HK1058764A - Compositions containing therapeutically active components having enhanced solubility - Google Patents

Description

Compositions comprising therapeutically active components with enhanced solubility

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional application No. 60/218,206 filed on 14/7/2000.

Background

The present invention relates to compositions comprising therapeutically active components with improved solubility. More particularly, the present invention relates to compositions comprising Therapeutically Active Components (TACs) and components effective to increase the solubility of the TACs at therapeutically effective concentrations.

It is often beneficial when the TACs in the liquid composition are dissolved in the liquid carrier of the composition. Such solubility facilitates uniform and accurate administration. In addition, the dispensed or administered TACs should be soluble in the biological system or environment to which they are administered, e.g., to effectively achieve or enhance in vivo diffusion through cell membranes or lipid bilayers. In addition, solubilized TACs provide other benefits, such as reduced irritation to tissues with which the TACs interact.

It is sometimes desirable to include a solubilizing agent in the composition to solubilize the TACs. However, the addition of a solubilizer may reduce the effectiveness of the preservative in the composition.

For example, cyclodextrins are substances well known in the literature to increase the solubility of poorly water-soluble therapeutically active components. However, at standard concentrations in these compositions, cyclodextrins render typical preservatives relatively ineffective.

There remains a need to provide new compositions containing TACs.

Summary of The Invention

Novel TAC-containing compositions have been found. In the compositions of the present invention, the solubility of the TAC is increased while substantially not adversely affecting the preservatives used. Solubility Enhancing Components (SECs) have been found to be very effective in enhancing the solubility of TACs in the compositions of the invention, and preferably in the biological systems or environments in which they are incorporated. Such solubilization also preferably allows for the provision of more reliable and reproducible pharmaceutical dosage forms. According to the present invention, enhanced solubility is achieved without substantially reducing preservative effectiveness. In addition, TAC-containing compositions that include preservatives have been found to have many practical advantages, such as reduced adverse interactions with the TACs and/or with the patient using the compositions, while maintaining preservative effectiveness.

The compositions of the present invention comprise an oxygen-chlorine component (oxy-chlorine component) which is effective in: at least helps to preserve the composition without adversely affecting TACs and without substantially adversely affecting SECs. In addition, the oxy-chloro components of the present invention provide a preservative effect that reduces or is substantially free of any deleterious or irritating effects on the tissue to which the compositions of the present invention are applied.

The SECs of the present invention are preferably effective in enhancing the dissolution of TACs in the environment to which they are added, e.g., the biological environment. Such solubilization preferably facilitates the advantageous transport of the TACs across the lipid membrane.

Soluble TACs for use in the present invention include compositions, e.g., compounds, mixtures of other materials, that provide a therapeutically beneficial effect or effect when administered to a patient, e.g., a human patient. TACs useful in the present invention include, but are not limited to, antibacterial agents, antihistamines, decongestants, anti-inflammatory agents, antiparasitic agents, miotic agents, anticholinergic agents, adrenergic agents, antiviral agents, local anesthetics, fungicides, amoebicidals, trichomonacidal agents, analgesics, mydriatic agents, antiglaucoma agents, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic active agents as surgical adjuvants, chelating agents, antineoplastic agents, antihypertensive agents, muscle relaxants, diagnostic agents, and the like, and mixtures thereof. Specific examples of such TACs are conventional and well known in the art.

In one embodiment, the TACs include adrenergic agonists, precursors thereof, metabolites thereof, and combinations thereof. Preferably, the TACs include alpha-2 adrenergic agonists such as iminoimidazolines, imidazolines, imidazoles, aza , thiazines, oxazolines, guanidines, catecholamines, biocompatible salts and esters thereof, and mixtures thereof. In one embodiment, the TACs include quinoxaline components. The quinoxaline component includes quinoxaline, biocompatible salts thereof, esters thereof, other derivatives thereof, and the like, and mixtures thereof. The quinoxaline component including the quinoxaline derivative is preferably an alpha-2-adrenergic agonist. Non-limiting examples of quinoxaline derivatives include (2-imidazolin-2-ylamino) quinoxaline, 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline, and biocompatible salts and esters thereof and the like, preferably the tartrate salt of 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline and the like, and mixtures thereof. Hereinafter, the tartrate salt of 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline is referred to as "Brimonidine (Brimonidine tartrate)".

In one useful embodiment, the SEC is not a cyclodextrin and includes a polyanionic component. The term "polyanionic component" as used herein refers to a chemical entity, e.g., an ionically charged material, such as an ionically charged polymeric material, that comprises more than one dispersed anionic charge, i.e., a plurality of dispersed anionic charges. The polyanionic component is preferably selected from polymeric materials having multiple anionic charges and mixtures thereof.

Particularly useful polyanionic components are selected from: acrylic acid-derived anionic polymers (meaning to include polymers derived from acrylic acid, acrylates, and the like, and mixtures thereof), methacrylic acid-derived anionic polymers (meaning to include polymers derived from methacrylic acid, methacrylates, and the like, and mixtures thereof), alginic acid-derived anionic polymers (meaning to include polymers derived from alginic acid, alginates, and the like, and mixtures thereof), amino acid-derived anionic polymers (meaning to include polymers of amino acids, amino acid salts, and the like, and mixtures thereof), and the like, and mixtures thereof. Very useful polyanionic components are selected from anionic cellulose derivatives and mixtures thereof, especially carboxymethyl cellulose.

The polyanionic component preferably has sufficient anions to interact with, or affect, and particularly increase the solubility of, the TAC. The interaction is preferably sufficient to allow substantially complete dissolution of the TAC at a therapeutically effective concentration. The SEC content of the composition is preferably from about 0.1% (w/v) to about 30% (w/v), more preferably from about 0.2% (w/v) to about 10% (w/v), even more preferably from about 0.2% (w/v) to about 0.6% (w/v).

The oxy-chloro component included in the compositions of the present invention is effective at least in helping to preserve the composition. Any suitable oxy-chloro component that is effective at least to aid in preserving the composition may be employed. Such oxy-chloro components include, but are not limited to, hypochlorite components, perchlorate components, chlorite components, and the like, and mixtures thereof.

In one useful embodiment, the oxy-chloro component includes a chlorite component. The chlorite component preferably comprises stabilized chlorine dioxide, alkali metal chlorite salts and the like and mixtures thereof. The chlorite component is very effective in the compositions of the present invention and often provides preservative effectiveness at relatively low concentrations with little or no deleterious effect on the tissue to which the composition is applied. In addition, the oxy-chloro components, such as chlorite components, substantially maintain their preservative effectiveness in the presence of SECs, such as polyanionic components. While not wishing to be bound by any particular theory or mechanism of action, it is believed that such oxy-chloro components are substantially free, or do not substantially interact with, SECs in the presence of the SECs.

Oxy-chloro components in amounts less than about 1% (w/v) or about 0.8% (w/v) may be effective in the composition. In one useful embodiment, the oxygen-chlorine component may be present in the composition in an amount of about 500ppm (w/v) or less, preferably from about 10ppm (w/v) to about 200ppm (w/v).

In one embodiment, an additional preservative is used in the composition that is not an oxy-chloro component. Any suitable additional preservative component may be used in accordance with the present invention so long as it is compatible with the oxy-chloro component, TAC, and SEC. Preservative components well known and/or commonly used in the pharmaceutical art may be employed. Examples include, but are not limited to, sorbic acid, benzalkonium chloride, chlorobutanol, alkyl esters of para-hydroxybenzoic acid and the like and mixtures thereof. If additional preservative components are included, they are preferably present with the oxy-chloro component in an amount effective to preserve the composition.

The composition comprises a liquid carrier component, such as an aqueous liquid carrier component. The pH of the composition is preferably about 7 or above, more preferably from about 7 to about 9.

In one broad aspect, the present invention provides a composition comprising a TAC, a SEC, a chlorite component, and an aqueous liquid carrier. Preferably, the TAC is brimonidine. SEC is preferably an anionic cellulose derivative, more preferably carboxymethyl cellulose, and is present in an amount of, for example, about 0.2% to about 0.6% (w/v).

In another broad aspect, the present invention provides a composition comprising brimonidine, SEC, a chlorite component, and an aqueous liquid carrier component. Brimonidine is present in an amount effective to provide a desired effect on a human or animal upon administration of the composition to the human or animal, and the SEC is preferably carboxymethylcellulose.

In another broad aspect, the present invention provides a composition comprising TAC and a preservative component, wherein the preservative component is present in an amount effective to at least assist in preserving the composition. The preservative component preferably comprises a biologically acceptable, chemically stable, oxy-chloro component such as compounds, ions, complexes, and the like that does not substantially or significantly adversely affect the TACs in the composition or the patient to whom the composition is administered. Such compositions are preferably substantially free of cyclodextrin.

The compositions of the present invention are preferably ophthalmically acceptable, e.g., the compositions do not have deleterious or toxic properties that can harm the eye of a human or animal to whom the compositions are administered.

Any feature or combination of features described herein is included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art.

Additional advantages and aspects of the invention will become apparent from the following detailed description and claims.

Brief Description of Drawings

FIG. 1 is a graph of soluble brimonidine versus pH at various carboxymethylcellulose concentrations.

Detailed Description

The present invention provides compositions comprising TACs, SECs and oxy-chloro components. TACs in the compositions of the present invention are more water soluble and can be used more effectively as therapeutic agents. SECs suitable for solubilizing TACs may be used in the compositions of the present invention with the oxy-chloro component to increase the solubility of the TACs without substantially adversely affecting the preservative effectiveness of the oxy-chloro component. In other words, the SECs used in the compositions of the present invention are effective in increasing the solubility of the TACs while not substantially interfering with the function of the other components of the composition. The SECs used in the compositions of the present invention are effective in solubilizing ionized TACs, unionized TACs or both.

An oxygen-chlorine component is included in the composition to aid in the preservation of the composition. In particular, the presence of SECs in the composition does not substantially adversely affect the oxy-chloro component. In addition, the oxy-chloro component of the composition is effective without substantial undue deleterious or irritating effects on the tissue to which the composition of the present invention is applied.

The compositions of the present invention may and preferably do comprise a liquid carrier component. For example, such components often feature liquids, such as liquid solutions.

Preferably, the TACs useful in the present invention are selected to benefit from the presence of SECs and oxy-chloro components. In general, the presence of SECs increases the apparent solubility of TACs, preferably the apparent water solubility.

Preferably, the TACs in the present compositions at pH greater than 7 have increased solubility compared to the same TACs present in similar compositions without the SECs at comparable concentrations. More preferably, the TACs in the present compositions have increased solubility at a pH of about 7 to about 10 as compared to TACs present in comparable compositions without the SECs at comparable concentrations.

While not wishing to be bound by any theory or mechanism of action, it is believed that solubilized TACs are able to cross the lipid membrane better than non-solubilized TACs. It is also believed that solubilized TACs are smaller in physical size and therefore more able to physically penetrate or diffuse through the lipid membrane.

In one embodiment, the SECs of the present invention are capable of enhancing the solubility of therapeutically effective concentrations of TACs in the environment into which they are introduced. Preferably, the biological environment into which the compositions of the present invention are introduced has a pH of from about 7 to about 9. For example, a composition comprising SEC and TAC can be administered to the cornea of a human eye at a pH of about 7, wherein TAC is substantially solubilized at the administration area. Furthermore, in one embodiment, TACs solubilized by SECs are more readily diffused through the biolipid membrane at the site of administration than TACs not solubilized with SECs. Solubilized TACs preferably have reduced irritation to sensitive tissues in contact with or interacting with the TACs.

Examples of therapeutically active ingredients that may be included in the compositions of the present invention include, but are not limited to, antibacterial substances such as beta-lactam antibiotics, e.g., cefoxitin, n-formamido-sanamycin (n-formamidoylthienamycin) and other derivatives of sanamycin, tetracycline, chloramphenicol, neomycin, carbenicillin, colistin, penicillin G, polymyxin B, vancomycin, cefazolin, ceftiodine, rifamycin SV sodium, gramicidin, bacitracin, and sulfonamide drugs; aminoglycoside antibiotics such as gentamicin, kanamycin, amikacin, sisomicin, and tobramycin; nalidixic acid and analogs thereof such as antimicrobial combinations of norfloxacin and fluvalinate/tebuconazole, nitrofurazone and analogs thereof; antihistamines and decongestants such as pyrilamine, chlorpheniramine, tetrahydronaphazoline, antazoline, and analogs thereof; mast cell release of histamine inhibitors such as cromolyn sodium (cromolyn); anti-inflammatory agents such as cortisone, hydrocortisone acetate, betamethasone, dexamethasone sodium phosphate, prednisone, methylprednisolone, medrysone, fluoromethalone, prednisolone sodium phosphate, triamcinolone acetonide, indanethacin, sulindac, salts and corresponding sulfides, and the like; miotics and anticholinergics such as diethylphosphonothiocholine, pilocarpine, physostigmine salicylate, isoflurophosphate, epinephrine, pivaloyl, neostigmine, etidocromide, dibromide, carbachol, methacholine, carbamoylmethylcholine, and the like; mydriatic agents such as atropine, homatropine, scopolamine, oxypropylamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentadine, gastrin (oxypheninin), and bulgarian; and the like, and mixtures thereof.

Other TACs are: anti-glaucoma drugs such as timolol, and especially its maleate salt and R-timolol, and timolol or a combination of R-timolol and pilocarpine; other adrenergic agonists and/or antagonists such as the epinephrine and epinephrine complexes, or prodrugs such as bitartrate, borate, hydrochloride, and bispivalyl (dipivorine) derivatives; carbonic anhydrase inhibitors such as acetazolamide, dichlorofenamide, 2- (p-hydroxyphenyl) thiothiophenesulfonamide, 6-hydroxy-2-benzothiazylsulfonamide, and 6-pivaloyloxy-2-benzothiazylsulfonamide; antiparasitic and/or antiprotozoal compounds such as ivermectin, pyrimethamine, sulfadiazine, clindamycin and corticosteroid preparations; compounds with antiviral activity such as acyclovir, 5-iodo-2' -deoxyuridine (IDU), adenosine arabinoside (Ara-a), trifluorothymidine, interferon, and interferon inducers such as poly I: c; antifungal agents such as amphotericin B, nystatin, flucytosine, natamycin and miconazole; anesthetics such as etidocaine, cocaine, oxybuprocaine, dibucaine hydrochloride, dyclonine hydrochloride, naecaine, fenocaine hydrochloride, perocaine, proparacaine hydrochloride, tetracaine hydrochloride, hexylcaine, bupivacaine, lidocaine, mepivacaine, and prilocaine; ophthalmic diagnostic agents, for example: (a) those used for examining the retina, such as sodium fluorescein, (b) those used for examining the conjunctiva, cornea and lacrimal apparatus, such as fluorescein and rose bengal, and (c) those used for examining abnormal pupillary responses, such as methacholine, cocaine, epinephrine, atropine, hydroxyamphetamine and pilocarpine; ophthalmic actives such as alpha-chymotrypsin and hyaluronidase for use as surgical aids; chelating agents such as ethylenediaminetetraacetic acid (EDTA) and deferoxamine; immunosuppressants and antimetabolites such as methotrexate, cyclophosphamide, 6-mercaptopurine, and azathioprine, as well as combinations of the foregoing compounds, e.g., antibiotic/anti-inflammatory agent combinations, e.g., neomycin sulfate in combination with dexamethasone sodium phosphate, and combinations for concurrent treatment of glaucoma, e.g., timolol maleate in combination with quinuclidinol acetate; and the like, and mixtures thereof.

In preferred embodiments, useful TACs include adrenergic agonists. The adrenergic agonist is preferably an amine-containing molecule. The adrenergic agonist is also preferably an amine-containing molecule having a pKa value greater than 7, preferably from about 7 to about 9.

More preferably, useful TACs include alpha adrenergic agonists. Examples of alpha-adrenergic agonists include, but are not limited to, adrafinil, adrenolone, amifostine, apraclonidine, budralazine, clonidine, cyclopentamine, detomidine, difenofrin, ephedrine, epinephrine, fenozoline, guanabenz, guanfacine, hydroxyphenylpropylamine, ibopamine, indanzoline, isometheptene, mephenbutamine, metahydroxylamine, methoxyamine, methylhexane, metizolene, midodrine, naphazoline, norepinephrine, norphenylephrine, oxidrine, octopamine, oxymetazoline, neofodrine, phenylpropanolamine, phenylpropylmethylamine, fulledrine, propylhexedrine, pseudoephedrine, rilmendine, synephrine, tetrahydronaphazoline, tiazoline, trimazoline, isoheptamine, temazoline, tyramine, tyrosine, and mixtures thereof.

In a more preferred embodiment, useful TACs include alpha-2 adrenergic agonists. The term "alpha-2 adrenergic agonist" as used herein includes chemical entities, e.g., compounds, ions, complexes, etc., that produce a net anti-sympathetic response resulting in enhanced modulation, e.g., by binding to presynaptic alpha-2 receptors on sympathetic postganglionic nerve endings or, e.g., to postsynaptic alpha-2 receptors on smooth muscle cells. The anti-sympathetic response is characterized by an impulse effect that inhibits, reduces, or blocks transmission through the sympathetic nervous system. The alpha-2 adrenergic agonists of the invention bind presynaptic alpha-2 adrenergic receptors, cause negative feedback, and reduce the release of neuronal norepinephrine. In addition, they act on the postsynaptic alpha-2 adrenergic receptor, inhibiting beta-adrenergic receptor-stimulated cyclic AMP formation, and in addition to the effects of the postsynaptic alpha-2 adrenergic receptor on other intracellular pathways, they also lead to ciliary muscle relaxation. Activity at presynaptic or postsynaptic alpha-2 adrenergic receptors will result in a decrease in adrenergic effects. The reduced adrenergic effect results in an increased contraction resulting from cholinergic innervation. Alpha-2 adrenergic agonists also include compounds having neuroprotective activity. For example, 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline is an alpha-2-adrenergic agonist with neuroprotective activity via an unknown mechanism.

Without limiting the invention to the specific groups and compounds listed, representative alpha-2 adrenergic agonists that can be used in the invention are listed below: iminoimidazolines including clonidine, apremidine; imidazolines, including naphazoline, xmetazoline, tetrahydronaphazoline, and tramazoline; imidazoles, including detomidine, medetomidine, and dexmedetomidine; aza  classes including B-HT 920 (6-allyl-2-amino-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d ] -aza  and B-HT 933, thiazines including xylazine, oxazolines including rilmenidine, guanidines including guanabenz and guanfacine, catecholamines, and the like.

Particularly useful alpha-2 adrenergic agonists include quinoxaline components. In one embodiment, the quinoxaline component comprises quinoxaline, derivatives thereof and mixtures thereof. The quinoxaline derivative preferably comprises (2-imidazolin-2-ylamino) quinoxaline. The quinoxaline derivative more preferably comprises a 5-halo-6- (2-imidazolin-2-ylamino) quinoxaline. The "halo" of the 5-halo-6- (2-imidazolin-2-ylamino) quinoxaline may be fluorine, chlorine, iodine, or, preferably, bromine to form the 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline. Even more preferably, the quinoxaline derivative used according to the present invention comprises the tartrate salt of 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline, or brimonidine.

Other useful quinoxaline derivatives are well known. Useful derivatives of quinoxaline include, for example, those disclosed in U.S. patent No. 5,703,077 to Burke et al. See also Danielwicz et al 3,890,319. The disclosures of Burke et al and Danielwicz et al are incorporated herein by reference in their entirety.

Quinoxaline and derivatives thereof, such as brimonidine, are amine-containing compounds and preferably have a pKa value greater than 7, preferably from about 7.5 to about 9.

The invention also specifically includes analogs of the above compounds that act as alpha-2 adrenergic agonists.

Preferably, the alpha-2-adrenergic agonist, such as the alpha-2 adrenergic agonists listed above, is effective to activate one or more of the alpha-2A-adrenergic receptor, the alpha-2B-adrenergic receptor, and the alpha-2D-adrenergic receptor.

Other useful TACs include ocular hypotensive agents (wood et al U.S. Pat. No. 5,688,819), cyclosporines (Ding et al U.S. Pat. No. 5,474,979), androgenic tears (androgen patents) (Sullivan U.S. Pat. No. 5,620,921), pyranoquinolinone derivatives (Cairns et al U.S. Pat. No. 4,474,787), compounds having retinoid-like activity (Chandraratna U.S. Pat. No. 5,089,509), ketorolac/pyrrole-1-carboxylic acid (Muchowski et al U.S. Pat. No. 4,089,969), ofloxacin/benzoxazine derivatives (Hayakawa et al U.S. Pat. No. 4,382,892), memantine (Lipton et al U.S. Pat. No. 5,922,773), RAR antagonists (Klein et al U.S. Pat. 5,952,345), RAR- α agonists (Teng et al U.S. Pat. 5,856,490). The above patent publications are incorporated herein by reference in their entirety.

In one embodiment, the TACs, such as brimonidine, are substantially unionized in the composition. In another embodiment, the TACs are substantially unionized in the environment in which they are administered, such as the cornea of a human eye. While not wishing to be bound by any theory or mechanism of action, it is believed that the unionized form of TACs facilitates their permeation across lipid bilayer membranes.

Any suitable SEC that is not a cyclodextrin may be used in accordance with the present invention. In one embodiment, the SECs comprise a pyrrolidone component. Examples of pyrrolidone components are polyvinylpyrrolidone, its derivatives and mixtures thereof. In a preferred embodiment, the SECs comprise a polyanionic component. Useful polyanionic components include, but are not limited to, materials that are effective in increasing the apparent solubility, preferably the water solubility, of poorly soluble TACs and/or increasing the stability of TACs and/or mitigating undesirable side effects of TACs. In addition, the polyanionic component is preferably ophthalmically acceptable at the concentrations used. Furthermore, the polyanionic component preferably comprises three (3) or more anionic (or negative) charges. When the polyanionic component is a polymeric material, it is preferred that each repeating unit of the polymeric material includes a dispersed anionic charge. Particularly useful anionic components are those that are water soluble, e.g., soluble at the concentrations used in the liquid aqueous medium used in the present invention, e.g., a liquid aqueous medium containing a polyanionic component and a chlorite component.

The polyanionic component preferably has sufficient anions to interact with the TAC. Such interaction is believed to be beneficial in solubilizing TAC and/or maintaining such TAC dissolved in a carrier component, e.g., a liquid medium.

The polyanionic component also includes one or more polymeric materials having a plurality of anionic charges. Examples thereof include:

carboxymethyl starch metal salt

Carboxymethyl hydroxyethyl starch metal salt

Hydrolyzed polyacrylamides and polyacrylonitriles

Heparin

Homopolymers and copolymers of one or more of the following:

acrylic and methacrylic acids

Metal acrylate and metal methacrylate

Alginic acid

Alginate metal salt

Vinyl sulfonic acid

Vinylsulfonic acid metal salt

Amino acids such as aspartic acid, glutamic acid and the like

Amino acid metal salt

P-styrene sulfonic acid

Metal salt of p-styrene sulfonic acid

2-Methacryloyloxyethanesulfonic acid

2-Methacryloyloxyethanesulfonic acid metal salt

3-Methacryloyloxy-2-hydroxypropanesulfonic acid

3-Methacryloyloxy-2-hydroxypropanesulfonic acid metal salt

2-acrylamido-2-methylpropanesulfonic acid

2-acrylamido-2-methylpropanesulfonic acid metal salt

Allyl sulfonic acid

Metal salts of allylsulfonic acids, and the like.

In one embodiment, the polyanionic component includes anionic polysaccharides that are not cyclodextrins that tend to exist in ionized form at higher pH, e.g., pH of about 7 or higher. The following are some examples of anionic polysaccharides that may be used in accordance with the present invention.

Polydextrose (polydextrose) is a randomly bonded glucose condensation polymer that is only partially metabolized by mammals. The polymer may contain small amounts of bound sorbitol, citric acid, and glucose.

Chondroitin sulfate, also known as sodium chondroitin sulfate, is a mucopolysaccharide found in all parts of human tissue, particularly cartilage, bone, tendons, ligaments, and blood vessel walls. The polysaccharide has been extracted and purified from shark cartilage.

Carrageenans are linear polysaccharides having repeating galactose units and 3, 6-anhydrogalactose units, wherein both the galactose units and the 3, 6-anhydrogalactose units may be sulfated or unsulfated and are linked by alternating 1-3 and β 1-4 glycosidic linkages. Carrageenan is a hydrocolloid that is thermally extracted from several red seaweed and carrageenans.

Maltodextrins are water-soluble glucose polymers formed by reacting starch with an acid and/or an enzyme in the presence of water.

Other polysaccharides which have been found to be useful in the present invention are hydrophilic colloidal materials and include natural gums such as gellan gum, alginate gums, i.e., the ammonium and alkali metal salts of alginic acid and mixtures thereof. In addition, chitosan, which is the common name for chitosan, is also useful. Chitin is a natural product comprising poly- (N-acetyl-D-glucosamine). Gellan gum is produced by fermenting pseudomonas elodea to produce extracellular heteropolysaccharide. Alginates and chitosan are available as dry powders from Protan, inc. Gellan gum is available from Kelco Division of Merk & Co., Inc., San Diego, Calif.

In general, the alginate may be any water soluble alginate including alkali metal salts of alginic acid, such as sodium, potassium, lithium, rubidium and cesium salts of alginic acid, as well as ammonium salts, and soluble alginates of organic bases, such as monoethanolamine alginate, diethanolamine alginate, triethanolamine alginate, aniline alginate, and the like. The gel compositions of the present invention are generally obtained using from about 0.2% to about 1% by weight, preferably from about 0.5% to about 3.0% by weight, of gellan, alginate or chitosan ionic polysaccharide, the percentages being by weight of the composition.

One particularly useful class of polyanionic components includes anionic cellulose derivatives. Anionic cellulose derivatives include carboxymethyl cellulose metal salts, carboxymethyl hydroxyethyl cellulose metal salts and hydroxypropyl methyl cellulose and derivatives thereof.

The polyanionic components of the present invention are often present in an unionized state, such as in the solid state, in combination with a counter or counter ion, particularly a plurality of dispersed cations equal in number to the dispersed anionic charge, such that such unionized polyanionic components are electrically neutral. For example, the non-ionized polyanionic components of the present invention may be present in the acid form and/or with one or more metals. Because the polyanionic component is preferably ophthalmically acceptable, it is preferred that the metal combined with the unionized polyanionic component is ophthalmically acceptable at the use concentrations. Particularly useful metals include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and mixtures thereof. Sodium is well suited for providing counter ions in non-ionized polyanionic components. Polyanionic components in unionized state in combination with cations other than H + and metal cations are useful in the present invention.

In a preferred embodiment, the polyanionic polymer is cyclized. More preferably, the cyclized anionic polymer comprises 10 or less monomer units. Even more preferably, the cyclized polyanionic polymer comprises 6 or less monomer units.

The amount of SEC present in the compositions of the invention is not critical so long as the solubility of the alpha-2-adrenergic agonist component is at least somewhat enhanced and is present in a biologically acceptable amount. Such an amount should be effective to achieve the desired function in the composition of the invention and/or after administration to a human or animal. In one embodiment, the amount of SEC, preferably polyanionic component, should be sufficient to allow at least a majority, more preferably substantially all, of the TAC in the composition of the present invention to be complexed. In one useful embodiment, the polyanionic component is present in the compositions of the present invention in an amount from about 0.1% to about 30% (w/v) of the composition or more. Preferably, the polyanionic component is present in an amount of about 0.2% (w/v) to about 10% (w/v). More preferably, the polyanionic component is present in an amount of about 0.2% (w/v) to about 0.6% (w/v). Even more preferably, the polyanionic component is carboxymethylcellulose and is present in the composition in an amount from about 0.2% (w/v) to about 0.6% (w/v). A particularly useful concentration of carboxymethyl cellulose in the composition of the present invention is about 0.5%.

In one embodiment, carboxymethyl cellulose may help solubilize ionized TACs. In another embodiment, carboxymethylcellulose may help solubilize the unionized TACs. In a preferred embodiment, carboxymethyl cellulose aids in the dissolution of ionized brimonidine. More preferably, the carboxymethyl cellulose helps to dissolve unionized brimonidine.

In one broad embodiment, the preservative components are selected to be effective and highly effective preservatives in the compositions of the present invention in the presence of SECs, and they preferably have reduced toxicity, more preferably are substantially free of any toxicity, when administered to a human or animal.

Preservatives commonly used in pharmaceutical compositions are often less effective when used in the presence of solubilizing agents. In some cases, this reduced preservative efficacy can be compensated for by increasing the amount of preservative used. However, this approach may not be applicable when sensitive or delicate body tissues are involved, as the preservative itself may cause some adverse reactions or sensitivity in the human or animal to whom the composition is administered.

Preferably, the preservative component of the present invention, which is effective to aid in preserving the composition, is effective at a concentration of less than about 1% (w/v) or about 0.8% (w/v), and may be 500ppm (w/v) or less, such as from about 10ppm (w/v) or less to about 200ppm (w/v). Preservative components effective to aid in the preservation of the compositions of the present invention preferably include, but are not limited to, those that form complexes with polyanionic components to a lesser extent than benzalkonium chloride.

Examples of components effective to aid in the preservation of the compositions, preferably TACs in the compositions, include, but are not limited to, oxidative preservative components such as oxygen-Chlorine components, peroxides, persalts, peracids, and the like, and mixtures thereof. Specific examples of oxy-chlorine components that may be used as preservatives in the present invention include hypochlorite components such as hypochlorite; chlorate components such as chlorate; perchlorate components such as perchlorate; and a chlorite component. Examples of the chlorite component include Stabilized Chlorine Dioxide (SCD), metal salts of chlorous acid, such as alkali metal and alkaline earth metal salts of chlorous acid, and the like, and mixtures thereof. Technical grade (or USP grade) sodium chlorite is a very useful preservative component. The exact chemical composition of many chlorite components, such as SCD, is not fully understood. The production or preparation of certain chlorite components is described in U.S. patent No. 3,278,447 to McNicholas, which is incorporated herein by reference in its entirety. Specific examples of SCD products that may be used include those sold under the trade name Dura Klor by Rio Linda chemical company, Inc, and those sold under the trade name Anthium Dioxide by International Dioxide, Inc. Particularly useful SCDs are available under the trade name Purite^Those sold by Allergan, Inc. Other examples of oxidative preservative components include peroxygen components. For example, minor amounts of peroxygen components stabilized with hydrogen peroxide stabilizers such as diethylenetriamine penta (methylene phosphonic acid) or 1-hydroxyethylidene-1, 1-diphosphonic acid may be used as preservative components designed for use in ocular environment components. Moreover, virtually any peroxy component can be used, so long as it hydrolyzes in water to produce hydrogen peroxide. Examples of such sources of hydrogen peroxide that provide an effective generation amount of hydrogen peroxide include sodium perborate decahydrate, sodium peroxide, and urea peroxide. It has been found that peracetic acid, an organic peroxy compound, may not be stabilized with current systems. See, for example, Martin et al U.S. patent No. 5,725,887, which is incorporated herein by reference in its entirety.

In a broad embodiment of the invention, additional preservatives that are not oxidative preservative components may be included in the compositions. Preservatives may be selected according to the route of administration. Preservatives suitable for use in compositions administered by one route may have adverse properties that prevent their administration by another route. For nasal and ophthalmic compositions, preferred preservatives include quaternary ammonium compounds, particularly mixtures of alkylbenzyldimethyl ammonium compounds commonly referred to as "benzalkonium chloride", and the like. However, for compositions administered by inhalation, the preferred preservative is chlorobutanol or the like. Other preservatives may be used, particularly for rectally administrable compositions, including alkyl esters of p-hydroxybenzoic acid and the like and mixtures thereof, such as mixtures of the methyl, ethyl, propyl and butyl esters sold under the trade name "Nipastat".

In another broad aspect, the invention provides a composition comprising a TAC, a preservative component, wherein the preservative component is present in an effective amount at least to aid in preserving the composition and liquid carrier components, preferably in preserving the composition and liquid carrier components. Preferably, the preservative component comprises an oxy-chloro component such as a compound, ion, complex, or the like, having the following properties: (1) have no substantial or significant adverse effect on the TACs in the composition or on the patient to whom the composition is administered, and (2) are biologically acceptable and chemically stable in nature. Such inventive compositions comprise TAC, an oxy-chloro component, and a liquid carrier component, and are preferably substantially free of cyclodextrin.

The carrier components selected for use in the present invention are non-toxic and do not substantially adversely affect the composition of the present invention, the use of the composition, or the human or animal to whom the composition is administered. In one embodiment, the carrier component is a liquid component. In a preferred embodiment, the carrier component is a liquid aqueous carrier component. Particularly useful aqueous liquid carrier components are those derived from saline, such as conventional saline solutions or conventional buffered saline solutions. The pH of the aqueous liquid carrier is preferably from about 6 to about 9 or about 10, more preferably from about 6 to about 8, still more preferably about 7.5. The liquid medium preferably has an ophthalmically acceptable tonicity level, for example, of at least about 200mOsmol/kg, more preferably from about 200 to about 400 mOsmol/kg. In particularly useful embodiments, the osmolality (osmolality) or tonicity of the carrier component substantially corresponds to the tonicity of the fluid of the eye, particularly the human eye.

In one embodiment, the carrier component containing the TACs, SECs and preservatives has a viscosity greater than about 0.01 centipoise (cps), preferably greater than about 1cps, and even more preferably greater than about 10cps at 25 ℃. In a preferred embodiment, the composition has a viscosity of about 50cps at 25 ℃ and comprises a conventional buffered saline solution, carboxymethyl cellulose and brimonidine.

To ensure that the pH of the aqueous liquid carrier component, and thus the pH of the composition, is maintained within the desired range, the aqueous liquid carrier component may comprise at least one buffer component. Although any suitable buffering component may be used, it is preferred to choose not to generate significant amounts of chlorine dioxide or to release significant amounts of gases such as CO₂The buffer component of (1). The buffer component is preferably an inorganic component. Alkali metal and alkaline earth metal buffer components may be advantageously used in the present invention.

Any suitable ophthalmically acceptable tonicity component may be used, so long as such component is compatible with the other ingredients of the liquid aqueous carrier component and does not have deleterious or toxic properties that may impair the human or animal to whom the composition of the present invention is administered. Examples of useful tonicity components include sodium chloride, potassium chloride, mannitol, dextrose, glycerin, propylene glycol and mixtures thereof. In one embodiment, the tonicity component is selected from inorganic salts and mixtures thereof.

The compositions of the invention may suitably be solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions. The compositions of the present invention may contain one or more additional components such as diluents, flavoring agents, surfactants, thickeners, lubricants and the like, such as are commonly used in the same general type of compositions.

The compositions of the present invention in the form of aqueous suspensions may contain excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate and the like and mixtures thereof. Such aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin, and the like, and mixtures thereof.

The compositions of the present invention in the form of oil suspensions may be formulated in vegetable oils, such as olive oil, sesame oil or coconut oil, or in mineral oils, such as liquid paraffin. Such suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.

The compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or the like, and mixtures thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

The compositions of the present invention in the form of syrups and elixirs may be formulated with sweetening agents, for example those described herein. Such formulations may also contain a demulcent (demulcent), and flavoring and coloring agents.

The specific dosage level for any particular human or animal will depend upon a variety of factors including the activity of the active ingredient employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular condition being treated.

The following non-limiting examples illustrate some aspects of the invention.

Example 1

Brimonidine has a pKa of about 7.78. The pH-solubility profile of 0.5% (w/v) brimonidine in the formulation, ophthalmic solution was determined at 23 ℃ over a pH range of about 5 to about 8. Table 1. It is understood that adrenergic agonist concentrations other than 0.5% may be used, so long as they are therapeutically active. Likewise, the temperature can be varied, for example, a solubility curve can be prepared at 37 ℃ (98.6 ° F). The formulation vehicle was prepared as follows: polyvinyl alcohol (PVA) was first dissolved in water. PVA was added to about 1/3 total required amount of purified water with constant stirring. The slurry was stirred for 20-30 minutes and then heated to 80-95 ℃ with constant stirring. Within 1 hour after reaching the temperature of 80-90 ℃, the mixture was removed from the heating source and stirred for an additional 10 minutes to ensure homogeneity (part I). In a separate container, the other components of the ophthalmic solution, except brimonidine, were dissolved with an additional 1/3 total amount of purified water (part II). The PVA mixture (part I) was then quantitatively transferred to part II using several wash volumes of purified water. The solution was adjusted to the final volume with purified water without pH adjustment.

Brimonidine was weighed and transferred to a 10mL tube containing 5mL of the above formulated vehicle. The pH of each sample is then adjusted to the desired value using dilute sodium hydroxide and/or dilute hydrochloric acid. Placing the sample in a fixed frame on a stirring plate, and stirring at high speed to mix uniformly for 2 days; a spacer is placed between the holder and the stirring plate to prevent heat from diffusing from the stirring plate into the sample. The laboratory temperature was monitored throughout the experiment and found to be 23 ± 1 ℃.

At the end of the 2 day stirring, the pH of each sample was measured, and then approximately 1mL of each sample was placed in a microcentrifuge tube (polypropylene) and centrifuged at 4,000rpm for 10 minutes. The supernatant was filtered through a 1 μm filter device (Whatman, 13mm, PTFE). Discarding the first 3-4 drops of filtrate; the remaining filtrate was collected and quantitatively diluted with HPLC mobile phase. The diluted sample was then directly injected onto an HPLC column (Dupont Zorbax, 250 mm. times.4.6 mm, 5 μm) for determination of brimonidine to quantitatively determine the amount of brimonidine. A10.05% brimonidine control solution was prepared in the formulation vehicle at pH6.3-6.5 and assayed before (untreated) and after (treated) centrifugation and filtration. This was done to evaluate the possible loss of brimonidine in these two steps of preparing the samples. To ensure reproducibility, the experiment was repeated over successive days.

Table i. 0.5% brimonidine in ophthalmic solution

Component% (w/v)

Brimonidine 0.50

Benzalkonium chloride, NF 0.0050

Polyvinyl alcohol, USP 1.4

Sodium chloride, USP 0.66

Sodium citrate, dihydrate, USP 0.45

Hydrochloric acid, NF or for adjusting the pH

Sodium hydroxide, NF 5-8

Purified water, USP QS

Table II gives the solubility data for brimonidine in the formulated vehicle. The results show that the solubility of brimonidine is highly pH dependent, spanning more than two orders of magnitude over the pH range of 5-8. As pH increases, solubility decreases significantly. The results for the treated and untreated control solutions were very close, meaning that centrifugation and filtration did not cause any significant loss of brimonidine. The two solubility characteristics obtained over successive days are in line with each other.

Table ii solubility of brimonidine in ophthalmic solutions having pH of 5-8

Experiment 1 experiment 2

pH of the sample^aSolubility in water^e pH^aSolubility in water^e

1 5.55 ≥164.4^b 5.50 ≥200.6^b

2 5.92 132.6 5.92 160.8

3 6.14 30.4 6.06 50.1

4 6.57 7.55 6.90 3.19

5 7.00 2.69 7.40 1.19

6 7.45 1.17 7.77 0.63

7 7.83 0.62 7.86 0.58

8 - - 7.88 0.54

Contrast-

(untreated) -0.486^c - -

Contrast-

(treatment) -0.484^d - -

^aAfter stirring for 2 days, the samples were centrifuged and filtered as determined before.

^bRepresenting the theoretical concentration by weight of the sample. The sample solution was clear, indicating that all brimonidine had dissolved.

^cBrimonidine concentration in the control prior to centrifugation and filtration steps.

^dBrimonidine concentration in the control after centrifugation and filtration steps.

^e％w/v。

Example 2

The pH-solubility characteristics of brimonidine were determined in compositions (solutions) containing SECs and oxy-chloro components. In particular, the effect of sodium carboxymethylcellulose (CMC), SEC on brimonidine solubility at different pH conditions was determined. The different CMC concentrations tested with brimonidine were 0%, 0.056%, 0.17%, 0.5%, 1.5% (w/v), Table III.

The samples tested also contained an isotonic component, a buffer component, and stabilized chlorine dioxide (Purite)^TM) Table III. Sodium carboxymethylcellulose, sodium chloride, potassium chloride, calcium chloride dihydrate, and magnesium chloride hexahydrate are USP grades. Boric acid and sodium borate decahydrate are NF grades.

TABLE III

Sample 1, sample 2, sample 3, sample 4, sample 5 brimonidine 0.2%, 0.2%

(w/v)CMC 0.0％ 0.056％ 0.17％ 0.5％ 1.5％

(w/v) Stable bis 0.005% 0.005% 0.005% 0.005% 0.005% chlorine oxide^a (w/v) sodium chloride 0.58% 0.58% 0.58% 0.58% 0.58%

(w/v) Potassium chloride 0.14% 0.14% 0.14% 0.14% 0.14%

(w/v) calcium chloride bis 0.02% 0.02% 0.02% 0.02% 0.02% hydrate (w/v) magnesium chloride hexa0.006% 0.006% 0.006% 0.006% 0.006% 0.006% hydrate (w/v) boric acid 0.2% 0.2% 0.2%

(w/v) sodium tetraborate 0.14% 0.14% 0.14% decahydrate (w/v)

^aUnder the trade name Purite^TMSold by Allergan, Inc.

Each sample (1-5) was tested at a pH ranging from about 7 to about 10. Vials containing the sample solution were placed on a laboratory rotator and equilibrated at room temperature (-21 ℃) for 15 days. The sample solution was filtered using a 25mm diameter polysulfone cellulose acetate syringe-type filter with a pore size of 0.45 μm. The filtrate was assayed for brimonidine.

The concentration of dissolved brimonidine was determined and determined using conventional HPLC and detection techniques. Table IV. For each CMC concentration, the solubility was plotted against the pH. Fitting experimental data points to nonlinear least squares routine (Deltagrapersion 4.0 DeltaPoint, Inc.) was usedModified Henderson-Hasselbalch equation, FIG. 1. R²Values indicate a good agreement between experimental values and theoretical equations, better than 0.991.

TABLE IV

Solubility of brimonidine (%)

0％CMC 0.056％CMC 0.17％CMC 0.5％CMC 1.5％CMC pH6.67 0.9302 1.44646.68 1.4256 1.42006.93 0.73027.10 0.36937.11 0.2064 0.28287.35 0.19047.56 0.14517.68 0.07867.77 0.07217.81 0.07358.10 0.04988.46 0.0313B.50 0.02868.55 0.03288.67 0.03119.93 0.02349.94 0.025010.05 0.024110.09 0.021810.11 0.0222

Figure 1 clearly shows that the solubility of brimonidine tends to increase with increasing CMC concentration. For example, at pH7.5, a sample containing 0% CMC results in 1000ppm brimonidine; 0.056% CMC, 1300 ppm; 0.17% CMC, 1300 ppm; and 0.5%, 1600 ppm. At pH7.5, the sample containing 1.5% CMC resulted in about 1400ppm, lower than a similar solution containing 0.5% CMC. The cause of the observation at this point is unclear. However, the solubility of brimonidine in solutions containing 1.5% CMC was greater than that in solutions without CMC.

CMC is also effective in enhancing the dissolution of brimonidine in biological environments such as the corneal biological environment.

While the invention has been described in terms of various specific examples and embodiments, it is to be understood that the invention is not so limited, and that it can be variously practiced within the scope of the following claims.

Claims (52)

1. A composition comprising:

a therapeutically active component in an amount effective to provide a desired therapeutic effect to a patient to whom the composition is administered;

a solubilizing component other than a cyclodextrin in an amount effective to increase the solubility of the therapeutically active component in the composition relative to the solubility of the same therapeutically active component in a similar composition without the solubilizing component;

an amount of an oxy-chloro component effective to at least assist in preserving the composition; and

a liquid carrier component.

2. The composition of claim 1, wherein the therapeutically active component is selected from the group consisting of: antibacterial agents, antihistamines, decongestants, anti-inflammatory agents, antiparasitic agents, miotics, anticholinergics, adrenergic agents, antiviral agents, local anesthetics, fungicides, amoebicides, trichomonacides, analgesics, mydriatics, antiglaucoma drugs, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic active agents as surgical adjuvants, chelating agents, antineoplastic agents, antihypertensive agents, muscle relaxants, diagnostic agents, derivatives thereof, and mixtures thereof.

3. The composition of claim 1, wherein the therapeutically active component is selected from the group consisting of adrenergic agonists and mixtures thereof.

4. The composition of claim 1, wherein said therapeutically active component is selected from the group consisting of alpha-2-adrenergic agonists and mixtures thereof.

5. The composition of claim 1 wherein said therapeutically active component is selected from the group consisting of iminoimidazolines, imidazolines, imidazoles, aza  s, thiazines, oxazolines, guanidines, catecholamines, derivatives thereof, and mixtures thereof.

6. The composition of claim 1 wherein the therapeutically active component comprises a quinoxaline component.

7. The composition according to claim 6 wherein the quinoxaline component is selected from the group consisting of quinoxaline, derivatives thereof, and mixtures thereof.

8. The composition of claim 6 wherein the quinoxaline component is selected from the group consisting of quinoxalines, (2-imidazolin-2-ylamino) quinoxalines, 5-bromo-6- (2-imidazolin-2-ylamino) quinoxalines, and tartrates of 5-bromo-6- (2-imidazolin-2-ylamino) quinoxalines, derivatives thereof and mixtures thereof.

9. The composition of claim 1 wherein said therapeutically active component comprises the tartrate salt of 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline.

10. The composition of claim 1, wherein diffusion of the therapeutically active component across the lipid membrane is increased relative to the same therapeutically active component in a similar composition without the solubilizing component.

11. The composition of claim 1, wherein the solubilizing component is effective to increase the solubility of the therapeutically active component in the biological environment relative to the solubility of the same therapeutically active component in a similar composition without the solubilizing component in the biological environment.

12. The composition of claim 1, wherein the solubilizing component comprises a polyanionic component.

13. The composition of claim 12 wherein the polyanionic component is selected from the group consisting of anionic cellulose derivatives, anionic polymers derived from acrylic acid, anionic polymers derived from methacrylic acid, anionic polymers derived from alginic acid, anionic polymers derived from amino acids, and mixtures thereof.

14. The composition of claim 1, wherein the solubilizing component is selected from the group consisting of anionic cellulose derivatives and mixtures thereof.

15. The composition of claim 1, wherein the solubilizing component is selected from the group consisting of carboxymethylcellulose and mixtures thereof.

16. The composition of claim 1, wherein the solubilizing component is present in an amount of from about 0.1% (w/v) to about 30 (w/v).

17. The composition of claim 1, wherein the solubilizing component is present in an amount of about 0.2% (w/v) to about 10% (w/v).

18. The composition of claim 1, wherein the solubilizing component is present in an amount of about 0.2% (w/v) to about 0.6% (w/v).

19. The composition of claim 1, wherein the oxy-chloro component is selected from the group consisting of a hypochlorite component, a perchlorate component, a chlorite component, and mixtures thereof.

20. The composition of claim 1 wherein the oxy-chloro component comprises a chlorite component.

21. The composition of claim 1, wherein the oxy-chlorine component comprises stabilized chlorine dioxide.

22. The composition of claim 1, wherein the oxy-chloro component is present in an amount of about 500ppm (w/v) or less.

23. The composition of claim 1, wherein the oxy-chloro component is present in an amount of about 10ppm (w/v) to about 200ppm (w/v).

24. The composition of claim 1, wherein the composition further comprises an additional preservative component other than an oxy-chloro component in an amount effective to at least assist in preserving the composition.

25. The composition of claim 24 wherein the additional preservative component is selected from the group consisting of sorbic acid, benzalkonium chloride, alkyl esters of chlorobutanol and p-hydroxybenzoic acid and mixtures thereof.

26. The composition of claim 1, wherein the liquid carrier is an aqueous liquid carrier component.

27. The composition of claim 1, wherein the composition is a solution.

28. The composition of claim 1, wherein the pH of the composition is about 7 or greater.

29. The composition of claim 1, wherein the pH of the composition is from about 7 to about 9.

30. The composition of claim 1, wherein the composition is ophthalmically acceptable.

31. A composition comprising:

a therapeutically active component selected from the group consisting of alpha-2 adrenergic agonists and mixtures thereof in an amount effective to provide a therapeutic effect to a patient to whom the composition is administered;

a content of an anionic cellulose derivative effective to increase the solubility of the therapeutically active component;

a chlorite salt component in an amount effective to at least assist in preserving the composition; and

an aqueous liquid carrier component.

32. The composition of claim 31 wherein said therapeutically active component comprises the tartrate salt of 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline.

33. The composition of claim 31, wherein the anionic cellulose derivative comprises carboxymethyl cellulose.

34. The composition of claim 31, wherein the anionic cellulose derivative is present in an amount of about 0.2% to about 0.6% (w/v).

35. A composition comprising:

a content of a tartrate salt of 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline that is effective to provide a therapeutic effect to a patient to whom the composition is administered;

a solubilizing component in an amount effective to increase the solubility of the tartrate salt of 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline;

a chlorite salt component in an amount effective to at least assist in preserving the composition; and

an aqueous liquid carrier component.

36. The composition of claim 35, wherein the solubilizing component comprises carboxymethyl cellulose.

37. The composition of claim 35, wherein the composition is ophthalmically acceptable.

38. A composition comprising:

a therapeutically active component in an amount effective to provide a desired therapeutic effect to a patient to whom the composition is administered;

an amount of an oxy-chloro component effective to at least assist in preserving the composition; and

a liquid carrier component, wherein the composition is substantially free of cyclodextrin.

39. The composition of claim 38, wherein the therapeutically active component is selected from the group consisting of: antibacterial agents, antihistamines, decongestants, anti-inflammatory agents, antiparasitic agents, miotics, anticholinergics, adrenergic agents, antiviral agents, local anesthetics, fungicides, amoebicides, trichomonacides, analgesics, mydriatics, antiglaucoma drugs, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic active agents as surgical adjuvants, chelating agents, antineoplastic agents, antihypertensive agents, muscle relaxants, diagnostic agents, derivatives thereof, and mixtures thereof.

40. The composition of claim 38, wherein the therapeutically active component is selected from the group consisting of adrenergic agonists and mixtures thereof.

41. The composition of claim 38, wherein said therapeutically active component is selected from the group consisting of alpha-2-adrenergic agonists and mixtures thereof.

42. The composition of claim 38, wherein said therapeutically active component is selected from the group consisting of iminoimidazolines, imidazolines, imidazoles, aza  s, thiazines, oxazolines, guanidines, catecholamines, derivatives thereof, and mixtures thereof.

43. The composition of claim 38, wherein the therapeutically active component comprises a quinoxaline component.

44. The composition according to claim 43 wherein the quinoxaline component is selected from the group consisting of quinoxalines, derivatives thereof, and mixtures thereof.

45. The composition of claim 43 wherein the quinoxaline component is selected from the group consisting of tartrates of quinoxaline, (2-imidazolin-2-ylamino) quinoxaline, 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline, and 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline, derivatives thereof and mixtures thereof.

46. The composition of claim 38 wherein said therapeutically active component comprises the tartrate salt of 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline.

47. The composition of claim 38, wherein the composition further comprises a solubilizing component other than a cyclodextrin in an amount effective to increase the solubility of the therapeutically active component in the composition relative to the solubility of the same therapeutically active component in a similar composition without the solubilizing component.

48. The composition of claim 47, wherein the solubilizing component comprises a polyanionic component.

49. The composition of claim 38, wherein the oxy-chloro component is selected from the group consisting of a hypochlorite component, a perchlorate component, a chlorite component, and mixtures thereof.

50. The composition of claim 38 wherein the oxy-chloro component comprises a chlorite component.

51. The composition of claim 38, wherein the oxy-chlorine component comprises stabilized chlorine dioxide.

52. The composition of claim 38, wherein the composition is ophthalmically acceptable.