III
`
`11111
`
`III
`
`111111
`
`11111
`
`11111
`
`11111
`
`11111
`
`11111
`
`11111
`
`11111
`
`11111
`
`11111111
`
`III
`
`11111
`
`US005474979A
`Patent Number
`
`Date of Patent
`
`5474979
`Dec 12 1995
`
`4839342
`4990337
`4996193
`5051402
`5364632
`
`6/1989
`
`Kaswan
`
`2/1991
`Kurihara et al
`2/1991 Hewittetal
`
`9/1991
`
`Kurihara et al
`
`11/1994
`
`Benita et al
`
`514/11
`
`424/427
`
`514/11
`
`514/11
`
`14/943
`
`Russel
`Primary ExaminerJeffrey
`Attorney Agent or FirmWalter
`
`Hackler
`
`ABSTRACT
`
`at
`
`pharmaceutical composition is disclosed in the form of
`emulsion which
`one
`includes
`least
`
`nonirritating
`cyclosporin in admixture with
`higher fatty acid glyceride
`and polysorbate 80 More particularly the cyclosporin may
`be cyclosporin
`and the higher fatty acid glyceride may be
`castor oil Composition has been found to be of
`high
`comfort
`level and low irritation potential suitable for deliv
`ery of medications to sensitive areas such as ocular tissues
`In addition the composition has stability
`for up to nine
`months without crystallization of cyclosporin
`
`United States Patent
`
`Ding et
`
`NONIRRITAT1NG EMULSIONS FOR
`SENSITIVE TISSUE
`
`Tien both of
`Inventors Shulin Ding Walter
`Irvine Orest Olejnik Trabuco Canyon
`all of Calif
`
`Assignee Allergan Inc Irvine Calif
`
`Appi No 243279
`
`Filed
`
`May 17 1994
`
`mt ci.6
`U.S Cl
`
`A61K 38/13 A61K 47/34
`514/785 514/786
`514/11
`514/912 514/941 514/943 514/975
`5301317 321
`Field of Search
`514/9 11 785 786 912 913 914 915
`941 943 975 178 179 180 181 420
`784 A61K 9/107 47/14
`
`References Cited
`
`U.S PATENT DOCUMENTS
`
`4347238
`
`8/1982
`
`Hollingsbee
`
`514/179
`
`Claims No Drawings
`
`FAMY CARE - EXHIBIT 1006-0001
`
`

`
`5474979
`
`NONIIRITATING EMULSIONS FOR
`SENSITIVE TISSUE
`
`administered orally for the treatment of these symptoms the
`accompanying side effects due to systemic circulation may
`cause adverse
`such as hypertrichosis or renal
`reactions
`
`The present
`invention generally relates to novel pharma
`chemicals which are
`ceutical
`compositions incorporating
`poorly soluble in water and is more particularly related to
`novel ophthalmic emulsion including cyclosporin in admix
`ture with castor oil and polysorbate 80 with high comfort
`level and low irritation potential
`group of nonpolar cyclic oligopep-
`Cyclosporins are
`tides with known immunosuppressant activity
`In addition
`as set forth in U.S Pat No 4839342 cyclosporin some
`times referred to in the literature as cyclosporine has been
`found as effective in treating immune medicated keratocon
`sicca KCS or dry eye disease in
`junctivitis
`suffering therefrom
`As hereinabove
`noted cyclosporin comprises
`cyclic oligopeptides and the major component
`which has been identified
`C62H111N11012
`cyclosporin
`along with several other minor metabolites
`cyclosporin
`number of synthetic analogs have
`In addition
`through
`been prepared
`available cyclosporins may
`In general
`commercially
`contain mixture of several
`individual cyclosporins which
`cyclic peptide structure consisting of eleven
`amino acid residues with
`total molecular weight of about
`1200 but with different substituents or configurations of
`some of the amino acids
`to the term
`It should be appreciated
`reference
`is used throughout
`cyclosporin
`or cyclosporins
`present specification in order to designate
`the cyclosporin
`invention
`in the composition of the present
`component
`However
`to include
`this specific reference is intended
`any individual member of the cyclosporin group as well as
`admixtures of two or more individual cyclosporins whether
`natural or synthetic
`The activity of cyclosporins
`as hereinabove
`an immunosuppressant and in the enhancement
`of lacrimal gland tearing
`the solubility of cyclosporin in water is
`Unfortunately
`extremely low and as elaborated in U.S Pat No 5051402
`it has been considered not merely difficult but practically
`pharmaceutical composition con
`impossible to prepare
`taining cyclosporin dissolved in an aqueous medium
`As reported the solubility of cyclosporin in water
`between
`about 20 .i.g/mi
`to 30 fig/mi
`for cyclosporin
`Hence
`heretofore prepared
`formulations
`incorporating
`cyclosporin have been prepared as oily solutions containing
`ethanol However
`the bioavailabil
`these preparations limit
`ity to oral preparations and this is believed to be due to the
`of cyclosporin as
`solid immediately after it
`comes into contact with water such as in the mouth or eye
`
`patient
`
`group of
`thereof
`
`is
`
`that
`
`the
`
`noted is as
`
`or restoring
`
`is
`
`all share
`
`separation
`
`dysfunction
`On the other hand
`if oily preparations containing
`cyclosporin are applied directly to the eyes irritation or
`clouding of visual field may result This plus the difficulty in
`formulating cyclosporin limits its use in formulations
`that
`would be useful during keratoplasty as well
`in the treatment
`of herpetic keratitis and spring catarrh
`Heretofore as for example in U.S Pat No 5051402
`attempts have been made to dissolve sufficient cyclosporin
`in an aqueous
`solvent system so as to reach an effective
`concentration for treatment
`Importantly this solvent system
`does not contain any surface active agent such as polyoxy
`ethylated castor oil
`the purpose of dissolving the cyclosporin
`Conceptually
`in an aqueous solvent system is to enable contact with body
`fluids which would merely constitute dilution of the aqueous
`solvent system which hopefully would eliminate the imme
`diate precipitation of cyclosporin when contacted with the
`water content of the body fluids
`For direct use in the eye cyclosporin has been formu
`number of pharmaceutically acceptable excipi
`lated with
`ents for example animal oil vegetable oil an appropriate
`solvent an artificial
`tear solution
`organic or aqueous
`natural or synthetic polymer or an appropriate membrane
`Specific examples of these phannaceutically
`acceptable
`excipients which may be used solely or in combination are
`30 olive oil arachis oil castor oil mineral oil petroleum jelly
`dimethyl sulfoxide chremophor
`liposomes
`or liposome
`silicone fluid among others
`like products or
`great deal of effort has been expended
`In summary
`order to prepare
`pharmaceutical composition containing
`cyclosporin dissolved in an aqueous medium or cyclosporin
`as an oily solution However
`formula
`prepared
`successful
`tions have yet to be accomplished as evidenced by the lack
`of commercial products
`As hereinabove
`has
`been
`noted
`reported
`that
`cyclosporin has demonstrated some solubility in oily prepa
`rations containing higher fatty acid glycerides such as olive
`oil peanut oil andlor castor oil These formulations
`fre
`sensation when applied to the
`quently produce an unpleasant
`eye because of stimulation or the viscousness which is
`of these oils
`charactenstic
`
`in
`
`it
`
`10
`
`15
`
`20
`
`25
`
`35
`
`40
`
`45
`
`Another
`
`drawback
`
`of these formulations
`
`is that
`
`they
`
`contain
`
`of oils and oils exacerbate
`high concentration
`the
`symptoms of certain ocular surface
`such as dry
`diseases
`eyes indicated by cyclosporin Therefore these oily formu
`lations may not be clinically acceptable Additionally these
`due to
`formulations often suffer from physical
`instability
`propensity to undergo conformational
`change
`cyclosporin
`and crystallize out The crystallization
`problem has been
`noticed in formulations containing corn oil or medium chain
`low
`triglycerides Lastly these formulations often have
`degree
`saturation
`thermodynamic
`of
`activity
`cyclosporin which leads to
`poorer drug bioavailability
`It may be possible to minimize the problems related to
`and syndrome exacerbation by reduc
`unpleasant
`sensation
`ing the oil content and dispersing the oil phase in water into
`an emulsion However
`is not an easy task to formulate an
`ophthalmic emulsion because one indispensable class of
`ingredients in an emulsion system is emulstfiers and the
`majority of emulsifiers is highly irritating to the eyes
`The present
`invention is directed to an emulsion system
`in combina
`which utilizes higher fatty acid glycerides but
`tion with polysorbate 80 which results in an emulsion with
`
`of
`
`it
`
`50
`
`55
`
`65
`
`of
`
`in the
`
`if
`
`it
`
`is
`
`patient
`In the case of injectable preparations of cyclosporin they
`first must be diluted with physiological
`saline before intra
`but
`venous administration
`this is likely
`to result
`precipitation of cyclosporin and therefore may be considered
`undesirable for intravenous administration
`Surface active agents such as polyoxyethylated castor oil
`have been utilized as solubilizers to inject preparations in 60
`order to prevent cyclosporin from separating However
`this
`also may give rise to safety problems see U.S Pat No
`5051402
`The practical usefulness of cyclosporin would be greatly
`enhanced
`if administration thereof could be effective
`for
`example cyclosporin
`in the treatment of
`effectiveness
`ocular symptoms of Behcets Syndrome However
`
`FAMY CARE - EXHIBIT 1006-0002
`
`

`
`5474979
`
`level and low irritation potential suitable for
`high comfort
`delivery of medications to sensitive areas such as ocular
`tissues
`
`SUMMARY OF THE INVENTION
`
`In accordance with the present
`invention
`nonirritating
`pharmaceutical composition with high comfort
`level and
`low irritation potential suitable for delivery to sensitive areas
`such as ocular tissues comprises cyclosporin in admixture
`with an emulsifying amount of
`higher fatty acid glycerol
`and polysorbate 80 More particularly the composition may
`and the higher fatty acid glyceride
`comprise cyclosporin
`may comprise castor oil
`
`10
`
`ratio of
`the weight
`Preferably
`the
`castor oil
`to the 15
`polysorbate 80 is between about 0.3 to about 30 and weight
`is below 0.16 More
`ratio of the cyclosporin to castor oil
`preferably the weight ratio of castor oil
`to polysorbate 80 is
`between 0.5 and 12.5 and the weight ratio of cyclosporin to
`is between 0.12 and 0.02
`castor oil
`When cyclosporin is dissolved in the oil phase in accor
`invention the emulsion is found to be
`dance with the present
`physically stable upon long term storage No crystallization
`of cyclosporin was noticed after nine months at room
`the cyclosporin emulsion is formu
`temperature Moreover
`lated in such
`has reasonably high
`way that
`the drug
`the crystallization prob
`thermodynamic activity yet without
`lem
`
`20
`
`Goodrich for
`
`Pemulen is
`registered trademark of
`polymeric emulsifiers and commercially available from
`Chemicals Divi
`Goodrich Company Specialty Polymers
`sion Cleveland Ohio Pemulens are Acrylates/C10-30
`Alkyl Acrylate Cross-Polymers They are high molecular
`long chain alkyl
`weight co-polymers of acrylic acid and
`methacrylate cross-linked with allyl ethers of pentaerythri
`and not more
`less than 52.0 percent
`tol They contaln not
`than 62.0 percent of carboxylic acid groups The viscosity of
`aqueous dispersion is between
`neutralized 1.0 percent
`9500 and 26500 centipoises
`
`In addition the tonicity of the emulsions can be further
`if desired
`adjusted using glycerine mannitol or sorbitol
`The pH of the emulsions can be adjusted in
`conventional
`near physiological pH
`manner using sodium hydroxide to
`level and while buffering agents are not required suitable
`and
`buffers may include phosphates
`acetates
`citrates
`borates
`
`While the preferable medications in accordance with the
`other chemicals
`include cyclosporin
`present
`invention
`which are poorly soluble in water such as indomethacin and
`steroids such
`
`prednisolone
`as androgens prednisolone
`and dexamethasones may be
`acetate fluorometholone
`25 emulsified with castor oil and polysorbate 80 resulting in
`composition with similar low irritation potential
`The
`invention
`is further
`illustrated by the following
`examples with all parts and percentages
`expressed
`by
`weight The cyclosporin used in the examples was supplied
`30 by Sandoz
`
`DETAILED DESCRIPTION
`
`Example
`
`35
`
`pure
`
`Cyclosporin
`Castor oil
`Polysorbate 80
`Pemuleo
`
`Glycerine
`NaOFI
`
`0.40%
`
`5.00%
`
`1.00%
`
`0.05%
`
`2.20%
`
`0.20%
`
`5.00%
`
`1.00%
`
`0.05%
`
`2.20%
`
`0.20%
`
`2.50%
`
`1.00%
`
`0.05%
`
`2.20%
`
`0.10%
`
`1.25%
`
`1.00%
`
`0.05%
`
`2.20%
`
`0.05%
`
`0.625%
`
`1.00%
`
`0.05%
`
`2.20%
`
`qs
`
`qs
`
`qs
`
`qs
`
`qs
`
`qs
`7.27.6
`
`qs
`7.27.6
`
`qt
`7.27.6
`
`noted cyclosporin is avallable as mix
`As hereinabove
`ture in which the principal
`with
`is cyclosporin
`ingredient
`significant but smaller quantities of other cyclosporins such
`However
`as also hereinabove
`as cyclosporin
`through
`noted the present
`invention may be applied to either
`cyclosporin or to mixture of individual cyclosporins
`The discovery on which the present
`invention is founded
`combination of
`higher fatty acid glyceride and
`relates to
`an emulsifier and dispersing agent polysorbate 80 The 40
`selection of these components
`could not have been antici
`pated on the basis of conventional
`
`thinking
`
`Purified water
`pH
`
`qs
`7.27.6
`
`qs
`7.27.6
`
`Example
`
`Castor oil
`Polysorbate 80
`Pemulen lB
`
`Glycerioe
`NaOH
`Purified water
`pH
`
`5.00%
`
`1.00%
`
`0.05%
`
`2.20%
`
`2.50%
`
`1.00%
`
`0.05%
`
`2.20%
`
`1.25%
`
`1.00%
`
`0.05%
`
`2.20%
`
`qs
`
`qs
`
`qs
`
`qs
`7.27.6
`
`qs
`7.27.6
`
`qs
`7.27.6
`
`0.625%
`
`1.00%
`
`0.05%
`
`2.20%
`
`qs
`
`qs
`7.27.6
`
`Example
`
`Example
`
`2.50%
`
`0.75%
`
`0.05%
`
`2.20%
`
`qt
`
`qt
`7.27.6
`
`Castor oil
`Polysorbate 80
`Carbomer 1382
`
`Glycerine
`NaOH
`Purified water
`pH
`
`60
`
`65
`
`Castor oil
`
`5.00%
`
`For example although it
`is well-known that cyclosporin
`may be used in combination with castor oil
`this combination
`such as
`the eye Thus
`to sensitive tissues
`is irritating
`conventional
`teaching in the art is away from formulation
`which utilizes
`such as castor
`higher fatty acid glyceride
`oil and cyclosporin
`Stated another way there is no way of deducing
`that
`the
`use of an emulsifier and dispersing agent such as polysorbate
`80 will reduce the irritation potential of an emulsion utiliz
`ing castor oil There are no examples of polysorbate in
`when
`oil which
`combination with castor
`admixed to
`cyclosporin produces an emulsion with
`high comfort level
`and low irritation potential suitable for the delivery of
`medication to sensitive areas such as ocular tissues
`The present
`invention achieves
`stable solution state of
`cyclosporin This stable solution state is another important
`performance characteristic differentiating the present
`inven-
`tion from the conventional
`oil systems Cyclosporin
`notorious for its tendency
`to precipitate out in conventional
`oil systems in which it
`is fully dissolved initially
`In accordance with the present
`can be further stabilized using
`polyelectrolyte
`or poly-
`electrolytes if more than one from the family of cross-linked
`such as carbomers and Pemulen
`polyacrylates
`
`invention
`
`the emulsions
`
`is
`
`FAMY CARE - EXHIBIT 1006-0003
`
`

`
`5474979
`
`-continued
`
`invention as defined in the appended claims
`What
`is claimed is
`
`Polysorbate 80
`Carbomer 981
`
`Glycerin
`NaOH
`Purified water
`pH
`
`0.75%
`
`0.05%
`
`2.20%
`
`qs
`
`qs
`7.27.6
`
`forth in Examples 14 were made
`The formulations set
`sicca dry eye syn
`for treatment of keratoconjunctivitis
`drome with Examples
`and
`without
`the active ingre
`dient cyclosporin utilized to determine the toxicity of the
`emulsified components
`The formulations in Examples 14 were applied to rabbit
`times
`day for seven days and were found to
`eyes eight
`cause only slight to mild discomfort and slight hyperemia in
`the rabbit eyes Slit lamp examination revealed no changes
`in the surface tissue In addition the cyclosporin containing
`castor oil emulsion as hereinabove
`set forth in Examples
`lAiD was also tested for ocular bioavailability
`in rabbits
`and the therapeutic level of cyclosporin was found in the
`tissues of
`interest after dosage This substantiates
`that
`cyclosporin in an ophthalmic delivery system is useful for
`forth in U.S Pat No 4839342
`treating dry eye as set
`In addition no difference in toxicity was found between
`formulations with cyclosporin Examples 1A1D and for
`mulations without cyclosporin Examples 2-4
`The formulations set forth in Examples 14 were found to
`be physically stable upon long term storage With regard to
`formulations lAiD no crystallization of cyclosporin was
`noticed after nine months at room temperature
`
`Further other higher fatty acid glycerides such as olive
`oil peanut oil and the like may also be utilized with the
`polysorbate 80 with similar results regarding biotoxicity
`described
`Although there has been hereinabove
`lar pharmaceutical composition in the form of
`nonirritating
`emulsion for the purpose of illustrating the manner in which
`should be
`the invention may be used to advantage it
`limited thereto Accord
`the invention is not
`that
`appreciated
`ingly any and all modifications
`variations or equivalent
`arrangements which may occur
`to those skilled in the art
`should be considered to be within the scope of the present
`
`particu
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`for
`
`is present
`
`nonirritat
`
`to claim
`
`wherein the
`
`to claim
`
`pharmaceutical composition comprising
`ing emulsion of at
`least one cyclosporin in admixture with
`higher fatty acid glyceride polys orb ate 80 and an emulsion
`stabilizing amount of Pemulen in water suitable for topical
`application to ocular tissue
`The pharmaceutical composition according
`wherein the cyclosporin comprises cyclosporin
`The pharmaceutical composition according
`to claim
`wherein the weight ratio of the higher fatty acid glyceride to
`about 0.3 and about 30
`the polysorbate 80 is between
`The pharmaceutical composition according
`to claim
`wherein the higher fatty acid glyceride comprises castor oil
`is below
`and the weight
`ratio of cyclosporin to castor oil
`about 0.16
`The composition according
`to claim
`higher fatty acid glyceride and polysorbate 80 are present
`in
`amounts sufficient
`to prevent crystallization of cyclosporin
`period of up to about nine months
`pharmaceutical emulsion comprising of cyclosporin
`castor oil Pemulen glycerine
`polysorbate 80 water in
`amounts sufficient to prevent crystallization of cyclosporin
`for period of up to about nine months said pharmaceutical
`emulsion being suitable for topical application to ocular
`tissue
`The pharmaceutical emulsion according
`in an amount of
`wherein the cyclosporin
`is present
`about 0.05 to and about 0.40% by weight
`between
`the
`is present in an amount of between about 0.625%
`castor oil
`by weight and about 5.0% by weight
`the polysorbate 80 is
`present in an amount of about 1.0% by weight the Pemulen
`in an amount of about 0.05% by weight and the
`in an amount of about 2.2% by weight
`glycerine is present
`pharmaceutical emulsion consisting of between about
`0.05% and about 0.40% by weight cyclosporin
`between
`about 0.625% and about 5.0% by weight castor oil about
`1.0% by weight polysorbate 80 about 0.05% by weight
`Pemulen and about 2.2% by weight glycerine in water with
`pH of between
`about 7.2 and 7.6 suitable for topical
`application to ocular tissue
`
`FAMY CARE - EXHIBIT 1006-0004