AU775832B2 - Ophthalmic composition - Google Patents
Ophthalmic composition Download PDFInfo
- Publication number
- AU775832B2 AU775832B2 AU65655/00A AU6565500A AU775832B2 AU 775832 B2 AU775832 B2 AU 775832B2 AU 65655/00 A AU65655/00 A AU 65655/00A AU 6565500 A AU6565500 A AU 6565500A AU 775832 B2 AU775832 B2 AU 775832B2
- Authority
- AU
- Australia
- Prior art keywords
- composition
- weight
- ketotifen
- glycerol
- composition according
- 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.)
- Expired
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Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
P \OPER\Rdi\2004'J \2484091 in do 30/01/04 -1- OPHTHALMIC COMPOSITION This invention is directed to an ophthalmic composition comprising ketotifen as a pharmaceutically active agent.
An ophthalmic composition comprising ketotifen fumarate is already known, and already on the market. The composition of the present invention is superior compared to the known compositions in that it has a substantially lower dosage of the pharmaceutically active agent. In result said composition combines a high efficacy with a better tolerability.
A further surprising advantage of the composition as disclosed herein is seen in the fact that said composition can be sterilized without any significant decomposition of the pharmaceutically active agent, or other components of the composition.
In one aspect, the present invention provides a method for treating allergic conjunctivitis, comprising administering to a subject suffering from or susceptible to allergic conjunctivitis an effective amount of an ophthalmic composition consisting essentially of a ketotifen salt 15 in a concentration of 0.01 to 0.04 a non-ionic tonicity agent in an amount such that the total tonicity of the composition has an osmolarity in the range of 210 to 290 milliosmoles, optionally a preservative, and water, wherein said composition has a pH of between 4.4 and 5.8.
In a further aspect, the present invention provides for the use of a composition comprising a ketotifen salt in a concentration of 0.01 to 0.04 a non-ionic tonicity agent in an amount such that the total tonicity of the composition has an osmolarity in the range of 210 to 290 milliosmoles, acid or base for bringing the pH to weak acidity, and water in the preparation of a medicament for the treatment or temporary prevention of itching of the eye due to allergic conjunctivitis or the treatment or prevention of seasonal allergic 25 conjunctivitis.
The ophthalmic composition utilises a ketotifen salt in a concentration of 0.01 to 0.04 a non-ionic tonicity agent in an amount such that the total tonicity of the composition has an osmolarity in the range of 210 to 290 milliosmoles, optionally a preservative, and water, wherein said composition has a pH of between 4.4 and 5.8.
The ketotifen salt is preferably ketotifen fumarate. The concentration of the ketotifen salt is preferably 0.03 to 0.04 even more preferred 0.025 The non-ionic tonicity agent is P 'OPER\Rdi\2004\J\24S4091 rc doc-O.301/04 lapreferably glycerol. The non-ionic tonicity agent is preferably present in an amount such that the total tonicity of the composition has an osmolarity in the range of 230 to 260 milliosmoles, more preferred to 235 to 255 milliosmoles. If glycerol is used, the concentration of glycerol is preferably in the range of 1.5 to 2.5 A preservative is present for multi-dose units, but it is routinely not present in single dose units. If a preservative is present, the preferred preservative is benzalkonium chloride. Typically the amount of the preservative is 0.005 to 0.02 more preferred 0.01 An acid or base is used in small amounts, such as 0.05 to 0.1 for adjusting the pH, preferred is the use of small amounts of sodium hydroxide 1N, e.g. 0.075 of such solution. Acid or base may be used for bringing the pH of the composition to weak acidity. The pH of the composition is adjusted to weak acidity for optimization of stability and tolerability, and said pH of weak acidity is understood to mean preferably a pH of 4.4 to 5.8, more preferably a pH of 5 to and most preferably a pH of 5.3. The water present in the composition is typically water for injection.
S
*S *5 *o S *oo •,g *o o WO 01/07049 PCT/EPOO/07030 -2- A preferred composition of this invention comprises ketotifen fumarate, in a concentration of 0.03 to 0.04 glycerol in a concentration of 2 to 2.5 optionally benzalkonium chloride in an amount of 0.005 to 0.02 sodium hydroxide, and water. An even more preferred composition comprises ketotifen fumarate, in a concentration of 0.025 glycerol in a concentration of 2.125 optionally benzalkonium chloride in an amount of 0.01 sodium hydroxide, and water.
The ophthalmic composition of this invention is useful as eye drops, whether as a preserved multi dose unit, or as an unpreserved single dose unit. Said eye drops do have a high therapeutic value because they can be used for the treatment and the temporary prevention of itching of the eye due to allergic conjunctivitis, and they can be used for the treatment and prevention of signs and symptoms of seasonal allergic conjunctivitis.
Despite the low concentration of the pharmaceutically active ingredient, ketotifen fumarate, the recommended dosage is lower than for known ketotifen fumarate preparations. Thus, one drop of the composition of this invention should be applied advantageously two times per day, in contrast to 1 to 2 drops four times a day of the prior art compositions. The fact that the composition of this invention can be applied with an overall very low level of pharmaceutically active ingredient, especially ketotifen fumarate, is one of the surprising findings in the context of this invention. A further finding is that a stabilizer such as for example sodium edetate might be omitted.
Said ophthalmic composition can be manufactured by mixing the ingredients, and packaging the resulting mixture, both as known in the art. Sterilization of the composition and the primary package can be effected e.g. by gamma irradiation, by ethyleneoxide treatment, by electron beam, by autoclaving or by steam sterilization.
Example 1: Multidose Units: Ketotifen fumarate 0.25 mg (0.025 Benzalkonium chloride 0.10 mg (0.010 Glycerol 100 21.25 mg (2.125 Sodium hydroxide 1N about 0.75 mg 0.075 Water for injection ad ad 1.0 ml P OPER\Rdtla\2004jAu244091 rL doc-30/O1/04 -3- Example 2: Single dose Units: Ketotifen fumarate Glycerol 100 Sodium hydroxide 1N Water for injection ad 0.25 mg (0.025 21.25 mg (2.125 about 0.75 mg 0.075 ad 1.0 ml Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Claims (26)
1. An ophthalmic composition consisting essentially of a ketotifen salt in a concentration of 0.01 to 0.04% by weight of the ophthalmic composition, a non-ionic tonicity agent in an amount such that the total tonicity of the composition has an osmolarity in the range of 200 to 290 milliosmoles, optionally a preservative, acid or base such that the composition has a pH of between 4.4 and 5.8 and water.
2. The composition of claim 1 wherein the ketotifen salts is ketotifen fumarate.
3. The composition of claim 1 or 2 where the concentration of the ketotifen salt is 0.03 to 0.04% by weight of the ophthalmic composition.
4. The composition of any one of claims 1 to 3 wherein the non-ionic tonicity agent is glycerol.
The composition of claim 4 wherein the concentration of said glycerol is between and 2.5% by weight of the ophthalmic composition.
6. The composition of any one of claims 1 to 5 wherein a preservative is present.
The composition of claim 6 wherein said preservative is benzalkonium chloride.
8. The composition of any one of claims 1 to 5 wherein said preservative is absent.
S9. The composition of any one of claims 1 to 7 which comprises ketotifen hydrogen fumarate, in a concentration of 0.03 to 0.04%, glycerol in a concentration of from 2 to optionally benzalkonium chloride in an amount of from 0.005 to 0.02%, sodium hydroxide and water.
10. The composition of any one of claims 1 to 9 wherein the ketotifen salt is ketotifen fumarate and the concentration is about 0.0345%. i P \OPERUgc\65655-00 clOns doc-1 3/05
11. The composition according to any one of claims 1 to 10 wherein the non-ionic tonicity agent is glycerol and the composition has an osmolarity of from 238 to 240 milliosmoles.
12. An ophthalmic composition comprising about 0.0345% by weight of ketotifen hydrogen fumarate, and glycerol in an amount such that the composition has an osmolality of from 238 to 240 milliosmoles.
13. The composition according to claim 12 wherein disodium edetate is absent.
14. The composition according to claim 13 wherein chelating agents are absent.
The composition according to any one of claims 12 to 14 wherein the pH is between 5.18 and 5.32.
16. The composition according to any one of claims 12 to 15 wherein said glycerol is about 2.125% by weight.
17. The composition according to any one of claims 12 to 16 further comprising 20 benzalkonium chloride.
"18. The composition according to claim 17 wherein said benzalkonium chloride is S: about 0.01% by weight of the ophthalmic composition. 25
19. The composition according to any one of claims 1 to 18 wherein the amount of degradation products does not exceed 0.23% by weight of the ophthalmic composition.
20. An ophthalmic composition which consists essentially of 0.0345% by weight ketotifen hydrogen fumarate, 2.125% by weight glycerol, 0.01% by weight benzalkonium 30 chloride, 1N sodium hydroxide to adjust the pH to of from 5.18 to 5.32, and water.
21. The method for making an eye drop composition, comprising admixing the non- aqueous components ketotifen hydrogen fumarate, glycerol, and benzalkonium chloride with water such that a final concentration of the non-aqueous components is 0.0345% by P .OPERUVjcS6550 cdlins doc-19 5W4 -6- weight ketotifen hydrogen fumarate, 2.125% by weight glycerol, and 0.01% by weight benzalkonium chloride.
22. The method according to claim 21 wherein the pH of the composition is between 5.18 and 5.32.
23. Use of an ophthalmic composition according to any one of claims 1 to 20 as an eye-drop composition.
24. Use of a composition according to any one of claims 1 to 20 in the preparation of a medicament for use in eye-drop formulations.
Use of a composition according to any one of claims 1 to 20 in the manufacture of a medicament for temporary prevention of itching of the eye due to allergic conjunctivitis or the treatment or prevention of seasonal allergic conjunctivitis.
26. A method for the treatment of temporary prevention of itching of the eye due to allergic conjunctivitis or the treatment or prevention of seasonal allergic conjunctivitis by administering the composition according to any one of claims 1 to 20 to the eye. *o DATED this 19 t h day of May, 2004 Novartis AG 25 by DAVIES COLLISON CAVE Patent Attorneys for the Applicant ooeo
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU65655/00A AU775832B2 (en) | 1998-01-15 | 2000-07-21 | Ophthalmic composition |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98810016 | 1998-01-15 | ||
| AU26169/99A AU742920B2 (en) | 1998-01-15 | 1999-01-13 | Autoclavable pharmaceutical compositions containing a chelating agent |
| EP99114508 | 1999-07-23 | ||
| EP99114508 | 1999-07-23 | ||
| PCT/EP2000/007030 WO2001007049A2 (en) | 1999-07-23 | 2000-07-21 | Ophthalmic composition comprising ketotifen |
| AU65655/00A AU775832B2 (en) | 1998-01-15 | 2000-07-21 | Ophthalmic composition |
Related Parent Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU26169/99A Addition AU742920B2 (en) | 1998-01-15 | 1999-01-13 | Autoclavable pharmaceutical compositions containing a chelating agent |
| AU26169/99A Division AU742920B2 (en) | 1998-01-15 | 1999-01-13 | Autoclavable pharmaceutical compositions containing a chelating agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6565500A AU6565500A (en) | 2001-02-13 |
| AU775832B2 true AU775832B2 (en) | 2004-08-19 |
Family
ID=32870011
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU65655/00A Expired AU775832B2 (en) | 1998-01-15 | 2000-07-21 | Ophthalmic composition |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU775832B2 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999036055A1 (en) * | 1998-01-15 | 1999-07-22 | Novartis Ag | Autoclavable pharmaceutical compositions containing a chelating agent |
-
2000
- 2000-07-21 AU AU65655/00A patent/AU775832B2/en not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999036055A1 (en) * | 1998-01-15 | 1999-07-22 | Novartis Ag | Autoclavable pharmaceutical compositions containing a chelating agent |
Also Published As
| Publication number | Publication date |
|---|---|
| AU6565500A (en) | 2001-02-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |