WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 5 :
`
`(11) International Publication Number:
`
`PCf
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`wo 94/05298
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`A61K 31/66, 31/685, 31/20
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`Al
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`(43) International Publication Date:
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`17 March 1994 (17.03.94)
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`(21) International Application Number:
`
`PCT /US93/00044
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`(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).
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`(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(cid:173)
`son (IL). VERED, Micha ; 11 Weizmann Street, Rehovot
`(IL).
`
`(81) Designated States: AT, AU, BB, BG, BR, CA, CH, DE,
`DK, ES, FI, GB, HU, JP, KR, LK, LU, MG, MN, MW,
`NL, NO, NZ, PL, RO, RU, SD, SE, UA, European pa(cid:173)
`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
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`(57) Abstract
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`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 J.Lm and preferably between about 0.1
`and 0.3 J.Lm. 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(cid:173)
`fungal drug, an antiviral drug or combinations thereof and the vehicle described above. Methods of administering such vehicles
`or compositions to the eye of a patient while reducing irritation thereof and providing increased bioavailability of the drug.
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCf on the front pages of pamphlets publishing international
`applications under the PCf.
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`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`Fl
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`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d'lvoire
`Cameroon
`China
`Czechoslovakia
`C..zech Republic
`Germany
`Denmark
`Spain
`Finland
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`FR
`GA
`GB
`GN
`GR
`HU
`IE
`IT
`JP
`KP
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`KR
`KZ
`Ll
`LK
`LU
`LV
`MC
`MG
`ML
`MN
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`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
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`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`Sl
`SK
`SN
`TD
`TG
`UA
`us
`uz
`VN
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`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovak Republi~
`Senegal
`Chad
`Togo
`Ukraine
`United States of America
`Uzbekistan
`VietNam
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`SUBMICRON EMULSIONS AS
`OCULAR DRUG DELIVERY VEHICLES
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`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
`of these agents in a non-irritating submicron
`emulsion.
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`BACKGROUND OF THE PRESENT INVENTION
`The primary problem associated with topical
`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
`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
`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,
`increased patient compliance with the drug, and
`enhanced therapeutic efficacy of the drug.
`currently, aqueous solutions are by far the most
`common vehicles for ophthalmic drugs. Such vehicles
`have a serious drawback, however, in that the ocular
`bioavailability of drugs administered thereby is
`generally very poor due to rapid drainage and tear
`turnover. See Fitzgerald et al. (1987) J. Pharm.
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`Pharmacal. 39:487-490. A typical dose of ophthalmic
`solution is in the range of about 50-100 ~1, which far
`exceeds the normal lachrymal volume of about
`7-10 ~1. Thus, the portion of the dose that is not
`5 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
`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
`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
`20 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 al. (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
`30 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
`35 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
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`and hence some enhancement of the ocular bio(cid:173)
`availability, such carriers also produce various
`deleterious side effects. See Harmia et al., supra.,
`Saettone et al. (1988} J. Pharm. 43:67-70 and Meisner
`5 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.
`10 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.
`An emulsion is a dispersion of oil in water
`("ofw"), 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 ~m 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 ~m, is thermodynamically stable and is
`generally self emulsifying. See, e.g., Friberg et al.
`{1987} Microemulsions Structure and Dynamics, CRC
`Press Inc., Boca Raton, FL, pp. 154. Also, the
`30 proportion of surfactants to oil required to generate
`microemulsions is generally much higher than in
`macroemulsions.
`Emulsions developed specifically for ophthalmic
`use have attempted to solve the problem of inherent
`instability through the use of microemulsions or the
`addition of itabilizing polymers to classical
`emulsions.
`In several instances, specific drugs have
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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
`15 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
`25 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.
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`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
`5 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 ~m
`and preferably between about 0.1 and 0.3 ~m.
`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
`30 to 50%.
`The emulsifier is preferably a phospholipid
`compound or a mixture of phospholipids, such as
`lecithin, phosphatidylcholine, phosphatidyl(cid:173)
`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
`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
`30 adrenergic blocker or other autonomic system drugs, a
`local anesthetic, a steroid, a non-steroidal anti(cid:173)
`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
`typically present in an amount of about 0.05 to 5% by
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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
`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.
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`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
`30 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
`35 emulsion without pilocarpine, as per Fig. 3;
`Fig. 5 shows the IOP in human subjects following
`administration of a 2% pilocarpine containing emulsion
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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.
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`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
`15 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,
`25 while simultaneously providing enhanced
`bioavailability of certain drugs.
`In parallel, the
`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 ~m, and preferably about
`0.1 to 0.3 ~m. 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 ~m, but generally larger than those of a
`classical microemulsion, which, for practical
`purposes, has droplet sizes of less than 0.1 ~m.
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`These submicron emulsion can easily be sterilized
`by filtration, for example, in 0.45~m andjor 0.22~m
`filters, are more stable in long-term storage and can
`better withstand st~rilization 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, the following
`terms will be used:
`to denote the aqueous solution
`"aqueous phase" -
`in which the droplets or colloid particles are
`dispersed;
`to denote the oily cores of the
`"oily phase" -
`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
`30 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
`35 drug-induced irritation of various anti-glaucoma
`drugs, such as beta-adrenergic blockers or other
`autonomic system drugs, anesthetics, steroids, non-
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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
`5 exerting a pharmaceutical affect on the eye.
`A number of exempla.ry 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
`10 were administered together with the above colloid
`particles. These drugs include the water soluble
`drugs timolol and pilocarpine. Pilocarpine, 3-
`ethyldihydro-4-[(l-methyl-1H-imidazole-5-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.
`20 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
`30 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
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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
`5 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%
`15 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
`20 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
`25 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
`30 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
`35 hydroxyl groups. For example, ethoxylated andjor
`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
`20 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
`25 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 ~-adrenergic
`blockers, cannabinoids, cholinesterase inhibitors,
`sympathomimetic agents or carbonic anhydrase
`inhibitors.
`In the following description, concentrations will
`35 be indicated by % which denotes the concentration by
`weight of the component per 100 units volume of entire
`composition. All indicated concentrations should be
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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
`5 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%
`10 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
`15 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,
`25 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 composition, preferably about 0.1
`to 2.5%. Depending upon whether the drug is
`hydrophilic or hydrophobic, it will be physically
`30 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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`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
`5 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.
`
`10
`
`20
`
`EXAMPLES
`The present invention will now be illustrated
`15 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, M0 1 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) .
`
`25
`
`30 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)
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`35
`
`4.25%
`0.75%
`1. 0 %
`0.02%
`0.1 %
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`Preservatives (antibacterial)
`Chlorbutanol
`Thimerosal
`Glycerol (an osmotic agent)
`Distilled water
`
`0.2 %
`0.01%
`2.25%
`balance to 100.00%
`
`5
`
`The emulsion was prepared as follows:
`The aqueous and oily phases were separately prepared.
`The aqueous phase consisted of water, tyloxapol,
`10 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 ~m).
`15 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. The mixture was further heated
`to a temperature of 80-85°C. The coarse emulsion was
`further mixed by a high-shear mixer, POLYTRON (Kinematics,
`20 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 ~m) 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 ~m filter followed by a 0.22 ~m filter (i.e.,
`TE filters manufactured by Schleicher & Schull). The final
`preparation had an osmolarity of 298 mosmoljl and an initial
`pH of 6.47.
`
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`
`35 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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`In the preparation
`1.7% pilocarpine base (2% as Pilo-HCl).
`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
`initial pH of 5 and an osmolarity of 278 mosmoljl.
`Three additional pilocarpine compositions were prepared
`as above except that they contained 1.5% TYLOXAPOL,
`1% TWEEN-80 and 1% TWEEN-20, respectively.
`
`5
`
`10 Examples 6-8: Adaprolol Maleate Compositions
`This composition had the following constituents:
`Adaprolol maleate
`0.4 %
`MCT oil
`4.25%
`LIPOID E~80
`0.75%
`TWEEN-80
`1. 0 %
`a-tocopherol
`0.02%
`EDTA
`0.1 %
`Glycerol
`2.2 %
`Distilled water
`balance to 100.00%
`
`15
`
`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 mosmoljl.
`Two additional adaprolol compositions were prepared as
`above except that they contained 1 TYLOXAPOL and 1%
`TWEEN-20, respectively.
`
`30 Example 9: Betaxolol Composition
`This composition had the following constituents:
`MCT oil
`4.25%
`LIPOID E-80
`0.75%
`TWEEN-80
`0.5 %
`a-tocopherol succinate
`0.02%
`Betaxolol
`0.5 %
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`Glycerol
`Distilled water
`
`2.2 %
`balance to 100.00%
`
`The manner of preparation was the same as that of
`the adaprolol compositions of Examples 6-8 above.
`
`5
`
`~ 0
`
`~ 0
`
`3
`
`Indomethacin compositions
`Examples 10-11:
`This composition had the following constituents:
`Indomethacin
`0.4 %
`MCT oil
`17
`LIPOID E-80
`TWEEN-80
`a-tocopherol succinate
`Methyl paraben
`Propyl paraben
`Glycerol
`EDTA
`Distilled water
`
`1
`~ 0
`0.02%
`0.1 %
`0.02%
`2.25%
`0.1 %
`balance to 100.0 %
`
`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.
`
`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
`following application of a 25 ~1 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 number o