CN105233248B - Application of the Uropoly acid-peptide in preparation treatment scar drug - Google Patents
Application of the Uropoly acid-peptide in preparation treatment scar drug Download PDFInfo
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- CN105233248B CN105233248B CN201510562475.4A CN201510562475A CN105233248B CN 105233248 B CN105233248 B CN 105233248B CN 201510562475 A CN201510562475 A CN 201510562475A CN 105233248 B CN105233248 B CN 105233248B
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- peptide
- acid
- uropoly acid
- uropoly
- scar
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present invention relates to field of medicaments, more particularly to a kind of application of Uropoly acid-peptide, the application in the drug for the treatment of cicatrix of skin is prepared the present invention provides Uropoly acid-peptide, the Uropoly acid-peptide being capable of induced fibroblast apoptosis, inhibit its proliferation, and inhibition level increases with the increase of Uropoly acid-peptide concentration, experiment display, Uropoly acid-peptide is up to 88.45% for the inhibiting rate of fibroblast proliferation, can effectively treat cicatrix of skin.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of Uropoly acid-peptide is used to prepare the drug for the treatment of cicatrix of skin
New application.
Background technique
Uropoly acid-peptide (CDA-II) is that a kind of active skull cap components of the separating-purifying from Healthy People freshly voided urine form
The biological agent of non-cell toxicity, the analysis found that its main component has hippuric acid, phenylacetyl amido croak pyridine diketone, benzene second
Acid, heteroauxin, phenylacetylglutamine, heteroauxin and small-molecular peptides etc..
Uropoly acid-peptide can be used for advanced breast cancer, the auxiliary of non-small cell lung cancer is controlled mainly with chemotherapy combined application at present
It treats.CN 99122049 discloses a kind of Uropoly acid-peptide composition and application thereof, is mainly used for treating and preventing the recurrence of cancer；
CN200410000754.3 also relates to a kind of Uropoly acid-peptide composition and the application for treating and preventing cancer return；
CN200910305445.X is related to a kind of preparation method of Uropoly acid-peptide.
Scar is local connective tissue Tumor like hyperplasia and dysfunction and the pathologic structure that is formed after dermis of skin damage,
Its histological characteristic is a large amount of collagens in extracellular matrix, and proteoglycan and glycoprotein deposition, collagen are disorganized.He is wound
Afterwards, the especially common complication of burnt degree.The scar of hyperplasia can often destroy the integrality of human body surface or with various
The dysfunction of degree brings the dual pain on mind & body to patient.Modern cell biology and molecular biology are ground
Study carefully think fibroblastic a large amount of proliferation synthesized with Apoptosis inhibitor and extracellular matrix with degrade it is unbalance, Some cytokines
A large amount of generate constitutes the biological mechanism of scar.
The treatment of case scar mainly passes through surgical resection, mechanical pressure and laser therapy, radiation, freezing at present
With the therapies such as injection of hormone and drug.Drug for treating scar mainly has steroid hormone drug, and the categories of drugs is main
By inhibiting PDEF gene expression inhibition cell Proliferation to lead to c- in cicatricial tissue to inhibit the synthesis of I, type III collagen
Myc and P53 is increased, the apoptosis of final induced fibroblast；In addition there are some drugs relevant to cell factor, antihistamine
Drug.Chinese medicine achieves significant progress in terms for the treatment of scar in recent years, takes the course of its own on scar treatment.
Early in Western Han Dynastry's period just about the record of scar, such as " 52 lesion ", Holy Benevolent Prescriptions, " Prescriptions for Universal Relief "
Stagnation of QI-blood, obstruction of meridians and collaterals, phlegm wet is mainly summarised as to the understanding of scar Deng, Chinese medicine to fight knot, clinically also take activating microcirculation and removing stasis medicinal,
Resolving hard lump, the Chinese medicines such as remove obstruction in channels to relieve pain pass through inside and outside therapy or the treatment of the two combined techniques.At present to Chinese medicine treatment scar
Experimental study object focuses primarily upon in common activating microcirculation and removing stasis medicinal and Chinese herbal medicine extract and its effective component.
Drug for invigorating blood circulation and eliminating stasis such as Radix Salviae Miltiorrhizae, rhizome of chuanxiong, Radix Angelicae Sinensis etc. is the common drug of traditional scar treatment, after measured external people's hyperplasia
Property fibroblasts from hypertrophic scars3Dyeing calculates cell division index under H- thymidine intake value and mirror, finds Radix Salviae Miltiorrhizae
1.25mg/ml, 125 μ g/ml of rhizome of chuanxiong piperazine have an obvious inhibiting effect to scar fibroblast proliferation, and higher concentration and compared with
Under long duration of action, the growth inhibition for being applied cell is irreversibility.
Chinese medical extract is increasing to the research for the treatment of scar in recent years, main by inhibiting fibroblast growth, right
The influence of cell factor and the accumulation etc. of inhibition extracellular matrix are worked；The utilization such as Liu Dewu is extracted from Chinese medicine Stephania tetrandra
Tetrandrine observes the influence of the human skin fibroblasts growth in vitro culture, and discovery tetrandrine can inhibit into fiber
Cell growth, inhibiting effect are positively correlated with concentration, time；Extract-notoginseng total saponin of the identical research discovery Radix Notoginseng of Yao can press down
The growth cycle of fibroblasts from hypertrophic scars processed increases S phase cell than number.
Hu little Long etc. is using discovery curcumin Inhibiting proliferation scar after the curcumin processing human fibroblasts of various concentration
The fibroblastic proliferation of trace, and as drug concentration increases, the apoptosis rate of cell is also gradually increased.Centella triterpenes cream is existing rank
The effective component Asiaticoside of the drug of the clinically used treatment scar of section, the discovery centella triterpenes cream such as Zhao Wenlu can reduce TGF-
The mrna expression amount of β 1 has the function that inhibit scar.In the forming process of scar, extracellular matrix metabolism disorder is also its shape
At an important factor for, in extracellular matrix, and based on being increased with the synthesis of collagen, skin collagen has ten several, wherein I, type III
Collagen is its main component, and type III collagen content is higher, and collagenous fibres are thinner, and scar is lighter, and Fang Quan etc. is in Radix et Caulis Opuntiae Dillenii extract
Cactus is confirmed in the experiment influenced on collagen I in rabbit ear hypertrophic scar tissue block, III and Expression of MMP-1
Extract has the collagen I expression reduced in rabbit ear veutro cicatricial tissue block, promotes collagen I II expression, to mitigate scar increasing
It is raw, promote the softening of cicatricial tissue block.Discovery vitamin A acid can interfere fibroblastic DNA to synthesize recently, inhibit its proliferation, drop
Type i collagen is solved, there is certain therapeutic effect to the scar of rabbit scar model, thus is provided for clinical treatment hyperplastic scar
Certain theoretical foundation.But this kind of drug limits its clinical application because of the inconvenience of easy to recur and long term injections administration.
The report that the application of the drug for the treatment of scar is used to prepare in relation to Uropoly acid-peptide (CDA-II) is not yet found at present.
Summary of the invention
For the above state of the art, the present invention provides a kind of application of Uropoly acid-peptide in the drug of preparation treatment scar.
Uropoly acid-peptide of the present invention is in the application of the drug of preparation treatment scar, and as one of embodiment, the urine is more
Sour peptide can be the Uropoly acid-peptide in any source in this field comprising but be not limited to can be originated from it is commercially available, can also be by this field
Technical staff prepares according to means known in the art or common sense, and still, the Uropoly acid-peptide should be to meet national standard
Or premised on the relevant regulations in professional standard.
Uropoly acid-peptide of the present invention, as one of embodiment, works as subject in the application of the drug of preparation treatment scar
Application Uropoly acid-peptide for treat scar when, the dosage range include for 80~8000mg/ daily/everyone, preferably
200-6000mg/ daily/everyone, as the explanation of exemplary, for example, can for 80,100,150,200,250,300,350,
400、450、500...1000、1050...1500、1550...2000、2050...3000、3050...3500、
3550...4500,4550...5000,5050...5500,5550...5950 or 6000mg/ daily/everyone dosage；Wherein
Administration number of times and interval can carry out variation appropriate according to the difference of administration mode, be administered every time in usual one day time with
Period between secondary is identical, such as illustrative explanation, such as three times a day, usually each primary in the morning, afternoon and evening.
For Uropoly acid-peptide of the present invention in the application of the drug of preparation treatment scar, the administration mode of the Uropoly acid-peptide can be with
For administration mode commonly used in the art, the present invention includes but is not limited to injection, oral or external application.
Uropoly acid-peptide of the present invention is in the application of the drug of preparation treatment scar, as one of embodiment, when to tested
It includes 80~3500mg/ daily/every that person, which injects amount of the Uropoly acid-peptide for applying the Uropoly acid-peptide to patient when treating scar,
People, as illustrative explanation, such as can for 80,100,150,200,250,300,350,400,450,500...1000,
1050...1500,1550...2000,2050...3000,3050...3450 or 3500mg/ daily/everyone dosage.Administration
Number include be not limited to 1~3 time/daily；As illustrative explanation, such as once a day, twice or thrice.
When being administered in present invention application with injection system, made preparation includes but is not limited to injection, lyophilized preparation
Or powder injection formulation etc., wherein the amount in the ejection preparation containing Uropoly acid-peptide can combine the present invention by those skilled in the art
And this field correlation common sense is determined, as one of embodiment, the content of Uropoly acid-peptide includes in the unit preparation
But it is not limited to such as 35~60mg/ml.
Uropoly acid-peptide of the present invention is in the application of the drug of preparation treatment scar, as one of embodiment, when to tested
When person takes orally Uropoly acid-peptide, the dosage range be 80~8000mg/ daily/everyone, as illustrative explanation, such as
Can for 80,100,150,200,250,300,350,400,450,500...1000,1050...1500,1550...2000,
2050...3000、3050...3500、3550...4500、4550...5000、5050...5500、5550...5950、
6000...7000,7050...7500,7550...7950,8000mg/ daily/everyone dosage；Administration number of times includes being not limited to
1~3 time/daily；As illustrative explanation, such as once a day, twice or three times.
The present invention application in oral administration when, made oral preparation include but is not limited to tablet, capsule or
Soft capsule etc., in oral preparation of the present invention the amount containing Uropoly acid-peptide can be combined by those skilled in the art the present invention and this
Field correlation common sense is determined, and as one of embodiment, the content of Uropoly acid-peptide includes but not in the unit preparation
It is limited to such as 50-500mg.
Uropoly acid-peptide of the present invention is in the application of the drug of preparation treatment scar, as one of embodiment, when to tested
Person's external application Uropoly acid-peptide for when treating scar, the dosage range include for 80-8000mg/ daily/everyone is as showing
The explanation of example property, for example, can for 80,100,150,200,250,300,350,400,450,500...1000,
1050...1500、1550...2000、2050...3000、3050...3500、3550...4500、4550...5000、
5050...5500,5550...5950,6000...7000,7050...7500,7550...7950,8000mg/ daily/everyone
Dosage；Administration number of times include be not limited to 1~6 time/daily, preferably 1~4 time/daily；As illustrative explanation, such as daily
Once, twice, three times, four times, five times or six times etc..
When being administered in a manner of external application in present invention application, made preparation includes but is not limited to gelling agent, ointment, spray
Mist agent or transdermal patch etc., in the external preparation amount containing Uropoly acid-peptide can be combined by those skilled in the art the present invention and
This field correlation common sense is determined, and as one of embodiment, amount of the external preparation containing Uropoly acid-peptide accounts for the preparation
The percentage of gross mass include but is not limited to be 1%~48%, as exemplary illustration, for example, 1%, 2%, 4%, 8%,
16%, 32% or 48%；As one of embodiment, when for gel or ointment, as illustrative explanation, the unit
Amount in gel or ointment containing Uropoly acid-peptide can be 0.2~12.8mg/ml, can be for such as illustrative explanation
0.2, the Uropoly acid-peptide of 0.4,0.8,1.6,3.2,6.4 or 12.8mg/ml.
In the application of Uropoly acid-peptide preparation treatment scar drug of the present invention, it is any next that the Uropoly acid-peptide can be this field
The Uropoly acid-peptide in source, as one of embodiment, the Uropoly acid-peptide includes hippuric acid, phenylacetylglutamine, 4- hydroxy benzenes
Acetic acid and 5-HIAA；As one of embodiment, hippuric acid, phenylacetyl glutamy in Uropoly acid-peptide of the present invention
The percentage that amine, 4- hydroxyl phenylacetic acid and 5-HIAA amount account for gross mass is 28.5%~37.75%；As embodiment party
One of case, 0.10mg containing hippuric acid~0.15mg, phenylacetylglutamine 0.15mg in 1mg Uropoly acid-peptide of the present invention~
10 μ g of μ g~20 of 0.20mg, 4- hydroxyl phenylacetic acid, 2.5 μ of μ g~7.5 g of 5-HIAA.
It can adopt and prepare Uropoly acid-peptide of the present invention with the conventional methods in the field, it is described as one of embodiment
Method includes but is not limited to following method preparation:
1) freshly voided urine is taken, HCl is added and adjusts pH value, carries out ultrafiltration, collects the filtrate that molecular weight is lower than 10kD；Then will
Filtrate with XAD-8 silicagel column on 1.5l/min flow velocity, later first with 20L distilled water with 3l/min adsorption column, then with 15L ethyl alcohol with
The flow velocity of 1.0l/min is added in XAD-8 column, collects the eluent of coloured moiety；Vacuum drying treatment is to slowly warm up to 50 DEG C,
Until solvent all evaporates；Hereafter it is freeze-dried, obtains the dry product of Uropoly acid-peptide composition；
It 2) is 40mg/ml with distilled water dissolution dry product to concentration, it is molten to get Uropoly acid-peptide crude product to adjust pH value with NaOH
Liquid；Crude product solution is set into 4 DEG C of cryogenic conditions 120hr, supernatant is taken to carry out filtering with microporous membrane, filtrate ultrafiltration membrane ultrafiltration removes
Remove heat source and virus.
Uropoly acid-peptide of the present invention is in the application of the drug of preparation treatment scar, as one of embodiment, the step
1) pH value in is 1.5-3.0.
Uropoly acid-peptide of the present invention is in the application of the drug of preparation treatment scar, as one of embodiment, the step
2) pH value in is 6.5-7.5.
Uropoly acid-peptide of the present invention is in the application of the drug of preparation treatment scar, and as one of embodiment, the urine is more
Sour peptide is prepared with the following method:
1) freshly voided urine is taken, 1mol/lHCl is added and adjusts its pH to 2.0, urine, ultrafiltration apparatus is collected by filtration with nylon cloth
Ultrafiltration is carried out, deionized water is added in ultrafiltration apparatus, washes bubble ultrafiltration membrane, the urine of collection is poured into charging bucket, unlatching is received
The filtrate that molecular weight is lower than 10kD is collected in filter；XAD-8 silica gel is taken, is impregnated with 95% ethyl alcohol, is fitted into bag and is placed in modeling bucket,
Adsorption column is made, rinses pillar with 95% ethyl alcohol, washs adsorption column with the deionized water of same volume later；Then after filtering
Urine be added in column with the flow velocity of 1.5l/min, adsorption column is first added with 3l/min flow velocity with distilled water after adding, then use
95% ethyl alcohol is added in XAD-8 column with the flow velocity of 1.0l/min, collects coloured moiety eluent；Vacuum dried processing, slowly
It heats up and controls feed liquid temperature and all evaporated for 50 DEG C to solvent；Freeze-drying, obtains the dry product of Uropoly acid-peptide composition；
2) dried residue is dissolved with distilled water, makes its concentration 40g/ml, it is thick to adjust Uropoly acid-peptide with 2mol/l NaOH
The pH value of product places 120hr in 4 DEG C of cryogenic conditions, supernatant is taken, successively with 1 μm and 0.45 μm of miillpore filter mistake to after 7.4
Filter removes heat source then with the ultrafiltration membrane ultrafiltration of 10000 molecular weight, then through Ultipor VFTMDV50 (PALL company) filter
Except virus to get.
The application of Uropoly acid-peptide treatment scar of the present invention, can effectively treat scar, solve big currently on the market
The inapparent problem of part scar treatment curative effect of medication.
Through human dermal fibroblast cell experiment in vitro and zoopery, Uropoly acid-peptide has cicatrix of skin fibroblast
There is apparent apoptosis-induced effect, and significant in efficacy to rabbit ear scar treatment, thus can be used for preparing treatment cicatrix of skin
Drug.In vitro cell experiment and zoopery confirm that Uropoly acid-peptide is in addition to antitumaous effect, additionally it is possible to induced fibroblast
Apoptosis inhibits its proliferation, and inhibition level increases with the increase of Uropoly acid-peptide concentration, at apparent dose-effect relationship, and inhibiting rate
Up to 88.45%, and effective component-Asiaticoside of clinical treatment scar common drug, curcumin and vitamin A acid are several at present
The highest inhibiting rate of kind drug is 52.99%~75.69%.
Furthermore, zoopery also indicates that, the drug containing Uropoly acid-peptide is applied at rabbit ear scar, and after 28 days, scar is bright
Aobvious to reduce, scar proliferation block growth inhibition ratio is up to 89.28%, and common drug centella triterpenes cream and compound haparin natriuresis Bursin are solidifying
Glue and ointment containing Asiaticoside, curcumin, vitamin A acid and allantoin to scar proliferation block inhibiting rate be 50.46%~
76.68%, collagenous fibres surface density and the ratio of collagenous fibres I and III are significantly increased compared with other several drugs in scar.
Compared to the drug of other treatment scar, Uropoly acid-peptide curative effect of the present invention is more significant, will be for clinical treatment skin
One of preferable drug of skin scar.
Detailed description of the invention
Fig. 1: song is changed to people's scar fibroblast proliferation inhibiting rate to test 5 kinds of drugs used with drug concentration
Line, A: asiaticosid is to people's scar fibroblast proliferation inhibiting rate change curve；B: curcumin is to people's fibroblasts from hypertrophic scars
Proliferation inhibition rate change curve；C: vitamin A acid is to people's scar fibroblast proliferation inhibiting rate change curve；D: allantoin is to people
Scar fibroblast proliferation inhibiting rate change curve；E: Uropoly acid-peptide changes people's scar fibroblast proliferation inhibiting rate bent
Line；
When Fig. 2 is cell proliferation inhibition rate maximum, the respective inhibiting rate significance difference analysis histogram of 5 kinds of drugs；(its
Middle * P < 0.5, * * P < 0.01, n=3)；
Fig. 3 is to test 5 kinds of drugs used with medicament contg to rabbit ear scar proliferation block inhibiting rate change curve, A: accumulated snow
Careless glycosides is to rabbit ear scar proliferation block inhibiting rate change curve；B: curcumin is to rabbit ear scar proliferation block inhibiting rate change curve；C:
Vitamin A acid is to rabbit ear scar proliferation block inhibiting rate change curve；D: allantoin changes rabbit ear scar proliferation block inhibiting rate bent
Line；E: Uropoly acid-peptide is to rabbit ear scar proliferation block inhibiting rate change curve；
When Fig. 4 is rabbit ear scar proliferation block inhibiting rate maximum, the respective significance difference analysis histogram of 8 kinds of drugs.(its
Middle * P < 0.5, * * P < 0.01, * * P < 0.001, n=4).
Specific embodiment
Following embodiment does not limit effective range of the invention for the present invention is further explained in any manner.
The preparation and identification of embodiment 1, Uropoly acid-peptide
1. the preparation of Uropoly acid-peptide composition
20L freshly voided urine is taken, 1L 1mol/lHCl is added and adjusts its pH to 2.0, urine is collected by filtration with nylon cloth.Ultrafiltration
Equipment carries out ultrafiltration, and deionized water is added in ultrafiltration apparatus, washes bubble ultrafiltration membrane, the urine of collection is poured into charging bucket, is opened
Nanofiltration is opened, the filtrate that molecular weight is lower than 10kD is collected.
XAD-8 silica gel 10kg is taken, impregnates 20min with 25L95% ethyl alcohol, is fitted into bag and is placed in modeling bucket, absorption is made
Column rinses pillar with 95% ethyl alcohol (V/W=ethyl alcohol/silica gel=2), washs adsorption column 2 with the deionized water of same volume later
Secondary, in cleared pillar ethyl alcohol；Then filtered urine is added in column with the flow velocity of 1.5l/min, 20L is first used after adding
Adsorption column is added with 3l/min flow velocity in distilled water, then is added in XAD-8 column with 15L95% ethyl alcohol with the flow velocity of 1.0l/min, makes
The effective component of absorption disintegrates down, and collecting coloured moiety is effective eluent；The effective component of collection is vacuum dried
Processing, slowly heating up and controlling feed liquid temperature is 50 DEG C, until solvent all evaporates；Hereafter it is freeze-dried, it is more to obtain urine
The dry product of sour peptide combinations.
Dried residue is dissolved with distilled water, makes its concentration 40mg/ml, it is thick to adjust Uropoly acid-peptide with 2mol/l NaOH
The pH value of product to after 7.4 to get Uropoly acid-peptide crude product solution；Crude product is set into 4 DEG C of cryogenic conditions 120hr, removes crude product after handling
Supernatant, successively with 1 μm and 0.45 μm of filtering with microporous membrane, filtrate is Uropoly acid-peptide solution；With surpassing for 10000 molecular weight
Ultrafiltration through membranes remove heat source, then through Ultipor VFTMFor DV50 (PALL company) filter except virus, the rate of recovery is about 2.5%
(volume ratio).
2. each constituent structure confirmation and content detection in Uropoly acid-peptide composition
The Uropoly acid-peptide composition extracted from healthy human urine in the present invention contains four kinds of organic acids (hippuric acids, phenylacetyl paddy
Glutamine, 4- hydroxyl phenylacetic acid, 5-HIAA) and a series of small-molecular peptides isoreactivity ingredients, structural identification test master
To be directed to above-mentioned two major classes substance.Four kinds of organic acid high performance liquid chromatographies.Using sample-adding confirmation and separation determination and matter
Spectrometry measures molecular weight；Small-molecular peptides use liquid-mass chromatography, measure the molecular weight ranges of peptide, and be determined that two of them are main
The sequence of peptide.
Four kinds of organic acid structural identifications in 2.1 Uropoly acid-peptides
2.1.1 instrument analytic type HPLC, Japanese Shimadzu Corporation LC-10AVP.Chromatographic column: DikMA company, 5 μ 18 of Luna
(Z), 250 × 4.6mm (dm).
2.1.2 standard items 4- hydroxyl phenylacetic acid；5-HIAA；Hippuric acid；Phenylacetylglutamine is purchased
Sigma company.
2.1.3 chromatographic condition mobile phase: methanol: water: glacial acetic acid=50: 15: 1；Flow velocity: 1ml/min；Sample volume 20ul；
Detection wavelength: 260nm.
2.1.4 the preparation of reference substance solution
Respectively precision weigh 4- hydroxyl phenylacetic acid, 5-HIAA, hippuric acid, phenylacetylglutamine 45mg,
5.0mg, 45mg, 60mg are set in the measuring bottle of 4 50ml, add water about 40ml, and ultrasonic 30min dissolution is complete, later constant volume to scale,
It mixes.
2.1.5 the preparation of test sample solution
It takes Uropoly acid-peptide crude product appropriate, the solution in every 1ml containing 8mg is made.
2.1.6 measuring method and measurement result
Above-mentioned standard product solution and each 20ul injection chromatographic column of test solution are taken, with external standard method with 4 kinds of calculated by peak area
The content of organic acid.Measurement result is as follows:
Organic acid measurement result in table 1-1 Uropoly acid-peptide extract
The result shows that the retention time of each organic acid and reference substance are almost the same in test sample, provable this product contains above four
Kind organic acid.Content according to four kinds of organic acids in Peak area analysis Uropoly acid-peptide crude product test sample is respectively: hippuric acid
1.01mg/ml；Phenylacetylglutamine 1.43mg/ml；4- hydroxyl phenylacetic acid 0.12mg/ml；5-HIAA 0.04mg/
ml；0.126mg containing hippuric acid i.e. in 1mg Uropoly acid-peptide crude product, 15 μ g of phenylacetylglutamine 0.179mg, 4- hydroxyl phenylacetic acid,
5 μ g of 5-HIAA.The percentage that the gross mass of four kinds of organic acids accounts in Uropoly acid-peptide is 36%.
2.2 electrospray mass spectrographs measure peptide composition and partial peptide sequences measurement
Testing conditions: positive ion detection mode, capillary voltage 3000V, Cone voltage 50V, Collision voltage 30V,
Mep detects voltage 2000V.Peptide sequence analysis software is the Biolynx of Micromass company.Temperature: 22 DEG C；Detecting instrument name
Title and model: Q-T0F2ESI-MS/MS (Micromass).
2.2.1 analysis method:
(1) sample pretreatment: weighing Uropoly acid-peptide crude product about 10.0mg in 10ml plug test tube, and 5.0ml is added
Chloroform is sufficiently vibrated and is had children outside the state plan and extract 3min, stands 10min, chloroform is carefully sucked out with clean suction pipe；It is added
5ml petroleum ether is equally absorbed after ultrasound；5.0ml dehydrated alcohol is added, in triplicate with above step, residue is natural
Dry stand-by (about 40min).
(2) searching and identification of peptide components: the sample of above-mentioned processing is dissolved in 5ml1% formic acid deionized water, after centrifugation
1ul is taken to carry out capillary high performance liquid chromatography Nanoliter electrospray-level four bars flight time tandem mass spectrum automated analysis.
(3) sequencing of part peptide components: above-mentioned processed sample is dissolved in 5ml1% formic acid deionized water, from
It takes 1ul to carry out Nanoliter electrospray-level four bars flight time Tandem Mass Spectrometry Analysis after the heart, 1-2 main peak is selected to carry out sequencing.
2.2.2 result
(1) chromatography of ions figure shows that tri- region retention times of I, II, III are respectively as follows: 14~19min, 30~45min,
45~55min.
(2) total mass spectrogram in the area I is the result shows that a peptide, relative amount the higher person molecular ion peak are respectively more than 20
1218.69,1240.67,1251.69,1322.74,1452.81 (molecular weight=molecular ion peak -1.0078).
(3) total mass spectrogram in the area II does not find apparent quasi-molecular ions, aobvious with the map after special software MaxEnt3 conversion
Show that conversion front and back mass spectrogram is consistent, it can be seen that the peptide composition in the area is seldom.
(4) total mass spectrogram in the area III shows that as the area II, peptide composition is seldom, almost without.
2.2.3 the biggish particle of two intensity is selected to carry out Tandem Mass Spectrometry Analysis
The sequencing results sequence of m/z626.36 are as follows: AVEGPSSALGPLCGP, single isotopic mass
1250.7043Da, theoretical value 1250.6506Da, deviation 0.05Da；
The sequencing results of m/z609.84 are as follows: GPSTPGPPPNGGA, single isotopic mass 1217.6644Da, it is theoretical
Value is 1217.6040Da, deviation 0.06Da.
1 Uropoly acid-peptide of experimental example induces the experiment of human hypertrophic scar fibroblast (hHSF) apoptosis
1, the fibroblastic preparation of human hypertrophic scar
16-30 years old patient skin hyperplastic scar is taken, aseptically epidermis is removed and subcutaneous tissue, physiological saline is anti-
0.5-1.0mm is cut into after multiple flushing3Tissue block, appropriate FBS (calf serum) washs tissue block repeatedly, is inoculated with later
In in batch cultur bottle wall, the control of tissue block spacing is added DMEM culture solution of the 5ml containing 20%FBS and (contains in 0.3-0.5mm
Penicillin 100U/ml, streptomysin 100U/ml), in 37 DEG C, 5%CO2Culture, is changed weekly liquid 2 times, to primary in cell incubator
When cell growth merges in blocks substantially, culture solution is drawn, 0.25% trypsin digestion 1min is added after rinsing 2 times in PBS, wait see
It when observing space between cells increase, and seeing cytoplasm retraction under microscope, inhales and abandons pancreatin, the DMEM culture medium termination containing serum is added and disappears
Change, gently blowing and beating cell makes to be transferred in 15ml centrifuge tube in cell suspension, is centrifuged 3min in 1000r/min, abandons supernatant and add again
Enter the DMEM culture medium containing 10%FBS and cell is resuspended, passed in 1: 3 ratio, carries out following experiment for cell using 3-6.
2, influence of the Uropoly acid-peptide to people's fibroblasts from hypertrophic scars vigor
MTT (3- (4,5)-dimethylthiahiazo (- 2-y1) -3,5-di-phenytetrazoliumromide) ratio
Color method is detection cell survival and grows common method, and the succinate dehydrogenase in living cells mitochondria can be such that MTT is reduced to
The bluish violet of water-insoluble crystallizes first a ceremonial jade-ladle, used in libation, and dead cell cannot, DMSO (dimethyl sulfoxide) can dissolve the first a ceremonial jade-ladle, used in libation in cell,
And have maximum absorption band at 490nm, which reflects cell viability indirectly.
The present invention compares Asiaticoside (Asiaticoside, C48H78O19, the main component of centella triterpenes cream is purchased from
, Wei Jia Sigma-Aldrich, article No.: 43191), (Curcumin is purchased from Sigma-Aldrich, article No.: 08511) to curcumin
Acid (Tretinoin, C20H28O2, be purchased from Sigma-Aldrich, article No.: R2625), allantoin (Allantoin, C4H6N4O3It is multiple
And Uropoly acid-peptide (CDA-II) main component of square heparin sodium allantoin gel is purchased from Sigma-Aldrich, article No.: 93791)
(being made by 1 method of the embodiment of the present invention) influence of these four bulk pharmaceutical chemicals to people's fibroblasts from hypertrophic scars vigor.Cell viability is surveyed
It is as follows to determine method:
People's fibroblasts from hypertrophic scars of logarithmic growth phase is made 5 × 10 with the DMEM culture solution of 10%FBS4A/ml's
Cell suspension is inoculated in 3 96 well culture plates with every hole 200ul respectively, and edge hole is filled with Du Shi phosphate buffer (DPBS)；
37 DEG C, 5%CO2R for 24 hours is cultivated in incubator.By the above drug according to the dilution for being configured to various concentration shown in table 1-1.
Wherein curcumin and vitamin A acid are not soluble in water, therefore 10mg/ml mother liquor first is respectively configured with DMSO, later with DMEM culture medium by
Grade is diluted to concentration shown in table 1-1.Supernatant culture solution is abandoned after r for 24 hours, is separately added into the drug of 200ul various concentration, is compareed
DMEM culture solution of the 200ul containing 10%FBS is added in group, and each concentration of every kind of drug does 4 multiple holes, in 37 DEG C, 5%CO2Training
It supports and 20ul MTT (5mg/ml, i.e. 0.5%MTT) is added after cultivating 48hr in case, continue to cultivate 4hr, inhale and abandon culture solution, every hole adds
150ul DMSO, which is terminated, to react, and inhales brightness A in measurement on ELISA instrument after oscillation 15min490nmValue, the difference surveyed respectively
Concentration Uropoly acid-peptide different time cell proliferation inhibition rate (cell proliferation inhibition rate=(1- experimental group averagely inhale brightness value/
Control group averagely inhales brightness value) × 100%), using drug concentration as abscissa, cell proliferation inhibition rate is ordinate, draws medicine
Object dose-effect curve, as a result such as Fig. 1.Hereafter corresponding drug concentration when cell proliferation rate highest is selected to repeat to do three batches carefully
Born of the same parents' experiment, statisticallys analyze the average inhibition of three batches of experiments, and experimental group and control group is poor using the analysis of T-test statistical method
Different conspicuousness, as a result as shown in Figure 2.
The concentration table that table 1-1 different pharmaceutical is prepared
Asiaticoside reaches most people's cicatrical fibrosis cell proliferation inhibition rate when its concentration is 64mg/ml as seen from Figure 1
Big value 75.69%, curcumin cell proliferation inhibition rate when concentration is 0.016mg/ml reach maximum value 52.99%, vitamin A acid
When concentration is 0.32mg/ml, cell proliferation inhibiting rate reaches maximum value 67.93%, and allantoin is 0.16mg/ml in concentration
When cell proliferation inhibition rate reach maximum value 77.46%, and when Uropoly acid-peptide concentration is 6.4mg/ml, is thin to people's scar fibroblast
The inhibiting rate of born of the same parents is maximum, maximal percentage inhibition 88.45%, aobvious by the inhibiting rate of T check analysis Uropoly acid-peptide cell proliferation
It writes and is higher than other four kinds of drugs (* * P < 0.01), to the inhibition efficiency highest of people's fibroblasts from hypertrophic scars.
Table 1-2MTT method detects effect of the different pharmaceutical to fibroblasts from hypertrophic scars
Test example 2, Uropoly acid-peptide are to the Inhibition test of rabbit ear hyperplastic scar
1, the foundation of scar animal model
Take the Japanese screech owl white rabbit of 3-4 month sizes, male and female, weight 2.2-2.6kg, ketamine (15mg/kg) ear
Edge intravenous injection anesthesia, rabbit prostrate is fixed on station, and every rabbit facies ventralis of surveying performs the operation excision diameter as 10mm's
Full thickness skin, strikes off perichondrium, and two pick up the ears at 5 totally, each surface of a wound interval 15mm or more, surface of a wound exposure, to surface of a wound epithelialization 20d
Afterwards, scar proliferation block is formed.
2, Uropoly acid-peptide ointment preparation method
2.1 prepared by ointment bases:
Ointment bases ingredient borneol, menthol, camphor, thymol are ground into subdivision, and cross 120 meshes, according to need
This zoopery is wanted to need the matrix total amount used are as follows: the mass percent 52% of matrix (+48% vaseline of 0.5% borneol+
+ 0.5% thymol of+1% camphor of 2% menthol) each scar of * 180 surface of a wound * smears ointment amount 50mg=4680mg, altogether
Prepare the above-mentioned matrix of 5.2g.Vaseline 4.8g is weighed, is heated to 50~60 DEG C, it is made to melt into thick paste, constant temperature is placed spare.Respectively
The fine powder for having ground and being sieved: borneol 50mg, menthol 200mg, camphor 100mg, thymol 50mg is weighed, by above-mentioned fine powder
It is uniformly mixed, is added in vaseline liquid thick paste while stirring, until uniformly, constant temperature keeps thick paste state spare.
The preparation of the Uropoly acid-peptide ointment of 2.2 various concentrations:
According to table 2-2 different pharmaceutical ointment material composition mass percent table, it is known that Uropoly acid-peptide ointment test group sets 7 altogether
A various concentration, the Uropoly acid-peptide ointment of each concentration smear 5 surface of a wound in parallel, and each surface of a wound need to smear ointment bases 50mg,
Therefore the Uropoly acid-peptide ointment that can be calculated every kind of concentration needs to prepare: 5 parallel each scars of surface of a wound * smear ointment amount 50mg=
The Uropoly acid-peptide ointment of 250mg, the loss during preventing ointment from making and using, every kind of concentration prepare 300mg altogether.
Weigh 3mg, 6mg, 12mg, 24mg, 48mg, 96mg, 144mg Uropoly acid-peptide fine powder, add to respectively 141mg,
In 138mg, 132mg, 120mg, 96mg, 48mg, 0mg propylene glycol, Uropoly acid-peptide propylene glycol solution is stirred evenly to obtain.By above-mentioned solution,
It is separately added into 2.1 matrix for the 156mg that 7 parts have prepared, sufficiently stirs evenly condensation and Uropoly acid-peptide ointment is made, it will be above different
The Uropoly acid-peptide ointment formulation of concentration, is sealed, then irradiation sterilization with packaging of aluminium foil bag, is saved in 4 DEG C stand-by.
The preparation of 2.3 various concentration positive control drug ointment:
Other four kinds containing quality contained by drug in four kinds of Asiaticoside, curcumin, vitamin A acid and allantoin drug ointments
Percentage is such as shown in table 2-2, and preparation method is the same as 2.2.
The preparation of 2.4 blank control ointment:
The ointment of blank control group: weigh 144mg propylene glycol and 2.1 matrix that 156mg is prepared be sufficiently mixed it is uniformly cold
It is solidifying.
Table 2-1 different pharmaceutical ointment material composition mass percent table
Table 2-2 different pharmaceutical ointment formulation prescription table
3, the research that Uropoly acid-peptide influences the scar of rabbit ear scar model animal
This experiment is divided into 6 groups: (1) blank control group；(2) positive controls (2-1: curcumin, 2-2: vitamin A acid, 2-3:
Asiaticoside, 2-4: allantoin；(3) Uropoly acid-peptide group.
36 rabbits, every rabbit are equipped with 5 surface of a wound, amount to 180 surface of a wound.Every kind of ointment positive control medicine group,
There are 7 different ointment formulation prescriptions, every kind of ointment formulation prescription smears 5 surface of a wound, i.e. every kind of ointment positive control medicine in parallel
Group needs the 7*5=35 surface of a wound.Uropoly acid-peptide group and so on is also required to 35 surface of a wound.Blank ointment bases control group (is not added
Any raw material only adds matrix, and each matrix mass percent is as follows, propylene glycol: borneol: vaseline: menthol: camphor: thyme
Powder=48: 0.5: 48: 2: 1: 0.5) there was only 1 preparation prescription, smear 5 surface of a wound in parallel.So entire rabbit experiment needs: 4
Kind 7 preparation prescription * 5 of parallel+1 Uropoly acid-peptide testing drug ointment * of the surface of a wound of the preparation prescription * 5 of positive control ointment * 7
+ 1 surface of a wound=180 surface of a wound of preparation prescription * 5 of blank ointment * 1 of a parallel surface of a wound.Outside the position of rabbit ear cicatrization
Corresponding drug ointment is applied, and softly until medicaments uniformity；Once a day, every place's scar about 50mg, continuous processing 28 days, the 28th
Following index is detected after it:
Scar proliferation observation: hyperplasia block is cut in r for 24 hours after drug withdrawal in 4 weeks, weighs hyperplasia block weight, and calculate every group of hyperplasia
Block growth inhibition ratio, calculation formula are as follows:
Inhibiting rate=(1- medication group be averaged scar weight/blank control group be averaged scar weight) × 100%
As a result as shown in Figure 3, the results showed that four kinds of material quality percentages of 2-1 to 2-4 are followed successively by positive controls
32%, 0.16%, 3.2%, 1.6% when maximum is reached to the inhibiting rate of rabbit ear scar proliferation block, maximum value is respectively
76.68%, 50.46,56.78,68.93%；When Uropoly acid-peptide material quality percentage is 16%, to the scar proliferation block of rabbit ear
Inhibiting rate reaches maximum, inhibiting rate 89.28%.By T check analysis, as shown in figure 4, showing Uropoly acid-peptide to scar proliferation
The Emax (maximum efficiency) of block inhibiting rate is significantly higher than the Emax (* * P < 0.01) of other four kinds of positive control medicines.
2. collagenous fibres surface density in scar: by the every kind of drug cut to the maximum scar of rabbit ear scar proliferation block inhibiting rate
About 4 μm of slice is made in trace after fixation, dehydration, transparent, waxdip, embedding, is dyed using VG decoration method, i.e., uses after conventional dewaxing
Iron haematoxylin mixed liquor dyes 5min, and hydrochloride alcohol differentiation, ammonium hydroxide is anti-blue, and 1% acid fuchsin 2 of VG liquid drop, saturation picric acid 8 drips
5min is dyed, washes 1min using distillation between above every step, 95% alcohol breaks up and is dehydrated later, and dimethylbenzene is transparent, in
Property natural gum mounting.Center is sliced in scar and side respectively randomly selects 5 visuals field and takes pictures under the microscope, and collagenous fibres are contaminated through VG
It is red after color, Computer digital image analysis is utilized to calculate the averaged areal density of collagenous fibres.
3. scar I, type III collagen ratio: after medication 28d, in 2., taking every kind of drug to rabbit ear scar proliferation block
Slice is made in the maximum scar of inhibiting rate, dyes through picrosirius red staining, i.e., enters celestine blue liquid dye after conventional dewaxing
5min, distillation washing three times, are saturated picric acid dye liquor 30min, dehydrated alcohol differentiation and dehydration, dimethylbenzene with sirius red later
It is transparent, neutral gum mounting, later in polarized light microscopy under the microscope and save image, type i collagen fiber is shown in red or yellow
Color fibre, the shown in green reticular fibre of type III collagen are calculated shared by I, type III collagen using Computer digital image analysis
Area percent.
2.~collagenous fibres surface density that 3. each cicatricial tissue block measures in Testing index and I, type III collagen ratio above
As a result as shown in following table 2-3, the results showed that Uropoly acid-peptide makes in rabbit ear scar into fibre density and type i collagen and type III
Collagen ratio is remarkably decreased compared with other several drugs, and curative effect is most prominent.
Table 2-3 collagenous fibres surface density and I, type III collagen ratio test result
In conclusion the present invention subtracts the result shows that Uropoly acid-peptide can significantly inhibit the fibroblastic proliferation of cicatrix of skin
The index of few scar, thus can be used for preparing the drug for the treatment of scar.
Claims (9)
1. the application in a kind of drug of Uropoly acid-peptide preparation treatment scar, wherein every 1mg Uropoly acid-peptide in the Uropoly acid-peptide
Containing 0.10mg~0.15mg hippuric acid, 0.15mg~0.20mg phenylacetylglutamine, the 10 μ g 4- of μ g~20 hydroxyl phenylacetic acids,
2.5 μ of μ g~7.5 g of 5-HIAA.
2. application according to claim 1, which is characterized in that the Uropoly acid-peptide is the preparation containing Uropoly acid-peptide.
3. application according to claim 2, which is characterized in that the preparation is external preparation, and the external preparation is solidifying
Jelly, ointment, spray or transdermal patch.
4. application according to claim 3, which is characterized in that the amount in the external preparation containing Uropoly acid-peptide is in mass
For 1%-48%.
5. application according to claim 1, which is characterized in that the Uropoly acid-peptide includes hippuric acid, phenylacetyl glutamy
Amine, 4- hydroxyl phenylacetic acid and 5-HIAA, wherein the hippuric acid, phenylacetylglutamine, 4- hydroxyl phenylacetic acid and
The percentage that the amount of 5-HIAA accounts for gross mass is 28.5%~37.75%.
6. application according to claim 1, which is characterized in that the Uropoly acid-peptide is prepared with the following method:
1) freshly voided urine is taken, HCl is added and adjusts pH value, carries out ultrafiltration, collects the filtrate that molecular weight is lower than 10kD；Then by filtrate
With XAD-8 silicagel column on 1.5l/min flow velocity, later first with 20L distilled water with 3l/min adsorption column, then with 15L ethyl alcohol with
The flow velocity of 1.0l/min is added in XAD-8 column, collects the eluent of coloured moiety；Vacuum drying treatment is to slowly warm up to 50 DEG C,
Until solvent all evaporates；Hereafter it is freeze-dried, obtains the dry product of Uropoly acid-peptide composition；
2) it is 40mg/ml with distilled water dissolution dry product to concentration, adjusts pH value with NaOH to get Uropoly acid-peptide crude product solution；It will
Crude product solution sets 4 DEG C of cryogenic conditions 120hr, and supernatant is taken to carry out filtering with microporous membrane, and filtrate ultrafiltration membrane ultrafiltration removes heat source
And virus.
7. application according to claim 6, which is characterized in that the pH value in the step 1) is 1.5-3.0.
8. application according to claim 6, which is characterized in that the pH value in the step 2) is 6.5-7.5.
9. application according to claim 6, which is characterized in that the Uropoly acid-peptide is prepared with the following method:
1) take freshly voided urine, 1mol/l HCl be added and adjusts its pH to 2.0, be collected by filtration urine with nylon cloth, ultrafiltration apparatus into
Row ultrafiltration, is added deionized water in ultrafiltration apparatus, washes bubble ultrafiltration membrane, and the urine of collection is poured into charging bucket, opens nanofiltration,
Collect the filtrate that molecular weight is lower than 10kD；XAD-8 silica gel is taken, is impregnated with ethyl alcohol, is fitted into bag and is placed in modeling bucket, absorption is made
Column rinses pillar with 95% ethyl alcohol, washs adsorption column with the deionized water of same volume later；Then by filtered urine with
The flow velocity of 1.5l/min is added in column, is first added adsorption column with distilled water after adding with the flow velocity of 3l/min, then with 95% ethyl alcohol
It is added in XAD-8 column with the flow velocity of 1.0l/min, collects coloured moiety eluent；Vacuum dried processing, slowly heats up and controls
Feed liquid temperature processed is 50 DEG C and all evaporates to solvent；Freeze-drying, obtains the dry product of Uropoly acid-peptide composition；
2) dried residue is dissolved with distilled water, makes its concentration 40mg/ml, adjust Uropoly acid-peptide crude product with 2mol/l NaOH
PH value to after 7.4, place 120hr in 4 DEG C of cryogenic conditions, supernatant taken, successively with 1 μm and 0.45 μm of miillpore filter mistake
Filter removes heat source then with the ultrafiltration membrane ultrafiltration of 10000 molecular weight, then through Ultipor VFTMDV50 filter is except virus, i.e.,
?.
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| 尿多酸肽（CDA-Ⅱ）中抗肿瘤活性的物质基础研究;曹建华;《中国优秀博硕士学位论文全文数据库 (硕士) 医药卫生科技辑》;20060715(第07期);第E079-4页 |
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Effective date of registration: 20160405 Address after: 200020, 5 floor, city building, No. 45, Nanchang Road, Shanghai, Luwan District Applicant after: NT PHARMA (CHINA) INVESTMENT Co.,Ltd. Applicant after: Zhou Mingtao Applicant after: NT BIOPHARMACEUTICALS JIANGSU CO.,LTD. Applicant after: Tai Ling Pharmaceutical (Changsha) Co.,Ltd. Applicant after: Jiangsu No. 1 Pharmaceutical Co.,Ltd. Address before: 200020, 5 floor, city building, No. 45, Nanchang Road, Shanghai, Luwan District Applicant before: NT PHARMA (CHINA) INVESTMENT Co.,Ltd. Applicant before: Zhou Mingtao |
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Denomination of invention: Application of uroacitides to preparation of cicatrix treatment medicines Effective date of registration: 20200408 Granted publication date: 20190412 Pledgee: Haier financial factoring (Chongqing) Co.,Ltd. Pledgor: Suzhou First Pharmaceutical Co.,Ltd.|Tai Ling Pharmaceutical (Changsha) Co.,Ltd.|NT BIOPHARMACEUTICALS JIANGSU CO.,LTD.|NT PHARMA (CHINA) INVESTMENT Co.,Ltd.|Zhou Mingtao Registration number: Y2020310000007 |
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