United States Patent [19J
`Chowhan et al.
`
`[54] USE OF BORATE-POLYOL COMPLEXES IN
`OPHTHALMIC COMPOSITIONS
`
`[75]
`
`Inventors: Masood Chowhan; Nissanke L.
`Dassanayake, both of Arlington, Tex.
`
`[73] Assignee: Alcon Laboratories, Inc., Fort Worth,
`Tex.
`
`[ * l Notice:
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`[21] Appl. No.: 09/109,453
`
`[22]
`
`Filed:
`
`Jul. 2, 1998
`
`[62]
`
`[51]
`
`[52]
`
`[58]
`
`[56]
`
`Related U.S. Application Data
`
`Division of application No. 08/479,281, Jun. 7, 1995, Pat.
`No. 5,811,466, which is a division of application No.
`08/198,427, Feb. 22, 1994, Pat. No. 5,505,953, which is a
`continuation-in-part of application No. 08/118,833, Sep. 7,
`1993, Pat. No. 5,342,620, which is a continuation of appli(cid:173)
`cation No. 07/879,435, May 6, 1992, abandoned.
`Int. Cl? ............................... A61K 9/00; A61K 9/08;
`A61K 33/22
`U.S. Cl. ............................ 514/839; 422/28; 424/657;
`510!112; 514/840; 514/912; 514/915
`Field of Search ..................................... 514/840, 839,
`514/912, 915; 424/657, 658, 659, 660;
`422/28; 510!112
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,975,536
`4,029,817
`4,053,628
`4,410,442
`4,525,346
`4,559,186
`4,581,379
`4,710,313
`4,748,189
`4,758,595
`4,960,799
`5,011,661
`5,032,392
`5,141,665
`5,171,526
`5,188,826
`5,281,277
`5,342,620
`5,460,658
`
`8/1976 Stevenson et a!. .
`6/1977 Blanco eta!. .
`10/1977 Stevenson et a!. .
`10/1983 Lucas eta!. .
`6/1985 Stark.
`12/1985 Lee.
`4/1986 Nelson eta!. .
`12/1987 Miyajima et a!. .
`5/1988 Suet a!..
`7/1988 Ogunbiyi eta!. .
`10/1990 Nagy.
`4/1991 Schafer.
`7/1991 Varma.
`8/1992 Sherman.
`12/1992 Wong eta!..
`2/1993 Chandrasekaran .
`1!1994 Nakagawa et a!. .
`8/1994 Chowhan.
`10/1995 Nakagawa et a!. ....................... 134/42
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006143799A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,143,799
`*Nov. 7, 2000
`
`5,494,937
`5,505,953
`5,603,929
`5,604,190
`5,653,972
`5,672,213
`
`.. .... ... ... ... ... 514/772.3
`
`2/1996 Asgharian et a!.
`4/1996 Chowhan eta!. .
`2/1997 Desai et a!. .......................... 424/78.04
`2/1997 Chowhan eta!. ...................... 510/114
`8/1997 Desai et a!. .......................... 424/78.04
`9/1997 Asgharian et a!. ....................... 134/42
`
`FOREIGN PATENT DOCUMENTS
`
`0 109 561 A1
`0 436 726 A1
`2230358
`wo 93/21903
`
`5/1984
`7/1991
`12/1974
`11/1993
`
`European Pat. Off ..
`European Pat. Off ..
`France .
`WIPO.
`
`OTHER PUBLICATIONS
`
`Chemical Abstracts, vol. 101 (1984): 8688j, Hentschell et
`al., "Agent to preserve bacterialogical specimens".
`Chemical Abstracts, vol. 94 (1981): 135600g. Opus Chemi(cid:173)
`cal AB, "Borane complexes as bacterial preservatives".
`Gilman, H. et al. (eds.), "Organic Chemistry" vol. II, John
`Wiley & Sons, Inc., New York, pp 1606-1610 (1950).
`Gilman, H., et al. (eds), "Organic Chemistry" vol. I, John
`Wiley & Sons, Inc., New York, pp 432-433 (1950).
`Gilman, H., et al. (eds.), "Organic Chemistry" vol. II, John
`Wiley & Sons, Inc., New York, pp 1540-1542, 1588, 1589
`(1950).
`Morawetz, H., "Macromolecules in Solution", John Wiley &
`Sons, Inc., New York, pp 402-404 (1974).
`Okada, T.I., Chromatography, 403:27-33 (1987).
`Rakow, P.L., Contact Lens Forum, pp 41-46 (Jun., 1988).
`Remington's Pharmaceutical Sciences, Mack Publishing
`Company, Easton,PA, p. 1445 (1980).
`Sciarra, J., et al., J. Am. Pharm. Assoc., 49(2):115-117
`(1960).
`
`Primary Examiner-Robert H. Harrison
`Attorney, Agent, or Firm-Gregg C. Brown
`
`[57]
`
`ABSTRACT
`
`Water-soluble borate-polyol complexes are useful as buffers
`and/or antimicrobials in aqueous ophthalmic compositions,
`including those containing polyvinyl alcohol. These com(cid:173)
`positions have greater antimicrobial activity than compa(cid:173)
`rable 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 incompatibil(cid:173)
`ity problem typically associated with the combination of
`borate buffer and polyvinyl alcohol; therefore, the compo(cid:173)
`sitions disclosed herein may also contain polyvinyl alcohol.
`
`21 Claims, No Drawings
`
`1
`
`

`

`6,143,799
`
`1
`USE OF BORATE-POLYOL COMPLEXES IN
`OPHTHALMIC COMPOSITIONS
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`The present application is a division of application Ser.
`No. 08/479,281 file Jun. 7, 1995 (now U.S. Pat. No. 5,811,
`466), which is a division of application Ser. No. 08/198,427
`filed Feb. 22, 1994 (now U.S. Pat. No. 5,505,953), which is
`a continuation-in-part of application Ser. No. 08/118,833
`filed Sep. 7, 1993 (now U.S. Pat. No. 5,342,620), which is
`a continuation of application Ser. No. 07/879,435 filed May
`6, 1992 (now abandoned).
`
`2
`SUMMARY OF THE INVENTION
`
`This invention provides such ophthalmic compositions.
`5 The ophthalmic compositions of the present invention com(cid:173)
`prise borate-polyol complexes which have surprisingly been
`found to have increased antimicrobial activity as compared
`to boric acid or its salts, particularly with respect to organ-
`10 isms such as A. niger. Moreover, these complexes unexpect(cid:173)
`edly increase the antimicrobial efficacy of other antimicro(cid:173)
`bial agents when used in combination.
`
`15
`
`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. The resultant
`solution may then be used as a buffer and/or antimicrobial
`20 agent in aqueous ophthalmic compositions, even where such
`compositions also contain PYA The borate-polyol com-
`plexes of the present invention are also useful in unpre(cid:173)
`served saline solutions.
`
`The borate-polyol complexes of the present invention are
`particularly useful as adjunctive disinfecting agents in con(cid:173)
`tact lens disinfecting solutions containing monomeric qua(cid:173)
`ternary 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, Tex.) or polymeric biguanides (e.g., Dymed®,
`35 Bausch & Lomb, Rochester, N.Y.).
`
`The compositions of the present invention may optionally
`contain PYA; such compositions are particularly useful in
`contact lens care products which are targeted for wearers of
`rigid gas-permeable contact lenses (RGPs), who often com(cid:173)
`plain of discomfort. PYA is a viscosity enhancer and is used
`extensively in all types of RGP products in order to improve
`45 the comfort and wearing time of RGPs. PYA is also exten-
`sively used as a viscosity enhancer for pharmaceutical
`ophthalmic compositions such as eye drops, gels or ocular
`inserts.
`
`BACKGROUND OF THE INVENTION
`This invention relates to the use of borate-polyol com(cid:173)
`plexes in ophthalmic compositions. In particular, these com(cid:173)
`plexes are useful as buffers and/or antimicrobial agents in
`aqueous ophthalmic compositions, including those oph(cid:173)
`thalmic compositions containing polyvinyl alcohol.
`Ophthalmic compositions are generally formulated to
`have a pH between about 4.0 and 8.0. To achieve a pH in this
`range and to maintain the pH for optimal stability during the
`shelf life of the composition, a buffer is often included. 25
`Borate is the buffer of choice for use in ophthalmic
`compositions, since it has some inherent antimicrobial activ-
`ity and often enhances the activity of antimicrobials;
`however, when polyvinyl alcohol (PYA) is also an ingredi(cid:173)
`ent in the composition, borate and PYA form a water- 30
`insoluble complex which precipitates out of solution and
`acts as an irritant in the eye. This incompatibility of borate
`and PYA 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.
`Since borate is incompatible with PYA, ophthalmic com(cid:173)
`positions containing PYA are generally buffered with 40
`acetate, phosphate or other buffers. There are disadvantages
`to 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 preser-
`vatives.
`It is well known that small organic compounds, such as
`benzalkonium chloride (BAC), chlorhexidine, thimerosal 50
`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 55
`lenses. More recently, polymeric antimicrobials such as
`Polyquad® (polyquaternium-1) 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 60
`antimicrobial activity, they generally have relatively weak
`antifungal activity, especially against Aspergillus niger and
`Aspergillus fumigatus.
`As used herein, and unless otherwise indicated, the term
`A need therefore exists for ophthalmic compositions 65 "polyol" shall refer to any compound having at least two
`which have an optimal pH for stability and efficacy, but
`adjacent -OH groups which are not in trans configuration
`whose antimicrobial efficacy is not compromised.
`relative to each other. The polyols can be linear or circular,
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`As used herein, 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, mag(cid:173)
`nesmm borate, manganese borate, and other such borate
`salts.
`
`2
`
`

`

`3
`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 of the present 10
`invention may be formed by mixing borate with the polyol
`(s) of choice in an aqueous solution. These complexes can be
`used in conjunction with other known preservatives and
`disinfectants to meet preservative efficacy and disinfection
`standards. In such compositions, the molar ratio of borate to
`
`6,143,799
`
`4
`PYA's vary from 20,000 to 200,000. In general, PYA used
`in ophthalmic products has an average molecular weight in
`the range of 30,000 to 100,000 with 1 1% to 15% residual
`5 acetate. Compositions of the present invention generally
`contain such types of PYA at a concentration less than about
`10.0 wt %, preferably between about 0.1 and about 1.4 wt%
`and most preferably at a concentration of about 0.75 wt %.
`
`EXAMPLE 1
`
`The water-soluble borate-polyol complexes of the present
`invention may be prepared as illustrated below.
`
`INGREDIENT
`
`A
`
`FORMULATION (% weight/volume)
`
`B
`
`0.35
`0.11
`1.0
`
`c
`
`0.35
`0.11
`1.5
`
`D
`
`0.35
`0.11
`2.0
`
`E
`
`0.35
`0.11
`
`F
`
`0.35
`0.11
`
`G
`
`0.35
`0.11
`
`H
`
`0.35
`0.11
`
`0.35
`0.11
`0.5
`
`1.0
`0.5
`2.0
`1.5
`0.1
`0.1
`0.1
`0.1
`0.1
`0.1
`0.1
`0.1
`q.s.
`q.s.
`q.s.
`q.s.
`q.s.
`q.s.
`q.s.
`q.s.
`pH 7.4 pH 7.4
`pH 7.4 pH 7.4
`pH 7.4 pH 7.4 pH 7.4 pH 7.4
`0.001 + 0.001 + 0.001 + 0.001 + 0.001 + 0.001 + 0.001 + 0.001 +
`10% xs 10% xs 10% xs 10% xs 10% xs 10% xs 10% xs 10% xs
`
`Boric acid
`Sodium borate
`Mannitol
`Glycerin
`Na2EDTA
`Purified water
`HCl/NaOH
`Polyquad ®
`
`Preparation:
`
`Formulations A-H were prepared as follows. Tubular,
`labeled and 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 dis-
`40 solved by stirring the solution for about 25 minutes. At this
`time, disodium EDTA (ethylene diamine tetraacetic acid)
`was added with stirring. Purified water was added to bring
`the solutions almost to 100% (100 mL), pH was adjusted to
`approximately 7.4 and the osmolality was measured.
`Polyquad® was then added and the volume brought to 100%
`by the addition of purified water. pH was again measured
`and adjusted, if necessary, and the osmolality was measured
`50 again.
`
`45
`
`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 may also be used in unpre- 35
`served 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 between about 1:0.25 and about 1:0.75. Some
`borate-polyol complexes, such as potassium bora tartrate, are
`commercially available.
`The borate-polyol complexes are utilized in the campo-
`sitions of the present invention in an amount between about
`0.5 to about 6.0 percent by weight (wt %), preferably
`between about 1.0 to about 2.5 wt %. The optimum amount,
`however, will depend upon the complexity of the product,
`since potential interactions may occur with the other com-
`. .
`h
`.
`b
`ponents o a composition. Sue optimum amount can e
`f
`readily determined by one skilled in the formulatory arts.
`It is not always necessary to have an isotonic solution;
`The compositions of the present invention useful with
`however, if there is a need to have an isotonic solution, the
`RGPs or compositions such as eye drops, gels or ocular
`osmolality can be adjusted by incorporating polyol with OH
`inserts will preferably also contain PYA or other viscosity- 55 groups in trans position, sodium chloride, potassium
`enhancing polymers, such as cellulosic polymers or carboxy
`chloride, calcium chloride or other osmolality building
`vinyl polymers. PYA is available in a number of grades, each
`agents which are generally acceptable in ophthalmic formu(cid:173)
`differing in degree of polymerization, percent of hydrolysis,
`lations and known to those skilled in the art.
`and residual acetate content. Such differences affect the 60
`physical and chemical behavior of the different grades. PYA
`can be divided into two broad categories, i.e., completely
`hydrolyzed and partially hydrolyzed. Those containing 4%
`residual acetate content or less are referred to as completely
`hydrolyzed. Partially hydrolyzed grades usually contain
`20% or more residual acetate. The molecular weight of
`
`EXAMPLE 2
`
`65
`
`Aqueous ophthalmic compositions of the present inven(cid:173)
`tion may be prepared using the formulations illustrated
`below.
`
`3
`
`

`

`5
`
`6
`
`6,143,799
`
`INGREDIENT
`
`2
`
`3
`
`4
`
`5
`
`7
`
`8
`
`9
`
`FORMULATION (£ercent by weight)
`
`PVA
`Hydroxyethyl cellulose (HEC)
`Mannitol
`Boric acid
`Sodium borate
`Edetate disodium
`Sodium chloride
`Polyquad@
`Sucrose
`Polyhexamethylene biguanide
`BAC
`
`1.4
`
`0.75
`
`0.75
`0.75
`0.75
`0.75
`0.75
`0.28
`0.28
`0.28
`0.28
`0.75
`0.5
`2.0
`2.0
`2.0
`2.0
`2.0
`2.0
`0.35
`0.35
`0.35
`0.35
`0.35
`0.35
`0.35
`0.11
`0.11
`0.11
`0.11
`0.11
`0.11
`0.11
`0.1
`0.1
`0.1
`0.1
`0.1
`0.1
`0.1
`0.09
`0.09
`0.45
`0.09
`0.09
`0.09
`0.09
`0.001 0.001 0.001 0.001 0.001 0.001 0.001
`2.5
`
`0.75
`0.75
`2.0
`0.35
`0.11
`0.1
`0.09
`
`2.5
`0.0005
`
`0.75
`0.75
`2.0
`0.35
`0.11
`0.1
`0.09
`
`2.5
`
`0.004
`
`Preparation:
`Formulations 1-9 were prepared as follows. A first solu(cid:173)
`tion (Solution A) was prepared by adding 500 mL of warm
`purified water to a calibrated two liter aspirator bottle
`equipped with a magnetic stirrer. PYA and hydroxyethyl
`cellulose were then added to Solution A and the contents
`dispersed by stirring. After dispersal of the polymers, a filter
`assembly was attached to the aspirator bottle (142 mm 25
`Millipore filter holder with 0.2 filter), and this whole appa(cid:173)
`ratus autoclaved at 121 o C. for 30 minutes. Solution A with
`the filter assembly attached was then allowed to cool to room
`temperature with stirring. A second solution (Solution B),
`was prepared in a 500 mL beaker containing 300 mL of 30
`purified water by adding boric acid, sodium borate and
`mannitol and dissolving the contents by stirring for 25
`minutes. Edctatc disodium, sodium chloride, preservatives
`and other osmolality-building agents, as necessary, were
`added to Solution B and the contents dissolved with stirring. 35
`Solution B was then sterile filtered into the aspirator bottle
`containing Solution A The pH of the resultant solution was
`then adjusted and the volume brought to 100% by sterile
`filtering purified water.
`
`EXAMPLE 4
`The following is a typical wetting and soaking composi-
`20 tion of the present invention for use with RGPs.
`
`INGREDIENT
`
`AMOUNT (wt %)
`
`PVA
`HBC
`Boric acid
`Sodium borate
`Mannitol
`Potassium chloride
`Magnesium chloride
`Calcium chloride
`Sodium chloride
`Polysorbate 80
`Polyquad ®
`NaOH and/or HCl
`Purified water
`
`0.75
`0.38
`0.35
`0.11
`2.0
`O.D38
`0.02
`0.0154
`0.09
`0.005
`0.001
`pH 7.4
`q.s.
`
`EXAMPLE 3
`
`The following ophthalmic compositions of the present
`invention may also be prepared using the procedure detailed
`in Example 2.
`
`Preparation:
`In a suitable container containing approximately 30% of
`40 the final volume of purified water, PVAand HEC were added
`and dispersed. This solution was then autoclaved. The
`solution was allowed to cool to room temperature with
`stirring. In a separate container, containing approximately
`50% of the final volume of purified water, boric acid and
`sodium borate were added, and dissolved, followed by
`
`INGREDIENT
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`FORMULATION (percent by weight)
`
`PVA
`Naphazolene HCl
`Sodium sulfacetamide
`Fluorometholone
`Gentamycin sulfate
`Levobunolol HCl
`Mydrysone
`Pilocarpine nitrate
`Sodium metabisulfite
`Mannitol
`Boric acid
`Sodium borate
`Sodium chloride
`Edetate disodium
`BAC
`Polyquad@
`
`1.4
`0.1
`
`1.4
`0.1
`
`1.4
`
`1.4
`
`1.4
`
`1.4
`
`1.4
`
`1.4
`
`1.4
`
`1.4
`
`10.0
`
`0.1
`
`0.4
`
`0.5
`
`0.4
`2.0
`0.35
`0.11
`0.45
`0.1
`
`1.0
`
`2.0
`0.35
`0.11
`0.45
`0.1
`
`1.0
`
`1.0
`
`1.0
`
`2.0
`0.35
`0.11
`0.45
`0.1
`
`4.0
`0.35
`
`0.5
`0.5
`
`0.1
`
`0.1
`
`2.0
`2.0
`0.35 0.35
`0.11 0.11
`0.45
`0.1
`
`0.1
`
`2.0
`0.35
`0.11
`0.45
`0.1
`
`2.0
`0.35
`0.11
`0.45
`0.1
`
`2.0
`0.35
`0.11
`0.45
`0.1
`0.004
`
`0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001
`
`4
`
`

`

`6,143,799
`
`7
`mannitol. This second solution was then stirred for about 30
`minutes, then potassium chloride, calcium chloride, magne(cid:173)
`sium chloride, sodium chloride, polysorbate 80 and
`Polyquad® were added, with stirring. The second solution
`was then added to the first solution via a 0.2 i filter. Last, the 5
`pH was adjusted to 7.4 and the volume brought to 100% with
`purified water.
`
`8
`
`-continued
`
`INGREDIENT
`
`AMOUNT (w/v %)
`
`NaOH and/or HCl
`Purified water
`
`pH 7.4
`q.s.
`
`EXAMPLE 8
`
`The following is a typical RGP cleaner composition of the
`present invention which may be prepared m a manner
`similar to that detailed in Example 4.
`
`INGREDIENT
`
`AMOUNT (wt %)
`
`French Naturelle ® ES (Nylon
`11)
`Hydroxyethyl cellulose
`Sodium borate, decahydrate
`Boric acid
`Mannitol
`Miracare ® 2MCA)
`Isopropyl alcohol (v/v)
`NaOH and/or HCl
`Purified water
`
`2.5
`
`0.4
`0.25
`0.50
`3.5
`0.50
`10.0
`q.s. 7.4
`q.s.
`
`10
`
`15
`
`20
`
`25
`
`EXAMPLE 9
`
`30
`
`The following is a typical RGP wetting and/or soaking
`composition of the present invention, which may be pre(cid:173)
`pared in a manner similar to that detailed in Example 4.
`
`35
`
`40
`
`45
`
`50
`
`INGREDIENT
`
`AMOUNT (wt %)
`
`Methocel ® E4M
`Mannitol
`Sodium borate
`Boric acid
`Sodium chloride
`Disodium edetate
`Polyquad ®
`NaOH and/or HCl
`Purified water
`
`0.85
`2.00
`0.11
`0.35
`0.19
`0.1
`0.001
`pH 7.4
`q.s.
`
`EXAMPLE 10
`
`The following study compared the antimicrobial preser(cid:173)
`vative efficacy of two wetting, soaking and disinfecting
`solutions: one containing phosphate buffer (Formulation A);
`and the other containing a borate-polyol complex of the
`present invention (Formulation B).
`Formulations A and B are shown in the following table.
`
`EXAMPLE 5
`
`The following is a typical daily cleaner composition of the
`present invention for use with RGPs and may be prepared in
`a manner similar to that detailed in Example 4.
`
`INGREDIENT
`
`AMOUNT (wt %)
`
`Nylon 1111
`Dextran 70
`Sodium borate
`Boric acid
`Miracare ® 2MCA
`PDMA-1
`Propylene glycol
`Polyquad ®
`EDTA
`Mannitol
`NaOH and/or HCl
`Purified water
`
`2.50
`6.0
`0.25
`0.50
`0.50
`0.15
`10.0
`0.0055
`0.10
`1.20
`pH 7.4
`q.s.
`
`EXAMPLE 6
`
`The following is a typical wetting and soaking composi(cid:173)
`tion of the present invention which may be prepared in a
`manner similar to that detailed in Example 4.
`
`INGREDIENT
`
`AMOUNT (wt %)
`
`Hydroxypropyl
`methylcellulose
`(Methocel ® E4M)
`Mannitol
`Sodium borate
`Boric acid
`Sodium chloride
`Polyquad ®
`EDTA
`NaOH and/or HCl
`Purified water
`
`0.72
`
`1.0
`0.11
`0.35
`0.19
`0.0011
`0.10
`pH 7.4
`q.s.
`
`EXAMPLE 7
`
`The following is a typical comfort drop composition of
`the present invention which may be prepared in a manner
`similar to that detailed in Example 4.
`
`55
`
`INGREDIENT
`
`PVA
`HEC
`Mannitol
`Sodium borate
`Boric acid
`Sodium chloride
`Polyquad ®
`EDTA
`
`AMOUNT (w/v %)
`
`INGREDIENT
`
`0.75
`0.28
`2.0
`0.11
`0.35
`0.152
`0.00082
`0.10
`
`60
`
`65
`
`PVA
`HEC
`Sodium phosphate
`Sodium biophosphate
`Boric acid
`Sodium borate
`Mannitol
`Disodium edetate
`
`FORMULATION (wt %)
`
`A
`
`0.75
`0.5
`0.67
`0.017
`
`0.1
`
`B
`
`0.75
`0.5
`
`0.35
`0.11
`2.0
`0.1
`
`5
`
`

`

`6,143,799
`
`9
`
`-continued
`
`FORMULATION (wt %)
`
`INGREDIENT
`
`Sodium chloride
`Polysorbate 80
`Benzalkonium chloride
`Purified water
`
`A
`
`0.458
`0.005
`0.01
`q.s.
`
`B
`
`0.153
`0.005
`0.01
`q.s.
`
`Formulations A and B were tested against FDA challenge
`organisms. The log reductions after 1 hour are tabulated
`below:
`
`10
`that one contained a borate-polyol complex of the present
`invention (Formulation E) and the other contained the
`conventional borate buffer (Formulation F).
`An organism challenge approach based on the BP 1988
`5 Test for Efficacy of Preservatives in Pharmaceutical Prod(cid:173)
`ucts was used to evaluate the antimicrobial preservative
`efficacy of Formulations E and F. Formulation samples were
`inoculated with known levels of A. niger and sampled at
`predetermined intervals to determine if the is system was
`10 capable of killing or inhibiting the propagation of organisms
`introduced into the products.
`Formulations E and F are shown in the following table.
`
`FORMULATION
`(log reduction)
`
`TEST ORGANISM
`
`A. niger
`B. albicans
`P. aernginosa
`S. aureus
`E. coli
`
`A
`
`2.1
`4.0
`5.3
`5.5
`5.5
`
`B
`
`4.4
`5.3
`5.3
`5.2
`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 greater activity against certain organisms,
`such as A. niger.
`
`15
`
`20
`
`25
`
`FORMULATION (wt %)
`
`INGREDIENT
`
`Boric acid
`Sodium borate
`Mannitol
`Sodium citrate
`Citric acid
`Sodium chloride
`Pluronic P103
`Disodium edetate
`Polyquad ®
`NaOH and/or HCl
`Purified water
`
`E
`
`0.3
`0.11
`0.85
`0.56
`0.021
`0.48
`0.5
`0.05
`0.001
`pH 7.0
`q.s.
`
`F
`
`0.35
`0.11
`
`0.56
`0.21
`0.48
`0.5
`0.05
`0.001
`pH 7.0
`q.s.
`
`30
`
`EXAMPLE 11
`The following study compared the antimicrobial preser(cid:173)
`vative efficacy of two unpreserved saline solutions identical
`except that one contained a borate-polyol complex of the 35
`present invention (Formulation C) and the other contained
`the conventional borate buffer (Formulation D).
`An organism challenge approach based on the British
`Pharmacopoeia ("BP") 1988 Test for Efficacy of Preserva(cid:173)
`tives in Pharmaceutical Products was used to evaluate the 40
`antimicrobial preservative efficacy of Formulations C and D.
`Formulation samples were inoculated with known levels of
`A. niger and sampled at predetermined intervals to deter(cid:173)
`mine if the system was capable of killing or inhibiting the
`propagation of organisms introduced into the products.
`Formulations C and D are shown in the following table.
`
`45
`
`INGREDIENT
`
`Boric acid
`Sodium borate
`Mannitol
`Sodium chloride
`Disodium edetate
`NaOH and/or HCl
`Purified water
`
`FORMULATION (wt %)
`
`c
`
`1.0
`0.2
`1.5
`
`0.1
`pH 7.4
`q.s.
`
`D
`
`10
`0.2
`
`0.3
`0.1
`pH 7.4
`q.s.
`
`The results indicated that there was a 3.1 log reduction of
`A. niger with Formulation C and only 1.2 log reduction with
`Formulation D after 7 days. Formulation C met the BP
`standards for preservative efficacy against A. niger, while
`Formulation D failed to meet the BP standards.
`EXAMPLE 12
`The following study compared the antimicrobial preser(cid:173)
`vative efficacy of two disinfecting solutions identical except
`
`50
`
`65
`
`The results indicate that there was a 2.1 log reduction of
`A. niger with Formulation E and only 1.1 Ilog reduction with
`Formulation F after 7 days. Formulation E met the BP
`standards for preservative efficacy against A. niger, while
`Formulation F failed to meet the BP standards.
`The invention has been described by reference to certain
`preferred embodiments; however, it should be understood
`that it may be embodied in other specific forms or variations
`thereof without departing from its spirit or essential char(cid:173)
`acteristics. The embodiments described above are therefore
`considered to be illustrative in all respects and not
`restrictive, the scope of the invention being indicated by the
`appended claims rather than by the foregoing description.
`What is claimed is:
`1. In a method of preserving an aqueous ophthalmic
`composition from microbial contamination, the improve(cid:173)
`ment 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.
`2. A method according to claim 1, wherein the composi(cid:173)
`tion contains a preservative effective amount of an oph(cid:173)
`thalmically acceptable antimicrobial agent.
`3. A method according to claim 2, wherein the antimi(cid:173)
`crobial agent is selected from the group consisting of
`55 monomeric and polymeric quaternary ammonium com(cid:173)
`pounds and their ophthalmically acceptable salts, mono(cid:173)
`meric and polymeric biguanides and their ophthalmically
`acceptable salts, and combinations thereof.
`4. A method according to claim 3, wherein the borate-
`60 polyol complex is included in the composition in a concen(cid:173)
`tration of 1.0 to 2.5 wt %, and the molar ratio of borate to
`polyol is 1:0.25 to 1:2.5.
`5. A method according to claim 4, wherein the polyol is
`mannitol.
`6. A method according to claim 5, wherein the antimi(cid:173)
`crobial agent comprises a polymeric quaternary ammonium
`compound.
`
`6
`
`

`

`12
`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 1:0.1 to 1:10;
`an amount of an osmolality-building agent sufficient to
`render the solution isotonic; and
`water.
`15. A solution according to claim 14, wherein the polyol
`is mannitol.
`16. A solution according to claim 14, wherein the anti(cid:173)
`microbial agent is selected from the group consisting of
`polymeric quaternary ammonium compounds and polymeric
`biguanides.
`17. A solution according to claim 16, wherein the anti(cid:173)
`microbial agent is a polymeric quaternary ammonium com(cid:173)
`pound.
`18. A solution according to claim 17, wherein the poly(cid:173)
`meric quaternary ammonium compound is polyquaternium-
`20 1.
`
`11
`7. A method according to claim 6, wherein the polymeric
`quaternary ammonium compound is polyquaternium-1.
`8. A method according to claim 7, wherein the concen(cid:173)
`tration of polyquaternium- 1 in the composition is up to
`0.001 wt %.
`9. A method according to claim 5 wherein the antimicro(cid:173)
`bial agent comprises a polymeric biguanide.
`10. A method according to claim 9, wherein polymeric
`biguanide is polyhexamethylene biguanide.
`11. A saline solution for soaking, rinsing and storing 10
`contact lenses, comprising:
`an amount of a borate-polyol complex sufficient to pre(cid:173)
`serve 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.
`12. A solution according to claim 11, 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.
`13. A solution according to claim 12, wherein the polyol
`is mannitol.
`14. An aqueous solution for disinfecting contact lenses, 25
`comprising:
`a disinfecting amount
`antimicrobial agent;
`
`of an ophthalmically acceptable
`
`15
`
`6,143,799
`
`5
`
`19. A solution according to claim 18, wherein the solution
`contains polyquaternium-1 in a concentration of 0.001 wt %.
`20. A solution according to claim 16, wherein the anti(cid:173)
`microbial agent is a polymeric biguanide.
`21. A solution according to claim 20, wherein the poly(cid:173)
`meric biguanide is polyhexamethylene biguanide.
`
`* * * * *
`
`7
`
`