WO2009006130A2 - Salt free hyaluronate ophthalmic solution - Google Patents

Salt free hyaluronate ophthalmic solution Download PDF

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Publication number
WO2009006130A2
WO2009006130A2 PCT/US2008/068090 US2008068090W WO2009006130A2 WO 2009006130 A2 WO2009006130 A2 WO 2009006130A2 US 2008068090 W US2008068090 W US 2008068090W WO 2009006130 A2 WO2009006130 A2 WO 2009006130A2
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WIPO (PCT)
Prior art keywords
composition
agent
salt
amount
weight
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Application number
PCT/US2008/068090
Other languages
French (fr)
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WO2009006130A3 (en
Inventor
Srini Venkatesh
Erning Xia
Original Assignee
Bausch & Lomb Incorporated
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Publication of WO2009006130A2 publication Critical patent/WO2009006130A2/en
Publication of WO2009006130A3 publication Critical patent/WO2009006130A3/en

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • 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 relates to an ophthalmic composition in the form of a topical aqueous solution for human and veterinary use.
  • polymers alone or in combination with other polymers for the preparation of ophthalmic pharmaceuticals and artificial tear compositions.
  • the inclusion of the polymer aims at increasing the viscosity of the composition so as to provide for a longer contact time with the cornea of the eye, and, for example, in connection with ophthalmic drugs, to provide for a sustained release of the drug into the eye.
  • the U.S. Pat. Nos. 5,710,182 and 5,795,913 relate to ophthalmic compositions having decreased viscosity while still maintaining high polymer concentration.
  • the prior art teaches the use of inorganic salts and buffers to obtain desirable viscosity and maintain pH during storage and use. We have discovered certain salt and buffer free formulations have desirable viscosity and pH stability during storage.
  • the present invention thus provides a salt and buffer free ophthalmological composition in a liquid, easy-to-use form which contains a sufficient amount of polymer to provide for both an increased and prolonged absorption of active agent into the eye.
  • a stabilized, topical ophthalmic Levofloxacin composition wherein the improvement comprises a salt and buffer free composition.
  • a stabilized, topical ophthalmic Taurine composition wherein the improvement comprises a salt and buffer free composition.
  • a stabilized, topical ophthalmic Chloramphenicol composition wherein the improvement comprises a salt and buffer free composition.
  • a stabilized, topical ophthalmic Chondroitin Sulfate composition wherein the improvement comprises a salt and buffer free composition.
  • a stabilized, topical ophthalmic Dexamethasone and Neomycin composition wherein the improvement comprises a salt and buffer free composition.
  • a stabilized, topical ophthalmic Naphazoline and Chlorpheniramine composition wherein the improvement comprises a salt and buffer free composition.
  • a stabilized, topical ophthalmic Acyclovir composition wherein the improvement comprises a salt and buffer free composition.
  • the ion-sensitive hydrophilic polymer to be used according to the invention is typically hyaluronic acid.
  • Other ion sensitive polymers such as the polyacrylate elastomers commercially available as Carbopol would also be suitable according to the invention herein.
  • Other suitable ion sensitive polymers would be obvious to those of ordinary skill in the art.
  • the polymer is preferably used in an amount of 0.01 to 0.8. more preferably 0.01 to 0.4, and advantageously 0.04 to 0.4% by weight.
  • the pH of the composition is suitably from 5.0 to 8, preferably from 6.5 to 8.0.
  • a base as the active agent
  • the pH of the composition can be regulated by the amounts used of acidic polymer and basic active agent respectively.
  • the pH of the composition may be adjusted also by adding an additional base or an acid, as the case may be, such as an alkali metal hydroxide, especially sodium hydroxide, or ammonium hydroxide, or e.g. hydrochloric acid.
  • the ophthalmologically active agent is advantageously an antibiotic agent, anti-viral agent, anti-retroviral agent, antiglaucoma agent, nutrients, mucopolysaccharides, a sympathomimetic agent, a sympatholytic agent, such as a beta-blocker, a carbonic anhydrase inhibitor, antiinflammatory, adrenergic, antiallergic agent, etc., or a combination thereof.
  • the amount of active agent in the final composition may vary, such as between 0.001 to 7% by weight, usually however between 0.01 to 0.5% by weight, and typically between 0.1 and 0.5% by weight.
  • the composition contains in addition, in order to enhance the wetting effect thereof, a wetting agent, preferably a polyhydric alcohol, such as glycerol.
  • a wetting agent preferably a polyhydric alcohol, such as glycerol.
  • the amount of wetting agent is generally at the most 3.0%, such as of the order of 0.5 to 3.0% by weight.
  • preservatives e.g. benzalkonium bromide, benzalkonium chloride, benzyl alcohol, mercury salts, thimerosal, chlorhexidine or the like, as such or in combination.
  • the amount of preservative usually lies in the range of 0 to 0.03% by weight.
  • Viscosity was determined according to the method set forth in the 2005 Chinese Pharmacopeia using an Ostwald-type Viscometer.
  • EXAMPLE 13 The following compositions were made: EXAMPLE 14.

Abstract

The present invention is directed to an ophthalmic composition in the form of a topical aqueous solution consisting essentially of an ophthalmologically active agent, an ion sensitive, hydrophilic polymer in an amount a of 0.004 to 1.5% by weight, at least one salt selected from the group of inorganic salts and buffers in a total amount of from 0.01 to 2.0% by weight, a wetting agent in an amount of 0 to 3.0% by weight, a preservative in an amount of 0 to 0.02% by weight, water, and optionally a pH regulating agent in an amount sufficient to give a pH of 4.0 to 8.0 to the composition, the ratio between salt and polymer components being such that the solution exhibits a viscosity of less than 1000 mPas. The composition contains a sufficient amount of polymer to provide for a controlled absorption of the drug into the eye, its viscosity having been reduced to provide for better handling characteristics.

Description

SALT FREE HYALURONATE OPHTHALMIC SOLUTION BACKGROUND OF THE INVENTION
The present invention relates to an ophthalmic composition in the form of a topical aqueous solution for human and veterinary use.
It is well known to use polymers alone or in combination with other polymers for the preparation of ophthalmic pharmaceuticals and artificial tear compositions. The inclusion of the polymer aims at increasing the viscosity of the composition so as to provide for a longer contact time with the cornea of the eye, and, for example, in connection with ophthalmic drugs, to provide for a sustained release of the drug into the eye.
For example, the U.S. Pat. Nos. 5,710,182 and 5,795,913 relate to ophthalmic compositions having decreased viscosity while still maintaining high polymer concentration. The prior art teaches the use of inorganic salts and buffers to obtain desirable viscosity and maintain pH during storage and use. We have discovered certain salt and buffer free formulations have desirable viscosity and pH stability during storage. SUMMARY OF THE INVENTION
The present invention thus provides a salt and buffer free ophthalmological composition in a liquid, easy-to-use form which contains a sufficient amount of polymer to provide for both an increased and prolonged absorption of active agent into the eye.
More specifically, provided is a stabilized, topical ophthalmic Levofloxacin composition, wherein the improvement comprises a salt and buffer free composition.
In yet another embodiment, provided is a stabilized, topical ophthalmic Taurine composition, wherein the improvement comprises a salt and buffer free composition.
In yet another embodiment, provided is a stabilized, topical ophthalmic Chloramphenicol composition, wherein the improvement comprises a salt and buffer free composition.
In yet another embodiment, provided is a stabilized, topical ophthalmic Chondroitin Sulfate composition, wherein the improvement comprises a salt and buffer free composition.
In yet another embodiment, provided is a stabilized, topical ophthalmic Dexamethasone and Neomycin composition, wherein the improvement comprises a salt and buffer free composition.
In yet another embodiment, provided is a stabilized, topical ophthalmic Naphazoline and Chlorpheniramine composition, wherein the improvement comprises a salt and buffer free composition.
In yet another embodiment, provided is a stabilized, topical ophthalmic Acyclovir composition, wherein the improvement comprises a salt and buffer free composition. BRIEF DESCRIPTION OF THE DRAWINGS
None DETAILED DESCRIPTION OF THE INVENTION
The ion-sensitive hydrophilic polymer to be used according to the invention is typically hyaluronic acid. Other ion sensitive polymers such as the polyacrylate elastomers commercially available as Carbopol would also be suitable according to the invention herein. Other suitable ion sensitive polymers would be obvious to those of ordinary skill in the art.
The polymer is preferably used in an amount of 0.01 to 0.8. more preferably 0.01 to 0.4, and advantageously 0.04 to 0.4% by weight.
The pH of the composition is suitably from 5.0 to 8, preferably from 6.5 to 8.0. When using a base as the active agent, the pH of the composition can be regulated by the amounts used of acidic polymer and basic active agent respectively. However, if necessary, the pH of the composition may be adjusted also by adding an additional base or an acid, as the case may be, such as an alkali metal hydroxide, especially sodium hydroxide, or ammonium hydroxide, or e.g. hydrochloric acid.
The ophthalmologically active agent is advantageously an antibiotic agent, anti-viral agent, anti-retroviral agent, antiglaucoma agent, nutrients, mucopolysaccharides, a sympathomimetic agent, a sympatholytic agent, such as a beta-blocker, a carbonic anhydrase inhibitor, antiinflammatory, adrenergic, antiallergic agent, etc., or a combination thereof.
The amount of active agent in the final composition may vary, such as between 0.001 to 7% by weight, usually however between 0.01 to 0.5% by weight, and typically between 0.1 and 0.5% by weight.
According to an advantageous embodiment of the invention, the composition contains in addition, in order to enhance the wetting effect thereof, a wetting agent, preferably a polyhydric alcohol, such as glycerol. The amount of wetting agent is generally at the most 3.0%, such as of the order of 0.5 to 3.0% by weight.
As preservatives, e.g. benzalkonium bromide, benzalkonium chloride, benzyl alcohol, mercury salts, thimerosal, chlorhexidine or the like, as such or in combination. The amount of preservative usually lies in the range of 0 to 0.03% by weight.
The following examples illustrate the invention in more detail, without limiting the same. As used herein the following abbreviations have the given meanings:
EDTA Ethylenediamine tetraacetic acid
BAB Benzalkonium Bromide
BAK Benzalkonium Chloride
Borax Sodium borate
RT-6mos. 20° C. six month stability testing
Viscosity was determined according to the method set forth in the 2005 Chinese Pharmacopeia using an Ostwald-type Viscometer.
EXAMPLE 1 The following compositions were made:
Figure imgf000005_0001
EXAMPLE 2
The following compositions were made:
Figure imgf000006_0001
EXAMPLE 3 The following compositions were made:
Figure imgf000007_0001
EXAMPLE 4
The following compositions were made:
Figure imgf000008_0001
EXAMPLE 5 The following compositions were made:
Figure imgf000009_0001
EXAMPLE 6
The following compositions were made:
Figure imgf000010_0001
EXAMPLE 7 The following compositions were made:
FORMULATION -5 (400C)
Figure imgf000011_0001
EXAMPLE 8 The following compositions were made:
Figure imgf000012_0001
EXAMPLE 9 The following compositions were made:
Figure imgf000013_0001
EXAMPLE 10. The following compositions were made:
Figure imgf000014_0001
EXAMPLE 1 1. The following composition was made:
Figure imgf000015_0001
EXAMPLE 12. The following compositions were made:
Figure imgf000016_0001
EXAMPLE 13. The following compositions were made:
Figure imgf000017_0001
EXAMPLE 14.
The following compositions were made:
Figure imgf000018_0001

Claims

We claim:
1. A stabilized, topical ophthalmic Levofloxacin composition, wherein the improvement comprises a salt and buffer free composition.
2. A stabilized, topical ophthalmic Taurine composition, wherein the improvement comprises a salt and buffer free composition.
3. A stabilized, topical ophthalmic chlorhexidine composition, wherein the improvement comprises a salt and buffer free composition.
4. A topical ophthalmic active agent containing composition, wherein the improvement comprises a salt and buffer free composition and wherein the viscosity is less than 50 mm2/s.
5. The composition of claim 4 wherein the active agent is selected from the group consisting of an antibiotic agent, anti-viral agent, anti-retroviral agent, antiglaucoma agent, nutrients, mucopolysaccharides, a sympathomimetic agent, a sympatholytic agent, such as a beta-blocker, a carbonic anhydrase inhibitor, antiinflammatory, adrenergic, antiallergic agent, etc., or a combination thereof.
PCT/US2008/068090 2007-06-28 2008-06-25 Salt free hyaluronate ophthalmic solution WO2009006130A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94680107P 2007-06-28 2007-06-28
US60/946,801 2007-06-28

Publications (2)

Publication Number Publication Date
WO2009006130A2 true WO2009006130A2 (en) 2009-01-08
WO2009006130A3 WO2009006130A3 (en) 2009-09-17

Family

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110876714A (en) * 2019-11-22 2020-03-13 南京知和医药科技有限公司 Levofloxacin sustained-release eye drops and preparation process thereof
US10610499B2 (en) 2016-05-06 2020-04-07 SaCSh Corp. Ophthalmic compositions
WO2021156856A1 (en) * 2020-02-03 2021-08-12 Resdevco Research And Development Co. Ltd. Topical opthalmological composition containing hyaluronate and taurine having non-newtonian rheological properties

Citations (12)

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US5166331A (en) * 1983-10-10 1992-11-24 Fidia, S.P.A. Hyaluronics acid fractions, methods for the preparation thereof, and pharmaceutical compositions containing same
EP0807440A2 (en) * 1996-05-13 1997-11-19 Senju Pharmaceutical Co., Ltd. Chlorhexidine gluconate-containing stabilized aqueous pharmaceutical preparations
WO1999059543A1 (en) * 1998-05-20 1999-11-25 Highchem Company., Ltd. A pharmaceutical formulation for nasal administration
EP0976407A1 (en) * 1997-05-20 2000-02-02 Senju Pharmaceutical Co., Ltd. Antiseptic composition
WO2002049611A2 (en) * 2000-12-20 2002-06-27 Alcon, Inc. Ophthalmic lubricating solution adapted for use in lasik surgery
US20020183279A1 (en) * 2001-04-18 2002-12-05 Koichiro Tanaka Pharmaceutical composition containing viscoelastic substance and medication
US20030143274A1 (en) * 1991-10-30 2003-07-31 Viegas Tacey X. Medical uses of in situ formed gels
US20050080043A1 (en) * 2000-09-20 2005-04-14 Lee Shahinian Self-preserved antibacterial nasal, inhalable, and topical ophthalmic preparations and medications
WO2005110439A2 (en) * 2004-05-07 2005-11-24 S.K. Pharmaceuticals, Inc. Stabilized hyaluronan preparations and related methods
WO2006110482A2 (en) * 2005-04-11 2006-10-19 Advanced Medical Optics, Inc. Borate-polyol mixtures as a buffering system
WO2007003481A1 (en) * 2005-07-01 2007-01-11 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of l-carnitine or of alkanoyl l-carnitines for the preparation of a physiological supplement or medicament for ophthalmic use in the form of eye-drops
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US5166331A (en) * 1983-10-10 1992-11-24 Fidia, S.P.A. Hyaluronics acid fractions, methods for the preparation thereof, and pharmaceutical compositions containing same
US20030143274A1 (en) * 1991-10-30 2003-07-31 Viegas Tacey X. Medical uses of in situ formed gels
EP0807440A2 (en) * 1996-05-13 1997-11-19 Senju Pharmaceutical Co., Ltd. Chlorhexidine gluconate-containing stabilized aqueous pharmaceutical preparations
EP0976407A1 (en) * 1997-05-20 2000-02-02 Senju Pharmaceutical Co., Ltd. Antiseptic composition
WO1999059543A1 (en) * 1998-05-20 1999-11-25 Highchem Company., Ltd. A pharmaceutical formulation for nasal administration
US20050080043A1 (en) * 2000-09-20 2005-04-14 Lee Shahinian Self-preserved antibacterial nasal, inhalable, and topical ophthalmic preparations and medications
WO2002049611A2 (en) * 2000-12-20 2002-06-27 Alcon, Inc. Ophthalmic lubricating solution adapted for use in lasik surgery
US20020183279A1 (en) * 2001-04-18 2002-12-05 Koichiro Tanaka Pharmaceutical composition containing viscoelastic substance and medication
WO2005110439A2 (en) * 2004-05-07 2005-11-24 S.K. Pharmaceuticals, Inc. Stabilized hyaluronan preparations and related methods
WO2006110482A2 (en) * 2005-04-11 2006-10-19 Advanced Medical Optics, Inc. Borate-polyol mixtures as a buffering system
WO2007003481A1 (en) * 2005-07-01 2007-01-11 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of l-carnitine or of alkanoyl l-carnitines for the preparation of a physiological supplement or medicament for ophthalmic use in the form of eye-drops
WO2007039201A2 (en) * 2005-09-29 2007-04-12 Berlin-Chemie Ag Photostable pharmaceutical composition containing brivudine for the treatment of herpetic keratitis

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10610499B2 (en) 2016-05-06 2020-04-07 SaCSh Corp. Ophthalmic compositions
US10632083B2 (en) 2016-05-06 2020-04-28 SaCSh Corp. Ophthalmic compositions
CN110876714A (en) * 2019-11-22 2020-03-13 南京知和医药科技有限公司 Levofloxacin sustained-release eye drops and preparation process thereof
WO2021156856A1 (en) * 2020-02-03 2021-08-12 Resdevco Research And Development Co. Ltd. Topical opthalmological composition containing hyaluronate and taurine having non-newtonian rheological properties

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