KR20160102950A - Composition Comprising L-argnine and Acanthopanax sessiliflorus Extract for Stimulating Bone Growth - Google Patents

Abstract

The present invention provides a composition for promoting longitudinal bone growth, comprising L-arginine and an Acanthopanax sessiliflorus extract as active ingredients. The composition of the present invention exhibits an effect of promoting longitudinal bone growth.

Description

(Composition Comprising L-argnine and Acanthopanax sessiliflorus Extract for Stimulating Bone Growth) containing L-arginine and Ogaki extract as an active ingredient,

The present invention relates to a food composition for promoting growth of bone length comprising L-arginine and an extract of Ogaki as an active ingredient.

Short stature refers to a case where the height is less than 3% (third from the smallest of 100) in the normal distribution of children of the same age with the same sex. The causes of these short stature can be classified into normal stools with no disease, genetic tendency and constitutionally short stature, and short stature secondary to stool due to disease.

The normal mutation short stature may be again classified as familial short stature, constitutional growth delay, or idiopathic short stature. The familial short stature is genetically small, and the constitutional growth retardation is constitutionally late, and the height is now small but the puberty is late and the growth continues until late and the final adult height reaches the normal range. In addition, idiopathic short stature generally has a mean of -2 standard deviations below average or less than the third percentile, but has no cause to cause short stature, was born with normal weight at birth, (J Korean Pediatrics, Vol. 49, No. 7, 2006). In the present study, we examined the effects of growth hormone supplementation on growth hormone secretion in children.

On the other hand, short stature secondary to disease is divided into primary growth disorder (endogenous disorder) and secondary growth disorder (extrinsic disorder). The primary growth disorders include, but are not limited to, osteochondral dysplasia, short stature due to chromosomal anomalies (Down syndrome or Turner syndrome), unfavorable light weight (delayed in uterine growth), shortening due to Frederick-Willi Syndrome, , Short stature due to Noonan syndrome, and the like. The secondary growth disorders include short stature due to nutritional deficiency, short stature due to chronic system disease, short stature due to growth hormone deficiency, short stature due to hypothyroidism, short stature due to sexual maturity, short stature due to Cushing's syndrome, This can be.

The majority of children who visit a hospital with short stature are short stature that belongs to normal variation. According to foreign studies, 80% of families with familial and constitutional short stature, 10% with growth hormone deficiency, 4% with thyroid dysfunction, 3% with chronic diseases such as chronic renal failure, (1%), bone formation (1%), and mental illness (1%).

Growth hormone, which is mainly used for the treatment of short stature, was initially used only for short stature due to growth hormone deficiency in pediatric patients. However, its use expanded to extend to Turner syndrome, short stature due to chronic kidney failure and adult growth hormone deficiency, (Prader-Willi syndrome), and idiopathic short stature with a kidney of -2.25 SD or less (Kim et al., 2004), the indications for children with idiopathic short stature The effect of growth hormone on the growth of human pituitary dwarf. In Korea, in August 2009, recombinant human growth hormone was approved by the Korea Food and Drug Administration (KFDA) for a new indication for idiopathic short stature in children.

In particular, many children with idiopathic short stature have increased kidney growth after one or two years of growth hormone use but are uncertain as to whether the final adult height is increased. In the first year of growth, the growth rate was 2.86 cm higher than that of untreated children and 5.3 years for growth hormone, according to the Cochrane report. 6 cm larger. There is no consistent conclusion as to whether the final adult height increases as the growth hormone dose increases, until the final adult height is reached, and whether the child with short stature will gain psychological benefit after treatment with growth hormone , Korean J Ped. Vol. 49. No. 7. 2006). In addition, growth hormone administration in idiopathic short stature is an ethical treatment for children with no disease, and it is necessary to use a high dose, and it is expensive for the general public to use growth hormone, resulting in a 2.5 cm increase in final adult height of $ 35,000 . The longer the treatment period, the greater the capacity to grow and the longer the growth hormone, the shorter the growth rate temporarily, and the individual treatment effect is very different, there is no indicator to predict who will respond. It is not easy to determine the use of growth hormone in the absence of long-term observations of future problems with long-term use of high-dose growth hormones (Shin, J., Pedagogy, Novelty of Growth Hormone Therapy, 2006).

On the other hand, conventional growth hormone injections are scheduled to be subcutaneously injected at home before going to bed every 6 to 7 times a week. Growing children who need to be injected every day suffer physical pain and psychological burden, and there are few hassles and psychological burdens on the part of the guardian who should give injections to their children. In addition, there is a sense of psychological burden of injecting and avoiding the eyes of others outside of the family, and it is difficult to refrigerate and transport injections during travel or long-term outpatient care (Kang, Hye-young et al. Economic evaluation. As a result of the questionnaire survey of the parents of the infants taking the daily injections, the quality of life quality or utility value of the infants was 0.584 (0-100 scale) ) Was 58.4% of the normal quality of life (100 points). The average quality of life was estimated to be 0.784, which is 78.4% of the normal quality of life (Gang, Hye-young et al.). The growth hormone (GH) Economic evaluation. In general, 3% of children receiving growth hormone are known to experience adverse drug reactions. Arthralgia, myalgia, but may be less frequent than adults and may cause fat atrophy at the injection site and temporary gynecomastia. In addition, changes in hormones and metabolites, including thyroid hormones, may occur, and thyroid function tests are performed every 3 to 6 months. In some of the unjustified lightweight children, facial asymmetry may be exacerbated. Elevation of intracranial pressure is well developed in children, especially in Turner syndrome, chronic renal failure, and chronic growth hormone deficiency syndrome. However, when the growth hormone is withdrawn, , Recent advances in growth hormone therapy, Korean J Ped. Vol. 49. No. 7. 2006).

The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have published a report on long-term epidemiological studies in patients with "somatropin" injections in the "childhood" to report the risk of mortality in the "somatropin preparation" . An analysis of approximately 7,000 young adults receiving the drug across France showed that the mortality rate for patients who received "somatropin" was about 30% higher than for the general population (the French population) (Food and Drug Administration, 2010).

According to the distribution of population by national age in 2009, about 6 million people aged 5 to 14 years, which is the period of growth treatment, accounted for about 180,000 persons, 3% of whom were short stature. Of the total number of patients with short-term disease. The total number of patients who received the prescription of growth hormone under the support of health insurance was 12,000 in 2012 as of 2009, % Have not been treated for low - stature. Many of the patients with short stature are not treated because of insured growth hormone treatment costs of 250-300,000 won a year, and short stature, which accounts for about 80% of short stature Idiopathic insomnia is not covered 1 year It is estimated that the high cost of 1,000 ~ 15 million won can be an economic burden and also due to the physical pain and psychological burden of the child who should be injected every day.

Growth hormone therapy was proven to be superior to other methods in terms of growth effects, but the combination of various factors such as cost and convenience showed only 29.1% (Huh, Kyung, Park, In this study, we conducted a questionnaire survey of children who visited our clinic. There is a large market demand for the potential market for oral products of low-shortness drugs to be estimated to be over 5 billion dollars (Hanol Pharm, Company Presentation Session, 2009).

On the other hand, under oriental culture, Chinese medicine is very favored for the treatment of diseases and health promotion. As a result of research on parents of children visiting growth clinics, The access to herbal medicine is much higher than the growth hormone, which is 13 times that of the treatment. A survey of parents of 823 children (416 boys and 407 girls) who visited the Sanggye Paik Hospital Growth Clinic from 2006 to 2007 showed that 33.4% of all parents had artificial management to increase their height, Among them, 37.8% of them were using growth-promoting herbal medicines, 37.1% of them were supplements to help them grow, and 2.9% of them received 3.0% growth hormone therapy. , Park Mi-jung, and college hospital growth clinics, Korean Journal of Pediatrics Vol. 52, No. 5, 2009). Most of the prescriptions used in oriental medicine clinics have not been validated for the growth model and there is a lack of pharmacokinetic and pharmacodynamic indexes. For herbal medicine used clinically, firstly, it is necessary to develop a modern science and demonstrate the effectiveness of the growth model at the experimental animal level. Growth hormone treatment was the highest with growth hormone treatment (29.1%), fitness equipment (6.6%), herbal medicine (6.2%) and growth supplement (2.8%) were the lowest among the 823 parents who visited the growth clinic. Growth hormone injections were the most satisfying compared to other methods. The growth effect proved to be superior to other methods in terms of growth. However, only 29.1% of the growth hormone injections were combined with various factors such as cost and convenience. (P <.05). In addition, the results of this study are as follows.

Therefore, there is a demand for development of a preparation derived from a natural product and having excellent bone growth promoting effect.

L-arginine is a synonym of (S) - (+) - Arginine; 2-Amino-5-guanidinopentanoic Acid; 2-Amino-5-Guanidinovaleric Acid; Arg; Arginine; L - (+) - Arginine; L-Arginine Free Base is Sigma Grade Crystalline, the formula is C ₆ H ₁₄ N ₄ O ₂ , and the molecular weight is 174.20. Appearance is white crystal or crystalline powder, with a slight peculiar smell and bitter taste. It is soluble in water (14.8% at 20 ° C) and is insoluble in ethanol. In 1886, Schulze and Steiger were discovered and found in sediments obtained from water extracts of bean sprouts of lupine. Then Hedin (1891) made it clear that there is a large amount of a single separation in the hydrolyzate of casein, Kossel (1896), in the semen of fish. It is the most basic amino acid with a guanidine group (-NHC (= N) NH ₂ ). In the protamine of the fish protein, which is a highly basic protein, about 2/3 of the total constituent amino acids are occupied by this product. It is contained in glassy state in plant seeds and garlic. It is a non-essential amino acid in that it is synthesized in vivo in animals, but since sufficient amount for the growth of young animals is not biosynthesized, it needs to be ingested externally to growing animals, and in this respect it has become a mandatory amino acid. It is listed in [FCC]. It is a natural type L-amino acid which is widely present in nature and is relatively contained in sperm protein such as fish. It is also the most basic amino acid, and its aqueous solution is alkaline. Although it is an essential amino acid, it plays an important role in the urea synthesis reaction and is involved in elemental circuits.

In addition, Ogapi is the dried root of Ogalpia Acanthopanax sessiliflorus SEEMAN or other roots, stem and branches of five plants. In China, it originated from the dried root bark of A. gracilistylus WW SMITH. It is taken in summer and autumn, peeled off the root bark, and dried. Ogapi is mainly composed of syringin, eleutheroside B1, palmiticacid, linolenicacid, stearicacid, vitamin A and vitamin B, and polysaccharide. It has anti-inflammatory action, immunosuppressive action, sedative and analgesic action, anti-fatigue and anti- Have been reported.

However, there has been no report on bone length growth using L-arginine and Ogaki extract. Accordingly, the present inventors have studied the effect of L-arginine and Ogaki extract on bone length growth of such a complex, and completed the present invention.

Korea Patent Publication No. 2003-0030336

It is an object of the present invention to provide a food composition for promoting growth of bone length comprising L-arginine and an extract of Ogaki as an active ingredient.

The present invention provides a food composition for promoting bone length growth comprising L-arginine and an extract of Ogaki as an active ingredient.

In addition, the Ogaki extract may be extracted from water, an alcohol, or a mixed solvent thereof. The alcohol is preferably a C1-C4 lower alcohol, more preferably methanol or ethanol. The extraction method may be, but not limited to, shaking extraction, Soxhlet extraction, or reflux extraction. The extraction temperature is preferably 40 to 100 캜, more preferably 60 to 80 캜. The extraction time is preferably 2 to 24 hours, and the extraction time is preferably 1 to 5 times.

The L-arginine and Ogaki extract may be mixed at a weight ratio of 1: 1 to 1: 5, preferably 1: 2 to 1: 4, and the best bone length growth effect .

The food composition of the present invention comprising the L-arginine and the extract of Ogaki as an active ingredient has been found to be excellent in growth hormone level and thus can be used as a food composition for promoting bone length growth.

Since the food composition of the present invention has been found to have a bone length growth effect, it can be used for preventing or improving growth disorders.

The growth disorder may be short stature, short stature, or short stature secondary to disease. The normal mutated short stature may be familial short stature, constitutional growth retardation, and idiopathic short stature in agreement. The primary growth disorder may be osteochondral dysplasia, chromosomal aberration (Down syndrome or &lt; RTI ID = 0.0 &gt; Turner syndrome), short stature due to Russell-Silver syndrome, and short stature due to Noonan syndrome. The secondary growth disorders include chronic (chronic) Short stature due to systemic disease, short stature due to growth hormone deficiency, short stature due to hypothyroidism, short stature due to Cushing's syndrome, and psychosocial dwarfism.

Furthermore, since the food composition of the present invention contains a herbal composition, it can promote bone length growth without side effects.

In addition, since the food composition of the present invention has no toxicity and side effects, it can be safely used even when taken for a long time.

The food composition according to the present invention may further contain the L-arginine and the extract of Ogaki as it is, or may further contain an additive or the like in other food compositions, health functional foods or beverages.

For example, the food composition of the present invention may contain sweetening agents such as sucrose, fructose, glucose, D-sorbitol, mannitol, isomaltooligosaccharide, stevioside, aspartame, acesulfame potassium, sucralose, Preservatives such as malic acid, benzoic acid and derivatives thereof, various nutrients, vitamins, minerals (electrolytes), flavorings such as synthetic flavors and natural flavors, coloring agents and thickening agents (cheese, chocolate Etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. In addition, the food compositions of the present invention may contain flesh for the production of natural fruit juices and vegetable drinks. These additives may be used in a range of about 20 parts by weight or less per 100 parts by weight of the food composition of the present invention.

When the food composition of the present invention is a beverage, it may further include a flavoring agent or a natural carbohydrate conventionally contained in beverages. The natural carbohydrates may be monosaccharides such as glucose and fructose, polysaccharides such as disaccharides such as maltose and sucrose, dextrin, cyclodextrin or sugar alcohols such as xylitol, sorbitol and erythritol. The flavoring agent may be a natural flavoring agent such as tautatin, stevia extract (rebaudioside A, glycyrrhizin, etc.), or a synthetic flavor such as saccharin and aspartame. If the food composition is a beverage, the natural carbohydrate may generally comprise about 1 to 20 g, preferably about 5 to 12 g per 100 mL of the composition.

The food composition of the present invention may be prepared in the form of powder, granule, tablet, capsule or beverage, and may be used as food, beverage, gum, tea, vitamin complex, and health supplement food.

In addition, the food composition of the present invention may be added to medicines, foods, beverages and the like for promoting bone length growth. For example, the food composition of the present invention may be added to foods, beverages, gums, tea, vitamin complexes, health supplements and the like.

The food composition of the present invention may be added to foods or beverages to promote bone length growth. The composition of the present invention may be added at 1 to 5% by weight of the total weight of the food, and may be added at a ratio of 0.02 g to 10 g, preferably 0.3 g to 1 g, to 100 mL of the beverage.

The food composition containing the L-arginine and the extract of Ogaki as an active ingredient according to the present invention exhibits an effect of promoting the growth of bone length.

Fig. 1 is a photograph of a luminescence generated by depositing on a growth plate of a fossa tibia after deposition of tetracycline in a rat, and photographing it with a fluorescence microscope.
2 is a graph showing the degree of bone length growth in a rat.

Hereinafter, preferred embodiments and experimental examples are presented to facilitate understanding of the present invention. However, these examples and experimental examples are provided only for the purpose of easier understanding of the present invention, and the scope of the present invention is not limited by the following examples and experimental examples.

EXAMPLES Preparation of Composite Composition

L-arginine was purchased from Sigma, and acaphenic acid (Acanthopanax sessiliflorus) was purchased from medicaments and used after being validated by Kyunghee University College of Oriental Medicine. To prepare the extract, 5 g of 70% ethanol was added to 500 g of ogapi, followed by reflux extraction at 80 ° C for 3 hours, followed by filtration through a filter paper. The extract was concentrated under reduced pressure and freeze-dried to obtain 32.3 g (yield: 6.5%). L-arginine and Ogaki extract were mixed and administered in the same composition and weight ratio as in [Table 1].

[Table 1]

< Comparative Example  1 > L-arginine (L- arginine )

The L-arginine used was purchased from Sigma.

&Lt; Comparative Example 2 > Acanthopanax sessiliflorus ) Preparation of extract

Acanthopanax sessiliflorus was purchased from medicines and was used after being verified by Kyunghee University College of Oriental Medicine. To prepare the extract, 5 g of 70% ethanol was added to 500 g of ogapi, and the mixture was refluxed at 80 ° C for 3 hours and then filtered through a filter paper. The extract was concentrated under reduced pressure and freeze-dried to obtain 32.3 g (yield: 6.5%).

The compositions of Comparative Examples 1 and 2 were administered in the amounts shown in Table 2 below.

[Table 2]

Experimental Example Confirmation of Bone Length Growth Effect of Composite Composition of L-arginine and Ogaki Extract-Tetracycline Staining

<1-1> Preparation of experimental animals

A 4-week-old female sprague-dawley (Samtaco, Korea) female rat, weighing 100 g, was used as an experimental animal, and the feed and water were sufficiently supplied to adapt to the experimental environment. After an adaptation period of about one week, animal experiments were conducted.

<1-2> Confirmation of bone length growth effect

Two days after the start of administration in all experimental groups, 20 mg / kg of tetracycline hydrochloride (Sigma T7660) was intraperitoneally injected. Two days after the administration, the rats were sacrificed by sacrificing the cervical vertebra. The tibia of the right and left tibia was removed, fixed at 4 ° C for 3 days, fixed in 50 mM EDTA for 1 day, For protection, it was soaked in 30% sucrose overnight. The dehydrated bone tissue was frozen in the above manner and then the sagital section of the proximal part of the tibia was collected by cutting 40 쨉 m using a sliding microtome (HM440E, Zeiss, Germany) . For measurement of bone growth, proximal tibial sagittal slices collected at 40 ㎛ were placed on a slide glass, dried, and then photographed under ultraviolet light of 400 nm wavelength through a fluorescence microscope (see FIG. 1). The length of fluorescent bands formed by deposition of tetracycline in the growth plate and bone tissue was measured using ImageJ (NIH, USA) image analysis program. Student's t-test and ANOVA test Respectively.

<1-3> Administration of L-arginine

The L-arginine of Comparative Example 1 was dissolved in secondary distilled water at a concentration of 10 mg / kg in a volume of 1.0 ml per 100 g of rat body weight, and the control group was administered with the same volume of secondary distilled water. L-arginine was orally administered two days before the administration of tetracycline, and twice daily for four days from the end of the experiment.

&Lt; 1-4 > Administration of Ogphi Extract

The extract of Ogaki prepared in Comparative Example 2 was dissolved in secondary deionized water at a concentration of 30 mg / kg in a volume of 1.0 ml per 100 g of rat body weight, and the control group was administered with the same volume of secondary distilled water. The extracts were orally administered two days before the administration of tetracycline and twice a day for four days from the end of the experiment.

&Lt; 1-5 > Administration of Composite Composition (Example)

The composite composition prepared in this Example was dissolved in secondary distilled water at a volume of 1.0 ml per 100 g of rat body weight, and the control group was administered with the same volume of secondary distilled water. The composite composition was orally administered two days before the administration of tetracycline to the end of the experiment twice daily for four days.

<1-6> Administration of positive control group

Positive control groups were reported to have increased bone growth (recombinant human growth hormone (rhGH) (Isgaard J, Nilsson A, Lindahl A, Jansson JO, and Isxson OG: Effects of local administration of GH and IGF-1 on longitudinal bone 20 μg / kg of recombinant human growth hormone (rhGH; LG Lifescience, Eutropin®) was administered in a volume of 0.1 ml per 100 g of rat body weight . The positive control group was subcutaneously injected once a day for 2 days from the administration of tetracycline to the end of the experiment for 4 days.

<1-7> Confirmation of bone length growth effect of composite composition

Direct measurement of bone length by tetracycline staining revealed a significant bone length growth rate of 377.2 ± 27.5 ㎛ / day (n = 10) in the positive control and 348.9 ± 37.6 ㎛ / day (n = 10) , p < 0.01).

(N = 10) and 366.8 ± 19.1 ㎛ (n = 10) in the group administered with L-arginine 10 mg / kg (po) (Comparative Example 1) / day (n = 10) did not show any significant increase compared to the control group (0.0%, 5.1%, respectively).

On the other hand, it was confirmed that the bone growth effect was significantly higher than that of the normal control group by showing the bone length growth rate of 375.3 ± 40.5 μm / day (n = 10) in the group administered with the composite composition of L-arginine and Ogaki extract (7.6%, p < 0.05) (Fig. 2).

Therefore, it was confirmed that the bone length-growing effect, which was not observed when the L-arginine and the extract of Ogaki were administered separately, was remarkably increased in the composite composition.

The experimental results are summarized in Table 3 below.

[Table 3]

Claims (4)

L-arginine and an extract of Ogaki as an active ingredient. The food composition according to claim 1, wherein the safflower extract is extracted with water, a C1-C4 alcohol, or a mixed solvent thereof. The food composition according to claim 1, wherein the weight ratio of L-arginine and acai extract is from 1: 1 to 1: 5. The method according to claim 1, further comprising the step of administering to the subject a composition selected from the group consisting of familial short stature, constitutional growth retardation, idiopathic short stature, osteochondral dysplasia, short stature due to Down syndrome, short stature due to Turner syndrome, Growth disorders selected from the group consisting of short stature due to Russell-Silver syndrome, short stature due to Noonan syndrome, short stature due to chronic system disease, short stature due to growth hormone deficiency, short stature due to hypothyroidism, short stature due to Cushing's syndrome, and psychosocial dwarfism &Lt; / RTI &gt;

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