WO2017061663A1 - 티모신 베타 4를 포함하는 안약의 제조방법 - Google Patents

티모신 베타 4를 포함하는 안약의 제조방법 Download PDF

Info

Publication number
WO2017061663A1
WO2017061663A1 PCT/KR2015/013981 KR2015013981W WO2017061663A1 WO 2017061663 A1 WO2017061663 A1 WO 2017061663A1 KR 2015013981 W KR2015013981 W KR 2015013981W WO 2017061663 A1 WO2017061663 A1 WO 2017061663A1
Authority
WO
WIPO (PCT)
Prior art keywords
thymosin beta
composition
inert gas
thymosin
beta
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2015/013981
Other languages
English (en)
French (fr)
Korean (ko)
Inventor
이시영
강신욱
성지혜
엄태흠
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HLB Therapeutics Co Ltd
Original Assignee
G TreeBNT 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 G TreeBNT Co Ltd filed Critical G TreeBNT Co Ltd
Priority to JP2018511451A priority Critical patent/JP6996713B2/ja
Priority to HK18115713.4A priority patent/HK1256595A1/en
Priority to US15/752,118 priority patent/US10744088B2/en
Priority to EP15905904.7A priority patent/EP3342398A4/en
Publication of WO2017061663A1 publication Critical patent/WO2017061663A1/ko
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/1468—Containers characterised by specific material properties
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B23/00—Noble gases; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/10—Bag-type containers
    • A61J1/12—Bag-type containers with means for holding samples of contents

Definitions

  • the present invention relates to a method for the preparation of an ophthalmic eye containing thymosin beta 4.
  • the human eye is a part of the non-renewable body structure that is vulnerable to degenerative diseases such as retina, cornea, conjunctiva and uvea, eye diseases such as glaucoma and cataracts.
  • the cornea is part of the outer envelope that is exposed to the outside, which protects the eye and refracts the wavelengths coming into the eye and delivers it to the retina, but there is no structure that protects the cornea other than the eyelid. Vulnerable to trauma
  • there is no treatment for fatal damage other than the transplantation and even if the transplantation is not possible in vivo adaptation or side effects often occur.
  • eye diseases such as corneal surface damage and dry eye. Since the lens is worn by overlaying the surface of the cornea, oxygen cannot be supplied to the cornea and the tears secreted from the lacrimal glands are blocked to deepen the dryness of the cornea. Therefore, most people who wear lenses often use artificial tears or the like to relieve corneal dryness. If the cornea is intensified, treatment of the damaged cornea is essential to prevent further deepening of other eye diseases. Examples of treatment methods for corneal injury include the application of liquid drops, gels, ointments, and the like directly to the cornea.
  • eye drops of various formulation forms are important to be stably preserved to maintain activity.
  • the stability and pharmacological activity of the eye drops are influenced by the composition and content of the preparation itself, the processing conditions in the manufacturing process and distribution process.
  • the dehumidification and oxidation prevention of the preparation is very important during the manufacturing and distribution process.
  • the product is sterilized in a sealed package or colored in a glass bottle to prevent direct sunlight, and a dehumidifying agent such as silica gel is added to the product. Maintain quality.
  • quality maintenance due to seasonal temperature difference, humidity change, oxidation, etc. cannot be efficiently performed. Accordingly, there is a high demand for a formulation having excellent stability capable of keeping the pharmacological activity of the formulation constant.
  • thymosin beta 4 is the first protein found in the thymus in 1981, and is composed of 41 to 43 amino acids and has an isoelectric point of 5.1. Thymosin beta 4, first identified as an actin-sequestering molecule in animal cells by Leva et al. In 1991, has since been shown to be involved in immune regulation and the neuroendocrine system. Furthermore, thymosin beta 4 acts as a terminal deoxynucleotide transferase in thymocytes, increases macrophage migration and macrophage antigens, and luteinization by hypothalamic explants.
  • thymosin beta 4 having the pharmacological activity as described above for the treatment of eye diseases.
  • Republic of Korea Patent Publication No. 10-2008-0033939 is the use of eye drops containing thymosin beta 4 and bactericidal activity preservatives, the composition for the treatment of eye inflammation, eye infections (bacteria, fungi or viruses) and glaucoma
  • the composition has a drawback that thymosin beta 4, which is prepared by a lyophilization method, is vulnerable to temperature change, and may be denatured by temperature change, thereby reducing pharmacological activity.
  • Republic of Korea Patent Publication No. 10-2015-0080026 is a non-oxidizing gas after adding a pH buffer and antioxidant to an aqueous solution containing tetrahydrobiopterin (BH4) that can be administered orally, intravenous injection and food Is disclosed, and the aqueous solution is sealed in a container and formulated.
  • aqueous solution containing BH4 is made of a mixed solution containing BH4, pH buffer, antioxidant, etc., exposed to oxygen under normal atmosphere before sealing the container, it is sealed in the container in the presence of non-oxidizing gas, There is a disadvantage in that oxidation and impurities can not be blocked.
  • the present inventors are trying to prevent the denaturation of thymosin beta 4 to enhance the stability of the ophthalmic drug including the same and to maintain the pharmacological activity for a long time, using thymosin beta 4 and the same using an inert gas during ophthalmic preparation and encapsulation.
  • the present invention has been completed by confirming that it can enhance the stability of eye drops by blocking them from contacting oxygen.
  • the present invention provides a method for producing an ophthalmic ophthalmic containing thymosin beta 4 comprising the step of encapsulating a composition comprising thymosin beta 4 in a container in the presence of an inert gas.
  • the present invention provides an ophthalmic product prepared according to the above production method.
  • the preparation method of the present invention prepares eye drops containing thymosin beta 4 in the presence of an inert gas, thereby blocking the contact of thymosin beta 4 with oxygen so that thymosin beta 4 remains active without being oxidized by oxygen.
  • the ophthalmic product prepared by the preparation method of the present invention can stably maintain the pharmacological activity of thymosin beta 4 for a long time.
  • FIG. 1 is a schematic diagram showing a method for preparing an eye drop containing thymosin beta 4.
  • a method for preparing an ophthalmic eye comprising thymosin beta 4 which comprises the step of encapsulating a composition comprising thymosin beta 4 in a container in the presence of an inert gas.
  • thymosin beta 4" as used herein is a protein, also referred to as Thymosin beta-4 or Tbeta 4, isolated from the original thymus and consisting of 43 amino acids of 4.9 kDa identified in various tissues. to be.
  • the protein is a protein that is up-regulated during endothelial cell migration and differentiation in vitro, with many thymosin beta 4 iso forms identified, about 70%, or about 75%, with the known amino acid sequence of thymosin beta 4 Or, at least about 80% homology.
  • the thymosin beta 4 of the present invention can be applied to the N-terminal variant of wild type thymosin beta 4, and the C-terminal variant of Tbeta 4. Specifically, it means a protein having the amino acid sequence set forth in SEQ ID NO: 1.
  • composition comprising thymosin beta 4 may be encapsulated in a container in the presence of nitrogen or argon, specifically, nitrogen gas, and may be encapsulated together by filling an inert gas so that oxygen is not enclosed in the container.
  • nitrogen or argon specifically, nitrogen gas
  • inert gas helium, neon, etc.
  • nitrogen and argon relatively inexpensive nitrogen or argon is used in consideration of cost, and nitrogen is used in detail.
  • the inert gas is more stable than oxygen or hydrogen molecules, when the composition containing the thymosin beta 4 is enclosed in the presence of an inert gas, the thymosin beta 4 is oxidized by blocking contact between the composition and oxygen in the general atmosphere. It can prevent. In addition, since the inert gas is filled together so that oxygen is not present in the container, oxidation of thymosin beta 4 can be continuously prevented and pharmacological activity can be stably maintained.
  • the container may be a conventional material used for encapsulating a medicine, and in detail, a glass container, a polypropylene container, a low density polyethylene container, or the like may be used, and more specifically, a low density polyethylene container may be used.
  • the preparation method of the eye drops of the present invention can be carried out according to the following specific process.
  • composition comprising thymosin beta 4 is prepared by mixing a solvent and thymosin beta 4 in the presence of an inert gas.
  • thymosin beta 4 is mixed with a solvent from which impurities such as purified water, pure water and sterile water for injection are removed in the presence of an inert gas such as nitrogen or argon. Specifically, thymosin beta 4 is mixed while bubbling nitrogen to the solvent at a rate of 100 mL / min to 140 mL / min to remove oxygen dissolved in the solvent.
  • the thymosin beta 4 in the mixed composition may be 0.05% (w / v) to 0.5% (w / v) based on the total composition, and may be administered in a total dose of 0.08 mL to 2.0 mL per day.
  • the composition may be administered once or several times daily, and in detail, may be administered twice to five times daily.
  • the excipient may be a conventional one that can be added in the manufacture of a pharmaceutical, and in detail, may be sodium chloride, potassium chloride, calcium chloride hydrate, magnesium chloride hexahydrate, sodium acetate hydrate, sodium citrate hydrate and the like.
  • composition obtained above is adjusted to pH from 6.8 to 7.2 using acid and base.
  • the acid may be any one selected from hydrochloric acid, acetic acid, phosphoric acid, and the like, and specifically, hydrochloric acid.
  • the base may be any one base selected from sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate and the like, and specifically, may be sodium hydroxide.
  • the pH adjusted composition is filtered through a filter.
  • the composition is filtered using a filter, specifically, a sterile filter having pores of 1.0 mu m or less, and more particularly, a sterile filter having pores of 0.2 mu m or less, thereby removing impurities, bacteria, and the like.
  • An eye drop containing the composition comprising thymosin beta 4 prepared by the above production method is enclosed in a pouch in the presence of an inert gas.
  • the encapsulation can be carried out in the presence of nitrogen gas so that oxygen is not enclosed together during encapsulation.
  • FIG. 1 The detailed method of preparing eye drops including thymosin beta 4 as described above is shown in FIG. 1, and all steps can be performed in the presence of an inert gas to prevent contact of thymosin beta 4 with oxygen.
  • the present invention provides an ophthalmic product comprising thymosin beta 4 prepared by the above method.
  • the preparation of the ophthalmic drug containing thymosin beta 4 by performing the whole process in the presence of an inert gas to prevent the generation of oxides or incorporation of other substances in the eye drops to maintain a constant physical and chemical properties for a long time
  • the ophthalmic product of the present invention can maintain the pharmacological activity of thymosin beta 4 for a long time in a stable state.
  • Step 1 Preparation of an Eye Drop Composition Comprising Thymosin Beta 4
  • 630 g of sterile water for injection is placed in a pressurized stainless steel agitator and cooled to 5 ° C while bubbling nitrogen at a rate of about 120 mL / min through a sparger submerged in the liquid to remove oxygen dissolved in the liquid. It was. To the cooled solution, 4.89 g of sodium chloride, 573 mg of calcium chloride, 366.72 mg of calcium chloride hydrate, 229 mg of magnesium chloride hexahydrate, 2.98 g of sodium acetate hydrate, and 1.30 g of sodium citrate hydrate were added and dissolved by stirring while maintaining 3 to 7 ° C.
  • thymosin beta 4 acetate (Bachem, USA, SEQ ID NO: 1) (purity and corrected amount of peptide) were added, and stirred at 3 ° C. to 7 ° C. to dissolve all of them. Nitrogen dosing was continued during the dissolution of each component and thymosin beta 4 to prevent contact with oxygen. Sodium hydroxide and hydrochloric acid were added to the obtained solution to adjust the pH to 7.0, and then 82 g of sterile injectable water was added to adjust the concentration of thymosin beta 4 to 1 mg / mL. The resulting mixture was subjected to sterile filtration using a 0.2 ⁇ m polyethersulfone (PES) sterile filter (product number: MCY4440EKVPH4, Pall) under nitrogen pressure to obtain a filtered solution.
  • PES polyethersulfone
  • the sterile filtration solution obtained in step 1 was placed in low density polyethylene vials of 0.27 ml each and filled with nitrogen gas. The vials were then enclosed in aluminum pouches under nitrogen backflush to prepare eye drops. The prepared eye drops were refrigerated at 2 ° C to 8 ° C.
  • Eye drops were prepared in the same manner as in Example 1, except that the steps 1 and 2 of Example 1 were carried out under a general atmosphere (with O 2 ) without using an inert gas.
  • Eye drops were prepared in the same manner as in Example 1, except that the step 1 of Example 1 was carried out under a general atmosphere (with O 2 ) without using an inert gas.
  • Test Example 1 Confirmation of the stability of the composition containing thymosin beta 4
  • thymosin beta 4 sulfoxide was synthesized with reference to the method of Eur . J. Biochem . 223, 345-350 (1994), Nature Medicine 5 (12), 1424 (1999).
  • the thymosin beta 4 sulfoxide is a substance that is oxidized and denatured by thymosin beta 4, and when the thymosin beta 4 sulfoxide is denatured, pharmacological activity changes.
  • Synthesized thymosin beta 4 sulfoxide was determined by mass spectrometry (LC / MS) using a MALDI-TOF MS instrument to confirm molecular weight.
  • the analyzed molecular weight was 4,978.5, which is consistent with the literature value of 4,980 ⁇ 2.
  • Example 1 and Comparative Examples 1 and 2 The ophthalmic preparations prepared in Example 1 and Comparative Examples 1 and 2 and the synthesized thymosin beta 4 sulfoxide were analyzed under the same conditions by HPLC and LC / MS, and the retention time and the mass spectrometry were confirmed to be the same. It was confirmed that the single maximal impurities detected were thymosin beta 4 sulfoxide (see FIG. 2).
  • the eye drops of the examples prepared under inert gas filling maintain a higher purity than the eye drops of Comparative Examples 1 and 2 prepared by excluding inert gas in all processes and some processes. It was found to be very low.
  • the eye drops of the embodiment prepared under nitrogen filling can maintain high purity and maintain impurities similar to the original quality by blocking the generation of impurities.
  • Example 1 Comparative Example 1 Comparative Example 2 Analysis item water(%) Thymosin beta 4 sulfoxide (%) water(%) Thymosin beta4 sulfoxide (%) water(%) Thymosin beta4 sulfoxide (%) Initial value 99.10 0.29 96.30 2.90 97.90 0.70 1 month 99.43 0.57 94.76 3.30 97.20 1.20 2 months 99.35 0.65 95.56 4.00 99.00 0.90 3 months 99.39 0.61 91.81 5.90 99.00 0.80 6 months 99.28 0.72 95.18 4.00 98.10 0.90 9 months 99.27 0.65 90.30 6.40 98.80 0.90 12 months 99.09 0.81 94.43 3.90 98.30 0.90
  • the eye drops of the examples prepared under inert gas filling showed high purity and low impurity content immediately after preparation, under the conditions of 5 ⁇ 3 ° C and 25 ° C and 40% relative humidity.
  • the purity and impurity content was not large, and it was confirmed that even after 12 months, high purity and low impurity content were shown.
  • the eye drops of the comparative examples showed lower purity and higher impurity content immediately after preparation than the eye drops of the examples under conditions of 5 ⁇ 3 ° C. and 25 ° C. and a relative humidity of 40%. I could see that.
  • the eye drops of the embodiment prepared under nitrogen filling can maintain high purity for a long time by blocking the generation of impurities, and thus have excellent storage stability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
PCT/KR2015/013981 2015-10-06 2015-12-18 티모신 베타 4를 포함하는 안약의 제조방법 Ceased WO2017061663A1 (ko)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2018511451A JP6996713B2 (ja) 2015-10-06 2015-12-18 チモシンベータ４を含む眼科用製剤の製造方法
HK18115713.4A HK1256595A1 (en) 2015-10-06 2015-12-18 Method for preparing ophthalmic preparation containing thymosin beta-4
US15/752,118 US10744088B2 (en) 2015-10-06 2015-12-18 Method for preparing ophthalmic preparation containing thymosin beta-4
EP15905904.7A EP3342398A4 (en) 2015-10-06 2015-12-18 PROCESS FOR PREPARING AN OPHTHALMIC PREPARATION WITH THYMOSINE BETA-4

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20150140489 2015-10-06
KR10-2015-0140489 2015-10-06

Publications (1)

Publication Number Publication Date
WO2017061663A1 true WO2017061663A1 (ko) 2017-04-13

Family

ID=58487995

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2015/013981 Ceased WO2017061663A1 (ko) 2015-10-06 2015-12-18 티모신 베타 4를 포함하는 안약의 제조방법

Country Status (6)

Country Link
US (1) US10744088B2 (enExample)
EP (1) EP3342398A4 (enExample)
JP (2) JP6996713B2 (enExample)
KR (1) KR102487614B1 (enExample)
HK (1) HK1256595A1 (enExample)
WO (1) WO2017061663A1 (enExample)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210251970A1 (en) 2018-10-10 2021-08-19 Presbyopia Therapies Inc Compositions and methods for storage stable ophthalmic drugs
CA3114204A1 (en) * 2018-10-10 2020-04-16 Presbyopia Therapies, Inc. Compositions and methods for the treatment of presbyopia
CN112107678B (zh) * 2020-09-30 2022-11-18 辰欣药业股份有限公司 一种含有胸腺法新的冻干组合物及其制备方法
US12180206B2 (en) 2021-11-17 2024-12-31 Lenz Therapeutics Operations, Inc. Aceclidine derivatives, compositions thereof and methods of use thereof
US12414942B1 (en) 2024-03-15 2025-09-16 Lenz Therapeutics Operations, Inc. Compositions, methods, and systems for treating presbyopia

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19980703582A (ko) * 1995-04-04 1998-11-05 가와구치 시게키 염산 프로카테롤 수용액 제제를 보지하는 패키지 및 염산 프로카테롤 수용액 제제
KR20010099686A (ko) * 1998-10-14 2001-11-09 히라타 다다시 피라졸로아크리돈 유도체 수용액의 안정화 방법
KR20060051135A (ko) * 2004-09-15 2006-05-19 니프로 가부시키가이샤 안정화된 주사용 수용액 제재
US8143218B2 (en) * 1998-07-30 2012-03-27 Regenerx Biopharmaceuticals, Inc. Treatment of skin, and wound repair, with thymosin beta 4

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4150744A (en) * 1976-02-27 1979-04-24 Smith & Nephew Pharmaceuticals Ltd. Packaging
US6271216B1 (en) * 1989-07-24 2001-08-07 Allergan Stable solution of hyaluronate in a balanced salt medium
MX2007001181A (es) * 2004-07-30 2007-03-21 Otsuka Pharma Co Ltd Botella comprimible y envase con gotero oftalmico que usa el mismo.
CA2612522A1 (en) * 2005-06-17 2006-12-28 Regenerx Biopharmaceuticals, Inc. Lkktet and/or lkktnt peptide compositions and methods
ES2288118B1 (es) * 2006-05-10 2008-11-01 Bcn Peptides, S.A. Procedimiento para sintetizar timosinas.
WO2008108927A2 (en) * 2007-03-06 2008-09-12 Regenerx Biopharmaceuticals, Inc. Methods and compositions for stabilizing polypeptides
MX2009010977A (es) 2007-04-11 2010-02-12 Biomarin Pharm Inc Metodos de administracion de tetrahidrobiopterina, composiciones asociadas y metodos de medicion.
JP5990880B2 (ja) * 2011-08-31 2016-09-14 東レ株式会社 有用タンパク質組成物およびその製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19980703582A (ko) * 1995-04-04 1998-11-05 가와구치 시게키 염산 프로카테롤 수용액 제제를 보지하는 패키지 및 염산 프로카테롤 수용액 제제
US8143218B2 (en) * 1998-07-30 2012-03-27 Regenerx Biopharmaceuticals, Inc. Treatment of skin, and wound repair, with thymosin beta 4
KR20010099686A (ko) * 1998-10-14 2001-11-09 히라타 다다시 피라졸로아크리돈 유도체 수용액의 안정화 방법
KR20060051135A (ko) * 2004-09-15 2006-05-19 니프로 가부시키가이샤 안정화된 주사용 수용액 제재

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP3342398A4 *
SONSE, G. ET AL.: "Thymosin Beta 4 Promotes Corneal Wound Healing and Decreases Inflammation in Vivo Following Alkali Injury", EXPERIMENTAL EYE RESEARCH, vol. 74, 2002, pages 293 - 299, XP009096159 *

Also Published As

Publication number Publication date
HK1256595A1 (en) 2019-09-27
EP3342398A1 (en) 2018-07-04
JP2020183391A (ja) 2020-11-12
JP6996713B2 (ja) 2022-02-04
KR20170041109A (ko) 2017-04-14
EP3342398A4 (en) 2019-03-20
US20180228729A1 (en) 2018-08-16
JP2018531905A (ja) 2018-11-01
KR102487614B1 (ko) 2023-01-12
US10744088B2 (en) 2020-08-18

Similar Documents

Publication Publication Date Title
WO2017061663A1 (ko) 티모신 베타 4를 포함하는 안약의 제조방법
US7173008B2 (en) Lyophilized HGF preparations
WO2012121523A2 (en) Process for preparing pharmaceutical formulation in form of antioxidant-free solution for injection containing pemetrexed or its salt
WO2018159906A1 (ko) 티모신 베타 4를 유효성분으로 포함하는 안정화된 외용 제제
JPH10212241A (ja) Ｂｄｎｆを安定に含有する製剤
CN102670522B (zh) 含有重组人血清白蛋白-人粒细胞集落刺激因子融合蛋白的药物制剂及其制备
KR20090118030A (ko) Ｈｇｆ 제제
EP3715451A2 (en) Composition for promoting goblet cell proliferation or mucin secretion comprising thymosin beta 4 or derivative thereof as active ingredient
JP2001233787A (ja) 小・中サイズのペプチド含有薬学的組成物
WO2013023362A1 (zh) 静注巨细胞病毒人免疫球蛋白及其制备方法
CN104840418B (zh) 一种盐酸法舒地尔注射液组合物及其制备方法
EP2711374A1 (en) Novel metalloprotein and process for producing same, and prophylactic or therapeutic agent for corneal and conjunctival diseases comprising said metalloprotein
CN114191388A (zh) 一种卡贝缩宫素制剂的制备方法
US20150018287A1 (en) Eye drops
CZ277712B6 (en) Mixture containing alpha-interferon
CN102233130B (zh) 稳定的含有胸腺肽1衍生物的药物制剂
EP0547223B1 (en) Remedy for corneal damages
WO2016064078A1 (ko) 티모신 베타 4를 함유하는 조성물 및 이를 포함하는 약학적 제형
KR100671449B1 (ko) 송아지의 제단백 혈액 추출물을 함유하는 점안용 액제조성물
CN121197362A (zh) 多肽组合物及其制备方法
EP4279066A1 (en) Ophthalmic composition including tanfanercept and exhibiting stability without use of stabilizer
EP3287141A1 (en) Nerve growth factor composition and powder injection
EP3712164A1 (en) Pacap stabilized peptide
WO2023163508A1 (ko) 향상된 용해도를 가지는 닥티노마이신 함유 약학조성물의 제조방법
SE468973B (sv) Nytt terapeutiskt preparat innehaallande hydrerade ergotalkaloider och heparin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15905904

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15752118

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2018511451

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2015905904

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE