DE102020007979A1 - Composition for treating coronavirus infections - Google Patents

Abstract

The invention relates to pharmaceutical or homeopathic preparations for the treatment of infections with corona viruses, and also for the prevention of infections and for strengthening the immune system, which contain extracts of Artemisia annua and other plant extracts, other active ingredients and additional ingredients as active ingredients.

Description

field of invention

The invention relates to pharmaceutical or homeopathic preparations for the treatment of infections with corona viruses, which contain extracts of Artemisia annua and other plant extracts, other active ingredients and additives as active ingredients.

State of the art

Viruses within the Nidoviralis family are also called coronaviruses because they are roughly spherical in shape and have a ring of petal-like projections reminiscent of a solar corona. They belong to the RNA viruses and were already described in the mid-1960s. The representatives of this virus family cause very different diseases in all classes of terrestrial vertebrates. In humans, seven types of corona viruses are important as pathogens ranging from mild colds to severe and acute respiratory syndrome.

By overcoming the species barrier, humans are infected with the SARS coronavirus (SARS-CoV, sometimes also referred to as SARS-CoV-1) - the causative agent of the SARS pandemic - and with the Middle East respiratory syndrome coronavirus, which emerged in 2012 (MERS-CoV) emerged. The COVID-19 pandemic that emanated from the Chinese city of Wuhan is attributed to a previously unknown coronavirus (SARS-CoV-2).

In order to combat the corona virus, especially currently the SARS-CoV-2 coronavirus, the prevention of infection through suitable disinfectants and various hygiene measures has proven to be particularly effective. An article from March 2020 summarized the knowledge about the effect of disinfectants on all relevant corona types [G. Kampf et al.: Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. Journal of Hospital infection 104, 246-251 (2020)].

If the human organism is already infected, only a few drugs are suitable for healing, since viruses are often more difficult to influence than bacteria. This is particularly true for use in internal diseases, which is why the existence of only a few virucidal (virus-killing) or just virustatic (virus-inhibiting) agents is known. In the latter case, the human immune system has to do the rest of the work itself. It is clear that preference is given to virucidal substances, the number of which appears very small compared to antibiotics.

In the search for suitable active ingredients, old antimalarials for the treatment of the SARS-CoV-2 coronavirus were examined. Since the 17th century, cinchona and the quinine derived from it have been used to treat malaria, which is still important today, with some limitations. Synthetic antimalarials such as chloroquine, primachine, pyrimethamine and proagunil were not developed until the 20th century. After drugs such as chloroquine and hydroxychloroquine showed efficacy against the first SARS coronavirus, which only infected the lungs and not the throat, it was considered as a treatment for COVID-19. Here, too, promising results were shown in cell culture for both chloroquine and hydroxychloroquine.

However, there are conflicting results when it is used in humans. To prevent malaria, the recommended oral dose for adults is 500 mg chloroquine phosphate weekly. Efficacy and tolerability are predominantly rated negatively. Chloroquine can cause a variety of side effects, including corneal clouding and retinal changes in the eye, gastrointestinal distress, sleep disturbances, neuropsychiatric symptoms, and skin flushing. In some patients, chloroquine can cause abnormal heart rhythms, sometimes fatal.

Chlorhexidine can be considered as another active ingredient. Chemically, chlorhexidine is one of the bisguanidine compounds which Imperial Chemical Industries (ICI) initially tested for their suitability as antimalarial agents [Curd and Rose]. A whole series of chemically different derivatives were then synthesized, of which chlorhexidine, also known under the brand name Hibitan®, had optimal properties for human physiology [Swain and Rose]. Chlorhexidine is a substituted bisdiguanide molecule which has a double positive charge in a neutral aqueous solution. The molecule has a symmetrical structure and contains two benzene rings each substituted with a chlorine atom (Fig. 1). Since the chlorhexidine base is almost insoluble in aqueous systems, it is used in the form of more soluble salts and is sold as chloride, acetate or gluconate. Chlorhexidine digluconate is mostly used for medical applications because it is readily soluble in water.

Chlorhexidine derivatives are used in various applications. you find for example as an oral delivery system with an antibacterial and an anti-inflammatory agent, as in the document DE 60 2004 009 552 or as an absorbable molded mass based on collagen in the DD 146 548 described. Chlorhexidine salts are also used as hydrofluorides for dental care [ DE 41 35 397 ].

In a variety of documents DE 690 17 484 ; DE 602 22 557 ; DE 10 2005 00527 446 the delayed release of the active ingredients is described.

In the documents EP 0 199 792 ; DE 198 43 903 ; DE 699 29 278 active ingredients are also described in combination with polymers. The use of chlorhexidine and its salts against corona viruses is not yet known.

Novel EBOLA agents or AIDS preparations, the use of which is only moderately hoped for, are also not available for large population groups. These means are certainly not applicable for prevention, also due to their not inconsiderable toxicity. In the last century, nature was the inspiration for the development of newer antimalarial drugs that could also be suitable for combating corona viruses.

The antipyretic effect of extracts from Qinghaosu, Artemisia annua in German or annual mugwort, has been known for 2000 years, but without being able to assign the effect to a specific substance. The plants were formerly only grown in Vietnam and China and were traditionally used as a tea to reduce fever in various diseases. But they also grow in North America, Africa and Europe. The ingredients have only been examined more closely since the 1970s and the high effectiveness of the isolated artemisinin (Fig. 2) against the malaria pathogen was recognized. In contrast to other antimalarials, the active substance has hardly any side effects and also has a very favorable resistance situation, whereby it can also be combined with other substances. The need for artemisinin is very high and has not been met so far due to the widespread spread of malaria and the need for large areas for plant cultivation of annual mugwort.

The deposits in Austria, Liechtenstein and the Italian province of South Tyrol are very rare and often unstable. The distribution in Austria is limited to Lower Austria, Vienna and to fickle populations in Salzburg; there are also deposits in Switzerland, especially in southern Switzerland. In Germany, the annual mugwort is widespread along the Elbe, in addition to isolated localities. There it thrives in the annual rinsing fringes of the two-tooth mud bank community, where they grow up after the winter flood has drained away on the Elbe bank that has dried out during the summer low water level. Current research projects have demonstrated the successful cultivation of Artemisia annua in the state of Brandenburg.

In addition to using extracts from Artemisia annua, other herbal raw materials such as mistletoe, myrrh and frankincense are also used to combat infections.

Interactions of the plant extracts mentioned with one another in pharmaceutical or homeopathic preparations with regard to combating viral infections have not been known to date.

Mistletoe grows as a lush green or yellowish-green evergreen shrub, parasitizing on various trees and shrubs. As a semi-parasite, it sits on trees and extracts water and the mineral salts and nutrients dissolved in it from the wood part. Over the years, mistletoe often grows into large spherical bushes. The sessile leaves, which can be perennial, sit opposite at the ends of the stems.

A common form is the white-berry mistletoe (Viscum album), whose leaves do not last longer than two years and therefore only grow in the outer zone of the plant. The flowering period of the white-berry mistletoe extends from mid-January to early April in favorable weather conditions in Central Europe. The white-berry mistletoe is dioecious and has separate sexes. Three to five flowers are clustered together in the uppermost leaf axils. For the host plant, the parasitism of mistletoe can mean that branches or even the entire tree die off. The distribution area of the white-berry mistletoe is the mild-winter regions of southern Scandinavia and central and southern Europe. There it thrives in scattered to regionally very common, then perceived as a nuisance, on deciduous trees such as apple trees, lime trees, maples, birches, poplars and willows, hornbeams, hawthorns and particularly lush and broad-leaved on robinias. There are several subspecies within the species that have a connection to different host tree species.

Deciduous mistletoe (Viscum album L. subsp. album) occurs on poplars, willows and various fruit trees. It is also common on linden, maple, robinia and regionally on birch. The fir mistletoe (Viscum album subsp. abietis (Wiesb.) Janchen, Syn.: Viscum abietis (Wiesb.) Fritsch) grows as expected on individual fir species and extremely rarely on a spruce and on a deciduous tree species. The pine mistletoe and the pine mistletoe (Viscum album subsp. austriacum (Wiesb.) Vollm., syn.: Viscum laxum Boiss. & Reut.) grows preferentially on pine trees, more rarely on spruce and larch. The Cretan mistletoe (Viscum album subsp. creticum N. Böhling et al.) is another described subspecies that is endemic to Crete and grows there on the Calabrian pine.

Mistletoe was already known in ancient mythology and was used by the Gallic druids as a remedy and for ritual activities. The rare specimens that grew on oak trees were considered sacred by Celtic priests. It was not only considered a miracle plant against diseases, but was also revered as a sanctuary, as a sign of everlasting life and was a fertility symbol for Celts and Germans.

Some old customs are still maintained today. In some countries, such as Switzerland, mistletoe is a symbol of fertility. There is a ritual in England that a sprig of mistletoe is hung over the door at Christmas time and the young lady who is under the sprig of mistletoe may be kissed on the spot. In France, on New Year's Day, mistletoe is also hung over the door and everyone kisses relatives and friends underneath. A saying is also said: Au gui, l'an neuf, which means "With the mistletoe comes the New Year".

Myrrh consists of several species of myrrh shrub from the Balsamaceae family, primarily Commiphora myrrha. The thorny shrub, which can grow up to three meters high, mainly grows in Somalia. Other myrrh-producing species thrive in southern Arabia and Ethiopia. Myrrh was used for embalming in ancient Egypt 3000 years ago. The dried, yellow-brown resin granules have been used for thousands of years, especially in the countries of origin and were also part of cultic anointing. In the Middle Ages in Europe, remedies against the plague were made from myrrh resin, which was also said to have a fever-reducing effect.

In medieval medicine, myrrh resin was used, for example, to treat wounds, whereby a distinction was made between white and red varieties of myrrh resin. As a myrrh tincture, myrrh still has pharmaceutical importance in the treatment of inflammation of the oral mucosa, as it has a disinfecting effect and also has a haemostatic effect. Myrrh reduces the tension in the smooth intestinal muscles and therefore has an antispasmodic effect.

Frankincense is the air-dried gum resin obtained from various species of Boswellia. In addition to its medicinal use as a phytotherapeutic agent, frankincense is also used as a ritual incense. The smoke produced when burning is also called incense. Frankincense resin is coarse-grained to lumpy and translucent brown-yellow to reddish-brown in color. Frankincense resin is primarily derived from Boswellia sacra, Boswellia papyrifera, Boswellia serrata, and Boswellia frereana, each producing a slightly different type of resin. However, lesser known varieties such as Boswellia dalzielli, Boswellia nana, Boswellia neglecta and Boswellia rivae are also harvested and used.

Different locations and climatic conditions also influence the respective resin quality. A sticky, milky liquid escapes through cuts in the trunk and branches, which causes the incense resin to develop when it dries in the air.

Between the end of March and the beginning of April, incense production begins and lasts for several months. Some types of frankincense are harvested all year round. The first harvest yields a very poor quality resin that was previously unused but is now being marketed.

It is only three weeks later that an acceptable quality is harvested, which becomes better and purer over the next few weeks. The resin yield per tree depends on the age, size and condition of the tree and ranges from two to ten kilograms. More than 82% of frankincense production comes from Somalia, with the rest coming from neighboring southern Arabia and Central African countries.

Frankincense was already used by the ancient Egyptians for cultic purposes, in the mummification of prominent and wealthy people and at least in wealthy circles in everyday life as an aromatic, disinfecting and anti-inflammatory remedy.

In ancient times, frankincense was a highly paid and coveted commodity and was traded on the incense route and in long-distance trade to almost all areas of the ancient world and played a role in most religions and cultures of the time. The origin of incense was kept secret and trade routes were monitored.

Symbolically, the incense stands for purification, worship and prayer. According to Psalm 141 and In other Bible texts he describes the prayer of believers ascending to God. Frankincense is therefore considered a sign of the presence of God and the blowing of the Holy Spirit. From antiquity through the Middle Ages to the 18th century, frankincense resin was used directly as a powder or as an ingredient in healing plasters to treat wounds and erosions.

In Indian Ayurveda, frankincense is used in folk medicine, for example for rheumatic diseases or for joint and muscle problems. In classic European naturopathy, frankincense was used for various diseases, but was forgotten. In modern medicine, preparations made from frankincense with a standardized content of active ingredients are examined in the therapy of chronic inflammatory diseases. Individual case reports are available on attempts to treat frankincense in bronchial asthma. Long-term effects of taking frankincense are not known. Indian frankincense is described as a herbal medicinal substance in the European pharmacopoeia, and homeopathic preparations are already known.

Only the development of chemical-synthetic medicinal substances, especially in the class of antibiotics, caused frankincense to be forgotten as a medicinal product. Medical research was intensified in connection with the return to natural remedies and the promotion of natural remedy research.

Recently, research institutions have been researching target structures again at the molecular and cellular level in order to make the pharmacological effects of incense therapeutically usable. In East Africa, frankincense has traditionally been used to treat various bacterial diseases.

Another important medicinal plant with a wide range of possible uses is hemp. Hemp (Cannabis sativa L.), for example, has long been used in China and not only provided tasty seeds, but also stalks with their particularly long and almost versatile fibers. In a medical text written more than a hundred years before Christ, the Chinese author describes how hemp can be used as a remedy for malaria, rheumatism and many other ailments.

Hemp made its way around the world via India and the ancient civilizations. In Europe, the oldest finds come from the Eisenberg area in Thuringia. Pliny the Elder reports on the effectiveness of hemp for pain. From the Middle Ages to modern times, hemp was used to relieve labor cramps and other pain symptoms.

The research revealed a large number of medicinal effects of the herbal active ingredients listed. The combating of corona viruses by such herbal preparations, on the other hand, has not been described to date.

Various approaches are known in the literature for using plant-based pharmaceutical compositions for the treatment of infectious diseases. Homeopathic compositions for colds, infections and to strengthen the immune system are also used.

In the document DE 10 2015 121 607 describes a pharmaceutical composition for the treatment of colds and allergies, which is preferably used in the prophylactic or therapeutic treatment of respiratory diseases, in particular colds or allergies. It contains effective homeopathic active ingredients in the form of slime drugs or slime substances as components. Plant ingredients from the group of Drosera, in particular Drosera rotundifolia, Drosera intermedia or Drosera anglica, Arum triphyllum or Galphimia glauca are selected as homeopathic active ingredients

In the utility model specification DE 20 2008 000 653 describes a composition in the form of a pharmaceutical or homeopathic preparation for increasing the immune system and for the prophylactic or curative treatment of infections or colds. It primarily contains inorganic salts such as iron phosphate, potassium chloride and potassium phosphate as active ingredients

In the utility model specification DE 20 2015 106 754 a pharmaceutical composition is claimed, preferably for use in the prophylactic and/or therapeutic treatment of respiratory diseases, in particular colds or allergies, the composition in combination and in effective, in particular pharmaceutically effective amounts, containing at least one homeopathic active ingredient effective against colds and allergies and at least supposed to contain a slime drug

This is analogous to the document DE 10 2015 121 607 to ingredients isolated from plants, which from the group of Drosera, in particular Drosera rotundifolia, Drosera interme dia or Drosera anglica, Arum triphyllum or Galphimia glauca.

Epshtein et al. have developed a combination pharmaceutical composition and method for treating respiratory diseases. At the same time, it should be suitable for the treatment of diseases or conditions associated with respiratory diseases.

The combination pharmaceutical composition according to the document DE 11 2011 102 412 contains an activated and potentiated form of an antibody to bradykinin, an activated and potentiated form of an antibody to histamine and an activated and potentiated form of an antibody to morphine. Also claimed is the method of treating and preventing respiratory diseases by administering the combination composition.

From the same author appears in the document DE 11 2011 102 638 claimed a pharmaceutical composition comprising an activated and potentiated form of an antibody to HIV protein and a method of treating and preventing diseases caused by or associated with HIV, including AIDS.

Epshtein et al. have further developed a combination pharmaceutical composition and method for the treatment and prevention of infectious diseases. The combination pharmaceutical composition contains an activated and potentiated form of an antibody to at least one cytokine and an activated and potentiated form of an antibody to a variety of infectious diseases [ DE 11 2011 102 640 ].

Erhard Weber from Osnabrück invented homeopathic medicines that are suitable for the treatment of bronchial infections and allergies, as in the DE 10 2004 063 363 described. These medicines with the active ingredient capsaicin are suitable for internal, oral, per lingual, inhalative and infusion use. Combinations of dosage forms as well as with other broncholytic or spasmolytic natural substances and synthetically produced agents are successful. Side effects and contraindications are not known.

As a result of the research, it was found that there are approaches to achieving antiviral effects with the help of herbal active ingredients. So far, however, virustatic and virucidal pharmaceutical compositions are not known as homeopathic medicines against corona viruses.

The object of the invention is to develop a composition with virustatic and virucidal properties, in particular in the form of a pharmaceutical or homeopathic preparation, which is suitable for treating infections with corona viruses.

Detailed description of the invention

This object is achieved by using extracts from Artemisia annua and other plant extracts, active ingredients and additives according to the features of the preamble of claim 1.

This object has been achieved by the production of a plant extract which contains extracts from Artemisia annua, the annual Chinese mugwort as well as other plant extracts and other additives as the main component.

It has been found that extracts from Artemisia annua, which contain other active ingredients in addition to the active ingredient artemisinin (Fig. 2), have antiviral properties. Surprisingly, these effects can be increased synergistically by adding other plant extracts.

Extracts from different types of mistletoe, from myrrh and from frankincense as well as extracts containing cannabidiol are used as active components according to the invention. According to the invention, further active ingredients for the treatment of infections with corona viruses are chlorhexidine salts, atovaquone and proguanil and essential oils such as clove and mint oil, surfactants such as polysorbates, processing aids, aromas and flavorings, sweeteners, acidifiers, stabilizers, micronutrients and vitamins as further ingredients.

Extracts of the annual mugwort Artemisia annua form the main active ingredient of the homeopathic preparation according to the invention, which contains the organic peroxide artemisinin (Figure 2) as a relevant ingredient, which can be obtained by extraction with various solvents. Annual mugwort contains artemisinin in concentrations of 0.1 to 0.9% by weight in the flowers and leaves. The antimalarial action consists of an oxygen radical-mediated and heme-iron-catalyzed alkylation of the heme. This changes its structure in such a way that Plasmodium in its erythrocytic form of malaria can no longer use it as food.

In addition to artemisinin, the plant also contains other active ingredients which are used according to the invention but which have not been researched very much to date. According to the invention, active ingredients of the annual mugwort Artemisia annua are used in the form of a tincture, specifically a homeopathic concentrated mother tincture according to the Homeopathic Pharmacopoeia (HAB) from suitable starting materials that meet the requirements of the monograph “Homeopathic preparations (Praeparationes homoeopathicae)”.

The homeopathic mother tincture is made from dried plant material of annual mugwort (Artemisiae annuae herba) by maceration of the herb of appropriate quality, which has been ground and ground. The mother tincture is produced by maceration from one part dried herbal drug and nine parts ethanol 70% (v/v).

The maceration takes place over a period of 10 to 30 days, and shaking is required from time to time. Thin-layer chromatography and high-performance liquid chromatography-mass spectrometry (HPLC-MS) were used to characterize the homeopathic mother tincture of Artemisia annua.

The thin-layer chromatography of the Artemisia mother tincture was carried out using TLC plates Alugram Sil G/UV (Macherey-Nagel) and hexane-ethyl acetate mixtures as mobile phase. The artemisinin contained in the extract could be clearly detected in the extract using appropriate reagents. A detailed test description is shown in Example 2.

The content of artemisinin in the mother tincture could also be confirmed by the investigations using HPLC-MS. The corresponding mass spectrum is shown in Figure 3. The investigations and test conditions are detailed in Example 2.

Other active ingredients that are used according to the invention are mistletoe extracts. The use of mistletoe as a medicinal plant was already known in ancient times. The dried, young twigs with leaves, blossoms and fruits are used as a medicinal drug. Constituents are glycoproteins, viscotoxins, water-soluble polysaccharides, biogenic amines, flavonoids, ligans, cyclitols such as Viscumitol and phenolic carboxylic acids. Mistletoe tea or corresponding mistletoe extracts are traditionally used to support the circulatory system in hypertension and to prevent arteriosclerosis. There are also indications in terms of non-specific stimulation therapy that mistletoe preparations can inhibit tumor growth or even cure cancer.

To produce a mistletoe extract according to the invention, an aqueous-alcoholic extract is produced from fresh mistletoe plant material by maceration. The fresh plant of appropriate quality is used. The plant material is crushed in a suitable form to support complete maceration. The mother tincture is prepared according to regulation 1.1.3. Prepared "mother tinctures from fresh plant material". After determining the loss on drying (Regulation 2.2.32 HAB 2014), the appropriately comminuted plant material is immediately mixed with at least half its mass of ethanol 90% (v/v). The amount of ethanol 90% (V/V) that still has to be added is determined with the aid of the loss on drying, the weight of the plant material and the ethanol used up to now. Maceration takes place for at least 10 days in a tightly closed vessel with repeated shaking. The mixture is then squeezed out and the liquid obtained is filtered.

Myrrh extracts are obtained from a resinous raw material. Myrrh resin is the aromatic gum resin of several species of the myrrh shrub of the Balsamaceae family, primarily Commiphora myrrha. In addition to the effects already described, myrrh reduces inflammatory processes and has the ability to reduce the formation of free radicals and thus strengthen the antioxidant protection system.

Studies have shown that myrrh is also used internally to soothe bronchitis. Myrrh extracts primarily contain furanosesquiterpenes such as furanoeudesma-1,3-diene (major component), furanoeudesma-1,4-dien-6-one, lindestren, curzerenone, furanodiene, 2-methoxyfuranodiene, and 4,5-dihydrofuranodien-6-one, along with Sesquiterpenes such as α-copaen, elemen and bourbounes. Furanoeudesma-1,3-diene showed analgesic effects that could be reversed by naloxone, indicating binding to opioid receptors. Furthermore, growth-inhibiting effects have been demonstrated in various bacteria.

To produce a myrrh extract according to the invention, an aqueous-alcoholic extract is produced from the dried gum resin of the myrrh bush by maceration. The raw material is crushed in a suitable form to support complete maceration. The mother tincture is prepared according to regulation 1.1.8. Prepared "mother tinctures from dried plant material". The mother tincture is produced by maceration of dried herbal drug and appropriate proportions of ethanol 86% (v/v). The vessel is left tightly closed, protected from light, under between standing for an appropriate period of time while shaking, and then filter off.

Extracts of frankincense are also used as homeopathic active ingredients. Frankincense consists of a mixture of essential oils, resins, mucilage and proteins, the amounts of which vary depending on the species. The proportion of pure resin is about 50 to 80% by weight, a large part of the resin is made up of terpenes, which also include boswellic acids. Depending on the type, the rubber content in the resin is 10 to 30% by weight, the proportion of essential oils is between 5 and 12% by weight.

The "Indian frankincense" traditionally used in Indian Ayurveda medicine, extracted from the salai tree (Boswellia serrata), also listed in the European Pharmacopoeia (Ph. Eur.), contains approx. 5 to 9% by weight of essential oil (alpha-thujen, β-myrcene, p-cymene and methyleugenol, approx. 15 to 16% by weight of resin acids [such as boswellic acids, lupanic acids and tirucallenic acids; at least 1% by weight each of 3-O-acetyl-11-keto-β-boswellic acid (AKBA ) and 11-keto-β-boswellic acid (KBA)] and up to 20% by weight mucilage.

To produce an incense extract according to the invention, an aqueous-alcoholic extract of incense raw material is produced by maceration. The dried material of appropriate quality is used. It is crushed in a suitable form to support full maceration. The mother tincture is prepared according to regulation 1.1.8. Prepared "mother tinctures from dried plant material". The mother tincture is produced by maceration of dried herbal drug and appropriate proportions of ethanol 70% (v/v).

Extracts of the hemp plant, which contain cannabidiol and other active ingredients, are also used according to the invention as a homeopathic active ingredient.

Hemp species and cultivars are dioecious and have separate sexes, which means that male and female flowers grow on different plants. Different hemp varieties contain a different spectrum of active ingredients. The pharmacological effects of cannabis have only recently become the focus of medical research.

Responsible for the effects are ingredients called cannabinoids; especially tetrahydrocannabinol (THC) and cannabidiol (CBD). Studies indicate a possible medicinal potential of medical cannabis in certain forms of cancer.

According to the invention, a large number of hemp varieties can be used to produce the extracts. When using low-THC species, the extracts preferably contain cannabidiol as the active ingredient. Cannabidiol (CBD) is a non-psychoactive cannabinoid found in hemp that has been reported to have anticonvulsant, anti-inflammatory, anxiolytic, and anti-nausea effects. Cannabidiol is mainly present in the plant as CBD carboxylic acid. Cannabidiol binds to the cannabinoid receptors agonistically, but it can also block their activity through an unexplained mechanism. CBD is part of a medicinally used hemp extract that can be used in multiple sclerosis.

To produce a hemp extract according to the invention, an aqueous-alcoholic extract is produced from dried hemp blossoms by maceration. The raw material is crushed in a suitable form to support complete maceration. The mother tincture is prepared according to regulation 1.1.8. Prepared "mother tinctures from dried plant material". The mother tincture is produced by maceration of dried herbal drug and appropriate proportions of ethanol 70% (v/v). The vessel is left tightly closed and protected from light for an appropriate period of time, shaking occasionally.

Chlorhexidine salts are used as further active substances which are used according to the invention, of which chlorhexidine digluconate is preferably used because of its good solubility in water. Chlorhexidine has been used as a disinfectant in mouthwash solutions, in dentistry and in wound care for many decades. Due to its attachment to the oral mucosa and teeth and its slow release, chlorhexidine remains effective for a long time, with release occurring over a period of 8 to 12 hours. In addition to its very good effect against bacteria, it is also able to kill enveloped viruses such as SARS-CoV-2.

Thus, the effectiveness of chlorhexidine against SARS-CoV-2 has been demonstrated on a laboratory scale as when used as a mouthwash solution in patients. When used as a mouthwash, it led to an enormous reduction in the viral load in the saliva. This significantly reduces the risk of transmission by an infected person during this period. In addition, an uninfected person can minimize the risk of infection by using chlorhexidine because the pathogens are killed in the throat before infection. According to the invention, the chlorhexidine salts can be used both in homeopathic concentrations and in higher concentrations of up to 0.5% by weight.

The combination with essential oils such as clove or mint oil has also proven particularly advantageous. In addition to the virucidal effect of the active ingredient chlorhexidine alone or in combination with essential oils, it was surprisingly found that the additional use of extracts from Artemisia annua and other plant raw materials led to a synergistic intensification of the virucidal effect of the composition according to the invention. The oropharynx is particularly suitable for use, on the one hand to effectively reduce the risk of infection, but also to reduce the risk of infecting other people in people infected with SARS-CoV-2. Because of this, the use of the preparations according to the invention as an antiviral mouthwash solution is successful.

However, one difficulty that arises when treating with mouthwash solutions to reduce the viral load is the fact that mouthwashes do not wet all areas of the mouth and throat to a sufficient extent. Especially the area of the pharynx behind the anterior palatal arch is treated only very insufficiently due to the gag reflex. Wetting of the entire mouth and throat mucosa is improved by using a spray bottle with a mouth and throat applicator when using the composition according to the invention.

This is also where the mucous membranes of the pharynx or lower pharynx are reached, where most of the viruses are located in the event of an infection. In addition, this type of application offers the advantage of a quick and uncomplicated application that can also be carried out on people who are unable to gargle with mouthwash solutions for a long period of time.

Other active ingredients that are used according to the invention are atovaquone and proagunil, which are also used to treat malaria. Atovaquone is a drug used to treat protozoal diseases such as malaria and toxoplasmosis, as well as Pneumocystis pneumonia (PCP) caused by the fungus Pneumocystis jirovecii. Its mechanism of action is based on a disruption of the nucleic acid synthesis of the pathogen. Atovaquone is offered in combination with proguanil under the brand name Malarone for chemoprophylaxis and treatment of malaria. Proguanil is also used as a monopreparation and as a combination preparation for chemoprophylaxis and treatment of malaria.

The homeopathic concentrated mother tinctures of the two active ingredients are manufactured in accordance with the regulations of the Homeopathic Pharmacopoeia (HAB).

To improve the wettability of the human mucous membrane, the addition of surfactants, particularly of the polysorbate type, and the use of thickeners have also proven advantageous. In addition, processing aids that are required for technological reasons during processing of the preparation can also be used. Aromatic and flavoring substances of different types can also improve the application of the pharmaceutical preparation. While acidifiers such as citric acid or ascorbic acid mainly affect the pH value of the preparation in addition to modifying the taste of the preparation, sweeteners such as glucose, stevia and synthetic sweeteners make a particular contribution to improving the sensory properties. Stabilizers, micronutrients and vitamins can serve to further round off the pharmaceutical or homeopathic preparation.

To demonstrate the effectiveness of the compositions according to the invention, extensive tests were carried out on a large number of subjects who suffered from cold symptoms of different types and degrees.

The homeopathic formulation Artemisia annua D2 (Example 7) was administered to 20 volunteers with unspecified viral cold symptoms at intervals of eight hours in an amount of 20 drops each. After a treatment period of three days, the symptoms had largely subsided in 8 subjects. Another 20 subjects with unspecified viral cold symptoms were administered the homeopathic formulation of Artemisia annua D2, mistletoe D2, myrrh D2 and cannabidiol D2 (Example 11) at intervals of eight hours. in an amount of 20 drops each. Surprisingly, after a treatment period of 72 hours, the cold symptoms had completely disappeared in 15 subjects. This synergistic effect of the homeopathic active ingredients used was all the more surprising since older subjects in particular were freed from the symptoms of the disease.

In a further experiment on 20 volunteers with unspecified viral cold symptoms, the homeopathic formulation of Artemisia annua D1, 0.1% chlorhexidine digluconate and small additions of clove and mint oil (Example 16) were administered at intervals of four hours in an amount of 20 drops each. Surprisingly, after a treatment period of 72 hours, the cold symptoms had completely disappeared in 12 subjects. This synergistic effect of the active ingredients used was all the more surprising since in this case, too, older subjects in particular were freed from the symptoms of the disease. For comparison, the preparation according to the invention was applied as a spray solution under similar test conditions, with even more rapid elimination of the symptoms of the disease being observed.

The invention is to be explained in more detail with the aid of the following examples, without being restricted to these:

example 1

• Homeopathic mother tincture according to the Homeopathic Pharmacopoeia (HAB)
• (Regulation 4a; mother tincture of dried plant material)
• Plant: Artemisia annua L.
• Family: Asteracae (formerly Comopositae)

The mother tincture is produced by maceration of 1 part dried herbal drug and 10 parts ethanol 70% (v/v). The herbal drug is finely ground. The mortar serves to crush and break up the corresponding oil cells or the spaces in which the desired secondary plant substances are contained. Then the 70% ethanol is added and the mixture is left to macerate in a tightly closed vessel, protected from light, for 25 days. Intermittent shaking is performed every 24 hours. After 25 days, the residue is separated off by filtration, pressed out and the two macerates obtained are combined with one another.

This is followed by sampling and analysis of this sample under established criteria and specifications.

Key Ingredient: Artemisinin (Secocadinan-Type Sesquiterpene Lactone Endoperoxide)

example 2

Analytical detection of artemisinin in the mother tincture of Artemisia annua according to example 1,

a) Thin-layer chromatographic analysis Thin-layer chromatography of extracts from Artemisia annua experimental set-up

Thin-layer chromatography is performed in a simple TLC chamber without a ground-glass lid and without chamber saturation.

equipment and chemicals

TLC chamber without ground-glass lid, iodine chamber
TLC plates: Alugram Sil G/UV (Macherey-Nagel),
Pasteur pipettes
Artemisia annua extract, mother tincture from example 1
Artemisinsin, reference substance
hexane, ethyl acetate, iodine

test execution

1. 1. Die DC-Kammer wird mit ca. 2 ml Hexan/Essigester 9/1 (eine Pasteurpipette) beschickt. Auf die DC-Platte werden mittels Pasteurpipette Vergleichssubstanz und Urtinktur aufgetragen. Nach Chromatogrammlauf wird in der Iodkammer entwickelt. Artemisinin läuft. Rf-Wert: 0,16 Der Extrakt läuft als Band, Artemisinin ist als Fleck eindeutig zu identifizieren.
2. 2. Die DC-Kammer wird mit ca. 2 ml Hexan/Essigester 7/3 (eine Pasteurpipette) beschickt. Auf die DC-Platte werden mittels Pasteurpipette Vergleichssubstanz und Urtinktur aufgetragen. Nach Chromatogrammlauf wird in der Iodkammer entwickelt. Artemisinin läuft. Rf-Wert: 0,47 Der Extrakt läuft als Band, Artemisinin ist als Fleck eindeutig zu erkennen.

Approx. 10 mg artemisinin are dissolved in approx. 1 ml hexane as a comparison sample.

1. 1. The TLC chamber is filled with approx. 2 ml hexane/ethyl acetate 9/1 (a Pasteur pipette). Comparison substance and mother tincture are applied to the TLC plate using a Pasteur pipette. After the chromatogram run, development takes place in the iodine chamber. Artemisinin runs. Rf value: 0.16 The extract runs as a band, artemisinin can be clearly identified as a spot.
2. 2. The TLC chamber is filled with approx. 2 ml hexane/ethyl acetate 7/3 (a Pasteur pipette). Comparison substance and mother tincture are applied to the TLC plate using a Pasteur pipette. After the chromatogram run, development takes place in the iodine chamber. Artemisinin runs. Rf value: 0.47 The extract runs as a band, artemisinin can be clearly recognized as a spot.

b) Analysis by high-performance liquid chromatography-mass spectrometry (HPLC-MS) HPLC-MS of extracts from Artemisia annua Description of the method

The samples were analyzed on an Agilent Infinity HPLC 1260 system (with a binary pump, multi-column thermostat and auto-sampler) equipped with an Agilent G6470A Series Triple Quad mass spectrometer (both from Agilent Technologies Sales & Services GmbH & Co.KG, Waldbronn, Germany ) was paired with an electric spray (ESI) source was operating in positive ionization mode. The samples containing artemisinin were separated using a Kinetex C8 analytical column (2.6 pm, 100 A, 150 x 4.60 mm; Phenomenex, Torrance, CA, USA) maintained at a temperature of 30°C. The mobile phase consisted of eluent A (0.1% formic acid) and eluent B (acetonitrile) at a flow rate of 0.5 mL min ^-1 .

The following gradient conditions were applied: 100% A from 0 to 4 min, 100-0% A from 4 to 10 min, 0% A from 10 to 14 min, 0-100% A from 14 to 15 min, 100% A from 15 to 16 min. The column equilibration time between the individual runs was 4 min. 0 to 2 µL of the samples were injected. The temperature of the desolvation gas in the ionization source was set at 275°C. The gas flow was 11 L min ^-1 , the nebulizer pressure was 35 psi and the capillary tension was 5425 nA. The following MS/MS conditions were applied: collision gas: nitrogen, pressure: 3.66E ^-5 Torr, fragmentor voltage: 104 V, collision energy (CE, eV) was individually optimized, cell accelerator voltage: 5 kV, residence time: 200 ms. Detection was performed in Selected Reaction Monitoring (SRM) mode, monitoring a specific transition at a specific point in time according to the retention time of the compound. At least the seven most intense transitions in the production spectrum of the respective standard substance were selected. The samples were analyzed in duplicate. Then the relative abundance of each sample was measured considering the total area of all analyzed transitions. Thus, the following HPLC and mass spectrometric conditions were optimized: Determination of the retention time, optimization of the collision energy, selection of the transitions, method validation.

• Artemisinsin, Vergleichssubstanz
• Extrakt in 70%igem Ethanol, Urtinktur nach Beispiel 1

Rehearse:

• Artemisinsin, reference substance
• Extract in 70% ethanol, mother tincture according to example 1

Result:

Artemisinin could be clearly identified in the extract by means of HPLC. In addition to artemisinin, the extract contains a second peak with similar fragmentation behavior; it is probably an isomer of artemisinin.

The mass spectrum fragmentation results are similar to those found in the database (https://mona.fiehnlab.ucdavis.edu/spectra/display/CCMSLIB000 00080460; https://pubchem.ncbi.nlm.nih.gov/compound/artemisinin# section =Names-and-Identifiers) are reported. Powder: 0.5 µl injected corresponds to 0.5 µg.

The content of artemisinin could be confirmed by the mass spectrum (Fig. 3).

Example 3

Homeopathic mother tincture according to the Homeopathic Pharmacopoeia (HAB)

(Rule 1.1.3.; mother tincture from fresh plant material) Plant: Mistletoe, Viscum album L.

The appropriately comminuted plant material, the cut, dried, younger twigs with leaves, flowers and isolated fruits, after determining the drying loss (Regulation 2.2.32 HAB 2014), are immediately mixed with at least half their mass of ethanol 90% (V/ V) offset. The amount of ethanol 90% (V/V) that still has to be added is determined with the aid of the loss on drying, the weight of the plant material and the ethanol used up to now. Maceration takes place for 15 days in a tightly closed vessel with repeated shaking. The mixture is then squeezed out and the liquid obtained is filtered.

This is followed by sampling and analysis of this sample under established criteria and specifications.

example 4

Homeopathic mother tincture according to the Homeopathic Pharmacopoeia (HAB)

(Regulation 4a; mother tincture of dried plant material)
Plant: myrrh
Family: Burseraceae

The mother tincture is produced by maceration of 1 part dried herbal drug and 10 parts ethanol 86% (v/v). The herbal drug is finely ground. The mortar serves to crush and break up the corresponding oil cells or the spaces in which the desired secondary plant substances are contained. The 86% ethanol is then added and the mixture left to macerate in a tightly closed vessel, protected from light, for 25 days. Intermittent shaking is performed every 24 hours. After 25 days, the residue is separated off by filtration, pressed out and the two macerates obtained are combined with one another.

This is followed by sampling and analysis of this sample under established criteria and specifications. The mother tincture is a golden yellow to yellow-brown liquid with an aromatic odour.

Example 5

Homeopathic mother tincture according to the Homeopathic Pharmacopoeia (HAB)

(Prescription 4a; mother tincture of dried plant material) Indian frankincense Olibanum indicum, an air-dried gum resin obtained from the stems and branches of Boswellia serrata Roxb. ex Colebr. obtained by cutting

The mother tincture is produced by macerating 1 part of the dried resin and 10 parts of 70% (v/v) ethanol. The resin is finely ground to improve extractability of the active ingredients. The 70% ethanol is then added and the mixture left to macerate in a tightly closed vessel, protected from light, for 25 days. Intermittent shaking is performed every 24 hours. After 25 days, the residue is separated off by filtration, pressed out and the two macerates obtained are combined with one another.

This is followed by sampling and analysis of this sample under established criteria and specifications.
Main ingredients are: 11-keto-β-boswellic acid (C ₃₀ H ₄₆ O ₄ ; M _r 470.7) and acetyl-11-keto-β-boswellic acid (C ₃₂ H ₄₈ O ₅ ;
Mr _512.7 )

Example 6

Homeopathic mother tincture according to the Homeopathic Pharmacopoeia (HAB)

(Prescription 4a; mother tincture of dried plant material) Cannabis flowers
Plant: Cannabis sativa L. (Cannabaceae).

The mother tincture is produced by maceration of 1 part dried cannabis flowers and 10 parts ethanol 70% (V/V). Cannabis flowers are used, which mainly contain cannabidiol and only a small amount of tetrahydrocannabinol. The herbal drug is finely ground. The mortar serves to crush and break up the corresponding oil cells or the spaces in which the desired secondary plant substances are contained. The 70% ethanol is then added and the mixture left to macerate in a tightly closed vessel, protected from light, for 25 days. Intermittent shaking is performed every 24 hours. After 25 days, the residue is separated off by filtration, pressed out and the two macerates obtained are combined with one another.

This is followed by sampling and analysis of this sample under established criteria and specifications.
Main ingredient: cannabidiol

Example 7

Homeopathic formulation Artemisia annua D2

To prepare the homeopathic formulation, 1 part mother tincture and 9 parts ethanol 70% (v/v) are mixed homogeneously and shaken according to the homeopathic procedure. By using a low potency, both pharmacological and homeopathic modes of action come into play. The main active ingredient is artemisinin, a secocadinan-type sesquiterpene lactone endoperoxide.

example 8

Homeopathic formulation of Artemisia annua D2 and myrrh D2

To prepare the homeopathic formulation, 1 part mother tincture Artemisia annua, 1 part mother tincture myrrh and 8 parts ethanol 70% (v/v) are mixed homogeneously and shaken according to the homeopathic procedure. By using a low potency, both pharmacological and homeopathic modes of action come into play.

example 9

Homeopathic formulation of Artemisia annua D2 and mistletoe D2

To prepare the homeopathic formulation, 1 part mother tincture Artemisia annua, 1 part mother tincture mistletoe and 8 parts ethanol 70% (v/v) are mixed homogeneously and shaken according to the homeopathic procedure. By using a low potency, both pharmacological and homeopathic modes of action come into play.

Example 10

Homeopathic formulation of Artemisia annua D2, mistletoe D2 and frankincense D2

To prepare the homeopathic recipe, 1 part mother tincture Artemisia annua, 1 Part mother tincture mistletoe, 1 part mother tincture frankincense and 7 parts ethanol 70% (V/V) homogeneously mixed and shaken according to the homeopathic procedure. By using a low potency, both pharmacological and homeopathic modes of action come into play.

Example 11

Homeopathic formulation of Artemisia annua D2, mistletoe D2, myrrh D2 and cannabidiol D2

To prepare the homeopathic recipe, 1 part mother tincture Artemisia annua, 1 part mother tincture mistletoe, 1 part mother tincture myrrh, 1 part mother tincture cannabis flowers, which mainly contain cannabidiol, and 6 parts ethanol 70% (V/V) are mixed homogeneously and according to the homeopathic procedure spilled. By using a low potency, both pharmacological and homeopathic modes of action come into play.

Example 12

Spray solution with chlorhexidine

To prepare the spray solution, 0.532 g chlorhexidine digluconate solution 20% (w/v) is made up to 100 g with purified water.

Example 13

Spray solution with chlorhexidine and 24% (v/v) ethanol

To prepare the spray solution, 0.532 g of 20% (m/v) chlorhexidine digluconate solution and 20 g of 96% (v/v) ethanol are made up to 100 g with purified water.

Example 14

Chlorhexidine spray solution with ethanol and clove oil and mint oil

To prepare the spray solution, 0.532 g chlorhexidine digluconate solution 20% (m/v), 20.000 g ethanol 96% (v/v), 0.500 g polysorbate 80, 0.020 g clove oil and 0.020 g mint oil are made up to 100 g with purified water.

Example 15

Chlorhexidine spray solution with ethanol and essential oils

To prepare the spray solution, 0.532 g chlorhexidine digluconate solution 20% (m/v), 20.000 g ethanol 96% (v/v), 0.500 g polysorbate 80, 0.020 g clove oil, 0.020 g mint oil and 0.020 g oregano oil per 100 g with purified filled up with water.

Example 16

Chlorhexidine spray solution with ethanol, clove oil, mint oil and Artemisia annua D1

To prepare the spray solution, add 0.532 g chlorhexidine digluconate solution 20% (m/v), 20.000 g ethanol 96% (v/v), 10.000 g Artemisia annua D1, 0.500 g polysorbate 80, 0.020 g clove oil and 0.020 g mint oil to 100 g filled with purified water.

QUOTES INCLUDED IN DESCRIPTION

This list of documents cited by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent Literature Cited

• DE 602004009552 [0009]
• DD 146548 [0009]
• DE 4135397 [0009]
• DE 69017484 [0010]
• DE 60222557 [0010]
• DE 10200500527446 [0010]
• EP 0199792 [0011]
• DE 19843903 [0011]
• DE 69929278 [0011]
• DE 102015121607 [0038, 0041]
• EN 202008000653 [0039]
• EN 202015106754 [0040]
• EN 112011102412 [0043]
• EN 112011102638 [0044]
• EN 112011102640 [0045]
• DE 102004063363 [0046]

Claims (11)

Composition in the form of a pharmaceutical or homeopathic preparation for the treatment of infections with viruses, in particular corona viruses and also for the prevention of infections and for strengthening the immune system, characterized in that the active ingredients are extracts from Artemisia annua alone or in combination with various other plant extracts and other supplementary ingredients are included. composition after claim 1 characterized in that it contains exclusively extracts from Artemisia annua in an amount in the range from 0.00001 to 10% by weight, preferably in the range from 0.0001 to 5% by weight, as the pharmaceutical or homeopathic active substance. composition after claim 1 characterized in that extracts from Artemisia annua and mistletoe extracts are contained as pharmaceutical or homeopathic active ingredients in a quantity in the range from 0.00001 to 10% by weight, preferably in the range from 0.0001 to 5% by weight. composition after claim 1 characterized in that extracts from Artemisia annua and myrrh extracts are contained as pharmaceutical or homeopathic active ingredients in a quantity in the range from 0.00001 to 10% by weight, preferably in the range from 0.0001 to 5% by weight. composition after claim 1 characterized in that extracts from Artemisia annua and frankincense extracts are contained as pharmaceutical or homeopathic active ingredients in a quantity in the range from 0.00001 to 10% by weight, preferably in the range from 0.0001 to 5% by weight. composition after claim 1 characterized in that extracts from Artemisia annua and extracts containing cannabidiol are contained as pharmaceutical or homeopathic active ingredients in a quantity in the range from 0.00001 to 10% by weight, preferably in the range from 0.0001 to 5% by weight. composition after claim 1 until 6 characterized in that the active ingredients mentioned in the claims can be combined with one another in any way in the claimed concentrations. composition after claim 1 until 7 characterized in that the active ingredients as homeopathic components in the form of the homeopathic mother tincture in a decimal potency in the range from D1 to D30, in particular in the range from D2 to D15, preferably in the range from D3 to D10, preferably in the range from D4 to D7, based on the mother tincture of the homeopathic active ingredient is used. composition after claim 1 until 8th characterized in that the said active ingredients are suitably combined with the active ingredient chlorhexidine in the form of its salts in concentrations of 0.00001 to 0.5% by weight. composition after claim 1 until 9 characterized in that the active ingredients are combined as homeopathic components with the active ingredients atovaquone and proguanil in the form of homeopathic mother tinctures. composition after claim 1 until 9 characterized in that essential oils such as cloves and mint oil, surfactants such as polysorbates, processing aids, aromas and flavorings, sweeteners, acidifiers, stabilizers, micronutrients and vitamins and combinations thereof are used as additional ingredients.

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