CN1515315A - Stable composition containing epidermal growth factor and bletilla tuber extract - Google Patents
Stable composition containing epidermal growth factor and bletilla tuber extract Download PDFInfo
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- CN1515315A CN1515315A CNA031011136A CN03101113A CN1515315A CN 1515315 A CN1515315 A CN 1515315A CN A031011136 A CNA031011136 A CN A031011136A CN 03101113 A CN03101113 A CN 03101113A CN 1515315 A CN1515315 A CN 1515315A
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Abstract
The present invention relates to a stable composite containing epidermal growth factor (EGF) and bletilla extract. In said stable composite the EGF is its main active component, and can be used for promoting growth of skin, mucous membrane and corneol cell and promoting wound healing, and the bletilla extract is its matrix and active component, can obviously raise stability of EGF, and its self-body has the functions of astringing to arrest bleeding the relieving swelling and promoting the growth of new tissues, and has the synergistic action with EGF. The stable composite can be used in eye preparation, dermal preparation and face-beautifying preparation.
Description
Technical field:
The present invention relates to a kind of stable composition that contains epidermal growth factor (epidermal growth factor is called for short EGF, and the back together) and Pseudobulbus Bletillae (Rhizoma Bletillae) [Bletil la striata (Thunb.) Reichb.f.].
Background technology:
Somatomedin is a class material of regulating cell proliferation and differentiation.EGF is a kind of important somatomedin, and denier can promote the division and the growth of Skin Cell strongly.The single chain polypeptide that EGF is made up of 53 amino acid residues.It has three to keep the necessary disulfide bond of its biological activity.
Find that now EGF can stimulate various cells such as cornea, epithelium, mammary gland, liver, nerve, neuroglia, amniotic membrane and the adrenal medullary cell etc. of ectoderm and entoderm origin, makes its propagation.Its biological effect comprises: 1. promote low molecular weight compound initiatively to be transported to from the extracellular in the cell, to increase the nutrient substance of cell.2. activate glycolysis to increase respiratory metabolism, can the activating phosphatase fructokinase.3. irritation cell is outer macromolecular synthetic, as hyaluronic acid and glycoprotein.4. activate RNA and protein synthesis.5. promote synthesizing of DNA.6. promote cell proliferation.7. promote the secretion of some materials of body such as gastric acid, prostaglandin etc.
Everything biological effect shows that EGF can pass through conducted signal, causes a series of biochemical variations in the cell, starts the gene relevant with cell division, makes akinete enter cell division cycle, thereby makes cell proliferation.
Therefore, EGF has great importance at field of medicaments, can promote injured skin histology growth, the secretion of gastric acid inhibitory, can promote the growth of burned skin and the healing of skin ulcer, it will play an important role in dermatosis, gastrotherapy, corneal graft.
EGF can also be applied to cosmetics: American scholar studies show that the effect that epidermal growth factor has skin-cell aging delaying, impels the human skin cell to repair and grow makes skin smooth plump.
But EGF is unstable in preservation.-20 ℃ of following EGF preserve in PBS and are no more than 6 months.After the dilution, preserved 1 month at most down at 2-8 ℃.Prolong when preserving, need to avoid multigelation in-70 ℃ or-20 ℃ of freezing preservations.And the catabolite of EGF in the preservation process also may be induced allergy.In actual use, EGF is also unstable in the skin wound environment, the protease hydrolysis inactivation that it is existed in the wound, and the half-life only is 1 hour, but in the agglutination behind the skin injury, the synthetic of DNA but needs 8 hours to 12 hours.Therefore, single uses EGF that its healing is not had obvious facilitation on skin or corneal wound.Have only and repeatedly use repeatedly and could play the promotion curative effect its healing.Therefore, the practical application at medical science and cosmetic field is very limited.
After deliberation some EGF extended release preparations, they can provide EGF to wound continuously, reach the purpose of the curative effect that promotes wound healing.
United States Patent (USP) (USP4944948) discloses the EGF lipidosome gel preparation that EGF is provided to continuously wound.European patent (EP312208) discloses the aqueous compositions that can discharge EGF continuously of water solublity such as using cellulose or hydroexpansivity substrate.United States Patent (USP) (USP5130298) discloses and has used zinc ion to prevent the biodegrading process of EGF in aqueous solution.Chinese patent application discloses the method for carbomer as the EGF stabilization formulations of substrate of using.
Pseudobulbus Bletillae (Rhizoma Bletillae) is the dry tuber of orchid Bletilla striata (Thunb.) Reichb.f..Bitter, sweet, puckery, be slightly cold.Return lung, liver, stomach warp.Effect with astringing to arrest bleeding, detumescence and promoting granulation.The hemostasia and healing that is used for diseases such as skin breach and ulcerative hemorrhage.The contained phenanthrene derivative of Pseudobulbus Bletillae (Rhizoma Bletillae) can bacteria growing inhibiting, and wound is had protective effect.
The contained polysaccharide of Pseudobulbus Bletillae (Rhizoma Bletillae) comprises that phlegmatic temperament, Rhizoma Bletillae gel (glucosan that glucose molecule aggregates into) and bletilla mannan (4 parts of mannans and 1 part of glucomannan that glucosan is formed) are that Pseudobulbus Bletillae (Rhizoma Bletillae) can be used as the composition that pharmaceutical preparation substrate is used, and it also has covering and hemostatic function.
The bletilla polysaccharide constituents is as the host material of pharmaceutical preparation, and its characteristics are avirulence, nonirritant, and stable in properties is not found incompatibility with compatibility of drugs.As the substrate of membrane, abundant raw material, cheap, production technology is simple, and the film forming demoulding performance is good, can be prepared into certain pliability, and can bear the thin film of certain pulling force, meets the water formation protecting film that can expand rapidly, and the patient takes like a shot.
And key is that the inventor has been found that by a lot of researchs the polysaccharide composition of Pseudobulbus Bletillae (Rhizoma Bletillae) is good as the EGF stability of formulation of substrate, and enough promotion wound healing effects are arranged.
Content of the present invention
The purpose of this invention is to provide a kind of stable composition, include EGF and Pseudobulbus Bletillae (Rhizoma Bletillae).Wherein EGF is a main active; The bletilla polysaccharide constituents makes said composition become stable composition as substrate (base).Wherein EGF is a main active, and effect is the growth that promotes skin, mucosa and keratocyte, quickens the healing of damage.Pseudobulbus Bletillae (Rhizoma Bletillae) is substrate and active component.Pseudobulbus Bletillae (Rhizoma Bletillae) significantly increases the stability of EGF as substrate, and Pseudobulbus Bletillae (Rhizoma Bletillae) itself also has astringing to arrest bleeding, and the effect of detumescence and promoting granulation has synergism with EGF.Simultaneously, Pseudobulbus Bletillae (Rhizoma Bletillae) still is the active component of this stable composition.
The EGF active component can use recombinant DNA technology production or separate acquisition from natural origin.The content of EGF is with the total weight of compositions, at 0.05 μ gg in compositions
-1To 1500 μ gg
-1Scope in, and scope preferably is 0.5 μ gg
-1To 100 μ gg
-1, so that EGF is effective and reasonable on the pharmacology.The content of bletilla polysaccharide constituents is with the total weight of compositions, in the scope of 0.01 (w/w) % to 95 (w/w) % in compositions.Preferably in 4 to 8 scope, more preferably in 5 to 7 scope, the acid-base value of its aqueous solution is pH4 to pH8 to the pH of the present composition.
The wood inventive compositions can further contain pharmaceutically acceptable additive, for example stabilizing agent, excipient, isotropism agent, humidizer, pH controlling agent or the like.
The inventor has carried out stability test, trial target is according to the EGF compositions that contains the bletilla polysaccharide constituents of the present invention, reference substance is the EGF preparation (known more stable) that contains another kind of carboxymethyl cellulose-based matter, and the EGF that is dissolved in the 10mM phosphate buffer is as standard substance.Compare 4 ℃ and 25 ℃ of following stability of 4 months.Detect the content of EGF with the ELISA method.As a result, compare according to the EGF compositions that contains bletilla polysaccharide constituents substrate of the present invention and the EGF preparation that contains carboxymethyl cellulose-based matter and the EGF that is dissolved in phosphate buffer, all more stable under various concentration.Can determine from this result: according to the EGF the EGF of the containing compositions of the present invention, stablized as substrate by adding bletilla polysaccharide constituents (no matter matrix content how), therefore this bletilla polysaccharide constituents can be according to application target, select various concentration, add as substrate and stabilizing agent.
Compositions according to the EGF of containing of the present invention can be used for topical preparation: 1) ophthalmic preparation comprises eye drop, Eye ointments and ocular inserts.2) skin and mucosa preparation comprise deposited liquid, gel, unguentum or cream, the apply ointment or plaster membrane or the tablet of applying ointment or plaster.The preparation of said composition can be spread out on medical dressing and use.Said composition can freeze-dried store, and is dissolved in suitable solvent then when needs use.In addition, skin can be used for cosmetic formulation with topical formulations.
The present invention makes more specific description by the following example.But, be to be understood that the present invention is limited to these never in any form
Embodiment.
Embodiment 1
The eye drop that contains bletilla polysaccharide constituents (0.1%)
| An amount of water for injection of EGF 0.5mg bletilla polysaccharide constituents 0.1g mannitol 5g methyl p-hydroxybenzoate 0.04g propylparaben 0.01g pH adjusting agent is an amount of |
| Total amount 100g |
Said components is made preparation according to conventional method.Specifically, mannitol, methyl parahydroxybenzoate and propyl p-hydroxybenzoate are dissolved in the proper amount of water for injection, the adding bletilla polysaccharide constituents and the stirring of heating make its dissolving in this solution.After the cooling, regulate pH with sodium hydroxide, then with its sterilization, and with water for injection preparation through filtering and the EGF solution of sterilization mixes and obtains the 100g preparation.
Embodiment 2
The topical gel preparation that contains bletilla polysaccharide constituents (1%)
| An amount of water for injection of EGF 0.5mg bletilla polysaccharide constituents 1g propane diols 0.2g methyl p-hydroxybenzoate 20g NaOH is an amount of |
| Total amount 100g |
Said components is made preparation according to conventional method: methyl parahydroxybenzoate and bletilla polysaccharide constituents are mixed, add an amount of water for injection, stirring and dissolving, sodium hydroxide is regulated pH, add the propylene glycol mixing, heat sterilization, cooling back and the EGF solution mixing through filtering and sterilizing that uses water for injection to prepare obtain the 100g preparation.
Embodiment 3
The white preparation that contains bletilla polysaccharide constituents (0.1%)
| The poly-an amount of water for injection of oxyl ester 2.00g triethanolamine of EGF 0.05mg glycerine 4.5g methyl p-hydroxybenzoate 0.15g propylparaben 0.05g bletilla polysaccharide constituents 0.1g stearyl alcohol 1.75g cetanol 4.00g sapn #60 0.50g stearic acid #40 is an amount of |
| Total amount 100g |
Said components is made preparation according to conventional method: glycerol, methyl parahydroxybenzoate and bletilla polysaccharide constituents are added in the proper amount of water for injection, stirring and dissolving, add propyl p-hydroxybenzoate and other components and make its emulsifying by fusing, regulate pH with triethanolamine, sterilization, the EGF solution mixing through filtering and sterilizing with using the water for injection preparation obtains the 100g preparation.
Embodiment 4
The ointment that contains bletilla polysaccharide constituents (0.1%)
| EGF 0.5mg methyl p-hydroxybenzoate 0.10g propylparaben 0.05g bletilla polysaccharide constituents 0.1g beeswax 5g mineral oil 45g borax 0.2g microwax 7.00g paraffin 10g distilled water for injection is an amount of |
| Total amount 100g |
Said components is made preparation according to conventional method: methyl parahydroxybenzoate, propyl p-hydroxybenzoate and bletilla polysaccharide constituents are added in the proper amount of water for injection, stirring and dissolving, add the wax component stirring and emulsifying of heating, sterilization, the EGF solution mixing through filtering and sterilizing with using the water for injection preparation obtains the 100g preparation.
Embodiment 5
The plaster preparation that contains bletilla polysaccharide constituents (1%)
| EGF 1.0mg bletilla polysaccharide constituents 40g glycerol 3g water for injection is an amount of |
| Total amount 320g |
Said components is made preparation according to conventional method: bletilla polysaccharide constituents glycerol is dissolved in the water for injection, 100 ℃ of sterilizations, cooling back and the EGF solution mixing that uses water for injection to prepare through filtering and sterilizing, obtain 320g solution, pour this solution into film forming in the mould (diaphragm of applying ointment or plaster).
Comparative example 1
The 10mM phosphate buffer that contains EGF
| EGF 0.5mg dibastic sodium phosphate 0.14g sodium chloride 0.88g 20% phosphoric acid is an amount of |
| Total amount 100g |
Said components is made preparation according to conventional method.Specifically, dibastic sodium phosphate and sodium chloride are dissolved in the proper amount of water for injection, regulate the pH of this solution with 20% phosphoric acid, then with its sterilization, and with use the water for injection preparation through filtering and the EGF solution of sterilization mixes and obtains the 100g preparation.
Comparative example 2
The eye drop that contains sodium carboxymethyl cellulose (0.5%)
| An amount of water for injection of EGF 0.5mg sodium carboxymethylcellulose 0.5g D-sorbite 5.47g methyl p-hydroxybenzoate 0.05g NaOH is an amount of |
| Total amount 100g |
Said components is made preparation according to conventional method.Specifically, Sorbitol and methyl parahydroxybenzoate are dissolved in the proper amount of water for injection, adding sodium carboxymethyl cellulose and stirring make its dissolving in this solution.Regulate the pH of this solution with sodium hydroxide, then with its sterilization, and with use the water for injection preparation through filtering and the EGF solution of sterilization mixes and obtains the 100g preparation.
Experiment 1
Each stability of formulation test in the embodiments of the invention:
Trial target is the eye drop that contains the bletilla polysaccharide constituents of preparation among the embodiment 1,2,3,4 and 5, and reference substance is the EGF sample (as standard substance) of preparation in comparative example 1 and the EGF preparation that contains carboxymethyl cellulose (known more stable) of preparation in comparative example 2.Under 4 ℃ and 25 ℃ of following conditions of storage, the content of EGF assesses its stability over time by these three kinds of EGF samples relatively.Use ELISA method (Quantikine EGF ELISA test kit, R﹠amp; D, U.S.) the content that detects EGF.
Table 1 and table 2 show the result of trial target and the stability of reference substance under 4 ℃ and under 25 ℃ respectively.
Table 1
| Sample substrate | Initial concentration (%) | Concentration under 4 ℃ (%) | ||
| 4 weeks | 8 weeks | 16 weeks | ||
| Embodiment 1 0.1% bletilla polysaccharide constituents | ??100±1.5 | ??99.5±5.1 | ????98.2±2.8 | ??97.1±3.4 |
| Embodiment 2 1% bletilla polysaccharide constituents | ??100±1.5 | ??99.8±6.1 | ????98.6±3.8 | ??97.5±2.4 |
| Embodiment 3 0.1% bletilla polysaccharide constituents cream | ??100±1.5 | ??99.4±5.5 | ????98.1±1.8 | ??96.6±4.4 |
| Embodiment 4 0.1% bletilla polysaccharide constituents ointments | ??100±1.5 | ??100.3±7.1 | ????97.9±4.8 | ??96.8±5.4 |
| Embodiment 5 95% bletilla polysaccharide constituents plasters | ??100±1.5 | ??100.5±5.3 | ????99.2±6.8 | ??97.5±4.3 |
| Comparative example 1 10mM phosphate buffer | ??102.2±1.7 | ??97.2±16.0 | ????92.4±10.9 | ??91.4±6.8 |
| Comparative example 2 0.5% sodium carboxymethyl cellulose | ??100.4±1.5 | ??100.3±5.6 | ????98.4±3.1 | ??96.9±4.2 |
Table 2
| Sample | Initial concentration (%) | Concentration under 25 ℃ (%) | ||
| 4 weeks | 8 weeks | 16 weeks | ||
| Embodiment 1 0.1% bletilla polysaccharide constituents | 100±1.5 | ????92.3±6.1 | ????87.3±3.6 | ????80.5±5.9 |
| Embodiment 2 1% bletilla polysaccharide constituents | 100±1.5 | ????93.4±7.2 | ????86.5±5.4 | ????81.3±6.8 |
| Embodiment 3 0.1% bletilla polysaccharide constituents cream | 100±1.5 | ????90.5±2.6 | ????84.5±7.2 | ????75.5±2.7 |
| Embodiment 4 0.1% bletilla polysaccharide constituents ointments | 100±1.5 | ????89.7±4.2 | ????82.5±3.1 | ????73.9±3.7 |
| Embodiment 5 95% bletilla polysaccharide constituents plasters | 100±1.5 | ????88.3±4.0 | ????81.9±4.5 | ????75.4±3.9 |
| Comparative example 1 10mM phosphate buffer | 100±1.9 | ????88.4±6.9 | ????81.3±1.7 | ????72.5±3.3 |
| Comparative example 2 0.5% sodium carboxymethyl cellulose | 100±2.1 | ????88.4±0.2 | ????78.5±2.7 | ????48.7±9.3 |
Shown in the result who obtains in the above-mentioned experiment, the invention provides stable EGF compositions, the bletilla polysaccharide composition that it comprises is as substrate, makes that EGF has guaranteed stability in the preparation on biology and active physical chemistry.
Claims (16)
1. a stable composition includes epidermal growth factor (be called for short EGF, the back together) and Pseudobulbus Bletillae (Rhizoma Bletillae).
2. according to the stable composition of claim 1,, perhaps separate obtaining from natural origin as the wherein EGF use recombinant DNA technology production of main active.
3. according to the stable composition of claim 1, wherein the content of EGF is with the total weight of compositions, at 0.05 μ gg
-1To 1500 μ gg
-1Scope in, and scope preferably is 0.5 μ gg
-1To 100ugg
-1
4. according to the stable composition of claim 1, wherein the content of EGF is with the total weight of compositions, at 0.5 μ gg
-1To 100 μ gg
-1Scope in.
5. according to the stable composition of claim 1, wherein the content of Pseudobulbus Bletillae (Rhizoma Bletillae) is with the total weight of compositions, in the scope of 0.1 (w/w) % to 95 (w/w) %.
6. according to the stable composition of claim 1, the acid-base value of its aqueous solution is pH4 to pH8.
7. according to the stable composition of claim 1, it is a topical preparation.
8. according to the stable composition of claim 7, it is an ophthalmic preparation.
9. according to the stable composition of claim 8, it is an eye drop.
10. according to the stable composition of claim 8, it is an Eye ointments.
11. according to the stable composition of claim 8, it is an ocular inserts.
12. according to the stable composition of claim 7, it is skin and mucosa preparation.
13. according to the stable composition of claim 12, it is to apply liquid.
14. according to the stable composition of claim 12, it is a gel.
15. according to the stable composition of claim 12, it is unguentum or cream.
16. according to the stable composition of claim 12, it is the apply ointment or plaster membrane or the tablet of applying ointment or plaster.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031011136A CN1515315A (en) | 2003-01-08 | 2003-01-08 | Stable composition containing epidermal growth factor and bletilla tuber extract |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031011136A CN1515315A (en) | 2003-01-08 | 2003-01-08 | Stable composition containing epidermal growth factor and bletilla tuber extract |
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| Publication Number | Publication Date |
|---|---|
| CN1515315A true CN1515315A (en) | 2004-07-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031011136A Pending CN1515315A (en) | 2003-01-08 | 2003-01-08 | Stable composition containing epidermal growth factor and bletilla tuber extract |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103585097A (en) * | 2013-11-29 | 2014-02-19 | 广州市娇兰化妆品有限公司 | Epidermal growth factor-loaded bletilla rhizome polysaccharide compound, and preparation method and application thereof |
| CN105147722A (en) * | 2015-09-17 | 2015-12-16 | 广州赛莱拉干细胞科技股份有限公司 | Novel application of sulfated bletilla striata polysaccharide and preparation for treating ocular surface damage |
| CN105520844A (en) * | 2016-02-04 | 2016-04-27 | 长沙湘资生物科技有限公司 | Bletilla striata polysaccharide and paeonol composition product and application thereof |
| CN105663704A (en) * | 2016-01-25 | 2016-06-15 | 上海安信生物医药技术有限公司 | Skin mucosa and wound disinfectant |
-
2003
- 2003-01-08 CN CNA031011136A patent/CN1515315A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103585097A (en) * | 2013-11-29 | 2014-02-19 | 广州市娇兰化妆品有限公司 | Epidermal growth factor-loaded bletilla rhizome polysaccharide compound, and preparation method and application thereof |
| CN105147722A (en) * | 2015-09-17 | 2015-12-16 | 广州赛莱拉干细胞科技股份有限公司 | Novel application of sulfated bletilla striata polysaccharide and preparation for treating ocular surface damage |
| CN105663704A (en) * | 2016-01-25 | 2016-06-15 | 上海安信生物医药技术有限公司 | Skin mucosa and wound disinfectant |
| CN105520844A (en) * | 2016-02-04 | 2016-04-27 | 长沙湘资生物科技有限公司 | Bletilla striata polysaccharide and paeonol composition product and application thereof |
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