UA130077C2 - USE OF A HOMEOPATHIC COMPOSITION TO REGRESS INFLAMMATION IN A SUBJECT - Google Patents

Abstract

The present invention relates to a composition for use in resolving inflammation in a subject in need thereof, wherein said composition comprises the following ingredients: Achillea millefolium, Aconitum napellus, Arnica montana, Atropa bella-donna, Bellis perennis, Calendula officinalis, Echinacea purpurea, Echinacea, Hamamelis virginiana, Hepar sulfuris, Hypericum perforatum, Matricaria recutita, Mercurius solubilis Hahnemanni, and Symphytum officinale.

Description

The present invention relates to a composition for use in the regression of inflammation in a subject in need thereof, the aforementioned composition comprising the following ingredients: yarrow (Aspiea tigeifolia), toya (Aspiea parieta), arnica (Agrippina topia), belladonna (Aigora bei-doppa), perennial daisies (Veiiv regepiv), marigolds (SaIepacia oisiipaiiv), purple echinacea (Espipacea rigrigea), echinacea (Espipacea), witch hazel (Nat!teii5b migaipia), Nerag zi!yigis, St. John's wort (Nuregisit regiogasht), chamomile (Maigisaggia gesica), Mexisigpiiv5 zoiBi5 Nappetappi and comfrey (5utrpusht oyPisipaie). The invention also relates to a pharmaceutical composition comprising the above composition and an anti-inflammatory drug. Furthermore, the present invention also provides a kit for use in the regression of inflammation in a subject in need thereof, comprising (I) the above composition and (I) an anti-inflammatory drug.

Since the acute inflammatory response is a protective measure that develops to enable the repair of damaged tissues and the removal of invasive organisms, it is ideally self-limiting and leads to the complete elimination of leukocyte infiltrates and the removal of cellular debris, ensuring the possibility of a return to homeostasis (Zegppap, 2014).

Countless times a day, an acute inflammatory response protects against invading microbes, injuries, and internal insults, such as surgically induced tissue damage. These problems go unnoticed because they do not require treatment and resolve naturally without progression to chronic inflammation. Markers of inflammation in the peripheral blood are present in many common diseases, including inflammatory bowel disease, cardiovascular disease, neurodegenerative disease, and cancer. While acute inflammation is protective, excessive accumulation of neutrophils exacerbates the associated tissue damage and inflammation (Zegpap apa I emu, 2018).

For many years, regression of inflammation was considered a passive phenomenon associated with the removal of the inflammatory stimulus, cessation of chemoattractant synthesis, reduction of chemokine concentrations, and prevention of further leukocyte recruitment. However, data from several studies indicate that endogenous inhibitors of leukocyte migration act as a counter-mechanism against chemokine and adhesion molecules that are promoters of cell recruitment. In addition, there is evidence that regression of inflammation is an active process caused by the biosynthesis of active mediators, the so-called (5PM).

In this context, homeostasis is restored after the induction of 5RMs, which act on specific cellular receptors to regulate leukocyte migration and the production of inflammatory mediators at the blunt end, while also promoting the removal of dead cells and tissue repair (Zap5Bbygu apa 5riie, 2016).

The main features of regression include the limitation or cessation of cell efflux into the blood, the downregulation of chemokines and cytokines, the switching off of signaling pathways associated with leukocyte survival, the induction of leukocyte apoptosis and their subsequent removal by efferocytosis by macrophages, the reprogramming of macrophages from classically activated to alternatively activated cells, the return of non-apoptotic cells to the vasculature or lymph, and finally the initiation of the healing process. One or more failed steps in the regression of inflammation may be associated with the pathogenesis of several chronic human inflammatory diseases, such as impaired wound or tissue healing or fibrosis. In addition, chronic, unregressed inflammation may be associated with the development of an autoimmune response (Ziditoiio et al., 2016).

Various drugs have been reported to be modulators of inflammation. However, these drugs usually act antagonistically towards a pro-inflammatory environment (Zegpap, 2014).

The most prominent anti-inflammatory agents are nonsteroidal anti-inflammatory drugs, such as selective or nonselective cyclooxygenase 2 inhibitors. In addition, homeopathic medicinal compositions, such as Ttashteev (Vioiodiezespe NeutSchShe! Nee! StbN, Germany) have been reported to exhibit anti-inflammatory activity in acute inflammation (Ssppeideg, 2011).

Currently, there are only a limited number of regression-promoting agents undergoing clinical trials. Resolvin EI and its synthetic analogue KEH-100045 have been tested in a variety of inflammatory diseases (I ee, 2012). A compound based on I XA4 is being investigated for topical treatment of eczema (W/i ei et al., 2013). AP214, a melanocortin agonist, has shown regression-promoting effects in experimental systems and in kidney injury (Mopiego-Meiepä? ei et al., 2011).

There is a need for compositions that could eliminate inflammation in a subject for therapeutic interventions in pathophysiological conditions where regression of inflammation is impaired.

The technical problem underlying the present invention is considered to be the need to provide means and methods for satisfying the above-mentioned needs. This technical problem is solved through the embodiments characterized in the claims and the following description.

The present invention relates to a composition for use in the regression of inflammation in a subject in need thereof, said composition comprising the following ingredients: Aspirin, Aspirin, Agipina, Aigor, Brepa-dop, Vesiculosus, Salvia, Erysicarpa, Espipacea,

Espipasea, Natateii»v migdipiapa, Nerag z!yMygi5, Nuregisshit repogaisht, Maiygisagia hesciySha, Megsigi5 zYtsbii5 Nappetappi and zZutrpusht oyisipa!e.

The term "composition" in this context refers to a mixture of extracts, in particular from biological sources, such as plants, which are further defined in other sections of this document. In an optimal embodiment, the above composition may also include other ingredients, in an even more preferred embodiment, includes a pharmaceutically acceptable carrier and/or diluent.

Preferably, such additional ingredients may be stabilizers, wetting agents, pharmaceutical carriers, additional pharmaceutically active agents, release regulators, etc. Preferred diluents include water, alcohols, physiological saline solutions, buffers such as phosphate buffer solutions, syrup, oil, water, emulsions, various types of wetting agents, etc. Preferably, the present invention provides a composition that also includes at least one pharmaceutically acceptable carrier and/or diluent. The carriers should be acceptable in terms of compatibility with the other ingredients of the composition and not harmful to the recipient. The pharmaceutical carrier employed may include a solid, gel, or liquid. Typical solid carriers include lactose, kaolin, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, etc. Similarly, the carrier or diluent may include a time-delay material well known to those skilled in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. Suitable carriers include those mentioned above and others well known to those skilled in the art.

See, for example, Ketipdiope Rpagtasetsiisasa! Z5siepsez5, Mask Ribiispipd Sotrapu, Eaziop, RepppzuYmapia,

European Pharmacopoeia, US Homeopathic Pharmacopoeia or German Homeopathic Pharmacopoeia.

The pharmaceutically acceptable diluent is selected so that it does not affect the biological activity of the combination. Examples of such diluents are distilled water, saline, Ringer's solution, dextrose solution and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

The composition should be adapted for use in the regression of inflammation. Accordingly, it should be understood that, depending on the desired mode of administration, the composition should be formulated for systemic or local administration. In an optimal embodiment, the composition proposed by the authors is formulated for systemic or local administration. In an optimal embodiment, oral administration is envisaged, for example, in the form of tablets, solution or ampoules, or administration by injection. However, depending on the nature and mode of action, the composition can be administered by other routes, including cutaneous, intramuscular, subcutaneous, oral, intravenous or local. The composition is optimally formulated for bolus administration or for continuous administration, as detailed elsewhere herein. In an optimal embodiment, the composition according to the present invention is formulated as a medicament, as detailed elsewhere herein.

The term "inflammation" in this context refers to the pathophysiological response of a subject to a harmful effect, for example, from pathogens, cell damage, or irritants. Typical signs of inflammation are heat, pain, redness or other skin reactions, swelling, and impaired tissue function.

Inflammation may be acute inflammation or chronic inflammation. In a preferred embodiment, the inflammation referred to in the present invention is chronic inflammation. Inflammation, in particular chronic inflammation, in a preferred embodiment may be associated with a disease or disorder selected from the group consisting of: rheumatoid arthritis, osteoarthritis, peritonitis, irritable bowel syndrome, chronic obstructive pulmonary disease, systemic lupus erythematosus, multiple sclerosis, psoriasis, type 1 diabetes mellitus, musculoskeletal injuries, muscle inflammation, and joint inflammation, such as ankle sprain.

The term "regression of inflammation" in this context refers to an active process that results in the restoration of the integrity and function of tissue affected by inflammation. More specifically, inflammation is a pathophysiological process that occurs in response to infection or tissue damage.

The process is usually initiated when cells of the innate immune system, which reside in a tissue, detect infection or damage within the tissue. Secretion of chemical signals, such as chemokines and cytokines, leads to the recruitment of circulating neutrophils to the site of damage or infection.

Class switching of lipid mediators occurs as neutrophils accumulate in pus or purulent exudates. Lipoxins (LX) stimulate the recruitment of non-inflammatory monocytes. IX, resolvins (Rx), and other specialized regression mediators (RMs) are produced in pus to limit or stop further neutrophil infiltration into the tissue. 5RM, Em, maresins (McK), and protectins, which simulate efferocytosis of apoptotic neutrophils and cellular debris by macrophages. Macrophages that promote regression and apoptotic neutrophils also produce 5RM. Edema also contributes circulating n-3 polyunsaturated fatty acids (PUFAs) to the exudates for temporary conversion to

ZRM cells of exudate. Mac and specific Cm contribute to wound healing and tissue repair (Zetpap, 2017). After this, tissue homeostasis can be restored. There are various inflammatory diseases,

in which the regression of inflammation is clearly impaired, leading, for example, to chronic inflammation.

Regression of inflammation according to the present invention should be understood as the initiation of an active process of regression of inflammation and the possibility of regression of such processes of chronic inflammation. Typical characteristic changes of regression of inflammation are the synthesis of so-called specialized regression-promoting mediators (5PM) and the recruitment of macrophages, in particular those belonging to the regression-promoting phenotype. Thus, regression of inflammation, as indicated by the authors, optimally includes a decrease in the recruitment of neutrophils to the site of inflammation. Also optimally, regression of inflammation includes inducing the synthesis of at least one 5PM, in an even more preferred embodiment - at least one 5PM selected from the group consisting of: IxAl, IxBa, EMO", EmO5, Mag-2 and MPO:.

Such BRMs are preferably significantly increased 4 hours after administration of the composition to the subject compared to a control subject. In addition, regression of inflammation preferably includes recruitment of macrophages. In an even more preferred embodiment, the aforementioned macrophages are significantly increased at the site of inflammation 24 hours after administration of the composition to the subject compared to a control subject.

In the best case, regression of inflammation, as indicated by the authors, may refer to a significant improvement in its resolution, for example, by triggering 5RM synthesis and/or macrophage recruitment. However, in an even more preferred case, regression of inflammation means the cure of inflammation, such that homeostasis and tissue function are fully restored. As will be understood, regression of inflammation may not occur in 100 95 subjects administered the composition. However, the term requires that regression occur in a statistically significant proportion of subjects (e.g., in a cohort in a cohort study). Whether a proportion is statistically significant can be determined without particular difficulty by those skilled in the art through the use of various well-known statistical evaluation tools, for example, determination of confidence intervals, determination of p-value, Student's test, test

Mann-Whitney, etc. Details are presented in the publication Oomau apa M/vagdep, Ziaiviisv Tog Kezeeagsi, add.

UMIeu 5 5op5, Mem HogkK 1983. Optimal values of confidence intervals are at least 90 905, at least 95 95, at least 97 95, at least 98 95 or at least 99 95. The p-values are optimally 0.05, 0.01, 0.005 or 0.0001.

The term "subject" in this context refers to a mammal, preferably a human.

The aforementioned subject preferably requires regression of inflammation, i.e. exhibits acute or chronic inflammation. In a more preferred embodiment, the subject has chronic inflammation and/or also suffers from a disease associated therewith, preferably a disease or disorder selected from the group consisting of: rheumatoid arthritis, osteoarthritis, peritonitis, irritable bowel syndrome, chronic obstructive pulmonary disease, systemic lupus erythematosus, multiple sclerosis, psoriasis, type 1 diabetes mellitus, musculoskeletal injuries, muscle inflammation and joint inflammation, e.g., ankle sprain.

The plants mentioned according to the present invention, i.e., Aspidium sativum (common tree),

Asopistha pareiyy5 (true one), Agpis topiapa (mountain arnica), Aigora beiYiPa-doppa (common belladonna), VeiYiyiv regepiz (perennial daisies), SalIepacia oisipiay5 (marigolds), Espipacea rygrigea (purple coneflower), Espipacea (narrow-leaved coneflower), Nat!teii»5 migdipiapa (witch hazel), Nuregisit regiogaisht (St. John's wort), Maigisagaia geschia (chamomile) and

The plants of the genus Pisipaie (Comfrey), are well known to those skilled in the art and botanically characterized. Accordingly, the above-mentioned plants as starting material for the preparation of the composition according to the present invention are recognized, cultivated and/or harvested without undue difficulty. For example, the plants can be obtained by growing a developing seedling in a greenhouse under standard conditions of humidity, temperature and light to adult plants, cultivating the above-mentioned plants for a period of time sufficient to enable the production of secondary metabolites of the plants and harvesting the plants or parts thereof required for the extraction process, as defined in another section of this document. In addition, the above-mentioned plants as starting material for the preparation of the composition according to the present invention can also be obtained by harvesting in the wild. In this case, the plants are recognized using micro- and macroscopic testing methods.

Other components of the composition are also chemicals well known in homeopathy, such as

Nerage ziyygiz (calcium sulfide) and Megsygiy5 zoyYitsbiy5 Nappetappi (mercury amidonitrate). These components, particularly as homeopathic ingredients, are also well known among specialists in this field.

The composition according to the present invention includes the above-mentioned components in the following homeopathic dilutions:

AspiPea tiPetiisht OZ,

Asopisht pareinz 02,

Agpisa topiapa 02,

Aggora BeiIa-dopa 02,

Veiiiiz regepiz 02,

SaIepashia oisipaii5 02,

Espipacea rygrigea 02,

Espipassea 02,

Natatheis migdipiapa O1,

Nerag ziyyigiz Ob,

Nuregtisit repogast 02,

Maigisagya gesishsha 03,

Megsypivz zoiiYitsbii5 Nappetapgpi Ob and

The following is a summary of the work.

The term "AspjShea ptSheitoisht 03" in this context refers to the dilution of the matrix tincture

Aspiia tipegtoiiisht, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular, the German Homeopathic Pharmacopoeia (NAV), in the optimal version of 2017, or

European Pharmacopoeia (EP. Eig.), preferably version 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. The 100-dilution of the matrix tincture is prepared by using the following dilution scheme: 3 parts of the matrix tincture are diluted in 7 parts of ethanol (70-95 v/v) to obtain the O1 dilution.

This dilution is subjected to further processing as described below.

The term "Asopiste parein5 02" in this context refers to the dilution of the matrix tincture

Asopiišt pareišt5, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular, the German Homeopathic Pharmacopoeia (NAV), in the optimal version of 2017, or

European Pharmacopoeia (R.Eig.), preferably 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. 2 parts of the matrix tincture are diluted in 8 parts of ethanol (50-95 v/v) to obtain dilution 01.

This dilution is subjected to further processing as described below.

The term "Agpis topiapa 02" in this context refers to the dilution of the Agpis topiapa matrix tincture, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular,

German Homeopathic Pharmacopoeia (HAP), preferably 2017, or European Pharmacopoeia (R.Eig.), preferably 9.5. Preferably, the above-mentioned matrix tincture (corresponding to dilution 01) to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. 1 part of dilution O1 is then diluted in 9 parts of ethanol (90-95 v/v) to obtain dilution 02. This dilution is further processed as described below.

The term "Aggora BeiYia-doppa 02" in this context refers to the dilution of the Aigora matrix tincture.

BrePa-doppa, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular,

German Homeopathic Pharmacopoeia (HAP), preferably 2017, or European Pharmacopoeia (R.Eig.), preferably 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. 2 parts of the matrix tincture are diluted in 8 parts of ethanol (5095 v/v) to obtain dilution 01. This dilution is further processed as described below.

The term "Veiiii5 regepis 02" in this context refers to the dilution of the matrix tincture of Veiiib5 regepi5, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular,

German Homeopathic Pharmacopoeia (HAP), preferably 2017, or European Pharmacopoeia (R.Eig.), preferably 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. 2 parts of the matrix tincture are diluted in 8 parts of ethanol (5095 v/v) to obtain dilution 01. This dilution is further processed as described below.

The term "SaIepashia oiPisipaiv 02" in this context refers to the dilution of the matrix tincture

SaIepasha oyisipaye, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular, the German Homeopathic Pharmacopoeia (NAV), in the optimal version of 2017, or

European Pharmacopoeia (EPP), preferably 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. One part of the matrix tincture is diluted in 7 parts of ethanol (70-95 v/v) to obtain dilution 01.

This dilution is subjected to further processing as described below.

The term "Espipasea rigrigea 02" in this context refers to the dilution of the matrix tincture

Espipasea rigrigea, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular, the German Homeopathic Pharmacopoeia (HDP), in the optimal version of 2017, or

European Pharmacopoeia (EPP), preferably 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. One part of the matrix tincture is diluted in 7 parts of ethanol (70-95 v/v) to obtain dilution O1.

This dilution is subjected to further processing as described below.

The term "Espipasea 02" in this context refers to a dilution of the Espipapasea matrix tincture, which was prepared according to the current editions of the homeopathic pharmacopoeias, in particular the German Homeopathic Pharmacopoeia (HAP), preferably 2017, or the European Pharmacopoeia (R.Eig.), preferably 9.5. Preferably, the aforementioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. Part of the matrix tincture is diluted in 7 parts of ethanol (7095 v/v) to obtain dilution 01. This dilution is further processed as described below.

The term "Natateii" migdipia "apa 01" in this context refers to the dilution of the matrix tincture

Natateiyiv5 migdipiap, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular, the German Homeopathic Pharmacopoeia (NAV), in the optimal version of 2017, or

European Pharmacopoeia (EPP), preferably 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. The matrix tincture is further processed as described below.

The term "Nerag ziMigiz Ob" in this context refers to the dilution of the matrix tincture of Nerag ztsigije, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular,

German Homeopathic Pharmacopoeia (HAP), preferably 2017, or European Pharmacopoeia (R.Eig.), preferably 9.5. Preferably, the above-mentioned material to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. 1 part of the material is triturated with 9 parts of lactose monohydrate to obtain trituration 01. 1 part of trituration 01 is triturated with 9 parts of lactose monohydrate to obtain trituration 02. Trituration 02 is further triturated (1:10) as above to obtain triturations 03 and 04. Trituration 04 is further processed as described below.

The term "Nuregisit regpiogait 02" in this context refers to the dilution of the matrix tincture

Nuregisit repgpogaisht, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular, the German Homeopathic Pharmacopoeia (NAV), in the optimal version of 2017, or

European Pharmacopoeia (EPP), preferably 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. One part of the matrix tincture is diluted in 7 parts of ethanol (70-95 v/v) to obtain dilution 01.

This dilution is subjected to further processing as described below.

The term "Maigisagiia gescshya 03" in this context refers to the dilution of the matrix tincture

Maigisapa hestia, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular, the German Homeopathic Pharmacopoeia (NAV), in the optimal version of 2017, or

European Pharmacopoeia (EPP), preferably 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. One part of the matrix tincture is diluted in 7 parts of ethanol (70-95 v/v) to obtain dilution O1.

This dilution is subjected to further processing as described below.

The term "Megsiguis 5oYishbii5 Nappetappi Ob" in this context refers to the dilution of the matrix tincture of Megsiguis zoyiYitsbii Nappetappi, which was prepared according to the current editions of homeopathic pharmacopoeias, in particular the German Homeopathic Pharmacopoeia (HAP), in the optimal version 2017, or the European Pharmacopoeia (EP. Eich.), in the optimal version 9.5. In the optimal version, the aforementioned material to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. 1 part of the material is triturated with 9 parts of lactose monohydrate to obtain trituration 01. 1 part of trituration O1 is triturated with 9 parts of lactose monohydrate to obtain trituration 02.

Trituration 02 is further triturated (1:10) as above to obtain triturations OZ and 04.

Trituration 04 is further processed as described below.

The term "BZutrpuišt oyisipae Ob" in this context refers to the dilution of the matrix tincture

The preparation was prepared according to the current editions of homeopathic pharmacopoeias, in particular the German Homeopathic Pharmacopoeia (HDP), in the best version of 2017, or

European Pharmacopoeia (EP. Eig.), preferably 9.5. Preferably, the above-mentioned matrix tincture to be used for the composition according to the invention is characterized by the analytical parameters set out in the corresponding monogram. 1 part of dilution O1 is then diluted in 9 parts of ethanol (70 95 v/v) to obtain dilution O2. 1 part of dilution O2 is further diluted in 9 parts of ethanol (70 95 v/v) to obtain dilution OZ, 1 part of dilution OZ is then diluted in 9 parts of ethanol (50 95 v/v) to obtain dilution O4. This dilution is further processed as described below.

Dilution 01 Aspirin, dilution 01 Mycophenolate Mofetil and dilution 04 Zuprpust Oyisipaie are mixed and the mixture is diluted twice 1:10 with water for injection to obtain a dilution

OZ AspShea tyeytiiisht, breeding OZ Maigisapa gesshya and breeding Ob 5utrpuisht oyisipa!e.

Dilution 01 Asopisht pareiPi5, dilution 01 Aigora BrePa-doppa, dilution 01 Veii5 regeppiv, dilution 01 SaiIepasha oyisipai5, dilution 01 Espipasea, dilution O1 Espipasea rigrigea, dilution 01 Nuregissht repogaisht are mixed and the mixture is potentiated 1:10 with water for injection in order to obtain dilution 02 Asopisht pareiPsh5, dilution 02 Aigora reYiPa-doppa, dilution 02 Veii5 regeppizh, dilution 02 SaiIepasha oyisipaiie, dilution 02 EspPipasea, dilution 02 EspPipasea rigrigea, dilution 02 Nuregissht repogaisht.

Trituration 04 Nerag zyMigiz and trituration 04 Mexigiyyiv zoyYitsbiyiv Nappetappi are potentiated twice 1:10 with water for injection to obtain dilution Ob Nerag zyMigiz and dilution Ob Mexigiy5 zoyYSbiy5 Nappetappi, respectively.

The matrix tincture of Nataiteia migdipiapa is potentiated 1:10 with water for injection to obtain a dilution of 01 Nataiteia migdipiapa.

These final intended dilutions are then mixed with each other, with the Agpis Topiap dilution 02 and with water for injection and sodium chloride to obtain the composition to be used according to the present invention.

In the optimal embodiment, the composition provided for use according to the present invention is a pharmaceutical composition of Tgacee mass production in the form of drops, tablets, ointments, injection solution or gel (Violodizpe Neutinen! Neu! Stün, Germany).

The following components and the amount in which they are present in the composition for use according to the invention are listed for tablets, ointment, drops, gel and injection solution (ampoule):

Component Ointment Tablet Drops Gel (per 100 g) (per 300 mg) (per 100 g) (per 100 g) (per 22 g)

Nappetappi 74.652 g water, 9.342 g paraffin, purified; liquid; 8.007 g 18.653 g cetostearyl)| 6 mg ethanol 19.4 mg alcohol (type A), monohydrate (96 95); chloride

Excipients emulsifier; lactose; 2 g water, 1 g carbomer | sodium; 9.342 g paraffin, |1.5 mg purified (Sagroroy 2.1791 mg white soft; stearate 98OME); water for injection 60.579 g water, magnesium 2.3 hydroxide purified; 9.335 g sodium, ethanol (96 95) 18 95 solution (w/w)

Typically, the composition for use according to the present invention is intended to be administered in an amount sufficient to regress the inflammation. It should be understood that the dosage employed may depend on several factors well known to clinicians, including gender, age, body weight, and general health. In addition, the dosage will depend on the type of administration. Typically, topical administration may require a different dosage compared to systemic administration. Similarly, the mode of administration also affects the therapeutically effective dosage. For example, oral administration may require a different dosage compared to intraperitoneal injection. In a preferred embodiment, the composition according to the present invention is administered in the form of a solution. In a more preferred embodiment, the dosage administered to the subject should correspond to an amount that provides at least about 1.5 ml of the composition (injection solution) per kilogram of body weight for 10 days in mice.

If the composition for use according to the present invention is formulated as a solution, a 2.2 ml ampoule is administered per day (30 μl/kg body weight). This ampoule is optimally administered one to three times per week. However, the dose can be optimally increased 5-10 times the above-mentioned dose. In acute cases, the ampoule is optimally administered once a day.

In an optimal embodiment, the above-mentioned dose should be provided via a single administration (bolus) or can be achieved via more than one administration step throughout the day. Furthermore, it is also envisaged that the dose is optimally provided by the use of continuous release devices that provide continuous administration of the dose throughout the day.

Methods for appropriately formulating the composition to provide the above-mentioned daily dosage are well known to those skilled in the art. Typical compositions may be tablets, capsules, solutions such as tinctures for dermal application or liquids for oral administration, injectable solutions, gels or ointments.

The composition according to the present invention can be used together with anti-inflammatory drugs or together with other drugs that provide regression of inflammation. Anti-inflammatory drugs can be non-steroidal anti-inflammatory drugs (NSAIDs). Such NSAIDs can be selective or non-selective inhibitors of cyclooxygenase 2 (COX-2), which are widely used for anti-inflammatory therapy. Typical NSAIDs are salicylates, preferably aspirin, diflunisal, salicylic acid and other salicylates, salsalate, propionic acid derivatives, preferably ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, acetic acid derivatives, preferably indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, enolic acid derivatives (oxicam), preferably piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, anthranilic acid derivatives (fenamates), preferably mefenamic acid, meclofenamic acid, rlufenamic acid, tolfenamic acid, and selective COX-2 inhibitors. 2 (coxibs), preferably celecoxib, parecoxib and etoricoxib. In addition to NSAIDs, other homeopathic medicines or compositions may also be used together with the composition for use according to the present invention.

The above-mentioned anti-inflammatory drugs or other drugs that promote regression of inflammation are administered together with the composition according to the invention or sequentially, before or after the administration of the above-mentioned composition. If the composition is to be administered together with the above-mentioned anti-inflammatory drugs or other drugs that promote regression of inflammation, this is achieved by administering a single composition consisting of the composition for use according to the present invention and the above-mentioned anti-inflammatory drugs or other drugs that promote regression of inflammation, or they are administered as separate compositions.

According to the present invention, it was found that the composition comprising the above ingredients, when administered to mice suffering from zymosan-induced peritonitis, was able to significantly promote the regression of inflammation. The composition positively changed the kinetics of neutrophil recruitment and reduced the regression index by almost 6 hours compared to the control. In addition, macrophages were significantly increased compared to the control group at the site of inflammation, which also had a positive effect on the regression of inflammation after 24 hours. | Finally, it was observed that the synthesis of various 5PMs was significantly increased after 4 hours in the experimental group compared to the control. Accordingly, the composition for use according to the invention was determined to exhibit strong properties regarding the regression of inflammation in a model organism. Thanks to the present invention, it is possible to provide effective regression of inflammation, in particular chronic inflammation, in various pathological conditions.

In general, the present invention also relates to a method of regressing inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a composition comprising the following ingredients: AspPShea ptipetuyit, Asopist parein5, Agpis topiapa, Aigora rePa-dopa, Veiiyiv regepi5, Saiepatsia oisipaii5, Espipacea rigrigea, Espipacea, Natateiiv migdipiapa,

Nerag zyPygiz, Nuregisit repogaisht, Maigisapa gescia, Megsigpy5 zoiYitsbBiiv Nappetappi and Zutrpuit oyisipaie. Typically, a subject in need of regression of inflammation is a subject as defined elsewhere herein, in particular, a subject suffering from chronic inflammation or a disease associated therewith, as mentioned herein.

Below are presented specific optimal embodiments of the composition for use according to the present invention.

In one preferred embodiment of the composition for use, the aforementioned regression of inflammation includes reducing the recruitment of neutrophils to the site of inflammation.

In another preferred embodiment of the composition for use, the aforementioned regression of inflammation comprises inducing the synthesis of at least one specialized regression-promoting mediator (SPM). In a more preferred embodiment, the aforementioned at least one SPM is selected from the group consisting of: IxAl, IxBa, EMO", EMO", Mag-2 and MPO:. In a more preferred embodiment, the aforementioned at least one SPM is significantly increased 4 hours after administration of the composition to the subject compared to a control subject.

In a preferred embodiment of the composition for use, said regression of inflammation includes recruitment of macrophages. In a more preferred embodiment, said macrophages are significantly increased at the site of inflammation 24 hours after administration of the composition to the subject compared to a control subject.

In another preferred embodiment of the composition for use, the above-mentioned ingredients of the composition are used in the following homeopathic dilutions:

AspiPea tiPetiisht OZ,

Asopisht pareiins 02,

Agpisa topiapa 02,

Aggora BeiIa-dopa 02,

Veiiiiz regepiz 02,

SaIepashia oyisipaii5 02,

Espipacea rygrigea 02,

Espipassea 02,

Natatheis migdipiapa O1,

Nerag ziyyigiz Ob,

Nuregtisit repogast 02,

Maigisagya gesishsha 03,

Megsypivz zoiiYitsbii5 Nappetapgpi Ob and

The end of the year.

In a more preferred embodiment, the above composition should be administered in an amount corresponding to an amount provided by at least about 1.5 ml of the composition per kilogram of body weight for 6 days in mice.

In a preferred embodiment of the composition for use, the aforementioned inflammation is chronic inflammation. In a more preferred embodiment, the aforementioned inflammation is associated with a disease or disorder selected from the group consisting of: rheumatoid arthritis, osteoarthritis, peritonitis, irritable bowel syndrome, chronic obstructive pulmonary disease, systemic lupus erythematosus, multiple sclerosis, psoriasis, type 1 diabetes mellitus, musculoskeletal injuries, muscle inflammation, and joint inflammation, such as ankle sprains.

In a preferred embodiment of the composition for use, the above composition should be administered to the subject together with an anti-inflammatory drug.

In another preferred embodiment of the composition for use, the aforementioned composition is to be administered to a subject after treatment of the aforementioned subject with an anti-inflammatory drug.

In an even more preferred embodiment, the aforementioned anti-inflammatory drug is a non-steroidal anti-inflammatory drug (NSAID), most preferably selected from the group consisting of: salicylates, most preferably aspirin, diflunisal, salicylic acid and other salicylates, salsalate, propionic acid derivatives, most preferably ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, acetic acid derivatives, most preferably indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, enolic acid derivatives (oxicam), most preferably piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, anthranilic acid derivatives (fenamates), optimally - mefenamic acid, meclofenamic acid, rlufenamic acid, tolfenamic acid, and selective COX-2 inhibitors (coxibs), optimally - celecoxib, parecoxib and etoricoxib.

In a preferred embodiment of the composition for use, the aforementioned subject is a human.

The invention also relates to a pharmaceutical composition comprising a composition as described hereinabove and an anti-inflammatory drug, preferably as described hereinabove.

The present invention also provides a kit for use in regressing inflammation in a subject in need thereof, comprising (I) a composition as described above and (II) an anti-inflammatory drug, preferably as described above.

All sources cited in this description are incorporated herein by reference to the content of their description in its entirety and with reference to the content of the description to which it specifically refers.

figures

Figure 1: Neutrophil migration during zymosan-induced peritonitis. HE-100 and vehicle (1.5 ml/kg) were administered intraperitoneally once daily for 6 days. Peritonitis was induced 12-13 hours after the last injection by administration of zymosan (0.1 mg/mouse). At baseline and 4, 8 and 24 hours, mice (6-8 animals/group/time point) were euthanized, and peritoneal exudates were collected and analyzed by flow cytometry. HE-100 positively alters the kinetics of neutrophil recruitment and reduces the regression index (Ki) by almost 6 hours. The Ki for the test compound is defined as the time gain for the neutrophil count to decrease to 50 95 compared to the control condition: Ki-T50 vehicle - Tho compound.

Figure 2: Macrophage migration during zymosan-induced peritonitis. HE-100 and vehicle (1.5 ml/kg) were administered intraperitoneally once daily for 6 days. Peritonitis was induced 12-13 hours after the last injection by administration of zymosan (0.1 mg/mouse). At baseline and 4, 8 and 24 hours, mice were euthanized, and peritoneal exudates were collected and analyzed by flow cytometry. More macrophages were detected in the experimental group after 24 hours. Macrophages are involved in the removal of debris from the site of inflammation (efferocytosis). An increase in their number is considered to have a positive effect on regression. "p-value x0.05.

Figure 3: Synthesis of ZRM 4 hours after zymosan-induced peritonitis. HE-100 and vehicle (1.5 ml/kg) were injected intraperitoneally once daily for 6 days. Peritonitis was induced 12-13 hours after the last injection by administration of zymosan (0.1 mg/mouse). At baseline and after 4, 8 and 24 hours, mice were euthanized, and peritoneal exudates were collected and analyzed by liquid chromatography-tandem mass spectroscopy (LC-M5/M5). Increased synthesis

RM were detected in the experimental group after 4 hours. An increase in their number is considered to have a positive effect on the regression. "p-value x 0.05.

EXAMPLES

The invention is further illustrated by the Examples presented below, which should in no way be construed as limiting the scope of the invention in any way.

Example 1: HE-100 and vehicle (1.5 ml/kg) were administered intraperitoneally once daily for 6 days. Mice were weighed daily to adapt to the volume of compounds. 12-13 hours after the last injection, peritonitis was induced by administration of zymosan (0.1 mg/mouse). At the beginning of the time course and after 4, 8 and 24 hours, mice were euthanized (6-3 animals/group/time point). Inflammatory exudate was obtained by lavage of the abdominal cavity with phosphate-buffered saline PB5. Cells were immediately counted using a Zseries cell counter (MegsK Miyiroge) and labeled for subpopulation identification and quantification by cytometry (analyzer, MASZOcapi - Minepuy).

The exudates were centrifuged and suspended to obtain a suspension of 1 x 1059 cells/ml. The cells were then labeled with the following antibody (Mikepui Bioscience): CO45-myoIce (Mikepui); E4/80-RITS (Mikepui);

SK1-PE (Violetdepa). Among the CO45-positive cells, neutrophils were sorted as follows: SK1", E4/80-.

Example 2: HE-100 and vehicle (1.5 ml/kg) were administered intraperitoneally once daily for 6 days. Mice were weighed daily to adapt to the volume of compounds. 12-13 hours after the last injection, peritonitis was induced by administration of zymosan (0.1 mg/mouse). At the beginning of the time course and after 4, 8 and 24 hours, mice were euthanized (6-3 animals/group/time point). Inflammatory exudate was obtained by lavage of the abdominal cavity with phosphate-buffered saline PB5. Cells were immediately counted using a Zserie cell counter (MegsK Miyiroge) and labeled for subpopulation identification and quantification by cytometry (analyzer, MAC5300Chip - Minepuy).

The exudates were centrifuged and suspended to obtain a suspension of 1 x 109 cells/ml. After that, the cells were labeled with the following antibody (Mikepui Bioscience): CO45-myoIce (Mikepui); E4/80-RITS (Mikepui);

SKI1-PE (Vioidepa). Resident macrophages were sorted among CO45-positive cells as follows:

CB17, E4/80 group: monocyte infiltrates were sorted as CB17, E4/807.

Example 3: Extraction and Analysis Protocol | C/M5/M5 was performed as described (I e Raocadeg et al., 2013) and adapted from the Standard Operating Procedure of Atrbioiz. Specially selected peritoneal lavage samples were extracted using 96-well solid phase extraction cartridges Oazis HI B (U/aseg5). The analysis of C-M5/M5 was performed on the O-HRI C system (Adiepi I C1290

The mass spectrometer was connected to an Adipi 6490 triple quadrupole mass spectrometer (Adipi Tespoiodiev) equipped with electrospray ionization operating in negative mode. Reversed-phase HPLC was performed on a Kipex Virpepu! column (2.1 mm × 50 mm × 1.7 μm) (Rpepotex) maintained at 50 °C. For the observation and quantification of biologically active lipids, the analyses were performed in the detection mode with multiple reaction monitoring (MRM). Recognition was performed using pure authentic standards. Peak detection, integration and quantitative analysis were performed using the MazzNipeg quantitative analysis program (Adipi

The biologically active lipids that were quantified in the samples are:

TheirAz for arachidonic acid-derived mediators.

EMO", KmO5 and MPO: mediators derived from docosahexaenoic acid.

SOURCES OF INFORMATION:

Ge Raotsaeg, R. ei ai. (2013) ".S-M5/M5 teinoy og garid apa sopsotyapi diapiysayop oi rgo- ipYattayogu apa rgo-gezoMmipd roiuspzaiisgaiey iatsu asiy teiaboiyev", doigpa! oi Spgotaiyodgarnu V, 932, pp. 123-133. doi: 10.1016/.|spgotbr.2013.06.014.

Yee, S. N. (2012) "KezoMmipe az pemu Tazsipiped agid sapaidagez og iShattayogu diseazevz", Agspimev oy

RIpaptasai Kezeagsi, 35(1), pp. 3-7. doi: 10.1007/512272-012-0121-7.

Mopiego-Meyiepae7, T. ei et al. (2011) "The teiiJiaposopip adopibi AP214 exep5 apii-iShattagsogu apa rgogezoimipd rgorepievs", Ategisap Chocygpa! oi Raiiyodu. Eivemieg Ips., 179(1), pp. 259-269. doi: 10.1016/).airai.2011.03.042. Zapzrygu, V. E. and Srie, M. (2016) "Kezoyshiop oi assche ipiattayiop apa (pe goYe oi gezoimip5 ip iptytipu, ygotrobi5, ap mazsshiag BioIodu", Sigsshayop Kezeagsi, 119(1), pp. 113-130. abi: 10.1161/SIKSKEZANA.116.307308.

Zsppeideg, S. (2011) "Tgashteei!: ap etegdipd oriiop o popviegoida! apii-ipPattayogu dhide5 ip (Zhe tapadetepi oi ascie tyssshtshoz5kKeiiegai! ipiigiev", Ip(egpabopa! doigpai! oi Sepegai! Meaisipe, 4, pp. 225-234. doi: 10.2147/|dt.516709. Zseptpap, S. M. (2014) "Rgo-gezoMipud Iyrij teaiiyaig5 age Ivad5 yTog gezoJiishop rpuzioIodu", Maiisge, 510(7503), pp. 92-101. aoi: 10.1038/pasge13479. zegppap, S. M. (2017) ""Teaypd ipattaitsyop apa iptTesiop ip (pe 215i sepiigu: Mem/ pipiv iot desodipd gezoYshschiop tediaig5 apa tespapizitv", RABEV doyshgpai, 31(4), pp. 1273-1288. doi: 10.1096/).2016012221. zegppap, S. M. apa Gemu, V. 0. (2018) "KezoMmip5 ip ipyattatsop: Etegdepse oi She rgo-gezoMmipd zirepatiu oi tediaigv", doygpai oi Siipisa! Ipleziidaiop, 128(7), 2657-2669. adoi: 10.1172/2С197943.

Zyditoio, M. A. (2016) "KezoYshop oi ipPyattatsyop: UUpai sopigoi5 yb opvei?, Egopiegv5 ip

Ittypoiodu, 7(ARK). doi: 10.3389/ytty.2016.00160.

We, 5.-N. ei ai. (2013) "Epsasu apa zaieiu oi 15(K/5)-teiPu!-Iirohip A 4 ip orisa! igeaitepi oi iptapshShe esgeta", ViyizA doshigpai! oi Oeppatsoiodu, 168(1), pp. 172-178. doi: 10.1111/.1365-2133.2012.11177.x.

Neutrophils 1x107 -- Sven

The value (lakh Moitah and yako NEO 8x106

Э бх105 т DK k 6 ож щ ше

EX as10 «ex r and vevenetyoi vo M vo) zi - ; ok 2x106 ; ve

Steffennn

Time (hours)

Fig. 1

Ear macrophages? TO Basis

F CT NE-100

Ж бх1305 т дх105 5 2x106 Z and z

Time (hours)

Fig. 2 , I ii hai m Zh Kur? vay - ze sk t | g .

Time (hours) " "time (hours) " o Zh KkU05 zob MR J sh 300 . sh 400 z . "time (hours) 7 " Time (hours) 7

Fig. with

The invention relates to the use of a composition for the regression of inflammation in a subject in need thereof, the aforementioned composition comprising the following ingredients: Aspirin,

Asopipit pareYi", Atisa topiapa, Aikora rePa-doppa, VeTsikh regepi5, SaiIepdia ofisipaii",

Espipasea rigrigea, Espipasea, Natateiih uigripiapa, Nerak ziTsitgih, Nuregisit regogasht,

Maitisagia gesiya, Megsitiykh zoInbiyikh Nappetapni and 5utrpuit about isipa!e.

Claims (13)

1. Use of a composition for the regression of inflammation in a subject in need thereof, said composition comprising the following ingredients in the following homeopathic dilutions: Aspergillus spp. 10, Aspergillus parietalis 2, Atisa topia 2, Aitora repa-dopa P, Vey recap 2, Salvia officinalis 10, Esvpipasea rigricea 2, Esvpipasea 2, Natateii uiguipiapa PI, Neraki citricides OB, Nuretisit regogaiit I2, Maitisatia gesia 3, Metgisii chonobiih Nappetapnpi Pb and Butrvpuit officipaie re, wherein said composition is administered in an amount corresponding to the amount provided by intraperitoneal administration of 1.5 ml of the composition per kilogram of body weight of the body of mice, once a day for 6 days, 1 wherein said inflammation is associated with a disease or disorder selected from the group consisting of: rheumatoid arthritis, osteoarthritis, peritonitis, irritable bowel syndrome, chronic obstructive pulmonary disease, systemic lupus erythematosus, multiple sclerosis, psoriasis, type 1 diabetes mellitus, musculoskeletal injuries, muscle inflammation and joint inflammation such as ankle sprains. 2. The use according to claim 1, wherein said regression of inflammation includes a reduction in the recruitment of neutrophils to the site of inflammation. 3. The use according to claim 1 or 2, characterized in that said regression of inflammation includes inducing the synthesis of at least one specialized regression-promoting mediator (5PM). 4. The use according to claim 3, characterized in that said at least one 5RM is selected from the group consisting of: I xAl, I x Vi, Kur», KuY»z, Mag-2 and MRO!. 5. The use according to claim 3 or 4, characterized in that said at least one ZHRM is significantly increased 4 hours after administration of the composition to the subject compared to a control subject. b. The use according to any one of claims 1-5, characterized in that said regression of inflammation includes recruitment of macrophages. 7. The use according to claim b, characterized in that said macrophages are significantly increased at the site of inflammation 24 hours after administration of the composition to the subject compared to a control subject. 8. The use according to any one of claims 1-7, characterized in that said inflammation is chronic inflammation. 9. The use according to any one of claims 1-8, characterized in that said composition is to be administered to the subject together with an anti-inflammatory drug. 10. The use according to any one of claims 1-9, characterized in that said composition is to be administered to a subject after treatment of said subject with an anti-inflammatory drug. 11. The use according to claim 9 or 10, characterized in that said anti-inflammatory drug is a non-steroidal anti-inflammatory drug (NSAID). 12. The use according to claim 11, characterized in that said NSAID is selected from the group consisting of: salicylates such as aspirin, diflunisal, salicylic acid and other salicylates, salsalate, propionic acid derivatives such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, acetic acid derivatives such as indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, enolic acid derivatives (oxicams) such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, anthranilic acid derivatives (fenamates) such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and selective COX-2 inhibitors (coxibs), such as celecoxib, parecoxib, and etoricoxib. 13. The use according to any one of claims 1-12, characterized in that said subject is a human.