Process for targeted therapy of various preparations for controlling epidemic outbreak by using non-enveloped virus nucleic acid

Abstract

The invention relates to multiple preparation processes for targeted treatment of a class of non-enveloped virus nucleic acid or early-stage difficult-to-diagnose epidemic situation control. The key point is that different epidemic situations caused by enveloped or non-enveloped viruses are summarized and recognized from thousands of viruses and epidemic situations which are erupted all the time; the light is adopted to activate the methylene blue riboflavin, so that a plurality of enveloped viruses and a plurality of non-enveloped viruses can be respectively inactivated; the light-activated methylene blue riboflavin can be embedded into a virus nucleic acid chain to prevent replication so as to achieve targeted therapy, and the light-activated methylene blue riboflavin compound preparation is firstly used for treatment when virus types are difficult to diagnose in the early stage of an epidemic situation. In order to control epidemic situation propagation as soon as possible, after it is confirmed that enveloped virus infection or non-enveloped virus infection exists, light-activated methylene blue and a light-activated riboflavin preparation are adopted for targeted therapy. The light-activated methylene blue is adopted for treating three or five positive cases of hepatitis B once every two days by 120 milligrams every time, and all the cases are effectively turned to negative. The preparation process comprises the step of preparing the photoactivated methylene blue riboflavin and the capsule of the photoactivated methylene blue riboflavin.

Description

Technical Field

[0001] Fields of photoactivated antiviral targeted therapy and anti-epidemic transmission Background Art

[0002] After inquiry, no identical background art was found Summary of the Invention

[0003] It lies in summarizing and realizing from thousands of viruses and numerous past epidemics that different epidemic transmissions are caused by enveloped and non-enveloped viruses, and the difference lies in the presence or absence of an envelope. Utilizing this difference is the most crucial breakthrough point for coping with, solving, controlling, and treating epidemic transmission

[0004] It lies in that photoactivated methylene blue and riboflavin can effectively inactivate numerous enveloped viruses and numerous non-enveloped viruses respectively, which is the breakthrough point for coping with, solving, treating, and controlling epidemic transmission and epidemic outbreaks

[0005] It lies in using a photoactivation device to activate various photosensitizers to achieve targeted treatment of infectious diseases caused by enveloped and non-enveloped viruses, and to provide an effective method for effectively controlling epidemic transmission and effectively controlling epidemic outbreaks

[0006] Using a photoactivation device and a photoactivated methylene blue and riboflavin preparation to treat viral infectious diseases, control epidemic transmission and outbreaks, and achieve the avoidance of threats to human life and health, the public health system, and social economy caused by epidemic outbreaks Technical Solution

[0007] The scheme is based on Example 1. COVID-19 is transmitted by enveloped RNA / DNA coronaviruses

[0008] The scheme is based on Example 2. Viral hemorrhagic fever is an acute infectious disease with fever and bleeding as the main clinical symptoms, seriously threatening human health. The viral hemorrhagic fever epidemic is transmitted by enveloped RNA / DNA yellow fever virus, West Nile virus, dengue virus, Congo hemorrhagic fever virus, Ebola virus, and chikungunya virus

[0009] The scheme is based on Example 3. Hepatitis B is still a serious public health problem worldwide. There have been 2 billion people infected with hepatitis B virus worldwide, of which 350 million people have become hepatitis B virus patients, and approximately 1 million people die each year from liver failure, cirrhosis, and liver cancer caused by hepatitis B virus infection

[0010] The scheme is based on Example 4. Photoactivated methylene blue has good inactivation effects on enveloped human immunodeficiency virus, hepatitis B virus, hepatitis C virus, West Nile virus, herpes simplex virus, COVID-19 virus, Congo hemorrhagic fever virus, Nipah virus, Zika virus, yellow fever virus, Ebola virus, dengue virus, and chikungunya virus

[0011] Based on Example 5, for the inactivation mechanism of photoactivated methylene blue on enveloped viruses, methylene blue intercalates with the viral nucleic acid strand. Activated by visible light, energy transfer generates highly reactive singlet oxygen, which oxidizes guanosine in the viral nucleic acid strand, thereby destroying the viral nucleic acid strand and preventing the replication of the viral nucleic acid strand, achieving the inactivation of the virus.

[0012] Based on Example 6, as early as the beginning of the 20th century, it was found that the visible light activation of methylene blue can inactivate most lipid-enveloped DNA and RNA viruses. In the methylene blue molecule, S+phenothiazine-5 can be activated by visible light to be an organic ion catalyst, catalyzing the destruction of the membranes of enveloped and intracellular organelles to achieve inactivation.

[0013] Based on Example 7, for the inactivation effect on enveloped viruses, the enveloped lipid is the main component of the cell membrane and intracellular organelle membranes. The fluidity of the cell membrane is an important characteristic of the lipid membrane, and maintaining appropriate fluidity is very important for the normal function of the lipid membrane. The electron transport chain and other reactions in intracellular mitochondria will generate various reactive oxygen species, such as superoxide radicals, hydroxyl radicals, etc. These reactive oxygen species are prone to react with biomolecules, such as lipids, DNA, or protein molecules, changing their functions. Since the lipid membrane contains unsaturated lipids, it is easily affected by oxidants to cause lipid peroxidation. After lipid peroxidation, in addition to causing structural changes, it will also affect the normal fluidity of the lipid membrane, causing cell damage and leading to inactivation. The inactivation effect of photoactivated methylene blue on non-enveloped viruses is weak.

[0014] Based on Example 8, for the inactivation effect of riboflavin photoactivation on non-enveloped viruses, riboflavin has the advantages of a wide virus inactivation spectrum, good inactivation effect, safety and reliability, etc. Since the inactivation effect of methylene blue photoactivation on non-enveloped viruses is weak, the use of photoactivated methylene blue and photoactivated riboflavin can effectively prevent and control the epidemic caused by enveloped and non-enveloped viruses.

[0015] Based on Example 9, for the inactivation effect of riboflavin at a wavelength of 450 nm on pathogens, riboflavin has a total of 4 absorption peaks, 3 in the ultraviolet region with peak values of 221, 265, and 375 nm respectively, and 1 in the visible region with a peak value of 446 nm. Among them, the absorption peaks at 221 and 265 nm are high and narrow, and the absorption peaks at 375 and 446 nm are low and wide. Irradiation with visible light at 450 nm can effectively inactivate viruses.

[0016] Based on Example 10, for the mechanism of riboflavin photoactivation in inactivating viruses, riboflavin, that is, vitamin B2, has the characteristic of being activated and can be activated by ultraviolet light and visible light. After it inserts into the nucleic acid in a planar structure, through electron transfer, the guanine base in the nucleic acid is oxidized to form a covalent addition compound, resulting in the breakage of the nucleic acid backbone chain, achieving the purpose of inactivating pathogens.

[0017] The solution adopts a photoactivation device. After activating methylene blue and riboflavin, it is used to treat and prevent the spread of acute viral epidemics, especially in the early stage of the epidemic when it is not yet confirmed whether it belongs to an enveloped virus or a non-enveloped infection. At the same time, photoactivated methylene blue and riboflavin treatment is adopted to avoid the spread of the epidemic. After the virus type is confirmed, photoactivated methylene blue or photoactivated riboflavin targeted treatment is respectively adopted to achieve effective treatment as soon as possible and control the spread of the epidemic as soon as possible.

[0018] The solution prepares capsules from the samples of methylene blue and riboflavin activated by the photoactivation device according to a set dose. Example

[0019] For the photoactivation device, 6 pieces of 5-mm thick glass plates are used. Among them, 4 pieces are 660 mm long and 500 mm wide. One of them is used as the bottom, and 2 of them are used as the walls. The bottom is connected and fixed to the lower ends of the other two pieces on both sides. 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 glass on both sides. The fluorescent lamp is fixed inside the top cover glass, and the cover is covered during use. A stainless steel plate is set on the bottom of the device, and the upper plane of the stainless steel plate is 300 mm away from the fluorescent lamp in height, forming the photoactivation device.

[0020] Preparation of methylene blue sample No. 1: Take 20 g of methylene blue medicinal raw material powder and spread it on a stainless steel plate with a length of 500 mm and a width of 350 mm to form a 1-mm thick sample. Put 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 the sample twice again, and after activating it by light 3 times, collect the sample and seal it. It is numbered as methylene blue photoactivated sample No. 1.

[0021] Preparation of methylene blue sample No. 2: Take 20 g of methylene blue 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 the lid. Turn on the light. Under the condition of the same illuminance, activate it by light for 7 minutes each time, mix the sample 2 times again, and after activating it by light 3 times, collect the sample and seal it for storage. It is numbered as methylene blue photoactivated sample No. 2.

[0022] Preparation of methylene blue sample No. 3: Take 20 g of methylene blue 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 the lid. Turn on the light. Under the condition of the same illuminance, activate it by light for 10 minutes each time, mix the sample twice again, and after activating it by light 3 times, collect the sample and seal it for storage. It is numbered as methylene blue photoactivated sample No. 3.

[0023] Preparation of Riboflavin Sample No. 1: Take 5 grams of riboflavin pharmaceutical 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, cover it with the lid. Turn on the light. Under the condition of the same light intensity, activate it by light for 2 minutes each time, mix the sample twice more. After activating it by light 3 times, collect the sample and store it sealed. Label it as Riboflavin Photoactivated Sample 1.

[0024] Preparation of Riboflavin Sample No. 2: Take 5 grams of riboflavin pharmaceutical 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, cover it with the lid. Turn on the light. Under the condition of the same light intensity, activate it by light for 4 minutes each time, mix the sample twice more. After activating it by light 3 times, collect the sample and store it sealed. Label it as Riboflavin Photoactivated Sample 2.

[0025] Preparation of Riboflavin Sample No. 3: Take 5 grams of riboflavin pharmaceutical 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, cover it with the lid. Turn on the light. Under the condition of the same light intensity, activate it by light for 6 minutes each time, mix the sample twice more. After activating it by light 3 times, collect the sample and store it sealed. Label it as Riboflavin Photoactivated Sample 3.

[0026] Preparation of Methylene Blue Photoactivated Sample No. 1 Capsules: Take 12 grams of Methylene Blue Photoactivated Sample No. 1, add 0.6 grams of pharmaceutical starch, mix well, granulate, and fill it into No. 3 empty capsules, then package it. Label it as Methylene Blue Photoactivated Sample No. 1 Capsules, with a dose of 120 mg per capsule.

[0027] Preparation of Methylene Blue Photoactivated Sample No. 2 Capsules: Take 12 grams of Methylene Blue Photoactivated Sample No. 1, add 0.6 grams of pharmaceutical starch, mix well, granulate, and fill it into No. 3 sample empty capsules, then package it. Label it as Methylene Blue Photoactivated Sample No. 2 Capsules, with a dose of 120 mg per capsule.

[0028] Preparation of Methylene Blue Photoactivated Sample No. 3 Capsules: Take 12 grams of Methylene Blue Photoactivated Sample No. 1, add 0.6 grams of pharmaceutical starch, mix well, granulate, and fill it into No. 3 empty capsules, then package it. Label it as Methylene Blue Photoactivated Sample No. 3 Capsules, with a dose of 120 mg per capsule.

[0029] Preparation of Riboflavin Photoactivated Sample No. 1 Capsules: Take 1 gram of Riboflavin Photoactivated Sample No. 1, add 10 grams of pharmaceutical starch, mix well, granulate. Fill it into No. 3 empty capsules, then package it. Label it as Riboflavin Photoactivated Sample No. 1 Capsules, with a dose of 10 mg per capsule.

[0030] Preparation of Riboflavin Photoactivated Sample No. 2 Capsules: Take 1 gram of Riboflavin Photoactivated Sample No. 2, add 10 grams of pharmaceutical starch, mix well, granulate, and fill it into No. 3 empty capsules, then package it. Label it as Riboflavin Photoactivated Sample No. 2 Capsules, with a dose of 10 mg per capsule.

[0031] Preparation of riboflavin photoactivated sample No. 3 capsules: Take 1 g of riboflavin photoactivated sample No. 3, add 10 g of medicinal starch, mix evenly, granulate, fill into No. 3 empty capsules, and package. It is designated as riboflavin photoactivated capsule No. 3, with a dose of 10 mg per capsule.

[0032] In order to determine the medication time, based on the preliminary test, for the methylene blue photoactivated preparation, the color change of urine after medication was observed to find out how long it could be metabolized and excreted from the body after administration. As a result, it could be metabolized and excreted about 46 hours after administration. It can be set to take it once every two days, 120 mg each time.

[0033] Since the positive indicators of hepatitis B virus infection are widespread in China and there is currently no effective drug treatment. The preliminary test of using the methylene blue photoactivated preparation showed that taking the methylene blue photoactivated preparation No. 2 for 15 times could make all patients with three positive or five positive hepatitis B turn negative effectively. The methylene blue preparations No. 1 and No. 3 had no obvious therapeutic effect, indicating that the preparation process determines the curative effect.

[0034] For the photoactivation device made according to the technical solution of this application, photoactivation samples were made according to the solution, and capsules were prepared. The practical results showed that this solution was basically feasible.

Claims

1. A type of non-enveloped virus nucleic acid targeted treatment or early difficult to diagnose epidemic control with multiple preparation processes. The key is to summarize and recognize from thousands of viruses and from the outbreaks in the past that there are different epidemics caused by enveloped or non-enveloped viruses; the use of light-activated methylene blue riboflavin can be respectively targeted at inactivating many enveloped viruses and many non-enveloped viruses; the use of light-activated methylene blue riboflavin can be embedded in the viral nucleic acid chain to prevent replication to achieve targeted treatment. When it is suitable for the early stage of the epidemic, when the virus is difficult to diagnose, the light-activated methylene blue riboflavin compound preparation is used for treatment. In order to control the spread of the epidemic as soon as possible, after confirming and distinguishing whether it is an enveloped virus or a non-enveloped virus infection, light-activated methylene blue or light-activated riboflavin preparations are used for targeted treatment of enveloped or non-enveloped virus infection. The use of light-activated methylene blue 120 mg once every two days to treat three or five positive cases of hepatitis B has effectively turned negative. The preparation process includes the preparation of light-activated methylene blue riboflavin and its capsules. The photosensitizer includes methylene blue and riboflavin. The multiple preparation processes include: Photoactivation device, preparation of methylene blue photoactivated samples No. 1, No. 2, and No. 3, preparation of capsules of methylene blue photoactivated samples No. 1, No. 2, and No. 3; preparation of riboflavin photoactivated samples No. 1, No. 2, and No. 3, preparation of capsules of riboflavin photoactivated samples No. 1, No. 2, and No. 3; preparation of methylene blue and riboflavin photoactivated compound capsules No. 1, No. 2, and No.

3.

2. The visible light activated device according to claim 1, characterized in that: Six glass plates are used, four of which are 660 mm long, 500 mm wide and 5 mm thick. One of them is used as the bottom, two of them are used as the wall, and the lower ends of the two side walls are connected and fixed to the bottom along the length. Two of them are 400 mm wide and 500 mm high, respectively set at both ends of the three long glass connectors and fixed, and the remaining one is 660 mm long and 500 mm high as the cover, and a fluorescent lamp is installed inside the cover. The cover is closed when in use. A pad is arranged on the inner side of the bottom of the box, and the height of the pad is 300 mm away from the height of the lamp to form a light activation device.

3. The preparation of the methylene blue light activated sample 1 according to claim 1, characterized in that: Place methylene blue medicinal raw material powder on the pad of the light activation device. Under the same light intensity, light activation is performed for 4 minutes each time. The sample is mixed 3 times and the sample thickness is 1 mm. After light activation 3 times, the sample is collected and sealed and named methylene blue light-activated sample 1.

4. The preparation of the methylene blue light activated sample 2 according to claim 1, characterized in that: Place methylene blue medicinal raw material powder on the pad of the light activation device. Under the condition of the same light intensity, light activation is performed for 7 minutes each time. The sample is mixed 3 times and the sample thickness is 1 mm. After light activation 3 times, the sample is collected and sealed and named methylene blue light-activated sample 2.

5. The preparation of the methylene blue light activated sample 3 according to claim 1, characterized in that: Place methylene blue medicinal raw material powder on the pad of the light activation device. Under the condition of the same light intensity, light activation is performed for 10 minutes each time. The sample is mixed 3 times and the sample thickness is 1 mm. After light activation 3 times, the sample is collected and sealed and named methylene blue light-activated sample 3.

6. The method of claim 1, wherein: The riboflavin medicinal raw material powder was placed on the pad of the light activation device. Under the condition of the same light intensity, the light was activated for 2 minutes each time. The sample was mixed 3 times and the sample thickness was 1 mm. After light activation 3 times, the samples were collected and sealed and named as riboflavin light-activated sample 1.

7. The method of claim 1, wherein: The riboflavin medicinal raw material powder was placed on the pad of the light activation device. Under the condition of the same light intensity, the light was activated for 4 minutes each time. The sample was mixed 3 times and the sample thickness was 1 mm. After light activation 3 times, the samples were collected and sealed and named riboflavin light-activated sample 2.

8. The method of claim 1, wherein: The riboflavin medicinal raw material powder was placed on the pad of the light activation device. Under the condition of the same light intensity, the light was activated for 6 minutes each time. The sample was mixed 3 times and the sample thickness was 1 mm. After light activation 3 times, the samples were collected and sealed and named riboflavin light-activated sample 3.

9. The preparation of the methylene blue light activated capsules of sample 1, sample 2 and sample 3 according to claim 1, characterized in that: According to the set dosage of methylene blue, methylene blue light activated sample No. 1, sample No. 2, and sample No. 3 were taken, and medicinal starch was added respectively, mixed and granulated, and then loaded into No. 3 hollow capsules respectively, and packaged respectively. They were respectively named methylene blue light activated capsule No. 1, capsule No. 2, and capsule No.

3.

10. The preparation of riboflavin photoactivated capsules of sample 1, sample 2 and sample 3 according to claim 1, characterized in that: According to the set dosage of riboflavin, riboflavin light-activated sample 1, sample 2, and sample 3 were respectively added with medicinal starch, mixed, granulated, and filled into No. 3 hollow capsules for packaging. They were respectively named riboflavin light-activated capsule No. 1, capsule No. 2, and capsule No.

3.

11. In clinical observation and clinical application, according to actual needs, adjust the light activation time, number of activations, sample paving thickness, dosage, and preparation process, improve the structure of the light activation device, or increase the dosage form and indications.