EP4027977A1 - Pharmazeutische zusammensetzung von bimatoprost und timolol - Google Patents
Pharmazeutische zusammensetzung von bimatoprost und timololInfo
- Publication number
- EP4027977A1 EP4027977A1 EP20797887.5A EP20797887A EP4027977A1 EP 4027977 A1 EP4027977 A1 EP 4027977A1 EP 20797887 A EP20797887 A EP 20797887A EP 4027977 A1 EP4027977 A1 EP 4027977A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- timolol
- composition according
- bimatoprost
- solution
- dissolved
- 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.)
- Pending
Links
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 title claims abstract description 14
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical group CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 title claims abstract description 14
- 229960002470 bimatoprost Drugs 0.000 title claims abstract description 14
- 229960004605 timolol Drugs 0.000 title claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000011780 sodium chloride Substances 0.000 claims abstract description 6
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960002303 citric acid monohydrate Drugs 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 claims abstract description 4
- 230000004410 intraocular pressure Effects 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 claims description 4
- 229960005221 timolol maleate Drugs 0.000 claims description 4
- 238000010979 pH adjustment Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 208000010412 Glaucoma Diseases 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 abstract description 5
- 230000002335 preservative effect Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 10
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 238000005054 agglomeration Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000006172 buffering agent Substances 0.000 description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 2
- PYLIXCKOHOHGKQ-UHFFFAOYSA-L disodium;hydrogen phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O PYLIXCKOHOHGKQ-UHFFFAOYSA-L 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000002997 ophthalmic solution Substances 0.000 description 2
- 229940054534 ophthalmic solution Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 230000001131 transforming effect Effects 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000004683 dihydrates Chemical group 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- 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
- A61K9/08—Solutions
Definitions
- the present invention relates to a pharmaceutical composition of bimatoprost and timolol, for use in the reduction of intraocular pressure in a patient, which is a preservative-free sterile aqueous solution, and a method of its preparation.
- European patent EP 2 598 118 B1 discloses an ophthalmic solution of bimatoprost and timolol without preservatives, being an isotonic and sterile solution.
- the active substances are bimatoprost and timolol.
- the inactive ingredients are toning and buffering agents and purified water.
- the known preparation contains sodium phosphate dibasic heptahydrate (Na2HPC>4 x 7 H2O) and citric acid monohydrate as buffering agents, and sodium chloride as a tonicity adjusting agent.
- the object of the invention is to overcome the problems observed in the preparation of the prior art formulation which result from the tendency of sodium phosphate dibasic heptahydrate (Na2HPC>4 x 7 H2O) to clump.
- the invention relates to a composition and a method for its preparation as defined in the appended claims.
- a tonicity agent such as sodium chloride
- a tonicity agent such as sodium chloride
- a tonicity agent will be used in an amount to provide a final osmotic value of at least about 200 mOsm/kg, preferably from about 270 to about 320 mOsm/kg.
- the essence of the invention is related to the use of Na2HP04 x 12 H2O as one of the buffering agents included in the pharmaceutical preparation which is an ophthalmic solution of bimatoprost and timolol without preservatives.
- the buffering component proposed according to the invention i.e. Na2HPC>4 x I 2H2O, does not clump, which completely avoids the above-described problems observed during the industrial production of the preparation in question.
- the preparation according to the invention has other advantages.
- the preparation according to the invention is an eye drop product without preservatives, being a sterile solution that remains stable in a multi-dose container (for at least 90 days after opening the container).
- Na2HPC>4 I 2H2O is stable at temperatures up to 34 °C, above which it dehydrates, transforming into Na2HPC>4 7H2O, which is stable at temperatures up to 48 °C, above which it dehydrates, transforming into the dihydrate form (Na 2 HPC>4 2H 0).
- Example 1 Composition of the medicinal product Bimatoprost + timolol (0.3 mg + 5 mg)/ml, eye drops, solution, no preservatives.
- the order of adding the raw materials and maintaining the appropriate dissolution temperature is important, which allows to obtain the optimal dissolution time while obtaining appropriate osmolality and pH parameters of the solution.
- Disodium phosphate dodecahydrate, citric acid monohydrate, sodium chloride are dissolved successively in water at a temperature of 20-30 °C. Then, when heated to 30-40 ° C, bimatoprost is dissolved. Finally, when cooled to 20-30 °C, timolol maleate is dissolved.
- the pH of the resulting solution is adjusted to 7.3 with NaOH.
- a 10% NaOH solution is used which is prepared just before the pH adjustment.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL431139A PL431139A1 (pl) | 2019-09-13 | 2019-09-13 | Kompozycja farmaceutyczna bimatoprostu i tymololu |
| PCT/PL2020/050066 WO2021049963A1 (en) | 2019-09-13 | 2020-09-13 | Pharmaceutical composition of bimatoprost and timolol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP4027977A1 true EP4027977A1 (de) | 2022-07-20 |
Family
ID=73030187
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP20797887.5A Pending EP4027977A1 (de) | 2019-09-13 | 2020-09-13 | Pharmazeutische zusammensetzung von bimatoprost und timolol |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP4027977A1 (de) |
| PL (1) | PL431139A1 (de) |
| WO (1) | WO2021049963A1 (de) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024003078A1 (en) * | 2022-06-27 | 2024-01-04 | Warszawskie Zaklady Farmaceutyczne Polfa Sa | Preservative-free ophthalmic composition comprising a prostaglandin analogue |
| CN115998888A (zh) * | 2023-01-16 | 2023-04-25 | 广州楷石医药有限公司 | 用于治疗青光眼或高眼压症的药物组合物及其用途 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL2598118T3 (pl) * | 2010-07-29 | 2019-01-31 | Allergan, Inc. | Roztwory bimatoprost i tymolol bez środków konserwujących |
| GR1009006B (el) * | 2016-04-01 | 2017-04-04 | Φαρματεν Ανωνυμος Βιομηχανικη Και Εμπορικη Εταιρεια Φαρμακευτικων Ιατρικων Και Καλλυντικων Προϊοντων | Φαρμακευτικο σκευασμα ελευθερο συντηρητικου για οφθαλμικη χρηση περιεχον βιματοπροστη και τιμολολη |
| CN108236721A (zh) * | 2016-12-26 | 2018-07-03 | 上海创诺医药集团有限公司 | 一种稳定的贝伐单抗制剂 |
-
2019
- 2019-09-13 PL PL431139A patent/PL431139A1/pl unknown
-
2020
- 2020-09-13 WO PCT/PL2020/050066 patent/WO2021049963A1/en unknown
- 2020-09-13 EP EP20797887.5A patent/EP4027977A1/de active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| PL431139A1 (pl) | 2021-03-22 |
| WO2021049963A1 (en) | 2021-03-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20190010149A1 (en) | Sustained-release formulation for injection | |
| DE60006262T2 (de) | Topische suspensionsformulierungen enthaltend ciprofloxacin und dexamethason | |
| EP4027977A1 (de) | Pharmazeutische zusammensetzung von bimatoprost und timolol | |
| SK337492A3 (en) | Pharmaceutical preparations on base of plant curcuma longa | |
| JPH0128757B2 (de) | ||
| CN101991589B (zh) | 一种甘油果糖注射液及其制备方法 | |
| WO2013144814A1 (en) | Stable ready-to-use pharmaceutical composition of pemetrexed | |
| JP7494230B2 (ja) | 無菌眼用水性プロピオン酸フルチカゾンａ型ナノ結晶懸濁液の調製方法 | |
| EP0233615B1 (de) | Wässriges Präparat und Verfahren zu dessen Herstellung | |
| JP2916340B2 (ja) | ナトリウムクロモグリケートの水性医薬組成物 | |
| JP4757970B2 (ja) | 点眼剤組成物 | |
| JP2019019075A (ja) | ペメトレキセド含有液状医薬組成物 | |
| JP2809971B2 (ja) | 血液透析用製剤 | |
| EP0338670B1 (de) | Pharmazeutische Mischungen | |
| WO2007143895A1 (fr) | Solution supersaturée de chlorhydrate de gemcitabine et son procédé de préparation | |
| US4534911A (en) | Method for the preparation of p-butoxyphenylacetyl-hydroxamic acid in the finely divided state and a composition containing this acid | |
| WO1993023032A1 (en) | Remedy for cataract and production thereof | |
| CN111789827A (zh) | 一种硫酸依替米星雾化吸入用制剂及其制备方法 | |
| CN110898039A (zh) | 一种吸入用盐酸左旋沙丁胺醇溶液制剂及其制备方法 | |
| WO2011027365A9 (en) | Ophthalmic compositions containing dorzolamide, timolol and brimonidine | |
| US3322627A (en) | Method of treating herpes simplex infections with 5-methylamino-2'-deoxyuridine, and compositions therefor | |
| CN114668762B (zh) | 一种药物组合物 | |
| WO2023036227A1 (zh) | 阿托品滴眼液及其制备方法 | |
| JPH08104642A (ja) | ヒアルロン酸ナトリウム注射液用安定化組成物 | |
| HU228757B1 (en) | Pharmaceutical compositions containing piperidine derivatives as platelet aggregation inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
| 17P | Request for examination filed |
Effective date: 20220413 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
| DAV | Request for validation of the european patent (deleted) | ||
| DAX | Request for extension of the european patent (deleted) | ||
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
| 17Q | First examination report despatched |
Effective date: 20240430 |