United States Patent
`Ding et al.
`
`[19]
`
`US005474979A
`[ii] Patent Number:
`[45] Date of Patent:
`
`5,474,979
`Dec. 12, 1995
`
`[54] NONIRRTTATING EMULSIONS FOR
`SENSITIVE TISSUE
`
`[75]
`
`Inventors: Shulin Ding; Walter L. Tien, both of
`Irvine; Orest Olejnik, Trabuco Canyon,
`all of Calif.
`
`[73] Assignee; Allergan, Inc., Irvine, Calif.
`
`[21] Appl. No.: 243,279
`[22] Filed:
`May 17, 1994
`[51] Int. CI.6
`A61K 38/13; A61K 47/34
`[52] U.S. CI.
`514/11; 514/785; 514/786;
`514/912; 514/941; 514/943; 514/975
`[58] Field of Search
`530/317, 321;
`514/9, 11, 785, 786, 912, 913, 914, 915,
`941, 943, 975, 178, 179, 180, 181, 420,
`784; A61K 9/107, 47/14
`
`[56]
`
`4,347,238
`
`References Cited
`U.S. PATENT DOCUMENTS
`8/1982 Hollingsbee
`
`4,839,342
`4,990,337
`4,996,193
`5,051,402
`5,364,632
`
`6/1989 Kaswan
`2/1991 Kurihara et al.
`2/1991 Hewitt et al. ..
`9/1991 Kurihara et al.
`11/1994 Benita et al. ..
`
`. 514/11
`424/427
`. 514/11
`. 514/11
`514/943
`
`Primary Examiner—Jeffrey E. Russel
`Attorney, Agent, or Firm—Walter A. Hackler
`
`[57]
`ABSTRACT
`A pharmaceutical composition is disclosed in the form of a
`nonirritating emulsion which
`includes at
`least one
`cyclosporin in admixture with a higher fatty acid glyceride
`and polysorbate 80. More particularly, the cyclosporin may
`be cyclosporin A and the higher fatty acid glyceride may be
`castor oil. Composition has been found to be of a 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.
`
`514/179
`
`8 Claims, No Drawings
`
` EXHIBIT 1006
`
`

`
`5,474,979
`
`1
`NONIRRITATING EMULSIONS FOR
`SENSITIVE TISSUE
`
`2
`administered orally for the treatment of these symptoms, the
`accompanying side effects due to systemic circulation may
`cause adverse reactions such as hypertrichosis or renal
`The present invention generally relates to novel pharma­
`dysfunction.
`ceutical compositions incorporating chemicals which are 5
`On the other hand, if oily preparations containing
`poorly soluble in water and is more particularly related to a
`cyclosporin are applied directly to the eyes, irritation or a
`novel ophthalmic emulsion including cyclosporin in admix­
`clouding of visual field may result. This plus the difficulty in
`ture with castor oil and polysorbate 80 with high comfort
`formulating cyclosporin limits its use in formulations that
`level and low irritation potential.
`would be useful during keratoplasty as well in the treatment
`Cyclosporins are a group of nonpolar cyclic oligopep- 10 of herpetic keratitis and spring catarrh,
`tides with known immunosuppressant activity. In addition,
`"
`Heretofore, as for example in U.S. Pat. No. 5,051,402,
`as set forth in U.S. Pat. No. 4,839,342, cyclosporin (some­
`attempts have been made to dissolve sufEcient cyclosporin
`times referred to in the literature as "cyclosporine") has been
`in an aqueous solvent system so as to reach an effective
`found as effective in treating immune medicated keratocon­
`concentration for treatment. Importantly, this solvent system
`junctivitis sicca (KCS or dry eye disease) in a patient 15 does not contain any surface active agent such as polyoxy-
`sufifering therefrom.
`ethylated castor oil.
`As hereinabove noted, cyclosporin comprises a group of
`Conceptually, the purpose of dissolving the cyclosporin
`cyclic oligopeptides and the major component thereof is
`in an aqueous solvent system is to enable contact with body
`cyclosporin A (C62H111N11012) which has been identified
`fluids which would merely constitute dilution of the aqueous
`along with several other minor metabolites, cyclosporin B 20 solvent system which hopefully would eliminate the imme-
`through I. In addition, a number of synthetic analogs have
`diate precipitation of cyclosporin when contacted with the
`been prepared.
`water content of the body fluids.
`In general, commercially available cyclosporins may
`For direct use in the eye, cyclosporin has been formu­
`contain a mixture of several individual cyclosporins which
`lated with a number of pharmaceutically acceptable excipi-
`all share a cyclic peptide structure consisting of eleven 25 ents, for example, animal oil, vegetable oil, an appropriate
`amino acid residues with a total molecular weight of about
`organic or aqueous solvent, an artificial tear solution, a
`1,200, but with different substituents or configurations of
`natural or synthetic polymer or an appropriate membrane.
`some of the amino acids.
`Specific examples of these pharmaceutically acceptable
`It should be appreciated that reference to the term
`excipients, which may be used solely or in combination, are
`"cyclosporin" or "cyclosporins" is used throughout the 30 olive oil, arachis oil, castor oil, mineral oil, petroleum jelly,
`present specification in order to designate the cyclosporin
`dimethyl sulfoxide, chremophor, liposomes, or liposome-
`component in the composition of the present invention.
`like products or a silicone fluid, among others.
`However, this specific reference is intended to include
`In summary, a great deal of effort has been expended in
`any individual member of the cyclosporin group as well as
`order to prepare a pharmaceutical composition containing
`admixtures of two or more individual cyclosporins, whether 35 cyclosporin dissolved in an aqueous medium or cyclosporin
`natural or synthetic.
`prepared as an oily solution. However, successful formula­
`The activity of cyclosporins, as hereinabove noted, is as
`tions have yet to be accomplished as evidenced by the lack
`an immunosuppressant and in the enhancement or restoring
`of commercial products.
`of lacrimal gland tearing.
`As hereinabove noted, it has been reported that
`Unfortunately, the solubility of cyclosporin in water is 40 cyclosporin has demonstrated some solubility in oily prepa-
`extremely low and as elaborated in U.S. Pat. No. 5,051,402,
`rations containing higher fatty acid glycerides such as olive
`it has been considered not merely difficult but practically
`oil, peanut oil, and/or castor oil. These formulations fre­
`impossible to prepare a pharmaceutical composition con­
`quently produce an unpleasant sensation when applied to the
`taining cyclosporin dissolved in an aqueous medium.
`eye because of stimulation or the viscousness which is
`As reported, the solubility of cyclosporin in water is 45 characteristic of these oils,
`between about 20 ng/ml to 30 ng/ml for cyclosporin A.
`Another drawback of these formulations is that they
`Hence, heretofore prepared formulations incorporating
`contain a high concentration of oils, and oils exacerbate the
`cyclosporin have been prepared as oily solutions containing
`symptoms of certain ocular surface diseases such as dry
`ethanol. However, these preparations limit the bioavailabil­
`eyes, indicated by cyclosporin. Therefore, these oily formu-
`ity to oral preparations and this is believed to be due to the 50
`lations may not be clinically acceptable. Additionally, these
`separation of cyclosporin as a solid immediately after it
`formulations often suffer from physical instability due to
`comes into contact with water, such as in the mouth or eye
`cyclosporin's propensity to undergo conformational change
`of a patient.
`and crystallize out. The crystallization problem has been
`In the case of injectable preparations of cyclosporin, they
`noticed in formulations containing com oil or medium chain
`first must be diluted with physiological saline before intra- 55
`triglycerides. Lastly, these formulations often have a low
`venous administration but this is likely to result in the
`thermodynamic activity
`(degree of
`saturation) of
`precipitation of cyclosporin and therefore may be considered
`cyclosporin which leads to a poorer drug bioavailability.
`undesirable for intravenous administration.
`It may be possible to minimize the problems related to
`Surface active agents such as polyoxyethylated castor oil
`unpleasant sensation and syndrome exacerbation by reduc-
`ing the oil content and dispersing the oil phase in water into
`have been utilized as solubilizers to inject preparations in 60
`order to prevent cyclosporin from separating. However, this
`an emulsion. However, it is not an easy task to formulate an
`also may give rise to safety problems (see U.S. Pat. No.
`ophthalmic emulsion because one indispensable class of
`5,051,402).
`ingredients in an emulsion system is emulsifiers, and the
`The practical usefulness of cyclosporin would be greatly
`majority of emulsifiers is highly irritating to the eyes.
`enhanced if administration thereof could be effective; for 65
`The present invention is directed to an emulsion system
`example, cyclosporin's effectiveness in the treatment of
`which utilizes higher fatty acid glycerides but in combina­
`ocular symptoms of Behcet's Syndrome. However, if it is
`tion with polysorbate 80 which results in an emulsion with
`
`

`
`3
`a high comfort level and low irritation potential suitable for
`delivery of medications to sensitive areas such as ocular
`tissues.
`
`5,474,979
`
`20
`
`4
`Pemulen® is a registered trademark of B. F. Goodrich for
`polymeric emulsifiers and commercially available from B. F.
`Goodrich Company, Specialty Polymers & Chemicals Divi­
`sion, Cleveland, Ohio. Pemulens are Acrylates/C10-30
`SUMMARY OF THE INVENTION
`5 Alkyl Acrylate Cross-Polymers. They are high molecular
`weight co-polymers of acrylic acid and a long chain alkyl
`In accordance with the present invention, a nonirritating
`methacrylate cross-linked with allyl ethers of pentaerythri-
`pharmaceutical composition with high comfort level and
`tol. They contain not less than 52.0 percent and not more
`low irritation potential suitable for delivery to sensitive areas
`,
`„
`,
`^
`.
`.
`„
`such as ocular tissues comprises cyclosporin in admixture ^ 11131162-0 percent of carboxyhc acld g'0UPs-
`vlscoslty of
`a neutralized 1.0 percent aqueous dispersion is between
`with an emulsifying amount of a higher fatty acid glycerol
`9,500 and 26,500 centipoises.
`and polysorbate 80. More particularly, the composition may
`In addition, the tonicity of the emulsions can be further
`comprise cyclosporin A and the higher fatty acid glyceride
`adjusted using glycerine, mannitol, or sorbitol if desired.
`may comprise castor oil.
`The pH of the emulsions can be adjusted in a conventional
`Preferably, the weight ratio of the castor oil to the 15
`manner using sodium hydroxide to a near physiological pH
`polysorbate 80 is between about 0.3 to about 30 and a weight
`level and while buffering agents are not required, suitable
`ratio of the cyclosporin to castor oil is below 0.16. More
`buffers may include phosphates, citrates, acetates and
`preferably, the weight ratio of castor oil to polysorbate 80 is
`borates.
`between 0.5 and 12.5, and the weight ratio of cyclosporin to
`While the preferable medications in accordance with the
`castor oil is between 0.12 and 0.02.
`present invention include cyclosporin, other chemicals
`When cyclosporin is dissolved in the oil phase in accor­
`which are poorly soluble in water such as indomethacin and
`dance with the present invention, the emulsion is found to be
`steroids such as androgens, prednisolone, prednisolone
`physically stable upon long term storage. No crystallization
`acetate, fluorometholone,
`and dexamethasones, may be
`of cyclosporin was noticed after nine months at room
`25 emulsified with castor oil and polysorbate 80 resulting in a
`temperature. Moreover, the cyclosporin emulsion is formu­
`composition with similar low irritation potential.
`lated in such a way that the drug has reasonably high
`The invention is further illustrated by the following
`thermodynamic activity, yet without the crystallization prob­
`examples with all parts and percentages expressed by
`lem.
`weight. The cyclosporin used in the examples was supplied
`30 by Sandoz.
`
`DETAILED DESCRIPTION
`As hereinabove noted, cyclosporin is available as a mix­
`ture in which the principal ingredient is cyclosporin A with
`significant, but smaller, quantities of other cyclosporins such
`as cyclosporin B through 1. However, as also hereinabove 35
`noted, the present invention may be applied to either a pure
`Cyclosporin A
`cyclosporin or to a mixture of individual cyclosporins.
`Castor oil
`The discovery on which the present invention is founded
`Polysorbate 80
`relates to a combination of a higher fatty acid glyceride and
`.
`Pemulen ®
`an emulsifier and dispersing agent, polysorbate 80. The 40 Glycenne
`NaOH
`selection of these components could not have been antici­
`Purified water
`pated on the basis of conventional thinking.
`PH
`For example, although it is well-known that cyclosporin
`may be used in combination with castor oil, this combination
`is irritating to sensitive tissues such as the eye. Thus, 45
`conventional teaching in the art is away from a formulation
`Castor oil
`which utilizes a higher fatty acid glyceride, such as castor
`Polysorbate 80
`oil, and cyclosporin.
`Pemulen ®
`Stated another way, there is no way of deducing that the 50 Glycerine
`use of an emulsifier and dispersing agent such as polysorbate
`PurifiL water
`80 will reduce the irritation potential of an emulsion utiliz­
`PH
`ing castor oil. There are no examples of polysorbate in
`combination with castor oil which, when admixed to
`cyclosporin, produces an emulsion with a high comfort level 55
`and low irritation potential suitable for the delivery of
`medication to sensitive areas such as ocular tissues.
`Castor oil
`Polysorbate 80
`The present invention achieves a stable solution state of
`Carbomer 1382
`cyclosporin. This stable solution state is another important
`Glycerine
`performance characteristic differentiating the present inven- go NaOH
`tion from the conventional oil systems. Cyclosporin is
`Purified water
`pH
`notorious for its tendency to precipitate out in conventional
`oil systems in which it is fully dissolved initially.
`In accordance with the present invention, the emulsions
`can be further stabilized using a polyelectrolyte, or poly- 65
`electrolytes if more than one, from the family of cross-linked
`polyacrylates, such as carbomers and Pemulen®.
`
`Castor oil
`
`Example 1
`
`A
`
`B
`
`C
`
`D
`
`E
`
`0.40%
`5.00%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`0.20%
`5.00%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`0.20%
`2.50%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`0.10%
`1.25%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`0.05%
`0.625%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`Example 2
`
`A
`
`B
`
`C
`
`D
`
`5.00%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`2.50%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`1.25%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`0.625%
`1.00%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`Example 3
`
`A
`
`2.50%
`0.75%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`A
`
`5.00%
`
`Example 4
`
`

`
`5
`
`5,474,979
`
`-continued
`0.75%
`0.05%
`2.20%
`qs
`qs
`7.2-7.6
`
`6
`invention as defined in the appended claims.
`What is claimed is:
`1. A pharmaceutical composition comprising a nonirritat-
`ing emulsion of at least one cyclosporin in admixture with
`5 a higher fatty acid glyceride, polysorbate 80 and an emulsion
`stabilizing amount of Pemulen in water suitable for topical
`application to ocular tissue.
`2. The pharmaceutical composition according to claim 1
`wherein the cyclosporin comprises cyclosporin A.
`The formulations set forth in Examples 1-4 were made 10
`3. The pharmaceutical composition according to claim 2
`for treatment of keratoconjunctivitis sicca (dry eye) syn­
`wherein the weight ratio of the higher fatty acid glyceride to
`drome with Examples 2, 3 and 4 without the active ingre­
`the polysorbate 80 is between about 0.3 and about 30.
`dient cyclosporin utilized to determine the toxicity of the
`4. The pharmaceutical composition according to claim 3
`emulsified components.
`wherein the higher fatty acid glyceride comprises castor oil
`, ,
`. ,
`.
`_
`,
`.
`The formulations in Examples 1-4 were applied to rabbit , <•
`weight ratio of cyclosporin to castor oil is below
`eyes eight times a day for seven days and were found to
`311
`about 0.16.
`cause only slight to mild discomfort and slight hyperemia in
`5. The composition according to claim 1 wherein the
`the rabbit eyes. Slit lamp examination revealed no changes
`higher fatty acid glyceride and polysorbate 80 are present in
`in the surface tissue. In addition, the cyclosporin containing
`amounts sufficient to prevent crystallization of cyclosporin
`castor oil emulsion, as hereinabove set forth in Examples
`1A-1D, was also tested for ocular bioavailability in rabbits; 20 for a period of up to about nine months,
`and the therapeutic level of cyclosporin was found in the
`6. A pharmaceutical emulsion comprising of cyclosporin
`tissues of interest after dosage. This substantiates that
`A, castor oil, Pemulen, glycerine, polysorbate 80 water in
`cyclosporin in an ophthalmic delivery system is useful for
`amounts sufficient to prevent crystallization of cyclosporin A
`treating dry eye as set forth in U.S. Pat. No. 4,839,342.
`for a period of up to about nine months, said pharmaceutical
`25 emulsion being suitable for topical application to ocular
`In addition, no difference in toxicity was found between
`tissue.
`formulations with cyclosporin (Examples 1A-1D) and for­
`7. The pharmaceutical emulsion according to claim 6
`mulations without cyclosporin (Examples 2-4).
`wherein the cyclosporin A is present in an amount of
`The formulations set forth in Examples 1-4 were found to
`between about 0.05 to and about 0.40%, by weight, the
`be physically stable upon long term storage. With regard to 30
`castor oil is present in an amount of between about 0.625%,
`formulations 1A-1D, no crystallization of cyclosporin was
`by weight, and about 5.0%, by weight, the polysorbate 80 is
`noticed after nine months at room temperature.
`present in an amount of about 1.0%, by weight, the Pemulen
`Further, other higher fatty acid glycerides such as olive
`is present in an amount of about 0.05%, by weight, and the
`oil, peanut oil and the like may also be utilized with the
`glycerine is present in an amount of about 2.2%, by weight.
`polysorbate 80 with similar results regarding biotoxicity.
`8. A pharmaceutical emulsion consisting of between about
`Although there has been hereinabove described a particu­
`0.05% and about 0.40%, by weight, cyclosporin A, between
`about 0.625% and about 5.0%, by weight, castor oil, about
`lar pharmaceutical composition in the form of a nonirritating
`emulsion for the purpose of illustrating the manner in which
`1.0%, by weight, polysorbate 80, about 0.05%, by weight,
`the invention may be used to advantage, it should be
`Pemulen and about 2.2%, by weight, glycerine in water with
`appreciated that the invention is not limited thereto. Accord­
`a pH of between about 7.2 and 7.6 suitable for topical
`ingly, any and all modifications, variations, or equivalent
`application to ocular tissue.
`arrangements, which may occur to those skilled in the art,
`should be considered to be within the scope of the present
`
`Polysorbate 80
`Carbomer 981
`Glycerin
`NaOH
`Purified water
`pH
`
`35
`
`40