glucose is dropped in the water for injection, make into 50 ~ 60% dope.Stir, boil by technology, add/100 milliliters of activated charcoals of 0.3 gram, through boiling, take off and add main ingredient 60mg, citric acid 1mol/L solution 0.2ml behind the charcoal, with 1% NaOH adjustment pH to 5.0, add to the full amount of water for injection again, smart filter is to clarification, and embedding is sealed in legal containers such as 50ml or 100ml, 115 ℃, pressure sterilizing 30 minutes.At last, by the content of meglumine adenosine cycle phosphate in the method for quantitatively determining detection parenteral solution of meglumine adenosine cycle phosphate in the described meglumine adenosine cycle phosphate glucose injection in back, content is qualified can to dispatch from the factory.
Embodiment 3 meglumine adenosine cycle phosphate sodium chloride injections (being suitable for to use the complication with diabetes patient of glucose to use)
Prescription meglumine adenosine cycle phosphate 60mg
Sodium chloride 0.9g
Water for injection adds to 100ml
By prescription sodium chloride is dropped in the water for injection, make 20 ~ 25% strong solution, by technology, stir, boil, add the activated charcoal of dense liquid 0.3%, add main ingredient 60mg after taking off charcoal through boiling, add water for injection again to 80% of full dose,, adjust pH to 6.1 with 1% NaOH (or hydrochloric acid), add to the full amount of water for injection, smart filter is to clarification, and embedding is sealed in legal containers such as 50ml or 100ml, 115 ℃, pressure sterilizing 30 minutes.
2. the medium influence of oozing medium of infusion solutions to main ingredient stability
A. wait and ooze of the influence of medium 0.90% sodium chloride solution meglumine adenosine cycle phosphate stability
In order to investigate the influence of 0.9%NaCl to main ingredient MCA stability, experiment is made each 10 bottles of the infusion solutionses of different pH, every bottle of 150ml by the prescription of embodiment 3 and technology.Transferring the solution of pH is 1%HCl and 1%NaOH, and the pH value of infusion solutions is respectively 5.0,5.5,6.0,6.5,7.0 and 7.5 6 grades behind the pressure sterilizing.Observation index is the decomposition product that MCA content and paper chromatography show.The method of MCA assay: the described infusion solutions precision in back is measured 125ml, and 60 ℃ of decompression sterilizations are concentrated into about 3ml, are transferred in the 10ml measuring bottle, and wash cucurbit 3 times with a small amount of injection, add water to scale at last.Accurately sampling 10 μ l compose the method for quantitative measurement and measure MCA content by the paper of the described MCA in back.Check the Ultraluminescence speckle displacement on the paper spectrum before measuring earlier, and determine its decomposition product.Each sample is done three mensuration, and the content less than 0.5% belongs to error at measurment.The gained data are listed in table 2.
In the analytical table 2 data as seen, 0.90%NaCl does not almost have influence to the stability of MCA, with aqueous solution promptly before our observed basically identical as a result in little liquid drugs injection.The equivalent point of MCA is pH 6.20.MCA is easy to be dissociated into cAMP (Rf 0.45～0.50) under acid condition, cAMP and then be hydrolyzed into AMP (a phosphorus adenosine, Rf0.18～0.20), and AMP promptly resolves into adenosine (Rf 0.60～0.66).Under alkali condition, MCA also is easy to dissociate into cAMP, and then is hydrolyzed into AMP, is difficult for forming AR.So the stable pH range of MCA in 0.90%NaCl solution is in full accord with little liquid drugs injection 5.5～7.0.Proof thus, 0.9% NaCl is that a kind of inert etc. oozes medium, to both unprotect effects of the MCA in the infusion solutions, does not also play destruction.Again according to our long-term investigation, 42 batches of little liquid drugs injections of MCA (1993-2001), find room temperature preservation 5 years, the MCA of water breakthrough pin does not decompose, and promptly MCA content can not be surveyed variation, also lose the ultraviolet of AMP and AR spot (can detect the MCA of 0.5 μ g) is arranged, all between 5.9～6.3, so the best stabilized pH value of MCA liquid drugs injection is 6.1 ± 0.2, room temperature is deposited five-year period to its pH value, the pH value of little liquid drugs injection 0.1 unit that only descends is so the solution of liquid drugs injection is very stable.In like manner, the best stabilized pH value of MCA sodium chloride infusion solutions should be 6.1 ± 0.2, in the optimal pH scope, estimates that the MCA sodium chloride infusion solutions term of validity was 5 years.
B. wait and ooze of the influence of medium 5% glucose meglumine adenosine cycle phosphate stability
In order to investigate the influence of 5% glucose to main ingredient MCA stability, experiment is made each 15 bottles of the infusion solutionses of different pH groups, every bottle of 150ml by the prescription of embodiment 1 and technology.PH value after the sterilization is respectively 6.0,5.5,5.0,4.5,4.0 and 3.5, various pH preparations compare for each 3 bottles, all the other are all put into 80 ℃ of constant temperature ovens and are incubated in the 3rd, 6,8,10,18 day different pH group and respectively get two bottles, according to meglumine adenosine cycle phosphate content assaying method in the described meglumine adenosine cycle phosphate glucose injection in back, make the meglumine adenosine cycle phosphate assay, fluorescence speckle displacement before measuring on elder generation's inspection paper spectrum is to determine its decomposition product, and the gained result lists table 3 in.
This test shows, (1) chemical stability of pH scope (pH 6～3.5) meglumine adenosine cycle phosphates (MCA) in 5% glucose solution in research is good: 8 days ply of papers are analysed collection of illustrative plates and are not seen decomposition during 80 ℃ of pH 6.0, promptly there is not AMP (adenosine monophosphate spot), have only to 10 talentes and see tangible AMP ultraviolet spot, the MCA branch terminates an agreement 20%; 5.5,4.0 o'clock MCA of pH observe obvious decomposition 80 ℃ of 18 talent, decompose 16.7% and 5.8% respectively; (2) the best stabilized pH of MCA aqueous solution is 6.1 ± 0.2, as described above.This experiment finds that 5% glucose solution makes the decline of MCA best stabilized pH value, and range of stability is pH4.5～5.0, and promptly pH 4.75 ± 0.25.Glucose moves down MCA best stabilized pH value, has important practical usage, and the technical bottleneck of preparation MCA glucose infusion solutions is broken through, promptly MCA and glucose the two all comparatively stable p H scope be 3.5 ~ 5.5.
3. the method for quantitatively determining of meglumine adenosine cycle phosphate in the meglumine adenosine cycle phosphate glucose injection
(1) method feature
In view of this product contains 5% glucose, and MCA60mg, only account for 1.2% (1 percent two) of glucose total amount, its molecule despatch you than being 251: 1, so greatly different chemistry amount is poor, makes MCA stablize the pH value and moves down, and has produced useful effect, as described above.But it is then extremely unfavorable to its assay.Contain 284nm, 228nm and three characteristic absorption peaks of 217nm equally according to the uv absorption scanning discovery in the commercially available 5% glucose infusion solutions of two companies production again, and these uv absorption impurity and glucose can not come with existing separation method fractionation, and this just becomes the technical bottleneck that this infusion solutions of development at first will solve.We have set up the method that is suitable for meglumine adenosine cycle phosphate assay in this infusion solutions by experiment, and its feature comprises following main points:
A. utilize alkaline pH (8.0～9.0), make meglumine adenosine cycle phosphate be dissociated into adenosine cyclophosphate (electronegative) and meglumine (neutral).
B. with the strong-base anion-exchange resin absorption adenosine cyclophosphate and the phosphorus adenosine that may be decomposed to form.
C. upper prop effluent and washing effluent can be removed glucose, meglumine and other all uv absorption impurity in the parenteral solution.
D. use paper chromatography in 95% ethanol-4% ammonium acetate (5: 2) developping agent, to separate an adenosine cyclophosphate and a phosphorus adenosine again, and with its content of feature determination of uv absorption of adenosine cyclophosphate, calculate the content of meglumine adenosine cycle phosphate in view of the above.
(2) concrete operations step
Precision is measured this product 125ml, regulates pH to 8-9 with the 1mole/L sodium hydroxide solution, on the strong-base anion-exchange resin (Dowex 1 (U.S.) or homemade 717 etc.) handled well, the 100-200 order, Cl type post (the directly about 12mm of post, resin bed 4ml), last column flow rate 3～4ml/min, sample flow is during to cylinder, use distilled water 80ml instead and wash post, flow velocity is the same, discards effluent, use 0.075mole/L hydrochloric acid solution-0.2mole/L sodium chloride solution wash-out then, flow velocity 0.7ml/min.Collect the about 80ml of eluent, regulate pH value to 6.5 with the ammonium bicarbonate particle.Be evaporated to about 3ml below 60 ℃ then, be transferred in the 10ml measuring bottle, with water for injection washing cucurbit for several times, adding in the measuring bottle in the lump, and adding injection and be diluted with water to scale, as need testing solution.It is an amount of that other gets the adenosine cyclophosphate reference substance, the water that adds 60 ℃ is made the solution that contains 10mg among every 1ml, and product solution is tested according to paper chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 A) in contrast, the above-mentioned solution 10 μ l of accurate respectively absorption, the point on the chromatography filter paper that is about 30cm, be developping agent with 95% ethanol-4% ammonium acetate (5: 2), launch about 15 hours after, dry, put under the ultraviolet lamp (254nm) and inspect, exist together mutually, mark the test sample purple dot at the speckle displacement of reference substance.This spot is cut, and be cut into fine strip shape, put into test tube, precision adds 0.01mole/L hydrochloric acid solution 5ml, and jolting is placed after 1 hour, get supernatant,, measure absorbance log at the wavelength place of 257nm according to spectrophotometric method (two appendix IV of Chinese Pharmacopoeia version in 2000 A).Simultaneously, replace need testing solution with 5% glucose solution, with the method operation, as blank correction, by the absorption coefficient of CAMP is 447 to multiply by 0.6278 (0.6278 is the molecular weight ratio of adenosine cyclophosphate with Meglumine Cyclic Adenylate) calculating, promptly gets meglumine adenosine cycle phosphate content.
(3) recovery test of method
According to embodiment 1, with glucose dense join, add pin with charcoal, boil stirring, cooling after, take off charcoal, add injection and be diluted with water to 80% of full dose, add the solution (method with national drug standards regulation is demarcated) of the 15mg/ml that the MCA crystal powder makes again.Add 540mg MCA/L by full dose, hydrochloric acid with 1% or 1% NaOH are adjusted pH to 6.1.Add water to 90% by full dose again.Take out 180ml, add water to 200ml (No. 1 sample), take out three parts of this liquid respectively again, every part of each 180ml, add MCA 12mg respectively, 24mg, 36mg adds water to 200ml (should be No. 2 samples, No. 3 samples, No. 4 samples mutually) at last respectively, respectively by 0.22 μ miillpore filter, 115 ℃ of pressure sterilizings 30 minutes, sampling 100ml makes the MCA assay, and all the other are done other inspection and measure and use.Detailed data closes at table 4.Recovery test, amounts to 8 times and measures totally two batches (dividing two groups of first, second).Total recovery is 100.44 ± 1.166, in ply of paper is analysed the error at measurment scope.And linear relationship is good, linear equation: Y (MCA mg%)=a+b* Δ A
257, in the formula: first group: a=-0.0658, b=142.546; Second group: a=0.00236, b=142.483.Average 142.516, two class means of the first and second two groups of b are identical with four figures before the calculated value 142.538.Related coefficient is 0.99999.142.516 of the computational constant of the listed calculating formula of table 4 (142.538) and linear equation actual measurement, preceding four figures is identical, the optimum level that can reach for spectrophotometric method itself.
4. the performance index of product of the present invention: see Table 5.
The present invention has determined key condition that the meglumine adenosine cycle phosphate great transfusion preparation is stable and preparation method thereof and has solved the meglumine adenosine cycle phosphate content assaying method, help control to the meglumine adenosine cycle phosphate great transfusion preparation quality of production, thereby formulate suitable production technology, making the meglumine adenosine cycle phosphate great transfusion preparation be able to industrialized mass becomes possibility.Use this preparation, can avoid extracting the intermediate link that soup injects glucose or sodium chloride infusion solutions, stopped cross-infection and pollution in the medication process, make medication safer, convenient from little pin.The present invention can be made into plurality of specifications, generally may be made in the big preparation of specifications such as 50ml, 100ml, 250ml, 500ml, takes the circumstances into consideration to select for use for medical personnel.
Table 1. sterilization process is to the quality influence of meglumine adenosine cycle phosphate glucose injection
Infusion solutions is by the prescription and the technology of this formulation, in 115 ℃ of pressure sterilizings 30 minutes, puts and is chilled to about 50～60 ℃ and reduces to room temperature with tap water, measures each quality index, and observation index has pH value, color, clarity, A
284Be 5 hydroxymethyl furfural inspection and drug content.Transfer pH all to belong to physiologically substance, by the preparation of concentration shown in the table with solution.Every kind of preparation is done three parallel detections.
| Transfer pH | The processing of heating | The pH value | A 284 | Remarks | |||
| Before heating | After heating | Before heating | After heating | ||||
| 1%NaOH or 1%HCl | 115 ℃ 30 minutes | 6.00 | 4.75 | ＜0.1 | ＜0.15 | Colourless before color is heated, be lower than after heating yellow No. 1.Less than No. 1, standard, the back of heating was less than No. 1, standard before clarity was heated.Drug content can not be surveyed variation before and after heating | |
| Sodium bicarbonate 2ml 1mol/L | 115 ℃ 60 minutes | 7.00 | 5.40 | ＜0.1 | ＜0.15 | ||
| Citric acid 1mol/L | 0.1ml | 115 ℃ 30 minutes | 6.00 | 5.90 | ＜0.1 | ＜0.15 | |
| 0.3ml | 115 ℃ 30 minutes | 6.05 | 6.00 | ＜0.1 | ＜0.15 | ||
The high-temperature stability examination of table 2. meglumine adenosine cycle phosphate sodium chloride infusion solutions
| Group (pH after the sterilization) | MCA content | 60 ℃ of 60 days content | Ultraviolet spot on the paper spectrum *Rf (material) | ||
| mg/100ml | ％ | % content | Content | ||
| 5.0 | 59.62 | 99.36 | 97.31 | -2.05 | Principal spot 0.46 (cAMP), 0.65 (AR), 0.19 (AMP) |
| 5.5 | 59.50 | 99.17 | 97.97 | -1.20 | 0.46(cAMP)，0.66(AR) |
| 6.0 | 59.90 | 99.83 | 100.23 | +0.40 | (0.47 cAMP single-point) |
| 6.5 | 60.10 | 100.16 | 100.10 | +0.06 | (0.45 cAMP single-point) |
| 7.0 | 59.70 | 99.50 | 98.50 | -0.60 | 0.48 (cAMP), 0.2 (AMP is extremely weak) |
| 7.5 | 59.90 | 99.83 | 98.33 | -1.50 | 0.49(cAMP)，0.18(AMP) |
*CAMP is an adenosine cyclophosphate, and AMP is a phosphorus gland, and AR is an adenosine
Table 3. glucose solution pH is to the influence of meglumine adenosine cycle phosphate stability
Method for making is pressed embodiment 1, and solution is put in 80 ℃ of constant temperature ovens and is incubated, and in sampling in 0,3,5,8,10,18 day, the MCA assay was made in sampling.It is unlisted that content does not have significant change person's (＜3%).
| Solution | Content | Labelled amount | Content | Reduce | Paper spectrum ultraviolet spot (254nm) is checked explanation | ||
| The pH value | mg/100ml | ％ | Fate | Content mg/100ml | Labelled amount % | ％ | |
| 6.0 | 59.00 | 98.30 | 10 | 47.04 | 78.40 | 19.9 | Paper spectrum 10 days, the AMP spot is obvious |
| 5.5 | 59.27 | 98.78 | 18 | 49.2 | 82.00 | 16.78 | Paper spectrum 10 days, AMP appearred in 18 days in the cAMP single-point |
| 5.0 | 59.00 | 98.00 | 18 | 58.57 | 97.62 | 0 | Ply of paper is analysed collection of illustrative plates cAMP single-point |
| 4.5 | 59.30 | 98.83 | 18 | 58.32 | 97.20 | 0 | Ply of paper is analysed collection of illustrative plates cAMP single-point |
| 4.0 | 59.09 | 98.49 | 18 | 55.59 | 92.65 | 5.84 | Paper spectrum 10 days, the cAMP single-point had adenosine, and did not see AMP in 18 days |
| 3.5 | 59.00 | 98.30 | 18 | 51.92 | 88.00 | 10.00 | Paper spectrum 10 days, the cAMP single-point had obvious adenosine, micro-AMP in 18 days |
The MCA recovery test of table 4.MCA glucose injection
According to last method, make the paper spectrometry respectively and measure secondary, be decided to be the first and second two groups, three in every group of replicate determination sample
*
0.6278=cAMP branch/MCA molecular weight
* statistical procedures: the first and second two combinations and after, recovery average=100.44 of MCA; RSD=1.166%;
First group recovery average=100.67; RSD=1.356%; Second group recovery average=100.23; RSD=1.098%
Table 5
| Project | The name of an article | |
| Meglumine adenosine cycle phosphate glucose infusion solutions | Meglumine adenosine cycle phosphate sodium chloride infusion solutions | |
| Drug content | 54～66mg/100ml | 54～66mg/100ml |
| Deng oozing medium content | 4.75～5.25g/100ml | 0.85～0.95g/100ml |
| Proterties | Colourless or little yellow supernatant liquid | Colourless or almost colourless supernatant liquid |
| pH | 3.5～5.5 | 5.5～7.0 |
| Particulate matter | Should be up to specification | Should be up to specification |
| Heavy metal | Must not cross 5/1000000ths | Must not cross 5/1000000ths |
| 5 hydroxymethyl furfural | ＜0.27 | - |
| Other | Should meet every regulation relevant under the injection item | |
| The term of validity | Tentative 2 years | Tentative 2 years |
Claims (3)
1. the content assaying method of meglumine adenosine cycle phosphate in the meglumine adenosine cycle phosphate glucose infusion solutions is characterized in that may further comprise the steps:
A. utilize alkaline pH value 8.0～9.0, make meglumine adenosine cycle phosphate be dissociated into electronegative adenosine cyclophosphate and uncharged meglumine;
B. with the strong-base anion-exchange resin absorption adenosine cyclophosphate and the phosphorus adenosine that may be decomposed to form;
C. the solution that flows out when upper prop adsorbs of parenteral solution and the solution that flows out when cleaning pillar with pure water can be removed the glucose in the parenteral solution, meglumine and other all uv absorption impurity;
D. be to separate an adenosine cyclophosphate and a phosphorus adenosine in 5: 2 the developping agent with paper chromatography at 95% ethanol-4% ammonium acetate again, and with its content of feature determination of uv absorption of adenosine cyclophosphate, calculate the content of meglumine adenosine cycle phosphate in view of the above.
2. the content assaying method of meglumine adenosine cycle phosphate in the meglumine adenosine cycle phosphate glucose infusion solutions according to claim 1 is characterized in that comprising following concrete operations step:
Precision is measured meglumine adenosine cycle phosphate glucose injection 125ml, regulate pH to 8-9 with the 1mol/L sodium hydroxide solution, on the strong-base anion-exchange resin handled well, the 100-200 order, C1 type post, last column flow rate 3～4ml/min, sample flow is used distilled water 80ml instead and is washed post during to cylinder, flow velocity is the same, discard effluent, use 0.075mol/L hydrochloric acid solution-0.2mol/L sodium chloride solution wash-out then, flow velocity 0.7ml/min, collect the about 80ml of eluent, regulate pH value to 6.5 with the ammonium bicarbonate particle, be evaporated to about 3ml below 60 ℃ then, be transferred in the 10ml measuring bottle, with water for injection washing cucurbit for several times, add in the measuring bottle in the lump, and add the injection be diluted with water to scale, as need testing solution; It is an amount of that other gets the adenosine cyclophosphate reference substance, the water that adds 60 ℃ is made the solution that contains 10mg among every 1ml, product solution is tested according to paper chromatography in contrast, the above-mentioned solution 10 μ l of accurate respectively absorption, point is about on the chromatography filter paper of 30cm, with 95% ethanol-4% ammonium acetate ratio is developping agent at 5: 2, launch about 15 hours after, drying, put under the ultraviolet lamp 254nm and inspect, speckle displacement at reference substance exists together mutually, marks the test sample purple dot, and this spot is cut, and be cut into fine strip shape, put into test tube, precision adds 0.01mol/L hydrochloric acid solution 5ml, jolting, place after 1 hour, get supernatant,, be that the wavelength place of 257nm measures absorbance log according to spectrophotometric method, simultaneously, replace need testing solution with 5% glucose solution, with the method operation, as blank correction, absorption coefficient by CAMP is that the 447 molecular weight ratios 0.6278 that multiply by adenosine cyclophosphate and Meglumine Cyclic Adenylate calculate, and promptly gets the content of meglumine adenosine cycle phosphate.
3. the content assaying method of meglumine adenosine cycle phosphate in the meglumine adenosine cycle phosphate glucose infusion solutions according to claim 2 is characterized in that strong-base anion-exchange resin adopts the Dowex 1 of the U.S. or homemade 717, and cl type post is post footpath 12mm, resin bed 4ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510124456XA CN100342232C (en) | 2003-06-18 | 2003-06-18 | Method for determining cyclophosphadenosineglucamine content in its high-transfusion preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510124456XA CN100342232C (en) | 2003-06-18 | 2003-06-18 | Method for determining cyclophosphadenosineglucamine content in its high-transfusion preparation |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03124559 Division CN1275599C (en) | 2003-06-18 | 2003-06-18 | Cyclophosphadenosine glucosamine infusion prepn., and its prepn. process, and method for testing contents thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1776420A CN1776420A (en) | 2006-05-24 |
| CN100342232C true CN100342232C (en) | 2007-10-10 |
Family
ID=36766048
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200510124456XA Expired - Lifetime CN100342232C (en) | 2003-06-18 | 2003-06-18 | Method for determining cyclophosphadenosineglucamine content in its high-transfusion preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100342232C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721357B (en) * | 2008-10-31 | 2011-06-22 | 上海华中药业有限公司 | Method for filtering meglumine adenosine cycle phosphate high-capacity injection |
| CN106053642A (en) * | 2016-05-27 | 2016-10-26 | 扬子江药业集团广州海瑞药业有限公司 | Gadobenate dimeglumine content detection control method |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0456252A2 (en) * | 1990-05-11 | 1991-11-13 | Tanabe Seiyaku Co., Ltd. | Method for determination of pyrogen content |
| CN1070481A (en) * | 1992-08-22 | 1993-03-31 | 国营北京市东北旺制药厂 | The assay method of Mai Bai, the whole component concentrations of medecamycin |
| JP2002071658A (en) * | 2000-08-29 | 2002-03-12 | Shiseido Co Ltd | Liquid chromatographic device and flow cell |
| JP2002156327A (en) * | 2000-11-20 | 2002-05-31 | Japan Organo Co Ltd | Adsorption state determination method of material adsorbed on sample surface, and control method of water treatment system |
| CN1355430A (en) * | 2000-11-29 | 2002-06-26 | 中国石化集团齐鲁石油化工公司 | Method for testing carbon type of high-arylhydrocarbon oil for oil-extended rubber |
-
2003
- 2003-06-18 CN CNB200510124456XA patent/CN100342232C/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0456252A2 (en) * | 1990-05-11 | 1991-11-13 | Tanabe Seiyaku Co., Ltd. | Method for determination of pyrogen content |
| CN1070481A (en) * | 1992-08-22 | 1993-03-31 | 国营北京市东北旺制药厂 | The assay method of Mai Bai, the whole component concentrations of medecamycin |
| JP2002071658A (en) * | 2000-08-29 | 2002-03-12 | Shiseido Co Ltd | Liquid chromatographic device and flow cell |
| JP2002156327A (en) * | 2000-11-20 | 2002-05-31 | Japan Organo Co Ltd | Adsorption state determination method of material adsorbed on sample surface, and control method of water treatment system |
| CN1355430A (en) * | 2000-11-29 | 2002-06-26 | 中国石化集团齐鲁石油化工公司 | Method for testing carbon type of high-arylhydrocarbon oil for oil-extended rubber |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1776420A (en) | 2006-05-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101339178B (en) | Metformin hydrochloride enteric-coated tablets quality control method | |
| CN101439031B (en) | Pharmaceutical composition containing 18 kinds of amino acid | |
| CN1895251A (en) | Stabilized nalmefene hydrochloride injection and its preparation | |
| CN1275599C (en) | Cyclophosphadenosine glucosamine infusion prepn., and its prepn. process, and method for testing contents thereof | |
| CN1739550A (en) | Polycinnamic alcohol injection and its prepn | |
| CN100342232C (en) | Method for determining cyclophosphadenosineglucamine content in its high-transfusion preparation | |
| CN101040942A (en) | Active ingredient compound of Jianerqingjie solution and the control method | |
| CN1830440A (en) | Metronidazule injection and its preparation method and use | |
| CN102462659B (en) | Citicoline sodium injection and preparation method thereof | |
| CN1830428A (en) | Sodium ferulate injection and its preparation method | |
| CN101592637A (en) | A kind of detection method of new compound CTX sodium-tazobactam sodium | |
| CN102144963A (en) | Citicoline sodium glucose injecta and preparation process thereof | |
| CN107402277A (en) | The method of quality control of compound balloonflower root ephedrine syrup | |
| CN102813622A (en) | Ornidazole sodium chloride injection composition and preparation method thereof | |
| CN102539601A (en) | Determination method for contents of calcium and phosphorus in animal or mineral traditional Chinese medicine | |
| CN101664385A (en) | Ibutilide fumarate injection and preparation method thereof | |
| CN1830434A (en) | Preparation method of troxerutin injection | |
| CN104434788A (en) | Preparation method of atenolol injection | |
| CN101745117A (en) | Composition of cyclic adenosine monophosphate and polyvinylpyrrolidone and preparation method thereof | |
| CN1831535A (en) | ABO blood group back stereo-type kit | |
| CN112684021B (en) | Vitamin B12Method for detecting related substances of injection | |
| CN103239395A (en) | Houttuynia cordata injection and preparation method thereof | |
| CN1634054A (en) | Injectio for inhibiting platelet aggregation and its preparation process | |
| CN102266420B (en) | Method for preparing heartleaf houttuynia herb injection | |
| CN104215703B (en) | The detection method of glycoside macromolecular substances in a kind of injection Yiqi and vein recovery |
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 | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170331 Address after: 854000 Tibet City Economic Development Zone, Changdu economic and Technological Development Zone, biomedical industry park A Patentee after: Changdu Zhongqi Pharmaceutical Co.,Ltd. Address before: 212000 Xuzhou medical college dormitory, room 1, Jiangsu, 202 Patentee before: Zhao Chen |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 414000 Wangjia Fan Road, Yueyang Economic Development Zone, Yueyang, Hunan 106 Patentee after: Hunan Zhongqi Pharmaceutical Co.,Ltd. Address before: 854000 Tibet autonomous region Changcheng Changdu Economic Development Zone A area Biomedical Industry Park Patentee before: Changdu Zhongqi Pharmaceutical Co.,Ltd. |
|
| CX01 | Expiry of patent term | ||
| CX01 | Expiry of patent term |
Granted publication date: 20071010 |