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`
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`
`U.S. UTIUTY Patent Application
`
`end
`
`ISSUE DATE
`
`AsslsttntEnmfr':/ . .,-rr. ,'"
`
`Prlnery Erarnlnr
`
`TERMINAL
`otsct_AtMER
`
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`1
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`

`

`iN THE UNITED STATES PATENT AND TRADEIVIARK OFFICE
`
`PATENT
`
`In re: Bhag\-vati P. Kabra et al.
`
`U.S. Serial No.: TBD
`
`Confirmation No.: TBD
`
`Filed: 15 April2011
`
`Examiner: TBD
`
`Group Art Unit: TBD
`
`f hereby c,;:;rtify that this ::-:orrespm:dence is being
`submitted
`te
`!h;; Mail Stop Amendment;
`Commissim;er for Patents, P.O, Box 1450,
`Aleximdria.. VA 223l3·lil50 via EFS-W;;b on
`this date:
`
`April H, 20 ll.
`
`By: La~d?~n}_11QK.tnzj~t
`Barbara h1cl<>,or;zie
`
`For:
`
`SELF-PRESERVED AQUEOUS PHAR.Pv1ACElJTICAL COMPOSITIONS
`
`PRELilVIINARY Al\IIENDIVIENT
`
`Iv1ail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Dear Sir or :rv:ladam~
`
`Please enter the following amendL'1enls prior to formal examination of the
`
`above-ident1fied application.
`
`Amendments to the Specification begin on page 2 of this paper.
`
`Amendments to the Claims are reflected in the listing of claims that begins on page 3 of
`
`this paper.
`
`Amendments to the Drawings are reflected in the listing of clain1s that begins on page 6
`
`of this paper.
`
`Remarks begin on page 9 of this paper.
`
`2
`
`

`

`REPLACEI\tiENT SHEET
`
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`

`

`REPLACEMENT SHEET
`REPLACEMENT SHEET
`
`2/3
`
`Fm. 2
`
`30,0 ··-r----------------------------.
`
`~§w£i25firé mannitm. 15% Pmpyiene Gym! and {3.25% Berk:
`
`n: {315% Mminiimzmm 0?” Basic'sxm
`
`7
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`
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`
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`
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`

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`REPLACEMENT SHEET
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`
`5
`
`

`

`U.S. SedalNb.; TBD
`FHcd: A.prlJ 15, 201 1
`l\.tge9
`
`By this amendml~nt, Apj)lk:<::Hlts have can.~~cled claims 1 "'18 and added claims l9,..J1,
`/\pplicants believe claims 19-:31 Ht't~ in condition tor ai]~)vvance.
`
`CONCLUSION
`
`Should th(;~. Ex~nniner h~'IV(~ (:ltl)' question~ f(~ga.rding this Arrmnd.l.Treni, r1ease feel free
`to contact the un<.krsigned attorney at the phone number listed bckwv.
`
`AdJn.".:;~; l'ot Om:{::>pNld~ncc:
`Sc<Ht i\. Ch~Yppi..:;, lP Legal
`·
`Ak(m R~:sc<'l.r~h; Ud.
`62{)1 s. Fr~~~w~ty, ·n34-,s
`f<)tt.Wmth,.TX. 7ZH34-<Nl99
`J'>i:H:>lw: g 17-6 l 5~528S
`
`6
`
`

`

`Docket No. 3205 US
`
`Filed ElectTonically
`September 20, 2007
`
`SELF-PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
`
`Cross-Reference to Related Applications
`
`5
`
`The present application claims priority based on U.S. Provisional Patent
`Application Serial Nos. 60/827,411 filed September 28, 2006, and 60/826,529, filed
`
`September 21, 2006.
`
`10
`
`Background of the Invention
`
`The present
`invention
`is directed
`to
`self-preserved pharmaceutical
`compositions. More specifically, the invention is directed to the provision of aqueous,
`multi-dose pharmaceutical compositions that have been formulated so as to have
`sufficient antimicrobial activity to satisfy the preservation efficacy requirements of the
`United States Pharmacopeia ("USP") and analogous guidelines in other countries,
`without requiring a conventional antimicrobial preservative, such as benzalkonium
`chloride, polyquaternium-1, hydrogen peroxide (e.g., sodium perborate ), or chorine(cid:173)
`containing agents. The ability to achieve self-preservation is based on a unique
`combination of formulation components and criteria.
`
`Many pharmaceutical compositions are required to be sterile (i.e., free of
`bacteria,
`fungi and other pathogenic microorganisms).
`Examples of such
`compositions include: solutions and suspensions that are injected into the bodies of
`humans or other mammals; creams, lotions, solutions or other preparations that are
`topically applied to wounds, abrasions, burns, rashes, surgical incisions, or other
`conditions where the skin is not intact; and various types of compositions that are
`applied either directly to the eye (e.g., artificial tears, irrigating solutions, and drug
`products), or are applied to devices that will come into contact with the eye (e.g.,
`contact lenses).
`
`The foregoing types of compositions can be manufactured under sterile
`conditions via procedures that are well known to those skilled in the art. However,
`once the packaging for a product is opened, such that the composition contained
`therein is exposed to the atmosphere and other sources of potential microbial
`contamination (e.g., the hands of a human patient), the sterility of the product may be
`
`15
`
`20
`
`25
`
`30
`
`35
`
`7
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`compromised. Such products are typically utilized multiple times by the patient, and
`are therefore frequently referred to as being of a "multi-dose" nature.
`
`Due to the frequent, repeated exposure of multi-dose products to the risk of
`5 microbial contamination, it is necessary to employ a means for preventing such
`contamination from occurring. The means employed may be: (i) a chemical agent that
`prevents the proliferation of microbes in a composition, which is referred to herein as
`an "antimicrobial preservative"; or (ii) a packaging system that prevents or reduces the
`risk of microbes reaching a pharmaceutical composition within a container.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Prior multi-dose ophthalmic compositions have generally contained one or
`more antimicrobial preservatives in order to prevent the proliferation of bacteria, fungi
`and other microbes. Such compositions may come into contact with the cornea either
`directly or indirectly. The cornea is particularly sensitive to exogenous chemical
`agents. Consequently, in order to minimize the potential for harmful effects on the
`cornea, it is preferable to use anti-microbial preservatives that are relatively non-toxic
`to the cornea, and to use such preservatives at the lowest possible concentrations (i.e.,
`the minimum amounts required in order to perform their anti-microbial functions).
`
`Balancing the anti-microbial efficacy and potential toxicological effects of anti-
`microbial preservatives is sometimes difficult to achieve. More specifically, the
`concentration of an antimicrobial agent necessary for the preservation of ophthalmic
`formulations from microbial contamination may create the potential for toxicological
`effects on the cornea and/or other ophthalmic tissues. Using lower concentrations of
`the anti-microbial agents generally helps to reduce the potential for such toxicological
`effects, but the lower concentrations may be insufficient to achieve the required level
`of biocidal efficacy (i.e., antimicrobial preservation).
`
`The use of an inadequate level of antimicrobial preservation may create the
`potential for microbial contamination of the compositions and ophthalmic infections
`resulting from such contaminations. This is also a serious problem, since ophthalmic
`infections involving Pseudomonas aeruginosa or other virulent microorganisms can
`lead to loss of visual function or even loss of the eye.
`
`Thus, there is a need for a means of enhancing the activity of anti-microbial
`agents so that very low concentrations of the agents can be utilized without increasing
`the potential for toxicological effects or subjecting patients to unacceptable risks of
`microbial contamination and resulting ophthalmic infections.
`
`2
`
`8
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`Ophthalmic compositions are generally formulated as
`isotonic, buffered
`solutions. One approach to enhancing the anti-microbial activity of such compositions
`is to include multi-functional components in the compositions.
`In addition to
`performing their primary functions, these multi-functional components also serve to
`enhance the overall anti-microbial activity of the compositions.
`
`The following publications may be referred to for further background regarding
`the use of multi-functional components to enhance the antimicrobial activity of
`ophthalmic compositions:
`
`1.
`2.
`3.
`
`4.
`5.
`
`6.
`7.
`
`U.S. Patent No. 5,817,277 (Mowrey-McKee, et al; tromethamine);
`U.S. Patent No. 6,503,497 (Chowhan, et al.; borate/polyol complexes);
`U.S. Patent No. 5,741,817 (Chowhan, et al.; low molecular weight amino acids
`such as glycine);
`U.S. Patent No. 6,319,464 (Asgharian; low molecular weight amino alcohols);
`U.S. Patent Application Publication No. US 2002/0122831 AI (Mowrey(cid:173)
`McKee, et al.; bis-aminopolyols);
`U.S. Patent No. 6,348,190 (Illes, et al.; zinc); and
`JP 2003-104870 (zinc).
`
`The use of zinc to enhance the antimicrobial activity of pharmaceutical
`compositions, including ophthalmic solutions, is well known. See, for example, the
`following articles and patent publications, as well as U.S. Patent No. 6,348,190 and JP
`2003-104870, cited above:
`
`McCarthy, "Metal Ions and Microbial Inhibitors", Cosmetic & Toiletries, 100:69-72
`(Feb. 1985);
`
`Zeelie, et al., "The Effects of Selected Metal Salts on the Microbial Activities of
`Agents used in the Pharmaceutical and Related Industries", Metal Compounds in
`Environment and Life, 4:193-200 (1992);
`
`Zeelie, et al., "Effects of Copper and Zinc Ions on the Germicidal Properties of Two
`Popular Pharmaceutical Antiseptic Agents, Cetylpyridinium Chloride and Povidone(cid:173)
`iodine", Analyst, 123:503-507 (March 1998);
`
`10
`
`I 5
`
`20
`
`25
`
`30
`
`35
`
`3
`
`9
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`McCarthy, et al., "The Effect of Zinc Ions on the Antimicrobial Activity of Selected
`Preservatives", Journal ofPharmacy and Pharmacology, Vol. 41 (1989);
`
`U.S. Patent No. 6,482,799 (Tuse, et al.);
`
`5
`
`U.S. Patent No. 5,320,843 (Raheja, et al.);
`
`U.S. Patent No. 5,221,664 (Berkowitz, et al.);
`
`10 U.S. Patent No. 6,034,043 (Fujiwara, et al.);
`
`IS
`
`20
`
`2s
`
`30
`
`35
`
`U.S. Patent No. 4,522,806 (Muhlemann, et al.);
`
`U.S. Patent No. 6,017,861 (Fujiwara, et al.); and
`
`U.S. Patent No. 6,121,315 (Nair, et al.).
`
`The present invention is directed to the provision of improved preservative systems
`containing zinc ions.
`
`The compositions of the present invention are multi-dose products that do not
`require a conventional antimicrobial preservative (e.g., benzalkonium chloride), and
`yet are preserved from microbial contamination. Such compositions have been
`referred to in the art as being "preservative free" (see, e.g., U.S. Patent No. 5,597,559
`issued to Olejnik, et al.).
`Compositions that are preserved from microbial
`contamination as a result of the inherent antimicrobial activity of one or more
`components of the compositions are also referred to in the art as being "self(cid:173)
`preserved" (see, e.g., U.S. Patent No. 6,492,361 issued to Muller, et al.).
`
`The following publication may be referred to for further background regarding
`pharmaceutical compositions that are "preservative-free" or "self-preserving": Kabara,
`et al., Preservative-Free and Self-Preserving Cosmetics and Drugs - Princ~ples and
`Practice, Chapter 1, pages 1-14, Marcel Dekker, Inc. (1997).
`
`The multi-dose compositions of the present invention, which do not contain a
`conventional antimicrobial preservative, are referred to herein as being "self(cid:173)
`preserved".
`
`4
`
`10
`
`

`

`Docket No. 3205 US
`
`Summary of the Invention
`
`Filed Electronically
`September 20, 2007
`
`s
`
`The present invention is directed to the self-preservation of aqueous ophthalmic
`compositions via the use of very low concentration of zinc ions. The present
`invention is based in part on the finding that in order to utilize low concentrations of
`zinc ions to self-preserve multi-dose ophthalmic compositions having ophthalmically
`acceptable pH and osmolality values, certain formulation parameters must be
`maintained. Specifically, the concentration of buffering anions utilized to maintain
`the pH within an ophthalmically acceptable range must be limited to an amount of 15
`10 millimolar ("mM") or less in order to avoid interfering with the anti-microbial activity
`of the zinc ions.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`In addition, it has been determined that the antimicrobial activity of the zinc(cid:173)
`containing compositions of the present invention can be further enhanced by the use
`of zinc ions in combination with borate or a borate/polyol complex, and that if such a
`combination is utilized, the use of propylene glycol is strongly preferred, so as to
`avoid ionic interactions between anionic species generated by other polyols (e.g.,
`sorbitol) and the zinc cations.
`
`It has also been determined that the performance of the zinc-based preservative
`systems of the present invention is further enhanced by: (i) limiting the amount of
`multivalent metal cations other than zinc (e.g., calcium and magnesium) in the
`compositions of the present invention; and (ii) limiting the amount of ionized salts
`(e.g., sodium chloride and potassium chloride) in said compositions. As described in
`greater detail below, the compositions of the present invention are preferably free of
`or substantially free of both ionized salts and multivalent metal cations other than
`zmc.
`
`The self-preserved, multi-dose compositions of the present invention have
`several advantages over existing ophthalmic formulations that are either: (i) packaged
`as a "single dose" or "unit of use" product, so as to avoid the inclusion of any
`antimicrobial preservative (e.g., BION®TEARS Lubricant Eye Drops, which is
`marketed by Alcon Laboratories, Inc.), or (ii) preserved by means of a so-called
`"disappearing" preservatives, such as the chlorite-based system described in U.S.
`Patent Nos. 5,424,078; 5,736,165; 6,024,954; and 5,858,346 (e.g., the artificial tears
`product "REFRESH™ Tears", which is marketed by Allergan), or the peroxide(cid:173)
`containing system described in U.S. Patent Nos. 5,607,698; 5,683,993; 5,725,887; and
`
`5
`
`11
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`5,858,996 (e.g., the artificial tear product "GenTeal™ Tears", which is marketed by
`CIBA Vision).
`
`Unlike these existing products, the multi-dose ophthalmic compositions of the
`present invention are able to satisfy the USP preservative efficacy requirements, as
`well as analogous
`requirements
`in other countries,
`including
`the Japanese
`Pharmacopoeia (" JP 11
`) and European Pharmacopoeia ( 11EP") preservative efficacy
`standards, without employing any conventional antimicrobial preservatives, such as
`chlorite or hydrogen peroxide.
`
`The above-discussed findings regarding the zinc may be applied to enhance the
`antimicrobial activity of various types of pharmaceutical compositions. However, the
`present invention is particularly directed to the provision of aqueous ophthalmic
`solutions that are· effective in preventing microbial contamination in the absence of
`conventional antimicrobial preservatives, such as benzalkonium chloride ("BAC"),
`polyquaternium-1, chlorite or hydrogen peroxide.
`
`s
`
`10
`
`ts
`
`Brief Description of the Drawings
`
`20
`
`Figures 1-3 are graphs showing the interaction of boric acid and various
`polyols.
`
`Detailed Description of the Invention
`
`2s
`
`30
`
`The pharmaceutical compositions of the present invention contain zinc ions at a
`concentration of 0.04 to 0.9 millimoles/liter ("mM"), preferably 0.04 to 0.4 mM and
`most preferably 0.1 to 0.4 mM. The use of this very low concentration is particularly
`desirable in ophthalmic pharmaceutical compositions containing therapeutically active
`agents, such as prostaglandin analogues used to control intraocular pressure (e.g.,
`travoprost), because at higher concentrations the zinc ions may produce an astringent
`effect when applied to the eye. The zinc ions are preferably provided in the form of
`zinc chloride, at a concentration of 0.0005 to 0.012 percent by weight/volume
`("w/v% 11
`) , preferably 0.0005 to 0.005 w/v% and most preferably 0.001 to 0.005 w/v%.
`
`35
`
`The zinc may be provided in various forms, such as zinc chloride, zinc sulfate,
`zinc acetate or zinc carbonate. The use of zinc chloride is preferred.
`
`6
`
`12
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`As indicated above, the present invention is based on pm1 on a finding that
`anionic agents utilized to buffer the compositions of the present invention may
`interfere with the ability of zinc to exert antimicrobial activity. Such interference can
`be very detrimental to the ability of the compositions to maintain sufficient
`antimicrobial activity to meet preservative efficacy standards, particularly in view of
`the very low concentrations of zinc utilized in the present invention. Accordingly, it
`has been determined that the total concentration of anionic species in the compositions
`of the present invention should be limited. Specifically, it is preferred that the total
`concentration of anionic species, particularly buffering anions, should be limited to an
`amount of less than 15 mM, more preferably less than 10 mM, and most preferably
`less than 5 mM. For simplicity and clarity, the concentration of buffering anionic
`species in this patent application will be represented by the concentration of
`monovalent cations (such as sodium) that are present or needed to bring the pH to the
`specified value.
`
`As utilized herein, the phrase "less than" relative to a specified concentration
`(e.g., 15 mM) means that the specified component (e.g., buffering anions) is either not
`present in the composition at all or is present at a concentration less than the specified
`limit (e.g., 15 mM).
`
`It has been determined that multivalent buffering anions, particularly citrate
`and phosphate, have a significant adverse effect on the antimicrobial activity of the
`zinc-based preservative systems described herein. The compositions of the present
`invention therefore preferably do not contain any multivalent buffering anions, other
`than borate-polyol complexes, which may be multivalent under certain conditions
`(e.g., pH and/or borate: polyol ratio), or are substantially free of such buffering anions.
`As utilized herein, the phrase "substantially free of multivalent buffering anions"
`means that the composition either does not contain any multivalent buffering anions or
`contains an amount of said anions that does not inhibit the ability of the composition
`to satisfy specified preservative efficacy standards (e.g., USP, EP or JP). The amount
`of multivalent buffering anions in the compositions of the present invention is
`preferably less than 5 mM, with said concentration being determined in the same
`manner as specified in the preceding paragraph.
`
`As indicated above, it has been determined that the antimicrobial activity of the
`zinc-based preservative systems of the present invention is also adversely affected by
`other divalent cations, such as calcium and magnesium. The antimicrobial activity of
`divalent zinc ions (Zn2+) is based upon the ability of the ions to competitively bind and
`
`7
`
`5
`
`to
`
`IS
`
`20
`
`2s
`
`30
`
`35
`
`13
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`inactivate macromolecular complexes that are critical to the central metabolic activity
`In order for Zn2+ to kill, it must first gain access to the
`of the prokaryotic cell.
`cytoplasm and its charge density prevents its diffusion across the membrane at a
`physiologically significant rate. Therefore, the ability of Zn2
`+ ions to enter the cell
`5 must be facilitated by membrane transport proteins. Access to these transport proteins
`can be competitively inhibited by multivalent metal cations, particularly Mg2
`+, Ca2
`+,
`+, Ni2
`Mn2
`+, and Co2+. Thus, increasing the extracellular concentration of these
`inhibitory cations diminishes the capacity of Zn2
`+ ions to gain access to the cytoplasm
`and subsequently reduces its cytotoxic activity to the microorganism.
`
`10
`
`1s
`
`20
`
`25
`
`30
`
`35
`
`In view of the potential interference of multivalent metal cations other than
`zinc, the compositions of the present invention preferably do not contain such cations
`or are substantially free of said cations. As utilized herein, the phrase "substantially
`free of multivalent metal cations other than zinc" means that the composition either
`does not contain such cations or contains an amount of said cations that does not
`inhibit the ability of the composition to satisfy specified preservative efficacy
`standards (e.g., USP, EP or JP). The amount of multivalent metal cations other than
`zinc in the compositions of the present invention is preferably less than 5 mM.
`
`It has also been determined that ionized salts (e.g., sodium chloride and
`potassium chloride) adversely affect the antimicrobial activity of the preservative
`systems described herein. Accordingly, the compositions of the present invention
`preferably do not contain ionized salts, or are substantially free of ionized salts. As
`utilized herein, the phrase "substantially free of ionized salts" means that the
`composition either does not contain any ionized salt or contains an amount of ionized
`salt that does not inhibit the ability of the composition to satisfy specified efficacy
`standards (e.g., USP, JP or EP). The amount of ionized salt contained in the
`compositions of the present invention is preferably less than 50 mM.
`
`As used herein, the term "borate" includes boric acid, sodium borate and
`potassium borate. The use ofborates containing divalent cations (e.g., calcium borate)
`may adversely affect the antimicrobial action of zinc ions, by competing with zinc for
`binding sites on the cell walls of bacterial and other microbes, and is therefore should
`be avoided. For the same reason, the self-preserved compositions of the present
`invention are preferably free of or substantially free of other sources of divalent
`cations, such as calcium chloride.
`
`8
`
`14
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`The self-preserved compositions of the present invention preferably contain
`one or more borates in an amount of from about 0.1 to about 2.0°/o w/v, more
`preferably 0.3 to 1.5o/o w/v, and most preferably 0.5 to 1.2% w/v.
`
`As used herein, the term "polyol" includes any compound having at least one
`hydroxyl group on each of two adjacent carbon atoms that are not in trans
`configuration relative to each other. The polyols can be linear or cyclic, substituted or
`unsubstituted, or mixtures thereof, so long as the resultant complex is water soluble
`and pharmaceutically acceptable. Examples of 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, xylitol, sorbitol and
`propylene glycol.
`
`As indicated above, the use of propylene glycol is particularly preferred in
`order to limit the presence of anionic species. Boric acid interacts with polyols, such
`as glycerol, propylene glycol, sorbitol and mannitol, to form borate polyol complexes.
`The type and ratio of such complexes depends on the number of OH groups of a
`polyol on adjacent carbon atoms that are not in trans configuration relative to each
`other. For example, propylene glycol has only one OH group on each of two adjacent
`carbon atoms that are not in trans configuration. Consequently, one molecule of boric
`acid will interact and form a complex with one or two molecules of propylene glycol,
`resulting in a monovalent anion. However, in the case of sorbitol, mannitol and other
`sugar-type polyols, this interaction is much more complex, because one molecule of
`such polyols can complex with two molecules of borate and then further complex with
`two additional molecules of the polyol, resulting in a multivalent anion.
`
`When borate is present in the compositions of the present invention, the
`compositions preferably also contain one or more polyols, at a total concentration of
`0.25 to 2.5% w/v. The polyol preferably is propylene glycol at a concentration of0.25
`to 1.80% w/v, preferably 0.25 to 1.25o/o w/v. Although less preferable than propylene
`glycol, sorbitol and mannitol are also preferred polyols, and preferably are used at a
`concentration of 0.05 to 0.75% w/v, preferably 0.05 to 0.5% w/v.
`
`The compositions of the present invention preferably contain borate or a
`borate/polyol complex, most preferably a borate/polyol complex wherein the polyol
`portion of the complex is propylene glycol or a combination of propylene glycol and
`sorbitol. The preference for propylene glycol is based on a discovery that sorbitol and
`other polyols have a greater tendency to form anionic species at pH values of 7.5 or
`
`9
`
`s
`
`10
`
`15
`
`20
`
`2s
`
`30
`
`35
`
`15
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`less, and that such anionic species may interfere with the antimicrobial activity of
`zinc. The graphs shown in Figures 1-3 demonstrate that sorbitol has a much higher
`tendency to form anionic species in the presence of boric acid, compared to propylene
`glycol.
`
`The data shown in Figures 1-3 were compiled as follows: A 1 Kg solution
`containing the given concentrations of boric acid and propylene glycol or sorbitol or
`mannitol was prepared and the initial pH of the solution was determined. 1 N NaOH
`was then added to adjust the pH. The cumulative amount of sodium hydroxide used to
`adjust pH to different values was then recorded.
`
`As explained above, boric acid interacts and forms an ionic complex with
`species containing several hydroxyl groups, such as mannitol and sorbitol. However,
`the interaction between boric acid and propylene glycol is more limited than with
`other polyols. This is represented by the amount of sodium hydroxide needed to
`adjust pH, as shown in Figure 1. Sorbitol and mannitol significantly shift the curve
`relative to the amount of NaOH required to lower pH, whereas propylene glycol only
`slightly shifts the curve. This is further evident in Figure 2.
`
`The present invention is particularly directed to the provision of multi-dose,
`self-preserved ophthalmic compositions that have sufficient antimicrobial activity to
`allow the compositions to satisfy the USP preservative efficacy requirements, as well
`as other preservative efficacy standards for aqueous pharmaceutical compositions,
`without a conventional antimicrobial preservative.
`
`The preservative efficacy standards for multi-dose ophthalmic solutions in the
`U.S. and other countries/regions are set forth in the following table:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`10
`
`16
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`Preservative Efficacy Test ("PET") Criteria
`(Log Order Reduction of Microbial Inoculum Over Time
`
`USP27
`
`Japan
`
`Fungi
`Bacteria
`A reduction of 1 log (90%), The compositions must demonstrate over
`the entire test period, which means no
`by day 7; 3 logs (99.9%) by
`increases of 0.5 logs or greater, relative
`day 14; and no increase after
`to the initial inoculum.
`day 14
`3 logs by 14 days; and no No increase from initial count at 14 and
`14 28 days
`from
`mcrease
`day
`through day 28.
`Ph. Eur. A 1 A reduction of 2 logs (99o/o) A reduction of 2 logs (99%) by 7 days,
`by 6 hours; 3 logs by 24 and no increase thereafter
`hours; and no recovery after
`28 days
`A reduction of 1 log at 24 A reduction of 1 log (90%) by day 14,
`hours; 3 logs by day 7; and and no increase thereafter
`no increase thereafter
`A reduction of 3 logs from No increase higher than the initial value
`initial challenge at day 14; at day 14, and no increase higher than the
`and a reduction of 3 logs day 14 rechallenge count through day 28.
`from rechallenge
`
`Ph. Eur. B
`
`FDA/ISO
`14730
`
`5
`
`10
`
`1There are two preservative efficacy standards in the European Pharmacopoeia ' "A"
`and "B".
`
`The standards identified above for the USP 27 are substantially identical to the
`requirements set forth in prior editions of the USP, particularly USP 24, USP 25 and
`USP 26.
`
`The compositions of the present invention may optionally also include one or
`more low molecular weight amino alcohols as buffering agents. The amino alcohols
`15 which may be utilized in the present invention are water-soluble and have a molecular
`weight in the range of from about 60 to about 200. The following compounds are
`representative of the low molecular weight amino alcohols which may be utilized in
`the present
`invention: 2-amino-2-methyl-1-propanol
`(AMP), 2-dimethylamino(cid:173)
`methyl-1-propanol (DMAMP), 2-amino-2-ethyl-1 ,3-propanediol (AEPD), 2-amino-2-
`11
`
`17
`
`

`

`Docket No. 3205 US
`
`Filed Electronically
`September 20, 2007
`
`methyl-1 ,3-propanediol (AMPD), 2-amino-1-butanol (AB).
`"AMP (95o/o )", which
`refers to 95% pure AMP and 5% water, is the most preferred low molecular weight
`amino alcohol of the present invention.
`These amino alcohols are available
`commercially
`from Angus Chemical Company
`(Buffalo Grove,
`Illinois).
`Tromethamine may also be utilized in the compositions of the present invention.
`
`The amount of amino alcohol used will depend on the molecular weight of the
`amino alcohol selected, and the presence (or absence) of other ingredients in the
`composition (e.g., chelating agents, buffering agents and/or tonicity agents). The
`amino alcohol will generally be present in an amount necessary to enhance the
`antimicrobial activity of an aqueous self-preserved pharmaceutical composition of the
`type described herein. The amount of amino alcohol required for a particular
`composition can be determined through comparative testing. The above-described
`amino alcohols are also utilized in the compositions of the present invention to
`neutralize the pH of the borate or borate/polyol complex, or bring the composition to
`the desired pH level. The amount of amino alcohol required for this purpose is a
`function of the particular borate or borate/polyol mixture selected and
`the
`concentration thereof.
`In general, the self-preserved compositions of the present
`invention may optionally contain one or more amino alcohols at a total concentration
`of from about 0.01 to about 2.0 percent by weight/volume ("%w/v"), and preferably
`from 0.1 to 1.0 %w/v.
`
`The zinc, zinc/borate, zinc/polyol and zinc/borate/polyol systems described
`herein may be included in various types of pharmaceutical compositions to enhance
`anti-microbial activity and self-preserve the compositions, such as ophthalmic, otic,
`nasal and dermatological compositions, but is particularly useful in ophthalmic
`compositions. Examples of such compositions include: ophthalmic pharmaceutical
`compositions, such as topical compositions used in the treatment of glaucoma,
`infections, allergies or inflammation; compositions for treating contact lenses, such as
`cleaning products and products for enhancing the ocular comfort of patients wearing
`contact lenses; and various other types of ophthalmic compositions, such as ocular
`lubricating products, artificial tears, astringents, and so on. The compositions may be
`aqueous or non-aqueous, but will generally be aqueous.
`
`The compositions of the present invention may contain various