TWI680759B - Artemisinin-based combination therapy for treating viral mediated disease - Google Patents

Abstract

The present invention describes a method of treating individuals suffering from microbial infections, including a viral infection such as Dengue Fever, using an improved Artemisinin Combination Therapy (ACT), known as Tri-ACT. The improved ACT therapy includes administering a combination of three drugs. In one embodiment of the present invention, the method includes administering to an individual a first composition comprising a therapeutically effective amount of an artemether spray sublingually. The individual is then administered a second composition, a therapeutically effective amount of artesunate. A third composition, an effective amount of berberine, or its pharmaceutically acceptable derivatives or salts is then administered to the individual.

Description

Artemisinin-based combination therapy for treating virus-mediated diseases Cross-reference of related applications

According to 37 C.F.R.1.76, the claim of priority is included in the data sheet of the application filed at the same time. Therefore, the present invention claims the priority of US Patent Application No. 13/542,702 named "ARTEMISININ-BASED COMBINATION THERAPY FOR TREATING VIRAL MEDIATED DISEASE" filed on July 6, 2012 as a partial continuation application. This US patent application Case No. 13/542,702 is related to U.S. Patent Application No. 13/542,719 with the name "ARTEMISININ-BASED COMBINATION THERAPY FOR TREATING PARASITIC MEDIATED DISEASE" filed on July 6, 2012. The U.S. Patent Application No. 13/542,719 No. 12/U.S. Patent Application titled ``COMBINATIONS OE BERBERINE, ARTEMISININ AND THEIR DERIVATIVES TO TREAT MALARIA, DIARRHEA, TRAVELERS' DIARRHEA, DYSENTERY, DENGUE FEVER, PARASITES, CHOLERA AND VIRUSES'' filed on April 22, 2009 Part of the continuation application No. 428,465, the US Patent Application No. 12/428,465 claims the rights and interests of the US Provisional Patent Application No. 61/046,980 filed on April 22, 2008, and the same as July 6, 2012 The name of the daily application is "ARTEMISININ-BASED COMBINATION THERAPY FOR TREATING PARASITIC MEDIATED DISEASE” U.S. Patent Application No. 13/542,719; and the name of the application filed on February 9, 2011 is “COMBINATIONS OF BERBERINE, ARTEMISININ, LOPERAMIDE, AND THEIR DERIVATIVES TO TREAT MALARIA, DIARRHEA, TRAVELERS’ DIARRHEA, DYSENTERY, DENGUE FEVER, PARASITES, CHOLERA AND VIRUSES" US Patent Application No. 13/024,151, and the name of the application on February 9, 2011 is "COMBINATIONS OF BERBERINE, ARTEMISININ, LOPERAMIDE, AND THEIR DERIVATIVES TO TREAT MALARIA, DIARRHEA , TRAVELERS' DIARRHEA, DYSENTERY, DENGUE FEVER, PARASITES, CHOLERA AND VIRUSES, US Patent Application No. 13/024,161. This application also claims the priority of US Provisional Patent Application No. 61/878,848 with the name "ARTEMETHER SPRAY" filed on September 17, 2013. The content of the above-referenced application is incorporated by reference in its entirety.

The present invention relates to microbial therapy, and specifically a method of using modified artemisinin-based therapy to treat individuals suffering from virus-related diseases, and more specifically a method of using modified artemisinin combination therapy (ACT) to treat patients Dengue's individual approach.

Dengue fever is a virus-mediated disease that spreads through several species of mosquitoes in the genus Aedes (Aedes species), most often through the Aedes aegypti. Dengue fever is an acute multi-system virus infection, which is so dynamic that in a very short period of time, mild cases may be converted into severe cases. This is due to increased capillary permeability/fragility, resulting in increased plasma leakage, hypotension, Shock and death (if left untreated). According to the World Health Organization (WHO), dengue fever is the fastest-growing mosquito-borne virus disease in the world. In the past 50 years, the incidence has increased 30 times, and it has increasingly geographically expanded to new countries. It is caused by one of four similar RNA viruses of the Flaviviridae (Elaviviridae) family: DEN-1, DEN-2, Den-3, and DEN-4. All four serotypes can cause complete dengue fever. Infection with dengue fever serotypes can result from a series of clinical diseases ranging from non-specific viral syndromes to severe fatal bleeding disorders. The symptoms of dengue fever include sudden high fever about 4 to 7 days after the bite, usually within the range of 104-105 degrees in Chinese style. Several days after the onset of fever, a characteristic body rash similar to the rash seen in measles appears. In some cases, the disease progresses to hemorrhagic dengue fever, leading to bleeding, low platelet levels, plasma leakage, and dengue shock syndrome.

Dengue fever is the second most important infectious tropical disease after malaria, because more than one-third of the world's population lives in areas at risk of transmission. An estimated 200 million individuals are infected with the dengue virus each year, of which 10,000,000 patients are hospitalized for hemorrhagic dengue fever, and about 5% of these cases result in death. Dengue virus infection is endemic in more than 100 tropical countries, including countries in Asia, the Pacific, Africa, Latin America and the Caribbean. When such places tend to have unplanned and uncontrolled urbanization, and high poverty rates, increased air travel, lack of effective mosquito control, and military deployment to risk areas may lead to outbreaks in more developed countries. In 2009, Florida residents who reported that they did not travel outside the United States contracted dengue fever.

There are no known treatments or vaccines to prevent dengue virus infection. In fact, the most effective measure to prevent the disease is to avoid mosquito bites. Although protective clothing and mosquito irradiation programs theoretically provide protection, an easy-to-administer method for treating individuals suffering from dengue fever is needed in this technique.

The present invention describes a therapy for individuals suffering from viral infections based on artemisinin combination therapy (ACT). In contrast to most ACT therapies that use combination dual drug therapy, the present invention describes a method that uses a combination of three drugs. In a specific example of the invention, the method includes administering the first composition to the individual. The first composition contains a therapeutically effective amount of an artemisinin derivative or a salt thereof, such as artemether or artemether spray delivered sublingually. The second composition is then administered to the individual. The second composition contains a therapeutically effective amount of the second artemisinin derivative or salt thereof. The second artemisinin derivative is different from the first composition and is preferably artesunate. The third anti-microbial composition is administered to the individual. The third composition contains an effective amount of berberine or a pharmaceutically acceptable derivative or salt thereof. The second and third compositions are administered to the individual for an additional period of time, such as two or three days.

In an alternative embodiment, treatment is administered to individuals suffering from diseases transmitted by arthropods such as mosquitoes or ticks.

In an alternative embodiment, the treatment is administered to an individual suffering from a virus-mediated disease mediated by the Flaviviridae family virus.

In an alternative embodiment, the treatment is administered to an individual suffering from a disease mediated by a virus similar to a virus in the Flaviviridae virus.

In an alternative embodiment, the treatment is administered to an individual suffering from a disease mediated by the virus that causes hemorrhagic fever.

In an alternative embodiment, the treatment is administered to an individual suffering from a disease mediated by dengue virus.

In an alternative embodiment, the treatment is administered to an individual suffering from a disease mediated by a virus that causes dengue fever.

When used in individuals suffering from dengue fever, TriAct therapy has been proven safe and effective without death or adverse reactions. TriAct therapy shortens the disease process, reduces viral antigens (NS1) and reduces the risk of bleeding. TriAct therapy leads to faster standardization of blood charts and earlier resolution of clinical symptoms. When compared with the control group, individuals treated with TriAct therapy showed an enhancement of the immune system, allowing neutralizing antibodies to be produced earlier.

The present invention further describes an improved artemether-based supplement and/or pharmaceutical composition, which is administered in the form of a sublingual spray. Supplements and/or pharmaceutical compositions contain artemisinin derivatives, carriers for minimizing allergenicity, and mucosal absorption enhancers. The present invention further relates to a method of manufacturing artemether-based supplements and/or pharmaceutical compositions and their use for delivery to individuals in need.

As used herein, the term "flavivirus" includes about 70 members, which have a positive linear, single-stranded RNA genome. The family includes Flavivirus, Hepatitis C virus, Hepatitis G virus and Pestivirus. The main diseases caused by the Flaviviridae include: dengue fever, Japanese encephalitis, Kyasanur Forest disease, Murray Valley encephalitis, St. Louis encephalitis, ticks Tick-borne encephalitis, West Nile encephalitis, yellow fever and hepatitis C virus infection.

As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" generally refers to organic or inorganic materials, non-toxic, inert solids, semi-solid or liquid fillers, diluents , Encapsulating materials or formulation aids, which are of any type that cannot react with active ingredients. Excipients include (but are not limited to) sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose Vitamin Sodium, ethyl cellulose and cellulose acetate; powdered Yarrow; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; cocoa butter and suppository wax; vegetable oils such as peanut oil, cottonseed oil , Sesame oil, olive oil, corn oil and cocoa butter; esters such as (but not limited to) ethyl oleate and ethyl laurate; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene Glycol; agar; alginic acid; buffers, such as (but not limited to) magnesium hydroxide and aluminum hydroxide; pyrogen-free water; isotonic saline; and phosphate buffer solution; skimmed milk powder; and for pharmaceutical preparation Other non-toxic compatible substances in the substance. Wetting agents and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, flavoring agents, sweeteners, lubricants, release agents, fragrances, carriers, lozenges, stabilizers, antioxidants and preservatives Agents can also be present.

As used herein, "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compound that are biologically or otherwise desirable. Pharmaceutically acceptable salts refer to pharmaceutically acceptable salts of compounds derived from various organic and inorganic relative ions well known in the art and include (by way of example only) sodium, potassium, calcium, Magnesium, ammonium, tetraalkylammonium and the like; and when the molecule contains basic functional groups, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate , Maleate, oxalate and the like.

As used herein, the term "therapeutically effective amount" generally refers to an amount of an agent sufficient to effect a treatment as defined herein when administered to an individual in need of such treatment, such as a mammal, preferably a human, for example as an active ingredient The amount of the compound. The therapeutically effective amount of the compound, salt, analog or derivative of the present invention will depend on a variety of factors, including, for example, the age and weight of the individual, the precise condition requiring treatment and its severity, the nature of the formulation and the route of administration, and It will ultimately be at the discretion of the visiting physician.

As used herein, the term "treat/treating/treatment" refers to individuals who have shown at least one symptom of the disease, specific mammals, and more specifically humans to administer therapy to obtain the desired pharmacology and physiology Academic effect. The individual includes an individual diagnosed with a disease. The term can also include preventing disease, that is to say that the clinical symptoms of the disease are not produced in mammals that may be exposed to or susceptible to the disease but have not experienced or showing symptoms of the disease; inhibiting the disease, that is, curbing or reducing the disease or its clinical symptoms Development; or alleviation of the disease, that is, the regression of the disease or its clinical symptoms.

As used herein, "viruses that cause hemorrhagic fever" describe RNA viruses such as the Filoviridae, Arenaviridae, Bunyaviridae, or Flaviviridae viruses, including (but Not limited to) eboia virus, marburg virus, flexal virus, guanarito virus, jumin virus, lassa fever virus, Machupo virus, sabia virus, Crimea-congo hemorrhagic fever virus, rift valley fever virus, hantaan ) Virus, dengue virus, keasanur forest disease virus, omsk hemorrhagic fever virus and yellow fever virus. In one aspect of the invention, the hemorrhagic fever virus is a dengue virus.

Therefore, an object of the present invention is to provide an improved artemisinin combination therapy to individuals in need.

Another object of the present invention is to provide an improved artemisinin-based combination therapy to individuals suffering from viral diseases.

Another object of the invention is to treat diseases mediated by arthropods such as mosquitoes Individuals with toxic diseases provide an improved artemisinin-based combination therapy.

Another object of the present invention is to provide an improved artemisinin-based combination therapy to individuals suffering from viral diseases mediated by flaviviridae viruses.

Another object of the present invention is to provide an improved artemisinin-based combination therapy with sublingual delivery steps to individuals suffering from viral diseases.

Another object of the present invention is to provide an improved artemisinin-based combination therapy with sublingual delivery procedures to individuals suffering from viral diseases mediated by flaviviridae viruses.

Another object of the present invention is to provide an improved artemisinin-based combination therapy to individuals suffering from dengue fever, which also uses a sublingual spray-based administration delivery route to deliver artemisinin derivatives.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative And berberine or its derivatives are used in individuals suffering from viral diseases.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative And berberine or its derivatives, for individuals suffering from arthropod-mediated diseases.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative And berberine or its derivatives are used in individuals suffering from dengue fever.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative And berberine or its derivatives, for individuals suffering from arthropod-mediated diseases.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative It is safe and effective for individuals suffering from dengue fever and berberine or its derivatives.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative Biotin and berberine or its derivatives are used in individuals suffering from dengue fever, which shorten the disease process.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative And berberine or its derivatives, used in individuals suffering from dengue fever, which reduces NS1 virus antigens.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative And berberine or its derivatives are used in individuals suffering from dengue fever, which reduces the risk of bleeding.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative The substance and berberine or its derivatives are used in individuals suffering from dengue fever, which leads to faster standardization of blood charts and earlier resolution of clinical symptoms.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which also uses a sublingual spray-based administration delivery route to deliver artemisinin derivatives, and Oral delivery of the second independent artemisinin derivative and berberine or derivatives thereof for individuals suffering from dengue fever, which results in the strengthening of the immune system, allowing the early production of neutralizing antibodies.

An object of the present invention is to provide an improved artemether-based supplement and/or pharmaceutical composition for treating individuals suffering from disease.

Another object of the present invention is to provide an improved artemisinin-based combination therapy, which uses a sublingual spray-based delivery delivery route to deliver artemisinin derivatives, and oral delivery of a second independent artemisinin derivative And berberine or its derivatives, used in individuals suffering from diseases, in which artemether-based supplements and/or pharmaceutical compositions can be delivered in the form of a sublingual spray that treats individuals suffering from diseases and contains the risk of allergic reactions Minimized carrier.

Another object of the present invention is to provide an artemether supplement and/or pharmaceutical composition that can be delivered in the form of a sublingual spray for treating individuals suffering from disease and contains a carrier that promotes mucosal absorption.

Another object of the present invention is to provide an artemether supplement and/or pharmaceutical composition that can be delivered in the form of a sublingual spray for treating individuals suffering from disease and contains a carrier that minimizes the risk of allergic reactions and promotes mucosal absorption .

Other objects and advantages of the present invention will become apparent from the following description obtained in combination with any accompanying drawings, in which some specific examples of the present invention are set forth by way of illustration and example. Any drawings contained herein constitute a part of this specification and include illustrative specific examples of the present invention and illustrate its various objectives and features.

Figure 1 is a comparison of individuals diagnosed with dengue fever and treated with TriAct therapy with individuals diagnosed with dengue fever and treated with standard care protocols in terms of duration of fever Figure; Figure 2 is a comparison of the number of days suffering from abdominal pain in individuals diagnosed with dengue fever and treated with TriAct therapy and individuals diagnosed with dengue fever and treated with standard care protocols; Figure 3 is a diagnosis of dengue fever The comparison between individuals treated with TriAct therapy and individuals diagnosed with dengue fever and treated with standard care protocols in terms of the number of days of abdominal tenderness; Figure 4 shows individuals diagnosed with dengue fever and treated with TriAct therapy and their diagnosis Individuals with dengue fever treated with standard care protocols are compared with the number of days before the NS1 antigen test is negative; Figure 5 is an individual diagnosed with dengue fever treated with TriAct therapy and diagnosed with dengue fever and used Individuals treated with standard care regimens are compared in terms of days of standardized absolute platelet count; Figure 6 is an individual diagnosed with dengue fever treated with TriAct therapy and an individual diagnosed with dengue fever treated with standard care regimen. Comparison of the days in which IgM becomes positive; Figure 7 is the number of days that individuals diagnosed with dengue fever treated with TriAct therapy and individuals diagnosed with dengue fever treated with standard care regimens become positive for IgG Words for comparison.

Although the present invention allows specific examples in various forms, it has been shown and will be described below as preferred (but non-limiting) specific examples of the present invention. It should be understood that the present invention should be regarded as an example of the present invention and is not intended to be The invention is limited to the specific specific examples illustrated.

The present invention describes a novel combination therapy for the treatment of microbial infections, such as viral infections. As an illustrative example, the present invention has been found to be suitable for the treatment of arthropod-mediated diseases and/or viral infections from the Flaviviridae family, such as viruses that cause dengue fever. The combination therapy according to the present invention is based on artemisinin combination therapy (ACT). The present invention uses a triple therapy regimen and uses three compositions: a unique combination of artemether, artesunate, and berberine. The novel combination therapy may be generally referred to as TriACt therapy, out of the three components that constitute the combination therapy.

Artemisinin and artemisinin derivatives

Artemisinin has 3 R ,5a S ,6 R ,8a S ,9 R ,12 S ,12a R )-octahydro-3,6,9-trimethyl-3,12-epoxy-12 H- Piperano[4,3- j ]-1,2-benzodioxa-10(3 H )-one's IUPAC name, also known as Qinhaosu, is a Chinese herb known to have antiviral activity For natural products of the plant Artemisia annua, see Efferth et al. The Antiviral Activities of Artemisinin and Artesunate. Clin. Inf. Dis. 2008: 47: 804-11. It has the following chemical structure:

Artemisinin is a sesquiterpene lactone containing unusual peroxide bridges. Xianxin This peroxide is responsible for the mechanism of action of the drug. Very few other natural compounds with this peroxide bridge are known; see Artemisinin and a new generation of antimalarial drugs". Education in Chemistry. July 2006. http: //www.rsc.org/Education/EiC/issues/ 2006July/Artemisinin.asp. It is widely used to treat malaria, especially with other drugs such as mefloquine (ASMQ), benzfluorenol (such as sold under the trade name Coartem), paracetamol (such as sold under the trade name Camoquin, Flavoquine, ASAQ), piperaquine (Such as sold under the trade name Duo-Cotecxin), artemisinin and pyronaridine (such as sold under the trade name Pyramax) in combination. Artemisinin derivatives are typically used as prodrugs of the biologically active metabolite dihydroartemisinin, which is active during the stage when the parasite is inside the red blood cells. The mechanism by which Xianxin artemisinin derivatives kill parasites works by disrupting redox stabilization in the malaria parasite. Therefore, such compositions may include free radical production in parasite food bubbles and inhibition of parasite calcium ATPase. The key advantage of artemisinin is its rapid action relative to all red blood cell stage parasites including transmissive gametocytes, resulting in rapid clinical benefit and reduced malaria transmission; see Rosenthal, Artesunate for Treatment of Severe Falciparum Malaria, N. Engl J Med 2008, 358: 1829-1836.

、如美國專利6,984,640中所述之青蒿素內過氧化物、如美國專利6,906,205中所述之螺及二螺1,2,4-三氧雜環戊烷抗瘧疾藥、如美國專利6,906,098中所述之混合類固 醇1,2,4,5-四

化合物、如美國專利6,750,356中所述之蒿乙醚、如美國專利6,737,438中所述之經取代1,2,4-三

、如美國專利6,685,972中所述之黃花蒿提取物、如美國專利6,683,193中所述之蒿甲醚、如美國專利6,649,647中所述之基於青蒿素之三

衍生物、如U.S.RE38,117中所述之三

二聚體化合物、如美國專利6,461,603中所述之蒿醚林酸之共軛物、如美國專利6,346,631中所述之來自二氫青蒿素之蒿乙醚、如美國專利6,306,896中所述之青蒿素或青蒿烯衍生物、如美國專利6,160,004中所述之C-10碳取代青蒿素樣三

化合物、如美國專利6,136,847中所述之水溶性三

、如美國專利6,127,405中所述之α蒿乙醚、如美國專利5,856,351中所述之青蒿素二聚體、如美國專利5,225,562中所述之(+)-脫氧青蒿素及(+)-脫氧青蒿素之類似物及如美國專利5,225,427中所述之二氫青蒿素之10-取代醚衍生物，以及其鹽或其其他衍生物，如熟習此項技術者所已知。 One disadvantage of artemisinin is its poor physical properties, which leads to poor bioavailability, which limits its effectiveness. For example, the compound is sparingly soluble in water or oil and therefore cannot be easily absorbed by the gastrointestinal tract. Therefore, many semi-synthetic derivatives have been developed, including artesunate (water-soluble: oral, rectal, intramuscular or intravenous use), artemether (fat-soluble: oral, rectal or intramuscular) Use) Dihydroartemisinin, artemether acid, artemisinin and artemether. As used in the present invention, artemisinin derivatives include (but are not limited to) artesunate, dihydroartemisinin, dihydroartemisinin hemisuccinate, dihydroartemisinin succinate, artemisinin Sodium, stable form of artesunate, stable form of artesunate, dihydroartemisene dimer as described in US Patent 7,098,242, amine functionalization as described in US Patent 7,071,2261,2 ,4-three

, Artemisinin internal peroxides as described in U.S. Patent 6,984,640, spiro and dispiro 1,2,4-trioxolane antimalarial drugs as described in U.S. Patent 6,906,205, as in U.S. Patent 6,906,098 Mixed steroids 1,2,4,5-tetra

Compounds, artemether as described in U.S. Patent 6,750,356, substituted 1,2,4-tris as described in U.S. Patent 6,737,438

, Artemisia annua extract as described in U.S. Patent 6,685,972, artemether as described in U.S. Patent 6,683,193, artemisinin-based three as described in U.S. Patent 6,649,647

Derivatives, as described in USRE38, 117

Dimer compounds, conjugates of artemether acid as described in U.S. Patent 6,461,603, artemether from dihydroartemisinin as described in U.S. Patent 6,346,631, artemisia annua as described in U.S. Patent 6,306,896 Or artemisinin derivatives, C-10 carbon-substituted artemisinin-like three as described in US Patent 6,160,004

Compounds, water-soluble three as described in U.S. Patent 6,136,847

, Alpha artemether as described in US Patent 6,127,405, artemisinin dimer as described in US Patent 5,856,351, (+)-deoxyartemisinin and (+)-deoxygen as described in US Patent 5,225,562 Analogs of artemisinin and 10-substituted ether derivatives of dihydroartemisinin as described in US Patent 5,225,427, as well as salts or other derivatives thereof, are known to those skilled in the art.

Artemether is a methyl-ether derivative of dihydroartemisinin derived from artemisinin. It has (+)-(3-α,5a-β,6-β,8a-β,9-α,12-β,12aR)-decahydro-10-methoxy-3,6,9-tri The IUPAC chemical name of methyl-3,12-epoxy-12H-piperano(4,3-j)-1,2-benzodioxa and has the following chemical formula:

Artemether is known to be effective against blood schizonts of several malaria-causing parasites and is used as an ACT drug.

Artesunate, also known as dihydroartemisinin hemisuccinate and its salts, has 3R, 5aS, 6R, 8aS, 9R, 10S, 12R, 12aR)-decahydro-3,6,9-trimethyl The IUPAUC chemical name of yl-3,12-epoxy-12H-piperano(4,3-j)-1,2benzodioxa-10-alcohol hydrosuccinate has the following chemical formula:

Artesunate is mainly used for the treatment of malaria.

The dosage of artemisinin, artemisinin salt and derivatives.

The oral dosage of artemisinin, artemisinin salts and derivatives ranges from about 1 mg to about 1,500 mg per dose, administered one to three times a day. More preferably, if taken one to three times a day, the oral dosage of artemisinin, artemisinin salts and derivatives ranges from about 20 mg to about 250 mg per dose. Optimally, the oral dosage of artemisinin, artemisinin salts and derivatives ranges from about 40 mg to about 100 mg per dose, taken one to three times a day.

Berberine, its salts and berberine derivatives.

Berberine is a quaternary ammonium salt of the original berberine group from isoquinoline alkaloids. It has the IUPAC name of (5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxole[5,6-a]quinazine) , With the following chemical formula:

It is found in various plant species of the genus Berberis (for example, Berberis aquifolium (Oregon grape), Berberis vulgaris/Barberry, and Berberis aristata (tree turmeric)), and Other plant families, including (but not limited to) white buttercups (Hydrastis canadensis/Goldenseal), Phellodendron amurense/Amur Cork Tree/Huang Bai/Huang Po/Po Mu) and Coptis chinensis/Chinese Goldthread/Huang-Lian/ Huang-Lien) and Tinospora cordifolia, and to a lesser extent, they are found in thistle poppy (Argemone mexicana/Prickly Poppy) and Eschscholzia californica/Californian Poppy, Rhizoma coptidis Huanglian Jiedu decoction, San-Huang-Xie-Xin-Tang, Xietianwu, Gegen Quinlian and Shizhu. Berberine is mainly isolated from roots, rhizomes, stems and bark. Berberine has been used for medical purposes in Indian Ayurvedic medicine and Chinese medicine, and has recently been tested for antibacterial activity and use in diarrhea, prostate cancer, and diabetes. It is generally considered non-toxic and does not show genotoxic activity.

According to the present invention, berberine, berberine derivatives or salts thereof may include (but not limited to) berberine alkaloids, berberine base, berberine hydrochloride, berberine ( berberine), berberine red base (berberrubine), heterogeneous bicuculline (coreximine), tetrahydropalmatine (tetrahydropalmatine), jatrorrhizine (jatrorrhizine), 13- hydroxy berberine chloride (13-hydroxyberberine chloride), Methoxyberne (coralyne), Methoxyberne chloride, 7,8-dihydro-13-methylberberine, berberine acetone, 13-allylberberine, palmatine , 13-benzylberberine, tetrahydroberberine, tetrahydroproberberine 8-cyanodihydroberberine, dimer proberberine alkaloid, demethylated proberberine alkaloid Alkali, quaternary proberberine alkaloid, proberberine and proberberberine alkaloid, berberine salt, including berberine hydrochloride, berberine chloride, berberine sulfate, tannic acid Berberine and other salts known to those skilled in the art.

The dose range of berberine, its salts and derivatives.

The oral dose of berberine ranges from about 50 mg to about 1,500 mg, and is administered in a single dose of two to three times a day, not exceeding 4,500 mg per day. More preferably, the dose of berberine is a single human dose of about 100 mg to about 1,000 mg, no more than 3,000 mg per day, delivered one to three times per day. The optimal dose range of berberine in a single dose is about 200 mg to about 500 mg, taken one to three times a day.

The invention is further described by the following non-limiting examples. The following examples illustrate specific examples of administration routes and composition forms, but are preferred examples. Although the preferred forms and/or routes are described, other forms such as (but not limited to) lozenges, capsules, sachets, pills, caplets, dragees, dispersions, suspensions, solutions, syrups, granules, beads , Transdermal patches, gels, powders, pills, emulsions, lozenges, creams, pastes, plasters, lotions, discs, suppositories; liquid sprays for nasal or oral administration, Dry powder or aerosol formulation for inhalation, composition and formulation for intravesical administration. The composition can also be developed for inhalation, oral, rectal, transvaginal, parenteral, superficial, transdermal, transpulmonary, intranasal, buccal, transocular, intrathecal, intravenous, or any route of administration .

The dosage form of the present invention may include immediate release or controlled release forms. Each composition may be formulated and manufactured by procedures known to those skilled in the art, and may include a 100% composition or a mixture of one or more pharmaceutically acceptable excipients or pharmaceutically acceptable carriers. For the use of sublingual spray, liquid artemether can be prepared in spray form using, for example, the microfluidization method as described in US Patent 6,861,066.

The invention further describes an alternative sublingual spray artemether-based supplement and/or pharmaceutical composition, a method of manufacturing an improved artemether-based supplement and/or pharmaceutical composition, and its use for delivery to The use of the individual in need. Supplements and/or pharmaceutical compositions contain active compounds such as artemisinin derivatives, pharmaceutically non-allergenic acceptable carriers and mucosal absorption enhancers that reduce the risk of allergic reactions when administered to an individual. In a preferred embodiment, the sublingual spray supplement and/or pharmaceutical composition includes artemether; a pharmaceutically non-allergenic acceptable carrier, such as neutral oil, including such as olive oil (obtained from olive oil ( Olea europaea ) fruit) neutral oil; and quaternary ammonium salt such as benzalkonium chloride, which acts as a mucosal absorption enhancer.

The present invention includes improved artemether supplements and/or pharmaceutical compositions that use carriers that reduce the risk of allergic reactions when administered to individuals susceptible to food-based allergies. Although artemisinin and artemisinin derivatives for the treatment of diseases are known in the art, these components are prepared using peanut (arachis/peanut) oil. The use of this oil poses a problem for any supplement or pharmacological route of administration that needs to be delivered in the oral cavity, such as the mouth, whereby the active ingredient needs to diffuse into the circulatory system through the sublingual tissue. As a common trigger for those individuals suffering from food-induced allergic reactions, the use of peanut oil as a carrier for sublingual spray increases the risk of serious injury and even death.

In order to minimize the risk of potential allergic reactions, the supplement according to the invention and/or Or the pharmaceutical composition uses olive oil as a carrier for artemether because there is no known allergy to olive oil when taken by mouth.

Mucosal absorption enhancer:

Quaternary ammonium salts can be used to form supplements and/or pharmaceutical compositions. Such quaternary ammonium salts include those quaternary ammonium salts that are commonly used and considered safe for human use. These compounds are typically tetra-substituted ammonium salts, wherein the substituent is preferably a hydrocarbon compound connected to the nitrogen through N—C bond and is selected from the group consisting of substituted and unsubstituted, saturated and unsaturated , Aliphatic and aromatic and branched chain and normal chain groups. In all cases, the nitrogen atom is pentavalent and in the positively charged part of the molecule, so the quaternary ammonium salt is a cationic electrolyte.

Preferably, the mucosal absorption enhancer of the present invention is benzalkonium chloride, also known as alkyl dimethyl benzyl ammonium chloride, alkyl dimethyl (phenylmethyl), quaternary ammonium chloride, Ammonyx and Roccal. Benzalkonium chloride has the following chemical formula:

Benzalkonium chloride is commercially available in a suitable form and comes from a variety of sources, including Sigma Aldrich Chemical Company. Benzalkonium chloride is used in an amount effective to act as a membrane enhancer and preservative. Benzalkonium chloride may be between about 0.001% and about 0.1% by weight of the composition, and preferably between about 0.005% and about 0.05%, and more preferably 0.007% or about 0.007 by weight of the composition % Final concentration.

Table 1-5 illustrates the spray artemether supplement and/or pharmaceutical composition according to the present invention Examples of things.

Example: Method for preparing sublingual artemether spray, single dose 80 mg

For the preparation of artemether sublingual spray, powdered artemether was obtained. In preparing a single spray dose, 700 mL of extra virgin olive oil was heated to 130 degrees in a liter beaker. Cool olive oil to 70 degrees. Once at 70 degrees, add 80 grams of artemether powder. 80 g of artemether powder was slowly added to the cooled olive oil with continuous stirring until the powder dissolved, forming a clear Clear solution. 0.7ml of 10% benzalkonium chloride was added to artemether in solution with continuous stirring. The artemether solution was cooled to room temperature. The concentration of artemether was verified using HPLC.

Preferably, the artemether solution described above is packaged in a single-dose delivery system, such as an atomizing jet pump as described in US Patent No. 6,126,038, where the patient can only jet the composition to the desired placement , That is, under the tongue, until the bottle is completely emptied.

Treatment of individuals

Example 1: A method of treating an individual suffering from a disease mediated by a flaviviridae virus.

The method of treating an individual suffering from a disease mediated by a flaviviridae virus includes the following steps: (1) administering a first composition to a mammal, preferably a human, the first composition comprising a therapeutically effective amount of an artemisinin derivative , Preferably 50-80 mg per dose of artemether; (2) administering a second composition to the mammal, the second composition comprising a therapeutically effective amount of the second artemisinin derivative, the second green The artemisinin derivative is different from the first composition, and is preferably artesunate or a pharmaceutically acceptable derivative thereof, 1 mg to 1,500 mg per dose, preferably about 20 mg to about 250 mg per dose, three times a day, And optimally about 40mg to about 100mg per dose, three times a day; and (3) administering a third composition to the mammal, the third composition comprising a therapeutically effective amount of berberine or a pharmaceutically acceptable derivative thereof , About 1 mg to about 1,500 mg per dose, specifically about 100 mg to about 1,000 mg per dose, three times a day, and more specifically about 200 mg to about 400 mg per dose, two to three times a day.

The following describes an illustrative but preferred delivery schedule:

Day 1: Artemether-single dose delivery.

Deliver artesunate and berberine lozenges at a dose according to the age and/or weight of the user, every eighth hour.

Day 2: Delivery of artesunate and berberine lozenges, the dose according to the user's age and/or body weight, every eight hours.

Day 3: Delivery of artesunate and berberine lozenges, the dose is based on the user's age and/or body weight, every eight hours.

Example 2: Treatment of adults over 165 pounds (75Kg) with viral infection using subarterial delivery of artemether solution: dengue fever.

A method for treating an individual suffering from dengue fever, comprising the following steps: (1) administering a first composition to an adult mammal, preferably a human, the first composition comprising a therapeutically effective amount of artemether; (2) towards adulthood The second composition is administered to a mammal, and the second composition comprises a therapeutically effective amount of artesunate or a pharmaceutically acceptable derivative thereof; and (3) the third composition is administered to an adult mammal, the third The composition contains berberine or a pharmaceutically acceptable derivative thereof in a therapeutically effective amount.

Adults over 165 pounds (75 Kg) start the method according to the invention by administering the first starting dose of artemether. Artemether is preferably delivered to the individual using a single-dose sublingual spray bottle containing preferably 60 mg artemether solution per bottle. The use of spray provides advantages over injectable forms: provides an easy to administer, does not require trained medical professionals (such as doctors or nurses), and avoids needle-related problems, such as the spread of such as HIV or hepatitis C Fear of disease and proper delivery methods. In addition, sublingual drug delivery (specifically, spray) improves the absorption of active ingredients and enhances bioavailability.

In use, the user only removes the bottle from the shipping/delivery package and replaces any security features, such as any tamper proof external packaging secured to the bottle. Remove the password from the spray bottle After sealing the part, the adult individual lifts his tongue and pumps the spray bottle with artemether solution into the mouth, so the solution is delivered to the sublingual area. The bottle remains in this position until the contents of the bottle are completely delivered to the sublingual area. The liquid is preferably kept under the tongue for a predetermined period of time, preferably 30 seconds. Then swallow any liquid remaining in the user's mouth. After waiting for a predetermined period of time, such as 1 minute to 1 hour and more preferably 30 minutes, the user administers a second composition containing a certain amount of artesunate, such as 2×50 mg lozenges, 3 doses per day (300 mg per day) , Or every 8 hours for 2 days. The user administers a third composition containing a certain amount of berberine, such as 2×400 mg lozenges, 3 doses per day (2,400 mg), or every 8 hours. Alternatively, the second and third compositions can be administered simultaneously with the first composition.

Example 3: Treatment of adults with virus infection using sublingual delivery of artemether solution 66 lbs (30 kg)-165 lbs (75 kg): dengue fever.

Adults weighing 66 pounds (30 kg) to 165 pounds (75 Kg) start the method according to the invention by administering the first starting dose of artemether. Artemether is preferably delivered to the individual using a single-dose sublingual spray bottle containing preferably 60 mg artemether solution per bottle. The user only removes the bottle from the shipping/delivery package and replaces any security features, such as an external packaging that is secured to the bottle to indicate tampering. After removing the sealed portion from the spray bottle, the adult individual raises his tongue and pumps the spray bottle with artemether solution into the mouth, so the solution is delivered to the sublingual area. The bottle remains in this position until the contents of the bottle are completely delivered to the sublingual area. The liquid is preferably kept under the tongue for a predetermined period of time, preferably 30 seconds. Then swallow any liquid remaining in the user's mouth. After waiting for a predetermined period of time, such as 1 minute to 1 hour and more preferably 30 minutes, the user administers a second composition containing a certain amount of artesunate, such as a 1×50 mg tablet, 3 doses (150 mg) per day, Or every 8 hours for 2 days. The user administers a third composition containing a certain amount of berberine, such as 1×400 mg tablets, 3 doses per day (1200mg), or every 8 hours. Alternatively, the second and third compositions can be administered simultaneously with the first composition.

Example 4: Treatment of 33-pound (15kg) to 66-pound (30Kg) human children suffering from viral infections with sublingual delivery of artemether solution: dengue fever.

For children or individuals ranging from 33 pounds (15 kg) to 66 pounds (30 Kg), the treatment is the same as described in Example 3.

Example 5: Treatment of infants and young children up to 3 years old with 33 lbs (15 kg or less) suffering from viral infection using artemether solution delivered sublingually: dengue fever.

For infants and young children up to 3 years old and 33 lbs (under 15 kg), the treatment is similar to Example 1. The dosage delivered to the user includes preferably using a single dose of sublingual spray that preferably contains 60 mg of artemether solution per bottle of artemether delivered to the individual, 25 mg artesunate per dose, 3 doses per day (total 75 mg per day ), or every 8 hours for 2 days, and 200 mg of berberine per dose, 3 doses per day (total 600 mg per day), or every 8 hours. For infants and young children, lozenges can be ground and mixed with liquids that are allowed to be delivered to the user, such as milk, juice, and syrup.

Example 6: Treatment of an individual suffering from a viral infection using injectable artemether solution: dengue fever.

A method for treating an individual suffering from dengue fever, comprising the following steps: (1) administering a first composition to a mammal, preferably a human, the first composition comprising a therapeutically effective amount of artemether; (2) to a mammal Administering a second composition, the second composition comprising a therapeutically effective amount of artesunate or a pharmaceutically acceptable derivative thereof; and (3) administering a third composition to a mammal, the third composition comprising A therapeutically effective amount of berberine or its pharmaceutically acceptable derivatives.

In a preferred embodiment, the method of treatment can be facilitated by using a kit consisting of injectable artemisia in the form of a single dosage unit contained in ampoules, injection vials or in the form of individual single preloaded syringes with needles A methyl ether solution, a first packet containing artesunate tablets and a second packet containing berberine tablets. Individual users start the method according to the invention by administering a first starting dose of artemether. Artemether is delivered to the individual as an injection via intravenous or intramuscular administration. The second and third compositions are delivered as previously described in Examples 2 to 4, depending on the weight and age of the individual user.

As described in the above examples, the components of the present invention can be supplied in kits to help deliver and use the method according to the present invention for treatment in areas where distribution channels and/or medical communities are not easily accessible or established. According to the present invention, the kit may include a safe delivery package in the form of a self-sealing blister package, a zipper package, a stand-up bag, and a foil bag, which includes a single-use spray bottle and artesunate and berberine for one day, two days , Three days, four days, more than five days packaging. If injectable artemether is used, it may include needles, syringes, injection bottles or preloaded syringes with capped needles. The kit preferably contains instructions and/or any other instructions regarding proper use and storage of the kit components.

It also has the use of a modified and improved artemisinin-based combination therapy for the delivery of artemisinin derivatives using the sublingual spray-based delivery route.

Two hundred and eighty-eight (288) evaluable individuals were initially randomly divided into two groups: Group A, who received standard care plus TriAct therapy, and Group B, which received standard care only. Standard care programs include bed rest and fluids. Individuals use the World Health Organization (WHO) classification (dengue fever without warning signs (IA/IB), dengue fever with warning signs (IIA/IIB), and severe dengue fever (IIIA/IIIB) for analysis based on the symptoms presented.

All study participants confirmed the use of NS1 antigen as a substitute for viral load Dengue fever cases and comparing all clinical and laboratory parameters in the two groups. Group A shows: 1) The rapid elimination of viral antigens in the serum is the culprit for the further progression of the disease into serious forms such as plasma leakage and severe bleeding ; 2) The clinical signs of dengue fever and the rapid resolution of symptoms; 3) The rapid standardization of laboratory parameters such as white blood cells (WBC) and platelet counts. These observations were not noticed in the control group (Group B).

At the completion of the clinical study, statistics confirmed that the modified and improved artemisinin-based combination therapy treatment plan was demonstrated to be safe and effective without death or adverse reactions. Modified and improved artemisinin-based combination therapy treatment shortens the disease process, reduces viral antigens (NS1), reduces bleeding risk, standardizes blood charts faster, resolves clinical symptoms earlier, and strengthens the immune system, resulting in earlier development And antibodies.

Materials and methods:

The study conducted was a prospective, open-label randomized, controlled, single-center study with 300 registered individuals divided into two treatment groups: Group A, WHO standard care plus TriAct therapy, and Group B, WHO standard care only . Individuals include individuals aged 5 to 65 years who are admitted as dengue fever cases, and are screened by careful medical history and physical examinations that adhere to the inclusion criteria. All individuals were positive for dengue NS1 and/or dengue IgM/IgG. All individuals are informed and voluntarily sign a consent/assent form. The WHO/DOH Revised Dengue Guidelines were used to guide the study. Individuals in groups A and B are further divided into dengue fever without warning signs (dengue fever/DHF I), dengue fever with warning signs (DHF II) and severe dengue fever (DHF III/IV). The study individual is monitored at least 30 days after the last dose of test particles.

The study used a test drug combination of an initial dose of artemether (60 mg solution in the form of a sublingual nanometer spray), 50 mg of artesunate per tablet and 400 mg of berberine per tablet. based on Table VI provides instructions and dosages for age group and body weight.

封包A=青蒿琥酯 封包B=小蘗鹼

Packet A = artesunate packet B = berberine

All individuals perform daily CBC through actual platelet count assessment. NS1 determination is performed daily until the result becomes negative. Dengue fever IgM/IgG was also measured every day until the patient was discharged. Also perform other laboratory tests after registration, such as prothrombin time (PT), partial prothrombin time (PTT), blood on aspartate transaminase (AST), alanine transaminase (ALT) The test and urine test are repeated at least on the 7th day of the disease. Chest X-rays and abdominal ultrasound were performed on all individuals within the first 24 hours of fever. Repeat chest X-ray at least 72 hours later. Repeat abdominal ultrasound for those individuals with abnormal findings.

Daily evaluation of all individuals. Statistical analysis was performed using independent sample T-test and Chi Square test to test independence using SPSS 11.5.

Results: Of the 300 confirmed individuals registered, 288 were suitable for evaluation and the remaining individuals were unable to complete the required data set. Perform daily evaluation of clinical and laboratory parameters. The following parameters show the difference between group A and group B: days of disease, p=0.038, Cramer's V=0.201; days of patients with fever, p<0.001, Cramer's V=0.516; days of headache, p<0.001 , Cramer's V=0.389; days with physical discomfort, p<0.001, Cramer's V=0.389; suffering Days of joint pain, p=0.012, Cramer's V=0.210, days with nausea/vomiting, p=0.001, Cramer's V=0.265; days with abdominal pain, p<0.001, Cramer's V=0.540; suffering from abdominal tenderness Days, p<0.001, Cramer's V=0.586; days of standardized white blood cell count, p<0.001, Cramer's V=0.545; days of standardized heme, p<0.001, Cramer's V=0.311; days of standardized hematocrit, p <0.001, Cramer's V=0.360; days of standardized absolute platelet count, p<0.001, Cramer's V=0.610; for days before NS1 becomes negative, p<0.001, Cramer's V=0.589; for IgM before becoming positive Days, p<0.001, Cramer's V=0.343; for days before IgG becomes positive, p<0.001, Cramer's V=0.293; NS1 based on the number of disease days, p<0.001, Cramer's V=0.638.

For clinical parameters, the study drug group A showed faster recovery and regression of clinical signs and symptoms.

Group A achieved fever a day earlier than control group B (p<0.001), see Figure 1.

Compared with group B, all individuals in group A had discomfort and suborbital pain subsided within 3 days, and the above symptoms in group B continued to day 5 (respectively, p<0.001 and p=0.511) .

Compared to group B (p=0.012), the majority (98.6%) of individuals in group A had joint pain remission within a 2-day period.

The most significant observations between the two groups found differences in abdominal pain and abdominal tenderness (including nausea and vomiting), where almost all individuals in group A compared to group B with resolution on days 6 and 4 (Respectively, 98.6%, 98.6%, and 99.3%) had regression on day 3 (respectively, p<0.001, p<0.001, and p=0.001), see Figures 2 and 3.

In terms of laboratory parameters such as WBC and absolute platelet count, Do not spend 7 days (p<0.001) and 6 days (p<0.001) to reach the standardized control group (see Figure 5). All individuals in group A showed standardization within 4 days of treatment.

Compared with the control group in which 2.7% (p<0.001) and 4.1% (p<0.001) of the individuals remained unstable up to the 5th day, the individuals in group A remained stable in heme and hematocrit during the entire study. However, we expect that due to the standard care applied to the two treatment groups, there will be no significant difference in terms of the percentage increase in blood volume ratio.

The study further showed that there was early specific antibody production in group A (IgM 96.5% on day 3) compared to control group B (IgM 77.9%) with a p-value <0.001, see Figure 6. Xianxin early specific antibody production helps to quickly eliminate viruses in the body, reduce the chance of forming antigen-antibody complexes, and thus prevent possible plasma leakage. Figure 7 illustrates the number of days before IgG becomes positive for Group A and Control Group B.

The disintegration of NS1 antigen was observed relatively quickly in group A, and all individuals were negative on day 4. This finding was different for the control group B, which took up to 8 days to make some, but not all individuals became negative (p<0.001), see Figure 4.

It is assumed that the NS1 antigen may be necessary for dengue virus replication, so the earlier disintegration of the NS1 antigen means that viral replication has stopped, which may be the mechanism of action of TriAct therapy.

The reduction in the number of individuals exhibiting higher serum glutamate oxaloacetate transaminase (SGOT) means that compared to control group B (51/84) (p value = 0.044), group A (38/84) There is no further invasion of liver cells. However, both groups exhibit higher serum pyruvate transaminase (SGPT). Compared with group B, 51/84 (60.7%) (p=0.071), there was a continuous increase in SGPT in group A, 62/84 (73.8%).

The study of the present invention validates that TriACt therapy is effective for the treatment of dengue fever The use of effective combination therapy. Studies have shown that TriACt therapy is safe because no adverse reactions were recorded in the treatment group. It was found that the use of TriACt therapy provides several unexpected benefits as a treatment program. As documented by the disappearance of NS1, TriAct therapy eliminates fifty percent (50%) of the virus faster. Among those patients treated with TriAct therapy, the number of days of disease was significantly reduced by at least fifty percent (50%), which was unexpected. Among other patients treated with TriAct therapy, TriAct therapy reduced the number of incompetent days by at least fifty percent (50%). TriAct therapy group recovered faster from fever. Abdominal pain and abdominal tenderness in this treatment group were significantly reduced, which was a surprising discovery for the researchers. The treatment completely recovered the pain from the frame. The use of TriAct therapy leads to the rapid standardization of white blood cell and platelet counts. Bleeding is a crucial finding in this study. Individuals in the TriAct therapy group also showed a significant reduction in physical discomfort and joint pain. Earlier discontinuation of nausea/vomiting was obtained in the TriAct therapy group.

All patents and publications mentioned in this specification indicate the standard of those skilled in the art to which this invention belongs. All patents and publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually designated to be incorporated by reference.

It should be understood that although a certain form of the invention is illustrated, it is not limited to the specific form or configuration described and shown herein. It will be apparent to those skilled in the art that various changes can be made without departing from the scope of the invention and the invention should not be considered limited to what is shown and described in this specification and any drawings/drawings included herein content.

Those skilled in the art will readily understand that the present invention is very suitable for implementing these objectives and obtaining the mentioned objectives and advantages, as well as those inherent therein. The specific examples, methods, procedures, and techniques described herein currently represent preferred specific examples, are intended to be illustrative, and are not intended as limitations on the category. Those skilled in the art will think of being included in the spirit of the present invention and by the attached Changes and other uses defined in the scope of patent application. Although the invention has been described in conjunction with specific preferred specific examples, it should be understood that the invention as claimed should not be unduly limited to such specific specific examples. In fact, it is obvious to those skilled in the art that various modifications to the described modes for carrying out the invention are intended to be within the scope of the following patent applications.

Claims (17)

Use of a composition for the preparation of a medicinal product for treating individuals suffering from dengue fever, comprising: a first composition, the first composition comprising a therapeutically effective amount of artemisia under the tongue in the form of a spray Ether or a pharmaceutically acceptable salt thereof and a non-allergenic acceptable carrier; a second composition comprising a therapeutically effective amount of artesunate or a pharmaceutically acceptable salt thereof; Three compositions, the third composition comprising a berberine or a pharmaceutically acceptable salt thereof in a therapeutically effective amount. Use as in item 1 of the patent application scope, where the spray includes a mucosal absorption enhancer. For the use as claimed in item 1 of the patent scope, wherein the second and third components are delivered via the oral route. For the use as claimed in item 3 of the patent scope, wherein the second and third compositions are in the form of pills or capsules. For the purpose of claim 1, the artemether is administered in a single dose. For the application of item 1 of the patent application scope, in which an additional dose of the second and the third composition is administered for a predetermined period of time. A kit for administering a plurality of compositions to an individual suffering from dengue virus, comprising: a first composition, the first composition comprising a therapeutically effective amount of artemether or a pharmaceutically acceptable salt thereof and A non-allergenic acceptable carrier; a second composition comprising a therapeutically effective amount of artesunate or a pharmaceutically acceptable salt thereof; The third composition contains an effective amount of berberine or a pharmaceutically acceptable salt thereof. For example, item 7 of the patent application scope is used to administer a kit of multiple compositions to an individual suffering from dengue virus, wherein the second composition is artesunate, and the third composition is berberine. For example, the item 8 of the patent application scope is used to administer a kit of multiple compositions to an individual suffering from dengue virus, wherein the artemether is a spray. For example, item 8 of the patent application scope is used to administer a kit of multiple compositions to an individual suffering from dengue virus, wherein the artemether is in an injectable form. For example, item 10 of the patent application scope is used to administer a kit of multiple compositions to an individual suffering from dengue virus, wherein the artemether is preloaded into a syringe. For example, the item 8 of the patent application scope is used to administer a kit of multiple compositions to an individual suffering from dengue virus, wherein the second and third compositions are in a pre-filled dose. For example, item 8 of the patent application scope is used to administer a kit of multiple compositions to an individual suffering from dengue virus, wherein the artemether spray includes a mucosal absorption enhancer. A composition for the preparation of a medicinal product for the treatment of dengue fever, comprising: a first composition, the first composition comprising a therapeutically effective amount of artemether or a pharmaceutically acceptable salt thereof and a non-allergen Sexually acceptable carrier, wherein the artemether is administered sublingually to the subject's sublingual area via spray; a second composition, the second composition comprising a therapeutically effective amount of artesunate or its first dose A pharmaceutically acceptable salt; and a third composition, the third composition comprising a therapeutically effective amount of berberine or a pharmaceutically acceptable salt thereof; Wherein the artemether is administered sublingually to an individual suffering from or suspected of having dengue fever caused by one or more serotypes of dengue virus; wherein, after the artemether is administered, the artemisinin is administered Ester and berberine. For the purpose of claim 1, the non-allergenic acceptable carrier is olive oil. For example, item 7 of the patent application scope is used to administer a set of multiple compositions to an individual suffering from dengue virus, wherein the non-allergenic acceptable carrier is olive oil. For example, the composition of item 14 of the patent application scope is used for the preparation of a medicament for the treatment of dengue fever, wherein the non-allergenic acceptable carrier is olive oil.

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