CN110215510B - Application of polyprenozinc in preparing medicine for treating or relieving digestive tract injury caused by radiotherapy and chemotherapy - Google Patents
Application of polyprenozinc in preparing medicine for treating or relieving digestive tract injury caused by radiotherapy and chemotherapy Download PDFInfo
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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
- A61K38/05—Dipeptides
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
Abstract
The invention provides application of the polytrimethylene zinc in preparing a medicament for treating gastric injury caused by chemotherapy, the polytrimethylene zinc can reduce the rise of neurotransmitter 5-hydroxytryptamine and NF-kappa B in blood and brain tissues and related to emesis caused by radiotherapy and chemotherapy, reduce the irritation and injury of the radiotherapy and chemotherapy to digestive tract, and simultaneously can reduce the related symptoms of irritable bowel syndrome related to 5-hydroxytryptamine.
Description
The application is a divisional application of Chinese patent application with the application number of 2016109011015 and the application date of 2016, 10 and 17, and the invention name of 'application of the polyprenone in preparing medicines for treating digestive tract complications caused by chemotherapy'.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of polytrimethylene zinc in preparing a medicine for treating or relieving digestive tract injury caused by chemoradiotherapy.
Background
The radiotherapy and chemotherapy are the main means for treating tumors, and the radiotherapy and chemotherapy kill tumor cells and often cause uncomfortable symptoms such as nausea, vomiting and gastric mucosa damage of patients, so that the life quality of the patients is reduced, smooth progress of tumor treatment is prevented, and complications related to the tumor treatment, such as malnutrition, metabolic disorder, dehydration, gastrointestinal hemorrhage and the like are easily caused.
The polyprenol is a chelate of zinc and L-carnosine, the L-carnosine is an ideal transporter of zinc, can increase the absorption and metabolism of zinc in vivo, has anti-inflammatory and antioxidant functions, and has remarkable protection and repair effects on gastric mucosal injury caused by alcohol, acetic acid, hydrochloric acid, nonsteroidal anti-inflammatory drugs and the like.
The prior art discloses a plurality of techniques for treating digestive tract ulcers caused by gastric acid imbalance and other reasons, for example, CN201310227401.6 discloses a polyprenone compound which improves the efficacy of the mucosal defense effect by being adhered to the damaged part of the mucosa; the prior art also discloses the application of some polyprenol zinc in improving complications caused by radiotherapy and chemotherapy, such as the application of the polyprenol zinc in relieving bladder pain caused by cyclophosphamide and treating peripheral neuropathy caused by taxol. However, the prior art does not disclose the use of the polytrimethylene zinc for treating emesis and digestive tract injury caused by radiotherapy and chemotherapy.
Disclosure of Invention
The invention provides an application of polytrimethylene zinc in preparing a medicament for treating or relieving digestive tract complications caused by radiotherapy and chemotherapy.
Furthermore, the digestive tract complication caused by radiotherapy and chemotherapy is emesis caused by radiotherapy and chemotherapy.
Furthermore, the digestive tract complication caused by radiotherapy and chemotherapy is digestive tract injury caused by radiotherapy and chemotherapy.
The invention also provides application of the polytrimethylene zinc in preparing a medicament for treating or relieving irritable bowel syndrome.
Irritable bowel syndrome (irritable bowel syndrome, IBS) is a common functional bowel disorder with abdominal pain or discomfort as a major symptom, and is ameliorated after defecation, often accompanied by changes in bowel habits, and lack of morphological and biochemical abnormalities explaining the symptoms. The etiology is generally the result of interaction between stress response and psychological factors of the organism, and different individuals may involve genetic, environmental, psychological, social and gastrointestinal infections, so that gastrointestinal motility changes, brain-intestinal axis interaction disorders, autonomic nerves and hormone changes and the like, and patients with mental disorders (such as panic, anxiety, post-traumatic stress disorder and the like), sleep disorders and psychological coping disorders, and stress life events often lead to exacerbation of symptoms. The research shows that the symptoms of obviously increased 5-hydroxytryptamine level in the body are all generated in the patients with the irritable bowel syndrome, so that the 5-hydroxytryptamine level is inferred to be closely related to the irritable bowel syndrome, and the patients with the irritable bowel syndrome can treat the irritable bowel syndrome and relieve the uncomfortable symptoms of the irritable bowel syndrome by taking the polytrimethylene zinc to control the 5-hydroxytryptamine level in the body.
The invention also provides a preparation which comprises the polyprenone and a medicinal carrier.
Further, the preparation is a tablet, granule, capsule or pellet preparation.
Further, the preparation is preferably a tablet, and the tablet comprises the following components in parts by weight: 20-30 parts of polyprenone and a medicinal carrier, wherein the medicinal carrier comprises the following components in parts by weight:
the medicinal carrier consisting of pregelatinized starch, manna, sodium hydroxymethyl cellulose, maltitol and sodium lactate and the polyprenone are adopted to prepare the tablet together, so that the acting time of the tablet in the digestive tract can be prolonged, and the curative effect of treating or relieving digestive tract complications caused by radiotherapy and chemotherapy can be prolonged.
Further, the medicinal carrier also comprises the following components in parts by weight:
ethyl maltol 1-3
Ascorbyl palmitate 0.5-1.5.
The addition of ethyl maltol and ascorbyl palmitate in the tablet can further prolong the acting time of the tablet in the digestive tract, prolong the curative effect of the tablet in treating or relieving digestive tract complications caused by radiotherapy and chemotherapy, reduce one of the components, or change one of the components, so that the acting time of the tablet is shortened.
Further, the medicinal carrier also comprises the following components in parts by weight:
propyl gallate 0.2-0.8
Potassium sorbate 0.1-0.3.
The stability of the tablet can be improved by adding propyl gallate and potassium sorbate to the tablet, and the stability of the tablet is reduced by reducing one of the components or changing one of the components.
Further, the preparation method of the tablet comprises the following steps:
s1, dissolving sodium hydroxymethyl cellulose and half of mannan in distilled water with the mass of 10 times to prepare a mixed solution;
s2, uniformly mixing the zinc polytrimethylene, pregelatinized starch and the balance of mannans, and crushing to obtain microparticles with the particle size of 10-20 mu m;
s3, mixing the mixed solution obtained in the step S1 and the microparticles obtained in the step S2 to prepare a soft material, sieving with a 14-mesh sieve for granulating, drying, sieving with the 14-mesh sieve for granulating to obtain medicine particles;
s4, uniformly mixing the drug particles obtained in the step S3 with maltitol and sodium lactate, and then placing the mixture in a tablet press to prepare tablets.
Furthermore, the preparation is preferably granules, and the granules mainly comprise the following components in parts by weight: 4-10 of polyprenone and a medicinal carrier, wherein the medicinal carrier comprises the following components in parts by weight:
further, the preparation method of the granule comprises the following steps: mixing all the raw materials uniformly, adding into 60% ethanol water solution, stirring until all the raw materials are dissolved, granulating, and drying to obtain the granule.
Further, the preparation is preferably a pellet preparation, and the pellet preparation mainly comprises the following components in parts by weight: 4-10 of polyprenone and a medicinal carrier, wherein the medicinal carrier comprises the following components in parts by weight:
further, the preparation method of the pellet preparation comprises the following steps: respectively sieving the zinc polytrimethylene terephthalate, the hydroxypropyl methylcellulose, the hydroxypropyl cellulose and the crospovidone with a 100-mesh sieve, and fully and uniformly mixing to obtain a mixture; uniformly mixing the mixture with mannitol to prepare a soft material; putting the soft material into an extruder to be extruded into strip-shaped extrudate; and then adding the strip-shaped extrudate into a rounding machine to round for 5-8min, and drying to obtain the pellet preparation.
The invention also provides a sustained-release preparation which is a double-layer tablet consisting of a sustained-release layer and a quick-release layer, wherein the sustained-release layer is prepared from 8-15 parts by weight of maltodextrin, 5-10 parts by weight of polymethyl methacrylate, 5-10 parts by weight of microcrystalline cellulose, 1-3 parts by weight of maltitol and 0.5-1.5 parts by weight of myristyl alcohol, and the quick-release layer is prepared from 3-6 parts by weight of polytrimethylene zinc, 3-8 parts by weight of pregelatinized starch, 2-5 parts by weight of dextran, 2-5 parts by weight of sodium starch glycolate and 1-2 parts by weight of potassium alginate.
The solubility of the slow release layer prepared from maltodextrin, polymethyl methacrylate, microcrystalline cellulose, maltitol and myristyl alcohol is proper, and the slow release effect is achieved; the pregelatinized starch and the glucan in the quick-release layer can promote the absorption of human body to the polyprenone, and the sodium starch glycolate and the sodium cholate jointly play the role of the disintegrating agent, so that the disintegration time limit of the quick-release layer is lower than 10s.
Further, the preparation method of the sustained release preparation comprises the following steps: uniformly mixing the polyprenone, pregelatinized starch and glucan, crushing by a superfine crusher to obtain a micropowder with the particle size of 10-25 mu m, uniformly mixing the micropowder with sodium starch glycolate and potassium alginate, and granulating by a dry method to obtain first particles; uniformly mixing maltodextrin, polymethyl methacrylate, microcrystalline cellulose, maltitol and myristyl alcohol, and granulating by a dry method to obtain second granules; and (3) placing the first particles and the second particles in a double-layer tablet press to obtain the slow release preparation.
The invention provides application of the polytrimethylene zinc in preparing medicines for treating or relieving digestive tract complications and irritable bowel syndrome caused by radiotherapy and chemotherapy, the polytrimethylene zinc can reduce the rise of neurotransmitter 5-hydroxytryptamine and NF- κB related to emesis in blood and brain tissues caused by radiotherapy and chemotherapy, reduce the irritation and injury of radiotherapy and chemotherapy to digestive tracts, and simultaneously can relieve the related symptoms of the irritable bowel syndrome related to 5-hydroxytryptamine.
Drawings
FIG. 1 is a diagram showing the morphology and organization of small intestine cells of SD rat after 20 days of continuous administration;
FIG. 2 shows the morphology and structure of the forestomach cells of SD rats after 20 days of continuous administration;
FIG. 3 shows the morphology and org-chart of SD rat glandular cells after 20 days of continuous administration.
Detailed Description
Example 1
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
example 2
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
the preparation method of the tablet comprises the following steps:
s1, dissolving sodium hydroxymethyl cellulose and half of mannan in distilled water with the mass of 10 times to prepare a mixed solution;
s2, uniformly mixing the zinc polytrimethylene, pregelatinized starch and the balance of mannans, and crushing to obtain microparticles with the particle size of 10 mu m;
s3, mixing the mixed solution obtained in the step S1 and the microparticles obtained in the step S2 to prepare a soft material, sieving with a 14-mesh sieve for granulating, drying, sieving with the 14-mesh sieve for granulating to obtain medicine particles;
s4, uniformly mixing the drug particles obtained in the step S3 with maltitol and sodium lactate, and then placing the mixture in a tablet press to prepare tablets.
Example 3
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
example 4
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
example 5
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
the preparation method of the tablet comprises the following steps:
s1, dissolving sodium hydroxymethyl cellulose and half of mannan in distilled water with the mass of 10 times to prepare a mixed solution;
s2, uniformly mixing the zinc polytrimethylene, pregelatinized starch and the balance of mannans, and crushing to obtain microparticles with the particle size of 15 mu m;
s3, mixing the mixed solution obtained in the step S1 and the microparticles obtained in the step S2 to prepare a soft material, sieving with a 14-mesh sieve for granulating, drying, sieving with the 14-mesh sieve for granulating to obtain medicine particles;
s4, uniformly mixing the drug particles obtained in the step S3 with maltitol and sodium lactate, and then placing the mixture in a tablet press to prepare tablets.
Example 6
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
example 7
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
example 8
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
example 9
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
example 10
A granule is prepared from the following components in parts by weight:
example 11
A granule is prepared from the following components in parts by weight:
example 12
A granule is prepared from the following components in parts by weight:
example 13
A pellet preparation is prepared from the following components in parts by weight:
example 14
A pellet preparation is prepared from the following components in parts by weight:
example 15
A pellet preparation is prepared from the following components in parts by weight:
comparative example 1
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
comparative example 2
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
comparative example 3
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
comparative example 4
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
comparative example 5
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
comparative example 6
A tablet is prepared, and 100 tablets are prepared by the following components in parts by weight:
efficacy test of treatment or alleviation of digestive tract complications caused by radiotherapy and chemotherapy by Polymerrill zinc
1. Material
Powder of polyprenol zinc: jilin province Bodawei pharmaceutical Co., ltd;
sterile 0.9% sodium chloride injection: tianjin Baite medical supplies Co., ltd;
cisplatin for injection (lyophilized): qilu pharmaceutical Co Ltd;
cyclophosphamide for injection: jiangsu Hengrui medicine Co., ltd;
standard protein BSA: sigma Co;
5-HT Elisa assay kit: beijing winter Song industry Biotechnology Co., ltd;
NF- κB Elisa detection kit: beijing winter Song industry Biotechnology Co., ltd;
SD rats: 30, male and female halves, 140-160g, SPF grade animals, offered by China food and drug testing institute.
2. Instrument and equipment
Ultra-clean bench: the Beijing Xincheng county beam house-to-camp purification equipment factory;
oraus electronic precision balance: U.S. A OHAUS corp, measuring range is 0.01-510 g;
inverted microscope: NIKON of Japan;
PM-6 microscope: olympus;
centrifuge: race moeid T16-40;
enzyme-labeled instrument: a Diken Infinite F50;
medical purification workbench: the model CJ-2F of the limited equipment of von Willebrand laboratory animals in Suzhou, the purification grade of 100 (U.S. Federal standard 209E), the average colony count is less than or equal to 0.5 colony/dish, the average wind speed is 0.4+/-20%, the noise is less than or equal to 62dB (A), and the vibration is less than or equal to 3 mu m (X, Y, Z directions).
3. Test method
30 SD rats were randomly averaged into 5 groups as follows:
control group (C): normally raising;
cyclophosphamide group (CTX): the cyclophosphamide is used once every three days, and the dosage is 40mg/kg each time;
cisplatin group (DDP): cisplatin is used once every three days, and the dosage is 5mg/kg each time;
group (pz+ctx) of polypyridose zinc+cyclophosphamide: the polytrimethylene zinc powder is infused for 1 time in a fixed time every day, and the dosage is 200mg/kg each time; cyclophosphamide is used once every three days, and the dosage is 40mg/kg each time;
polytaprezin+cisplatin group (pz+ddp): the polytrimethylene zinc powder is infused for 1 time in a fixed time every day, and the dosage is 200mg/kg each time; cisplatin is administered once every three days, at a dose of 5mg/kg each time.
The test is carried out for 20 days, SD rats are bred in animal breeding chambers with barrier systems in the test process, the temperature of the breeding chambers is 22-25 ℃, the daily temperature difference is less than or equal to 3 ℃, the relative humidity is 40-60%, the light and shade of illumination are alternated for 12 hours, the air cleanliness is 100, the ammonia concentration is less than or equal to 14mg/m < 3 >, the noise is less than or equal to 60 dB, the working illuminance is 150-300LX, and the animal illuminance is 100-200LX; SD rats eat sterilized mouse feed and drink the filtered sterilized water freely. After 24 hours from the last dose, SD rats were sacrificed and body weights were weighed; then taking stomach and intestine tissues of each SD rat, adopting 10% formalin for fixation, HE staining and microscopic observation; taking brain tissue and serum of each SD rat to detect 5-hydroxytryptamine and NF- κB in the brain tissue and serum, wherein the 5-HT Elisa detection kit is adopted to detect the content of the 5-hydroxytryptamine in rat blood and brain tissue homogenate; the NF- κB content in rat blood and brain tissue homogenate is detected by NF- κB Elisa detection kit.
4. Statistical analysis
Data are expressed by + -S, the comparison among groups adopts t test, p value <0.05 is obvious, p value <0.01 is very obvious, and the data are statistically significant.
5. Test results
(1) The body weights of 5 groups of SD rats before and after the test were weighed, and the body weight changes before and after the test of SD rats were calculated, and the results are shown in Table 1.
Table 1 SD rat weight change statistics
Wherein: * Comparing with control group (C);
* Comparison with cyclophosphamide group (CTX);
* Comparison to cisplatin group (DDP).
From the above results, it was found that the weight of SD rats in cyclophosphamide group (CTX) and cisplatin group (DDP) was significantly lower than that of the control group after 20 days of administration, whereas the polyprenone+cyclophosphamide group (PZ+CTX) and the polyprenone+cisplatin group (PZ+DDP) showed that the weight loss was suppressed after administration of the polyprenone to SD rats, and that the weight change statistical comparison difference was significant between the polyprenone+cyclophosphamide group (PZ+CTX) and the polyprenone+cisplatin group (PZ+DDP) compared with cyclophosphamide group (CTX) and cisplatin group (DDP), indicating that the polyprenone can effectively treat or reduce digestive tract complications caused by radiotherapy and chemotherapy.
(2) Serum and brain tissue of each SD rat were collected, and neurotransmitter 5-hydroxytryptamine and NF- κB associated with emesis were detected in the serum and brain tissue of SD rat after the end of the test, and the detection results of each group were compared, and the results are shown in Table 2.
TABLE 2 detection results of 5-hydroxytryptamine and NF- κB in SD rat
Wherein: * Compared to cyclophosphamide group (CTX);
* Comparison to cisplatin group (DDP).
From the above results, SD rats of cyclophosphamide group (CTX) and cisplatin group (DDP) were significantly elevated in 5-hydroxytryptamine and NF- κB values after 20 days with CTX or DDP alone compared to the control group; and the combination drug of the gastric-irrigation polytrimethylene zinc is adopted by the polytrimethylene zinc and cyclophosphamide group (PZ+CTX) and the polytrimethylene zinc and cisplatin group (PZ+DDP), the values of 5-hydroxytryptamine and NF-kappaB are obviously reduced relative to those of the cyclophosphamide group (CTX) and the cisplatin group (DDP), and the statistical comparison difference is obvious, so that the polytrimethylene zinc can effectively treat or relieve the vomiting symptoms caused by radiotherapy and chemotherapy.
(3) Small intestine, forestomach and adenogastric tissues of each SD rat were individually collected, fixed with 10% formalin, HE stained, and then observed under a 400x microscope, the results of which are shown in fig. 1-3.
As can be seen from fig. 1: the control group (C) has normal small intestine tissue structure of SD rats and orderly arranged cells; cyclophosphamide group (CTX) SD rat small intestine cell gap broadening; cisplatin group (DDP) SD rat nuclear contractile cell atrophy; the small intestine structure of the SD rat of the group of the polyprenozinc and cyclophosphamide (PZ+CTX) is clear; the arrangement of intestinal villi of SD rats of the group of the polyprenozinc and the cisplatin (PZ+DDP) is basically normal, and the structure is clear.
As can be seen from fig. 2: control (C) SD rats had normal anterior gastric squamous epithelium; cyclophosphamide group (CTX) SD rats have forestomach cell enlargement and abscission; cisplatin group (DDP) SD rat forestomach cell enlargement, shedding; the anterior gastric squamous epithelium of the polyprenozinc + cyclophosphamide group (PZ + CTX) SD rats is clear; polypregrezinc plus cisplatin group (PZ+DDP) SD rat anterior gastric squamous epithelium structure is clear, and cell morphology is basically normal
As can be seen from fig. 3: the control group (C) has normal morphology of SD rat adenogastric cells, complete villus and orderly arrangement of glands; cyclophosphamide group (CTX) SD rat glandular gastric cell gap is widened and cells are atrophic; cisplatin group (DDP) SD rat glandular stomach cell structure is unclear, villus atrophy; the stomach cells of the SD rat of the polyprenozinc and cyclophosphamide group (PZ+CTX) are orderly arranged, and the morphology is basically normal; the polyprenozinc plus cisplatin group (PZ+DDP) SD rat adenoma and stomach villus are complete, and the glands are orderly arranged.
From the above observations, it can be seen that: CTX or DDP administered to the abdominal cavity of SD rats causes damage to the mucous membrane of the small intestine and the stomach, whereas the polyprenone has an effect of effectively treating or reducing damage to the digestive tract caused by chemoradiotherapy.
Comparative test of effects of Polyprimizine and other medicines for treating gastric ulcer and antiemetic medicines on treating or relieving digestive tract complications caused by radiotherapy and chemotherapy
1. Material
Powder of polyprenol zinc: jilin province Bodawei pharmaceutical Co., ltd;
sterile 0.9% sodium chloride injection: tianjin Baite medical supplies Co., ltd;
cisplatin for injection (lyophilized): qilu pharmaceutical Co Ltd;
cyclophosphamide for injection: jiangsu Hengrui medicine Co., ltd;
standard protein BSA: sigma Co;
5-HT Elisa assay kit: beijing winter Song industry Biotechnology Co., ltd;
NF- κB Elisa detection kit: beijing winter Song industry Biotechnology Co., ltd;
SD rats: 30, male and female halves, 140-160g, SPF grade animals, offered by China food and drug testing institute.
2. Instrument and equipment
Ultra-clean bench: the Beijing Xincheng county beam house-to-camp purification equipment factory;
oraus electronic precision balance: U.S. A OHAUS corp, measuring range is 0.01-510 g;
centrifuge: race moeid T16-40;
enzyme-labeled instrument: a Diken Infinite F50;
medical purification workbench: the model CJ-2F of the limited equipment of von Willebrand laboratory animals in Suzhou, the purification grade of 100 (U.S. Federal standard 209E), the average colony count is less than or equal to 0.5 colony/dish, the average wind speed is 0.4+/-20%, the noise is less than or equal to 62dB (A), and the vibration is less than or equal to 3 mu m (X, Y, Z directions). 3. Test method
30 SD rats were randomly averaged into 3 groups, each of test 1-3. All SD rats were treated with cyclophosphamide at 40mg/kg every three days; wherein, the test 1 group adopts the polytrimethylene zinc powder to irrigate the stomach for 1 time at fixed time every day, and the dosage of each time is 200mg/kg; the palonosetron powder is used for gastric lavage for 1 time in the test 2 groups at a fixed time every day, and the dosage of the palonosetron powder is 20mg/kg each time; the test 3 groups are subjected to gastric lavage with bismuth potassium citrate powder for 1 time at a fixed time every day, and the dosage is 100mg/kg each time.
The test is carried out for 20 days, SD rats are bred in animal breeding chambers with barrier systems in the test process, the temperature of the breeding chambers is 22-25 ℃, the daily temperature difference is less than or equal to 3 ℃, the relative humidity is 40-60%, the light and shade of illumination are alternated for 12 hours, the air cleanliness is 100, the ammonia concentration is less than or equal to 14mg/m < 3 >, the noise is less than or equal to 60 dB, the working illuminance is 150-300LX, and the animal illuminance is 100-200LX; SD rats eat sterilized mouse feed and drink the filtered sterilized water freely. After 24 hours from the last dose, SD rats were sacrificed and body weights were weighed; taking brain tissue and serum of each SD rat to detect 5-hydroxytryptamine and NF- κB respectively, wherein the 5-HT Elisa detection kit is adopted to detect the content of 5-hydroxytryptamine in rat blood and brain tissue homogenate respectively; the NF- κB content in rat blood and brain tissue homogenate is detected by NF- κB Elisa detection kit.
4. Statistical analysis
Data are expressed by + -S, the comparison among groups adopts t test, p <0.05 is obvious in difference, p <0.01 is very obvious in difference, and the data are statistically significant.
5. Test results
(1) The weights of the SD rats of the test groups 1 to 3 before and after the test were weighed, and the weight changes before and after the test of the SD rats were calculated, and the results are shown in Table 3.
Table 3 SD rat weight change statistics
Wherein: the P values are all compared to the test 1 group.
From the above results, the SD rats in the test group 2 and the test group 3 are significantly lighter in weight than those in the test group 1 after 20 days of administration, and the statistical comparison difference of the weight changes is significant, which indicates that the zinc polyprenone is more effective in treating or relieving digestive tract complications caused by radiotherapy and chemotherapy than the antiemetic drug palonosetron and the gastric ulcer drug bismuth potassium citrate.
(2) Serum and brain tissue of each SD rat were collected, and neurotransmitter 5-hydroxytryptamine and NF- κB associated with emesis were detected in the serum and brain tissue of SD rat after the end of the test, and the detection results of each group were compared, and the results are shown in Table 4.
TABLE 4 detection results of 5-hydroxytryptamine and NF- κB in SD rat
Wherein: the P values are all compared to the test 1 group.
From the results, the 5-hydroxytryptamine and NF- κB values of SD rats in the test 2 group and the test 3 group are obviously higher than those of SD rats in the test 1 group after 20 days, and the statistical comparison difference is obvious, so that the effect of the polyprenone on treating or relieving vomiting symptoms caused by radiotherapy and chemotherapy is better compared with that of an antiemetic drug palonosetron and a gastric ulcer treatment drug bismuth potassium citrate.
Evaluation of in vitro Release of tablets
The tablets of examples 3, 6 and comparative examples 1 to 4 were taken and placed in a drug eluting apparatus, and samples were taken at 1h, 2h, 4h, 6h, 12h, 16h and 24h, respectively, and the percentage of eluted tablets were measured by high performance liquid chromatography, and the cumulative percentage of released tablets were calculated, and the results are shown in Table 5.
Table 5 cumulative percent (%) released test results for tablets
| Time (h) | Example 3 | Example 6 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 1 | 39 | 22 | 52 | 49 | 36 | 34 |
| 2 | 62 | 38 | 75 | 70 | 59 | 55 |
| 4 | 85 | 52 | 97 | 93 | 80 | 78 |
| 6 | 91 | 64 | 100 | 100 | 90 | 88 |
| 12 | 99 | 78 | -- | -- | 97 | 96 |
| 16 | 100 | 90 | -- | -- | 100 | 100 |
| 24 | -- | 99 | -- | -- | -- | -- |
From the above test results, the tablets provided in example 3 of the present invention can be sustained to release slowly within 16 hours, while the tablets provided in comparative examples 1 and 2 are completely released within 6 hours, which indicates that the tablets provided in the present invention can prolong the acting time in the digestive tract, and prolong the therapeutic effect of treating or alleviating digestive tract complications caused by radiotherapy and chemotherapy.
The tablets provided in the embodiment 6 of the invention can be continuously and slowly released for more than 24 hours, and the tablets provided in the embodiment 3, the comparative example 3 and the comparative example 4 can be completely released within 16 hours, which shows that the addition of ethyl maltol and ascorbyl palmitate into the tablets can further prolong the acting time of the tablets in the alimentary canal, prolong the curative effect of the tablets in treating or relieving the complications of the alimentary canal caused by chemoradiotherapy, reduce one component, or change one component, and shorten the acting time of the tablets.
Evaluation of tablet stability
1. Acceleration test
Taking the tablets of the examples 6, 9 and the comparative examples 5-6, placing the tablets for 6 months at the temperature of 40+/-2 ℃ and the relative humidity of 75+/-5%, sampling once respectively at the end of 1 month, 2 months, 3 months and 6 months during the test period, and detecting the properties, the color, the smell, the content of main components (marked weight percent) and the moisture of the tablets, wherein the tablets of the example 9 are found to have no obvious change in all indexes; the tablets of example 6 and comparative examples 5-6 exhibited various degrees of moisture content increase and color darkening.
2. Long-term test
Taking tablets of examples 6, 9 and comparative examples 5-6, placing the tablets for 12 months at the temperature of 25+/-2 ℃ and the relative humidity of 60+/-10%, sampling once at the end of 0 month, 3 months, 6 months, 9 months and 12 months respectively during the test period, and detecting the properties, the color, the main component content (marked weight percent) and the moisture of the tablets, wherein the tablets of example 9 have no obvious change in various indexes; the tablets of example 6 and comparative examples 5-6 exhibited various degrees of moisture content increase and color darkening.
From the results of the above-described acceleration test and long-term test, it was found that the addition of propyl gallate and potassium sorbate to tablets significantly improved the stability of the tablets, reduced one of the components, or changed one of the components, and the stability of the tablets was lowered.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (1)
1. The preparation is a tablet, and the tablet is mainly prepared from the following components in parts by weight: 20-30 parts of polyprenone and a medicinal carrier, wherein the medicinal carrier comprises the following components in parts by weight:
pregelatinized starch 8-12
Mannans 3-6
Sodium hydroxymethylcellulose 1-3
Maltitol 0.5-2
Sodium lactate 0.1-0.3
Ethyl maltol 1-3
Ascorbyl palmitate 0.5-1.5
Propyl gallate 0.2-0.8
Potassium sorbate 0.1-0.3.
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Non-Patent Citations (2)
| Title |
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| Polaprezinc protects normal intestinal epithelium against exposure to ionizing radiation in mice;Soichi Odawara et al;《Molecular and Clinical Oncology》;20160808;第5卷(第4期);第377-381页 * |
| The usefulness of pharmacokinetic modulating chemotherapy(UFT plus 5FU) in the treatment of unresectable colorectal carcinomas;Masato Kusunoki et al;《ONCOLOGY REPORTS》;19991231;第6卷;第547-552页 * |
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