KR20030022655A - Pharmaceutical Compositions and Health Foods for Inducing IGF-1 Secretion - Google Patents

Abstract

The present invention relates to a pharmaceutical composition and a health food comprising a pharmaceutically effective amount of a baekshou extract, a health extract, a gilge extract or a mixture thereof, comprising a pharmaceutically acceptable carrier, wherein the pharmaceutical composition of the present invention Since the extracts of Baek Sewao, Health and Giltyeong, which have been used as herbal medicines in the past, as an active ingredient, are stable to the human body, and the extracts of Baekshou, Health and Giltyeong, including IGF-1 secretion inducing components, are simple processes. It can be produced in large quantities and economically very useful, it can contribute significantly to secure a large amount of raw materials for IGF-1 secretion promoter that has not been solved in the prior art.

Description

Pharmaceutical Compositions and Health Foods for Inducing IGF-1 Secretion

The present invention relates to a pharmaceutical composition and a health food for inducing IGF-1 secretion, and more particularly, comprising a pharmaceutically effective amount of a medicinal herb extract, health extract, Giltung extract or mixtures thereof. A pharmaceutical composition comprising an acceptable carrier and a health food.

Insulin-like Growth Factor-1 (IGF-1) is a single-chain polypeptide consisting of 70 amino acids and is primarily secreted by the liver. IGF-1 exerts its function through the IGF-1 receptor. Many studies have been conducted on the in vivo function of IGF-1, and such studies have identified various functions other than promoting growth of IGF-1 (eg, promoting protein synthesis, reducing blood glucose levels, and promoting cell differentiation).

For example, Arsenijevic Y. et al, J. Neurosci. , 15; 21 (18): 7194 (2001) report that IGF-1 is essential for the proliferation of neuronal stem cells, and Cappola AR. et al., J. Clin. Endocrinol. Metab. , 86 (9): 4139 (2001) report a direct link between decreased muscle strength and decreased motor activity and decreased in vivo concentrations of IGF-1 in older women.

In addition, reports that skeletal muscle regeneration can be accomplished via IGF-1 have been reported by Shiotani A. et al., Gene Ther. 8 (14): 1043 (2001), and it has been reported that the bioavailability of IGF-1 is significantly reduced after ethanol overdose (Rojdmark S. et al., J. Endocrinol. Invest. , 24 (7): 476 (2001). On the other hand, it has been reported that IGF-1 plays an important role in cell proliferation (Singleton JR. Et al., Neurobiol. Dis. 8 (4): 541 (2001)), and diabetic patients (types 1 and 2). It has also been reported that IGF-1 has therapeutic effects in the form (Thraikill KM, Diabetes Technol Ther., 2 (1): 69-80 (2000)).

Seck T. et al. Found that low blood levels of IGF-1 were directly associated with femoral decline in postmenopausal women ( Clin. Endocrinol. , 55 (1): 101 (2001)), Conti. E. et al. Reported a rapid decrease in IGF-1 in the acute stage of myocardial infarction ( J. Am. Coll. Cardiol. , 38 (1): 26 (2001)).

Various reports have shown that IGF-1 has cellular protection against ischemia-reperfusion injury in various organs. Nakao Y. et al., J. Thorac Cardiovasc. Surg. , 122 (1): 136 (2001) report that IGF-1 has the ability to inhibit neuronal cell death. In addition, IGF-1 deficiency leads to a lack of postnatal growth, delayed mental development, microcephaly and insensitivity of sensory nerves, and in patients with these symptoms, growth hormone is normally secreted and signaling by growth hormone is normally achieved. However, it has been reported that IGF-1 is not produced locally or systemically (Woods KA. Et al., N. Engl. J. Med. , 335: 1363 (1996)). On the other hand, administration of IGF-1 to patients deficient in IGF-1 has been reported to improve gymnastics, insulin sensitivity, bone mineral density and length growth (KA Woods. Et al., J. Clin. Endocri. Met., 85: 1407 (2000).

See also Blum et al. ( J. Clin. Endocrinol. Metab. 76: 1610-1616 (1993)) reports that children with low levels of IGF-1 and IGF binding protein 3 (IGFBP-3) in the blood are short and tall Older children reported high levels of IGF-1. In another paper, long-term treatment of IGF-1 has been reported to be effective in increasing key growth rates (Ranke et al., Horm. Res. 44: 253-264 (1995)). It was found to be effective in the treatment of patients lacking growth hormone.

As described above, IGF-1 functions in vivo in a variety of functions, acts cooperatively or separately with the growth hormone, and in vivo by the growth hormone signal or individually. It can be seen that it has various functions.

Therefore, there is a need for a substance capable of promoting the production of IGF-1 in vivo.

Throughout this specification, a number of articles are referenced and their citations are indicated in parentheses. The disclosures of cited papers are incorporated herein by reference in their entirety, and the level of the technical field to which the present invention belongs and the contents of the present invention are explained in more detail.

As a result of earnest research efforts to solve the above-described needs of the art, the inventors of IGF-1 exhibiting the various in vivo functions described above by Baek Sewage Extract, Health Extract, Gilge Extract or a mixture thereof. The present invention has been completed by demonstrating the effect of inducing secretion and confirming that the medicines and foods containing the aforementioned extracts are harmless to humans.

Accordingly, an object of the present invention to provide a pharmaceutical composition for inducing IGF-1 secretion.

Another object of the present invention is to provide a health food for enhancing and physiological activity for the treatment and prevention of various physiological diseases caused by aging, and growth support purposes.

Still another object of the present invention is to provide a method for producing a component having IGF-1 secretion inducing activity from Baek Sewao, Health or Giltung.

Figure 1a is a graph showing the change in the concentration of blood IGF-1 by the extract of Baek Sewao of the present invention;

Figure 1b is a graph showing the concentration change of blood IGF-1 by the health extract of the present invention;

Figure 1c is a graph showing the change in the concentration of IGF-1 in blood by the gilyeong extract of the present invention; And

Figure 2 is a photograph showing the length growth of the thigh according to long-term administration of the extract of the present invention.

According to one aspect of the present invention, the present invention provides a pharmaceutical composition comprising (a) a pharmaceutically effective amount of baekshou extract, a health extract, a gilyeong extract or a mixture thereof; And (b) provides a pharmaceutical composition for the treatment or prevention of diseases caused by the reduction of insulin-like growth factor-1 (IGF-1) comprising a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention which induces the above-described IGF-1 secretion may be administered to a subject having reduced in vivo production of IGF-1 to improve various symptoms and diseases. For example, it can improve gymnastics, insulin sensitivity, bone mineral density and length growth, and also inhibit mental retardation, microcephaly, insensitivity of sensory nerves and femoral decline in postmenopausal women, and inhibit the proliferation of nerve cells. It can promote and can suppress the decrease of muscle strength and the decrease of exercise ability in an elderly woman. And it can promote growth for children and adolescents whose growth plates are not closed but who are slow or lacking.

The candidate substance that can be used as a secretion inducing agent of IGF-1 having such various functions was used as a herbal medicine in the present invention, because the herbal medicine is a natural substance and has been used as a medicine in the past and its stability has been proved. Among the herbs, Cynanchum wilfordii (Max) Hem & ley , Zingiberis officinale ROSC and Gildy Radix showed excellent induction of IGF-1 secretion.

On the other hand, the process of separating the physiologically active substances from natural products and separating them into meaningful purity should be accompanied by effective process development research. In particular, there are many considerations in terms of economics of production methods, maintenance and verification of the physiological activity of manufactured materials. Therefore, the present inventors have developed and confirmed a method for producing a large amount of extracts of IGF-1 secretion inducing components from natural herbal medicines without loss of efficacy. In particular, since herbal medicines are generally expensive, economical aspects are a very important consideration in the method of separating bioactive substances.

In the pharmaceutical composition of the present invention, the extract is an extract obtained by extracting the above-described herbal medicine by hot water heating and then filtering with an ultrafiltration membrane. The solvent used at the time of extraction by heating is water, which is intended to ensure that the resulting composition is not harmful to the human body, and an organic solvent such as methanol is not used in the present invention.

On the other hand, the heating is preferably carried out at 60 ° C-95 ° C, and when it is 60 ° C or less, the active ingredient is not well extracted from the herbal medicine, and when it exceeds 95 ° C, destruction of the active ingredient may be accelerated. Heating temperature becomes like this. More preferably, it is 80 degreeC-90 degreeC. The heat-extracted extract is then decanted and then the precipitate is removed by centrifugation or filter paper.

The clear extract from which the precipitate is removed is then separated according to the molecular weight to obtain an extract of low molecular weight. Separation according to the molecular weight that can be used in the present invention is carried out by an ultrafiltration method, which is selected from the various methods in consideration of the yield, convenience and economy.

In the present invention, the ultrafiltration membrane used for ultrafiltration is preferably molecular weight cut off of 30,000-100,000, and if MWCO is less than 30,000, it takes a long time to separate the extract. There is a problem in economics, when using a membrane of more than 100,000 MWCO there is a problem that the relative purity of the extract of the present invention is finally lowered because the separation of the bioactive component and the macromolecular substance is lowered. As for the ultrafiltration membrane in this invention, what uses MWCO 50,000-100,000 more preferably.

In the present invention, more preferably, the concentration step is performed following the ultrafiltration process. By the concentration step, an extract containing a high concentration of pharmacological components is prepared. Concentration can be carried out in a variety of methods commonly used in the art, for example, by reduced pressure heating. On the other hand, if necessary, the finally prepared extract may be powdered by drying under reduced pressure.

The above-described preparation method for preparing the composition of the present invention has the advantage that can be easily carried out, while separating the key components having a high purity, high yield and economically IGF-1 secretion action.

Diseases that can be treated or prevented by the pharmaceutical compositions of the present invention include all diseases caused by a decrease in IGF-1, but preferably are femoral bone decline, worsening of length growth, reduction of bone mineral density, aging or gymnastics Worsening, more preferably femoral decline or length growth worsening, most preferably femoral decline.

The pharmaceutical composition of the present invention has the activity of promoting bone formation by inducing secretion of IGF-1 in vivo, and has the activity of inhibiting bone loss.

According to a preferred embodiment of the present invention, the pharmaceutical composition of the present invention further comprises calcium, arginine, lysine, carboxymethyl cellulose or mixtures thereof. Among the additional components, calcium is the main inorganic component of bone, arginine enhances the secretion of growth hormone in the body, lysine enhances the action of arginine, and carboxymethyl cellulose inhibits the infiltration of the composite composition, This is because the possibility of proliferation can be reduced and at the same time it facilitates uniform mixing of several substances. When the pharmaceutical composition of the present invention further comprises the above ingredients, based on 100 parts by weight of the extract as an active ingredient, 65 to 80 parts by weight calcium, 25 to 40 parts by weight arginine, 5 to 20 parts by weight lysine and carboxymethyl 2-8 weight part of cellulose is more preferable.

Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like In addition, the above components may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like.

Suitable dosages of the pharmaceutical compositions of the invention vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to reaction, Usually a skilled practitioner can easily determine and prescribe a dosage effective for the desired treatment or prophylaxis. According to a preferred embodiment of the present invention, when orally administering the pharmaceutical composition of the present invention, a suitable dosage is 0.3 to 3 g once per day on an adult basis of Baek Sewage Extract, Health Extract, Gilge Extract or a mixture thereof. Will be administered. The route of administration of the pharmaceutical composition of the present invention may be oral or parenteral, but oral administration is preferred.

The pharmaceutical composition of the present invention may be formulated in a unit dose form by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by those skilled in the art. Formulated or incorporated into a multi-dose container, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium or in the form of extracts, powders, granules, tablets or capsules, dispersants or stabilizers It may further include.

According to another aspect of the present invention, there is provided a health food composition for inducing IGF-1 secretion, comprising as an active ingredient a white sewage extract, a health extract, a Gilt extract or a mixture thereof.

The health food of the present invention may include ingredients that are commonly added during food production. For example, when prepared with a drink, in addition to the active ingredient of the present invention, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, tofu extract, jujube extract, licorice extract, and the like may be further included in powder form. When prepared, the active ingredient of the present invention may be powdered, and then essential ingredients such as lysine, arginine, ornithine, glycine and tryptophan, and components such as niacin and gamma hydroxy butyrate may be further included.

The composition of the present invention comprising a Baek Sewao extract, health extract, Gil Gyeong extract or a mixture thereof may be used for various purposes such as adult-oriented weak constitution and anti-aging, osteoporosis prevention, gymnastic improvement.

Since the composition of the present invention not only promotes the secretion of IGF-1 effectively but also uses white sewage, Giltyeong and health, which has been proved to be safe and already used as a herbal medicine, there are few side effects on the human body.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it is to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. Will be self-evident.

Example

Example material

BaekHasuo, Health and Gilkyung purchased the dried products in the shade at Gyeongdong Market, located in Jongno-gu, Seoul, Korea, and used them to manufacture extracts.

Example 1: Preparation of Active Ingredient

Baek sewage extract, health extract and Gilgyeong extract, which are active ingredients of the pharmaceutical composition for inducing IGF-1 secretion, were prepared, respectively.

Example 1-1 Preparation of White Sewage Extract (I)

50 g of white sewage was immersed in 1.5 L of distilled water, and heated and filtered at 90 DEG C for 2 hours to obtain 0.7 L of an aqueous extract. 0.7 L of the obtained extract was stored at room temperature, 0.7 L of distilled distilled water was added to the filtered solid, and the aqueous extract obtained by heating and filtering at 90 ° C. for 2 hours was mixed with the extract stored at room temperature. Heating at 90 ° C. yielded 500 ml of concentrated extract. Subsequently, the supernatant was obtained by centrifugation at 3000 xg for 10 minutes in a table top centrifuge, and a stirred cell apparatus (Amicon, USA) using 3 atmospheres of nitrogen and a 50,000 MWCO (76 mm diameter) ultrafiltration membrane was used. Filtration was used. At this time, if clogging occurred in the concentration of the extract was replaced with a new ultrafiltration membrane and continued operation, the clogged membrane was washed with a washing solution (0.1 N caustic soda, 20% ethanol) and reused.

In order to measure the extraction efficiency in the extraction step and the filtration step, the extraction efficiency was calculated based on the weight of the powder obtained by drying the extract obtained in each step (freeze dryer, Edwards, U.S.A.).

Example 1-2: Preparation of White Sewage Extract (II)

A white sewage extract was prepared in the same manner as in Example 1-1 except that an ultrafiltration membrane of 100,000 MWCO (76 mm in diameter) was used instead of an ultrafiltration membrane having a molecular weight of 50,000 MWCO (76 mm in diameter). The extraction efficiency of was calculated and then compared with the extract prepared in Example 1-1. The results are shown in Table 1.

division Weight (g) Extraction efficiency (%) Early herbs 50 100 Heating and extraction stage 15 30 50,000 MWCO Filtration 9 18 100,000 MWCO Filtration 11 22

Example 1-3 Preparation of Health Extracts (I)

Except for using 50 g of health instead of 50 g of Baek Shou, healthy extracts were prepared using the same method as in Example 1-1, and their extraction efficiency was calculated.

Example 1-4 Preparation of Health Extracts (II)

Same as Example 1-1, except that 50 g of health was used instead of 50 g of White Sea and 100,000 MWCO (76 mm in diameter) ultrafiltration membrane in place of 50,000 MWCO (76 mm in diameter) ultrafiltration membrane. Health extracts were prepared using the method, their extraction efficiency was calculated, and then compared with the extracts prepared in Examples 1-3. The results are shown in Table 2.

division Weight (g) Extraction efficiency (%) Early herbs 50 100 Heating and extraction stage 9.5 19 50,000 MWCO Filtration 2 4 100,000 MWCO Filtration 3 6

Example 1-5: Preparation of Gilt Extract (I)

Except for using 50 g of long diameter instead of 50 g of white sewage, Giltung extracts were prepared using the same method as in Example 1-1, and their extraction efficiency was calculated.

Example 1-6 Preparation of Gilt Extract (II)

Same as Example 1-1, except that 50 g of long diameter was used instead of 50 g of white sewage, and 100,000 MWCO (76 mm in diameter) ultrafiltration membrane was used instead of 50,000 MWCO (76 mm in diameter) ultrafiltration membrane. Gilyeong extracts were prepared using the method, their extraction efficiency was calculated, and then compared with the extracts prepared in Examples 1-5. The results are shown in Table 3.

division Weight (g) Extraction efficiency (%) Early herbs 50 100 Heating and extraction stage 9.5 19 50,000 MWCO Filtration 4.3 8.5 100,000 MWCO Filtration 5.5 11

As can be seen from Tables 1 to 3, considering both the extraction efficiency and the degree of purification of the IGF-1 secretion component, it can be seen that it is preferable to use an ultrafiltration membrane having a MWCO of 100,000 or less.

Example 2: In vivo IGF-1 secretion induction effect of the extract of the present invention

First, 252 mg of each powder extract prepared in Examples 1-1, 1-3, and 1-5 were dissolved in 1 ml of distilled water, respectively, to prepare respective dosage solutions.

Meanwhile, in order to increase the responsiveness to growth hormone secretion stimulation, a 9-week old male Sprague Dawley rat having an average weight of about 300 g was fasted for a day according to a conventional method, and they used an oral syringe. Then, a control group administered orally with 1 ml of distilled water, Experimental group 1, in which the Baek-Siao extract was administered in the same manner, Experimental group 2, in which the health extract was administered in the same manner, and Experimental group 3, in which the Gilkyung extract was administered in the same manner, were prepared. In addition, in order to measure the concentration of IGF-1 in each control group and the experimental group, blood was collected from the tail 2 hours before administration, and from the tail after 2 hours, 4 hours, 6 hours, 8 hours and 10 hours after administration. Anesthetics that could affect the growth hormone secretion pattern were not used.

Each blood sample was applied to an EIA (enzyme immunoassay) kit (Diagnostic System Laboratory, U.S.A.) to quantify the amount of IGF-1 contained in each blood sampled. The results are shown in Figures 1a to 1c.

1A to 1C are graphs showing the concentration of IGF-1 in blood changed over time. As can be seen in Figures 1a to 1c, the concentration of IGF-1 in the experimental group increases compared to the control group as time passes from 4 hours after administration, this aspect showed a maximum after 8 hours of administration, after Gradually decreased. In addition, over time, it can be seen that the concentration of IGF-1 in the blood as a whole decreases, which is a natural phenomenon according to the biological rhythm in the rats used as the experimental group, it is accurately determined the effect of the pharmaceutical composition of the present invention In order to compare the absolute amount of IGF-1 concentration with time, the IGF-1 concentration of the control group and the IGF-1 concentration of the experimental group should be compared at each time period.

Therefore, it can be seen that the Baekshou, Health and Giltung extracts of the present invention induce the secretion of IGF-1.

Example 3: Confirmation of length growth promotion by the extract of the present invention

The powder extracts prepared in Examples 1-1, 1-3, and 1-5 were added to the feed with the compositions shown in Table 4 to prepare feed for IGF-1 secretion.

ingredient Content (per 15 g of feed) White Sea Extract 15 mg Health extract 15 mg Gilt Extract 20 mg Seaweed calcium 37.5 mg Arginine 16.8 mg Lee Sin 5.6 mg CMC (carboxy methyl cellulose) 2.25 mg Etc -

Then, the control group fed the composition to the three-week-old male Sprague Dawley rats for 8 weeks and the composition missing the active ingredient under the same conditions, and prepared a control group and the femoral bones of the experimental group was extracted to change the length growth Was measured. The result is shown in FIG.

In FIG. 2, the bone present on the right side of the center line is the thigh bone extracted from four experimental groups, and the bone on the left side is the thigh bone extracted from four control groups. As can be seen in Figure 2, when feeding the composition of the present invention, it was found that the length of the femoral bone, which is an indicator of the length growth of the animal increases.

Preparation example: health food drink

80 mg of distilled water obtained by dissolving 15 mg of white sewage extract, 15 mg of health extract and 20 mg of Gilkyung extract obtained in Examples 1-1, 1-3 and 1-5, 10 ml of liquid fructose, 0.5 ml of citric acid and licorice extract 9.5 ml were mixed to prepare a drink of the present invention.

As described in detail above, the present invention provides a pharmaceutical composition and a health food composition comprising an IGF-1 secretion inducing component. The pharmaceutical composition of the present invention is stable to the human body, since each of the extracts of Baekshou, health and Giltyeong, which has been conventionally used as a herbal medicine, as an active ingredient, is stable to the human body, and the Baekshou, health and Each extract of Gilgil can be produced in a large amount by a simple process, so it is economically very useful, and can significantly contribute to securing a large amount of IGF-1 secretion promoter raw materials that were not solved in the art. In addition, the Baek Shou, health and Giltyeong extract of the present invention can be administered orally in the form of medicines or health foods to children and adults with low IGF-1 secretion.

Claims (10)

(a) a pharmaceutically effective amount of baekshou extract, health extract, gil dynasty extract, or mixtures thereof; And (b) a pharmaceutical composition for the treatment or prevention of diseases caused by a reduction in insulin-like growth factor-1 (IGF-1) comprising a pharmaceutically acceptable carrier. A health food composition for inducing secretion of IGF-1 comprising Baek Shou extract, health extract, Gil Kyung extract or a mixture thereof as an active ingredient. The composition of claim 1 or 2, wherein the extract is prepared by a method comprising the following steps: (a) extracting white sewage, health, gil dynasty or mixtures thereof with hot water at 60-95 ° C. to obtain a crude extract; And (b) filtering the initial extract using an ultrafiltration membrane having a molecular weight cutoff of 30,000-100,000. 4. The composition of claim 3, wherein the temperature of the hot water is 80-90 ° C. The composition according to claim 3, wherein the molecular weight cutoff of the ultrafiltration membrane is 50,000-100,000. The method of claim 1, wherein the pharmaceutical composition further comprises calcium, arginine, lysine, carboxymethyl cellulose, or a mixture thereof, wherein the medicament for the treatment or prevention of diseases caused by the reduction of IGF-1. Pharmaceutical composition. 2. The reduction of IGF-1 according to claim 1, wherein the disease caused by the reduction of IGF-1 is selected from the group consisting of femoral decline, deterioration in length growth, reduction of bone mineral density, deterioration of aging and gymnastics. Pharmaceutical compositions for the treatment or prevention of diseases caused by. 8. The pharmaceutical composition for the treatment or prophylaxis of a disease caused by a decrease in IGF-1 according to claim 7, wherein the disease caused by a decrease in IGF-1 is femoral decline or length growth worsening. The composition of claim 1 or 2, wherein the composition has an activity of promoting bone formation. The composition of claim 1 or 2, wherein the composition has an activity of inhibiting bone loss.