PACKAGING MATERIALS FOR FORMULATIONS CONTAINING 2-PYRROLIDONE DERIVATIVES
Packaging materials substantially lacking adsorptive and absorptive properties for 2-pyrrolidone derivatives are provided. The packaged products described herein provide for retention of the 2-pyrrolidone derivative within the formulation thereby maintaining the integrity of such formulations. Packaged products are useful for ophthalmic, otic, and nasal applications. Ophthalmic application includes therapeutic uses and contact lens care uses.
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This application claims priority to U.S. Provisional Application, U.S. Ser. No. 60/854,320 filed Oct. 24, 2006.
FIELD OF THE INVENTIONThe present invention relates to the field of packaging materials that maintain the integrity of formulations comprising 2-pyrrolidone derivative compounds.
BACKGROUND OF THE INVENTIONTraditional glass containers and vials are generally considered inert to aqueous-based pharmaceutical formulations. The chemical inertness of glass renders it a desirable material for containing and distributing such formulations; however, glass is breakable, difficult to handle, and inconvenient for patient use. Molded polymer containers are frequently an acceptable substitute for packaging liquid formulations for distribution and use, particularly containers made from polymers such as low or high density polyethylene (LDPE or HDPE), polypropylene (PP), or polyethylene terephthalate (PETE).
Any inappropriate chemical or physical interaction between a polymeric material of a container and ingredients of a formulation contained therein may drastically affect the concentration of an ingredient and the efficacy of that ingredient within the formulation. Components of the formulation may absorb into the polymer material of a container over time or may adsorb to the interior surface of the container. Further, leaching or “blooming” of impurities or additives from the container polymeric material into the formulation may adversely affect the formulation and its subsequent use.
International PCT application US2004/039547 published as WO 2005/053757, Jun. 16, 2005, to Bausch & Lomb, Inc. reportedly provides poly(ethylene terephthalate) as the container material for contact lens care solutions based upon a desire to minimize migration of resin additives of high density polyethylene (HDPE) bottles to the surfaces of the bottle and potentially interacting with lens care solution ingredients, an effect that is termed “blooming” and which is reported to be exacerbated by presence of surfactants. The WO 2005/053757 published application at page 5 particularly cites quaternary ammonium salts that do not include significant hydrophobic portions, i.e., alkyl chains having more than six carbon atoms, as having enhanced properties when packaged in PET containers. Further, at page 9, nonionic surfactants having polymeric components with (—O—R—) repeat units where R has 2-6 carbon atoms are reported as having enhanced properties when packaged in PET containers. A problem not addressed by the Bausch & Lomb Inc. published application is that of adsorption or absorption of formulation ingredients to the bottle material, thereby reducing the intended efficacy of the formulation.
SUMMARY OF THE INVENTIONFiled concurrently herewith are patent applications commonly assigned to Alcon Manufacturing, Ltd. where 2-pyrrolidone derivative-containing formulations are provided as preservation agents (“2-Pyrrolidone Derivatives For Preservation Of Ophthalmic, Otic And Nasal Compositions” to Bhagwati Kabra, Atty Docket No. 45263-P034V1), as anti-bacterial agents for treatment of infections (“2-Pyrrolidone Derivatives For Treatment Of Ophthalmic, Otic And Nasal Infections” to Bhagwati Kabra, et al., Atty Docket No. 45263-P028V1), and as agents in combination formulations for ionic-type contact lens care (“Compositions Comprising A Quaternary Ammonium Compound And A 2-Pyrrolidone Derivative For Ionic-Type Contact Lens Care” to Masood A. Chowhan; Atty Docket No. 45263-P033V1). Said patent applications are incorporated by reference herein. In the process of packaging such formulations, the present inventors unexpectedly discovered that certain types of common packaging material adsorb or absorb the 2-pyrrolidone derivative, thus removing it from the formulation and rendering the formulation ineffective for its intended purpose.
In particular, the present inventors have discovered that low density polyethylene (LDPE), a common and generally desirable packaging material due to its flexibility, is ineffective for packaging 2-pyrrolidone derivative-containing formulations. Further, polypropylene (PP) packaging material was also found to be ineffective.
Embodiments of the present invention provide a packaged product comprising a formulation for ophthalmic, otic, or nasal use, the formulation comprising 5-(R1)-N-(R2)-2-pyrrolidone and a container comprising a material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone, where the formulation is packaged in the container. For the 5-(R1)-N-(R2)-2-pyrrolidone, R1 is H, methyl or ethyl; and R2 is C6-C12 straight-chain, branched, substituted or unsubstituted alkyl, oxyalkyl, amidoalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, or alkylaryl.
In an embodiment of the invention, the material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone is a polyethylene terephthalate (PETE). In another embodiment of the invention, the material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone is a fluoropolymer. In yet another embodiment of the invention, the material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone is a polystyrene (PS).
The container of the packaged product may consist essentially of the material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone. In a further embodiment of the invention, the container may have an inner lining where material of the inner lining substantially lacks absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone; and the container other than the inner lining is made from a polyethylene or a polypropylene, which materials are demonstrated herein to have such adsorptive and absorptive properties. In one embodiment of the invention, the material of the inner lining is a polyethylene terephthalate. In another embodiment of the invention, the material of the inner lining is a fluoropolymer. In yet another embodiment of the invention, the material of the inner lining is a polystyrene.
In a further embodiment of the packaged product, the product may have a coating that provides a layer that is gas impermeable. Such a coating is generally present as a middle layer between an outer container and an inner lining such as for a laminate. A gas impermeable material may be a metallic film, for example, an aluminum film.
In a further embodiment of the invention, the container of the packaged product may include several parts or pieces that are joined together either by physical means or bonding and may have separate functions. Such parts or pieces of the container may include but are not limited to a bottle or primary container for the formulation, a plug or tip for dispensing the formulation, and a closure or cap. Any or all of these parts or pieces of the container, or any portion of them, may be comprised of a material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone.
A method of minimizing absorption and adsorption of a 5-(R1)-N-(R2)-2-pyrrolidone compound to a container material therefor is an embodiment of the invention. The method comprises packaging a 5-(R1)-N-(R2)-2-pyrrolidone-containing formulation in a container made from a polyethylene terephthalate, a fluoropolymer, or a polystyrene; or packaging a 5-(R1)-N-(R2)-2-pyrrolidone-containing formulation in a container having an inner lining; the inner lining made from a material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone; and the container other than the inner lining is made from a polypropylene or a polyethylene. For the 5-(R1)-N-(R2)-2-pyrrolidone-containing formulation, R1 is H, methyl or ethyl, and R2 is C6-C12 straight-chain, branched, substituted or unsubstituted alkyl, oxyalkyl, amidoalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, or alkylaryl.
Use of any of the embodiments as set forth herein in the manufacture of a packaged product comprising a formulation comprising 5-(R1)-N-(R2)-2-pyrrolidone and a container comprising a material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone, where the formulation is packaged in the container is also an embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTIONPackaging materials substantially lacking adsorptive and absorptive properties for 2-pyrrolidone derivatives described herein provide for retention of the 2-pyrrolidone derivative within the packaged formulation so as to preserve the formulation's efficacy. Data provided by examples infra demonstrate that 2-pyrrolidone derivative compounds as set forth herein, when packaged in common packaging material such as polyethylene bottles or polypropylene bottles, become unavailable for its intended use within as short a period of time as one day. Packaging materials are provided that substantially avoid this adsorption or absorption effect and, therefore, the 2-pyrrolidone derivative is available for preservation, anti-microbial activity, or for contact lens care as intended and as described by the concurrently filed patent applications cited supra. Packaged products set forth by the invention are useful for ophthalmic, otic, and nasal applications. Ophthalmic applications include contact lens care uses.
A material substantially lacking absorptive and adsorptive properties for a 5-(R1)-N-(R2)-2-pyrrolidone. A material substantially lacking absorptive and adsorptive properties for a 5-(R1)-N-(R2)-2-pyrrolidone is determined by packaging a 5-(R1)-N-(R2)-2-pyrrolidone-containing formulation in a bottle made from a test material, removing samples from the formulation at different storage times, and testing for the presence of the 2-pyrrolidone derivative. For example, presence of N-dodecyl-2-pyrrolidone (DDP) within a test sample is determined quantitatively using HPLC analysis as described in the examples provided infra. An amount of loss of 5-(R1)-N-(R2)-2-pyrrolidone from the formulation as compared to a control formulation such that efficacy of the formulation is compromised indicates that the packaging material is inadequate for storage of formulations provided herein.
An example of a material substantially lacking absorptive and adsorptive properties for a 5-(R1)-N-(R2)-2-pyrrolidone as set forth herein is a polyethylene terephthalate. Polyethylene terephthalate (PET, PETE) is a thermoplastic polymer resin of the polyester family that may be transparent (amorphous) or opaque and white (semi-crystalline). PETE may be a homopolymer or may be copolymerized with small amounts of cyclohexane dimethanol, for example. Further, some of the 1,4-(para-) linked terephthalate units of the polymer may be replaced by isophthalic acid.
A further example of a material substantially lacking absorptive and adsorptive properties for a 5-(R1-N-(R2)-2-pyrrolidone as set forth herein is a polystyrene. Pure solid polystyrene is a colorless, hard plastic with limited flexibility but can be melted at higher temperature for molding or extrusion, then resolidified. Examples of polystyrenes include, but are not limited to, styrene acrylonitrile (SAN), acrylonitrile butadiene styrene (ABS), acetyl polystyrene, aniline polystyrene, and benzhydryl alcohol polystyrene, and expanded polystyrenes. Polystyrenes are provided for use, for example, in containers where a pump is used for delivery.
A further example of a material substantially lacking absorptive and adsorptive properties for a 5-(R1)-N-(R2)-2-pyrrolidone as set forth herein is a fluoropolymer such as polytetrafluoroethylene (PTFE), and fluorinated polymers available from E.I. du Pont de Nemours and Company (Wilmington, Del.) having brand names TEFLON® and TEFZEL® such as perfluoroalkoxy polymer (PFA), fluorinated ethylene propylene copolymer (FEP), and ethylenetetrafluoroethylene copolymer (ETFE). Other examples of fluoropolymers include but are not limited to copolymers and blended polymers of such resins as polytetrafluoroethylene-perfluoromethylvinylether, ethylene chloro-trifluoroethylene, polyvinylidene fluoride, and tetrafluoroethylene hexafluoropropylene vinylidene fluoride.
A material substantially lacking absorptive and adsorptive properties for a 5-(R1)-N-(R2)-2-pyrrolidone as set forth herein may be employed in a natural state or may contain one or more added colorants, such as titanium dioxide, a white colorant, or other colorants or pacifiers known to one of ordinary skill in the art.
Inner lining. Packaging materials that substantially lack absorptive and adsorptive properties for a 5-(R1)-N-(R2)-2-pyrrolidone as set forth herein may be a singular, uniform material having such properties or may have an inner lining having such properties. For example, a plastic material for a bottle formed from polypropylene or low density polyethylene (which materials adsorb or absorb 2-pyrrolidone derivatives as set forth herein) has an inside lining of a material substantially lacking such properties as set forth herein. Such a lining may be a thin film and may be applied by lamination or by means such as thermal, chemical or mechanical cladding, for example.
Polyethylene terephthalate, fluoropolymers, and polystyrenes are examples of materials that substantially lack absorptive and adsorptive properties for a 5-(R1)-N-(R2)-2-pyrrolidone. Such materials are gas permeable and, in some embodiments of the invention, a coating is applied to such a material to reduce the gas permeability. The coating may be a metallic film or other gas impermeable material applied to, or as a laminate with, a gas permeable material. Examples of metallic films are aluminum or tin. Such a coating is generally present as a middle layer between an outer container and an inner lining such as for a laminate.
A 2-pyrrolidone derivative: Substituents of 5-(R1)-N-(R2)-2-pyrrolidone of embodiments of the present invention are as follows: R1 is H, methyl or ethyl; and R2 is C6, C7, C8, C9, C10, C11 or C12 straight-chain, branched, substituted or unsubstituted alkyl, oxyalkyl, amidoalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, or alkylaryl. Solubility, wetting, viscosity building, emulsifying and complexing properties of alkyl pyrrolidones as well as methods of synthesis are set forth by U.S. Pat. No. 5,294,644 to Login et al., filed Feb. 12, 1991. Method of synthesis of derivatives at the 1 and 5 positions of 2-pyrrolidone are provided by Manzer in several applications and patents assigned to DuPont, for example, U.S. Pat. No. 7,030,249 filed Sep. 8, 2004; U.S. Published Application No's. 2005/0059829 filed Oct. 15, 2004, in which 5-methyl-N-methyl-2-pyrrolidone is reported useful in antimicrobial formulations for the preservation of animal silage; 2004/0192938 filed Mar. 24, 2003; and 2004/0204593 filed Mar. 24, 2003.
Alkyl groups useful as R2 include straight-chain, branched or cyclic isomers of hexane, heptane, octane, nonane, decane, undecane, or dodecane. Representative examples of substituted alkyls include alkyls substituted by one or more functional groups as described herein. Cyclic isomers include cyclohexane, for example. Alkylcycloalkyl is a cyclic alkyl having an alkyl substituent.
Alkenyl groups useful as R2 include straight-chain, branched or cyclic isomers of hexene, heptene, octene, nonene, decene, undecene, or dodecene. Representative examples of substituted alkenyls include alkenyls substituted by one or more functional groups as described herein.
Alkynyl groups useful as R2 include straight-chain, branched or cyclic isomers of hexyne, heptyne, octyne, nonyne, decyne, undecyne, or dodecyne. Representative examples of substituted alkynyls include alkynyls substituted by one or more functional groups as described herein.
Hydroxyalkyl groups include alcohols of alkyl groups as described herein. The term “hydroxyalkyl” is meant to include glycols and diols of alkyls.
Oxyalkyl groups include the alkyl groups as herein described having ether linkages. “oxyalkyl” is meant to include polyethers with one or more functional groups. Amidoalkyl groups include the alkyl groups as herein described having nitrogen linkages.
Aryl groups include molecules having an aromatic ring structure characteristic of the 6-carbon ring of benzene, for example. An example of an alkylaryl is benzyl.
Functional substituents contemplated herein include halo substituents such as chloride, bromide, fluoride and iodide; and those that are carboxy-, sulfur-, nitrogen-, oxygen- or phosphorous-containing.
In one embodiment of the formulation of the invention, R1 is H or methyl and R2 is C6-C12 straight-chain alkyl. In another embodiment of the invention, R1 is H and R2 is C8 straight-chain alkyl such that the 5-(R1)-N-(R2)-2-pyrrolidone is N-octyl-2-pyrrolidone. In yet a further embodiment of the invention, R1 is H and R2 is C12 straight-chain alkyl such that the 5-(R1)-N-(R2)-2-pyrrolidone is N-dodecyl-2-pyrrolidone.
N-alkyl-2-pyrrolidones are nonionic surfactants that exhibit pseudo cationicity at a low pH. As the carbon number of the alkyl group increases, the solubility of N-alkyl pyrrolidones in water decreases. For example, the N-octyl-2-pyrrolidone is soluble in water up to 0.124% and the N-dodecyl-2-pyrrolidone is soluble up to 0.002%, which solubility can be improved by adding a solubility enhancer such as a surfactant or a co-solvent. N-alkyl-2-pyrrolidones are commercially available from International Specialty Products (Wayne, N.J.) or BASF Corporation (Mount Olive, N.J.), for example.
The concentration of an N-alkyl-2-pyrrolidone where the alkyl is 8-12 carbons in formulations as set forth herein is from about 0.00001 w/v % to about 1.0 w/v %, from about 0.0005 w/v % to about 1.0 w/v %, or from about 0.0001 w/v % to about 0.1 w/v %, or from 0.001 w/v % to about 0.1 w/v %, or from about 0.0005 w/v % to about 0.01 w/v %, or from about 0.001 w/v % to about 0.005 w/v %, or from about 0.002 w/v % to about 0.05 w/v % or from about 0.01 w/v % to about 0.05 w/v %, or about 0.02 w/v % or about 0.03 w/v % or about 0.04 w/v %, or about 0.05 w/v %.
Ophthalmic active, otic active, or nasal active. An active included in formulations herein include an ophthalmic, otic or nasal pharmaceutical agent that can be topically applied. For example, active pharmaceuticals may include (but are not limited to): anti-glaucoma agents, such as beta-blockers; muscarinics (e.g., pilocarpine), prostaglandins, prostaglandin analogues; carbonic anhydrase inhibitors (e.g., brinzolamide, acetazolamide, methazolamide and ethoxzolamide), dopaminergic agonists and antagonists, and alpha adrenergic receptor agonists, such as dipivefrin, epinephrine, proepinephrine, norepinephrine; pronorepinephrine, para-amino clonidine (also known as apraclonidine) and brimonidine; anti-infectives; non-steroidal and steroidal anti-inflammatories; proteins; growth factors, such as EGF; serotonergic agents such as AL-37807; and anti-allergic agents, such as cromolyn sodium, emedastine and olopatadine. Compositions of embodiments of the present invention may also include combinations of active ingredients. The active component may be present at a level of about 0.0001 w/v % to 10.0 w/v %, from about 0.001 w/v % to 5.0 w/v %, from about 0.01 w/v % to 1.0 w/v %, from about 0.1 w/v % to 0.5 w/v %, 0.0001 w/v % to 4.0 w/v %, from about 0.001 w/v % to 1.0 w/v %, from about 0.001 w/v % to 0.5 w/v %, or from about 0.002 w/v % to 0.5 w/v %.
Examples of beta-blocker actives include acebutolol, atenulol, azotinolol (S-596), befunolol, betaxolol, bunalol, bupranolol, carteolol, celiprolol, diacetolol, esmalol, hepunolol, isoxaprolol, labetalol, levobetaxolol, metaprolol, metipranolol, pindolol, propranolol, salbutamol, timolol, and the like.
Examples of prostaglandin analogue actives include cloprostenol, fluprostenol, latanoprost, bimatoprost, or travoprost.
Examples of anti-infective actives include fluoroquinolones, such as ciprofloxcin, moxifloxacin, trovafloxacin, ofloxacin, gatifloxacin, and levofloxacin.
Examples of a steroidal anti-inflammatory active include glucocorticoids such as dexamethasone and derivatives thereof such as the 21-ether derivatives, loteprednol, rimexolone, prednisolone, fluorometholone, and hydrocortisone particularly for ophthalmic and otic use, and mometasone, fluticasone, beclomethasone, flunisolide, triamcinolone and budesonide particularly for nasal use.
Examples of a nonsteroidal anti-inflammatory active include agents such as prostaglandin H synthetase inhibitors (Cox I or Cox II), also referred to as cyclooxygenase type I and type II inhibitors, such as diclofenac, flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indomethacin, naproxen, ibuprofen, bromfenac, ketoprofen, meclofenamate, piroxicam, sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetome, etodolac, phenylbutazone, aspirin, oxyphenbutazone, NCX-4016, fICT-1026, NCX-284, NCX-456, tenoxicam and carprofen; cyclooxygenase type II selective inhibitors, such as NS-398, vioxx, celecoxib, P54, etodolac, L-804600 and S-33516; PAF antagonists, such as SR-27417, A-137491, ABT-299, apafant, bepafant, minopafant, E-6123, BN-50727, nupafant and modipafant; PDE IV inhibitors, such as ariflo, torbafylline, rolipram, filaminast, piclamilast, cipamfylline, CG-1088, V-11294A, CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636, BAY-19-8004, and roflumilast; inhibitors of cytokine production, such as inhibitors of the NFkB transcription factor; or other anti-inflammatory agents known to those skilled in the art. The concentration of the anti-inflammatory agent is an effective amount and is typically an amount of from about 0.01 to about 1.0 weight %.
The term “anionic active,” as used herein, means an active ingredient that has, or is capable of having a negative charge during formulation of the final product or as formulated in the final product. Diclofenac and suprofen are examples of anionic actives.
The term “cationic active,” as used herein, means an active ingredient that has, or is capable of having a positive charge during formulation of the final product or as formulated in the final product. Betaxolol, timolol, and apraclonidine are examples of cationic actives.
N-alkyl-2-pyrrolidones as provided herein are particularly useful in formulations comprising anionic actives or anionic polymers such as anionic polyelectrolytes or negatively charged ion exchange resins since common preservatives such as BAC are positively charged and tend to complex with such anionic ingredients.
Further Ingredients. Formulations as provided herein for packaging may contain further topically acceptable or pharmaceutically acceptable ingredients for ophthalmic, otic or nasal use such as a further preservative, a preservative aid, a viscosity modifying agent, a tonicity agent, a buffer, a pH adjusting agent, a drug carrier, a surfactant, a chelating agent, a sustained release agent, a comfort-enhancing agent, a solubilizing aid, an antioxidant, a stabilizing agent, or a combination thereof, for example. One of ordinary skill in the art realizes that a formulation component may contribute more than one property to the formulation.
Examples of further preservatives include those known to one of ordinary skill in the art such as monomeric or polymeric quaternary ammonium preservatives, such as benzalkonium halides (benzalkonium chloride (BAC) or benzalkonium bromide, for example) and polyquaternium-1 (also known as ONAMER M®), (Onyx Chemical Corporation)) or as POLYQUAD® (Alcon Laboratories, Inc., Fort Worth, Tex.)). In general, the amount of further preservative present in the compositions herein is from about 0.00001 w/v % to 5.0 w/v %, or from about 0.00005 w/v % to 1.0 w/v %, or from about 0.0001 w/v % to 0.5 w/v %, or from about 0.0005 w/v % to 0.1 w/v %, or from about 0.001% to 0.05%, from 0.00001 w/v % to 4.0 w/v %, from about 0.001 w/v % to 1.0 w/v %, or from about 0.01 w/v % to 0.5 w/v %, 1 w/v % to about 0.6 w/v %, or from about 0.3 w/v % to about 0.4 w/v %. In the case of benzalkonium chloride, the preservative is present in an amount from about 0.001 w/v % to 0.02 w/v %, or from about 0.005 w/v % to 0.01 w/v %. In the case of polyquaternium-1, the preservative is present in an amount of about 0.00001 w/v % or about 0.0001 w/v % to 0.005 w/v % or about 0.001 w/v %. In the case of zinc, it is present in an amount to contain zinc ions at a concentration between about 0.04 mmol/L and 4 mmol/L, or about 0.4 mmol/L.
Further examples of preservatives or preservation aids include, for example, chlorobutanol, cetylpyridinium chloride, chlorine dioxide, parabens, biguanides such as chlorhexidine, polyhexamethylene biguanide, and polyaminopropyl biguanide, boric acid, benzoic acid, salicylic acid, sorbic acid, lactic acid, acetic acid, and topically acceptable salts thereof, borate/polyol complexes, or a combination thereof, and chelating agents such as ethylenediamine tetraacetic acid (EDTA) and salts thereof. A further preservation aid is lauroyl sarcosine available from W. R. Grace (Lexington, Mass.) as HAMPOSYL®L.
The use of viscosity enhancing agents to provide the formulations herein with viscosities greater than the viscosity of simple aqueous solutions may be desirable to increase ocular absorption of the active compounds by the target tissues or increase the retention time in the eye, ear or nose. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, cationic cellulosic polymers, carbomers, xanthan gum, gellan gum, guar gum, a combination thereof, or other agents know to those skilled in the art. Such agents are typically employed at a level of from 0.01% to 2% by weight.
Embodiments of formulations herein may contain a topically acceptable tonicity-adjusting agent such as, for example, metal chloride salts such sodium chloride, potassium chloride, calcium chloride or magnesium chloride; sodium citrate, and non-ionic tonicity-adjusting agents such as mannitol, sorbitol, dextrose, glycerine, propylene glycol, polyethylene glycol or a combination thereof. The amount of tonicity adjusting agent contained in the compositions is an amount sufficient to cause the composition to have an osmolality of about 150 to about 400 milliosmoles per kilogram of water, or about 230-350 mOsm/kg, or about 260-330 mOsm/kg. The concentration of tonicity agent in the composition may be from about 0.1 w/v % to about 10 w/v %, from about 0.2 w/v % or 0.3 w/v % to about 5 w/v %, or from about 0.5 w/v % or 1.0 w/v % to about 2.0 w/v %. For example, where the tonicity adjusting agent is a combination of sodium chloride and mannitol, the amount of sodium chloride is about 0.1 w/v % to about 0.8 w/v % or 0.9 w/v % and the amount of mannitol is about 1 w/v % to 5 w/v % or 10 w/v % in the final product.
Embodiments of compositions of the present invention have a pH from about 3.5 to 9.0 or from about pH 5.0 to 9.0, about pH 6.0 to 8.0, or about pH 7.0 to 7.9 or about pH 7.4 to 7.9 or about pH 7.6, or about pH 7.5, or about pH 7.4. The compositions contain a topically acceptable pH-adjusting agent or buffer in order to achieve the desired pH. Topically acceptable pH adjusting agents and buffers are known and include, for example, hydrochloric acid (HCl), sodium hydroxide (NaOH), triethanolamine, borates, borates/polyols, phosphates, citrates, acetates, carbonates, tris-hydroxymethylaminomethane (tromethamine), or a combination thereof.
The solubility of 2-pyrrolidone derivatives of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition in an amount from about 0.01 w/v %-10 w/v %, from 0.02 w/v % to about 5.0 w/v %, or from about 0.05 w/v % to about 1.0 w/v %. A surfactant may be nonionic, anionic, cationic, amphoteric, or amphiphilic. Exemplary nonionic surfactants or co-solvents include tyloxapol; polyoxyethylene sorbitan esters, such as polysorbate 20, polysorbate 60, and polysorbate 80; polyethoxylated castor oils, such as Cremaphor EL; polyethoxylated hydrogenated castor oils, such as HCO-40; poloxamers, polyoxyethylene/polyoxypropylene surfactants (e.g., PLURONIC® series such as F-68 and P-103; TETRONIC® series such as, 1304 1301 (grades of polyoxyethylene and polyoxypropylene polymerized surfactants; BASF, Mt. Olive, N.J.), polyoxyethylene lauryl ether, polyoxyethylene stearate, polyoxyethylene propylene glycol stearate, hydroxyalkylphosphonate, a combination thereof, or other agents known to those skilled in the art.
Anionic surfactant agents include those described in U.S. Pat. No. 6,211,238, the contents of which are incorporated by reference herein. For example, AMILITE™ GCK-12 is commercially available from Ajinomoto Co., Inc. (Tokyo, Japan), lauroyl sarcosine is available from W. R. Grace (Lexington, Mass.) as HAMPOSYL®L, and PATIONIC® 122A is available from RITA, Corp. (Woodstock, Ill.). Amphoteric surfactant agents include betaines, sultaines, hydroxysultaines such as cocamidopropyl hydroxysultaine, alkyl amphodiacetates, alkyl amphodipropionates such as cocamphodipropionate, and imidazolines, for example. Phospholipids are diglycerides of fatty acids linked to an ester of phosphoric acid and, as such, phospholipids are termed amphiphilic, i.e., having polar heads and non-polar tails. Phospholipids include phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, and phosphatidyl inositol, for example. Examples of co-solvents include propylene glycol, polyethylene glycol, and glycerol. Examples of complexing agents include caffeine and cyclodextrins, either natural or derivatized.
Formulations provided herein for packaging may be in the form of a solution, dispersion or emulsion, for example. A 2-pyrrolidone derivative may be incorporated into liposomes or micelles for use in the present invention. Liposomes may be prepared by any number of techniques that include freeze-thaw, sonication, chelate dialysis, homogenization, solvent infusion, microemulsification, spontaneous formation, solvent vaporization, reverse phase, French pressure cell technique, or controlled detergent dialysis, for example. Liposomes employed in the present invention may be of any one of a variety of sizes, preferably the less than about 100 nm in outside diameter, more preferably less than about 50 nm. Micelles may be prepared by suspension of a 2-pyrrolidone derivative and lipid compound(s) in an organic solvent, evaporation of the solvent, resuspension in an aqueous medium, sonication and then centrifugation. Alternatively, the 2-pyrrolidone derivative may be added to preformed micelles.
In one embodiment of the formulation of the invention, the formulation comprises a micelle-forming surfactant at a concentration of less than about 1 w/v % or less than about 0.3 wt/v %. In another embodiment of the formulation, such a micelle-forming surfactant is HCO-40, Cremophor EL, polysorbate 80, or tyloxapol.
Embodiments of formulations herein may contain a chelating agent such as, for example, ethylene diamine tetraacetic acid (EDTA); ethylene glycol-bis-(b-aminoethylether)-N,N,N′,N′-tetraacetic acid (EGTA), 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA), ethylene-N,N′-diglycine (EDDA), 2,2′-(ethylendiimino)-dibutyric acid (EDBA), diethyleneamine pentaacetate, topically acceptable salts thereof, and the like. A topically acceptable salt, for example, of EDTA is edetate disodium, edetate trisodium or edetate tetrasodium. Further examples of a chelating agent include low molecular weight amino acids having an alpha carboxylic acid group such as those set forth by U.S. Pat. No. 5,741,817 to Chowhan et al., issued Apr. 21, 1998, herein incorporated by reference. In general, the amount of chelating agent present in the compositions herein is from about 0.001% to about 1%, about 0.01% to about 0.2%, or about 0.01% to about 0.1%. Chelating agents are also described as preservation aids.
An ion exchange resin component of the formulations of the present invention provides a means of sustained release of an active having a positive or negative charge. In addition, use of an ion exchange resin reduces irritation of charged actives. The average particle size of the commercially available forms of the resins is about 40 to 150 microns. For topically administrable compositions, particularly ophthalmic compositions, commercially available resin particles are reduced by known techniques, including grinding, ball milling and microfluidization, to a particle size of about 20 microns or less, such that the average particle size is about 10 microns or less. Ion exchange resins are typically used in an amount from about 0.05 w/v % to about 10 w/v %, for from about 0.1 w/v % to 1.0 w/v % or about 0.5 w/v %. An ion exchange resin is generally used in a 0.25:1 to 2.5:1 ratio with the active and in another embodiment is used in a 1:1 ratio with the active.
Topical grade ion exchange resins are available, for example, under the “AMBERLITE®” trade name from Rohm & Haas and under the “DOWEX®” trade name from Dow Chemical Co. Suitable resins include, for example, AMBERLITE® IRP-69, AMBERLITE® IR-118H and AMBERLYST® 131 (4% cross-linking).
A carboxyvinyl polymer (carbomers or carboxypolymethylenes) may also be present as a thickening or physical stability-enhancing agent. Carbomers are commercially available from sources such as Noveon, Inc. (CARBOPOL®, Cleveland, Ohio). Carbopol polymers are acrylic acid-based polymers cross-linked with allyl sucrose or allylpentaerythritol; an example of which is CARBOPOL® 974P. The concentration of carbomer in the compositions of the present invention will generally range from about 0.05% to about 1%, from about 0.05% to about 0.6%, from about 0.1% to about 0.5% and about 0.2%. Anionic polyelectrolytes, such as high molecular weight (e.g., 50,000-6,000,000), may also serve as sustained release agents. Further anionic agents include anionic mucomimetic polymers (e.g., carboxyvinyl polymers, such as CARBOPOL®, and xanthan gum), and cationic exchange resins.
Formulations as provided herein include those formulated for the treatment of dry eye-type diseases and disorders. Such compositions may comprise aqueous carriers designed to provide immediate, short-term relief of dry eye-type conditions. Such carriers can be formulated as a phospholipid carrier or an artificial tears carrier, or mixtures thereof. As used herein, “phospholipid carrier” and “artificial tears carrier” refer to aqueous compositions that: (i) comprise one or more phospholipids (in the case of phospholipid carriers) or other compounds, that lubricate, “wet,” approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration; (ii) are safe; and (iii) provide the appropriate delivery vehicle for the topical administration of an effective amount of one or more actives. Examples of artificial tears compositions useful as artificial tears carriers include, but are not limited to, commercial products, such as TEARS NATURALE®, TEARS NATURALE II®, TEARS NATURALE FREE®, and BION TEARS® (Alcon Laboratories, Inc., Fort Worth, Tex.). Examples of phospholipid carrier formulations include those disclosed in U.S. Pat. Nos. 4,804,539 (Guo et al.), 4,883,658 (Holly), 4,914,088 (Glonek), 5,075,104 (Gressel et al.), 5,278,151 (Korb et al.), 5,294,607 (Glonek et al.), 5,371,108 (Korb et al.), 5,578,586 (Glonek et al.); the foregoing patents are incorporated herein by reference to the extent they disclose phospholipid compositions useful as phospholipid carriers of the present invention.
Molded containers are generally used for packaging formulations of the present invention and are made from packaging materials that substantially lack absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone, such as polyethylene terephthalate (PETE), fluoropolymer materials, or polystyrene. Polyethylene and polypropylene materials are not appropriate for packaging materials of the present invention unless they are formed with an inner lining material that substantially lacks absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone. Ophthalmic, otic or nasal products are typically packaged in unit dose (single dose) or multidose form. Containers such as bottles are made by blow molding, stretch blow molding, and one-step and two-step molding, for example, as known by one of ordinary skill in the art.
The formulations provided herein may be in the form of a solution, suspension, emulsion, gel, or ointment, for example. The packaging material is of a size and shape for ease of use, such as for topical administration, for administration directly to the nasal and sinus area, via, for example, nose drops, an aerosolized preparation, or by inhalation via an inhaler or a nebulizer, for example.
The following examples are presented to further illustrate embodiments of the invention.
EXAMPLES Retention of N-Dodecyl-2-Pyrrolidone in Various Packaging MaterialsThe serotonergic formulation set forth in Table 1 was compounded in a glass bottle using techniques known to those skilled in the art. The formulation was tested for starting DDP concentration and then a volume was filled into different types of packaging materials as set forth in Table 2. The filled packages were then stored at the conditions indicated in Table 2, either room temperature or constant temperature ovens at 40° C. and 60° C. The formulation in the various packaging containers was tested for DDP concentration at the time intervals indicated in Table 2. The thermal exposure testing was used to simulate the ability of container material to retain and deliver DDP in solution over a period of time or after prolonged increased thermal exposure. The tests were performed on duplicate containers to verify DDP concentration remaining in solution.
Concentration of DDP in each formulation was determined by chromatographic separation. The tests were performed on a WATERS ALLIANCE HPLC system with a CADENZA C18 column using a mobile phase consisting of 85% acetonitrile and 15% 1-octanesulfonic acid/water at room temperature. Absorbance was monitored at 220 nm, the known absorption wavelength of DDP. Linear range of detection for DDP was from 1.0 to 100.0 ppm. Retention time of DDP using this system is 8.3 minutes.
In further reference to Table 2, “Glass Vial” is a 1.5 mL clear borosilicate glass vial sealed with a TEFLON® lined septa and aluminum crimp seal (AGILENT HPLC vials part number 5182-0543). “White PETE” is a 60 mL cylindrical bottle made from polyethylene terephthalate (PETE) resin containing a white colorant, titanium dioxide (ALCON part number X04715). “Natural sPP” is a 4 mL oval bottle made from syndiotactic polypropylene (sPP) resin without colorant, i.e., natural (ALCON part number 281277). “Natural TEFLON®” is a 30 mL cylindrical bottle made from fluorinated ethylene propylene (TEFLON® FEP) polymer without colorant by NALGENE® (VWR part number 16071-008).
The data for Tests 1, 2, and 3 obtained after thermal exposure for various times indicate that DDP concentration drops significantly in the sPP container, whereas the concentration of DDP in the Table 1 formulation contained in the PETE and TEFLON® containers is similar to that in the Glass Vial. The absorption or adsorption of DDP in the sPP container effectively renders the contained solution ineffective as a DDP delivery medium, whereas the PETE and the TEFLON® containers are more effective in their ability to deliver DDP under these exposure conditions. The “drop off” in DDP concentration that occurs in the Glass Vial is relatively constant for the three temperatures studied and provides a control value for the studies herein. The PETE and sPP containers show greater loss of DDP at higher temperatures and longer times than the Glass Vial. While not wanting to be bound by theory, DDP appears to be lost to either or both surface adsorption and absorption to or into the packaging material. The container size and fill volume do not appear to have a significant effect on loss of DDP from the formulation. The presence or absence of colorant also appears to have no effect on the loss of DDP to the various container materials.
The serotonergic formulation set forth in Table 3 was compounded in the same manner as the Table 1 formulation. The test, the method of testing, and the packaging were as for the Table 1 formulation. The results are shown in Table 4.
Similar to the results of Table 2, Tests 1, 2, and 3, the sPP packaging in Table 4, Tests 4, 5, and 6 shows significant reduction in available DDP in the contained solution relative to the Glass Vial, PETE, and TEFLON® containers. For all the containers tested, loss of DDP from the Formulation in Table 3 is less as a percent of the initial DDP concentration than from the Formulation in Table 1. This enhanced retention of DDP may be due to the presence of the surfactant, Polyoxyl 40 hydrogenated castor oil, in the Formulation of Table 3, or may be due to the higher initial concentration of DDP (that of 0.002% vs. 0.001%).
The formulation set forth in Table 5 was compounded in the same manner as the Table 1 formulation. The test, the method of testing, and the packaging were as for the Table 1 formulation. The results are shown in Table 6.
Similar to the results of Table 2, Tests 1, 2, and 3, the sPP packaging in Table 6, Tests 7, 8, and 9 shows significant reduction in available DDP in the contained solution relative to the Glass Vial and PETE containers. Loss of DDP to the Glass Vial from the formulation in Table 5 is similar to that observed for the formulation in Table 1. However, loss of DDP to the PETE and sPP containers from the formulation in Table 5 as compared to that of the formulation in Table 1 may be due to the viscosity of the formulation of Table 1 due to the presence of Carbopol 974P. The formulation of Table 5 is no more viscous than water. The higher viscosity of the formulation in Table 1 may limit diffusion into the container material and therefore slow loss of DDP relative to the non-viscous formulation in Table 5. In both cases, loss of DDP is less in the PETE package than in the sPP package.
The formulation set forth in Table 7 was compounded in the same manner as the Table 1 formulation. The test, the method of testing, and the packaging were as for the Table 1 formulation, except as indicated. “White LDPE” is an 8 mL cylindrical bottle made from low-density polyethylene (LDPE) with white colorant and is ALCON part number 277027. “Natural Polystyrene” is a 150 mL cylindrical bottle made of polystyrene polymer without colorant and is CORNING filter flask product 431153. The results are shown in Table 8.
The results in Table 8, Tests 10, 11, and 12 are similar to those seen for the previous formulations and the previous tests. The presence of the surfactant, Polyoxyl 40 hydrogenated castor oil, in the formulation in Table 7 appears to assist in reducing the loss of DDP to packaging materials shown in Table 8 as compared to the formulation in Table 5 and packaging materials of Table 6. The larger fill volume of 50 mL in the PETE container in Table 8 also appears to assist in reducing loss of DDP, possibly due to decreased surface to volume ratio as compared to the 10 mL fill volume of the PETE container of Table 6. Again, loss of DDP from the formulation in the sPP container is much greater than that of the Glass Vial or PETE containers, and loss of DDP from the formulation in the White LDPE container is even more severe than the sPP container. The Natural Polystyrene container is essentially equivalent to the PETE container in retaining DDP in the formulation, and both the PETE and Polystyrene are dramatically superior to the sPP or LDPE containers in retaining DDP.
The presence or absence of a colorant appears not to affect the loss of DDP to the various containers. Fill volume may be a factor in loss of DDP when the fill volume is significantly less than the total volume of the container. However, for containers of the same size, shape, and fill volume, containers made of PETE, TEFLON®, and Polystyrene resins retain a greater percentage of DDP in the formulation than containers made of sPP and LDPE resins.
The references cited herein, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated by reference.
Those of skill in the art, in light of the present disclosure, will appreciate that obvious modifications of the embodiments disclosed herein can be made without departing from the spirit and scope of the invention. All of the embodiments disclosed herein can be made and executed without undue experimentation in light of the present disclosure. The full scope of the invention is set out in the disclosure and equivalent embodiments thereof. The specification should not be construed to unduly narrow the full scope of protection to which the present invention is entitled.
As used herein and unless otherwise indicated, the terms “a” and “an” are taken to mean “one”, “at least one” or “one or more.”
Claims
1. A packaged product comprising:
- a formulation for ophthalmic, otic, or nasal use, the formulation comprising 5-(R1)-N-(R2)-2-pyrrolidone, wherein R1 is H, methyl or ethyl, and wherein R2 is C6-C12 straight-chain, branched, substituted or unsubstituted alkyl, oxyalkyl, amidoalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, or alkylaryl; and
- a container comprising a material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone,
- wherein the formulation is packaged in the container.
2. The packaged product of claim 1 wherein the container consists essentially of the material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone.
3. The packaged product of claim 1, wherein the container comprises an inner lining; the material of the inner lining substantially lacks absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone; and the container other than the inner lining is made from a polypropylene or a polyethylene.
4. The packaged product of claim 1, wherein the container further comprises a coating, wherein the coating is made of a gas impermeable laminate material.
5. The packaged product of claim 1, wherein the material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone is selected from the group consisting of polyethylene terephthalate; a flouropolymer; and polystyrene.
6. The packaged product of claim 5 wherein the fluoropolymer is selected from the group consisting of polytetrafluoroethlyene; perfluoroalkoxy polymer; fluorinated ethylene propylene copolymer; and ethylenetetrafluoroethylene copolymer.
7. The packaged product of claim 5, wherein the container has a coating of a gas impermeable material.
8. The packaged product of claim 7, wherein the gas impermeable material is a metallic film.
9. The packaged product of claim 1, wherein R1 is H or methyl and R2 is C6-C12 straight-chain alkyl.
10. The packaged product of claim 9 wherein R1 is H and R2 is C8 straight-chain alkyl such that the 5-(R1)-N-(R2)-2-pyrrolidone is N-octyl-2-pyrrolidone.
11. The packaged product of claim 9 wherein R1 is H and R2 is C12 straight-chain alkyl such that the 5-(R1)-N-(R2)-2-pyrrolidone is N-dodecyl-2-pyrrolidone.
12. The packaged product of claim 1 wherein the formulation further comprises a micelle-forming surfactant at a concentration of less than about 0.3 wt/v %.
13. A packaged product for ophthalmic, otic, or nasal use, comprising:
- a container made from a material consisting essentially of polyethylene terephthalate; and
- a formulation comprising a 5-(R1)-N-(R2)-2-pyrrolidone, wherein R1 is H, methyl or ethyl, and wherein R2 is C6-C12 straight-chain, branched, substituted or unsubstituted alkyl, oxyalkyl, amidoalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, or alkylaryl.
14. A packaged product for ophthalmic, otic, or nasal use, comprising:
- a container made from a material consisting essentially of polytetrafluoroethlyene, perfluoroalkoxy polymer, fluorinated ethylene propylene copolymer, or ethylenetetrafluoroethylene copolymer; and
- a formulation comprising a 5-(R1)-N-(R2)-2-pyrrolidone, wherein R1 is H, methyl or ethyl, and wherein R2 is C6-C12 straight-chain, branched, substituted or unsubstituted alkyl, oxyalkyl, amidoalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, or alkylaryl.
15. A method of minimizing absorption and adsorption of a 5-(R1)-N-(R2)-2-pyrrolidone compound to a container material therefor, comprising:
- packaging a 5-(R1)-N-(R2)-2-pyrrolidone-containing formulation in a container made from polyethylene terephthalate, a fluoropolymer, or polystyrene;
- or
- packaging a 5-(R1)-N-(R2)-2-pyrrolidone-containing formulation in a container having an inner lining; the inner lining made from a material substantially lacking absorptive and adsorptive properties for the 5-(R1)-N-(R2)-2-pyrrolidone; and the container other than the inner lining is made from a polypropylene or a polyethylene; wherein R1 is H, methyl or ethyl, and wherein R2 is C6-C12 straight-chain, branched, substituted or unsubstituted alkyl, oxyalkyl, amidoalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, or alkylaryl.
16. The method of claim 15, wherein the container is made from a fluoropolymer and the fluoropolymer consists essentially of polytetrafluoroethylene, perfluoroalkoxy polymer; fluorinated ethylene propylene copolymer; or ethylenetetrafluoroethylene copolymer.
17. The method of claim 15, wherein the container is made from polyethylene terephthalate.
18. The method of claim 15, wherein the container is coated with a gas impermeable material and wherein the container has an inner lining and the inner lining is made from a soluble fluoropolymer.
19. The method of claim 15 wherein R1 is H and R2 is C8 straight-chain alkyl such that the 5-(R1)-N-(R2)-2-pyrrolidone is N-octyl-2-pyrrolidone.
20. The method of claim 15, wherein R1 is H and R2 is C12 straight-chain alkyl such that the 5-(R1)-N-(R2)-2-pyrrolidone is N-dodecyl-2-pyrrolidone.
Type: Application
Filed: Oct 24, 2007
Publication Date: Apr 24, 2008
Applicant: Alcon Manufacturing Ltd. (Fort Worth, TX)
Inventors: Wesley Wehsin Han (Arlington, TX), Masood A. Chowhan (Arlington, TX), Jang-Shing Chiou (Arlington, TX), L. Wayne Schneider (Crowley, TX), Bhagwati P. Kabra (Euless, TX)
Application Number: 11/923,032
International Classification: B65D 81/26 (20060101);
