CA2132826C - Use of borate-polyol complexes in ophthalmic compositions - Google Patents
Use of borate-polyol complexes in ophthalmic compositionsInfo
- Publication number
- CA2132826C CA2132826C CA002132826A CA2132826A CA2132826C CA 2132826 C CA2132826 C CA 2132826C CA 002132826 A CA002132826 A CA 002132826A CA 2132826 A CA2132826 A CA 2132826A CA 2132826 C CA2132826 C CA 2132826C
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- CA
- Canada
- Prior art keywords
- polyol
- borate
- complex
- water
- antimicrobial agent
- 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.)
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Classifications
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- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Water-soluble borate polyol complexes are useful as buffers and/or antimicrobials in aqueous ophthalmic compositions, including those containing polyvinyl alcohol. These compositions have greater antimicrobial activity than comparable compositions containing typical borate buffers and unexpectedly increase the antimicrobial efficacy of other antimicrobial agents when used in combination. In addition, use of the borate-polyol complexes avoids the incompatibility problem typically associated with the combination of borate buffer and polyvinyl alcohol; therefore, the compositions disclosed herein may also contain polyvinyl alcohol.
Description
~ 8 ~ 6 USE OF BORATE-POLYOL COMPLEXES IN OPHTHALMIC COMPOSITIONS
The invention relates to the use of borate-polyol complexes in ophthalmic compositions. In particular, these complexes are useful as buffers and/or antimicrobial agents in aqueous ophthalmic compositions, including those 5 ophthalmic compositions containing polyvinyl alcohol.
Ophthalmic compositions often include such adjuvants as buffers, tonicity-adjusting agents and viscosity-enhancing agents. Such adjuvants are discussed, for example, in EP-A-109561, FR-A-230358 and EP-A-0436726. Polyvinyl alcohol (PVA) is a viscosity-enhancer and is used extensively in all types of products for 10 rigid gas-permeable contact lenses (RGPs) in order to improve the comfort and wearing time of RGPs. PVA is also extensively used as a viscosity-enhancer for pharmaceutical ophthalmic compositions such as eye drops, gels or ocular inserts.
Ophthalmic compositions are gnerally formulated to have a pH between about 4.0 and 8Ø To achieve a pH in this range and to maintain the pH for 15 optimal stability during the shelf life of the composition, a buffer is often included.
Borate is the buffer of choice for use in ophthalmic compositions, since it has some inherent antimicrobial activity and often enhances the activity of antimicrobials. However, when polyvinyl alcohol (PVA) is also an ingredient in the composition, borate and PVA form a water-insoluble complex which precipitates 20 out of solution and acts as an irritant in the eye. This incompatibility of borate and PVA in contact lens solutions is well-known, and has been discussed, for example, in an article by P.L. Rakow in Contact Lens Forum, (June 1988), pages 41-46.
Moreover, borate buffer cannot be effectively used below pH 7.0 due to its low buffering capacity to lower pH.
A
The invention relates to the use of borate-polyol complexes in ophthalmic compositions. In particular, these complexes are useful as buffers and/or antimicrobial agents in aqueous ophthalmic compositions, including those 5 ophthalmic compositions containing polyvinyl alcohol.
Ophthalmic compositions often include such adjuvants as buffers, tonicity-adjusting agents and viscosity-enhancing agents. Such adjuvants are discussed, for example, in EP-A-109561, FR-A-230358 and EP-A-0436726. Polyvinyl alcohol (PVA) is a viscosity-enhancer and is used extensively in all types of products for 10 rigid gas-permeable contact lenses (RGPs) in order to improve the comfort and wearing time of RGPs. PVA is also extensively used as a viscosity-enhancer for pharmaceutical ophthalmic compositions such as eye drops, gels or ocular inserts.
Ophthalmic compositions are gnerally formulated to have a pH between about 4.0 and 8Ø To achieve a pH in this range and to maintain the pH for 15 optimal stability during the shelf life of the composition, a buffer is often included.
Borate is the buffer of choice for use in ophthalmic compositions, since it has some inherent antimicrobial activity and often enhances the activity of antimicrobials. However, when polyvinyl alcohol (PVA) is also an ingredient in the composition, borate and PVA form a water-insoluble complex which precipitates 20 out of solution and acts as an irritant in the eye. This incompatibility of borate and PVA in contact lens solutions is well-known, and has been discussed, for example, in an article by P.L. Rakow in Contact Lens Forum, (June 1988), pages 41-46.
Moreover, borate buffer cannot be effectively used below pH 7.0 due to its low buffering capacity to lower pH.
A
2 ~ 2 ~
Since borate is incompatible with PVA, ophthalmic compositions containing PVA are generally buffered with acetate, phosphate or other buffers. There are disadvantages of using these alternative buffers: for example, acetate is a weak buffer (PKa of about 4.5), so a relatively large amount is needed; on the other hand, phosphate is a good buffer but, when used in concentrations generally found in ophthalmic formulations. it reduces the antimicrobial activity of preservatives.
It is well known that small organic compounds, such as benzal~onium chloride (BAC), chlorhexidine, thimerosal have excellent antimicrobial activity; however, it is now known that these small organic antimicrobials are often toxic to the sensitive tissues of the eye and can accumulate in contact lenses, particularly soft, hydrophilic contact lenses. More recently, polymeric antimicrobials such as Polyquad~ (polyquaternium-l) and Dymed~
(polyhexamethylene biguanide) have been used in contact lens care products as disinfectants and preservatives. While these polymeric antimicrobials exhibit a broad spectrum of antimicrobial activity, they generally have relatively weak antifungal activity, especially against Aspergillus niger and Aspergillus fumigatus.
A need therefore exists for ophthalmic compositions which have an optimal pH for stability and efficacy, but whose antimicrobial efficacy is not compromised.
This invention provides such ophthalmic compositions. The ophthalmic compositions of the present invention comprise polyvinyl alcohol (PVA) and borate-polyol complexes, which have surprisingly been found to have increased antimicrobial activity as compared to bo~ic acid or its salts, particularly with respect to organisms such as A. niger. Moreover, these complexes unexpectedly increase the antimicrobial efficacY of other an~imicrobial agents when used in combination. ~ O~Cs~
Z ~ 3~8~
Since borate is incompatible with PVA, ophthalmic compositions containing PVA are generally buffered with acetate, phosphate or other buffers. There are disadvantages of using these alternative buffers: for example, acetate is a weak buffer (PKa of about 4.5), so a relatively large amount is needed; on the other hand, phosphate is a good buffer but, when used in concentrations generally found in ophthalmic formulations. it reduces the antimicrobial activity of preservatives.
It is well known that small organic compounds, such as benzal~onium chloride (BAC), chlorhexidine, thimerosal have excellent antimicrobial activity; however, it is now known that these small organic antimicrobials are often toxic to the sensitive tissues of the eye and can accumulate in contact lenses, particularly soft, hydrophilic contact lenses. More recently, polymeric antimicrobials such as Polyquad~ (polyquaternium-l) and Dymed~
(polyhexamethylene biguanide) have been used in contact lens care products as disinfectants and preservatives. While these polymeric antimicrobials exhibit a broad spectrum of antimicrobial activity, they generally have relatively weak antifungal activity, especially against Aspergillus niger and Aspergillus fumigatus.
A need therefore exists for ophthalmic compositions which have an optimal pH for stability and efficacy, but whose antimicrobial efficacy is not compromised.
This invention provides such ophthalmic compositions. The ophthalmic compositions of the present invention comprise polyvinyl alcohol (PVA) and borate-polyol complexes, which have surprisingly been found to have increased antimicrobial activity as compared to bo~ic acid or its salts, particularly with respect to organisms such as A. niger. Moreover, these complexes unexpectedly increase the antimicrobial efficacY of other an~imicrobial agents when used in combination. ~ O~Cs~
Z ~ 3~8~
The borate-polyol complexes are formed by mixing boric acid and/or its salts with polyols, such as mannitol, glycerin or propylene glycol, in an aqueous solution. PVA is then added thereto, and the resultant solution may then be usedas a buffer and/or antimicrobial agent in aqueous ophthalmic compositions, even where such compositions also contain PVA. The borate-polyol complexes contained in the ophthalmic compositions of the present invention are also useful in unpreserved saline solutions.
The borate-polyol complexes contained in the ophthalmic compositions of the present invention are particularly useful as adjunctive disinfecting agents in contact lens disinfecting solutions containing monomeric quaternary ammonium compounds (e.g., benzalkonium chloride) or biguanides (e.g., chlorhexidine) or polymeric antimicrobials, such as polymeric quaternary ammonium compounds (e.g., Polyquad~), Alcon Laboratories, Inc., Fort Worth, Texas) or polymeric biguanides (e.g., Dymed~, Bausch & Lomb, Rochester, New York).
The compositions of the present invention containing PVA are particularly useful in contact lens care products which are targeted for wearers of rigid gas-permeable contact lenses (RGPs), who often complain of discomfort. PVA is used extensively in all types of RGP products in order to improve the comfort and wearing time of RGPs.
Thus, according to one aspect of the invention an aqueous ophthalmic composition comprising polyvinyl alcohol and a water-soluble borate-polyol complex, wherein the water-soluble borate-polyol complex is present at a concentration between about 0.5 and about 6.0 wt%.
A
~ ~ 3~
- 3a -According to another aspect of the invention a method of preparing an aqueous ophthalmic composition, comprising the steps of preparing a water-soluble borate-polyol complex by mixing borate and a polyol together in an aqueous solvent and adding polyvinyl alcohol thereto, wherein the borate-polyol 5 complex is present at a concentration of 0.5 to 6.0 wt% and the molar ratio of borate to polyol is 1:0.1 to 1:10.
According to another aspect of the invention in a method of preserving an aqueous ophthalmic composition from microbial contamination, the improvement which comprises including 0.5 to 6.0 wt% of a water-soluble borate-polyol complex 10 in the composition, said complex containing borate and polyol in a molar ratio of 1:0.1 to 1:10, whereby the antimicrobial activity of the composition is enhanced.
According to another aspect of the invention in a method of disinfecting a contact lens by means of soaking the lens in an aqueous disinfectant solution containing a disinfecting amount of an antimicrobial agent, the improvement which 15 comprises including 0.5 to 6.0 wt% of a water-soluble borate-polyol complex in the disinfectant solution, said complex containing borate and polyol in a molar ratio of 1:1 to 1:10, whereby the antimicrobial activity of the disinfectant solution is enhanced .
According to another aspect of the invention a saline solution for soaking, 20 rinsing and storing contact lenses, comprising an amount of a borate-polyol complex sufficient to preserve the solution from microbial contamination, said complex containing borate and polyol in a molar ratio of 1:0.1 to 1:1; an amount of an osmolality-building agent sufficient to render the solution isotonic; and water.
- 3b - ~! ~ 3 ~
According to yet another aspect of the invention an aqueous solution for disinfecting contact lenses, comprising a disinfecting amount of an ophthalmically acceptable antimicrobial agent; an amount of a borate-polyol complex sufficient to enhance the antimicrobial efficacy of the antimicrobial agent, said complex 5 containing borate and polyol in a molar ratio of 1:1 to 1:2.5; an amount of an osmolality-building agent sufficient to render the solution isotonic; and water.
As used therein, the term "borate" shall refer to boric acid, salts of boric acid and other pharmaceutically acceptable borates, or combinations thereof.
Most suitable are: boric acid, sodium borate, potassium borate, calcium borate, 10 magnesium borate, manganese borate, and other such borate salts.
As used herein, and unless otherwise indicted, the term "polyol" shall refer to any compound having at least two adjacent -OH groups which are not in trans , . ...
'A
The borate-polyol complexes contained in the ophthalmic compositions of the present invention are particularly useful as adjunctive disinfecting agents in contact lens disinfecting solutions containing monomeric quaternary ammonium compounds (e.g., benzalkonium chloride) or biguanides (e.g., chlorhexidine) or polymeric antimicrobials, such as polymeric quaternary ammonium compounds (e.g., Polyquad~), Alcon Laboratories, Inc., Fort Worth, Texas) or polymeric biguanides (e.g., Dymed~, Bausch & Lomb, Rochester, New York).
The compositions of the present invention containing PVA are particularly useful in contact lens care products which are targeted for wearers of rigid gas-permeable contact lenses (RGPs), who often complain of discomfort. PVA is used extensively in all types of RGP products in order to improve the comfort and wearing time of RGPs.
Thus, according to one aspect of the invention an aqueous ophthalmic composition comprising polyvinyl alcohol and a water-soluble borate-polyol complex, wherein the water-soluble borate-polyol complex is present at a concentration between about 0.5 and about 6.0 wt%.
A
~ ~ 3~
- 3a -According to another aspect of the invention a method of preparing an aqueous ophthalmic composition, comprising the steps of preparing a water-soluble borate-polyol complex by mixing borate and a polyol together in an aqueous solvent and adding polyvinyl alcohol thereto, wherein the borate-polyol 5 complex is present at a concentration of 0.5 to 6.0 wt% and the molar ratio of borate to polyol is 1:0.1 to 1:10.
According to another aspect of the invention in a method of preserving an aqueous ophthalmic composition from microbial contamination, the improvement which comprises including 0.5 to 6.0 wt% of a water-soluble borate-polyol complex 10 in the composition, said complex containing borate and polyol in a molar ratio of 1:0.1 to 1:10, whereby the antimicrobial activity of the composition is enhanced.
According to another aspect of the invention in a method of disinfecting a contact lens by means of soaking the lens in an aqueous disinfectant solution containing a disinfecting amount of an antimicrobial agent, the improvement which 15 comprises including 0.5 to 6.0 wt% of a water-soluble borate-polyol complex in the disinfectant solution, said complex containing borate and polyol in a molar ratio of 1:1 to 1:10, whereby the antimicrobial activity of the disinfectant solution is enhanced .
According to another aspect of the invention a saline solution for soaking, 20 rinsing and storing contact lenses, comprising an amount of a borate-polyol complex sufficient to preserve the solution from microbial contamination, said complex containing borate and polyol in a molar ratio of 1:0.1 to 1:1; an amount of an osmolality-building agent sufficient to render the solution isotonic; and water.
- 3b - ~! ~ 3 ~
According to yet another aspect of the invention an aqueous solution for disinfecting contact lenses, comprising a disinfecting amount of an ophthalmically acceptable antimicrobial agent; an amount of a borate-polyol complex sufficient to enhance the antimicrobial efficacy of the antimicrobial agent, said complex 5 containing borate and polyol in a molar ratio of 1:1 to 1:2.5; an amount of an osmolality-building agent sufficient to render the solution isotonic; and water.
As used therein, the term "borate" shall refer to boric acid, salts of boric acid and other pharmaceutically acceptable borates, or combinations thereof.
Most suitable are: boric acid, sodium borate, potassium borate, calcium borate, 10 magnesium borate, manganese borate, and other such borate salts.
As used herein, and unless otherwise indicted, the term "polyol" shall refer to any compound having at least two adjacent -OH groups which are not in trans , . ...
'A
configuration relative to each other. The polyols can be linear or circular, substituted or unsubstituted, or mixtures thereof, so long as the resultant complex is water-soluble and pharmaceutically acceptable. Such compounds include sugars, sugar alcohols, sugar acids and uronic acids. Preferred polyols are sugars, sugar alcohols and sugar acids, including, but not limited to: mannitol,glycerin, propylene glycol and sorbitol. Especially preferred polyols are mannitol and glycerin; most preferred is mannitol.
The water-soluble borate-polyol complexes contained in the compositions of the present invention may be formed by mixing borate with the polyol(s) of choice in an aqueous solution. PVA is then added thereto. The borate-polyol complexes can be used in conjunction with other known preservatives and disinfectants to meet preservative efficacy and disinfection standards. In such compositions, themolar ratio of borate to polyol is generally between about 1:0.1 and about 1:10,and is preferably between about 1:0.25 and about 1:2.5. The borate-polyol complexes are particularly useful in unpreserved salines to meet preservative efficacy standards. In these unpreserved salines, the molar ratio of borate to polyol is generally between about 1:0.1 and about 1:1, and is especially betweenabout 1:0.25 and about 1:0.75. Some borate-polyol complexes, such as potassium borotartrate, are commercially available.
The borate-polyol complexes are utilized in the compositions of the present invention in an amount between about 0.5 to about 6.0 percent by weight (wt%), preferably between about 0.5 to 3.0 wt%, more preferably between about 1.0 to about 2.5 wt%, and most preferably between about 1.0 to about 2.0 wt%. The optimum amount, however, will depend upon the complexity of the product, since ,-~
A
~ ~ 3 ~
- 4a -potential interactions may occur with the other components of a composition.
Such optimum amount can be readily determined by one skilled in the formulatory arts.
The compositions of the present invention also contain PVA, which renders 5 them useful with RGPs or compositions such as eye drops, gels or ocular inserts.
PVA is available in a number of grades, each differing in degree of polymerization, percent of hydrolysis, and residual acetate content. Such differences affect the physical and chemical behaviour of the different grades. PVA can be divided into two broad categories, i.e., completely hydrolyzed and partially ,. ~.
WO 93/21903 213 2 8 2 ~ PCI/US93/04226 hydrolyzed. Those coi)lai,)i,)g 4% residu~l ~ce!a~e conl~nl or less are referred to as completely hydrolyzed. Partially hydrolyzed grades usually contain 20% or more resid~ cet~te. The molecular weight of PVA's vary from 20,000 to 200,000. In general, PVA used in ophthalmic products has an average molecular weight in the range of 30,000 to 100,000 with 11% to 15% residu~l ~cet~le. Compositions of the,uresent invention generally contain such types of PVA at a conc~"l,dlior, less than about 10.0 wt%, prefer~bly between about 0.1 and about 1~4 wt% and most prerer~bly at a concentration of about 0.75 wt%.
The water-soluble borate-polyol complexes of the present invention may be prepared as illustrated below.
FORMULATION ~% weigl ~'V~,~l r) IN~F~ul~rJT A B C D E F G H
Bonc acid0.35 0.35 0.35 0.35 0 35 0 35 0 35 0 35 Sodium 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 1 ~ borab Mannitol 0.5 1.0 1.5 2.0 -- -- -- _ Glycerin -- -- -- -- 0.5 1.0 1.5 2.0 Na2EDTA 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Puriffedq.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
water HCUNaOHpH 7.4pH 7.4 pH 7.4 pH 7.4 pH 7.4pH 7.4 pH 7.4 pH 7.4 Polyquad~0.001 + 0.001 +0.001 +0.001 +0.001 +0.001 +0.001 + 0.001 +
10% xs109~ xs10% xs 10% xs 10% xs10% xs 10% xs 10% xs r~par~liGI ~:
Formulalions A - H were prepared as follows. Tubular, l~beled and 2~ calibrated 150 milliliter (mL) beakers were each filled with about 90 mL of purified water. Boric acid, sodium borate and mannitol or glycerin were then added and dissolved by stirring the solution for about 2~ minutes. At this time, disor~ m EDTA (ethylene diamine tet~cetic acid) was added with stirring. Purified water WO 93/21903 2 1 ~ 2 8 2 6 6 PCr/US93/04226 was added to bring the solutions almost to 100% (100 mL), pH was adjusted to appro)~i",ately 7.4 and the osmolality was measured. Polyquad~) was then added and the volume brought to 100% by the ~ddilion of purified water. pH was again measured and ~r~justed, if necess~ry, and the osmolality was measured again.
It is not always necessA~y to have an isotonic solution; however, if there is a need to have an isotonic solution, the osmolality can be adjusted by incorj~orali"9 polyol with OH groups in trans posiliGn, sodium chloride, potassium chloride, calcium chloride or other osmolality building agents which are generally acceptable in ophthalmic formulations and known to those skilled in the art.
F~AMPI F ~
A~ueo!Js o~lltl,all"ic compositions of the present invention may be prepared using the formulations illustrated below.
FORMULATiON (peroent by weight) INGiREDlENT 1 2 3 4 6 6 7 8 PVA 0.75 1.4 0.75 0.75 0.75 0.75 0.75 0.75 0.75 ,JI oellubse -- -- 0.75 0.28 0.28 0.28 0.28 0.75 0.75 (HEC) Mannitol 2.0 2.02.0 2.0 2.0 2.0 0.5 2.0 2.0 Boricacid 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Sodiumborate0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 Edetate disodium 0.10.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Sodium chloride 0.05 0.09 0.05 0.09 0.45 0.09 0 09 0.09 o 09 r~ E 0.001 0.001 0.001 0.001 0.001 0.001 0.001 Suc~o# ~ 2.5 -- 2.5 2.5 Ft,l)l 'h,bl.r, -- -- -- -- -- -- -- 0.0005 bbuanide BAC ~ 0.004 WO 93/21903 213 2 8 2 6 Pcr/US93/04226 Preparation:
Formulations 1 - 9 were prepared as follows. A first solution (~Solution A) was prepared by adding 500 mL of warm purified water to a calibrated two liter aspirator bottle equipped with a magnetic stirrer. PVA and hydroxyethyl cellulose were then added to Solution A and the contents dispersed by stirring. After dispersal of the polymers, a filter assembly was allac:l ,ed to the aspiraLor bottle (142 mm Millipore filter holder with 0.2 ,u filter), and this whole apparatus A~tocl~vcd at 121~C for 30 minutes. So' ltion Awith the filter assembly attachedwas then allowed to cool to room temperature with stirring. A second sol ~tion (Solution B), was prapared in a 500 mL beaker containing 300 mL of purified water by adding boric acid, sodium borate and mannitol and dissolving the conte, lls by stirring for 25 minutes. Fdet~te disodium, sodium chloride, preservatives and other osmolality-building agents, as necess~y, were added to Solution B and the contents d;ssolv0d with stirring. Sal ~tion B was then sterile filtered into theaspirator bottle contc,i"ing .Sol ~tion A. The pH of the resultant solution was then adjusted and the volume brought to 100% by sterile filtering purified water.
wo 93~21903 213 2 8 2 6 -8- PCr/US93/04226 The following opllll,al~"ic compositions o~ the present invention may also be prepared using the procedure detriled in Example 2.
FORMULl~TlON ~percent by weight) INGREDIENT 10 11 12 13 14 16 . 16 17 18 19 PVA 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 I; p~ HCI 0.1 0.1 ~
Sodium -- -- -- 10.0 -- -- -- -- _ _ ~,, ,,, . ,, _ _ _ _ o,1 t~ lbib -- -- -- -- -- 0.4 La~ lHCI -- -- 0.5 wne -- -- -- -- -- -- 1.0 Pi ~ nitrab -- -- -- -- -- -- -- 1.0 1.0 1.0 Sodium -- -- 0.4 .. ..
Mannitol 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 4.0 0.5 Boric acid 0.35 0.35 0.350.35 0.35 0.35 0.35 0.35 035 0.5 Sodium borate 0.11 0.11 0.110.11 0.11 0.11 0.11 0.11 Sodium chbride 0.45 0.450.45 -- 0.45 0.45 0.45 0.45 Edetate disodium 0.1 0.1 0.1 0.1 0.1 0.1 0~1 0.1 0.1 o 1 BAC 0.004 r~,., ui _ o.oo1 o.oo1 o.oo1 o.oo1 o.oo1 o.oo1 o.oo1 o.oo~ o.oo~
WO 93/21903 2 1 3 2 8 2 6 Pcr/US93/04226 ~ g FXAMPl F 4 The following is a typical wetting and soaking composition of the present invention for use with RGPs.
INGREDIENT AMOUNT (wt%) PVA 0.75 HEC 0.38 Boric acid 0.35 Sodium borate 0. 11 Mannitol 2.0 Potassium chloride 0.038 Magnesium chloride 0.02 Calcium cl ,loride 0.0154 Sodium chloride 0.09 Polysorbate 80 0.005 Polyquad~9 0 001 NaOH and/orHCI pH 7.4 Purified water q.s.
r~e~aralion:
In a suitable coi ,tainer containing approximately 30% of the final volume of 20 purified water, PVA and HEC were added and dispersed. This solution was then ~ ~tocl~ved. The scl ~tion was allowed to cool to room temperature with stirring. In a separate container, containing approximately 50% of the final volume of purified water, boric add and sodium borate were added, and dissolved, followed by mannitol. This second solution was then stirred for about 30 minutes, then 25 potassium chloride, calcium chloride, magnesium chloride, sodium chloride, - polysorbate 80 and Polyquadt!~ were added, with stirring. The second solution was then added to the first solution via a 0.2 ,u filter. Last, the pH was adjusted to 7.4 and the volume brought to 100% with purified water.
WO 93/21903 13 ~ ~ 2 6 PCI /US93/04226 The following is a typical daily cleaner composition of the prese,)l invention for use with RGPs and may be prepared in a manner similar to that detailed in Example 4.
INGREDIENT ~MOUNT (wtZ) Nylon 11 2.50 Dextran 70 6.0 Sodium borate 0.25 Boric acid 0.50 Miracar~) 2MCA 0.50 PDMA-1 0. 15 Propylene glycol 10.0 Polyquad~) 0.0055 EDTA 0.10 Mannitol 1.20 NaOH and/or HCI pH 7.4 Purified water q.s.
WO 93/21903 2 1 3 2 8 2 6 Pcr/US93/04226 The following is a typical wetting and soaking composition of the present invention which may be ,crepared in a manner similar to that detailed in Example 4.
INGREDIENT AMOUNT (wt~~) Hydroxypropyl 0.72 methylcellulose (Methocel~ E4M) Mannitol 1.0 Sodium borate 0.11 Boric acid 0.35 Sodium ci ,loride 0.19 Polyquad~9 0.001 1 EDTA 0. 10 NaOH and/or HCI pH 7.4 Purified water q.s.
WO 93/21903 213~82 B PCI'/US93/04226 The ra"Dv.;ng is a typical comro,l drop composition of the pres~nl invention which may be prepared in a manner similar to that detailed in Example 4.
INGREDIENT AMOUNT (w/v%) PVA 0.75 HEC 0.28 Mannitol 2.0 Sodium borate 0. 11 Boric acid 0.35 Sodium chloride 0.152 Polyquad~ 0.00082 EDTA 0.10 NaOH and/or HCI pH 7.4 Pur~led water q.s.
wo 93/21903 2 1 ~ 2 8 2 6 Pcr/us93/o4226 The following is a typical RGP cleaner composition of the present invention which may be prepared in a manner similar to that rlet~ile~l in Example 4..
INGREDIENT AMOUNT ~wt%) Frencn Naturelle~ ES 2.5 (Nylon 11) Hydroxyethyl cellulose 0.4 Sodium borate, decahydrate0.25 Boric acid 0.50 Mannitol 3.5 Mira~r~) 2MCA) 0.50 Isopropyl alcohol (v/v) 10.0 NaOH andlor HCI q.s. 7.4 Purified water q.s.
WO 93/21903 X 1 3 i g 2 6 PCI/US93/04226 FXAMpl F 9 The following is a typical RGP wetting and/or soahin~ com~osi(ion of the ,~resent invention., which may be prepared in a manner similar to that ~let~ilerl in Example 4.
INGREDIENT AMOVNT (wt%) Methocel~ E4M 0.85 Mannitol 2.00 Sodium borate 0.11 Boric acid 0.35 Sodium chloride 0.19 Disodium edeta~e 0.1 Polyquad~ 0.001 NaOH and/or HCI pH 7.4 Purified water q.s.
W O 93/21903 21 3 2 8 ~ 6 Pc~r/us93/o4226 E~MPI F 10 The following study compared the antimicrobial preservative efficacy of two wetting, soaking and disinfecting sohltions: one conlaining phosphate buffer (Formulation A); and the other containing a borate-polyol complex of the presentJ invention (Formulation B).
Formulations A and B are shown in the following table.
FORMULATION (wt%) INGREDIENT
A B
PVA 0.75 0.75 HEC 0.5 0.5 ~iJ Sodium phosphate 0.67 Sodium biophGs,cl ,ale 0.017 Boric acid -- 0.35 Sodium borate -- 0.11 M~l 1, lilol 2.0 Disodium edeti~te 0.1 0.1 Sodium chloride 0.458 0.153 Polysorbate 80 0.005 0.005 Benzalkonium chloride 0.01 0.01 Purified water q.s. q.s.
Formulations A and B were tested against FDA challenge organisms. The log rerl~ ~ctions after 1 hour are ti~hula~ecl below:
WO 93/21903 21328~ 6 PCI/US93/04226 .
FORMULATION
TEST ORGANISM (log reduction) A ¦ B
A. niger 2.1 4.4 B. albicans 4.0 5.3 P. aeruginosa 5.3 5.3 S. al~reus 5.5 5~2 E coli 5.5 5.5 The results shown above indicate that Formulation B (containing borate-polyol complex) has a broader spectrum of activity than Formulation A (containing phosphate buffer), and has y,ea~er activity agairist certain organisms, such as A.
10 niger.
The following study compared the antimicrobial preservative efficacy of two unpreserved saline solutions identical except that one contained a borate-polyolcomplex of the present invention (Formulation C) and the other contained the 15 conventional borate buffer (Formulation D).
An orga"is,n challenge approach based on the British Pharmacopoeia ("BP") 1988 Test for ~rricac~ of Preservatives in Pharm~ceutic~l Products was used to evaluate the antimicrobial preservative efficacy of Formulations C and D.
Formulation samples were inoc~ ted with known levels of A. niger and sampled at 20 predeterrnined intervals to determine if the system was c~p~hle of killing or inhibiting the propag~tion of orgar,isr"s introduced into the products.
Formulations C and D are shown in the following table.
WO 93/21903 '- 2 1 3 2 8 2 6 Pcr/US93/04226 FORMULAnON (wt%) INGREDIENT
C I D
Boric acid 1.0 1.0 Sodium borate 0.2 0.2 Mannitol 1.5 ~
Sodium chloride 0.3 Disodium edetate 0.1 0.1 NaOH and/or HCI pH 7.4 pH 7.4 Purified water q.s. q.s.
The results in~lic~ted that there was a 3.1 log rech~ction of A. nigerwith 10 Formulation C and only 1.2 log reduction with Formulation D after 7 days.
Formulation C met the BP slandards for preservative efficacy against A. niger, while Formulation D failed to meet the BP standards.
The following study compared the antimicrobial preservative efficacy of two 15 disi,lfecting so' ~tions idenlical except that one contained a borate-polyol complex of the present invention (Formulation E) and the other contained the convenlional borate buffer (Formulation F).
An oryanis"~ challenye approacl1 based on the BP 1988 Test for crr~ca~iy of Preservatives in Pharm~ceutic~l Products was used to evaluate the antimicrobial 20 preservative efficacy of Formulations E and F. Formulation samples were inou~l~ted with known levels of A. niger and sampled at predetermined intervals to determine if the system was capable of killing or inhibiting the prop~tion of organis,ns introd~ ~ced into the prod~cts, -18~
Formulations E and F are shown in the following table.
FORMUi~TlON (wP~0) I~GREDIENT E ¦ F
Boric acid 0 3 0 35 Sodium borate 0.1 1 0.1 1 Mannitoi 0.85 Sodium citrate 0.56 0.56 Citric acid 0.021 0.21 Sodium chloride 0.48 0.48 Pluronic P103 - 0.~. 0.5 Disodium edetate 0.0~ 0.05 Polyquad~ 0.001 0.001 NaOH andJor HCI pH 7.0 pH 7.0 Purified water q.s. q.s.
The results indicate that there was a 2 1 log reduction of A niger with Formuiation E and only 1.1 log reduction with Formulation F after 7 days.
Formulation E rriet the BP standards for preservative efficacy against A. niger, while Forrnulation F failed to meet the BP standards.
Trade Mark '~4
The water-soluble borate-polyol complexes contained in the compositions of the present invention may be formed by mixing borate with the polyol(s) of choice in an aqueous solution. PVA is then added thereto. The borate-polyol complexes can be used in conjunction with other known preservatives and disinfectants to meet preservative efficacy and disinfection standards. In such compositions, themolar ratio of borate to polyol is generally between about 1:0.1 and about 1:10,and is preferably between about 1:0.25 and about 1:2.5. The borate-polyol complexes are particularly useful in unpreserved salines to meet preservative efficacy standards. In these unpreserved salines, the molar ratio of borate to polyol is generally between about 1:0.1 and about 1:1, and is especially betweenabout 1:0.25 and about 1:0.75. Some borate-polyol complexes, such as potassium borotartrate, are commercially available.
The borate-polyol complexes are utilized in the compositions of the present invention in an amount between about 0.5 to about 6.0 percent by weight (wt%), preferably between about 0.5 to 3.0 wt%, more preferably between about 1.0 to about 2.5 wt%, and most preferably between about 1.0 to about 2.0 wt%. The optimum amount, however, will depend upon the complexity of the product, since ,-~
A
~ ~ 3 ~
- 4a -potential interactions may occur with the other components of a composition.
Such optimum amount can be readily determined by one skilled in the formulatory arts.
The compositions of the present invention also contain PVA, which renders 5 them useful with RGPs or compositions such as eye drops, gels or ocular inserts.
PVA is available in a number of grades, each differing in degree of polymerization, percent of hydrolysis, and residual acetate content. Such differences affect the physical and chemical behaviour of the different grades. PVA can be divided into two broad categories, i.e., completely hydrolyzed and partially ,. ~.
WO 93/21903 213 2 8 2 ~ PCI/US93/04226 hydrolyzed. Those coi)lai,)i,)g 4% residu~l ~ce!a~e conl~nl or less are referred to as completely hydrolyzed. Partially hydrolyzed grades usually contain 20% or more resid~ cet~te. The molecular weight of PVA's vary from 20,000 to 200,000. In general, PVA used in ophthalmic products has an average molecular weight in the range of 30,000 to 100,000 with 11% to 15% residu~l ~cet~le. Compositions of the,uresent invention generally contain such types of PVA at a conc~"l,dlior, less than about 10.0 wt%, prefer~bly between about 0.1 and about 1~4 wt% and most prerer~bly at a concentration of about 0.75 wt%.
The water-soluble borate-polyol complexes of the present invention may be prepared as illustrated below.
FORMULATION ~% weigl ~'V~,~l r) IN~F~ul~rJT A B C D E F G H
Bonc acid0.35 0.35 0.35 0.35 0 35 0 35 0 35 0 35 Sodium 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 1 ~ borab Mannitol 0.5 1.0 1.5 2.0 -- -- -- _ Glycerin -- -- -- -- 0.5 1.0 1.5 2.0 Na2EDTA 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Puriffedq.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
water HCUNaOHpH 7.4pH 7.4 pH 7.4 pH 7.4 pH 7.4pH 7.4 pH 7.4 pH 7.4 Polyquad~0.001 + 0.001 +0.001 +0.001 +0.001 +0.001 +0.001 + 0.001 +
10% xs109~ xs10% xs 10% xs 10% xs10% xs 10% xs 10% xs r~par~liGI ~:
Formulalions A - H were prepared as follows. Tubular, l~beled and 2~ calibrated 150 milliliter (mL) beakers were each filled with about 90 mL of purified water. Boric acid, sodium borate and mannitol or glycerin were then added and dissolved by stirring the solution for about 2~ minutes. At this time, disor~ m EDTA (ethylene diamine tet~cetic acid) was added with stirring. Purified water WO 93/21903 2 1 ~ 2 8 2 6 6 PCr/US93/04226 was added to bring the solutions almost to 100% (100 mL), pH was adjusted to appro)~i",ately 7.4 and the osmolality was measured. Polyquad~) was then added and the volume brought to 100% by the ~ddilion of purified water. pH was again measured and ~r~justed, if necess~ry, and the osmolality was measured again.
It is not always necessA~y to have an isotonic solution; however, if there is a need to have an isotonic solution, the osmolality can be adjusted by incorj~orali"9 polyol with OH groups in trans posiliGn, sodium chloride, potassium chloride, calcium chloride or other osmolality building agents which are generally acceptable in ophthalmic formulations and known to those skilled in the art.
F~AMPI F ~
A~ueo!Js o~lltl,all"ic compositions of the present invention may be prepared using the formulations illustrated below.
FORMULATiON (peroent by weight) INGiREDlENT 1 2 3 4 6 6 7 8 PVA 0.75 1.4 0.75 0.75 0.75 0.75 0.75 0.75 0.75 ,JI oellubse -- -- 0.75 0.28 0.28 0.28 0.28 0.75 0.75 (HEC) Mannitol 2.0 2.02.0 2.0 2.0 2.0 0.5 2.0 2.0 Boricacid 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Sodiumborate0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 Edetate disodium 0.10.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Sodium chloride 0.05 0.09 0.05 0.09 0.45 0.09 0 09 0.09 o 09 r~ E 0.001 0.001 0.001 0.001 0.001 0.001 0.001 Suc~o# ~ 2.5 -- 2.5 2.5 Ft,l)l 'h,bl.r, -- -- -- -- -- -- -- 0.0005 bbuanide BAC ~ 0.004 WO 93/21903 213 2 8 2 6 Pcr/US93/04226 Preparation:
Formulations 1 - 9 were prepared as follows. A first solution (~Solution A) was prepared by adding 500 mL of warm purified water to a calibrated two liter aspirator bottle equipped with a magnetic stirrer. PVA and hydroxyethyl cellulose were then added to Solution A and the contents dispersed by stirring. After dispersal of the polymers, a filter assembly was allac:l ,ed to the aspiraLor bottle (142 mm Millipore filter holder with 0.2 ,u filter), and this whole apparatus A~tocl~vcd at 121~C for 30 minutes. So' ltion Awith the filter assembly attachedwas then allowed to cool to room temperature with stirring. A second sol ~tion (Solution B), was prapared in a 500 mL beaker containing 300 mL of purified water by adding boric acid, sodium borate and mannitol and dissolving the conte, lls by stirring for 25 minutes. Fdet~te disodium, sodium chloride, preservatives and other osmolality-building agents, as necess~y, were added to Solution B and the contents d;ssolv0d with stirring. Sal ~tion B was then sterile filtered into theaspirator bottle contc,i"ing .Sol ~tion A. The pH of the resultant solution was then adjusted and the volume brought to 100% by sterile filtering purified water.
wo 93~21903 213 2 8 2 6 -8- PCr/US93/04226 The following opllll,al~"ic compositions o~ the present invention may also be prepared using the procedure detriled in Example 2.
FORMULl~TlON ~percent by weight) INGREDIENT 10 11 12 13 14 16 . 16 17 18 19 PVA 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 I; p~ HCI 0.1 0.1 ~
Sodium -- -- -- 10.0 -- -- -- -- _ _ ~,, ,,, . ,, _ _ _ _ o,1 t~ lbib -- -- -- -- -- 0.4 La~ lHCI -- -- 0.5 wne -- -- -- -- -- -- 1.0 Pi ~ nitrab -- -- -- -- -- -- -- 1.0 1.0 1.0 Sodium -- -- 0.4 .. ..
Mannitol 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 4.0 0.5 Boric acid 0.35 0.35 0.350.35 0.35 0.35 0.35 0.35 035 0.5 Sodium borate 0.11 0.11 0.110.11 0.11 0.11 0.11 0.11 Sodium chbride 0.45 0.450.45 -- 0.45 0.45 0.45 0.45 Edetate disodium 0.1 0.1 0.1 0.1 0.1 0.1 0~1 0.1 0.1 o 1 BAC 0.004 r~,., ui _ o.oo1 o.oo1 o.oo1 o.oo1 o.oo1 o.oo1 o.oo1 o.oo~ o.oo~
WO 93/21903 2 1 3 2 8 2 6 Pcr/US93/04226 ~ g FXAMPl F 4 The following is a typical wetting and soaking composition of the present invention for use with RGPs.
INGREDIENT AMOUNT (wt%) PVA 0.75 HEC 0.38 Boric acid 0.35 Sodium borate 0. 11 Mannitol 2.0 Potassium chloride 0.038 Magnesium chloride 0.02 Calcium cl ,loride 0.0154 Sodium chloride 0.09 Polysorbate 80 0.005 Polyquad~9 0 001 NaOH and/orHCI pH 7.4 Purified water q.s.
r~e~aralion:
In a suitable coi ,tainer containing approximately 30% of the final volume of 20 purified water, PVA and HEC were added and dispersed. This solution was then ~ ~tocl~ved. The scl ~tion was allowed to cool to room temperature with stirring. In a separate container, containing approximately 50% of the final volume of purified water, boric add and sodium borate were added, and dissolved, followed by mannitol. This second solution was then stirred for about 30 minutes, then 25 potassium chloride, calcium chloride, magnesium chloride, sodium chloride, - polysorbate 80 and Polyquadt!~ were added, with stirring. The second solution was then added to the first solution via a 0.2 ,u filter. Last, the pH was adjusted to 7.4 and the volume brought to 100% with purified water.
WO 93/21903 13 ~ ~ 2 6 PCI /US93/04226 The following is a typical daily cleaner composition of the prese,)l invention for use with RGPs and may be prepared in a manner similar to that detailed in Example 4.
INGREDIENT ~MOUNT (wtZ) Nylon 11 2.50 Dextran 70 6.0 Sodium borate 0.25 Boric acid 0.50 Miracar~) 2MCA 0.50 PDMA-1 0. 15 Propylene glycol 10.0 Polyquad~) 0.0055 EDTA 0.10 Mannitol 1.20 NaOH and/or HCI pH 7.4 Purified water q.s.
WO 93/21903 2 1 3 2 8 2 6 Pcr/US93/04226 The following is a typical wetting and soaking composition of the present invention which may be ,crepared in a manner similar to that detailed in Example 4.
INGREDIENT AMOUNT (wt~~) Hydroxypropyl 0.72 methylcellulose (Methocel~ E4M) Mannitol 1.0 Sodium borate 0.11 Boric acid 0.35 Sodium ci ,loride 0.19 Polyquad~9 0.001 1 EDTA 0. 10 NaOH and/or HCI pH 7.4 Purified water q.s.
WO 93/21903 213~82 B PCI'/US93/04226 The ra"Dv.;ng is a typical comro,l drop composition of the pres~nl invention which may be prepared in a manner similar to that detailed in Example 4.
INGREDIENT AMOUNT (w/v%) PVA 0.75 HEC 0.28 Mannitol 2.0 Sodium borate 0. 11 Boric acid 0.35 Sodium chloride 0.152 Polyquad~ 0.00082 EDTA 0.10 NaOH and/or HCI pH 7.4 Pur~led water q.s.
wo 93/21903 2 1 ~ 2 8 2 6 Pcr/us93/o4226 The following is a typical RGP cleaner composition of the present invention which may be prepared in a manner similar to that rlet~ile~l in Example 4..
INGREDIENT AMOUNT ~wt%) Frencn Naturelle~ ES 2.5 (Nylon 11) Hydroxyethyl cellulose 0.4 Sodium borate, decahydrate0.25 Boric acid 0.50 Mannitol 3.5 Mira~r~) 2MCA) 0.50 Isopropyl alcohol (v/v) 10.0 NaOH andlor HCI q.s. 7.4 Purified water q.s.
WO 93/21903 X 1 3 i g 2 6 PCI/US93/04226 FXAMpl F 9 The following is a typical RGP wetting and/or soahin~ com~osi(ion of the ,~resent invention., which may be prepared in a manner similar to that ~let~ilerl in Example 4.
INGREDIENT AMOVNT (wt%) Methocel~ E4M 0.85 Mannitol 2.00 Sodium borate 0.11 Boric acid 0.35 Sodium chloride 0.19 Disodium edeta~e 0.1 Polyquad~ 0.001 NaOH and/or HCI pH 7.4 Purified water q.s.
W O 93/21903 21 3 2 8 ~ 6 Pc~r/us93/o4226 E~MPI F 10 The following study compared the antimicrobial preservative efficacy of two wetting, soaking and disinfecting sohltions: one conlaining phosphate buffer (Formulation A); and the other containing a borate-polyol complex of the presentJ invention (Formulation B).
Formulations A and B are shown in the following table.
FORMULATION (wt%) INGREDIENT
A B
PVA 0.75 0.75 HEC 0.5 0.5 ~iJ Sodium phosphate 0.67 Sodium biophGs,cl ,ale 0.017 Boric acid -- 0.35 Sodium borate -- 0.11 M~l 1, lilol 2.0 Disodium edeti~te 0.1 0.1 Sodium chloride 0.458 0.153 Polysorbate 80 0.005 0.005 Benzalkonium chloride 0.01 0.01 Purified water q.s. q.s.
Formulations A and B were tested against FDA challenge organisms. The log rerl~ ~ctions after 1 hour are ti~hula~ecl below:
WO 93/21903 21328~ 6 PCI/US93/04226 .
FORMULATION
TEST ORGANISM (log reduction) A ¦ B
A. niger 2.1 4.4 B. albicans 4.0 5.3 P. aeruginosa 5.3 5.3 S. al~reus 5.5 5~2 E coli 5.5 5.5 The results shown above indicate that Formulation B (containing borate-polyol complex) has a broader spectrum of activity than Formulation A (containing phosphate buffer), and has y,ea~er activity agairist certain organisms, such as A.
10 niger.
The following study compared the antimicrobial preservative efficacy of two unpreserved saline solutions identical except that one contained a borate-polyolcomplex of the present invention (Formulation C) and the other contained the 15 conventional borate buffer (Formulation D).
An orga"is,n challenge approach based on the British Pharmacopoeia ("BP") 1988 Test for ~rricac~ of Preservatives in Pharm~ceutic~l Products was used to evaluate the antimicrobial preservative efficacy of Formulations C and D.
Formulation samples were inoc~ ted with known levels of A. niger and sampled at 20 predeterrnined intervals to determine if the system was c~p~hle of killing or inhibiting the propag~tion of orgar,isr"s introduced into the products.
Formulations C and D are shown in the following table.
WO 93/21903 '- 2 1 3 2 8 2 6 Pcr/US93/04226 FORMULAnON (wt%) INGREDIENT
C I D
Boric acid 1.0 1.0 Sodium borate 0.2 0.2 Mannitol 1.5 ~
Sodium chloride 0.3 Disodium edetate 0.1 0.1 NaOH and/or HCI pH 7.4 pH 7.4 Purified water q.s. q.s.
The results in~lic~ted that there was a 3.1 log rech~ction of A. nigerwith 10 Formulation C and only 1.2 log reduction with Formulation D after 7 days.
Formulation C met the BP slandards for preservative efficacy against A. niger, while Formulation D failed to meet the BP standards.
The following study compared the antimicrobial preservative efficacy of two 15 disi,lfecting so' ~tions idenlical except that one contained a borate-polyol complex of the present invention (Formulation E) and the other contained the convenlional borate buffer (Formulation F).
An oryanis"~ challenye approacl1 based on the BP 1988 Test for crr~ca~iy of Preservatives in Pharm~ceutic~l Products was used to evaluate the antimicrobial 20 preservative efficacy of Formulations E and F. Formulation samples were inou~l~ted with known levels of A. niger and sampled at predetermined intervals to determine if the system was capable of killing or inhibiting the prop~tion of organis,ns introd~ ~ced into the prod~cts, -18~
Formulations E and F are shown in the following table.
FORMUi~TlON (wP~0) I~GREDIENT E ¦ F
Boric acid 0 3 0 35 Sodium borate 0.1 1 0.1 1 Mannitoi 0.85 Sodium citrate 0.56 0.56 Citric acid 0.021 0.21 Sodium chloride 0.48 0.48 Pluronic P103 - 0.~. 0.5 Disodium edetate 0.0~ 0.05 Polyquad~ 0.001 0.001 NaOH andJor HCI pH 7.0 pH 7.0 Purified water q.s. q.s.
The results indicate that there was a 2 1 log reduction of A niger with Formuiation E and only 1.1 log reduction with Formulation F after 7 days.
Formulation E rriet the BP standards for preservative efficacy against A. niger, while Forrnulation F failed to meet the BP standards.
Trade Mark '~4
Claims (60)
1. An aqueous ophthalmic composition comprising polyvinyl alcohol and a water-soluble borate-polyol complex, wherein the water-soluble borate-polyol complex is present at a concentration between about 0.5 and about 6.0 wt%.
2. The aqueous composition of claim 1, wherein the water-soluble borate-polyol complex is present at a concentration between about 1.0 and 2.5 wt%.
3. The aqueous composition of claim 1, wherein the water-soluble borate-polyol complex comprises borate and polyol in a molar ratio between about1:0.1 and about 1:10.
4. The aqueous composition of claim 3, wherein the water-soluble borate-polyol complex comprises borate and polyol in a molar ratio between about1:0.25 and about 1:2.5.
5. The aqueous composition of claim 1, wherein the water-soluble borate-polyol complex comprises a polyol selected from the group consisting of sugars, sugar alcohols and sugar acids.
6. The aqueous composition of claim 5, wherein the polyol is selected from the group consisting of mannitol, glycerin, propylene glycol and sorbitol.
7. The aqueous composition of claim 6, wherein the polyol is selected from the group consisting of mannitol and glycerin.
8. The aqueous composition of claim 7, wherein the polyol is mannitol.
9. The aqueous composition of any one of claims 1-8, wherein the concentration of polyvinyl alcohol is less than or equal to about 10 wt%.
10. The aqueous composition of claim 9, wherein the polyvinyl alcohol is present at a concentration between about 0.1 and about 1.4 wt%.
11. The aqueous composition of any one of claims 1-10, further comprising an ophthalmically acceptable antimicrobial agent.
12. The aqueous composition of claim 11, wherein the opthalmically acceptable antimicrobial agent is selected from the group consisting of: monomeric and polymeric quaternary ammonium compounds and their opthalmically acceptable salts, monomeric and polymeric biguanides and their opthalmically acceptable salts, and combinations thereof.
13. A method of preparing an aqueous ophthalmic composition, comprising the steps of preparing a water-soluble borate-polyol complex by mixing borate and a polyol together in an aqueous solvent and adding polyvinyl alcohol thereto, wherein the borate-polyol complex is present at a concentration of 0.5 to 6.0 wt% and the molar ratio of borate to polyol is 1:0.1 to 1:10.
14. The method of claim 13, wherein the water-soluble borate-polyol complex comprises borate and polyol in a molar ratio between about 1:0.25 and about 1:2.5
15. The method of claim 13, wherein the concentration of the water-soluble borate-polyol complex in the final composition is between about 0.5 and about 3.0 wt%
16. The method of claim 15, wherein the concentration of the water-soluble borate-polyol complex in the final composition is between about 1.0 and about 2.0 wt%.
17. The method of claim 13, wherein the water-soluble borate-polyol complex comprises a polyol selected from the group consisting of sugars, sugar alcohols and sugar acids.
18. The method of claim 17, wherein the polyol is selected from the group consisting of mannitol, glycerin, propylene glycol and sorbitol.
19. The method of claim 18, wherein the polyol is selected from the group consisting of mannitol and glycerin.
20. The method of claim 19, wherein the polyol is mannitol.
21. Use of a water-soluble borate-polyol complex as an ophthalmic antimicrobial agent.
22. In a method of preserving an aqueous ophthalmic composition from microbial contamination, the improvement which comprises including 0.5 to 6.0 wt% of a water-soluble borate-polyol complex in the composition, said complex containing borate and polyol in a molar ratio of 1:0.1 to 1:10, whereby the antimicrobial activity of the composition is enhanced.
23. A method according to claim 22, wherein the composition contains a preservative effective amount of an ophthalmically acceptable antimicrobial agent.
24. A method according to claim 23, wherein the antimicrobial agent is selected from the group consisting of monomeric and polymeric quaternary ammonium compounds and their ophthalmically acceptable salts, monomeric and polymeric biguanides and their ophthalmically acceptable salts, and combinations thereof.
25. A method according to claim 24, wherein the borate-polyol complex is included in the composition in a concentration of 1.0 to 2.5 wt%, and the molar ratio of borate to polyol is 1:0.25 to 1:2.5.
26. A method according to claim 25, wherein the polyol is mannitol.
27. A method according to claim 26, wherein the antimicrobial agent comprises a polymeric quaternary ammonium compound.
28. A method according to claim 27, wherein the polymeric quaternary ammonium compound is polyquaternium-1.
29. A method according to claim 28, wherein the concentration of polyquaternium-1 in the composition is up to 0.001 wt%.
30. A method according to claim 26, wherein the antimicrobial agent comprises a polymeric biguanide.
31. A method according to claim 30, wherein the polymeric biguanide is polyhexamethylene biguanide.
32. In a method of disinfecting a contact lens by means of soaking the lens in an aqueous disinfectant solution containing a disinfecting amount of an antimicrobial agent, the improvement which comprises including 0.5 to 6.0 wt% of a water-soluble borate-polyol complex in the disinfectant solution, said complex containing borate and polyol in a molar ratio of 1:1 to 1:10, whereby the antimicrobial activity of the disinfectant solution is enhanced.
33. A method according to claim 32, wherein the antimicrobial agent is selected from the group consisting of monomeric and polymeric quaternary ammonium compounds and their ophthalmically acceptable salts, monomeric and polymeric biguanides and their ophthalmically acceptable salts, and combinations thereof.
34. A method according to claim 33, wherein the borate-polyol complex is included in the composition in a concentration of 1.0 to 2.5 wt%, and the molar ratio of borate to polyol is 1:1 to 1:2.5.
35. A method according to claim 34, wherein the polyol is mannitol.
36. A method according to claim 35, wherein the antimicrobial agent comprises a polymeric quaternary ammonium compound.
37. A method according to claim 36, wherein the polymeric quaternary ammonium compound is polyquaternium-1.
38. A method according to claim 37, wherein the concentration of polyquaternium-1 in the composition is up to 0.001 wt%.
39. A method according to claim 32, wherein the antimicrobial agent comprises a polymeric biguanide.
40. A method according to claim 39, wherein the polymeric biguanide is polyhexamethylene biguanide.
41. A saline solution for soaking, rinsing and storing contact lenses, comprising:
an amount of a borate-polyol complex sufficient to preserve the solution from microbial contamination, said complex containing borate and polyol in a molar ratio of 1:0.1 to 1:1;
an amount of an osmolality-building agent sufficient to render the solution isotonic; and water.
an amount of a borate-polyol complex sufficient to preserve the solution from microbial contamination, said complex containing borate and polyol in a molar ratio of 1:0.1 to 1:1;
an amount of an osmolality-building agent sufficient to render the solution isotonic; and water.
42. A solution according to claim 41, wherein the solution comprises 0.5 to 6.0 wt% of the borate-polyol complex, and the molar ratio of borate to polyol is 1:0.25 to 1:0.75.
43. A solution according to claim 42, wherein the polyol is mannitol.
44. An aqueous solution for disinfecting contact lenses, comprising:
a disinfecting amount of an ophthalmically acceptable antimicrobial agent;
an amount of a borate-polyol complex sufficient to enhance the antimicrobial efficacy of the antimicrobial agent, said complex containing borate and polyol in a molar ratio of 1:1 to 1:2.5;
an amount of an osmolality-building agent sufficient to render the solution isotonic; and water.
a disinfecting amount of an ophthalmically acceptable antimicrobial agent;
an amount of a borate-polyol complex sufficient to enhance the antimicrobial efficacy of the antimicrobial agent, said complex containing borate and polyol in a molar ratio of 1:1 to 1:2.5;
an amount of an osmolality-building agent sufficient to render the solution isotonic; and water.
45. A solution according to claim 44, wherein the polyol is mannitol.
46. A solution according to claim 45, wherein the antimicrobial agent is selected from the group consisting of polymeric quaternary ammonium compounds and polymeric biguanides.
47. A solution according to claim 46, wherein the antimicrobial agent is a polymeric quaternary ammonium compound.
48. A solution according to claim 47, wherein the polymeric quaternary ammonium compound is polyquaternium-1.
49. A solution according to claim 48, wherein the solution contains polyquaternium-1 in a concentration of 0.001 wt%.
50. A solution according to claim 46, wherein the antimicrobial agent is a polymeric biguanide.
51. A method according to claim 50, wherein the polymeric biguanide is polyhexamethylene biguanide.
52. A method according to claim 32, wherein the polyol is selected from the group consisting of mannitol, glycerin, propylene glycol and sorbitol.
53. A method according to claim 32, wherein the polyol comprises mannitol.
54. A method according to claim 32, wherein the polyol comprises glycerin.
55. A method according to claim 32, wherein the polyol comprises propylene glycol.
56. A method according to claim 32, wherein the polyol comprises sorbitol.
57. A method according to claim 56, wherein the antimicrobial agent comprises a polymeric quaternary ammonium compound.
58. A method according to claim 57, wherein the polymeric quaternary ammonium compound comprises polyquaternium-1.
59. A method according to claim 52, wherein the antimicrobial agent comprises a polymeric biguanide.
60. A method according to claim 59, wherein the polymeric biguanide comprises polyhexamethylene biguanide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US87943592A | 1992-05-06 | 1992-05-06 | |
| US879,435 | 1992-05-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2132826A1 CA2132826A1 (en) | 1993-11-11 |
| CA2132826C true CA2132826C (en) | 1999-01-05 |
Family
ID=25374152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002132826A Expired - Lifetime CA2132826C (en) | 1992-05-06 | 1993-05-04 | Use of borate-polyol complexes in ophthalmic compositions |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5342620A (en) |
| EP (1) | EP0639070B2 (en) |
| JP (2) | JP3337218B2 (en) |
| AT (1) | ATE300936T1 (en) |
| AU (1) | AU674852B2 (en) |
| CA (1) | CA2132826C (en) |
| DE (1) | DE69333850T3 (en) |
| DK (1) | DK0639070T4 (en) |
| ES (1) | ES2246491T5 (en) |
| HK (1) | HK1011615A1 (en) |
| WO (1) | WO1993021903A1 (en) |
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| EP0639070B2 (en) * | 1992-05-06 | 2010-09-08 | Alcon Laboratories, Inc. | Use of borate-polyol complexes in ophthalmic compositions |
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| US20070297990A1 (en) * | 2006-06-27 | 2007-12-27 | Shah Mandar V | Self-preserving composition |
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| US8629099B2 (en) * | 2008-03-25 | 2014-01-14 | Bausch & Lomb Incorporated | Ophthalmic compositions comprising a dipeptide |
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| US8431751B1 (en) | 2008-12-24 | 2013-04-30 | Alcon Research, Ltd. | Polymeric quaternary ammonium compounds with vicinal hydroxy groups |
| TW201038295A (en) | 2009-04-17 | 2010-11-01 | Alcon Res Ltd | Aqueous ophthalmic compositions containing anionic therapeutic agents |
| TWI489997B (en) * | 2009-06-19 | 2015-07-01 | Alcon Res Ltd | Aqueous pharmaceutical compositions containing borate-polyol complexes |
| TWI547522B (en) * | 2009-07-07 | 2016-09-01 | 愛爾康研究有限公司 | Ethyleneoxide butyleneoxide block copolymer compositions |
| WO2011153349A1 (en) | 2010-06-02 | 2011-12-08 | Alcon Research, Ltd. | Ophthalmic compositions comprising pbo-peo-pbo block copolymers |
| JP5870459B2 (en) | 2010-08-27 | 2016-03-01 | わかもと製薬株式会社 | Aqueous composition for eye drops |
| TWI544922B (en) | 2011-05-19 | 2016-08-11 | 愛爾康研究有限公司 | High concentration olopatadine ophthalmic composition |
| JP2013129618A (en) * | 2011-12-21 | 2013-07-04 | Nippon Tenganyaku Kenkyusho:Kk | Levofloxacin-containing water liquid medicine that improves antiseptic efficacy and physical properties |
| US8324171B1 (en) | 2012-02-06 | 2012-12-04 | Bausch & Lomb Incorporated | Ophthalmic compositions containing diglycine |
| US8664180B2 (en) | 2012-02-06 | 2014-03-04 | Bausch & Lomb Incorporated | Ophthalmic compositions containing diglycine |
| WO2019191200A1 (en) | 2018-03-27 | 2019-10-03 | American Genomics, Llc | Method and formulation for producing anesthesia of internal aspect of eye wall by topical application |
| CN113056199A (en) | 2018-11-08 | 2021-06-29 | 陈煌兴 | Trisubstituted biguanide compounds and uses thereof |
| AU2020245203A1 (en) * | 2019-03-26 | 2021-11-11 | Martin Uram | Anesthetic composition and method of anesthetizing the eye |
| PT3769753T (en) * | 2019-07-23 | 2022-02-15 | Nicox Ophthalmics Inc | Process for the preparation of sterile ophthalmic aqueous fluticasone propionate form a nanocrystals suspensions |
| CN117813116A (en) * | 2021-08-06 | 2024-04-02 | 株式会社大塚制药工场 | Disinfecting composition |
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| US4029817A (en) * | 1973-09-24 | 1977-06-14 | Allergan Pharmaceuticals | Soft contact lens preserving solutions |
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| US4820352A (en) * | 1983-01-10 | 1989-04-11 | Bausch & Lomb Incorporated | Cleaning and conditioning solutions for contact lenses and methods of use |
| US4748189A (en) * | 1985-04-19 | 1988-05-31 | Ciba-Geigy Corporation | Ophthalmic solutions and methods for improving the comfort and safety of contact lenses |
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| US5035859A (en) * | 1989-11-21 | 1991-07-30 | Schering Corporation | Contact lens disinfecting system |
| JP3058656B2 (en) * | 1990-06-18 | 2000-07-04 | トーメー産業株式会社 | Contact lens solution composition and method for cleaning or storing contact lenses using the same |
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| JP3346586B2 (en) * | 1991-08-29 | 2002-11-18 | 富山化学工業株式会社 | Pharmaceutical composition containing pyridonecarboxylic acid or salt thereof and method for stabilizing solution of pyridonecarboxylic acid or salt thereof |
| EP0639070B2 (en) * | 1992-05-06 | 2010-09-08 | Alcon Laboratories, Inc. | Use of borate-polyol complexes in ophthalmic compositions |
-
1993
- 1993-05-04 EP EP93911061A patent/EP0639070B2/en not_active Expired - Lifetime
- 1993-05-04 DE DE69333850T patent/DE69333850T3/en not_active Expired - Lifetime
- 1993-05-04 JP JP51960893A patent/JP3337218B2/en not_active Expired - Lifetime
- 1993-05-04 DK DK93911061.5T patent/DK0639070T4/en active
- 1993-05-04 AT AT93911061T patent/ATE300936T1/en active
- 1993-05-04 WO PCT/US1993/004226 patent/WO1993021903A1/en active IP Right Grant
- 1993-05-04 AU AU42336/93A patent/AU674852B2/en not_active Expired
- 1993-05-04 CA CA002132826A patent/CA2132826C/en not_active Expired - Lifetime
- 1993-05-04 ES ES93911061T patent/ES2246491T5/en not_active Expired - Lifetime
- 1993-09-07 US US08/118,833 patent/US5342620A/en not_active Expired - Lifetime
-
1998
- 1998-12-04 HK HK98112850A patent/HK1011615A1/en not_active IP Right Cessation
-
2001
- 2001-09-27 JP JP2001297487A patent/JP3527721B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07506377A (en) | 1995-07-13 |
| JP2002177369A (en) | 2002-06-25 |
| WO1993021903A1 (en) | 1993-11-11 |
| DK0639070T4 (en) | 2010-12-13 |
| AU674852B2 (en) | 1997-01-16 |
| DK0639070T3 (en) | 2005-11-28 |
| ES2246491T5 (en) | 2011-01-31 |
| EP0639070B2 (en) | 2010-09-08 |
| US5342620A (en) | 1994-08-30 |
| EP0639070B1 (en) | 2005-08-03 |
| ATE300936T1 (en) | 2005-08-15 |
| JP3337218B2 (en) | 2002-10-21 |
| HK1011615A1 (en) | 1999-07-16 |
| JP3527721B2 (en) | 2004-05-17 |
| ES2246491T3 (en) | 2006-02-16 |
| EP0639070A1 (en) | 1995-02-22 |
| DE69333850D1 (en) | 2005-09-08 |
| DE69333850T2 (en) | 2006-01-12 |
| AU4233693A (en) | 1993-11-29 |
| DE69333850T3 (en) | 2011-03-17 |
| CA2132826A1 (en) | 1993-11-11 |
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| EEER | Examination request |