CN109589306A - Liposome is preparing the purposes in the pharmaceutical preparation for removing protein binding toxin - Google Patents
Liposome is preparing the purposes in the pharmaceutical preparation for removing protein binding toxin Download PDFInfo
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- CN109589306A CN109589306A CN201710944029.9A CN201710944029A CN109589306A CN 109589306 A CN109589306 A CN 109589306A CN 201710944029 A CN201710944029 A CN 201710944029A CN 109589306 A CN109589306 A CN 109589306A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
- A61M1/1654—Dialysates therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
Abstract
It is 50 ~ 500nm that the present invention, which provides a kind of liposome preparing the purposes in the pharmaceutical preparation for removing protein binding toxin, the diameter of the liposome,.By removing protein binding toxin using liposome, cost can be substantially reduced, and work well.
Description
Technical field
The present invention relates to liposomes to prepare the purposes in the pharmaceutical preparation for removing protein binding toxin, especially needle
To in the blood dialysis of renal hypofunction patient.
Background technique
Uremia refers to constantly to be stored in blood and tissue when the decline with renal function, kidney decline the clearance rate of solute
It accumulates and has virose substance.European working group, uremic toxins is classified as three greatly according to its Biochemical Characteristics and reset mode
Class: 1) water-soluble, not with protein bound small-molecule substance, molecular mass is usually less than 500, such as urea, creatinine, such object
Matter is easy to be removed by haemodialysis；2) medium molecular substance, molecular weight are typically larger than 500, and such as parathormone, substance of this kind is conventional
Haemodialysis elimination effect is undesirable, can only be removed by the blood purification mode of large aperture dialysis membrane；3) protein binding poison
Element, such as indoxyl sulfate, sulfuric acid paracresol, most of blood purification modes are poor to the elimination effect of substance of this kind.It grinds at present
Study carefully and shows that protein binding toxin and the first cause cardiovascular event of CKD (chronic kidney disease) death are closely related.
The main reset mode of protein binding toxin is added in dialyzate in the blood dialysis of the prior art
Albumin, but the preferable still higher cost of such reset mode effect.
Liposome (liposome) is a kind of artificial membrane.In water in phospholipid molecule hydrophilic head insertion water, liposome is dredged
Air is stretched in water tail portion, and the spherical liposomes of the double-deck rouge molecule are formed after agitation, and 25~1000nm of diameter is differed.Liposome is available
In transgenosis, or the drug of preparation, using liposome can and the characteristics of cell membrane fusion, drug is sent into cell interior.
Not yet occur at present about using liposome be used to remove the report of uremic patient vivo protein combination toxin with
Document.
Summary of the invention
In view of the foregoing deficiencies of prior art, the purpose of the present invention is to provide a kind of liposomes is used for clearly in preparation
Purposes in the pharmaceutical preparation of removing protein combination toxin adds albumin cost mistake for solving in dialyzate in the prior art
Height, ineffective problem.
Discovery based on experiment, it is found by the applicant that liposome can binding protein combination toxin, and work well.
In order to achieve the above objects and other related objects, the present invention provides a kind of liposome in preparation for removing albumen knot
The purposes in the pharmaceutical preparation of toxin is closed, the diameter of the liposome is 50~500nm.
The protein binding toxin can be multiple protein combination toxin, such as the severe acute kidney of multiple organ failure
Damage the protein binding toxin generated.
Further, the protein binding toxin refers to the intracorporal protein binding toxin of uremic patient.
The liposome can be prepared according to method in the prior art.The liposome can be single layer or multilayer
, it can be different size, institute is electrically charged also unrestricted, can be different the vesica of feature for water-bearing media packet
It wraps up in.
Preferably, the main component of lipid tunic is selected from natural phospholipid or synthetic phospholipid in the liposome.
Preferably, the phosphatide is soybean lecithin, any one or two kinds in hydrogenated soy phosphatidyl choline.
Further, the phosphatide be distearoylphosphatidylglycerol (DSPG), it is dioleyl lecithin (DOPC), two hard
Any one or a few in acyl phosphatidyl choline (DSPC).
The pharmaceutical preparation can be directly added into blood dialysis solution in the prior art for the removing in haemodialysis
Protein binding toxin.
Preferably, the diameter of the liposome is 100~200nm.
Preferably, the diameter of the liposome is 200~300nm.
Further, the pharmaceutical preparation refers to the preparation used in following arbitrary process: Intermittent hemodialysis, abdomen
Film dialysis, continuous renal replacement therapy.
The Intermittent hemodialysis is the prior art, in particular to acute or chronic renal failure kidneys of patients replacement therapy
One of mode.It by by internal blood drainage to external, through one by the dialyzer that is formed without several hollow fibres, blood
Electrolyte solution (dialyzate) similar with concentration containing body carries out object inside and outside hollow fibre one by one, through disperse/convection current
Mass transter removes intracorporal metabolic waste, maintains electrolyte and acid-base balance；Remove excessive moisture in vivo simultaneously, and will be through
Cross the whole process of the blood recovery of purification.
Peritoneal dialysis is a kind of dialysis using the peritonaeum of human body itself as dialysis membrane.By pouring into the saturating of abdominal cavity
Analysis liquid in the capillary of the peritonaeum other side plasma composition progress solute and moisture exchange, remove the metabolism of internal retention
Product and excessive moisture, while substance necessary to body is supplemented by dialyzate.By constantly updating peritoneal dialysis liquid, reach
The purpose of kidney substitution or supportive treatment.
Continuous renal replacement therapy is also known as continuous blood purification (CBP), is a kind of new blood purification side carried out
Method.Nineteen ninety-five first international continuous renal replacementtherapy meeting regulation, using continuous 24 hours daily or close to 24 hours
A kind of continuous blood purification therapy, substitute the purification style of impaired renal function, as continuous renal replacementtherapy.
Continuous renal replacementtherapy includes continuity arteriovenous, quiet venous hemofiltration (CAVH, CVVH), continuity arteriovenous, quiet
Venous blood is dialysed (CAVDH, CVVDH), continuity arteriovenous, the silently moulds such as arteries and veins hemodiafiltration (CAVHDF, CVVHDF)
Formula.
Further, protein binding toxin sole active ingredient is removed in the pharmaceutical preparation or principle active component is
Liposome.
Further, the concentration that the liposome is added when use is 30~50g/l.
Guarantee to be 30 using the concentration of liposome in system when specifically referring to for pharmaceutical preparation being added to using in system~
50g/l.It is described to generally refer to dialyzate using system.
It finds that the above dosage is optimal dose by experiment, further increases lipid ball concentration and remove the efficiency of toxin not
It can be further up.
Preferably, the amount that the liposome is added is that 40g is added in every liter of dialyzate.
Another aspect of the present invention provides a kind of dialyzate, includes liposome in the dialyzate.
Preferably, the concentration of liposome is 30~50g/l in the dialyzate.
Preferably, the diameter of the liposome is 100~200nm.
Preferably, the dialyzate is Intermittent hemodialysis dialyzate, peritoneal dialysis solution or Continuous renal replacement therapy
Treat any one in dialyzate.
Another aspect of the present invention discloses above-mentioned dialyzate for removing protein binding toxin purposes.
Another aspect of the present invention provides a kind of for removing the pharmaceutical preparation of protein binding toxin, the drug
Effective ingredient in preparation is liposome, and the diameter of the liposome is 50~500nm.
Further, the diameter of the liposome is 100~200nm.
Preferably, the main component of lipid tunic is selected from natural phospholipid or synthetic phospholipid in the liposome.
Preferably, the phosphatide is soybean lecithin, any one or two kinds in hydrogenated soy phosphatidyl choline.
Further, the phosphatide be distearoylphosphatidylglycerol (DSPG), it is dioleyl lecithin (DOPC), two hard
Any one or a few in acyl phosphatidyl choline (DSPC).
Another aspect of the present invention provides a kind of method for removing patient's body protein binding toxin, the method
Including providing liposome to the blood of patient, protein binding toxin is removed using liposome.
Further, the main component of lipid tunic is selected from natural phospholipid or synthetic phospholipid in the liposome.
Preferably, the phosphatide is soybean lecithin, any one or two kinds in hydrogenated soy phosphatidyl choline.
Further, the phosphatide be distearoylphosphatidylglycerol (DSPG), it is dioleyl lecithin (DOPC), two hard
Any one or a few in acyl phosphatidyl choline (DSPC).
Further, the method refers in Intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy process
It is middle that liposome is added into dialyzate.
Further, the protein binding toxin refers to the intracorporal protein binding toxin of uremic patient.
Preferably, the amount that liposome is added in the dialyzate when use is 30~50g/l.
Preferably, the diameter of the liposome is 50~500nm, more preferably 100~200nm.
As described above, liposome of the invention is preparing the purposes in the pharmaceutical preparation for removing uremic toxins, tool
Have it is following the utility model has the advantages that
Since the cost of liposome greatly reduces cost when dialysis well below albumin, and effect is preferable,
Medical expense is greatly reduced for many patients.Such as once dialyse what needs were spent in the current method using albumin dialysis
Price is about 10,000 yuan, and according to liposome, expense will be reduced to 1,000 yuan hereinafter, highly beneficial in level of human health
Raising.
Detailed description of the invention
Fig. 1 is shown as liposome to the adsorption rate of sulfuric acid paracresol PCS.
Fig. 2 shows liposome to the adsorption rate of indoxyl sulfate IS.
Fig. 3 shows liposome to the adsorption rate of hippuric acid HA.
The dose-effect curve of Fig. 4 liposome absorption sulfuric acid paracresol p-cresyl sulfate.
The dose-effect curve of Fig. 5 liposome absorption indoxyl sulfate indoxyl sulfate.
The dose-effect curve of Fig. 6 liposome absorption hippuric acid hippuric acid.
Removing percentage of Fig. 7 PCS in the dialysis of disposable Fast-Balance.
Removing percentage of Fig. 8 IS in the dialysis of disposable Fast-Balance.
Removing percentage of Fig. 9 IS in the dialysis of disposable Fast-Balance.
The external closed circulation ideograph of Figure 10.
Elimination effect (A blood side) of the tri- kinds of modes of Figure 11 a to paracresol p-cresol.
Elimination effect (B dialysis fluid side) of the tri- kinds of modes of Figure 11 b to paracresol p-cresol.
Elimination effect (A blood side) of the tri- kinds of modes of Figure 12 a to indoxyl sulfate indoxyl sulfate.
Elimination effect (B dialysis fluid side) of the tri- kinds of modes of Figure 12 b to indoxyl sulfate indoxyl sulfate.
Elimination effect (A blood side) of the tri- kinds of modes of Figure 13 a to hippuric acid hippuric acid.
Elimination effect (B dialysis fluid side) of the tri- kinds of modes of Figure 13 b to hippuric acid hippuric acid.
Elimination effect (A blood side) of the tri- kinds of modes of Figure 14 a to heteroauxin indole-3-acetic acid.
Elimination effect (B dialysis fluid side) of the tri- kinds of modes of Figure 14 b to heteroauxin indole-3-acetic acid.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.It should be clear that the process equipment or device that are not indicated specifically in the following example
It is all made of conventional equipment or device in the art.In addition, it should also be understood that, one or more method and step mentioned in the present invention is simultaneously
Do not repel and may be used also before and after the combination step there may also be other methods step or between these explicitly mentioned steps
To be inserted into other methods step, unless otherwise indicated；It should also be understood that one or more equipment/device mentioned in the present invention it
Between combination connection relationship do not repel before and after the unit equipment/device there may also be other equipment/device or at this
It can also be inserted into other equipment/device between the two equipment/devices specifically mentioned a bit, unless otherwise indicated.Moreover, unless another
It is described, the number of various method steps is only the convenient tool of identification various method steps, rather than is the row of limitation various method steps
Column order limits the scope of the invention, and relativeness is altered or modified, without essence change technology contents
In the case of, when being also considered as the enforceable scope of the present invention.
1 liposome preparation of embodiment
0.6g Tween-80,0.6g cholesterol, 0.6g deoxysodium cholate and 2.4g soybean lecithin are weighed respectively, are added
100mL methylene chloride is allowed to be completely dissolved.Mixed liquor is added in clean anhydrous flask, is rotated under 30 degree of reduced pressures
Film (night keeps organic solvent volatilization thorough).
The glucose for weighing gross mass 10% is added in film forming flask, in 37 degree of water-baths after being dissolved with 100mL ultrapure water
Rotation makes film aquation.
After taking out mixed liquor after the complete aquation of film, by liquid be added graceful homogeneous instrument (setting pressure 400bar,
30min) homogeneous 30min.
It is freeze-dried and collects after taking-up.After measured, the diameter of liposome is 100~200nm.
The verifying of 2 liposome adhesion protein combination uremic toxins concept of embodiment
I. 3 kinds of initial option representative protein binding uremic toxins:
1. sulfuric acid paracresol (p-cresyl sulfate, PCS, molecular weight 188Da, albumin Percentage bound~95%)
2. indoxyl sulfate (indoxyl sulfate, IS, molecular weight 212Da, albumin Percentage bound~90-95%)；
3. hippuric acid (hippuric acid, HA, molecular weight 179Da, albumin Percentage bound~50%)
II. the Preliminary Determination of liposome adhesion protein combination uremic toxins:
1. method
(1) reagent
Bovine serum albumin(BSA) BSA (sigma, purity >=98%)
Phosphate buffer 1 × PBS (Beijing Solarbio Science&Technology Co.)
Sulfuric acid paracresol PCS (APExBIO)
Indoxyl potassium sulfate IS (sigma)
Hippuric acid HA (sigma)
(2) super filter tube
Ultra 0.5mL super filter tube (Millipore, molecule interception 3KD)
(3) operating procedure
A. distinguish accurate weighing PCS 10mg, IS 11.4mg, HA18.9mg, be dissolved in phosphate buffer (1xPBS,
PH7.2-7.4), it is settled to 265ml, is placed on shaking table, room temperature is protected from light, and is shaken up overnight, spare.
B. above-mentioned solution 16ml is taken, is packed as 8 parts, every part of 2ml, is separately added into BSA and liposome, preparing ultimate density is
BSA 40g/L, liposome are respectively 10g/L, 20g/L, 40g/L, 80g/L, 120g/L, 160g/L.
C. after 30min, after 60min, after 120min and above-mentioned uremic toxins containing protein binding are taken after 240min
BSA solution or various concentration liposome solutions 0.4ml, be added 0.5ml super filter tube in, 12000 revs/min, 4 DEG C, centrifugation 30
Minute, take ultrafiltrate.
D. the BSA Percentage bound or liposome adsorption rate of above-mentioned toxin are calculated
BSA Percentage bound or liposome adsorption rate=100x (total concentration-ultrafiltrate concentration)/total concentration
E. it repeats the above steps 3 times.
2. detection method
Albumen is measured using high-efficient liquid phase chromatogram HPLC (high-performance liquid chromatography)
In conjunction with the concentration of toxin.
3. statistical method
It is handled with 21.0 statistical software of SPSS, data are indicated with mean+SD.Comparison between two groups is adopted
With independent samples t test, more comparison among groups use one-way analysis of variance.P < 0.05 is that difference is statistically significant.
4. result
As shown in Figure 1, when BSA concentration is 40g/L, when 30min the BSA protein binding rate of PCS be 93.80% ±
0.92%, after BSA combination PCS, with the extension of time, substantially without dissociation.When 30min, the liposome of 10g/L inhales PCS
Attached rate is 79.1% ± 2.82%, and when 60min, 120min, 240min respectively compared with 30min, absorption of the liposome to PCS
Rate has no significant change (p > 0.05).When 30min, with the increase of concentration of liposomes, the adsorption rate of PCS is also gradually increased.
As shown in Fig. 2, when BSA concentration is 40g/L, when 30min the BSA protein binding rate of IS be 94.07% ±
2.09%, after BSA combination IS, with the extension of time, substantially without dissociation.When 30min, the liposome of 10g/L adsorbs IS
Adsorption rate highest when rate is 51.11% ± 1.40%, 120min, up to 63.81% ± 3.73%, 60min, when 240min, inhales
Attached rate adsorption rate no difference of science of statistics (p > 0.05) compared with 30min.When 30min, with the increase of concentration of liposomes, to IS
Adsorption rate also gradually increase.
As shown in figure 3, when BSA concentration is 40g/L, when 30min the BSA protein binding rate of HA be 58.46% ±
4.18%, after BSA combination HA, with the extension of time, substantially without dissociation.When 30min, the liposome of 10g/L adsorbs HA
Rate is 57.30% ± 1.40%, and when 60min, 120min, 240min respectively compared with 30min, adsorption rate of the liposome to HA
Have no significant change (p > 0.05).When 30min, with the increase of concentration of liposomes, the adsorption rate of HA is had no and obviously increases (p
> 0.05).
The concentration dependent of 3 liposome adhesion protein combination uremic toxins of embodiment
1. method
(1) reagent
Bovine serum albumin(BSA) BSA (sigma, purity >=98%)
Phosphate buffer 1 × PBS (Beijing Solarbio Science&Technology Co.)
Sulfuric acid paracresol PCS (APExBIO)
Indoxyl potassium sulfate IS (sigma)
Hippuric acid HA (sigma)
(2) super filter tube
Ultra 0.5mL super filter tube (Millipore, molecule interception 3KD)
(3) operating procedure
A. above-mentioned solution 10ml is taken in the same way, is packed as 10 parts, and every part of 1ml is separately added into liposome, preparation
Liposome ultimate density is respectively 5g/L, 10g/L, 20g/L, 30g/L, 40g/L, 60g/L, 80g/L, 100g/L, 120g/L, and
160g/L。
B. the liposome solutions 0.5ml that the various concentration of the above-mentioned uremic toxins containing protein binding is taken after 120min, adds
Enter in 0.5ml super filter tube, 12000 revs/min, 4 DEG C, is centrifuged 30 minutes, takes ultrafiltrate.
D. the liposome adsorption rate of above-mentioned toxin is calculated
Liposome adsorption rate=100x (total concentration-ultrafiltrate concentration)/total concentration
E. it repeats the above steps 3 times.
2. detection method: ibid.
3. statistical method
It is handled with 21.0 statistical software of SPSS, data are indicated with mean+SD.Comparison between two groups is adopted
With independent samples t test, more comparison among groups use one-way analysis of variance.P < 0.05 is that difference is statistically significant.
4. result
As shown in figure 4, when concentration of liposomes is 5g/L, when 120min to the adsorption rate of PCS be 70.38% ±
3.73%, and as adsorption rate of the increase of concentration of liposomes to PCS gradually increases, it is right when concentration of liposomes is 60g/L
The adsorption rate of PCS is 90.70% ± 0.45%, and when concentration of liposomes increases to 160g/L, the adsorption rate to PCS is
98.58% ± 0.14%.
As shown in figure 5, be 39.60% ± 1.20% to the adsorption rate of IS when 120min when concentration of liposomes is 5g/L,
And as adsorption rate of the increase of concentration of liposomes to IS gradually increases, when concentration of liposomes is 60g/L, to the adsorption rate of IS
It is 83.63% ± 1.59%, later as adsorption rate of the increase of concentration of liposomes to IS gradually tends towards stability, when liposome is dense
When degree increases to 160g/L, the adsorption rate to IS is 91.12% ± 1.76%.
As shown in fig. 6, be 59.06% ± 2.74% to the adsorption rate of IS when 120min when concentration of liposomes is 5g/L,
As the increase of concentration of liposomes has no evident regularity to the adsorption rate of HA, when concentration of liposomes increases to 160g/L, to HA
Adsorption rate be 54.78% ± 4.61%.
The external static dialysis of embodiment 4
1. method
(1) reagent
Bovine serum albumin(BSA) BSA (sigma, purity >=98%)
Phosphate buffer 1 × PBS (Beijing Solarbio Science&Technology Co.)
Sulfuric acid paracresol PCS (APExBIO)
Indoxyl potassium sulfate IS (sigma)
Hippuric acid HA (sigma)
(2) capital equipment
Single-Use RED(rapid equilibrium dialysis)Plate(Thermo ScientificTM, point
Sub- interception 8000Da)
(3) operating procedure
A. accurate weighing 0.8g BSA contains PCS with above-mentioned, and the solution of IS and HA protein binding uremic toxins is settled to
The ultimate density of 20ml, BSA are 40g/L, in ambient temperature overnight on shaking table.
B. as shown in table 1, following solution successively are added in Sample Chambers and Buffer Chambers, each
Hole is loaded twice:
C. after adding sample, the RED board is covered with sealing strip, RED board is placed on shaking table, in 37 DEG C, 250 revs/min, incubated
It educates 4 hours.
D. sealing strip is removed, the sample in Sample Chambers is transferred in 1.5ml EP pipe, is calculated after being incubated for 4h
Each toxin concentration in sample.
Removing percentage (Percent removal, %)=(C pre-incubation-C post incubation)/
C pre-incubation in Sample Chambers
E. it repeats the above steps 3 times.
2. detection method: ibid.
3. statistical method
It is handled with 21.0 statistical software of SPSS, data are indicated with mean+SD.Comparison between two groups is adopted
With independent samples t test, more comparison among groups use one-way analysis of variance.P < 0.05 is that difference is statistically significant.
4. result
It is (1) the reference of dialysis equilibrium time with sample, after 37 DEG C are incubated for 4 hours, in Sample Chamber, PCS concentration
Removing percentage is that 46.53% ± 2.24%, IS concentration removing percentage is that 53.30% ± 1.10%, HA concentration removes percentage
Than being 49.09% ± 5.14%, show that incubation in 4 hours can achieve the equilibrium dialysis time.
As shown in fig. 7, PBS group Sample Chamber be incubated for 4 hours after, PCS remove percentage be 2.34% ±
After 1.93%, 5g/L liposome group Sample Chamber are incubated for 4 hours, it is 6.42% ± 1.64% that PCS, which removes percentage, compared with
PBS group increased (p < 0.05), as concentration of liposomes increases, in Sample Chambers the removing percentage of PCS by
Cumulative to add, it is 27.74% ± 1.57% that 40g/L liposome, which removes PCS percentage, removes PCS percent effect with 40g/L BSA
Similar (27.74% ± 1.57%vs.29.14% ± 5.01%).
As shown in figure 8, PBS group Sample Chamber be incubated for 4 hours after, IS remove percentage be 4.42% ±
After 1.39%, 5g/L liposome group Sample Chamber are incubated for 4 hours, it is 7.41% ± 1.48% that PCS, which removes percentage, compared with
PBS group increased (p=0.03), and as concentration of liposomes increases, in Sample Chambers, the removing percentage of IS is gradually
Increase, it is 29.72% ± 4.66% that 60g/L liposome, which removes PCS percentage, removes PCS percent effect ratio with 40g/L BSA
Compared with no difference of science of statistics (29.72% ± 4.66%vs.34.00% ± 2.55%).
As shown in figure 9, PBS group Sample Chamber be incubated for 4 hours after, HA remove percentage be 22.99% ±
After 2.97%, 5g/L liposome group Sample Chamber are incubated for 4 hours, it is 28.47% ± 4.31% that PCS, which removes percentage,
No difference of science of statistics (p=0.08) compared with PBS group, as concentration of liposomes increases, the removing of HA in Sample Chambers
Percentage gradually increases, but increases trend and be not so good as PCS and IS.60g/L liposome remove PCS percentage be 41.79% ±
4.69%, no difference of science of statistics (41.79% ± 4.69%vs.47.99% compared with removing HA percent effect with 40g/L BSA
± 7.84%).
The external closed circulation of embodiment 5
1. method
(1) reagent
Bovine serum albumin(BSA) BSA (sigma, purity >=98%)
Phosphate buffer 1 × PBS (Beijing Solarbio Science&Technology Co.)
Sulfuric acid paracresol PCS (APExBIO)
Paracresol (p-cresol, sigma)
Indoxyl potassium sulfate IS (sigma)
Heteroauxin (indole-3-acetic acid, 3-IAA, molecular weight 175Da, albumin Percentage bound~75%)
Hippuric acid HA (sigma)
(2) key instrument and equipment
Ultra 0.5mL super filter tube (Millipore, molecule interception 3KD)；
Small peristaltic pump (VWR company, the U.S.)
Microstrainer (Weigao Group Co., Ltd.)
Extracorporeal circulation pipeline (VWR company, the U.S.)
(3) operating procedure
I. sulfuric acid paracresol p-cresyl sulfate and paracresol p-cresol are compared with BSA Percentage bound
Method is the same, utilizesUltra 0.5mL super filter tube measures sulfuric acid paracresol p-cresyl sulfate
Protein binding rate be about 93%-95%, the protein binding rate of paracresol p-cresol is 93%-95%, the albumen knot of the two
Conjunction rate is similar, therefore external closed circulation represents one of protein binding toxin using paracresol p-cresol.
II. external closed circulation
A. blood side (side B) solution is prepared:
Accurate weighing bovine serum albumin(BSA) BSA 20g, paracresol 10.8mg, indoxyl potassium sulfate 17.0mg, hippuric acid
35.8mg is dissolved in phosphate buffer PBS, and accurate weighing heteroauxin 13.2mg is dissolved in 500ml PBS, 50ml is taken to add
Enter above-mentioned containing BSA, paracresol, in the PBS solution of indoxyl sulfate and hippuric acid, is finally settled to 500ml, room temperature, on shaking table
It shakes up overnight spare.The blood side capacity recycled every time is 50ml.
B. dialyzate (side D) component
The dialyzate capacity recycled every time is 100ml, is divided into three groups by its ingredient difference, every group circulation 3 times, respectively
1. PBS is as a control group, 2. 40g/L BSA is dissolved in PBS, and as BSA group, 3. 40g/L liposome is dissolved in PBS as lipid
Body group.
C. dialysis parameters are arranged
As shown in Figure 10, blood side (side B) blood flow Qb=5.0ml/min, dialysis fluid side (side D) dialysate flow Qd=
5ml/min, circulation carries out 360min every time.Two sides are first rushed with physiological saline in advance after extracorporeal circulation apparatus connects.Two sides
Beaker is placed on magnetic stirring apparatus to guarantee that solution is uniformly mixed always in dialysis procedure.
D. collection of specimens and detection
0min, 10min, 30min, 60min, 90min, 120min, 150min, 180min, the 210min recycled in vitro,
240min, 270min, 300min, 330min and 360min extract 150ul sample in two sides respectively, be placed in -80 DEG C it is to be measured.Containing rouge
The sample treatment of plastid: drawing sample solution 100ul, and acetonitrile 300ul, which is added, makes liposomal pellets, in 4 DEG C, with 12000
Rev/min, it is centrifuged 30min, takes supernatant 100ul inspection.
2. detection method: ibid.
3. statistical method
It is handled with 21.0 statistical software of SPSS, data are indicated with mean+SD.Comparison between two groups is adopted
With independent samples t test, more comparison among groups use one-way analysis of variance.P < 0.05 is that difference is statistically significant.
4. result
1) in external closed circulation p-cresol elimination effect
As shown in figures 11a and 11b, in the blood side BSA solution of preparation, the initial concentration of paracresol p-cresol is about
200umol/L, because the protein binding rate of paracresol p-cresol is up to 93%-95%, free level is very low when dialysis starts, and is
12.80 ± 1.44umol/L, in dialysis cyclic process in 6 hours, control group (PBS) blood side reduces speed and dialysis fluid side
It increases speed always relatively slowly, control group blood side p-cresol rate of descent be 8.01% ± 1.73% originated when 6h, thoroughly
P-cresol concentration is 7.01 ± 0.80umol/L at the end of analysing the dialysis of liquid side.BSA group and liposome group blood side p-
Fall off rate is most fast during 1h before dialysis by cresol, and rate of descent is respectively 50.08% ± 5.04% He originated when 1h
Fall off rate then slows down during 49.44% ± 24.4%, the 2h that dialyses, BSA group and liposome group blood side p- when 2h
Cresol rate of descent is respectively 56.34% ± 2.47% and 62.18 ± 16.08% originated.BSA group and liposome group after 2h
Blood side p-cresol fall off rate then obviously slows down, and 4h rate of descent is respectively 64.89% ± 3.50% and 70.18% ±
10.7%.BSA group and the concentration of liposome group blood side p-cresol tend towards stability substantially after the 4h that dialyses.Equally, BSA group
It advances the speed during circulation originates 1h with liposome group dialysis fluid side p-cresol concentration most fast, two groups of dialysis when lh
Liquid side p-cresol concentration is respectively 40.26 ± 4.78umol/L and 43.16 ± 10.69umol/L, is recycled two during 2h
Group dialysis fluid side p-cresol concentration increase then obviously slows down, and two groups of dialysis fluid side p-cresol concentration are respectively 49.07 when 2h
Two groups of dialysis fluid side p-cresol concentration still have slow rising, 4h after ± 6.31umol/L and 49.83 ± 13.20umol/L, 2h
When two groups of dialysis fluid side p-cresol concentration be respectively 60.06 ± 7.66umol/L and 64.81 ± 10.86umol/L, Zhi Houtou
The concentration of the analysis two groups of p-cresol in liquid side tends towards stability substantially.
2) in external closed circulation indoxyl sulfate elimination effect
As shown in figures 12 a and 12b, the change of three groups of blood sides and dialysis fluid side indoxyl sulfate in dialysis procedure
Change similar with p-cresol.In the blood side BSA solution of preparation, the initial concentration of indoxyl sulfate indoxyl sulfate is about
For 150umol/L, protein binding rate is 95.48% ± 1.79%, when dialysis starts blood side its it is free it is horizontal for 7.83 ±
2.31umol/L, in dialysis cyclic process in 6 hours, the reduction speed of control group (PBS) blood side indoxyl sulfate
Increase speed always relatively slowly with dialysis fluid side, when 6h control group blood side p-cresol rate of descent be originate 8.75% ±
1.80%, p-cresol concentration is 8.55 ± 1.64umol/L at the end of dialysis fluid side is dialysed.BSA group and liposome group blood
Fall off rate is most fast during 1h before dialysis by side indoxyl sulfate, when 1h rate of descent be respectively originate 48.69% ±
Fall off rate then slows down during 0.74% and 47.76% ± 17.19%, the 2h that dialyses, BSA group and liposome group blood when 2h
Liquid side indoxyl sulfate rate of descent is respectively 56.74% ± 2.26% and 55.82 ± 9.44% originated.BSA group after 2h
Then obviously slow down with liposome group blood side indoxyl sulfate fall off rate, 4h rate of descent is respectively when originating
62.55% ± 1.70% and 59.32% ± 7.75%.BSA group and liposome group blood side indoxyl after the 4h that dialyses
The concentration of sulfate also tends towards stability substantially.Equally, BSA group and liposome group dialysis fluid side indoxyl sulfate concentration
It advances the speed during circulation originates 1h most fast, two groups of dialysis fluid side indoxyl sulfate concentration are respectively when lh
36.69 ± 5.80umol/L and 31.81 ± 12.58umol/L recycles two groups of dialysis fluid side p-cresol concentration during 2h
Increase then obviously slows down, when 2h two groups of dialysis fluid side indoxyl sulfate concentration be respectively 41.14 ± 8.14umol/L and
Two groups of dialysis fluid side indoxyl sulfate concentration still have a slow rising after 35.79 ± 11.30umol/L, 2h, when 4h two groups it is saturating
Analysing liquid side indoxyl sulfate concentration is respectively 49.98 ± 6.71umol/L and 43.08 ± 4.75umol/L, is dialysed later
The concentration of two groups of indoxyl sulfate of liquid tends towards stability substantially.
3) in external closed circulation hippuric acid elimination effect
As shown in figures 13a andb, three groups of blood side and dialysis fluid side hippuric acid hippuric acid in dialysis procedure
Variation and p-cresol and indoxyl sulfate it is then different.In the blood side BSA solution of preparation, hippuric acid
The initial concentration of hippuric acid is about 400umol/L, and protein binding rate is 60.89% ± 3.82%, when dialysis starts
Its free level of blood side is 156.42 ± 15.29umol/L, in dialysis cyclic process in 6 hours, control group (PBS) blood
The reduction speed of side hippuric acid and increasing speed compared with p-cresol and indoxyl sulfate for dialysis fluid side,
It reduces or increasing degree obviously increases.PBS group, BSA group and liposome group blood side hippuric acid concentration are being dialysed
Fall off rate is most fast during the 1h started, and hippuric acid concentration rate of descent is to originate when PBS group blood side 1h
When 22.84% ± 6.70%, BSA group 1h blood side hippuric acid concentration rate of descent be starting 43.07% ±
12.27%, rate of descent obviously increases (43.07% ± 12.27%vs.22.84% ± 6.70%, p < compared with PBS group
0.05), hippuric acid concentration rate of descent in blood side is the 33.01% ± 11.69% of starting when liposome group 1h, effect
Rate is between other two groups.Three groups are slowed down compared with 1h in 2h blood side rate of descent, when PBS group blood side 2h
Blood side hippuric acid is dense when hippuric acid concentration rate of descent is 32.08% ± 3.04%, the BSA group 2h of starting
Degree rate of descent is the 62.74% ± 10.58% of starting, and rate of descent also obviously increases (62.74% ± 10.58% compared with PBS group
Vs.32.08% ± 3.04%, p < 0.05), blood side hippuric acid concentration rate of descent is starting when liposome group 2h
49.94% ± 9.45%, efficiency between other two groups, compared with PBS group rate of descent also obviously increase (49.94% ±
9.45%vs.32.08% ± 3.04%, p < 0.05), compared with BSA group, no difference of science of statistics (49.94% ± 9.45%
Vs.62.74% ± 10.58%, p > 0.05).Three groups of blood side hippuric acid concentration declines then obviously slow down after 2h, 4h
When, PBS group blood side hippuric acid concentration rate of descent is 50.95% ± 5.51%, the BSA group blood side of starting
Hippuric acid concentration rate of descent is the 77.18% ± 4.43% of starting, compared with PBS group, still there is statistical difference
(77.18% ± 4.43%vs.50.95% ± 5.51%, p < 0.05).Liposome group blood side hippuric acid concentration
Rate of descent is the 56.23% ± 5.19% of starting, is better than PBS group (56.23% ± 5.19%vs.50.95% ± 5.51%, p <
0.05), it is inferior to BSA group (56.23% ± 5.19%vs.77.18% ± 4.43%, p < 0.05).Three groups of blood sides after dialysis 4h
The concentration of hippuric acid tends towards stability substantially.The 1h that three groups of dialysis fluid side hippuric acid concentration start in dialysis
It advances the speed in the process most fast, PBS group dialysis fluid side concentration when dialysis originates 1h is 69.16 ± 20.97umol/L, BSA
Concentration is 69.16 ± 20.97umol/L, the statistically significant (69.16 ± 20.97vs.69.16 of increase compared with PBS group when group 1h
± 20.97umol/L, p=0.02), when liposome group 1h dialysis fluid side hippuric acid concentration be 61.88 ±
21.39umol/L, between PBS group and BSA group.Tri- groups of dialysis fluid side hippuric acid concentration of 2h of dialysing increase speed
Rate then slows down, and hippuric acid concentration is 104.61 ± 30.65umol/L when BSA group 2h, be higher than PBS group (104.61 ±
30.65vs.64.50 ± 7.59umol/L, p < 0.01), when liposome group 2h hippuric acid concentration be 87.68 ±
25.45umol/L is better than PBS group (p=0.014), compared with BSA group, no difference of science of statistics (p > 0.05).After 2h three groups it is saturating
Analyse the increase of liquid side hippuric acid concentration then more slowly, when 4h, PBS group dialysis fluid side hippuric acid concentration is
99.56 ± 13.71umol/L, BSA group are that 139.24 ± 18.95umol/L still has statistical difference (p < compared with PBS group
0.05).Liposome group is 111.71 ± 21.16umol/L, is fallen between.Three groups of dialysis fluid sides after dialysis 4h
The concentration of hippuric acid tends towards stability substantially.
4) in external closed circulation indole-3-acetic acid elimination effect
As shown in figure 14 a and 14b, the variation of three groups of blood sides and dialysis fluid side heteroauxin 3-IAA in dialysis procedure
It is also different from p-cresol and indoxyl sulfate.In the blood side BSA solution of preparation, the initial concentration of 3-IAA is about
15umol/L, protein binding rate are 75% ± 2.38%, when dialysis starts blood side its it is free horizontal for 3.75 ±
1.29umol/L.Fall off rate is most fast during the 1h that dialysis starts for three groups of blood side 3-IAA concentration, PBS group blood
Blood side 3-IAA concentration when 3-IAA concentration rate of descent is 30.19% ± 13.94%, the BSA group 30min of starting when the 30min of side
Blood side 3-IAA concentration rate of descent is starting when rate of descent is 53.27% ± 27.71%, the liposome group 30min of starting
40.46% ± 24.46%, the no significant difference (p > 0.05) between three groups.Three groups of blood side 3-IAA concentration when 1h
Rate of descent be respectively originate 34.91% ± 12.07%, 55.45% ± 21.09%, 47.28% ± 28.07%, three groups it
Between difference it is still not statistically significant (p > 0.05).Tri- groups of the 2h rates of descent in blood side are recycled to slow down compared with 1h process,
The rate of descent of PBS group blood side 3-IAA concentration is respectively that 42.96% ± 9.20%, the BSA group originated is better than PBS group when 2h, poor
It is different that there is statistical significance (60.75% ± 9.10%vs.42.96% ± 9.20%, p=0.038), liposome group 2h blood
The rate of descent of side 3-IAA concentration be 64.24 ± 17.59%, be higher than PBS group (64.24 ± 17.59%vs.42.96% ±
9.20%, p=0.03).Recycle after 2h the decline of three groups of blood side 3-IAA concentration then more slowly, PBS group blood side 3- when 4h
The rate of descent of IAA concentration is respectively that 51.15% ± 7.95%, the BSA group originated is higher than PBS group (68.82 ± 3.31%
Vs.51.15% ± 7.95%, p=0.012) liposome group also above PBS group (75.19 ± 10.24%, p=0.01), and
BSA group and liposome group no significant difference (p > 0.05).The concentration for recycling three groups of blood side 3-IAA after 4h becomes
In steady.Similarly, three groups of dialysis fluid side 3-IAA concentration increasing degree during circulation originates 1h is most fast, three groups when 1h
Dialysis fluid side 3-IAA concentration is respectively 2.83 ± 1.01umol/L, 2.71 ± 1.23umol/L, 3.06 ± 1.81umol/L, three
No significant difference (p > 0.05) between group.It is more slow to recycle the three groups of dialysis fluid side 3-IAA concentration increases of 2h process
Slowly, when 2h, liposome group dialysis fluid side 3-IAA concentration be 4.33 ± 1.06umol/L, be higher than PBS group (4.33 ±
1.06vs.3.36 ± 0.66, p=0.047), BSA group is 3.39 ± 1.47umol/L, compared with PBS group, no statistical difference
Meaning (p > 0.05).Three groups of dialysis fluid side 3-IAA concentration gradually tend to platform, and the 3- of liposome group dialysis fluid side after 2h
IAA concentration is consistently higher than PBS group (the equal < 0.05 of p).The 3-IAA concentration of BSA group dialysis fluid side is compared with PBS group, until dialysis
At the end of difference have statistical significance (5.52 ± 1.27vs.4.21 ± 0.59umol/L, p=0.031).
5) blood side BSA concentration changes during external closed circulation
As shown in table 2, in vitro in cyclic process, three groups of blood side BSA concentration are slightly decreased in 30min before dialysis,
But statistics difference is not reached, three groups of blood side BSA concentration nothing is substantially change after 30min.
The variation of 2 During Cpb each group blood side (side B) BSA concentration of table
Above embodiment is can not to be interpreted as in order to illustrate embodiment disclosed by the invention to limit of the invention
System.In addition, in various modifications and invention listed herein method, composition variation, do not departing from the scope of the present invention
Be obvious for those skilled in the art under the premise of spirit.Although having combined of the invention a variety of specific
Preferred embodiment has carried out specific description to the present invention, it is to be understood that, the present invention should not be limited only to these specific embodiments.
In fact, various obviously modify as described above for those skilled in the art to obtain invention all should include
Within the scope of the invention.
Claims (10)
1. a kind of liposome is preparing the purposes in the pharmaceutical preparation for removing protein binding toxin, the diameter of the liposome
For 50~500nm.
2. purposes according to claim 1, it is characterised in that: the protein binding toxin refers to that uremic patient is intracorporal
Protein binding toxin.
3. purposes according to claim 1, it is characterised in that: the diameter of the liposome is 100~200nm.
4. purposes according to claim 1, it is characterised in that: the pharmaceutical preparation refer to it is following any one during
The preparation used: Intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy.
5. purposes according to claim 1, it is characterised in that: removing protein binding toxin in the pharmaceutical preparation uniquely has
It imitates ingredient or principle active component is liposome.
6. purposes according to claim 1, it is characterised in that: the concentration that the liposome is added when use is 30~50g/
l。
7. a kind of dialyzate, which is characterized in that include liposome in the dialyzate.
8. dialyzate according to claim 7, which is characterized in that the concentration of liposome is 30~50g/ in the dialyzate
l。
9. dialyzate according to claim 7, it is characterised in that: the diameter of the liposome is 100~200nm.
10. dialyzate according to claim 7, it is characterised in that: the dialyzate be Intermittent hemodialysis dialyzate,
Any one in peritoneal dialysis solution or continuous renal replacementtherapy dialyzate.
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| PCT/CN2018/082552 WO2019062071A1 (en) | 2017-09-30 | 2018-04-10 | Use of liposome in preparing pharmaceutical preparation for removing protein-bound toxin |
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| CN111821263A (en) * | 2019-04-19 | 2020-10-27 | 上海交通大学医学院附属第九人民医院 | Liposome, dispersion liquid containing liposome, preparation method and application of liposome and dispersion liquid |
| CN111939126A (en) * | 2019-05-15 | 2020-11-17 | 上海交通大学医学院附属第九人民医院 | Cationic liposome, dispersion liquid containing same, and preparation method and application thereof |
| CN112294763A (en) * | 2019-07-30 | 2021-02-02 | 上海交通大学医学院附属第九人民医院 | Liposome dispersion liquid for peritoneal dialysis and preparation method and application thereof |
| WO2022147962A1 (en) * | 2021-01-05 | 2022-07-14 | 上海交通大学医学院附属第九人民医院 | Fat emulsion dialysate, and preparation method therefor and use thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111821263A (en) * | 2019-04-19 | 2020-10-27 | 上海交通大学医学院附属第九人民医院 | Liposome, dispersion liquid containing liposome, preparation method and application of liposome and dispersion liquid |
| CN111821263B (en) * | 2019-04-19 | 2023-03-21 | 上海交通大学医学院附属第九人民医院 | Liposome, dispersion liquid containing liposome, preparation method and application of liposome and dispersion liquid |
| CN111939126A (en) * | 2019-05-15 | 2020-11-17 | 上海交通大学医学院附属第九人民医院 | Cationic liposome, dispersion liquid containing same, and preparation method and application thereof |
| CN112294763A (en) * | 2019-07-30 | 2021-02-02 | 上海交通大学医学院附属第九人民医院 | Liposome dispersion liquid for peritoneal dialysis and preparation method and application thereof |
| WO2022147962A1 (en) * | 2021-01-05 | 2022-07-14 | 上海交通大学医学院附属第九人民医院 | Fat emulsion dialysate, and preparation method therefor and use thereof |
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