(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`23 March 2002 (28.03.2002)
`
`
`
`PCT
`
`(10) International Publication Number
`w() ()2/241 16 A1
`
`(51) International Patent Classificationlz
`A61K 47/30
`
`A61F 2/14,
`
`(21) International Application Number:
`
`PCT/US01/29485
`
`(22) International Filing Date:
`20 September 2001 (20.09.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/234,319
`
`20 September 2000 (20.09.2000)
`
`US
`
`(71) Applicant: SHAHINIAN, Lee, Jr. [US/US]; 1506 Coun-
`try Club Drive, Los Altos, CA 94024 (US).
`
`(74) Agent: VERNY, Hana; Peters, Verny, Jones & Biksa,
`LLP, Suite 6, 385 Sherman Avenue, Palo Alto, CA 94306
`(US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK,
`SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD,
`TG).
`
`Published:
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`wo02/24116A1||||||||||||||ll|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| sE
`
`
`
`(54) Title: SELF—PRESERVED NASAL, INHALABLE, AND TOPICAL OPHTHALMIC PREPARATIONS AND MEDICA-
`Z
`
`Abstract: Self—preserVed nasal, inhalable and topical ophthalmic preparations and medications which destroy, inhibit or thera-
`peutically significantly limit microbial growth within said preparations or medications. The nasal, inhalable, and topical ophthalmic
`preparations and medications are mildly buffered and maintain a stable pH at pH 3.5 or lower.
`
`000001
`
`ARGENTUM PHARM. 1013
`
`ARGENTUM PHARM. 1013
`
`000001
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`WO 02/24116
`
`PCT/US01/29485
`
`SELF-PRESERVED NASAL,
`
`INHALABLE,
`
`AND TOPICAL OPHTHALMIC PREPARATIONS AND MEDICATIONS
`
`This application is based on and claims priority of the
`
`Provisional ‘application Serial No.
`
`60/234,319,
`
`filed on
`
`September 20, 2000.
`
`Field of the Invention
`
`10
`
`15
`
`20
`
`25
`
`30
`
`The current
`
`invention concerns buffered,
`
`low pH,
`
`self-
`
`preserved nasal, inhalable and.topical ophthalmic preparations
`
`and medications which destroy,
`
`inhibit or sufficiently limit
`
`microbial growth within said preparations or medications.
`
`In
`
`particular,
`the current
`invention involves nasal,
`inhalable
`and topical ophthalmic preparations and medications having low
`pH of about 3.5 or lower, to inhibit microbial growth, wherein
`
`immediately upon application to the eye surface or a mucosal
`
`surface,
`
`the pH rises to physiologic levels.
`
`BACKGROUND OF THE INVENTION
`
`To prevent
`
`infection with use,
`
`currently available
`
`multidose preparations and medications are sterilized during
`
`manufacture and have a variety of preservatives added to
`
`‘destroy or inhibit the growth of microorganisms inadvertently
`
`introduced into the product after opening.
`
`It is well
`
`recognized that
`
`the preservatives used in
`
`topical ophthalmic medications and preparations can be toxic
`
`to the eye surface and respiratory mucosa. The most widely
`
`used ophthalmic preservative, benzalkonium chloride (BAK), can
`
`cause damage
`
`to the conjunctival
`
`and corneal epithelium
`
`(Cornea,
`
`l:22l—225 (1992); Arch Opthalmol,
`
`llO:528—532 (1992)
`
`and CLAO J,
`
`l8:260—266 (1992)).
`
`BAK is now thought to be also
`
`a significant cause of rhinitis medicamentosa, as described in
`
`Allergy, 52:627—632 (1997), and has been also shown to damage
`
`respiratory mucosa (Am Rev Res ir Dis,
`
`l4l:l405—1408'(l990)
`
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`WO 02/24116
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`PCT/US01/29485
`
`2
`
`and Acta Otolar n ol,
`
`l16:868—875
`
`(1996)). Reducing the
`
`concentration of BAK reduces its toxic effect, but at too low
`
`a concentration, BAK is no longer effective as a preservative.
`
`Although alternatives to BAK are available, all preservatives
`
`5
`
`have some potential for toxicity.
`
`10
`
`15
`
`Pressurized aerosol containers used for inhalation or as
`
`a spray are an exception, needing no preservative since no air
`
`or contamination enters the container as doses are extracted.
`
`However,
`
`such packaging is relatively bulky and expensive,
`
`often contains CFC propellants which can harm the atmosphere,
`
`and precludes drop administration.
`
`In recent years, preparations and medications have been
`
`packaged in unit-dose containers,
`
`thus avoiding the need for
`
`potentially toxic preservatives.
`
`In this arrangement,
`
`a
`
`single dose of medicine is provided.by a given container. With
`
`sterile packaging, microbial contamination is theoretically
`
`not a concern,
`
`since the consumer/patient is instructed to
`
`discard the container after each single use. However,
`
`there
`
`are several problems with unit dose containers. First,
`
`the
`
`20
`
`packaging is bulky and inconvenient. Second, cost per dose is
`
`significantly higher than with multidose containers. Third,
`
`patients often retain the opened container for many hours or
`
`even more
`
`than
`
`one
`
`day,
`
`contradicting
`
`the
`
`package
`
`instructions. This pattern of use increases the probability of
`
`microbial contamination of the medication or preparation.
`
`Thus,
`
`it
`
`would
`
`be
`
`desirable
`
`to
`
`have
`
`available
`
`preservative-free preparations and medications suitable for
`
`topical, mucosal and inhalation use that could be stored in
`
`multi—dose containers without risk of:microbial contamination.
`
`All patents, patent applications and publications are
`
`25
`
`30
`
`hereby incorporated by reference.
`
`SU1‘4MA_RY OF THE INVENTION
`
`One
`
`aspect of
`
`the current
`
`invention is
`
`a
`
`topical
`
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`
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`
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`3
`
`ophthalmic, nasal, or
`
`inhalable preparation or medication
`
`which is self—preserved,
`
`that is, which destroys,
`
`inhibits or
`
`sufficiently limits growth and
`
`nmltiplication of various
`
`microorganisms without the addition of preservative agents.
`
`Another aspect of
`
`the current
`
`invention is a ndldly
`
`buffered, topical ophthalmic, nasal, or inhalable preparation
`
`which is self—preserved by having a pH of from about 1.5 to
`
`about 3.5 with preferred pH at about 2.5 or lower.
`
`Another aspect of
`
`the current
`
`invention is a self-
`
`preserved topical ophthalmic, nasal, or inhalable preparation
`
`or medication
`
`comprising
`
`a pharmaceutically
`
`acceptable
`
`excipient or additive selected from the group consisting of
`
`dextrose,
`
`polyethylene
`
`glycol
`
`(PEG);
`
`hydroxypropyl
`
`methylcellulose
`
`(HPMC), sodium chloride, potassium chloride,
`
`calcium chloride, magnesium chloride,
`
`phosphoric
`
`acid,
`
`disodium
`
`edetate,
`
`bicarbonate,
`
`phosphate,
`
`povidone,
`
`carboxymethylcellulose,
`
`hydroxyethylcellulose,
`
`methylcellulose, microcrystalline
`
`cellulose,
`
`glycerin,
`
`polyvinyl alcohol, dextran 40, dextran 70, mannitol, gelatin,
`
`polyol, polysorbate
`
`80, propylene glycol,
`
`zinc
`
`sulfate,
`
`poloxamer 188, 282, 407, ephedrine hydrochloride, naphazoline
`
`hydrochloride,
`
`oxymetazoline hydrochloride,
`
`phenylephrine
`
`hydrochloride, tetrahydrozoline hydrochloride, xylometazoline
`
`hydrochloride,
`
`lecithin, oleic acid,
`
`sorbitan, pheniramine
`
`maleate, pyrilamine maleate, antazoline phosphate, glycine,
`
`camphor, eucalyptol, menthol, benzyl alcohol,
`
`lavender oil,
`
`tyloxapol, bornyl acetate,
`
`and phenylethyl alcohol,
`
`and a
`
`buffering agent, said preparation or medication adjusted to a
`
`low pH between about 1.5 to about pH 3.5, with most preferred
`
`pH at about
`
`pH 2.5 or
`
`lower,
`
`said medication optionally
`
`containing
`
`analgesics,
`
`anti-inflammatories, mast
`
`cell
`
`stabilizers, diagnostic aids, antibiotics, antiglaucoma drugs,
`
`decongestants,
`
`bronchodilators,
`
`vasoconstricting
`
`or
`
`10
`
`15
`
`20
`
`25
`
`30
`
`..
`
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`
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`
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`
`WO 02/24116
`
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`
`4
`
`hypertonicity agents, astringents and topical anesthetics.
`
`Still another aspect of
`
`the current
`
`invention.
`
`is a
`
`physiologically compatible self—preserved lightly buffered
`
`topical
`
`ophthalmic,
`
`nasal,
`
`or
`
`inhalable
`
`preparation or
`
`medication containing no preservation agents,
`
`formulated and
`
`maintained at about pH 2.5 or lower, wherein immediately upon
`
`application to the eye or a mucosal surface, such preparation
`
`permits the pH to rise to physiologic levels to maintain
`
`patient comfort, prevent
`
`tissue damage,
`
`and. enhance drug
`
`10
`
`delivery.
`
`Still yet another aspect of the current
`
`invention is a
`
`multidose topical ophthalmic, nasal, or inhalable preparation
`
`or medication lightly buffered to maintain a stable pH in the
`
`multidose container,
`
`thereby maintaining its self—preserving
`
`15
`
`characteristic.
`
`Still another aspect of the current invention is a method
`
`for preparation of a topical ophthalmic, nasal or inhalable
`
`self—preserved solution comprising steps of:
`
`a) preparing a formulation comprising
`
`a pharmaceutically acceptable excipient or additive
`
`selected from the group consisting of dextrose, polyethylene
`
`glycol
`
`(PEG), hydroxypropyl methylcellulose
`
`(HPMC),
`
`sodium
`
`chloride, potassium. chloride,
`
`calcium chloride, magnesium
`
`chloride, phosphoric acid,
`
`disodium. edetate, bicarbonate,
`
`phosphate,
`
`povidone,
`
`carboxymethylcellulose,
`
`hydroxyethylcellulose, methylcellulose, microcrystalline
`
`cellulose, other cellulose derivatives, glycerin, polyvinyl
`
`alcohol, dextran 40, dextran 70, mannitol, gelatin, polyols,
`
`polysorbate 80, propylene glycol, zinc sulfate, poloxamer 188,
`
`282, 407, ephedrine hydrochloride, naphazoline hydrochloride,
`
`oxymetazoline hydrochloride,
`
`phenylephrine hydrochloride,
`
`tetrahydrozoline hydrochloride,xylometazolinehydrochloride,
`
`lecithin,
`
`oleic acid and ‘sorbitan,
`
`pheniramine maleate,
`
`20
`
`25
`
`30
`
`000005
`
`000005
`
`

`
`WO 02/24116
`
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`
`5
`
`pyrilamine maleate, antazoline phosphate, glycine, camphor,
`
`eucalyptol, menthol, benzyl alcohol,
`
`lavender oil,
`
`tyloxapol,
`
`bornyl acetate, phenylethyl alcohol, alone or in admixture;
`
`and
`
`a buffering agent; and
`
`b) adjusting pH of said formulation to from about pH 1.5
`
`to pH about 3.5.
`
`As used herein:
`
`DEFINITIONS
`
`10
`
`15
`
`20
`
`25
`
`30
`
`"Preparation" means
`
`a
`
`topical ophthalmic, nasal, or
`
`inhalable preparations,
`
`including topical eye preparations
`
`such. as artificial
`
`tears, contact
`
`lens solutions and eye
`
`irrigating solutions; nasal preparations such as saline; and
`
`inhalable preparations.
`
`“Medication” means
`
`topical
`
`ophthalmic,
`
`nasal,
`
`or
`
`inhalable preparations
`
`comprising a pharmaceutical
`
`agent
`
`suitable
`
`for
`
`topical
`
`ophthalmic,
`
`nasal
`
`or
`
`inhalable
`
`administration.wherein.the pharmaceutical agent for ophthalmic
`
`use
`
`is
`
`an astringent,
`
`analgesic, hypertonicity agent,
`
`antihistamine, anti—inflammatory drug, mast cell stabilizer,
`
`diagnostic aid, anesthetic, antibiotic, antiglaucoma drug and
`
`vasoconstricting agent,
`
`the
`
`agent
`
`for nasal use
`
`is a
`
`decongestant
`
`and
`
`the
`
`agent
`
`for
`
`inhalable
`
`use
`
`is
`
`a
`
`bronchodilator
`
`"Physiologically compatible"
`
`means
`
`a preparation or
`
`medication which
`
`contains
`
`pharmaceutically
`
`acceptable
`
`excipients and additives dissolved or suspended in purified
`
`water which is physiologically compatible with.the eye surface
`
`or the nasal/respiratory mucosa.
`
`"Preservative" means an additive intended to destroy or
`
`limit growth and multiplication of microorganisms.
`
`"Self—preserved" means a preservative—free preparation or
`
`medication that destroys or inhibits microbial growth without
`
`000006
`
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`6
`
`the addition of preservatives such as benzalkonium chloride
`
`(BAK).
`
`"Preservative effectiveness testing” or “PET” means the
`
`standardized microbiological testing specified by the USP 24
`
`to determine preservative effectiveness.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`This
`
`invention is Ibased. on the finding‘
`
`that certain
`
`pharmaceutical preparations andlnedications, when adjusted.and
`
`maintained at a low pH of from about pH 1.5 to about pH 3.5,
`
`are
`
`self-preserved
`
`and
`
`possess
`
`antimicrobial
`
`growth
`
`properties.
`
`The
`
`invention,
`
`therefore,
`
`concerns buffered,
`
`low pH,
`
`topical
`
`self-preserved ophthalmic,
`
`nasal,
`
`or
`
`inhalable
`
`preparations or medications for multidose administration of
`
`various drugs and pharmaceuticals topically or by inhalation.
`
`These preparations or medications generally comprise one or
`
`more pharmaceutically acceptable excipients or additives, such
`
`as,
`
`for
`
`example,
`
`dextrose,
`
`polyethylene
`
`glycol
`
`(PEG),
`
`hydroxypropyl methylcellulose
`
`(HPMC),
`
`sodium chloride,
`
`potassium. chloride,
`
`calcium. chloride, magnesium. chloride,
`
`phosphoric acid, disodium edetate, bicarbonate, phosphate,
`
`povidone,
`
`carboxymethylcellulose,
`
`hydroxyethylcellulose,
`
`methylcellulose, microcrystalline cellulose, other cellulose
`
`derivatives, glycerin, polyvinyl alcohol, dextran 40, dextran
`
`70, mannitol, gelatin, polyols, polysorbate 80, propylene
`
`glycol,
`
`zinc sulfate, poloxamer 188,
`
`282,
`
`407,
`
`ephedrine
`
`hydrochloride,
`
`naphazoline
`
`hydrochloride,
`
`oxymetazoline
`
`hydrochloride, phenylephrine hydrochloride,
`
`tetrahydrozoline
`
`hydrochloride, xylometazoline hydrochloride,
`
`lecithin, oleic
`
`acid and sorbitan, pheniramine maleate, pyrilamine maleate,
`
`antazoline phosphate, glycine, camphor, eucalyptol, menthol,
`
`benzyl alcohol,
`
`lavender oil,
`
`tyloxapol, bornyl acetate,
`
`phenylethyl alcohol, analgesics,
`
`anti—inflammatories, mast
`
`10
`
`15
`
`20
`
`25
`
`30
`
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`
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`7
`
`cell stabilizers, diagnostic aids, antibiotics, antiglaucoma
`
`medications, and topical anesthetics, and a buffering agent,
`
`said preparation or medication adjusted to a low pH between
`
`about 1.5 to about pH 3.5, with the most preferred pH at about
`
`5
`
`pH 2.5 or
`
`lower.
`
`These preservations and medications are
`
`self—preserved by means of low pH.
`
`The
`
`invention.
`
`is based on observations made during
`
`studies performed to determine the stability of amino ester
`
`topical anesthetics wherein microbial growth was observed to
`
`10
`
`be moderately inhibited by diluted solutions of these topical
`
`anesthetics when the solutions were formulated at pH 3.5 to
`
`enhance the anesthetic’s stability.
`
`A. further series of
`
`experiments discovered and demonstrated that microbial growth
`
`is still somehow inhibited at
`
`this pH (3.5)
`
`even if the
`
`15
`
`anesthetic is removed.
`
`These studies, described in greater
`
`detail below, showed.that for adequate destruction, inhibition
`
`or
`
`sufficient
`
`limitation of microbial
`
`growth
`
`to meet
`
`preservative effectiveness testing (PET)
`
`standards,
`
`the pH
`
`should be not much higher thaniapproximately 2.5 up to pH 3.5
`
`20
`
`at most.
`
`Moreover, it was further discovered that with appropriate
`
`mild or moderate buffering,
`
`these preparations or medications
`
`may be advantageously administered to the eye surface or to
`
`the nasal or respiratory mucosa without
`
`a harmful effect
`
`25
`
`caused by such low pH because the mild buffer, under these
`
`conditions,
`
`permits
`
`instant
`
`adjustment
`
`of
`
`the
`
`pH
`
`to
`
`physiologic levels upon administration to the eye topically or
`
`to nasal or respiratory mucosa.
`
`The
`
`invention,
`
`therefore,
`
`in its broadest
`
`aspect,
`
`30
`
`concerns the discovery that the self-preserved properties of
`
`the topical ophthalmic, nasal or
`
`inhalable preparation or
`
`medication can be achieved with a mild buffering and with
`
`maintenance of low pH under 3.5, preferably pH about 2.5 or
`
`000008
`
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`
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`
`WO 02/24116
`
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`
`8
`
`lower
`
`and
`
`that
`
`this preparation or medication can be
`
`advantageously administered to the eye surface or to the nasal
`
`or respiratory mucosa without causing irritation or injury.
`
`I.
`
`Preservative Effectiveness Testing
`
`In order to determine the optimal composition and pH of
`
`the
`
`self—preserved preparation,
`
`various
`
`combinations of
`
`components and variable pH were tested using preservative
`
`effectiveness testing (PET).
`
`PET procedure,
`
`description of which can be found in USP
`
`10
`
`24, §51,
`
`pp.l809—181l, Antimicrobial Effectiveness Testing,
`
`was first performed on the following solutions formulated at
`
`pH values from 2.5 to 6.5.
`
`Solutions Group A
`
`Solution A.consisted of the following components:
`
`15
`
`Dextrose
`
`Polyethylene Glycol 400
`Hydroxypropyl methylcellulose
`Edetate Disodium
`Sodium Citrate
`
`Purified Water
`
`pH adjusted from 2.5 to 6.5
`
`O-4.0%
`
`0.00l—8.0
`0.30
`O—0.02
`0.01-0.05
`
`QS
`
`20
`
`25
`
`30
`
`35
`
`At pH 5.5 to 6.5,
`
`there was
`
`inadequate inhibition of
`
`microbial growth.
`
`At pH 4.5 to 5.5,
`
`inhibition of microbial
`
`growth did not meet PET standards.
`
`At pH 3.5 to 4.5 the
`
`inhibition of microbial growth was inconsistent.
`
`At pH 2.5 to
`
`3.5,
`
`the inhibition of microbial growth met the PET standards.
`
`This was still true as the percentages of dextrose,
`
`and edetate disodium were varied as shown above.
`
`PEG 400,
`
`However,
`
`inhibition of microbial growth improved as the pH approached
`2.5.
`I
`
`Solutions Group B
`
`The above testing clearly indicated that the solutions in
`
`Group A having pH above approximately 3.5 did not sufficiently
`
`inhibit microbial growth and the best inhibition was seen at
`
`pH 2.5.
`
`Consequently,
`
`two solutions were subjected to further
`
`studies performed at pH of about 2.5.
`
`However,
`
`to reach and
`
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`
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`
`9
`
`maintain the pH at 2.5 using a sodium citrate buffer was found
`
`to be difficult. Citric acid was,
`
`therefore, used to replace
`
`sodium citrate in the low pH solutions to achieve a stable pH
`
`2.5 for long periods of time.
`
`5
`
`The following two representative formulations, Solutions
`
`1 and 2, both adjusted to pH 2.5, show excellent inhibition of
`
`microbial growth and pH stability.
`
`Group B, Solution 1
`
`Polyethylene glycol 400
`Hydroxypropyl methylcellulose 2910
`Citric acid
`Purified water
`
`pH 2.5
`
`Group B, Solution 2
`Dextrose
`
`Polyethylene glycol 400
`Hydroxypropyl methylcellulose 2910
`Citric acid
`Purified water
`
`pH 2.5
`
`10
`
`15
`
`20
`
`8.00%
`0.30
`0.01
`QS
`
`4.00%
`
`1.00
`0.30
`0.01
`QS
`
`Both solutions were again tested by the PET procedure.
`
`Results of these testings on five types ofimicroorganisms
`
`25
`
`are described below in Tables 1-4. The results seen in Tables
`
`1-4 clearly show that when the solution comprising a viscosity
`
`and/or
`
`tonicity agent,
`
`here
`
`represented by polyethylene
`
`glycol, dextrose and hydroxypropyl methylcellulose,
`
`and a
`
`buffering agent, here represented by citric acid,
`
`is adjusted
`
`30
`
`to around pH 2.5, it possesses a definite ability to inhibit
`
`microbial growth. Both solutions are also able to maintain
`
`this pH (2.5)
`
`for at least two months or longer at 40°C, and
`
`therefore,
`
`they have a good stability and long shelf-life.
`
`II.
`
`Low pH, Self-Preserved Preparations and.Medications
`
`35
`
`The preparations and medications of the invention are
`
`formulated as a solution or suspension comprising components
`
`in jpercentages
`
`shown in the Group Zl solutions, described
`
`above. The pH of
`
`the invention is optimally about 2.5 or
`
`lower. This
`
`is in contrast
`
`to the physiologic pH of 7.4,
`
`40
`
`typically used for these types of formulations.
`
`000010
`
`000010
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`10
`
`The only disclosed use for low pH is a preservative—free
`
`beverage composition with pH 2.2-2.7 described in U.S. Pat.
`
`No. 5,417,994.
`
`Self—preserved, pharmaceutically acceptable preparations
`
`or medications for topical use utilizing pH 2.5 or below have
`
`not been previously described or suggested and such self-
`
`preserved low pH preparation or medication for
`
`topical
`
`ophthalmic, mucosal or
`
`inhalable administration are not
`
`available.
`
`In practice of the current invention,
`
`the pH is adjusted
`
`to approximately 2.5 with an acid such as hydrochloric or
`
`sulphuric acid or a base such as sodium or ammonium.hydroxide.
`
`Citric acid, acetic,
`
`formic, glutaric, glycolic,
`
`lactic,
`
`maleic,
`
`tartaric acid or other weak acid or a salt thereof,
`
`such as sodium citrate, may be used to buffer the preparation
`
`or medication. Citric acid is the preferred component for a
`
`buffer.
`
`It has been. discovered as part of
`
`the current
`
`invention that the desirable concentration of citric acid is
`
`approximately 0.01%,
`
`to lightly buffer the preparation and
`
`allow the pH to rise rapidly when the preparation is applied
`to the tissue surface.
`
`The function of low pH is very important from the point
`
`of view of this invention.
`
`It is well known that certain drug
`
`solutions are unstable when formulated at or near physiologic
`
`pH. For example, pilocarpine is relatively unstable at pH 6.8,
`
`but very stable at pH 5.0.
`
`The concept of lightly buffering
`
`such formulations to make
`
`them physiologically compatible
`
`despite the low pH used for drug stability has been previously
`
`10
`
`15
`
`20
`
`25
`
`known. However, using very low pH such as pH 2.5 or lower with
`
`30
`
`a preparation
`
`or medication for
`
`any purpose,
`
`and more
`
`specifically for the purpose of self—preservation of multidose
`
`preparations
`
`or medications,
`
`has
`
`not
`
`been previously
`
`described.
`
`The preparations described herein contain and may
`
`35
`
`additionally contain.
`
`and. be
`
`freely exchangeable with any
`
`00001 1
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`000011
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`
`ll
`
`example, dextrose, polyethylene glycol
`
`(PEG),
`
`hydroxypropyl
`
`methylcellulose
`
`(HPMC), sodium chloride, potassium.chloride,
`
`calcium chloride,
`
`magnesium chloride,
`
`phosphoric
`
`acid,
`
`disodium
`
`edetate,
`
`bicarbonate,
`
`phosphate,
`
`povidone,
`
`carboxymethylcellulose,
`
`hydroxyethylcellulose,
`
`methylcellulose, microcrystalline cellulose, other cellulose
`
`derivatives, glycerin, polyvinyl alcohol, dextran 40, dextran
`
`70, mannitol, gelatin, polyols, polysorbate 80,
`
`propylene
`
`glycol,
`
`zinc sulfate, poloxamer 188,
`
`282,
`
`407,
`
`ephedrine
`
`hydrochloride,
`
`naphazoline
`
`hydrochloride,
`
`oxymetazoline
`
`hydrochloride, phenylephrine hydrochloride,
`
`tetrahydrozoline
`
`hydrochloride, xylometazoline hydrochloride,
`
`lecithin, oleic
`
`acid and sorbitan, pheniramine maleate, pyrilamine maleate,
`
`antazoline phosphate, glycine, camphor, eucalyptol, menthol,
`
`benzyl alcohol,
`
`lavender oil,
`
`tyloxapol, bornyl acetate,
`
`phenylethyl alcohol, and other excipients and additives which
`
`are pharmaceutically acceptable.
`
`These excipients and additives are dissolved or suspended
`
`in sterile distilled or sterile purified water up to the
`
`volumes to provide a solution or suspension containing these
`
`~components in the desired ratios to each other.
`
`Additionally,
`
`the preparations described herein are
`
`advantageously formulated into medications by combining said
`
`excipient with pharmaceutical agents,
`
`such as analgesics,
`
`anti—inflammatories, antihistamines, mast cell stabilizers,
`
`diagnostic aids,
`
`such as fluorescein, anesthetic solutions,
`
`miotics, mydriatics, antibiotics, antivirals, antifungals,
`
`antiglaucoma drugs, hypertonic agents, astringents, and local
`
`anesthetics
`
`such as proparacaine,
`
`tetracaine,
`
`lidocaine,
`
`benoxinate, and bupivicaine, etc., and such other therapeutic
`
`agents which are typically used for administration to the eye
`
`surface andinasal or respiratory mucosa. These pharmaceutical
`
`agents are present in from about 0.001% to about 8%.
`
`These solutions are suitable for use as artificial tears
`
`and as
`
`solution.
`
`for administration. of various drugs
`
`and
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`000012
`
`000012
`
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`
`12
`
`lenses. The solutions are self—preserved without the addition
`of any preservative agent.
`.Additionally, when administered to
`
`the eye, or other mucosal surface,
`
`these solutions permit
`
`rapid adjustment of pH to the physiologic levels.
`
`5
`
`For artificial
`
`tears,
`
`the formulation. comprises
`
`from
`
`about 0.001 to about 8% of one or two or more viscosity and/or
`
`tonicity-providing agents,
`
`and.
`
`fronx about 0.005 to about
`
`0.02%, preferably above 0.01% of a mild buffering agent.
`
`The
`
`above components are dissolved in purified water up to 100%
`
`10
`
`and pH is appropriately adjusted with an acid or a base to
`
`levels lower than pH 3.5.
`
`.The percentage of the agents can be
`
`increased or decreased to vary the tonicity as desired.
`
`For
`
`example,
`
`the eye can usually tolerate solutions with tonicity
`
`equivalent to that provided by 0.5% to 1.8% sodium chloride.
`
`15
`
`III. Testing of Representative Embodiments
`
`One representative embodiment for an ophthalmic demulcent
`
`(artificial tear) is a formulation designated solution 1 which
`
`comprises about 8% of polyethylene glycol 400 (PEG 400), about
`
`0.3% of HPMC 2910 and about 0.01% of citric acid dissolved in
`
`20
`
`100 ml of purified water and adjusted to about pH 2.5.
`
`This formulation has been shown to significantly inhibit
`
`the growth of microorganisms, such as P. aeruginosa, E. coli,
`
`S. aureus, C. albicans and A. niger for at least 28 days, as
`
`seen.
`
`in Table 1.
`
`In.
`
`this formulation,
`
`PEG 400 provides
`
`25
`
`tonicity and viscosity.
`
`The HPMC provides viscosity, and the
`
`citric acid lightly buffers the preparation.
`
`Preservative Effectiveness Testin for Solution 1
`
`
`TABLE 1,
`
`
`
`
`
`
`
`
`
`30
`
`4-M05
`1.6x10“ 5.6xlO5
`
`5.8xl05
`
`7.8x1O5
`
`3.4x1O5
`
`6.4x105
`
`6.Ox1O5
`
`14 Days
`
`28 days
`
`3.4x10‘
`
`2.7x10‘
`
`1.7xl0‘
`
`2.0x10‘
`
`2.6x10‘
`
`000013
`
`
`
`4.1x10‘ 2.6x10‘
`352-om 1-W
`
`000013
`
`

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`
`13
`
`3.9x1O5
`
`2.2x10‘
`
`1.3x10‘
`
`1.0xl05
`
`3.0x103
`
`<1000
`
`l.7x10‘ 8.4x1O5 4.8xl05
`6.1x10“ 5.0x10“
`1.9x10“
`3.1x10“
`2.8x105 1.7x105
`1.4x1O5
`5.0x10“
`
`5
`
`2.9x105
`1.9x10“
`3.3x10“
`
`2.9x105
`2.2xl0“
`8.0xl0“
`
`
`
`1.4xl05
`1.1x10“
`1.4x10“
`
`Table 1 shows that the concentration in colony forming
`
`units (CFU)/ml for the three bacterial organisms inoculated in
`Solution 1 decreased by greater than 3
`logs at 14 days and
`
`remained at
`
`that
`
`level
`
`for 28 days,
`
`thus meeting the PET
`
`requirements.
`
`Both C. albicans and A. niger met or exceeded the PET
`
`requirement for yeasts and molds to remain at or below the
`
`initial concentration.
`
`TABLE 2
`
`pH Testing for Solution 1
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`2.35
`
`2.42
`
`2.40
`
`2.39
`
`2.35
`
`As seen in Table 2, Solution 1 maintained its pH close to
`
`its original pH value 2.5 for at least 28 days in the presence
`
`of all tested organisms.
`
`Solution 1 was also pH stable when incubated at 40°C for
`
`greater than two months.
`
`Another
`
`representative embodiment
`
`for
`
`an artificial
`
`demulcent
`
`is
`
`a
`
`formulation designated solution 2, which
`
`comprises
`
`4%
`
`of
`
`dextrose,
`
`1%
`
`of
`
`PEG
`
`400,
`
`0.3% of
`
`hydroxypropylmethyl cellulose 2910 and 0.01% of citric acid,
`
`dissolved in 100 ml of purified water and pH adjusted to 2.5.
`
`In this solution,
`
`the dextrose and PEG 400 both serve as
`
`tonicity agents. This formulation, designated as Solution 2,
`
`000014
`
`000014
`
`

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`
`Table 3.
`
`14
`
`TABLE 3
`
`Preservative Effectiveness Testin for Solution 2
`
`
`21 Days
`
`28 DaY5
`
`5.8x105
`
`7.8x1O5
`
`3.4x105
`
`6.4x1O5
`
`6.ox1o-'-
`
`3.4x10‘
`
`2.7x10‘
`
`1.7xlO‘
`
`2.0x10‘
`
`2.6x10‘
`
`1.6x10‘ 5.6x10"’
`
`
`
`4.1x10‘ 2.6x10‘
`
`5
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`
`15
`
`20
`
`25
`
`<1,ooo
`3.0x103
`1.0xl0"’
`1.3x10‘
`3.9x10° 2.2x10‘
`
`5.8x102
`2.0x10“
`l.9x10‘ 8.621105 1.7xlO5
`l.4x105
`2.9x105
`2.6x105
`1.7x1o6 8.4x105 4.8x105
`1.0x10“
`1.5x10“
`2.4xlO“
`7.sx1o4 1.9x10“
`1.4x10"
`2.7x10“
`
`2-axles 1-mos
`1-4x105 s.sx1o41.4x1o4
`
`Table 3 shows that Solution 2 was also able to meet or
`
`exceed the PET standards for inhibition of the growth of all
`
`tested microorganisms over the 28 day test.
`
`TABLE 4
`
`pH Testing for Solution 2
`
`_
`
`
`
`
`
`2-41
`
`2-36
`
`
`
`Solution 2 was also able to maintain a stable pH of
`
`around 2.0 to 2.5 for at least 28 days in the presence of all
`
`30
`
`tested organisms, as seen in Table 4,
`
`and for up to three
`
`months when incubated at 40°C.
`
`_
`
`These findings clearly show that
`
`the solutions of the
`
`invention are able to destroy,
`
`inhibit and therapeutically
`
`significantly limit
`
`the microbial growth when the pH is
`
`35 maintained at pH about pH 2.5 or lower.
`
`000015
`
`000015
`
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`
`15
`
`All excipients and additives, alone or in varieties of
`
`combinations,
`
`in percentages as disclosed, with or without the
`
`presence of a pharmaceutical agent, are intended to be within
`
`the scope of this invention as long as they are formulated and
`
`5 maintained at pH lower than 3.5.
`
`EXAMPLE 1
`
`Artificial Tears Formulation
`
`This
`
`example describes preparation and
`
`testing of
`
`Solutions 1 and 2.
`
`10
`
`One
`
`formulation of
`
`the
`
`invention was prepared for
`
`artificial tears.
`
`The formulation consists of polyethylene
`
`glycol 400 (PEG 400)
`
`%, HPMC 0.3%, citric acid 0.01%, and
`
`purified water QS, with pH adjusted to 2.5 with hydrochloric
`
`acid.
`
`15
`
`This
`
`formulation was
`
`instilled in one
`
`eye of
`
`ten
`
`subjects.
`
`The other
`
`eye was
`
`treated with Genteal,
`
`a
`
`commercially available artificial tear. The formulation drops
`
`were
`
`consistently at
`
`least
`
`as
`
`comfortable
`
`as Genteal,
`
`administered in the fellow eye. There was variable slight to
`
`20 moderate
`
`stinging in most
`
`subjects
`
`if
`
`the citric acid
`
`concentration was
`
`increased to 0.02 or 0.039.
`
`Therefore,
`
`approximately 0.01 %
`
`is the :maximum desired citric acid
`
`concentration for comfort.
`
`25
`
`The same formulation was used in a further pilot clinical
`experiment
`to test; safety. Following baseline slit
`lamp
`examination, one%drop of the formulation was placed in the
`right eye of the subject every 15 minutes for eight hours. The
`
`left eye was similarly treated with Genteal artificial tears
`
`as a control. Drop instillation was completely comfortable in
`
`30
`
`both eyes. Follow—up slit lamp examination revealed no corneal
`
`fluorescein staining in either eye.
`
`The same formulation and
`
`control solution were used in a similar manner in one subject
`
`wearing soft contact
`
`lenses. Again, drop instillation was
`
`comfortable in both eyes, and no corneal fluorescein staining
`
`35
`
`was seen on follow—up examination.
`
`000016
`
`000016
`
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`
`16
`
`was
`
`filled with the preparation of Solution 1.
`
`It was
`
`repeatedly sprayed into the right and left nostril of the
`
`subject.
`
`No irritation or unpleasant sensation was noted on
`
`either side.
`
`Another formulation of the invention for artificial tears
`
`consists of dextrose 4.0%,
`
`PEG 400 1.0%, HPMC 0.3%, citric
`
`acid 0.01 %,
`
`and purified water OS,
`
`with the pH adjusted to
`
`2.5 with hydrochloric acid.
`
`In this formulation,
`
`dextrose is
`
`the main tonicity agent. Similar molecules such as mannitol,
`
`or electrolytes such as sodium chloride, can also be used to
`
`adjust
`
`the tonicity.
`
`This formulation, described above as
`
`Solution 2, was tested in the same manner as Solution 1.
`
`' EXAMPLE 2
`
`Preparation of Solutions 1 and 2
`
`This example describes a procedure used for preparation
`
`of Solutions
`
`1
`
`and.
`
`2
`
`and with. moderate modifications
`
`is
`
`suitable for preparation of all
`
`combinations of various
`
`excipients and/or additives and pharmaceutical agents
`
`and
`
`salts thereof.
`
`Solutions were prepared as follows:
`
`All of
`
`the
`
`solutions were prepared using Class A
`
`volumetric flasks and pipettes.
`
`Test solutions were prepared
`
`on weight basis, except for the pH adjustments which were made
`
`volumetrically.
`
`One (1)
`
`liter of each test solution was made.
`
`The hydroxypropyl methylcellulose was weighed out and
`
`mixed.
`
`into 500 mL of
`
`cold. de-ionized. water
`
`(4°C).
`
`The
`
`solution was mixed using a stir bar and stir plated until the
`
`cellulose dissolved completely.
`
`The rest of the ingredients
`
`were then added in the following order: polyethylene glycol,
`
`citric acid, glucose (if used), another 400 mL of de-ionized
`
`water was added, stirred and adjusted to the correct pH with
`
`hydrochloric acid (0.1 N).
`
`The solutions were then made up to
`
`volume with de-ionized water and allowed to sit overnight.
`
`The
`
`pH was
`
`rechecked and adjusted,
`
`if needed,
`
`and then
`
`filtered through a one
`
`(1)
`
`liter 0.22 pm polyethersulfone
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`000017
`
`000017
`
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`17
`
`EXAMPLE 3
`
`Stability and Storage
`
`This example describes conditions suitable for stability
`
`and storage.
`
`5
`
`The formulations disclosed in Example 1 was
`
`stored at
`
`40°C for more than 2 months
`
`for accelerated pH stability
`
`testing.
`
`The solution was sterilized before storage.
`
`The pH
`
`was tested weekly for 11 weeks.
`
`.All samples tested were found
`
`to be
`
`stable with pH around 2.5 for the 11 weeks.
`
`10
`
`000018
`
`000018
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`
`WHAT IS CLAIMED
`
`18
`
`l.
`
`A
`
`self—preserved
`
`preservative—free
`
`topical
`
`ophthalmic,
`
`inhalable or nasal formulation comprising:
`
`a pharmaceutically acceptable excipient or