(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0198828A1
`(43) Pub. Date:
`Oct. 7, 2004
`Abelson et al.
`
`US 2004O198828A1
`
`(54) COMBINATIONAL USE OF LONG-ACTING
`AND SHORTACTING ANTI-HISTAMINES
`FOR OCULARALLERGIES
`
`(76) 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 02210-2600 (US)
`(21) Appl. No.:
`10/762,201
`(22) Filed:
`Jan. 20, 2004
`
`Related U.S. Application Data
`(60) Provisional application No. 60/440,730, filed on Jan.
`17, 2003.
`
`Publication Classification
`
`(51) Int. Cl. ................................................ A61K 31/192
`(52) U.S. Cl. .............................................................. 514/571
`
`ABSTRACT
`(57)
`The present invention features the combinational use of
`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.
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1039, Page 1
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`US 2004/O198828A1
`
`Oct. 7, 2004
`
`COMBINATIONAL USE OF LONG-ACTING AND
`SHORTACTING ANTI-HISTAMINES FOR
`OCULARALLERGIES
`
`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.
`0003. In the US, an estimated 80 million people experi
`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%. A preferred 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.
`0.015 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
`0008 FIGS. 1A and 1B are bar graphs showing mean
`ocular global redneSS Scores and mean ocular itching Scores
`
`1. General
`0018. The invention is based in part on the surprising
`discovery that combinational use of short-acting anti-hista
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1039, Page 25
`
`

`

`US 2004/O198828A1
`
`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/).
`0020. As used herein, the term “anti-histamine agent”
`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, hydroxy Zine, 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
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1039, Page 26
`
`

`

`US 2004/O198828A1
`
`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%.
`0.027 AS used herein, the term “pheniramine' may
`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.
`0030 Alternatively, antazoline or pharmaceutically
`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.
`or pharmaceutically
`0.031
`Alternatively,
`ketotifen
`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.
`0032. Alternatively, azelastine or pharmaceutically
`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.
`
`0033. In one embodiment, an effective concentration of
`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 C- 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.
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1039, Page 27
`
`

`

`US 2004/O198828A1
`
`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.
`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.
`0.038
`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 NaHPO,
`NaHPO, and KHPO) 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.
`0.039
`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,
`CaCl, KBr, KCl, LiCl, Nal, NaBr or NaCl, NaSO 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-(Cs-Cs 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(EII or Sorbic
`acid. Preferred preservatives are quaternary ammonium
`compounds, in particular benzalkonium chloride or its
`derivative such as Polyguad (see U.S. Pat. No. 4,407,791),
`alkyl-mercury Salts and parabens. Where appropriate, a
`Sufficient amount of preservative is added to the ophthalmic
`composition to ensure protection against Secondary con
`taminations during use caused by bacteria and fungi.
`0041. In another embodiment, the pharmaceutical com
`positions of this invention may not include a preservative.
`Such formulations would be useful for patients who wear
`contact lenses, or those who use Several topical ophthalmic
`
`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.
`0042 A pharmaceutical composition may additionally
`require the presence of a Solubilizer, in particular if the
`active or the inactive ingredients tends to form a Suspension
`or an emulsion. A Solubilizer Suitable for an above con
`cerned composition is for example Selected from the group
`consisting of tyloxapol, fatty acid glycerol polyethylene
`glycol esters, fatty acid polyethylene glycol esters, polyeth
`ylene glycols, glycerol ethers, a cyclodextrin (for example
`alpha-, beta- or gamma-cyclodextrin, e.g. alkylated,
`hydroxyalkylated, carboxyalkylated or alkyloxycarbonyl
`alkylated derivatives, or mono- or diglycosyl-alpha-, beta
`or gamma-cyclodextrin, mono- or dimaltosyl-alpha-, beta
`or gamma-cyclodextrin or panosyl-cyclodextrin), polysor
`bate 20, polysorbate 80 or mixtures of those compounds. A
`Specific example of an especially preferred Solubilizer is a
`reaction product of castor oil and ethylene oxide, for
`example the commercial products Cremophor ELE) or Cre
`mophor RH40OR). Reaction products of castor oil and ethyl
`ene oxide have proved to be particularly good Solubilizers
`that are tolerated extremely well by the eye. Another pre
`ferred solubilizer is selected from tyloxapol and from a
`cyclodextrin. The concentration used depends especially on
`the concentration of the active ingredient. The amount added
`is typically Sufficient to Solubilize the active ingredient. For
`example, the concentration of the solubilizer is from 0.1 to
`5000 times the concentration of the active ingredient.
`0043. An above pharmaceutical composition may com
`prise further non-toxic excipients, Such as, for example,
`emulsifiers, wetting agents or fillers, Such as, for example,
`the polyethylene glycols designated 200, 300, 400 and 600,
`or Carbowax designated 1000, 1500, 4000, 6000 and 10000.
`Other excipients that may be used if desired are listed below
`but they are not intended to limit in any way the Scope of the
`possible excipients. The amount and type of excipient added
`is in accordance with the particular requirements and is
`generally in the range of from approximately 0.0001 to
`approximately 90% by weight.
`0044) The pharmaceutical composition of the invention
`may comprise further demulcents Such as povidone (see
`U.S. Pat. No. 6,274,626), a Category I demulcent in the OTC
`Ophthahnic Drug Products Monograph of the USFDA.
`Polyvinylpyrrolidone (PVP) is a linear homopolymer or
`copolymer comprising at least about 80%, preferably at least
`about 90% of repeat units derived from 1-vinyl-2-pyrroli
`done monomers, the polymer more preferably comprising at
`least about 95% or essentially all of such repeat units, the
`remainder Selected from polymerization-compatible mono
`mers, preferably neutral monomers, Such as alkenes or
`acrylates. Other synonyms for PVP include povidone, pol