Light-activated methylene blue preparation process for targeted therapy of various cancers and various hyperplasia cardio-cerebral thrombosis diseases

Abstract

The invention relates to a light-activated methylene blue preparation process for targeted therapy of various cancers and various hyperplasia cardio-cerebral thrombosis diseases. The death rate of cancer patients is about 80%, heart and cerebral thrombosis severely endangers life, and the occurrence rate of hyperplasia diseases of old people is more than 75%. The key point is that the methylene blue can dye the cells, but after the cells are colored, normal cells can decolor the methylene blue, and cancer cell hyperplasia cells and thrombus cells lose the capability of decoloring the methylene blue. The key point is that methylene blue is a molecule with positive charges, and can be embedded into DNA and RNA of cancer cell hyperplasia cells and thrombus cells after light activation, so that replication is prevented, and targeted therapy is achieved. The traditional Chinese medicine composition is orally taken once every two days by adopting light-activated methylene blue, 120 milligrams of the traditional Chinese medicine composition are orally taken each time, and the traditional Chinese medicine composition is taken for 30-60 times, and has a targeted treatment effect on cancer hyperplasia heart-cerebral thrombosis diseases, and the curative effect is determined by a preparation process. The method for activating methylene blue by light is an effective way for targeted therapy of various cancers and various hyperplasia heart and cerebral thrombosis diseases. The preparation process comprises a preparation process of photo-activated methylene blue and capsule tablet granules.

Description

Technical Field

[0001] It belongs to the field of new drugs for targeted treatment of various cancers, various hyperplasias, and cardio-cerebral thrombosis diseases.

[0002] It belongs to the industrial technology field of various preparations of photoactivated methylene blue. Background Art

[0003] After inquiry, no same background art was found. Summary of the Invention

[0004] The key lies in utilizing the staining and decolorization characteristics of methylene blue. Methylene blue can stain cells, but after the cells are stained, normal cells can decolorize methylene blue, while cancer cells, hyperplastic cells, and thrombus cells lose the ability to decolorize methylene blue.

[0005] The key lies in utilizing the characteristics of photoactivated methylene blue. Methylene blue is a positively charged molecule. After being photoactivated, it can be embedded in the DNA and RNA of cancer cells, hyperplastic cells, and thrombus cells and cannot replicate, achieving targeted therapy.

[0006] The key lies in that multiple organ thromboembolism is the direct cause of myocardial infarction and cerebral infarction, and photoactivated methylene blue is used to achieve targeted therapy for myocardial infarction and cerebral infarction thromboembolism diseases.

[0007] A photoactivation device is adopted. Under set conditions, photoactivated methylene blue is used to achieve targeted therapy for various cancers, various hyperplasias, myocardial infarction, and cerebral infarction thromboembolism diseases.

[0008] Photoactivated methylene blue is respectively made into capsules, tablets, and granules for targeted therapy of various cancers, various hyperplasias, myocardial infarction, and cerebral infarction thromboembolism diseases.

[0009] Effective photoactivation conditions are explored, effective treatment doses and effective administration times are explored to achieve the purpose of targeted therapy.

[0010] Explore the use of photoactivated methylene blue and explore the targeted therapy approaches for targeted therapy of various cancers, various hyperplasias, myocardial infarction, and cerebral infarction thromboembolism diseases. Technical Solution

[0011] Basis of the solution 1: Malignant tumors are a class of frequently-occurring diseases that seriously threaten human life and health. Approximately 6 million people develop cancer worldwide every year, and about 4.3 million people die from cancer every year. In China, the number of newly-occurring cancer patients is more than 1.2 million every year, and about 1 million people die from cancer every year.

[0012] Basis of the solution 1: According to the data of the 2021 National Cancer Report of the National Cancer Center, the incidence of pancreatic cancer in China ranks eighth and the mortality ranks sixth, and the number of new cases and deaths is similar, and the challenge to life has reached the limit.

[0013] Basis of the solution 1: One-fourth of the pancreatic cancers worldwide occur in China. According to data from the International Agency for Research on Cancer, in 2020, there were more than 490,000 newly diagnosed pancreatic cancer patients worldwide, and in China, there were more than 120,000 newly diagnosed pancreatic cancer patients, that is, one-fourth of the newly diagnosed pancreatic cancers in the world are in China.

[0014] Basis of the solution 3: There are 2 billion people who have been infected with the hepatitis B virus worldwide, among which 350 million people have become hepatitis B virus patients. Every year, about 1 million people die from liver cancer, liver cirrhosis, and liver failure caused by hepatitis B virus infection.

[0015] Basis of the solution 5: Cardiovascular and cerebrovascular diseases, acute myocardial infarction and cerebral infarction are mainly caused by blood viscosity forming thrombus, leading to multi-organ embolism, thus endangering life.

[0016] Example of basis of the solution 1: The key lies in that methylene blue can stain cells, but normal cells can decolorize methylene blue after cell coloring, while cancer cells, proliferating cells, and thrombus cells lose the ability to decolorize methylene blue.

[0017] Example of basis of the solution 2: The key lies in that methylene blue is a positively charged molecule. After being photo-activated, it can be embedded in the DNA and RNA of cancer cells, proliferating cells, and thrombus cells to prevent replication, achieving the purpose of targeted therapy.

[0018] Example of basis of the solution 3: Animal experiments have confirmed that methylene blue shows a significant inhibitory effect on the proliferation of Ehrlich ascites carcinoma L1210 leukemia and P388 leukemia cancer cells in mice. The average lifespan of the mice in the drug administration group was significantly extended compared with the control group. The curative effect on L1210 leukemia was significantly better than that of 5-Fu. For the curative effect on P388 leukemia, not only was the average lifespan significantly extended compared with the control group, but more than 2 / 3 of the animals survived healthily for more than 60 days to achieve complete cure. When methylene blue was given simultaneously with adriamycin, the survival time of the mice could be extended, and the acute toxic effect of adriamycin could be reduced.

[0019] Direct killing effect: The cell growth inhibition experiment and the cell colony formation ability experiment were used to study the effect of methylene blue on the human colorectal cancer cell line LOVO cultured in vitro. At the same time, the damaged parts of the cancer cells were observed by transmission electron microscopy technology. The results showed that 13.25 μmol / L methylene blue could kill all colorectal cancer cells after acting for 24 hours, and 0.27 μmol / L methylene blue could significantly inhibit the proliferation of human colon cancer cells. The research results show that methylene blue has a significant killing and inhibitory effect on the human colorectal cancer cell LOVO cultured in vitro, and the damaged part of the cancer cells is in the mitochondria.

[0020] Based on Example 4, 14 cases of thromboangiitis were injected with 0.5% methylene blue into the artery at a dose of 1-2 mg / kg. It was injected once a week, and 3-5 times constituted one course of treatment. As a result, all 14 patients were cured, and there was no recurrence during the follow-up period of 3 months to 9 years. Among the patients with combined hypertension, the blood pressure could also decrease after the medication.

[0021] The scheme uses a photoactivation device. The methylene blue sample is placed on the device backing plate according to the set thickness. The methylene blue is activated by setting the sample thickness, illumination intensity, light activation time, number of light activations, and mixing the sample 3 times. And the photoactivated methylene blue samples are numbered.

[0022] The activated methylene blue samples are prepared into capsules, tablets, and granules respectively according to the sample numbers and the set doses. Example

[0023] For the production of the photoactivation device, 6 pieces of 5-mm thick glass plates are used to form a cuboid glass box. Among them, 4 pieces are 660 mm long and 500 mm wide. One of them is used as the bottom. At both sides of the bottom, the lower ends of the other two glass plates are connected and fixed to the bottom. Then, two glass plates with a width of 400 mm and a height of 500 mm are respectively set at both ends and connected and fixed to the bottom and the side glass plates. The fluorescent lamp is fixed on the inner side of the top cover glass, and a stainless steel plate is set on the bottom of the device. The upper plane of the stainless steel plate is 300 mm away from the fluorescent lamp. When in use, cover the lid to form the photoactivation device.

[0024] To prepare the photoactivated methylene blue Sample No. 1, take 50 g of methylene blue medicinal raw material powder, spread it on a stainless steel plate that is 500 mm long and 350 mm wide to form a 1-mm thick sample, place it on the backing plate of the photoactivation device, and cover the lid. Turn on the light. Under the condition of the same illumination intensity, each light activation lasts for 4 minutes, and the sample is mixed and leveled twice again. After 3 times of light activation, collect the sample and seal it. It is numbered as Photoactivated Methylene Blue Sample No. 1.

[0025] To prepare the photoactivated methylene blue Sample No. 2, take 50 g of methylene blue medicinal raw material powder, spread it on a stainless steel plate that is 500 mm long and 350 mm wide with a sample thickness of 1 mm, place it on the backing plate of the photoactivation device, and cover the lid. Turn on the light. Under the condition of the same illumination intensity, each light activation lasts for 7 minutes, and the sample is mixed and leveled 2 times again. After 3 times of light activation, collect the sample and store it sealed. It is numbered as Photoactivated Methylene Blue Sample No. 2.

[0026] Prepare the photoactivated methylene blue No. 3 sample. Take 50 grams of the medicinal raw material powder of methylene blue and spread it on a stainless steel plate with a length of 500 mm and a width of 350 mm. The thickness of the sample is 1 mm. Place it on the backing plate of the photoactivation device and cover it with the lid. Turn on the light. Under the condition of the same illuminance, activate it by light for 10 minutes each time. Mix and flatten the sample twice. After photoactivation for 3 times, collect the sample and store it sealed. Label it as the photoactivated methylene blue No. 3 sample.

[0027] Preparation of the capsule of the photoactivated methylene blue No. 1 sample. Take 12 grams of the photoactivated methylene blue No. 1 sample and add 0.6 grams of medicinal starch. Mix the two evenly, granulate, fill into No. 3 hollow capsules, and package. Label it as the photoactivated methylene blue No. 1 capsule, with a dose of 120 mg per capsule.

[0028] Preparation of the tablet of the photoactivated methylene blue No. 1 sample. Take 12 grams of the photoactivated methylene blue No. 1 sample and add 0.6 grams of medicinal starch. Mix the two evenly, granulate, press into tablets, and package. Label it as the photoactivated methylene blue No. 1 tablet, with a dose of 120 mg per tablet.

[0029] Preparation of the granule of the photoactivated methylene blue No. 1 sample. Take 12 grams of the photoactivated methylene blue No. 1 sample and 0.6 grams of medicinal starch. Mix the two evenly, granulate, and pack it into an aluminum-plastic film bag and seal it. Label it as the photoactivated methylene blue No. 1 granule, with a dose of 120 mg per bag.

[0030] Preparation of the capsule of the photoactivated methylene blue No. 2 sample. Take 12 grams of the photoactivated methylene blue No. 2 sample and 0.6 grams of medicinal starch. Mix the two evenly, granulate, fill into No. 3 hollow capsules, and package. Label it as the photoactivated methylene blue No. 2 sample capsule, with a dose of 120 mg per capsule.

[0031] Preparation of the tablet of the photoactivated methylene blue No. 2 sample. Take 12 grams of the photoactivated methylene blue No. 2 sample and 0.6 grams of medicinal starch. Mix the two evenly, granulate, press into tablets, and package. Label it as the photoactivated methylene blue No. 2 tablet, with a dose of 120 mg per tablet.

[0032] Preparation of the granule of the photoactivated methylene blue No. 2 sample. Take 12 grams of the photoactivated methylene blue No. 2 sample and 0.6 grams of medicinal starch. Mix the two evenly, granulate, and sub-pack it into aluminum-plastic film bags, seal it, and package. Label it as the photoactivated methylene blue No. 2 granule, with a dose of 120 mg per bag.

[0033] Preparation of the capsule of the photoactivated methylene blue No. 3 sample. Take 12 grams of the photoactivated methylene blue No. 3 sample and 0.6 grams of medicinal starch. Mix the two evenly, granulate, fill into No. 3 hollow capsules, and package. Label it as the photoactivated methylene blue No. 3 capsule, with a dose of 120 mg per capsule.

[0034] Preparation of the photoactivated methylene blue No. 3 sample tablets: Take 12 g of the photoactivated methylene blue No. 3 sample and 0.6 g of medicinal starch. Mix the two, granulate, press into tablets, and package. Labeled as photoactivated methylene blue No. 3 tablets, with a dose of 120 mg / tablet.

[0035] Preparation of the photoactivated methylene blue No. 3 sample granules: Take 12 g of the photoactivated methylene blue No. 3 sample and 0.6 g of medicinal starch. Mix the two, granulate, and subpackage into aluminum-plastic film bags, seal, and package. Labeled as photoactivated methylene blue No. 3 granules, with a dose of 120 mg / bag.

[0036] The purpose of preparing each sample into capsules, tablets, and granules is as follows: From the perspective of the absorption rate in the body, granules are absorbed quickly, capsules are absorbed relatively slowly, and tablets are absorbed the slowest according to clinical needs; from the perspective of patient adaptability, sugar-coated tablets and granules need to contain sugar, which is not suitable for diabetic patients with complications; in order to observe the results, additives in the preparation should be minimized as much as possible.

[0037] The preparations in this scheme are for patients with various cancers, various hyperplasias, cardio-cerebral thrombosis embolism diseases, different conditions. Different patients have differences in the activation time of light irradiation and different preparations. Different light irradiation times and different samples are used to observe the treatment effects, which is convenient for clinical application.

[0038] To determine the medication time, observe how long it can be metabolized and excreted from the body after taking the medicine by the change in the color of urine after taking the medicine. As a result, it can be metabolized and excreted about 46 hours after taking. It can be set to take once every two days, and observe the dosage of 120 mg each time.

[0039] Preliminary observation shows that the effect of sample No. 2 is the best when taking the photoactivated methylene blue No. 1, No. 2, and No. 3 preparations once every two days for 15 to 30 times. The results show that the preparation technology determines the drug effect.

[0040] For the samples prepared according to the technical scheme of this application and various preparations prepared, the practical results show that the technical scheme of this application is basically feasible.

Claims

1. A process for preparing a photoactivated methylene blue preparation for targeted treatment of various cancers, various hyperplastic diseases, and cardio-cerebral vascular diseases. The mortality rate of cancer patients is about 80%. Cardio-cerebral vascular diseases seriously endanger life. The incidence rate of hyperplastic diseases in the elderly is over 75%. The key lies in that methylene blue can stain cells, but normal cells can decolorize methylene blue after cell coloring, while cancer cells, hyperplastic cells, and thrombus cells lose the ability to decolorize methylene blue. The key is that methylene blue is a positively charged molecule, which can be embedded into the DNA and RNA of cancer cells, hyperplastic cells, and thrombus cells after photoactivation, preventing replication and achieving targeted treatment. Multiple organ thromboembolism is the direct cause of myocardial infarction and cerebral infarction. Observe the in vivo metabolism process and dosing interval of orally administered photoactivated methylene blue. The preliminary results show that the urine turns blue after oral administration of this product. Judge the metabolic situation according to the change of urine color. Excretion starts 3 - 6 hours after oral administration, and the urine turns blue. The blue color of the urine gradually fades until there is no blue after 9 - 12 hours. Using photoactivated methylene blue, adults take it orally once every two days, 120 mg each time, for 15 to 30 times, which has a targeted therapeutic effect on cancer, hyperplasia, and cardio-cerebral vascular diseases. Its preparation process determines the curative effect. Using photoactivated methylene blue is an effective way for targeted treatment of various cancers, various hyperplastic diseases, and cardio-cerebral vascular diseases. The said preparation process includes a photoactivation device and the preparation of photoactivated methylene blue samples No. 1, No. 2, and No.

3. The preparation processes of capsules, tablets, and granules of photoactivated methylene blue samples No. 1, No. 2, and No.

3.

2. The fabrication of the photoactivation device according to claim 1, characterized in that: Use 6 glass plates, 4 of which are 660 mm long, 500 mm wide, and 5 mm thick. Use 1 of them as the bottom, 2 of them as the walls, and connect and fix the lower ends of the two side walls to the bottom along the length. The other 2 are 400 mm wide and 500 mm high, and are respectively set at both ends of the three-piece long glass connection body and fixed. Use the remaining 1 glass plate that is 660 mm long and 500 mm high as the cover to form a glass box. Set the fluorescent lamp at the lower end of the box cover, and set a backing plate on the inner side of the box bottom. The plane of the backing plate is 300 mm high from the lamp to form a photoactivation device.

3. The preparation of the methylene blue light-activated sample 1 according to claim 1, wherein: Put the methylene blue sample on the backing plate of the photoactivation device. Under the condition of the same illuminance, each time the light activation is 4 minutes, the sample is mixed and leveled 3 times, the light activation is 3 times, the sample thickness is 1 mm. After the light activation ends, collect the sample and seal it. It is numbered as photoactivated methylene blue sample No.

1.

4. The preparation of the methylene blue light-activated sample 2 according to claim 1, wherein: Put the methylene blue sample on the backing plate of the photoactivation device. Under the condition of the same illuminance, each time the light activation is 7 minutes, the sample is mixed and leveled 3 times, the light activation is 3 times, the sample thickness is 1 mm. After the light activation ends, collect the sample and seal it. It is numbered as photoactivated methylene blue sample No.

2.

5. The preparation of the methylene blue light-activated sample 3 according to claim 1, characterized in that: Put the methylene blue sample on the backing plate of the photoactivation device. Under the condition of the same illuminance, each time the light activation is 10 minutes, the sample is mixed and leveled 3 times, the light activation is 3 times, the sample thickness is 1 mm. After the light activation ends, collect the sample and seal it. It is numbered as photoactivated methylene blue sample No.

3.

6. The preparation of the methylene blue light-activated sample capsule according to claim 1, characterized in that: According to the set dosage, add Sample 1, Sample 2, and Sample 3 respectively to 5% medicinal starch, mix well to granulate, and then fill them into hollow capsules respectively for packaging. They are respectively numbered as Methylene Blue Light-Activated Sample 1 Capsule, Methylene Blue Light-Activated Sample 2 Capsule, and Methylene Blue Light-Activated Sample 3 Capsule.

7. The preparation of the methylene blue light-activated sample tablet according to claim 1, characterized in that: According to the set dosage, add Sample 1, Sample 2, and Sample 3 respectively to 5% medicinal starch, mix well to granulate, and then press them into tablets respectively for packaging. They are respectively numbered as Methylene Blue Light-Activated Sample 1 Tablet, Methylene Blue Light-Activated Sample 2 Tablet, and Methylene Blue Light-Activated Sample 3 Tablet.

8. The preparation of the methylene blue light-activated sample granule according to claim 1, wherein: According to the set dosage, add 5% of medicinal starch to Sample 1, Sample 2, and Sample 3 respectively, mix well to granulate, and then separately pack them into aluminum-plastic bags for granule agents for packaging. They are respectively numbered as Methylene Blue Light-Activated Sample 1 Granule Agent, Methylene Blue Light-Activated Sample 2 Granule Agent, and Methylene Blue Light-Activated Sample 3 Granule Agent.

9. According to the actual application needs of clinical observation, the illumination time, illumination frequency, sample thickness can be adjusted, the structure of the photoactivation device can be changed to be suitable for activating various photosensitizers, the preparation process can be improved, and the preparation process parameters can be improved to be suitable for the preparation of various preparations. Adjust the dosage of each dosage form or increase the dosage form and indication.