United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,985,310
`
`Castillo et al.
`
`[45] Date of Patent:
`
`*Nov. 16, 1999
`
`USO0S985310A
`
`[54]
`
`PRESERVATIVE SYSTEMS FOR
`PHARMACEUTICAL COMPOSITIONS
`
`WO 96/148293
`W0 97/10805
`
`5/1996 WIPO.
`3/1997 WIPO ~
`
`CONTAINING CYCLODEXTRINS
`
`0.1HER PUBUCAHONS
`
`[751
`
`IHVCUIOTS3 Ernest‘) J- C3511110a /\1’11ng10T1; R3010“
`L- E5P1I10, Clcbllfflfis 130111 01 T°X~
`
`[73] Assignee: Alcon Laboratories, Inc., Fort Worth,
`Tex.
`
`[1] Notice:
`
`Appl. No.:
`.
`.
`PCT Flled’
`pCT NO‘;
`
`This patent issued on a continued Pros—
`ccufiofl application filed under 37 CFR
`1.53(d), and is SLIDJCCI to the twenty year
`provisions of 35 USE‘
`09/029,943
`
`Aug‘ 8’ 1997
`PCT/US97/14119
`
`Mar' 109 1998
`§371 Date:
`§ 102(0) Date, Man 10’ 1998
`
`PCT Pub. N02 W098/05381
`—,
`.
`FLT Pub’ Date’ Feb 19’ 1998
`Related U_S_ Application Data
`Provisional application No. 60/022,453, Aug. 9, 1996.
`
`Kubo et al., “Ophthalmic Solutions of Aspartic Acid Salts
`Containing Cyclodextrins With No Eye Irritation,” Chemi-
`caIAbstracts, vol. 125(16), Abstract No. 204583 (1996).
`Ioftsson et al., “Interactions Between Preservatives and
`2-Hydroxypropyl-[3-Cyclodextrin,” Drug Development
`Ezflgcigvgnduslrial Pharmacy, V01. 18(3), pp. 14774484
`Malakhova et al “Cyclodextrins ” CyclodextrirtNew5 vol
`801)’ pp. 159_177’ (1994),
`Miyajima et al., “Interaction of Short—Chain Alkylammo-
`nium Salts with Cyclodextrins in Aqueous Solutions,”
`Chem. Pharm. Bull, vol. 35(1), pp. 389-393 (1987).
`Shinohara et al., “Ophthalmic Solutions Containing Cationic
`Antiseptics,
`Cyclodextrins,
`and
`EDT ,”
`Chemical
`Abstracts, vol. 125(14), Abstract No. 177471 (1996).
`Simpson, “Neutralization of the Antibacterial Action of
`Quaternary Ammonium Compounds With Cyclodextrins,”
`FEMS Microbiology Letters, vol. 90, pp. 197-200 (1992).
`Takeuchi et al., “Anti-inflammatory Eyedrops,” Chemical
`Abstracts, vol. 125(14), Abstract No. 177444 (1996).
`Wakamoto Pliariii Co., Ltd, “Storage Stabilised Antiplilo-
`gistic Eye Drop Containing Diclofenac Sodium Salt Water
`Soluble Cyclodextrin Compound,” Derwent Database Week
`9403! AN 944161985 1181 (1994)
`
`Int. c1.° ......................... .. A61K 47/40; A61K 47/18
`U.s.c1. .......................... .. 424/427; 514/58; 514/740;
`
`PrimaryE>rmnin<*r—Gol1am1Idi.S. Kishore
`Allamey: A8642 or FW’/—Patr1Ck M Ryan
`
`Field of Search .......... ..
`
`424/427; 514/58,
`514/743, 740, 553
`
`References Cited
`Us. PATENT DOCUMENTS
`
`'
`
`' 930 Mayhew ................... .,
`4,209,449
`988 Pitha
`.
`4,727,064
`' 989
`4,870,060
`' 994
`5,286,719
`994
`5,310,429
`' 994
`5322667
`994
`5,376,645
`.... ..
`'995 Tsaietal.
`5,411,598
`FOREIGN PATENT DOCUMENTS
`
`..
`
`260/403
`. 514/58
`. 514/58
`514/114
`.. 134/6
`
`.
`
`.
`
`.
`
`O 076 136
`0 119 737 A2
`U 149 197 131
`99449539
`01016718
`6016547
`W0 95/30420
`W0 95730425
`
`.
`982 European Pat. Off.
`V 934 European Pa1~ 0ff~ ~
`' 985
`European 1’a1~ 015 ~
`985
`Japan '
`’ " 989
`Japan .
`994
`Japan .
`11/ 995 WIPO .
`11/ 995 WIPO .
`
`Disclosed are preservative systems useful in aqueous pliar-
`maceutical compositions containing an active agent and a
`cyclodextrin. The preservative systems comprise boric acid
`and. one or more compounds selected from the group con-
`sisting of C15 benzalkonium halide compounds, polymeric
`quatemary a1‘J111‘lO111111Tl compounds, and quatemary amino-
`nium alkylene glycol phospholipid derivatives of the fol-
`lowing Structure
`
`R3
`0
`I
`,
`ll
`I
`R—C—X—R“N+‘Y—CH(0H>CH20
`R3
`
`0
`\
`ll
`P—(0H,>b
`
`where a+b=3; R1 is C3-C2 alkyl or alkene; X is NH, O, or
`CH2; R2 is C2-C6 alkyl; each R3 is independently C1-C12
`alkyl or alkene; and Y is nothing or C1-C6 alkyl or alkene;
`.,
`V H
`and pharmaceutieally acceptable salts thereof.
`
`13 Claims, No Drawings
`
`APOTEX EX1046
`
`Page 1
`
`

`
`5,985,310
`
`1
`PRESERVATIVE SYSTEMS FOR
`PHARMACEUTICAL COMPOSITIONS
`CONTAINING CYCLODEXTRINS
`
`This application claims priority from U.S. Provisional
`Application Ser. No. 60/022,453 filed Aug. 9, 1996. This
`application is also a 371 of PCT/US97/14119 filed Aug. 8,
`1997.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`The present invention relates generally to the antimicro-
`bial preservation of aqueous pharmaceutical compositions.
`In particular, the present invention relates to the antimicro-
`bial preservation of pharmaceutical compositions containing
`cyclodextrins.
`2. Description of Related Art
`Cyclodextrins are known to possess a number of uses in
`pharmaceutical formulations. For example, cyclodextrins
`are known to increase the solubility of insoluble or poorly
`soluble drug compounds, to increase the stability of chemi-
`cally labile drugs in pharmaceutical formulations, and to
`increase the comfort or mask the taste of active drugs. See,
`U.S. Pat. No. 4,727,064 (Pitha) and EP 0 149 197 B1
`(Janssen Pharmaceutica N.V.).
`There have been a number of attempts to derivative
`cyclodextrins in order to decrease toxicity or increase solu-
`bility. For example, hydroxy-propyl-beta-cyclodextrin is a
`derivative which has been shown to have a relatively low
`toxicity and a high aqueous solubility as compared to the
`parent compound, beta-cyclodextrin. In addition to hydroxy-
`propyl derivative of beta cyclodextrin, a number of other
`cyclodextrin derivatives are known. See, for example, U.S.
`Pat. Nos. 5,376,645 (Stella et al.) and 4,870,060 (Muller).
`Typically, multi-dose pharmaceutical products contain
`preservatives in order to maintain sterility after opening and
`during use. Antimicrobial preservation of cyclodextrin-
`containing formulations can present special problems. For
`example, Loftsson et al., Drug Development and Industrial
`Pharmacy, 18 (13), 1477-1484 (1992), have investigated
`interactions between several commonly used preservatives
`and 2-hydroxypropyl-[3-cyclodextrin (HPBCD). Loftsson et
`al. report that the interactions were twofold:
`the preser-
`vative molecule can displace a drug molecule from the
`cyclodextrin cavity, thus reducing the solubilizing effects of
`the cyclodextrin; and (ii) the antimicrobial activity of the
`preservative can be reduced by the formation of
`preservative-cyclodextrin inclusion complexes. Specifically,
`Loftsson et al. report that chlorobutanol, methylparaben and
`propylparaben have little or no preservative activity in the
`tested HP[3CD solutions. Additionally, Loftsson et al. found
`that benzalkonium chloride (with the possible exception of
`the micro-organism, Ps. aeruginosa) and chlorhexidine glu-
`conate did possess significant preservative activity.
`In
`contrast, Simpson, FEMS Microbiology Letters, 90,
`197-200 (1992), reports that cyclodextrins can inactivate the
`antimicrobial activity of certain quaternary ammonium com-
`pounds. See also, Miyajima et al., Chem. Pharm. Bull.,
`35(1), 389-393 (1987), regarding the interaction of short-
`chain alkylammonium salts with cyclodextrins in aqueous
`solutions, which concluded that (X-, [3-, and y-cyclodextrins
`form complexes with alkylammonium salts having alkyl
`groups longer than n-butyl, n-hexyl, and n-decyl, respec-
`tively.
`Benzalkonium chloride (BAC) is the most popular pre-
`servative for ophthalmic drug preparations. BAC, as defined
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`an
`is
`in United States Pharmacopeia XIX,
`alkylbenzyldimethyl-ammonium chloride mixture with
`alkyl chains or homologs beginning with n-C8H17 and
`extending through higher homologs of C10-, C12-, C14-, and
`C16-alkyl chains. In our attempts to preserve pharmaceutical
`formulations containing a cyclodextrin with BAC, however,
`we have found that cyclodextrin-preservative interactions
`can significantly reduce or inactivate the preservative effi-
`cacy of BAC, when BAC is employed at non-toxic levels.
`EP 0 119 737 A2 (Takeda Chem. Ind., Ltd.) discloses
`aqueous pharmaceutical compositions comprising an active
`ingredient, a cyclodextrin and a phenol derivative as a
`preservative. The phenol derivative has the formula
`
`(R)n OH
`
`_ | _
`(X)m
`
`where R is alkyl, X is halogen, n is an integer of 0 to 2, and
`m is an integer of 1 to 3. According to this reference,
`formulations containing a cyclodextrin and a paraben pre-
`servative (methyl-, ethyl-, propyl-, and butylparaben) suf-
`fered a significant decrease in the antimicrobial activity of
`the preservative, while formulations containing a cyclodex-
`trin and a phenol derivative of the formula above did not.
`JP 60149530 A(Takeda Chem. Ind., Ltd.) discloses aque-
`ous compositions of a principal agent and a cyclodextrin
`where the compositions contain as a preservative a chlo-
`rhexidine derivative of the formula
`
`A NH C NH C NH (CH2)N-NH C NH C
`NH
`NH
`NH
`NH
`
`NHA
`
`where Ais [independently] (un)substituted phenyl; n is 3-9;
`and the polymethylene chain may be interrupted by an
`oxygen atom or an aromatic ring.
`JP 01016728 A (Santen Seiyaku KK) discloses antiseptic
`aqueous preparations containing a drug, a cyclodextrin and
`a cationic surfactant as a preservative. By adding a cyclo-
`dextrin or cyclodextrin derivative, cationic surfactants com-
`monly incompatible with certain drugs can be combined.
`Disclosed cationic surfactants are benzalkonium chloride,
`benzethonium chloride or chlorohexidine gluconate. Dis-
`closed drugs include sodium hyaluronate, pilocarpine
`hydrochloride, lysosyme chloride, Na2 chondroitin sulfate,
`glycyrrhetinate, pirenoxine, sodium chromoglycate, and
`dimethylisopropylazulene sodium sulfate.
`JP 6016547 A (Wakamoto Pharm. Co. Ltd.) discloses eye
`drop compositions containing diclofenac sodium and a water
`soluble cyclodextrin compound. The reference also dis-
`closes that these compositions can be preserved using ben-
`zalkonium chloride, benzethonium chloride and chlorhexi-
`dine gluconate as cationic surfactants; methylparaben,
`ethylparaben, propylparaben and butylparaben as parabens;
`and phenylethyl alcohol and benzyl alcohol as alcohols.
`Even if their antimicrobial preservative efficacy is not
`significantly reduced by interactions with cyclodextrins,
`benzyl or phenylethyl alcohol and paraben preservatives
`may present cytotoxicity, evaporation loss, comfort and/or
`stability problems. Other compounds or systems capable of
`effectively preserving pharmaceutical formulations contain-
`ing cyclodextrins are desirable.
`SUMMARY OF THE INVENTION
`
`According to the present invention, aqueous pharmaceu-
`tical compositions containing a pharmaceutically active
`
`Page 2
`
`Page 2
`
`

`
`5,985,310
`
`3
`compound and a cyclodextrin can be preserved using a
`preservative system comprising a combination of boric acid
`and one or more compounds selected from the group con-
`sisting of C16 benzalkonium halide compounds, polymeric
`quaternary ammonium compounds, and quaternary ammo-
`nium alkylene glycol phospholipid derivatives.
`Thus, the present invention relates to aqueous composi-
`tions containing a pharmaceutically active drug compound,
`a cyclodextrin, and a preservative system selected as
`described above. The present invention also relates to a
`method of preserving aqueous pharmaceutical compositions
`containing a cyclodextrin, wherein the method comprises
`adding to the composition a preservative system of the type
`described above.
`
`Among other factors, the present invention is based on the
`discovery that, unlike BAC, C16 benzalkonium halide
`compounds, polymeric quaternary ammonium compounds
`and quaternary ammonium alkylene glycol phospholipid
`derivatives do not interact with cylodextrins in a way that
`significantly reduces or eliminates their antimicrobial pre-
`servative activity.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The aqueous compositions of the present invention com-
`prise a pharmaceutically active drug compound,
`a
`cyclodextrin, and a preservative system, wherein the pre-
`servative system comprises a combination of boric acid and
`one or more compounds selected from the group consisting
`of C16 benzalkonium halide compounds, polymeric quater-
`nary ammonium compounds, and quaternary ammonium
`alkylene glycol phospholipid derivatives.
`The C16 benzalkonium halide compounds useful in the
`compositions of the present invention have the following
`structure
`
`+
`
` CH2N(CH3)2C1sH33 X"
`
`where X=Cl, Br, I, or F. These compounds are known in the
`art and are either commercially available or can be made
`using known methods. The most preferred C16 benzalko-
`nium halide compound is C16 benzalkonium chloride. The
`C16 benzalkonium halide compound is typically used in the
`compositions of the present invention in an amount from
`about 0.001 to 1%, preferably from about 0.01 to 0.5%. The
`most preferred concentration of the C16 benzalkonium
`halide compounds in the compositions of the present inven-
`tion is about 0.02%. (Unless indicated otherwise, all per-
`centages referred to herein are on a w/w basis).
`The polymeric quaternary ammonium compounds useful
`in the compositions of the present invention are those which
`have an antimicrobial effect and which are pharmaceutically
`acceptable. The most preferred polymeric ammonium com-
`pounds are those known as polyquaternium-1, otherwise
`known as Polyquad® or Onamer M®, with a number
`average molecular weight between 2,000 to 30,000.
`Preferably,
`the number average molecular weight of the
`polyquaternium-1 is between 3,000 to 14,000.
`The polymeric quaternary ammonium compounds are
`generally used in the compositions of the present invention
`in an amount from about 0.001 to about 3%, preferably from
`about 0.001 to about 0.1%. The most preferred concentration
`of polymeric quaternary ammonium compounds is about
`0.01%.
`
`4
`The quaternary ammonium alkylene glycol phospholipid
`derivatives useful in the compositions of the present inven-
`tion include those having the structure
`
`0
`
`R3
`
`0
`
`R1—C—x—R2—N+—Y—CH(oH)CH2o
`R3
`
`at
`
`P—(oH)b
`
`where a+b=3; R1 is C8—C22 alkyl or alkene; X is NH, O, or
`CH2; R2 is C2-C6 alkyl; each R3 is independently C1—C12
`alkyl or alkene; and Y is nothing or C1-C6 alkyl or alkene.
`In addition to the acid form of the structure shown above,
`pharmaceutically acceptable salts of the acid form are also
`within the scope of present invention. Examples of such salts
`include the sodium chloride, potassium chloride, and cal-
`cium and magnesium salts of the structure shown above.
`Preferred are the following synthetic phopholipids: cocami-
`dopropyl propylene glycol-dimonium chloride phosphate
`(sodium chloride salt where R1 is a coconut oil fatty acid
`alkyl mixture; X is NH; R2 is propyl; R3 is methyl; and Y is
`CH2); borageamidopropyl phosphatidyl propylene glycol-
`dimonium chloride (sodium chloride salt where R1 is a
`boraginaceae oil fatty acid alkyl mixture; X is NH; R2 is
`propyl; R3 is methyl; and Y is CH2); and cocophosphatidyl
`propylene glycol-dimonium chloride (sodium chloride salt
`where R1 is a coconut oil fatty acid alkyl mixture; X is O;
`R2 is propyl; R3 is methyl; and Y is CH2). The phospholipid
`compounds described above can be synthesized using
`known techniques. The three preferred phospholipids are
`commercially available from,
`for example, MONA
`Industries, Patterson, N.J.
`The amount of quaternary ammonium alkylene glycol
`phospholipid derivatives in the compositions of the present
`invention may range from about 0.01 to about 2%, prefer-
`ably from about 0.03 to 1.5%. When concentrations
`approaching the upper limits of these ranges are employed
`in compositions intended for contact with sensitive tissues,
`such as topically administrable ophthalmic formulations, the
`comfort of the compositions may be reduced and additional
`comfort-enhancing ingredients may be needed (such as
`emollients typical in the ophthalmic industry: polyethylene
`glycol, hydroxypropylmethylcellulose, polyvinylalcohol,
`etc.).
`The boric acid used in the compositions of the present
`invention includes not only boric acid, but also its pharma-
`ceutically acceptable acid addition salts. Accordingly, as
`used herein, “boric acid” refers to boric acid and its phar-
`maceutically acceptable acid addition salts. In general, an
`amount from about 0.3 to about 5% of boric acid is used in
`the compositions of the present invention. It is preferred to
`use from about 0.3 to about 3.0%, and it most preferred to
`use from about 0.5 to about 2.0%.
`Suitable cyclodextrins for use in the compositions of the
`present
`invention include pharmaceutically acceptable
`cyclodextrins and cyclodextrin derivatives. Nonionic cyclo-
`dextrins are preferred. Most preferred are alkyl derivatives,
`such as hydroxy-propyl-beta-cyclodextrin. Generally,
`the
`concentration of cyclodextrins present in the compositions
`of the present invention ranges from about 0.5 to about 20%,
`preferably from about 1 to about 10%.
`Any pharmaceutical agent may be included in the com-
`positions of the present
`invention, particularly both
`positively-charged and neutral agents (negatively-charged
`agents may form undesirable complexes with the positively-
`charged preservative ingredient). For example, pharmaceu-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 3
`
`Page 3
`
`

`
`5,985,310
`
`5
`
`5
`6
`transition upph exposure to physical or chemical stimuli,
`tical agents which may be incorporated into the composi-
`tions of the present invention include, but are not limited to,
`such as changes in pH,
`ion concentration, and/or
`the racemic and enantiomeric forms and pharmaceutically
`temperature, may be added to the compositions of the
`acceptable salts, amides, esters and prodrugs of the follow-
`present invention as desired or as necessary.
`1
`1
`1
`.
`ing types of drugs: adrenocorticoids; glucocorticoids; anti-
`The e0mP051t10h5 Of the Preseht 1hVeht10h may he fer‘
`coagulants; anticonvulsants; antidepressants; antidiabetics;
`mutated aCC0rd1hg t0 teehhlqhes kh0Wh 1h the art ahd
`antihistamines; decongestants; antithyroid agents; antimus-
`administered in a variety of ways. For example, the com-
`carinics; etc. Preferred are ophthalmic agents including
`positions of the present invention may be formulated for
`anti-glaucoma agents, such as carbonic anhydrase inhibitors,
`Pmstaglahdihs ahd Pmstaglahdih deriVatiVeS; anti‘ 10 parenteral, oral or topical administration. Topically admin-
`lhhahhhatory agehtsa Hlchldlhg but heththlted to these
`istrable ophthalmic compositions are preferred.
`classified as aryl- or heteroaryl- alkanoic acids, such as
`.
`.
`.
`.
`The following examples are presented to illustrate further
`diclofenac, bromfenac, flurbiprofen, suprofen, ketorolac,
`.
`.
`.
`.
`various aspects of the present invention, but are not intended
`.
`.
`.
`.
`.
`indomethacin and ketoprofen; anti-bacterial and anti-
`.
`.
`.
`.
`.
`.
`to limit the scope of the invention in any respect.
`.
`.
`.
`.
`.
`.
`infective agents, such as sulfacetamide sodium, penicillins 15
`and cephalosporins; mydriatic and cycloplegic agents, such
`~
`~
`~
`~
`.
`as phenylephrine, hydroxyamphetamine, tropicamide, and
`diagnostic agents such as sodium fluorescein. Combinations
`of pharmaceutical agents may also be used in the composi-
`110115 of the present invention.
`.
`.
`.
`.
`The aqueous compositions of the present invention may
`additionally include other pharmaceutically acceptable com-
`pgnents. F01‘ example, CQ[nf0r[ enhancing agents, buffers,
`surfactants, tonicity agents, antioxidants, chelating agents,
`binding agents, complexing agents, and viscosity modifying
`agents, including polymers which will undergo a sol-to-gel
`
`EXAMPLE 1
`
`1
`.
`The Eollowing formulatlons were prepared‘ En Table 1::
`20 below, BAC means benzalkonium .Chl0I‘1dC. . C12 BAC
`'
`'
`(6
`15
`theahs the C12 h0th010g Of hehzahmhlhth ehtehde (dedeeyl
`hehzahmhhhh eh10r1de)-
`C14 BAC theahs the C14
`hOIIlOlOg Of bCl'lZalkO1'l11lIIl Cl'llOI'1dC (tetradecyl benzalko-
`I111lII1 Ch10r1d€).
`“C15 BAC” means the C15 homolog Of
`benzalkonium chloride (hexadecyl benzalkonium chloride).
`“HPBD” means hydroxy-propyl-beta-cyclodextrin.
`
`Ingredient
`
`A
`
`B
`
`C
`
`E
`
`F
`
`G
`
`H
`
`TABLE 1
`FORMULATION
`
`D
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`—
`—
`—
`0.012
`0.03
`—
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`—
`—
`—
`0.015
`0.03
`—
`
`2
`—
`—
`—
`—
`—
`—
`
`2
`—
`—
`—
`—
`—
`—
`FORMULATION
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`0.01
`—
`—
`—
`—
`—
`
`2
`—
`—
`—
`—
`—
`—
`
`0.25
`0.5
`0.6
`0.01
`q.s. pH =
`6.5
`0.01
`—
`—
`—
`0.03
`0.1/
`0.03
`—
`—
`—
`—
`—
`—
`—
`
`0.25
`0.5
`0.6
`0.01
`q.s. pH =
`6.5
`0.01
`—
`—
`—
`—
`0.1/
`0.03
`—
`—
`—
`—
`—
`—
`—
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`—
`0.012
`—
`—
`0.03
`
`2
`—
`—
`—
`—
`—
`—
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`—
`—
`0.012
`—
`0.03
`
`2
`—
`—
`—
`—
`—
`—
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`0.01
`—
`—
`—
`0.03
`
`2
`—
`—
`—
`—
`—
`—
`
`I
`
`Suprofen
`Boric Acid
`NaCl
`Edetate Disodium
`NaOH/HCl
`BAC
`C12 BAC
`C14 BAC
`C15 BAC
`Hamposyl ® L
`Monobasic/Dibasic
`Na Phosphate
`HP[5CD
`Glycacil
`Polyquaternium-1
`dowicil
`cetrimide
`lysozyme
`phospholipidl
`
`Ingredient
`
`Suprofen
`Boric Acid
`NaCl
`Edetate Disodium
`NaOH/HCl
`BAC
`C12 BAC
`C14 BAC
`C15 BAC
`Hamposyl ® L
`Monobasic\basic
`Na Phosphate
`HP[5CD
`Glycacil
`Polyquaternium-1
`dowicil
`
`J
`
`K
`
`L
`
`M
`
`N
`
`O
`
`P
`
`Q
`
`R
`
`0.25
`0.5
`0.8
`0.01
`q.s. pH =
`6.5
`0.01
`—
`—
`—
`—
`0.1/
`0.03
`—
`—
`—
`—
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`—
`—
`—
`—
`—
`—
`
`2.0
`0.03
`—
`—
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`—
`—
`—
`—
`—
`—
`
`2.0
`—
`0.01
`—
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`—
`—
`—
`—
`—
`—
`
`2.0
`—
`0.005
`—
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`
`0.25
`1.0
`0.3
`0.01
`q.s. pH =
`6.5
`
`0.25
`0.5
`0.7
`0.01
`q.s. pH =
`6.5
`
`0.015
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`
`2.0
`
`0.03
`
`Page 4
`
`Page 4
`
`

`
`cetrimide
`lysozyme
`phospholipidl
`
`lcocamidopropyl PG-dimonium chloride phosphate
`
`EXAMPLE 2
`
`In addition to the suprofen formulations appearing in
`Table 1 above, the betaxolol formulations shown in Table 2,
`below, were also prepared.
`
`TABLE 2
`
`FORMULATION
`
`AA
`
`0.56
`7.5
`0.5
`0.3
`0.01
`—
`—
`0.01
`7.0
`QS
`
`AB
`
`0.56
`7.5
`0.5
`0.3
`0.01
`0.015
`—
`—
`6.6
`QS
`
`AC
`
`0.56
`7.5
`0.5
`0.3
`—
`—
`0.03
`—
`6.58
`QS
`
`COMPONENTS
`
`Betaxolol HCl
`HPBCD
`Boric Acid
`Sodium Chloride
`EDTA
`BAC
`Phospholipidl
`POLYQUAD
`NaOH/HCl QS to pH
`Purified Water
`
`1 = cocamidopropyl PG-dimonium chloride phosphate
`
`EXAMPLE 3
`
`5,985,310
`
`TABLE 1-continued
`
`0.01
`
`microbial activity of the test compositions. As shown in
`Table 3, an abbreviated time pull schedule was employed.
`Based on the data collected, projected pass/fail determina-
`tions were made by comparing the log reductions in the
`respective organism populations to the standards shown in
`Table 3.
`
`TABLE 3
`
`Abbreviated Schedule of Compendial Preservative Effectiveness
`Requirements for Ophthalmic Compositions
`
`Log Reduction of Organism Population
`
`10
`
`15
`
`20
`
`25
`
`Ph. Eur.
`A
`
`(Target)
`
`Ph. Eur.
`B
`
`(Min)
`
`Time Pull
`
`USP
`
`30
`
`For Bacteria:
`
`The antimicrobial preservative effectiveness of the com-
`positions of Examples 1 and 2 was determined using an
`organism challenge test according to the methods described
`in the United States Pharmacopeia (USP) and European
`Pharmacopoeia (Ph.Eur.). Samples were inoculated with
`known levels of gram-positive (Staphyl-ococcas aareas
`ATCC 6538) and gram-negative (Pseadomonas aeraginosa
`ATCC 9027 and Escherichia coli ATCC 8739) vegetative
`bacteria, yeast (Candida albicans ATCC 10231) and mold
`(Aspergillas niger ATCC 16404) and sampled at specified
`intervals to determine if the antimicrobial preservative sys-
`tem was capable of killing or inhibiting the propagation of
`organisms purposely introduced into the formulation.
`Despite the fact that the compositions of the present inven-
`tion are not limited to ophthalmic preparations, USP and/or
`Ph.Eur. preservative efficacy standards for ophthalmic
`preparations were used for purposes of comparing the anti-
`
`35
`
`40
`
`45
`
`6 hours
`24 hours
`
`7 days
`For Fungi:
`
`7 days
`
`—
`—
`
`3
`
`—
`
`2
`3
`
`—
`
`2
`
`—
`1
`
`3
`
`1
`
`— = No requirement at this time pull
`
`The preservative efficacy results for the formulations of
`Example 1 are shown in Table 4 below, and those for the
`formulations of Example 2 are shown in Table 5 below.
`
`TABLE 4
`
`Projected Preservative Eflicacy Test Results For Formulations of Example 1
`
`Formulation Sa
`
`6 Hr
`Pa
`
`Q’-nrnUGU:I>
`
`G(repeat)
`
`0.4
`0.0
`0.0
`5.0
`5.1
`0.0
`2.4
`0.4
`2.5
`
`0.4
`0.1
`0.1
`1.3
`2.7
`0.3
`5.0
`2.0
`5.0
`
`Log Reduction
`
`24 Hr
`Sa
`Pa
`
`2.1 1.2
`0.0 0.3
`0.0 0.8
`5.0 2.5
`5.1 3.9
`0.2 0.6
`3.7 5.0
`2.0 2.2
`4.2 5.0
`
`Day 7
`Pa
`
`ND
`ND
`ND
`ND
`5.0
`ND
`5.0
`2.4
`5.0
`
`Sa
`
`ND
`ND
`ND
`ND
`5.1
`ND
`5.0
`5.1
`5.0
`
`An
`
`ND
`ND
`ND
`ND
`4.9
`ND
`ND
`3.9
`ND
`
`Projected Decision
`USP
`PhEurA PhEurB
`
`—
`—
`—
`—
`P
`—
`P
`F
`P
`
`F
`F
`F
`F
`P
`F
`P
`F
`P
`
`—
`F
`F
`—
`P
`F
`P
`F
`P
`
`Page 5
`
`

`
`9
`
`TABLE 4-continued
`
`5,985,310
`
`10
`
`Projected Preservative Eflicacy Test Results For Formulations of Example 1
`
`Log Reduction
`
`Formulation
`
`Sa
`
`6 Hr
`Pa
`
`24 Hr
`Sa
`Pa
`
`H(repeat)
`I
`J
`K
`K(repeat)
`K(repeat)*
`L
`M
`N
`O
`P
`Q
`Q(repeat)**
`R
`
`0.1
`5.0
`0.2
`3.4
`3.1
`2.7
`2.6
`0.2
`0.2
`0.1
`5.1
`3.1
`4.8
`5.3
`
`1.6
`3.4
`0.3
`5.0
`5.1
`5.0
`5.1
`3.0
`2.2
`0.5
`5.0
`5.0
`3.6
`2.1
`
`1.4 2.0
`5.0 5.0
`0.3 0.4
`3.4 5.0
`4.0 5.1
`3.8 5.0
`3.7 5.1
`5.1 5.0
`0.2 3.5
`0.1 1.2
`5.1 5.0
`5.3 5.0
`5.1 5.1
`5.3 3.3
`
`* Boric acid = 1.0%, NaCl = 0.3%
`**Boric acid = 0.3%, NaCl = 0.7%
`ND = not measured
`
`Day 7
`Pa
`
`2.4
`5.0
`ND
`5.0
`5.1
`5.0
`5.1
`ND
`ND
`ND
`5.0
`5.0
`5.1
`4.1
`
`Sa
`
`3.8
`5.0
`ND
`5.1
`5.1
`5.3
`5.1
`ND
`ND
`ND
`5.1
`5.3
`5.1
`5.3
`
`An
`
`3.9
`ND
`ND
`ND
`1.1
`1.5
`0.8
`ND
`ND
`ND
`ND
`1.6
`1.0
`5.1
`
`Projected Decision
`USP
`PhEurA PhEurB
`
`F
`P
`—
`P
`P
`P
`P
`—
`—
`—
`P
`P
`P
`P
`
`F
`P
`F
`P
`F
`F
`F
`F
`F
`F
`P
`F
`F
`P
`
`
`
`v-u’-u’-u’-u’-11*-x1|'-11'-u’-u’-u’-11>-u’-11
`
`TABLE 5
`
`Projected Preservative Eflicacy
`Test Results For Formulations of Example 2
`
`Log Reduction
`
`Formulation
`
`6 Hr
`Sa Pa
`
`24 Hr
`Sa
`Pa
`
`Projected Decision
`Day 7
`Pa An USP PhEurA PhEurB
`
`Sa
`
`AA
`AB
`AC
`
`1.8
`5.3 5.1 5.3 5.1 5.3 5.1
`0.0 2.8 0.1 4.1 1.0 5.1 2.7
`0.0 1.8 1.1 4.6 2.4 5.1 2.1
`
`P
`F
`F
`
`F
`F
`F
`
`P
`F
`F
`
`As illustrated in Table 4, formulations containing HPBCD
`and a preservative system comprising boric acid and a
`preservative compound selected from the group consisting
`of C16 benzalkonium halide compounds, polymeric quater-
`nary ammonium compounds, and alkylaminopropylene gly-
`col phospholipid compounds (Formulations D, E, K, L, P, Q,
`and R) possess superior preservative efficacy compared to
`those formulations containing HPBCD, boric acid, and other
`preservatives, such as BAC, C12- or C14-benzalkonium
`chloride, etc. (Formulations A, B, C, F, J, M, N, & O).
`Formulations G, H & I (all of which contained boric acid and
`BAC), also performed well
`in the preservative efficacy
`assay, but none of these formulations contained HPBCD.
`As shown in Table 5, Formulation AA (preservative
`system=polyquaternium-1 and boric acid) possesses supe-
`rior preservative efficacy compared to formulation AB
`(preservative system=boric acid and BAC). Formulation AC
`(preservative system=boric acid and cocamidopropyl
`PG-dimonium chloride phosphate) did not meet the preser-
`vative efficacy standards, although Formulations P & Q in
`Table 4 (containing a different active but the same preser-
`vative system) were able to meet the efficacy 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-
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 preserved aqueous pharmaceutical composition
`comprising a therapeutically effective amount of a pharma-
`ceutically active agent, a chelating agent, a cyclodextrin and
`an antimicrobial preservative, the improvement wherein the
`preservative comprises a combination of boric acid and an
`antimicrobial preservative compound consisting essentially
`of a compound selected from the group consisting of C16
`benzalkanium halide compounds in an amount from about
`0.01—0.5% by weight and polymeric quaternary ammonium
`compounds in an amount from about 0.001—3% by weight.
`2. The composition of claim 1 wherein the preservative
`compound is a C16 benzalkonium halide and the halide is
`selected from the group consisting of chloride, bromide,
`iodide, and fluoride.
`3. The composition of claim 1 wherein the preservative
`compound is a polymeric quaternary ammonium compound.
`4. The composition of claim 3 wherein the polymeric
`quaternary ammonium compound is polyquaternium-1.
`5. The composition of claim 4 wherein the concentration
`of the preservative compound is from about 0.001 to about
`0.1% (w/w).
`6. The composition of claim 1 wherein the concentration
`of boric acid is from about 0.3 to about 5 percent by weight.
`7. The composition of claim 1 wherein the concentration
`of cyclodextrin is from about 0.5 to about 20% (w/w).
`8. The composition of claim 7 wherein the cyclodextrin is
`hydroxy-propyl-beta-cyclodextrin.
`9. A method of antimicrobial preservation of an aqueous
`pharmaceutical composition comprising a therapeutically
`effective amount of a pharmaceutically active agent, a
`chelating agent and a cyclodextrin wherein the method
`comprises adding to the composition a combination of boric
`acid and an antimicrobial preservative compound consisting
`essentially of a compound selected from the group consist-
`ing of C16 benzalkonium halide compounds in an amount
`
`Page 6
`
`

`
`5,985,310
`
`11
`from about 0.01—0.5% by weight and polymeric quaternary
`ammonium compounds in an amount from about 0.001—3%
`by Weight.
`10. The method of claim 9 wherein the preservative
`compound is a C16 benzalkonium halide and the halide is
`selected from the group consisting of chloride, bromide,
`iodide, and fluoride.
`
`5
`
`12
`11. The method of claim 9 wherein the preservative
`compound is a polymeric quaternary ammonium compound.
`12. The method of claim 11 wherein the polymeric
`quaternary ammonium compound is polyquaternium-1.
`13. The method of claim 9 wherein the concentration of
`
`cyclodextrin is from about 0.5 to about 20% (w/w).
`*
`*
`*
`*
`*
`
`Page 7
`
`Page 7