WO2021049963A1 - Pharmaceutical composition of bimatoprost and timolol - Google Patents
Pharmaceutical composition of bimatoprost and timolol Download PDFInfo
- Publication number
- WO2021049963A1 WO2021049963A1 PCT/PL2020/050066 PL2020050066W WO2021049963A1 WO 2021049963 A1 WO2021049963 A1 WO 2021049963A1 PL 2020050066 W PL2020050066 W PL 2020050066W WO 2021049963 A1 WO2021049963 A1 WO 2021049963A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- timolol
- composition according
- bimatoprost
- solution
- dissolved
- Prior art date
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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.
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP20797887.5A EP4027977A1 (en) | 2019-09-13 | 2020-09-13 | Pharmaceutical composition of bimatoprost and timolol |
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 |
| PLP.431139 | 2019-09-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2021049963A1 true WO2021049963A1 (en) | 2021-03-18 |
Family
ID=73030187
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL2020/050066 WO2021049963A1 (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) |
Cited By (1)
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012015998A2 (en) * | 2010-07-29 | 2012-02-02 | Allergan, Inc. | Preservative free bimatoprost and timolol solutions |
| WO2017167457A1 (en) * | 2016-04-01 | 2017-10-05 | Pharmathen S.A. | 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
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012015998A2 (en) * | 2010-07-29 | 2012-02-02 | Allergan, Inc. | Preservative free bimatoprost and timolol solutions |
| WO2017167457A1 (en) * | 2016-04-01 | 2017-10-05 | Pharmathen S.A. | 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 |
Cited By (1)
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| PL431139A1 (en) | 2021-03-22 |
| EP4027977A1 (en) | 2022-07-20 |
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