WO1994015597A1 - Ophthalmic compositions comprising benzyllauryldimethylammonium chloride - Google Patents
Ophthalmic compositions comprising benzyllauryldimethylammonium chloride Download PDFInfo
- Publication number
- WO1994015597A1 WO1994015597A1 PCT/US1994/000188 US9400188W WO9415597A1 WO 1994015597 A1 WO1994015597 A1 WO 1994015597A1 US 9400188 W US9400188 W US 9400188W WO 9415597 A1 WO9415597 A1 WO 9415597A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chloride
- present
- ophthalmic solution
- lauralkonium
- solution
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title abstract description 19
- JBIROUFYLSSYDX-UHFFFAOYSA-M benzododecinium chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 JBIROUFYLSSYDX-UHFFFAOYSA-M 0.000 title description 2
- IBNQLYMPUGQNLN-UHFFFAOYSA-M benzyl-[2-(4-dodecanoylphenoxy)ethyl]-dimethylazanium;chloride Chemical compound [Cl-].C1=CC(C(=O)CCCCCCCCCCC)=CC=C1OCC[N+](C)(C)CC1=CC=CC=C1 IBNQLYMPUGQNLN-UHFFFAOYSA-M 0.000 claims abstract description 26
- 229950007325 lauralkonium chloride Drugs 0.000 claims abstract description 26
- 229960000686 benzalkonium chloride Drugs 0.000 claims abstract description 23
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 239000002997 ophthalmic solution Substances 0.000 claims abstract description 17
- 229940054534 ophthalmic solution Drugs 0.000 claims abstract description 15
- 230000002378 acidificating effect Effects 0.000 claims abstract description 12
- 239000003755 preservative agent Substances 0.000 claims abstract description 11
- 230000002335 preservative effect Effects 0.000 claims abstract description 10
- 239000013583 drug formulation Substances 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 20
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- AUAGTGKMTMVIKN-UHFFFAOYSA-M sodium;2-(3-fluoro-4-phenylphenyl)propanoate Chemical compound [Na+].FC1=CC(C(C([O-])=O)C)=CC=C1C1=CC=CC=C1 AUAGTGKMTMVIKN-UHFFFAOYSA-M 0.000 claims description 7
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 claims description 4
- 239000001103 potassium chloride Substances 0.000 claims description 4
- 235000011164 potassium chloride Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 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 description 3
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- 229960000999 sodium citrate dihydrate Drugs 0.000 claims description 3
- 229910001868 water Inorganic materials 0.000 claims description 3
- 238000009472 formulation Methods 0.000 abstract description 7
- 230000000845 anti-microbial effect Effects 0.000 abstract description 5
- 150000002500 ions Chemical class 0.000 abstract description 5
- 230000003993 interaction Effects 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 4
- 229960002390 flurbiprofen Drugs 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- 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
Definitions
- the present invention generally relates to improved ophthalmic formulations and solutions and more particularly to improved preservative systems for ophthalmologically acceptable drug formulations which have 0 an incompatibility with benzalkonium chloride. More specifically, the present invention pertains to the preservative for an anti-inflammatory drug such as sodium flurbiprofen (Ocufer ).
- an anti-inflammatory drug such as sodium flurbiprofen (Ocufer ).
- Benzalkonium chloride is a mixture of alkyldimethylbenzyl- ammonium chloride of the general formula as shown below in which R represents a mixture of the alkyls from CgH j ⁇ to C j gH ⁇
- the present invention specifically relates to the discovery that a particular member of a group of compounds, generally known as benzalkonium chloride, exhibits properties totally different from other members of the group and different from the gross properties of the mixture known as benzalkonium chloride.
- Table 1 shows the ingredients for Examples A and B, with the formulations being identical, except that Example A utilizes benzalkonium chloride and Example B utilizes lauralkonium chloride in the same amounts, i.e., 0.005%, by weight per volume.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
An ophthalmic solution generally includes an ophthalmologically acceptable drug formulation incompatible with benzalkonium chloride and lauralkonium chloride present in an anti-microbially effective amount. The incompatibility of the ophthalmologically acceptable drug manifests itself by forming insoluble ion pairs with the benzalkonium chloride. It has been found that lauralkonium chloride which is the C12 homolog of benzalkonium chloride is effective as a preservative without apparent interaction with the acidic ophthalmologically acceptable drug and formulations maintain their antimicrobial efficiency over periods of up to one year or more.
Description
OPHTHALMIC COMPOSITIONS COMPRISING BENZYLLAURYLDIMETHYLAMMONIUM CHLORIDE
The present invention generally relates to improved ophthalmic formulations and solutions and more particularly to improved preservative systems for ophthalmologically acceptable drug formulations which have 0 an incompatibility with benzalkonium chloride. More specifically, the present invention pertains to the preservative for an anti-inflammatory drug such as sodium flurbiprofen (Ocufer ).
Ophthalmologically acceptable drug formulations generally contain 5 effective compounds and a number of ophthalmologically acceptable excip- ients. Such excipients generally include solutions, ointments, and suspensions, etc. More specifically, such excipients include stabilizing agents, surfactants, buffering systems, chelating systems, viscosity agents, and, importantly, a preservative. 0
Ophthalmic formulations, understandably, must be sterile and if a multi-dose regime is intended, the formulation must be preserved with an effective antimicrobial agent.
5 As discussed in U.S. Patent No. 5,110,493, organo-mercurials have been used extensively as the preservatives in ophthalmic solutions. As reported in this reference, these compounds pose difficulties due to potential mercury toxicity as well as poor chemical stability.
Therefore, benzalkonium chloride, which is a quaternary ammonium compound, has been widely used in ophthalmic solutions. It is also well- known, however, that benzalkonium chloride is considered incompatible with anionic drugs, forming insoluble compounds which cause the solution to turn cloudy.
This is because of the fact that many acidic drug entities carry a negative charge at physiological pH. In fact, all acidic drug entities will carry a negative charge at all pH above their pKa.
In the case of benzalkonium chloride, which is a positively charged preservative, ion pairs can be formed with negatively charged drug compounds, forming an insoluble ion pair which causes the drug to precipitate out of solution. Concomitant with the removal of the drug from solution is the removal of benzalkonium chloride, thereby rendering this quaternary germicide incapable of performing its function as an antimicrobial agent.
Benzalkonium chloride is a mixture of alkyldimethylbenzyl- ammonium chloride of the general formula as shown below in which R represents a mixture of the alkyls from CgHjγ to CjgH γ
As hereinbefore noted, it is well-known that benzalkonium chloride is generally incompatible with anionic detergents or anionic drug compounds.
See U.S. Patent No. 5,110,493, and The Merck Index. 11th Edition, Merck & Co., Inc., 1989.
The present invention specifically relates to the discovery that a particular member of a group of compounds, generally known as benzalkonium chloride, exhibits properties totally different from other members of the group and different from the gross properties of the mixture known as benzalkonium chloride.
This discovery by the applicant must be taken in the context that all compositions are made of the same substances, retaining their fixed chemical properties. The elements are capable of an infinity of permutations, and selection of that group or element of a group which proves serviceable to a given need requires a high degree of originality. This general premise relates to the invention at hand. The applicant has discovered that lauralkonium chloride, which is the C^ homolog of benzalkomum chloride, is compatible with acidic drug entities with apparently no insoluble ion pairs being formed therewith. This is contrary to the properties of the mixture of alkyldimethylbenzylammonium chloride, known as benzalkonium chloride, which includes a mixture of the alkyls from CgHjγ to CjgHjγ.
SUMMARY OF THE INVENTION
An ophthalmic solution, in accordance with the present invention, generally includes an ophthalmologically acceptable drug formulation incompatible with benzalkonium chloride and lauralkonium chloride present in an antimicrobially effective amount. More specifically, flurbiprofen is an example of an acidic drug that forms an insoluble ion-
pair with benzalkonium chloride. However, when combined with lauralkonium chloride, no apparent insoluble ion pairs are formed.
More particularly, in accordance with the present invention, the ophthalmic solution may further include citric acid monohydrate, sodium citrate dihydrate, polyvinyl alcohol, edetate disodium dihydrate, sodium chloride, potassium chloride and water.
The amount of lauralkonium chloride is any antimicrobially effective amount and preferably may be up to about 0.005% by weight per volume of the solution, and the amount of sodium flurbiprofen may be present in any effective amount and preferably about 0.03% by weight per volume.
The combination of lauralkonium chloride is further emphasized in that it can be combined with an acidic ophthalmologically acceptable drug formulation having a negative charge at physiological pH, and further the fact that the acidic ophthalmologically acceptable drug is capable of forming an insoluble ion-pair with benzalkonium chloride, no apparent insoluable ion-pairs are produced when the drug is in combination with lauralkonium chloride, taken itself.
Further, the invention includes a method for preserving an acidic ophthalmologically acceptable drug solution, comprising adding to the ophthalmologically acceptable drug solution an antimicrobially effective amount of lauralkonium chloride.
DETAILED DESCRIPTION
Flurbiprofen is a classic example of an acidic drug that forms an insoluble ion-pair with benzalkonium chloride. It has been discovered that this interaction (insoluble ion-pair formation) can be overcome by formulating the flurbiprofen with the Cj2 homolog of benzalkomum chloride and lauralkonium chloride.
The lauralkonium chloride utilized will comprise at least 95% and preferably about 97.8% of the C/ homolog, 1.5% of the CJ homolog, and 0.7% of the C^ homolog.
The following examples, illustrating the utility of lauralkonium chloride as opposed to benzalkonium chloride, include the preparation or compounding of flurbiprofen formulations as follows.
Compounding occurs in two parts:
Part 1: Disperse polyvinyl alcohol in rapidly stirring purified water and heat to 85° C. Maintain temperature and stirring for one hour to dissolve the polyvinyl alcohol.
Part 2: While mixing a bulk of purified water of at least 50% of the final lot volume, add edetate disodium, benzalkonium chloride or lauralkonium chloride, potassium chloride, sodium chloride, sodium citrate and citric acid allowing each to dissolve or mix well before adding the next. Adjust the pH to 6.4-6.6 with dilute sodium hydroxide and/or hydrochloric acid. Add sodium flurbiprofen to the bulk and mix well.
While mixing Part 2, add Part 1 and mix thoroughly. Adjust the pH to 6.4-6.6 with dilute sodium hydroxide and/or hydrochloric acid. Sterilize the lot by filtration (0.22μ) and aseptically fill units into pre-sterilized containers.
The benzalkonium chloride and the lauralkonium chloride utilized in the present examples were obtained from E.M. Industries, Inc. of Hawthorne, NY and Triple Crown Ammerica, Inc. of Perkasie, PA, respectively.
Example
Table 1 shows the ingredients for Examples A and B, with the formulations being identical, except that Example A utilizes benzalkonium chloride and Example B utilizes lauralkonium chloride in the same amounts, i.e., 0.005%, by weight per volume.
TABLE 1
OCULEN® FORMULATIONS
Example A results in a cloudy solution with precipitate and loss of antimicrobial efficacy while Example B remains as a solution and the solution maintains its antimicrobial efficacy. Example A failed to pass the preservative effectiveness test as described in the British Pharmacopeia while Example B passes the British Pharmacopieia preservative effectiveness test.
In addition, the ability of lauralkonium chloride to stay in solution and to maintain its antimicrobial effectiveness as a function of time was also monitored. Table 2 shows the concentration of lauralkonium chloride in the formulation described in Example B. Table 3 shows the ability of lauralkonium chloride to maintain its antimicrobial efficacy over a period of up to one year or more.
TABLE 2
TABLE 3
Although there has been hereinabove described a specific ophthalmic solution and method in accordance with the present invention, for the purpose of illustrating the manner in which the invention may be used to advantage, it should be appreciated that the invention is not limited thereto. Accordingly, any and all modifications, variations, or equivalent arrangements which may occur to those skilled in the art, should be considered to be within the scope of the present invention as defined in the appended claims.
Claims
1. An ophthalmic solution comprising: an ophthalmologically acceptable drug formulation incompatible with benzalkonium chloride; and a preservative consisting essentially of lauralkonium chloride and present in an antimicrobially effective amount.
2. The ophthalmic solution according to Claim 1 wherein said ophthalmologically acceptable drug formulation comprises sodium flurbiprofen.
3. The ophthalmic solution according to claim 2 further comprising citric acid monohydrate, sodium citrate dihydrate, polyvinyl alcohol, edetate disodium dihydrate, sodium chloride, potassium chloride, and water.
4. The ophthalmic solution according to Claims 1, 2 or 3 wherein said lauralkonium chloride is present in an amount up to about 0.005% by weight per volume of the solution.
5. The ophthalmic solution according to claim 2 or 3 wherein the sodium flurbiprofen is present in an amount up to about 0.03% by weight per volume of the solution and the lauralkonium chloride is present in an amount up to about 0.005% by volume of the solution.
6. An ophthalmic solution comprising: an acidic ophthalmologically acceptable drug formulation having a negative charge at physiological pH; and a preservative consisting essentially of lauralkonium chloride and present in an antimicrobially effective amount.
7. The ophthalmic solution according to Claim 6 wherein said ophthalmologically acceptable drug formulation comprises sodium flurbiprofen.
8. The ophthalmic solution according to Claim 7 further comprising citric acid monohydrate, sodium citrate dihydrate, polyvinyl alcohol, edetate disodium dihydrate, sodium chloride, potassium chloride, and water.
9. The ophthalmic solution according to Claims 6, 7 or 8 wherein said lauralkonium chloride is present in an amount up to about 0.005% by weight per volume of the solution.
10. The ophthalmic solution according to Claim 7 or 8 wherein the sodium flurbiprofen is present in an amount up to about 0.03% by weight per volume of the solution and the lauralkonium chloride is present in an amount up to about 0.005% by volume of the solution.
11. A method for preserving an acidic ophthalmically acceptable drug solution comprising adding to said ophthalmically acceptable drug solution an antimicrobially effective amount of lauralkonium chloride.
12. An ophthalmic solution comprising: an acidic ophthalmologically acceptable drug capable of forming an insoluble ion-pair with benzalkonium chloride; and a preservative consisting essentially of lauralkonium chloride and present in an antimicrobially effective amount.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU60217/94A AU6021794A (en) | 1993-01-11 | 1994-01-06 | Ophthalmic compositions comprising benzyllauryldimethylammonium chloride |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US310793A | 1993-01-11 | 1993-01-11 | |
| US08/003,107 | 1993-01-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994015597A1 true WO1994015597A1 (en) | 1994-07-21 |
Family
ID=21704192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1994/000188 WO1994015597A1 (en) | 1993-01-11 | 1994-01-06 | Ophthalmic compositions comprising benzyllauryldimethylammonium chloride |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU6021794A (en) |
| WO (1) | WO1994015597A1 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996014829A1 (en) * | 1994-11-16 | 1996-05-23 | Alcon Laboratories, Inc. | Preserved ophthalmic drug compositions containing polymeric quaternary ammonium compounds |
| US5558876A (en) * | 1995-03-29 | 1996-09-24 | Alcon Laboratories, Inc. | Topical ophthalmic acidic drug formulations |
| WO2000064429A1 (en) * | 1999-04-22 | 2000-11-02 | Dr. Gerhard Mann Chem.-Pharm. Fabrik Gmbh | Pharmaceutical composition effective against pathological conditions caused by bacteria, viruses, fungi, yeasts and protozoa |
| US6599944B1 (en) * | 1996-04-15 | 2003-07-29 | Bausch & Lomb Incorporated | Ophtalmic compound with extended dwell time on the eye |
| WO2005102303A3 (en) * | 2004-04-21 | 2006-08-24 | Advanced Ocular Systems Ltd | Antiprostaglandins for the treatment of ocular pathologies |
| US8871813B2 (en) | 2003-01-21 | 2014-10-28 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| WO2019118928A1 (en) * | 2017-12-15 | 2019-06-20 | Tarsus Pharmaceuticals, Inc. | Isoxazoline parasiticide formulations and methods for treating blepharitis |
| US12257263B2 (en) | 2014-08-04 | 2025-03-25 | Tarsus Pharmaceuticals, Inc. | Pharmaceutical compositions for demodex related blepharitis and eyelid crusting |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57102817A (en) * | 1980-12-18 | 1982-06-26 | Kaken Pharmaceut Co Ltd | Antiphlogistic ophthalmologic agent |
| JPH01246227A (en) * | 1988-03-28 | 1989-10-02 | Santen Pharmaceut Co Ltd | Prevention of incompatibility of compounding of aqueous preparation containing benzalkonium chloride |
-
1994
- 1994-01-06 WO PCT/US1994/000188 patent/WO1994015597A1/en active Application Filing
- 1994-01-06 AU AU60217/94A patent/AU6021794A/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57102817A (en) * | 1980-12-18 | 1982-06-26 | Kaken Pharmaceut Co Ltd | Antiphlogistic ophthalmologic agent |
| JPH01246227A (en) * | 1988-03-28 | 1989-10-02 | Santen Pharmaceut Co Ltd | Prevention of incompatibility of compounding of aqueous preparation containing benzalkonium chloride |
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 112, no. 16, 16 April 1990, Columbus, Ohio, US; abstract no. 145590h * |
| DATABASE WPI Week 8231, Derwent World Patents Index; AN 82-64749E (31) * |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996014829A1 (en) * | 1994-11-16 | 1996-05-23 | Alcon Laboratories, Inc. | Preserved ophthalmic drug compositions containing polymeric quaternary ammonium compounds |
| US5603929A (en) * | 1994-11-16 | 1997-02-18 | Alcon Laboratories, Inc. | Preserved ophthalmic drug compositions containing polymeric quaternary ammonium compounds |
| US5653972A (en) * | 1994-11-16 | 1997-08-05 | Alcon Laboratories, Inc. | Preserved ophthalmic drug compositions containing polymeric quaternary ammonium compounds |
| AU686917B2 (en) * | 1994-11-16 | 1998-02-12 | Alcon Laboratories, Inc. | Preserved ophthalmic drug compositions containing polymeric quaternary ammonium compounds |
| US5558876A (en) * | 1995-03-29 | 1996-09-24 | Alcon Laboratories, Inc. | Topical ophthalmic acidic drug formulations |
| WO1996030022A1 (en) * | 1995-03-29 | 1996-10-03 | Alcon Laboratories, Inc. | Topical ophthalmic formulations comprising an acidic drug, vitamin e tpgs, benzalkonium chloride and caffeine |
| US6599944B1 (en) * | 1996-04-15 | 2003-07-29 | Bausch & Lomb Incorporated | Ophtalmic compound with extended dwell time on the eye |
| WO2000064429A1 (en) * | 1999-04-22 | 2000-11-02 | Dr. Gerhard Mann Chem.-Pharm. Fabrik Gmbh | Pharmaceutical composition effective against pathological conditions caused by bacteria, viruses, fungi, yeasts and protozoa |
| US9561277B2 (en) | 2003-01-21 | 2017-02-07 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US8871813B2 (en) | 2003-01-21 | 2014-10-28 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US8927606B1 (en) | 2003-01-21 | 2015-01-06 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US9144609B2 (en) | 2003-01-21 | 2015-09-29 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| WO2005102303A3 (en) * | 2004-04-21 | 2006-08-24 | Advanced Ocular Systems Ltd | Antiprostaglandins for the treatment of ocular pathologies |
| US12257263B2 (en) | 2014-08-04 | 2025-03-25 | Tarsus Pharmaceuticals, Inc. | Pharmaceutical compositions for demodex related blepharitis and eyelid crusting |
| US11690826B2 (en) | 2017-12-15 | 2023-07-04 | Tarsus Pharmaceuticals, Inc. | Methods for treating demodex blepharitis using lotilaner formulations |
| US10835517B2 (en) | 2017-12-15 | 2020-11-17 | Tarsus Pharmaceuticals, Inc. | Methods for treating ocular demodex using isoxazoline parasiticide formulations |
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