EP4027977A1 - Pharmaceutical composition of bimatoprost and timolol - Google Patents
Pharmaceutical composition of bimatoprost and 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)
Abstract
A pharmaceutical composition of bimatoprost and timolol for use in lowering an intraocular pressure in a patient is disclosed, which is a preservative -free sterile aqueous solution having the following formula: 0.03 wt % of bimatoprost, 0.5 wt % of timolol, 0.358 wt % of sodium phosphate dibasic dodecahydrate, 0.014 wt % citric acid monohydrate, 0.72 wt % of sodium chloride, water with a pH of 7.3.
Description
Pharmaceutical composition of bimatoprost and timolol
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.
It was observed that the storage conditions of Na2HPC>4 x 7 H2O at the temperature (5-30 °C) and normal air humidity used in the industrial production of pharmaceutical preparations increase the tendency of this component to clump. This adversely affects the efficiency of technological operations during the preparation of the raw material mass, deteriorates the accuracy of its dosing and hinders the dissolution of this substance in the reactor. Adding clumped raw material to the tank extends the preparation process, e.g. dissolution time, and increases the risk of agglomerated raw material fragments being deposited in the mixing vessel dead zones.
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.
Unexpectedly, the above technical problem has been solved by the present invention.
The invention relates to a composition and a method for its preparation as defined in the appended claims.
Preferably, a tonicity agent, such as sodium chloride, 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.
Unexpectedly, it turned out that during storage at normal temperature (5-30 °C) and air humidity, 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.
At the same time, 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).
In the course of work leading to the present invention, it was surprisingly found that the problem of agglomeration of Na2HPC>4 x 7H2O under ordinary storage conditions results from the temperature passing through the peritectic point. When Na2HPC>4 12H2O is heated above about 34 to 35 °C (peritectic temperature), water is released and Na2HPC>4 7H2O is formed. As a result, possible agglomeration of Na2HPC>4 I 2H2O can only take place above this temperature, with partial or full conversion to Na2HP04 7H2O.
The situation is different in the case of Na2HP04 7H2O cooling. The conversion to Na2HPC>4 I 2H2O requires the addition of water. As a result, the phosphate becomes hygroscopic, thereby absorbing moisture from the air. Therefore, the use of Na2HPC>4 7H2O below the peritectic temperature, i.e. at room temperature, leads to its agglomeration. Storage of Na2HPC>4 7H2O to prevent its clumping at room temperature would require complete isolation from water vapor, i.e. a very tight closure. Under normal industrial conditions, when working with an open substance (weighing, dosing process) at room temperature (or lower), the substance absorbs water, which affects both agglomeration and the mass content of pure Na2HPC>4.
Therefore, in industrial practice, the storage and use of Na2HPC>4 I 2H2O is much more advantageous. 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 (Na2HPC>4 2H 0).
To better explain the essence of the invention, it is presented in the following examples.
Example 1. Composition of the medicinal product Bimatoprost + timolol (0.3 mg + 5 mg)/ml, eye drops, solution, no preservatives.
1 a 10% NaOH solution is used, which is prepared just before the pH adjustment in - Water for Injections.
Example 2. Preparation of the finished product.
In the technological process of preparing the pharmaceutical composition according to the invention, 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. Preferably, the pH of the resulting solution is adjusted to 7.3 with NaOH. Preferably, a 10% NaOH solution is used which is prepared just before the pH adjustment.
Claims
1. A pharmaceutical composition of bimatoprost and timolol, for use in reducing intraocular pressure in a patient, characterized in that it is a preservative-free sterile aqueous solution with the following formula: 0.03% w/v of bimatoprost, 0.5% w/v of timolol, 0.358% w/v of sodium phosphate dibasic dodecahydrate, 0.014% w/v of citric acid monohydrate, 0.72% w/v of sodium chloride, water with a pH of 7.3.
2. The composition according to claim 1 , characterized in that the timolol is timolol maleate at a concentration of 0.68% by weight.
3. The composition according to claim 1 or 2, characterized in that the pH of the solution has been adjusted to a value of 7.3 by adding a suitable amount of NaOH to the solution containing dissolved timolol, preferably timolol maleate.
4. The composition according to claim 1 , characterized in that it is intended for the treatment of glaucoma.
5. The composition according to claim 1 , characterized in that it is contained in a unit dose set.
6. The composition according to claim 1 , characterized in that it is to be administered once daily to each eye.
7. The composition according to claim 1 , characterized in that it is a solution contained in a unit dose vial.
8. The composition according to claim 1 , characterized in that it is a solution contained in a multi-dose container.
9. The composition according to claim 8, characterized in that it remains stable for at least 90 days after the container is first opened.
10. The method of obtaining a pharmaceutical composition of bimatoprost and timolol, characterized in that: a) in water at a temperature of 20-30 °C, disodium phosphate dodecahydrate, citric acid monohydrate, sodium chloride are successively dissolved, b) when heated to 30-40 °C, bimatoprost is dissolved, c) after cooling to 20-30 °C, timolol maleate is dissolved.
11. The method according to claim 10, characterized in that the pH of the solution obtained in step c) is adjusted to a pH value of 7.3, preferably with NaOH.
12. The method according to claim 11 , characterized in that a 10% NaOH aqueous solution is used, which is prepared immediately before the pH adjustment.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL431139A PL431139A1 (en) | 2019-09-13 | 2019-09-13 | Pharmaceutical composition of bimatoprost and timolol |
| 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 (en) | 2022-07-20 |
Family
ID=73030187
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP20797887.5A Pending EP4027977A1 (en) | 2019-09-13 | 2020-09-13 | Pharmaceutical composition of bimatoprost and timolol |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP4027977A1 (en) |
| PL (1) | PL431139A1 (en) |
| WO (1) | WO2021049963A1 (en) |
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 (en) * | 2023-01-16 | 2023-04-25 | 广州楷石医药有限公司 | Pharmaceutical composition for treating glaucoma or ocular hypertension and use thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2807081C (en) * | 2010-07-29 | 2018-09-18 | Allergan, Inc. | Preservative free bimatoprost and timolol solutions |
| GR1009006B (en) * | 2016-04-01 | 2017-04-04 | Φαρματεν Ανωνυμος Βιομηχανικη Και Εμπορικη Εταιρεια Φαρμακευτικων Ιατρικων Και Καλλυντικων Προϊοντων | Preservative free pharmaceutical composition for ophthalmic administration containing bimatoprost and timolol |
| CN108236721A (en) * | 2016-12-26 | 2018-07-03 | 上海创诺医药集团有限公司 | A kind of bevacizumab preparation of stabilization |
-
2019
- 2019-09-13 PL PL431139A patent/PL431139A1/en unknown
-
2020
- 2020-09-13 EP EP20797887.5A patent/EP4027977A1/en active Pending
- 2020-09-13 WO PCT/PL2020/050066 patent/WO2021049963A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021049963A1 (en) | 2021-03-18 |
| PL431139A1 (en) | 2021-03-22 |
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