WO2017142193A1 - Composition ophtalmique sous forme d'une solution aqueuse comprenant de la cyclosporine et de l'acide hyaluronique ou un sel correspondant - Google Patents
Composition ophtalmique sous forme d'une solution aqueuse comprenant de la cyclosporine et de l'acide hyaluronique ou un sel correspondant Download PDFInfo
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- WO2017142193A1 WO2017142193A1 PCT/KR2017/000034 KR2017000034W WO2017142193A1 WO 2017142193 A1 WO2017142193 A1 WO 2017142193A1 KR 2017000034 W KR2017000034 W KR 2017000034W WO 2017142193 A1 WO2017142193 A1 WO 2017142193A1
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- Prior art keywords
- ophthalmic composition
- cyclosporin
- polyethylene glycol
- hyaluronic acid
- salt
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
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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
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
Definitions
- the present invention relates to an ophthalmic composition in the form of an aqueous solution comprising cyclosporin and hyaluronic acid or a salt thereof. More particularly, the present invention relates to ophthalmic compositions having good physical and chemical stability, including d- ⁇ -tocopherol polyethylene glycol succinate as stabilizer.
- the most common method of dry eye treatment is to temporarily relieve symptoms by administering artificial tears to the eye whenever the symptoms of dry eye appear.
- Artificial tears contain viscoelastic substances such as carboxymethyl cellulose, chondroitin sulfate, and sodium hyaluronate, which replenish moisture and stabilize the tear film.
- Sodium hyaluronate exhibits excellent water retention by retaining water molecules in the molecule, thereby relieving dryness of the corneal conjunctiva, which is the external eye tissue of the eye, and healing epithelial cells of the cornea.
- artificial tears containing these substances have limited therapeutic effects because they differ physically and physiologically from natural tears.
- cyclosporin reduces the number of T-lymphocytes in the conjunctival tissue, inhibits cytokine production, regulates the inflammatory response of the ocular surface and lacrimal glands, and increases the number of conjunctival goblet cells. It is known to promote tear production.
- Restasis TM a cyclosporine ophthalmic emulsion 0.05%) by Allergan, USA is marketed as a cyclosporine-containing ophthalmic composition for the treatment of dry eye.
- the formulation contains castor oil as the solubilizer of cyclosporin and is in the form of an emulsion obtained using a crosslinked polyacrylate emulsifier and a surfactant such as polysorbate 80 to emulsify the oil component in an aqueous solution. 368,181).
- An emulsion refers to a liquid-liquid dispersion system in which at least one liquid phase is dispersed in one liquid phase, and generally has a size distribution of 0.1 ⁇ m to several tens of ⁇ m.
- Such emulsions are thermodynamically unstable and have the property of separating into various forms such as coagulation, sedimentation, creaming, grain growth, and coalescence.
- Commercially available restissis has oily eye irritation, emulsion particles are uneven and sufficient stability is not secured before use.
- US Pat. No. 6,677,304 discloses a topical ophthalmic composition in the form of an aqueous solution comprising cyclosporin and sodium hyaluronate and comprising polysorbate 80 as a stabilizer. According to the patent, it is disclosed that it is stable without deposit formation at room temperature for 12 months.
- ophthalmic preparations in the form of aqueous solutions containing cyclosporin and hyaluronic acid or salts thereof have excellent physical and chemical stability, using certain additives, d- ⁇ -tocopherol polyethylene glycol succinate, as stabilizers. .
- an ophthalmic composition in the form of an aqueous solution comprising cyclosporin and hyaluronic acid or salts thereof comprising d- ⁇ -tocopherol polyethylene glycol succinate as a stabilizer.
- an ophthalmic composition in the form of an aqueous solution comprising cyclosporin and hyaluronic acid or a salt thereof, wherein the ophthalmic composition comprises d- ⁇ -tocopherol polyethylene glycol succinate as a stabilizer.
- the ophthalmic composition of the present invention may comprise d- ⁇ -tocopherol polyethylene glycol succinate at a concentration of 0.01 to 5.00 w / v%, preferably 0.10 to 1.00 w / v%.
- the ophthalmic composition of the present invention may further comprise at least one stabilizing aid selected from the group consisting of polyoxyl 35 castor oil, polysorbate 80, and polyethylene glycol 200.
- Stabilizing aids such as polyoxyl 35 castor oil, polysorbate 80, polyethylene glycol 200, etc. may be included independently at a concentration of 0.10 to 5.00 w / v%.
- the ophthalmic preparation in the form of an aqueous solution containing cyclosporin and hyaluronic acid or a salt thereof has excellent physical and chemical stability, and thus, It has been found that they can meet the permit criteria.
- the ophthalmic composition of the present invention can be sterilized using a conventional antibacterial filter by having an aqueous solution form. Therefore, the ophthalmic composition according to the present invention can be usefully used for the treatment of dry eye and the like.
- Figure 2 shows the results of evaluating the effect of dry eye syndrome according to the National Eye Institute (NEI) grading system through corneal staining using a fluorescent dye (fluorescein).
- NKI National Eye Institute
- the present invention provides an ophthalmic composition
- an ophthalmic composition comprising an d- ⁇ -tocopherol polyethylene glycol succinate as a stabilizer in an ophthalmic composition in the form of an aqueous solution comprising cyclosporin and hyaluronic acid or a salt thereof.
- Cyclosporin and hyaluronic acid or salts thereof contained as an active ingredient for treating dry eye in the ophthalmic composition of the present invention may be used in therapeutically effective amounts, respectively.
- the cyclosporin includes various cyclosporine analogs, such as cyclosporin A, B, C, D, G, and may preferably be cyclosporin A.
- Cyclosporin, such as cyclosporin A may be present in an aqueous solution of, for example, 0.01 to 2.00 w / v%, preferably 0.01 to 0.20 w / v%, more preferably about 0.05 w / v%, but is not limited thereto. It doesn't happen.
- the hyaluronic acid or a salt thereof (for example sodium hyaluronate) is, for example, in an aqueous solution of 0.01 to 2.00 w / v%, preferably 0.10 to 0.50 w / v%, more preferably about 0.30 w / v% It may be present in a concentration of, but is not limited thereto.
- D- ⁇ -Tocopherol polyethylene glycol succinate used as a stabilizer in the pharmaceutical composition of the present invention is' d- ⁇ -Tocopherol polyethylene glycol 1000 succinate (d- ⁇ -Tocopherol polyethylene glycol) 1000 succinate) ',' vitamin E TPGS ',' TPGS 'and the like.
- the d- ⁇ -tocopherol polyethylene glycol succinate may be used in an amount to maintain the stability of the ophthalmic composition in the form of an aqueous solution, for example, 0.01 to 5.00 w / v% in an aqueous solution, preferably 0.10 to 1.00 w / v%, more preferably at a concentration of about 0.50 w / v%.
- the present invention provides an ophthalmic composition
- an ophthalmic composition comprising 0.05 w / v% cyclosporin, 0.30 w / v% hyaluronic acid or a salt thereof, and 0.50 w / v% d- ⁇ -tocopherol polyethylene glycol succinate.
- the pharmaceutical compositions of the invention may include a stabilizing aid, such as polyoxyl 35 castor oil (polyoxyl 35 castor oil) [for example, "Crescent mode pore TM ELP (Cremophor TM ELP)"], polysorbate 80, and at least one stabilizing aid selected from the group consisting of polyethylene glycol 200.
- a stabilizing aid such as polyoxyl 35 castor oil, polysorbate 80, polyethylene glycol 200, and the like may be independently included, for example, at a concentration of 0.10 to 5.00 w / v%.
- the present invention provides 0.05 w / v% of cyclosporin, 0.30 w / v% of hyaluronic acid or a salt thereof, 0.50 w / v% of d- ⁇ -tocopherol polyethylene glycol succinate, 1.00 w / of polyoxyl 35 castor oil.
- An ophthalmic composition comprising v%, and polysorbate 80 0.50 w / v%.
- the invention provides 0.05 w / v% of cyclosporin, 0.30 w / v% of hyaluronic acid or a salt thereof, 0.50 w / v% of d- ⁇ -tocopherol polyethylene glycol succinate, and 2.00 w of polyoxyl 35 castor oil.
- an ophthalmic composition comprising / v%.
- the present invention provides 0.05 w / v% of cyclosporin, 0.30 w / v% of hyaluronic acid or a salt thereof, 0.50 w / v% of d- ⁇ -tocopherol polyethylene glycol succinate, 2.00 w of polyoxyl 35 castor oil. / v%, and polyethylene glycol 200 1.00 w / v%.
- Ophthalmic compositions in the form of aqueous solutions of the present invention may include additives commonly used in the field of ophthalmic compositions.
- the additives include pH adjusting agents such as monosodium phosphate and disodium phosphate; Isotonic agents, such as glycerin, sorbitol, mannitol and the like.
- the pH adjusting agent is used to maintain the pH of the resulting ophthalmic composition is 7.0 to 7.5, it may be added in the form of a phosphate buffer.
- the ophthalmic composition of this invention can be sterilized using a conventional disinfection filter (for example, a 0.22 micrometer filter). Since the ophthalmic composition of the present invention has an aqueous solution form, unlike an emulsion preparation containing an oil component, sterilization using a conventional antibacterial filter is possible.
- a conventional disinfection filter for example, a 0.22 micrometer filter
- Example 1-25 Vitamin E TPGS Preparation of ophthalmic composition containing as stabilizer
- solution-A Completely dissolve cyclosporin A or cyclosporin A and a stabilizing aid in vitamin E TPGS (solution-A).
- Sodium hyaluronate, monosodium phosphate, disodium phosphate, and glycerin were added to sterile purified water to obtain a solution (solution-B).
- solution-B sterile purified water was added to adjust the total volume to 100 mL, and then filtered through a 0.22 ⁇ m filter to prepare an ophthalmic composition.
- the pH of the obtained ophthalmic composition is as described in following Tables 1-3.
- Ophthalmic composition containing stabilizer and stabilizing aid
- Ophthalmic composition containing stabilizer and stabilizing aid
- Comparative example 1 to 10 Polysorbate Preparation of an ophthalmic composition containing 80 as a stabilizer
- ophthalmic composition was prepared containing the polysorbate 80 disclosed in US Pat. No. 6,677,304 as a stabilizer with the ingredients and contents of Table 4 below.
- Table 4 and Table 5 above The content of each component described represents w / v% unless otherwise indicated.
- Cyclosporin A was completely dissolved in polysorbate 80 (solution-A).
- Sodium hyaluronate, sodium hydrogen phosphate 12-hydrate, and sorbitol were added to sterile purified water to obtain a solution (solution-B).
- solution-A was sufficiently mixed with Solution-B, sterile purified water was added to adjust the total volume to 100 mL, and then filtered through a 0.22 ⁇ m filter to prepare an ophthalmic composition.
- the pH of the obtained ophthalmic composition is as described in following Tables 4-5.
- ophthalmic compositions ie, ophthalmic compositions prepared in Examples 8, 13, and 23
- ophthalmic compositions prepared in Examples 8, 13, and 23 containing cyclosporin A and sodium hyaluronate, respectively, 0.05 w / v% and 0.30 w / v%, and Comparative Examples 6-10
- the prepared ophthalmic composition was stored for 6 months under accelerated storage conditions (40 ⁇ 2 ° C./relative humidity 25% or less), and the chemical stability was evaluated. Chemical stability was measured under the following HPLC analysis conditions for cyclosporin A content at the time of initial, 3 months and 6 months, with each composition stored for 6 months under accelerated storage conditions. The results are shown in Table 7 below.
- UV absorbance photometer (wavelength 210 nm)
- the therapeutic effect of the cornea damaged by dry eye syndrome was evaluated by corneal staining using a fluorescent dye (Fluorescein) as follows.
- Example 8 As a test for drug efficacy, a vehicle, a cyclosporin A alone preparation, a sodium hyaluronate alone preparation, a cyclosporine A and a sodium hyaluronate containing preparation (Example 8) were used as shown in Table 8 below.
- the vehicle, the cyclosporin A-containing formulation and the sodium hyaluronate-only formulation were prepared in the same manner as in Example 8 except for the use of cyclosporin A and sodium hyaluronate, respectively.
- the content of each component described in Table 8 below represents w / v% unless otherwise indicated.
- mice were bred from the start of dry eye induction to the end of the experiment (21 days) in a controlled environment chamber (CEC) set at a temperature of 21-23 ° C., a relative humidity of 30% or less, and airflow 15 L / min. 1% atropine sulphate was added twice per day for 2 days (09 o'clock and 21 o'clock), and 2 ⁇ l were inoculated into the mouse eye using a micro pipette. Scopolamine was injected subcutaneously into mice at the dose of 0.5 mg / 0.1 mL / head three times / day (09, 13 and 21 hours) from the start of dry eye induction to the end of the experiment.
- CEC controlled environment chamber
- the trigger score was evaluated by corneal fluorescent dye staining on the 3rd day (early) (before the administration of the test substance and before 09 o'clock) after the dry eye was induced for 2 days. Mice were anesthetized with Zoletil 50 (VIRBAC, France) and xylazine (Rompun ® , Bayer AG, Germany), followed by 2 ⁇ l of 1% fluorescein. The conjunctival sac was instilled into the cornea, and after 3 minutes, the cobalt blue light was used to measure and record the staining score of the cornea surface.
- the scores of the five corneal zones in the National Eye Institute (NEI) grading system of FIG. 1 are as follows.
- the dry eye syndrome evaluation result performed as described above is shown in FIG.
- the ophthalmic composition-administered group prepared according to the present invention showed effective therapeutic activity against corneas damaged by dry eye syndrome, and thus the composition of the present invention can be usefully used as a treatment for dry eye syndrome. have.
Abstract
La présente invention concerne une composition ophtalmique sous la forme d'une solution aqueuse comprenant de la cyclosporine et de l'acide hyaluronique ou un sel correspondant, la composition ophtalmique contenant du succinate de D-α-tocophérol polyéthylène glycol comme stabilisant et présentant une excellente stabilité physique et chimique.
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KR10-2016-0017015 | 2016-02-15 | ||
KR1020160017015A KR101635915B1 (ko) | 2016-02-15 | 2016-02-15 | 사이클로스포린과 히알루론산 또는 이의 염을 포함하는 수용액 형태의 안과용 조성물 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11090356B2 (en) | 2015-01-15 | 2021-08-17 | Newport Research, Inc. | Aqueous suspensions of cyclosporin |
US11324800B2 (en) | 2015-01-15 | 2022-05-10 | Wellspring Ophthalmics, Inc. | Aqueous suspensions of cyclosporin |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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KR101635915B1 (ko) * | 2016-02-15 | 2016-07-04 | 삼천당제약주식회사 | 사이클로스포린과 히알루론산 또는 이의 염을 포함하는 수용액 형태의 안과용 조성물 |
KR20180030323A (ko) * | 2016-09-13 | 2018-03-22 | 주식회사 코아팜바이오 | 사이클로스포린의 안구필름 제형 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US6677304B2 (en) * | 2000-04-07 | 2004-01-13 | Laboratorie Medidom S.A. | Ophthalmic formulations |
US20050196370A1 (en) * | 2003-03-18 | 2005-09-08 | Zhi-Jian Yu | Stable ophthalmic oil-in-water emulsions with sodium hyaluronate for alleviating dry eye |
US20120028910A1 (en) * | 2007-10-08 | 2012-02-02 | Jean-Philippe Combal | Storage-stable aqueous ophthalmic formulations |
US20130108674A1 (en) * | 2010-06-11 | 2013-05-02 | Medivis S.R.L. | Ophthalmic compositions for the administration of liposoluble active ingredients |
US20150352176A1 (en) * | 2014-06-06 | 2015-12-10 | Newport Research, Inc. | Oil-free and fat-free aqueous suspensions of cyclosporin |
KR101635915B1 (ko) * | 2016-02-15 | 2016-07-04 | 삼천당제약주식회사 | 사이클로스포린과 히알루론산 또는 이의 염을 포함하는 수용액 형태의 안과용 조성물 |
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- 2016-02-15 KR KR1020160017015A patent/KR101635915B1/ko active IP Right Grant
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- 2017-01-03 WO PCT/KR2017/000034 patent/WO2017142193A1/fr active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6677304B2 (en) * | 2000-04-07 | 2004-01-13 | Laboratorie Medidom S.A. | Ophthalmic formulations |
US20050196370A1 (en) * | 2003-03-18 | 2005-09-08 | Zhi-Jian Yu | Stable ophthalmic oil-in-water emulsions with sodium hyaluronate for alleviating dry eye |
US20120028910A1 (en) * | 2007-10-08 | 2012-02-02 | Jean-Philippe Combal | Storage-stable aqueous ophthalmic formulations |
US20130108674A1 (en) * | 2010-06-11 | 2013-05-02 | Medivis S.R.L. | Ophthalmic compositions for the administration of liposoluble active ingredients |
US20150352176A1 (en) * | 2014-06-06 | 2015-12-10 | Newport Research, Inc. | Oil-free and fat-free aqueous suspensions of cyclosporin |
KR101635915B1 (ko) * | 2016-02-15 | 2016-07-04 | 삼천당제약주식회사 | 사이클로스포린과 히알루론산 또는 이의 염을 포함하는 수용액 형태의 안과용 조성물 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11090356B2 (en) | 2015-01-15 | 2021-08-17 | Newport Research, Inc. | Aqueous suspensions of cyclosporin |
US11324800B2 (en) | 2015-01-15 | 2022-05-10 | Wellspring Ophthalmics, Inc. | Aqueous suspensions of cyclosporin |
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