US008859623Bl
`
`(12) United States Patent
`Witham et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 8,859,623 B1
`Oct. 14, 2014
`
`(54) METHODS AND COMPOSITIONS OF
`STABLE PHENYLEPHRINE FORMULATIONS
`
`(71) Applicant: Paragon BioTeck, Inc., Portland, OR
`(US)
`
`(72)
`
`Inventors: Patrick H. Witham, Eugene, OR (US);
`Sailaja Machiraju, Beaverton, OR
`(US); Lauren Mackensie-Clark Bluett,
`Milwaukie, OR (US)
`
`(73) Assignee: Paragon Bioteck, Inc., Portland, OR
`(US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. l54(b) by 0 days.
`
`(21) Appl.No.: 14/080,771
`
`(22)
`
`Filed:
`
`Nov. 14, 2013
`
`(51)
`
`Int. Cl.
`A61K 31/137
`
`(2006.01)
`
`(52) U.S. Cl.
`CPC .................................. .. A61K31/137(2013.0l)
`USPC ........................................................ .. 514/653
`
`(58) Field of Classification Search
`None
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4/1981 Valle ........................... .. 424/720
`4,260,600 A *
`OTHER PUBLICATIONS
`
`Akorn, Inc., package insert for phenylephrine hydrochloride solu-
`tion/drops,
`at
`http://dailyrned.nlm.nih.gov/dailymed/lookup.
`cfm?setid:c5c51d8b-b50b-4c77-9d55-f64c14b0d0e5, revised Sep.
`201 1 .*
`
`synephrine
`and
`“Activities of octopamine
`al.,
`et
`Brown,
`stereoisomers on 01-adrenoceptors.” Br. J. Pharmacol. (1988), 93,
`417-429.
`El-Shibini, et al. “The Stability of Phenylephrine—Part 1: The Rate
`of Degradation of the Amino Group.” Arzneimittelforschung. Apr.
`1969;19(4):676-8.
`El-Shibini, et al. “The Stability of Phenylephrine—Part 2: The
`discolouration reaction and the influence of some ions on the rate of
`degradation
`of
`the
`drug” Arzneimittelforschung. May
`1969;19(5):828-31.
`El-Shibini, et al. “The Stability of Phenylephrine—Part 3: The
`racemisation
`reaction.”
`Arzneimittelforschung.
`Sep.
`1969;19(9):1613-4.
`Millard, et al., “The Stability ofAqueous Solutions of Phenylephrine
`at Elevated Temperatures: Identification of the Decomposition Prod-
`ucts.” J. Pharm. Pharn1ac., 1973, 25. Suppl., 24P-31P.
`“Report of the International Workshop on in Vitro Methods for
`Assessing Acut Systemic Toxicity.” Results ofan International Work-
`shop Organized by the Interagency Coordinating Committee on the
`Validation ofAlternative Methods (ICCVAM) and the National Toxi-
`cology Program (NTP) Interagency Center for the Evaluation of
`Alternative Toxicological Methods (NICEATM); pp. 1-370.
`Zaczek, et. al., “The effect of phenylephrine on pain and flare inten-
`sity in
`eyes with uveitis.” Acta Ophthalmol Scand. Oct.
`2000;78(5):516-8.
`
`* cited by examiner
`
`Primary Examiner — David J Blanchard
`Assistant Examiner — Barbara Frazier
`
`(74) Attorney, Agent, or Firm — Wilson Sonsini; Goodrich
`& Rosati
`
`(57)
`
`ABSTRACT
`
`The invention is directed to methods and compositions of
`stabilizing phenylephrine formations. The composition has
`good time-dependent stability at low temperature and has no
`change in its outward appearance even after having been
`stored at least 6 months.
`
`13 Claims, 4 Drawing Sheets
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`Exhibit 1001- Page 1 of 12
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`Exhibit 1001- Page 1 of 12
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`Oct. 14, 2014
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`Sheet 1 014
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`US 8,859,623 B1
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`Figure1
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`Exhibit 1001- Page 2 of 12
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`U.S. Patent
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`Oct. 14, 2014
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`Sheet 2 of4
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`Figure2
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`Exhibit 1001- Page 3 of 12
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`U.S. Patent
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`Oct. 14, 2014
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`Sheet 3 of4
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`Figure3
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`area:$é¥54,3+'¥
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`Exhibit 1001- Page 4 of 12
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`U.S. Patent
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`Exhibit 1001- Page 5 of 12
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`US 8,859,623 B1
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`1
`METHODS AND COMPOSITIONS OF
`STABLE PHENYLEPHRINE FORMULATIONS
`
`2
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`patent, or patent application was specifically and individually
`indicated to be incorporated by reference.
`
`BACKGROUND OF THE INVENTION
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Phenylephrine is a selective 0L1-adrenergic receptor ago-
`nist used primarily as a decongestant, as an agent to dilate the
`pupil, and to increase blood pressure. Phenylephrine is mar-
`keted as a substitute for the decongestant pseudoephedrine,
`though clinical studies differ regarding phenylephrine’s
`effectiveness in this role.
`
`SUMMARY OF THE INVENTION
`
`In accordance with the present invention, the present inven-
`tion provide a composition comprising at least 95% R-phe-
`nylephrine hydrochloride and an aqueous buffer, wherein the
`composition substantially maintains an initial chiral purity of
`R-phenylephrine hydrochloride for at least 6 months stored
`between -10 to 10 degree Celsius.
`In another aspect, provided herein are methods of stabiliz-
`ing a phenylephrine hydrochloride composition comprising
`storing a solution of aqueous R-phenylephrine hydrochloride
`at less than 10 degree Celsius, wherein the composition sub-
`stantially maintains the initial chiral purity of R-phenyleph-
`rine hydrochloride for at least 6 months.
`In one aspect, provided herein are methods of assaying
`chiral purity of R-phenylephrine hydrochloride, wherein the
`chiral purity is determined by chiral colunm chromatography,
`optical rotation, capillary electrophoresis, circular dichroism,
`or Nuclear Magnetic Resonance.
`In another aspect provides compositions comprising
`R-phenylephrine hydrochloride, wherein the composition
`substantially maintains the initial chiral purity of R-phenyle-
`phrine hydrochloride for at least 6 months.
`In another aspect provides methods of dilating the pupil
`comprising administering a composition comprising R-phe-
`nylephrine hydrochloride topically to a mammal, wherein the
`composition substantially maintains the initial chiral purity of
`R-phenylephrine hydrochloride for at least 6 months.
`In another aspect provides methods of treating Uveitis in a
`subject comprising administering a composition comprising
`R-phenylephrine hydrochloride to said subject, wherein the
`composition substantially maintains the initial chiral purity of
`R-phenylephrine hydrochloride for at least 6 months
`In another aspect provides methods of performing certain
`ocular testing such as ultrasonography, provocative closed
`angle glaucoma test, Retinoscopy, compromised circulation
`(i.e., blanching test), Refraction, fundus examination com-
`prising administering a composition comprising R-phenyle-
`phrine hydrochloride, wherein the composition substantially
`maintains the initial chiral purity of R-phenylephrine hydro-
`chloride for at least 6 months.
`
`In another aspect provides methods of aiding surgical pro-
`cedures requiring visualization ofthe posterior chamber com-
`prising administering a composition comprising R-phenyle-
`phrine hydrochloride to a subject, wherein the composition
`substantially maintains the initial chiral purity of R-phenyle-
`phrine hydrochloride for at least 6 months.
`
`INCORPORATION BY REFERENCE
`
`All publications, patents, and patent applications men-
`tioned in this specification are herein incorporated by refer-
`ence to the same extent as if each individual publication,
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`The novel features of the invention are set forth with par-
`ticularity in the appended claims. A better understanding of
`the features and advantages of the present invention will be
`obtained by reference to the following detailed description
`that sets forth illustrative embodiments, in which the prin-
`ciples of the invention are utilized, and the accompanying
`drawings of which:
`FIG. 1 shows a HPLC chromatogram of racemic R-phe-
`nylephrine hydrochloride by a chiral colunm purification
`(OJ-RH (150><4.6) mm). Two peaks at the retention time
`5.225 minutes and 6.444 minutes are shown.
`
`FIG. 2 shows a HPLC chromatogram of the exemplary
`R-Phenylephrine Hydrochloride Opthalmic Solution (10%)
`before storage. The chiral purity was determined to be 99.3%
`ee based on the peaks at 5.184 minutes (area: 9931.84) and at
`6.425 minutes (area: 32.5748).
`FIG. 3 shows a HPLC chromatogram of the exemplary
`R-Phenylephrine Hydrochloride Opthalmic Solution (10%)
`stored at 2 to 8° C. after 6 months. The chiral purity was
`determined to be 99.3% ee based on the peaks at 5.089 min-
`utes (area: 8454.34) and at 6.363 minutes (area: 30.7874).
`FIG. 4 shows a HPLC chromatogram of the purified
`“impurity” which is a S-Phenylephrine Hydrochloride. The
`chiral purity was determined to be 82.4% ee based on the
`peaks at 5.183 minutes (area: 255.971) and at 6.347 minutes
`(area: 2851.08).
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Phenylephrine differs chemically from epinephrine only in
`lacking one hydroxyl group (OH) in the four position on the
`benzene ring. It is a bitter-tasting crystalline material soluble
`in water and alcohols, with a melting point of 140°-145° C.
`Chemically it is Benzenemethanol, 3-hydroxy-ot-[(methy-
`lamino)methyl]-, hydrochloride or (R)-(—)-m-hydroxy-0t-
`[methylamino)methyl]benzyl alcohol hydrochloride with the
`following chemical structure.
`
`HO
`
`- HCI
`
`It is known in the art that a Phenylephrine Hydrochloride
`solution should be stored protected from light. The benzylic
`hydrogen is acidic and can be deprotonated easily. The
`hydroxyl group may be oxidized to form a carbonyl moiety
`conjugated with phenyl group, especially with help of the
`adjacent basic amino group. Thus, it is known in the art that a
`Phenylephrine Hydrochloride solution should be stored pro-
`tected from light. For example, an insert from a commercially
`available Phenylephrine Hydrochloride Ophthalmic Solution
`provides that the solution should be stored at 20° to 25° C.
`(USP controlled room temperature) and keep container
`tightly closed. Do not use if solution is brown or contains
`precipitate. (AKORN Package Insert)
`However, a solution under such condition often turns
`brown over time despite of carefully keeping container tightly
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`Exhibit 1001- Page 6 of 12
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`Exhibit 1001- Page 6 of 12
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`US 8,859,623 B1
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`3
`closed at 20° to 25° C. (USP controlled room temperature).
`Those packages containing the brown solution cannot be used
`and thus create waste.
`
`The present invention provides the improvement to over-
`come such instability problem.
`In some embodiments, there are provided a composition
`comprising at least 95% R-phenylephrine hydrochloride and
`an aqueous buffer for substantially maintaining chiral purity
`of R-phenylephrine hydrochloride for at least 6 months, the
`improvement comprising storing the composition between
`-10 to 10 degree Celsius. In certain embodiments, the com-
`position is stored between 2 to 8 degree Celsius. In certain
`embodiments, the composition comprises at least 99% or
`99.3%, R-phenylephrine hydrochloride. In certain embodi-
`ments, the chiral purity of R-phenylephrine hydrochloride is
`at least 95%, 97%, 99%, or 99.5% of the initial chiral purity
`after 6 months. In certain embodiments, the composition
`comprises 2.5% w/v or 10% w/v R-phenylephrine hydrochlo-
`ride by weight. In certain embodiments, the composition
`further comprises a preservative such as benzalkonium chlo-
`ride, stearalkonium chloride, polyarninopropyl biguanide, or
`the like. In some embodiments, the composition is in a 1-15
`ml plastic or glass bottle. In some embodiments, the compo-
`sition is in a glass or plastic bottle of about 2 ml, about 3 ml,
`about 5 ml, about 10 ml or about 15 ml. In certain embodi-
`ments, the plastic or glass bottle is opaque.
`In some embodiments provide methods of stabilizing a
`phenylephrine hydrochloride composition such as a solution
`of aqueous R-phenylephrine hydrochloride at less than 10
`degree Celsius wherein the composition substantially main-
`tains the initial chiral purity of R-phenylephrine hydrochlo-
`ride for at least 6 months.
`
`In some embodiments provide herein compositions com-
`prising R-phenylephrine hydrochloride, wherein the compo-
`sition substantially maintains the initial chiral purity of
`R-phenylephrine hydrochloride for at least 6 months.
`In some embodiments, the composition is stored at -10 to
`10 degree Celsius. In certain embodiments, the composition
`is stored at -5 to 10 degree Celsius. In certain embodiments,
`the composition is stored at 0 to 10 degree Celsius. In certain
`embodiments, the composition is stored at 2 to 8 degree
`Celsius.
`
`The term “substantial” or “substantially maintains”
`described herein refers to not more than 15% deviation of the
`
`initial purity. In some embodiments, the chiral purity of the
`composition is at least 85%, 90%, 95%, 97%, 99%, 99.1%,
`99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or
`99.9% of the initial chiral purity.
`In some embodiments provide herein methods of assaying
`chiral purity of R-phenylephrine hydrochloride, wherein the
`chiral purity is determined by chiral colunm chromatography,
`optical rotation, capillary electrophoresis, circular dichroism,
`or Nuclear Magnetic Resonance.
`In certain embodiments, the chiral purity is determined by
`chiral column chromatography.
`Chiral Column Chromatography
`Chiral column chromatography is a variant of column
`chromatography in which the stationary phase contains a
`single enantiomer of a chiral compound rather than being
`achiral. The two enantiomers of the same analyte compound
`differ in afiinity to the single-enantiomer stationary phase and
`therefore they exit the column at different times.
`The chiral stationary phase can be prepared by attaching a
`suitable chiral compound to the surface of an achiral support
`such as silica gel, which creates a Chiral Stationary Phase
`(CSP). Many common chiral stationary phases are based on
`oligosaccharides such as cellulose or cyclodextrin (in particu-
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`lar with [3-cyclodextrin, a seven sugar ring molecule). As with
`all chromatographic methods, various stationary phases are
`particularly suited to specific types of analytes.
`The packing material of the chiral column may be amylose
`tris(3,5-dimethylphenylcarbamate),
`[3-cyclodextrin, cello-
`biohydrolase,
`selector R-(—)-N-(3,5-dinitrobenzoyl)-phe-
`nylglycine,
`cellulose
`tris(3,5-dimethylphenylcarbamate),
`cellulose tris(3,5-dichlorophenylcarbarnate), or combina-
`tions thereof. In some embodiments, the chiral column for
`analytical purpose is packed with amylose tris(3,5-dichlo-
`rophenylcarbarnate). The column may have a packing particle
`of a size of about 3 um to about 50 um. In some embodiments,
`the column has a packing particle a size of about 3 pm, 5 pm,
`10 um, 20 um, 30 um, 40 um, or 50 um. In certain embodi-
`ments, the column has a packing particle a size of about 3 pm.
`In some embodiments, when using a chiral column system,
`the first mobile phase is non-polar solvent such as n-hexane,
`n-pentane, and the like, and the second mobile phase is polar
`solvent such as isopropanol, ethanol, methanol, or the like. In
`certainly embodiments, the mobile phase comprises small
`amount of amine such as ethylenediamine. The first mobile
`phase may be present in an amount of about 75% to about
`95% by volume and the second mobile phase is present in an
`amount of about 5% to about 25% by volume. In some
`embodiments, the first mobile phase is present in an amount
`of about 85% by volume and the second mobile phase is
`present in an amount ofabout 15% by volume with or without
`ethylenediamine.
`Other Chiral Compound Analysis Methods
`There are several chiral compound purification and analy-
`sis methods available besides chiral column chromatography.
`For example, it is known in the art chiral purity can be deter-
`mined by optical rotation. In some embodiments, the chiral
`purity of R-phenylephrine hydrochloride in the stabilized
`compositions and methods thereof can be determined by
`comparison of optical rotation of pure R-phenylephrine
`hydrochloride.
`Optical Purity Measured by Optical Rotation
`Molecules with chrial centers cause the rotation of plane
`polarised light and are said to be “optically active” (hence the
`term optical isomers). Enantiomeric molecules rotate the
`plane in opposite directions but with the same magnitude.
`This provides a means of measuring the “optical purity” or
`“enantiomeric excess (ee)” of a sample of a mixture of enan-
`tiomers.
`
`Specific rotation is a physical property like boiling point
`and can be looked up in references. It is defined according to
`the following equation based on the experimental measure-
`ments: Specific rotation [(X]D:(X0bJCl where “cxobs” is the
`experimentally observed rotation, “c” is the concentration in
`g/ml and “l” is the path length ofthe cell used expressed in dm
`(10 cm).
`A non-racemic mixture of two enantiomers will have a net
`
`optical rotation. It is possible to determine the specific rota-
`tion of the mixture and, with knowledge of the specific rota-
`tion of the pure enantiomer, the optical purity can be deter-
`mined.
`
`% Optical purity of sample:100*(specific rotation of
`sample)/(specific rotation of a pure enantiomer)
`
`there are provided methods of
`In some embodiments,
`assaying chiral purity of R-phenylephrine hydrochloride,
`wherein the chiral purity is determined by optical rotation. In
`certain embodiments, the optical rotation is determined by
`comparison of optical rotation of pure R-phenylephrine
`hydrochloride.
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`
`Capillary Electrophoresis
`Capillary electrophoresis (CE), also known as capillary
`zone electrophoresis (CZE), can be used to separate ionic
`species by their charge and frictional forces and hydrody-
`namic radius.
`
`Capillary electrophoresis (CE) in general offers highly
`efiicient separations. To achieve chiral separation, the capil-
`lary is filled with a separation buffer containing a chiral addi-
`tive. Although many chiral selectors have been used success-
`fully, the most comprehensive separation strategies have been
`achieved with highly sulfated cyclodextrins. In some embodi-
`ments, the chiral purity ofthe compositions provided herein is
`determined by capillary electrophoresis. In certain embodi-
`ments, the capillary electrophoresis uses cyclodextrin or its
`derivatives (such as sulfated cyclodextrins).
`Chiral Purity Measured by Circular Dichroism
`Circular dichroism (CD) refers to the differential absorp-
`tion of left and right circularly polarized light. This phenom-
`enon is exhibited in the absorption bands of optically active
`chiral molecules. CD spectroscopy has a wide range of appli-
`cations in many different fields. For example, vibrational
`circular dichroism, which uses light from the infrared energy
`region, is used for structural studies of small organic mol-
`ecules, and most recently proteins and DNA. In general, this
`phenomenon will be exhibited in absorption bands of any
`optically active molecule. As a consequence, circular dichro-
`ism is exhibited by biological molecules, because of their
`dextrorotary and levorotary components. Even more impor-
`tant is that a secondary structure will also impart a distinct CD
`to its respective molecules.
`Optical rotation and circular dichroism stem from the same
`quantum mechanical phenomena and one can be derived
`mathematically from the other if all spectral information is
`provided. In some embodiments, the chiral purity is deter-
`mined by circular dichroism. In certain embodiments, the
`chiral purity is determined by Fourier transform infrared
`vibrational circular dichroism (FTIR-VCD). A skilled person
`in the art can readily apply the general knowledge and pro-
`cedure to determine chirality of the compositions provided
`herein.
`
`NMR Spectroscopy of Stereoisomers
`It is known in the art that NMR spectroscopy techniques
`can determine the absolute configuration of stereoisomers
`such as cis or trans alkenes, R or S enantiomers, and R,R or
`R,S diastereomers. In a mixture of enantiomers, these meth-
`ods can help quantify the optical purity by integrating the area
`under the NMR peak corresponding to each stereoisomer.
`Accuracy of integration can be improved by inserting a chiral
`derivatizing agent with a nucleus other than hydrogen or
`carbon, then reading the heteronuclear NMR spectrum: for
`example fluorine-19 NMR or phosphorus-31 NMR. Mosh-
`er’ s acid contains a —CF3 group, so ifthe adduct has no other
`fluorine atoms, the 19F NMR of a racemic mixture shows just
`two peaks, one for each stereoisomer. In some embodiments,
`the chiral purity of the compositions provided herein is deter-
`mined by Nuclear Magnetic Resonance Spectroscopy
`(NMR). In certain embodiments, a chirally pure complexing
`reagent (i.e., a chiral derivatizing agent) is used in measuring
`NMR. A skilled person in the art can readily utilize NMR and
`any suitable chiral complexing agent to determine the chiral-
`ity of the compositions provided herein.
`Dosage Forms and Strengths
`In some embodiments, the stabilized compositions pro-
`vided herein comprise a solution of 2.5% w/v or 10% w/v
`R-phenylephrine hydrochloride by weight.
`In certain
`embodiments,
`the compositions further comprise sodium
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`phosphate monobasic, sodium phosphate dibasic, boric acid
`and benzalkonium chloride. The followings are non-limited
`exemplary compositions:
`Phenylephrine Hydrochloride Ophthalmic Solution, 2.5%
`is a clear, colorless to yellowish, sterile topical ophthalmic
`solution containing phenylephrine hydrochloride 2.5%.
`Phenylephrine Hydrochloride Ophthalmic Solution, 10%
`is a clear, colorless to yellowish, sterile topical ophthalmic
`solution containing phenylephrine hydrochloride 10%.
`Application of the Stabilized Compositions Comprising
`R-Phenylephrine Hydrochloride
`It has been established that Phenylephrine Hydrochloride
`Ophthalmic Solution is recommended as a vasoconstrictor,
`decongestant, and mydriatic in a variety of ophthalmic con-
`ditions and procedures. Some of its uses are for pupillary
`dilation in uveitis (to prevent or aid in the disruption of pos-
`terior synechia formation), for many ophthalmic surgical pro-
`cedures and for refraction without cycloplegia. Phenyleph-
`rine Hydrochloride Ophthalmic Solution may also be used for
`funduscopy and other diagnostic procedures.
`For example, R-Phenylephrine is used to dilate the iris
`through ot-adrenergic stimulation of the iris dilator muscle.
`Sympathetic stimulation of the ciliary muscle is believed to
`be inhibitory, decreasing accommodative amplitude. R-Phe-
`nylephrine is formulated in an eye drop to dilate the pupil in
`order to facilitate visualization ofthe retina. It is often used in
`
`combination with tropicamide as a synergist when tropicam-
`ide alone is not sufficient. Surprisingly it was found that
`S-Phenylephrine dilated the eye only slightly more than that
`was untreated. Thus it is important that an eye drop containing
`Phenylephrine Hydrochloride used for dilation of the pupil
`contains predominantly the R-isomer in order to maintain
`maximum efiicacy of the ophthalmic solution.
`Sympathetic innervation leads to pupillary dilation. It is
`innervated by the sympathetic system, which acts by releas-
`ing noradrenaline, which acts on otl-receptors causing dila-
`tion.
`
`(0.1) adrenergic receptor is a G protein-
`The alpha-l
`coupled receptor (GPCR) associated with the Gq heterotrim-
`eric G-protein. It consists of three highly homologous sub-
`types,
`including
`011A-,
`(X13-,
`and
`(X1D-adrenergic.
`Catecholamines like norepinephrine (noradrenaline) and epi-
`nephrine (adrenaline) signal through the (X 1-adrenergic recep-
`tor in the central and peripheral nervous systems.
`Phenylephrine is a selective (X1 -adrenergic receptor agonist
`used primarily as a decongestant, as an agent to dilate the
`pupil, and to increase blood pressure. Dilation is controlled
`by the dilator pupillae, a group ofmuscles in the peripheral 2/3
`of the iris. Sympathetic innervation begins at the cortex with
`the first synapse at the cilliospinal center (also known as
`Budge’s center after German physiologist Julius Ludwig
`Budge). Post synaptic neurons travel down all
`the way
`through the brain stem and finally exit through the cervical
`sympathetic chain and the superior cervical ganglion. They
`synapse at the superior cervical ganglion where third-order
`neurons travel through the carotid plexus and enter into the
`orbit through the first division of the trigeminal nerve.
`In the anesthetized rats, infusion of large amount of (+)-
`epinephrine, (+)-norepinephrine, epinine, and (—)- or (+)-
`phenylephrine induces tachyphylaxis to vasopressor effect of
`(—)-epinephrine,
`(—)-norepinephrine, and tetraethylammo-
`nium. The tachyphylactic potency of the amines was (—)-
`phenylephrine (R-phenylephrine)>epinine>(+)-norepineph-
`rine:(+)-epinephrine>(+)-phenylephrine.
`Two ophthalmic formulations, formulated 10% Phenyle-
`phrine hydrochloride (S -isomer) and the exemplary invention
`composition, 10% Phenylephrine hydrochloride (R-isomer)
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`were tested for their ocular activity in NZW rabbits. It was
`observed that formulated S-isomer showed minimal dilation,
`responded to light exposure and constricted slightly more
`slowly than the untreated eye, where as the exemplary inven-
`tion composition, 10% Phenylephrine hydrochloride showed
`maximal dilation with in 15 min of dosing and the pupil did
`not respond to light and remained dilated for 4 hrs.
`According to the above study it could be postulated that,
`when an ophthalmic solution of phenylephrine hydrochlo-
`ride, (R-isomer) containing S-isomer as an impurity is used
`for dilation of pupil, the s-isomer may cause the saturation of
`the a-adrenergic receptors resulting in the decrease in the
`response of the drug after its administration (tachyphylasis).
`Furthermore, the presence of S-isomer in the ophthalmic
`solution may lead to poor/delayed dilation of the pupil.
`In some embodiments provide methods of dilating the
`pupil comprising administering a composition comprising
`R-phenylephrine hydrochloride topically to a mammal,
`wherein the composition substantially maintains the initial
`chiral purity of R-phenylephrine hydrochloride for at least 6
`months. It is evident from the literature that the pharmaco-
`logical evaluation of both R & S-Phenylephrine hydrochlo-
`ride is not same. R-Phenylephrine is referenced as useful
`synthetic adrenergic drug.
`Uveitis
`
`Uveitis is, broadly, inflammation of the uvea. The uvea
`consists of the middle, pigmented, vascular structures of the
`eye and includes the iris, ciliary body, and choroid. Uveitis
`requires an urgent referral and thorough examination by an
`ophthalmologist or Optometrist and urgent treatment to con-
`trol the inflammation. Anterior uveitis (iritis) affects the front
`portion of the eye, intermediate uveitis (cyclitis) affects the
`ciliary body, and posterior uveitis (choroiditis) affects the
`back portion ofthe uvea. Diffuse uveitis affects all portions of
`the uvea. Anterior uveitis commonly occurs in conjunction
`withjuvenile rheumatoid arthritis, but does not manifest in all
`juvenile arthritis patients. Uveitis is most likely to be present
`injuvenile arthritis patients with pauciarticular disease (fewer
`than five joints involved), a positive anti-nuclear antibody
`test, and a negative rheumatoid factor test. It has been dem-
`onstrated that after phenylephrine hydrochloride ophthalmic
`solution instillation, flare intensity and pain were signifi-
`cantly decreased only in eyes with iridocyclitis and without
`fibrinoid reaction (FR). The decreasing level offlare intensity,
`and paralysis of the pupil after phenylephrine instillation
`seem to alleviate pain in those eyes. See e.g., Zaczek, et. al.,
`Acta Ophthalmol Scand. 2000 October; 78(5):5l6-8.
`In some embodiments provide methods of treating Uveitis
`in a subject comprising administering a composition com-
`prising R-phenylephrine hydrochloride to said subject,
`wherein the composition substantially maintains the initial
`chiral purity of R-phenylephrine hydrochloride for at least 6
`months.
`
`In some embodiments provide methods of performing cer-
`tain ocular testing such as ultrasonography, provocative
`closed angle glaucoma test, Retinoscopy, compromised cir-
`culation (i.e., blanching test), Refraction, fundus examination
`comprising administering a composition comprising R-phe-
`nylephrine hydrochloride, wherein the composition substan-
`tially maintains the initial chiral purity of R-phenylephrine
`hydrochloride for at least 6 months.
`In some embodiments provide methods of aiding surgical
`procedures requiring visualization of the posterior chamber
`comprising administering a composition comprising R-phe-
`nylephrine hydrochloride, wherein the composition substan-
`tially maintains the initial chiral purity of R-phenylephrine
`hydrochloride for at least 6 months.
`
`10
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`15
`
`20
`
`25
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`30
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`35
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`40
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`45
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`50
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`55
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`60
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`65
`
`8
`After presentation of R-phenylephrine hydrochloride oph-
`thalmic solution 2.5% or 10% to the ocular surface, a broad
`variation in the delay of onset of dilation is widely reported,
`varying between 20-to-30 minutes and as much as up to 60
`minutes. While a number of contributors to this delay of onset
`have been theorized, the absence of phenylephrine hydro-
`chloride’s pharmacologic activity in the eye due to the pres-
`ence of S-phenylephrine may in fact be the explanation for
`such delay.
`Dropper Bottle or Storage Bottle
`Conventional dropper bottles for administering oph-
`thalmic fluid are well known in the prior art. The basic com-
`mercial design of such dropper bottles has remained fairly
`unchanged over the last several decades: a squeezable con-
`tainer is provided with a tapered dispenser that terminates in
`a discharge aperture. To administer ophthalmic fluid, the dis-
`charge aperture is aligned above a target eye and the bottle is
`squeezed to urge out a drop or dose of the fluid.
`Alternatively, liquid dispensers have been developed in
`which the formulation is supplied from a storage bottle
`through a dropper, for example (dropper bottles or EDO-
`Ophthiols). The aqueous formulation usually flows out ofthe
`dropper opening as a result of manual pressure being applied
`to the compressible storage bottle.
`In some embodiments, the composition described herein is
`stored in a plastic or glass bottle. In certain embodiments, the
`plastic bottle is a low-density polyethylene bottle. In certain
`embodiments, the composition described herein is stored in a
`glass bottle with or without a liquid dispenser. In certain
`embodiments, the plastic or glass bottle is opaque.
`Additionally, the compositions described herein are either
`packaged for single use or for multiple uses with or without a
`preservative.
`Certain Pharmaceutical and Medical Terminology
`The term “acceptable” with respect to a formulation, com-
`position or ingredient, as used herein, means having no per-
`sistent detrimental effect on the general health of the subject
`being treated.
`The term “carrier,” as used herein, refers to relatively non-
`toxic chemical compounds or agents that facilitate the incor-
`poration of a compound into cells or tissues.
`The terms “co-administration” or the like, as used herein,
`are meant to encompass administration of the selected thera-
`peutic agents to a single patient, and are intended to include
`treatment regimens in which the agents are administered by
`the same or different route of administration or at the same or
`different time.
`
`The term “diluent” refers to chemical compounds that are
`used to dilute the compound of interest prior to delivery.
`Diluents can also be used to stabilize compounds because
`they can provide a more stable environment. Salts dissolved
`in buffered solutions (which also can provide pH control or
`maintenance) are utilized as diluents in the art, including, but
`not limited to a phosphate buffered saline solution.
`The terms “effective amount” or “therapeutically effective
`amount,” as used herein, refer to a suflicient amount of an
`agent or a compound being administered which will relieve to
`some extent one or more of the symptoms of the disease or
`condition being treated. The result can be reduction and/or
`alleviation of the signs, symptoms, or causes of a disease, or
`any other desired alteration of a biological system. For
`example, an “effective amount” for therapeutic uses is the
`amount of the composition comprising a compound as dis-
`closed herein required to provide a clinically significant
`decrease in disease symptoms. An appropriate “effective”
`amount in any individual case may be determined using tech-
`niques, such as a dose escalation study.
`
`Exhibit 1001- Page 9 of 12
`
`Exhibit 1001- Page 9 of 12
`
`

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`US 8,859,623 B1
`
`9
`The terms “enhance” or “enhancing,” as used herein,
`means to increase or prolong either in potency or duration a
`desired effect. Thus, in regard to enhancing the effect of
`therapeutic agents, the term “enhancing” refers to the ability
`to increase or prolong, either in potency or duration, the effect
`of other therapeutic agents on a system. An “enhancing-
`effective amount,” as used herein, refers to