WO2015088094A1 - Composition pharmaceutique pour prévenir ou traiter une cicatrice suite à une chirurgie de filtration de glaucome - Google Patents

Composition pharmaceutique pour prévenir ou traiter une cicatrice suite à une chirurgie de filtration de glaucome Download PDF

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Publication number
WO2015088094A1
WO2015088094A1 PCT/KR2014/000039 KR2014000039W WO2015088094A1 WO 2015088094 A1 WO2015088094 A1 WO 2015088094A1 KR 2014000039 W KR2014000039 W KR 2014000039W WO 2015088094 A1 WO2015088094 A1 WO 2015088094A1
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Prior art keywords
pharmaceutical composition
chondrocyte
derived extracellular
pcdecm
surgery
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PCT/KR2014/000039
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English (en)
Korean (ko)
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양재욱
김정림
강미선
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인제대학교 산학협력단
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Publication of WO2015088094A1 publication Critical patent/WO2015088094A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

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  • the present invention relates to a pharmaceutical composition containing a porcine chondrocyte derived extracellular membrane (PCDECM) derived from animal knee cartilage cells and provided for preventing or treating scar formation after filtration surgery in a glaucoma patient.
  • PCDECM porcine chondrocyte derived extracellular membrane
  • Filtration is the most effective treatment for reducing intraocular pressure (IOP) in glaucoma patients.
  • IOP intraocular pressure
  • postoperative conjunctival wounds and Tenon's capsules at sclerostomy sites cause filtration and failure of intraocular pressure control and consequent glaucoma optic papillary depression and vision loss.
  • Evidence suggests a persistent inflammatory response around the blebs.
  • angiogenesis is an important factor in the proliferation stage of wound healing, providing oxygen and nutrient supply for the rapid growth of cells that induce healing processes. It plays an important role, and such angiogenesis blockade can reduce the migration and proliferation of fibroblasts.
  • ECM scaffolds composed of cartilage matrix molecules comprising glycosaminoglycan sulfates (GAGs) and collagen type II secreted from animal knee cartilage. It does not cause degradability and rejection to the living body, and shows the characteristic of porosity. It has also been reported that cartilage ECM molecules or fragments derived from ECM exhibit anti-angiogenic activity.
  • GAGs glycosaminoglycan sulfates
  • porcine chondrocyte derived extracellular membrane (PCDECM) of animal knee cartilage cells showed low hypertrophy and vascular involvement in tissue-enhanced cartilage using mesenchymal stem cells on in situ.
  • the present inventors completed the present invention by confirming the effect of PCDECM inhibiting subangular epithelial neovascularization and fibrosis during the study of corneal neovascularization and visual acuity using PCDECM.
  • the present invention uses a pharmaceutical composition comprising a porcine chondrocyte derived extracellular membrane (PCDECM) from animal knee cartilage cells to prevent or treat scars formed on the wound site after filtration surgery for glaucoma patients.
  • PCDECM porcine chondrocyte derived extracellular membrane
  • the present invention aims to provide a pharmaceutical composition for preventing or treating inflammation and visual acuity loss due to filtration and failure of IOP due to scarring.
  • the present invention provides a pharmaceutical composition for preventing or treating scar formation of the scar area after filtration surgery of a glaucoma patient by containing the chondrocyte-derived extracellular matrix as an active ingredient.
  • the chondrocyte-derived extracellular matrix may be chondrocyte-derived extracellular matrix formed by secretion from the animal's knee tube insulated bone cells.
  • the chondrocyte-derived extracellular matrix may inhibit scar formation by inhibiting fibrosis and neovascularization of the wound site after filtration surgery.
  • the chondrocyte-derived extracellular matrix may be contained in an amount of 0.01 to 10 parts by weight based on 100 parts by weight of the total pharmaceutical composition.
  • the pharmaceutical composition may be provided as eye drops or injections in the form of eye drops, or ophthalmic ointments or injections in the form of gels by mixing the chondrocyte-derived extracellular matrix with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a porcine chondrocyte derived extracellular membrane (PCDECM) derived from animal knee cartilage cells according to the present invention
  • PCDECM porcine chondrocyte derived extracellular membrane
  • scars are suppressed by inhibiting fibrosis and neovascularization of the vesicle-forming site after filtration surgery in glaucoma patients.
  • Preventing or treating the production can prevent or inhibit filtration surgery failure in glaucoma patients leading to vision loss.
  • (C) is the result of hematoxylin & eosin staining of physiological saline group after surgery
  • (D) is the result of Mason Trichrome staining of physiological saline group and severe inflammatory infiltration in the scleral membrane of sclera membrane of physiological saline group as a control group. This was confirmed.
  • FIG. 2 shows the results of CD31 immunochemical staining analysis.
  • A is a result of staining of the sclera membrane of the PCDECM group after surgery
  • B is a result of staining of the sclera membrane of the control group. Confirmed.
  • the present invention provides a pharmaceutical composition for preventing or treating scar formation of a wound site of filtration surgery in a glaucoma patient by containing chondrocyte-derived extracellular matrix as an active ingredient.
  • the chondrocyte-derived extracellular matrix may be chondrocyte-derived extracellular matrix formed by secretion from the knee articular chondrocytes of an animal.
  • the chondrocyte-derived extracellular matrix may inhibit scar formation by inhibiting fibrosis and neovascularization of the wound site after filtration surgery.
  • PCDECM porcine chondrocyte derived extracellular membrane
  • the degree of fibrosis of the PCDECM group was 1.57 ⁇ 0.53, and the control group was 3.00 ⁇ 0.00, indicating that the fibrosis was suppressed in the PCDECM group as compared to the control group.
  • Neovascularization was also confirmed that many neovascularizations were formed in the control group compared to the PCDECM group after filtration as shown in FIG.
  • PCDECM was found to be able to prevent or treat scar formation by inhibiting fibrosis and neovascularization of the wound site.
  • the chondrocyte-derived extracellular matrix may be contained in an amount of 0.01 to 10 parts by weight based on 100 parts by weight of the total pharmaceutical composition.
  • the pharmaceutical composition may be provided as eye drops or injections in the form of eye drops, or ophthalmic ointments or injections in the form of gels by mixing the chondrocyte-derived extracellular matrix with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition for preventing or treating scars after glaucoma filtration surgery comprising the PCDECM as an active ingredient
  • the PCDECM as an active ingredient
  • the pharmaceutical composition for preventing or treating scars after glaucoma filtration surgery comprising the PCDECM as an active ingredient
  • the pharmaceutical composition for preventing or treating scars after glaucoma filtration surgery comprising PCDECM as an active ingredient is a suitable carrier, excipient, disintegrant, sweetener, coating agent that is commonly used in the manufacture of pharmaceutical compositions.
  • a suitable carrier excipient, disintegrant, sweetener, coating agent that is commonly used in the manufacture of pharmaceutical compositions.
  • the carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil can be used, and solid preparations for oral administration include tablets, pills, powders, granules, capsules.
  • solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like in the composition.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin and the like
  • lubricants such as magnesium styrate and talc may also be used.
  • Oral liquid preparations include suspensions, solvents, emulsions, syrups, and the like, and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • Witsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like may be used as the base material of the suppository.
  • the pharmaceutical composition is intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, nasal, inhaled, topical, rectal, oral, intraocular or intradermal Via the route can be administered to the subject in a conventional manner.
  • the preferred dosage of the PCDECM may vary depending on the condition and weight of the subject, the type and extent of the disease, the form of the drug, the route of administration, and the duration, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, but not limited thereto, the daily dosage may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg. Administration may be administered once a day or divided into several times, thereby not limiting the scope of the invention.
  • the 'subject' may be a mammal including a human, but is not limited thereto.
  • Inflammation, fibrosis and neovascularization of the two groups were quantified and compared.
  • ECM scaffolds by previously reported methods (Jin CZ, Park SR, Choi BH, Park KD, Min BH (2007) In vivo cartilage tissue engineering using a cell-derived extracellular matrix (ECM) scaffold.Artif Organs 31: 183-92) was prepared from porcine chondrocytes. First, primary chondrocytes derived from pig knee articular cartilage were expanded by monolayer culture for 3 weeks, and further cultured for 3 weeks with 3D pellets. In order to remove cellular constituents of tissues such as three-dimensional cartilage, a porous sponge-like skeleton was prepared by lyophilization at -56 ° C. and 5 m Torr for 48 hours.
  • the membrane made by the above method was treated with 200 U / mL DNase I and washed three times with phosphate buffered saline (PBS; Gibco, Carlsbad, CA).
  • PBS phosphate buffered saline
  • Ketamine hydrochloride (30 mg / kg body weight, Huons, Jecheon, Korea) and xylazine chloride (2.5 mg / kg, Bayer Korea Ltd., Seoul, Korea) , Korea) was injected into the muscle of rabbits under general anesthesia and local anesthesia with alkane propparacaine eye drops (Alcon Inc., Seoul, Korea). Anesthetized rabbits underwent a modified trabeculectomy.
  • the conjunctival sections were closed with 8-0 polyglactin (Vicryl ® , Ethicon, Somerville, NJ, USA) sutures in order to close and close the tenon sac and prevent water from entering.
  • 8-0 polyglactin Vicryl ® , Ethicon, Somerville, NJ, USA
  • the right eye of all rabbits was filtered and randomly divided into 2 groups and 25 mg / mL immediately after surgery in another group of 6 eyes and the surgical-physiological saline group in which 0.9% NaCl was injected immediately into the 6 eyes as a control group.
  • PCDECM was divided into surgical-PCDECM group injected with lysis in phosphorylated buffer (PBS; 10 mL).
  • pentobarbital salt was rapidly perfused through the ear vein in rabbits, and 12 eyes of conjunctival and subconjunctival tissues were removed, and the eyes were fixed with formalin solution for 24 hours. It was then dried and embedded in paraffin wax.
  • the frontal section of the eyeball including the cornea, sclera, conjunctiva and sclera plate, was vertically sectioned to 4 ⁇ m thick, dried and stained with hematoxylin-eosin on 4 ⁇ m thick tissue for pathological analysis of inflammation.
  • the samples were also subjected to Mason Trichrome staining in order to display collagen fibers and to grade scar tissue formation, and were classified into grades 0-4 according to the reported method (Ozkan et al).
  • the inflammatory response consisted of lymphocytes, plasma cells, tissue cells and multinuclear leukocytes, and depending on the inflammatory grade, grade 0 was no inflammatory response; Grade 1 includes some lymphocytes and plasma cells below epithelial cells; 2 is not only densely packed under epithelial cells, but also with mild inflammation, lymphocytes, plasma cells and multinuclear leukocyte infiltration; Grade 3 is neutrophils in epithelial cells in addition to grade 2; Grade 4 was graded to the extent of ulcers and high concentrations of lymphocytes, plasma cells, multinuclear leukocytes and histocytes, as well as in the epithelium.
  • Fibrosis was also classified into grades 0-4 based on the amount of collagen formation, grade 0 being no fibrosis; Grade 1 is a mild peripheral fibrosis reaction (a thin band right next to the muscle that can only be found through collagen staining); Grade 2 is a thick band that is easily identified; Grade 3 is a well developed and dense collagen band; Grade 4 was classified as severe fibrosis, replacing most areas.
  • immunohistochemical analysis was performed using 4 ⁇ m thick tissue.
  • Angiogenesis was assessed by microvascular counts (MVC) performed at high power magnification ( ⁇ 200), with mean microvascular counts of the five largest vascular regions selected through MVD, representing the absolute number of microvessels per 0.74 mm 2 .
  • the pharmaceutical composition containing the chondrocyte derived extracellular matrix (CDECM) derived from animal knee cartilage cells prevents scar formation by inhibiting fibrosis and neovascularization of the vesicle-forming site after filtration surgery in glaucoma patients. Or showed an excellent effect on treatment. Therefore, the pharmaceutical composition can prevent or suppress failure of filtration due to scar formation after filtration of glaucoma patients leading to visual loss. In addition, it is very useful because it can be used as a therapeutic composition of various forms.

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Abstract

La présente invention concerne une composition pharmaceutique contenant, en tant que substance active, une membrane extracellulaire dérivée de chondrocyte porcin (PCDECM), pour prévenir ou traiter une cicatrice formée après une chirurgie de filtration de glaucome, et plus spécifiquement, la membrane extracellulaire dérivée de chondrocyte porcin (PCDECM) prévient ou traite une cicatrice formée après une chirurgie de filtration de glaucome par inhibition de la fibrose et l'angiogenèse d'un site de plaie après une chirurgie de filtration sur un patient atteint de glaucome, et ainsi, les problèmes d'inflammation et de perte de vue dus à un échec de chirurgie de filtration, tel qu'un échec de filtration et de contrôle de la pression oculaire dû à une cicatrice, peuvent être résolus.
PCT/KR2014/000039 2013-12-10 2014-01-03 Composition pharmaceutique pour prévenir ou traiter une cicatrice suite à une chirurgie de filtration de glaucome WO2015088094A1 (fr)

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KR10-2013-0153012 2013-12-10
KR1020130153012A KR20150067517A (ko) 2013-12-10 2013-12-10 녹내장 여과수술 후 흉터 예방 또는 치료용 약학조성물

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RU2680210C2 (ru) * 2016-01-28 2019-02-18 Федеральное государственное автономное учреждение "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации Способ профилактики развития рубцовых трансформаций после фистулизирующей антиглаукоматозной операции

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KR20100061676A (ko) * 2007-09-11 2010-06-08 몬도바이오테크 래보래토리즈 아게 녹농균 감염 치료에서 치료제로서의 멜라닌세포-자극 호르몬 방출-저해 인자의 용도

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20100061676A (ko) * 2007-09-11 2010-06-08 몬도바이오테크 래보래토리즈 아게 녹농균 감염 치료에서 치료제로서의 멜라닌세포-자극 호르몬 방출-저해 인자의 용도

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JIN, C. Z. ET AL.: "In vivo cartilage tissue engineering using a cell -derived extracellular matrix scaffold", ARTIFICIAL ORGANS, vol. 31, no. 3, 2007, pages 183 - 192 *
PRIGLINGER, S. G. ET AL.: "Potential role of tissue transglutaminase in glaucoma filtering surgery", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 47, no. 9, 2006, pages 3835 - 3845 *
SEHER, A. ET AL.: "Gene expression profiling of connective tissue growth factor (CTGF) stimulated primary human tenon fibroblasts reveals an inflammatory and wound healing response in vitro", MOLECULAR VISION, vol. 17, 2011, pages 53 - 62 *
WONG, T. T. L. ET AL.: "Matrix metalloproteinase inhibition modulates postoperative scarring after experimental glaucoma filtration surgery", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 44, no. 3, 2003, pages 1097 - 1103 *

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