CN106038533B - Application of the 5 hydroxymethyl furfural in anti-ovarian-senescedrug drug is prepared - Google Patents
Application of the 5 hydroxymethyl furfural in anti-ovarian-senescedrug drug is prepared Download PDFInfo
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- CN106038533B CN106038533B CN201610426020.4A CN201610426020A CN106038533B CN 106038533 B CN106038533 B CN 106038533B CN 201610426020 A CN201610426020 A CN 201610426020A CN 106038533 B CN106038533 B CN 106038533B
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- hydroxymethyl furfural
- ovarian
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- ovary
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- 239000003814 drug Substances 0.000 title claims abstract description 30
- 229940079593 drug Drugs 0.000 title claims abstract description 19
- NOEGNKMFWQHSLB-UHFFFAOYSA-N 5-hydroxymethylfurfural Chemical compound OCC1=CC=C(C=O)O1 NOEGNKMFWQHSLB-UHFFFAOYSA-N 0.000 title claims description 68
- RJGBSYZFOCAGQY-UHFFFAOYSA-N hydroxymethylfurfural Natural products COC1=CC=C(C=O)O1 RJGBSYZFOCAGQY-UHFFFAOYSA-N 0.000 title claims description 58
- 208000002500 Primary Ovarian Insufficiency Diseases 0.000 claims abstract description 8
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- 208000011580 syndromic disease Diseases 0.000 claims abstract description 6
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of 5 hydroxymethylfurfurals in anti-ovarian-senescedrug drug is prepared.5 hydroxymethylfurfurals can treat a variety of ovary wasting conditions, and such as Stein-Leventhal syndrome, dysfunctional uterine bleeding, premature ovarian failure or climacteric syndrome have remarkable result.The present invention is oral administration, percutaneous dosing or the drug administration by injection 5 hydroxymethylfurfurals being made for treating ovary wasting conditions.
Description
Technical field
The present invention relates to the medical usage of 5 hydroxymethyl furfural, i.e. 5 hydroxymethyl furfural is effectively treating a variety of ovary declines
Application in disease medicament.
Background technology
The complicated bioprocess that ovarian-senescence is a multifactor interaction, builds up.As year day passes ovum
Bubble constantly consumption, Follicle number decline are the main causes of ovarian-senescence；And microenvironment changes in body intracellular metabolite Product bulk ovary,
Such as the damage of free radical, advanced glycation end products to ovarian follicle, and Mitochondrial DNA Mutation, telomere such as shorten at the continuous accumulation of factor,
The quality of remaining ovarian follicle also reduces at the same time；The expression of series of genes changes with function in ovary, and H-P-O axis
（Hypothalamus-Pituitary-Ovary Axis, hypothalamic-pituitary-ovarian axis）The secretion precision control ovary of hormone
Function.Ovarian failure, that is, ovarian-senescence, using menopause as performance, menopause in the past in 40 years old is known as premature ovarian failure（Premature
Ovarian Failure, POF）, i.e. pathologic ovarian-senescence.Ovarian failure can trigger ovarian dysfunction disease（Such as
Stein-Leventhal syndrome, dysfunctional uterine bleeding etc.）, then exhaustion initiation perimenopausal syndrome, these diseases are successive
There is each tract senile disease：Coronary heart disease, cerebrovascular disease incidence significantly improve in the circulatory system, central nervous system
In easily hair alzheimer's disease, depression, due to calcium loss sharply increases and osteoporosis is occurred frequently etc..In recent years, with life
Living tempo increase and learning pressure are excessive, occur ovary wasting conditions relevant disease in women it is existing it is obvious it is increased become
Gesture.Since there are young, middle age or elderly woman in each family, the above-mentioned disease that ovarian-senescence produces becomes generally closes
The social concern of the heart, the research to the disease have become the hot and difficult issue of domestic and international reproductive development circle.
Research both at home and abroad at present thinks ovarian-senescence and hereditary, immune, metabolism, virus infection and the factor such as iatrogenic
It is related.It is summarised as the following aspects：1 karyotype is abnormal, passes through the organon to chromosome abnormality ovarian-senescence patient
Phase, some syndrome genes are concentrated mainly on X chromosome and autosome, and how much the exception of karyotype has with familial inheritance
Close, in addition gene mutation caused by environmental factor is also to cause the key factor of this illness.2 immune sexual factors, may be with cell
Factor induced particle cell and lutein cell, mainly histocompatibility complex（MHC）Class antigen presentation, induces body oneself
Body immune response, make granular cell and ovarian follicle destroyed it is related.Think that ovarian failure is anti-with ovary itself in addition, also having
The generation of body and the autoimmune disease for merging other endocrinal glands or system, such as autoimmune thyroiditis, are
System property lupus erythematosus, myasthenia gravis, parathyroid function decline, rheumatoid arthritis, idiopathic thrombocytopenic are purple
Purplish or white patches on the skin, diabetes etc. are related.3 promoting sexual gland hormone and its receptor abnormality, promoting sexual gland hormone FSH, LH and its acceptor（FSHR、LHR）'s
Conduction defect can cause ovarian failure.4 azymias can cause galactosemia, galactosemia and ovarian failure
Generation is related.Galactolipin can directly damage egg mother cell, its metabolite can substantially produce infringement, gala sugar to ovary again
The infiltration of son can also change the activity of promoting sexual gland hormone, so as to cause the exhaustion of folliculus ovarii.5 ovary destructive factors, with female
Property social activities it is increasingly frequent, it is not intended to Long Term Contact reflected ray stimulate, or because work, disease, contingency receive heavy dose
Or the radioactive ray of long-term, it can destroy ovary.6 other dangerous factors, smoking, depression, it is long-term largely contact it is exogenous
E2There is close relationship with nullipara and ovary decline.And influence research of the heavy metal classes environmental hormone to ovarian failure is also
Blank, with China's rapid development of economy, this kind of environmental factor our people's healthy reproduction will can be produced it is long-range not
Profit influences.
Hormone replacement therapy（Hormone replacement therapy, HRT）It is that current Modern medical therapy ovary declines
The important method of old related symptoms and disease, but existing research clearly shows that it, with a variety of side effects and carcinogenicity at a specified future date, makes
Its clinical practice is subject to significant restrictions.This corresponding state, Traditional Chinese medical theory is followed in China, advocates that " kidney tonifying benefit is cloudy, soothing the liver
Blood-nourishing " and delay ovarian-senescence, treated using Chinese medicinal formulae, but deposited at present in the case where not getting its cause of disease, pathology clear also
In the mistaken ideas abused medicine, disorderly treated, and compound medicine treatment, there are effective material base is unclear, mechanism of action is unknown to be lacked
Fall into, traditional Chinese medicine can not be made to move towards modernization, move towards internationalization.
5 hydroxymethyl furfural（5-hydroxymethyl-2-furfural, 5-HMF）Also known as HMF 5 hydroxymethyl 2 furaldehyde（Knot
Structure such as schemes I）, produced by monose chemical combination heat resolve.Polysaccharide and glycosides compound are hydrolyzed into monose under concentrated acid effect, single
The sugar furfural compounds of generation with furan ring structure under concentrated acid heat effect.5 hydroxymethyl furfural is primarily present in may hair
In the food and plant of raw sugar degradation reaction and Maillard reaction, such as there is hair in dairy products, honey, raisins and most fruit
It is existing.Also it is found in many autonomic drugs in recent years.
The pharmacological research of 5-HMF is shown in recent years：5 hydroxymethyl furfural has antioxidation activity, resist myocardial ischemia work
With, anti-tumour cell proliferative activity, improve hemorheology, adjust Ca2+Balance, antityrosinase, influence radix glycyrrhizae acid metabolic, kill
Worm etc. acts on.At present not yet have been reported that application 5 hydroxymethyl furfural being used to prepare in anti-ovarian-senescedrug drug.
（Ⅰ）
The content of the invention
The technical problems to be solved by the invention are to provide 5 hydroxymethyl furfural answering in anti-ovarian-senescedrug drug is prepared
With.The 5 hydroxymethyl furfural（5-hydroxymethyl-2-furfural, 5-HMF）With such as lower structure：
The present invention relates to the application of 5 hydroxymethyl furfural (Luteolin) ovarian senescence resistance disease, particularly to polycystic ovary
Diseases such as syndrome, dysfunctional uterine bleeding, premature ovarian failure or climacteric syndrome etc. have it is notable the effect of, and
It is safe to use and can be long-term use of for having the characteristics that during such use.Therefore, 5 hydroxymethyl furfural can prepare anti-ovary
Applied in senescence drug, which has the purposes for treating a variety of ovary wasting conditions.
5 hydroxymethyl furfural can be derived from commercially available or is prepared using the prior art.
The 5 hydroxymethyl furfural that the present invention applies can be with any one auxiliary material or drug excipient system for pharmaceutically allowing
Into medicine, its preparation can be any one formulation pharmaceutically allowed, include but not limited to liquid preparation, granule, tablet,
Electuary, soft capsule, soft capsule, pill, ointment or injection.
Medicine provided by the invention, its form of medication mainly include oral administration, percutaneous dosing or drug administration by injection.
The dosage of 5 hydroxymethyl furfural in the present invention, it is different because the state of patient, weight, administering mode etc. are different, its
It is characterized in 5 hydroxymethyl furfural and pharmaceutical carrier that the medicine contains 1-1000mg.
Beneficial effects of the present invention compared with the prior art：5 hydroxymethyl furfural has in vitro gonad granulocyte notable
Proliferation function, the estrogen and progestogen secretion level of in vitro gonad granulocyte can be significantly improved, it is big naturally-aged to be dramatically increased
The secretion of mouse estrogen and progestogen, can reduce Model of Polycystic Ovarian Syndrome mouse FSH, LH, T level, can be to caused by cyclophosphamide ovary
Early ageing rat has sex hormone regulation effect.Therefore, 5 hydroxymethyl furfural can be applied in anti-ovarian-senescedrug drug is prepared, particularly
Applied in ovarian senescence resistance symptom is prepared as the medicine of premature ovarian failure and resistant ovary syndrome.The present invention is 5- methylol chaffs
Aldehyde provides novel clinical use, expands its application range.
Embodiment
The present invention is further elaborated below with reference to specific embodiment, these examples are for illustration purposes only, without
For limiting the scope of the invention.The experimental animal of the present invention, purchased from Academy of Military Medicine, PLA experimental animal
Center（Production licence number：SCXK (army) 2007-004）, select the clinical Estradiol Valerate for having good therapeutic effect to do positive control.
5 hydroxymethyl furfural reference substance（Sigma Co., USA）, purity >=98%, is dissolved in tri-distilled water and is configured to administration concentration.
Proliferation function of [embodiment one] 5 hydroxymethyl furfural in vitro gonad granulocyte（Mtt assay）
Take 22-27 age in days female rats, cervical dislocation is put to death after 48 h of conventinal breeding, the sterile bilateral ovum for winning rat
Nest, ovary, which is crushed, discharges granular cell, is diluted with DMEM-F12 nutrient solutions of the 2mL containing penicillin and streptomysin, and gently
Featheriness is beaten, and it is dispersed into individual cells.Granular cell is collected in centrifugal filtration.By a certain concentration cell suspension inoculation in 24 holes
Plate, per 80 μ l of hole, cell density is adjusted per 120 μ l nutrient solutions of Kong Zaijia to 200 μ l/ holes, every group sets 6 parallel holes.Put
In 5%CO224h is cultivated in incubator.Take CO2The granular cell suspension of 24 h has been cultivated in incubator, modeling is successively added per hole
Concentration caddy and various concentrations 5 hydroxymethyl furfural sample（1.0mg·mL-1、0.1mg·mL-1、0.01mg·mL-1）, it is parallel
Set Normal group（Physiological saline）And model group（Caddy and physiological saline）.20 h of cellar culture is added after in every hole
MTT solution（5 mg·mL-1）20 μ L continue to cultivate 4 h, and three liquid of 80 μ L are added per hole, are incubated overnight, and select 570 nm
Wavelength, each hole absorbance is measured on enzyme-linked immunosorbent assay instrument, the results are shown in Table 1.The results show model group and Normal group are equal
There is significant difference（p<0.01）, in vitro gonad granulocyte propagation effect after positive drug, the effect of various dose 5 hydroxymethyl furfural
Fruit has significant difference with model group（Equal p<0.01）.
Proliferation function of 15 hydroxymethyl furfural of table in vitro gonad granulocyte
Estrogen and progestogen secretion of [embodiment two] 5 hydroxymethyl furfural in vitro gonad granulocyte（Radio-immunity
Method）
Take 22-27 age in days female rats, cervical dislocation is put to death after 48 h of conventinal breeding, the sterile bilateral ovum for winning rat
Nest, ovary, which is crushed, discharges granular cell, is diluted with DMEM-F12 nutrient solutions of the 2ml containing penicillin and streptomysin, and gently
Featheriness is beaten, and it is dispersed into individual cells.Granular cell is collected in centrifugal filtration.By a certain concentration cell suspension inoculation in 24 holes
Plate, per 80 μ l of hole, cell density is adjusted per 120 μ l nutrient solutions of Kong Zaijia to 200 μ l/ holes, every group sets 6 parallel holes.Put
In 5%CO224h is cultivated in incubator.Take CO2The granular cell suspension of 24 h has been cultivated in incubator, modeling is successively added per hole
Concentration caddy and various concentrations 5 hydroxymethyl furfural sample, parallel setting Normal group（Physiological saline）And model group（Chlorine
Cadmium and physiological saline）.It is placed on 5%CO224h is cultivated in incubator.Its cell supernatant of centrifuging and taking, uses radioimmunological kit
Measure E2, P content, the results are shown in Table 2.The results show model group has significant difference with Normal group（p<0.01）, sun
Property medicine, in vitro gonad granulocyte estrogen and progestogen secretion level is carried than model group after the effect of various dose 5 hydroxymethyl furfural
Height, there is significant difference（p<0.01）.
Estrogen and progestogen secretion of 25 hydroxymethyl furfural of table in vitro gonad granulocyte
The influence that [embodiment three] 5 hydroxymethyl furfural secretes naturally-aged rat estrogen and progestogen（Radioimmunology）
Using the senilism model of naturally-aged.Choose 14 month female SD rats, weight (270 ± 30) g, Animal adaptability
Feed after a week, make colpocytology smear, continuously observe 4 oestrous cycles, extended with the colpocytology performance oestrous cycle,
Afterwards Constant Estrus, repeatedly false pregnancy cell phase when, as female aged model success.Naturally-aged rat is randomly divided into mould
Type group, 5 hydroxymethyl furfural (10mg/kg, 30mg/kg, 50mg/kg) group and positive drug group, separately took for 4 monthly ages female by every group each 10
Property rat 11 is Normal group, and daily gavage 1 time, Normal group and model group give isometric(al) physiological saline, continuously
After administration 30 days, before administration and blood is taken from rat orbital venous plexus after the last administration, centrifuges, takes serum, with radioimmunology point
Not Ce Ding the content of estrogen and progesterone in serum, the results are shown in Table 3.The results show model group has conspicuousness with Normal group
Difference（p<0.01）, gavage positive drug, 5 hydroxymethyl furfural（Senior middle school's low dosage）There is aobvious estrogen and progestogen with model group after 30 days
Write sex differernce（p<0.01）.
The comparison of 35 hydroxymethyl furfural group of table and control group estrogen and progestogen level
Influence of [example IV] 5 hydroxymethyl furfural to Model of Polycystic Ovarian Syndrome rat
24d ages teenage SD female rats, 1 hypodermic injection of weight 30-40g, 0.5mg18- methylnorethindron day,
During 27d ages, add with 2 hypodermic injections of HCG 1.5IU days, co-injection 21d.After modeling success, model group, sample are randomly divided into
(senior middle school's low dosage) group and positive drug group（Melbine 0.018g/d）, every group each 10, separately take 45d ages SD female rats 10
For Normal group, daily gavage 1 time, Normal group and model group give isometric(al) physiological saline, and successive administration is after 15 days,
Take blood examination to survey FSH, LH, T concentration in serum after the last administration, the results are shown in Table 4.The results show model group has with Normal group
Significant difference（p<0.01）, gavage positive drug, 5 hydroxymethyl furfural（Senior middle school's low dosage）After 15 days FSH, LH, T level with
Model group has the difference of different conspicuousnesses.
The comparison of FSH, LH, T concentration in 45 hydroxymethyl furfural group of table and control group serum
Influence of [embodiment five] 5 hydroxymethyl furfural to premature ovarian failure sex hormone level in rats
Using 9d age SD female rats, 14 days endoxan 8mg/ are continuously injected intraperitoneally（kg·d）Modeling.Modeling success
Afterwards, model group, sample (senior middle school's low dosage) group and positive drug group are randomly divided into（Premarin 0.075mg/kg）, every group each 10,
Another to take 23d ages SD female rats 10 be Normal group, and daily gavage 1 time, Normal group and model group give isometric(al)
Physiological saline, successive administration take blood examination to survey FSH, E in serum after the last administration after 35 days2Concentration, the results are shown in Table 5.The results show
Model group has significant difference with Normal group（p<0.01）, gavage positive drug, 5 hydroxymethyl furfural（High middle dosage）35
FSH, E after it2Level has the difference of different conspicuousnesses from model group.
FSH, E in 55 hydroxymethyl furfural group of table and control group serum2The comparison of concentration
[embodiment six] 5 hydroxymethyl furfural capsule
5 hydroxymethyl furfural 100g, starch 80g, sodium carboxymethyl starch 24g, dextrin 17g, 70% appropriate amount of ethanol, is made
1000 (every contains 5 hydroxymethyl furfural 100mg).
[embodiment seven] 5 hydroxymethyl furfural capsule
5 hydroxymethyl furfural 15g, starch 10g, sodium carboxymethyl starch 4g, dextrin 12g, 70% appropriate amount of ethanol, is made 1000
Grain (every contains 5 hydroxymethyl furfural 15mg).
[embodiment eight] 5 hydroxymethyl furfural piece
5 hydroxymethyl furfural 1000g, lactose 55g, amylum pregelatinisatum 15g, hydroxypropylcellulose 10g, magnesium stearate 5g, 70%
Appropriate amount of ethanol, is made 1000 (every contains 5 hydroxymethyl furfural 1000mg).
[embodiment nine] 5 hydroxymethyl furfural granule
5 hydroxymethyl furfural 6g, lactose powder 800g, magnesium stearate 194g, 70% appropriate amount of ethanol, it is (every to be made 1000 grams of particles
Contain 5 hydroxymethyl furfural 6mg in g particle systems).
[embodiment ten] 5 hydroxymethyl furfural soft capsule
5 hydroxymethyl furfural 20g, soybean oil 10g, gelatin 5g, glycerine 5g, distilled water 7g, being made 1000, (every contains 5-
Hydroxymethylfurfural 20mg).
[embodiment 11] 5 hydroxymethyl furfural emulsifiable paste
5 hydroxymethyl furfural 1g, stearic acid 100g, hexadecanol 20g, glycerin monostearate 10g, white oil 10g, hydroxyl
Benzene methyl 0.8g, butyl hydroxybenzoate 0.2g, glycerine 140g, potassium hydroxide 5g, ethanol 10g, distilled water add to 1000g.
[embodiment 12] 5 hydroxymethyl furfural emulsifiable paste
5 hydroxymethyl furfural 0.5g, stearic acid 100g, hexadecanol 20g, glycerin monostearate 10g, white oil 10g,
Methyl hydroxybenzoate 0.8g, butyl hydroxybenzoate 0.2g, glycerine 140g, potassium hydroxide 5g, ethanol 10g, distilled water add to 1000g.
[embodiment 13] 5 hydroxymethyl furfural gel
5 hydroxymethyl furfural 0.5g, PEG400450g, hexylene glycol 80g, Tween 80 20g, carbomer 30g, monoethanolamine 6ml,
Phenmethylol 10g, distilled water add to 1000g.
[embodiment 14] 5 hydroxymethyl furfural parenteral solution
5 hydroxymethyl furfural 25.0g, is dissolved in 1000ml waters for injection, is sufficiently stirred dissolving, and benefit injects water to
2000ml, adds pin activated carbon 2.5g, is heated to 60 DEG C and stirs 30 minutes, and carbon-point filtering, filtrate is through 0.25 μm of miillpore filter
Filtration sterilization, is sub-packed in 1000 cillin bottles, loading amount 2.0ml/ branch, seals, sterilizing, to obtain the final product.
Claims (5)
- Application of the 1.5- hydroxymethylfurfurals as sole active agent in anti-ovarian-senescedrug drug is prepared.
- 2. application according to claim 1, it is characterised in that the ovarian-senescence symptom is Stein-Leventhal syndrome, function is lost Tonality uterine hemorrhage, premature ovarian failure or climacteric syndrome.
- 3. apply according to claim 1, it is characterized in that the medicine contains the 5 hydroxymethyl furfural of 1-1000mg and medicinal Carrier.
- 4. apply according to claim 1, it is characterized in that the formulation of the medicine is any type formulation pharmaceutically approved.
- 5. apply according to claim 4, it is characterized in that the formulation of the medicine includes granule, tablet, electuary, flexible glue Capsule, pill, ointment or injection.
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