KR20210157892A - Pharmaceutical composition for preventing or treating obesity comprising a natural substance as an active ingredient - Google Patents

Abstract

A pharmaceutical composition for the treatment and prevention of obesity and insomnia is disclosed. The pharmaceutical composition according to an embodiment of the present invention includes a norepinephrine release substance and a GABA-A receptor activator extracted from natural substances.

Description

Pharmaceutical composition for the prevention or treatment of obesity comprising a natural substance as an active ingredient {PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING OBESITY COMPRISING A NATURAL SUBSTANCE AS AN ACTIVE INGREDIENT}

The present invention relates to a pharmaceutical composition comprising a natural substance as an active ingredient, and more particularly, to a pharmaceutical composition for preventing or treating obesity comprising a natural substance as an active ingredient.

The prevalence of obesity in both children and adults is rising in first world countries, particularly the United States, as well as in many developing countries, such as China and India. Many aspects of a person's life are affected by obesity, from physical problems such as knee and ankle joint devastation to emotional problems resulting from self-esteem problems and social attitudes toward people who are heavy. The medical problems caused by obesity can be serious and often life threatening, and include diabetes, shortness of breath and other respiratory problems such as asthma and pulmonary hypertension, gallbladder disease, dyslipidemia (eg, high cholesterol or high levels of triglycerides) and dyslipidemic hypertension, osteoarthritis and other orthopedic problems, reflux esophagitis (heartburn), snoring, sleep apnea, irregular menstruation, infertility, problems related to pregnancy, gout, cardiovascular problems such as coronary artery disease and other heart diseases, muscular dystrophy, and metabolic disorders such as hypoalphalipoproteinemia, familial combined hyperlipidemia, and syndrome X, including insulin resistance syndrome X. Obesity is also associated with an increased incidence of certain cancers, particularly cancers of the colon, rectum, prostate, breast, uterus and cervix.

Obesity substantially increases the risk of hypertension, dyslipidemia, type II diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, and morbidity of endometrial, breast, prostate and colon cancers. Higher body weight is also associated with an increase in all-cause mortality. Many of these problems are alleviated or ameliorated when the afflicted individual undergoes significant, permanent weight loss. Weight loss in these individuals can also promote a significant increase in lifespan.

Strategies for the treatment of obesity and related disorders include dietary restriction, increased physical activity, pharmacological approaches, and even surgery, which depend, at least in part, on the degree of weight loss the individual is attempting to achieve, as well as the severity of the obesity exhibited by the subject. is selected according to For example, treatments such as a low-calorie, low-fat diet and/or regular exercise are often appropriate for only mildly overweight individuals. However, difficulties in maintaining long-term weight loss through diet and behavioral modifications have led to increased interest in other treatment modalities, particularly pharmacotherapy.

Traditional pharmacological interventions typically lead to weight loss of 5 to 15 kilograms; When drug treatment is stopped, weight gain resumption often occurs one after another. Surgical treatment is highly successful and is indicated for patients with extreme obesity and/or serious medical complications.

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

Society has made great strides in the field of pharmaceuticals, but there are, of course, drawbacks to the administration of any given medicament. Often, a disadvantage or “side effect” is severe enough to preclude administration of a therapeutically effective amount of a particular agent. In addition, many agents within the same therapeutic class exhibit a similar side-effect profile, meaning that the patient must either precede therapy or suffer from varying degrees of side effects associated with the chosen medication.

-D-프룩토피라노스 술파메이트)는 특정 발작 장애의 치료 및 편두통의 예방에 대해 FDA 및 많은 다른 국가의 규제 기관에 의해 승인된 광범위 신경치료제이다 (문헌 [E. Faught et al. (1996) Neurology 46:1684-90]; [Karim et al. (1995) Epilepsia 36 (S4):33]; [S. K. Sachdeo et al. (1995) Epilepsia 36(S4):33]; [T. A. Glauser (1999) Epilepsia 40 (S5):S71-80]; [R. C. Sachdeo (1998) Clin. Pharmacokinet. 34:335-346]). 또한, 토피라메이트가 당뇨병 (미국 특허 제7,109,174호 및 제6,362,220호), 신경계 장애 (미국 특허 제6,908,902호), 우울증 (미국 특허 제6,627,653호), 정신병 (미국 특허 제6,620,819호), 두통 (미국 특허 제6,319,903호) 및 고혈압 (미국 특허 제6,201,010호)의 치료에서 효과적이라는 증거가 존재한다. 그러나, 인간에서 토피라메이트의 사용과 관련된 유해 효과, 예컨대 인지 둔감 및 단어 찾기의 어려움이 존재하며, 이는 많은 비만 환자가 이 약물을 섭취하는 것을 단념시킬 수 있다.Topiramate (2,3,4,5-bis-O-(1-methylethylidene)-

-D-fructopyranose sulfamate) is a broad-spectrum neurotherapeutic agent approved by the FDA and many other national regulatory agencies for the treatment of certain seizure disorders and the prevention of migraine headaches (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]; (S5):S71-80]; [RC Sachdeo (1998) Clin. Pharmacokinet. 34:335-346]). Topiramate has also been used in diabetes (US Pat. Nos. 7,109,174 and 6,362,220), neurological disorders (US Pat. No. 6,908,902), depression (US Pat. No. 6,627,653), psychosis (US Pat. No. 6,620,819), headache (US Pat. No. 6,319,903) and hypertension (U.S. Pat. No. 6,201,010), there is evidence to be effective. However, there are adverse effects associated with the use of topiramate in humans, such as cognitive blunting and word-finding difficulties, which may discourage many obese patients from taking this drug.

Phentermine was approved by the FDA as an appetite suppressant in 1959, and phentermine hydrochloride has been used as a weight loss agent since the 1970s, for example, Adipex-P®, Pastin®, Zantril®. ® has been used under trade names such as Regarding combining phentermine with a second active agent following reports of heart and lung problems associated with the "Fen-Phen" product, wherein phentermine was combined with fenfluramine and then with the related drug, dexfenfluramine. Although the FDA has warned, a safe and effective weight loss by combining phentermine with an active agent that alleviates the side effects of phentermine and enables administration of phentermine in doses that are significantly lower than "phenphen" (containing 30 mg or 37.5 mg of phentermine hydrochloride). It has been found that weight loss therapy is provided.

In this regard, recently, Patent Document 1, which is a US patent, has been registered on that a combination product of topiramate and phentermine in a lower dose is effective in achieving weight loss, treatment of obesity, and treatment of conditions related to obesity and excess weight. It is commercially available at home and abroad under the trademark of ^{Qsymia TM.}

However, topiramate and phentermine contained in Qsymia products are also synthetic substances, and it is known that there are side effects of Paresthesia, Alopecia, Parosmia, Amenorrhea, and Aphasia. Yes ([Korean J Obes 2015 March;24(1):17-27, Innov Clin Neurosci. 2011 Aug; 8(8): 14-16.]).

Accordingly, the present inventors have found a natural material that can reduce the side effects of conventional compositions for preventing and treating obesity containing topiramate or phentermine and can replace them, and contain natural materials that can minimize side effects as an active ingredient. An object of the present invention is to provide a pharmaceutical composition for the treatment and prevention of obesity and insomnia.

Patent Document 1: US Registered Patent Publication No. 8,580,298

One object of the present invention is to provide a pharmaceutical composition for preventing or treating obesity comprising a natural substance as an active ingredient.

Another object of the present invention is to provide a health functional food for preventing obesity or tea comprising the above-described pharmaceutical composition.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those of ordinary skill in the art from the following description.

According to an embodiment of the present invention, a pharmaceutical composition for preventing or treating obesity, comprising a norepinephrine release material and a GABA-A receptor activator material extracted from a natural material provided

In the present invention, the norepinephrine release substance is catechin, cathinone, tyramine, P-octopamine, P-Octopamine, P-tyramine, cine. It may include any one or more selected from the group consisting of prine (Synephrine) and ephedrine (Ephedrine).

In the present invention, the GABA-A receptor activator material is selected from the group consisting of baicalin, baicalein, valerenic acid and hispidulin. It may include any one or more.

In the present invention, P-Octopamine and Synephrine may be included as the norepinephrine release material, and Hispidulin may be included as the GABA-A receptor activator material.

In the present invention, the norepinephrine release substance and the GABA-A receptor activator substance may be included in a weight ratio of 1:2 to 2:1.

In the present invention, the composition may be a pharmaceutical composition for preventing or treating obesity, characterized in that it suppresses appetite by increasing the secretion of norepinephrine.

In the present invention, the composition may be a pharmaceutical composition for preventing or treating obesity, which increases energy consumption through induction of brown fat differentiation.

In the present invention, the composition may be a pharmaceutical composition for preventing or treating obesity, characterized in that it increases energy consumption by stimulating the activity of lipoprotein lipase in skeletal muscle.

According to another embodiment of the present invention, it may be a health functional food for preventing or treating obesity, including the pharmaceutical composition for preventing or treating obesity.

The pharmaceutical composition for preventing or treating obesity provided in the present invention includes a norepinephrine-releasing material and a GABA-A receptor activator material extracted from natural substances, and has a preventive and therapeutic effect on obesity. In particular, the pharmaceutical composition of the present invention reduces the side effects of conventional anti-obesity and treatment compositions containing topiramate or phentermine, and contains natural substances that can replace them as an active ingredient to minimize side effects while preventing or treating obesity It may have excellent efficacy in treatment.

However, it is not limited to the above-described effects, and it should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims.

1 to 3 are graphs showing the viability of 3T3-L1 preadipocyte cells treated with Hispidulin, Synephrine and P-Octopamine (Octopamine hydrochloride).
4 is an image showing the result of intracellular fat accumulation (adipocyte differentiation inhibition rate) when Hispidulin, Synephrine and P-Octopamine (Octopamine hydrochloride) were treated with different amounts of 3T3-L1 cells cultured in a post-confluent state.
5 to 7 are graphs schematically illustrating the results of FIG. 4 .
8 is an image showing the results of intracellular fat accumulation (adipocyte differentiation inhibition rate) when 3T3-L1 cells cultured in a post-confluent state were treated with different combinations of Hispidulin, Synephrine and P-Octopamine (Octopamine hydrochloride).
9 to 12 are graphs schematically illustrating the results of FIG. 8 .

Hereinafter, to help the understanding of the present invention, examples will be described in detail. 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 embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art. The present invention is not limited to the embodiments presented herein, and may be embodied in other forms.

According to an embodiment of the present invention, a pharmaceutical composition for preventing or treating obesity, comprising a norepinephrine release material and a GABA-A receptor activator material extracted from a natural material it's about

As used herein, the term "extracted substance" or "extract" refers to an extract obtained by extraction treatment, a diluted or concentrated solution of the extract, a dried product obtained by drying the extract, a prepared or purified product of the extract, or a mixture thereof and the like, including extracts of all formulations that can be formed using the extract itself and the extract.

In the present invention, drying of the extract may be carried out by a known method in the range in which useful components are not destroyed from the collected natural material, for example, it may be carried out by a method of natural drying in the shade. In addition, crushing or pulverization can be pulverized by crushing or pulverizing to the extent that useful components of plants can be sufficiently extracted in the subsequent extraction process. The drying, crushing, or pulverizing processes may be performed in reverse order or repeated if necessary.

In the extraction of the present invention, the extraction method is not particularly limited, and extraction may be performed according to a method commonly used in the art. Non-limiting examples of the extraction method include hot water extraction, ultrasonic extraction, filtration, and reflux extraction, and these may be performed alone or in combination of two or more methods.

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

As used herein, the term “compound” refers to a product obtained by performing fractionation in order to separate a specific component or a specific component group from a mixture including various components.

The separation method for obtaining the compound in the present invention is not particularly limited, and may be performed according to a method commonly used in the art. Non-limiting examples of the separation method include a method of obtaining a compound from the extract by treating the natural substance extract with a predetermined solvent.

The norepinephrine release substance of the present invention is catechin, cathinone, tryptamine, P-octopamine, P-Octopamine, P-tyramine, cine It may be a pharmaceutical composition for preventing or treating obesity, including any one or more selected from the group consisting of prine (Synephrine) and ephedrine (Ephedrine).

As used herein, the term norepinephrine refers to acting as a neurotransmitter in the nerve junction between the brain and muscle, and as a hormone regulating fuel metabolism in the liver and muscle.

In the present invention, the pharmaceutical composition for preventing or treating obesity may be a compound that stimulates the hypothalamus to increase norepinephrine secretion, and specifically increases the concentration of norepinephrine at synapses to activate hypothalamic POMC neurons to suppress appetite and energy It may be a compound that increases consumption.

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

아드레날린 수용체(Alpha, beta Adrenergic receptor)에 작용하여, 식욕억제 효과를 나타낸다. 상기 카티논은 암페타민(Amphetamine)보다 CNS 활성 효과가 더 크다([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)]).The cathinone may be extracted from Catha edulis , Khat, and catecholamine, for example, dopamine, norepinephrine through TAAR1 activation like amphetamine. ), release epinephrine, α and

It acts on adrenergic receptors (Alpha, beta Adrenergic receptor), and exhibits an appetite suppressant effect. The catinone has a greater CNS activation 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)]).

The tryptamine can be extracted from Vachellia aroma , increases insulin in the pancreas through the TAAR1 receptor, reduces fasting blood sugar in the liver, and delays gastric emptying time By increasing GLP-1&PYY by increasing GLP-1&PYY, it can act as a substance for the prevention and treatment of obesity with a complex mechanism including the effect of reducing the excretion of glucose ([Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges], [ Pharmacology & Therapeutics, Volume 180, December 2017, Pages 161-180]).

The P-octopamine (P-Octopamine) can be extracted from Bitter Orange (Citrus aurantium ), and by increasing the release of serotonin through the TAAR1 receptor, the feeling of satiety is increased, and thereby, the effect of reducing food intake It can act as a substance for the prevention and treatment of obesity as a bogeum. In addition, P-octopamine acts on Beta 3 Adrenergic Receptor of adipocytes to activate Beta 3 Adrenergic Receptor, and induces white fat to be converted into brown fat through Norepinephrine binding and UCP-1 protein activation of adipocytes, By showing the effect of increasing energy consumption through thermogenesis by brown fat, it can act as a substance for the prevention and treatment of obesity ([Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges], [Pharmacology] & Therapeutics, Volume 180, December 2017, Pages 161-180]).

The P-tyramine (P-Tyramine) can be extracted from Bitter Orange (Citrus aurantium ) or Musa sapientum L (Musa sapientum L), and by increasing insulin in the pancreas through the TAAR1 receptor, fasting blood sugar in the liver It can act as a substance for the prevention and treatment of obesity with a complex mechanism including the effect of reducing the excretion of glucose from the body by increasing GLP-1&PYY by delaying the gastric emptying time ([Pharmacology of human trace amine -associated receptors: Therapeutic opportunities and challenges], [Pharmacology & Therapeutics, Volume 180, December 2017, Pages 161-180]).

3 아드레날린 수용체(Beta 3 adrenergic receptor)와 결합하여 지방분해를 활성화시키며, 노르에피네프렌(Norepinephrine)을 증가시켜 에너지 활성에 효능을 보임으로서 비만의 예방 및 치료를 위한 물질로 작용할 수 있다([Phytother Res. 2017 Oct; 31(10): 1463-1474.]).The synephrine can be extracted from Bitter Orange, Citrus aurantium , and releases catecholamines through TAAR1 activation,

It binds to 3 adrenergic receptor (Beta 3) to activate lipolysis, and by increasing norepinephrine, it can act as a substance for the prevention and treatment of obesity ([Phytother] Res. 2017 Oct; 31(10): 1463-1474.]).

아드레날린 수용체에 주로 작용하고, 교감신경을 자극하여 시냅스 틈의 노르에피네프렌을 증가시켜 에너지 활성에 효능을 보임으로서 비만의 예방 및 치료를 위한 물질로 작용할 수 있다([Anesth Prog. 2012 Winter; 59(4): 159-169.]).The Ephedrine may be extracted from ephedra ( Ephedra sinica ), α and

It mainly acts on adrenergic receptors and stimulates the sympathetic nerve to increase norepinephrine in the synaptic cleft, thereby showing an effect on energy activity, so it can act as a substance for the prevention and treatment of obesity ([Anesth Prog. 2012 Winter; 59 (4): 159-169.]).

The GABA-A receptor activator material of the present invention is any one selected from the group consisting of baicalin, baicalein, valerenic acid and hispidulin It may be a pharmaceutical composition for preventing or treating obesity, including one or more.

As used herein, the term "GABA-receptor" refers to a receptor protein on which GABA, a neurotransmitter, acts, and the pharmaceutical composition for preventing or treating obesity stimulates the activity of LPL (lipoprotein lipase) in brown fat and skeletal muscle. It may be a compound that increases thermogenesis and suppresses appetite by suppressing the excitatory signal through the activation of GABA-A receptors. In addition, GABA is a major inhibitory neurotransmitter of the central nervous system, and it may act as a substance for treating insomnia through a sedative effect by activating the GABA-A receptor through the pharmaceutical composition for preventing or treating obesity of the present invention.

The baicalin and the baicalein can be extracted from the root of gold ( Baikal Skullcap ), specifically gold, binds to a Benzodiazepine (BZD) receptor, and induces activation of a GABA-A receptor to interact with GABA By increasing affinity and increasing GABA and chlorine ions in post synapse, it can act as a substance for the prevention and treatment of obesity ([Journal of Ethnopharmacology, Volume 135, Issue 2, 17 May 2011, Pages 359-368], [Phytochemical and biological analysis of Skullcap (Scutellaria lateriflora L.): A medicinal plant with anxiolytic properties, December 2003, Phytomedicine 10(8):640-9]).

The valerenic acid can be extracted from Valeriana officinalis , has a mechanism similar to that of Benzodiazepine (BZD), and binds to and activates the beta portion of the GABA A receptor to activate GABA and chlorine ions in post synapse. It can act as a substance for the prevention and treatment of obesity by showing the effect of increasing thermogenesis and suppressing appetite by decreasing the action potential through increase and hyperpolarization ([European Journal of Pharmacology, Volume 537, Issues 1-3, 10] May 2006, Pages 64-69], [The Mechanism of Action for Valerian (Valeriana officinalis) In the Treatment of Insomnia]).

The hispidulin can be extracted from sage (Salvia officinalis ), acts as an antiepileptic such as topiramate, and inhibits k+ channels and ca2+ channels and glutamate, and is a potent benzodiazezepine. (BZD) As a receptor ligand, it can act as a substance for the prevention and treatment of obesity by increasing thermogenesis and appetite suppression by increasing GABA and chloride ions in postsynapse ([Medicinal importance, pharmacological activities, and analytical aspects of hispidulin: A concise report], [J Tradit Complement Med. 2017 Jul; 7(3): 360-366.]).

P-Octopamine and Synephrine as the norepinephrine release material of the present invention, and Hispidulin as the GABA-A receptor activator material. A pharmaceutical for preventing or treating obesity It may be a composition.

In the present invention, the pharmaceutical composition for preventing or treating obesity includes at least one selected from the group consisting of the norepinephrine-releasing substances Catechin, Cathinone, Tryptamine, P-Octopamine, P-Tyramine, Synephrine and Ephedrine and the GABA-A receptor activity. It may contain any one or more selected from the group consisting of factor substances Baicalin, Baicalein, Valerenic acid and Hispidulin, and preferably, the norepinephrine-releasing substance P in terms of having an excellent effect in inhibiting differentiation of fat cells while minimizing side effects -Octopamine and Synephrine and Hispidulin, which is the GABA-A receptor activator, may be included.

The norepinephrine release substance and the GABA-A receptor activator substance of the present invention are included in a weight ratio of 1:2 to 2:1. A pharmaceutical for preventing or treating obesity It may be a composition.

In the present invention, the norepinephrine release substance and the GABA-A receptor activator substance are 1:3 to 3:1, 1:2.7 to 2.7:1, 1:2.5 to 2.5 It may be :1, 1:2.3 to 2.3:1, preferably 1:2 to 2:1, and more preferably 1 in terms of inducing norepineprene release and GABA-A receptor activity while minimizing side effects. : 1.5 to 1.5 : 1 may be. In addition, the norepinephrine release substance and the GABA-A receptor activator substance are each in terms of having an excellent effect in preventing or treating obesity while being safe for side effects and taking long-term use. 5 to 40 μM may be included.

The composition of the present invention may be a pharmaceutical composition for preventing or treating obesity, characterized in that it suppresses appetite by increasing the secretion of norepinephrine.

Specifically, when it binds to beta 3-adrenergic receptor due to increased norepinephrine secretion, cAMP-dependent protein kinase A (PKA) is activated to induce transcription of UCP1 gene, and to induce oxidative phosphorylation in mitochondria. It may be that fat is consumed and heat is generated through an electron transfer process.

Accordingly, it is easily understood by those of ordinary skill in the art that it is effective in preventing or treating obesity and treating insomnia through norepinephrine-releasing substances.

The composition of the present invention may be a pharmaceutical composition for preventing or treating obesity, which increases energy consumption through induction of brown fat differentiation.

In the present invention, it is possible to induce the formation of brown adipocytes in white adipocytes, and as the number of brown adipocytes increases, the body's energy is converted into thermal energy, thereby preventing the accumulation of excess energy as white fat and increasing the basal metabolic rate. It could be a strategic approach.

The composition of the present invention may be a pharmaceutical composition for preventing or treating obesity, characterized in that it increases energy consumption by stimulating the activity of lipoprotein lipase in skeletal muscle.

As used herein, the term "lipoprotein lipolytic enzyme" is an enzyme that mainly exists in the inner walls of capillaries, such as adipose tissue or muscle, and functions to break down triglycerides contained in chylomicrons or VLDL into free fatty acids and glycerol so that they can be used as energy sources. means

Accordingly, it is easily understood by those skilled in the art that it is effective in preventing or treating obesity through the activity of lipoprotein lipolytic enzyme.

In the present invention, the "prevention" refers to any action that inhibits or delays arthritis, and the "treatment" refers to any action in which the symptoms of obesity or insomnia are suspected and the symptoms of the affected individual are improved or changed advantageously. In addition, the pharmaceutical composition may be provided as a pharmaceutical composition including an active ingredient alone, or one or more pharmaceutically acceptable carriers, excipients or diluents. As used herein, 'pharmaceutically acceptable' refers to a composition that is physiologically acceptable and does not normally cause allergic reactions or similar reactions when administered to humans.

Furthermore, the pharmaceutical composition may be provided by mixing with a conventionally known anti-obesity substance. That is, the pharmaceutical composition may be administered in parallel with a known compound having an effect of preventing or treating obesity.

The "administration" means introducing a predetermined substance to an individual by an appropriate method, and "individual" means all animals, such as mice, mice, and livestock, including humans, that have or may develop obesity. As a specific example, it may be a mammal including a human.

If necessary, the pharmaceutical composition may further include a compound for preventing and treating insomnia. The insomnia (insomnia) means the inability to sleep, and the degree may vary depending on the type and degree of progression of a mental illness, and the term "sleep" in the present invention refers to a state in which sleeping or activities are resting. Metaphorically speaking, it refers to a physiological state of loss of consciousness in which fatigue-accumulated brain activity is periodically restored. Specifically, sleep refers to a state of immobility in which the ability to recognize and respond to the external environment is reversible, repetitive, and normally stopped. Compounds for preventing and treating such insomnia include, but are not limited to, adenosine, cordycepin, serotonin and melanin derivatives.

Also, in the present invention, "obesity" means that it is caused by an energy imbalance, and the cause of obesity is complexly related to changes in hormones, genetics, mental health problems, socioeconomic factors, and the like. Specifically, it means that it can be caused by energy imbalance, genetic factors, neuroendocrine factors, and environmental factors.

The route of administration of the pharmaceutical composition is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or work is included.

The pharmaceutical composition can be administered orally or parenterally, and when administered parenterally, it is preferable to select an injection method for external application or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. , but is not limited thereto, preferably oral administration from the viewpoint of selecting a more effective absorption route.

In the case of formulations for oral administration, the composition of the present invention is formulated using methods known in the art as powders, granules, tablets, pills, powders, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. can be angry For example, oral preparations can be obtained by mixing the active ingredient with a solid excipient, grinding it, adding suitable adjuvants, and processing it into a mixture of granules to obtain tablets or dragees. Examples of suitable excipients include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches, including corn starch, wheat starch, rice starch and potato starch, cellulose, Cellulose, including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, and the like, fillers such as gelatin, polyvinylpyrrolidone, calcium carbonate, and the like may be included. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . In addition, if necessary, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant. Furthermore, the pharmaceutical composition of the present invention may further include an anti-aggregating agent, a lubricant, a fragrance, an emulsifier and a preservative.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a suppository base, witepsol, macrogol, tween 61, cacao butter, laurin, glycero geratin and the like can be used. In addition, it can be formulated in the form of injections, creams, lotions, external ointments, oils, moisturizers, gels, aerosols and nasal inhalants by methods known in the art. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a recipe commonly known to all pharmaceutical chemistry.

The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the patient, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the severity of the disease. Preferably, the preferred total dose of the composition of the present invention may be from about 0.01 μg to 1,000 mg, most preferably from 0.1 μg to 100 mg per kg of body weight of the patient per day. However, the dosage of the composition is determined by considering various factors such as the age, weight, health status, sex, severity of disease, diet and excretion rate of the patient as well as the route of administration and number of treatments of the pharmaceutical composition, and the effective dosage for the patient is determined. Therefore, in consideration of this point, those of ordinary skill in the art will be able to determine an appropriate effective dosage according to the specific use of the composition as a preventive or therapeutic agent for obesity. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as the effect of the present invention is exhibited. When formulating the pharmaceutical composition, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.

In addition, the pharmaceutical composition of the present invention can be used in the form of veterinary medicines as well as medicines applied to humans. Here, the animal is a concept including livestock and pets.

According to another embodiment of the present invention, it relates to a health functional food for preventing or treating obesity comprising the pharmaceutical composition for preventing or treating obesity.

The health functional food may be formulated into one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, and liquid formulations, further including one or more of carriers, diluents, excipients and additives. Examples of foods to which the acteoside or a pharmaceutically acceptable salt thereof can be added include various foods, powders, granules, tablets, capsules, syrups, beverages, gums, tea, vitamin complexes, nutritional supplements, health functional foods, and food additives, etc.

Additives that may be further included in the health functional food include natural carbohydrates, flavoring agents, nutrients, vitamins, minerals (electrolytes), flavoring agents (synthetic flavoring agents, natural flavoring agents, etc.), coloring agents, fillers (cheese, chocolate, etc.) , facic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, antioxidants, glycerin, alcohol, carbonation agent and at least one component selected from the group consisting of pulp can be used. have.

Examples of the natural carbohydrate include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the flavoring agent, natural flavoring agents (taumartin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. Nutrients, vitamins, minerals (electrolytes), synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, It may contain a pH adjuster, a stabilizer, a preservative, glycerin, alcohol, a carbonation agent used in carbonated beverages, etc. In addition, the health functional food may contain pulp for the production of natural fruit juices and vegetable beverages. These components may be used independently or in combination.

Specific examples of the carrier, excipient, diluent and additive include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium Silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and at least one selected from the group consisting of mineral oil is preferably used.

In the case of formulating the health functional food, it is prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant that are usually used.

Hereinafter, examples will be described in detail for a more detailed description.

Example

manufacturing example. 3T3-L1 cell culture

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

As a normal group, preadipocyte cells were used, and as a control group, preadipocyte cells cultured to a post-confluent state after seeding were induced to differentiate for 3 days using Zenbio DM medium according to Zenbio manual. Adipocytes were maintained for 4 days by exchange.

The experimental group was treated with Hispidulin, Synephrine and P-Octopamine (Octopamine hydrochloride) at a concentration of 0, 5, 10, 20 or 40 μM in the same culture conditions as the control group, respectively.

Experimental Example 1. Cell viability test

The effects of Hispidulin, Synephrine and P-Octopamine (Octopamine hydrochloride) on cell viability were evaluated using 3T3-L1 cells, which are adipogenic cells derived from mice.

The normal group of Preparation Example, 3T3-L1 preadipocyte cells were seeded in a 96-well plate at 1Х10 ⁴ per well, and then cultured under the same conditions for 24 hours to stabilize the cells. After that, Hispidulin, Synephrine, and P-Octopamine at concentrations of 0, 5, 10, 20 or 40 μM were each treated and incubated for 24 hours under the same conditions. After that, EZ-Cytox cell viability assay solution (100 μL; Daeil Lab Service, Seoul) was added to the plate and incubated for 40 minutes. Next, the absorbance of the sample in the well plate was measured using a PowerWave XS microplate reader (Bio-Tek Instruments, Winooski, VT, USA) at a wavelength of 450 nm to measure the cell viability.

1 to 3 are graphs showing the viability results of 3T3-L1 cells treated with Hispidulin, Synephrine and P-Octopamine at concentrations of 0, 5, 10, 20 or 40 μM, respectively, Table 1 below is a graph showing FIGS. 1 to 3 is the result shown in a table of the graph of

According to FIGS. 1 to 3 and Table 1 below, the difference between the number of 3T3-L1 cells in the control (0 μM) and 3T3-L1 cells treated at a concentration of 5, 10, 20 or 40 μM for all of P-Octopamine, Synephrine, and Hispidulin is small. can check that Therefore, it can be confirmed that 5, 10, 20 or 40 μM of Hispidulin, Synephrine and P-Octopamine are all non-toxic to 3T3-L1 cells.

Experimental Example 2. Adipocyte differentiation inhibitory effect

1. Hispidulin, Synephrine and P-Octopamine inhibitory effect on adipocyte differentiation

3T3-L1 cells were treated with Hispidulin, Synephrine, and P-Octopamine (Octopamine hydrochloride) at a concentration of 0, 5, 10, 20 or 40 μM in the same culture conditions as the control of Preparation Example, respectively. Then, in order to confirm the effect of Hispidulin, Synephrine and P-Octopamine on fat accumulation, the culture medium of each group was removed and the amount of intracellular fat accumulation was compared and confirmed through the Oil red O test.

4 is an image of 3T3-L1 cells treated with Hispidulin, Synephrine and P-Octopamine at concentrations of 0, 5, 10, 20 or 40 μM, respectively, and FIGS. 5 to 7 are the intracellular fat accumulation (fat) of FIG. cell differentiation inhibition rate), and Table 2 below shows the results of the graphs of FIGS. 5 to 7 as a table.

Specifically, according to FIG. 4, it can be confirmed that the number of cells decreases as the concentration increases during the treatment of Hispidulin and Synephrine, but it can be confirmed that there is no difference in the number of cells regardless of the concentration in the treatment of P-Octopamine.

According to FIG. 5 and Table 2 below, it can be confirmed that when Hispidulin was treated at a concentration of 20 to 40 μM, the inhibition of adipocyte differentiation was 1.8 times higher than that of the control (0 μM), which was effective in inhibiting the differentiation of 3T3-L1 cells.

According to FIG. 6 and Table 2 below, when Synephrine was treated at a concentration of 5 to 10 μM, the inhibition of adipocyte differentiation was 1.16 times higher than that of the control (0 μM), and when treated at a concentration of 20 to 40 μM, the inhibition of adipocyte differentiation was 2 compared to the control (0 μM). It can be confirmed that the effect is excellent in inhibiting differentiation of 3T3-L1 cells by more than twice.

According to FIG. 7 and Table 2 below, when P-Octopamine was treated at a concentration of 0 to 40 μM, the inhibition of adipocyte differentiation was 1.12 times or less compared to the control (0 μM). can

Therefore, it is suggested that Hispidulin and Synephrine are effective in inhibiting adipocyte differentiation at concentrations of 20 to 40 μM through FIGS. 4 to 7 and Table 2.

2. Adipocyte differentiation inhibitory effect according to the concentration and combination of Hispidulin, Synephrine and P-Octopamine

3T3-L1 cells were treated with Hispidulin, Synephrine, and P-Octopamine (Octopamine hydrochloride) at a concentration of 0, 5, 10, 20, or 40 μM in the same culture conditions as the control in Preparation Example 1:1 after combining them. Then, in order to confirm the effect of the combination of Hispidulin, Synephrine and P-Octopamine on fat accumulation, the culture medium of each group of cells was removed and the amount of intracellular fat accumulation was compared and confirmed through the Oil red O test.

As shown in FIG. 8, Hispidulin and Synephrine, Synephrine and P-Octopamine, Hispidulin and P-Octopamine or a combination of Hispidulin, Synephrine and P-Octopamine were treated with 0, 5, 10, 20 or 40 μM concentration of 3T3-L1 cells, respectively. 9 to 12 are graphs showing the results of intracellular fat accumulation (adipocyte differentiation inhibition rate) of FIG. 8, and Table 3 below is the results of the graphs of FIGS. 9 to 12 as a table.

Specifically, according to FIG. 8, it can be seen that the number of 3T3-L1 cells decreases rapidly as the concentration increases when treated with the combination of Hispidulin and Synephrine, and when treated with the combination of Synephrine and P-Octopamine and Hispidulin and P-Octopamine It can be seen that the number of 3T3-L1 cells is reduced compared to the control (0 μM), but it can be confirmed that the combination of Hispidulin and Synephrine is better. In addition, it can be confirmed that the treatment with the combination of Hispidulin, Synephrine and P-Octopamine has a similar effect to the combination of Hispidulin and Synephrine.

According to FIG. 9 and Table 3 below, when Hispidulin and Synephrine were combined at a concentration of 5 μM, respectively, the inhibition of adipocyte differentiation was 1.8 times or more compared to the control (0 μM). It can be confirmed that the inhibition rate of adipocyte differentiation is 2.68 times higher than that of the control (0 μM) when treated in combination with 3T3-L1 cells, and the effect of inhibiting differentiation of 3T3-L1 cells is remarkably excellent.

According to FIG. 10 and Table 3 below, the inhibition rate of adipocyte differentiation when treated with a combination of Synephrine and P-Octopamine at a concentration of 5 to 10 μM, respectively, was insignificant compared to that of the control (0 μM), but fat when treated with a combination of 20 to 40 μM. It can be confirmed that the cell differentiation inhibition rate is 1.7 times or more compared to the control (0 μM), which shows that the differentiation inhibition of 3T3-L1 cells is excellent.

According to Figure 11 and Table 3 below, the inhibition rate of adipocyte differentiation when treated with a combination of Hispidulin and P-Octopamine at a concentration of 5 to 10 μM, respectively, was insignificant compared to that of the control (0 μM), but fat when treated with a combination of 20 to 40 μM. It can be seen that the cell differentiation inhibition rate is 1.8 times higher than that of the control (0 μM), indicating that the differentiation inhibition of 3T3-L1 cells is excellent.

According to FIG. 12 and Table 3 below, when the combination of Hispidulin, Synephrine and P-Octopamine was combined at a concentration of 5 to 10 μM, respectively, the inhibition of adipocyte differentiation was 1.9 times or more compared to the control (0 μM), indicating that the effect was excellent even at a small concentration. It can be confirmed that, when combined at a concentration of 40 μM, the inhibition of adipocyte differentiation was 2.77 times compared to the control (0 μM), indicating that the effect of inhibiting differentiation of 3T3-L1 cells was remarkably excellent. In addition, it can be confirmed that the combination of Hispidulin, Synephrine, and P-Octopamine of FIG. 12 has more excellent inhibition of adipocyte differentiation compared to the combination of Hispidulin and Synephrine of FIG. 9 .

Therefore, according to FIGS. 8 to 12 and Table 3, Hispidulin and Synephrine were combined at a concentration of 5 to 40 μM, respectively, and the effect on the inhibition of adipocyte differentiation was excellent, and Hispidulin, Synephrine and P-Octopamine were added at a concentration of 5 to 40 μM, respectively. It suggests that the effect on the inhibition of adipocyte differentiation is remarkably excellent when treated in combination with

In the foregoing, exemplary embodiments of the present invention have been described, but the present invention is not limited thereto, and those of ordinary skill in the art are within the scope not departing from the concept and scope of the claims described below. It will be understood that various changes and modifications are possible.

Claims (9)

A pharmaceutical composition for preventing or treating obesity, comprising a norepinephrine release material and a GABA-A receptor activator material extracted from a natural material. The method of claim 1,
The norepinephrine release material is Catechin, Cathinone, Tryptamine, P-Octopamine, P-Tyramine, Synephrine and Ephedrine comprising any one or more selected from the group consisting of, obesity prevention or treatment pharmaceutical composition. The method of claim 1,
The GABA-A receptor activator (GABA-A receptor activator) material is Baicalin, Baicalein, Valerenic acid, and a pharmaceutical composition for the prevention or treatment of obesity comprising any one or more selected from the group consisting of Hispidulin. The method of claim 1,
A pharmaceutical composition for preventing or treating obesity, comprising P-Octopamine and Synephrine as the norepinephrine release material, and Hispidulin as the GABA-A receptor activator material. The method of claim 1,
The norepinephrine release (Norepinephrine release) substance and the GABA-A receptor activator (GABA-A receptor activator) substance is a pharmaceutical composition for preventing or treating obesity that is included in a weight ratio of 1:2 to 2: 1. The method of claim 1,
The composition is a pharmaceutical composition for preventing or treating obesity, characterized in that it suppresses appetite by increasing the secretion of norepinephrine. The method of claim 1,
The composition is a pharmaceutical composition for preventing or treating obesity that increases energy consumption through induction of brown fat differentiation. The method of claim 1,
The composition is a pharmaceutical composition for preventing or treating obesity, characterized in that it increases energy consumption by stimulating the activity of lipoprotein lipase in skeletal muscle. A health functional food for preventing or treating obesity, comprising the pharmaceutical composition for preventing or treating obesity according to any one of claims 1 to 8.

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