United States Patent
`
`[19]
`
`lllllllllllllllllllllllllllllllllllllllllllllllIlllllllllllllllllllllllllll
`U5005336508A
`
`[11] Patent Number:
`
`5,336,508
`
`Marty
`[45] Date of Patent:
`Aug. 9, 1994
`
`[54] PRESERVATIVE FOR PHARMACEUTICAL
`PRODUCTS
`
`[75]
`
`Inventor:
`
`Herbert Marty, Uitikon, Switzerland
`
`Similasan Corporation, Kent, Wash.
`[73] Assignee:
`[21] App]. No.: 3,335
`
`[22] Filed:
`
`Jan. 11, 1993
`
`Related US. Application Data
`
`[63]
`
`Continuation of Ser. No. 763,341, Sep. 20, 1991, aban-
`doned.
`
`Int. (31.5 ...................... A61K 33/38; A61K 33/14
`[51]
`
`[52] us. c1. ...._
`................. 424/618; 424/663;
`514/912
`[53] Field of Search ................. 424/663, 618; 514/912
`[56]
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,043,932 8/1977 Fresenius et al.
`
`..................... 252/95
`
`OTHER PUBLICATIONS
`
`Brussieux et a1., Annales de Pediatric. 38(9):637—641
`(1991).
`Gutman et a1., Amer J. Ophthal. 65:183—187 (1968).
`Hanna et a1., Arch Ophthalmol. 92:18—22 (1974).
`Moss et a1., Arch Ophthalmol. 97:906-907 (1979).
`Pifer et a1., Scand J Work Environ Health. 15:210—221
`(1989).
`Schnetkamp et al., J. Membrane Biol.
`(1989).
`Bartley, Arch Ophthalmol. 110:596 (1992).
`Duke—Elder, “Diseases of the Outer Eye, Part II”, p.
`990 (1965).
`Scroggs et a1., Cornea. 11(3):264-269 (1992).
`Abelson et a1., Thimerasol Update. Exerpta. (1982).
`Gardner, Optometric Monthly. Nov.:631—635 (1982).
`Mondino et a1., Survey of Ophthalmol. 26(6):337—344
`(1982).
`Reitschel et a1., Arch Dermatol. 118:147—149 (1982).
`
`108:91—102
`
`Wright et a1., Trans ophthalmol Soc UK 102(3):3—6
`(1982).
`Binder et al., Arch Ophthalmol. 99:87—90 (1981).
`Wilson et a1., Ophthalmology 88(8):804—809 (1981).
`Mondino et al., Arch Ophthalmol. 98:1767—1770 (1980).
`Shaw, Contact Lens. 6(3):273—277 (1980).
`Wilson, Contact Lens Jnl. 9(9):21—24 (1980).
`Morgan, Ophthalmology 86(6):1107—1119 (1979).
`Grant, “Toxicology of the Eye” 2nd Ed., 909-918
`(1974).
`Wallace, “Clinical Ocular Pharmacology”, 530—531
`(1989).
`fikoglund et a1., Scand. J. Dent. Res. 99:320-328 (1991).
`Olveti, Contact Dermatitis 24:57 (1991).
`Burrows, Int. Dental Jnl. 35(1):30—34 (1986).
`Montoya—Cabrera et a1., Gaceta Medica de Mexido
`127(3):267—270 (1991).
`San et al., Jnl. Amer. Acad. Dermatol. 25(5):915—919
`(1991).
`Kanluen et 3.1., Arch. Pathol. Lab Med. 115:56—60
`(1991).
`Rowens et 3.1., Chest. 99(1):185—l90 (1991).
`Rosenman et a1., Jnl. Occupational Med. 21(6):430—435
`(1979).
`Rungby, Acta Neuropathol. 37(5) (1990).
`Rungby
`et
`a1., Pharmacology
`and Toxicoloty
`70:205—207 (1992).
`Wan et a1., Clin. Chem. 37(10):1683—1687 (1991).
`Cai et a1., Current Eye Research 7(4):34l—351 (1988).
`Abelson, Ophthalmology Times 12/1:32-33 (1982).
`
`Primary Examiner—Zohreh Fay
`Attorney, Agent, or Firm—Weingarten, Schurgin,
`Gagnebin & Hayes
`
`[57]
`
`ABSTRACT
`
`A pharmaceutical composition comprising at least one
`active ingredient, a carrier substance and a preservative
`dissolved in the carrier substance, the preservative com-
`prising sodium silver chloride compound, is disclosed.
`
`12 Claims, No Drawings
`
`Argentum Pharm. LLC V. Alcon Research, Ltd.
`Case IPR2017-01053
`
`ALCON 2036
`
`

`

`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`The invention refers to a preservative for pharmaceu
`tical products, especially for ophthalmic pharmaceuti
`cals, nasal spray, ear drops and corresponding veteri
`nary products.
`Pharmaceutical products in the form of solutions,
`suspensions or ointments which are applied directly
`from a container may get in contact with the body ?uids
`of the user or microorganisms of the environment.
`Therefore, there is a danger of contamination of the
`product in the container by bacteria contained in the
`body ?uid. On the other hand the use of preservatives in
`pharmaceuticals is limited in that any interference with
`the pharmaceutically active ingredients and any nox
`ious effect to the user is to be avoided.
`2. Description of the Prior Art
`Especially for preserving ophthalmic pharmaceuti
`cals it has been well documented in the literature that
`benzalkonium chloride, chlorobutanol, thimerosal,
`methyl and propyl parabens have many drawbacks and
`disadvantages. The most common complaints included
`burning, stinging, and irritation upon instillation. Also,
`there is a 5% to 15% incidence of allergic reactions to
`these preservatives. Thimerosal has been shown to ex
`hibit an allergic response as high as 20% in some stud
`ies. Thimerosal is a mercurial derivative, therefore, has
`raised concerns for long-term usage as well. As a result
`of allergic reactions to thimerosal, almost all ophthal
`mic products that contained thimerosal have had for
`mulation changes to one of the other available preserva
`tives.
`Another characteristic of these preservatives is that
`they have been shown to cause a disruption of the cor
`nea epithelium upon instillation. Documentation via
`SEM (scanning electron microscopy) has demonstrated
`these epithelial changes in the literature.
`Obviously, a lot of other preservative substances are
`known for several purposes and applications. Among
`them a sodium silver chloride compound has been used
`for sterilizing water, especially drinking water, and
`other aqueous solutions as e. g. homeopathic solutions.
`
`25
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`45
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`50
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`55
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`The invention will be better understood and objects
`other than those set forth above will become apparent
`when consideration is given to the following detailed
`description thereof.
`The following examples of pharmaceuticals in which
`a sodium silver chloride compound salt is used as a
`preservative mainly refer to ophthalmic pharmaceuti
`cals in the form of solutions, suspensions and ointments.
`The drugs and drug categories as such are known to the
`man skilled in the art and the invention is not limited to
`these drug categories. Sodium silver chloride com
`pounds used in the invention are known as such.
`Preferably this sodium silver chloride compound
`contains Ag't-ions replacing part (in the range of 1%)
`of the Na't-ions in the NaCl basis, so that there is an
`excess of NaCl which allows on one hand more accu
`rate dosing and on the other hand provides the neces
`sary amount of effective reagent.
`It has been found in sterility tests that the sodium
`silver chloride compound in concentrations of 1 to 2
`mg/ 100 ml is effective against the following micro
`organismus:
`Escherichia coli ATCC 8739
`Pseudomas aeruginosa ATCC 9027
`Staphylococcus aureus ATCC 6538
`Candida albicans ATCC 10231
`Aspergillus niger ATCC 16404
`The test arrangements were in accordance with USP
`XXI.
`
`1
`
`5,336,508
`
`PRESERVATIVE FOR PHARMACEUTICAL
`PRODUCTS
`
`This application is a continuation of application Ser.
`No. 07/763,341, ?led Sep. 20, 1991, now abandoned
`entitled: PRESERVATION FOR PHARMACEUTI
`CAL PRODUCTS.
`
`5
`
`2
`less for the user of the pharmaceuticals and does not
`interfere with the medical treatment.
`These objects are achieved by using a sodium silver
`chloride compound as a preservative in pharmaceutical
`products. Though, as already mentioned the sterilizing
`effect of this substance in water was known as such, it
`surprisingly has been found that this substance is espe
`cially advantageous as a preservative in pharmaceuti
`cals, especially ophthalmic drugs, nasal sprays, ear
`drops and corresponding veterinary products and there
`fore is suited to replace the prior used substances
`thereby avoiding the above mentioned problems, espe
`cially allergic reactions to the known preservatives in
`pharmaceuticals.
`It is sufficient to add an amount of 0.0005 to 0.1
`weight % of sodium silver chloride compound to the
`pharmaceutical composition to be preserved in order to
`keep it sterile for the time of use.
`
`15
`
`20
`
`SUMMARY OF THE INVENTION
`Hence, it is an object of the invention to provide a
`preservative for use in a wide range of pharmaceutical
`substances and compositions, i.e. substances containing
`pharmaceutically active ingredients as e.g. antibiotics,
`anti-in?ammatories or anti-infectives etc. and which in
`use may be contaminated by body ?uids of the user or
`microorganisms of the environment.
`It is a further object of the invention to provide a
`preservative for use in pharmaceuticals which preserva
`tive is chemically inert towards the major pharmaceuti
`cally active ingredients and has a high bacteriocidal and
`bacteriostatic effect against possible contaminations in
`pharmaceuticals.
`Still another object of the invention is to provide a
`preservative for use in pharmaceuticals which is harm
`
`65
`
`EXAMPLE 1
`Antibiotics
`An ophthalmic antibiotic in the form of a solution or
`a suspension contains 0.001 weight % of sodium silver
`chloride complex as preservative. The active agent may
`be a single ingredient (gentamicin, tobramycin, o?oxa
`cin), a combination of ingredients ( neomycin/
`polymyxin, gramicidin), a single ingredient with ste
`roids (gentamicin, prednisolone acetate) or combina
`tions with steroids (neomycin, polymyxin/dexametha
`sone). In the case of eye drops containing tobramycin as
`a single active ingredient the composition comprises:
`0.3 weight % tobramycin ( active ingredient ); 0.001
`weight % sodium silver chloride compound (preserva
`tive); excip. ad collyrium tamponat. The indications are
`bacterial infections of the eye.
`
`

`

`5,336,508
`
`3
`EXAMPLE 2
`Anti-Allergy
`An ophthalmic anti-allergic-composition in the form
`of a solution or suspension comprises as active agents
`0.5 weight % of antazolin. sulfuric. and 0.025 weight %
`of naphazoline. nitric. As preservative 0.001 weight %
`of sodium silver chloride compound is provided. Indi
`cations are allergic affections of the conjunctiva.
`
`5
`
`EXAMPLE 3
`Anti-glaucoma
`An anti-glaucoma preparation in liquid form com
`prises: pilocarpine hydrochloride ( 5 mg ) as active
`agent: hydroxypropylmethylcellulose; sodium silver
`chlorid compound (0.01 mg) as preservative; excip. ad
`collyr. ad 1 ml. Other anti-glaucoma ophthalmic prod
`ucts include epinephrine, dipivefrin, carbachol. Other
`20
`major categories include: Prostaglandins, topical car
`bonic Anhydrase Inhibitors, BetaBlockers, ACE and
`Renin Inhibitors, Calcium Channel Blockers, Forskolln
`and Analogues. These products are used topically for
`lowering intraocular pressure and will bene?t from use
`of sodium silver chloride compound as a preservative.
`
`25
`
`15
`
`4
`EXAMPLE 8
`Contact Lens Solutions
`Contact lens solutions are isotonic solutions used for
`cleaning and desinfecting contact lenses and for soaking
`and wetting the same. In these isotonic solutions the
`preservative of the invention can be contained as a
`bacteriostatic agent in a concentration of 0.001 to 0.002
`weight %.
`
`EXAMPLE 9
`Decongestants
`Phenylephrine I-ICl (0.1%-10%) is an example for a
`known decongestant ophthalmic agent. A decongestant
`composition in the form of eye drops contains tetrahy
`drazoline or phenylephrine HCl (0.12%), hydroxypro
`pyl-methylcellulose (0.5% ), sodium silver chloride
`complex (0.001% ) as preservative and excip. ad collyr
`ium tamponat.
`
`EXAMPLE 10
`Diagnostic Agents
`Diagnostic ophthalmic agents are used for a diagnos
`tic dilatation of the pupil of the eye, which e. g. can be
`effected by tropicamide (0.5%) in the form of eye drops.
`As a preservative sodium silver chloride compound
`(0.001%) is added.
`
`EXAMPLE 4
`Anti-Herpetic/Anti-Viral Agents
`Idoxurin is an active agent for use in eye drops (0.1%)
`or ointments (0.25%) and is effective as an antiherpetic
`composition. The composition further comprises 0.001
`weight % of sodium silver chloride compound as a
`preservative.
`
`30
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`35
`
`EXAMPLE 5
`Anti-Infectives
`As ophthalmic anti-infective sodium sulfacetamide is
`known as single ingredient in eye drops (10%). The
`solution is preserved by sodium silver chloride com
`pound (0.001%). Other anti-infective eye drops may
`comprise combinations of ingredients or a single ingre
`dient with steroids. An example for the last mentioned
`type is sodium sulfacetamide (10%)/prednisolone
`45
`(0.25%) which also can be preserved by 0.001 weight %
`of sodium silver chloride compound.
`
`EXAMPLE 6
`Anti-inflammatories
`Dexa-methasone is a known anti-in?ammatory agent.
`A pharmaceutical composition in the form of eye drops
`contains dexamethasone ( 0.1% ), hydroxypropylme
`thylcellulose (0.5%), sodium silver chloride compound
`55
`as preservative (0.001%) and excip. ad collyrium tam
`ponat.
`
`50
`
`EXAMPLE 7
`Arti?cial Tears/ Ocular Lubricants
`As can be seen from the above examples, several
`pharmaceutical compositions comprise hydroxypropyl
`methylcellulose. This is a substance with abirritant ef
`fect to the eyes. The preservative of the invention can
`be used with this substance in arti?cial tear composi
`tions comprising e.g. hydroxypropyl-methylcellulose
`(1%); sodium silver chloride compound (0.001%); ex
`cip. ad collyrium tamponat.
`
`65
`
`EXAMPLE 11
`Hypertonic Solutions
`Hypertonic saline ointments and solutions with NaCl
`concentrations of 2 to 5% are used e. g. for the treatment
`of edema of the cornea. Since sodium silver chloride
`compound is NaCl based it is especially suited as a pre
`servative for such compositions at a concentration of
`0.001% to 0.002%.
`
`EXAMPLE 12
`Irrigation Solutions
`Ophthalmic irrigation solutions are sterile balanced
`salt solutions for the external irrigation of the eye. The
`sterility is maintained by sodium silver chloride com
`plex. A irrigation solution e.g. contains: sodium chlo
`ride (0.64% ), potassium chloride (0.075% ), calcium
`chloride (0.048% ), magnesium chloride (0.03% ), so
`dium acetate (0.39%), sodium citrate (0.17%), sodium
`silver chloride compound (0.001% ) and puri?ed water.
`
`EXAMPLE 13
`Topical Anesthetics
`Topical anesthetics are used for surface anesthesia in
`ophthalmology. As the active ingredient proparacaine
`(proxymetacaine-hydrochloride) is used in a concentra
`tion of 0.5% in combination with sodium silver chloride
`compound (0.001%) as preservative in excip. ad collyr
`ium tamponat.
`As already mentioned above sodium silver chloride
`compound can be used also as preservative in nasal
`spray or ear drops, which during their application may
`be contaminated in the container by body fluids of the
`user.
`The preceding examples illustrate the wide range of
`application of sodium silver chloride compound for the
`preservation of pharmaceutical products which makes
`
`

`

`5,336,508
`5
`6
`4. The pharmaceutical composition of claim 1,
`it suited to generally replace a lot of known preserva
`tives for drugs especially for ophthalmic drugs.
`wherein said active ingredient is NaCl in a hypertonic
`concentration.
`While there are described present preferred embodi
`5. The pharmaceutical composition of claim 1 for
`ments of the invention, it is to be understood that the
`ophthalmic use as arti?cial tears.
`invention is not limited thereto, but may be otherwise
`6. The pharmaceutical composition of claim 1 for
`variously embodied and practiced within the scope of
`ophthalmic use as contact lens solution.
`the following claims.
`7. The pharmaceutical composition of claim 1 for
`I claim:
`ophthalmic use as topical anesthetic.
`1. A pharmaceutical composition comprising a thera
`8. The pharmaceutical composition of claim 1 for
`peutically effective amount of at least one active ingre
`ophthalmic use as diagnostic agent.
`dient, a carrier substance and a preservative dissolved in
`9. The pharmaceutical composition of claim 1,
`said carrier substance, said preservative comprising
`wherein said sodium silver chloride compound com
`sodium silver chloride compound.
`prises a NaCl basis in which part the Na+-ions are
`replaced by Ag+-ions.
`2. The pharmaceutical composition of claim 1,
`10. The pharmaceutical composition of claim 9
`wherein said at least one active ingredient is selected
`wherein about 1% of the Na+-ions are replaced by
`from the group consisting of an antibiotic agent, an
`Ag+-ions.
`anti-allergy agent, and anti-glaucoma agent, an anti-her
`11. The pharmaceutical composition of claim 10,
`petic agent, and anti-infective agent, an anti-in?amma
`wherein said sodium silver chloride compound is pro
`tory agent, a decongestant agent and a topic anesthetic
`vided in a concentration from 0.0005 to 0.1 weight %.
`agent.
`12. The pharmaceutical composition of claim 1,
`3. The pharmaceutical composition of claim 1,
`wherein said carrier is a solution, suspension or oint
`wherein said active ingredient is a diagnostic agent for
`ment.
`diagnostic dilatation of the pupil.
`
`* * * * *
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`65
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