CN105797143A - Application of ulinastatin containing composition to preparation of medicines for treating bladder cancers - Google Patents
Application of ulinastatin containing composition to preparation of medicines for treating bladder cancers Download PDFInfo
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- CN105797143A CN105797143A CN201610374777.3A CN201610374777A CN105797143A CN 105797143 A CN105797143 A CN 105797143A CN 201610374777 A CN201610374777 A CN 201610374777A CN 105797143 A CN105797143 A CN 105797143A
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- somatostatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
The invention belongs to the technical field of medicines and particularly discloses application of an ulinastatin containing composition to preparation of medicines for treating bladder cancers. The composition comprises ulinastatin and somatostatin. According to animal experiments, the composition has an evident inhibition effect on human bladder cancer xenografts in nude mice, and the composition is low in toxic and side effect and can be used as a medicine for treating bladder cancers.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically disclose the purposes in preparation treatment bladder cancer medicine of the compositions containing ulinastatin.
Background technology
Bladder cancer refers to the malignant tumor occurred in bladder mucosa.It is the modal malignant tumor of urinary system, one of big kinds of tumor in the Ye Shi world ten.Account for first of China's Genitourinary system sickness rate, and its sickness rate is only second to carcinoma of prostate in west, occupies the 2nd.Bladder cancer can betide any age, even child, and its sickness rate increases with the age and increases, 50～70 years old age occurred frequently.Male bladder cancer morbidity is 3～4 times of women.In bladder cancer, 70～80% is superficial bladder cancer, and the Health and Living quality of people in serious threat.
The cause of disease of bladder cancer is complicated, and the inherited genetic factors of existing inherence has again external environmental factors.Comparatively clear and definite two are big, and Causal risk factors is smoking and Exposed aromatic amine chemical substance.Urothelial Carcinoma of Bladder is divided into non-Myometrial involvement bladder transitional cell carcinoma and Myometrial involvement bladder transitional cell carcinoma.Non-Myometrial involvement bladder transitional cell carcinoma patient's many employings underwent transurethral resection of bladder tumor, but the postoperative recurrence of patient's transurethral prostate resection of about 70%, postoperative irrigation bladder bacillus calmette-guerin vaccine or Chemotherapeutic treatments can make relapse rate reduce to 25%～40%, and conventional perfusion chemotherapy medicine has mitomycin, amycin, thiotepa, hydroxy camptothecin etc..Myometrial involvement bladder transitional cell carcinoma and bladder scale cancer, the treatment of adenocarcinoma patients's many employings radial cystectomy art, some patient can adopt partial cystectomy to treat.The method that Myometrial involvement bladder transitional cell carcinoma patient also can first carry out new adjuvant chemotherapy+operative treatment.Transitivity bladder cancer is based on chemotherapy, conventional chemotherapy regimen has M-VAP (methotrexate+vincaleucoblastine+amycin+cisplatin) and GC (gemcitabine+cisplatin) and MVP (methotrexate+vincaleucoblastine+cisplatin) scheme, and the effective percentage of chemotherapy is 40%～65%.Therefore, find new Drug therapy and Therapeutic Method is the problem that urgent clinical needs solve.
Ulinastatin is to separate purification urinating from healthy male and obtain, and molecular weight is about the acidoglycoprotein of 67000Da, is the protease inhibitory preparation of a kind of wide spectrum, it is possible to suppress the activity of multiple protein, sugar and lipid hydrolyzing enzyme.It mainly synthesizes in liver, renal metabolism discharge with urine, and its low molecular weight compositions being decomposed to form also has the very strong effect suppressing hydrolytic enzyme.Within 1985, first developed listing by Japan, be usually used in treatment acute pancreatitis, chronic recurrent pancreatitis at present, also can be used for the rescue adjuvant drug of acute circulatory failure.Also there are some researches show that the cancer cell such as pulmonary carcinoma, gastric cancer, hepatocarcinoma, breast carcinoma, cervical cancer are had good inhibiting effect by ulinastatin.
Somatostatin was separated first in 1973 from the hypothalamus of sheep, gained the name because finding it to have the effect suppressing hypophysis growth hormone releasing, and its structure is the tetradecapeptide of a kind of ring-type.The esophageal veins that somatostatin is applicable to caused by Cirrhotic Portal Hypertension is hemorrhage；Upper gastrointestinal hemorrhage caused by peptic ulcer stress ulcer, erosive gastritis；Prevent and treat acute pancreatitis and complication thereof；Pancreas, gallbladder, intestinal fistula auxiliary treatment；Other: acromegaly, gastrinoma, insulinoma and vasoactive intestinal peptide tumor.
Through retrieval, there is no discovery has the independent medication of ulinastatin, somatostatin, and ulinastatin and somatostatin composite reagent are at the correlational study treating bladder cancer.
Summary of the invention
It is an object of the invention to provide the purposes in preparation treatment bladder cancer medicine of the compositions containing ulinastatin.
Technical scheme is as follows: the purposes in preparation treatment bladder cancer medicine of the compositions containing ulinastatin, described compositions includes ulinastatin and somatostatin.The form that ulinastatin, somatostatin use with independent and combination is carried out antihuman bladder cancer T24 cell strain active testing by the present invention, find that human bladder cancer's T24 cell is had certain inhibited proliferation by ulinastatin, and somatostatin is more weak to the inhibited proliferation of human bladder cancer's T24 cell, but when ulinastatin and somatostatin combine and use, then show and human bladder cancer's T24 cell is had obvious inhibited proliferation.The invention provides the above-mentioned compositions containing ulinastatin new opplication in preparation treatment bladder cancer medicine for this, namely said composition can as the drug use for the treatment of bladder cancer.
Further, the weight ratio of described ulinastatin and somatostatin is 1:(0.2～0.6).Now the compositions of ulinastatin and somatostatin effect in suppressing bladder cancer is notable, compared with individually dosed ulinastatin or somatostatin, has synergism in suppressing bladder cancer.
Further, the weight ratio of described ulinastatin and somatostatin is 1:0.4.Now the compositions of ulinastatin and somatostatin is suppressing human bladder cancer's T24 cel l proliferation the strongest.Through the Effect study to human bladder cancer's transplanted tumor in nude mice, confirm that tumor bearing nude mice tumor is had obvious inhibitory action by ulinastatin+somatostatin compositions, with matched group comparing difference, there is statistical significance (P < 0.01), and be better than existing drugs Cisplatin.Meanwhile, experiment mice does not occur that movable minimizing shows with lethargy etc., and during experiment, mice feed is without significantly reducing, and without substantially becoming thin, without nude mice death, transplanted tumor place skin is without ulceration or erosion, and body weight all increases to some extent.These results show that bladder cancer is had good therapeutical effect by said composition.
In order to better express the form of said composition, compositions of the present invention is lyophilized injectable powder or injection.
Further, described lyophilized injectable powder or injection are equipped with one or more medicine acceptable carrier or additives.
Further, described lyophilized injectable powder pharmacy acceptable carriers or additive are selected from the one in mannitol, lactose, gelatin hydrolysate, sodium chloride or glucose or its any mixture；Described injection acceptable carriers or additive are selected from the one in water for injection, mannitol, sodium chloride or glucose or its any mixture.
Therefore, present invention have an advantage that the compositions that the invention provides containing ulinastatin new application in preparation treatment bladder cancer medicine, namely the compositions of ulinastatin and somatostatin can as the drug use for the treatment of bladder cancer, open up the application direction of ulinastatin and somatostatin, there is provided a kind of new drug also to vast bladder cancer patients simultaneously, it is evident in efficacy, and toxic and side effects is low.
Detailed description of the invention
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but is defined in the claims.
Embodiment 1
| Ulinastatin | 57.14mg |
| Somatostatin | 11.428mg |
Preparation technology: take ulinastatin and the somatostatin of recipe quantity, is dissolved in 500ml0.9% normal saline solution, filters, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 2
| Ulinastatin | 57.14mg |
| Somatostatin | 22.856mg |
Preparation technology: take ulinastatin and the somatostatin of recipe quantity, is dissolved in 500ml0.9% normal saline solution, filters, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 3
| Ulinastatin | 57.14mg |
| Somatostatin | 34.284mg |
Preparation technology: take ulinastatin and the somatostatin of recipe quantity, adds 20 grams of mannitol and dissolves, and regulates PH to neutral, inject water to 2000 milliliters, add sodium chloride and regulate isotonic, aseptic filtration, it is sub-packed in 1000 cillin bottles, lyophilization under aseptic condition, to obtain final product.
Embodiment 4, antihuman bladder cancer T24 cell strain active testing
1, material
Human bladder carcinoma cell line T24, purchased from Shanghai Chinese Academy of Sciences cell bank；Somatostatin, purchased from Hainan Zhonghe Pharmaceutical Co., Ltd, the quasi-word H20034151 of traditional Chinese medicines.
2, the cultivation of cell: with containing 10% hyclone, 100U/mL penicillin, 100 μ g/mL streptomycins RPMI-1640 culture fluid, at 37 DEG C, 5%CO2When, cultivates, trophophase cell of taking the logarithm during experiment.
3, the mensuration of inhibitory rate of cell growth: cell concentration is adjusted to 0.5 × 105·mL-1, every hole 200 μ L is inoculated in 96 orifice plates and cultivates 24h, adds following culture fluid, and following concentration is final concentration:
Culture fluid 1:2mg mL-1Ulinastatin+0.4mg mL-1Somatostatin
Culture fluid 2:2mg mL-1Ulinastatin+0.8mg mL-1Somatostatin
Culture fluid 3:2mg mL-1Ulinastatin+1.2mg mL-1Somatostatin
Culture fluid 4:2mg mL-1Ulinastatin
Culture fluid 5:2mg mL-1Somatostatin
Continue to cultivate 72h after adding above-mentioned culture fluid, respectively set 4 multiple holes.After cultivating 72h, every hole adds 5mg mL-1MTT20 μ L, is further cultured for 4h, inhales and abandons culture fluid in hole, and every hole adds DMSO100 μ L, makes crystallization fully dissolve, and microplate reader measures absorbance, wavelength 490nm.Inhibitory rate of cell growth (%)=(1-process group absorbance/matched group absorbance) × 100%.
4, result
Antihuman bladder cancer T24 cell strain active testing result is shown in Table 1.
The different culture fluid of table 1 is to T24 inhibitory rate of cell growth
| Group | Inhibitory rate of cell growth (%) |
| Culture fluid 1 | 49.65±7.06 |
| Culture fluid 2 | 65.48±10.58 |
| Culture fluid 3 | 46.12±6.76 |
| Culture fluid 4 | 35.84±3.02 |
| Culture fluid 5 | 8.29±1.78 |
As can be seen from Table 1, T24 Growth of Cells is all had certain effect by each culture fluid, and the suppression ratio of culture fluid 1～3 ulinastatin+somatostatin compositions is apparently higher than being used alone ulinastatin or somatostatin, wherein with culture fluid 2 (2mg mL-1Ulinastatin+0.4mg mL-1Somatostatin) suppression ratio the highest, illustrate that ulinastatin+somatostatin inhibitory action when weight ratio is 1:0.4 is the strongest.
Embodiment 5, Effect study to human bladder cancer's transplanted tumor in nude mice
1, material
Animal: BALB/c nude mice 32,4～5 weeks ages of Mus, body weight 16～20g, Guangdong Medical College's animal experimental center provide；Cell strain: BIU-87 bladder cancer cell line, purchased from Shanghai cell biological institute cell bank；Cisplatin, purchased from Nanjing Pharmaceutical Factory Co., Ltd., the quasi-word H20104016 of traditional Chinese medicines；Somatostatin, purchased from Hainan Zhonghe Pharmaceutical Co., Ltd, the quasi-word H20034151 of traditional Chinese medicines.
2, method
(1) cell is cultivated and Animal Model: BIU-87 cell behaviour urothelium tumor cell line, with containing 10% hyclone, 2.0mmol/LL-glutamine, 100U/mL penicillin, 100 μ g/mL streptomycins RPMI-1640 culture fluid, at 37 DEG C, 5%CO2When, cultivates, every 3d with 0.125% trypsin and 0.02%EDTA had digestive transfer culture after continue cultivate.The cell of trophophase of taking the logarithm after the sufficient amount that goes down to posterity is configured to cell suspension.Collecting enzyme-cell solution, 1000r/min is centrifuged 6min, washes 1 time with culture fluid, and single cell suspension is adjusted cell concentration to 1 × 10 by re-suspended cell Trypan Blue after reaching 90% with cattle Bao counting chamber living cell counting number8·mL-1Prepare to be seeded to nude mice.0.2mL tumor cell suspension is extracted (containing viable count 1 × 10 with No. 6 needle applicators7) to be all inoculated in forelimb rear portion on the right side of 32 nude mices subcutaneous.Whole operating process all requires sterile working.
(2) packet of mouse model and medication: after inoculation, 4d becomes tumor, after reaching experimental standard, 32 tumor bearing nude mices are randomly divided into 4 experimental grouies, often group 8.
Matched group: tail vein injection 10ml/kg normal saline；
Ulinastatin: tail vein injection 20mg/kg ulinastatin；
Ulinastatin+somatostatin group: tail vein injection 20mg/kg ulinastatin+8mg/kg somatostatin；
Cisplatin group: tail vein injection 3mg/kg cisplatin.
Each group timed drug administrations every day 1 time, is used in conjunction 2 weeks.Treat latter 15 days cervical dislocation and put to death whole mices, peel off the subcutaneous tumor body of mice and claim tumor weight, the average tumour inhibiting rate (inhibitoryrate, IR) of tumor, IR=(1-treatment group average tumor quality/average tumor quality of matched group) × 100% is calculated by formula.
Statistical analysis: each group data are measurement data, use statistical analysis software SPSS17.0, adopts one factor analysis of variance and t inspection to carry out statistical analysis, and P < 0.05 represents that difference is statistically significant.
3, result
See table 2 below.
The comparison of nude mice body weight, transplanted tumor weight and tumour inhibiting rate respectively organized by table 2
| Group | n | Transplanted tumor weight (g) | Tumour inhibiting rate (%) | Nude mice body weight (g) |
| Matched group | 8 | 1.13±0.12 | - | 26.12±4.23 |
| Ulinastatin group | 8 | 0.58±0.08** | 48.67%** | 25.34±4.18 |
| Ulinastatin+somatostatin group | 8 | 0.33±0.06** | 70.80%** | 24.84±4.15 |
| Cisplatin group | 8 | 0.60±0.10** | 46.90%** | 22.95±3.86 |
* compared with matched group, P < 0.01.
(1) untoward reaction is observed and the impact on tumor bearing nude mice body weight of each treatment group: the performances such as movable minimizing and lethargy does not occur in ulinastatin+somatostatin group mice; during experiment, mice feed is without significantly reducing; without substantially becoming thin; dead without nude mice, transplanted tumor place skin is without ulceration or erosion.Each experimental group nude mouse weight average slowly increases, and wherein each medication group nude mice body weight increases slightly slower than matched group, but no significant difference.
(2) each treatment group impact on tumor bearing nude mice tumor weight and tumour inhibiting rate: put to death nude mice in after medication terminates the 15th day, cut skin visual tumors open and present similar round or nodositas, dissect other organs and have no neoplasm metastasis focus.Each medication group and matched group comparing difference have statistical significance (P < 0.01), and wherein, the suppression ratio of tumor bearing nude mice tumor is higher than ulinastatin group and existing drugs Cisplatin group by ulinastatin+somatostatin group.
Although the present invention is own with preferred embodiment openly as above, but they are not for limiting the present invention, and protection scope of the present invention should be as the criterion with the content that claims hereof protection domain defines.Any it has the knack of the art person, without departing from the spirit and scope of the present invention, the various changes made or equivalent replace, all should belong to protection scope of the present invention.
Claims (6)
1. the compositions containing ulinastatin treats the purposes in bladder cancer medicine in preparation, it is characterised in that described compositions includes ulinastatin and somatostatin.
2. purposes according to claim 1, it is characterised in that the weight ratio of described ulinastatin and somatostatin is 1:(0.2～0.6).
3. purposes according to claim 2, it is characterised in that the weight ratio of described ulinastatin and somatostatin is 1:0.4.
4. purposes according to claim 1, it is characterised in that described compositions is lyophilized injectable powder or injection.
5. purposes according to claim 4, it is characterised in that described lyophilized injectable powder or injection are equipped with one or more medicine acceptable carrier or additives.
6. purposes according to claim 5, it is characterised in that described lyophilized injectable powder pharmacy acceptable carriers or additive are selected from the one in mannitol, lactose, gelatin hydrolysate, sodium chloride or glucose or its any mixture；Described injection acceptable carriers or additive are selected from the one in water for injection, mannitol, sodium chloride or glucose or its any mixture.
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Application publication date: 20160727 |