United States Patent [19J
`Bergamini et al.
`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`US005597560A
`5,597,560
`[11] Patent Number:
`[45] Date of Patent:
`Jan.28, 1997
`
`[54] DICLOFENAC AND TOBRAMYCIN
`FORMULATIONS FOR OPHTHALMIC AND
`OTIC TOPICALUSE
`
`[75]
`
`Inventors: Michael V. W. Bergamini, Alella; Jose
`A. Vallet Mas, Barcelona; Gemma T.
`Cabello, El Masnou; Antonio L.
`Cabrera, Barcelona, all of Spain
`
`[73] Assignee: Laboratorios Cusi, S.A., Spain
`
`[21] Appl. No.: 419,387
`
`[22] Filed:
`
`Apr. 10, 1995
`
`[30]
`
`Foreign Application Priority Data
`
`May 17, 1994
`
`[ES]
`
`Spain ..................................... 9401078
`
`Int. Cl.6
`•.•..•.•.••.•.•.•.•.•••••..••..••••.••.••••.••.•.•••. A61K 31n4
`[51]
`[52] U.S. Cl ...................................... 424/78.04; 424178.05;
`5141912; 514/914
`[58] Field of Search .............................. 424178.04, 78.05;
`5141912, 914
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,087,538
`4,407,792
`4,478,822
`4,668,506
`4,829,088
`
`5/1978 Portnoff .................................. 514/420
`1011983 Schoenwald et al ................... 514/397
`1011984 Hasarn et al ........................... 424/94.6
`5/1987 Bawa ...................................... 424/429
`511989 Doulakas ................................ 514/567
`
`FOREIGN PATENT DOCUMENTS
`
`2013188
`0038698A2
`0306984A1
`W089/09057
`
`911990
`10/1981
`311989
`1011989
`
`Canada.
`European Pat. Off ..
`European Pat. Off ..
`WIPO.
`
`OTHER PUBLICATIONS
`
`Human Conjunctivitis, Howard M. Leibowitz, MD, et al.,
`Arch Ophthalmol, vol. 94, Oct. 1976, pp. 1752-1756.
`Association diclofenac-dexamethasone dans le traitement
`de ['inflammation postoperatoire: etude prospective en
`double-insu, Dr. Philippe Othenin-Girard, et al., Klin. Mbl.
`Augenheilk, 200, 1992, pp. 362-366.
`
`The Effect of O.I% Indomethacin Eyedrops on Cataract
`Surgery, Journal of Ocular Pharmacology, vol. 7, No. 1,
`1991, pp. 77-81.
`The Effect of Ketorolac Tromethamine in Reducing Postop(cid:173)
`erative Infiamation: Double-Mask Parallel Comparison
`with Dexamethasone, Allan J. Flach, MD, et al., Ann Oph(cid:173)
`thalmoll989; 21:407-411.
`Infections of the Eye-35. Endophthalmitis, David W. Parke
`II, et al., pp. 563-583.
`Incompatibility of indometacin and benzalkonium in eye
`drops due to ion-pair formation, S. M. Dreijer-Van Der
`Glas, et al., vol. 9, 1987, Pharmaceutisch Weekblad Scien(cid:173)
`tific Edition, pp. 29-32.
`Effects of Pretreatment with Mydriatics on Intraocular Pen(cid:173)
`etration ofO.I% Pranoprofen, Takahiro Ogawa, et al., Jpn J
`Ophthalmol, vol. 37: 47-55, 1993.
`Prediction of Skin Permeability of Drugs: Comparison of
`Human and Hairless Rat Skin, Yasunori Morimoto, et al., J.
`Pharm. Pharmacal. 1992, 44: 634-639.
`Binary Diclogenac Diethylamine-Water Systems: Micelles,
`Vesicles and Lyotropic Liquid Crystals, Katrin Kriwet, et al.,
`Eur. J. Pharm. Biopharm, 39 (6) 234-238, 1993.
`Degradation of Tobramycin in Aqueous Solution, Michael
`Brandl and Leo Gu, Drug Development and Industrial
`Pharmacy, 18(13), 1423-1436, 1992.
`
`(List continued on next page.)
`
`Primary Examiner-Carlos Azpuru
`Attorney, Agent, or Firm-Wigman, Cohen, Leitner &
`Myers, P.C.
`
`[57]
`
`ABSTRACT
`
`This invention includes a pharmaceutically acceptable for(cid:173)
`mulation of Diclofenac, Tobramycin, a solubility agent and,
`optionally, excipients, tonicifiers, buffers, viscosity modify(cid:173)
`ing agents, preservatives, and chelating agents, at a pH from
`greater than 7.0 to about 9. The invention also discloses the
`use of this pharmaceutically acceptable formulation of an
`antibiotic and NSAIDs to treat eye and ear conditions
`accompanied by infection and inflammation.
`
`96 Claims, 4 Drawing Sheets
`
`/00
`
`80
`
`3000
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`2000
`
`1600
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`1200
`
`BOO
`
`400
`
`Innopharma EX1019, Page 1
`
`

`
`5,597,560
`Page 2
`
`OTHER PUBLICATIONS
`
`Spectrophotometric Method for Determination ofTobramy(cid:173)
`cin, Apramycin and Kanamycin in Formulations, P. R.
`Bontchev, et al., Mikrochimica Acta (wien) 1984 III,
`459-465.
`The Top Ten NSA!Ds - A molecular modelling study, S.
`Winiwarter, et al., Pharrnaceutica Acta Helvetiae 68 (1994)
`181-189.
`Conjunctival Disorders, Current Veterinary Therapy X
`Small Animal Practice, Cecil P. Moore, D.V.M., 1989, pp.
`673-678.
`
`A New Corticosteroid-Antibiotic Preparation in Eye and
`Ear Infections, General Practitioner Clinical Trials, Alex(cid:173)
`ander, J. et al., Jul., 1966, vol. 197: 94-96.
`Canine Conjunctiva and Nictitating Membrane, Veterinary
`Ophthalmology, Dennis E. Brooke, pp. 290-304, 1991.
`Diseases of the Ear, Textbook of Veterinary Internal Medi(cid:173)
`cine- Diseases of the Dog and Cat, vol. I, Dennis W. Macy,
`pp. 246-257.
`American Academy of Ophthalmology, Final Program, Sci(cid:173)
`entific Posters, p. 101.
`XXVIIth International Congress of Ophthalmology '94,
`Final Program, Scientific Papers.
`
`Innopharma EX1019, Page 2
`
`

`
`U.S. Patent
`
`Jan. 28, 1997
`
`Sheet 1 of 4
`
`5,597,560
`
`-I e
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`0
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`
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`
`Innopharma EX1019, Page 3
`
`

`
`U.S. Patent
`
`Jan.28, 1997
`
`Sheet 2 of 4
`
`5,597,560
`
`-I c
`
`8 -
`
`3:JN'Ill/WSNtflll%
`
`Innopharma EX1019, Page 4
`
`

`
`U.S. Patent
`
`Jan. 28, 1997
`
`Sheet 3 of 4
`
`5,597,560
`
`.,_
`I
`c3
`
`3:JN'Ill/WSN'Illl%
`
`Innopharma EX1019, Page 5
`
`

`
`U.S. Patent
`
`Jan.28, 1997
`
`Sheet 4 of 4
`
`5,597,560
`
`,/ ..
`--...........
`_____ .. _ .. ,__...,
`--.r.·-··----··/
`_____ ·:=:·.:::.::::::.
`
`.s
`~ u
`d -
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`Innopharma EX1019, Page 6
`
`

`
`5,597,560
`
`1
`DICLOFENAC AND TOBRAMYCIN
`FORMULATIONS FOR OPHTHALMIC AND
`OTIC TOPICALUSE
`
`FIELD OF THE INVENTION
`
`The present invention relates to medical formulations
`used in the treatment of eye and ear conditions which may
`be accompanied by infection and inflammation.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`2
`application WO 89/09057, herein incorporated by reference,
`where Cagle uses the steroids Dexamethasone, Fluo(cid:173)
`romethalone and Fluoromethalone acetate with Tobramycin
`for treatment of eye infections accompanied by inflamma-
`tion and by Leibowitz HM et al. 1976 as previously men(cid:173)
`tioned.
`The use of a NSAID with an antibiotic, however, is not
`well documented, and no combination of a NSAID and an
`antibiotic has been marketed. Canadian Patent Application
`10 No. 2,013,188 (Fu et al.), describes an ophthalmic formu(cid:173)
`lation comprising an NSAID with Tobramycin in a solution
`with a suitable preservative. The preferred ophthalmic for(cid:173)
`the NSAID ketorolac
`mulation of Fu et al. used
`tromethamine with the antibiotic Tobramycin. The preferred
`15 ophthalmic formulation of Fu et al. comprises ketorolac
`trometharnine, Tobramycin, a non-ionic surface active
`agent, preferably Octoxymol40, and a preservative selected
`from the group of quaternary ammonium compounds. Fu et
`al. reports that the use of non-ionic surface active agents,
`20 especially polyoxyethylene alkylphenol surfactants, avoids
`the unacceptable interactions between NSAID and quater(cid:173)
`nary ammonium compounds, wherein the NSAID and qua(cid:173)
`ternary ammonium compound form a complex that is either
`insoluble or retards the absorption of the NSAID.
`However, as will be described in greater detail hereinafter,
`when we attempted to prepare a formulation of Tobramycin
`and Diclofenac, as possibly suggested by Fu et al., we
`discovered
`that
`the
`formulation of Tobramycin and
`Diclofenac formed a precipitate which would be pharma-
`30 ceutically unacceptable in a formulated product.
`Hence, up until our invention, there still was a need for a
`pharmaceutically acceptable formulation ofTobramycin and
`Diclofenac for ophthalmological and otic use.
`
`In ophthalmology, the use of a combination of an antibi(cid:173)
`otic and an anti-inflammatory drug for the treatment of
`inflammation associated with infection of the anterior ocular
`segment, especially conjunctivitis, has been found useful.
`For example, Leibowitz HM et al. Human Conjunctivitis.
`Arch Ophthalmol, 1976; 94:1752-6 report that the combi(cid:173)
`nation of a corticosteroid and an antibiotic is more effective
`than the antibiotic alone in the treatment of bacterial acute
`conjunctivitis.
`Non-steroid anti-inflammatory drugs (NSAIDs) were
`introduced to ophthalmology as an alternative to corticos(cid:173)
`teroids. It is presently thought that the efficacy of available
`NSAIDs is comparable to that of the weaker corticosteroids. 25
`However, NSAIDs lack the adverse side effects associated
`with corticosteroids such as the increase in intraocular
`pressure and the unfavorable immune-suppressant effect that
`corticosteroids have with viral, fungal, tubercular and other
`types of infections.
`In surgical treatment of the anterior segment of the eye,
`for example, in cataract surgery, post-operative inflamma(cid:173)
`tion can be reduced by the pre-operative and post-operative
`use of NSAIDs administered to the eye.
`There is a correlation between the blepharoconjunctival
`microbial flora present in the pre-operative stage of cataract
`surgery and the infectious agents isolated from post-opera(cid:173)
`tive endooophthalmitis. For this reason, it is common prac(cid:173)
`tice to sterilize or disinfect the external eye structure, both 40
`prior to surgery and post-operatively, until there is no longer
`a possibility of infection in the surgical wound, by treatment
`with an antibiotic. A combination of antibiotics and either
`asteroid or a NSAID is also used for treatment of ear
`infections and ear injuries. This was described by Alexander 45
`J et al. A new corticosteroid-antibiotic preparation in eye and
`ear infections. General Practitioner Clinical Trials 1966;
`176:94-96 herein incorporated by reference.
`The use of a combination of asteroid and an antibiotic for
`treatment of eye and ear disorders in veterinary medicine is 50
`well known. The same drugs used to treat humans are also
`used to treat animals, since the eye and ear disorders that are
`common in veterinary practice have the same physiopathol(cid:173)
`ogy as human disorders. This is described by Moore CP.
`Conjuntival disorders. In Current Veterinary Therapy, X 55
`Small Animal Practice. Philadelphia: WB Saunders Com(cid:173)
`pany, 1989, herein incorporated by reference, Brooks DE.
`Canine conjunctiva and nictating membrane. In Veterinary
`Ophthalmology. 2nd Ed. Edited by Gelatt KN. Philadelphia:
`Lea and Febiger, 1991, herein incorporated by reference and
`Macy DW. Diseases of the ear. In Textbook of Veterinary
`Internal Medicine. Diseases of the dog and cat. Edited by
`Ettinger SJ. Philadelphia: Saunders Company, 1989, herein
`incorporated by reference.
`The use of steroidal anti-inflammatory agents with anti- 65
`biotics in general and with Tobramycin in particular is well
`known. This has been described by Cagle et al. in their PCT
`
`35
`
`60
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to a composition-and
`method of using the composition-which comprises a non(cid:173)
`steroidal anti-inflammatory drug, Diclofenac, an antibiotic
`of the arninoglycoside family, Tobramycin, a solubility
`agent and the preservatives, excipients, buffers and tonici(cid:173)
`fiers needed for an acceptable medicament. This composi(cid:173)
`tion of the present invention is a pharmaceutically accept(cid:173)
`able solution; it has an acceptable shelf-life and does not
`form a pharmaceutically unacceptable precipitate over its
`shelf life. This composition can be used to treat eye and ear
`conditions accompanied by infection and inflammation.
`The pathological eye conditions that can be treated with
`the formulation described in the present invention include
`conjunctivitis, eye trauma caused by an accident or surgery,
`eye inflammation and eye infections.
`The pathological ear infections that can be treated include
`otitis externia, otitis meatus, ear inflammation, ear infections
`and ear trauma.
`The formulation can also be used in veterinary practice to
`treat eye and ear inflammation and eye and ear trauma in a
`similar manner to the treatment of human eye and ear
`infections and trauma.
`
`DEFINITIONS
`
`The following terms are defined below:
`The term "q.s." means adding a quantity sufficient to
`achieve a stated function, for example, to bring a solution to
`a desired volume or adjust pH to a desired value.
`
`Innopharma EX1019, Page 7
`
`

`
`5,597,560
`
`4
`that is to say no precipitate will form over the shelf life of
`the formulation, that an effective and potent concentration of
`NSAID and antibiotic will remain at the end of the shelf-life
`and that the formulation will be able to pass the U.S.
`5 Pharmacopeia's antimicrobial challenge at the end of the
`formulation shelf life. The formulations in accordance with
`the invention meet these requirements.
`DESCRIPTION OF THE INVENTION
`
`3
`The term "treatment" or "treating" means any treatment
`of a disease or condition, including:
`(1) prophylaxis-preventing the disease or condition, that
`is to say, causing the clinical symptoms of disease not
`to develop or occur;
`(2) inhibiting the disease or condition, that is to say,
`preventing the development of clinical symptoms; and
`(3) relieving the disease or condition, that is to say,
`causing the regression of clinical symptoms.
`The term "needs of manufacturing specifications" means
`the variation in concentration range acceptable in good
`manufacturing process (GMP) in order to foresee the pos(cid:173)
`sible variations during the production of different batches of
`the product.
`Unless stated to the contrary, the percentages stated
`hereinafter are weight percentages, i.e., grams of material
`per 100 milliliters of solution, or, for hydrogels, grams of
`material per 100 grams of final product.
`The term "Diclofenac" refers to any pharmaceutically 20
`acceptable salt, ester, isomer, or derivative of ortho-(2,6-
`dichlorophenyl) arninophenyl acetic acid and has the struc(cid:173)
`tural formula (I).
`
`10
`
`15
`
`A formulation in accordance with the invention comprises
`a solution of Diclofenac, Tobramycin and a solubility agent
`to cause Diclofenac and Tobramycin to remain in solution
`for the shelf life of the product. The formulations used for
`treatment of either the eye or ear may be identical.
`Diclofenac or its pharmaceutically acceptable ester, salt,
`derivative or isomer, has a concentration between about
`0.001% and about 0.20%, preferably from about 0.01% to
`about 0.15%, more preferably from about 0.05% to about
`0.10% Diclofenac; Tobramycin has a concentration between
`about 0.001% to about 1.0%, preferably from about 0.001%
`to about 0.50%, more preferably from about 0.05% to about
`0.40%, and most preferably from about 0.10% to about
`0.35%.
`The formulations according to the present invention use
`as solubility agents or surfactants, polyoxysorbates, fatty(cid:173)
`acid glycerol-polyethylene glycol esters or a mixture
`thereof. These compounds are used at a concentration
`between about 1.0% to about 8.5%, preferably from about
`2.0% to about 7.5%, more preferably from about 3.0% to
`30 about 7.0%. Other solubility agents such as Octoxynol 40,
`Tyloxapol and Pluronics can be used as well. The concen(cid:173)
`tration of solubility agent is determined by the need to keep
`the Diclofenac and Tobramycin in solution. For example, a
`solution which contains 0.14% Diclofenac and 0.45%
`35 Tobramycin includes 3.0% solubility agent to maintain the
`active ingredients in solution at a pH of 7.5.
`Diclofenac is a well known NSAID with a safety profile
`that is well known after years of experience with the drug.
`Diclofenac has good systemic and topical efficacy, good
`40 systemic and local tolerance and a good topical profile.
`Diclofenac also does not lead to an increase in intraocular
`pressure even when Diclofenac is used extensively.
`Tobramycin is a well known antibiotic with a good safety
`45 profile that is well known after years of pharmaceutical use
`in ophthalmology. Tobramycin has a broad spectrum of
`activity and is active against both Gram positive and Gram
`negative bacteria. The sensitivity shown towards Tobramy(cid:173)
`cin by most Gram positive and Gram negative bacteria
`involved in eye and ear infections is currently adequate, and
`Tobramycin seems to have a better profile and work better
`than other antibiotics.
`Tonicity compounds which can be employed are sodium
`chloride, sodium sulfate, glycerol, mannitol, and sorbitol, as
`55 well as any other commonly used tonicity agent. These
`components are typically used at a level between 0.4% and
`7.5%, with the level being selected so as to achieve a
`formulation of appropriate tonicity.
`The formulation also includes pH buffers, such as citrates,
`borates, phosphates, tris(hydroxymethyl)-arnino-methane,
`and amino acids, such as glycine, lysine, glutamic acid,
`arginine, and aspartic acid. These pH buffers are introduced
`into the product to maintain a stable pH and to improve
`product tolerance by the user. The pH buffers are typically
`65 used at levels between about 0.01% to about 3.0%, prefer(cid:173)
`ably from about 0.05% to about 2.5%, more preferably from
`about 0.10% to about 2.0%.
`
`25
`
`CHzCOOH
`
`Cl
`
`(I)
`
`o-~-o
`
`Cl
`The term "Tobramycin" refers to any pharmaceutically
`acceptable salt, ester, isomer, or derivative of 4-[2,6-di(cid:173)
`arnino-2,4,6-trideoxy-alpha-D-glycopyranosyl
`]-6-]3-
`arnino-3-deoxy-alpha-D-glycopyranosyl]-2-deox(cid:173)
`ystreptarnine and has the structural formula II.
`
`(II)
`
`H3NCH2
`
`~~ )JNHz
`
`NHz
`
`50
`
`Tobramycin has a broad spectrum of actions against both
`Gram positive as well as Gram negative organisms, sensitive
`bacteria include Staphylococcus aureus, Staphylococcus
`epidermidis, Streptococcus pneumoniae, Pseudomonas
`aeruginosa, Escherichia coli, Enterobacter aero genes, Pro(cid:173)
`teus mirabelis, Klebsiella pneumoniae, Morganella morga(cid:173)
`nii, Haemophilus
`infiuenzae, Haemophilus aegyptius,
`Moraxlea lacumata, and Acinetobacter calcoaceticus.
`The terms "trometharnine," "tromethanol," "trometamol,"
`are synonyms of the chemical compound trihydroxymethy- 60
`larninomethane.
`The present invention includes isomers, derivatives and
`pharmaceutically acceptable salts of Diclofenac and Tobra(cid:173)
`mycin.
`A formulation in accordance with the invention will have
`a shelf-life of at least 1 year and preferably 1-2 years. This
`means that the formulation will remain physically stable,
`
`Innopharma EX1019, Page 8
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`

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`5,597,560
`
`5
`
`6
`Pharmaceutical Sciences, 17th Ed., 1985; 1553-1566,
`herein incorporated by reference. The otic formulations can
`be substantially the same as the ophthalmic formulations.
`The present invention will become more readily apparent
`from the comparative examples and working examples
`which follow.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. l(a)-(c). FIG. l(a). infra-red spectra of sodium
`Diclofenac; FIG. l(b ). infra-red spectra ofTobramycin; FIG.
`l(c). infra-red spectra ofthe precipitate from the formulation
`of 0.1% sodium Diclofenac, 0.3% Tobramycin, 0.01% BAC,
`1.0% Octoxymol 40, pH 8.0. The bands in FIG. l(c) at
`approximately 1500 cm-1 are characteristic of the carboxyl
`group of sodium Diclofenac and one band at approximately
`1050 cm-1 is characteristic of the C-N and C-0 group of
`Tobramycin is present.
`FIG. 2. Differential Scanning Calorimetry profile from the
`physical mixture (M) of sodium Diclofenac and Tobramycin
`and from the precipitate (P) of the formulation of sodium
`Diclofenac and Tobramycin described in FIG. l(c) .
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`COMPARATIVE EXAMPLE A
`
`Under the conditions described by Fu et a!, a formulation
`0.3%
`Tobramycin,
`0.5% Ketorolac
`compnsmg
`trometharnine, 0.01% benzalkonium chloride (BAC) and
`0.01% Octoxynol40 (70% aqueous solution) at pH 7.4 was
`prepared and yielded a clear, transparent and ophthalmo(cid:173)
`logically useful solution. However, when 0.3% Tobramycin,
`0.5% sodium Diclofenac, 0.01% benzalkonium chloride
`(BAC) and 0.01% Octoxynol 40 (70% aqueous solution)
`was formulated under the conditions described by Fu et al.,
`that formulation yielded a cloudy solution with suspended
`particles that was not pharmaceutically acceptable.
`
`COMPARATIVE EXAMPLE B
`
`The experiment of Example A was repeated using 0.3%
`Tobramycin, 0.1% sodium Diclofenac (the concentration
`normally used in ophthalmology), 0.01% benzalkonium
`chloride (BAC) and 0.01% Octoxynol 40 (70% aqueous
`solution) at pH 7.4. This formulation again yielded a cloudy
`solution with suspended particles that was not pharmaceu(cid:173)
`tically acceptable. The presence of suspended particles is
`due to the formation of an insoluble complex between
`50 Diclofenac and Tobramycin, which was identified by thin(cid:173)
`layer chromatography (TLC), HPLC, infra-red spectroscopy
`(FIG. 1) and DSC (FIG. 2), as will be discussed in greater
`detail in the following comparative example.
`
`5
`The formulation typically includes viscosity modifying
`agents, which improve the residence time of the product
`where it is applied. Typical examples of viscosity modifying
`agents would include polyvinyl alcohol, polyvinylpyrroli(cid:173)
`done, methylcellulose, hydroxypropylcellulose, hydroxy(cid:173)
`ethylcellulose, carboxymethylcellulose and hydroxypropyl(cid:173)
`methylcellulose. These compounds are typically used at
`levels between about 0.01% to about 10.0%, preferably from
`about 0.05% to about 5% and more preferably from about
`0.10% to about 3%. The amount of the viscosity modifying 10
`agent should be selected so as to obtain a formulation with
`the desired residence time.
`Chelating agents are used in the formulation to eliminate
`heavy metals and improve the action of the preservative.
`Examples of chelating agents would include citric acid, 15
`ethylene diarninetetraacetic acid (EDTA), EDTA sodium
`salts, and ethylene glycol-bis(P-arninoethyl ether) N,N,N',
`N'-tetraacetic acid (EGTA). These compounds are used at a
`concentration between about 0.01% to about 3.0%, prefer(cid:173)
`ably from about 0.05% to about 2.0%, and most preferably 20
`from about 0.10% to about 1.0%.
`Preservatives, used to inhibit microbial contamination of
`the product when it is dispensed in multidose containers, can
`include: quaternary ammonium derivatives, (benzalkonium
`chloride, benzylammonium chloride, cetylmethyl ammo- 25
`nium bromide, cetylpyridinium chloride), benzethonium
`chloride, organomercury compounds (Thimerosal, phenylm(cid:173)
`ercury acetate, phenylmercury nitrate), methyl and propyl
`p-hydroxy-benzoates and salts thereof, betaphenylethyl
`alcohol, benzyl alcohol, phenylethyl alcohol and phenoxy- 30
`ethanol. The formulation according to the invention can also
`include mixtures of the preservatives. These compounds are
`used at effective concentrations, typically from about
`0.005% to about 5.0%, depending on the preservative(s)
`selected. The mount of the preservative used should be 35
`enough so that the solution is physically stable, i.e. a
`precipitate is not formed, and antibacterially effective, that is
`the formulation with preservative can pass the U.S. Phar(cid:173)
`macopeia antimicrobial challenge by a panel of microbes.
`The formulation can, as an option, include excipients 40
`normally used to obtain pharmaceutical hydrogels. These
`excipients would include poly(hydroxymethylmethacry(cid:173)
`late), poly(N-vinylpyrrolidone), polyvinyl alcohol and
`acrylic acid polymers such as Carbopol. These compounds
`are typically used at levels between 0.01% and 25.0%, 45
`preferably 0.05% to 15%, more preferably 0.10% to 7%.
`The pH of the formulation is chosen so that the formu(cid:173)
`lation remains as a stable, clear and transparent solution. The
`pH can vary from more than 7.0 to about 9, preferably from
`about 7.5 to about 9, and most preferably 8.4. To adjust the
`pH of the formulation to the desired value, the use of acids
`such as hydrochloric acid or sulfuric acid or bases such as
`sodium or potassium hydroxide can be used with the pH
`buffers.
`Otic formulations are similar to ophthalmic formulations
`and the formulations can be used interchangeably. If one
`were to specifically formulate an otic formulation, one
`would use more excipient to form a more viscous solution.
`Hydrogel forming excipients, as was previously described,
`would be the preferred excipients.
`The formulations represented by the invention are physi(cid:173)
`cally stable, remain clear and transparent for a useful shelf(cid:173)
`life of one to two years and remain antimicrobially effective
`for the useful shelf life of the product.
`For a more detailed discussion of ophthalmic formula(cid:173)
`tions, their preparation and administration, see Remington's
`
`55
`
`COMPARATIVE EXAMPLE C
`
`60
`
`A formulation was prepared using 0.1% sodium
`Diclofenac, 0.3% Tobramycin, 0.01% benzalkonium chlo(cid:173)
`ride, 1.0% Octoxynol40 (70% aqueous solution) and the pH
`was adjusted to 8.0. As comparative controls, two more
`formulations were prepared, one with sodium Diclofenac as
`the active ingredient and the other formulation with Tobra(cid:173)
`mycin as the active ingredient. Samples of the three formu(cid:173)
`lations were stored at 4° C. and 22° C. with the formation of
`65 precipitate being followed. The storage temperature of 4° C.
`was intended to represent a critical storage condition from
`the point of view of the appearance of a precipitate, but
`
`Innopharma EX1019, Page 9
`
`

`
`5,597,560
`
`15
`
`7
`realistic from the point of view of the environmental con(cid:173)
`ditions which a preparation may encounter during its shelf
`life as a pharmaceutical product. After 41 days at 4 o C., the
`formulation of Diclofenac and Tobramycin developed a
`precipitate, while the formulations of Diclofenac alone or 5
`Tobramycin alone did not develop a precipitate. None of the
`formulations at 22° C. developed a precipitate after 7.5
`months.
`The precipitate formed was separated and then analyzed
`by thin layer chromatography (1LC), HPLC and Infra-Red 10
`(IR) spectroscopy. The analysis detected the presence of
`Diclofenac and Tobramycin. TheIR spectrum (FIG. 1) of the
`precipitate shows
`the characteristic bands of sodium
`Diclofenac and Tobramycin that are not found in the spec(cid:173)
`trum of the separate compounds. The analysis by differential
`scanning calorimetry (DSC) (FIG. 2) of the precipitate
`shows a profile clearly different from the profile obtained
`from the individual compounds as well as the profile
`obtained from the simple physical mixing of sodium
`Diclofenac and Tobramycin.
`The results obtained show different solubility behavior 20
`between Ketorolac and Diclofenac, showing the existence of
`an interaction between sodium Diclofenac and Tobramycin.
`The special characteristics of Diclofenac have been dis(cid:173)
`closed by Kriwet K and Muller-Goyman C. Binary
`Diclofenac Diethylamine Water systems: micelies, vesicles 25
`and lyotropic liquid crystals. Eur J Pharm Biopharm 1993;
`39(6):234--238; and Winiwarter S and Roth HJ. The top ten
`NSAIDs. Pharmaceutica Acta Helvetica 1994; 68:181-189,
`both herein incorporated by reference.
`However, the appearance of a precipitate within 3 days, at 30
`22° C., was observed with a formulation that contained
`0.15% sodium Diclofenac, 0.45% Tobramycin, 1.0% Octox(cid:173)
`ynol 40 (70% aqueous solution) and 0.01% benzyl ammo(cid:173)
`nium chloride (BAC) at a pH of 8.0. These concentrations,
`which are within the concentrations claimed by Fu et a!., 35
`were chosen because it is considered that these concentra(cid:173)
`tions are the maximums at which a formulation of
`Diclofenac and Tobramycin could be found within the
`normal concentrations used
`in ophthalmology 0.1%
`Diclofenac and 0.3% Tobramycin. The concentration of 40
`0.15% Diclofenac and 0.45% Tobramycin would take into
`account the needs of manufacturing specifications, the
`potential need for overdosing because of the instability of
`the Diclofenac and/or the Tobramycin, and the concentration
`of the formulated product due to evaporative losses from the 45
`containers normally used to store these products.
`For the purpose of determining the conditions under
`which a precipitate occurs, the concentration of sodium
`Diclofenac, the concentration of Octoxymol 40 (70% aque(cid:173)
`ous solution) and the pH of the final solution was varied 50
`while the concentration of benzalkonium chloride (BAC)
`(0.01 %) and Tobramycin (0.3%) was held constant. The
`concentration of sodium Diclofenac was varied between
`0.05 and 0.5%, the concentration of Octoxynol 40 (70%
`aqueous solution) was varied from 0.01% to 1.0%. The pH 55
`values of 6, 7 and 8 were studied. The rest of the components
`needed for an acceptable ophthalmological medicament
`were used at the concentrations described in Fu eta!., herein
`incorporated by reference. The initial experimental approach
`corresponded to a factorial design 33
`, and, as results were 60
`observed, new formulations were developed for the purpose
`of exploring the conditions that yielded clear and transparent
`solutions of sodium Diclofenac and Tobramycin. Based on
`these experiments, the use of high concentrations of surface
`active agent and alkaline conditions were found to provide 65
`the best conditions for obtaining clear and transparent solu(cid:173)
`tions.
`
`8
`We discovered that after 7 months of storage in a refrig(cid:173)
`erator, clear and transparent solutions were obtained only
`from the following formulations:
`
`% sodium Diclofenac
`
`pH
`
`% Octoxynol 40
`(70% aqueous solution)
`
`0.05
`0.05
`0.05
`0.05
`
`6
`7
`8
`8
`
`1.0
`1.0
`0.5
`1.0
`
`We also discovered that after 7 months storage at 22° C.,
`clear and transparent solutions were obtained only from the
`following experimental conditions:
`
`% sodium Diclofenac
`
`pH
`
`% Octoxyno1 40
`(70% aqueous solution)
`
`0.05
`0.05
`0.05
`0.05
`0.05
`0.05
`0.10
`
`6
`7
`7
`8
`8
`8
`8
`
`1.0
`1.0
`0.5
`0.25
`0.5
`1.0
`1.0
`
`The other formulations studied did not provide clear and
`transparent solutions because a precipitate was obtained
`either on mixing or during storage. The following formula(cid:173)
`tions yielded a precipitate either on mixing or during stor(cid:173)
`age:
`
`% sodium Diclofenac
`
`pH
`
`% Octoxynol 40
`(70% aq. soln.)
`
`0.5
`0.5
`0.5
`0.05
`0.05
`0.05
`0.5
`0.5
`0.5
`0.25
`0.25
`0.25
`0.5
`0.05
`0.1
`0.1
`0.1
`0.05
`0.05
`
`8
`7
`6
`8
`7
`6
`8
`7
`6
`8
`8
`8
`8
`6
`8
`7
`6
`7
`6
`
`1.0
`1.0
`1.0
`O.Dl
`0.01
`0.01
`0.01
`0.01
`0.01
`0.01
`0.5
`1.0
`0.5
`0.5
`0.5
`1.0
`1.0
`0.25
`0.25
`
`It is noteworthy that Fu et a!. prefer a pH of 7.4±o.4 for
`their formulations, and that even with the greatest concen(cid:173)
`tration of surface active agent described (1.0% Octoxynol
`40), a pharmaceutically acceptable, clear and transparent
`solution cannot be obtained with a concentration. of 0.1%
`sodium Diclofenac and 0.3% Tobramycin at a pH of 7.
`As a result of these experiments, we discovered the
`preferred conditions (pH between 8 and 9; high concentra(cid:173)
`tion of solubility agent) necessary to obtairi a pharmaceuti(cid:173)
`cally acceptable solution of Diclofenac and Tobramycin,
`thus overcoming the precipitation problems of the Fu et a!
`formulations. The discovered conditions also permit includ(cid:173)
`ing in the formulation quaternary ammonium compounds as
`preservatives, since these same conditions also inhibit the
`unacceptable interaction between Diclofenac and the qua(cid:173)
`ternary ammonium compounds.
`
`Innopharma EX1019, Page 10
`
`

`
`5,597,560
`
`9
`It is well known that combinations of antibiotics and
`antiinflammatory agents intended for topical application are
`often used to treat different external organs of the body; for
`example, formulations intended for the topical treatment of
`the eye are also used for topical treatment of the ear, and, 5
`therefore, a combination of antibiotics with an NSAID
`would be analogously used.
`The following formulations are given as representative
`examples of the compositions included in the present inven- 10
`tion, and they should not be considered as restrictions of the
`scope of the present invention.
`
`10
`EXAMPLE 3
`
`COMPOSITION
`
`AMOUNT PER 100 mi.
`
`Sodium Diclofenac
`Tobramycin
`Benzalkonium chloride
`Glycerol-polyethyleneglycol
`ricinoleate
`Tromethamine
`EDTANa2
`NaCI q.s.
`H2S04 and NaOH q.s.
`Purified water q.s.
`
`0.100 g.
`0.300 g.
`0.010 g.
`3.500 g.
`
`0.600 g.
`0.100 g.
`300 mOsmollkg
`pH 8.4 ± 0.4
`100 ml.
`
`EXAMPLE 1
`
`COMPOSITION
`
`AMOUNT PER 100 ml.
`
`Sodium Diclofenac
`Tobramycin
`Benzalkonium chloride
`Polysorbate 80
`Boric acid
`So