`

`

`

`5,558,876
`
`1
`TOPICAL OPHTHALMIC ACIDIC DRUG
`FORMULATIONS
`
`FIELD OF THE INVENTION
`
`2
`BAC, and caffeine. Types of acidic drugs can include
`NSAIDs, antibacterials, diagnostic agents, antiinfective
`agents, and prostaglandins. Methods for the compositions'
`usc are also disclosed.
`
`This application is directed to stable and comfortable
`preserved ophthalmic formulations containing an acidic
`drug.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`FIG. 1 shows the effect of caffeine concentration on the
`preservative efficacy of BAC.
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`The compositions of the present invention comprise an
`acidic drug, Vitamin E TPGS, BAC, or mixtures of BAC
`homologues, such as C 12 and C 14 and caffeine. As used
`herein the term "acidic" means the drug contains a carboxyl
`moeity or a salt thereof and/or a sulfamide group or a salt
`thereof.
`Acidic drugs which can be formulated according to the
`present invention include NSAIDs, including, but not lim(cid:173)
`ited to, diclofenac, bromfenac, fiurbiprofen, naproxen,
`ketorolac, suprofen, ibuprofen, and tolmetin, including their
`25 pharmaceutically acceptable salts, esters, and prodrugs;
`prostaglandins; antibacterial and antiinfective aoents; and
`diagnostic agents. BAC is used to preserve the fo~ulations.
`The Vitamin E TPGS is used to solubilize the acidic drug
`and reduce ocular discomfort in aqueous conditions. The
`30 caffeine is added to reduce ocular discomfort, but surpris(cid:173)
`ingly, it was found that it acts synergistically with Vitamin
`E TPGS to reduce discomfort and it also potentiates the
`preservative efficacy of BAC.
`In the formulations, the acidic drug is present at concen-
`trations from 0.001 weight percent (wt. %) to 2.5 wt. %,
`preferably 0.01 to 1.0 wt. %. The Vitamin E TPGS concen(cid:173)
`tration is 0.0001 to 30 wt. %, preferably 0.01 to 10 wt. %.
`BAC or its homologue mixtures are present at concentra(cid:173)
`tions from 0.00001 to 0.02 wt. %, preferably 0.0001 to 0.01
`40 wt. %; and the caffeine concentration is from 0.001 to 5.0 wt.
`%, preferably 0.01 to 1.0 wt. %.
`The compositions of the invention may also contain other
`components such as, but not limited to, those listed below:
`1. Buffers (e.g., phosphate, borate, citrate, acetate, car(cid:173)
`bonate, borate-polyol complexes, etc.);
`2. Tonicity agents (e.g. mannitol, sodium chloride, xylitol,
`etc.)
`3. Viscosity building agents, e.g., carboxylic polymers
`like Carbopol® (carbomers), Noveon® (polycarbophils),
`etc.; cellulose derivatives including alkyl and hydroxyalkyl
`cellulose like methylcellulose, hydroxypropylcellulose, car(cid:173)
`boxymethylcellulose, etc.; gums like locust beam, xanthan,
`agarose, karaya, guar, etc.; and other polymers including but
`55 not limited to polyvinyl alcohol, polyvinyl pyrollidone,
`polyethylene glycol, Pluronic® (Poloxamers), tragacanth,
`and hyaluronic acid.
`4. Phase-transition polymers for providing sustained and
`controlled delivery of enclosed medicaments to the eye (e.g.,
`60 alginic acid, carrageenans (e.g., Eucheuma), xanthan and
`locust bean gum mixtures, pectins, cellulose acetate phtha(cid:173)
`late, alkylhydroxyalkyl cellulose and derivatives thereof,
`hydroxyalkylated polyacrylic acids and derivatives thereof,
`poloxamers and their derivatives, etc. The phase-transition
`in these polymers can be mediated by changes in environ(cid:173)
`mental factors such as ionic strength, pH, or temperature
`alone or in combination with other factors.
`
`Carboxyl containing compounds, including most non(cid:173)
`steroidal antiinflammatory drugs (NSAIDs), are difficult to
`formulate into stable, preserved, comfortable, ophthalmic
`compositions. Acidic drugs with carboxyl groups are inher(cid:173)
`ently irritating to the eye. In addition, the drugs tend to form 15
`insoluble complexes with quaternary ammonium preserva(cid:173)
`tives, such as benzalkonium chloride (BAC). Many NSAIDs
`have been formulated with other than desirable preservatives
`(e.g. sorbic acid, thimerosal) because the compounds com(cid:173)
`plex with desired preservatives, such as, quaternary ammo- 20
`nium compounds, particularly BAC. In addition, it has
`proved difficult to formulate carboxyl containing com(cid:173)
`pounds that are comfortable when applied topically to the
`·eye.
`There are ophthalmic products containing acidic drugs.
`Commonly, these drugs are NSAIDs containing a carboxyl
`group. Examples of these products are suprofen (Profenal®,
`Alcon Laboratories, Inc. which is preserved with thimero(cid:173)
`sal); diclofenac sodium (Voltaren OphthalmicTM, Ciba
`Vision Ophthalmics which is preserved with sorbic acid);
`tlurbiprofen sodium (Ocufen®, Allergan Medical Optics
`which
`is preserved with
`thimerosal); and ketorolac
`tromethamine (Acular®, Allergan, Inc. which is preserved
`with BAC and Octoxynol 40).
`U.S. Pat. No. 5,110,493 discloses aqueous, ophthalmic,
`non-steroidal anti-inflanunatory formulations which include
`a preservative system formed of a quaternary ammonium
`compound and a nonionic surfactant which is an ethoxylated
`alkyl phenol, such as Octoxynol 10 or 40.
`WO 94/15597 discloses the use oflauralkonium chloride,
`a C 12 homologue of BAC, which is compatible with acidic
`drug entities in ophthalmic formulations.
`U.S. Pat. No. 4,960,799 discloses an ophthalmic formu(cid:173)
`lation of a salt of ortho-(2,6-dichlorophenyl) aminopheny- 45
`!acetic acid, EDTA, a solubilizer, and a bacteriostat.
`EP 0,621,036-Al discloses ophthalmic formulations of
`particular arginine amides and either cyclodextrin or caf(cid:173)
`feine. The application discloses that the use of cyclodextrin
`or caffeine improves the arginine amide solubility in water 50
`and that the caffeine can stabilize the compound in water.
`U.S. Pat. No. 4,559,343 discloses ophthalmic formula(cid:173)
`tions containing NSAIDs and a xanthine derivative to reduce
`ocular discomfort.
`The compositions of the present invention are stable, yet
`they contain an acidic drug and the desired preservative,
`BAC, or mixtures of at least two homologues of BAC. In
`addition, the compositions are comfortable upon topical
`instillation in the eye.
`
`35
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed to stable, comfortable,
`and preserved topical ophthalmic formulations comprising
`an acidic drug, Vitamin E Tocopherol Polyethylene Glycol
`1000 Succinate (TPGS) (Eastman Chemical Co., Kingsport,
`Tenn., BAC, or mixtures of at least two homologues of
`
`65
`
`Innopharma EX1006, Page 3
`
`

`

`4
`-continued
`
`Ingredients
`
`Disodium EDTA
`HCJJNaOH
`Purified Water
`
`Concentration (% w/w)
`
`0.1
`q.s. pH 7.4
`q.s. 100%
`
`5,558,876
`
`5
`
`3
`5. Other excipients include but are not limited to: anti(cid:173)
`oxidants (ascorbic acid, sodium metabisulfite, etc.), com(cid:173)
`plexing agents (cyclodextrins and derivatives thereof), drug
`carriers or drug-laden ion exchange carriers, such as,
`Amberlite® and Duolite®, and some chelating agents.
`The ophthalmic compositions can be administered topi(cid:173)
`cally to the eye as suspensions, emulsions, ointments, gels,
`or solutions. The compositions may be aqueous or nonaque(cid:173)
`ous, but are preferably aqueous. The compositions may have
`the drugs incorporated and/or encapsulated in microcap- 10
`sules, nanocapsules, nanoparticles, or liposomes which are
`dispersed in an aqueous or nonaqueous medium.
`The preferred formulation of this invention comprises
`diclofenac sodium, as illustrated in Example 2.
`The following Examples are illustrative, but not limiting:
`Examples 1 and 2 are useful in treating ophthalmic
`inflammation. The formulations are administered 1--4 times
`daily according to the routine discretion of a skilled clini-
`cian.
`
`Compounding Procedure:
`A. Preparing 10% Vitamin E TPGS stock solution
`Deionized water (70% of final weight of TPGS stock
`solution) was taken in a large beaker and brought to boiling
`with heat. The required quantity of Vitamin E TPGS was
`added in small proportions under stirring. Final weight was
`adjusted to 100% with additional d.i. water after all of
`15 Vitamin E TPGS had gone in solution.
`B. Preparing 2% HPMC (Hydroxypropyl methyl cellu(cid:173)
`lose) stock solution
`HPMC wad added in small proportions under constant
`20 stirring into a beaker containing deionized water which was
`70% of final weight of HPMC stock solution. Final weight
`was adjusted to 100% with additional d.i. water after all of
`the added FIPMC had dissolved completely.
`C. Ingredients were added in the order suggested below
`and each ingredient was dissolved completely under
`constant stirring before the next one was added:
`0.2 g of caffeine was weighed in a tared vessel containing
`a stir bar and d.i. water which is 40% of final weight. Then
`0.1 g of diclofenac, 20 g of 10% Vitamin E TPGS stock
`30 solution, 1.2 g oftromethamine, 0.6 g of boric acid, 0.1 g of
`disodium EDTA, 0.01 g of BAC, 4.2 g of mannitol and 5 g
`of 2% HPMC stock solution were added sequentially.
`Weight was adjusted to 95% of final weight with d.i. water.
`Next, pH was measured and if necessary, it was adjusted to
`35 7.4 with O.lN NaOH or O.lN HCJ. Finally weight was
`adjusted to 100 g with additional d.i. water.
`
`25
`
`EXAMPLE 1
`
`Ingredients
`
`Concentration (% wt./vol.)
`
`NSAID
`HPMC
`Tromethamine
`Boric Acid
`Vit E TPGS
`Caffeine
`Mannitol
`Benzalkonium Chloride
`or its homologue mixtures
`Disodium EDTA
`HC!/NaOH
`Purified Water
`
`0.1-2.5
`0.05-1.0
`0.1-1.2
`0.01-1.0
`0.1-5.0
`0.01-2.0
`2.0-4.4
`0.005--D.Ol
`
`O.Dl--D.l
`q.s. to pH 7.4
`q.s. 100%
`
`Example 3
`
`Examples of other NSAID and prostaglandin formulations
`
`Formulation
`
`Ingredient
`
`A
`
`B
`
`% weight by volume
`c
`
`D
`
`E
`
`F
`
`45
`
`Compounding Procedure:
`To a tared glass vessel containing purified water, first
`caffeine is added. The solution is stirred until the caffeine 40
`dissolves. Next, the rest of the ingredients are added in the
`order given below and each ingredient is completely dis-
`solved by stirring before the next one is added.
`NSAID
`Vitamin E TPGS
`Tromethamine
`Boric acid
`Disodium EDTA
`Benzalkonium chloride
`Mannitol
`HPMC
`The formulation is then brought to 95% of its final weight.
`The pH is adjusted to about 7-7.4 using NaOH or HCl. The
`final weight is adjusted to 100% with purified water. The
`formulation's tonicity is 300 mOsms.
`
`55
`
`Ingredients
`
`Concentration (% w/w)
`
`Diclofenac Sodium
`HPMC
`Tromethamine
`Boric Acid
`Vit E TPGS
`Caffeine
`Mannitol
`Benzalkonium Chloride
`
`0.1
`0.1
`1.2
`0.6
`2.0
`0.2
`4.2
`0.01
`
`65
`
`Caffeine
`Flurbiprofen
`Bromfenac
`Suprofen
`Suprofen
`50 Prostaglandin
`(PG~)
`Prostaglandin
`(PGF2,J
`10% Vitamin E
`TPGS Stock Soln.
`tromethamine
`boric acid
`Disodium EDTA
`Benzalkoni urn
`Chloride (BAC)
`Cl2 and Cl4
`60 homologues of BAC
`(80:20)
`Mannitol
`2% HPMC Stock
`So ln.
`O.lN NaOH or O.!N
`HCl to adjust pH
`Deionized water qs to
`
`0.2
`
`0.2
`
`0.2
`
`0.2
`
`0.2
`
`0.2
`0.03
`
`0.05
`
`0.25
`
`0.25
`
`0.1
`
`0.1
`
`20.0
`
`20.0
`
`15.0
`
`20.0
`
`25.0
`
`25.0
`
`1.0
`0.6
`0.05
`0.01
`
`1.0
`0.6
`0.05
`0.01
`
`1.2
`0.6
`0.05
`
`0.01
`
`1.2
`0.6
`0.05
`0.01
`
`1.0
`0.6
`0.05
`0.01
`
`1.0
`0.6
`0.05
`
`0.01
`
`4.2
`15.0
`
`4.2
`15.0
`
`3.8
`15.0
`
`7.4
`
`7.4
`
`7.4
`
`100
`
`100
`
`100
`
`3.8
`15.0
`
`7.4
`
`100
`
`4.0
`15.0
`
`4.0
`15.0
`
`7.4
`
`7.4
`
`100
`
`100
`
`Innopharma EX1006, Page 4
`
`

`

`5,558,876
`
`5
`
`Compounding Procedure:
`Formulations A-F are prepared by adding caffeine to a
`tared glass vessel containing deionized water. The solution
`is stirred until caffeine is dissolved. Next, the remaining
`ingredients are added sequentially as listed and after the 5
`previous ingredient has completely dissolved. The solution
`is then brought to 95% of final weight with water and the pH
`is adjusted to 7 .4. The final weight is then made 100% with
`water.
`
`6
`shows that the required 3.0 log reduction is achieved by 7
`days at higher caffeine concentration rather than on 14 days.
`The formulation of Example 2 above showed the S.
`aureus log reduction values of 3.1 and 5.1 on days 7 and 14,
`respectively, when the S. aureus screen was performed.
`Thus, surprisingly caffeine was found to potentiate the
`preservative efficacy of BAC in the formulations of the
`invention.
`We claim:
`1. A topical ophthalmic aqueous solution comprising an
`acidic drug, tocophersolan, benzalkonium chloride or mix(cid:173)
`tures of at least two homologues of benzalkonium chloride,
`and caffeine.
`2. The composition of claim 1 having the following
`15 concentrations; 0.001 to 2.5 wt. % acidic drug; 0.0001 to 30
`wt. % tocophersolan; 0.00001 to 0.02 wt. %benzalkonium
`chloride; and 0.001 to 5.0 wt. % caffeine,
`3. The composition of claim 2 wherein the acidic drug is
`selected from the group consisting of a non-steroidal anti-
`inflammatory drug and a prostaglandin.
`4. The composition of claim 3 wherein the acidic drug is
`a non-steroidal anti-inflammatory drug.
`5. The composition of claim 4 wherein the non-steroidal
`anti-inflammatory drug is selected from the group consisting
`25 of diclofenac, bromfenac, flurbiprofen, naproxen, ketorolac,
`suprofen, ibuprofen, and tolmetin and their salts and esters.
`6. The composition of claim 5 wherein the non-steroidal
`anti-inflammatory drug is diclofenac.
`7. A topical ophthalmic composition comprising 0.01 to
`30 2.5 wt. % non-steroidal anti-inflammatory drug, 0.0001 to
`30 wt. % tocophersolan, 0.00001 to 0.02 wt. % benzalko(cid:173)
`nium chloride or mixtures of at least two homologues of
`benzalkonium chloride, and 0.001 to 5.0 wt. % caffeine.
`8. The composition of claim 7 wherein the non-steroidal
`35 anti-inflammatory drug is selected from the group consisting
`of diclofenac, bromfenac, flurbiprofen, naproxen, ketorolac,
`suprofen, ibuprofen, and tolmetin and their salts and esters.
`9. The composition of claim 8 wherein the non-steroidal
`anti-inflammatory drug is diclofenac.
`10. A method for treating inflammation of the eye, which
`comprises, applying the composition of claim 7 to the
`inflammed eye.
`11. The method of claim 10 wherein the non-steroidal
`anti-inflammatory drug is diclofenac.
`12. A method for treating an eye with an acidic drug,
`which comprises, applying the composition of claim 1 to the
`eye.
`
`10
`
`20
`
`EXAMPLE 4
`
`A simplified preservative efficacy screen based on the
`United States Pharmacopeia (USP) XXII, 1990 Antimicro(cid:173)
`bial Preservative Effectiveness standards was performed
`against Staphylococcus aureus for the compositions shown
`in the following table. The screen entailed challenging the
`formulations with the gram-positive bacteria, S. aureus, and
`sampling at 7 and 14 days. The initial preservative efficacy
`test for the formulations had indicated that the formulations
`had poor preservation only against S. aureus, whereas the
`formulations exhibited appropriate preservative efficacy
`according to USP against the other organisms such as
`gram-negative
`(Pseudomonas aeruginosa)
`and
`fungi
`(Aspergillus niger) at 7 and 14 days.
`
`Formulation
`Ingredient
`
`Caffeine
`Diclofenac Sodium
`Vitamin E TPGS
`Tromethamine
`Boric acid
`Disodium EDTA
`BAC
`Mannitol
`HPMC
`NaOH or HO, qs to
`adjust pH to
`Purified Water, qs to
`
`A
`
`0.0
`0.1
`1.5
`1.2
`0.6
`0.1
`0.01
`4.4
`0.1
`7.4
`
`B
`
`0.2
`0.!
`1.5
`1.2
`0.6
`0.1
`0.01
`4.4
`0.1
`7.4
`
`c
`
`0.75
`0.1
`1.5
`1.2
`0.6
`0.1
`0.01
`3.8
`0.1
`7.4
`
`100
`
`100
`
`100
`
`D
`
`1.25
`0.1
`1.5
`1.2
`0.6
`0.!
`0.01
`3.2
`0.!
`7.4
`
`100
`
`40
`
`According to the USP preservative efficacy standards for
`S. aureus, a formulation has to exhibit a minimum of 3.0 log
`reduction on day 14 and no increase in count between 14 to
`28 days. FIG. 1 shows the results for the S. aureus screen for
`the formulations in the above table. The formulations had 45
`similar compositions except for the varying concentrations
`of caffeine from 0.0% to 1.25%. As shown in FIG. 1, the
`higher the caffeine concentration in the formulation the
`higher was the S. aureus log reduction value. The figure also
`
`* * * * *
`
`Innopharma EX1006, Page 5
`
`