Preparation process for targeted therapy of various cancers and various hyperplasia heart and cerebral thrombosis diseases by light-activated methylene blue riboflavin

Abstract

The invention relates to a preparation process for targeted therapy of various cancers and various hyperplasia heart and cerebral thrombosis diseases by light-activated methylene blue riboflavin. 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 to prevent replication after light activation. Light-activated riboflavin can promote apoptosis of tumor cells to achieve targeted therapy, and primary observation shows that 120 mg of light-activated methylene blue each time, and the light-activated methylene blue has a targeted therapy effect on cerebral infarction, cerebral thrombosis and prostatic hyperplasia once every two days. The light-activated methylene blue riboflavin initiates a new field of targeted therapy of various cancers and various hyperplastic heart and cerebral thrombosis diseases. The preparation process comprises a preparation process of photo-activated methylene blue riboflavin and capsules.

Description

Technical Field

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

[0002] It belongs to the technical field of preparation of various targeted preparations of photo-activated methylene blue riboflavin. Background Art

[0003] After inquiry, no identical 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 photo-activated methylene blue. Methylene blue is a positively charged molecule. After photo-activation, it can be embedded in the DNA and RNA of cancer cells, hyperplastic cells, and thrombus cells to prevent replication, achieving targeted therapy.

[0006] The key lies in utilizing photo-activated riboflavin to promote apoptosis of tumor cells to achieve targeted therapy.

[0007] The key lies in the fact that multi-organ thromboembolism is the direct cause of myocardial infarction and cerebral infarction, and photo-activated methylene blue is used to achieve targeted therapy for myocardial infarction and cerebral infarction thromboembolism diseases.

[0008] Explore the photo-activation conditions, adopt a photo-activation device, and under the set conditions, use photo-activated methylene blue riboflavin to achieve targeted therapy for various cancers, various hyperplasias, myocardial infarction, and cerebral infarction thromboembolism diseases.

[0009] Use photo-activated methylene blue to prepare capsule preparations respectively for targeted therapy of various cancers, various hyperplasias, myocardial infarction, and cerebral infarction thromboembolism diseases.

[0010] Explore the photo-activation conditions, explore the effective treatment dose and effective administration time to achieve the purpose of targeted therapy.

[0011] Exploring photo-activated methylene blue riboflavin is the breakthrough point for targeted therapy of various cancers, various hyperplasias, myocardial infarction, and cerebral infarction thromboembolism diseases, and it is also an effective way for targeted therapy of various cancers, various hyperplasias, and cardio-cerebral thrombosis diseases. Technical Solution

[0012] Based on Scenario 1, malignant tumors are a common disease that seriously threatens human life and health. Approximately 6 million people develop cancer worldwide each year, and about 4.3 million people die from cancer annually, with a mortality rate of 71.66%. In China, the number of newly diagnosed cancer patients each year is over 1.2 million, and about 1 million people die from cancer annually, with a mortality rate of 83.33%.

[0013] Based on Scenario 2, according to data from the International Agency for Research on Cancer, in 2020, there were over 490,000 newly diagnosed pancreatic cancer patients worldwide, and in China, there were over 120,000 newly diagnosed pancreatic cancer patients, accounting for 1 / 4 of the global total.

[0014] Based on Scenario 3, according to the data of the National Cancer Center's 2021 National Cancer Report, pancreatic cancer ranks eighth in terms of incidence and sixth in terms of mortality in China. The number of new cases and deaths is similar, with a mortality rate close to 100%. The disease progresses rapidly and has a high degree of malignancy, so it is known as the "king of cancers." The challenge to life has reached its limit, and currently, there are no targeted therapeutic drugs.

[0015] Based on Scenario 4, a total of 2 billion people worldwide have been infected with the hepatitis B virus, and 350 million of them have become hepatitis B virus patients. Approximately 1 million people die each year from liver cancer, liver cirrhosis, and liver failure caused by hepatitis B virus infection. Currently, there are no targeted therapeutic drugs.

[0016] Based on Scenario 5, acute myocardial infarction and cerebral infarction seriously endanger life, and currently, there are no targeted therapeutic drugs.

[0017] Based on Scenario 6, multi-organ thromboembolism is the direct cause of myocardial infarction and cerebral infarction, with an extremely high disability rate and a relatively high fatality rate. It is one of the most major diseases endangering human life and health in the world today, and currently, there are no targeted therapeutic drugs.

[0018] Based on Scenario 7, the incidence of prostate hyperplasia is high. Approximately 75% of men aged 60 - 70 have prostate hyperplasia, and the incidence is even higher in men over 70 years old. Currently, there are no targeted therapeutic drugs.

[0019] Based on Scenario 8, the incidence of breast hyperplasia is high, accounting for 75% of all breast diseases. Currently, there are no targeted therapeutic drugs.

[0020] Based on Scenario 9, the incidence of endometrial hyperplasia is high, and there is a risk of canceration. Currently, there are no targeted therapeutic drugs.

[0021] Based on Scenario 10, methylene blue can stain cells, but after cell staining, normal cells can decolorize methylene blue, while cancer cells, hyperplastic cells, and thrombus cells lose the ability to decolorize methylene blue.

[0022] According to Scheme 11, methylene blue is a positively charged molecule that can be embedded into the DNA and RNA of cancer cells, proliferating cells, and thrombocytes after photoactivation, preventing replication and achieving the purpose of targeted therapy.

[0023] According to Scheme 12, animal experiments have confirmed that methylene blue shows significant inhibitory effects 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 to the control group. The therapeutic effect on L1210 leukemia was significantly better than that of 5-Fu. For the therapeutic effect on P388 leukemia, not only was the average lifespan significantly extended compared to 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 administered simultaneously with adriamycin, it could extend the survival time of mice and reduce the acute toxic effects of adriamycin.

[0024] According to Scheme 13, using the methods of direct killing effect, cell growth inhibition experiment, and cell colony formation ability experiment, the effect of methylene blue on the human colorectal cancer cell line LOVO cultured in vitro was studied. At the same time, the damaged parts of cancer cells by this drug were observed using transmission electron microscopy technology. The results showed that 13.25 μmol / L of methylene blue could kill all colorectal cancer cells after acting for 24 hours, and 0.27 μmol / L of methylene blue could significantly inhibit the proliferation of human colon cancer cells. The research results indicate that methylene blue has significant killing and inhibitory effects on the human colorectal cancer cell LOVO cultured in vitro, and the damaged part of the cancer cells is in the mitochondria.

[0025] According to Scheme 14, photoactivated riboflavin can promote the apoptosis of tumor cells.

[0026] As an example in Scheme 15, 14 cases of thromboangiitis obliterans were injected intra-arterially with 0.5% methylene blue at a dose of 1 - 2 mg / kg. Injection was given 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 drug was used.

[0027] The scheme uses a photoactivation device. The methylene blue riboflavin samples are placed on the device backing plate according to the set thickness, and the methylene blue riboflavin is activated by setting the sample thickness, light illumination intensity, light activation time, number of light activations, and mixing the samples 3 times. And the photoactivated methylene blue riboflavin samples are numbered.

[0028] The scheme prepares the activated methylene blue riboflavin samples into capsules according to the sample numbers and the set doses respectively. Example

[0029] To fabricate a photoactivation device, use six 5-mm thick glass plates to form a cuboid glass box. Four of the plates are 660 mm long and 500 mm wide. Use one of them as the bottom, and connect and fix the lower ends of the other two glass plates to the bottom on both sides. Then, use two glass plates that are 400 mm wide and 500 mm high to be respectively set at both ends, and connect and fix them to the bottom and the glass plates on both sides. Fix a fluorescent lamp inside the top cover glass, and set a stainless steel plate 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.

[0030] To prepare the photoactivated methylene blue sample No. 1, take 50 g of methylene blue pharmaceutical raw material powder and 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 illuminance, activate it by light for 4 minutes each time. Mix and flatten the sample twice. After activating it by light three times, collect the sample and seal it. Label it as the photoactivated methylene blue sample No. 1.

[0031] To prepare the photoactivated methylene blue sample No. 2, take 50 g of methylene blue pharmaceutical raw material powder and 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 illuminance, activate it by light for 7 minutes each time. Mix and flatten the sample twice. After activating it by light three times, collect the sample and store it sealed. Label it as the photoactivated methylene blue sample No. 2.

[0032] To prepare the photoactivated methylene blue sample No. 3, take 50 g of methylene blue pharmaceutical raw material powder and 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 illuminance, activate it by light for 10 minutes each time. Mix and flatten the sample twice. After activating it by light three times, collect the sample and store it sealed. Label it as the photoactivated methylene blue sample No. 3.

[0033] To prepare the capsule of the photoactivated methylene blue sample No. 1, take 12 g of the photoactivated methylene blue sample No. 1 and add 0.6 g of pharmaceutical starch. Mix the two, granulate, fill into No. 3 hollow capsules, and package. Label it as the photoactivated methylene blue capsule No. 1 with a dose of 120 mg per capsule.

[0034] To prepare the capsule of the photoactivated methylene blue sample No. 2, take 12 g of the photoactivated methylene blue sample No. 2 and take 0.6 g of pharmaceutical starch. Mix the two, granulate, fill into No. 3 hollow capsules, and package. Label it as the photoactivated methylene blue sample capsule No. 2 with a dose of 120 mg per capsule.

[0035] Preparation of the photoactivated methylene blue No. 3 sample capsules: Take 12 g of the photoactivated methylene blue No. 3 sample and 0.6 g of medicinal starch. Mix the two, granulate, fill into No. 3 empty capsules, and package. Label it as the photoactivated methylene blue No. 3 capsules, with a dose of 120 mg per capsule.

[0036] Preparation of the riboflavin No. 1 sample: Take 5 g of riboflavin medicinal raw material powder and spread it on a stainless steel plate with a length of 500 mm and a width of 350 mm, with a thickness of 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, irradiate and activate for 2 minutes each time. Mix the sample twice more. After irradiating and activating 3 times, collect the sample and store it sealed. Label it as the photoactivated riboflavin sample 1.

[0037] Preparation of the riboflavin No. 2 sample: Take 5 g of riboflavin medicinal raw material powder and spread it on a stainless steel plate with a length of 500 mm and a width of 350 mm, with a thickness of 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, irradiate and activate for 4 minutes each time. Mix the sample twice more. After irradiating and activating 3 times, collect the sample and store it sealed. Label it as the photoactivated riboflavin sample 2.

[0038] Preparation of the riboflavin No. 3 sample: Take 5 g of riboflavin medicinal raw material powder and spread it on a stainless steel plate with a length of 500 mm and a width of 350 mm, with a thickness of 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, irradiate and activate for 6 minutes each time. Mix the sample twice more. After irradiating and activating 3 times, collect the sample and store it sealed. Label it as the photoactivated riboflavin sample 3.

[0039] Preparation of the photoactivated riboflavin No. 1 sample capsules: Take 1 g of the photoactivated riboflavin No. 1 sample, add 10 g of medicinal starch, mix well, and granulate. Dispense into No. 3 empty capsules, package, and label it as the photoactivated riboflavin No. 1 capsules, with a dose of 10 mg per capsule.

[0040] Preparation of the photoactivated riboflavin No. 2 sample capsules: Take 1 g of the photoactivated riboflavin No. 2 sample, add 10 g of medicinal starch, mix well, granulate, and dispense into No. 3 empty capsules, and package. Label it as the photoactivated riboflavin No. 2 capsules, with a dose of 10 mg per capsule.

[0041] Preparation of the photoactivated riboflavin No. 3 sample capsules: Take 1 g of the photoactivated riboflavin No. 3 sample, add 10 g of medicinal starch, mix well, granulate, and dispense into No. 3 empty capsules, and package. Label it as the photoactivated riboflavin No. 3 capsules, with a dose of 10 mg per capsule.

[0042] The preparations in this scheme are for patients with various cancers, various hyperplasias, cardio-cerebral thrombosis embolism diseases. Due to different conditions of the diseases and different patients, there are differences in the time of photoirradiation activation and different preparations. Different photoirradiation times and different samples are used to observe the therapeutic effects, which is convenient for clinical application.

[0043] To determine the medication time, the change in urine color after medication was observed to see how long it took to be metabolized and excreted from the body after ingestion. As a result, it could be metabolized and excreted about 46 hours after ingestion. It could be set to take the medication once every two days, and 120 mg was taken each time by observing the dosage.

[0044] Preliminary observation showed that when taking the photoactivated methylene blue No. 1, No. 2, and No. 3 preparations once every two days for 15 to 30 times, the No. 2 capsule had a targeted therapeutic effect on cerebral infarction, cerebral thrombosis, and prostate hyperplasia. The No. 2 sample had the best effect. The results indicated that the preparation technology determined the drug efficacy.

[0045] For the samples prepared according to the technical solution of this application and various preparations prepared, the practical results showed that the technical solution of this application was basically feasible.

Claims

1. A preparation process of photoactivated methylene blue riboflavin 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, and 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 lies in 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 to prevent replication. Photoactivated riboflavin can promote the apoptosis of tumor cells to achieve targeted treatment. Multiple organ thromboembolism is the direct cause of myocardial infarction and cerebral infarction. The use of photoactivated methylene blue and riboflavin has a targeted therapeutic effect on cancer cells, hyperplastic cells, and thrombus cells, and has no effect on normal cells. The use of photoactivated methylene blue riboflavin is the breakthrough point for targeted treatment of various cancers, various hyperplastic diseases, and cardio-cerebral vascular diseases, and is also an effective way for targeted treatment of various cancers, various hyperplastic diseases, and cardio-cerebral vascular diseases. It has opened up a new field for targeted treatment of various cancers, various hyperplastic diseases, and cardio-cerebral vascular diseases. The metabolic process of photoactivated methylene blue in vivo has been initially observed. According to the change of urine color, it starts to excrete 3 to 6 hours after oral administration, and the urine is almost colorless at about 6 to 12 hours. It shows that normal cells have metabolized and excreted methylene blue out of the body. After that, the urine may turn blue once or twice, indicating that there are differences in the action time of methylene blue on cancer cells, hyperplastic cells, and thrombus cells. A photoactivated methylene blue capsule is excreted out of the body in about 46 hours. It has been initially observed that taking 120 mg of photoactivated methylene blue once every two days has a targeted therapeutic effect on cerebral infarction, cerebral thrombosis, and prostatic hyperplasia. The preparation process includes the production of a photoactivation device, the preparation of photoactivated methylene blue samples No. 1, No. 2, and No. 3, the preparation of capsules of photoactivated methylene blue samples No. 1, No. 2, and No. 3, the preparation of photoactivated riboflavin samples No. 1, No. 2, and No. 3, and the preparation of their capsules.

2. Manufactured according to the optical activation device described in 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 a 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, activate it by light for 4 minutes each time, mix and flatten the sample 3 times, activate it by light 3 times, and the thickness of the sample is 1 mm. After the light activation ends, collect the sample and seal it. Label it as photoactivated methylene blue sample No.

1.

4. The preparation of the methylene blue light-activated sample 2 according to claim 1, wherein: Place the methylene blue sample on the backing plate of the photoactivation device. Under the condition of the same illuminance, activate it by light for 7 minutes each time, mix and flatten the sample 3 times, activate it by light 3 times, with the sample thickness being 1 mm. After the light activation ends, collect the sample and seal it. Label it as the methylene blue photoactivation sample No.

2.

5. The preparation of the methylene blue light-activated sample 3 according to claim 1, characterized in that: Place the methylene blue sample on the backing plate of the photoactivation device. Under the condition of the same illuminance, activate it by light for 10 minutes each time, mix and flatten the sample 3 times, activate it by light 3 times, with the sample thickness being 1 mm. After the light activation ends, collect the sample and seal it. Label it as the methylene blue photoactivation 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 into 5% medicinal starch respectively, mix well and granulate, then fill them into hollow capsules respectively and package. Label them as the capsule agents of methylene blue photoactivation sample No. 1, methylene blue photoactivation sample No. 2, and methylene blue photoactivation sample No. 3 respectively.

7. The preparation of the riboflavin photoactivated sample 1 according to claim 1, wherein: Put the riboflavin medicinal raw material powder on the backing plate of the photoactivation device. Under the condition of the same illuminance, activate it by light for 2 minutes each time, mix the sample 3 times, with the sample thickness being 1 mm. After activating it by light 3 times, collect the sample and seal it. Label it as riboflavin photoactivation sample 1.

8. The preparation of the riboflavin photoactivated sample 2 according to claim 1, wherein: Put the riboflavin medicinal raw material powder on the backing plate of the photoactivation device. Under the condition of the same illuminance, activate it by light for 4 minutes each time, mix the sample 3 times, with the sample thickness being 1 mm. After activating it by light 3 times, collect the sample and seal it. Label it as riboflavin photoactivation sample 2.

9. Prepared according to claim 1 for riboflavin photoactivated sample 3, characterized in that: Put the riboflavin medicinal raw material powder on the backing plate of the photoactivation device. Under the condition of the same illuminance, activate it by light for 6 minutes each time, mix the sample 3 times, with the sample thickness being 1 mm. After activating it by light 3 times, collect the sample and seal it. Label it as riboflavin photoactivation sample 3.

10. Preparation of riboflavin photoactivated sample 1, sample 2, and sample 3 capsules according to claim 1, characterized in that: According to the set dosage of riboflavin, take riboflavin photoactivation sample 1, sample 2, and sample 3 respectively, add medicinal starch respectively, mix well respectively, granulate respectively, and fill them into No. 3 hollow capsules respectively and package. Label them as riboflavin photoactivation capsule No. 1, riboflavin photoactivation capsule No. 2, and riboflavin photoactivation capsule No. 3 respectively.

11. In clinical observation and clinical application, adjust the photoactivation time, activation times, sample paving thickness, dosage, and preparation process according to actual needs, improve the structure of the photoactivation device, or add dosage forms and indications.