CN103145799A - Group of polypeptides having percutaneous and transmembrane penetration promoting effect, and applications thereof - Google Patents
Group of polypeptides having percutaneous and transmembrane penetration promoting effect, and applications thereof Download PDFInfo
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- CN103145799A CN103145799A CN2013100526582A CN201310052658A CN103145799A CN 103145799 A CN103145799 A CN 103145799A CN 2013100526582 A CN2013100526582 A CN 2013100526582A CN 201310052658 A CN201310052658 A CN 201310052658A CN 103145799 A CN103145799 A CN 103145799A
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Abstract
The invention discloses a group of polypeptides having a percutaneous and transmembrane penetration promoting effect, and applications thereof, and is suitable for the fields of transdermal and transmembrane drug delivery systems and cosmetics. Each of the polypeptides has eleven amino acid residues, and has an annular structure formed by nine amino acid residues and a disulfide bond, and the structure of each of the polypeptides is characterized in that the N-5 and N-6 positions of the N-terminal of each of the polypeptides are alkaline amino acids or the C-terminal is amidated. The polypeptides synthesized through substituting the N-5 or N-6 position of the N-terminal by an alkaline amino acid and C-terminal amidated polypeptides have substantially higher insulin transdermal and transmembrane penetration capabilities than reported polypeptides having penetration promoting activities. The transdermal and transmembrane penetration promoting capabilities of the polypeptides obtained after the simultaneous substitution of the N-5 and N-6 positions of the N-terminal by the alkaline amino acids are further enhanced, the blood sugar reducing effects of diabetic rats are substantially improved through insulin common transdermal drug delivery, the in-vivo blood sugar level of the diabetic rats within 8h after the transdermal drug delivery is reduced to 20-30% of the original level, and the group of the polypeptides disclosed in the invention can be used in solutions, gels and ointments to promote the percutaneous and transmembrane absorption of biological macromolecular drugs comprising insulin, vaccines and the like.
Description
Technical field
The present invention relates to one group and have promotion through skin and the chemosmotic polypeptide of cross-film and application thereof, be applicable to through skin with through membrane drug delivery system and cosmetic field.
Background technology
Percutaneous dosing refers to that medicine passes through skin with certain speed, absorb through capillary vessel and enter the body circulation and the generation drug effect, refer to that also medicine absorbs by skin, enter epidermis, corium or subcutis, the performance local therapeutic effects refers to that through the film administration medicine enters the recycle system by microbial film and produces curative effect.Compare many advantages with traditional administering mode: can reduce or avoid the first-pass effect of liver through skin and cross-film administration, reduce toxic side effect; Avoid affecting the various factors that the medicine stomach and intestine absorb, as the combination of pH value, enzyme, medicine and food, the impact of medicine is had slow releasing function simultaneously; Can keep blood level to be stabilized in treatment effective concentration scope; Simultaneously can stop at any time administration.Although these administering modes are the easy desirable route of administration of enzymolysis large hydrophilic molecular such as Regular Insulin, but because large hydrophilic molecular passes through microbial film, especially stratum corneum absorbs low, the tradition medicine-feeding technology can't satisfy the treatment requirement, the macromolecular drugs such as present Regular Insulin are mainly with the injection system administration, and patient adaptability is relatively poor.Therefore, how to realize that effective percutaneous dosing of large hydrophilic molecular medicine becomes a major challenge of formulation art (Shaikh et al.2005, Cur.Pharma.Bio.6:387; Huang et al.2006, Jour.of control.Rel., 113:9-14; Li et al.2008, Bio.﹠amp; Pharma.Bull.31:1574).
Have at present report can promote large hydrophilic molecular to pass skin to mainly contain following method: iontophoresis (Kanikkannan et al.1999, Jour.of control.Rel.59:99.), iontophoresis (Boucaud et al.2002Jour.of control.Rel.81:113.), electroporation method (Sen et al.2002, Bio.et bio.acta1564:5.) and micropin introductory technique (Zhou et al.2010, Inter.Jour.of pharma., 392:127.) etc.In addition, there is research to report respectively polypeptide
With
Can promote the insulin type large hydrophilic molecular to absorb (Chen et al.2006, Nature bio.24:455 through the mouse skin; Hou et al.2007, Exp.Derma.16:999-1006; Hsu et al.2011, Proc.Natl.Acad.Sci.108:15816).If studies show that the large hydrophilic molecular drug main enters (Carmichael et al.2010 in body by the hair follicle position, Pain, 149:316.), and the existing short polypeptide that oozes exists Regular Insulin through the short lower problem of usefulness of oozing of skin, due to human body hair follicle comparatively small amt (Prausnitz, 2006, Nature bio.24:416.), therefore, that biopharmaceutical macromolecular drug is had a higher short polypeptide that oozes effect is very urgent and necessary in research and development.
people mainly concentrate in the research aspect drug transport the cell-penetrating peptide that is rich in basic aminoacids to peptide at first, touch sufficient peptide Antp(Derossi et al.1994 as fruit bat, The Jour.of bio.chem.269:10444), human immunodeficiency virus's trans-activator TAT(Brooks et al.2005, Adv.Dru.Del.Rev.57:559), PEP-1(Hallbrink et al.2001, Bio.et bio.acta1515:101.) and poly arginine (Futaki et al.2001, The Jour.of bio.chem.276:5836.) etc., these wear film peptide itself can pass human or animal's skin, part is worn the film peptide and can also be carried albumen by the mode that links with the albumen covalency and pass skin or microbial film (Lopes et al.2005, Pharma.Res.22:750.Patel et al.2009, Mol.Pharma.6:492.).Ooze aspect mechanism short, people have found that Methionin or arginic basic group have material impact (Beerens et al.2003 to the penetration enhancing activity of wearing the film peptide, Curr.gene therapy3:486.), the film peptide of wearing that is rich in basic group of finding simultaneously highly-hydrophilic promotes hydrophilic medicament transmembrane transport (Ohtake et al.2002 by reversible loose intercellular tight connection, J.controlled release, 82:263).
At present mainly adopt animal at the body experimental technique to polypeptide through the screening method of skin penetration enhancing activity, the method is consuming time, due to animal individual difference, needs a large amount of animal specimen and analyzes poor stability.The Caco-2 cell is widely used in estimating the ability of medicine cross-film infiltration and infiltration accelerating agent to in-vitro evaluation (the Torres-Lugo et al.2002 of medicine mechanism, Biotechnol.Prog.18:612), have the report show epithelium and Caco-2 cell monolayer film similar, exist intercellular tight junction (Morita et al.2003, J.Dermatol.Sci.31:81).
Summary of the invention
The present invention is intended to by to existing penetration enhancing activity polypeptide
Structure of modification provides one group of new and effective promotion through skin and the chemosmotic polypeptide of cross-film, improves the macromolecular drugs such as Regular Insulin and vaccine through skin and cross-film penetrating power and the correlation technique means are provided.
The technical solution used in the present invention is: at polypeptide
On the basis, scan by basic aminoacids, clear and definite basic aminoacids kind, quantity and site are on improving polypeptide through the impact of skin penetration enhancing activity.By to existing penetration enhancing activity polypeptide structure transformation, synthetic more efficiently through skin and the short polypeptide that oozes of cross-film.This group polypeptide contains 11 amino-acid residues, and consists of ring texture by 9 amino-acid residues with disulfide linkage, and the N-5 of N-end and N-6 site are made of alkaline amino acid residue, concrete structure:
Or the amidation of C-end, concrete structure:
Polypeptide and original polypeptide that the basic aminoacids in other sites replaces
There is no significant difference through skin and cross-film mechanism.
Technique scheme adopts basic aminoacids-arginine or Methionin scanning, and research basic aminoacids kind, quantity and site are on the impact through skin and cross-film penetration enhancing activity.Clear and definite polypeptide
N-5 in structure, the N-6 position is the structure of modification avtive spot, employing basic aminoacids-Methionin (K) and arginine (R) replacement or the amidated polypeptide of C-end can significantly improve the penetration enhancing activity to the Regular Insulin transdermal penetration, can assist the large hydrophilic molecular medicine to pass the various preparations of skin and microbial film barrier, comprise Regular Insulin and various vaccines etc.Polypeptide can adopt the solid-phase polypeptide synthesis method to synthesize.
The invention has the beneficial effects as follows: described have the short polypeptide that oozes effect of transdermal and cross-film and contain 11 amino-acid residues, and consist of ring texture by 9 amino-acid residues with disulfide linkage, to polypeptide
Middle N-5, the synthetic a plurality of peptide sequences of N-6 position basic aminoacids replacement are with polypeptide
Compare, all being significantly improved through skin and cross-film penetrating power of large hydrophilic molecular, to N-5, the N-6 position is further strengthened with the polypeptide penetration enhancing activity that K and/or R replace simultaneously, improved the hypoglycemic effect of Regular Insulin percutaneous dosing to diabetes rat, in percutaneous dosing 8h, diabetes rat at the 20-30% of body glucose level to previous level, can also significantly improve the turn-over capacity of Regular Insulin cross-cell membrane in addition.
Embodiment
Below further describe the present invention by indefiniteness embodiment:
Embodiment 1
Diabetes rat model is set up: the fasting of SD rat was weighed after one night, pressed the 70mg/kg corresponding streptozotocin of body weight injection on an empty stomach, and injection is complete in 30min.The SD rat that blood glucose value 20-30mmol/L is chosen in modeling after about 10 days carries out the polypeptide screening experiment.With the wetting belly wool that cuts off of physiological saline, make the area of rat skin exposure at 4cm
2Effect is also cleaned with physiological saline.After percutaneous dosing, observe SD rat blood sugar rheological parameters' change with time and research polypeptide promotion Regular Insulin transdermal penetration ability at body, to screening through the short ability of oozing of skin of synthetic serial polypeptide.
Embodiment 2
The Caco-2 cell culture processes: with the Caco-2 cell kind in 40-60 generation in 25cm
2In Tissue Culture Flask.Contain in the DMEM substratum: 20% bovine serum too, 1% (v/v) nonessential amino acid, 2mmol/L L-glutaminate, 100IU/mL penicillin, 100 μ g/mL Streptomycin sulphates (pH=7.4).Culture condition is 37 ° of C, 5%CO
2, 95% air and 90% relative humidity are changed weekly three subcultures.
Embodiment 3
The experiment of Regular Insulin transmembrane transport: the Caco-2 cell is inoculated in 12 hole Transwell culture plates, and inoculum density is 2 * 105cells/mL.Cultivate and form the cell monolayer film after 20-22 days.Before transport experiment, Caco-2 cell monolayer film is hatched 10min with the HBSS of 37 ° of C.Detect simultaneously the resistance value of cell monolayer film to guarantee cell membrane integrity.Select resistance value greater than 400 Ω cm
2The cell monolayer film carry out transport experiment.The BL side adds the 1.5mL21IU/mL insulin solutions, perhaps 1.5mL21IU/mL Regular Insulin and 5 μ mol/mL polypeptide (sequence 1-10) solution, and the AP side adds 0.5mL Hank ' s solution to add.(0.5h, 1h, 1.5h and 2h) gets from the AP side draught cross-film resistance that 100 μ L receiving liquids detect the cell monolayer film simultaneously respectively at different time points, and the HPLC method detects insulin concentration in receiving liquid.Observe insulin concentration rheological parameters' change with time and research polypeptide promotion Regular Insulin cross-film penetrating power, the short ability of oozing of the cross-film of synthetic serial polypeptide is screened.Regular Insulin cross-film permeability coefficient changing conditions sees Table 1.
Embodiment 4
With peptide sequence 1
Be example, illustrate and adopt the synthetic polypeptide of solid phase synthesis process.
Adopt the microwave-assisted polypeptide solid-state reaction method: take the Wang resin as solid phase carrier, HBTU-HOBt is condensing agent, and Fmoc is the synthesis strategy of alpha-amino group protecting group.
Take the Fmoc-glycine of 0.1mmol-Wang resin in solid phase reactor, add the DCM swelling resin 30min of 10mL, treat the abundant swelling of resin, vacuum is drained solvent.Wash once with 20% piperidines/DMF10mL; add 20% piperidines/DMF10mL and be placed in the microwave-assisted Solid-state synthesizer in resin; in 60 ° of C; under the 20W condition, reaction 3min removes the Fmoc protecting group; successively with DCM, DMF washing; protecting group removes and adopts the Kaiser method to detect, and tests positive can continue reaction.Fmoc-amino acid-OH, HBTU and the HOBt of 3eq are dissolved with DMF, and the standing 2min of DIEA that drips 5eq fully activates it, adds in solid phase reactor, in 60 ° of C, reacts 5min under the 20W condition, after condensation is completed, uses DCM, and DMF is washing resin successively.Repeat above each step reaction and obtain required straight-chain polypeptide, use TFA/TIS/H
2O is 95:2.5:2.5 solution 10mL; normal-temperature reaction 2h removes N-end and Side chain protective group and excises resin; with DCM washing three times; after filtrate is concentrated into minimum volume, add 30 times of volume ice ether, under 4 ° of C conditions; the centrifugal 15min of 10000r/min; abandoning supernatant repeats crystallization twice, and vacuum-drying obtains the polypeptide linear product.Polypeptide is dissolved in 25% methanol aqueous solution, and minute 5 every minor tick 30min add 2.5eq iodine to carry out oxidizing reaction, and are concentrated after stirring at room reaction 2h, obtain thick product.Purifying adopts gel chromatography chromatogram Sephadex G-15, and elutriant is 50% methanol aqueous solution, and product is identified through HPLC and ESI-MS.
Embodiment 5
Peptide sequence 9
Solid phase synthesis process.
Adopt the acid amides mbha resin of 0.1mmol to carry out solid phase synthesis, other steps are with embodiment 2.
Embodiment 6
0.5 μ mol polypeptide (sequence 1-9) is mixed with 2.1IU Regular Insulin respectively, then be dissolved in respectively in 100mg physiological saline, evenly be applied to the diabetes rat belly 4cm of embodiment 1
20h after administration, 2h, 5h, 8h tail venous blood sampling detects SD rat blood sugar level simultaneously, and the blood glucose in diabetic rats changing conditions sees Table 2.
Embodiment 7
With PEG4000 and PEG400 according to the melting of 2:3 Hybrid Heating, the preparation ointment base, 0.05 ~ 1.5 μ mol polypeptide (sequence 1-9) is mixed with 0.21 ~ 2.1IU Regular Insulin respectively, more evenly be mixed with into the 100mg ointment base respectively and contain the short Regular Insulin ointment that oozes polypeptide.
Embodiment 8
Preparation Carbopol941 gel matrix (contains 1%wt Carbopol941, the 1.2%wt trolamine, pH=6 ~ 7), 0.05 ~ 1.5 μ mol polypeptide (sequence 1-9) is mixed with 0.21 ~ 2.1IU Regular Insulin respectively, evenly mix with the 100mg gel matrix respectively again, be prepared into and contain the short Regular Insulin gel that oozes polypeptide.
The contrast experiment 1
0.5 μ mol contrast polypeptide (sequence 10) is mixed with 2.1IU Regular Insulin, be dissolved in 100mg physiological saline, evenly be applied to the diabetes rat belly 4cm of embodiment 1
20h after administration, 2h, 5h, 8h tail venous blood sampling detects SD rat blood sugar level simultaneously, and the blood glucose in diabetic rats changing conditions sees Table 2.
The contrast experiment 2
2.1IU Regular Insulin is dissolved in 100mg physiological saline solution in contrast, evenly is applied to the diabetes rat belly 4cm of embodiment 1
20h after administration, 2h, 5h, 8h tail venous blood sampling detects SD rat blood sugar level simultaneously.Part embodiment to the diabetes rat percutaneous dosing after, the blood glucose in diabetic rats changing conditions sees Table 2.
The Caco-2 RBC membrane permeabilily of table 1 Regular Insulin
Table 2 blood glucose in diabetic rats rheological parameters' change with time
* P＜0.05, * * P＜0.005 (n=6 compares with the contrast polypeptide).
Peptide sequence described in the present invention:
＜110〉Dalian University of Technology
＜120〉one group has promotion through skin and the chemosmotic polypeptide of cross-film and application thereof
＜130〉files reference number
＜140〉application number
<141>2013-02-17
<160>9
<210>1
<211>11
<212>PRT
＜213〉artificial synthesized sequence
<220>
＜221〉disulfide linkage
<222>（2）...（10）
＜223〉polypeptide of design based on the position and the charging property that change amino-acid residue in sequence, increases skin and the biomembranous short effect of oozing to reach. and (Designed peptide based on site and charge of amino acid residue to act as a enhancement activity on transdermal and membranous delivery)
<440>1
Ala Cys Ser Ser Lys Pro Ser Lys His Cys Gly
1 5 10
<210>2
<211>11
<212>PRT
＜213〉artificial synthesized sequence
<220>
＜221〉disulfide linkage
<222>（2）...（10）
＜223〉polypeptide of design based on the position and the charging property that change amino-acid residue in sequence, increases skin and the biomembranous short effect of oozing to reach. and (Designed peptide based on site and charge of amino acid residue to act as a enhancement activity on transdermal and membranous delivery)
<440>2
Ala Cys Ser Ser Ser Lys Ser Lys His Cys Gly
1 5 10
<210>3
<211>11
<212>PRT
＜213〉artificial synthesized sequence
<220>
＜221〉disulfide linkage
<222>（2）...（10）
＜223〉polypeptide of design based on the position and the charging property that change amino-acid residue in sequence, increases skin and the biomembranous short effect of oozing to reach. and (Designed peptide based on site and charge of amino acid residue to act as a enhancement activity on transdermal and membranous delivery)
<440>3
Ala Cys Ser Ser Arg Pro Ser Lys His Cys Gly
1 5 10
<210>4
<211>11
<212>PRT
＜213〉artificial synthesized sequence
<220>
＜221〉disulfide linkage
<222>（2）...（10）
＜223〉polypeptide of design based on the position and the charging property that change amino-acid residue in sequence, increases skin and the biomembranous short effect of oozing to reach. and (Designed peptide based on site and charge of amino acid residue to act as a enhancement activity on transdermal and membranous delivery)
<440>4
Ala Cys Ser Ser Ser Arg Ser Lys His Cys Gly
1 5 10
<210>5
<211>11
<212>PRT
＜213〉artificial synthesized sequence
<220>
＜221〉disulfide linkage
<222>（2）...（10）
＜223〉polypeptide of design based on the position and the charging property that change amino-acid residue in sequence, increases skin and the biomembranous short effect of oozing to reach. and (Designed peptide based on site and charge of amino acid residue to act as a enhancement activity on transdermal and membranous delivery)
<440>5
Ala Cys Ser Ser Lys Lys Ser Lys His Cys Gly
1 5 10
<210>6
<211>11
<212>PRT
＜213〉artificial synthesized sequence
<220>
＜221〉disulfide linkage
<222>（2）...（10）
＜223〉polypeptide of design based on the position and the charging property that change amino-acid residue in sequence, increases skin and the biomembranous short effect of oozing to reach. and (Designed peptide based on site and charge ofamino acid residue to act as a enhancement activity on transdermal and membranous delivery)
<440>6
Ala Cys Ser Ser Arg Arg Ser Lys His Cys Gly
1 5 10
<210>7
<211>11
<212>PRT
＜213〉artificial synthesized sequence
<220>
＜221〉disulfide linkage
<222>（2）...（10）
＜223〉polypeptide of design based on the position and the charging property that change amino-acid residue in sequence, increases skin and the biomembranous short effect of oozing to reach. and (Designed peptide based on site and charge of amino acid residue to act as a enhancement activity on transdermal and membranous delivery)
<440>7
Ala Cys Ser Ser Arg Lys Ser Lys His Cys Gly
1 5 10
<210>8
<211>11
<212>PRT
＜213〉artificial synthesized sequence
<220>
＜221〉disulfide linkage
<222>（2）...（10）
＜223〉polypeptide of design based on the position and the charging property that change amino-acid residue in sequence, increases skin and the biomembranous short effect of oozing to reach. and (Designed peptide based on site and charge of amino acid residue to act as a enhancement activity on transdermal and membranous delivery)
<440>8
Ala Cys Ser Ser Lys Arg Ser Lys His Cys Gly
1 5 10
<210>9
<211>11
<212>PRT
＜213〉artificial synthesized sequence
<220>
＜221〉disulfide linkage
<222>（2）...（10）
＜223〉polypeptide of design based on the position and the charging property that change amino-acid residue in sequence, increases skin and the biomembranous short effect of oozing to reach. and (Designed peptide based on site and charge of amino acid residue to act as a enhancement activity on transdermal and membranous delivery)
<440>9
Ala Cys Ser Ser Ser Pro Ser Lys His Cys Gly-NH2
1 5 10
Claims (2)
1. one group has promotion through skin and the chemosmotic polypeptide of cross-film, polypeptide contains 11 amino-acid residues, and consist of ring texture by 9 amino-acid residues with disulfide linkage, it is characterized in that: the N-5 of N-end in described polypeptide or/and the N-6 site consisted of by alkaline amino acid residue, concrete structure:
And C-end amidation polypeptide, concrete structure:
2. one group according to claim 1 has through the short polypeptide that oozes effect of skin and cross-film and uses, and it is characterized in that: described polypeptide is for the preparation of through skin with through solution, gelifying agent and the ointment of film administration.
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| CN105491982A (en) * | 2013-08-12 | 2016-04-13 | 3M创新有限公司 | Peptides for enhancing transdermal delivery |
| CN105566452A (en) * | 2016-01-22 | 2016-05-11 | 北京农学院 | Antibacterial peptide with annular structure and preparation method and application thereof |
| CN106084006A (en) * | 2016-06-23 | 2016-11-09 | 普锐尼斯生物科技有限公司 | A kind of transdermal peptide and application thereof |
| CN107226840A (en) * | 2017-05-04 | 2017-10-03 | 西安交通大学 | A kind of cell-penetrating peptide skin penetration enhancer and its preparation method and application |
| CN108113897A (en) * | 2018-02-26 | 2018-06-05 | 成都元素平衡生物科技有限公司 | It is a kind of to remove wrinkle cosmetic composition and its preparation method and application containing Argireline |
| CN108371392A (en) * | 2017-01-31 | 2018-08-07 | 株式会社三养社 | For skin-lifting or the bonding elastic webbing of enhancing skin elasticity |
| CN112007167A (en) * | 2020-08-29 | 2020-12-01 | 南京中医药大学 | Application of toad venom polypeptide as bufadienolide penetration enhancer |
| CN114632139A (en) * | 2022-04-02 | 2022-06-17 | 北京双吉制药有限公司 | Erythromycin ointment and preparation method thereof |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105491982B (en) * | 2013-08-12 | 2019-09-10 | 3M创新有限公司 | For enhancing the peptide of transdermal delivery |
| CN105491982A (en) * | 2013-08-12 | 2016-04-13 | 3M创新有限公司 | Peptides for enhancing transdermal delivery |
| CN105566452A (en) * | 2016-01-22 | 2016-05-11 | 北京农学院 | Antibacterial peptide with annular structure and preparation method and application thereof |
| CN105566452B (en) * | 2016-01-22 | 2020-04-07 | 北京农学院 | Antibacterial peptide with cyclic structure and preparation method and application thereof |
| CN106084006A (en) * | 2016-06-23 | 2016-11-09 | 普锐尼斯生物科技有限公司 | A kind of transdermal peptide and application thereof |
| CN106084006B (en) * | 2016-06-23 | 2019-09-10 | 普锐尼斯生物科技有限公司 | A kind of transdermal peptide and its application |
| CN108371392A (en) * | 2017-01-31 | 2018-08-07 | 株式会社三养社 | For skin-lifting or the bonding elastic webbing of enhancing skin elasticity |
| CN107226840A (en) * | 2017-05-04 | 2017-10-03 | 西安交通大学 | A kind of cell-penetrating peptide skin penetration enhancer and its preparation method and application |
| CN108113897A (en) * | 2018-02-26 | 2018-06-05 | 成都元素平衡生物科技有限公司 | It is a kind of to remove wrinkle cosmetic composition and its preparation method and application containing Argireline |
| CN112007167A (en) * | 2020-08-29 | 2020-12-01 | 南京中医药大学 | Application of toad venom polypeptide as bufadienolide penetration enhancer |
| CN112007167B (en) * | 2020-08-29 | 2023-01-24 | 南京中医药大学 | Application of toad venom polypeptide as bufadienolide penetration enhancer |
| CN114632139A (en) * | 2022-04-02 | 2022-06-17 | 北京双吉制药有限公司 | Erythromycin ointment and preparation method thereof |
| CN114632139B (en) * | 2022-04-02 | 2023-04-07 | 北京双吉制药有限公司 | Erythromycin ointment and preparation method thereof |
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