WO2001074393A1 - Agents de protection des tissus vitaux - Google Patents

Agents de protection des tissus vitaux Download PDF

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Publication number
WO2001074393A1
WO2001074393A1 PCT/JP2001/002919 JP0102919W WO0174393A1 WO 2001074393 A1 WO2001074393 A1 WO 2001074393A1 JP 0102919 W JP0102919 W JP 0102919W WO 0174393 A1 WO0174393 A1 WO 0174393A1
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WO
WIPO (PCT)
Prior art keywords
corneal
protective agent
tissue
effect
protective
Prior art date
Application number
PCT/JP2001/002919
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English (en)
Japanese (ja)
Inventor
Hiroshi Takahashi
Kiyoshi Akiba
Ryoki Takahashi
Original Assignee
Wakamoto Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wakamoto Pharmaceutical Co., Ltd. filed Critical Wakamoto Pharmaceutical Co., Ltd.
Priority to AU2001246829A priority Critical patent/AU2001246829A1/en
Publication of WO2001074393A1 publication Critical patent/WO2001074393A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
    • 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

Definitions

  • the present invention relates to a biological tissue protective agent having an excellent protective effect on biological tissues, and more particularly to a corneal protective agent effective for preventing or treating various eye diseases exhibiting corneal endothelial disorder and corneal parenchymal disorder.
  • transplantation medical care in Japan has included transplantation of organs removed from the body after cardiac arrest and living donor transplantation of organs removed from immediate family members.
  • transplantation of organs removed from the body after cardiac arrest has included transplantation of organs removed from immediate family members.
  • the success or failure of such an organ transplant is greatly affected by the condition of the organs removed from the body or the living body.
  • the corneal endothelial cell density decreases with age and becomes brittle against external forces.However, the life of the cornea is said to be about 200 years. In some cases, the corneal endothelial cell density has been shown to be important for the success of transplantation. Needless to say, the shorter the time between eyeball extraction and transplant surgery, the better.
  • the medical institution cannot predict when the donor will appear, and it will be a very urgent operation, and the patient will have to wait for a long time or emergency hospital due to the cornea which is not known when it will be provided. You will be forced.
  • to collect strict information on the presence or absence of diseases of the donor of the eyeballs used and to collect blood from actual donors to confirm the presence of diseases such as HIV, HTLV infection, and Cruetzfeld-Jacob disease. It is said that ⁇ 72 hours are needed.
  • the eye bank needs some time to make the choice of placement at a medical institution. Therefore, in order to perform corneal transplantation, it is important to keep the number of corneal endothelial cells of the provided ocular tissue from decreasing during storage, and to store it for a longer period of time.
  • the provided eye tissue preservation method is to preserve the extracted eyeball as it is
  • the former can be stored for two days, but the latter is expected to become more widespread in the future because the storage period is relatively long, about 10 days, and the cornea can be evaluated during storage.
  • the cornea can be evaluated during storage.
  • PEA Ultrasonic phacoemulsification
  • PEA has a problem in that iatrogenic corneal endothelial disorder and corneal parenchymal disorder are more likely to occur compared to extracapsular extraction, which is one of the same cataract surgery methods.
  • the cause is reported to be ultrasonic waves or heat generated by ultrasonic waves, bubbles, etc., which are serious problems peculiar to PEA. Therefore, it is very important to suppress corneal endothelial cell damage and corneal stromal damage caused by ultrasound during the operation of ultrasonic phacoemulsification in surgery.
  • the rate of reduction of corneal endothelial cells due to PEA intraocular surgery has decreased due to the development of surgical instruments and techniques such as lens nucleus fractionation, and the use of viscoelastic substances and improvement of intraocular perfusion fluid. It is not yet satisfactory, and there is a strong need for better methods.
  • the corneal endothelium is composed of a single cell layer on the back of the cornea, and its functions are to pump water from the corneal stroma to the anterior chamber (pump function) and to prevent water and substance movement from the anterior chamber to the cornea ( Barrier function).
  • Human corneal endothelial cells have almost no ability to divide, and when cells fall out due to injury, surrounding residual cells expand, extend, migrate, and repair endothelial damage, resulting in endothelial damage.
  • the resulting cell loss reduces cell density. Its function is maintained up to a certain cell density (300-600 mm 2 ), but below that, it becomes dysfunctional, resulting in bullous keratopathy with edema clouding throughout the cornea.
  • This bullous keratopathy is mostly iatrogenic and is caused by corneal endothelial damage caused by corneal transplantation or cataract surgery or other internal eye surgery, and edema and pain are strong. Become.
  • perinastatin has an action of promoting adhesion and spreading of corneal epithelial cells and promoting proliferation, and also has a remarkable action to prevent damage to corneal epithelial cells due to ultraviolet irradiation. It has been found (Japanese Patent Application No. 10-184840). However, the effect of perinastatin on corneal endothelial damage and corneal stromal damage was unknown. Summary of the Invention
  • the present invention has been made in view of the above-mentioned circumstances, and has been devised to prevent or treat various types of eye diseases presenting corneal endothelial disorder or corneal stromal disorder, in particular, a biological tissue protective agent that prevents inferiority of organs for transplantation and the like. It is intended to provide a corneal protective agent.
  • the present invention is a biological tissue protective agent containing a protease inhibitor as an active ingredient and having a protective effect on a biological tissue.
  • the proteolytic enzyme inhibitor is preferably perinastatin, and examples of the living tissue include cells, tissues, and organs.
  • the present invention is also a corneal protective agent containing perinastatin as an active ingredient and having a corneal endothelium-protecting effect and a Z- or corneal-stromal protective effect.
  • the protective action of the corneal endothelium is as follows: argon laser surgery or ultrasonic lens emulsification Suppresses corneal endothelial damage caused by aspiration, suppresses corneal endothelial damage caused by preserving ocular tissue including human corneal tissue, and suppresses corneal endothelial damage after corneal transplantation
  • argon laser surgery or ultrasonic lens emulsification Suppresses corneal endothelial damage caused by aspiration, suppresses corneal endothelial damage caused by preserving ocular tissue including human corneal tissue, and suppresses corneal endothelial damage after corneal transplantation
  • the corneal stromal protective action include an action of suppressing corneal stromal damage caused by argon laser surgery, excimer laser surgery, or ultrasonic phacoemulsification.
  • the corneal protective agent of the present invention can be used as an intraocular perfusion / cleaning agent, an anterior chamber retention agent, a preservative for eye tissues including human corneal tissue, and an eye drop.
  • FIG. 1 is a graph showing the relationship between the concentration of pelinastatin and the number of dead cells in Test Example 1.
  • FIG. 2 is a diagram showing the results of morphological observation of human sclerocorneal pieces by an optical microscope in Test Example 2, in which (a) shows a state after 2 weeks without addition of perinastatin, (B) is a diagram showing a state 4 weeks after addition of perinastatin, (c) is a diagram showing a state 2 weeks after addition of perinastatin, and (d) is a diagram showing 4 weeks after addition of perinastatin It is a figure showing a state.
  • FIG. 3 is a diagram showing the results of vital staining in Test Example 3. Detailed Disclosure of the Invention
  • the biological tissue protective agent of the present invention contains a protease inhibitor as an active ingredient.
  • the proteolytic enzyme inhibitor is not particularly limited, but is preferably a high-molecular substance, and includes aprochen, perinastatin, inter-trypsin inhibitor, hi-trypsin inhibitor, 2-macroglobulin, itosori 14 metal-protease inhibitors, Proteinase inhibitors such as cystatins; non-proteinaceous proteins such as gabexate mesylate and nafamostat mesylate Zein inhibitors can be mentioned.
  • perinastatin human urinary trypsin inhibitor (UTI)
  • UTI human urinary trypsin inhibitor
  • the above-mentioned pelinastatin is a glycoprotein having a molecular weight of about 67000 (measured by gel filtration chromatography) or a molecular weight of about 34000 (measured by SDS-polyacrylamide gel electrophoresis), of which about 35% is composed of a sugar moiety. It is a known substance (Medical Science and Pharmacy, Vol. 33, No. 5, 1089-1097, 1995). Linastatin is marketed by Mochida Pharmaceutical under the trade name Miracrid.
  • Perinastatin can be obtained from healthy male fresh urine by a general purification method, for example, by adsorbing on kieselguhr and silica gel, and then sequentially combining and purifying an ion exchange resin, gel filtration and the like.
  • perinastatin is composed of several isomers.
  • the difference between these isomers is characterized by the degree of sulfonation of their constituent sugar moieties. It is considered that there is no difference in other points (antitrypsin activity, amino acid composition, N-terminal amino acid sequence, C-terminal amino acid sequence, sialic acid content, and peronic acid content) (Yuki, Y., eta) 1 .: B iochimicaet B iop hysica Acta, 1 203, 298-303 (1993)). It is clear that any of these isomers of perinastatin can be used in the present invention.
  • the biological thread protective agent of the present invention has a protective effect on biological tissues.
  • Examples of the living tissue include cells, tissues, organs, and the like. These may be those extracted from a living body or a corpse, or artificially created. Examples of the above cells include various cells of humans and other animals, ova, sperm, fertilized eggs, bone marrow cells such as ES cells, pluripotent stem cells, nerve cells, glial cells, and the like.
  • tissue examples include a cut piece of skin, liver, cornea, limb, ear, nose, finger, blood vessel, bone, cartilage, bone marrow fluid and the like.
  • organs examples include kidney, heart, liver, and kidney.
  • the protective action varies depending on the tissue or the like to which it is applied. However, in a normally removed organ, the number of cells is reduced due to apoptosis and necrosis. It can prevent cell loss and reduce the rate of cell number reduction.
  • the biological tissue protective agent of the present invention can be produced according to a conventional method by adding a pharmacologically acceptable additive to a proteolytic enzyme inhibitor as an active ingredient.
  • the biological tissue protective agent of the present invention is used by adding it to a preservation solution or perfusion solution of cells, tissues, and organs to prevent deterioration such as a decrease in the number of cells and a decrease in activity of cells, tissues, and organs. it can.
  • a preservation solution or perfusion solution of cells, tissues, and organs to prevent deterioration such as a decrease in the number of cells and a decrease in activity of cells, tissues, and organs. it can.
  • it When performing bone marrow transplantation, it may be added directly to the bone marrow fluid.
  • the biological tissue protective agent of the present invention contains a biological thread and tissue protective agent by previously adding a preservative solution component usually used for preserving cells, tissues, and organs to a proteolytic enzyme inhibitor as an active ingredient. It may be used as a preservation solution or perfusion solution for cells, tissues and organs. The above preservation solution and perfusion solution may also be used as a washing solution at the time of extraction and transplantation.
  • a corneal protective agent containing perinastatin as an active ingredient and having a corneal endothelium protective effect and / or a corneal stromal protective effect can be exemplified.
  • perinastatin human urinary trypsin inhibitor (UTI)
  • UTI human urinary trypsin inhibitor
  • It is also useful as a protective agent for preventing corneal stromal damage, and is also useful as a protective agent for preventing corneal endothelial damage due to argon laser surgery and corneal stromal damage and excimer laser surgery.
  • pelinastatin is added to the preservation solution to suppress the decrease in the number of corneal endothelial cells due to preservation. It was also clarified that it was useful as an eye drop as a prognosis improving agent.
  • the protective action of the corneal endothelium is not particularly limited.
  • the action of suppressing corneal endothelial damage caused by argon laser surgery or ultrasonic phacoemulsification, preserving eye tissue including human corneal tissue the action of suppressing corneal endothelial damage caused by the corneal endothelium, the action of suppressing corneal endothelial damage after corneal transplantation, and the like can be mentioned.
  • corneal endothelial disorder examples include bullous keratopathy, Fuchs corneal endothelial degeneration and the like.
  • the corneal stromal protective action is not particularly limited, and examples thereof include corneal stromal disorders caused by argon laser surgery, excimer laser surgery, and ultrasonic phacoemulsification. .
  • the use of the corneal protective agent of the present invention is not particularly limited, and includes, for example, intraocular perfusion / cleansing agent, anterior chamber retention agent, preservative for ocular tissues including human corneal tissue, and eye drops as prognostic improver after corneal transplantation Agents and the like.
  • the corneal protective agent of the present invention When used as a lavage agent for intraocular perfusion, it may be in the form of a liquid preparation in which linastatin, which is an active ingredient of the present invention, is previously dissolved in a physiologically isotonic straight solution or the like, or However, it may be used by dissolving as a solid agent at the time of use.
  • linastatin which is an active ingredient of the present invention
  • a physiologically isotonic straight solution or the like or a physiologically isotonic straight solution
  • the solution of the solid agent for example, purified water, physiological saline, or a physiologically isotonic saline solution can be used.
  • the solid agent include a lyophilized agent and the like, which can be appropriately produced by a known method.
  • the active ingredient of the present invention is previously dissolved in a viscoelastic substance such as a hyaluronic acid solution for maintaining the anterior chamber space at the time of surgery. Or they may be mixed at the time of use.
  • a viscoelastic substance such as a hyaluronic acid solution for maintaining the anterior chamber space at the time of surgery. Or they may be mixed at the time of use.
  • the active ingredient of the present invention, perinastatin may be previously dissolved in a corneal nutrient solution or the like to prepare a liquid preparation, Alternatively, it may be used by dissolving it as a solid agent at the time of use.
  • the solid agent for example, purified water, physiological saline, physiologically isotonic saline, corneal nutrient solution, and the like can be used.
  • the solid agent include a freeze-dried agent and the like, which can be appropriately produced by a known method.
  • the corneal protective agent of the present invention When used as an eye drop, it can be produced by further adding a known additive to perinastatin and dissolving it in a suitably selected buffer according to a known method.
  • a known additive to perinastatin and dissolving it in a suitably selected buffer according to a known method.
  • the above-mentioned various preparations are preferably sterilized by a known method such as sterile filtration.
  • the content of perinastatin in the corneal protective agent of the present invention is slightly different depending on the individual preparation, and is determined in consideration of various factors such as corneal endothelium protection, osmotic pressure, and ion balance. It is preferably in the range of 50 units Zml to 600,000 units Zml. It is more preferably in the range of 100 units / mL to 300,000 units 111 1 ⁇ , and even more preferably in the range of 500 units / mL to 3,000 units / mL. You. BEST MODE FOR CARRYING OUT THE INVENTION
  • a sterile preparation was prepared by a known method and used as an intraocular perfusion-detergent.
  • the pH was 7.4 and the osmotic pressure ratio was 1.1.
  • a sterile preparation was prepared by a known method and used as an anterior chamber retention agent.
  • the pH was 7.4 and the osmotic pressure ratio was 1.1.
  • Table 2
  • a sterile preparation was prepared by a known method and used as an ocular tissue preservative.
  • the pH was 7.4 and the osmotic pressure ratio was 1.1.
  • the cultured cells were irradiated with ultrasonic waves using an ultrasonic emulsification suction device (NI DEC CV-12000) at an output of 60% and a frequency of 60 kHz for 30 seconds.
  • the ultrasonic tip was made of titanium and had a bevel surface of 30 °.
  • the handpiece was fixed to a stand with a movable handle and the center of the culture dish.
  • the shortest distance between the tip of the ultrasonic tip and the cultured cell surface was set to 7 mm, and the angle between the ultrasonic tip and the cell surface was set to 90 °. No perfusion was performed at the time of ultrasonic irradiation.
  • the dead cell rate was calculated using the method. That is, the cultured cells after the ultrasonic irradiation were immersed in 0.3% trypan blue / isotonized phosphate buffer (pH 7.4) for 90 seconds, and then immersed in 2% formalin Z Hank's salt buffer (pH 7.4). ) And photographed an area of 2.40 mm 2 in the microscope observation frame at the center of the culture dish, and counted the number of dead cells whose nuclei were stained blue. In addition, cells were fixed with 70% ethanol for the purpose of staining all cells, and trypan-staining was performed in the same manner to count the number of cells. Then, the percentage of the number of dead cells after the ultrasonic treatment was calculated as the dead cell rate.
  • the human scleral corneal slices stored in (Ch iron) were cut in half and stored for another 2 to 4 weeks with Optisol-GS supplemented with 1500 units / mL of pelinastatin or Optisol-GS without perinastatin.
  • the stored human sclerocorneal sections were stained with trypan blue to determine cell damage. In addition, according to trypan blue staining, only dead cells are stained.
  • thin sections were prepared by cutting human sclerocorneal slices in the thickness direction, and the thin sections were subjected to HE staining, and morphological examination was performed using an optical microscope according to a conventional method. Table 4 shows the trypan blue staining rate of the cells, and FIG. 2 shows the results of morphological observation of the cells using a light microscope. Table 4
  • sclerocorneal keratoplasty for corneal transplantation of 3 eyes No. 1 to 3 for left and right eyes, stored for 23 to 28 days with OPTIZO-LU-GS (manufactured by Chiron), was used for research. Received. Of the left and right eyes, one sclerocorneal piece was kept at a low temperature for another 14 days with Optisol-GS supplemented with 1500 units / mL of pelinastatin and the other with Optisol-GS without perinastatin.
  • the preserved sclerocorneal sections were subjected to a living body staining method (0.25% trypan blue staining Z 0.2% arizarin red S staining) to calculate the endothelial cell damage rate.
  • the preserved sclerocorneal pieces were left at room temperature for 1 hour, washed with physiological saline, and several drops of 0.25% trypan blue solution were dropped on the endothelium side, and left for 1 minute and 30 seconds. After washing with physiological saline, a few drops of 0.2% arizarin red S solution was dropped and left for 4 minutes, washed with physiological saline, observed with a stereoscopic microscope, and photographed.
  • Endothelial cell injury rate is the ratio of the area of stained (cytotoxic area) to the total area of endothelium. Expressed as a percentage.
  • the biological tissue protective agent of the present invention has a protective effect on a biological tissue by containing a protease inhibitor as an active ingredient, and can prevent deterioration such as a decrease in cell number and activity.
  • the corneal protective agent of the present invention is excellent in protecting corneal endothelial cells and corneal parenchyma which are most susceptible to ultrasonic damage in intraocular surgery, particularly cataract surgery, and is therefore a corneal protective agent of the present invention. According to this, intraocular surgery can be performed safely.
  • the corneal protective agent of the present invention has a protective effect on corneal endothelium during preservation of human corneal tissue or after corneal transplantation and improves retention of ocular tissue. It can be used advantageously for the treatment of corneal disorders, especially for corneal transplantation, as a preservative for ocular tissues, including eye drops for improving prognosis.

Abstract

L'invention concerne des agents de protection des tissus vitaux, permettant d'empêcher la destruction des organes pour une transplantation, etc. En particulier, l'invention concerne des nouveaux agents de protection de la cornée permettant d'empêcher ou de traiter diverses maladies de l'oeil associées à une insuffisance de l'endothélium cornéen ou à une insuffisance parenchymateuse de la cornée. Ces agents vitaux contiennent un inhibiteur de protéase comme ingrédient actif et ils ont pour effet de protéger les tissus vitaux.
PCT/JP2001/002919 2000-04-04 2001-04-04 Agents de protection des tissus vitaux WO2001074393A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001246829A AU2001246829A1 (en) 2000-04-04 2001-04-04 Vital tissue-protecting agents

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JP2000-102134 2000-04-04
JP2000102134 2000-04-04

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WO2001074393A1 true WO2001074393A1 (fr) 2001-10-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009028631A1 (fr) * 2007-08-29 2009-03-05 Senju Pharmaceutical Co., Ltd. Agent pour favoriser l'adhérence cellulaire endothéliale cornéenne

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5104787A (en) * 1990-03-05 1992-04-14 Lindstrom Richard L Method for apparatus for a defined serumfree medical solution useful for corneal preservation
EP1060748A1 (fr) * 1998-02-25 2000-12-20 Wakamoto Pharmaceutical Co., Ltd. Medicaments destines aux troubles de l'epithelium corneen

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5104787A (en) * 1990-03-05 1992-04-14 Lindstrom Richard L Method for apparatus for a defined serumfree medical solution useful for corneal preservation
EP1060748A1 (fr) * 1998-02-25 2000-12-20 Wakamoto Pharmaceutical Co., Ltd. Medicaments destines aux troubles de l'epithelium corneen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
T. OKAMOTO ET AL.: "Use of ulinastatin for improving the viability of liver grafts", TRANSPLANTATION PROCEEDINGS, vol. 25, no. 5, 1993, pages 2961 - 2964, XP002942264 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009028631A1 (fr) * 2007-08-29 2009-03-05 Senju Pharmaceutical Co., Ltd. Agent pour favoriser l'adhérence cellulaire endothéliale cornéenne
US9248125B2 (en) 2007-08-29 2016-02-02 Senju Pharmaceutical Co., Ltd. Agent for promoting corneal endothelial cell adhesion
US11633404B2 (en) 2007-08-29 2023-04-25 Senju Pharmaceutical Co., Ltd. Agent for promoting corneal endothelial cell adhesion
US11839618B2 (en) 2007-08-29 2023-12-12 Senju Pharmaceutical Co., Ltd. Agent for promoting corneal endothelial cell adhesion

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