WO2009097123A1

WO2009097123A1 - Device for in-situ generation of povidone-iodine compositions

Info

Publication number: WO2009097123A1
Application number: PCT/US2009/000563
Authority: WO
Inventors: Joseph A. Capriotti; Bo Liang; C. Michael Samson; Jason Stein; Michael Weiser
Original assignee: Foresight Biotherapeutics, Inc.
Priority date: 2008-01-28
Filing date: 2009-01-28
Publication date: 2009-08-06

Abstract

Disclosed herein is a device for the in-situ preparation of a pharmaceutical composition comprising povidone-iodine and a steroid or non-steroidal anti- inflammatory, each component present within a range of concentrations useful in the treatment of acute viral infections of the eyelids and ocular surfaces of humans and other mammals.

Description

TITLE OF INVENTION Device For In-Situ Generation Of Povidone-Iodine Compositions

BACKGROUND Infectious conjunctivitis is an ophthalmic disorder characterized by inflammation of the conjunctiva secondary to invasion of a microbe. Microbes capable of causing conjunctivitis in humans include bacteria (including Mycobacteria sp), viruses, fungi, or amoebae. Current treatment for bacterial conjunctivitis consists of antibiotic drops. Because antibiotic drops are ineffective against viral conjunctivitis, treatment of such infections consists only of relieving symptoms. Treatments for fungi and amoeba conjunctivitis consist of a small selection of medications which lacks anti-bacterial or anti-viral activity and which, in addition, is toxic to the ocular surface.

Topical corticosteroids are routinely used to control ocular inflammation. Their mechanism of action involves the inhibition of the immune response and the subsequent tissue destruction that severe inflammation may cause. Corticosteroid has the undesirable side effect of limiting the body's intrinsic ability to fight infection. In fact, inopportune steroids usage can worsen the course of an infection secondary to mycobacteria, virus, or fungus. Thus, the use of a combined antimicrobial-steroid medication in ocular infections is recommended only under careful observation of a trained ophthalmologist because of these significant risks.

Though apparently unrelated to ophthalmic infections, ear infection (particularly in children) is one of the many diseases that have become hard to treat with traditional antibiotic drugs because of antibiotic resistant bacteria and antibiotic-resistant microorganisms. Most cases of otitis media (OM), for example, are caused by one of several major pathogens, Streptococcus pneumonia, Haemophilus influenza, Moraxella catarrhalia, Staphylococcus aureus, Staphylococcus epidermidis, or Pseudomonas aeruginosa. There is thus an urgent need to develop new, non-antibiotic approaches to prevent and manage these diseases.

Otic infections are often accompanied by inflammation and pain in the infected otic tissues. There is a need for otic pharmaceutical compositions that combine broad anti-infective activity with the anti-inflammatory activity. Recently, in United States Patent Application Publication 2007/0219170 of

Samson et al., it was shown that combinations of iodine and steroid can be prepared, and are useful to treat ophthalmic disorders such as infectious conjunctivitis of viral origin.

What is needed is a way to maximize the potency of such formulations, and to extend the shelf-life and stability of such formulations.

SUMMARY OF THE INVENTION

In one embodiment, the invention includes a device for in-situ preparation of a PVP-I/dexamethasone composition comprising a sealed outer compartment and a sealed and frangible inner compartment disposed within the outer, sealed compartment. A first component comprising PVP-I is contained within the inner compartment; and a second component comprising dexamethasone is contained within the outer compartment

In an aspect, the outer compartment comprises a resealable opening. In another aspect, the resealable opening comprises a filter. In an aspect, the outer compartment comprises an opening covered by a frangible cap. In an aspect, the inner compartment is made of glass.

In an aspect, the first component is in liquid form. In another aspect, the first component is in powder form.

In one embodiment, the invention includes a device for in-situ preparation of a PVP-I/dexamethasone composition comprising a sealed outer compartment, a sealed and frangible inner compartment disposed within the outer, sealed compartment. A first component comprising dexamethasone is contained within the inner compartment; and a second component comprising PVP-I is contained within the outer compartment.

The invention includes a device, wherein the PVP-I concentration is 0.1%-2.0% (weight/weight or weight/volume), and wherein the concentration of PVP-I is measured with respect to a final composition consisting of the first and second compositions. In another aspect, the PVP-I concentration is selected from the group consisting of 0.10%, 0.20%, 0.30%, 0.35%, 0.36%, 0.40%, 0.45%, 0.48%, 0.50%, 0.55%, 0.60% or 0.65% (weight/ weight or weight/volume), wherein the concentration of PVP-I is measured with respect to a final composition consisting of the first and second compositions.. In one embodiment, the invention includes a device comprising an indicator disposed on the outer compartment. In an aspect, the indicator is disposed at the opening of the outer compartment.

In an aspect, the device comprises an applicator. In an aspect, the applicator comprises an indicator of the physical mixing of the first and second components. In another aspect, the applicator comprises an indicator of a first use of the composition resulting from the mixture of the first and second components.

In an aspect, a composition is a pharmaceutical composition. In another aspect, a composition is an ophthalmic composition. In another aspect, a composition is an otic composition.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates a device for in-situ generation of PVP-I compositions.

DETAILED DESCRIPTION OF THE IN VENTION

In certain embodiment, the invention includes a device for in-situ preparation of a composition, the device comprising an outer compartment and one or more sealed inner compartments disposed within the outer compartment.

In an aspect, the outer compartment is also sealed. A sealed outer compartment may have a portion that can be opened or is otherwise accessible in order to access the composition inside, as set forth in detail elsewhere herein. In another aspect, the outer compartment comprises a resealable or reclosable opening, with a sealing portion disposed thereon, as disclosed elsewhere herein.

In an aspect, the inner compartment is sealed. In another embodiment, the inner compartment is comprised of a frangible material. In another aspect, the inner compartment is comprised of a material that allows the opening of the inner compartment to liberate the contents therein without resulting in the fracturing or destruction of the inner compartment. In one embodiment, at least a portion of the contents of the inner compartment are released when the inner compartment is opened. In one embodiment, the inner compartment can release at least 90%, by weight or volume, of its contents when the inner compartment is opened. In yet another embodiment, the inner compartment can release at least 95%, by weight or volume, of its contents when the inner compartment is opened.

Accordingly, in an aspect, the device comprises two or more compartments which separate two or more components of a final composition, until such time when the user desires to mix the multiple components to thereby form the final composition. In an embodiment, one or both compartments are vials.

The device generates compositions in situ, compositions such as, but not limited to, a solution, a suspension, a mixture, or otherwise a combination of the components of the outer compartment and at least one inner compartment. In an embodiment, an in-situ generated composition comprises povidone-iodine

(PVP-I) and at least one additional component, by first separating PVP-I and the other components until mixing is desired. By allowing the user the choice of when to initiate the mixing process, the device enables the preparation of, by way of a non-limiting example, a PVP-I + steroid (or PVP-I plus non-steroidal anti-inflammatory) in-situ composition having optimal stability, potency and/or shelf-life. The subsequent use of the mixed composition will be understood by the skilled artisan, when considering the components of the in-situ generated composition.

For example, a PVP-I + dexamethasone composition may be used for treatment of active ophthalmic infections from bacterial, mycobacterial, viral, fungal, or amoebal causes, as well as treatment to prevent such infections where appropriate, provides the clinician with the knowledge of the exact vintage of the mixed preparation, allowing the clinician to properly evaluate the dosage and predict the expected response to the administration of the composition to a subject.

In an aspect of the invention, as illustrated in Figure 1, an exemplary device comprises an outer vial 10 having a cap 11 covering a dispensing tip 12. As set forth in detail herein, a cap 1 1 may be integral with the outer vial 10 such that the entire outer vial

10 is sealed until such time when a cap 1 1 (e.g., a frangible cap) is removed to unseal the outer vial. In another aspect, the cap 1 1 is removably and resealably attached to the outer vial 10 in such a way as to cover the dispensing tip 12. The device may comprise a liquid solution 14 in which a breakable, sealed inner vial 13 is disposed. In an embodiment, an outer vial 10 comprises two or more frangible inner vials 13. When there are multiple inner vials 13, multiple inner vials may contain the same component, or each vial may contain a different component.

An inner compartment may be made of any material that will allow the inner compartment to separate the inner contents from the environment outside the inner compartment until such time when the user desires to liberate the contents of the inner compartment. Suitable materials include, but are not limited to, glass, plastic, and metal, as well as various polymers and naturally-derived substances.

An outer compartment may be made of any material that will allow the containment of a solution or powder therein, along with at least one inner compartment. In an aspect, the outer compartment is flexible or malleable such that the outer compartment can be physically manipulated in order to break, open or otherwise access the inner compartment in order to liberate the contents of the inner compartment and allow mixing of the multiple components to form a final composition.

In an aspect, the inner and/or outer compartments are made of a material that will not react with the contents of the compartment. In an embodiment, a compartment is high-density polyethylene (HDPE). In another embodiment, a compartment is glass. In another aspect, the inner compartment is made of a material such that the contents of the inner compartment can be liberated without resulting in the fracturing, breakage, or destruction of the inner compartment. By way of a non-limiting example, the inner compartment is made of a plastic that can be opened by application of physical pressure, wherein the opening of the inner compartment does not result in the breakage or destruction of the plastic material comprising the inner compartment.

In an embodiment, a device comprises an outer compartment that is not malleable or flexible. In another embodiment, a device comprises an inner compartment that may be broken by vigorous shaking of the outer compartment.

A device may have a sealed outer compartment. An outer compartment may be accessed by any means that will not result in the indiscriminate liberation of the contents therein. In another aspect, a sealed outer compartment may comprise a portion that is scored and/or perforated in a way such that the outer compartment remains sealed but can readily be opened or unsealed by removing the scored and/or perforated portion of the outer compartment. In another aspect, a device of the invention may have a reversibly covered or resealable opening from which to dispense the final composition. In an embodiment, a device has a resealable cap disposed on the outer compartment. In another embodiment, a device has a cap that is not resealable after removal from the outer compartment. In an aspect, a non-resealable, removable cap is integrally part of the outer compartment of the device. In an embodiment, a non-resealable cap is frangible. In another embodiment, a non-resealable cap can be opened or otherwise removed from the outer compartment without resulting in the fracturing, breakage, or destruction of the cap.

In an embodiment, a device comprises an applicator (e.g., a liquid drop dispenser) disposed on the outer compartment.

In an embodiment, an opening on the device, such as on the outer compartment, is designed to prevent the passage of any materials resulting from the breakage of an inner compartment, as well as to prevent the passage of the inner compartment itself. In an embodiment, an opening comprises a filter to prevent the passage of such materials. A filter may be comprised of any material that is compatible with the composition comprised in the outer compartment, as well as compatible with the final mixed composition. Such filter materials include, but are not limited to, a fabric-based filter, a plastic filter, a metal filter, and a gel-based filter.

In an aspect of the invention, the device further comprises an indicator of the mixing of the components contained in two or more compartments (e.g., vials). In an embodiment, the outer compartment comprises an indicator. An indicator may be disposed on the inner surface of the outer compartment, on the outer surface of the outer compartment, or integrated within an opening or applicator that is part of the outer compartment of the device. The indicator will preferably not detect the component contained within the outer compartment, but will detect the mixed composition that is prepared upon liberation of the component from the inner vial. The indicator may therefore detect the mixed composition, the component of the inner vial, or both.

In another aspect, the device comprises an indicator of the first use of the mixed composition contained therein. In an embodiment, the device comprises and indicator integrated within an applicator. By way of a non-limiting example, the applicator may comprise a material that changes color when contacted with iodine (e.g., such as from contact with PVP-I), thus providing an indication that the components contained within have been mixed to form a final composition, and the resultant composition used at least once.

In an aspect, disclosed herein is a device for generating in-situ composition comprising PVP-I and a steroid anti-inflammatory agent. Also disclosed herein is a device for generating in-situ composition comprising PVP-I and a non-steroidal antiinflammatory agent. In an aspect, the device provides a way to increase, enhance and/or maximize the shelf-life and stability of a composition comprising PVP-I and a steroid or non-steroidal anti-inflammatory. In another aspect, the device provides a way to increase, enhance and/or maximize the potency of a composition comprising PVP-I and a steroid or non-steroidal anti-inflammatory. Compositions include, but are not limited to, pharmaceutical compositions, ophthalmic compositions, and otic compositions.

The affinity of free iodine for reaction with —OH, --SH and -NH functional groups is well described in the literature and forms the basis for the anti-microbial activity of iodine-containing solutions (Rackur H. J. Hosp. Infect., 1985; 6: 13-23, and references therein). Dexamethasone (9-Fluoro-l lβα, 17, 21-tri hydroxy- 16α- methylpregna-1, 4-diene-3, 20-dione) contains three such moieties (—OH) at the 1 1, 17 and 21 positions and two double bonds. One of skill in the art would conclude that these hydroxyl groups would be prone to covalent substitution reactions by the free iodine generated in the solution equilibrium reaction described above for PVP-I₂, and the double bonds would be prone to electrophilic iodination reactions.

Accordingly, in one embodiment, the present invention provides a device, such as packaging, and methods of packaging formulations of PVP-I and a steroid, or PVP-I and an anti-inflammatory, to solve problems of long-term stability, and efficacy. As set forth in U.S. Patent Application Publication No. 2007/0219170 (U.S. Patent Application No. 1 1/636,293, the entirety of which is hereby incorporated by reference herein), various PVP-I solutions, such as a 1% PVP-I solution, are effective for treatment of infection or prophylaxis of infections when combined with dexamethasone. The literature has previously indicated that while 1% PVP-I is desirable, the side effects of ocular administration, for example, such as pain and irritation, precluded its use. As set forth in U.S. Patent Application No. 11/636,293, various solutions of PVP- I and dexamethasone remain stable for many months, when prepared according to the compositions disclosed therein. Based on the stability data disclosed, such compositions may be stable for years. The reaction of dexamethasone and PVP-I does not proceed to any appreciable extent at room temperature, in light or dark, or over time. After 8 weeks, the available iodine in the combination (0.3% PVP-I starting concentration) decreased by 20%.

It was also shown that PVP-I reacted with Ketorolac (a non-steroidal anti- inflammatory) rapidly and that the Ketorolac was completely consumed and the available iodine in the PVP-I complex was reduced significantly depending on the ratio between Ketorolac and PVP-I. The combination of PVP-I and dexamethasone sodium phosphate also proved to be less stable, but not overly reactive (some dissociation of PVP-I complex to an unknown polymeric complex was observed in the UV spectra and the iodine concentration was reduced approximately 5% after 12 weeks. It was further observed that PVP-I reacts immediately with proparacaine and releases free iodine rapidly.

Previously, for a dexamethasone/PVP-I composition, the available iodine of a 0.625% PVP-I solution was determined to be 91% at 25° C and 98% at 4° C after 5 weeks storage, respectively. (Iryo Yakugaku 2003, 29(1), 62-65). Dexamethasone/PVP-I compositions set forth herein showed demonstrated a stabilized dilute PVP-I solution. After 8 weeks at room temperature, the available iodine in solutions with 0.5% and 1% PVP-I were over 99%.

Nonetheless, therapeutic PVP-I compositions (e.g., PVP-I + dexamethasone) sometimes require storage for extended periods of time and/or under severe conditions (e.g., elevated temperatures, in a lighted environment, etc.). The preparation of such PVP-I-containing compositions will begin the process of the degradation of the composition over time. Added stability for compositions set forth herein, as well as compositions set forth in U.S. Patent Application No. 1 1/636,293, and for compositions known in the art (e.g., PVP-I and ketorlac, PVP-I and other antiinflammatories), is provided by a device of the present invention. A device is provided to generate compositions in-situ, the compositions comprising PVP-I in a range from 0.01% to 10% (weight/weight or weight/volume) in suitable drug delivery vehicles with or without a steroid or non-steroidal antiinflammatory agents. In an embodiment, PVP-I is in the range of 0.1-2.0%, in another embodiment, from 0.2-2.0%, in another embodiment, from 0.3-1.0%, in another embodiment, from 0.4-1.0%, in another embodiment, from 0.5-1.0%, and in another embodiment, from 0.6-0.8%. In an embodiment, the PVP-I concentration is 0.10%, 0.20%, 0.30%, 0.35%, 0.36%, 0.40%, 0.45%, 0.48%, 0.50%, 0.55%, 0.60% or 0.65%. The compositions are useful in the treatment of active infections from bacterial, mycobacterial, viral, fungal, or amoeba causes, as well as treatment to prevent such infections in appropriate clinical settings. In an embodiment, a device of the invention surprisingly provides a PVP-I + steroid composition that is unexpectedly non-reactive and stable. In an aspect, the steroid is dexamethasone. In an aspect of the invention, a first component comprising PVP-I is contained within the inner compartment; and a second component comprising dexamethasone is contained within the outer compartment. In an embodiment, PVP-I in powder form is stored in a sealed glass vial, which is inserted into a plastic vial containing a suitable drug delivery vehicle, such as with a steroid or non-steroidal anti-inflammatory agent, and optionally, one or more additional components of a pharmaceutical or ophthalmic composition. By application of physical force to the outer (plastic) vial, inner (glass) vial can be cracked. Depending upon the amount of PVP-I in the inner vial and the volume of aqueous drug delivery vehicle in the outer vial, a 0.01% - 10% (weight/weight or weight/volume) composition of povidone iodine can be generated in-situ for a single use or multiple use in the treatment of active infections from bacterial, mycobacterial, viral, fungal, or amoeba causes, as well as treatment to prevent such infections in appropriate clinical settings. Compositions include pharmaceutical compositions, ophthalmic compositions, and otic compositions, among others.

In another embodiment, PVP-I in liquid form is stored in a sealed glass vial, which is inserted into a plastic vial containing a suitable drug delivery vehicle, such as with a steroid or non-steroidal anti-inflammatory agent, and optionally, one or more additional components of a pharmaceutical or ophthalmic composition. Based on the disclosure set forth herein, the skilled artisan will know how to prepare and manipulate PVP-I components and steroid/non-steroidal anti-inflammatory components in order to obtain a final solution having a desired concentration of PVP-I, steroid, or any other component of the resulting composition.

In an embodiment, a suitable drug delivery vehicle is stored in a sealed glass vial, comprising a steroid or non-steroidal anti-inflammatory agent, and optionally, one or more additional components of a pharmaceutical or ophthalmic composition, wherein the sealed glass vial is inserted into a plastic vial containing PVP-I in powder form. In another embodiment, a suitable drug delivery vehicle is stored in a sealed glass vial, comprising a steroid or non-steroidal anti-inflammatory agent, and optionally, one or more additional components of a pharmaceutical or ophthalmic composition, wherein the sealed glass vial is inserted into a plastic vial containing PVP-I in liquid form.

A device of the present invention may comprise, in one or more of the compartments, one or more of an excipient, an antimicrobial agent, a preservative, a cosolvent, a surfactant, a viscosity agent, and/or a bioadhesive agent, as set forth in detail elsewhere herein. Such additional agents may be included in the drug delivery vehicle component comprising the steroid or non-steroidal anti-inflammatory, in the PVP-I component, or in both components. In an aspect, an agent in the PVP-I component is in liquid form. In another aspect, an agent in the PVP-I component is in dry or powder form. It will be understood that the physical form of an agent combined with the PVP-I component may be selected based on the physical form of the PVP-I component.

A composition may comprise one or more lubricants including, but not limited to, propylene glycol, glycerin, polyethylene glycol, dextran, blended polyvinyl alcohols, polyvinyl alcohol, polyethylene glycol, light mineral oil, hydroxypropyl methylcellulose, hypromellose, carbopol, carbomer 940 (polyacrylic acid), polyvinyl pyrrolidone, white petrolatum, soy lecithin, and sodium carboxyl methylcellulose, as well as other agents known to those skilled in the art, or any combination thereof. Typically, such lubricants are employed at a level of from 0.1% to 2% by weight. In an embodiment, the lubricants are 1.0% Propylene glycol, 0.3% glycerin, 2.7% blended polyvinyl alcohols, 1% polyvinyl alcohol, 1% polyethylene glycol, light mineral oil, 0.3% hydroxypropyl methylcellulose, 1.0% soy lecithin, 0.25% or 0.5% sodium carboxyl methylcellulose. In another embodiment, the total weight of a PVP-I, artificial-tear based lubricant is between 0.1% and 4.5%.

Suitable antiinflammatories include, but are not limited to, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen or rofecoxib.

Non-limiting examples of suitable steroids include: Dexamethasone alcohol, dexamethasone sodium phosphate, fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, and lodoxamide tromethamine. A steroid is used at a concentration of 0.01%-2.0% by weight of the final composition.

Suitable antibiotic /antimicrobial agents include, but are not limited to, fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, gatifloxacin, and the like); Aminoglycosides (tobramycin, gentamicin, neomycin, and the like); Polymyxin B Combinations (polymyxin B/trimethoprim, Polysporin polymyxin B/bacitracin Neosporin polymyxin B/neomycin/ gramicidin, and the like) and other antibiotics (azithromycin, ilotycin, erythromycin, bacitracin, and the like).

Anti-allergic components include, but are not limited to, epinastine, emedastine difumarate azelastine hydrochloride, olopatadine hydrochloride, olopatadine, ketotifen fumarate, pemirolast potassium, nedocromil, lodoxamide, cromolyn and cromolyn salts.

Preservative agents include benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, EDTA, sorbic acid, Onamer M, other agents known to those skilled in the art, or a combination thereof. Typically such preservatives are employed at a level of from 0.001% to 1.0% by weight of final composition.

The compositions of the invention may contain an optional co-solvent. The solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition. Such cosolvents/surfactants include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-68, F-84 and P- 103), cyclodextrin, tyloxapol, other agents known to those skilled in the art, or a combination thereof. Typically such co-solvents are employed at a level of from 0.01% to 2% by weight of the final composition.

Furthermore, the compositions may comprise an effective amount of a chemical agent to provide a cooling sensation to relieve mild ocular irritation, enhance ocular comfort, provide a refreshing effect, and improved sensation, when the PVP-I solution is applied to the eye. Such an agent encompasses various chemicals and chemical classes, including, but not limited to, cooling agents such as menthol, menthol derivatives including methone glycerin acetyl and menthyl esters, carboxamides, menthane glycerol ketals, alkyl substituted ureas, sulfonamides, terpene analogs, furanones, and phosphine oxides; or camphor, and borneol.

In any of the compositions of this disclosure for topical administration, such as topical administration to the eye, the mixtures are preferably formulated as aqueous solutions at a pH of 3.5 to 6.5. Preferably, the pH is adjusted to between 4 and 5. This pH range may be achieved by the inclusion of suitable acids/bases in the composition. The compositions of the invention may contain an optional viscosity agent - that is, an agent that can increase viscosity. Viscosity increased above that of simple aqueous solutions may be desirable to increase ocular absorption of the active compound, to decrease variability in dispensing the formulation, to decrease physical separation of components of a suspension or emulsion of the formulation and/or to otherwise improve the ophthalmic formulation. Such viscosity builder agents include as examples polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, other agents known to those skilled in the art, or a combination thereof. Such agents are typically employed at a level of from 0.01% to 2% by weight of the final composition. Bioadhesive agents can be used in the compositions to increase the retention time of the drug gradient over the biological substrates. The bioadhesive agents may include but not limited to: polyvinylpyrrolidone (PVP), xanthan gum, locust bean gum, acacia gum, hydroxypropyl methylcellulose (HPMC), sodium alginate, pectin, gelatin, carbomer, polyvinylalcohol, gellan gum, tragacanth, acacia, and sodium carboxymethyl cellulose. In another embodiment, the invention provides topical pharmaceutical compositions for use in treating and relieving the symptoms of ear, including, but not limited to, otitis media and otitis externa (both acute and chronic). The compositions comprise PVP-I in an amount effective to reduce the growth of infection causing microbes and a pharmaceutically acceptable carrier therefor. PVP-I is present in an otic composition in the range of 0.1%- 10%. The otic compositions may additionally comprise a steroid, such as, but not limited to, dexamethasone.

The invention has been described herein by reference to certain preferred embodiments. However, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto. All patents, patent applications, and references cited anywhere is hereby incorporated by reference in their entirety.

Claims

CLAIMS:

1. A device for in-situ preparation of a PVP-I/anti-inflammatory composition having a PVP-I concentration of 0.1%- 10.0% (weight/weight or weight/volume), the device comprising, an outer compartment; a sealed inner compartment disposed within the outer compartment; a first component comprising PVP-I contained within the inner compartment; and a second component comprising an anti-inflammatory contained within the outer compartment; wherein the concentration of PVP-I is measured with respect to a final composition comprising a mixture including (i) at least a portion of the first component; and, (ii) the second component.

2. The device of claim 1, wherein the anti-inflammatory is a steroid.

3. The device of claim 2, wherein the steroid is dexamethasone.

4. The device of claim 1, wherein the inner compartment is comprised of a frangible material.

5. The device of claim 1, wherein the inner compartment is comprised of a material that is not frangible.

6. The device of claim 1, wherein the outer compartment comprises a resealable opening.

7. The device of claim 6, wherein the resealable opening comprises a filter.

8. The device of claim 1, wherein the outer compartment comprises an opening covered by a removable and resealable cap.

9. The device of claim 1, wherein the inner compartment is made of glass.

10. The device of claim 1, wherein the first component is in liquid form.

1 1. The device of claim 1, wherein the first component is in powder form.

12. A device for in-situ preparation of a PVP-I/dexamethasone composition having a PVP-I concentration of 0.1%- 10.0% (weight/weight or weight/volume), the device comprising, an outer compartment, a sealed inner compartment disposed within the outer compartment, a first component comprising dexamethasone contained within the inner compartment; and a second component comprising PVP-I contained within the outer compartment, wherein the concentration of PVP-I is measured with respect to a final composition consisting of the first and second components.

13. A device of claim 1 or claim 12, wherein the PVP-I concentration is 0.1%- 2.0% (weight/weight or weight/volume), wherein the concentration of PVP-I is measured with respect to a final composition consisting of the first and second compositions.

14. A device of claim 1 or claim 12, wherein the PVP-I concentration is selected from the group consisting of 0.10%, 0.20%, 0.30%, 0.35%, 0.36%, 0.40%, 0.45%, 0.48%, 0.50%, 0.55%, 0.60% or 0.65% (weight/weight or weight/volume), wherein the concentration of PVP-I is measured with respect to a final composition consisting of the first and second compositions.

15. A device of claim 1 , further comprising an indicator disposed on the outer compartment.

16. The device of claim 15, wherein the indicator is disposed at the opening of the outer compartment.

17. The device of claim 15, wherein the device comprises an applicator.

18. The device of claim 17, wherein the applicator comprises an indicator of the physical mixing of the first and second components.

19. The device of claim 17, wherein the applicator comprises an indicator of a first use of the composition resulting from the mixture of the first and second components.

20. The device of claim 1, wherein the composition is selected from the group consisting of a pharmaceutical composition, an ophthalmic composition, and an otic composition.