CN101130087A - Medicament carrier solution for abdominal cavity chemotherapy and pharmaceutical composition thereof - Google Patents
Medicament carrier solution for abdominal cavity chemotherapy and pharmaceutical composition thereof Download PDFInfo
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Abstract
The invention provides a medium-molecular-weight hydroxyethylated starches applied to abdominal cavity chemotherapy drug carrier agent, wherein the molecular weight Mw of the medium-molecular-weight hydroxyethylated starches is 60000-600000 dalton, molar degree of substitution is 0. 15-0. 5 and hydroxyethylating substitution ratio in C2 and C6 is >=5. The invention provides carrier liquid including the medium-molecular-weight hydroxyethylated starches and the chemotherapy drug to make the big bulk extend existing time in the abdominal cavity with lasting high concentration through using the carrier liquid, which can contact the drug with the visceral and peritoneal surface in a large area to invade the remained nodules and caner stove to enhance antineoplastic effect to reduce the abdominal cavity adhesion.
Description
Technical field
The present invention relates to a kind of intraperitoneal chemotherapy medicine carrier solution and pharmaceutical composition.
Background technology
Gastrointestinal cancer is clinical common malignancy, over nearly 30 years, although updating and the development of radiotherapy, chemotherapy, biological immune therapy and Chinese medicine of surgical method, but gastrointestinal cancer patient's prognosis and mortality rate not yet be improved significantly, 5 years survival rates of gastric cancer only are 46%, 5 years survival rates of colorectal cancer also are 50%, trace it to its cause, mainly be that postoperative local recurrence and plantation transfer still do not have special therapy measure so far, the relapse and metastasis rate of gastric cancer, colorectal cancer is respectively 30-80%, 37%.Recurrence that gastrointestinal cancer is common and metastasis site are the excision position successively, peritoneal surface and liver, intraperitoneal chemotherapy is at this biological behaviour, make cancer therapy drug directly act on the recurrence and the metastasis site of tumor, for the auxiliary treatment of abdominal cavity malignant tumor provides a kind of new approach, now become abdominal cavity malignant tumor especially gastrointestinal cancer postoperative local recurrence and the important prophylactico-therapeutic measures of planting transfer, obtained certain effect aspect raising patient's survival rate and quality of life.Studies show that 5 years survival rates of III phase postoperative gastric cancer intraperitoneal chemotherapy have improved 30.7%, intraperitoneal chemotherapy can prolong life span in the colorectal cancer patients operation associating art, improves the quality.Lot of documents also shows that intraperitoneal chemotherapy compares with intravenous chemotherapy, advantage is to obtain the chemotherapeutics of high local concentrations and less system toxicity, its advantage can be strengthened by the time of contact that prolongs big volumetrical chemotherapy liquid of high concentration and tumor body, peritoneal surface, help killing abdominal cavity free cancer cell and small cancer, can effectively prevent and treat the plantation transfer and the postoperative local recurrence of abdominal cavity malignant tumor.
Yet intraperitoneal chemotherapy remains at two large problems at present: one is the penetrance problem of anticarcinogen; It two is the intraperitoneal chemotherapy carrier problems that can keep constant lasting high concentration.The curative effect of intraperitoneal chemotherapy not only depends on chemotherapeutics, also depends on selected carrier solution.Perspective clinical research shows that biggest obstacle that intraperitoneal chemotherapy obtains desirable curative effect is not that the cytotoxicity of cancer therapy drug is not enough.The chemotherapy carrier is great to the pharmacokinetics and the curative effect influence of intraperitoneal chemotherapy, and especially to high molecular, metabolism is chemotherapeutics slowly.It is two key factors effectively killing the intraperitoneal residual cancer cell that chemotherapeutics is distributed in equably that whole abdominal cavity and cancer be exposed in the chemotherapy liquid for a long time.The intraperitoneal amount of liquid is the principal element that influences the distribution of chemotherapeutics.Big volumetrical chemotherapy liquid can make abdominal part moderately expand, and chemotherapeutics can distribute more uniformly at intraperitoneal like this; Therefore the retention time that prolongs big volume chemotherapy liquid can improve the curative effect of intraperitoneal chemotherapy, should be full of whole abdominal cavity in big for a long time volume high concentration ground as the carrier solution of intraperitoneal chemotherapy.Can keep constant high concentration chemotherapeutics and it is uniformly distributed in the intraperitoneal chemotherapy carrier solution on peritoneum and abdominal viscera surface, become the new and main research direction in intraperitoneal chemotherapy field, be the break-through point that intraperitoneal chemotherapy improves curative effect, gradually become the focus of foreign study.Still do not have ideal carrier solution at present, explore and develop a kind of clinical applied widely, economical and effective, ideal intraperitoneal chemotherapy carrier solution that toxic and side effects is little, become problem that is significant of medical circle.
The part of employing dialysis solution is also arranged as the intraperitoneal administration carrier solution in the existing experimentation.But well-known, chemotherapy uses the intraperitoneal administration carrier solution mechanism of action and action effect and purpose all inequality.Chemotherapy is to utilize carrier solution to be difficult for absorbed characteristics with the intraperitoneal administration carrier solution; make carrier solution keep long relatively time and higher capacity at intraperitoneal; thereby delay chemotherapeutics entrained in the carrier solution and be absorbed at intraperitoneal; guarantee the contact of the local high drug level of chemotherapeutics and large tracts of land, thereby provide a comparatively ideal topical therapeutic platform for chemotherapeutics.Peritoneal dialysis solution then is by carrying electrolyte solution and regulate osmotic pressure, the ion exchange of promotion dialysis solution and body, thereby removing metabolic waste.The basic principle of peritoneal dialysis formula of liquid is: (1) dialysis solution water must strict aseptic and no endotoxin.(2) dialysis solution electrolyte concentration and normal plasma are close, and can be adjusted by clinical setting.Existing peritoneal dialysis solution electrolyte concentration is: 1. Na ion concentration is 132mmol/L; 2. chlorine ion concentration is 103mmol/L; 3. calcium ion concentration is 1.25～1.75mmol/L; 4. magnesium ion concentration is 0.25～0.75mmol/L.Generally do not conform to potassium ion in the dialysis solution, help removing in the body too much potassium ion, keep normal concentration of blood kalium, but when hypokalemia is arranged, can add potassium salt temporarily in dialysis solution, every liter of peritoneal dialysis solution adds 10% Klorvess Liquid 3ml, the nearly 4mmol/L of its potassium concn.(3) dialysate concentration is generally a little more than infiltration of plasma concentration, and water is removed in the favourable body, so can suitably improve the osmotic concentration of dialysis solution according to water retention degree in the body.How to keep osmotic concentration with glucose at present, generally use 1.5% glucose peritoneal dialysis solution as the basis, its osmotic concentration is 346m0sm/L; If need to increase moisture removing in the body, available 2.5% concentration of glucose.(4) the peritoneal dialysis solution pH value is 5.0～5.8.Clinically, because drug interaction, be added with the peritoneal dialysis solution of electrolyte solution and be not suitable as the pharmaceutical carrier of intraperitoneal chemotherapy, the osmotic concentration of dialysis solution neither intraperitoneal chemotherapy pharmaceutical carrier solution ideal infiltration concentration, because the solution of different osmotic concentrations, chemotherapeutics is different to the fragmentation effect (penetration) of tumor body.Therefore, directly that dialysis solution is unsatisfactory as chemotherapy carrier solution effect, therefore do not obtain clinical practice widely at present.
The most frequently used pharmaceutical carrier solution of intraperitoneal chemotherapy oozes saline solution for waiting at present, contain sugared peritoneal dialysis liquid as normal saline, 1.5%, but this low-molecular-weight solution can be absorbed rapidly by peritoneum, this has limited the curative effect of intraperitoneal chemotherapy to a great extent, can not reduce the system toxicity of chemotherapeutics well.Experiment in vitro shows that hypotonic solution can increase accumulative effect and the cytotoxicity of cisplatin at tumor cell.Also the someone attempts macromolecular compound as chemotherapy liquid carrier, but polymer substance deposition in vivo easily, it is unsatisfactory equally with solution to be used for intraperitoneal chemotherapy.The intraperitoneal chemotherapy medicine is kept composition with the colloid osmotic pressure that is contained in the carrier solution and mostly is polymer.Owing to have the enzymoprivic situation of various metabolism in the abdominal cavity, therefore the problem that when the molecular weight of colloid composition increases, can cause this composition to be difficult to degrade.When the inadequate drainage of treatment back, polymer residence time in the corner in abdominal cavity is long, may cause the appearance of complication such as infecting.
The ideal carrier solution of being expected clinically should have following characteristics: (1) prolongs the time of contact of intraperitoneal tumor surface and high concentration anticarcinogen as far as possible; (2) keep big volumetrical chemotherapy liquid for a long time; (3) low abdominal cavity clearance rate; (4) and stronger tumor penetration arranged.(5) retain for a long time in the abdominal cavity peritoneum is had no side effect.
Summary of the invention
The object of the invention is to provide a kind of intraperitoneal chemotherapy medicine carrier solution, with the time of contact of prolongation intraperitoneal tumor surface and medicine, and is easy to remove, and has stronger tumor penetration.
One aspect of the present invention provides a kind of middle application of molecular weight hydroxyethyl starch in the intraperitoneal chemotherapy pharmaceutical carrier.
Typical hetastarch is by from the starch hydrolysis of corn, Maninot esculenta crantz., the various natural products of Rhizoma Solani tuber osi and carry out hydroxyethylation and produce.Outside α-1,4 glycosidic bond, α-1,6 glycosidic bond of significant proportion is arranged in specific hetastarch, its content is relevant according to the raw material of preparation starch.The biological degradation rate of α-1,6 glycosidic bond side chain is starkly lower than α-1,4 glycosidic bond, and the liquid reserve capability of hetastarch is improved behind hydroxyethylation.It is produced by the starch hydrolysis, and the product of different molecular weight and molar substitution is arranged.The common name of medicine all indicates molecular weight and molar substitution, to distinguish different products.
The preferred molecular weight Mw of molecular weight hydroxyethyl starch is 60000-600000 dalton in above-mentioned, it is desirable to 80000-400000 dalton; More preferably Mw is 100000-300000 dalton.By a series of researchs, the inventor finds that molar substitution is 0.15-0.6, be preferably 0.43-0.5, optimum has better effect for the described hetastarch of 0.43-0.48, the ethoxy of C2 and C6 position replaces than for having effect preferably at 〉=5 o'clock in the described hetastarch, the preferred replacement than being 〉=8,, optimum is 9-20.
The present invention provides a kind of intraperitoneal chemotherapy pharmaceutical carrier solution on the other hand, wherein contains above-mentioned middle molecular weight hydroxyethyl starch.
The concentration of hetastarch should be different in the above-mentioned carrier solution, it is desirable to 4%-15% (W/W), and that better is 4%-10% (W/W), it would be desirable that the compositions of about 6% (W/W) is used for intraperitoneal perfusion.
Preferred a kind of monosaccharide or the disaccharidase of adding in the described carrier solution, as glucose, maltose, fructose etc., concentration is in 5%-10% (W/W) scope.
Preferably contain a kind of buffer system in the carrier solution of indication intraperitoneal administration of the present invention, the selection of buffer system should be different, and the pH value of keeping solution is in the 6-8 scope.Comprising a kind of carboxylic acid and salt or ester, the general structural formula of carboxylic acid is RCOOX, and wherein R is alkyl, alkene or aromatic radical, and they can be that straight chain can be a side chain also, contain 1-32 carbon atom.Preferably acetate, lactate, citrate, pyruvate etc.; X is hydrogen or sodium or other biologically compatible ion that can be connected with oxygen, or the alkyl of short chain or side chain.
The carrier solution of the intraperitoneal administration of indication of the present invention can comprise that examples of suitable lubricants is as lecithin etc.Medicine is evenly distributed in the abdominal cavity and with tumor tissues to be contacted widely.
The carrier solution of the intraperitoneal administration of indication of the present invention can comprise antibiotic, and plays infection mitigation or suppress bacteriogenic other composition.These compositions have good effect to the healing of wound and the prevention of postoperative complication.
One side more of the present invention provides a kind of chemotherapy medicine, the hetastarch of molecular weight and the antitumor drug of effective dose in containing in this medicine.At least contain antitumor drug, buffer system.Also can include lubricant and/or above mentioned antibiotic in addition.
Artificial colloid in the possible medicine of indication can comprise dextran, dextrin etc., and concentration is in 5%-15% (W/W) scope.
The indication antitumor drug can comprise: plant alkaloid and other natural drug (as: camptothecine, harringtonine, etoposide, paclitaxel), cytotoxin class antibiotic (as: bleomycin, Bleomycin A5, actinomycin D), antimetabolite (as: methotrexate, fluorouracil, ftorafur), alkylating agent (as: cyclophosphamide, busulfan, semustine) and other antineoplastic agent (as: asparamide enzyme, along pool, all kinds of antitumor drug such as Ka Bo) through the gastrointestinal tract external administration.
The carrier solution of the intraperitoneal administration of indication of the present invention under the physiology body temperature and the chemical stability under the higher high temperature good.Can also can satisfy the requirement of abdominal cavity thermochemotherapy 37 ℃ of safe handlings down.The chemical stability of carrier solution in 40-50 ℃ of scope is good.The equipment that is adopted is routine clinical intraperitoneal administration device.
Inventing mentioned hetastarch can prepare by U.S. Pat 5218018 described methods.
The preparation method of carrier solution provided by the present invention is as follows:
(1) prepare corresponding raw material, comprising: hetastarch, selectivity add sodium chloride, buffer composition;
(2) obtain solution: water for injection is injected Agitation Tank, add hetastarch and stirring and make it to dissolve, add other composition stirring then and make it dissolving, be diluted to final concentration with water for injection at last.The solution for preparing is sterilized through fill.
Available if necessary an amount of hydrochloric acid or sodium hydroxide are regulated pH value to 6.0-7.0 in step (2).
The molecular weight hydroxyethyl starch carrier solution can prolong big volumetrical chemotherapy liquid in Intraabdominal retention time in of the present invention, keep it in Intraabdominal constant persistent high concentration, make chemotherapeutics and abdominal viscera and peritoneal surface carry out fully effective large-area contact, further immerse residual tumor body and cancer, increase its antitumous effect, but also reduce the generation of abdominal adhesions.
The specific embodiment
Below in conjunction with specific embodiment technology contents of the present invention is further detailed, but is to be understood that protection scope of the present invention is not subjected to the restriction of the specific embodiment.
Embodiment 1
Purpose: hetastarch is as the pharmacokinetic of intraperitoneal chemotherapy carrier solution.
Method:, adopt the healthy SD rat with the chemotherapeutics of 5-fluorouracil (5-Fu) as intraperitoneal perfusion.Earlier the SD rat is divided into 3 medicine groups at random, 30 every group (male and female half and half) inject the different carriers solution that is dissolved with 5-fluorouracil (5-FU) respectively.These three drug components Wei hetastarch 6% (hetastarch 200/0.5, replace than be 5), 0.9% sodium chloride, 1.5% contains sugared peritoneal dialysis liquid.Before injection after (basis), the injection 1,3,6,18,24 hour respectively, get blood sample through eyeball, place the centrifuge tube of heparinization, taking off the neck method afterwards puts to death, dissect immediately, gather liver, stomach, colon, kidney, lungs device, write down the residual quantity of intraperitoneal perfusion liquid at each time point simultaneously, the drug level analysis in the sample adopts HPLC (high performance liquid chromatography) method to measure.
The result:
1-hydrodynamics relatively
At the lh time point, the average intraperitoneal clearance rate of hetastarch group is all significantly less than 1.5% glucose peritoneal dialysis solution group (P=0.01), intraperitoneal retains rate then significantly greater than this group (P=O.02), compare with the normal saline group, the rate that retains is big, little but the there was no significant difference of clearance rate, there was no significant difference between 1.5% glucose peritoneal dialysis solution group and the normal saline group; At the 3h time point, 1.5% glucose peritoneal dialysis solution group intraperitoneal clearance rate is significantly greater than hetastarch group and normal saline group (the P value is respectively 0.00,0.01), the hetastarch group is compared with the normal saline group, and clearance rate is little, the rate that retains is big, but difference does not have significance; At the 6h time point, the hetastarch group retains rate significantly greater than normal saline group, 1.5% glucose peritoneal dialysis solution group (the P value is respectively 0.04,0.000), clearance rate is significantly less than 1.5% glucose peritoneal dialysis solution group (P=0.000), 1.5% glucose peritoneal dialysis solution group retains rate significantly less than hetastarch group, normal saline group (the P value is respectively 0.00,0.02), and clearance rate is significantly greater than these two groups (the P value is respectively 0.000,0.006); And at the 12h time point, containing sugared dialysis solution group does not have peritoneal fluid and retains, and the hetastarch group retains rate significantly greater than normal saline group and dialysis solution group (the P value is 0.000), and clearance rate is significantly less than normal saline group (P=0.002); At the 18h time point, normal saline group and 1.5% glucose peritoneal dialysis solution group all do not have peritoneal fluid and retain rate, and the on average rate of retaining of hetastarch group when being 22.54%:24h three groups all do not have peritoneal fluid and retain (table 1).
Injecting infusion liquid pneumoretroperitoneum liquid stream body dynamics in the table 1:SD rat abdominal cavity changes
| Project | Grouping * | 1h | 3h | 6h | 12h | 18h | 24h |
| Clearance rate (ml/h) retains rate (V 1/V 2) | The saline group contains sugared peritoneal dialysis liquid group hetastarch group saline group and contains sugared peritoneal dialysis liquid group hetastarch group | 3.744±1.11 6.264±3.79 2.444±0.97 0.834±A.91E-02 0.758±0.12 0.899±5.6E-02 | 1.65±0.39 4.80±2.79 1.17±0.39 0.616±0.420 0.5ll±0.30 0.844±4.8E-02 | 1.64±0.55 3.25±1.2l 0.78±0.13 0.562±0.157 0.2964±0.238 0.799±2.8E-02 | 1.46±0.23 --------- 1.02±0.14 0.363±0.265 0.00±0.00 0.421±8.7E-02 | ≥1.20±0.15 -------- 0.9514±4.2E-02 0.00±0.00 0.00±0.00 0.23±2.8E-02 | -------- -------- -------- 0.00±0.00 0.00±0.00 0.004±0.00 |
*Every group of each 5 SD rat
2. pharmacokinetics relatively
2.1 5-Fu concentration in the peritoneal fluid (table 2-4)
At the 3h time point, 5-Fu concentration is significantly higher than normal saline and 1.5% glucose peritoneal dialysis solution group (the P value is 0.001) in the hetastarch group peritoneal fluid, at 12h, 18h time point, hetastarch group peritoneal fluid 5-Fu concentration is significantly higher than normal saline and 1.5% glucose peritoneal dialysis solution group, and (the P value is 0.000,1.5% glucose peritoneal dialysis solution group has not had peritoneal fluid and has retained during 12h, the normal saline group has not had peritoneal fluid and has retained during 18h, and 5-Fu concentration is pressed 0.0000mg/L and calculated).At 1h, 6h time point, 5-Fu concentration there was no significant difference between each group.
2.2 peritoneal fluid 5-Fu total amount (table 2-4)
At the 1h time point, the 5-Fu total amount is respectively normal saline group, 1.5% glucose peritoneal dialysis solution group 2.4 times and 40.9 times in the hetastarch group peritoneal fluid, then be respectively 10.5 times and 13.3 times at the 3h time point, then be respectively 1.3 times, 1.1 times at the 6h time point.At the 12h time point, hetastarch group peritoneal fluid 5-Fu is 1.2096 μ g, and the normal saline group then is 0.0000 μ g, and the dialysis solution group has not had peritoneal fluid and retained; At the 18h time point, hetastarch group peritoneal fluid 5-Fu total amount is 0.6479 μ g, and this moment in addition two groups all do not have peritoneal fluid and retain.
2.3 5-Fu concentration in the portal vein (table 2-4)
At the 1h time point, 5-Fu concentration is significantly higher than 1.5% glucose peritoneal dialysis solution and hetastarch group (the P value is 0.000) in the normal saline group portal vein, there was no significant difference between back two groups; At 3h, 24h time point, 5-Fu concentration is significantly higher than normal saline and dialysis solution group (the P value is 0.001) in the hetastarch group portal vein, both there was no significant differences of back; At 6h, 12h time point, difference that there are no significant between three groups; At the 18h time point, the hetastarch group is significantly higher than the normal saline group, dialysis solution group and the above two there are no significant difference.
2.4 5-Fu concentration in the postcava blood (table 2-4)
At 1h, 3h, 6h, 12h, 8h, 24h time point, 5-Fu concentration there are no significant difference in the postcava blood between three groups.
2.5 5-Fu concentration in the gastric tissue (table 2-4)
At 3h, 6h time point, 5-Fu concentration is significantly higher than 1.5% glucose peritoneal dialysis solution group (P=0.03) in the hetastarch group gastric tissue; At the 12h time point, 5-Fu concentration is significantly higher than normal saline group (P=0.04) in the hetastarch group gastric tissue; At the 18h time point, 5-Fu concentration is significantly higher than normal saline group and 1.5% glucose peritoneal dialysis solution group (the P value is respectively 0.011,0.015) in the hetastarch group gastric tissue; At 1h, 24h time point, there was no significant difference between three groups.
2.6 5-Fu concentration in the colon (table 2-4)
At the 18h time point, 5-Fu concentration is significantly higher than normal saline group and 1.5% glucose peritoneal dialysis solution group (the P value is respectively 0.007,0.002) in the hetastarch group colon; 5-Fu concentration is significantly higher than 1.5% glucose peritoneal dialysis solution group (P=0.04) in 24h colon; At point At All Other Times, there was no significant difference between three groups.
2.9 5-Fu concentration in the liver organization (table 2-4)
At the 3h time point, 5-Fu concentration is significantly higher than normal saline and 1.5% glucose peritoneal dialysis solution group (the P value is respectively 0.02,0.01) in the hetastarch group liver organization; At the 6h time point, 5-Fu concentration is significantly higher than normal saline and 1.5% glucose peritoneal dialysis solution group (P is 0.01) in the hetastarch group liver organization; At the 18h time point, 5-Fu concentration is significantly higher than 1.5% glucose peritoneal dialysis solution group (P=0.02) in the normal saline group liver organization; At the 24h time point, 5-Fu concentration is significantly higher than normal saline and 1.5% glucose peritoneal dialysis solution group (P is 0.000) in the hetastarch group liver organization.
2.8 5-Fu concentration in the nephridial tissue (table 2-4)
At 1h, 3h, 6h, 12h, 8h, 24h time point, 5-Fu concentration there are no significant difference in the nephridial tissue between three groups.
2.9 5-Fu concentration in the lung tissue (table 2-4)
At the 3h time point, 5-Fu concentration is significantly higher than normal saline and 1.5% glucose peritoneal dialysis solution group (P is respectively 0.01,0.02) in the hetastarch group lung tissue; At the 18h time point, 5-Fu concentration is significantly higher than hetastarch group and normal saline group (P is respectively 0.012,0.007) in the 1.5% glucose peritoneal dialysis solution group lung tissue; At the 24h time point, 5-Fu concentration also is significantly higher than hetastarch group and normal saline group (P is respectively 0.015,0.000) in the 1.5% glucose peritoneal dialysis solution group lung tissue.
Inject in the table 2SD rat abdominal cavity normal saline infusion liquid pneumoretroperitoneum liquid, portal vein, postcava blood, stomach, colon, liver, kidney, lung tissue 5-FuC-T data (
N=5)
| Time (h) | 1 | 3 | 6 | 12 | 18 | 24 | |
| 5-Fu concentration (μ g ml -1) | Peritoneal fluid PV blood ICV blood agglomeration intestinal | 266.9417±120. 9010 7.7406±1.2377 5.9506±3.5119 1.6834±0.6355 | 12.9407±0.975 3 0.8794±0.2394 1.7397±3.1246 0.6961±0.5772 | 6.7375±5.3568 0.3375±0.4421 0.1012±0.1197 0.4306±0.3260 | 0.0000±0.0000 1.12E-02±2.5E -02 1.95E-02±4.35 E-02 .2202±6.4E-02 | There are not 0.0000 ± 0.0000 6.78E-03 ± 1.52 E-02 6.26E-0 ± 4.25E-02 | Do not have 0.0000 ± 0.0000 0.0000 ± 0.0000 0.1727 ± 0.1123 |
| Stomach Liver and kidney lung | 1.8105±1.0238 0.4720±0.1205 2.4240±1.2838 1.9319±1.1824 6 | 0.3185±0.2373 0.1554±0.1043 0.3370±0.0041 0.2947±0.2627 | 0.5036±0.4764 1.4367E-03±2. 8733E-03 0.2790±0.3965 0.6565±1.1774 | 9.10E-02±9.30 E-02 7.97E-02±.100 5 0.5286±1.0919 0.1767±0.2803 | 3.92E-02±3.16 E-02 9.70E-02±.101 5 2.64E-02±5.90 E-02 9.41E-03±2.10 E-02 | 0.0000±0.0000 3.36E-03±7.50 E-03 2.95E-02±6.59 E-02 0.000±0.0000 |
Inject in the table 3SD rat abdominal cavity 1.5% glucose peritoneal dialysis solution carrier pneumoretroperitoneum liquid, portal vein, postcava blood, stomach, colon, liver, kidney, lung tissue 5-FuC-T data (
N=5)
| Time (h) | 1 | 3 | 6 | 12 | 18 | 24 | |
| 5-Fu concentration (μ g ml -1) | Peritoneal fluid PV blood ICV blood agglomeration the intestines and stomach Liver and kidney lung | 296.1377±38.9 852 4.4566±1.2474 5.6618±1.9875 1.6897±0.5111 1.1596±0.4420 0.5026±0.4378 1.6451±0.6556 1.4706±0.1220 | 10.1430±2.944 8 2.2754±1.7488 0.1503±3.0780 E-02 0.4814±42932 E-02 0.2721±2.9580 E-02 4.5819E-02±4. 9012E-02 0.3052±7.4097 E-02 0.4081±0.4389 | 9.5161±6.3512 0.5530±0.1145 6.4165E-02±7. 3172E-02 0.5337±0.3765 4.4879E-02±5. 2556E-02 7.2848E-02±0. 1506 0.1935±0.1967 1.1854±1.3464 | There are not 0.2728 ± 0.2549 0.0000 ± 0.0000 6.42E-02 ± 7.32 E-02,0.3367 ± 6.74E-, 02 0.4405 ± 0.8934 0.7533 ± 1.0351 9.24E-02 ± 6.11 E-02 | There are not 0.1021 ± 0.1422 0.0000 ± 0.0000 4.02E-02 ± 7.08 E-02 9.18E-02 ± 0.13 41 2.46E-03 ± 5.51 E-03 1.69E-02 ± 3.29 E-02 0.8768 ± 0.7297 | There is not 0.0000 ± 0.0000 0.0000 ± 0.0000 0.0000 ± 0.0000 4.06E-02 ± 9.06 E-02,0.0000 ± 0.0000 8.22E-02 ± 0.11 37 0.2661 ± 5.98E-02 |
Inject in the table 4SD rat abdominal cavity He Si infusion liquid pneumoretroperitoneum liquid, portal vein, postcava blood, stomach, colon, liver, kidney, lung tissue 5-FuC-T data (
N=5)
| Time (h) | 1 | 3 | 6 | 12 | 18 | 24 | |
| 5-Fu concentration (μ g ml -1) | Peritoneal fluid PV blood ICV blood agglomeration the intestines and stomach liver | 608.6842±729. 8478 4.1957±0.6952 8.5828±8.9442 0.8870±0.7135 1.9967±2.0322 0.6775959±0.5 388 | 102.0768±57.9 479 3.3071±5.9796 0.9201±11978 1.3031±0.9531 0.5920±0.2758 0.6472685±0.5 256 | 6.1370±8.7170 0.1818±0.1631 2.4766±5.0152 0.6878±0.5033 0.4723±0.4719 0.8606826±0.7 155 | 0.1344±0.1229 0.6203±0.9935 1.85E-02±2.10 E-02 0.6313±1.0421 0.4464±0.4087 4.45E-02±3.30 E-02 | 0.1295854±0.1 508 0.3725±0.3871 3.82E-03±5.26 E-03 0.1730±4.46E- 02 0.9486±0.8173 7.4E-02±2.35E -02 | 0 0.2469±0.1457 0.0000±0.0000 0.3355±0.4004 7.57E-02±0.11 56 8.63E-02±3.99 E-02 |
| The kidney lung | 2.1921±1.8532 1.9782±0.7219 | 0.8685±0.7665 7 1.0990±0.5499 | 0.4496±0.1117 4 0.1288±8.83E- 02 | 8.91E-02±6.88 E-02 0.4004±0.4844 | 0.5118±0.9168 8.86E-02±6.68 E-02 | 0.0000±0.0000 0.1108±0.1372 |
Conclusion
Hetastarch in this research (HAES-steri) is the low level hetastarch that replaces of a kind of middle molecular weight, pharmacokinetics result shows, at 3h, 12h, 18h time point, 5-Fu concentration is significantly higher than normal saline and 1.5% glucose peritoneal dialysis solution group in the hetastarch group peritoneal fluid, illustrate that hetastarch can not only keep big volumetrical chemotherapy liquid measure lastingly, compare the chemotherapeutics that higher concentration can also be provided with normal saline, 1.5% glucose peritoneal dialysis solution.And at the 1h time point, the 5-Fu total amount is respectively normal saline group, 1.5% glucose peritoneal dialysis solution group 2.4 times and 40.9 times in the hetastarch group peritoneal fluid, then be respectively 10.5 times and 13.3 times at the 3h time point, then be respectively 1.3 times, 1.1 times at the 6h time point.At the 12h time point, hetastarch group peritoneal fluid 5-Fu is 1.2096 μ g, and the normal saline group then is 0.0000 μ g, and the dialysis solution group has not had peritoneal fluid and retained; At the 18h time point, hetastarch group peritoneal fluid 5-Fu total amount is 0.6479 μ g, and this moment in addition two groups all do not have peritoneal fluid and retain, as seen hetastarch is as the intraperitoneal chemotherapy carrier, compare with normal saline and dialysis solution conventional carriers, can make peritoneum, organ surface be exposed to more substantial cancer therapy drug lastingly, increase the continuous action time and the action intensity of cancer therapy drug.The blood drug level result shows in the portal vein, except that 1h normal saline blood drug level is significantly higher than hetastarch group (may be because normal saline is due to intraperitoneal is absorbed rapidly), at 3h, 24h time point, 5-Fu concentration is significantly higher than normal saline and dialysis solution group in the hetastarch group portal vein, be significantly higher than the normal saline group at 18h, show that hetastarch can make the cancerous cell that dissociates in the Portal system be subjected to the attack of higher drug level as the intraperitoneal chemotherapy carrier, may more effectively prevent the postoperative hepatic metastases of gastrointestinal cancer.And at 3h, 6h time point, 5-Fu concentration is significantly higher than normal saline and 1.5% glucose peritoneal dialysis solution group in the hetastarch group liver organization, at the 18h time point, be significantly higher than 1.5% glucose peritoneal dialysis solution group, at the 24h time point, be significantly higher than the normal saline group, show that the hetastarch carrier more helps preventing and treating the hepatic metastases of human primary gastrointestinal cancers postoperative liver.And in the postcava 5-Fu concentration at each time point, difference that there are no significant between three groups, show that the hetastarch vehicle group not only improves local drug concentration in peritoneal fluid, portal vein, the liver, and its system toxicity with other two groups compare and, also obtain more effectively controlling for significantly increasing.Cavity of resorption gastric tissue Chinese medicine concentration results shows, at 3h, 6h, 18h time point, 5-Fu concentration is significantly higher than 1.5% glucose peritoneal dialysis solution group in the hetastarch group gastric tissue, at the 12h time point, be significantly higher than the normal saline group, illustrating that hetastarch is compared with normal saline, dialysis solution as 5-Fu intraperitoneal chemotherapy carrier can strengthen its tissue penetration degree, more helps the treatment of intraperitoneal cancerous node.Nephridial tissue Chinese medicine concentration is in each time point there are no significant difference, and only at the 3h time point, 5-Fu concentration is significantly higher than normal saline and 1.5% glucose peritoneal dialysis solution group in the hetastarch group lung tissue, at 18h, 24h time point, 5-Fu concentration is significantly higher than hetastarch group and normal saline group in the 1.5% glucose peritoneal dialysis solution group lung tissue, show that once more hetastarch is as the intraperitoneal chemotherapy carrier, when raising was effectively treated concentration, its system toxicity was also controlled preferably.
In a word, hetastarch is during as 5-Fu intraperitoneal chemotherapy carrier solution, compare with conventional carriers solution normal saline, 1.5% glucose peritoneal dialysis solution, its pharmacokinetics is with the obvious advantage: the peritoneal fluid drug level is significantly higher, more help killing intraperitoneal free cancer cell and small cancer, prevent and treat human primary gastrointestinal cancers postoperative intraperitoneal local recurrence and plantation transfer; Cancer therapy drug is also significantly higher in portal vein, the liver organization, makes in the Portal system in free cancerous cell and cancer embolus, the liver and shifts the attack that cancer all is subjected to the higher concentration cancer therapy drug, more helps preventing and treating the hepatic metastases of human primary gastrointestinal cancers postoperative; Can improve remarkable 5-Fu to intraperitoneal gastrointestinal tissue penetrance, more help treatment the intraperitoneal cancerous node; And the system toxicity of intraperitoneal chemotherapy is also controlled preferably, and can be used as intraperitoneal chemotherapy ideal carrier solution, solve the bottleneck problem in the intraperitoneal chemotherapy evolution, improve the therapeutic effect of intraperitoneal chemotherapy.
Claims (10)
1. the application of molecular weight hydroxyethyl starch in the intraperitoneal chemotherapy pharmaceutical carrier in a kind, described in molecular weight hydroxyethyl starch molecular weight Mw be 60000-600000 dalton.
2. application according to claim 1 is characterized in that, described middle molecular weight hydroxyethyl starch molecular weight Mw80000-400000 dalton; Preferably Mw is 100000-300000 dalton.
3. application according to claim 1 and 2 is characterized in that described hetastarch molar substitution is 0.15-0.6, is preferably 0.43-0.5, optimum is 0.43-0.48, in the described hetastarch ethoxy of C2 and C6 position replace than be 〉=5, the preferred replacement than being 〉=8,, optimum is 9-20.
4. an intraperitoneal chemotherapy pharmaceutical carrier solution is characterized in that wherein containing middle molecular weight hydroxyethyl starch, and described middle molecular weight hydroxyethyl starch molecular weight Mw is 60000-600000 dalton, it is desirable to 80000-400000 dalton; More preferably Mw is 100000-300000 dalton.
5. carrier solution according to claim 4 is characterized in that the weight ratio concentration of described hetastarch is 4%-15%, and that better is 4%-10%, it would be desirable 6%.
6. according to claim 4 or 5 described carrier solutions, it is characterized in that described hetastarch molar substitution is 0.15-0.6, be preferably 0.43-0.5, optimum is 0.43-0.48.
7. according to claim 4 or 5 described carrier solutions, it is characterized in that in the described hetastarch ethoxy of C2 and C6 position replace than be 〉=5, the preferred replacement than being 〉=8,, optimum is 9-20.
8. according to claim 4 or 5 described carrier solutions, it is characterized in that alternative a kind of monosaccharide or the disaccharidase of adding in the described carrier solution, as glucose, maltose, fructose etc., weight ratio concentration is in the 5%-10% scope, the alternative lubricant that adds is as lecithin etc., the also alternative antibiotic that adds in the carrier solution in the carrier solution.
9. according to claim 4 or 5 described carrier solutions, it is characterized in that alternative contains a kind of buffer system in the carrier solution, the pH value of keeping solution is in the 6-8 scope, comprising a kind of carboxylic acid and salt or ester, the general structural formula of carboxylic acid is RCOOX, and wherein R is alkyl, alkene or aromatic radical, and they can be that straight chain also can be a side chain, contain 1-32 carbon atom, preferably acetate, lactate, citrate, pyruvate etc.; X is hydrogen or sodium or other biologically compatible ion that can be connected with oxygen, or the alkyl of short chain or side chain.
10. a chemotherapy medicine is characterized in that containing in this medicine the hetastarch of middle molecular weight and the antitumor drug of effective dose, and described middle molecular weight hydroxyethyl starch molecular weight Mw is 60000-600000 dalton.
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| CNA2007101202458A CN101130087A (en) | 2007-08-14 | 2007-08-14 | Medicament carrier solution for abdominal cavity chemotherapy and pharmaceutical composition thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749710A (en) * | 2016-12-27 | 2017-05-31 | 武汉华科大生命科技有限公司 | A kind of narrow ditribution HES and its application |
| CN107206016A (en) * | 2015-01-30 | 2017-09-26 | 费森尤斯卡比德国有限公司 | Application of the mixture of modified glucose polymer in metastases are reduced |
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2007
- 2007-08-14 CN CNA2007101202458A patent/CN101130087A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107206016A (en) * | 2015-01-30 | 2017-09-26 | 费森尤斯卡比德国有限公司 | Application of the mixture of modified glucose polymer in metastases are reduced |
| CN106749710A (en) * | 2016-12-27 | 2017-05-31 | 武汉华科大生命科技有限公司 | A kind of narrow ditribution HES and its application |
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