(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0198828 A1
`Abelson et al.
`(43) Pub. Date:
`Oct. 7, 2004
`
`US 20040198828A1
`
`(54) COMBINATIONAL USE OF LONG-ACTING
`AND SHORT-ACTING ANTI-HISTAMINES
`FOR OCULAR ALLERGIES
`
`(75)
`
`Inventors: Mark B. Abelson, Andover, MA (US);
`Matthew J. Chapin, Haverhill, MA
`(US); Paulo J. Gomes, Haverhill, MA
`(US)
`
`Correspondence Address:
`Foley Hoag LLP
`155 Seaport Blvd.
`Boston, MA 022104600 (Us)
`
`(21) Appl. No.;
`
`10/762,201
`
`(22) Filed:
`
`Jan. 20, 2004
`
`Related US, Application Data
`
`Provisional application No. 60/440,730, filed on Jan.
`17, 2003.
`
`Publication Classification
`
`Int. Cl.7 ................................................ .. A61K 31/192
`(51)
`(52) U.S. Cl.
`............................................................ .. 514/571
`
`(57)
`
`ABSTRACT
`0
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`invention teatures the combinational use oi
`The present
`short-acting anti—histamine agents in combination with long-
`acting anti—histamine agents to provide rapid, synergistic
`and long lasting relief towards ocular allergy signs and
`symptoms.
`
`APOTEX 1052
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`Page 1
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`Page 24
`
`Page 24
`
`
`
`

`
`US 2004/0198828 A1
`
`Oct. 7, 2004
`
`COMBINATIONAL USE OF LONG-ACTING AND
`SHORT-ACTING ANTI-HISTAMINES FOR
`OCULAR ALLERGIES
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims priority to U.S. Provisional
`Application Serial No. 60/440,730 filed Jan. 17, 2003.
`BACKGROUND
`
`[0002] The eye, particularly the conjunctiva, has a rela-
`tively large number of mast cells. When allergens are
`present, they can bind to immunoglobulins on the surface of
`these mast cells and trigger the release of cellular contents,
`known as degranulation. Upon degranulation, mast cell
`components, including histamine, are released into the envi-
`ronment outside the mast cell. In seasonal or perennial
`allergic conjunctivitis, these components, particularly hista-
`mine are responsible for signs and symptoms associated
`with allergic responses such as itching, redness, lid swelling,
`chemosis, tearing, and mucus discharge. In extreme severe
`chronic cases of ocular allergy (atopic keratoconjunctivitis
`(AKC) or vernal keratoconjunctivitis (VKC), the sustained
`reaction produces an inflammatory condition that leads to
`tissue damage which may result in corneal ulcers.
`
`In the US, an estimated 80 million people experi-
`[0003]
`ence ocular allergies, according to the American Academy of
`Allergy, Asthma, and Immunology, and the incidence
`appears to be on the rise. 90-95% of cases of ocular allergy
`are either seasonal or perennial allergic conjunctivitis. Aller-
`gic symptoms often interfere with everyday activities, such
`as reading, working on a computer, driving and playing
`sports. As such, there is a need for pharmaceutical formu-
`lations that provide rapid relief from ocular allergic symp-
`toms. Such formulations should also have a long duration of
`action to eliminate the need for frequent dosing.
`SUMMARY
`
`[0004] The invention features novel pharmaceutical com-
`positions of long acting anti-histamine agents and short
`acting anti-histamine agents that provide synergistic effects
`towards alleviating the signs and symptoms of ocular aller-
`gies. A preferred combination includes an effective concen-
`tration of ketotifen and an effective concentration of phe-
`niramine. Another preferred combination includes
`an
`effective concentration of azelastine and an effective con-
`centration of antazoline.
`
`[0005] A preferred concentration of ketotifen is in the
`range of about 0.04% to 0.06%. Apreferred concentration of
`pheniramine is in the range of about 0.4% to 0.6%. A
`preferred concentration of antazoline is in the range of about
`0.4% to 0.6% and a preferred concentration of azelastine is
`in the range of about 0.04% to 0.06%.
`
`[0006] The invention also provides for methods of using
`combinations of long acting anti-histamine agents and short
`acting anti-histamine agents to treat ocular allergies.
`
`[0007] Other features and advantages of the invention will
`become apparent from the following detailed description
`and claims.
`
`of subjects treated with placebo or with 0.05% ketotifen
`(keto) for 15 minutes or 16 hours.
`
`[0009] FIGS. 2A and 2B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.5% pheniramine
`(phen) for 15 minutes or 16 hours.
`
`[0010] FIGS. 3A and 3B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.04% ketotifen
`(keto) in combination with 0.5% pheniramine (phen) for 16
`hours. FIG. 3C is a bar graph comparing median ocular
`itching scores of subjects treated with placebo or with 0.04%
`ketotifen (keto) in combination with 0.5% pheniramine
`(phen) for 16 hours.
`
`[0011] FIGS. 4A and 4B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.05% ketotifen
`(keto) in combination with 0.5% pheniramine (phen) for 15
`minutes or 16 hours. FIG. 4C is a bar graph comparing
`median ocular itching scores of subjects treated with placebo
`or with 0.05% ketotifen (keto) in combination with 0.5%
`pheniramine (phen) for 16 hours.
`
`[0012] FIGS. 5A and 5B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.06% ketotifen
`(keto) in combination with 0.5% pheniramine (phen) for 16
`hours. FIG. 5C is a bar graph comparing median ocular
`itching scores of subjects treated with placebo or with 0.06%
`ketotifen (keto) in combination with 0.5% pheniramine
`(phen) for 16 hours.
`
`[0013] FIG. 6A is a graph showing mean redness efficacy
`by treatment with 0.04%, 0.05% or 0.06% ketotifen (keto) in
`combination with 0.5% pheniramine (phen). FIG. 6B is a
`graph showing mean itching efficacy by treatment with
`0.04%, 0.05% or 0.06% ketotifen (keto)in combination with
`0.5% pheniramine (phen).
`
`[0014] FIGS. 7A and 7B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.05 % azelastine for
`15 minutes or 4 hours.
`
`[0015] FIGS. 8A and 8B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.05% azelastine in
`combination with 0.5% pheniramine for 15 minutes or 4
`hours.
`
`[0016] FIGS. 9A and 9B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.5% antazoline for
`15 minutes.
`
`[0017] FIGS. 10A and 10B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`of subjects treated with placebo or with 0.5% antazoline in
`combination with 0.05% azelastine for 15 minutes or 16
`hours.
`
`DETAILED DESCRIPTION
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`1. General
`
`[0008] FIGS. 1A and 1B are bar graphs showing mean
`ocular global redness scores and mean ocular itching scores
`
`[0018] The invention is based in part on the surprising
`discovery that combinational use of short-acting anti-hista-
`
`Page 25
`
`Page 25
`
`

`
`US 2004/0198828 A1
`
`Oct. 7, 2004
`
`mine agents such as pheniramine or antazoline, in combi-
`nation with long-acting anti-histamine agents such as keto-
`tifen or azelastine provide rapid, synergistic and long lasting
`relief towards ocular allergy signs and symptoms.
`
`2. Combinational Use of Long-Acting and
`Short-Acting Anti-Histamines
`
`[0019] The present invention features the combinational
`use of a long-acting anti-histamine agent and a short-acting
`anti-histamine agent in the treatment of ocular allergy signs
`and symptoms such as eye itching, redness, chemosis, lid
`swelling, tearing and mucus discharge. The term “ocular
`allergy” refers to any allergic disease of the eye. Examples
`of such ocular allergies include but are not
`limited to
`seasonal/perennial allergic conjunctivitis, vernal keratocon-
`junctivitis, giant papillary conjunctivitis, perennial allergic
`conjunctivitis and atopic keratoconjunctivitis. “Seasonal and
`perennial allergic conjunctivitis” typically occurs in the
`individual with sensitivities to air borne allergens such as
`pollens, dust, and animal danders. It is typically seasonal,
`unlike its year-long cousin, “perennial allergic conjunctivi-
`tis”. Both seasonal allergic or perennial allergic conjunctivi-
`tis are allergic reactions to materials that do not usually
`produce such reactions in the normal population. The symp-
`toms of exposure to the material
`to which the allergic
`individual is sensitive can include: itchy, running nose with
`sneezing, and itchy, watery, red, swollen eyes. “Giant pap-
`illary conjunctivitis” typically occurs in allergy-prone indi-
`viduals who wear soft contact
`lenses.
`It can occur in
`
`individuals who wear other types of contact lenses, but it is
`more common in soft lens wearers. It occurs as a result of
`
`adherence of airborne allergens onto the surface of the
`contact lens, with eventual development of bumps in the
`conjunctiva lining the upper eyelid as the allergic/inflam-
`matory response develops over a period of months. The
`symptoms of this disorder include decreased comfort with
`contact
`lens wear, mild itching, excessive contact
`lens
`movement, and excessive mucus production. “Vernal kera-
`toconjunctivitis” involves a more complex immunologic/
`inflammatory process. This disease has major potential for
`damage to the cornea and loss of vision. The disease affects
`young people, much more often than older people, is con-
`siderably more common in males than in females, and
`generally occurs in the spring, in temperate climates and is
`much more common in warmer climates than in temperate
`or cold climates. It is particularly prevalent in the Middle
`East and is characterized by the development of very large
`bumps on the lining of the upper eyelid.
`Itching is a
`prominent symptom. Other symptoms and signs include
`ocular burning, foreign body sensation, excessive tearing,
`excess mucus production, and blurred vision. “Atopic kera-
`toconjunctivitis” is also a serious allergic eye disease with
`major blinding potential. It typically occurs in young adults
`and adults with atopic dermatitis (eczema). Ocular itch is the
`primary beginning symptom but foreign body sensation,
`ocular burning, excessive tearing, mucus production, and
`blurred vision generally eventually occur (http://www.u-
`veitis.org/).
`
`the term “anti-histamine agent”
`[0020] As used herein,
`may include drugs that counteract the action of histamine.
`Generally, allergy drugs may include drugs that are more
`selective for certain sub-types of histamine receptors such as
`H1 histamine receptor, H2, H3 or H4 receptors. Some
`anti-histamine agents have less selectivity, and thus more
`
`activity across the different histamine receptors, and may
`even possess activity against other receptors (e.g. cholin-
`ergic or adrenergic) which may be involved in regulation of
`the vasculature. Other anti-histamine agents may addition-
`ally act on certain cells, called mast cells, to prevent them
`from releasing substances that cause the allergic reaction
`and may also have anti-inflammatory properties.
`
`[0021] The term “short-acting anti-histamine agent” may
`apply to an anti-histamine agent that is typically applied or
`taken more than once per day or an anti-histamine agent that
`has varying specificity for histamine receptors and acts to
`block not just H1 but also to some degree H2, H3, H4
`histamine receptors, or other receptors. Such anti-histamine
`agents may also possess other desirable anti-allergy activi-
`ties and still have a short duration of action. As used herein
`
`“short-acting anti-histamine agent” may include but is not
`limited to pheniramine (Naphcon-A), chlorpheniramine,
`dexbrompherniramine,
`pyrilamine,
`diphenhydramine
`(Benadryl), promethazine, hydroxyzine, antazoline, emdas-
`tine
`(Emadine)
`and pharmaceutically acceptable
`salts
`thereof.
`
`[0022] The term “long-acting anti-histamine agent” may
`apply to an anti-histamine agent that is typically applied or
`taken once or twice per day or an anti-histamine agent that
`is generally more selective for a particular receptor such as
`the H1 histamine receptor. Such agents may additionally act
`on certain cells, called mast cells,
`to prevent them from
`releasing substances that cause the allergic reaction and may
`also have anti-inflammatory properties. As used herein
`“long-acting anti-histamine agent” refers to but is not lim-
`ited to ketotifen (Zaditor), loratadine (Claritin), mizolastine,
`ebastine, fexofenadine (Allegra), Cetrizine (Zyrtec), azelas-
`tine, olopatadine (Patanol), desloratadine, carebastine, levo-
`ceterizine, astemizole,
`tecastemizole, epinastine (Elestat),
`levocabastine (Livostin) and pharmaceutically acceptable
`salts thereof.
`
`[0023] Particular preferred combinations of long-acting
`anti-histamine agents and short-acting anti-histamine agents
`reduce ocular redness in about 1 minute, 3 minutes, 5
`minutes, 7 minutes, 10 minutes, 15 minutes or 20 minutes.
`Such combinations may also reduce ocular redness for a
`duration of 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-22,
`or 22-24 hours. Particular preferred combinations of long-
`acting anti-histamine agents and short-acting anti-histamine
`agents reduce ocular itching in about 1 minute, 3 minutes, 5
`minutes, 7 minutes, 10 minutes, 15 minutes or 20 minutes.
`Such combinations may also reduce ocular itching for a
`duration of 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-22,
`or 22-24 hours.
`
`[0024] A preferred combination of long-acting anti-hista-
`mine agent and short-acting anti-histamine agent is ketotifen
`or pharmaceutically acceptable salt thereof and pheniramine
`or pharmaceutically acceptable salt
`thereof. Yet another
`preferred combination of long-acting anti-histamine agent
`and short-acting anti-histamine agent is azelastine or phar-
`maceutically acceptable salt thereof and antazoline or phar-
`maceutically acceptable salt thereof.
`
`[0025] As used herein, the term “ketotifen” may include a
`pharmaceutically acceptable salt of ketotifen such as keto-
`tifen fumarate. Particularly preferred concentrations of keto-
`tifen or a pharmaceutically acceptable salt thereof, are in the
`
`Page 26
`
`Page 26
`
`

`
`US 2004/0198828 A1
`
`Oct. 7, 2004
`
`range of about 0.01 to 0.10%, more preferably in the range
`of about 0.040 to 0.045%, 0.046 to 0.050%, 0.051 to 0.055%
`or 0.056 to 0.060%.
`
`[0026] As used herein, the term “azelastine” may include
`a pharmaceutically acceptable salt of azelastine such as
`azelastine acetate, azelastine guconate, azelastine lactate or
`azelastine maleate. Particularly preferred concentrations of
`azelastine or a pharmaceutically acceptable salt thereof, are
`in the range of about 0.01 to 0.10%, more preferably in the
`range of about 0.040 to 0.045%, 0.046 to 0.050%, 0.051 to
`0.055% or 0.056 to 0.060%, more preferably about 0.05%.
`
`the term “pheniramine” may
`[0027] As used herein,
`include a pharmaceutically acceptable salt of pheniramine or
`derivatives of pheniramine such as brompheniramine male-
`ate (Demitane), chlorpheniramine maleate (Chlor-Trime-
`ton), dexbrompheniramine maleate, dexchlorpheniramine
`maleate (Polaramine), and pheniramine maleate (Naphcon-
`A). Particularly preferred concentrations of pheniramine or
`a pharmaceutically acceptable salt thereof, are in the range
`of about from 0.1 to 1%, more preferably in the range of
`about 0.40 to 0.45%, 0.46 to 0.50%, 0.51 to 0.55%, or 0.56
`to 0.60%, more preferably about 0.5%.
`
`[0028] As used herein, the term “antazoline” may include
`a pharmaceutically acceptable salt of antazoline. Particularly
`preferred concentrations of antazoline or a pharmaceutically
`acceptable salt thereof, are in the range of about 0.1 to 1%,
`more preferably in the range of about 0.40 to 0.45%, 0.46 to
`0.50%, 0.51 to 0.55%, or 0.56 to 0.60%, more preferably
`about 0.5%.
`
`[0029] Alternatively, pheniramine or pharmaceutically
`acceptable salt of pheniramine may be used in combination
`with another long-acting anti-histamine agent
`that may
`include but is not limited to loratadine (Claritin), mizolas-
`tine, ebastine, fexofenadine (Allegra), Cetrizine (Zyrtec),
`olopatadine (Patanol), desloratadine, carebastine, levoceter-
`izine, astemizole, tecastemizole, epinastine (Elestat), eme-
`dastine (Emadine) or pharmaceutically acceptable salts
`thereof.
`
`pharmaceutically
`or
`antazoline
`[0030] Alternatively,
`acceptable salt of antazoline may be used in combination
`with another long-acting anti-histamine agent
`that may
`include but is not limited to ketotifen (Zaditor), loratadine
`(Claritin), mizolastine, ebastine,
`fexofenadine (Allegra),
`Cetrizine (Zyrtec), olopatadine (Patanol), desloratadine,
`carebastine, levoceterizine, astemizole, tecastemizole, epi-
`nastine (Elestat), emedastine (Emadine) and pharmaceuti-
`cally acceptable salts thereof.
`
`pharmaceutically
`or
`ketotifen
`[0031] Alternatively,
`acceptable salt of ketotifen may be used in combination with
`another short-acting anti-histamine agent that may include
`but
`is not
`limited to chlorpheniramine, dexbromphe-
`niramine, pyrilamine, diphenhydramine (Benadryl), promet-
`hazine, hydroxyzine, antazoline, levocabastine (Livostin) or
`pharmaceutically acceptable salts thereof.
`
`pharmaceutically
`or
`azelastine
`[0032] Alternatively,
`acceptable salt of azelastine may be used in combination
`with another short-acting anti-histamine agent
`that may
`include but is not limited to chlorpheniramine, dexbromphe-
`niramine, pyrilamine, diphenhydramine (Benadryl), promet-
`hazine, hydroxyzine, levocabastine (Livostin) or pharma-
`ceutically acceptable salts thereof.
`
`In one embodiment, an effective concentration of
`[0033]
`ketotifen or a pharmaceutically acceptable salt thereof may
`be administered separately from an effective concentration
`of pheniramine or
`a pharmaceutically acceptable salt
`thereof. As used herein, the term “effective concentration”
`refers to the concentration sufficient to effect a beneficial or
`
`desired clinical effect on signs and/or symptoms of ocular
`allergy upon treatment. An effective concentration of keto-
`tifen may be administered first to the eye surface followed
`by the administration of an effective concentration of phe-
`niramine. Alternatively, an effective concentration of phe-
`niramine may be administered first
`to the eye surface
`followed by the administration of an effective concentration
`of ketotifen. In another embodiment of the invention, an
`effective concentration of ketotifen may be administered in
`combination with an effective concentration of pheniramine
`at the same time.
`
`In another embodiment, an effective concentration
`[0034]
`of azelastine or a pharmaceutically acceptable salt thereof
`may be administered separately from an effective concen-
`tration of antazoline or a pharmaceutically acceptable salt
`thereof. An effective concentration of azelastine may be
`administered first to the eye surface followed by the admin-
`istration of an effective concentration of antazoline. Alter-
`
`natively, an effective concentration of antazoline may be
`administered first to the eye surface followed by the admin-
`istration of an effective concentration of azelastine.
`In
`another embodiment of the invention, an effective concen-
`tration of azelastine may be administered in combination
`with an effective concentration of antazoline at the same
`time.
`
`[0035] A pharmaceutical composition of the invention
`may be formulated with any of a variety of carriers including
`water, mixtures of water and water-miscible solvents, such
`as C1- to C7-alkanols, vegetable oils or mineral oils com-
`prising from 0.5 to 5% by weight hydroxyethyicellulose,
`ethyl oleate, carboxymethyl-cellulose, polyvinyl-pyrroli-
`done and other non-toxic water-soluble polymers, in par-
`ticular for ophthalmic uses, such as, for example, cellulose
`derivatives, such as methylcellulose, alkali metal salts of
`carboxymethylcellulose, hydroxymethylcellulose, hydroxy-
`ethylcellulose, methylhydroxypropylcellulose and hydrox-
`ypropylcellulose, acrylates or methacrylates, such as salts of
`polyacrylic acid or ethyl acrylate, polyacrylamides, natural
`products, such as gelatin, alginates, pectins,
`tragacanth,
`karaya gum, xanthan gum, carrageenin, agar and acacia,
`starch derivatives, such as starch acetate and hydroxypropyl
`starch, and also other synthetic products, such as polyvinyl
`alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, poly-
`ethylene oxide, preferably cross-linked polyacrylic acid,
`such as neutral Carbopol, or mixtures of those polymers.
`Preferred carriers are water, cellulose derivatives, such as
`methylcellulose, alkali metal salts of carboxymethylcellu-
`lose, hydroxymethylcellulose, hydroxyethylcellulose, meth-
`ylhydroxy-propylcellulose
`and
`hydroxypropylcellulose,
`neutral Carbopol, or mixtures thereof. A highly preferred
`carrier is water or saline solution. The concentration of the
`
`carrier is, typically, from 1 to 100000 times the concentra-
`tion of the active ingredient. The term “aqueous” typically
`denotes an aqueous composition wherein the carrier is to an
`extent of >50%, more preferably >75% and in particular
`>90% by weight water.
`
`Page 27
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`Page 27
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`

`
`US 2004/0198828 A1
`
`Oct. 7, 2004
`
`[0036] A composition of the invention may include but is
`not limited to a solution, a suspension, a gel, an ointment, an
`emulsion and/or a mixture thereof.
`
`drops and/or those with an already compromised ocular
`surface (e.g. dry eye) wherein limiting exposure to a pre-
`servative may be more desirable.
`
`[0037] Further preference is given to pharmaceutical com-
`positions which are suitable for ocular administration.
`Therefore such a pharmaceutical composition preferably
`comprises a pharmaceutically acceptable carrier that include
`ingredients that meet the prerequisites for ocular tolerability.
`These further ingredients may include but is not limited to
`tonicity enhancers, preservatives, solubilizers, non-toxic
`excipients, demulcents, sequestering agents and pH adjust-
`ing agents.
`
`[0038] For the adjustment of the pH, preferably to a
`physiological pH, buffers may especially be useful. The pH
`of the present solutions should be maintained within the
`range of 4.0 to 8.0, more preferably about 4.0 to 6.0, more
`preferably about 6.5 to 7.8. Suitable buffers may be added,
`such as boric acid, sodium borate, potassium citrate, citric
`acid, sodium bicarbonate, TRIS, and various mixed phos-
`phate buffers
`(including combinations of Na2HPO4,
`NaH2PO4 and KHZPO4) and mixtures thereof. Borate buffers
`are preferred. Generally, buffers will be used in amounts
`ranging from about 0.05 to 2.5 percent by weight, and
`preferably, from 0.1 to 1.5 percent.
`
`[0039] Tonicity is adjusted if needed typically by tonicity
`enhancing agents. Such agents may, for example be of ionic
`and/or non-ionic type. Examples of ionic tonicity enhancers
`are alkali metal or earth metal halides, such as, for example,
`CaCl2, KBr, KCl, LiCl, Nal, NaBr or NaCl, Na2SO4 or boric
`acid. Non-ionic tonicity enhancing agents are, for example,
`urea, glycerol, sorbitol, mannitol, propylene glycol, or dex-
`trose. The aqueous solutions of the present invention are
`typically adjusted with tonicity agents to approximate the
`osmotic pressure of normal
`lachrymal
`fluids which is
`equivalent to a 0.9% solution of sodium chloride or a 2.5%
`solution of glycerol. An osmolality of about 225 to 400
`mOsm/kg is preferred, more preferably 280 to 320 mOsm.
`
`[0040] A preservative may typically be selected from a
`quaternary ammonium compound such as benzalkonium
`chloride, benzoxonium chloride or the like. Benzalkonium
`chloride is better described as: N-benzyl-N-(C8-C18 alkyl)-
`N,N-dimethylammonium chloride. Examples of preserva-
`tives different from quaternary ammonium salts are alkyl-
`mercury salts of thiosalicylic acid, such as, for example,
`thiomersal, phenylmercuric nitrate, phenylmercuric acetate
`or phenylmercuric borate, sodium perborate, sodium chlo-
`rite, parabens, such as,
`for example, methylparaben or
`propylparaben, alcohols, such as, for example, chlorobu-
`tanol, benzyl alcohol or phenyl ethanol, guanidine deriva-
`tives, such as, for example, chlorohexidine or polyhexam-
`ethylene biguanide, sodium perborate, Germal®II or sorbic
`acid. Preferred preservatives are quaternary ammonium
`compounds,
`in particular benzalkonium chloride or
`its
`derivative such as Polyquad (see U.S. Pat.