`
`International Bureau
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(11) International Publication Number:
`
`WO 94/05298
`
` (51) International Patent Classification 5 3
`
`A61K 31/66, 31/685, 31/20
`
`(43) International Publication Date:
`
`17 March 1994 (17.03.94)
`
`A,
`
`(21) International Application Number:
`
`PCT/US93/00044
`
`(22) International Filing Date:
`
`5 January 1993 (05.01.93)
`
`(74) Agents: TERZIAN, Berj, A. et al.; Pennie & Edmonds,
`1155 Avenue of the Americas, New York, NY 10036
`(US).
`
`(30) Priority data:
`102984
`103907
`
`28 August 1992 (28.08.92)
`27 November 1992 (27.11.92)
`
`IL
`IL
`
`(71) Applicant: PHARMOS CORPORATION [US/US]; 599
`Lexington Avenue, New York, NY 10022 (US).
`
`(72) Inventors: AVIV, Haim ; 9 Habrosh Street, Rehovot (IL).
`FRIEDMAN, Doron ; 33 Alon Street, Carmei Yossef
`(IL). BAR-ILAN, Amir ; 14 Tamar Street, Neve Mons-
`son (IL). VERED, Micha ; ll Weizmann Street, Rehovot
`(IL).
`
`
`
`(81) Designated States: AT, AU, BB, BG, BR, CA, CH, DE,
`DK, ES, Fl, GB, HU, JP, KR, LK, LU, MG, MN, MW,
`NL, NO, NZ, PL, RO, RU, SD, SE, UA, European pa-
`tent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT,
`LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG,
`CI, CM, GA, GN, ML, MR, SN, TD, TG).
`
`Published
`With international search report.
`
`
`
`(54) Title: SUBMICRON EMULSIONS AS OCULAR DRUG DELIVERY VEHICLES
`
`
`
`or compositions to the eye of a patient while reducing irritation thereof and providing increased bioavailability of the drug.
`
`»
`
`(57) Abstract
`
`An ocular drug delivery vehicle of an oil-in~water submicron emulsion comprising about 0.5 to 50 % of a first component
`of an oil, about 0.1 to 10 % of a second component of an emulsifier, about 0.05 to 5 % of a non-ionic surfactant and an aqueous
`component, with the mean droplet size being in the submicron range, i.e., below about 0.5 pm and preferably between about 0.1
`and 0.3 um. Also, topical pharmaceutical compositions containing a drug such as an anti-glaucoma drug, beta adrenergic blocker
`or other autonomic system drug, a local anesthetic, a steroid, a non-steroidal anti-inflammatory drug, an antibiotic drug, an anti-
`fungal drug, an antiviral drug or combinations thereof and the vehicle described above. Methods of administering such vehicles
`
`Page 1' of 33
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`LUPIN EX 1068
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`LUPIN EX 1068
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`Page 1 of 33
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`
`
`\(
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCI‘ on the front pages of pamphlets publishing international
`applications under the PCT.
`
`Viet Nam
`
`France
`Gabon
`United Kingdom
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Madagascar
`Mali
`Mongolia
`
`AT
`AU
`an
`in:an
`no
`8.]
`an
`av
`CA
`CF
`co
`CH
`CI
`CM
`CN
`cs
`cz
`DE
`ox
`as
`P]
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland ’
`Céte d’lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`
`Page 2 of 33
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`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`'
`Sweden
`Slovenia
`Slovak Republic
`Senegal
`Chad
`Togo
`Ukraine
`United States of America
`Uzbekistan
`
`Page 2 of 33
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`W0 94/05298
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`PCT/ US93/00044
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`SUBMICRON EMULSIONS AS
`OCULAR DRUG DELIVERY VEHICLES
`
`FIELD OF THE INVENTION
`
`The present invention relates to the field of
`
`drug delivery and, particularly,
`
`to the administration
`
`of various pharmaceutical agents to a patient through
`
`the eye by application of the innovative compositions
`
`10
`
`of these agents in a non-irritating submicron
`
`emulsion.
`
`BACKGROUND OF THE PRESENT INVENTION
`
`The primary problem associated with topical
`
`15
`
`appliCations of drugs to the eye is that the human eye
`
`is a very sensitive organ and any substance which is
`
`not compatible with it causes irritation and pain.
`
`This evokes blinking and reflex—tearing, whiCh is a
`
`physiological reaction intended for removal of the
`
`20
`
`irritating substance from the ocular surface.
`
`Irritation is a major cause of poor patient compliance
`
`with many ophthalmic drugs. This phenomenon is
`
`aggravated by the need to include relatively high
`
`concentrations of a drug in such ophthalmic
`
`25
`
`compositions in order to obtain a therapeutic effect,
`
`since bioavailability of topically applied ophthalmic
`
`drugs is generally very poor. Thus,
`
`there is no doubt
`
`that a reduction in the irritating effect of a drug
`
`will enable increased ocular drug bioavailability,
`
`30
`
`increased patient compliance with the drug, and
`
`enhanced therapeutic efficacy of the drug.
`Currently, aqueous solutions are by far the most
`
`Such vehicles
`common vehicles for ophthalmic drugs.
`have a serious drawback, however,
`in that the ocular
`
`35
`
`bioavailability of drugs administered thereby is
`
`generally very poor due to rapid drainage and tear
`turnover.
`See Fitzgerald et al.
`(1987) J. Pharm..
`
`Page 3 of 33
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`Page 3 of 33
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`W0 94/05298
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`PCT/US93/00044
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`Pharmacol. 39:487-490.
`
`A typical dose of ophthalmic
`
`solution is in the range of about 50-100 pl, which far
`
`exceeds the normal
`
`lachrymal volume of about
`
`7-10 pl. Thus,
`
`the portion of the dose that is not
`
`eliminated by spillage from the pulberal fissure is
`
`quickly drained. Furthermore,
`
`lachrymation and
`
`physiological tear turnover, which in humans is about
`
`16% per minute under normal conditions,
`
`increases
`
`after the introduction of the solution, resulting in
`
`10
`
`rapid dilution of the remaining amount of drug that
`
`has not been spilled or drained. As a consequence,
`
`the contact time with the absorbing surfaces of the
`
`eye (i.e., the cornea and sclera) of drugs which are
`
`applied to the eye via liquid aqueous compositions is
`
`15
`
`less than about two minutes.
`
`Another drawback of aqueous vehicles is that many
`
`drugs which may potentially be used in eye therapy are
`
`'hydrophobic and their delivery into the eye by such
`
`aqueous vehicles is not possible. While such
`
`hydrophobic drugs may potentially be administered to
`
`the eye in conjunction with various organic Solvents,
`
`the use of such solvents usually causes irritation and
`
`inflammatory reactions.
`
`See Harmia et a1.
`
`(1987)
`
`Pharm. Acta Helv.
`
`62:322—332.
`
`Attempts have been made to develop various
`
`delivery vehicles in which the drug residence time in
`
`the eye is increased.
`
`The most direct approach for
`
`achieving this goal is by an increase in the viscosity
`
`of the vehicle. Thus, various viscous vehicles, such
`
`as hydrogels or ointments, have been attempted,
`
`some
`
`of which also enable delivery of hydrophobic drugs
`
`into the eye. Additionally, many attempts to use
`
`various non-conventional carriers, such as liposomes,
`
`micellar solutions and nanoparticles, as vehicles of
`ophthalmic drugs have also been made. While the use
`of such delivery systems may provide limited success
`
`in prolonging the residence time of drugs in the eye
`
`20
`
`25
`
`30
`
`35
`
`Page 4 of 33
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`Page 4 of 33
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`
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`wo 94/05293
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`‘
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`Pcr/US93/00044
`
`and hence some enhancement of the ocular bio—
`
`availability, such carriers also produce various
`
`deleterious side effects.
`
`See Harmia et al., su ra.,
`
`Saettone et al.
`
`(1988) J. Pharm. 43:67-70 and Meisner
`
`et al.
`
`(1989) Int. J. Pharm. 55:105-113.
`
`Emulsions have also been suggested as vehicles
`
`for delivery of drugs to the eye in references such as
`
`EP 391,369, Ellis et al.
`
`(1987) J. Ocular Pharmcol.
`
`(U.S.) 3:121—128, and Shell
`
`(1984) Surv. Ophthalmol.
`
`29:177—178.
`
`Nevertheless,
`
`the practical inability to
`
`realize the potential of emulsion systems for ocular
`
`drug delivery stems predominantly from two problems.
`
`First, ocular drug formulations must be comfortable to
`
`the patient as well as safe, due to the sensitivity of
`
`the delicate eye tissues involved.
`
`Second, emulsions
`
`are generally metastable dispersions of immiscible
`
`fluids and these instability problems must be
`overcome.
`V
`
`An emulsion is a dispersion of oil in water
`
`("o/w"), and can be defined as either a macroemulsion
`
`or a microemulsion.
`
`A macroemulsion is a clOudy
`
`turbid composition having an oil-droplet size of 0.5
`
`to 100 um and is generally thermodynamically unstable.
`
`In comparison, a microemulsion is a translucent to
`
`transparent composition having a droplet size of
`
`0.005 to 0.5 pm,
`
`is thermodynamically stable and is
`
`generally self emulsifying.
`See, e.g., Friberg et al.
`(1987) Microemulsions Structure and Dynamics, CRC
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`the
`Press Inc., Boca Raton, FL, pp. 154. Also,
`proportion of surfactants to oil required to generate
`
`microemulsions is generally much higher than in
`
`macroemulsions.
`
`'
`
`' Emulsions developed speCifically for ophthalmic
`
`35
`
`use have attempted to solve the problem of inherent
`_instability through the use of microemulsions or the
`addition of stabilizing polymers to classical
`
`emulsions.
`
`In several instances, specific drugs have
`
`Page 5 of 33
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`Page 5 of 33
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`PCT/US93/00044
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`been formulated successfully in microemulsions.
`
`Examples of this approach include ophthalmic
`
`microemulsions of tepoxalin, as disclosed in
`
`EP 480,690, or flurbiprofen, as disclosed in
`
`EP 253,472.
`
`An alternative approach to solve the problem of
`
`emulsion instability utilizes lightly crosslinked
`
`polymers, as exemplified by the autoclavable emulsions
`
`for ophthalmic use which are disclosed in EP 028,110.
`
`In addition,
`
`the use of emulsions in ophthalmic
`
`preparations has been limited to a large extent by the
`
`inclusion of surfactants in the emulsions which
`
`surfactants are highly irritating to the eye.
`
`For
`
`example,
`
`the use of the emulsion preparations of
`
`EP 391,369 are limited considerably by the irritating
`
`effect of the ionic surfactants which are used in
`
`those emulsions. Thus,
`to date no commercially
`successful ophthalmic compositions in the form of
`oil-in-water emulsions are available.
`
`The present invention solves the problem of
`
`emulsion instability without resorting to either of
`
`the prior art suggestions by instead converting
`
`classical emulsions to submicron emulsions with the
`
`input of energy by shear forces and homogenization to
`
`provide submicron emulsions possessing substantially
`
`reduced eye irritation properties. Also,
`
`the
`
`irritation of the eye is further reduced through the
`
`use of non—irritating non-ionic surfactants in such
`
`emulsions. Thus, when drugs are included with these
`
`submicron emulsions,
`
`the present invention provides
`
`ophthalmic compositions which are improved over those
`
`which are currently available in the art.
`
`In
`
`accordance with the present invention, effective means
`
`for reducing irritation of the eye, particularly such
`
`irritation which is drug-induced,
`
`is provided for the
`
`first time and thereby a long felt need has been
`
`fulfilled.
`
`10
`
`15
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`20
`
`25
`
`30
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`35
`
`Page 6 of 33
`
`Page 6 of 33
`
`
`
`WO 94/05298
`
`PCT/ US93/00044
`
`SUMMARY OF THE INVENTION
`
`The present invention provides an ocular drug
`
`delivery vehicle of an oil-in-water submicron emulsion
`
`comprising about 0.5 to 50% of a first component of an
`
`oil, about 0.1 to 10% of a second component of an
`
`emulsifier, about 0.05 to 5% of a non—ionic surfactant
`
`and an aqueous component, with the mean droplet size
`
`being in the submicron range, i.e., below about 0.5 pm
`
`and preferably between about 0.1 and 0.3 um.
`
`10
`
`The first component may be a medium_chain
`
`triglyceride oil, a vegetable oil, a mineral oil or
`
`mixtures thereof, and is usually present in an amount
`
`of about 1 to 20%.
`
`For viscous compositions or
`
`creams,
`
`the oil may be present in an amount of about
`
`15
`
`30 to 50%.
`
`'
`
`'
`
`The emulsifier is preferably a phospholipid
`
`compound or a mixture of phospholipids, such as
`lecithin, phosphatidylcholine, phosphatidyl-V
`
`ethanolamine or mixtures thereof, and is preferably
`
`20
`
`present in an amount of about 0.2 to 1%.
`
`The surfactant is preferably a non-ionic alkylene
`
`oxide condensate of an organic compound which contains
`
`one or more hydroxyl groups, such as an ethoxylated
`
`alcohol or ester compound, and is preferably present
`
`25
`
`in an amount of about 0.2 to 1%.
`
`This vehicle may be used to prepare topical
`
`ophthalmic compositions which include an effective
`amount of an ophthalmic drug.
`In these compositions,
`
`the drug can be an anti-glaucoma drug, such as a beta
`
`adrenergic blocker or other autonomic system drugs, a
`
`local anesthetic, a steroid, a non-steroidal anti-
`
`inflammatory drug, an antibiotic drug, an antifungal
`
`drug, an antiviral drug or combinations thereof.
`
`Moreover,
`
`the drug may be hydrophilic or amphiphilic,
`
`such as pilocarpine or timolol, or hydrophobic, such
`
`as indomethacin, betaxolol or adaprolol.
`
`The drug is
`
`30
`
`35
`
`typically present in an amount of about 0.05 to 5% by
`
`Page 7 of 33
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`Page 7 of 33
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`
`weight depending upon the specific drug to be used.
`
`If desired,
`
`these compositions may also include a
`
`preservative, an antioxidant or an osmotic agent such
`
`as an osmotic pressure regulator.
`
`The present invention also provides a method for
`
`reducing eye irritation which comprises topically
`
`administering to the eye the oil—in-water submicron
`
`emulsion described above.
`
`A particular aspect of this
`
`embodiment of the present invention is the combined
`
`10
`
`topical administration to the eye of the submicron
`
`emulsion defined above and an effective amount of a
`
`drug,
`
`in order to reduce irritation which may
`
`otherwise be induced by the drug. This enables
`
`increased amounts of the drug to be administered
`
`15
`
`without irritation.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`In the following detailed description of the
`
`invention, reference will be made to the annexed
`
`20
`
`drawings,
`
`in which:
`
`Fig.
`
`1 shows the baseline intraocular pressure
`
`("IOP")
`
`in eyes of rabbits and the IOP following
`
`administration of a pilocarpine containing emulsion
`
`which includes the non-ionic surfactant TYLOXAPOL;
`
`Fig.
`
`2 shows the IOP results from the
`
`contralateral eyes of the rabbits which received the
`
`pilocarpine emulsion as per Fig. 1;
`Fig.
`3 shows miosis in an eye of human subjects
`
`following treatment with a 2% pilocarpine emulsion
`
`composition compared to the same emulsion without
`
`pilocarpine;
`
`Fig.
`
`4 shows miosis in the contralateral eye of
`
`human subjects following treatment with a 2%
`pilocarpine emulsion composition compared to the same
`
`emulsion without pilocarpine, as per Fig. 3;
`
`Fig.
`
`5 shows the IOP in human subjects following
`
`administration of a 2% pilocarpine containing emulsion
`
`25
`
`30
`
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`Page 8 of 33
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`versus baseline in both treated and contralateral eyes
`
`with a comparison to the administration of the same
`
`emulsion without pilocarpine; and
`
`Fig.
`
`6
`
`shows the change in IOP versus baseline
`
`level in human subjects following administration of a
`
`2% pilocarpine containing emulsion versus for both
`
`treated and contralateral eyes with a comparison to
`
`the administration of the same emulsion without
`
`pilocarpine.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention has for the first time
`
`achieved emulsions effective as a general drug
`
`delivery vehicle for ophthalmological use.
`
`The
`
`present invention provides stable pharmaceutical
`
`preparations which are oil-in-water emulsions having
`
`droplets or colloidal particles of a submicron size
`and utilizing surfactants that are non-ionic.
`
`The ingredients in the composition of the present
`
`invention are preferably those which are compatible
`
`physiologically with the eye, i.e., those which do not
`
`cause irritation to the eye by themselves.
`
`The
`
`judicious optimization of such ingredients enables
`
`reduced irritation of commonly used ophthalmic drugs,
`
`while simultaneously providing enhanced
`
`the
`In parallel,
`bioavailability of certain drugs.
`intrinsic problems of instability of drug containing
`
`emulsions have been solved by providing the droplet
`
`size of the oil phase in the submicron range.
`
`The term "submicron" is used herein to mean a
`
`size of about 0.05 to 0.5 pm, and preferably about
`
`0.1 to 0.3 um. Thus, a submicron emulsion having
`
`droplets of these sizes would be smaller than those of
`
`a Classical macroemulsion, which has droplet sizes of
`
`above 0.5 um, but generally larger than those of a
`classical microemulsion, which, for practical
`
`purposes, has droplet sizes of less than 0.1 um.
`
`10
`
`15
`
`20
`
`25
`
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`Page 9 of 33
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`These submicron emulsion can easily be sterilized
`
`by filtration, for example,
`
`in 0.45um and/or 0.22um
`
`filters, are more stable in long-term storage and can
`
`better withstand sterilization in an autoclave.
`
`An oil—in-water emulsion is a dispersion of
`
`droplets or colloidal particles in an aqueous medium,
`
`with the colloid particles having an oily core
`
`surrounded by an interfacial film of the emulsifiers
`
`and surface acting agents or surfactants.
`
`For clarity
`
`in understanding the present invention,
`terms will be used:
`
`the following
`
`"aqueous phase“ - to denote the aqueous solution
`
`. in which the droplets or colloid particles are
`
`dispersed;
`
`"oily phase" — to denote the oily cores of the
`
`droplets or colloidal particles; and
`
`"amphiphilic phase" - to denote the interfacial
`films of emulsifier and surfactant surrounding the
`
`oily phase of the droplets or colloidal particles.
`
`These colloidal particles have a soothing effect
`
`on the eye by a physiological mechanism which has not
`
`yet been elucidated. Owing to this soothing effect,
`
`the topical ophthalmic compositions of the invention
`
`having a certain drug concentration will have a
`
`smaller irritating effect than a prior art composition
`
`having the same drug concentration. This is
`
`surprisingly the case both with respect to hydrophilic
`
`and hydrophobic drugs.
`
`The surprising fact that the
`
`soothing and irritation reducing effect occurs also
`
`where the drug is hydrophilic, i.e. water soluble,
`
`shows that the reduced irritation does not result
`
`merely by containment of the drug in the colloid
`
`particles but rather by some other mechanism.
`
`The present invention is useful for reducing
`
`drug-induced irritation of various anti-glaucoma
`
`drugs, such as beta-adrenergic blockers or other
`
`.autonomic system drugs, anesthetics, steroids, non—
`
`10
`
`15
`
`20
`
`25
`
`30
`
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`Page100f33
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`Page 10 of 33
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`steroidal anti—inflammatory drugs, antibiotic drugs,
`
`anti-fungal drugs, antiviral drugs or combinations
`
`thereof.
`
`The term "effective amount" is used herein
`
`to denote an amount of a drug which is effective in
`
`exerting a pharmaceutical affect on the eye.
`
`A number of exemplary drugs which are known to
`
`induce irritation were tested in accordance with the
`
`invention, and in all cases the drug-induced
`
`irritation was considerably reduced when the drugs
`
`were administered together with the above colloid
`
`particles. These drugs include the water soluble
`
`drugs timolol and pilocarpine. Pilocarpine,
`
`3—
`
`ethyldihydro-4-[(l-methyl-lH-imidazole-S-yl)methyl]-
`
`2(3H)-furanon,
`
`is a drug which is soluble in water and
`
`sparingly soluble in oil, which is used in the
`
`treatment of glaucoma. Also, water insoluble drugs,
`
`such as indomethacin, betaxolol and adaprolol
`(adaprolol being an experimental soft beta blocker
`
`disclosed in U.S. Patent No. 4,289,080), can be used.
`
`Owing to the reduced irritability, compositions of the
`
`present invention may contain higher concentrations of
`
`drugs than prior art compositions.
`
`The oily phase comprises an oil which may be a
`
`vegetable oil, a mineral oil, a medium chain
`
`triglyceride (MCT) oil, i.e. a triglyceride oil in
`
`which the carbohydrate chain has 8—12 carbons, or a
`
`combination of two or three of such oils. Although
`MCT oil can be considered as a component of vegetable
`
`oil, it is separately identified herein because of its
`
`particular utility as a preferred oil for use in the
`
`present emulsions.
`
`In addition, MCT oil is available
`
`commercially.
`
`Examples Of such MCT oils include TCR
`
`(trade name of Societe Industrielle des Oleagineaux,
`
`France for a mixture of triglycerides wherein about
`
`95% of the fatty acid chains have 8 or 10 carbons) and
`
`MIGLYOL 812 (trade name of Dynamit Nobel, Sweden for a
`
`mixed triester of glycerine and of caprylic and capric
`
`10
`
`15
`
`20
`
`25
`
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`acids).
`
`Examples of vegetable oils include soybean
`
`oil, cotton seed oil, olive oil, sesame oil and castor
`
`oil.
`
`The mineral oils may be natural hydrocarbons or
`
`their synthetic analogs. Oily fatty acids, such as
`
`oleic acid and linoleic acid, fatty alcohols, such as
`
`oleyl alcohol, and fatty esters, such as sorbitan
`
`monooleate and sucrose mono- di- or tri-palmitate, can
`
`be used as the oil component, although these are not
`
`as preferred as the other oils mentioned above.
`
`The amphiphilic phase comprises the emulsifiers
`
`and surfactants. Preferred emulsifiers include a
`
`phospholipid compound or a mixture of phospholipids.
`
`Suitable components include lecithin; EPICURON 120
`
`(Lucas Meyer, Germany) which is a mixture of about 70%
`
`of phophatidylcholine,
`
`12% phosphatidylethanolamine
`
`and about 15% other phospholipids; OVOTHIN 160 (Lucas
`
`Meyer, Germany) which is a mixture comprising about
`
`- 60% phosphatidylcholine,
`
`18% phosphatidylethanolamine
`
`and 12% other phospholipids; a purified phospholipid
`
`mixture; LIPOID E-75 or LIPOID E—80
`
`(Lipoid, Germany)
`
`which is a phospholipid mixture comprising about 80%
`
`phosphatidylcholine,
`
`8% phosphatidylethanolamine, 3.6%
`
`non—polar lipids and about 2% sphingomyelin. Purified
`
`egg yolk phospholipids, soybean oil phospholipids or
`
`other purified phospholipid mixtures are useful as
`this component. This listing is representative and
`
`not limiting, as other phospholipid materials which
`are known to those Skilled in the art can be used.
`
`The surfactant chosen should be non-ionic and one
`
`skilled in the art can conduct tests to routinely
`
`select specific surfactants which induce minimal
`
`(and
`
`preferably no)
`
`irritation of the eye. Generally,
`
`the
`
`surfactant is a non-ionic alkylene oxide condensate of
`
`an organic compound which contains one or more
`
`hydroxyl groups.
`
`For example, ethoxylated and/or
`
`propoxylated alcohol or ester compounds or mixtures
`
`thereof are commonly available and are well known to
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`those skilled in the art. Suitable surfactants
`
`include, but are not limited to, TYLOXAPOL; POLOXAMER
`
`4070; POLOXAMER 188; POLYOXYL 40 Stearate; POLYSORBATE
`
`80, and POLYSORBATE 20, as well as various compounds
`
`sold under the trade name TWEEN (ICI American Inc.,
`
`Wilmington, Delaware, U.S.A.), PLURONIC F-68 (trade
`
`name of BASF, Ludwigshafen, Germany for a copolymer of
`
`polyoxyethylene and polyoxypropylene).
`
`The TYLOXAPOL
`
`and TWEEN surfactants are preferred because they are
`
`FDA approved for human use.
`
`The aqueous component will be the continuous
`
`phase of the emulsion and may be water, saline or any
`
`other suitable aqueous solution which can yield an
`
`isotonic and pH controlled preparation.
`
`In addition,
`
`the compositions of the invention
`
`may also comprise conventional additives such as
`
`preservatives, osmotic agents or pressure regulators
`and antioxidants. Typical preservatives include
`
`Thimerosal, chlorbutanol, and methyl, ethyl, propyl or
`
`butyl parabens. Typical osmotic pressure regulators
`
`include glycerol and mannitol, with glycerol being
`
`preferred.
`
`’The preferred oil phase antioxidant is
`
`a-tocopherol or a-tocopherol succinate.
`
`The aqueous
`
`phase may also include an antioxidant of a polyamine
`
`carboxylic acid such as ethylene diamino tetraacetic
`
`acid, or a pharmaceutically acceptable salt thereof.
`
`If desired,
`the compositions of the present
`invention may also include additional drugs which are
`
`effective in decreasing the intraocular pressure of
`
`the eye.
`
`Such drugs may for example be B-adrenergic
`
`blockers, cannabinoids, cholinesterase inhibitors,
`
`sympathomimetic agents or carbonic anhydrase
`
`inhibitors.
`
`In the following description, concentrations will
`
`be indicated by % which denotes the concentration by
`
`weight of the component per 100 units volume of entire
`
`composition. All
`
`indicated concentrations should be
`
`10
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`25
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`understood as standing each by itself, and not
`
`cumulative.
`
`It should be appreciated by the artisan,
`
`however,
`
`that there is some dependency between the
`
`concentrations of the components, e.g., higher
`
`concentrations of the oil will generally require
`
`higher concentrations of the emulsifier and
`
`surfactant.
`
`The emulsion used in the ophthalmic compositions
`
`of the present invention may comprise about 0.5 to 50%
`
`oil, about 0.1 to 10% emulsifier and about 0.05 to 5%
`
`surfactants. Generally,
`
`increasing the concentration
`
`of the non—aqueous phase, i.e., the combined
`
`concentration of the oily and the amphiphilic phase,
`
`increases visCosity of the composition.
`
`In order to
`
`obtain a non-Viscous composition,
`
`the concentration of
`
`the non-aqueous phase should generally not exceed
`about 25%.
`
`Preferred concentrations of the components are as
`
`follows: about 1 to 20% oil, most preferably about 1
`
`to 10% for a composition intended to be fluid, or
`
`about 30 to 50% for a viscous composition which may be
`
`useful as a cream or ointment; about 0.2 to 5% of the
`
`emulsifier, with about 0.2 to 1% being particularly
`
`preferred; and about 0.2 to 5% for the surfactant,
`
`with about 0.2 to 1% being particularly-preferred.
`
`The drug is present in an amount of abOut 0.05 to
`5% by weight of the compositibn, preferably about 0.1
`I to 2.5%. Depending upon whether the drug is
`
`hydrophilic or hydrophobic, it will be physically
`
`present in the oily phase or the aqueous component.
`
`Also,
`
`the pH of these compositions should be in a
`
`‘range which is suitable for the stability of the drug,
`
`but as close to neutral as possible for compatibility
`
`with the eye.
`
`The present invention is also based on the
`
`surprising finding that the colloidal particles of the
`
`oil-in—water emulsions disclosed herein have a
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`10
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`15
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`20
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`25
`
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`-13—
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`soothing and irritation reducing effect on the eye.
`
`Thus, where a drug which otherwise causes an
`
`irritating effect on the eye is administered together
`
`with such colloidal particles,
`
`the irritation which
`
`would have otherwise occurred,
`
`is reduced
`
`considerably.
`
`The soothing effect of the composition
`
`of the present invention also occurs where an emulsion
`
`without a drug is administered to an already irritated
`
`eye. Thus,
`
`the submicron emulsions of the present
`
`invention are useful for reducing drug-induced
`
`irritation of a number of pharmaceuticals.
`
`EXAMPLES
`
`The present invention will now be illustrated
`
`with reference to several non—limiting embodiments
`
`described in the following examples, which utilize the
`
`following ingredients:
`
`MCT oil: TCR - Societe Industrielle des
`
`Oleagnieux, St. Laurent, Blangy, France.
`
`LIPOID E-75 or E-80: Lipoid, Ludwigshafen,
`
`Germany.
`
`a—tocopherol, a-tocopherol succinate and
`
`glycerol: Sigma, St. Louis, MO, U.S.A.,
`
`in conformity
`
`with U.S.P. specifications.
`
`Pilocarpine base: Merck, Darmstadt, Germany,
`
`in
`
`conformity with U.S.P. and B.P.
`
`EDTA: ethylene diamine tetraacetate disodium
`dihydrate).
`7'
`
`Example 1:
`
`A blank oil-in-water type emulsion
`
`(without a drug) was prepared from the following
`
`ingredients:
`
`MCT (medium chain triglyceride) oil
`
`LIPOID E-75
`
`'
`
`TYLOXAPOL (a non-ionic surfactant)
`
`a-tocopherol
`
`(an oil phase antioxidant)
`
`EDTA (an aqueous phase antioxidant)
`
`4.25%
`
`0.75%
`
`1.0 %
`
`0.02%
`
`0.1 %
`
`10
`
`15
`
`20
`
`25
`
`3O
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`Preservatives (antibacterial)
`
`Chlorbutanol
`
`Thimerosal
`
`Glycerol
`
`(an osmotic agent)
`
`0.2 %
`
`0.01%
`
`2.25%
`
`Distilled water
`
`balance to 100.00%
`
`The emulsion was prepared as follows:
`
`10
`
`15
`
`20
`
`The aqueous and oily phases were separately prepared.
`
`The aqueous phase consisted of water,
`
`tyloxapol,
`
`Chlorbutanol,
`
`thimerosal and glycerol; and the oily phase
`
`consisted of the MCT oil,
`
`lecithin and a—tocopherol.
`
`The pH
`
`of the aqueous phase was adjusted to pH 6.8 and the two
`
`phases were filtered (TE and BA filter types, Schleicher &
`
`Schull, Dassel, Germany, having a pore size of 0.22 pm).
`
`Next,
`
`the two phases were heated separately to over 50°C and
`
`then were combined and stirred with a magnetic stirrer to
`
`produce a coarse emulsion.
`to a temperature of 80-85°C.
`
`The mixture was further heated
`The coarse emulsion was
`
`further mixed by a high—shear mixer, POLYTRON (Kinematics,
`
`Switzerland), for 3 minutes, and then was rapidly cooled to
`
`below 40°C. After cooling,
`
`the emulsion was homogenized by
`
`a 2-stage homogenizer
`
`(APV Montin Gaulin, Germany) at
`
`8000 psi and then cooled again to storage (i.e., room)
`
`temperature. After adjusting the pH to 6.8-7,
`
`the emulsion
`
`25'
`
`was filtered through a membrane filter (TE, Schleicher &
`
`Schull, having a pore size of 0.45 pm) and transferred to
`
`plastic bottles that were sealed under nitrogen atmosphere.
`The emulsions were then sterilized either by a steam
`
`autoclave at 121°C or by a double stage membrane filtration,
`
`through a 0.45 pm filter followed by a 0.22 um filter (i.e.,
`
`TE filters manufactured by Schleicher & Schull).
`
`The final
`
`preparation had an osmolarity of 298 mOsmol/l and an initial
`
`pH of 6.47.
`
`Examples 2—5: Pilocarpine Compositions
`
`This composition had the same constituents as the
`
`composition of Example 1 above, except with the addition of
`
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`1.7% pilocarpine base (2% as Pilo-HCl).
`
`In the preparation
`
`process, pilocarpine was added to the aqueous phase and the
`
`solutions were mixed at about 50°C due to the heat
`
`sensitivity of the drug.
`
`The resulting composition had an
`
`5
`
`initial pH of 5 and an osmolarity of 278 mOsmol/l.
`
`Three additional pilocarpine compositions were prepared
`
`as above except that they contained 1.5% TYLOXAPOL,
`
`1% TWEEN-BO and 1% TWEEN-20, respectively.
`
`10 Examples 6-8: Adaprolol Maleate Compositions
`
`This composition had the following constituents:
`
`Adaprolol maleate
`
`MCT Oil
`
`LIPOID E480
`
`15
`
`TWEEN-BO
`
`a-tocopherol
`
`EDTA
`
`Glycerol
`
`0.4 %
`
`4.25%
`
`0.75%
`
`1.0 %
`
`0.02%
`
`0.1 %
`
`2.2 %
`
`Distilled water
`
`balance to 100.00%
`
`20
`
`The composition was prepared in a similar manner to
`
`that described above in Example 1 except that adaprolol was
`
`added during preparation to the oil phase.
`
`The resultant
`
`composition had an initial pH of 6.5 and an osmolarity of
`
`25
`
`338 mOsmol/l.
`
`Two additional adaprolol compositions were prepared as
`above except that they contained 1 TYLOXAPOL and 1%
`TWEEN-ZO. respectively.
`
`30 Example 9: Betaxolol Composition
`
`This composition had the following constituents:
`
`MCT oil
`
`'
`
`LIPOID E-80’
`
`'
`
`TWEEN-BO
`
`35
`
`a-tocopherol succinate
`
`Betaxolol
`
`4.25%
`
`0.75%
`
`0.5 %
`
`0.02%
`
`0.5 %
`
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`
`Glycerol
`
`2.2 %
`
`Distilled water
`
`balance to 100.00%
`
`The manner of preparation was the same as that of
`
`5
`
`the adaprolol compositions of Examples 6-8 above.
`
`Examples 10-11:
`
`Indomethacin Compositions
`
`This composition had the following constituents:
`
`Indomethacin
`
`10
`
`MCT Oil
`
`LIPOID E-80
`
`TWEEN-BO
`
`.
`
`a-tocopherol succinate
`
`Methyl paraben
`
`15
`
`Propyl paraben ‘
`
`Glycerol
`
`EDTA
`
`0.4 %
`
`17
`
`3
`
`l
`
`%
`
`%
`
`%
`
`0.02%
`
`0.1 %
`
`0.02%
`
`2.25%
`
`0.1 %
`
`Distilled water
`
`balance to 100.0 %
`
`20
`
`A second composition (Example 11) was made similar to
`
`that of Example 10, except that it contained 0.2% of
`
`indomethacin.
`
`The manner of preparation was the same as
`
`that of the adaprolol composition of Example 6 above.
`
`The
`
`initial pH of these compositions was about 5.
`
`25
`
`30
`
`Examples 12-13: Ocular Irritation Tests
`
`. Acute irritative response and long term irritative
`
`response of animal eyes to various ophthalmic preparations
`
`were tested as follows:
`
`Example 12: Acute Irritative Response Tests
`
`The acute response was quantified using the guinea pig
`
`blinking test.
`
`In this test,
`
`the number of blinks during a
`
`5 minute period was counted in 0.5 minute increments
`
`35
`
`following application of a 25 ul drop of test solution.
`
`Each eye was first tested with normal saline (0.9% NaCl) and
`
`then with the test formulation, with at least a 30—minute
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`
`interval between the two tests.
`
`The number of blinks of
`
`both eyes of each animal was averaged and entered as a
`
`single value.
`
`Two parameters were calculated from the data
`
`thus obtained:
`
`Maximal Blinking Ratio (MBR):
`
`The highest