Diarylheptanoid-based pharmaceutical preparations and method for producing the same

Abstract

Provided are diarylheptanoid-based pharmaceutical preparations and a method for producing the same. **Solution**: This disclosure relates to a pharmaceutical preparation in which a mixture of a diarylheptanoid complex and the essential oil of turmeric is embedded in a diarylheptanoid metal complex. Also disclosed is a preparation method in which a complex is formed by the reaction of a diarylheptanoid with a cation in the presence of an oil. The diarylheptanoid metal complex containing the embedded oil has been shown to improve the general health of birds and mammals. It has been found that the improvement of the health of birds and mammals has effects such as a decrease in mortality, an improvement in weight gain, an improvement in meat quality, bone density, an improvement in eggshell thickness, an improvement in immunomodulatory activity, an improvement in liver condition, and a decrease in the occurrence of drug-induced lipid abnormalities. In addition, this pharmaceutical is effective in preventing the occurrence of mastitis, treating hypocalcemia, Alzheimer's disease, and stress-related problems, has an antioxidant effect, and also has an improved analgesic effect.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical preparation comprising a free-flowing stain-free composition containing a mixture of diarylheptanoid complexes and the essential oil of turmeric, wherein the oil is embedded in the diarylheptanoid metal complex. The present invention also discloses a method for manufacturing and an application method of a pharmaceutical preparation comprising an organic active ingredient that forms a salt or complex with a metal and a mineral.

Background Art

[0002] Diarylheptanoids are a kind of relatively small plant secondary metabolite with low toxicity and broad biological activities. One well-known diarylheptanoid is curcumin, which is obtained from the rhizome of the plant Curcuma longa (turmeric). The curcumin of turmeric is used for its medicinal effect and coloring power. Curcumin is the main metabolite contained in the rhizome of turmeric and its medical effect has been demonstrated. Studies have shown that other metabolites of turmeric, such as bisdemethoxycurcumin and demethoxycurcumin, also have remarkable biological activities.

[0003] Curcumin is also used in the food industry because of its coloring properties. See U.S. Patent 4,263,333, which discloses curcumin-tin and curcumin-zinc complexes as coloring pigments. The coloring properties of curcumin pigments make it difficult to use industrially because of the low bioavailability of curcuminoids. There have been few attempts to prepare metal complexes of curcumin, and U.S. Patent 8,759,562 relates to a curcumin-zinc complex for the treatment of dementia. U.S. Patent 4,263,333 relates to curcumin-tin and curcumin-zinc complexes used as coloring pigments. U.S. Patent Application 2009 / 0098226 relates to a cosmetic formulation containing curcumin and a metal salt, and the formulation may contain a curcumin-metal complex. The prior art does not teach the pharmaceutical use of metal complexes, especially in the poultry industry or in animal health. Furthermore, most of the teachings from the prior art are limited to curcumin only, and other diarylheptanoids have been largely ignored.

[0004] There is little literature on diarylheptanoids other than curcumin. For example, European Patent 0839037 relates to a formulation containing curcuminoids and curcuminoid complexes with antibacterial effects. European Patent 2694020 relates to an oral composition using curcumin and its similar complexes for dental health. A composition containing a free-flowing stain-free mixture of a diarylheptanoid complex and an oil, with the oil embedded in the diarylheptanoid metal complex, is not known in the art. Furthermore, the advantages of the oil with respect to the metal complex have not been known. There is a need for a diarylheptanoid that is a metal complex embedded with an oil having pharmaceutical use and a commercially feasible method for producing the same. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0005] The main object of the present invention is to produce a free-flowing diarylheptanoid complex embedded with oil. Another object of the present invention is the pharmaceutical use of such a diarylheptanoid complex.

Means for Solving the Problems

[0006] The present invention relates to a pharmaceutical preparation comprising a free-flowing stain-free composition containing a mixture of a diarylheptanoid complex and an essential oil of turmeric embedded in the diarylheptanoid metal complex. Here, the diarylheptanoid complex has the following formula.

Chemical formula

[0007] Formula I Here, R 1 , R 2 , R 3 , and R 4 are selected from the group consisting of hydrogen, -OH, -OCH 3 , -OCOCH 3 , -OCO-CHR-NH 2 , O-piperoyl, -O-galloyl, and -O-terpenoid.

[0008] L 1 and L 2 are selected from the group consisting of -OH, -OH 2 , Cl - , amine, diarylheptanoid, flavonoid, phenolic acid, stilbene, saponin, and tannin, D1 and D2 are selected from the group consisting of a single bond and a double bond, M is selected from the group consisting of an alkali metal, an alkaline earth metal, a transition metal, a lanthanide, and an actinide.

[0009] The composition contains at least 5% by weight of the essential oil of turmeric, preferably 5 - 40%, more preferably 20 - 25% of the essential oil of turmeric is contained in the form embedded in the diarylheptanoid complex. The diarylheptanoid metal complex constitutes 1% - 90% of the composition, preferably 60% - 90% of the composition.

[0010] A pharmaceutical preparation comprising a free-flowing stain-free composition containing a mixture of a diarylheptanoid complex and the essential oil of turmeric embedded in the diarylheptanoid metal complex. In the present invention, it has been found that by administering the pharmaceutical preparation, the general health conditions of birds and mammals are improved. The general health conditions of birds and mammals include, but are not limited to, reduction in mortality, improvement in weight gain, improvement in meat quality, prevention of hypocalcemia, improvement in bone density, improvement in eggshell thickness, improvement in immunomodulatory activity, improvement in hepatoprotective activity, improvement in analgesic properties, prevention of mastitis in dairy cows, prevention of drug-induced lipid abnormalities, treatment of stress, treatment of Alzheimer's disease, antioxidant activity, etc. The diarylheptanoid complex has been found to show remarkable results in the treatment of coccidiosis infection. It can also be administered to control parasites in mammals and birds. It can also be administered to improve the condition of the liver and acts as an immunomodulatory agent. The pharmaceutical preparation is useful for reducing the mortality of mammals and birds, improving weight gain, and preventing hypocalcemia. The pharmaceutical preparation is also effective in improving eggshell quality.

[0011] The pharmaceutical preparation can be administered alone or, depending on the method of administration to birds and mammals, can also be administered in admixture with a pharmaceutically acceptable carrier or diluent. It can be administered orally, parenterally and topically. It can be administered orally in the form of tablets, capsules, granules, powders, lozenges, syrups, elixirs, solutions, and suspensions in accordance with standard pharmaceutical practices. Carriers useful for formulating the preparation are commonly used pharmaceutically acceptable non-toxic carriers such as gelatin, lactose, sodium citrate, salts of phosphoric acid, starch, magnesium stearate, sodium lauryl sulfate, talc, and polyethylene glycol. The carrier may be used together with other additives such as diluents, binders, buffers, preservatives, sweeteners, flavoring agents, glidants, disintegrants, coating agents, emulsifying agents, and suspending agents. Parenteral administration includes intramuscular, intraperitoneal, subcutaneous, and intravenous administration, and the effective dosage of the pharmaceutical preparation is 50 to 1000 mg twice a day.

[0012] In addition, the present invention discloses a method for preparing the pharmaceutical preparation containing a mixture of a diarylheptanoid complex and an essential oil of turmeric in a form embedded in the diarylheptanoid metal complex of formula I, which method includes the following steps. a) Extracting the washed turmeric rhizome using an organic solvent, preferably ethyl acetate, to obtain a solvent portion and a residual portion; b) Separating and concentrating the solvent portion from the residual portion to obtain an oleoresin; c) Cooling the oleoresin to a temperature of 4°C to crystallize curcuminoids and separating the curcuminoid crystals from the oleoresin; d) Dissolving the remaining oleoresin in methanol to obtain a solution; e) Adding a calcium source dispersed in water to the solution obtained as a result of step d); f) Maintaining the solution obtained as a result at a temperature of 27°C and stirring until a precipitate is formed. g) Separating the precipitate, washing with water and methanol, and drying to obtain a calcium diarylheptanoid complex with essential oil embedded in the aggregates. Here, the calcium source can be selected from lime, calcium salts, and calcium oxide made from eggshells. The organic solvent used for the extraction of turmeric rhizomes is ethyl acetate, and the solvent used to dissolve the remaining oleoresin in step d) is methanol.

Brief Description of the Drawings

[0013] Various features and advantages of the present invention should become apparent from the following figures of the accompanying drawings showing the process steps and their results included in various process tests carried out based on specific preferred embodiments of the present invention.

[0014]

Figure 1

[0015]

Figure 2

Modes for Carrying Out the Invention

[0016] It relates to a pharmaceutical preparation containing a free-flowing stain-free composition containing a mixture of a diarylheptanoid complex and the essential oil of turmeric, and the oil is embedded in the diarylheptanoid metal complex.

[0017] The advantage of the diarylheptanoid in complex form is that it is very easy to handle because it does not get dirty. The complex is formed by the reaction of a diarylheptanoid with a cation in the presence of oil. The present invention also relates to various pharmaceutical uses of the composition.

[0018] The diarylheptanoid complexes disclosed herein are in the form of Formula I shown below. [Chemical Formula]

[0019] Formula I Wherein, R 1 , R 2 , R 3 , and R 4 are each independently -OH, -OCH 3 , -OCOCH 3 , -OCO-CHR-NH 2 , O-piperoyl, -O-galloyl, and -O-terpenoid. L1 and L2 are each independently -OH, -OH 2 , Cl-, amine, flavonoid, phenolic acid, stilbene, saponin, tannin, or a similar diarylheptanoid. D1 and D2 are each independently a single bond or a double bond, and M is a cation. The cation is selected from alkali metals, alkaline earth metals, transition metals, lanthanoids, and actinoids. More specifically, suitable metal cations that form a bond with the diketone of the diarylheptanoid are shown in Formula 2. Examples of such metal cations include potassium, zinc, calcium, magnesium, selenium, copper, chromium, vanadium, iron, manganese, palladium, gallium, indium, silver, tin, aluminum cations, and the like. In most cases, a stable structure with a stoichiometry of 1:1 or 2:1 (ligand:metal) is observed for divalent cations.

[0020] The metal complex is biologically potent. The metal interacts with the diarylheptanoid ligand, causing a change in the overall structure of the diarylheptanoid and enhancing its biological efficacy. Furthermore, the metal is known as an enzyme co-activator, and the diarylheptanoid-metal complex can interact with the active site of an enzyme and induce multiple cellular processes. The metal complex is more stable than the diarylheptanoid in photochemical, thermal, and hydrolytic decompositions. The diarylheptanoid is the ligand shown in Formula 1 and thus forms stable metal complexes with cations in monodentate (1:1) and bidentate (2:1) ligand-to-cation stoichiometries.

[0021] In the composition, the diarylheptanoid complex has a tendency to aggregate around the oil in a controlled morphological structure. The diarylheptanoid complex is formed in the presence of the oil, and the oil is embedded during aggregation.

[0022] The terms lipid and oil may be used interchangeably herein. Oils include essential oils derived from plants, oleoresins derived from plants, mono-, sesqui-, di- and triterpenoids, animal fats, and mono-, di- and triglycerides. More specifically, there are turmeric essential oil, ginger essential oil, pepper oil, boswellia oil, sesame oil, fish oil, coconut oil, palm oil, olive oil, sunflower oil, mustard oil, lemongrass oil, bran oil, peanut oil, lavender oil, linseed oil, grape seed oil, almond oil, avocado oil, soybean oil, walnut oil, cashew nut oil, canola oil, corn oil, safflower oil, cottonseed oil, ramtil oil, niger oil, hemp oil, ginger oil, animal fats, medium-chain mono-, di-, and triglycerides or combinations thereof.

[0023] In one embodiment, a composition comprising a mixture of a diarylheptanoid complex and an oil is disclosed. The metal cation forms a chelate at the beta-diketone moiety of the diarylheptanoid. Preferably, the composition is in powder form in which the oil is embedded in microaggregates to form an oil-embedded system. The diarylheptanoid complex is as shown in Formula 1, and most of the diarylheptanoid complexes are in 1:1 and 2:1 (ligand: cation) configurations.

[0024] Furthermore, the composition contains at least 5% oil. Since the oil particles are between the voids of the microaggregates of the diarylheptanoid complex, the composition is fluid even if the oil content of the composition exceeds 20% by weight. The oil content can be increased up to 40% by weight. When a two-component oil is added to a three-component diarylheptanoid complex, the resulting mixture becomes oily and solidifies but does not become a fluid powder. As is clear from SEM instrument analysis, 20-25% of turmeric oil is embedded in the diarylheptanoid complex during aggregation.

[0025] 1. SEM Analysis The SEM micrograph (Figure 1) shows that the particles are aggregated and there are voids and plate-like structures. When the diarylheptanoid complex is formed in the presence of a volatile oil, the oil is embedded during aggregation.

[0026] 2. Fluorescence Spectroscopy Figure 2 shows the fluorescence spectrum of the diarylheptanoid complex. The volatile oil embedding technique is supported by fluorescence imaging. The volatile oil is strongly colored by the fluorescent dye Nile Red. The oil droplets are embedded in the diarylheptanoid complex.

[0027] Furthermore, the diarylheptanoid complex contains at least a curcuminoid complex, and the curcuminoid complex is composed of curcumin, bisdemethoxycurcumin, and demethoxycurcumin complexes. The curcuminoid complex constitutes 3% - 99% of the diarylheptanoid complex, or the curcuminoid complex constitutes 1% - 90% of a composition that is a mixture of the diarylheptanoid complex and oil. In one embodiment, the curcumin complex constitutes at most one-third of the curcuminoid complex. In yet another embodiment, the curcumin complex constitutes 60% - 90% of the composition.

[0028] In one embodiment, microaggregates of a diarylheptanoid complex containing oil embedded in aggregates are disclosed. The diarylheptanoid complex disclosed herein is in the form of Formula I. Here, R1, R2, R3, R4 can each be any one of -OH, -OCH3, -OCOCH3, -OCO-CHR-NH2, O-piperoyl, -O-galloyl, and -O-terpenoid. L1 and L2 can each be any one of OH, -OH2, Cl-, amine, flavonoid, phenolic acid, stilbene, and tannin or a similar diarylheptanoid. D1 and D2 are each either a single bond or a double bond, and M is a cation. The cation is selected from alkali metals, alkaline earth metals, transition metals, lanthanides, and actinides. More specifically, a suitable metal cation that forms a bond with the diketone of the diarylheptanoid is shown in Formula 2. Examples of such metal cations include potassium, zinc, calcium, magnesium, selenium, copper, chromium, vanadium, iron, manganese, palladium, gallium, indium, silver, tin, and aluminum cations. Generally, for divalent cations, a stable structure is formed with a stoichiometry of 1:1, 2:1 (ligand:metal).

[0029] In yet another embodiment, the composition comprises a diarylheptanoid complex of calcium and oil. The oil constitutes 1 to 40%, more preferably 5 to 20% by weight of the composition. Preferably, the composition is in powder form with the oil embedded in the interstitial spaces of the microaggregates of the diarylheptanoid calcium complex. In the composition, the complex chelates calcium with one diarylheptanoid at a ratio of 1:1 (ligand:calcium) and with two diarylheptanoids at a ratio of 2:1 (ligand:calcium). The oil in the composition is preferably an essential oil or a vegetable oil, more preferably the essential oil of turmeric. In some embodiments, free diarylheptanoids can also be present in the composition, and the free diarylheptanoids are part of the microaggregates. The composition has at least 1% of the curcuminoid calcium complex and can increase up to 90% by weight ratio. The curcumin complex in the curcuminoid complex ranges from one-third to three-fourths of the curcuminoid complex.

[0030] In yet another embodiment, the composition comprises a mixture of different diarylheptanoid complexes and different oils. The mixture is a mixture of diarylheptanoid complexes having different cations. The cations can be selected from the group consisting of potassium, zinc, calcium, magnesium, selenium, copper, chromium, vanadium, iron, manganese, palladium, gallium, indium, silver, tin and aluminum. Preferably, the composition is in powder form comprising an oil embedded in the interstitial spaces of microaggregates of diarylheptanoid calcium complexes. The oils used in the production of each cation complex may be the same or different, and may be different for different cations. The oil in the composition may be an essential oil or a vegetable oil, more preferably an essential oil of turmeric or ginger. In some embodiments, free diarylheptanoids can also be present in the composition, and the free diarylheptanoids are part of the microaggregates. The composition contains at least 1% of curcuminoid calcium complex and can be increased up to 90% by weight. The curcumin complex in the curcuminoid complex can be increased from one-third to three-fourths of the curcuminoid complex. The oils used to make each cation complex may be the same or different, and may also be different for different cations. The oil in the composition is an essential oil or a vegetable oil, more preferably an essential oil of turmeric.

[0031] The composition of the present invention can be administered alone or in admixture with a pharmaceutically acceptable carrier or diluent depending on the mode of administration. The composition of the present invention can be administered to birds and mammals. Oral administration is preferred, but parenteral and topical administrations can also be used. In the case of oral administration, the composition of the present invention can be used in the form of tablets, capsules, granules, powders, lozenges, syrups, elixirs, solutions, suspensions, etc. according to standard pharmaceutical practices.

[0032] Birds include, but are not limited to, ostriches, chickens, ducks, pigeons, quails, flamingos, loons, pigeons, sparrows, fish owls, frogmouths, little grebes, cranes, wading birds, swifts, swallows, warblers, nightjars, kagus, avocets, toothbills, penguins, storks, horses, pelicans, herons, eagles, hawks, owls, quetzals, pheasants, Japanese nightingales, woodpeckers, seriemas, falcons, parrots, and passerine birds.

[0033] Mammals include, but are not limited to, mice, cats, dogs, bats, whales, dolphins, sheep, horses, camels, goats, cows, pigs, and humans.

[0034] Carriers useful for formulating the preparation are commonly used pharmaceutically acceptable non-toxic carriers such as gelatin, lactose, sodium citrate, salts of phosphoric acid, starch, magnesium stearate, sodium lauryl sulfate, talc, and polyethylene glycol. The carrier can also be used together with other additives such as diluents, binders, buffers, preservatives, sweeteners, flavoring agents, glidants, disintegrants, coating agents, emulsifying agents, and suspending agents.

[0035] In the case of parenteral administration, including intramuscular, intraperitoneal, subcutaneous, and intravenous administration, usually, a sterile solution of the active ingredient is prepared, and the pH of the solution is appropriately adjusted and buffered. In the case of intravenous administration, it is necessary to control the total concentration of the solute to make the preparation isotonic.

[0036] The daily dosage can be determined as appropriate and is not particularly limited. However, in the case of adults, usually, a dose of 50 - 1000 mg administered twice a day is an effective amount.

[0037] Another aspect of the disclosure is a method for preparing a composition. A composition containing diarylheptanoids and an oil is dissolved in a solvent to obtain a first solution. A cationic salt dispersed in water is slowly added to the first solution to obtain a master solution. The master solution is stirred at a constant temperature for a certain period of time. When a precipitate begins to form in the master solution, the precipitate is removed and dried to obtain the desired diarylheptanoid complex.

[0038] In one embodiment, a method for economically producing a diarylheptanoid complex embedded with an oil is disclosed. Oleoresin is obtained from the solvent extraction of a plant part rich in diarylheptanoids. The oleoresin is dissolved in a solvent, and a cationic salt dispersed in water is slowly added to the solution. The solution is stirred at a constant temperature for a certain period of time. When a precipitate begins to form in the solution, the precipitate is removed and dried to obtain the desired diarylheptanoid complex.

[0039] In one embodiment, an economical method for producing a diarylheptanoid complex from turmeric is disclosed. The rhizome of turmeric is extracted with an organic solvent, preferably ethyl acetate. After extracting the solvent portion and obtaining a residue, the solvent portion is separated from the residue and concentrated. Lime is dispersed in water and added to the concentrated solvent portion. The solution is maintained at 40 °C or higher and stirred until a precipitate is formed. The precipitate is removed and dried to obtain a calcium diarylheptanoid complex containing essential oil embedded in aggregates. This composition is rich in calcium curcuminoid complexes. Although a calcium salt can be used instead of lime for complex formation, those skilled in the art may also be able to use other salts. In one embodiment, eggshells and limestone are used as sources of calcium and other cations.

[0040] In one embodiment, an economical method for producing diarylheptanoid complexes from turmeric is disclosed. The rhizomes of turmeric are extracted with an organic solvent, preferably ethyl acetate. After extracting the solvent portion to obtain a residue, the solvent portion is separated from the residue and concentrated to obtain an oleoresin. The oleoresin is cooled to crystallize the curcuminoids. The curcuminoid crystals are removed from the oleoresin, and the remaining oleoresin is dissolved in a solvent to obtain a solution. Lime is dispersed in water and added to the solution. The solution is maintained at 40 °C or higher and stirred until a precipitate is formed. The precipitate is removed and dried to obtain a calcium diarylheptanoid complex containing the essential oil embedded in the aggregate. This composition contains a calcium curcuminoid complex, but the composition of bisdemethoxycurcumin and demethoxycurcumin is higher than that of curcumin. A calcium salt can be used instead of limestone for complex formation, but those skilled in the art can also use other salts. In one embodiment, eggshells are used as a source of calcium and other cations.

[0041] Another aspect of the present invention is that the diarylheptanoid metal complex embedded with lipid / essential oil exhibited superior medical properties compared to its corresponding diarylheptanoid. Studies were conducted in animals using the calcium diarylheptanoid complex.

[0042] A method for improving the general health of poultry by administering an effective amount of the diarylheptanoid complex of formula 1. The general health of poultry includes, but is not limited to, a decrease in mortality, an improvement in weight gain, an improvement in meat quality, a prevention of hypocalcemia, an improvement in bone density, an improvement in eggshell thickness, an improvement in immunomodulatory activity, an improvement in liver protection activity, an improvement in analgesic properties, etc. In certain embodiments, the diarylheptanoid complex showed remarkable results in the treatment of coccidiosis infections.

[0043] In one embodiment, the effectiveness of diarylheptanoid metal complexes as a prophylactic agent against blackhead disease in Histomonas or turkeys was studied. The diarylheptanoid metal complex was found to be effective in reducing inflammation of the intestine and liver caused by Histomonas. Histomonas meleagridis is a protozoan that parasitizes various galliform birds and causes a type of enteritis hepatitis (inflammation of the intestine and liver) called histomoniasis or "blackhead disease."

[0044] In another embodiment, the effectiveness of different dosages of diarylheptanoid metal complexes on the productivity, immunity, and intestinal health of broiler chickens infected with Eimeria spp. was studied. In this study, the effectiveness of diarylheptanoid metal complexes on the productivity, immunity, welfare, and intestinal health characteristics of broilers infected with Eimeria spp. under cage and deep litter rearing systems was also determined. The parameters analyzed included immunological determinants, hematological and serological analyses, lesions and histological scores, and physical observations.

[0045] A method of improving the general health of an animal by administering an effective amount of the diarylheptanoid complex of formula 1. The general health of the animal includes, but is not limited to, a decrease in mortality, an improvement in weight gain, an improvement in meat quality, prevention of hypocalcemia, an improvement in bone density, an improvement in immunomodulatory activity, prevention of mastitis in dairy cows, treatment of mastitis, an improvement in liver protection activity, an improvement in analgesic properties, etc.

[0046] In one embodiment, the efficacy and immunomodulatory ability of diarylheptanoid metal complexes against mastitis were studied. The parameters analyzed were serum calcium, serum protein, total blood cell count, calcium-phosphorus ratio, cytokines, immunoglobulins, serum albumin, vitamin D3, nutrient absorption, milk quality (fat%, SNF%, lactose, coliform count (E.coli), milk protein casein, whey protein), curcumin content in milk, rumen fluid protozoa, etc.

[0047] A method of improving overall human health by administering an effective amount of a diarylheptanoid complex of formula 1. Overall human health includes, but is not limited to, prevention of hypocalcemia, improvement of bone density, improvement of immunomodulatory activity, prevention of drug-induced lipid abnormalities, treatment of stress, treatment of Alzheimer's disease, antioxidant activity, improvement of analgesic properties, etc. In one embodiment, the diarylheptanoid complex has higher bioavailability than a normal diarylheptanoid, and further, the diarylheptanoid complex embedded with oil has higher bioavailability than the diarylheptanoid complex alone.

[0048] In one embodiment, the efficacy of a diarylheptanoid metal complex against bovine anthelmintics was studied. Amphistomum egg-positive cows were selected and treated with the diarylheptanoid metal complex. Bovine anthelmintics are important for several reasons. First, internal parasites or worms can cause significant harm to the health and productivity of cows. These parasites can damage the digestive tract of cows, leading to a decrease in feed intake, weight loss, and a decrease in growth rate. In severe cases, it can even lead to death due to internal parasites. Second, internal parasites can have an economic impact on the farm. Infected cows may have a decrease in milk production and a decrease in meat quality, resulting in potential economic losses for farmers. Third, internal parasites can also be a source of infection for other animals on the farm. Some parasites can be transmitted from cow to cow or from cows to other species such as sheep and goats. After treatment with the diarylheptanoid calcium complex for 30 days, the number of eggs in the feces becomes zero compared to untreated controls.

[0049] In cattle suffering from filariasis, the liver protection effect of diarylheptanoid metal complexes is being studied. "Liver protection" refers to substances or drugs that help protect the liver from damage and disease. SGOT (serum glutamate oxaloacetate transaminase) and SGPT (serum glutamate pyruvate transaminase) are two liver enzymes. When the values of these enzymes increase, it may be a sign of liver damage or disease. When animals were administered a diarylheptanoid calcium complex, the levels of SGOT and SGPT decreased to the normal range.

[0050] In another embodiment, the effect of the diarylheptanoid calcium complex on the immunity of cattle is being studied. The IgG value of cows after parturition refers to the level of immunoglobulin G (IgG) antibodies in the blood of cows during the period immediately after parturition. IgG is a type of antibody that plays an important role in the immune system of cows, as well as in other mammals including humans. Animals administered the diarylheptanoid calcium complex showed an increase in IgG value.

[0051] In another embodiment, the effect of the diarylheptanoid calcium complex on the mortality rate of broiler chickens is studied. The mortality rate of broiler chickens can occur for various reasons such as disease, malnutrition, environmental stress, and inappropriate management methods. Environmental stress factors such as high temperature, low humidity, poor ventilation, overcrowding, and exposure to harmful gases such as ammonia can also cause the mortality rate of broiler chickens. The mortality rate of chickens given the diarylheptanoid calcium complex decreased to 3% compared to the 5% mortality rate of the standard drug.

[0052] In another embodiment, the efficacy of the diarylheptanoid calcium complex on the weight gain of piglets is studied. The average weight of newborn piglets is about 1.1 - 1.5 kilograms. After administering the diarylheptanoid calcium complex to piglets, the average weight increased to 2.5 kilograms on the 15th day and to 11.1 kilograms on the 45th day.

[0053] In another embodiment, the effect of diarylheptanoid calcium complexes in preventing post-partum hypocalcemia in cows is studied. Hypocalcemia, also known as milk fever, is a metabolic disorder commonly seen in dairy cows. It occurs when the calcium concentration in the blood drops below normal levels, usually around the time of calving. At this time, the cow's demand for calcium rapidly increases as it produces colostrum and milk for the newborn calf. If the cow is unable to meet this demand through dietary intake or mobilization of calcium from bones, hypocalcemia may occur. Supplementation with diarylheptanoid calcium complexes increased serum calcium concentrations compared to the untreated control group.

[0054] In another embodiment, the effect of diarylheptanoid calcium complexes in improving eggshell quality in laying hens with calcium deficiency is studied. Supplementation with diarylheptanoid calcium complexes increased the proportion of normal eggs compared to the untreated control group. In the group administered with diarylheptanoid calcium complexes, the proportions of cracked eggs, eggs without shells, and wavy eggs decreased compared to the untreated control group.

[0055] In another embodiment, the effect of diarylheptanoid calcium complexes as a preventive measure for reducing the incidence of mastitis is studied in dairy cows. Supplementation with diarylheptanoid calcium complexes maintained the white blood cell ×10 3 / μL level in the range of 4 - 12×10 3 / μL, and it was confirmed that the udder was not infected. The proportion of neutrophils was also in the range of 15 - 33%, indicating no damage to the udder tissue.

[0056] Examples Specific embodiments of the present invention are described with reference to the following general manufacturing methods and examples. It should be understood that these examples are disclosed only for the purpose of illustrating the present invention and do not limit the scope of the present invention. These examples do not limit the foregoing description.

Examples

[0057] Method for producing diarylheptanoid calcium complex embedded with oil Dissolve 10 kg of curcuminoid and 30 kg of turmeric essential oil in 60 L of solvent to obtain a first solution. Disperse 1 kg of lime in 2 L of water to obtain a lime solution. Slowly add the lime solution to the first solution to obtain a master solution. Stir the master solution at room temperature for 2 - 3 hours. A precipitate is formed, the precipitate is filtered, washed with water, and then washed with methanol. The precipitate is dried at 80 °C to form a diarylheptanoid calcium complex. The dried precipitate had the desired composition and contained at least about 80% diarylheptanoid calcium complex and at least about 20% oil. The resulting composition was a free-flowing reddish-brown powder that did not stain the surface.

Example

[0058] Method for producing diarylheptanoid zinc complex containing embedded oil Dissolve 10 kg of curcuminoid and 30 kg of zedoary essential oil in 60 L of solvent to obtain a first solution. Disperse 10 kg of zinc salt in 25 L of water to obtain a solution. Slowly add the zinc salt solution to the first solution, and then dissolve 15 kg of sodium bicarbonate in 100 L of water to obtain a master solution. Stir the master solution at room temperature for 1 - 2 hours. A precipitate is formed, the precipitate is filtered, washed with water, and then washed with methanol. The precipitate is dried at 80 °C to form a diarylheptanoid zinc complex. The dried precipitate had the desired composition and contained at least about 80 °C diarylheptanoid zinc complex and at least about 20% oil. The resulting composition was a free-flowing orange-yellow powder that did not stain the surface.

Example

[0059] Method for producing diarylheptanoid calcium complex using embedded oil from zedoary rhizome 100 kg of turmeric rhizomes were placed in a reactor and repeatedly extracted with 300 L of ethyl acetate to obtain a residue and a supernatant. The supernatant was filtered, and the solvent was removed from the supernatant to obtain an oleoresin. The oleoresin was dissolved in methanol. 1 kg of lime was dispersed in 2 L of water and slowly added to the supernatant. The resulting slurry was stirred at room temperature for 2 - 3 hours. A precipitate was formed, and the precipitate was filtered, washed with water, and then washed with methanol. The precipitate was dried at 80 °C to form a diarylheptanoid calcium complex. The dried precipitate had the desired composition and contained at least about 30% of the diarylheptanoid calcium complex and at least about 20% of oil. The resulting composition was free-flowing and did not stain the surface.

Example

[0060] Method for producing diarylheptanoid calcium complex using embedded oil from turmeric rhizomes 100 kg of turmeric rhizomes were placed in a reactor and repeatedly extracted with 300 L of ethyl acetate to obtain a residue and a supernatant. The supernatant was filtered, and the solvent was removed from the supernatant to obtain an oleoresin. The oleoresin was cooled to 4 °C to crystallize curcuminoids. The curcuminoids were removed from the oleoresin, and the remaining oleoresin was dissolved in methanol. 1 kg of lime was dispersed in 2 L of water and slowly added to the methanol solution. The resulting slurry was stirred at room temperature for 2 - 3 hours. A precipitate was formed, and the precipitate was filtered, washed with water, and then washed with methanol. The precipitate was dried at 80 °C to form a diarylheptanoid calcium complex. The dried precipitate had the desired composition and contained at least about 10% of the diarylheptanoid calcium complex and at least about 20% of oil. The resulting composition was free-flowing and did not stain the surface.

Example

[0061] Effect of diarylheptanoid calcium complex on deworming cattle Twenty cattle positive for amphistome eggs were selected. The cattle were divided into four groups of five each and classified as follows.

Table 1

Table 2

[0062] After 30 days of treatment with the diarylheptanoid calcium complex, the number of eggs in the feces was zero compared to the untreated control group. In Group 3, animals treated with the normal turmeric extract showed some effect on the reduction of eggs, but the group administered the diarylheptanoid calcium complex had a complete reduction in the number of eggs compared to the standard drug albendazole.

Example

[0063] Hepatoprotective effect of diarylheptanoid calcium complex The hepatoprotective effect of the diarylheptanoid calcium complex was studied in cattle suffering from filariasis. Twenty cattle were selected and divided into four groups. Group 1 was the untreated control group. Group 2 was given the standard drug Liv 52 at a dose of 1.5 g per day for 15 days. The animals in Group 3 were given the normal turmeric extract at a dose of 1 g per day for 15 days. The animals in Group 4 were given the diarylheptanoid calcium complex at a dose of 1 g per day for 15 days. After 15 days of treatment, SGOT and SGPT were analyzed. Table 2: Effect of diarylheptanoid calcium complex on the state of the cattle liver

Table 3

[0064] The SGPT level in the animals in Group 4 decreased to the normal level compared to the standard drug Liv 52.

Example

[0065] Effect of the diarylheptanoid calcium complex on immunity Six-year-old pregnant cows were selected and divided into four groups of five cows each. Four months before parturition, the cows in each group were given the diarylheptanoid calcium complex and the normal turmeric extract (1 g supplement) and the standard drug Immunol X (50 ml per day per cow). The IgG value was examined three days after parturition. The cows were classified as follows. Group 1: Untreated control group Group 2: Positive control (Immunol X, 50 ml / day per cow) Group 3: Normal turmeric extract (1 g / day) Group 4: Diarylheptanoid calcium complex (dosage: 1 g supplement per day) Table 3: Effect of the diarylheptanoid calcium complex on the immunity of cows

Table 4

[0066] The animals in Group 4 given the diarylheptanoid calcium complex had an increase in IgG value by 76 g / L. On the other hand, the IgG level in the untreated control group was 38 g / L.

Example

[0067] Effect of diarylheptanoid calcium complex on the mortality of birds 4000 broiler chickens in a stressed state were selected for the study. The chickens were divided into 4 groups of 1000 each. Group 1 was the untreated control group. The chickens in Group 2 were given the standard drug Groviplex (0.05 ml / bird / day) for 42 days. The chickens in Group 3 were given the normal turmeric extract at a dose of 5 mg / bird / day daily with feed for 42 days. The chickens in Group 4 were given the diarylheptanoid calcium complex at a dose of 5 mg / bird / day daily with feed for 42 days. Table 4: Effect of diarylheptanoid calcium complex on the mortality of poultry

Table 5

Example

[0068] Study on the weight gain of piglets using diarylheptanoid calcium complex 80 piglets were selected for the study and divided into 4 groups of 20 each. Group 1 was the normal control group. Group 2 was given the standard drug Fat plus at 1 g / piglet / day along with creep feed. Groups 3 and 4 were given the normal turmeric extract and diarylheptanoid calcium complex at 500 mg / piglet / day along with creep feed. Weight gain was observed on the 15th and 45th days after feeding. Table 5: Effect of diarylheptanoid calcium complex on the body weight gain of piglets [Table 6] The average body weight of newborn piglets is about 1.1 - 1.5 kg. After administering the diarylheptanoid calcium complex to the piglets, the average body weight increased to 2.5 kg on the 15th day and 11.1 kg on the 45th day. On the other hand, the average body weight gain of the normal control group was 1.8 kg on the 15th day and 8.5 kg on the 45th day. The standard drug also brought about almost the same body weight gain as the diarylheptanoid calcium complex.

Example

[0069] Effect of diarylheptanoid calcium complex on preventing postpartum hypocalcemia This study was conducted on a dairy farm raising 20 dairy cows in their third and fourth lactations, which were divided into four groups of 5 cows each. The normal calcium concentration in dairy cows is 8.5 - 10.5 mg / dl. The first group was the untreated control group, and the second group was the dairy cows administered 100 ml of the standard drug Mifex twice a day. The third group was administered 1 g of the usual turmeric extract supplement, and the fourth group was administered 1 g of the diarylheptanoid calcium complex supplement for 30 days. Table 6: Effect of diarylheptanoid calcium complex on serum calcium concentration

Table 7

Example

[0070] Evaluation of the effect of diarylheptanoid calcium complex on improving eggshell quality in laying hens 4,000 laying hens aged 50 to 60 weeks with calcium deficiency were selected for the study. The hens were divided into four groups of 1,000 each. Group 1 was the untreated control group. The hens in Group 2 were given Hymecromone (0.05 ml / hen / day), a standard drug, for 45 days. The hens in Group 3 were given ordinary turmeric extract at a dose of 100 ppm / hen / day together with feed every day for 45 days. The hens in Group IV were given a diarylheptanoid calcium complex at a dose of 100 ppm / hen / day together with feed every day for 45 days. The shell quality was analyzed by the candling method. Table 7: Effect of diarylheptanoid calcium complex on eggshell quality

Table 8

Example

[0071] Effect of diarylheptanoid calcium complex used as a preventive measure to reduce the occurrence of mastitis in dairy cows This study was conducted on a dairy farm raising 20 dairy cows and lactating cows. These cows were divided into four groups of 5 each. The normal white blood cells (WBC) of cows are 4×10 3 / μL to 12×10 3 / μL, and the proportion of normal neutrophils is about 15 - 33%. The first group was the untreated control group, and the second group was cows treated with 1 g per day per head of the standard supplement MINTREX® chelated trace minerals. The third group was given 1 g of the usual turmeric extract supplement, and the fourth group was given 1 g of the diarylheptanoid calcium complex supplement for 30 days. Table 8: Effect of diarylheptanoid calcium complex on white blood cell ×10 3 / μL level

Table 9

Table 10

[0072] In the present invention, the novel features of the present invention are clarified by explaining some of its preferred embodiments, so that those skilled in the art can understand and imagine the present invention. It is also understood that the above invention is not limited to the details described in the above description or shown in the drawings in its application. The expressions and terms used herein are for the purpose of explanation only and should not be regarded as limiting. The present invention, although in its preferred embodiments, can be modified and amended within the scope of the present invention as described above and defined in the appended claims.

Claims

1. 1. A pharmaceutical formulation comprising a free-flowing stain-free composition containing a mixture of a diarylheptanoid complex and an essential oil of turmeric embedded in a diarylheptanoid metal complex, wherein the diarylheptanoid complex has the following chemical formula: 【Chemistry 1】 Formula I In the formula, R １ , R ２ , R ３ , and R ４ is hydrogen, -OH, -OCH ３ , -OCOCH ３ , -OCO-CHR-NH ２ -O-piperoyl, -O-galloyl, and -O-terpenoid; L １ and L ２ is -OH, -OH ２ , Cl － , amines, diarylheptanoids, flavonoids, phenolic acids, stilbenes, saponins, and tannins; D1 and D2 are selected from the group consisting of a single bond and a double bond; M is selected from the group consisting of alkali metals, alkaline earth metals, transition metals, lanthanides, and actinides; A pharmaceutical formulation comprising a free-flowing stain-free composition.

2. 10. The pharmaceutical formulation comprising the free-flowing stain-free composition of claim 1, wherein the composition contains at least 5% turmeric oil by weight.

3. 10. The pharmaceutical formulation comprising the free-flowing stain-free composition of claim 1, wherein the composition contains 5-40% by weight of turmeric essential oil embedded in the diarylheptanoid complex.

4. 10. The pharmaceutical formulation comprising the free-flowing stain-free composition of claim 1, wherein the composition contains 20-25% by weight of turmeric essential oil embedded in the diarylheptanoid complex.

5. 10. A pharmaceutical formulation comprising the free-flowing stain-free composition of claim 1, wherein the curcuminoid complex comprises 1-90%, or 60-90% of the composition.

6. 10. A pharmaceutical formulation comprising the free-flowing stain-free composition of claim 1 administered alone or with a pharmaceutically acceptable carrier or diluent.

7. 1. A pharmaceutical formulation comprising a free-flowing, color-free composition, For controlling parasites in birds and mammals, To improve liver disease in birds and mammals, To improve immunity in birds and mammals, To reduce bird and mammal mortality, To improve weight gain in birds and mammals, To prevent hypocalcemia in birds, To improve eggshell quality in birds, or 10. A pharmaceutical formulation comprising the free-flowing stain-free composition of claim 6 for use in preventing mastitis in mammals.

8. 10. A pharmaceutical formulation comprising the free-flowing stain-free composition of claim 7, which can be administered orally, parenterally, and topically to birds and mammals, comprising: the birds are ostriches, chickens, turkeys, quails, ducks, flamingos, grebes, and pigeons; The pharmaceutical formulation comprising a free-flowing stain-free composition, wherein the mammal is a rat, a cat, a dog, a bat, a sheep, a horse, a camel, a goat, a cow, a pig, and a human.

9. 10. A pharmaceutical formulation comprising the free-flowing stain-free composition of claim 7, which can be administered orally in the form of tablets, capsules, granules, powders, lozenges, syrups, elixirs, solutions, and suspensions in accordance with standard pharmaceutical practice.

10. Carriers useful in formulating the above preparations include common pharmaceutically acceptable non-toxic carriers such as gelatin, lactose, sodium citrate, phosphate, starch, magnesium stearate, sodium lauryl sulfate, talc, and polyethylene glycol, or 10. The pharmaceutical formulation comprising the free-flowing stain-free composition of claim 7, wherein the carrier may be used with other additives such as diluents, binders, buffers, preservatives, sweeteners, flavoring agents, glazing agents, disintegrants, coating agents, emulsifiers, and suspending agents.

11. 10. The pharmaceutical formulation comprising the free-flowing stain-free composition of claim 8, wherein parenteral administration includes intramuscular, intraperitoneal, subcutaneous, and intravenous use.

12. 8. A pharmaceutical formulation comprising the free-flowing stain-free composition of claim 7, wherein the effective dosage for an adult is 50 to 1,000 mg twice daily.

13. 1. A method for formulating a free-flowing stain-free composition containing a mixture of a diarylheptanoid complex and turmeric essential oil embedded in a diarylheptanoid metal complex, wherein the diarylheptanoid complex has the chemical formula shown in Formula I as set forth in claim 1, comprising the following steps: a) extracting the washed turmeric rhizomes with an organic solvent, preferably with ethyl acetate, to obtain a solvent fraction and a residual fraction; b) separating and concentrating the solvent portion from the residue portion to obtain oleoresin; c) cooling the oleoresin to a temperature of 4°C to crystallize the curcuminoids and separating the curcuminoid crystals from the oleoresin; d) dissolving the remaining oleoresin in methanol to obtain a solution; e) adding a calcium source dispersed in water to the solution resulting from step d); f) maintaining the resulting solution at a temperature of 27°C and stirring until a precipitate forms; g) separating the precipitate, washing with water and methanol and drying to obtain calcium diarylheptanoid complexes with essential oils embedded in the aggregates; 1. A method for formulating a free-flowing stain-free composition comprising:

14. 14. A method for formulating a free-flowing stain-free composition according to claim 13, wherein the calcium source is selected from lime, calcium salts, and calcium oxide made from eggshells.

15. 14. A method for formulating a free-flowing stain-free composition as claimed in claim 13, wherein the organic solvent used for extraction of the turmeric rhizome is ethyl acetate or the solvent used to dissolve the remaining oleoresin in step d) is methanol.

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