CN104666333A - Peritoneal dialysis solution (lactate) composition - Google Patents
Peritoneal dialysis solution (lactate) composition Download PDFInfo
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- CN104666333A CN104666333A CN201310614108.5A CN201310614108A CN104666333A CN 104666333 A CN104666333 A CN 104666333A CN 201310614108 A CN201310614108 A CN 201310614108A CN 104666333 A CN104666333 A CN 104666333A
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Abstract
The invention relates to peritoneal dialysis solution (lactate) composition. The peritoneal dialysis solution (lactate) composition contains 1.5-4.25% of glucose, 0.4-0.7% of sodium oxide, 0.02-0.03% of calcium chloride, 0.01-0.02% of magnesium chloride and 0.4-0.6% of sodium lactate. The peritoneal dialysis solution (lactate) composition is characterized in that pH value is adjusted to be 7.3-7.7 by adopting inorganic base.
Description
Technical field
The present invention relates to a kind of weakly alkaline peritoneal dialysis solution (lactate) compositions.
Background technology
Peritoneal dialysis (peritoneal dialysis, PD) be the important renal replacement therapy (CRRT) of end stage renal failure patient, due to compared with hemodialysis, have applied widely, dialytic efficiency is high, residual renal function is kept, patients ' life quality advantages of higher, occupies more and more consequence in the alternative medicine of chronic renal failure.The key of successful peritoneal dialysis is the peritoneum that ultrafiltration function is good and peritoneal dialysis solution.Due to the chronicity of peritoneal dialysis treatment, the ultrafiltration performance of peritoneum often affects by various factors and changes over the course for the treatment of, and this change is irreversible, and patient's peritoneum ultrafiltration function finally can be caused to lose, and cannot carry out abdomen again and thoroughly treat.Peritoneal fibrosis and ultrafiltration caused by the poor biocompatibility of wherein peritoneal dialysis solution (peritoneal dialysis fluid, PDF) unsuccessfully become the major issue that current peritoneal dialysis is badly in need of and must be solved.Abdomen abdomen dialysis solution (peritoneal dialysis fluid, PDF) be core link in PD, the ultimate principle of peritoneal dialysis, utilize different the formed electrochemistry potential energy difference of the concentration of each composition between patients serum from peritoneal dialysis liquid in peritoneal cavity exactly, correct in uremic patient blood by disperse and Ultrafiltration physically different.The setting of each composition of peritoneal dialysis liquid and compatibility are mainly based on this principle.Desirable peritoneal dialysis liquid not only fully can remove toxin, ultrafiltration moisture, can also protect peritoneal membrane function, reduces the generation of ultrafiltration exhaustion (UFF).The lactate dialysate that traditional peritoneal dialysis liquid is is penetrating agent with the glucose of variable concentrations; clinical practice for many years shows; although PD has played very important effect in the treatment of chronic kidney hypofunction; but from human physiology's angle; the dialysis solution that current routine uses is still outstanding exists following problem: (1) dialysis solution is main penetrating agent with glucose; because it can be absorbed by peritoneum, therefore its osmosis is held time very short, is difficult to reach desirable liquid and Solute removal; (2) in dialysis solution, some composition (glucose and base etc.) can activate inflammatory cytokine (somatomedin, nitric oxide synthetase); life-time service can cause peritoneum chronic inflammatory to change, and promotes peritoneal fibrosis and thickens; (3) after the glucose in dialysis solution is decomposed in vivo; the non-product of a large amount of advanced glycosylation endproducts (AGEs) can be produced; the latter can extensively deposit in vivo, especially interstitial can be caused to thicken after blood vessel wall and peritoneum interstitial deposition, cause ultrafiltration function to decline; (4) glucose degradable in high-temperature sterilization forms a series of glucose degradation products (GDPs), and GDPs can coup injury peritoneal cell, and promotes that AGE is formed; (5) in dialysis solution, buffer base adopts lactate mostly, and they must first after the metabolic conversion of liver be bicarbonate, can play and correct acidosic effect, therefore often has certain limitation to the patient that a part is associated with hepatic disease.
Glucose is as traditional peritoneal dialysis solution penetrating agent, although itself is without direct biology toxicity, but a large amount of virose glucose degradation products (glucose degradation products.GDPs) can be produced in the process of high temperature sterilize and single bag of long term storage, research finds that the pH value condition (5.5 ~ 6.5) in heating disinfection process residing for traditional PD F significantly can increase acetaldehyde, formaldehyde, methylglyoxal, 3-deoxyfructose (3-deoxy-glucosone, 3-DG), 3, the two deoxyglucose keto-aldehyde-3-alkene (3 of 4-, 4-dideoxyglucosone-3-ene, 3, 4-DGE), the generation of the GDPs such as 5 hydroxymethyl furfural.When GDPs enters abdominal cavity, Peritoneal Mesothelial Cells function will be damaged, and cause a large amount of cytokine as IL-6, TGF-β, the generations such as VEGF.Therefore can induce as peritoneal tissues is exposed in the peritoneal dialysis solution of high GDPs for a long time and increases the weight of Peritoneal Mesothelial Cells transdifferentiation and new vessels formation, in addition, non-enzyme material can also be attached to albumen and lipid by GDPs, and then form advanced glycation end products (advanced glycation end products, AGE), AGE is attached to the Peritoneal Mesothelial Cells layer containing AGE receptor (RAGE), increase the weight of peritoneal injury, and AGE can enter blood circulation, increase the weight of atherosclerosis and amyloidosis etc., therefore the prolonged application of conventional peritoneal dialysis liquid can cause the failure of peritoneum ultrafiltration function and PD technology, due to the representative that to generally believe 5 hydroxymethyl furfural (5-HMF) be glucose degradation products (GDPs), so in Glucose Liquid body preparation general 5 hydroxymethyl furfural (5-HMF) as evaluation index.Although glucose has above-mentioned deficiency, but at present because other penetrating agent are also immature, document " Development outline of peritoneal dialysis solution " (Zhu Hong, Journal of Chinese Hospital Pharmacy, 2000,5th phase) point out that aminoacid, glucose polimer, small molecule crystals glycerol, Sorbitol, xylitol and fructose, macromolecular colloid gelatin, polycation, dextran and polypeptide all can be used as penetrating agent, but up to the present still do not find the penetrating agent of alternative glucose.
Generally believe that glucose solution is stablized in acid condition at present, and bibliographical information (pH value is on the impact of five kinds of infusion solutions stability, practical medical technologies magazine, 2007, 8, 3236) glucose solution semi-finished product pH value is higher, finished product pH value fall is larger, it is larger that content declines, it is more that 5 hydroxymethyl furfural (5-HMF) produces, medicinal liquid variable color is darker, simultaneously other documents also have similar report (pH value are on the impact of glucose injection stability, modern combination of Chinese and Western medicine magazine, 1999, 8, 1221), be 3.2-6.5 for glucose injection PH claimed range in Chinese Pharmacopoeia (2010 editions), be 3.5-5.5 for Dextrose and Sodium Chloride Inj. PH claimed range, also illustrate that above-mentioned viewpoint.Just because of peritoneal dialysis solution pH value all≤7, in use there are some problems in peritoneal dialysis solution, first the body fluid of normal person is in alkalescence substantially, such as pH value of blood 7.35 ~ 7.45, the pH value 7.0 ~ 7.5 of tissue fluid, the pH value 7.20 ~ 7.45 of Cell sap, equal≤7 peritoneal dialysis solution of pH value and body fluid gap cause larger zest compared with conference, damage is caused to peritoneum, secondly end stage renal failure patient often all has acidosic problem, and the conventional peritoneal dialysis liquid of life-time service acidity can increase the weight of this point undoubtedly.
In addition in peritoneal dialysis solution also containing a large amount of divalent calcium, magnesium ion as buffer salt, it is generally acknowledged the calcium salt in dialysis solution in the basic conditions, magnesium salt meeting and base, as hydroxyl, carbonate react and cause precipitation.
Just because of the requirement of the buffer salt stability of glucose, divalent calcium, magnesium ion, research worker can not get both between the puzzled effect in medicine, stability, zest, untoward reaction always, cannot accept or reject, so in order to ensure that current peritoneal dialysis solution is still penetrating agent with glucose, with valency calcium, magnesium ion for buffer salt, so peritoneal dialysis solution pH value still≤7.
So the pH value of current peritoneal dialysis solution all≤7, even adding base is also solved by the method for two rooms bag system, deposit in the bag of two rooms respectively by base and other divalent calcium, magnesium ion, in use base is mixed mutually with divalent ion, but this kind of method cost is higher, easily there is partial over saturation phenomenon in bicarbonate and divalent calcium, magnesium ion simultaneously in mixing, increases the possibility that insoluble microparticle produces, but also cannot detect, add the risk of patient.
Summary of the invention
In the present invention, " peritoneal dialysis solution (lactate) " name is called that State Food and Drug Administration is the title of such dialysis solution Uniform provisions, specifically see State Food and Drug Administration standard YBH12272006, below can by peritoneal dialysis solution (lactate) referred to as peritoneal dialysis solution.
Through Literature Consult and research, we find in fact no matter glucose all degradation reaction can occur after acid condition or alkali condition store certain hour, relatively little in acid condition (especially under high temperature) 5 hydroxymethyl furfural degradation reaction, past is in order to emphasize the stability of product, so the PH of the peritoneal dialysis solution of glucose is controlled in acid condition always, but the peritoneum of acid meeting to human body, body fluid causes harmful effect, the glucose degradation products simultaneously affecting peritoneum also comprises formaldehyde, the material that the toxicity such as acetaldehyde are higher, 5 hydroxymethyl furfural is the one in glucose degradation products, in glucose degradation products, only measure 5 hydroxymethyl furfural and there is certain one-sidedness using this material as the index of product quality, in fact formaldehyde, the far super 5 hydroxymethyl furfural of toxicity of the materials such as acetaldehyde.Relatively many by alkalescence peritoneal dialysis solution (lactate) 5 hydroxymethyl furfural compared with acidity in the stability experiment accelerated test of known 4 months, but the formaldehyde that toxicity is larger, acetaldehyde is less, gap is little generally for the toxicity that catabolite produces, and alkalescence peritoneal dialysis solution (lactate) 5 hydroxymethyl furfural compared with acidity after the ordinary temperature stability test of 12 months, the formaldehyde that toxicity is larger, it is less that acetaldehyde increases, the toxicity that catabolite produces is less generally, so in peritoneum infringement experiment, we are by finding that the impact that pH value compares peritoneum at the alkalescence peritoneal dialysis solution (lactate) of 7.3-7.7 and the acid peritoneal dialysis solution (lactate) of PH≤7 of same prescription is less.And pH value can also improve the problem of the blood pH decline that the acid peritoneal dialysis solution (lactate) of life-time service is caused at the alkalescence peritoneal dialysis solution (lactate) of 7.3-7.7, be conducive to the accumulation alleviating body inner acidic.
Simultaneously under weak basic condition, base and other divalent calcium, magnesium ion can not form precipitation under low consistency conditions.
Simultaneously in preparation, original technique is after peritoneal dialysis solution configures, regulate pH value to be carry out high temperature sterilize under alkaline case, under causing alkali condition, comparatively acid condition is more for catabolite, then after peritoneal dialysis solution is configured in the present invention, with alkaline regulator solution high temperature sterilize respectively, the problem that the method then mixed thus the catabolite that under avoiding alkali condition, high temperature sterilize causes increase, and adopt low concentration, the method that slowly adds can avoid base and divalent calcium, magnesium ion to be formed precipitating.
A kind of peritoneal dialysis solution, glucose containing 1.5-4.25%, the sodium chloride of 0.4-0.7%, the calcium chloride of 0.02-0.03%, the magnesium chloride of 0.01-0.02%, and the sodium lactate of 0.4-0.6%, is characterized in that described inorganic base used for peritoneal dialysate regulates pH value to 7.3-7.7, pH value is preferably 7.3-7.6, and pH value most preferably is 7.4.
Above-mentioned peritoneal dialysis solution, it is characterized in that also containing 0.001% ~ 0.01% sodium pyrosulfite, sodium sulfite or sodium sulfite.
Above-mentioned peritoneal dialysis solution, is characterized in that formula is the sodium chloride of 0.56%, the calcium chloride of 0.026%, the magnesium chloride of 0.015%, the sodium lactate of 0.5, the sodium pyrosulfite of 0.005%, and the glucose of 1.5% or 2.5% or 4.25% and surplus water for injection composition.
Above-mentioned peritoneal dialysis solution, it is characterized in that inorganic base is sodium salt, be preferably one or more in sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium acetate, be preferably one or more in sodium hydroxide, sodium bicarbonate, sodium carbonate, be preferably one or more in sodium hydroxide, sodium bicarbonate, most preferably be sodium bicarbonate.
The preparation method of above-mentioned peritoneal dialysis solution, it is characterized in that step one is by the glucose of 1.5-4.25%, the sodium chloride of 0.4-0.7%, the calcium chloride of 0.02-0.03%, the magnesium chloride of 0.01-0.02%, and the sodium lactate of 0.4-0.6% and water mix, sterilizing, step 2 is that inorganic base and water are formed solution, sterilizing, step 3 obtains the pH value of liquid at 7.3-7.7 with the liquid regulating step one that step 2 obtains, packaging.
The preparation method of above-mentioned peritoneal dialysis solution, is characterized in that sterilizing methods is high temperature or High Temperature High Pressure.
The preparation method of above-mentioned peritoneal dialysis solution, is characterized in that inorganic base and water form content≤0.05% of solution.
Above-mentioned peritoneal dialysis solution reduces the application in peritoneal fibrosis medicine in preparation.
In case of no particular description, in the present invention, the content of compositions is w/v, and the sodium chloride of such as 0.4-0.7% is the sodium chloride having 0.4-.07g in 100ml water.
The content of the glucose in the present invention, calcium chloride, magnesium chloride calculates with Dextrose monohydrate, calcium chloride dihydrate, magnesium chloride hexahydrate respectively, the glucose of such as 1.5-4.25% is actually 1.5-4.25% Dextrose monohydrate, the glucose of such as 1.5-4.25% is the Dextrose monohydrate having 1.5-4.25g during 100ml water contains, instead of 100ml water contain in have the glucose of 1.5-4.25g.
Embodiment
In case of no particular description, the glucose in embodiment, calcium chloride, magnesium chloride refer to Dextrose monohydrate, calcium chloride dihydrate, magnesium chloride hexahydrate respectively.
Example of formulations 1
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 1-1 | 1-2 | 1-3 |
| Glucose (g) | 15 | 15 | 15 |
| Sodium chloride (g) | 4 | 5.6 | 7 |
| Calcium chloride (g) | 0.2 | 0.25 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.15 | 0.2 |
| Sodium lactate (g) | 4 | 5 | 6 |
| PH | 7.7 | 7.4 | 7.3 |
1. dope preparation: the water for injection getting recipe quantity 10%, after other compositions adding recipe quantity are stirred to and all dissolve, then add after medicinal charcoal 0.1 ~ 1% stirs, to place after 10 ~ 20 minutes after 0.22 μm of end-filtration 115 DEG C of steam sterilizations 15 minutes, obtain dope for subsequent use.
2. Alkali liquid compounding: configuration content, lower than 0.05% sodium bicarbonate solution, then adds after medicinal charcoal 0.1 ~ 1% stirs, places after 10 ~ 20 minutes after 0.22 μm of end-filtration, 115 DEG C of steam sterilizations 10 minutes, obtain alkali liquor for subsequent use.
3, dope, alkali liquor are at the uniform velocity mixed, by alkali liquor, water for injection, regulate solution to 1000ml, pH value is the numerical value in upper table, by embedding after 0.22 μm of end-filtration (every bag of 1000ml or 2000ml).
In preparation process step 3, note mixing velocity, precipitation must not be occurred.
Nitrogen protection is adopted when preparation and embedding.
4, sterilizing: 115 DEG C of constant temperature 10 minutes
Nitrogen protection is adopted when preparation and embedding.
Example of formulations 2
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 2-1 | 2-2 | 2-3 |
| Glucose (g) | 15 | 15 | 15 |
| Sodium chloride (g) | 4 | 5.6 | 7 |
| Calcium chloride (g) | 0.2 | 0.25 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.15 | 0.2 |
| Sodium lactate (g) | 4 | 5 | 6 |
| PH | 7.7 | 7.4 | 7.3 |
Preparation method is with embodiment 1, but alkali liquor is 0.01% sodium hydroxide.
Example of formulations 3
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 3-1 | 3-2 | 3-3 |
| Glucose (g) | 25 | 25 | 25 |
| Sodium chloride (g) | 4 | 5.6 | 7 |
| Calcium chloride (g) | 0.2 | 0.25 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.15 | 0.2 |
| Sodium lactate (g) | 4 | 5 | 6 |
| PH | 7.7 | 7.4 | 7.3 |
Preparation method is with embodiment 1.
Example of formulations 4
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 4-1 | 4-2 | 4-3 |
| Glucose (g) | 25 | 25 | 25 |
| Sodium chloride (g) | 4 | 5.6 | 7 |
| Calcium chloride (g) | 0.2 | 0.25 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.15 | 0.2 |
| Sodium lactate (g) | 4 | 5 | 6 |
| PH | 7.7 | 7.4 | 7.3 |
Preparation method is with embodiment 1, but alkali liquor is 0.01% sodium hydroxide.
Example of formulations 5
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 5-1 | 5-2 | 5-3 |
| Glucose (g) | 42.5 | 42.5 | 42.5 |
| Sodium chloride (g) | 4 | 5.6 | 7 |
| Calcium chloride (g) | 0.2 | 0.25 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.15 | 0.2 |
| Sodium lactate (g) | 4 | 5 | 6 |
| PH | 7.7 | 7.4 | 7.3 |
Preparation method is with embodiment 1.
Example of formulations 6
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 6-1 | 6-2 | 6-3 |
| Glucose (g) | 42.5 | 42.5 | 42.5 |
| Sodium chloride (g) | 4 | 5.6 | 7 |
| Calcium chloride (g) | 0.2 | 0.25 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.15 | 0.2 |
| Sodium lactate (g) | 4 | 5 | 6 |
| PH | 7.7 | 7.4 | 7.3 |
Preparation method is with embodiment 1, but alkali liquor is 0.01% sodium hydroxide.
Example of formulations 7
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 7-1 | 7-2 | 7-3 |
| Glucose (g) | 15 | 15 | 15 |
| Sodium chloride (g) | 4 | 5.6 | 7 |
| Calcium chloride (g) | 0.2 | 0.25 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.15 | 0.2 |
| Sodium lactate (g) | 4 | 5 | 6 |
| PH | 7.7 | 7.4 | 7.3 |
Preparation method: the water for injection getting recipe quantity 50%, after other compositions adding recipe quantity are stirred to and all dissolve, sodium bicarbonate solution (alkali liquor), water for injection is regulated to regulate pH value to be numerical value in upper table with content lower than 0.05% and volume standardize solution is 100% of total amount, then add after medicinal charcoal 0.1 ~ 1% stirs, to place after 10 ~ 20 minutes after 0.22 μm of end-filtration 115 DEG C of steam sterilizations 20 minutes, embedding (every bag of 1000ml or 2000ml).
, precipitation must not be there is in alkali liquor and the liquid mixed attention mixing velocity of pastille in preparation process step.
Nitrogen protection is adopted when preparation and embedding.
Example of formulations 8
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 8-1 | 8-2 | 8-3 |
| Glucose (g) | 42.5 | 42.5 | 42.5 |
| Sodium chloride (g) | 4 | 5.6 | 7 |
| Calcium chloride (g) | 0.2 | 0.25 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.15 | 0.2 |
| Sodium lactate (g) | 4 | 5 | 6 |
| PH | 7.7 | 7.4 | 7.3 |
Preparation method is with embodiment 7, but alkali liquor is 0.01% sodium hydroxide.
Example of formulations 9
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 9-1 | 9-2 | 9-3 | 9-4 | 9-5 |
| Glucose (g) | 42.5 | 42.5 | 42.5 | 42.5 | 42.5 |
| Sodium chloride (g) | 4 | 5.6 | 7 | 5.6 | 5.6 |
| Calcium chloride (g) | 0.2 | 0.25 | 0.3 | 0.25 | 0.25 |
| Magnesium chloride (g) | 0.1 | 0.15 | 0.2 | 0.15 | 0.15 |
| Sodium lactate (g) | 4 | 5 | 6 | 5 | 5 |
| Sodium pyrosulfite (g) | 0.01 | 0.05 | 0.1 | ||
| Sodium sulfite (g) | 0.05 | ||||
| Sodium sulfite (g) | 0.05 | ||||
| PH | 7.7 | 7.4 | 7.3 | 7.4 | 7.4 |
Preparation method is with embodiment 1.
Comparative examples 1
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 1-1 | 1-3 |
| Glucose (g) | 15 | 15 |
| Sodium chloride (g) | 4 | 7 |
| Calcium chloride (g) | 0.2 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.2 |
| Sodium lactate (g) | 4 | 6 |
| PH | 3.5 | 6.5 |
1. dope preparation: get 20% water for injection, puts into the glucose, sodium chloride, calcium chloride, magnesium chloride, the sodium lactate that weigh up and is stirred to dissolve, and after being heated to all to dissolve, regulates pH value as above show and be settled to full dose with 5%HCl solution, water for injection.Then add medicinal charcoal 0.1 ~ 1%(g/ml) stir after, medicinal liquid through 0.22 μm of ultimate filter be filtered to visible foreign matters qualified after embedding (every bag of 1000ml or 2000ml)
2. sterilizing: 115 DEG C of constant temperature 20 minutes
Nitrogen protection is adopted when preparation and embedding.
Comparative examples 3
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 3-1 | 3-3 |
| Glucose (g) | 25 | 25 |
| Sodium chloride (g) | 4 | 7 |
| Calcium chloride (g) | 0.2 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.2 |
| Sodium lactate (g) | 4 | 6 |
| PH | 3.5 | 6.5 |
Preparation method is with comparative examples 1.
Comparative examples 5
Formula is as following table, and subpackage specification is 1000ml/ bag, and in table, data are amount to the formula of every bag of dialysis solution
| Embodiment is numbered | 5-1 | 5-3 |
| Glucose (g) | 42.5 | 42.5 |
| Sodium chloride (g) | 4 | 7 |
| Calcium chloride (g) | 0.2 | 0.3 |
| Magnesium chloride (g) | 0.1 | 0.2 |
| Sodium lactate (g) | 4 | 6 |
| PH | 3.5 | 6.5 |
Preparation method is with comparative examples 1.
Stability test 1
The peritoneal dialysis solution (using the crude drug of same batch, adjuvant, water for injection) embodiment, comparative examples obtained divides into groups according to group number, often organize 10 bags, every bag of 100ml, stores respectively, detects in the stipulated time under thermostatic accelerated experiment, room temperature long term test condition.
1, the amount of 5 hydroxymethyl furfural, acetaldehyde, formaldehyde is measured.
Thermostatic accelerated experiment condition: by commercially available back, temperature 40 DEG C ± 2 DEG C, places under the condition of relative humidity 75% ± 5%.
Room temperature long term test condition: commercially available back, temperature 25 DEG C ± 2 DEG C, places under the condition of relative humidity 60% ± 10%.
The content of acetaldehyde, formaldehyde adopts external standard method vapor phase method to measure, and actual conditions is as follows:
Chromatograph: Hewlett-Packard 5890 type gas chromatograph, fid detector.
Chromatographic column: chromatographic column internal diameter 2mm, long 1.5mm glass column, carrier: the white monomer of silanization 102 (60-80 order), fixative: SE-30
Operating condition: column temperature 190 DEG C, detector: 250 DEG C, vaporizer: 200 DEG C
Sample size: 1 μ l
Acetaldehyde and formaldehyde (both are added) the content meansigma methods (n=10) in embodiment, comparative examples peritoneal dialysis solution:
5 hydroxymethyl furfural content assaying method is according to national drug standards WS
1the method of-XG-002-2007 measures, and measurement result is absorbance, and absorbance is higher, and 5 hydroxymethyl furfural content is higher.
5 hydroxymethyl furfural measures absorbance (n=10, mean ± SD)
| Group number | Thermostatic accelerated experiment 120 days measured values | Room temperature long term test 365 days measured values |
| Embodiment 1-1 | 0.243±0.022 | 0.238±0.024 |
| Embodiment 1-2 | 0.230±0.024 | 0.227±0.025 |
| Embodiment 1-3 | 0.239±0.025 | 0.234±0.023 |
| Embodiment 2-1 | 0.248±0.023 | 0.241±0.024 |
| Embodiment 2-2 | 0.238±0.025 | 0.233±0.024 |
| Embodiment 2-3 | 0.243±0.025 | 0.238±0.025 |
| Embodiment 3-1 | 0.257±0.024 | 0.251±0.026 |
| Embodiment 3-2 | 0.240±0.026 | 0.235±0.028 |
| Embodiment 3-3 | 0.248±0.025 | 0.244±0.024 |
| Embodiment 4-1 | 0.268±0.025 | 0.260±0.025 |
| Embodiment 4-2 | 0.249±0.027 | 0.243±0.025 |
| Embodiment 4-3 | 0.260±0.025 | 0.252±0.024 |
| Embodiment 5-1 | 0.265±0.023 | 0.259±0.026 |
| Embodiment 5-2 | 0.248±0.023 | 0.241±0.022 |
| Embodiment 5-3 | 0.255±0.024 | 0.252±0.023 |
| Embodiment 6-1 | 0.270±0.026 | 0.267±0.025 |
| Embodiment 6-2 | 0.249±0.025 | 0.246±0.024 |
| Embodiment 6-3 | 0.264±0.023 | 0.260±0.025 |
| Embodiment 7-2 | 0.292±0.023 | 0.284±0.025 |
| Embodiment 8-2 | 0.298±0.023 | 0.290±0.023 |
| Embodiment 9-1 | 0.256±0.020 | 0.252±0.025 |
| Embodiment 9-2 | 0.239±0.022 | 0.232±0.024 |
| Embodiment 9-3 | 0.249±0.023 | 0.245±0.022 |
| Embodiment 9-4 | 0.246±0.023 | 0.241±0.023 |
| Embodiment 9-5 | 0.249±0.021 | 0.242±0.024 |
| Comparative examples 1-1 | 0.214±0.018 | 0.217±0.019 |
| Comparative examples 1-3 | 0.221±0.020 | 0.220±0.018 |
| Comparative examples 3-1 | 0.217±0.022 | 0.219±0.021 |
| Comparative examples 3-3 | 0.222±0.019 | 0.225±0.020 |
| Comparative examples 5-1 | 0.220±0.021 | 0.222±0.020 |
| Comparative examples 5-3 | 0.225±0.023 | 0.228±0.022 |
Known by above-mentioned inspection, in the accelerated test of 4 months, alkalescence peritoneal dialysis solution (lactate) 5 hydroxymethyl furfural compared with acidity is relatively many, but the formaldehyde that toxicity is larger, acetaldehyde are less, gap is little generally for the toxicity that catabolite produces, and that the alkalescence peritoneal dialysis solution (lactate) after the ordinary temperature stability test of 12 months 5 hydroxymethyl furfural, formaldehyde that toxicity is larger, acetaldehyde compared with acidity increase is less, the toxicity that catabolite produces generally may be less.
Add the materials such as sodium pyrosulfite to have certain effect for the stability tool of peritoneal dialysis solution, it is best wherein to add sodium pyrosulfite effect simultaneously.
Use national drug standards WS
1analytical method in-XG-002-2007 measures calcium chloride, content of magnesium chloride in example of formulations 1-1 to 8-3, and the content of calcium chloride, magnesium chloride is all between the 90-110% of recipe quantity.
The embodiment used in effect example, the peritoneal dialysis solution of comparative examples are all temperature 25 DEG C ± 2 DEG C, place the product of 12 months under the condition of relative humidity 60% ± 10%.
Effect example 1 peritoneum impact test
Laboratory animal: SD rat, male, body weight 200 ± 10g
Test method: by rat random packet, often organize 10, blank group accepts normal saline 2Oml lumbar injection every day, embodiment 1-1 to 8-3 group gives the peritoneal dialysis solution lumbar injection of the corresponding group number of embodiment group to rat, every day 100ml/Kg, matched group 1-1 to 5-3 group gives the peritoneal dialysis solution lumbar injection in the corresponding group number of comparative examples group to rat, and every day, 100ml/Kg, injected 28 days continuously.29th, within 30 days, injection is stopped, within 31st day, measure animal peritoneal function, every rat 10% chloral hydrate anesthesia pneumoretroperitoneum injects 4.25% glucose peritoneal dialysis solution 25ml, and 4h tailing edge hunter's line cuts off stomach wall, accurately measure intraperitoneal liquid, leave and take 0 and 4h peritoneal dialysis liquid and blood preparation simultaneously.Blood preparation is centrifugal 10 minutes with 5000 revs/min, and peritoneal dialysis liquid specimen is centrifugal 5 minutes with 1500 revs/min, measures concentration of glucose with automatic clinical chemistry analyzer.
Ultrafiltration volume (ultrafiltration, UF)=(last water yield-25);
Glucose transport amount (mass transfer of glucose, MTG)=(dialysis solution initial glucose concentration × injection dialysis liquid measure)-(last dialysis solution output at last concentration of glucose × end of dialysing).
Put to death animal afterwards, HE(hematoxylin-eosin staining method carried out to parietal peritoneum tissue), Masson dyeing, measure peritoneum thickness.Masson staining procedure: paraffin-embedded tissue is cut into 3m section, dewaxes to water, the blue dye liquor dye of celestite 6 ~ 10min, running water, WeigerShi Garapa element liquid dye 5 ~ 10min, running water, Ponceaux acid fuchsin liquid (2:1) contaminates l5 ~ 20min, 1% phosphomolybdic acid aqueous solution and 1% glacial acetic acid break up fast, viride nitens solution-dyed 2 ~ 10min, again break up fast with phosphomolybdic acid aqueous solution and glacial acetic acid, 95% dehydration of alcohol, dry, dimethylbenzene is transparent, neutral gum mounting.Get 12 high power fields and measure peritoneum thickness, average as the standard judging peritoneum thickness.
Result:
Each group of rat 4 weeks posterior peritoneum thickness, glucose transport amount, ultrafiltration volumes compare (n=10, mean ± SD)
| Group number | Peritoneum thickness (μm) | Ultrafiltration volume (ml) | Glucose transport amount (mmol/kg) |
| Blank group | 13.71±1.45 | 7.97±0.89 | 12.98±0.42 |
| Embodiment 1-1 | 20.84±1.53 | 4.59±0.38 | 14.51±0.48 |
| Embodiment 1-2 | 20.02±1.49 | 4.90±0.42 | 14.15±0.49 |
| Embodiment 1-3 | 20.31±1.42 | 4.72±0.43 | 14.32±0.47 |
| Embodiment 2-1 | 21.48±1.38 | 4.31±0.46 | 14.82±0.45 |
| Embodiment 2-2 | 21.16±1.40 | 4.52±0.41 | 14.53±0.41 |
| Embodiment 2-3 | 21.37±1.37 | 4.45±0.39 | 14.63±0.52 |
| Embodiment 3-1 | 23.05±1.52 | 4.08±0.43 | 14.79±0.51 |
| Embodiment 3-2 | 22.22±1.45 | 4.21±0.40 | 14.49±0.42 |
| Embodiment 3-3 | 22.69±1.39 | 4.15±0.44 | 14.68±0.45 |
| Embodiment 4-1 | 23.98±1.53 | 3.92±0.35 | 14.90±0.48 |
| Embodiment 4-2 | 23.01±1.51 | 4.09±0.37 | 14.77±0.45 |
| Embodiment 4-3 | 23.38±1.46 | 4.04±0.38 | 14.84±0.47 |
| Embodiment 5-1 | 25.35±1.48 | 3.70±0.34 | 15.41±0.47 |
| Embodiment 5-2 | 24.86±1.50 | 3.91±0.36 | 15.18±0.46 |
| Embodiment 5-3 | 24.99±1.41 | 3.86±0.37 | 15.21±0.52 |
| Embodiment 6-1 | 26.09±1.62 | 3.55±0.33 | 15.76±0.46 |
| Embodiment 6-2 | 25.27±1.59 | 3.69±0.35 | 15.30±0.42 |
| Embodiment 6-3 | 25.86±1.51 | 3.67±0.35 | 15.51±0.50 |
| Embodiment 7-1 | 22.83±1.43 | 3.82±0.39 | 14.83±0.49 |
| Embodiment 7-2 | 21.92±1.31 | 4.07±0.40 | 14.41±0.51 |
| Embodiment 7-3 | 22.18±1.40 | 3.94±0.38 | 14.62±0.48 |
| Embodiment 8-1 | 28.17±1.38 | 3.32±0.31 | 16.53±0.55 |
| Embodiment 8-2 | 27.22±1.31 | 3.53±0.31 | 15.91±0.54 |
| Embodiment 8-3 | 27.53±1.40 | 3.47±0.33 | 16.03±0.56 |
| Comparative examples 1-1 | 25.48±1.36 | 3.55±0.39 | 15.43±0.59 |
| Comparative examples 1-3 | 24.76±1.43 | 3.81±0.42 | 15.16±0.51 |
| Comparative examples 3-1 | 28.91±1.50 | 3.13±0.38 | 16.68±0.52 |
| Comparative examples 3-3 | 27.68±1.41 | 3.28±0.41 | 16.24±0.48 |
| Comparative examples 5-1 | 31.88±1.59 | 2.75±0.37 | 17.52±0.61 |
| Comparative examples 5-3 | 30.79±1.51 | 2.87±0.32 | 17.10±0.63 |
Proved by above-mentioned experiment, alkaline peritoneal dialysis solution is with acid to compare the impact that peritoneum thickens less, and ultrafiltration volume, glucose transport amount are closer to normal physiological condition simultaneously, and PH is in about 7.4 comparatively 7.7,7.3 better effects if simultaneously.This experimental result can infer that 5 hydroxymethyl furfural index is not the key index causing peritoneum to affect in addition, and other high toxicity glucose degradation products such as pH value, formaldehyde, acetaldehyde have larger power of influence.
Effect example 2 blood PH recovers test
Laboratory animal: SD rat, male, body weight 200 ± 10g
Peritoneal dialysis causes peritoneum injured rats model preparation method: to rats by intraperitoneal injection control formulation embodiment 5-1 group peritoneal dialysis solution, and every day, 100ml/Kg, injected 28 days continuously, within the 29th, 30 day, stopped injection, and within the 31st day, survival rats is considered as modeling success.
Test method: peritoneal dialysis is caused peritoneum impaired modeling success rat random packet, often organize 10, base set directly measures the pH value of one group of rats with left strength arterial blood, blank group accepts normal saline 20ml lumbar injection every day, embodiment 1-1 to 8-3 group is to the peritoneal dialysis solution of the corresponding group number of rats by intraperitoneal injection embodiment group, every day 100ml/Kg, matched group 1-1 to 5-3 group gives the peritoneal dialysis solution lumbar injection in the corresponding group number of comparative examples group to rat, every day 100ml/Kg, continuous injection 14 days, injection is stopped within 1 day, to measure the pH value of each group of rats with left strength arterial blood afterwards.Get the healthy rat before modeling 10 and be only set to healthy group, measure the pH value of rats with left strength arterial blood.
The pH value of rats with left strength arterial blood uses blood gas analyzer analysis.
Experimental result (n=10, mean ± SD)
| Group number | PH |
| Healthy group | 7.40±0.09 |
| Base set | 7.27±0.10 |
| Blank group | 7.28±0.08 |
| Embodiment 1-1 | 7.36±0.06 |
| Embodiment 1-2 | 7.35±0.07 |
| Embodiment 1-3 | 7.34±0.09 |
| Embodiment 2-1 | 7.37±0.07 |
| Embodiment 2-2 | 7.36±0.09 |
| Embodiment 2-3 | 7.35±0.08 |
| Embodiment 3-1 | 7.35±0.10 |
| Embodiment 3-2 | 7.35±0.08 |
| Embodiment 3-3 | 7.33±0.09 |
| Embodiment 4-1 | 7.36±0.07 |
| Embodiment 4-2 | 7.36±0.07 |
| Embodiment 4-3 | 7.35±0.10 |
| Embodiment 5-1 | 7.34±0.08 |
| Embodiment 5-2 | 7.34±0.11 |
| Embodiment 5-3 | 7.31±0.10 |
| Embodiment 6-1 | 7.35±0.08 |
| Embodiment 6-2 | 7.34±0.07 |
| Embodiment 6-3 | 7.32±0.09 |
| Embodiment 7-1 | 7.35±0.09 |
| Embodiment 7-2 | 7.34±0.08 |
| Embodiment 7-3 | 7.33±0.10 |
| Embodiment 8-1 | 7.36±0.08 |
| Embodiment 8-2 | 7.36±0.07 |
| Embodiment 8-3 | 7.35±0.09 |
| Comparative examples 1-1 | 7.20±0.08 |
| Comparative examples 1-3 | 7.23±0.09 |
| Comparative examples 3-1 | 7.19±0.09 |
| Comparative examples 3-3 | 7.23±0.10 |
| Comparative examples 5-1 | 7.18±0.08 |
| Comparative examples 5-3 | 7.21±0.09 |
Claims (10)
1. peritoneal dialysis solution (lactate) compositions, glucose containing 1.5-4.25%, the sodium chloride of 0.4-0.7%, the calcium chloride of 0.02-0.03%, the magnesium chloride of 0.01-0.02%, and the sodium lactate of 0.4-0.6%, it is characterized in that described inorganic base used for peritoneal dialysate regulates pH value to 7.3-7.7.
2. peritoneal dialysis solution as claimed in claim 1, it is characterized in that also containing 0.001% ~ 0.01% sodium pyrosulfite, sodium sulfite or sodium sulfite.
3. peritoneal dialysis solution as claimed in claim 1, the content of its feature sodium chloride is 0.56%, the content of calcium chloride is 0.026%, the content of magnesium chloride is 0.015%, the content of sodium lactate is 0.5%, the content of sodium pyrosulfite is 0.005%, and the content of glucose is 1.5%, 2.5% or 4.25%.
4. peritoneal dialysis solution as claimed in claim 1, is characterized in that inorganic base is sodium salt.
5. peritoneal dialysis solution as claimed in claim 1, is characterized in that inorganic base is one or more in sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium acetate.
6. peritoneal dialysis solution as claimed in claim 1, is characterized in that inorganic base is sodium bicarbonate.
7. the preparation method of peritoneal dialysis solution as claimed in claim 1, it is characterized in that step one is by the glucose of 1.5-4.25%, the sodium chloride of 0.4-0.7%, the calcium chloride of 0.02-0.03%, the magnesium chloride of 0.01-0.02%, and the sodium lactate of 0.4-0.6% and part water mix, sterilizing, step 2 is that inorganic base and part water are formed solution, sterilizing, step 3 is that the pH value that alkali liquor, the water for injection regulating step one obtained by step 2 obtains liquid regulates total amount to 100% at 7.3-7.7.
8. the preparation method of peritoneal dialysis solution as claimed in claim 1, is characterized in that sterilizing methods is high temperature or High Temperature High Pressure.
9. the preparation method of peritoneal dialysis solution as claimed in claim 8, is characterized in that inorganic base and water form content≤0.05% of solution.
10. the application of peritoneal dialysis solution as claimed in claim 1 in preparation reduction peritoneal fibrosis medicine.
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| CN112505175A (en) * | 2020-11-20 | 2021-03-16 | 西安乐析医疗科技有限公司 | Method for determining content of impurities in peritoneal dialysis solution |
| CN115624557A (en) * | 2022-12-22 | 2023-01-20 | 广东省人民医院 | Peritoneal dialysis solution for preventing peritoneal infection and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112505175A (en) * | 2020-11-20 | 2021-03-16 | 西安乐析医疗科技有限公司 | Method for determining content of impurities in peritoneal dialysis solution |
| CN115624557A (en) * | 2022-12-22 | 2023-01-20 | 广东省人民医院 | Peritoneal dialysis solution for preventing peritoneal infection and preparation method and application thereof |
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