a2) United States Patent
`US 6,635,654 Bl
`(10) Patent No.:
`Changctal.
`Oct. 21, 2003
`(45) Date of Patent:
`
`US006635654B1
`
`(54) OPHTHALMIC COMPOSITIONS
`CONTAINING LORATADINE
`
`(75)
`
`Inventors: Chin-Ming Chang, Tustin, TX (US);
`Eldon Q. Farnes, Laguna Beach, CA
`(US); Orest Olejnik, Coto De Caza,
`CA (US); James N. Chang, Newport
`Beach, CA (US)
`
`(73) Assignee: Allergan, Inc., Irvine, CA (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`US.C. 154(b) by 0 days.
`
`(21) Appl. No.: 10/340,355
`
`(22) Filed:
`Jan. 9, 2003
`(BV)
`Tint, C0) ieee ceceeeee eee ececeseeseee ee eeeeteee A6IK 31/44
`(52) US. Ch. ees eeteteseecncessenerereneeseseeseteceeae 514/290
`(58) Field of Search 0.0... cece eee eee 514/290
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,282,233 A
`5,441,958 A
`5,496,811 A
`5,578,586 A
`5,668,133 A
`5,981,607 A
`6,132,758 A
`6,267,985 Bl
`6,495,160 B2
`2002/0032171 A1
`2002/0034539 Al
`2002/0107265 Al *
`
`8/1981 Vilani
`8/1995 Yanni etal.
`3/1996 Avivetal.
`11/1996 Glonek et al.
`9/1997 Yanni et al.
`11/1999 Ding etal.
`10/2000 Munayyeretal.
`7/2001 Chenetal.
`12/2002 Esposito et al.
`3/2002 Chenetal.
`3/2002 Esposito etal.
`8/2002 Chenet al. on. 514/310
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`FP
`EP
`EP
`WO
`WoO
`WO
`WO
`
`5/1981
`0028110 A2
`6/1991
`0433766 Al
`4/1992
`0480690 Al
`3/1997
`0759773 B1
`* 10/1998
`0 872 236 Al
`0 978 281 Al *
`2/2000
`10446781
`10/2000
`WO 97/15307
`5/1997
`WO 98/48803
`11/1998
`WO 99/62516
`12/1999
`WO 01/89527
`11/2001
`
`OTHER PUBLICATIONS
`
`Ableson, M.B., et al., Effects of Topically applied ocular
`decongestant and antihistamine, American Journal of Oph-
`thalmology, 90:254—-257, 1980.
`
`Abelson, M.B., Evaluation of olopatadine, a new oph-
`thalmic antiallergic agent with dual activity, using the
`conjunctival allergen challenge model, Ann Allergy Asthma
`Immunol 1998:81:211-218.
`
`Berdy, G.J., ct al., Allergic Conjunctivitis: a survey of New
`antihistamines, vol. 7, No. 4, 1991: Mary Ann Liebert, Inc.
`Publishers., pp. 313-324.
`Dechant, K.L., et al., Levocabastine, A reviewof its phar-
`macological properties and therapeutic potential as a topi-
`cal antihistaminein allergic rhinitis and conjunctivitisDrugs
`1991: 41 (2): 202-24.
`Doughty, M.J.., Levocabastine, a topical ocular antihista-
`mine available as a pharmacy medicine—a literature review,
`The Pharmaceutical Journal, vol. 268, Mar. 16, 2002, pp.
`367-370.
`
`Miller, J., ct al., Antazoline phosphate and naphazoline
`hydrochloride, singly and in combination for the treatment
`of allergic conjunctivitis—a controlled double-blind clinical
`trial, Annals of Allergy, Antazoline Phosphate, vol. 35, Aug.
`1975, pp. 81-86.
`et al, Abstract, Efficacy of
`Vandewalker, M. L.
`vasocon—a—and its components with conjunctival provoca-
`tion testing (CP1), #523 (No date available).
`Internet Article: Medem, Inc. Eye Allergies and Allergic
`Conjunctivitis, Medical Library: Eye Allergies and Allergic
`Conjunctivitis, American College of Allergy, Asthma &
`Immunology-www.medem.com/medlb/article detaillb for
`printer.cfm, printed Dec. 9, 2002, 4 pgs.
`Internet Article: Allergic Conjunctivitis, http;://familydoc-
`tor.org/handounts/678.html printed Dec. 9, 2002 printed
`Dec. 9, 2002, 2 pgs, American Academy of Family Physi-
`cians.
`
`Internet Article: Review of Optometry, Ocular Allergy
`Treatment Drugs, May 15, 2002, www.revoptom.com/drug-
`guide.asp?show =view& articleid +4, printed Dec. 9, 2002,
`6 pgs.
`
`* cited by examiner
`
`Primary Examiner—Raymond Henley,III
`(74) Attorney, Agent, or Firm—Brent A. Johnson; Martin
`A. Voet; Robert J. Baran
`
`(57)
`
`ABSTRACT
`
`The present invention is directed to an ophthalmic formu-
`lation which comprises a therapeutically effective amount of
`ethyl 4-(8-chloro-5,6-dihydro-11-benzo[5,6]cyclohepta[1,2-
`b]pyridin-11-ylidene)-1-piperidinecarboxylate, known as
`loratadine, a fatty acid ester, and a surfactant, which has
`been found to be usetul in treating ocular allergies, espe-
`cially allergic conjunctivitis, and related conditions.
`
`24 Claims, No Drawings
`
`FAMY CARE- EXHIBIT 1028-0001
`
`FAMY CARE - EXHIBIT 1028-0001
`
`

`

`US 6,635,654 Bl
`
`1
`OPHTHALMIC COMPOSITIONS
`CONTAINING LORATADINE
`
`FIELD OF THE INVENTION
`
`The present invention relates to a pharmaceutical com-
`position for relieving ocular allergies. More particularly, the
`present invention relates to ophthalmic compositions com-
`prising cthyl 4-(8-chloro-5,6-dihydro-11-benzo[5,6]
`cyclohepta[1,2-b]pyridin-11-ylidene)-1-
`piperidinecarboxylatc, othcrwisc knownasloratadine.
`BACKGROUNDOF THE INVENTION
`
`10
`
`15
`
`Allergic conjunctivitis is an ocular allergy characterized
`by redness, itching and swelling of the eyes. Allergic con-
`junctivitis is a similar reaction to allergies of the sinuses,
`nose, or lungs, in that it is characterized by the release of
`histamines from contact with allergens such as pollen, pet
`hair or dander,or dust. H, histamine receptor antagonists are ,
`used widely in the systemic treatment of allergies, and have
`recently been shownto be effective when used topically on
`the eye.
`(Doughty, The Pharmaceutical Journal, 268,
`367-370, Mar. 16, 2002). Two H, histamine receptors,
`emedastine and levocabastine, are currently available in eye
`drop formulations for treatmentof allergic conjunctivitis and
`related conditions. Another H, histamine receptor,
`Loratadine, sold by Schering-Plough under the brand name
`Claritin®, is used widely in the oral dosages formsof tablets
`and syrup for the systemic treatment of allergies. However,
`no topical ophthalmic product containing loratadine is cur-
`rently available duc to its insolubility and instability in
`aqueous solutions. The low water solubility of loratadine
`results in poor delivery of the drug topically, resulting in
`limited ocular activity. For water insoluble active agents
`such as loratadine, ophthalmic formulations typically com-
`prise a suspension or a solution containing solubilizers such
`as surfactants, cosolvents and complexing agents to enhance
`the solubility of the compound.
`The manufacturer of Claritin®, Schering-Plough, has
`experimentally prepared an ophthalmic formulation of lora-
`tadine using Tween-80®, a surfactant, as a solubilizer.
`(W09715307) This formulation required at
`least 2.3%
`Tween-80® to solubilize 0.05% loratadine in solution.
`However,
`the relatively high concentration of surfactant
`increases eye irritation, which is counterproductive in a
`product intended to reduce ocular discomfort andirritation.
`Claritin® syrup is formulated at pH 2.5-3.1, at which pH
`loratadine is more soluble. However, this acidic pH is not
`suitable for ophthalmic liquids. In addition to being less
`soluble at the desirable ophthalmic pH range of 6-8, lora-
`tadine is also chemically unstable at this pH range. The
`cleavage of the ester linkage leads to the formation of the
`corresponding acid and ethyl alcohol much more readily in
`neutral or basic aqueous solutions.
`Schering-Plough also formulated eye drops containing
`loratadine metabolites or derivatives that had some
`
`25
`
`30
`
`35
`
`40
`
`50
`
`55
`
`improved properties (WO 9848803). However, despite these
`efforts, no topical ophthalmic product containing loratadine
`as the active ingredient is currently available, although the
`patent for loratadine (U.S. Pat. No. 4,282,233) issued in
`1981. Given the importance of loratadine in treating sys-
`temic allergies, one skilled in the art would expect that a
`topical ophthalmic product containing loratadine would also
`make a significant contribution to the treatment of ocular
`allergies. The lack of an available topical ophthalmic prod-
`uct containing loratadine therefore showsthat difficulties in
`
`60
`
`65
`
`2
`formulating loratadine have not been overcome, and that a
`need still exists to formulate the compound into effective
`topical ophthalmic product.
`SUMMARYOF TIE INVENTION
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Unexpectedly, we have foundthat the difficulties experi-
`enced by others in formulating loratadine arc overcome by
`the present invention, which delivers loratadine in an aque-
`ous ophthalmic cmulsion composition.
`In the present
`invention, the loratadine is dissolved in the oil phase of an
`oil-in-water emulsion system. This confers three main
`advantages to this invention over previous topical oph-
`thalmic loratadine products. These advantages are higher
`drug absorption, minimal decomposition of loratadine by
`hydrolysis, and lubrication and improved comfortto the eye.
`We have found that the solubility of loratadine in veg-
`etable oils is great enough to formulate an effective amount
`of the agent into an ophthalmic emulsion formulation (see
`Table 1) to be used for allergic conjunctivitis and
`
`TABLE1
`
`Solubility of Loratadine in Vegetable Oils
`
`oil
`Castor Oil
`Corn Oil
`Miglyol 810N
`Peanut Oil
`Sesame Oil
`Soybean Oil
`Polysorbate 80 (Nonionic surfactant)
`
`Solubility (mg/mL)
`85
`25
`15
`15
`15
`15
`25
`
`related conditions. The solubility of loratadine in vegetable
`oils is comparable ta or better than its solubility in a
`surfactant. In particular, castor oil dissolves more than three
`times as much loratadine as Polysorbate 80, a commonly
`used surfactant in ophthalmic solutions. By contrast to the
`irritation to the eye caused by the surfactant alone, it has
`been shownin commonly assigned U.S. Pat. No. 5,668,133,
`incorporated herein by reference, that an emulsion actually
`provides lubrication and improved comfortto the cyc. It has
`also been shown, in European Patent No. 1044678, that an
`cmulsion of vegetable oil and water delivers a higher
`concentration of the drug cyclosporin A to the conjunctiva of
`a rabbit eye than the individual oil. Additionally, dissolving
`the hydrophobic loratadine in the oil phase of an emulsion
`significantly reduces the contact of the hydrophobic lorata-
`dine with water, enabling a formulation to be prepared in the
`ophthalmically useful pH range of 6-8. This is in contrast
`with aqueous solutions where the loratadine is readily
`hydrolyzed in the desired ophthalmic pH range, greatly
`reducing the activity and the shelf life of the product.
`The present invention is directed to an ophthalmic for-
`mulation which comprises a therapeutically effective
`amount of loratadine, a fatty acid ester, and a surfactant. In
`the preferred embodiment of this invention, the fatty acid
`ester is a vegetable oil. A fatty acid ester has the meaning
`commonly understood in the art, being an ester formed
`between an alcohol and a fatty acid. While not intending to
`limit the scope of this invention, some examples ofreadily
`available fatty acid esters are triglyceride esters commonly
`known as vegetable oils, mono and diglyceride esters of
`fatty acids, and fatty acid methyl esters. The fatty acid ester
`may be a mixture of several chemical compounds or an
`
`FAMY CARE- EXHIBIT 1028-0002
`
`FAMY CARE - EXHIBIT 1028-0002
`
`

`

`US 6,635,654 Bl
`
`4
`In the preferred embodimentof this invention the weight
`ratio of castor oil to Polysorbate 80 is from about 0.3 to
`about 30. In a more preferred embodimentof this invention,
`the weight ratio is from about 0.5 to about 12.5.
`In another preferred embodiment of this invention, a
`buffering agent is used to maintain the pH in the therapeu-
`tically useful range of about 6-8. Buttering agents used are
`those known to those skilled in the art, and, while not
`intending to be limiting, some examplesare acetate, borate,
`carbonate, citrate, and phosphate buffers. In the most pre-
`ferred embodiment of this invention, boric acid is the
`buffering agent.
`In another preferred embodiment of this invention, a
`tonicity agent
`is used to adjust
`the composition of the
`formulation to the desired isotonic range. Tonicity agents are
`knownto those skilled in the ophthalmicart, and, while not
`intending to be limiting, some cxamplcs include glycerin,
`mannitol, sorbitol, sodium chloride, and other electrolytes.
`In the most preferred cmbodiment of this invention,
`the
`tonicity agent is glycerin.
`In another preferred embodiment of this invention, a
`preservative is used. Preservatives are used to prevent bac-
`terial contamination in multiple-use ophthalmic
`preparations, and, while not
`intending to be limiting,
`examples include benzalkonium chloride, stabilized oxy-
`chloro complexes (otherwise known as Purite®), phenylm-
`ercuric acetate, chlorobutanol, benzyl alcohol, parabens, and
`thimerosal.
`In the most preferred embodiment of this
`invention, the preservative is Purite®.
`In another preferred embodiment of this invention, a
`chelating agent is used to enhance preservative effective-
`ness. Suitable chelating agents are those known in the art,
`and, while not intending to be limiting, edetate salts like
`(OCH;CH;),OH
`edetate disodium,edetate calcium disodium, edetate sodium,
`(OCHCH),0._(CH3)7 (CHa);
`
`35
`edetate trisodium, and edetate dipotassium are examples of
`HO,(H)CH;CO)
`‘
`useful preservatives.
`The best mode of making and using the present invention
`are described in the following examples. These examplesare
`given only to provide direction and guidance in how to make
`and use the invention, and are not intendedto limit the scope
`of the invention in any way.
`
`3
`essentially pure compound.Preferably, the fatty acid ester is
`a vegetable oil. Examples of vegetable oils include castor
`oil, sesameoil, soybean oil, cottonseedoil, olive oil, peanut
`oil, safflower oil, sunflower oil, palm oil, palm kernel oil,
`canola oil, and Miglyol oil. Most preferably, the fatty acid
`ester is castor oil.
`‘The determination of a therapeutically effective amount of
`loratadine usedin this formulation can be readily determined
`by one skilled in the art. Preferably, the concentration of
`loratadine is between about 0.01% and about 1.5%. More
`preferably, the concentration of loratadine is about 0.0125%
`or abaut 0.0625%.
`The term surfactant used in this invention has the meaning
`commonly understoodin the art. Surfactants are used to both
`help facilitate the formation of the emulsion and improveits
`stability. Anionic, cationic, amphoteric, zwitterionic, and
`nonionic surfactants may all be uscd in this invention.
`Preferably, a nonionic surfactant is used in this invention.
`While not intending to limit the scope of the invention, some
`examples of useful nonionic surfactants are polysorbates,
`poloxamers, alcohol ethoxylates, ethylene glycol-propylene
`glycol block copolymers, fatty acid amides, alkylphenol
`ethoxylates, and phospholipids. Most preferably, Polysor-
`bate 80 is used as the surfactant. Polysorbate 80 is a mixture
`of oleate esters of sorbitol and sorbitol anhydrides, consist-
`ing predominantly of the monoester, condensed with
`approximately 20 moles of ethylene oxide.
`It conforms
`generally to the formula:
`
`(OCHCH;),,OH
`
`ToO
`
`where w+x+y+z has an average value of 20. Polysorbate 80
`is available from ICI Americas, Inc., Wilmington, Del.
`In another preferred embodiment of this invention, an
`emulsion stabilizing polymeris used. While not intending to
`limit the scope of the invention, emulsion stabilizing poly-
`mers generally contain hydrophilic groups such as ccllulosc,
`sugars, ethylene oxide, hydroxide, carboxylic acids or other
`polyclectrolytcs. While not wishing to limit the scope of the
`invention by theory, it is believed that these polymers help
`to stabilize emulsions by increasing the viscosity of the
`formulation as well as by reducing the interfacial tension.
`While not intending to limit the scope of the invention, some
`examples of emulsion stabilizing polymers useful in this
`invention are carbomers, Pemulen®, sodium
`carboxymethylcellulose, hydroxypropylmethylcellulose,
`povidone, polyvinyl alcohol, and polyethylene glycol. In the
`most preferred embodimentof this invention, Pemulen® is
`used as the polymeric based stabilizer.
`Pemulen® is a registered trademark of B.F. Goodrich for
`polymeric emulsifiers and commercially available from B.F.
`Goodrich Company, Specialty Polymers & Chemicals
`Division, Cleveland, Ohio. Pemulens® are Acrylates/C10-
`30 Alkyl Acrylate Cross-Polymers.‘They are high molecular
`weight co-polymers of acrylic acid and a long chain alkyl
`methacrylate cross-linked with allyl ethers of pentaerythri-
`tol. They contain not less than 52.0 percent and not more
`than 62.0 percent of carboxylic acid groups. The viscosityof
`a neutralized 1.0 percent aqueous dispersion is between
`9,500 and 26,500 centipoises.
`
`15
`
`25
`
`30
`
`40
`
`FORMULATION EXAMPLES
`
`Ophthalmic [formulations 1 and 2 containing loratadine
`were formulated with the compositions shown in Table 2.
`Emulsions were prepared according to the method described
`in USS. Pat. No. 5,981,607, incorporated herein by reference,
`with the loratadine being added to the castor oil before
`introducing the oil into the emulsion.
`
`TABLE2
`
`Example Loratadine Emulsion Formulations
`Amount, % wiw
`
`Ingredient
`Loratadine
`Castor Oil
`Polysorbate 80
`Pemulen @
`Glycerin
`Boric Acid
`Purite ® 0.0075
`Purified Water
`
`Placebo
`0
`1.25
`1.0
`0.1
`1.0
`0.6
`0.0075
`qs. ad. 100
`
`Formulation 1
`0.0125
`1.25
`1.0
`0.1
`1.0
`0.6
`0.0075
`qs. ad. 100
`
`Formulation 2
`0.0625
`1.25
`1.0
`G1
`1.0
`0.6
`
`qs. ad. 100
`
`The physical stability of the example loratadine emulsion
`formulations was monitored and the results are provided in
`
`50
`
`55
`
`60
`
`65
`
`FAMY CARE- EXHIBIT 1028-0003
`
`FAMY CARE - EXHIBIT 1028-0003
`
`

`

`US 6,635,654 Bl
`
`3
`Table 3. The emulsions were allowedto stand for 5.5 months
`at 20-25° C., and the emulsion droplet sizes were measured.
`The emulsion droplet sizes within experimental error, were
`identical at 5.5 months to those measured right after the
`emulsions were prepared, suggesting that
`there was no
`significant coalescence of the emulsion droplets.
`Additionally, no creaming of the formulations or precipita-
`tion of solid loratadine was observed. These results demon-
`strate that the emulsions prepared in these formulations have
`superior physical stability.
`
`TABLE 3
`
`Physical Stability and Droplet Size of Loratadine Formulations
`
`Timepoint Test Parameter
`
`Placebo
`
`Formulation 1
`
`Formulation 2
`
`0
`
`5.5
`months
`
`Mean Droplet
`Size (micron)
`Mean Droplet
`Size (micron)
`Creaming
`Mean Droplet
`Size (micron)
`Mean Droplet
`Size (micron)
`Creaming
`
`0.163
`
`0.121
`
`none
`not
`measured
`not
`measured
`none
`
`0.114
`
`0.111
`
`none
`0.115
`
`0.112
`
`none
`
`0.0987
`
`0.0935
`
`none
`0.100
`
`0.0965
`
`none
`
`TREATMENT EXAMPLE
`
`Several drops of Formulations 1 are administered to the
`eyes of a patient suffering from allergic conjunctivitis.
`Reduction of the symptoms becomesnoticeable within one
`hour. The treatment is repeated one or more times daily
`while the condition persists.
`Whatis claimedis:
`1. An aqueous ophthalmic emulsion composition com-
`prising a therapeutically effective amount of loratadine, a
`fatty acid ester and a surfactant.
`2. An aqueous ophthalmic emulsion composition accord-
`ing to claim 1 wherein the concentration of loratadine is
`between about 0.01% and about 1.5%.
`3. An aqueous ophthalmic emulsion composition accord-
`ing to claim 1 wherein the concentration of loratadine is
`about 0.0125% or about 0.0625%.
`4. An aqueous ophthalmic emulsion composition accord-
`ing to claim 1 which further comprises an emulsion stabi-
`lizing polymer.
`5. An aqueous ophthalmic emulsion composition accord-
`ing to claim 4 which further comprises a buffering agent.
`6. An aqueous ophthalmic emulsion composition accord-
`ing to claim 5 wherein the pH of the composition is between
`about 6 and about8.
`7. An aqueous ophthalmic emulsion composition accord-
`ing to claim 6 wherein the fatty acid ester is a vegetable oil.
`8. An aqueous ophthalmic emulsion composition accord-
`ing to claim 7 wherein the surfactant is a nonionic surfactant.
`9. An aqueous ophthalmic emulsion composition accord-
`ing to claim 8 which further comprises a tonicity agent and
`a preservative.
`10. An aqueous ophthalmic emulsion composition accord-
`ing to claim 9 which further comprises a chelating agent.
`
`
`
`
`
`6
`11. An aqueous ophthalmic emulsion composition accord-
`ing to claim 10 wherein the chelating agent is an ededate
`salt.
`
`12. An aqueous ophthalmic emulsion composition accord-
`ing to claim 9 wherein the vegetable oil is castor oil, the
`surfactant is Polysorbate 80, the emulsion stabilizing poly-
`meris Pemulen®, the tonicity agent is glycerin, the buffer-
`ing agent is boric acid, and the preservative is Purite®.
`13. An aqueous ophthalmic emulsion composition accord-
`ing to claim 12 wherein the weight ratio of castor oil to
`Polysorbate 80 is from about 0.3 to about 30.
`14. An aqueous ophthalmic emulsion composition accord-
`ing to claim 12 wherein the weight ratio of castor oil to
`Polysorbate 80 is from about 0.5 to about 12.5.
`15. An aqueous ophthalmic emulsion composition accord-
`ing to claim 12 wherein the concentration of castor oil is
`about 1.25%, the concentration of Polysorbate 80 is about
`1.0%, the concentration of Pemulen® is about 0.1%, the
`concentration of glycerin is about 1.0%, the concentration of
`boric acid is about 0.6%, and the concentration of Purite®
`is about 0.0075%.
`16. An aqueous ophthalmic emulsion composition accord-
`ing to claim 15 wherein the concentration of loratadine is
`between about 0.01% and about 1.5%.
`17. An aqueous ophthalmic emulsion composition accord-
`ing to claim 15 wherein the concentration of loratadine is
`about 0.0125% or about 0.0625%.
`18. A method of treating ocular allergies in an affected
`person comprising administering to the eye of the affected
`person and effective amount of an aqueous ophthalmic
`cmulsion composition comprising a therapeutically cffcctive
`amountof loratadine, a fatty acid ester and a surfactant.
`19. The method of claim 18 wherein the fatty acid ester is
`a vegetable oil and the surfactant is a nonionic surfactant.
`20. The method of claim 19 wherein said aqueous oph-
`thalmic emulsion composition further comprises an emul-
`sion stabilizing polymer, a buffering agent, a tonicity agent,
`and a preservative; and wherein the pH of said ophthalmic
`emulsion composition is between about 6 and about 8.
`21. The method of claim 20 wherein the vegetable oil is
`castor oil, the surfactant is Polysorbate 80,
`the emulsion
`stabilizing polymer is Pemulen®,
`the tonicity agent
`is
`glycerin, the buffering agent is boric acid, and the preser-
`vative is Purite®.
`22. The method of claim 21 wherein the concentration of
`loratadine is between about 0.01% and about 1.5%.
`23. The method of claim 22 wherein the concentration of
`castor oil is about 1.25%, the concentration of Polysorbate
`80 is about 1.0%, the concentration of Pemulen® is about
`0.1%,
`the concentration of glycerin is about 1.0%,
`the
`concentration of boric acid is about 0.6%, and the concen-
`tration of Purite® is about 0.0075%.
`24. The method of claim 23 wherein the concentration of
`loratadine is about 0.0125% or about 0.0625%.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`50
`
`55
`
`FAMY CARE- EXHIBIT 1028-0004
`
`FAMY CARE - EXHIBIT 1028-0004
`
`

`

`UNITED STATES PATENT AND TRADEMARKOFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.—: 6,635,654 B1 Page 1 of 1
`
`
`DATED
`: October 21, 2003
`INVENTOR(S): Chang etal.
`
`It is certified that error appears in the above-identified patent and that said Letters Patentis
`hereby corrected as shown below:
`
`Title page,
`Item [75], Inventors, the state of residence for the first inventor, “TX” is replaced with
`-- CA --
`
`Column 4,
`Line 63, Table 2, under the column labeled “Ingredient”, “Purite® 0.0075” is replaced
`with -- Purite® --
`Line 63, Table 2, under the column labeled “Formulation 2”, the empty entry is replaced
`with -- 0.0075 --
`Line 32, “and”is replaced with -- an --
`
`Signed and Sealed this
`
`Twenty-seventh Dayof January, 2004
`
`on WDale
`
`JON W. DUDAS
`Acting Director of the United States Patent and Trademark Office
`
`FAMY CARE- EXHIBIT 1028-0005
`
`FAMY CARE - EXHIBIT 1028-0005
`
`