Obesity-preventing or pharmaceutical composition comprising garcinia cambogia extract, and injection including same

Abstract

The present invention relates to an obesity-preventing or pharmaceutical composition comprising an herbal medicine mixture and an injection. Specifically, the obesity-preventing or pharmaceutical composition comprises: an exothermic agent; a complex formulation; a branched chain amino acid (BCAA) containing one or more selected from the group consisting of leucine, isoleucine, and valine; calcium pantothenate; nicotinamide; crystalline cellulose; magnesium stearate; hydroxypropyl methylcellulose; and calcium carboxymethylcellulose, wherein the complex formulation includes a garcinia cambogia extract, an ephedra extract, and an active amino acid, and the exothermic agent comprises a zeolite anhydride, calcium chloride, and kaolin and, when friction occurs, releases heat to raise the temperature of the obesity-preventing or pharmaceutical composition to 25-35°C, inclusive.

Description

Obesity prevention or pharmaceutical composition comprising Garcinia cambogia extract and injectable composition comprising the same

[0001] The present invention relates to an obesity prevention or pharmaceutical composition comprising Garcinia cambogia extract and an injectable preparation comprising the same.

[0002] Recently, as mortality rates due to lifestyle diseases have increased, attention has been focused on obesity. Consequently, various health supplements with anti-obesity efficacy are being successively launched in the pharmaceutical industry, not only domestically but also globally. Furthermore, as economic growth has led to improved dietary habits while a severe lack of exercise persists, the number of obese individuals is surging, and the resulting rise in lifestyle diseases is emerging as a social issue. Additionally, as the dietary habits of the Korean population become Westernized, chronic lifestyle diseases such as lifestyle-related illnesses are expected to increase in the future. Moreover, with the country entering an aging society, the demand for products targeting the elderly, such as "silver foods," is also projected to rise.

[0003] Obesity occurs when the supply of energy significantly exceeds the demand, leading to the accumulation of excessive energy due to metabolic imbalance. Clinically, it contributes to the development of or exacerbates various diseases; obesity-related diseases include hypertension, arteriosclerosis, diabetes, fatty liver, and gallstones. In particular, endometrial cancer, gallbladder cancer, cervical cancer, ovarian cancer, and breast cancer are common in women, and in the case of endometrial cancer, the increase in incidence and mortality rates due to obesity is reported to be the most significant compared to other types of cancer. Furthermore, the mortality rate in obese individuals is reported to be more than 1.3 times higher than that of individuals with normal weight.

[0004] Strategies for treating obesity and related disorders include dietary restriction, increased physical activity, pharmacological approaches, and even surgery, which are selected based at least in part on the severity of obesity exhibited by the subject as well as the degree of weight loss the individual attempts to achieve. For example, for individuals who are only mildly overweight, treatments such as low-calorie, low-fat diets and / or regular exercise are often appropriate. However, due to the difficulty of maintaining long-term weight loss through dietary and behavioral modifications, interest in other treatment methods, particularly pharmacotherapy, has increased.

[0005] Traditional pharmacological interventions typically induce a weight loss of 5 to 15 kilograms; when drug treatment is discontinued, weight gain often resumes. Surgical treatment is considerably successful and is scheduled for patients with extreme obesity and / or serious medical complications.

[0006] The above treatment can be enhanced by the controlled use of over-the-counter appetite suppressants, such as caffeine, ephedrine, and phenylpropanolamine (Acutrim, Dexatrim). Furthermore, prescription drugs including amphetamine, diethylpropion (Tenuate, mazindol (Mazanor, Sanorex)), phentermine (Fastin, Ionamin)), phenmetrazine (Preludin)), phendimetrazine (Bontrol, Plegine, Adipost, Dital, Dyrexan, Melfiat, Prelu-2, Rexigen Forte)), benzphetamine (Didrex) and fluoxetine (Prozac) are often used in the treatment of subjects or patients with severe overweight and / or obesity.

[0007] Society has made vast progress in the pharmaceutical field, but of course, there are drawbacks to the administration of any available drug. Often, disadvantages or "side effects" are severe enough to exclude the administration of a specific agent at a therapeutically effective dose. Furthermore, many agents within the same class of therapeutic agents exhibit similar side effect profiles, which means that patients must undergo a treatment regimen or suffer from varying degrees of side effects associated with the selected drug treatment.

[0008] Topiramate (2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranos sulfamate) is a broad-spectrum neurotherapeutic agent approved by the FDA and regulatory agencies in many other countries for the treatment of certain seizure disorders and the prevention of migraines (references [E. Faught et al. (1996) Neurology 46:1684-90]; [Karim et al. (1995) Epilepsia 36 (S4):33]; [SK Sachdeo et al. (1995) Epilepsia 36(S4):33]; [TA Glauser (1999) Epilepsia 40 (S5):S71-80]; [RC Sachdeo (1998) Clin. Pharmacokinet. 34:335-346]). Furthermore, there is evidence that topiramate is effective in the treatment of diabetes (U.S. Patents No. 7,109,174 and 6,362,220), neurological disorders (U.S. Patent No. 6,908,902), depression (U.S. Patent No. 6,627,653), psychosis (U.S. Patent No. 6,620,819), headache (U.S. Patent No. 6,319,903), and hypertension (U.S. Patent No. 6,201,010). However, adverse effects associated with the use of topiramate in humans, such as cognitive decline and difficulty finding words, exist, which may deter many obese patients from taking this drug.

[0009] Phentermine was approved by the FDA in 1959 as an appetite suppressant, and phentermine hydrochloride has been used as a weight loss agent since the 1970s under brand names such as Adipex-P®, Fastin®, and Zantril®. Although the FDA warned against combining phentermine with a second activator following reports of heart and lung problems associated with "Fen-Phen" products (where phentermine was combined with fenfluramine, and later with the related drug, dexfenfluramine), it was found that a safe and effective weight loss treatment is provided by combining phentermine with an activator that mitigates the side effects of phentermine and enables the administration of much lower doses of phentermine than "Fen-Phen" (containing 30 mg or 37.5 mg of phentermine hydrochloride).

[0010] In this regard, Qsymia, a product containing a lower-dose combination of topiramate and phentermine, was recently [released] TM It is currently being sold domestically and internationally under the trademark.

[0011] However, topiramate and phentermine, which are included in Qsymia products, are also synthetic substances and are known to cause side effects such as paresthesia, alopecia, parosmia, amenorrhea, and aphasia ([Korean J Obes 2015 March;24(1):17-27, Innov Clin Neurosci. 2011 Aug; 8(8): 14-16.]).

[0012] Accordingly, the inventors have discovered a composition capable of eliminating or reducing the side effects of conventionally known obesity prevention and treatment compositions and replacing them, and thus intend to provide a pharmaceutical composition for the treatment and prevention of obesity comprising a natural substance as an active ingredient capable of minimizing side effects.

[0013] At this time, in order to achieve a more definite effect, the aforementioned pharmaceutical composition for the prevention or treatment of obesity is administered via intramuscular injection, which has good stability and absorption; however, while intramuscular injection offers greater stability compared to intravenous injection, it suffers from the problem of poor absorption.

[0014] Therefore, research is needed on injectables that can ensure efficacy and minimize side effects when administering pharmaceutical compositions for the prevention or treatment of obesity.

[0015] One objective of the present invention is to provide a pharmaceutical composition for the prevention or treatment of obesity comprising: a pyrogenic agent; a complex preparation; a branched-chain amino acid (BCAA) comprising one or more selected from the group consisting of leucine, isoleucine, and valine; calcium pantothenate; nicotinamide; crystalline cellulose; magnesium stearate; hydroxypropylmethylcellulose; and calcium carboxymethylcellulose; wherein the complex preparation comprises Garcinia cambogia extract; Ephedra extract; and an effective amino acid; and the pyrogenic agent comprises anhydrous zeolite; calcium chloride; and kaolin, wherein the pyrogenic agent generates heat upon physical friction to form the temperature of the pharmaceutical composition for the prevention or treatment of obesity at 25°C or higher and 35°C or lower.

[0016] Another objective of the present invention is to provide an injectable preparation for the prevention or treatment of obesity comprising the above-described composition.

[0017] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art from the description below.

[0018] According to one embodiment of the present invention, a pharmaceutical composition for preventing or treating obesity is provided, comprising: a pyrogenic agent; a complex preparation; a branched-chain amino acid (BCAA) comprising one or more selected from the group consisting of leucine, isoleucine, and valine; calcium pantothenate; nicotinamide; crystalline cellulose; magnesium stearate; hydroxypropylmethylcellulose; and calcium carboxymethylcellulose; wherein the complex preparation comprises Garcinia cambogia extract; Ephedra extract; and an effective amino acid; and the pyrogenic agent comprises anhydrous zeolite; calcium chloride; and kaolin, wherein the pyrogenic agent generates heat upon physical friction to form the temperature of the pharmaceutical composition for preventing or treating obesity at 25°C or higher and 35°C or lower.

[0019] The present invention provides a pharmaceutical composition for preventing or treating obesity, wherein the effective amino acid comprises L-arginine and L-carnitine, and the L-arginine and L-carnitine are included in a weight ratio of 1:0.01 to 1:0.25.

[0020] The present invention provides a pharmaceutical composition for the prevention or treatment of obesity, further comprising one or more selected from the group consisting of catechin, catinone, tryptamine, P-octopamine, P-tyramine, and synephrine.

[0021] The present invention provides a pharmaceutical composition for preventing or treating obesity, wherein the effective amino acid is included in an amount of 15 parts by weight or less based on 100 parts by weight of the complex formulation.

[0022] According to another embodiment of the present invention, a pharmaceutical composition for preventing or treating obesity is provided, wherein the fever agent comprises 5 parts by weight or more and 20 parts by weight or less per 100 parts by weight of the pharmaceutical composition for preventing or treating obesity.

[0023] According to another embodiment of the present invention, the exothermic agent comprises an anhydrous zeolite: calcium chloride: kaolin in a weight ratio of 1:0.5:0.1, thereby providing a pharmaceutical composition for preventing or treating obesity.

[0024] Finally, the present invention provides an injectable drug comprising a pharmaceutical composition for the prevention or treatment of obesity according to the present invention.

[0025] The pharmaceutical composition for preventing or treating obesity provided in the present invention comprises Garcinia cambogia extract, Ephedra extract, L-arginine, and L-carnitine, and exhibits effects of preventing and treating obesity.

[0026] In particular, the pharmaceutical composition of the present invention includes natural substances such as Garcinia cambogia extract, L-arginine, and L-carnitine as active ingredients that can reduce side effects caused by conventional synthetic drugs and replace them, thereby having excellent efficacy in preventing and treating obesity while minimizing side effects.

[0027] In addition, the pharmaceutical composition of the present invention has anti-obesity and anti-inflammatory effects, as well as antioxidant and detoxification effects, i.e., detoxification.

[0028] Furthermore, the pharmaceutical composition of the present application is characterized by containing a specific amount of a specific pyrogenic agent. The pharmaceutical composition of the present invention is administered as an injectable rather than orally, and is specifically used for intramuscular injection rather than intravenous injection. In the case of intravenous injection, the active ingredient is administered directly through the blood vessel, and is characterized by a higher absorption rate and immediate effect compared to oral or other intramuscular injections; however, since the injection solution is administered into the vein, severe side effects such as embolism may occur if air bubbles are included, making it unsuitable for portable or convenient use.

[0029] Accordingly, the injectable formulation according to the present application is intended for arterial injection, but unlike intravenous injection, it is an intramuscular injection, which results in a lower absorption rate of the active ingredient. That is, in the case of an intramuscular injection, absorption is slower than with intravenous injection, but there is less pain and a larger amount can be administered. In order to accelerate absorption with an intramuscular injection, the injection site is physically rubbed after administration. At this time, to enhance absorption characteristics, the formulation is characterized by including a fever agent capable of matching the body temperature.

[0030] However, it should be understood that the effects are not limited to those mentioned above and include all effects that can be inferred from the composition of the invention described in the detailed description or claims.

[0031] In order to facilitate understanding of the present invention, examples will be described in detail below. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the art. The present invention is not limited to the examples presented herein and may be embodied in other forms.

[0032] In order to facilitate understanding of the present invention, examples will be described in detail below. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the art. The present invention is not limited to the examples presented herein and may be embodied in other forms.

[0033] According to one embodiment of the present invention, a pharmaceutical composition for preventing or treating obesity is provided, comprising: a pyrogenic agent; a complex preparation; a branched-chain amino acid (BCAA) comprising one or more selected from the group consisting of leucine, isoleucine, and valine; calcium pantothenate; nicotinamide; crystalline cellulose; magnesium stearate; hydroxypropylmethylcellulose; and calcium carboxymethylcellulose; wherein the complex preparation comprises Garcinia cambogia extract; Ephedra extract; and an effective amino acid; the temperature of the pharmaceutical composition for preventing or treating obesity is 5°C to 10°C, and the pyrogenic agent generates heat when reacting with secretin, thereby forming the temperature of the pharmaceutical composition for preventing or treating obesity to 20°C or higher and 25°C or lower.

[0034] In the present invention, the terms “extracted substance” or “extract” include the extract itself and all formulations of extracts that can be formed using the extract, such as an extract obtained by an extraction process, a diluted or concentrated extract of said extract, a dried product obtained by drying said extract, a modified or purified product of said extract, or a mixture thereof.

[0035] In the present invention, the drying of the extract can be carried out by known methods to the extent that useful components from the collected natural material are not destroyed, for example, by natural drying in the shade. Additionally, crushing or grinding can be performed to powder the material to the extent that useful components of the plant can be sufficiently extracted during the subsequent extraction process. The drying and crushing or grinding processes may be performed in the reverse order or repeatedly as necessary.

[0036] In the extraction of the present invention, the extraction method is not particularly limited and can be performed according to methods commonly used in the relevant technical field. Non-limiting examples of the extraction method include hot water extraction, ultrasonic extraction, filtration, and reflux extraction, and these may be performed individually or in combination of two or more methods.

[0037] In the present invention, the type of extraction solvent used to extract natural substances is not particularly limited, and any solvent known in the relevant technical field may be used. In the present invention, the extract may be obtained by extraction with water, C1 to C4 lower alcohols, or a mixture of these solvents. In addition, non-limiting examples of the extraction solvent may include water; C1 to C4 lower alcohols such as methanol, ethanol, propyl alcohol, butyl alcohol; polyhydric alcohols such as glycerin, butylene glycol, propylene glycol; and hydrocarbon solvents such as methyl acetate, ethyl acetate, acetone, benzene, hexane, diethyl ether, and dichloromethane; or mixtures thereof. Specifically, water, lower alcohols, 1,3-butylene glycol, and ethyl acetate may be used alone or in a mixture of two or more.

[0038] As used in the present invention, the term "compound" refers to a result obtained by performing fractionation to separate a specific component or a specific group of components from a mixture containing various constituent components.

[0039] In the present invention, the separation method for obtaining the compound is not particularly limited and may be carried out according to methods commonly used in the art. A non-limiting example of the separation method is a method of obtaining the compound from a natural substance extract by treating the extract with a predetermined solvent.

[0040] The above Garcinia cambogia is known to be effective in suppressing obesity, and as a tropical fruit tree of the Guttiferae family, it is known that the product obtained by extracting the peel of the Garcinia cambogia fruit is used for the prevention or treatment of obesity.

[0041] The above Garcinia cambogia extract contains hydroxycitric acid (HCA), an inhibitor of enzymes involved in the synthesis of fatty acids and cholesterol, thereby providing the function of inhibiting fat synthesis, suppressing appetite, and promoting the breakdown of fat. The above HCA is a compound that is very similar to citric acid but has a hydroxyl group attached; it inhibits the process in which citrate is converted into acetyl-coenzyme A (acetyl-Co-A) in vivo, thereby suppressing the synthesis of fatty acids, promoting oxidation, and converting it into glycogen synthesis to increase energy production. Furthermore, the above HCA is known to have various physiological functions, such as suppressing appetite and promoting fat breakdown.

[0042] In other words, Garcinia cambogia extract blocks the pathway through which excess carbohydrates are synthesized in the spleen, acting as a factor that hinders fat synthesis; this prolongs energy production within the body and increases total energy production. In particular, since Garcinia cambogia extract reduces acetyl-Co-A in the human body, it consequently increases the rate of liver and glycogen synthesis.

[0043] Accordingly, when an excess amount of glycogen accumulates, the hypothalamus in the brain recognizes that sufficient energy required by the body has been accumulated, so the consumer reduces further energy intake. That is, when consuming the pharmaceutical composition for preventing or treating obesity, the health functional food composition, or the health functional food additive composition according to the present invention, appetite is naturally suppressed and weight loss occurs.

[0044] The above Garcinia cambogia extract can be obtained in powder form by freeze-drying the peel of the Garcinia cambogia fruit, grinding it to 100 mesh or less, extracting it with 70% ethanol at a temperature of 80°C or higher, and then concentrating and freeze-drying it.

[0045] The above L-arginine is one of the amino acids that make up proteins and belongs to the protamine protein found in fish sperm. As a semi-essential amino acid required for the growth of children and animals, it has been reported that the intake of L-arginine promotes the secretion of glucagon, which directly accelerates the breakdown of adipose tissue in the human body (Kalkhoff RK, et al., N Engl J Med 289: 465-467).

[0046] The above L-carnitine has the chemical name α-hydroxy-γ-N-trimethylaminobutyrate and is an amino acid analog similar to choline in structure. However, strictly speaking, L-carnitine is not a true vitamin because a portion of its requirements can be met through biosynthesis, and it can be described as a vitamin-like nutrient such as choline, taurine, and inositol.

[0047] The most important biological mechanism of L-carnitine is its role as a transport molecule and an essential cofactor for fatty acid metabolism, facilitating the smooth transport of fatty acids into mitochondria to convert fat into cellular energy. This role improves intracellular fatty acid and glucose metabolism.

[0048] In particular, long-chain fatty acids are activated at the outer membrane of mitochondria and oxidized in the mitochondrial matrix. These long-chain fatty acids cannot pass through the inner membrane of mitochondria without a special transport mechanism, and L-carnitine acts as this transport mechanism. In this way, the long-chain fatty acids activated at the outer membrane of mitochondria temporarily bind to the hydroxyl group of L-carnitine to form the long-chain fatty acid acyl-carnitine, which is then transported into the mitochondria and metabolized.

[0049] In addition, L-carnitine has been proven to reduce lipid accumulation in the blood and tissues in various biological conditions for weight loss, and since it supplies the energy essential for muscles to work, it provides effects such as improved cardiac function, increased oxygen intake, maintenance of physical strength, and fat reduction.

[0050] The above L-carnitine may be L-carnitine tartrate, which has improved preservation by combining a tartrate.

[0051] In the present application, the Ephedra extract can be obtained using a solvent extraction method. Specifically, the extract can be prepared by adding an extraction solvent to Ephedra, stirring, and then filtering.

[0052] In an exemplary embodiment of the present invention, an ephedra extract can be obtained by adding 1 to 100 mL, preferably 5 to 50 mL, of extraction solvent per 1 g of dried ephedra and stirring. At this time, the extraction temperature may be room temperature to 100°C, preferably 40 to 60°C, and the extraction time may be 30 minutes to 10 hours, preferably 1 to 5 hours.

[0053] In one embodiment of the present invention, supercritical extraction may be used as the extraction method. Supercritical extraction is an extraction method using a supercritical fluid, which is a fluid in a state exceeding a critical temperature and boundary pressure; carbon dioxide may be used as the supercritical fluid, and an organic solvent may be used as an auxiliary solvent. When using supercritical extraction, only the extractable component can be easily obtained because the fluid vaporizes at atmospheric pressure, and since carbon dioxide, which is inert, tasteless, odorless, and harmless, is used, it can be safely used in the manufacture of food or pharmaceuticals.

[0054] In one embodiment of the present invention, it is also possible to use a pressing method in which pressure is applied to the raw material for extraction as an extraction method. For example, Ephedra is extracted at 100 to 2,000 kg / cm² 2 An extract can be prepared by pressing under pressure for 1 minute to 1 hour.

[0055] In the present invention, it is also possible to improve extraction efficiency by performing ultrasonic treatment, heat treatment, acid treatment, etc., when preparing the extract.

[0056] According to the present invention, when an ephedra extract is applied to food, it can improve intestinal immunity and enhance intestinal function by improving the intestinal microbial flora, thereby improving constipation and diarrhea, and can exhibit effects such as inhibiting body fat, and can be effectively used in functional foods that improve intestinal health.

[0057] In the present application, the complex formulation comprises Garcinia cambogia extract; Ephedra extract; and an effective amino acid.

[0058] One embodiment of the present application provides a pharmaceutical composition for preventing or treating obesity, wherein the effective amino acid comprises L-arginine and L-carnitine, and the L-arginine and L-carnitine are included in a weight ratio of 1:0.01 to 1:0.25.

[0059] In another embodiment, the effective amino acid comprises L-arginine and L-carnitine, and the L-arginine and L-carnitine may be in a weight ratio of 1:0.01 to 1:0.25, specifically 1:0.05 to 1:0.25, and specifically 1:0.25 may be satisfied.

[0060] The present application provides a pharmaceutical composition for preventing or treating obesity, wherein, based on 100 parts by weight of the complex preparation, the cambogia extract comprises 30 parts by weight or more and 40 parts by weight or less; and the ephedra extract comprises 40 parts by weight or more and 60 parts by weight or less.

[0061] In another embodiment, based on 100 parts by weight of the above-mentioned complex preparation, the above-mentioned cambogia extract may be 30 parts by weight or more and 40 parts by weight or less, specifically 35 parts by weight or more and 37 parts by weight or less, and preferably 35 parts by weight.

[0062] In another embodiment, based on 100 parts by weight of the above-mentioned complex preparation, the ephedra extract may be 40 parts by weight or more and 60 parts by weight or less; specifically, 45 parts by weight or more and 55 parts by weight or less, preferably 55 parts by weight.

[0063] In the present application, the effective amino acid may comprise 15 parts by weight or less based on 100 parts by weight of the complex formulation; specifically, 10 parts by weight.

[0064] In the present application, the exothermic agent comprises an anhydrous zeolite; calcium chloride; and kaolin, and the exothermic agent generates heat upon physical friction to form the temperature of the pharmaceutical composition for preventing or treating obesity at 25°C or higher and 35°C or lower.

[0065] The thermal agent according to the present application is used for intramuscular injection, and in particular, for intramuscular injection, after injecting the active ingredient through the muscle, the skin is rubbed. At this time, the thermal agent according to the present application generates heat upon external impact, and accordingly, the temperature of the composition is formed within the above range, thereby facilitating absorption into the muscle.

[0066] In the present application, based on 100 parts by weight of the pharmaceutical composition for preventing or treating obesity, the fever agent may be 5 parts by weight or more and 20 parts by weight or less, preferably 7 parts by weight or more and 15 parts by weight or less, and includes 10 parts by weight.

[0067] With the above-mentioned range, the active ingredient can be easily absorbed into the muscle, and safety can also be ensured by including it within a range that does not cause problems in the body.

[0068] The composition of the present invention may further include one or more of catechin, catinone, tryptamine, P-octopamine, P-tyramine, and synephrine, which are norepinephrine-releasing substances, meaning that the norepinephrine acts as a neurotransmitter at the synapses of the brain and muscles and acts as a hormone that regulates fuel metabolism in the liver and muscles.

[0069] In the present invention, the pharmaceutical composition for preventing or treating obesity may be a compound that stimulates the hypothalamus to increase the secretion of norepinephrine, and specifically, may be a compound that increases the concentration of norepinephrine at the synapse to activate hypothalamic POMC neurons, thereby suppressing appetite and increasing energy consumption.

[0070] The above catechin can be extracted from the tea tree (Camellia sienesis) and can act as a substance for the prevention and treatment of obesity by inhibiting the COMT (catechol O-methyltransferase) enzyme and increasing norepinephrine in the synaptic cleft, thereby showing efficacy in energy activity ([Korean J Clin Pharm 2018;28(4):342-346, ARYA Atheroscler. 2014 Jan; 10(1): 55-58.]).

[0071] The above catinone can be extracted from Catha edulis (Khat) and, like amphetamine, releases catecholamines such as dopamine, norepinephrine, and epinephrine through TAAR1 activation, and acts on alpha and beta adrenergic receptors to exhibit an appetite-suppressing effect. The above catinone has a greater CNS activating effect than amphetamine ([Cathinone (Khat) and Methcathinone (CAT)in Urine Specimens: A Gas Chromatographic-Mass Spectrometric Detection Procedure], [MECHANISM OF ACTION OF CATHINONE: THE ACTIVE INGREDIENT OF KHAT (CATHA EDULIS)]).

[0072] The above-mentioned tryptamine can be extracted from Vachelia aroma and can act as a substance for the prevention and treatment of obesity through a complex mechanism that includes increasing insulin in the pancreas via the TAAR1 receptor to reduce fasting blood glucose in the liver, and delaying gastric emptying time to increase GLP-1 & PYY, thereby reducing glucose excretion from the body ([Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges], [Pharmacology & Therapeutics, Volume 180, December 2017, Pages 161-180]).

[0073] The above-mentioned P-octopamine can be extracted from bitter oranges (Citrus aurantium) and can act as a substance for the prevention and treatment of obesity by increasing the release of serotonin through TAAR1 receptors, thereby increasing satiety and consequently reducing food intake. In addition, P-octopamine can act as a substance for the prevention and treatment of obesity by acting on the Beta 3 Adrenergic receptors of adipocytes to activate them, inducing the conversion of white fat into brown fat through the activation of norepinephrine binding and UCP-1 protein activation in adipocytes, and increasing energy consumption through thermogenesis by brown fat ([Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges], [Pharmacology & Therapeutics, Volume 180, December 2017, Pages 161-180]).

[0074] The above-mentioned P-tyramine can be extracted from bitter orange (Citrus aurantium) or Musa sapientum L. and can act as a substance for the prevention and treatment of obesity through a complex mechanism that includes increasing insulin in the pancreas via TAAR1 receptors to reduce fasting blood glucose in the liver, and delaying gastric emptying time to increase GLP-1 & PYY, thereby reducing glucose excretion from the body ([Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges], [Pharmacology & Therapeutics, Volume 180, December 2017, Pages 161-180]).

[0075] The above-mentioned synephrine can be extracted from bitter orange (Citrus aurantium) and can act as a substance for the prevention and treatment of obesity by releasing catecholamines through TAAR1 activation, activating lipolysis by binding to the beta 3 adrenergic receptor, and showing efficacy in energy activity by increasing norepinephrine ([Phytother Res. 2017 Oct; 31(10): 1463-1474.]).

[0076] The pharmaceutical composition of the present invention preferably comprises catechin as a norepinephrine-releasing substance.

[0077] The above Garcinia cambogia extract and the above catechin may be included in a weight ratio of 1:0.5 to 1:2, and if the content of the above catechin is less than 0.5 times the content of the above Garcinia cambogia extract, the effect of inhibiting adipocyte differentiation is reduced, and if it exceeds 2 times, a problem of cytotoxicity occurs.

[0078] For example, the above composition may be included in a weight ratio of 1 : 0.015 to 0.05 : 0.05 to 0.4 : 0.1 to 0.2 to maximize the effect of inhibiting adipocyte differentiation while preventing or minimizing cytotoxicity.

[0079] In the present invention, the composition may further comprise one or more branched-chain amino acids (BCAA) selected from the group consisting of leucine, isoleucine, and valine, calcium pantothenate, nicotinamide, crystalline cellulose, magnesium stearate, hydroxypropylmethylcellulose, and calcium carboxymethylcellulose.

[0080] The above branched-chain amino acids (BCAAs) are among the essential amino acids that have a close relationship with muscles, and the above calcium pantothenate (molecular formula C 18 H 32 O 10 N2Ca is a white, odorless, slightly bitter calcium salt fortifier that acts as a coenzyme in the body, which is necessary for the normalization of tissue function, physical growth, and the maintenance of health.

[0081] The aforementioned nicotinamide is a type of vitamin added for the purpose of suppressing obesity and aiding in weight loss; it refers to vitamins B1, B2, B6, B12, C, D3, and nicotinamide. Vitamins B, C, D, and nicotinamide act as coenzymes in the TCA cycle, which breaks down glucose to produce energy. Without vitamins, this process cannot proceed, and nutrients cannot be consumed as energy but are instead converted into body fat and accumulated in the body. In other words, if vitamins are insufficient, ingested food cannot be used as energy and accumulates in the body, ultimately leading to obesity.

[0082] The above crystalline cellulose is an additive used in food as an anti-caking agent, stabilizer, emulsifier, and dietary fiber, the above magnesium stearate provides mineral components by supplying magnesium, and the above hydroxypropylmethylcellulose (hypromellose, HPMC) and the above carboxymethylcellulose calcium act as viscosity regulators.

[0083] Additionally, the above composition may further include additives such as zinc oxide and silicon dioxide.

[0084] In the present invention, "prevention" refers to any act of suppressing or delaying obesity, and "treatment" refers to any act of improving or beneficially altering the symptoms of an individual suspected of or suffering from obesity. Furthermore, the pharmaceutical composition may be provided as a pharmaceutical composition comprising an active ingredient alone, or comprising one or more pharmaceutically acceptable carriers, excipients, or diluents. In the above, "pharmaceutically acceptable" refers to a composition that is physiologically acceptable and, when administered to humans, typically does not cause an allergic reaction or a similar reaction.

[0085] Furthermore, the above pharmaceutical composition may be provided in combination with a conventionally known obesity treatment substance. That is, the above pharmaceutical composition may be administered in combination with a known compound having the effect of preventing or treating obesity.

[0086] The term "administration" above refers to the introduction of a specific substance into an individual by an appropriate method, and the term "individual" refers to all animals, including humans, rats, mice, and livestock, that have developed or may develop obesity. Specific examples may include mammals, including humans.

[0087] Furthermore, in this invention, "obesity" refers to conditions caused by energy imbalance, and the causes of obesity are complexly related to hormonal changes, genetics, mental health issues, and socioeconomic factors. Specifically, it refers to conditions that may be caused by energy imbalance, genetic factors, neuroendocrine factors, and environmental factors.

[0088] The routes of administration of the above pharmaceutical composition are not limited to these but include oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, or rectal.

[0089] Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As bases for suppositories, Witepsol, Macrogol, Tween 61, cocoa oil, laurin oil, glycerogelatin, etc., may be used. In addition, formulations may be made in the form of injectables, creams, lotions, topical ointments, oils, moisturizers, gels, aerosols, and nasal inhalants by methods known in the art. These formulations are described in the literature [Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour], which is a prescription generally known in all pharmaceutical chemistry.

[0090] The preferred dosage of the above pharmaceutical composition varies depending on the patient's condition and weight, the severity of the disease, the drug form, the route of administration, and the duration, but can be appropriately selected by a person skilled in the art. However, for a desirable effect, the content of the active ingredient in the pharmaceutical composition of the present invention may vary depending on the severity of the disease. Preferably, the preferred total dosage of the composition of the present invention may be about 0.01 μg to 1,000 mg per kg of patient body weight per day, most preferably 0.1 μg to 100 mg. However, since the effective dosage for a patient is determined by considering various factors such as the patient's age, weight, health status, gender, severity of the disease, diet, and excretion rate, as well as the route of administration and the number of treatments of the pharmaceutical composition, a person with ordinary knowledge in the art will be able to determine an appropriate effective dosage for a specific use as a preventive or therapeutic agent of obesity by taking these points into account. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, route of administration, and method of administration as long as it exhibits the effects of the present invention. When formulating the above pharmaceutical composition, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

[0091] In addition, the pharmaceutical composition of the present invention can be used not only as a medicine for human application but also in the form of an animal medicine. Here, the term "animal" includes livestock and pets.

[0092] Below, for a more specific explanation, examples will be provided to describe the details.

[0093] Examples

[0094] Example 1

[0095] A complex formulation was prepared by mixing 35 mg (ml) of Garcinia cambogia extract obtained by extracting freeze-dried Garcinia cambogia extract powder, 55 mg (ml) of Ephedra extract, 8 mg of L-arginine powder, and 2 mg of L-carnitine powder.

[0096] Then, 70 parts by weight of the complex preparation and 10 parts by weight of a heat agent mixed in a ratio of anhydrous zeolite:calcium chloride:kaolin = 1:0.5:0.1 are added.

[0097] The final composition was prepared by adding 20 parts by weight of an additional mixed component to the above composition, which additionally mixed 0.5 mg of BCAA mix, 0.5 mg of calcium pantothenate, 0.5 mg of nicotinamide, 15 mg of crystalline cellulose, 1 mg of magnesium stearate, 1 mg of hydroxypropylmethylcellulose, and 1.5 mg of calcium carboxymethylcellulose.

[0098]

[0099] Comparative Example 1

[0100] The above Example 1 was prepared in the same manner as Example 1, except that it did not include a pyogenic agent. In this case, 10 parts by weight of a composite preparation were added instead of 10 parts by weight of a pyogenic agent.

[0101]

[0102] Comparative Example 2

[0103] The above Example 1 was prepared in the same manner as Example 1, except that it did not include a heating agent. In this case, 10 parts by weight of an additional mixed component were added instead of 10 parts by weight of the heating agent.

[0104]

[0105] Comparative Example 3

[0106] In the above Example 1, the product was prepared in the same manner as Example 1, except that 90 mg (ml) of Garcinia cambogia extract was used instead of 35 mg (ml) of Garcinia cambogia extract and 55 mg (ml) of Ephedra extract extracted from freeze-dried Garcinia cambogia extract powder.

[0107]

[0108] Comparative Example 4

[0109] In the above Example 1, the product was prepared in the same manner as Example 1, except that 90 mg (ml) of only Ephedra extract was used instead of 35 mg (ml) of Garcinia cambogia extract and 55 mg (ml) of Ephedra extract extracted from freeze-dried Garcinia cambogia extract powder.

[0110]

[0111] Preparation Example 1. INS-1 cell culture

[0112] Rat pancreatic β-cells (INS-1) purchased from Biohermes (Shanghai, China) were cultured in RPMI-1640 (Cellgro, Manassas, VA, USA) containing 11 mM D-glucose, 10% fetal bovine serum, 1% penicillin / streptomycin (Invitrogen Co., Grand Island, NY, USA), 0.05 mM 2-mercaptoethanol, 2 mM L-glutamine, 10 mM hydroxyethylpiperazine ethanesulfonic acid (HEPES), and 1 mM sodium pyruvate under conditions of 37°C, 5% CO2, and 95% humidity.

[0113] Preparation Example 2. 3T3-L1 cell culture

[0114] 3T3-L1 preaidpocyte cells purchased from ATCC (American Type Culture Collection, USA) are subcultured in DMEM (containing 10% Bovine Serum, 100 units / ml penicillin, 100 µg / ml streptomycin) medium and used to induce adiocyte differentiation and adipogenesis.

[0115] Preadipocyte cells were used as the normal group, and as a control group, preadipocyte cells cultured to the post-confluent state after seeding were induced to differentiate for 3 days using Zenbio DM medium according to the Zenbio manual, and then maintained as adipocytes for 4 days by changing the medium every two days using Zenbio AM medium.

[0116] The experimental group was treated with Hispidulin, Synephrine, and P-Octopamine (Octopamine hydrochloride) at concentrations of 0, 5, 10, 20, or 40 μM each time DM medium and AM medium were treated under the same culture conditions as the control group.

[0117]

[0118] Experimental Example 1. Cell viability experiment and adipocyte differentiation inhibitory effect

[0119] Using 3T3-L1 cells, which are adipogenic cells derived from mice, the effects of Hispidulin, Synephrine, and P-Octopamine (Octopamine hydrochloride) on cell viability were evaluated as follows.

[0120] Normal group of Preparation Example, 3T3-L1 preadipocyte cells were placed in a 96-well plate at a rate of 1 x 10⁶ per well. 4After dispensing, the cells were cultured under the same conditions for 24 hours to stabilize.

[0121] Subsequently, the compositions of the above examples and comparative examples at a concentration of 200 μg / ml were each cultured under the same conditions for 24 hours after treatment. Then, EZ-Cytox cell viability assay solution (100 μL; Daiel Lab Service Co., Ltd., Seoul) was added to the plate and cultured for 40 minutes. Next, the cell viability was measured by measuring the absorbance of the samples in the well plate at a wavelength of 450 nm using a PowerWave XS microplate reader (Bio-Tek Instruments, Winooski, VT, USA).

[0122] It was confirmed that there was no significant difference in the number of 3T3-L1 cells in both the compositions of the examples and comparative examples. Therefore, it was confirmed that both the compositions of the examples and comparative examples are non-toxic to 3T3-L1 cells.

[0123] In addition, 3T3-L1 cells were treated with the compositions of the Examples and Comparative Examples, respectively, during DM medium treatment and AM medium treatment under the same culture conditions as the control group of the Preparation Example. Then, to confirm the effect of the compositions of the Examples and Comparative Examples on fat accumulation, the culture medium of the cells in each group was removed, and the amount of intracellular fat accumulation was compared and confirmed through the Oil red O test using Table 1.

[0124] Example Cell Viability (%) Oil Red O (%) Example 1 96.5±2.5 32.1±3.2 Comparative Example 196.1±2.7 66.3±2.2 Comparative Example 294.5±3.4 49.2±2.3 Comparative Example 395.6±1.9 47.6±2.1 Comparative Example 494.5±3.4 65.3±2.2

[0125] Experimental Example 2. Stability Evaluation. Factors related to bacterial infection were evaluated 20 hours after storage for the compositions of the experimental example and comparative example, and the results are shown in Table 2 below. In addition, whether embolism occurred when the respective compositions were administered to rats purchased from Biohermes (Shanghai, China) is shown in Table 2 below. At this time, the injection of the injectable agent generally underwent the same pretreatment to remove air bubbles, and the injection site was gently rubbed with the hand after injection.

[0126] Examples Bacterial Infection Rate (%) Incidence of Embolism (%) Example 1 0.2±0.03 0.1±0.06 Comparative Example 10.2±0.03 0.2±0.06 Comparative Example 20.35±0.01 0.3±2.1 Comparative Example 30.3±0.01 0.6±2.1 Comparative Example 40.3±0.04 0.1±0.06

[0127] When the injectables of the examples and comparative examples were administered intramuscularly, it was confirmed that safety (embolism, bacterial infection) could be secured along with the desired obesity prevention effect. This corresponds to the results of intramuscular injection, which has higher safety compared to intravenous injection. In addition, as shown in Table 1, the results of intracellular fat accumulation (adipocyte differentiation inhibition rate) when treated with the compositions according to the examples were photographed under a microscope at 20x magnification.

[0128] It can be confirmed that when treated with the composition of Example 1 of the present invention, the effect of inhibiting adipocyte differentiation is inhibited by about 50% or more, and up to 60% or more. However, unlike this, when treated with the compositions of Comparative Examples 1 to 4, it can be confirmed that the effect of inhibiting adipocyte differentiation is weak, at about 20 to 30%.

[0129] In particular, it can be confirmed that the composition of Example 1 has an effect of inhibiting adipocyte differentiation of about 62%.

[0130] When treated with the above Example 1, it was confirmed that the effect of inhibiting the differentiation of 3T3-L1 cells was approximately twice as good as that of Comparative Example 4, which had the best inhibition rate of adipocyte differentiation among the Comparative Examples.

[0131] Comparative examples do not include a fever agent or do not satisfy the composition of the present application, and the effect of inhibiting adipocyte differentiation is negligible, amounting to about 30%.

[0132] Although exemplary embodiments of the present invention have been described above, the present invention is not limited thereto, and those skilled in the art will understand that various changes and modifications are possible within the scope and concept of the claims set forth below.

Claims

1. A pharmaceutical composition for the prevention or treatment of obesity comprising: a pyrogen; a complex preparation; a branched-chain amino acid (BCAA) comprising one or more selected from the group consisting of leucine, isoleucine, and valine; calcium pantothenate; nicotinamide; crystalline cellulose; magnesium stearate; hydroxypropylmethylcellulose; and calcium carboxymethylcellulose; The above-mentioned complex preparation comprises Garcinia cambogia extract; Ephedra extract; and effective amino acids; and The above-mentioned exothermic agent comprises anhydrous zeolite; calcium chloride; and kaolin, and A pharmaceutical composition for preventing or treating obesity that generates heat upon physical friction, thereby forming the temperature of the pharmaceutical composition for preventing or treating obesity to 25°C or higher and 35°C or lower.

2. In Claim 1, The above effective amino acids include L-arginine and L-carnitine, and A pharmaceutical composition for preventing or treating obesity, comprising the above L-arginine and L-carnitine in a weight ratio of 1:0.01 to 1:0.

25.

3. In Paragraph 1, A pharmaceutical composition for the prevention or treatment of obesity, further comprising one or more selected from the group consisting of catechin, catinone, tryptamine, P-octopamine, P-tyramine, and synephrine.

4. In Paragraph 1, A pharmaceutical composition for preventing or treating obesity, comprising, based on 100 parts by weight of the above-mentioned complex preparation, 30 parts by weight or more and 40 parts by weight or less of the above-mentioned cambogia extract; and 40 parts by weight or more and 60 parts by weight or less of the above-mentioned ephedra extract.

5. In Paragraph 1, A pharmaceutical composition for the prevention or treatment of obesity, wherein the effective amino acid is included in an amount of 15 parts by weight or less based on 100 parts by weight of the above-mentioned complex preparation.

6. In Paragraph 1, A pharmaceutical composition for preventing or treating obesity, comprising at least 5 parts by weight and no more than 20 parts by weight of the fever agent based on 100 parts by weight of the above pharmaceutical composition for preventing or treating obesity.

7. In Paragraph 1, The above-mentioned exothermic agent is a pharmaceutical composition for the prevention or treatment of obesity comprising anhydrous zeolite:calcium chloride:kaolin in a weight ratio of 1:0.5:0.

1.

8. An injectable preparation comprising a pharmaceutical composition for the prevention or treatment of obesity according to any one of paragraphs 1 to 7.