CN107072974A

CN107072974A - The composition comprising L arginine and Panax sessiliflorus extract for promoting longitudinal bone growth

Info

Publication number: CN107072974A
Application number: CN201580026746.2A
Authority: CN
Inventors: 金护哲; 金智暎; 朴珠妍; 权容凡; 宋美庚; 李东宪
Original assignee: Industry Academic Cooperation Foundation of Kyung Hee University
Current assignee: Industry Academic Cooperation Foundation of Kyung Hee University
Priority date: 2014-03-26
Filing date: 2015-03-25
Publication date: 2017-08-18
Anticipated expiration: 2035-03-25
Also published as: KR101774085B1; KR20150112082A; CN107072974B; WO2015147538A1

Abstract

Present disclose provides a kind of composition for being used to promote longitudinal bone growth, it contains L arginine Panax sessiliflorus extracts as active component.The composition display of the disclosure promotes the effect of longitudinal bone growth.

Description

For promote longitudinal bone growth comprising L-arginine and Panax sessiliflorus extract Composition

Technical field

This disclosure relates to the pharmaceutical composition for promoting longitudinal bone growth, it is carried comprising L-arginine and Panax sessiliflorus Thing (Acanthopanax sessiliflorus extract) is taken as active component.

The disclosure further relates to the food compositions for promoting longitudinal bone growth, and it includes L-arginine and Panax sessiliflorus Extract is used as active component.

Background technology

Short stature (short stature) means that wherein height is less than same age and the normal body of the children of sex The situation of 3% (the 3rd in 100 children since most short) in height distribution.Such short stature is former according to it Because being categorized as：It is attributed to genetic predisposition (predisposition) and constitutional short and small tendentious, without any disease Normal variant short stature disease (normal variant short stature), and be attributed to disease Secondary cases stature it is short Small disease.

Normal variant short stature disease can be categorized further, as to familial short stature (familial short Stature), constitutional delay of growth (constitutional growth delay) and idiopathic short stature (idiopathic short stature).Familial short stature corresponds to height situation low in heredity, and body Matter growth delay is to be grown in constitutionally evening and current height is low but be due to late puberty and grow and be continued until very Big age and the situation of final adult height arrival normal range (NR).Finally, idiopathic short stature can be defined as so Children：Its suffer from short stature, with than since average height -2 standard deviations (SD) it is short or below the 3rd hundredths Height, without result in the cause specific of short stature, be born with normal birth weight, with normal four limbs and stem length Degree ratio, takes in enough nutrition, and without psychosocial problems, and (Shin et al., current growth swashs normal secretions growth hormone Use (Current use of growth hormone in children) of the element in children, Korean J Ped.Vol.49.No.7.2006)。

On the other hand, Primary growth obstacle (endogenous barrier can be included by being attributed to the Secondary cases short stature of disease Hinder) and secondary growth obstacle (exogenous growth obstacle).The example of Primary growth obstacle can include bone cartilage development not Good (osteochondrodysplasia), it is attributed to the of short and small stature of chromosome abnormality (chromosomal abnormality) Disease (Down syndrome (Down Syndrome) or Turner syndrome (Turner Syndrome)), less than gestational age (small for Gestational age) (intrauterine growth retardation (intrauterine growth retardation)), be attributed to pula moral- The short stature of Willi Syndrome (Prader-Willi Syndrome), it is attributed to Russell-Silver syndrome The short stature of (Russell-Silver Syndrome) and the body for being attributed to Noonan syndrome (Noonan Syndrome) Material dwarfism.In addition, the example of secondary growth obstacle can include the stature for being attributed to malnutritive (malnutrition) Dwarfism, the short stature for being attributed to chronic systemic disease (chronic systemic disease), it is attributed to growth The short stature of anhormonia (growth hormone deficiency), it is attributed to hypothyroidism (hypothyroidism) short stature, it is attributed to sex premature (precocious puberty) short stature, returns Because in Cushing syndrome (Cushing ' s Syndrome) short stature and social mentality's sexual dwarfism (psychosocial dwarfism)。

Most of children gone to see a doctor by short stature are classified as normal variant short stature disease.External grinds Study carefully and report, the reason for the patient with short stature in, familial and constitution short stature account for its 80%, growth swashs Element, which lacks, accounts for 10%, and dysthyreosis accounts for 4%, chronic disease such as chronic kidney failure (chronic renal ) etc. failure 3% is accounted for, chromosome abnormality accounts for 1%, skeleton development is bad to account for 1%, and mental illness accounts for it 1% (with growth Regulate and control establishment (the Establishment of function evaluation system of related functional evaluation system Related to growth regulation), 2003).

The growth hormone agent for being mainly used in treating short stature is initially only applied to being attributed to growth hormone deficiency Short stature children, but its application is expanded to the body for being attributed to Turner syndrome and chronic kidney failure Material dwarfism and adult growth hormone deficiency.In nearest FDA reports, it is treated indication and expanded in growth side Face is difficult to children up to standard, including torments, has less than gestational age, by Prader-Willi syndrome and idiopathic short stature (Lee Kyong-A et al., growth hormone therapy is with idiopathic short stature for those of height less than -2.25SD Effect (Effects of growth hormone therapy in children with idiopathic in children Short stature) .2005, Raben MS. using human growth hormone (HGH) pituitary dwarfism treatment (Treatment of a pituitary dwarf with human growth hormone).1958).Supervised in August, 2009 by Korean foods medicine Superintend and direct management board (Korea Food and Drug Administration) and newly have approved human growth hormone recombinant in children The treatment indication of idiopathic short stature.

Specifically, it has been observed that children of many with idiopathic short stature are using after growth hormone 1 to 2 Height increase is shown in year, it can be difficult to determining whether final adult height increases.Swashed based on Cochrane on growth The comprehensive report of plain therapy effect, when without using growth hormone compared with, using growth hormone First Year growth rate increase Add about 2.86cm, and when using growth hormone in the average value of 5.3 years, final adult height adds 4 to 6cm.Most The increase of whole adult height is bigger with the increase of the amount of growth hormone, and persistently needs to use growth hormone to reach Whether final adult height, psychological benefit can be obtained as the children with short stature after growth hormone therapy Place, in the absence of consistent conclusion.(Shin et al., use (Current use of of the current growth hormone in children Growth hormone in children), Korean J Ped.Vol.49.No.7.2006).In addition, because by therapeutic agent For the children of not any disease, to idiopathic short stature apply growth hormone be ethically problematic, and Also have the disadvantage in that, it is largely used and high price, 35 are amounted in order to which final adult height is increased into 2.5cm, 000 is beautiful Member.By longer treatment stage, growth result reduction, and therefore need to increase the amount of added growth hormone.When stopping When only using growth hormone, growth rate is temporarily reduce further, and in addition, therapeutic effect is equal for everyone Difference, and can predict the indication of sound response effect without proposition.In addition, being given birth to not used for long-term a large amount of use of detection In the case of the result of the long-term observation for the problem of being likely to occur after long hormone, it is difficult to determine use (Shin etc. of growth hormone People, use (Current use of growth hormone in children) of the current growth hormone in children, Korean J Ped.Vol.49.No.7.2006)。

Meanwhile, routine growth hormone injection be in it is hypodermic before sleep every night, 6 to 7 times weekly.Quilt daily The children grown up the experience physical distress and psychological pressure of injection, and the care-giver's incident being inoculated with to their child Meet mixedization (complication) and psychological burden.When travelling or carrying out long trips, the stored under refrigeration of injection and transport It is difficult, and there is the psychological pressure that those people beyond family are hidden with such inoculation.(Kang et al., for treating Economic evaluation (the Economic evaluation of a of the release injectable of the growth hormone of children with growth hormone deficiency sustained-release injection of growth hormone for the treatment of children with growth hormone deficiency).2009).Care-giver's based on the child patient injected daily at present asks The result of investigation is rolled up, the effectiveness weight (utility weight) of the quality of the life for the child patient injected daily is 0.584 Average value (being 0 to 1 scoring yardstick by 0 to 100 reaction spatial scaling), equivalent to normal healthy state (100 points) 58.4%.In weekly injection, expected quality of the life is 0.784 average value, equivalent to normal healthy state 78.4% (Kang Hye-Young et al., the release injectable of the growth hormone for treating the children with growth hormone deficiency Economic evaluation (Economic evaluation of a sustained-release injection of growth hormone for the treatment of children with growth hormone deficiency).2009)。 It is known that, conventionally, 3% children for being administered growth hormone show side effect.Such children may meet with arthralgia (arthralgia) or myalgia (myalgia), but its frequency of occurrences is lower than being grown up, and may go out around injection areas Existing lipoatrophia.And Gynecomastia (gynecomastia) may temporarily occur.Furthermore, it is possible to occur including The change of hormone including thyroid hormone and metabolin, and therefore need to carry out thyroid function examination every 3 to 6 months Test, and in addition, in the asymmetric exacerbation of some patient's septum resets less than gestational age.May especially it be suffered from often in children Cause increased intracranial pressure in the patient of Turner syndrome, chronic kidney failure and organic growth anhormonia, still Part is recurred when it mitigates when stopping applying growth hormone and may reuse growth hormone.(Shin et al., when Use (Current use of growth hormone in children) of the preceding growth hormone in children, Korean J Ped.Vol.49.No.7.2006)。

Based on disclosed in France [on the long-term epidemiological study for the somatropin preparation for being applied to child patient (Long-term epidemiological studies with somatropin formulation administered To child patients)], eaten according to European drug administration (European Medicines Agency, EMA) and the U.S. Product Drug Administration (Food and Drug Administration, FDA), has begun to examine due to giving birth to using children Increase the risk of child mortality caused by long deficiency therapeutic agent " somatropin preparation ".As in whole France about 7, 000 application of same preparation young analysis result, use the death rate of patient of " somatropin preparation " higher than general Logical people's (whole France's population) about 30%, and the risk of the death rate increases (Korean foods due to the dosage more than allowance Drug Administration, 2010).

In South Korea's population distribution according to the age, such as 2009, receive the quantity of the population of 5 to 14 years old of growth treatment About 6,000,000, wherein the quantity of the population with short stature is about 180,000 people, account for its 3%.Participating insurance Number was 36,000 people in 2009, equivalent to its about 20%, and according to Health Insurance Review Agency (Health Insurance Review＆Assessment Service), receive the guarantor of the growth hormone therapy for treating short stature The total number of persons of the people of dangerous compensation was 12,012 people in 2009, and therefore as the people of participating insurance, with of short and small stature 24,000 people (about 66.6%) in the patient of disease do not receive the treatment of short stature.A large amount of patients for suffering from short stature The reason for not receiving such treatment is as follows：The patient with short stature is grown by insurance coverage even if working as During hormonotherapy, the expense for amounting to 2,500,000 to 3,000,000 won/year is also produced, and in addition, account for short stature The idiopathic short stature of case about 80% is not covered by insurance, it is undesirable to which ground generates 10,000,000 to 15,000,000 The high cost of won/year and the physical distress of children to injecting daily and psychological burden.

Although it have been demonstrated that growth hormone therapy have the growth result more outstanding than other therapys, due to including into Various factors including sheet, convenience etc., is only 29.1% (Huh Kyoung, Park Mi-Jung, to university to its satisfaction Promote the analysis (Questionnaire-based based on questionnaire of the trial of growth in the children for growing clinic analysis of growth-promoting attempts among children visiting a university Growth clinic), Korean Journal of Pediatrics Vol.52, No.5,2009).For short stature The world market potentiality of Orally taken product of therapeutic agent estimate as 5,000,000,000 dollars of (Hanall Biopharma, Corporate Presentation, 2009).

Meanwhile, in the culture of sub- state, Chinese medicine is very preferably used for therapeutic treatment and health is lifted.Based on being examined to growth The investigation result of the father and mother gone to a doctor, the quantity for taking the case for promoting the Chinese medicine grown increase child height is to carry out growth to swash 13 times of the quantity of the case of plain therapy, and the receiving to Chinese medicine compared with growth hormone is very high.According to from 2006 to 2007 to medical 823 of Shang Xibai hospitals of Ren Ji universities (Inje University Sanggye Paik Hospital) The investigation result of the father and mother of children's (416 male childrens and 407 Female Childrens), carries out manual therapeutic to increase the disease of height Example ratio be 33.4%, wherein by Chinese herbalist clinic apply promote growth Chinese medicine case account for its 37.8%, take supplement The case that product are used to increase height accounts for 37.1%, and the case for being related to exercise/body-building equipment therapy accounts for 3.0%, and is grown The case of hormonotherapy accounts for 2.9%, and (Huh Kyoung, Park Mi-Jung grow in the children of clinic to university and promoted Analysis (the Questionnaire-based analysis of growth-promoting based on questionnaire of the trial of growth Attempts among children visiting a university growth clinic), Korean Journal Of Pediatrics Vol.52, No.5,2009).Most of prescriptions for being used for clinical Chinese medicine not yet disclose it in growth model In effect and its pharmacokinetics and pharmacodynamics index lack., it is necessary to by dynamic for clinically available Chinese medicine Thing test scientifically proves its material of effect and exploitation with high effect in growth model.According to growth clinic just The investigation result of the father and mother of 823 children examined, be to the satisfaction for growing therapy：The highest for growth hormone therapy, It is 6.6% for exercise/body-building equipment therapy for 29.1%, is 6.2% for Chinese medicine, and mended for growth Fill minimum for product, be 2.8%.Compared with other method, Crescormon shows very high satisfaction, and Through confirming that its growth result is excellent according to medical research, but it is attributed to various factors, such as cost, convenience, to it Satisfaction be only 29.1%.(Huh Kyoung, Park Mi-Jung grow to university and promote life in the children of clinic Analysis (the Questionnaire-based analysis of growth-promoting based on questionnaire of long trial Attempts among children visiting a university growth clinic), Korean Journal Of Pediatrics Vol.52, No.5,2009).

Accordingly, it would be desirable to develop from natural material and to promoting the highly effective preparation of longitudinal bone growth.

The synonym of L-arginine has (S)-(+)-arginine, 2- amino -5- guanidinopentanoic acids (Guanidinopentanoic Acid), 2- amino -5- guanidinopentanoic acids (Guanidinovaleric Acid), Arg, arginine, L- (+)-arginine and L- essences The Sigma grades of crystallizations of propylhomoserin free alkali, and with C₆H₁₄N₄O₂Chemical formula and 174.20 molecular weight.L-arginine has white The outward appearance of color crystal or crystalline powder and the slightly smell and bitter taste of characteristic, are highly soluble in water (14.8% at 20 DEG C), and And insoluble in ethanol.In 1886, Schulze and Steiger were being obtained from the water extract of lupin (lupine) bud Found in sediment and named L-arginine.Afterwards, Hedin has separated L-arginine from the hydrolysate of casein , and Kossel has found that it is largely present in fish sperm (1896) (1891).As with guanidine radicals (- NHC (=N) NH₂) High alka amino acid, L-arginine constitute fry in protamine (it is a kind of protein of high alka) whole ammonia About 2/3rds of base acid.It is included in vegetable seeds and garlic with free state.As disclosed in [FCC], L- essence ammonia Acid is nonessential amino acid, because it can be synthesized in animal body, but be considered semi-dispensable amino acid, because can not give birth to Thing synthesis is sufficiently used for the amount of young animal growth, and therefore the animal in growth needs to obtain it from outside.It is deposited extensively It is in natural system, and especially, contains natural L-amino acids more in large quantities in the sperm protein of fish etc..This Outside, L-arginine is that have very high alkaline amino acid, and therefore its aqueous solution is alkaline.Although it is nonessential Amino acid, L-arginine plays an important roll and relevant with urea cycle in urea synthesizing.

In addition, Panax sessiliflorus is from the dry Panax sessiliflorus (Acanthopanax for belonging to Araliaceae (Araliaceae) Sessiliflorus SEEMAN) or the root of other plant of same genus, stem and branch skin.In China, it derives from slender acanthopanax The dry root skin of (Acanthopanax gracilistylus WW SMITH.).It is collected in summer and autumn and by its root Skin is peeled off and then dried.Panax sessiliflorus is main by syringin, Acankoreoside A B1, palmitic acid, leukotrienes, stearic acid, vitamin A and dimension Compositions such as raw element B, polysaccharide and it is reported that with antiphlogistic effects, immunosupress facilitation effect, calmness and analgesic effect, antifatigue With compressive resistance effect, blood sugar decreasing effect etc..

However, not yet report utilizes L-arginine and the longitudinal bone growth of Panax sessiliflorus extract research.Therefore, it is of the invention Inventor have studied the effect of L-arginine and Panax sessiliflorus extract and have determined the longitudinal direction of combinations thereof Bone growth effect, therefore complete the disclosure.

Disclosure

Technical problem

The purpose of the disclosure is to provide the pharmaceutical composition for promoting longitudinal bone growth, and it includes L-arginine and nothing Stalk slender acanthopanax extract is used as active component.

Another object of the present disclosure is to provide the food compositions for promoting longitudinal bone growth, and it includes the smart ammonia of L- Acid and Panax sessiliflorus extract are used as active component.

A further object of the present disclosure is to provide to be used to prepare comprising L-arginine and Panax sessiliflorus extract and is used to treat The purposes of the medicine of growth disorder.

Another purpose of the disclosure be to provide prevention or treatment growth disorder method, methods described include apply comprising L-arginine and Panax sessiliflorus extract as active component composition.

Technical scheme

Pharmaceutical composition

The disclosure provides a kind of pharmaceutical composition for being used to promote longitudinal bone growth, and it is comprising L-arginine and without stalk five Plus extract is used as active component.

Panax sessiliflorus can be extracted in water, alcohol or their mixture.Alcohol is preferably C1-C4 lower alcohols, and more excellent Choosing includes methanol or ethanol.Extraction process can include, but not limited to mechanical shaking extraction, surname extraction (Soxhlet ) or refluxing extraction extraction.Extracting temperature is preferably 40 to 100 DEG C, and more preferably 60 to 80 DEG C.In addition, when extracting Between be preferably 2 to 24 hours, and extraction process is preferred carries out 1 to 5 time.

In this way, can be carried with 1: 1 to 1: 5 and preferably 1: 2 to 1: 4 weight than mixing L-arginine and Panax sessiliflorus Take thing.When such weight ratio falls in the above range, excellent longitudinal bone growth effect can be obtained.

Such as in the application of growth hormone therapy, discovery contains L-arginine and Panax sessiliflorus extract as active component The pharmaceutical composition according to the disclosure there is outstanding longitudinal bone growth effect, and therefore may be used as be used for promote to indulge To the pharmaceutical composition of bone growth.

It was found that longitudinal bone growth effect is had according to the pharmaceutical composition of the disclosure and therefore can be used for prevention or Treat growth disorder.

Meanwhile, growth disorder can include normal variant short stature disease or be attributed to disease Secondary cases it is of short and small stature Disease.Normal variant short stature disease can include familial short stature, constitutional delay of growth or idiopathic body in the narrow sense Material dwarfism.In addition, Primary growth obstacle (endogenous sexual dysfunction) can be included by being attributed to the Secondary cases short stature of disease Or secondary growth obstacle (exogenous growth obstacle).The example of Primary growth obstacle can include osteochondrodysplasia, Be attributed to chromosome abnormality short stature (Down syndrome or Turner syndrome), less than gestational age (intrauterine growth retardation), The short stature that is attributed to Prader-Willi syndrome, the short stature for being attributed to Russell-Silver syndrome and The short stature of Noonan syndrome is attributed to, and the example of secondary growth obstacle can include being attributed to chronic systemic The short stature of disease, the short stature for being attributed to growth hormone deficiency, the stature for being attributed to hypothyroidism Dwarfism, the short stature for being attributed to Cushing syndrome and social mentality's sexual dwarfism.

In addition, containing herb ingredients according to the pharmaceutical composition of the disclosure, and it therefore can promote longitudinal bone growth Without any side effect.

In the disclosure, preferably contained with the weight of gross weight 0.1 to 50 % of the pharmaceutical composition based on disclosure amount L-arginine and Panax sessiliflorus extract.However, the scope of amount is not necessarily limited to this above, and can be according to the shape of patient State, the type of disease and disease development degree and change.

In the pharmaceutical composition of the disclosure, L-arginine and Panax sessiliflorus extract can with for adult about 1mg to 1g, preferably 30mg to 120mg amount are administered once a day or are divided into multiple apply daily for several times.However, it is possible to according to disease The state of people, such as patient's condition seriousness, age, sex, weight, the formulation of medicine, and route of administration and cycle, suitably adjust The L-arginine and the amount of Panax sessiliflorus extract applied.

In the pharmaceutical composition of the disclosure, L-arginine and Panax sessiliflorus extract can with for adult about 10mg to 2g, preferably 300mg to 1200mg amount are administered once a day or are divided into multiple apply daily for several times.However, it is possible to root According to the state of patient, such as patient's condition seriousness, age, sex, weight, the formulation of medicine, and route of administration and cycle, suitably The amount of the applied L-arginine of regulation and Panax sessiliflorus extract.

Because the pharmaceutical composition of the disclosure both no toxicity or had been free from side effects, or even it can also in chronic administration Safely use.

In the range of the effect of the disclosure is not damaged, the pharmaceutical composition of the disclosure can include medical additive, such as Diluent, adhesive, disintegrant, lubricant, pH controlling agents, antioxidant, solution adjuvant etc..

Diluent can include sugar, starch, microcrystalline cellulose, lactose (lactose hydrous), glucose, D-mannital, Alginate, alkali salt, clay, polyethylene glycol, calcium phosphate dibasic anhydrous or their mixture.

Adhesive can include starch, microcrystalline cellulose, high degree of dispersion silica, mannitol, D-mannital, sugarcane Sugar, lactose hydrous, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone copolymer (copolyvidone (copovidone)), hydroxypropyl methyl cellulose, hydroxypropyl cellulose, natural gum, rubber polymer, copolyvidone, gelatin or it Mixture.

Disintegrant can include starch or modified starch, such as Explotab, cornstarch, farina or pre- Gelling starches；Clay, such as bentonite, montmorillonite or aluminium-magnesium silicate (aluminium-magnesium silicate (veegum))；Cellulose, such as crystallite are fine Dimension element, hydroxypropyl cellulose or carboxymethyl cellulose；Seaweeds, such as sodium alginate or alginic acid；Cross-linked cellulose, is such as crosslinked Sodium carboxymethylcellulose；Glue, such as guar gum or xanthans；Cross-linked polymer, such as PVPP (Crospovidone)； Effervescent agent, such as sodium acid carbonate or citric acid；Or their mixture.

Lubricant can include talcum, stearic acid, magnesium stearate, calcium stearate, NaLS, hydrogenated vegetable oil, Sodium benzoate, stearyl fumarate, Compritol 888 ATO, glyceryl monooleate, glycerin monostearate, palmitic, stearic Glyceride, colloidal silica or their mixture.

PH controlling agents can include acidulant, such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, etherificate sodium The carbon of (sodium etherate), malic acid, butanedioic acid, tartaric acid, fumaric acid or citric acid, and basifier, such as precipitation Sour calcium, ammoniacal liquor, meglumine (meglumine), sodium carbonate, magnesia, magnesium carbonate, sodium citrate or tricalcium phosphate.

Antioxidant can include dibutyl hydroxy toluene, butylated hydroxy anisole (BHA), tocopherol acetate, tocopherol, Propylgallate (propyl galate), sodium hydrogensulfite, sodium pyrosulfite etc..Solution adjuvant can include lauryl sulphur Sour sodium, polyoxyethylene sorbitan fatty acid esters such as polysorbate, dioctyl sodium sulfosuccinate (docusate Sodium), poloxamer (poloxamer) etc..

For orally administering, the pharmaceutical composition of the disclosure can with solid pharmaceutical preparation for example tablet, pill, powder, The form of grain or capsule is provided, and such solid pharmaceutical preparation can be by by L-arginine and Panax sessiliflorus extract and extremely Few a kind of excipient such as starch, calcium carbonate, sucrose or lactose or gelatin are mixed and prepared.In addition to simple excipient, Available is lubricant such as magnesium stearate or talcum.Alternatively, pharmaceutical compositions for oral administration can be with liquid preparation Form such as supensoid agent, oral solution, emulsion or syrup is provided, and can not be used only water and atoleine but also Using various excipient liquid preparation is prepared as such as wetting agent, sweetener, essence, preservative.

For parenteral administration, the pharmaceutical composition of the disclosure can include aseptic aqueous solution, non-aqueous solution, suspension Agent, emulsion, the dosage form of lyophilized products or suppository are provided.

Non-aqueous solution or supensoid agent can include propane diols, polyethylene glycol, vegetable oil such as olive oil and injectable esters such as oil Acetoacetic ester.Matrix for suppository can include Witepsol, Macrogol, Tween 61, cupu oil, laurin (laurin) oil, glycerin gelatine etc..

As used in this article, term administering " refers to the drug regimen of the disclosure by any appropriate method Thing is introduced in patient., can be without restriction using any typical case way as the route of administration of the pharmaceutical composition of the disclosure Footpath, as long as it reaches destination organization.Its instantiation can include, but not limited to orally administer, intraperitoneal is applied, quiet Administration in arteries and veins, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, intrapulmonary administration, apply in straight enteral administration, vitreum Applied and intrathecal applied with, intraperitoneal.For example, can by oral, rectum, vein, muscle, it is subcutaneous, in utero, epidural space Or intraventricular injection is administered.

Can be with applied once according to the pharmaceutical composition of the disclosure, or multiple apply with predetermined time interval can be divided into Administered several times.

In addition, the pharmaceutical composition of the disclosure can also comprising the extra activity with treatment growth disorder effect into Point.

It can be used alone or treated with any other method such as hormonotherapy or medicine according to the pharmaceutical composition of the disclosure Method is applied in combination, so as to prevent or treat growth disorder.

Food compositions

The present disclosure proposes the food compositions for promoting longitudinal bone growth, it includes L-arginine and Panax sessiliflorus Extract is used as active component.

Can with pharmaceutical composition identical mode prepare L-arginine and Panax sessiliflorus extract.

The food compositions of the disclosure can individually include L-arginine and Panax sessiliflorus extract, or can also include It is generally used for the additive of any other food compositions, functional health food or beverage.

For example, the food compositions of the disclosure can contain sweetener, such as white sugar, crystal diabetin, glucose, D- sorboses Alcohol, mannitol, isomaltosylfructoside-oligosaccharides, steviol glycoside, Aspartame, fourth sulfanilamide (SN) potassium (acesulfame potassium), Sucralose etc., acidulant, such as anhydrous citric acid, DL-malic acid, butanedioic acid and its salt, preservative such as benzoic acid and its derivative Thing, various nutriments, vitamin, mineral matter (electrolyte), spices such as synthetic perfume and natural perfume material, colouring agent, reinforcing agent (cheese, chocolate etc.), pectic acid and its salt, alginic acid and its salt, organic acid, protective colloid thickener, pH controlling agents, surely Determine agent, antiseptic, glycerine, alcohol, and the carbonating agent for soda.In addition, the food compositions of the disclosure can contain Pulp for preparing fruit juice and plant beverage.The amount of additive can fall the food in the disclosure based on 100 parts by weight In scope below the parts by weight of product composition about 20.

When the food compositions of the disclosure are beverages, it can also include flavor enhancement or be generally used for the natural carbon of beverage Hydrate.Natural carbohydrate can include monose such as glucose or fructose, disaccharides such as maltose or sucrose, polysaccharide such as paste Essence or cyclodextrin, or sugar alcohol such as xylitol, D-sorbite or antierythrite.In addition, flavor enhancement can include natural flavouring such as Talin or stevia extract (Rebaudiodside A (Rebaudioside) A, glycyrrhizin (Glycyrrhizin) etc.) or synthesis are adjusted Taste agent such as saccharin, Aspartame etc..When food compositions are beverages, generally with based on 100mL compositions about 1 to 20g and Preferably from about 5 to 12g amount contains natural carbohydrate.

The food compositions of the disclosure can be prepared in the form of powder, particle, tablet, capsule or beverage, and therefore It may be used as food, beverage, glue, tea, vitamin complex or healthy complementary goods.

Furthermore, it is possible to which the food compositions of the disclosure are added into medicine, food and beverage to promote longitudinal bone life It is long.For example, the food compositions of the disclosure can be added to food, beverage, glue, tea, vitamin complex, healthy complementary goods In.

The food compositions of the disclosure can be added into Foods or drinkses to promote longitudinal bone growth.The disclosure Composition can be added with the amount of the weight of gross weight 1 to 5 % based on food, and can with based on 100mL beverages 0.02g extremely 10g and preferably 0.3g to 1g amount addition.

Prevention, the method for improving or treating growth disorder

The disclosure proposes a kind of method for preventing, improving or treating growth disorder, and it includes its object to needs and applied Pharmaceutical composition, food compositions or fodder compound.In the disclosure, object also includes mammal, especially people.

In the disclosure, growth disorder can include normal variant short stature disease or be attributed to the Secondary cases stature of disease Dwarfism.Normal variant short stature disease can include familial short stature, constitutional delay of growth or special hair in the narrow sense Property short stature.Be attributed to disease Secondary cases short stature can include Primary growth obstacle (endogenous sexual dysfunction) or Secondary growth obstacle (exogenous growth obstacle).The example of Primary growth obstacle can include osteochondrodysplasia, return Because in the short stature (Down syndrome or Turner syndrome) of chromosome abnormality, less than gestational age (intrauterine growth retardation), return Because of the short stature in Prader-Willi syndrome, it is attributed to the short stature of Russell-Silver syndrome and returns Cause can include being attributed to chronic systemic disease in the short stature of Noonan syndrome, and the example of secondary growth obstacle The short stature of disease, the stature for being attributed to the short stature of growth hormone deficiency, being attributed to hypothyroidism are short Small disease, the short stature for being attributed to sex premature, the short stature for being attributed to Cushing syndrome and social mentality's property dwarf Disease.

Beneficial effect

According to the disclosure, contain L-arginine and Panax sessiliflorus extract as the pharmaceutical composition or food of active component Composition is to promoting longitudinal bone growth effective.Therefore, it is possible to use according to the pharmaceutical composition or food compositions of the disclosure Effectively prevent, improve or treatment growth disorder.

Brief description of the drawings

Fig. 1 illustrates the shin bone epiphyseal growth plate production by depositing after tetracycline (tetracycline) is injected to rat Raw luminous fluorescence microscopy images；And

Fig. 2 is the chart for illustrating longitudinal bone growth degree in rat.

Mode for invention

By following examples and experimental example, (it is the model that is not necessarily to be construed as limiting the disclosure in order to illustrate to provide them Enclose) being better understood from for the disclosure can be obtained.

The preparation of the complex composition of the disclosure extract of preparation example 1.

L-arginine is purchased from Sigma.Panax sessiliflorus is purchased from Yaksudang, and by oriental medicinal drug institute of Kyung Hee University Herbal pharmacology system (Dept.of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University) checking after use.In order to prepare Panax sessiliflorus extract, 5L 70% ethanol is added to 500g's In Panax sessiliflorus, in 80 DEG C of refluxing extractions 3 hours, and filtered afterwards with filter paper.By resulting extract liquid in decompression It is lower to concentrate and freeze afterwards, therefore obtain 32.3g (yield 6.5%) Panax sessiliflorus extract.

L-arginine and Panax sessiliflorus extract are applied after with the content of table 1 below and the mixing of content ratio.

[table 1]

Preparation example 2.L- is arginic to be prepared

L-arginine is purchased from Sigma.

The preparation of the Panax sessiliflorus extract of preparation example 3.

Panax sessiliflorus is purchased from Yaksudang, and by herbal pharmacology system of oriental medicinal drug institute of Kyung Hee University (Dept.of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University used after) verifying.In order to prepare Panax sessiliflorus extract, 5L 70% ethanol is added to 500g without stalk In slender acanthopanax, in 80 DEG C of refluxing extractions 3 hours, and filtered afterwards with filter paper.Resulting extract liquid is dense under reduced pressure Contract and freeze afterwards, therefore obtain 32.3g (yield 6.5%) Panax sessiliflorus extract.

The composition of embodiment 2 and 3 is applied with the content of table 2 below.

[table 2]

Evaluation --- the tetracycline of longitudinal bone growth effect of ＜ embodiment ＞ L-arginines and Panax sessiliflorus extract Decoration method

The preparation of ＜ 1-1 ＞ experimental animals

As experimental animal, the Sprague-Dawley female rats for four week old for weighing about 100g are bought and looked after (Samtako, South Korea) while enough feeds and water are supplied so that adapt it to experimental situation.Environment was adapted at about 1 week After stage, animal testing is carried out.

The evaluation of ＜ 1-2 ＞ longitudinal directions bone growth effect

Two days after administration, by 20mg/kg tetracycline hydrochloride (Sigma T7660) intraperitoneal injection to all examinations Test group.Two days afterwards, rat is put to death via cervical dislocation, left and right shin bone is removed afterwards, it is fixed in 4 DEG C of fixed solution 3 days, it is stood 1 day in 50mM EDTA, go in mineral matter, and 30% sucrose of immersion to stay overnight to protect freezing.Will thus The bone tissue freezing of dehydration, and 40 μm of section is cut into using sliding microtome (HM440E, Zeiss, Germany), thus collect Sagittal (sagittal) section of the proximal part of shin bone.In order to measure bone growth, by each arrow of the proximal part of shin bone Shape section (40 μ m-thick) is placed on slide, is dried, and afterwards using fluorescence microscope in the case where wavelength is 400nm UV light Observe (Fig. 1).Using image analysis software ImageJ (NIH, the U.S.), measurement by growth plate and bone tissue tetracycline it is heavy Length between fluorescent belt formed by product, and examined for Xue Shengshi (Student ' s) t for being compared with control group and ANOVA is examined so that it is determined that growth result.

Administration --- the comparative example 1 of ＜ 1-3 ＞ L-arginine extracts

It is dissolved in after redistilled water, is applied in 1.0ml/100g rat weight in the concentration with 10mg/kg The L-arginine extract prepared in preparation example 2, and as a control group, using the redistilled water of same volume.From administration Start within 2 days before tetracycline until experiment closing day, L-arginine extract is orally administered twice daily, is amounted to four days.

Administration --- the comparative example 2 of ＜ 1-4 ＞ Panax sessiliflorus extracts

The Panax sessiliflorus extract prepared in preparation example 3 is dissolved in second distillation in the concentration with 30mg/kg After water, applied with 1.0ml/100g rats weight, and as a control group, using the redistilled water of same volume.From applying Started, until experiment closing day, Panax sessiliflorus extract to be orally administered twice daily, is amounted to four days with 2 days before tetracycline.

Administration --- the embodiment of the complex composition of the ＜ 1-5 ＞ disclosure

By the complex composition prepared in preparation example 1 after having dissolved, applied with 1.0ml/100g rats weight, And as a control group, using the redistilled water of same volume.Until experiment terminates 2 days before tetracycline is applied Day, complex composition is orally administered twice daily, is amounted to four days.

The administration of ＜ 1-6 ＞ positive controls

Based on using human growth hormone recombinant (Isgaard J, Nilsson A, Lindahl A, Jansson JO and Isaksson OG：Effect (Effects of locals of the GH and IGF-1 to the local application of longitudinal bone growth in rat administration of GH and IGF-1on longitudinal bone growth in rats).Am J Physiol.250：E367-72., the report of bone growth 1986) is increased, as positive controls, with 0.1ml/100g rats The volume of weight applies 20 μ g/kg human growth hormone recombinant (rhGH；LG Lifescience,).For sun Property control group for, since apply tetracycline before 2 days s until test closing day, recombinant human growth is subcutaneously injected once a day Hormone, is amounted to 4 days.

The evaluation of longitudinal bone growth effect of the complex composition of ＜ 1-7 ＞ disclosure extracts

Based on the result measured directly of longitudinal bone growth via tetracycline staining method, the vertical of positive controls is found It is 377.2 ± 27.5 μm/day (n=10) to bone growth speed, than 348.9 ± 37.6 μm/day (n=in Normal group 10) it is high, and obvious bone growth effect (8.6%, p ＜ 0.01) is therefore shown compared with Normal group.

(p.o.) (comparative example 1) is applied in the L-arginine for applying 10mg/kg or applies 30mg/kg Panax sessiliflorus extraction In the group of thing (p.o.) (comparative example 2), respectively 348.9 ± 39.1 μm/day (n=10) or 366.8 ± 19.1 μm/day (n= 10) obvious bone growth effect (being respectively 0.0%, 5.1%), but compared with Normal group is not shown.Meanwhile, In group using L-arginine and the complex composition of Panax sessiliflorus extract, longitudinal bone growth speed is 375.3 ± 40.5 μ M/ days (n=10) and thus it is confirmed that obvious bone growth effect (7.6%, p ＜ 0.05) (Fig. 2).

Therefore, when applying complex composition, it can confirm that longitudinal bone growth effect is dramatically increased, this is being applied respectively Do not seen when L-arginine or Panax sessiliflorus extract.

Test result is summarised in table 3 below.

[table 3]

Industrial usability

It is vertical to promoting as the composition of active component comprising L-arginine and Panax sessiliflorus extract according to the disclosure It is effective to bone growth.Therefore, its purposes that can effectively serve as preventing, alleviate or treating growth disorder.

Claims

1. a kind of pharmaceutical composition for being used to promote longitudinal bone growth, described pharmaceutical composition is comprising L-arginine and without stalk five Plus extract is used as active component.

2. the pharmaceutical composition described in claim 1, wherein extracting described without stalk in water, C1-C4 alcohol or their mixture Slender acanthopanax extract.

3. the weight ratio of the pharmaceutical composition described in claim 1, wherein L-arginine and Panax sessiliflorus extract is 1: 1 to 1: 5。

4. the pharmaceutical composition described in claim 1, wherein growth disorder are selected from the group by being constituted including following disease： Familial short stature, constitutional delay of growth, idiopathic short stature, osteochondrodysplasia, it is attributed to chromosome Abnormal short stature (Down syndrome or Turner syndrome), less than gestational age (intrauterine growth retardation), be attributed to pula moral- The short stature of Willi Syndrome, the short stature for being attributed to Russell-Silver syndrome, it is attributed to Noonan syndrome Short stature, be attributed to the short stature of chronic systemic disease, be attributed to growth hormone deficiency short stature, The short stature that is attributed to hypothyroidism, the short stature for being attributed to sex premature, it is attributed to Cushing syndrome Short stature and social mentality's sexual dwarfism.

5. a kind of food compositions for being used to promote longitudinal bone growth, described pharmaceutical composition is comprising L-arginine and without stalk five Plus extract is used as active component.

6. a kind of method for preventing, improving or treating growth disorder, methods described includes will be according to any in claim 1 to 5 Composition described in is applied to the object for needing to apply.

7. composition according to any one of claim 1 to 5, which is used to prepare, to be used to preventing, improve or treating growth disorder Medicine purposes.