CN106692949A - Medicine for treating eye diseases and composition of medicine - Google Patents
Medicine for treating eye diseases and composition of medicine Download PDFInfo
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- CN106692949A CN106692949A CN201611204462.0A CN201611204462A CN106692949A CN 106692949 A CN106692949 A CN 106692949A CN 201611204462 A CN201611204462 A CN 201611204462A CN 106692949 A CN106692949 A CN 106692949A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/2292—Thymosin; Related peptides
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Abstract
The invention provides application of a pharmaceutical composition containing recombinant human prothymosin beta4 in preparation of a medicine for treating eye diseases and particularly application in the treatment of xerophthalmia. The pharmaceutical composition is characterized in that the concentration of the recombinant human prothymosin beta4 is 1ug/mL-1000ug/mL. The invention further provides the pharmaceutical composition containing pharmaceutically acceptable carriers.
Description
Technical field
The present invention relates to biochemistry and protein engineering field, specifically, it is related to one kind to treat dry eyes comprehensive
Medicine of simulator sickness and combinations thereof.
Background technology
Xerophthalmia refers to the tear matter that any reason is caused or amount exception or dynamics exception, under causing tear film stability
Drop, and with ophthalmic uncomfortable and (or) the general name of various diseases of ocular lesion tissue feature.Also known as angle xerosis of conjunctiva.Often
See symptom include eye it is dry and astringent, easily tired, eye itch, have sticky, afraid of the wind foreign body sensation, scorching hot pain, secretion, photophobia and externally
Boundary stimulates sensitive;Sometimes because of basic oligodacrya, eye is excessively dry and astringent, and reflectivity lacrimal secretion is stimulated on the contrary, and causes often
Shed tears;More severe case eyes occur red and swollen, congested and keratinization, exfoliation of corneal epithelium and have filiform to adhere to, this damage
With the passing of time angle conjunctive disorder can be then caused, and can be affected one's power of vision.Be defined as xerophthalmia in 2007 by international dry eyes working group:It is many
A kind of tear and eye surface diseases caused by kind of factor, including ocular malaise symptoms, eyesight change and tear film it is unstable and with
Potential ocular surface injury, raises and ocular inflammatory reaction with tear osmotic pressure.Xerophthalmia clinical manifestation is dry and astringent, furious, easy
Fatigue, burn feeling, foreign body sensation, photophobia, visual fatigue and pain, severe patient can cause visual impairment even to be blinded.
The pathogenesis of xerophthalmia mainly has inflammation, Apoptosis, sex hormone level imbalance etc., and wherein inflammation is to cause to do
The key factor of eye disease morbidity.The ultimate aim of dry eye treatment is to protect the visual function of patient, suppresses the inflammatory reaction of ocular,
Recover the normal configuration and function of eye surface.Current dry eye treatment method has drug therapy and operative treatment, mainly with medicine
Based on thing treatment.Common drug has artificial tears or autoserum, anti-inflammatory drug etc., and based on eye drops, such as recombinant bovine is alkaline
Fibroblast growth factor eye drops, sodium hyaluronate eye drops etc..Although clinically many using medicine, can not all reach
Satisfied therapeutic effect.
Extrasin beta 4（Hereinafter referred to as T β 4）It is naturally occurring a kind of small peptide material in human body, T β 4 are in people's spleen, chest
Content highest in gland, lung and peritoneal macrophages, next to that brain, liver, kidney, testis and heart.Natural T β 4 contain 43
Amino acid, molecular weight about 5kD, isoelectric point is 5.1.
Tbeta4 in recent years（Tβ4）It is the focus of drug research.Further investigation is verified：T β 4 are a kind of many work(
Can molecule, promoting wound and corneal wound healing, myocardial repair, promotion organization regeneration, angiogenesis, anti-apoptotic and resisting
The aspects such as inflammation play an important role.
Extrasin beta 4 is disclosed in CN100360174C（Tβ4）Promote eye degeneration to reverse or suppress the medicine of eye degeneration
Application in thing.Sosne G et al. report extrasin beta 4 and can reduce dry eye condition in mouse xerophthalmia model（Expert
Opinion on Biological Therapy, 15: sup1, 155-161）, animal experiment dosage is 0.1%.
The extrasin beta 4 having been reported is synthesized using chemical synthesis process, and its structure is consistent with natural T β 4, contains
43 amino acid.Its shortcoming is that chemical synthesis purity is low, containing organic impurities and inorganic impurity that structure is similar to, can produce poison
Side effect.Meanwhile, clinically dosage is big for the extrasin beta 4 of chemical synthesis, and clinical effectiveness is general.Meanwhile, chemical synthesis it is many
Peptide yields poorly, and industrialized production difficulty is big, it is impossible to meet Clinical practice.The present inventor is using the method for genetic engineering to natural chest
The N- ends of thymosin beta 4 are subject to pointed decoration, it is easy to which prepare with scale, cost is relatively low, and environment is not polluted, it is sufficient to meet
Clinical demand.Meanwhile, surprisingly, it was found that the recombination human thymosin beta 4 for obtaining activity in terms of xerophthalmia is treated is obvious
Higher than natural extrasin beta 4.
The content of the invention
Recombination human thymosin beta 4 in the present invention is the polypeptide pharmaceutical grade protein produced by technique for gene engineering, its knot
Structure is different from natural structure, and containing 44 amino acid, its N- terminal sequence is different with natural amino acid N- ends, by natural extrasin beta 4
N- ends acetylation removal, and add a Gly or Ala, the mutant of the natural extrasin beta 4 for obtaining, increased in vivo
Bioactivity.Recombination human thymosin beta of the present invention 4 is sequence 1 and sequence 2, i.e. Gly- rh T β 4 and Ala-rh T β 4.
The derivative and its amino acid sequence are disclosed in CN100582121C.
It is an object of the present invention to a kind of pharmaceutical composition containing recombination human thymosin beta 4 is preparing ophthalmology disease
Medicine in application, it is preferable that be the application in terms of xerophthalmia, it is characterised in that the concentration of described recombination human thymosin beta 4
It is 1 μ g/mL -1000 μ g/mL.
In some embodiments, the concentration of described recombination human thymosin beta 4 is 1 μ g/mL -500 μ g/mL.
In some embodiments, the concentration of described recombination human thymosin beta 4 is 10 μ g/mL -100 μ g/mL.
It is another object of the present invention to described pharmaceutical composition contains pharmaceutically acceptable carrier.Described
Pharmaceutical carrier includes one or more of pH adjusting agent, osmotic pressure regulator, promotion absorbent, sterile water for injection.
Heretofore described pH adjusting agent includes hydrochloric acid, NaOH, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate
One or more.
Osmotic pressure regulator of the present invention is the reagent for adjusting osmotic pressure, including but not limited to sodium chloride, Portugal
One or more of grape sugar, sorbierite, glycerine, PEG, propane diols, mannitol, boric acid, borax, sodium sulphate.
Promotion absorbent of the present invention includes but is not limited to sulfoxide type, pyrrolidinone compounds, fitter acids and its ester, table
One or more of face activating agent, propane diols, glycerine etc., it is therefore preferable to propane diols, glycerine, nitrogen are tall and erect, cyclodextrin, lecithin, beans
One or more of phosphatide, phosphatidyl glycerol, phosphatidyl-ethanolamine.
It is another object of the present invention to described medicine is used for local administration.
It is another object of the present invention to, described pharmaceutical composition form can for eye drops, gel, solution,
Emulsifiable paste, ointment, lotion, freeze-dried powder, preferably eye drops, gel.
Brief description of the drawings
Fig. 1：Rh-T β 4 are to the anterior ocular segment photograph result after the treatment of rat xerophthalmia model
Fig. 2：Rh-T β 4 are to cornea HE and the PAS coloration result after the treatment of rat xerophthalmia model
Following examples are used for illustrating the present invention, but are not limited to the present invention.
Embodiment
Embodiment one determines rh T 4 influences to MUC5AC, MUC1 mRNA gene expressions of β by RT-PCR
Medicament sources：Natural β 4 in this experiment is obtained by chemical synthesis, and recombination human thymosin beta 4 is by Beijing Nuo Silande
Biotechnology Ltd. provides, respectively Gly- rh T β 4 and Ala-rh T β 4, every kind of each two specifications of sample（50,
100μg/mL）.
Donation eyeball is taken from eye bank and separate conjunctival cells, and carry out Conjunctival Goblet Cells in vitro culture and purifying, cultivated
Different extrasin beta 4s are added in journey（The μ of 4 50 μ g/mL, Gly-rh T β of Gly-rh T β, 4 100 μ g/mL, Ala-rh T β 4 50
g/mL, Ala-rh Tβ4 100μg/mL）, natural T β 4 are chemical synthesis T β 4（0.1% i.e. 1mg/mL, as positive control）,
Negative control group (negative control) give PBS.Extrasin beta 4 pair is determined by RT-PCR and Western blot
The influence of mucin expression related gene MUC5AC, MUC1 mRNA.
Vitro Experimental Results show：Rh-T 4 can promote the propagation of people's goblet cell, promote MUC5AC and MUC1 mRNA's
Expression, and promote the expression of MUC1 mucins.Compared with positive controls, the expression of MUC5AC has conspicuousness to four groups of test groups
Difference, P<0.05, MUC1 expression is also apparently higher than positive controls.4 groups and Ala-rh T 4 groups of β of Gly- rh T β
MUC5AC, MUC1 gene expression results are similar.Testing result is shown in Table 1.
The RT-PCR of table 1 determines the expression of MUC5AC, MUC1 gene
| Packet | Dosage | MUC5AC（2^ΔΔCT） | MUC1（2^ΔΔCT） |
| Negative Control | -- | 1±0 | 1±0 |
| Positive controls T β 4 | 1mg/mL | 0.62±0.30 | 1.32±0.27 |
| Gly- rh Tβ4 | 50ug/mL | 1.61±0.77* | 1.52±0.31 |
| Gly- rh Tβ4 | 100ug/mL | 1.65±0.42 | 1.57±0.43 |
| Ala-rh Tβ4 | 50ug/mL | 1.60±0.40* | 1.54±0.26 |
| Ala-rh Tβ4 | 100ug/mL | 1.69±0.25* | 1. 63±0.24 |
Note：Compared with positive controls, * P<0.05.
The rh-T β 4 of embodiment two are to rat xerophthalmia model corneal fluorescein sodium appraisal result
The rat xerophthalmia model prepared with 0.3% benzalkonium chloride, xerophthalmia animal is randomly divided into 6 groups, every group 6, gives respectively
rh-Tβ4（4 50 4 100 μ g/mL, Ala-rh T β of μ g/mL, Gly- rh T β of Gly- rh T β 4 50 μ g/mL, Ala-rh T
β4 100μg/mL）, natural T β 4 (0.1% i.e. 1mg/mL, positive controls）And PBS（Negative control group）, it is daily to be added dropwise 3 times,
Successive administration 7 days.The corneal fluorescein sodium scorings of observation rh-T β 4.Result shows that rh-T 4 and positive controls are with negative right
Compare according to group, scoring has downward trend, and the μ g/mL dosage groups of Gly- rh T β 4100 and the μ g/mL dosage of Ala-rh T β 4 100
Group is notable with negative control group comparing difference（p< 0.05）.The μ g/mL dosage groups of Ala- rh T β 4100, the μ of Gly-rh T β 4 50
G/mL dosage groups and the μ g/mL dosage groups of Gly-rh T β 4 100 compare with positive controls, and as a result there were significant differences.Result is shown in
Table 2.
The corneal fluorescein sodium of table 2 scores
Note：Compared with negative control group, * P<0.05.
The rh-T β 4 of embodiment three are commented the photograph of slit-lamp anterior ocular segment, fluorescein sodium dyeing after the treatment of rat xerophthalmia model
Divide result
The rat xerophthalmia model prepared with 0.3% benzalkonium chloride, xerophthalmia animal is randomly divided into 6 groups, every group 6, gives respectively
Different rh-T β 4（The μ g/mL of 4 50 μ g/mL, Gly- rh T β of Gly- rh T β, 4 100 μ g/mL, Ala- rh T β 4 50,
Ala- rh Tβ4 100μg/mL）, natural T β 4 (0.1% i.e. 1mg/mL, positive controls）And PBS（Negative control group）, daily
It is added dropwise 3 times, successive administration 7 days.Result is shown in Fig. 1.Fluorescein sodium chromoscopy result is visible, the μ g/mL of Gly- rh T β 4 100
Most substantially, there were significant differences with positive control drug for dosage group and the effect of the μ g/mL dosage groups corneal restorations of Ala-rh T β 4 100,
Gly-rh T 4 50 μ g/mL dosage groups of β are basically identical with positive controls, and the μ g/mL of Ala-rh T β 4 50 and negative control
Group no significant difference.
Example IV pathological examination results
Cornea HE and PAS coloration result after rh-T β 4 are treated to rat xerophthalmia model is that pathological examination result is shown in Fig. 2.
Normal group：The cornea and the visible normal organization of conjunctival epithelium of HE dyeing, goblet cell is visible in PAS dyeing；
Model group：Cornea and conjunctival epithelium come off；
Negative control group：Epithelial tissue has a certain degree of reparation, it is seen that a small amount of goblet cell；
Positive controls：Epithelial tissue is repaired preferable, it is seen that goblet cell；
The 50ug/mL groups of Ala-rh T β 4：Epithelial tissue has a certain degree of reparation, but unobvious；
The 100ug/mL groups of Ala-rh T β 4：Epithelial cell repairs more perfect, and goblet cell is evenly distributed；
The μ g/mL groups of Gly-rh T β 4 50：Epithelial tissue is repaired preferable, it is seen that goblet cell；
The μ g/mL groups of Gly-rh T β 4 100：Epithelial cell repairs more perfect, and goblet cell is evenly distributed；
Conclusion：The 100ug/mL groups of Gly-rh T β 4 and the μ g/mL groups epithelial tissues of Ala-rh T β 4 100 repair preferable, connect substantially
It is near normal, and better than positive controls.
<110>Beijing Nuosilande biotechnology Co., Ltd
<120>A kind of medicine for treating eye disease and combinations thereof
<160> 2
<210> 1
<211> 44
<212> PRT
<213>Artificial sequence
<400> 1
Gly Ser Asp Lys Pro Asp Met Ala Glu Ile Glu Lys Phe Asp Lys
1 5 10 15
Ser Lys Leu Lys Lys Thr Glu Thr Gln Glu Lys Asn Pro Leu Pro
20 25 30
Ser Lys Glu Thr Ile Glu Gln Glu Lys Gln Ala Gly Glu Ser
35 40
<210>2
<211>44
<212>PRT
<213>Artificial sequence
<400>2
Ala Ser Asp Lys Pro Asp Met Ala Glu Ile Glu Lys Phe Asp Lys
1 5 10 15
Ser Lys Leu Lys Lys Thr Glu Thr Gln Glu Lys Asn Pro Leu Pro
20 25 30
Ser Lys Glu Thr Ile Glu Gln Glu Lys Gln Ala Gly Glu Ser
35 40
Claims (11)
1. application of a kind of pharmaceutical composition containing recombination human thymosin beta 4 in the medicine for preparing ophthalmology disease, wherein recombinating
The amino acid sequence of human thymosin beta 4 is as shown in the sequence 1 in sequence table.
2. application of a kind of pharmaceutical composition containing recombination human thymosin beta 4 in the medicine for preparing ophthalmology disease, wherein recombinating
The amino acid sequence of human thymosin beta 4 is as shown in the sequence 2 in sequence table.
3. the application according to claim 1 and 2, it is preferable that be the application in terms of xerophthalmia, it is characterised in that described weight
The concentration of group human thymosin beta 4 is 1 μ g/mL -1000 μ g/mL.
4. application according to claim 3, the concentration of described recombination human thymosin beta 4 is 1 μ g/mL -500 μ g/mL.
5. application according to claim 3, the concentration of described recombination human thymosin beta 4 is 10 μ g/mL -100 μ g/mL.
6. the application according to claim any one of 1-5, described pharmaceutical composition contains pharmaceutically acceptable carrier.
7. application according to claim 6, described pharmaceutical carrier includes pH adjusting agent, osmotic pressure regulator, promotes to inhale
Receive one or more of agent, sterile water for injection.
8. the application according to claim any one of 1-7, wherein described medicine is the medicine of local administration.
9. the application according to claim any one of 1-7, the form of described pharmaceutical composition can be eye drops, coagulate
Glue, solution, emulsifiable paste, ointment, lotion, freeze-dried powder.
10. the form of pharmaceutical composition according to claim 9, it is therefore preferable to eye drops.
The form of 11. pharmaceutical compositions according to claim 9, it is therefore preferable to gel.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108853483A (en) * | 2018-08-10 | 2018-11-23 | 北京诺思兰德生物技术股份有限公司 | Modified extrasin beta 4 is in the purposes for treating cerebral ischemia re-pouring injured aspect |
| CN109077992A (en) * | 2018-08-09 | 2018-12-25 | 北京汇恩兰德制药有限公司 | A kind of 4 ocular in-situ gel preparation of recombination human thymosin beta of responsive to temperature type |
| CN110891591A (en) * | 2017-06-14 | 2020-03-17 | 汇恩斯株式会社 | Pharmaceutical composition comprising glycine-thymosin β 4(Gly-T β 4) for the treatment of dry eye |
| CN111386337A (en) * | 2017-11-24 | 2020-07-07 | Gtreebnt科技有限公司 | Composition for promoting goblet cell proliferation or mucin secretion comprising thymosin β 4 or a derivative thereof as an active ingredient |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1638789A (en) * | 2001-03-15 | 2005-07-13 | 雷金纳克斯生物制药公司 | Methods of treating disorders of the eye and surrounding tissue with thymosin beta4 (t beta 4), analogues, isoforms and other derivatives |
| US20070015698A1 (en) * | 1998-07-30 | 2007-01-18 | United States Of America As Represented By The Secretary Of Health | Treatment of skin, and wound repair, with thymosin beta 4 |
| CN100582121C (en) * | 2005-07-15 | 2010-01-20 | 北京诺思兰德生物技术有限责任公司 | Thymosin beta 4 derivatives and use thereof |
-
2016
- 2016-12-23 CN CN201611204462.0A patent/CN106692949B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070015698A1 (en) * | 1998-07-30 | 2007-01-18 | United States Of America As Represented By The Secretary Of Health | Treatment of skin, and wound repair, with thymosin beta 4 |
| CN1638789A (en) * | 2001-03-15 | 2005-07-13 | 雷金纳克斯生物制药公司 | Methods of treating disorders of the eye and surrounding tissue with thymosin beta4 (t beta 4), analogues, isoforms and other derivatives |
| CN100582121C (en) * | 2005-07-15 | 2010-01-20 | 北京诺思兰德生物技术有限责任公司 | Thymosin beta 4 derivatives and use thereof |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110891591A (en) * | 2017-06-14 | 2020-03-17 | 汇恩斯株式会社 | Pharmaceutical composition comprising glycine-thymosin β 4(Gly-T β 4) for the treatment of dry eye |
| JP2020530435A (en) * | 2017-06-14 | 2020-10-22 | ヒューオンス カンパニー, リミテッドHuons Co., Ltd. | A pharmaceutical composition for the treatment of xerophthalmia containing Gly-Tβ4 (Gly-thymosin β4). |
| CN111386337A (en) * | 2017-11-24 | 2020-07-07 | Gtreebnt科技有限公司 | Composition for promoting goblet cell proliferation or mucin secretion comprising thymosin β 4 or a derivative thereof as an active ingredient |
| JP2021504349A (en) * | 2017-11-24 | 2021-02-15 | ジー−トゥリー・ビーエヌティ・カンパニー・リミテッドＧ−Ｔｒｅｅｂｎｔ Ｃｏ．， Ｌｔｄ． | A composition for promoting goblet cell proliferation or mucin secretion containing thymosin β4 or a derivative thereof as an active ingredient. |
| EP3715451A4 (en) * | 2017-11-24 | 2021-07-21 | G-Treebnt Co., Ltd. | Composition for promoting goblet cell proliferation or mucin secretion comprising thymosin beta 4 or derivative thereof as active ingredient |
| CN109077992A (en) * | 2018-08-09 | 2018-12-25 | 北京汇恩兰德制药有限公司 | A kind of 4 ocular in-situ gel preparation of recombination human thymosin beta of responsive to temperature type |
| CN109077992B (en) * | 2018-08-09 | 2021-11-16 | 北京汇恩兰德制药有限公司 | Temperature-sensitive recombinant human thymosin beta 4 ophthalmic in-situ gel preparation |
| CN108853483A (en) * | 2018-08-10 | 2018-11-23 | 北京诺思兰德生物技术股份有限公司 | Modified extrasin beta 4 is in the purposes for treating cerebral ischemia re-pouring injured aspect |
| CN108853483B (en) * | 2018-08-10 | 2022-03-15 | 北京诺思兰德生物技术股份有限公司 | Use of modified thymosin beta 4 for the treatment of cerebral ischemia reperfusion injury |
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