CN106943590B - Pharmaceutical composition containing NGF for treating corneal epithelial injury - Google Patents
Pharmaceutical composition containing NGF for treating corneal epithelial injury Download PDFInfo
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- CN106943590B CN106943590B CN201710216999.7A CN201710216999A CN106943590B CN 106943590 B CN106943590 B CN 106943590B CN 201710216999 A CN201710216999 A CN 201710216999A CN 106943590 B CN106943590 B CN 106943590B
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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
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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Abstract
The present invention discloses a pharmaceutical composition for the treatment of corneal epithelial injury comprising NGF, said pharmaceutical composition comprising NGF (preferably of human origin). The pharmaceutical composition (preferably in the form of eye drops) of the present invention not only can promote the proliferation and colony formation of limbal stem cells, but also can effectively promote the repair of corneal epithelial injuries, including the repair of persistent corneal epithelial injuries, the treatment of diabetic keratopathy, the treatment of neurogenic keratitis, and the treatment of limbal stem cell deficiency.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition containing NGF for treating corneal epithelial injury.
Background
The transparency and functional integrity of the cornea depends on the structural and metabolic normality of the tissues of the layers of the cornea, for which the corneal epithelial tissue located at the outermost layer certainly plays a considerable role. Corneal epithelial damage can be caused by various physical, chemical, mechanical, pathogenic microorganisms, endocrine, and immunological factors. The corneal epithelium is a physical barrier against invasion by external pathogenic agents, and the maintenance of its integrity is dependent on the intercellular, tight and anchored junctions between cells and basement membranes of epithelial cells and on the continuous self-renewal of epithelial cells. The damage of the corneal epithelial layer can affect the connection between cells, cause the change of the permeability and selectivity of cell membranes, thereby affecting the barrier function of the cell membranes, and lead the cornea to be easily attacked by external pathogenic factors to cause inflammation, cause corneal opacity and even cause blindness. Sustained corneal epithelial damage is disrupted by the normal intact epithelial barrier function, which can lead pathogenic microorganisms to easily penetrate the anterior elastic layer and invade the corneal parenchyma layer, causing corneal inflammation, corneal stroma opacity, collagen melting to form corneal ulcer, corneal perforation, even eyeball loss, and serious consequences.
Currently, traditional treatment methods for persistent corneal epithelial injury include: tear substitutes, corneal contact lenses, eyelid sutures, growth factors, autologous serum, etc., are not effective.
Nerve Growth Factor (NGF) is the first neurotrophic factor found by Levi-Montalcini in mouse sarcoma cells in the early 50 th century, and is an active protein produced by neurons, innervated target tissues or glial cells that promotes differentiation, growth and survival of central and peripheral nerves. In recent years, many in vivo and in vitro experimental studies at home and abroad show that NGF has better curative effects on optic atrophy caused by diseases of the visual system, such as retinitis pigmentosa, optic neuritis, optic contusion, glaucoma and the like, ischemic optic neuropathy, poor visual function after retinal detachment and the like. For example, US2012102591 discloses a method for treating a retinitis pigmentosa, comprising the steps of topically applying an NGF-containing preparation to the ocular surface of a subject to elevate the NGF content in retinal ganglion cells; patent document CN201210008398.4 discloses a nerve growth factor ophthalmic gel for repairing nerve injury of the eye. OPG (osteoprotegerin) is commonly used for the treatment of osteoporosis. However, there has been no report that NGF-containing drugs, alone or in combination with other active ingredients, are used to repair corneal epithelial injury.
Disclosure of Invention
The invention provides a pharmaceutical composition for treating corneal epithelial injury, which comprises NGF.
Preferably, the content of NGF in the pharmaceutical composition is 0.1-10 wt%;
preferably, the pharmaceutical composition further comprises OPG;
preferably, the content of OPG in the pharmaceutical composition is 0.001-0.1 wt%;
preferably, the NGF is murine NGF or human NGF, more preferably human NGF;
in a preferred embodiment of the invention, the human NGF is human recombinant NGF.
Preferably, the OPG is murine OPG or human OPG, and more preferably human OPG;
in a preferred embodiment of the present invention, the human OPG is human recombinant OPG.
Preferably, the pharmaceutical composition can be prepared into various preparations for local administration, gastrointestinal administration or parenteral administration; the topical preparation is a preparation for ocular administration, such as: eye drops, injections, powder injections, eye ointments, emulsions, liposomes, microcapsules, gels, implants, inserts, eye films, inclusion eye drops and other dosage forms which can be used for eye administration; the parenteral preparation is suitable for intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosal administration, inhalation administration and other dosage forms;
in a preferred embodiment of the invention, the pharmaceutical composition is a formulation for ocular administration, preferably selected from: eye drops, eye ointments, gels, and ophthalmic films;
when the pharmaceutical composition of the present invention for treating dry eye is used as an ophthalmic solution, it is provided as any dosage form for an ophthalmic solution, for example, an aqueous eye drop (e.g., aqueous ophthalmic solution, aqueous suspension ophthalmic solution, viscous ophthalmic solution, solubilized ophthalmic solution, etc.), or a non-aqueous eye drop (e.g., non-aqueous ophthalmic solution and non-aqueous suspension ophthalmic solution).
Preferably, the pharmaceutical composition is an aqueous eye drop, wherein the content of NGF is 10-1000 μ g/ml, preferably 50-500 μ g/ml, more preferably 100-300 μ g/ml; and/or the content of OPG is 1ng/ml-100ng/ml, preferably 10-50 ng/ml;
preferably, the pharmaceutical composition further comprises pharmaceutically acceptable additives;
preferably, the additive is selected from: one or more of bacteriostatic agent, pH regulator, osmotic pressure regulator, solubilizer (stabilizer), thickener, chelating agent, etc.;
preferably, the bacteriostatic agent includes but is not limited to: thimerosal, quaternary ammonium salts, domiphen bromide, chlorhexidine, chlorobutanol, parabens, sorbic acid; preferably, the quaternary ammonium salt bacteriostatic agent is benzalkonium chloride, benzalkonium bromide, and parabens such as ethylparaben;
preferably, the content of the preservative in the pharmaceutical composition is 0.001-1.0%;
preferably, the pH adjusting agents include, but are not limited to: one or more of phosphate, acetate, citric acid and its salt, carbonate solution, sodium hydroxide, potassium hydroxide, hydrochloric acid, boric acid, phosphoric acid, etc.;
preferably, the pH of the pharmaceutical composition is 5.5-7.5;
preferably, the tonicity adjusting agent includes, but is not limited to: sugars (e.g., sorbitol, glucose, mannitol), polyols (e.g., glycerol, polyethylene glycol, polypropylene glycol), salts such as sodium chloride;
preferably, the solubilizing agents include, but are not limited to: cyclodextrin and its derivatives, water-soluble polymer (such as polyvinylpyrrolidone), surfactant (such as polysorbate 80, trade name: tween 80);
preferably, the thickener is selected from the group consisting of: one or more of methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and salts thereof;
preferably, the chelating agent includes, but is not limited to: sodium edetate, sodium citrate, and sodium polyphosphate.
In one embodiment of the invention, the pharmaceutical composition is an ophthalmic gel, an ophthalmic ointment, which further comprises a base compound;
preferably, the ointment base comprises vegetable oils, animal fats, and semi-solid hydrocarbons derived from petroleum, such as: lanolin, vaseline, liquid paraffin, mineral oil, etc.;
preferably, the gel matrix compound is a biocompatible gel-forming polymer, such as: poloxamer, gellan gum, chitosan, sodium alginate, sodium hyaluronate, hydroxypropyl methylcellulose, xanthan gum, carbomer and the like;
preferably, the preparation of the pharmaceutical composition includes a general preparation, a controlled release preparation, a targeting preparation, and the like.
The pharmaceutical composition can also be used in synergy with other known methods and/or agents for treating corneal epithelial injury, and the invention provides a synergistic pharmaceutical composition for treating and/or preventing corneal epithelial injury, which comprises the pharmaceutical composition and a corneal epithelial injury treating agent.
Preferably, the corneal epithelial injury comprises persistent corneal epithelial injury, diabetic keratopathy, neurogenic keratitis, and limbal stem cell deficiency.
In another aspect, the present invention provides a contact lens comprising, carrying, or associated with the above pharmaceutical composition, wherein the contact lens is worn by a patient for the purpose of administering a therapeutic treatment.
The pharmaceutical composition provided by the invention can promote the proliferation and the cloning formation capability of the limbal stem cells, and can effectively promote the damage repair of corneal epithelium, including the repair of continuous corneal epithelium damage, the treatment of diabetic keratopathy, the treatment of neurogenic keratitis and the treatment of limbal stem cell deficiency. In the pharmaceutical composition provided by the invention, NGF and OPG are preferably humanized, adverse reactions are small, and the compliance of patients can be greatly improved.
Detailed Description
The active ingredient in the pharmaceutical composition of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount sufficient to treat (therapeutically or prophylactically) the target disorder when administered in an appropriate dosage regimen. For example, an effective amount is sufficient to reduce or improve the severity, duration, or progression of the treated disorder, prevent advancement of the treated disorder, cause regression of the treated disorder, or enhance or improve the prophylactic or therapeutic effect of another therapy.
The term "treatment" includes both therapeutic treatment and prophylactic treatment (reducing the likelihood of development). The term refers to reducing, inhibiting, attenuating, shrinking, halting, or stabilizing the development or progression of a disease (e.g., a disease or condition described herein), lessening the severity of the disease or improving symptoms associated with the disease.
Another embodiment of the invention relates to pharmaceutical compositions contained within a swab or sponge that can be applied to the ocular surface.
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
NGF and OPG for use in the present invention are commercially available or may be extracted according to methods disclosed in the prior art, such as from tissues such as male mice, human placenta, etc., or may be prepared according to methods disclosed in the prior art, such as by genetic engineering methods, or may be used as drug substitutes for NGF or OPG disclosed in the prior art, such as those extracted from snake venom, without limiting the scope of the present invention, although NGF and OPG used in the following examples are both human recombinant NGF and OPG.
EXAMPLE 1 eye drops
The eye drops are prepared according to the preparation method known in the field, and the main components and the content are as follows:
example 2 eye drops
The eye drops are prepared according to the preparation method known in the field, and the main components and the content are as follows:
example 3 eye drops
The eye drops are prepared according to the preparation method known in the field, and the main components and the content are as follows:
example 4 eye drops
The eye drops are prepared according to the preparation method known in the field, and the main components and the content are as follows:
EXAMPLE 5 ophthalmic gel
The ophthalmic gel is prepared according to the preparation method known in the art, and the main components and the contents of the ophthalmic gel are as follows:
example 6 ophthalmic ointment
The ophthalmic ointment is prepared according to the preparation method known in the art, and the main components and the contents of the ointment are as follows:
EXAMPLE 7 ophthalmic film preparation
The preparation method of the ophthalmic film agent is known in the field, and the main components and the content of the ophthalmic film agent are as follows:
example 8 drug efficacy test
1. Normal corneal epithelium injury repair test
1.1 Experimental materials and conditions
And (3) testing a sample: eye drops prepared in examples 1 to 4;
comparative sample: eye drops prepared in examples 1 to 4 with OPG removed;
control sample: physiological saline;
test animals: c57BL/6 mice, 6-8 weeks old.
1.2 Experimental methods
The epithelium was removed from the central 3mm area of the cornea of the right eye of the mouse using a 3mm trephine and an epithelial spatula. The epithelial injury repair of mice was observed using sodium fluorescein staining and slit lamp photography.
1.3 results of the experiment
The result shows that compared with a control sample, the tested sample and the control sample can effectively promote the corneal epithelial injury repair, and the repair effect of the tested sample group is obviously superior to that of the control sample group.
STZ-induced diabetic corneal epithelial injury repair test
2.1 Experimental materials and conditions
And (3) testing a sample: eye drops prepared in examples 1 to 4;
comparative sample: eye drops prepared in examples 1 to 4 with OPG removed;
control sample: physiological saline;
test animals: STZ-induced C57BL/6 diabetic mice, 6-8 weeks old.
2.2 Experimental methods
The epithelium was removed from the central 3mm area of the cornea of the right eye of the mouse using a 3mm trephine and an epithelial spatula. The epithelial injury repair of mice was observed using sodium fluorescein staining and slit lamp photography.
2.3 results of the experiment
The result shows that compared with a control sample, the tested sample and the control sample can effectively promote the STZ-induced diabetic corneal epithelial injury repair, and the repair effect of the tested sample group is obviously superior to that of the control sample group.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents and the like included within the spirit and scope of the present invention.
Claims (12)
1. The pharmaceutical composition for treating and/or preventing corneal epithelial injury comprises NGF and OPG, wherein the pharmaceutical composition is an aqueous eye drop, the content of the NGF is 100-300 mu g/mL, and the content of the OPG is 10-50 ng/mL.
2. The pharmaceutical composition of claim 1, wherein the NGF is murine NGF or human NGF; and/or the OPG is murine OPG or human OPG.
3. The pharmaceutical composition of claim 2, wherein said human NGF is human recombinant NGF; and/or the human OPG is human recombinant OPG.
4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising a pharmaceutically acceptable additive; the additive is selected from: one or more of bacteriostatic agent, pH regulator, osmotic pressure regulator, solubilizer, thickener and chelating agent.
5. The pharmaceutical composition of claim 4, wherein said bacteriostatic agent is selected from the group consisting of: one or more of thimerosal, quaternary ammonium salts, domiphen bromide, chlorhexidine, chlorobutanol, parabens and sorbic acid.
6. The pharmaceutical composition of claim 4, wherein the pH modifying agent is selected from the group consisting of: one or more of phosphate, acetate, citric acid and its salt, carbonate solution, sodium hydroxide, potassium hydroxide, hydrochloric acid, boric acid and phosphoric acid.
7. The pharmaceutical composition of claim 4, wherein said tonicity modifier is selected from the group consisting of: one or more of saccharides, polyols and salts.
8. The pharmaceutical composition according to claim 4, wherein the solubilizing agent is selected from the group consisting of: one or more of cyclodextrin and its derivatives, water-soluble polymers and surfactants.
9. The pharmaceutical composition of claim 4, wherein said thickening agent is selected from the group consisting of: one or more of methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose and salts thereof.
10. The pharmaceutical composition of claim 4, wherein the chelating agent is selected from the group consisting of: one or more of sodium edetate, sodium citrate and sodium polyphosphate.
Use of NGF in combination with OPG in the preparation of a medicament for the treatment of corneal epithelial injury, said medicament being an eye drop, wherein the NGF content is 100-300 μ g/mL and the OPG content is 10-50 ng/mL.
12. The use of claim 11, wherein the corneal epithelial injury is diabetic corneal epithelial injury.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710122828 | 2017-03-03 | ||
| CN2017101228288 | 2017-03-03 |
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| CN106943590A CN106943590A (en) | 2017-07-14 |
| CN106943590B true CN106943590B (en) | 2022-07-26 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108379556A (en) * | 2018-05-18 | 2018-08-10 | 吉林大学 | Purposes of the Bone Morphogenetic Protein-4 in the drug for the treatment of keratonosus |
| CN111700912B (en) * | 2020-06-03 | 2022-04-19 | 青岛海尔生物科技有限公司 | Eye drops suitable for limbal stem cell deficiency and preparation |
| CN112206312A (en) * | 2020-11-19 | 2021-01-12 | 北京大学第三医院（北京大学第三临床医学院） | Pharmaceutical composition for treating dry eye comprising PEDF |
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2017
- 2017-04-05 CN CN201710216999.7A patent/CN106943590B/en active Active
Non-Patent Citations (4)
| Title |
|---|
| Steven等.RANK, RANKL, OPG, and M-CSF Expression in Stromal Cells during Corneal Wound Healing.《Investigative Ophthalmology & Visual Science》.2004,第45卷(第7期),第2201页左栏第3段. * |
| 刘强等.NGF 对角膜缘干细胞体外扩增的影响.《局解手术学杂志》.2013,第22卷(第2期),摘要. * |
| 李翔等.影响角膜愈合的相关因素与处理.《中国中医眼科杂志》.2005,第15卷(第4期),摘要. * |
| 邱良秀等.神经生长因子对角膜上皮细胞增殖的影响.《华中科技大学学报( 医学版)》.2003,第32卷(第5期),摘要. * |
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