WO2022124961A1

WO2022124961A1 - A composition comprising a vitamin d and acetylsalicylic acid.

Info

Publication number: WO2022124961A1
Application number: PCT/SE2021/051204
Authority: WO
Inventors: Bo-Christer JACOBSSON
Original assignee: Jacobsson Bo Christer
Priority date: 2020-12-07
Filing date: 2021-12-06
Publication date: 2022-06-16

Abstract

A composition comprising a vitamin D and acetylsalicylic acid is suitable for use in the treatment of side-effect and/or late effect of a viral diseases, notably COVID-19.

Description

A COMPOSITION COMPRISING A VITAMIN D AND ACETYLSALICYLIC ACID.

FIELD

The present invention relates to a composition comprising a D-vitamin and acetylsalicylic acid for the treatment of undesired side effects or consequences of e.g. a viral disease notably a coronaviral disease. The undesired side effects are typically tiredness, less energy, muscle pain, joint pain, sore joints and bones etc.

BACKGROUND

Coronaviruses are a group of RNA viruses that causes diseases in mammals. They cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include case of common cold, while more lethal varieties can cause SARS, MERS and COVID-19.

Coronaviruses constitute the subfamily Orthocoronavirinae in the family Coronaviridae, order Nidovirales and realm Ribiviria. They are enveloped viruses with a positive-sense single-stranded RNA genome end a nucleocapsid of helical symmetry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the strain of coronavirus that causes coronavirus disease 2019 (COVID 19), which is respiratory illness responsible for the COVID-19 pandemic. It is also referred to as 2019 novel coronavirus (2019-nCoV) or human coronavirus 2019 (HCoV-19 or hCoV-19). SARS-CoV2 is a Baltimore class IV positive-sense single-stranded RNA virus that is contagious in humans. It is the successor to SARS-CoV-1 , the strain that caused the 2002-2004 SARS outbreak.

SARS-CoV2 is a strain of severe acute respiratory syndrome-related coronavirus (SARSr-CoV). It is believed to have zoonotic origins and has close genetic similarity to bat coronaviruses, suggesting it emerged from a bat-borne virus.

Many people suffering from corona or other viral or bacterial disease experiences disease- associated effects such as tiredness, less energy, muscle pain, joint pain, sore joints and bones etc. The effects do not necessary disappear when the main disease has been combatted. Thus about 10-20% of persons having been infected with COVID-19 experience late effects after several months.

During the pandemic COVID-19 situation it is clear that there is a need for effective therapies to combat or alleviate side-effects of diseases including viral diseases like coronaviruses such as COVID-19. SUMMARY

In its broadest aspect, the present invention relates to a composition comprising vitamin D and acetylsalicylic acid.

Vitamin D is a group of fat-soluble secosteroids known for increasing intestinal absorption of caldum, magnesium, phosphate and many other biological effects. In humans the most important vitamin Ds are vitamin D₃ (also known as cholecaldferol) and vitamin D₂ (also known as ergocaldferol).

Acetylsalicylic acid (aspirin) is a non-steroid anti-inflammatory substance normally used for the treatment of pain, for reduction of fever and as an anti-inflammatory drug substance.

The present inventor has found that a combination of vitamin D and acetylsalicylic acid can be used in effective treatment of side-effects of diseases including viral diseases like COVID-19. Thus, in an aspect the invention relates to the use of such a combination for the treatment of one or more side-effects like e.g. tiredness, less energy, muscle pain, joint pain, sore joints and bones etc.

DETAILED DESCRIPTION

The present invention relates to a composition comprising a vitamin D and acetylsalicylic add.

Vitamin D is a group of fat-soluble secosteroids known for increasing intestinal absorption of caldum, magnesium, phosphate and many other biological effects.

Five different vitamin D's are known: vitamin D₁ (also known as a 1 :1 mixture of ergocalciferol and lumisterol), vitamin D₂ (also known as ergocalciferol, which can be made from ergosterol), vitamin D₃ (also known as cholecalciferol, which can be made from 7-dehydrocholesterol), vitamin D₄ (also known as 22-dihydrocalciferol), and vitamin D₅ (also known as sitocalciferol, which can be made from 7-dehydrositosterol). Vitamin D used in the present invention is selected from vitamin D₁, vitamin D₂, vitamin D₃, vitamin D₄, vitamin Ds or a mixture thereof.

In humans the most important vitamin D's are vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocaldferol). These are known collectively as calciferol. Vitamin D₂ was chemically characterized in 1931. In 1935, the chemical structure of vitamin D₃ was established and proven to result from the ultraviolet irradiation of 7-dehydrocholesterol.

Chemically, the various forms of vitamin D are secosteroids, i.e., steroids in which one of the bonds in the steroid rings is broken. The structural difference between vitamin D₂ and vitamin D₃ is the side chain of D₂ that contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.

Accordingly, vitamin D₂ and D₃ are especially preferred in a composition of the invention. Most preferred is vitamin D₃. The major natural source of the vitamin is synthesis of Cholecalciferol in the lower layers of skin epidermis through a chemical reaction that is dependent on sun exposure (specifically UVB radiation). Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements. Only a few foods, such as the flesh of fatty fish, naturally contain significant amounts of vitamin D. In the U.S. and other countries, cow's milk and plant-derived milk substitutes are fortified with vitamin D, as are many breakfast cereals. Mushrooms exposed to ultraviolet light contribute useful amounts of vitamin D. Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, as sun exposure in the population is variable and recommendations about the amount of sun exposure that is safe are uncertain in view of the skin cancer risk.

Vitamin D from the diet, or from skin synthesis, is biologically inactive. It is activated by two protein enzyme hydroxylation steps, the first in the liver and the second in the kidneys. As vitamin D can be synthesized in adequate amounts by most mammals if exposed to sufficient sunlight, it is not essential, so technically not a vitamin. Instead it can be considered a hormone, with activation of the vitamin D pro-hormone resulting in the active form, calcitriol, which then produces effects via a nuclear receptor in multiple locations. Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol); ergocalciferol is converted to 25-hydroxyergocalciferol. These two vitamin D metabolites (called 25-hydroxyvitamin D or 25(OH)D) are measured in serum to determine a person's vitamin D status. Calcifediol is further hydroxylated by the kidneys to form calcitriol (also known as 1 ,25-dihydroxycholecaldferol), the biologically active form of vitamin D. calcitriol circulates as a hormone in the blood, having a major role regulating the concentration of calcium and phosphate, and promoting the healthy growth and remodeling of bone. calcitriol also has other effects, induding some on cell growth, neuromuscular and immune functions, and reduction of inflammation.

Vitamin D has a significant role in caldum homeostasis and metabolism. Its discovery was due to effort to find the dietary substance lacking in children with rickets (the childhood form of osteomalacia). Vitamin D supplements are given to treat or to prevent osteomalacia and rickets. The evidence for other health effects of vitamin D supplementation in the general population is inconsistent. The effect of vitamin D supplementation on mortality is not clear, with one meta- analysis finding a small decrease in mortality in elderly people, and another conduding no clear justification exists for recommending supplementation for preventing many diseases, and that further research of similar design is not needed in these areas.

The active vitamin D metabolite caldtriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells. The binding of caldtriol to the VDR allows the VDR to act as a transcription factor* that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine. The vitamin D receptor belongs to the nudear receptor superfamily of steroid/thyroid hormone receptors, and VDRs are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast.

VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.

One of the most important roles of vitamin D is to maintain skeletal calcium balance by promoting calcium absorption in the intestines, promoting bone resorption by increasing osteoclast number, maintaining calcium and phosphate levels for bone formation, and allowing proper functioning of parathyroid hormone to maintain serum calcium levels. Vitamin D deficiency can result in lower bone mineral density and an increased risk of reduced bone density (osteoporosis) or bone fracture because a lack of vitamin D alters mineral metabolism in the body. Thus, vitamin D is also critical for bone remodeling through its role as a potent stimulator of bone resorption.

The VDR regulates cell proliferation and differentiation. Vitamin D also affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T and B. In vitro, vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells, and affects the synthesis of neurotrophic factors, nitric oxide synthase and glutathione.

Vitamin D receptor expression decreases with age and findings suggest that vitamin D is directly related to muscle strength, mass and function, all being important factors to an athlete's performance.

In general, vitamin D functions to activate the innate and dampen the adaptive immune systems with antibacterial, antiviral and anti-inflammatory effects. Deficiency has been linked to increased risk or severity of viral infections, including HIV and COVID-19. Low levels of vitamin D appear to be a risk factor for tuberculosis, and historically it was used as a treatment.

Supplementation slightly decreases the risk and severity of acute respiratory tract infections, and also the exacerbation of asthma. There is no evidence for vitamin D affecting respiratory infections in children under five years of age. Vitamin D supplementation substantially reduces the rate of moderate or severe exacerbations of COPD in people with baseline 25(OH)D levels under 25 nmol/L but not in those with less severe deficiency.

Thus, vitamin D is a well-known and safe active substance for use in medicine. The present inventor has found that especially the use of vitamin D in combination with acetylsalicylic acid offers advantages in the treatment of viral diseases, notably infections with SARS-CoV2.

The present invention provides Vitamin D in combination with acetylsalicylic acid for use in the treatment and/or prevention of viral diseases.

Acetylsalicylic acid is also a well-known and safe active substance for use in medicine. Thus, it is used to reduce pain, fever, or inflammation. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever. Aspirin given shortly after a heart attack decreases the risk of death. Aspirin is also used long-term to help prevent further heart attacks, ischaemic strokes and blood dots in people at high risk. It may also decrease the risk of certain types of cancer, particularly colorectal cancer. For pain or fever, effects typically begin within 30 minutes. Aspirin is a non-steroid anti-inflammatory drug (NSAID) and works similarly to other NSAIDs but also suppresses the normal functioning of platelets.

One common adverse effect is an upset stomach. More significant side effects include stomach ulcers, stomach bleeding, and worsening asthma. Bleeding risk is greater among those who are older, drink alcohol, take other NSAIDs, or are on other blood thinners. Aspirin is not recommended in the last part of pregnancy.

Acetylsalicylic acid is one of the most widely used medications globally, with an estimated 40,000 tonnes (44,000 tons) (50 to 120 billion pills) consumed each year. It is on the WHO's List of Essential Medicines. It is available as a generic medication. In 2017, it was the 42nd most commonly prescribed medication in the United States, with more than 17 million prescriptions, (from Wikipedia)

A composition of the invention may be in the form of a single composition comprising both vitamin D and acetylsalicylic acid, but it may also be in the form of two discrete compositions, one comprising vitamin D and one comprising acetylsalicylic add. In any event, the two drug substances must be administered almost at the same time.

The drug substances should be administered to the skin and/or a mucosa. Therefore, a composition of the invention should be designed for application to the skin or mucosa, notably to the skin in the armpits and the mucosa in the ears. Suitable types of compositions include a composition in the form of a liquid such as a solution, an emulsion, or a suspension. Both vitamin D and acetylsalicylic acid are commercially available in liquid form. Accordingly, such compositions may be used separately (but administered almost at the same time), i.e., as two discrete compositions. They may also be admixed to a single composition comprising the desired dosage of both vitamin D and acetylsalicylic acid.

In the event that the two drug substances are contained in one composition the composition comprises an oil to dissolve vitamin D and to dissolve or suspend acetylsalicylic acid. Suitable oils include natural oils such as a vegetable oil extracted from seed or other parts of fruits or plants. Soybean oil, rapeseed oil and cocoa butter are examples of vegetable oils derived from seeds. Other sources are palm, sunflower seed, peanut, cottonseed, palm kernel, olive, almond, avocado, cashew, corn, hazelnut, linseed, rice bran, sesame, coconut oil, olive oil, grape seed oil, palm oil etc. A commercially available vitamin D composition comprises coconut oil. Thus, coconut oil is a preferred oil.

It is preferred that both vitamin D and acetylsalicylic acid are contained in a single composition as it will make it much easier to apply. It is preferred that the composition can be administered in the form of drops, notably ear drops and that the dosing of the drops correspond to from 10 to 15 drops pr. administration. One dose should contain from about 10 to about 40 microgram vitamin D and from about 25 to about 150 mg of acetylsalicylic add.

2 microgram of vitamin D corresponds to 100 IU.

In a composition of the invention, the concentration of vitamin D is from 500 lU/mL to 2500 lU/ml such as from 750 lE/mL to 2250 lU/mL, from 1000 lU/mL to 2000 lU/mL, from 1250 lU/mL to 1750 lU/mL, from 1500 lU/mL to 1700 lU/mL such as about 1600 lU/mL.

The concentration of acetylsalicylic add in a composition of the invention is from 20 mg/mL to 500 mg/mL such as from 25 mg/mL to 400 mg/mL, from 30 mg/mL to 350 mg/mL, from 35 mg/mL to 300 mg/mL, from 35 mg/mL to 200 mg/mL, from 35 mg/mL to 100 mg/mL such as from about 35 mg/mL to about 75 mg/mL or about 40 mg/mL, about 50 mg/mL or about 60 mg/mL.

Preferably, in a composition of the invention the concentration of vitamin D is in a range from 1250 lU/mL to 1750 lU/ml and the concentration of acetylsalicylic add is in a range from 35 mg/mL to 100 mg/mL.

It is to be understood that the dose depends on the body weight of the person to which the composition is given. The doses are given herein is for a person having a body weight of 75 kg and the doses are adjusted if the body weight of the person is different from 75 kg.

If the two drug substances are contained in one and the same composition, the concentration of vitamin D and acetylsalicylic add is as described above. If vitamin D is in one composition and acetylsalicylic add in another separate composition, then the vitamin D composition and the acetylsalicylic add composition have the concentrations mentioned above.

In a composition of the invention, the ratio vitamin D : acetylsalicylic add is in a range from about 500 lU/mL : 20 mg/mL to about 2500 lU/mL : 500 mg/mL such as from 1250 lU/mL : 25 mg/mL to about 1750 lU/mL : 300 mg/mL or the ratio is about 1600 lU/mL vitamin D : 60 mg/mL, 1600 IU : 50 mg/mL or about 1600 IU/60 mg/mL.

The dosage of vitamin D and acetylsalicylic add is typically in a ratio vitamin D : acetylsalicylic add in a. range from about 250 IU : 10 mg to about 1250 IU : 250 mg such as from 625 IU : 15 mg to 875 IU : 150 mg or the dosage is about 800 IU : 30 mg, about 800 IU : 25 mg or about 800 IU : 20 mg.

As mentioned above, a composition of the invention is designed for application to the skin or mucosa. A suitable mucosa is ear mucosa such as middle ear mucosa, and a suitable site of the skin is an armpit.

There may be situations, where e.g., vitamin D is administered to the ear and acetylsalicylic add to the armpit or vice versa. In such a case the composition is in the form of two separate compositions, one containing vitamin D (typically in the form of ear drops) and the other containing acetylsalicylic acid (typically in the form of a topical composition).

Topical compositions may be solutions, emulsions, suspensions, cremes, lotions, gels, patches etc.

In an aspect of the invention, a composition is for use in medicine.

Of particular interest is the use in the treatment of side-effects and/or late effects of a viral disease such as in the treatment of a coronaviral disease such as e.g. SARS-CoV2.

Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds,. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the common cold (which is also caused by other viruse, predominantly rhinoviruses), while more lethal varieties can cause SARS, MERS, and COVID-19.

Coronaviruses constitute the subfamily Orthocoronavirinae, in the family Coronaviridae, order Nidovirales, and realm Riboviria. They are enveloped viruses with a positive-sense single-stranded RNA genome and a nucleocapsid of helical symmetry. The genome size of coronaviruses ranges from approximately 26 to 32 kilobases, one of the largest among RNA viruses. They have characteristic club-shaped spikes that project from their surface, which in electron micrographs create an image reminiscent of the solar corona, , from which their name derives.

Coronaviruses are large, roughly spherical particles with unique surface projections. Their size is highly variable and generally is an average diameter of 120 nm. Extreme sizes are known from 50 to 200 nm in diameter. The total molecular weight is on average 40,000 kDa. They are enclosed in an envelope embedded with a number of protein molecules. The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host cell.

Coronavirus disease 2019 (COVID-19) is a contagious respiratory and vascular disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Common symptoms of COVID-19 include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms begin one to fourteen days after exposure to the virus. While most people have mild symptoms, some people develop acute respiratory distress syndrome (ARDS). ARDS can be precipitated by cytokine storms, multi-organ failure, septic shock and blood clots Longer-term damage to organs (in particular, the lungs and heart) has been observed.

COVID-19 spreads via a number of means, primarily involving saliva and other bodily fluids and excretions. These fluids can form small droplets and aerosols, , which can spread as an infected person breathes, coughs, sneezes, sings, or speaks. This is suspected to be the main mode of transmission. The virus may also spread via contaminated surfaces and direct contact. Infection mainly happens when people are near each other long enough. It can spread as early as two days before infected persons show symptoms (presymptomatic), and from asymptomatic (no symptoms) individuals. People remain infectious for up to ten days in moderate cases, and two weeks in severe cases.

Side-effects and/or late effects include one or more of tiredness, less energy, muscle pain, joint pain, sore joints and bones etc.

It has been found that the composition of the invention is effective if administered in the morning before lunch or after lunch.

In addition to administration of a composition according to the invention, a composition comprising melatonin may be given in the evening. Typically, melatonin is administered in a relatively low dose such as in a dose of from 0.01 mg to 0.5 mg. Melatonin is typically administered to the superior labial frenulum, i.e. just under the superior lib and above the front teeth.

It should be understood that any feature and/or aspect discussed above in connections with the composition according to the invention apply by analogy to the other aspects described herein.

The following example is provided to illustrate the present invention. It is intended to be illustrative and are not to be construed as limiting in any way.

EXAMPLE

A male earlier diagnosed with COVID-19 and having side-effect and late effects of tiredness and less energy was subject to the following dosis regimen:

10-15 drops of a composition containing vitamin D₃ and acetylsalicylic acid in coconut oil. 10 drops correspond to 0.5 ml and 0.5 ml contains 800 IE vitamin D₃ and 30 mg acetylsalicylic acid.

10-15 drops are applied to ear mucosa as ear drop 1-3 times a day for 7-14 days.

The side-effects disappeared after 3-5 days.

Claims

1. A composition comprising a vitamin D and acetylsalicylic acid.

2. A composition according to claim 1, wherein the vitamin D is selected from vitamin D1, vitamin D₂, vitamin D₃, vitamin D₄, vitamin D₅ or a mixture thereof.

3. A composition according to claim 1 or 2, wherein the vitamin D is vitamin D₃.

4. A composition according to any one of the preceding claims in the form of a liquid composition.

5. A composition according to claim 4, wherein the liquid composition is in the form of a solution, an emulsion or a suspension.

6. A composition according to any one of the preceding claims, wherein the concentration of vitamin D is from 500 lU/mL to 2500 lU/ml such as from 750 lE/mL to 2250 lU/mL, from 1000 lU/mL to 2000 lU/mL, from 1250 lU/mL to 1750 lU/mL, from 1500 lU/mL to 1700 lU/mL such as about 1600 lU/mL.

7. A composition according to any one of the preceding claims, wherein the concentration of acetylsalicylic acid is from 20 mg/mL to 500 mg/mL such as from 25 mg/mL to 400 mg/mL, from 30 mg/mL to 350 mg/mL, from 35 mg/mL to 300 mg/mL, from 35 mg/mL to 200 mg/mL, from 35 mg/mL to 100 mg/mL such as from about 35 mg/mL to about 75 mg/mL or about 40 mg/mL, about 50 mg/mL or about 60 mg/mL.

8. A composition according to any one of the preceding claims, wherein the ratio vitamin D : acetylsalicylic acid is in a range from about 250 lU : 10 mg to about 1250 lU : 250 mg such as from 625 lU : 15 mg to 875 lU : 150 mg or the dosage is about 800 lU : 30 mg, about 800 lU : 25 mg or about 800 lU : 20 mg.

9. A composition according to any one of the preceding claims, wherein the concentration of vitamin D is in a range from 1250 lU/mL to 1750 lU/ml and the concentration of acetylsalicylic acid is in a range from 35 mg/mL to 75 mg/mL.

10. A composition according to any one of the preceding claims for application to the skin or mucosa.

11. A composition according to any one of the preceding claims designed for application to the mucosa such as ear mucosa.

12. A composition according to any one of claims 1-10 designed for application to the skin such as the skin in an armpit.

13. A composition according to any one of the preceding claims for use in medicine.

14. A composition according to any one of claims 1-12 for use in the treatment of one or more side- effects selected from tiredness, less energy, muscle pain, joint pain, sore joints and bones etc.

15. A composition for use according to claim 14, wherein the side-effects are effects of a viral disease such as a coronaviral disease.

16. A composition for use according to claim 15, wherein the coronaviral disease is SARS-CoV2.