CN106110312A - Ulinastatin purposes in preparation treatment carcinoma of gallbladder medicine - Google Patents
Ulinastatin purposes in preparation treatment carcinoma of gallbladder medicine Download PDFInfo
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- CN106110312A CN106110312A CN201610562452.8A CN201610562452A CN106110312A CN 106110312 A CN106110312 A CN 106110312A CN 201610562452 A CN201610562452 A CN 201610562452A CN 106110312 A CN106110312 A CN 106110312A
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- 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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Abstract
The invention belongs to pharmaceutical technology field, specifically disclose ulinastatin purposes in preparation treatment carcinoma of gallbladder medicine.Confirming through animal experiment, ulinastatin has obvious inhibitory action to Human gallbladder carcinoma transplanted tumor in nude mice, and its toxic and side effects is low, and safety is high, can be as the drug use for the treatment of carcinoma of gallbladder.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically disclose ulinastatin use in preparation treatment carcinoma of gallbladder medicine
On the way.
Background technology
In Gallbladder cancer, carcinoma of gallbladder (carcinoma of the gall-blader) accounts for first place, and other still has meat
Tumor, carcinoid, primary malignant melanoma, giant cell adenocarcinoma etc..Primary gallbladder cancer is the most rare, in the long period
Do not cause the attention of people, only account for about the 1% of all cancers sum according to domestic textbook report.Due to images such as B ultrasonic, CT
Learning extensively carrying out of inspection, carcinoma of gallbladder is the most gradually realized, and discovery rate increases.But the morbidity of carcinoma of gallbladder has significantly
District's difference, and many compared with male 2～4 times of the sickness rate women of carcinoma of gallbladder patient, be more common in 50～70 years old, and within more than 50 years old, person accounts for
90%.
The induction of carcinoma of gallbladder and cholelithiasis, typhoid fever, cyst of bile duct, cystic polyp, porcelain gallbladder, nitrosamines chemicals
Matter, obesity etc. are relevant.Carcinoma of gallbladder has multiple different organization type, but all lacks specific clinical manifestation, and carcinoma of gallbladder is the biggest
Majority is adenocarcinoma, accounts for 80%, and wherein 60% is rigid adenocarcinoma, and 25% is papillary adenocarcinoma, and 15% is mucinous adenocarcinoma, and remaining is
Undifferentiated carcinoma accounts for 6%, and scale cancer accounts for 3%, and mixed tumor or acanthoma account for 1%, still has other rare tumors to include carcinoid, sarcoma,
Melanoma and lymphoma etc..
Owing to the grade malignancy of carcinoma of gallbladder is high, shifts the most in early days, be difficult to early discovery, to spies such as chemotherapeutics are insensitive
Point, has belonged to middle and advanced stage when therefore Most patients is made a definite diagnosis.At present, the Therapeutic Method of carcinoma of gallbladder mainly includes surgical operation, radiation
Treatment, chemotherapy and Chinese medicine.The carcinoma of gallbladder great majority of clinical findings are patients with terminal, therefore current Resection Rate is very
Low, the curative effect after excision is the most very poor；Chemotherapy is the treatment means that Advanced Gallbladder Cancer is important, and it has relatively straightforward suppression to cancerous protuberance
Effect.Carcinoma of gallbladder chemotherapeutics conventional clinically has mitomycin, 5-fluorouracil, CCNU, cisplatin etc., these medicines
Thing is all respectively arranged with pluses and minuses, such as cisplatin and has that anticancer spectrum is wide, act on strong advantage, but easily causes Toxicity of Kidney；Mitomycin has
Efficiency is higher, but bone marrow inhibition is the strongest.The advantage for the treatment of by Chinese herbs carcinoma of gallbladder is there is tumor certain inhibitory action, nothing
Side effect, can improve body immunity, lowers chemotherapeutics toxicity, improves life in patients, extends life span.Control at present
The Chinese medicine kind treating carcinoma of gallbladder is more, but quality is very different.Therefore, find new Drug therapy and Therapeutic Method is clinical anxious
The problem that need to solve.
Ulinastatin is isolated and purified and obtain from healthy male is urinated, and molecular weight is about the acidoglycoprotein of 67000Da, is
The protease inhibitory preparation of a kind of wide spectrum, it is possible to suppression multiple protein, sugar and the activity of lipid hydrolyzing enzyme.It is mainly in liver
Synthesis, is discharged with urine by renal metabolism, and its low molecular weight compositions being decomposed to form also has the strongest suppression hydrolytic enzyme
Effect.Within 1985, first developed listing by Japan, be usually used at present treating acute pancreatitis, chronic recurrent pancreatitis, also may be used
Rescue adjuvant drug for acute circulatory failure.Also there are some researches show ulinastatin to pulmonary carcinoma, gastric cancer, hepatocarcinoma, breast carcinoma, palace
The cancer cell such as neck cancer have good inhibiting effect, but through retrieval, there is no and be found to have ulinastatin being correlated with at treatment carcinoma of gallbladder
Research.
Summary of the invention
It is an object of the invention to provide ulinastatin purposes in preparation treatment carcinoma of gallbladder medicine.Demonstrate,prove through animal experiment
Real, ulinastatin has obvious inhibitory action to Human gallbladder carcinoma transplanted tumor in nude mice, and ulinastatin is to Human gallbladder carcinoma nude mice model
The treatment of tumor is dose dependent, and during experiment, mice does not occurs that movable minimizing shows with lethargy etc. simultaneously, and mice is taken food
Without significantly reducing, without substantially becoming thin, dead without nude mice, at transplanted tumor, skin is without ulceration or erosion, and body weight all increased, and
And the most there is not exception in the heart of checkout facility nude mice, liver, kidney, lung, spleen, thymus, intestinal, stomach.These results show crow department
His fourth has preferable therapeutical effect to carcinoma of gallbladder, and safety is high.
Further, described medicine is lyophilized injectable powder or injection.
Further, described lyophilized injectable powder or injection are equipped with the acceptable additive of one or more medicines.
The described acceptable additive of lyophilized injectable powder pharmacy is selected from mannitol, lactose, gelatin hydrolysate, sodium chloride or Fructus Vitis viniferae
One in sugar or its any mixture；The acceptable additive of described injection selected from water for injection, mannitol, sodium chloride or
One in glucose or its any mixture.
Therefore, present invention have an advantage that a kind of new opplication that the invention provides ulinastatin at field of medicaments, i.e. crow
Si Tading can open up the application direction of ulinastatin as the drug use for the treatment of carcinoma of gallbladder, the most also gives vast gallbladder
Cancer patient provides a kind of new drug, and 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 concrete real
Execute any restriction of example, but be defined in the claims.
Embodiment 1, prepare ulinastatin freeze-dried powder
Taking filtration sterilization ulinastatin aqueous solution 200,000,000 unit, add 20 grams of mannitol and dissolve, regulation PH, to neutral, adds
Water for injection, to 2000 milliliters, adds sodium chloride regulation isotonic, and aseptic filtration is sub-packed in 1000 cillin bottles, under aseptic condition
Lyophilization, to obtain final product.
Embodiment 2, prepare Ulinastatin injection
Take ulinastatin aqueous solution 100,000,000 unit of filtration sterilization, add 20 grams of mannitol and dissolve, regulation PH to neutrality,
Inject water to 2000 milliliters, add sodium chloride regulation isotonic, aseptic filtration, in 1000 cillin bottles of subpackage, to obtain final product.
Embodiment 3, the ulinastatin Effect study to Human gallbladder carcinoma transplanted tumor in nude mice
1, material
Animal: BALB/c-nu/nu Female nude mice 46, Mus age 7～8 weeks, body weight 18～20g, by Guangdong Medical College animal
Experimental center provides；Cell strain: Human gallbladder carcinoma cell strain GBC-SD, purchased from cell institute of middle section；Cisplatin, has purchased from Nanjing Pharmaceutical Plant
Limit company, traditional Chinese medicines quasi-word H20104016.
2, method
(1) Human gallbladder carcinoma Nude Mouse Model is set up:
A, cell recovery: after being taken out by frozen Human gallbladder carcinoma cell in liquid nitrogen, be immediately placed in 37 DEG C of water-baths recovery 10
～15 minutes.
B, the poly-propanol centrifuge tube of the recovery cell suspension also 15ml that transfers to cleaning will add 10ml serum-free
1640 culture medium, mix gently, and 4000rpm abandons supernatant after being centrifuged 5 minutes.
C, the 15%FBS-1640 culture medium of addition 1ml are uniform by mixing with cells after flicking.
D, take 4 9mm cleaning culture dishs and add appropriate 15%FBS-1640 culture medium.
E, the cell suspension of step c is divided into quarter adds in culture dish, mix gently.
F, cell put 37 DEG C of cell culture incubators, and 5% carbon dioxide conditions is cultivated.
G, the growing state of observation of cell also changed fresh culture fluid into every 2～3 days.
H, the cell of trophophase of taking the logarithm become 1 × 10 with normal saline6Concentration, 0.5ml/ is only to 10 experiment nude mices
Carry out subcutaneous injection, observe the situation of tumor growth.
I, taking normal tumor bearing nude mice, cervical dislocation is put to death, 75% alcohol disinfecting skin, shells with eye scissors and ophthalmic tweezers
Take out transplanted tumor, be placed in add in anti-normal saline and rinse, reject fibrous capsule and hemorrhagic necrosis part, cut well-grown, light
Red, the tumor tissue of flesh of fish shape, the tumor tissue fritter being cut into several about 1.5mm × 1.5mm × 1.5mm is standby.Grab
Take animal, fixing, skin of sterilizing, with No. 20 trocars, the tumor tissue sheared migrated to nude mice right dorsal part forelimb nearly armpit skin
Under.Carry out the subcutaneous transplantation of 46 nude mices as stated above.
(2) packet of mouse model and medication: after 6d becomes tumor to reach experimental standard after inoculation, select tumor size similar
(rejecting tumor excessive or too small) nude mice is randomly divided into 5 experimental grouies, often organizes each 8.
Matched group: 10ml/ (kg d) normal saline, tail vein injection is administered；
Ulinastatin low dose group: 1000 units/(kg d) Ulinastatin injection, tail vein injection is administered；
Dosage group in ulinastatin: 5000 units/(kg d) Ulinastatin injection, tail vein injection is administered；
Ulinastatin high dose group: 10000 units/(kg d) Ulinastatin injection, tail vein injection is administered；
Cisplatin group: 2mg/ (kg d) cisplatin injections, tail vein injection is administered.
Each group timed drug administrations every day 1 time, is used in conjunction 21d.After drug withdrawal, the 4th day cervical dislocation puts to death whole mices, peels off little
Mus subcutaneous tumor body also claims tumor weight, calculates the average tumour inhibiting rate (inhibitory rate, IR) of tumor by formula, and (1-controls IR=
Treatment group average tumor quality/matched group average tumor quality) × 100%.And nude mice corpse is carried out comprehensive postmortem, and perusal is naked
The change of the major organs such as the Mus heart, liver, kidney, lung, spleen, thymus, intestinal.
Statistical analysis: each group data are measurement data, use statistical analysis software SPSS 17.0, use single factor test
Variance analysis and t inspection carry out statistical analysis, and P ＜ 0.05 represents that difference is statistically significant.
3, result
See table 1.
Table 1 respectively organizes nude mice body weight, transplanted tumor weight and the comparison of tumour inhibiting rate
| Group | n | Transplanted tumor weight (g) | Tumour inhibiting rate (%) | Nude mice body weight (g) |
| Matched group | 8 | 1.86±0.29 | - | 26.11±3.10 |
| Ulinastatin high dose group | 8 | 0.83±0.14** | 40.21% | 23.76±2.64 |
| Dosage group in ulinastatin | 8 | 0.88±0.16** | 38.54% | 23.95±2.36 |
| Ulinastatin low dose group | 8 | 1.00±0.24** | 31.84% | 24.87±2.02 |
| Cisplatin group | 8 | 0.92±0.18** | 40.35% | 21.94±2.18 |
* 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: each ulinastatin medication group mice is not
Appearance activity minimizing and lethargy etc. show, and during experiment, mice feed is without significantly reducing, without substantially becoming thin, dead without nude mice
Dying, at transplanted tumor, skin is without ulceration or erosion.Each experimental group nude mouse weight average slowly increases, and the most each medication group nude mice body weight increases
Long slightly slower than matched group, but no significant difference.Additionally, each ulinastatin medication group mice is carried out comprehensive postmortem, knot
Fruit finds that exception the most do not occur in the heart of nude mice, liver, kidney, lung, spleen, thymus, intestinal, stomach, shows the peace that ulinastatin is administered
Full property is higher.
(2) each treatment group is on tumor bearing nude mice tumor weight and the impact of tumour inhibiting rate: each medication group and matched group comparing difference
There is statistical significance (P ＜ 0.01), ulinastatin to the inhibition of Human gallbladder carcinoma transplanted tumor in nude mice close to existing medicine,
And ulinastatin is dose dependent to the treatment of Human gallbladder carcinoma transplanted tumor in nude mice.
Although the present invention is own open as above with preferred embodiment, but they are not for limiting the present invention, the present invention's
Protection domain should be as the criterion with the content that claims hereof protection domain is defined.Any it is familiar with the art person,
Without departing from the spirit and scope of the present invention, the various changes made or equivalent, all should belong to the protection of the present invention
Scope.
Claims (4)
1. ulinastatin purposes in preparation treatment carcinoma of gallbladder medicine.
Purposes the most according to claim 1, it is characterised in that described medicine is lyophilized injectable powder or injection.
Purposes the most according to claim 2, it is characterised in that described lyophilized injectable powder or injection are equipped with one or more
The acceptable additive of medicine.
Purposes the most according to claim 3, it is characterised in that the described acceptable additive of lyophilized injectable powder pharmacy is selected from
One in mannitol, lactose, gelatin hydrolysate, sodium chloride or glucose or its any mixture；Described injection is acceptable
Additive is selected from the one in water for injection, mannitol, sodium chloride or glucose or its any mixture.
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| CN201610562452.8A CN106110312A (en) | 2016-07-14 | 2016-07-14 | Ulinastatin purposes in preparation treatment carcinoma of gallbladder medicine |
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| CN201610562452.8A CN106110312A (en) | 2016-07-14 | 2016-07-14 | Ulinastatin purposes in preparation treatment carcinoma of gallbladder medicine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108048401A (en) * | 2018-01-03 | 2018-05-18 | 浙江大学 | People's biliary tract cancerous cell line and application |
| CN111529696A (en) * | 2020-06-19 | 2020-08-14 | 广东天普生化医药股份有限公司 | Application of ulinastatin in preparing medicine for preventing nasopharyngeal cancer metastasis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104203281A (en) * | 2012-03-30 | 2014-12-10 | 东丽株式会社 | Pharmaceutical composition for treatment and/or prevention of gall bladder cancer |
| CN105597091A (en) * | 2016-02-24 | 2016-05-25 | 广东天普生化医药股份有限公司 | Application of ulinastatin to preparation of medicine for treating skin injury caused by radiotherapy/chemotherapy |
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2016
- 2016-07-14 CN CN201610562452.8A patent/CN106110312A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104203281A (en) * | 2012-03-30 | 2014-12-10 | 东丽株式会社 | Pharmaceutical composition for treatment and/or prevention of gall bladder cancer |
| CN105597091A (en) * | 2016-02-24 | 2016-05-25 | 广东天普生化医药股份有限公司 | Application of ulinastatin to preparation of medicine for treating skin injury caused by radiotherapy/chemotherapy |
Non-Patent Citations (3)
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| 庄鹏远 等: "胆囊癌的靶向治疗", 《世界华人消化杂志》 * |
| 朱锦辉 等: "原发性胆囊癌中VEGF-C表达及与肿瘤恶性特征的相关性研究", 《浙江医学》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108048401A (en) * | 2018-01-03 | 2018-05-18 | 浙江大学 | People's biliary tract cancerous cell line and application |
| CN111529696A (en) * | 2020-06-19 | 2020-08-14 | 广东天普生化医药股份有限公司 | Application of ulinastatin in preparing medicine for preventing nasopharyngeal cancer metastasis |
| CN111529696B (en) * | 2020-06-19 | 2021-02-19 | 广东天普生化医药股份有限公司 | Application of ulinastatin in preparing medicine for preventing nasopharyngeal cancer metastasis |
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Application publication date: 20161116 |