Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to compositions containing therapeutic components, hereinafter TCs, for example, alpha-2-adrenergic agonists. More particularly, the invention relates to such compositions including such TCs, and advantageously one or more other components, in which compositions the TCs preferably have enhanced pharmaco inetic characteristics.
• TCs therapeutic components
• alpha-2-adrenergic agonists for example, alpha-2-adrenergic agonists.
• the invention relates to such compositions including such TCs, and advantageously one or more other components, in which compositions the TCs preferably have enhanced pharmaco inetic characteristics.
• a TC includes any chemical entity, such as a compound, an ion, a complex and the like, which is effective to act on and/or bind to receptors and provide a therapeutic effect.
• the TC may be an agonist, an antagonist, precursors thereof, metabolites thereof and combinations thereof.
• compositions having TCs are able to render such compositions more effective.
• One way to render the TCs more effective is to enhance their pharmacokinetic dispositions.
• the dispensed or administered TCs should advantageously be permeable through lipid cell membranes so that the agonist may reach the target receptor to impart a therapeutic effect.
• One possible reason for why certain TCs permeate poorly through a lipid membrane is that these components may be charged ions at physiological pH.
• an enhancement of pharmacokinetic disposition may mean an enhancement in permeability
• an enhancement of pharmacokinetic disposition may also mean an enhancement in, for example, bioavailability, sequestration and/or release characteristics of the TCs.
• the present compositions contain certain materials which are effective in enhancing the efficacy of the TCs of the compositions. Without limiting the invention to any particular theory or mechanism of operation, it is believed that the efficacy of the TCs is enhanced because of improved pharmacokinetics, for example, increased permeability of the TCs through lipid bilayers. In one embodiment, these materials enhance the bioavailability of the TCs in the eye. Preferably, the materials are able to enhance the pharmacokinetics of the TCs under physiological conditions, for example at pHs of about 6.5 to about 9.
• the TCs are advantageously ionized or ionizable at physiological pHs, for example, about pH 6.0 to about pH 9.0. In one embodiment, the TCs are ionized or ionizable at about pH 7.
• TCs employed in the present compositions include those compounds, mixtures of compounds, mixtures of other materials, which are useful to provide a therapeutic benefit or effect when administered to a patient, e.g. a human patient.
• the TCs useful in this invention include, without limitation, NMDA antagonists, antibacterials, antihistamines, decongestants, antiinflammatory, antiparasitics, miotics, anticholinergics, adrenergics, antivirals, local anesthetics, antifungals, amoebicidals, trichomonocidals, analgesics, mydriatics, antiglaucoma drugs, neuroprotective agents, antiaugiogenic agents, ophthalmic diagnostic agents, ophthalmic agents used as adjuvants in surgery, chelating agents, antineoplastics, antihypertensives, muscle relaxants, diagnostics and the like and mixtures thereof. Specific examples of such TCs are conventional and well known in the art.
• the TCs may include alpha-2-adrenergic agonists.
• Alpha-2-adrenergic agonists include imin ⁇ -imidazolines, imidazolines, imidazoles, azepines, thiazines, oxazolines, guanidines, catechola ines, biologically compatible salts and esters and mixtures thereof.
• the alpha-2-adrenergic agonist may include quinoxaline components.
• Quinoxaline components include quinoxaline, biologically compatible salts thereof, esters thereof, other derivatives thereof and the like, and mixtures thereof.
• Non-limiting examples of quinoxaline derivatives include (2-imidozolin-2-ylamino) quinoxaline, 5-bromo-6- (2-imidozolin-2-ylamino) quinoxaline, and biologically compatible salts thereof and esters thereof, for example, the tartrate of 5- bromo-6- (2-imidozolin-2-ylamino) quinoxaline, and the like and mixtures thereof.
• 5-bromo-6- (2- imidozolin-2-ylamino) quinoxaline is referred to as “brimonidine”
• the tartrate of 5-bromo-6- (2- imidozolin-2-ylamino) quinoxaline is referred to as "brimonidine tartrate .
• alpha-2-adrenergic agonists such as those listed above, may be specific for the alpha-2A- adrenergic receptors, alpha-2B-adrenergic receptors and/or alpha-2D-adrenergic receptors or any combination thereof.
• EECs efficacy enhancing components
• the EEC includes fatty acids, saturated and/or unsaturated.
• the fatty acids of the present invention may have more than 12 carbons, for example docosahexanoic acid and linolenic acid.
• the fatty acids of the present invention comprise about 12 carbons to about 26 carbons.
• the fatty acids of the present invention comprise about 16 carbons to about 24 carbons.
• the EECs themselves are effective to provide at least one therapeutic effect.
• the TC and the EEC form and/or are present in the form of a complex in the compositions of the present invention.
• the TC and the EEC form a complex in solution, for example, a complex may be formed in a solution at a pH of about 5 to about 9, for example, about pH 7 to about pH 9.
• the EEC and the TC form a complex that is an ion pair, for example, in an aqueous component.
• the TC and EEC are able to form a complex present as a separate phase, for example a salt-like material and or oil phase, outside of a solution.
• compositions may include carrier components.
• the compositions have pHs of about 7 or greater.
• the compositions may have pHs of between about 7 and about 9, and preferably are ophthalmically acceptable.
• a solubilizer component may be included in the present compositions.
• the solubilizer component is present in an amount effective to enhance the solubility of the complexes in the present compositions.
• the solubilizer component is advantageously nonionic.
• useful solubilizer components include poly (oxyethylene) - poly (oxypropylene) block polymers, polysorbate 80, polyvinyl alcohol, polyvinylpyrrolidine, hydroxypropylmethyl cellulose and the like and mixtures thereof.
• the present compositions may include an effective amount of a nonionic tonicity component.
• Nonlimiting examples of useful nonionic tonicity components are mannitol, glycerine and mixtures thereof.
• the EEC and TC advantageously are present in amounts so that the ratio of electrical charge from the EEC to electrical charge from the TC is in range of about 0.9 to about 1.5. In a preferred embodiment, the ratio of electrical charge from the EEC to electrical charge from the TC is in a range of about 0.95 to about 1.4, for example, about 1.0 to about 1.3.
• the present compositions may include a buffer component. Although any suitable buffer component may be employed, it is advantageous to employ a buffer component which is effective at reduced concentrations, for example, to assist in reducing the ionic concentration in the present compositions.
• the buffer component is present in a range of about 0.001 molar or about 0.005 molar to about 0.05 molar about 0.1 molar.
• the buffer component is a phosphate buffer component.
• compositions comprising therapeutic components, TCs, and efficacy enhancing components, EECs.
• the EECs employed in the present compositions may be effective in enhancing the pharmacokinetics of the TCs.
• the EEC may enhance the therapeutic effect of the therapeutic component.
• the present compositions may further include liquid carrier components and have the characteristics of liquid, for example, aqueous liquid, solutions.
• the TC and the EEC form complexes.
• the complexes formed may be a "loose” ion pair or a "tight” ion pair.
• the complex of the present invention is a "tight" ion pair.
• the complexes of this invention are adequately “tight” as to not dissociate in high dielectric constant solvent, such as water or aqueous solutions.
• One advantage of such a "tight" ion pair complex is that the complex may be contained in an aqueous solution, for example saline, which may be used in an ophthalmic environment .
• the complex is able to dissociate under certain conditions. For example, after the complex crosses the lipid layer, the TC may activate a targeted molecule more effectively if it is not complexed to an EEC. Therefore, in one embodiment, the TC and the EEC exist as a complex for the purpose of enhancing the pharmacokinetic disposition of the TC and thereafter dissociate to allow the TC to act more effectively at a receptor.
• a single TC may form a complex with more than one EEC, for example two or three EECs.
• a single EEC may form a complex with more than one TC, for example two or three TCs.
• a single TC molecule may form a complex with one or more EEC molecules, for example, one, two or three EEC molecules may form a complex with one TC molecule.
• a single EEC molecule may form a complex with more than one TC molecules, for example, two or three TC molecules may form a complex with one EEC molecule.
• the presently useful TCs preferably are chosen to benefit from the presence of the EECs.
• the TCs are provided with enhanced ability to cross a lipid membrane when they complex with the EECs .
• the TCs are basic molecules. In another embodiment, the TCs are cations.
• TCs which may be included in the present compositions include, but are not limited to, NMDA antagonists; antibacterial substances such as beta- lactam antibiotics, such as cefoxitin, n- formamidoylthienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, carbenicillin, colistin, penicillin G, polymyxin B, vancomycin, cefazolin, cephaloridine, chibrorifamycin, gramicidin, bacitracin and sulfonamides; aminoglycoside antibiotics such as gentamycin, kanamycin, amikacin, sisomicin and tobramycin; nalidixic acid and its analogs such as norfloxacin and the antimicrobial combination fluoroalanine/pentizidone, nitrofurazones and analogs thereof; antihistaminics and decongestants such as pyrilamine, chlorpheniramine,
• TCs are: antiglaucama drugs, for example, timolol, and especially its maleic salt and R- timolol and a combination of timolol or R-timolol with pilocarpine; other adrenergic agonists and/or antagonists such as epinephrine and an epinephrine complex, or prodrugs such as bitartrate, borate, hydrochloride and dipivefrine derivatives; carbonic anhydrase inhibitors such as acetazolamide, dichlorphenamide, 2- (p-hydroxyphenyl) -thiothiophene- sulfonamide, 6-hydroxy-2-benzothiazolesulfonamide, and 6-pivaloyloxy-2-benzothiazolesulfonamide; antiparasitic compounds and/or anti-protozoal compounds such as ivermectin, pyrimethamine, trisulfapidimidine, clindamycin and cor
• the useful TCs include adrenergic agonists.
• the adrenergic agonists may be molecules containing amines.
• the adrenergic agonists may be amine-containing molecules with pKa's of greater than 7, preferably about 7 to about 9.
• the useful TCs include alpha- adrenergic agonists.
• alpha-adrengergic agonists include, but not limited to, adrafinil, adrenolone, amidephrine, apraclonidine, budralazine, clonidine, cyclopentamine, detomidine, dimetofrine, dipivefrin, ephedrine, epinephrine, fenoxazoline, guanabenz, guanfacine, hydroxyamphetamine, ibopamine, indanazoline, isometheptene, mephentermine, metaraminol, methoxamine, methylhexaneamine, metizolene, midodrine, naphazoline, norepinephrine, norfenefrine, octodrine, octopamine, oxymetazoline, phenylephrine, phenylpropanolamine
• the TCs include alpha-2- adrenergic agonists.
• alpha-2 adrenergic agonist includes chemical entities, such as compounds, ions, complexes and the like, that may produce a net sympatholytic response, resulting in increased accommodation, for example, by binding to presynaptic alpha-2 receptors on sympathetic postganglionic nerve endings or, for example, to postsynaptic alpha-2 receptors on smooth muscle cells.
• a sympatholytic response is characterized by the inhibition, diminishment, or prevention of the effects of impulses conveyed by the sympathetic nervous system.
• the alpha-2 adrenergic agonists of the invention may bind to the alpha-2 adrenergic receptors presynaptically, causing negative feedback to decrease the release of neuronal norepinephrine. Additionally, they also may work on alpha-2 adrenergic receptors postsynaptically, inhibiting beta-adrenergic receptor- stimulated formation of cyclic AMP, which contributes to the relaxation of the ciliary muscle, in addition to the effects of postsynaptic alpha-2 adrenergic receptors on other intracellular pathways. Activity at either pre- or postsynaptic alpha-2 adrenergic receptors may result in a decreased adrenergic influence.
• Alpha-2 adrenergic agonists also include compounds that have neuroprotective activity.
• 5-bromo-6- (2- imidozolin-2-ylamino) quinoxaline is an alpha-2- adrenergic agonist which has a neuroprotective activity through an unknown mechanism.
• alpha-2 adrenergic agonists useful in this invention: imino- imidazolines, including clonidine, apraclonidine; imidazolines, including naphazoline, xymetazoline, tetrahydrozoline, and tramazoline;, imidazoles, including detomidine, medetomidine, and dexmedetomidine; azepines, including B-HT 920 (6-allyl-2-amino-5, 6, 7, 8 tetrahydro- 4H-thiazolo [4, 5-d] -azepine 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.
• the quinoxaline components include quinoxaline, derivatives thereof and mixtures thereof.
• the derivatives of quinoxaline include, without limitation, (2-imidozolin- 2-ylamino) quinoxaline.
• the derivatives of quinoxaline include 5-halide-6- (2- imidozolin-2-ylamino) quinoxaline.
• the "halide" of the 5-halide-6- (2-imidozolin-2-ylamino) quinoxaline may be a fluorine, a chlorine, an iodine, or preferably, a bromine, to form 5-bromo-6- (2-imidozolin-2-ylamino) quinoxaline.
• Other useful quinoxaline derivatives are well known.
• useful derivatives of a quinoxaline include the ones disclosed by Burke et al U.S. Patent No. 5,703,077. See also Danielwicz et al 3,890,319. Each of the disclosures of Burke et al and Danielwicz et al is incorporated in its entirety by reference herein.
• the quinoxaline and derivatives thereof are amine-containing and preferably have pKa's of greater than 7, preferably about 7.5 to 9. Analogs of the foregoing compounds that function as alpha-2 adrenergic agonists also are specifically intended to be embraced by the invention.
• alpha-2-adrenergic agonists for example the ones listed above, may be effective toward activating one or more of alpha-2A-adrenergic receptors, alpha-2B- adrenergic receptors and alpha-2D-adrenergic receptors.
• the composition of the present invention includes a TC other than an alpha-2-adrenergic agonist.
• a composition in accordance with the present invention may include a TC which is not a quinoxaline such as 5-bromo-6- (2-imidozolin-z-ylamino) quinoxaline (brimonidine) .
• TCs include ocular hypotensive agents (Woodward et al U.S. Patent No. 5,688,819), pyranoquinolinone derivatives (Cairns et al U.S. Patent No. 4,474,787), compounds having retinoid-like activities (Chandraratna U.S. Patent No. 5,089,509), ketorolac/pyrrole-1-carboxylic acids (Muchowski et al U.S. Patent No. 4,089,969), ofloxacins/benzoxazine derivatives (Hayakawa et al U.S Patent No. 4,382,892), memantines (Lipton et al U.S. Patent No. 5,922,773).
• ocular hypotensive agents Woodward et al U.S. Patent No. 5,688,819
• pyranoquinolinone derivatives Cairns et al U.S. Patent No. 4,474,
• the amount of TC in the present composition is in the range of about 0.05% to about 30% (w/v) .
• the amount of TC may be in the range of about 0.1% (w/v) to about 10% (w/v) .
• the amount of TC may be in the range of about 0.1% (w/v) to about 0.6% (w/v).
• the TC is an adrenergic agonist and is present in the composition in the range of about 0.1% (w/v) to about 0.6% (w/v), for example, about 0.13%.
• EECs are acidic molecules.
• EECs are anions.
• EECs include fatty acids or derivatives thereof.
• the fatty acids may possess a long hydrophobic carbon chain and a terminal carboxyl group.
• the chain may be saturated, or it may have one or more double bonds.
• fatty acids may contain triple bonds.
• Fatty acids may differ, for example, in length and in the number and position of their unsaturated bonds.
• saturated fatty acids include lauric acid, myristic, palmitic, stearic, arachidic, lignoceric, derivatives thereof, and the like and mixtures thereof.
• Non-limiting examples of unsaturated fatty acids include palmitoleic, oleic, linoleic, linblenic, arachidonic, derivatives thereof, and the like and mixtures thereof.
• Other examples of some unusual fatty acids include trans-Vaccenic acid, lactobacillic, tuberculostearic, cerebronic, derivatives thereof, and the like and mixtures thereof.
• the EEC includes a docosahexanoic acid. In another embodiment, the EEC includes a linolenic acid.
• the fatty acids of the present invention comprises about 12 carbon atoms to about 26 carbon atoms. In another embodiment, the fatty acids of the present invention comprises about 16 carbon atoms to about 24 carbons.
• an EEC has a direct therapeutic effect.
• an EEC may include eicosanoids, such as prostanoids .
• a prostanoid is any group of complex fatty acids derived from arachidonic acid, being 20 carbon in length with an internal 5 or 6 carbon ring, for example prostaglandin, protanoic acid and thromboxanes . Prostanoids are known to reduce intraocular pressure.
• a composition according to the invention comprises a complex having a TC and a therapeutically effective EEC.
• a composition according to the present invention may comprise a complex of an adrenergic agonist and a prostanoid.
• Both the adrenergic agonist and the prostanoid may act, via different mechanisms, to provide an additive therapeutic effect, for example, to reduce intra-ocular pressure.
• the EEC may exert its therapeutic effects when it is still bound to a complex, or the EEC may exert its effects when it is free from the complex.
• fatty acids are preferred as counter ions to form complexes with TCs, such as the adrenergic agonists, other molecules may be used as counter ions to form complexes with the TCs.
• the complexes formed are able to enhance the movement of the TCs across lipid layers.
• these complexes are able to solubilize the TCs in solution, preferably solutions with pHs of about 7 to about 10.
• EECs other than fatty acids include anionic polymers derivatives thereof, and the like and mixtures thereof.
• the anionic polymers are added to a solution containing TCs to form a complex with the TCs therein.
• the anionic polymer is ophthalmically acceptable at the concentrations used.
• the anionic polymer may include one or more, for example, two (2) or three (3) , anionic (or negative) charges.
• anionic polymers with more than 1 anionic site may be employed to reduce the osmotic pressure of a solution containing TCs. For example, a solution having a complex wherein several TCs complex to a single anionic polymer has a lower osmotic pressure than a similar solution wherein the TCs are not complexed.
• anionic polymers which may have multiple anionic charges include:
• 2-acrylamido-2-methylpropanesulfonic acids metal 2-acrylamido-2-methylpropanesulfonates allylsulfonic acid metal allylsulfonate and the like cellulose derivatives: carboxymethylcelluloses metal carboxymethylhydroxyethylcelluloses hydroxypropylmethylcelluloses
• the anionic polymers include anionic polysaccharides which tend to exist in ionized forms at higher pHs, for example, pHs of about 7 or higher.
• anionic polysaccharides which may be employed in accordance with this invention.
• Polydextrose is a randomly bonded condensation polymer of dextrose which is only partially metabolized by mammals.
• the polymer may contain a minor amount of bound sorbitol, citric acid, and glucose.
• Chondroitin sulfate also known as sodium chondroitin sulfate is a mucopolysaccharide found in human tissue, specifically cartilage, bones, tendons, ligaments, and vascular walls . This polysaccharide has been extracted and purified from the cartilage of sharks .
• Carrageenan is a linear polysaccharide having repeating galactose units and 3,6 anhydrogalactose units, both of which can be sulfated or nonsulfated, joined by alternating 1-3 and beta 1-4 glycosidic linkages.
• Carrageenan is a hydrocolloid which is heat extracted from several species of red seaweed and irish moss. Maltodextrins are water soluble glucose polymers which are formed by the reaction of starch with an acid and/or enzymes in the presence of water.
• anionic polysaccharides found useful in the present invention are hydrophilic colloidal materials and include the natural gums such as gellan gum, alginate gums, i.e., the ammonium and alkali metal salts of alginic acid and mixtures thereof.
• chitosan which is the common name for deacetylated chitin is useful.
• Chitin is a natural product comprising poly-(N-acetyl-D-glucosa ine) .
• Gellan gum is produced from the fermentation of Pseudomonas elodea to yield an extracellular heteropolysaccharide.
• the alginates and chitosan are available as dry powders from Protan, Inc., Commack, N.Y. Gellan gum is available from the Kelco Division of Merk & Co., Inc., San Diego, Calif.
• the alginates can be any of the water-soluble alginates including the alkali metal alginates, such as sodium, potassium, lithium, rubidium and cesium salts of alginic acid, as well as the ammonium salt, and the soluble alginates of an organic base such as mono-, di-, or triethanolamine alginates, aniline alginates, and the like.
• gellan, alginate or chitosan ionic polysaccharides are used to obtain the gel compositions of the invention.
• the anionic polysaccharides may be cyclized.
• the cyclized anionic polysaccharides may include less than ten monomer units.
• the cyclized polysaccharides include less than six monomer units.
• a particularly useful group of cyclized anionic polysaccharides includes the cyclodextrins .
• the cyclodextrin group include, but are not limited to: ⁇ -cyclodextrin, derivatives of ⁇ -cyclodextrin, ⁇ -cyclodextrin, derivatives of ⁇ -cyclodextrin, ⁇ -cyclodextrin, derivatives of ⁇ -cyclodextrin, carboxymethyl- ⁇ - cyclodextrin, carboxymethyl-ethyl- ⁇ -cyclodextrin, diethyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, random methyl- ⁇ -cyclodextrin, glucosyl- ⁇ - cyclodextrin, maltosyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ - cyclodextrin, hydroxypropy
• Sulfobutylether- ⁇ -cyclodextrin is a preferred cyclized anionic polyasaccharide in accordance with the present invention. It is advantageous that the EECs, including the above mentioned cyclodextrins, employed in this invention be, at the concentration employed, non-toxic to a mammal, for example a human.
• the term "derivatives,” as it relates to a cyclodextrin, means any substituted or otherwise modified compound which has the characteristic chemical structure of a cyclodextrin sufficiently to function as a cyclodextrin component, for example, to enhance the solubility and/or stability of active components and/or reduce unwanted side effects of the active components and/or to form inclusive complexes with active components, as described herein.
• cyclodextrins and/or their derivatives may be employed as EECs
• one embodiment of the invention may include EECs other than cyclodextrins and/or their derivatives.
• anionic polymer includes anionic cellulose derivatives.
• Anionic cellulose derivatives include metal carboxymethyl- celluloses, metal carboxymethylhydroxyethylcelluloses and hydroxypropylmethylcelluloses and derivatives thereof.
• a complex of a TC and a EEC may exist as a salt-like material and/or an oil phase outside of a solution.
• a complex of brimonidine and linoleic acid may be a powder.
• this complex may be added to a solution, for example a saline solution.
• the TC and the EEC still remain as a complex.
• the solution containing the complex for example a complex of brimonidine and linoleic acid, is administered to the eye to treat glaucoma.
• the complex remains intact at the site where the therapeutic component may exert a therapeutic effect.
• the complex dissociates at or near the site where the therapeutic component may exert a therapeutic effect.
• a complex of brimonidine and linolenic acid may dissociate to release brimonidine at or near the ciliary body in the eye, wherein the brimonidine can act on receptors located on the ciliary body to reduce the production of aqueous solutions, thereby treating glaucoma.
• a EEC is added to a solution containing TC to form a complex with the TC therein.
• the complex is formed only in solution. The amount of EEC added is such that the pharmacokinetics of the TC is at least somewhat increased.
• one or more EECs which may include an anionic polymer, are present in an amount sufficient to form a complex with at least a portion or substantially all of the TC present in a present composition.
• the EEC is present in an effective amount, but less than the amount required to form an emulsion, for example, with the water present in the composition.
• the complex is not present in an emulsion, for example, an EEC/water emulsion.
• the present compositions preferably includes no emulsions, for example, as described herein.
• At least about 10% or about 30% or about 50% or about 70% of the TC in the present compositions preferably is present in the form of a complex with the EEC(s) . More preferably, more preferably about 80% or about 90% to about 100% of ,the TC present is in such a complex.
• the amount of EEC, for example, an anionic polymer, in the present composition is in the range of about 0.1% to about 30% (w/v) or more of the composition.
• the amount of EEC is in the range of about 0.2% (w/v) to about 10% (w/v) .
• the amount of EEC is in the range of about 0.2% (w/v) to about 0.6% (w/v).
• the EEC is carboxymethylcellulose and is present in the composition in the range of about 0.2% (w/v) to about 0.6% (w/v).
• One useful concentration of carboxymethylcellulose in the present compositions is about 0.5%.
• the TCs and the EECs form complexes at pHs of greater than 7.
• the TCs and the EECs form complexes at pHs between about 7 to about 10.
• At least one element which contributes to complex stabilization and/or inhibition of complex disassociation is an interaction of the non-polar or hydrophobic hydrocarbon portion or tail of the EEC with the TC.
• This interaction may act in combination with the ionic interaction between the EEC and the TC to enhance complex stabilization and/or inhibit complex disassociation.
• This interaction may also be involved in enhancing ⁇ complex formation.
• the effects of the hydrophobic interaction and ionic interaction may be synergistic in nature.
• compositions of the present invention may advantageously include solubilizer components which at least assist in maintaining the TC-EEC complex in solution or dispersed in the composition.
• a solubilizer component may be useful to maintain the TC-EEC complex in solution under conditions which, in the absence of a solubilizer component, would result in insolubility and/or precipitation of the TC-EEC complex. These conditions include one or more of certain pH values, certain concentrations of the TC and/or EEC, certain ionic concentrations and the like.
• the presence of a solubilizer component preferably reduces the solubility sensitivity of the present complexes to these conditions and allows for more flexibility in formulating the present compositions.
• the solubilizer component is nonionic to reduce the ionic concentration in the present compositions and still provide the benefits to be attained from the solubilizer component.
• nonionic solubilizer components include, without limitation, poly (oxyethylene) - pol (oxypropylene) block polymers, polysorbate 80, polyvinyl alcohol, polyvinylpyrrolidine, hydroxypropylmethyl cellulose and the like and mixtures thereof.
• the complex according to the present invention may serve as a delay release system for the TCs and/or the EECs.
• a TC may be pharmacologically inactive when it is part of a complex.
• the complexation of TCs with EECs may further help to solubilize the TCs in solution and preferably reduces irritation when the TCs are administered to sensitive tissues.
• an eye drop solution having a pH of about 7 may contain insoluble TC ions, such as brimonidine tartrate ions. If such a solution is administered to the eye, a sensitive tissue, the insoluble TC ions may cause discomfort and irritation.
• a complex of TC and EEC may help solubilize the TC in such a solution.
• the solution containing a solubilized TC results in less irritation as the solution is applied to a sensitive tissue, for example the eye.
• the solution containing solubilize TC results in little or no irritation when the solution is administered to a sensitive tissue.
• the compositions may also include preservative components or components which assist in the preservation of the composition.
• the preservative components selected so as to be effective and efficacious as preservatives in the present compositions, that is in the presence of EECs, and preferably have reduced toxicity and, more preferably, substantially no toxicity when the compositions are administered to a human or animal.
• Preservatives or components which assist in the preservation of the composition which are commonly used in pharmaceutical compositions are often less effective when used in the presence of solubilizing agents or solubilizing component. In certain instances, this reduced preservative efficacy can be compensated for by using increased amounts of the preservative. However, where sensitive or delicate body tissue is involved, this approach may not be available since the preservative itself may cause some adverse reaction or sensitivity in the human or animal, to whom the composition is administered.
• the present preservative components or components which assist in the preservation of the composition are effective in concentrations of less than about 1% (w/v) or about 0.8% (w/v) and may be 500 ppm (w/v) or less, for example, in the range of about 10 ppm(w/v) or less to about 200 ppm (w/v).
• Preservative components in accordance with the present invention preferably include, but are not limited to, those which form complexes with the anionic polymer, or EEC, to a lesser extent than does benzalkonium chloride.
• oxidative preservative components include, but are not limited to oxidative preservative components, for example oxy-chloro components, peroxides, persalts, peracids, and the like, and mixtures thereof.
• oxy-chloro components useful as preservatives in accordance with the present invention include hypochlorite components, for example hypochlorites; chlorate components, for example chlorates; perchlorate components, for example perchlorates; and chlorite components.
• chlorite components include stabilized chlorine dioxide (SCD) , metal chlorites, such as alkali metal and alkaline earth metal chlorites, and the like and mixtures therefore.
• Technical grade (or USP grade) sodium chlorite is a very useful preservative component.
• trace amounts of peroxy components stabilized with a hydrogen peroxide stabilizer such as diethylene triamine penta (methylene phosphonic acid) or 1-hydroxyethylidene-l, 1-diphosphonic acid, may be utilized as a preservative for use in components designed to be used in the ocular environment.
• a hydrogen peroxide stabilizer such as diethylene triamine penta (methylene phosphonic acid) or 1-hydroxyethylidene-l, 1-diphosphonic acid
• a hydrogen peroxide stabilizer such as diethylene triamine penta (methylene phosphonic acid) or 1-hydroxyethylidene-l, 1-diphosphonic acid
• a hydrogen peroxide stabilizer such as diethylene triamine penta (methylene phosphonic acid) or 1-hydroxyethylidene-l, 1-diphosphonic acid
• any peroxy component may be used so long as it is hydrolyzed in water to produce hydrogen peroxide.
• sources of hydrogen peroxide which provide an effective resultant amount
• Preservatives other than oxidative preservative components may be included in the compositions.
• the choice of preservatives may depend on the route of administration. Preservatives suitable for compositions to be administered by one route may possess detrimental properties which preclude their administration by another route.
• preferred preservatives include quaternary ammonium compounds, in particular the mixture of alkyl benzyl dimethyl ammonium compounds and the like known generically as "benzalkonium chloride.”
• benzalkonium chloride for compositions to be administered by inhalation, some preferred preservatives are chlorbutol and the like.
• compositions to be administered rectally include alkyl esters of p-hydroxybenzoic acid and mixtures thereof, such as the mixture of methyl, ethyl, propyl, butyl esters and the like which is sold under the trade name "Nipastat.”
• compositions which comprise a TC-EEC complex, a preservative component in an effective amount to at least aid in preserving the compositions and a liquid carrier component.
• the preservative components include oxy-chloro components, such as compounds, ions, complexes and the like which (1) do not substantially or significantly detrimentally affect the TC in the compositions or the patients to whom the compositions are administered, and (2) are substantially biologically acceptable and chemically stable.
• compositions in accordance with the present invention comprise a complex of alpha-2-adrenergic agonist- linolenic acid, an oxy-chloro component, and a liquid carrier component, for example, an aqueous component.
• the carrier components useful in the present invention are selected to be non-toxic and preferably have no substantial detrimental effect on the present compositions, on the use of the compositions or on the human or animal to whom the compositions are administered.
• the carrier component is a liquid carrier.
• the carrier component is a liquid carrier component, for example, an aqueous component.
• a particularly useful liquid carrier component is that derived from saline, for example, a conventional saline solution or a conventional buffered saline solution.
• the liquid carrier preferably has a pH in the range of about 6 to about 9 or about 10, more preferably about 6 to about 8, and still more preferably about 7.5.
• the liquid medium preferably has an ophthalmically acceptable tonicity level, for example, of at least about 200 mOsmol/kg, more preferably in the range of about 200 to about 400 mOsmol/kg.
• the osmolality or tonicity of the carrier component substantially corresponds to the tonicity of the fluids of the eye, in particular the human eye.
• nonionic tonicity components are used.
• the carrier components containing the EECs and the TCs may have viscosities of more than about 0.01 centipoise (cps) at 25°C, for example, more than about 1 cps at 25°C or, for example, more than about 10 cps at 25°C.
• the composition has a viscosity of about 50 cps at 25°C and comprises a conventional buffer saline solution, a carboxymethylcellulose and a brimonidine tartrate.
• a nonionic tonicity component is used in place of saline.
• the liquid carrier component may include at least one buffer component.
• any suitable buffer component may be employed, it is preferred to select such component so as not to produce a significant amount of chlorine dioxide or evolve significant amounts of gas, such as CO.
• the buffer component may be inorganic. Alkali metal and alkaline earth metal buffer components are advantageously used in the present invention.
• phosphate buffers may be used in accordance with the present invention.
• One or more buffer components may be used in a composition of the present invention.
• the term "complex" refers to a close association between one or more EECs and one or more TCs.
• the electrical charge of an TC in solution may maintain one or more EECs comprising an opposite electrical charge in close association.
• the present complexes are ion pair complexes in which the electric charge of the EECs and the TC are substantially or even completely balanced. It should be noted, however, that the present invention is not intended to be limited to only such ion pair complexes .
• any complex or related combination of EEC(s) and TC component (s) which preferably remain substantially intact in an aqueous environment, and which exhibit one or more of the enhanced effects set forth herein, is to be considered within the scope of the present invention.
• an TC-EEC complex may produce an overall diminishment in the net electrical charge of the TC.
• the ratio of electrical charge from the' EEC to electrical charge from the TC may be in the range of about 0.9 to about 1.5, preferably, in the range of about 1.0 to about 1.3.
• an EEC may have one negative charge per molecule and a TC may have two positive charges per molecule.
• a molar ratio of EEC to TC of 2 in a composition will result in a ratio of electrical charge of 1.
• the concentration of EEC in a composition of the invention is less than required to form an emulsion, for example, an EEC/water emulsion in the composition.
• the amount of EEC is preferably controlled so that enough EEC is present to complex with substantially all of the TC present, and less EEC is present than that needed to form an emulsion in the composition.
• compositions of the present invention include a reduced concentration of buffer component.
• concentrations of buffer component for example, phosphate buffer, may be present in compositions of the present invention in an amount in a range of about 0.0001 molar to about 1.0 molar.
• the buffer component preferably is present in a concentration in a range of about 0.001 molar to about 0.1 molar or about 0.2 molar, more preferably in a range of about 0.005 molar to about 0.1 molar.
• any suitable ophthalmically acceptable tonicity component or components may be employed, provided that such component or components are compatible with the other ingredients of the liquid carrier component and do not have deleterious or toxic properties which could harm the human or animal to whom the present compositions are administered.
• the tonicity component is selected from inorganic salts and mixtures thereof. Examples of useful tonicity components include sodium chloride, potassium chloride, and mixtures thereof.
• nonionic tonicity components be used in the present compositions. Examples of such nonionic tonicity components include, without limitation, mannitol, dextrose, glycerin, propylene glycol and the like and mixtures thereof.
• compositions may conveniently be presented as solutions or suspensions in aqueous liquids or non-aqueous liquids, or as oil-in-water or water-in- oil liquid emulsions.
• the present compositions may include one or more additional ingredients such as diluents, flavoring agents, surface active agents, thickeners, lubricants, and the like, for example, such additional ingredients which are conventionally employed in compositions of the same general type.
• compositions in the form of aqueous suspensions may include excipients suitable for the manufacture of aqueous suspensions .
• excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinylpyrrolidone, gun tragacanth and gun 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, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan mono- oleate, and the like and mixtures thereof.
• compositions in the form of oily suspensions may be formulated in a vegetable oil, for example, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• a vegetable oil for example, olive oil, sesame oil or coconut oil
• a mineral oil 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 present compositions 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, and 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, soya bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan mono-oleate.
• the emulsions may also contain sweetening and flavoring agents.
• compositions in the form of syrups and elixirs may be formulated with sweetening agents, for example, as described elsewhere herein. Such formulations may also contain a demulcent, and flavoring and coloring agents.
• the specific dose level for any particular human or animal depends upon a variety of factors including the activity of the active component 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 undergoing therapy.
• the data below shows the percent change with time of Intra Ocular Pressure after administration of Brimonidine-linoleic acid at time 0.
• the treatment is an ion pair formulation of 0.131% Brimonidine and 0.126% linoleic acid.
• test compounds were coded: 62-Saline, 65-
• Test Compound Administration animal #1 week 1 week 2 week 3
• the first reading after dosing 0.5 hr-time point, the monkeys were quiet and easy to handle. In general, the animals started to show low activity when brought into the test room at the lhr time.
• the dosing with Brimonidine-linoleic acid complex appear to cause more sedation in the monkeys than dosing with saline.
• dosing with Brimonidine tartrate causes more sedation than dosing with Brimonidine- linoleic acid.
• the monkeys were dosed with Brimonidine tartrate on average they became sleepy and inactive with heavy eyes. This observation was seen usually at the 2-hour time point and most of the animals remained this way through the end of observations.
• Brimonidine-linoleic acid complex causes less sedation than Brimonidine tartrate is that it partitions more in the lipid compartments .
• the Brimonidine-linoleic acid complex is more trapped in the lipid compartments, and are not as available to circulate in the blood stream to eventually travel to the brain to cause sedation.
• test compound (20 ⁇ L of 0.2% Brimonidine-linoleic acid ion pair complex) was administered to the surface of the cornea using an automatic pipette or an appropriate device.
• a reading is conducted at 0, 2, 4, 6, 24, 26, 28, 30, 48, 50, 52, 54, 72, 74, 76, 78, 96, 98, 100, and 102 hours.
• the pneumatonometer is calibrated before use with a manometer and the probe tip is wiped with an alcohol swab.
• One drop of 0.25% proparacaine Opthetic®, a corneal anesthetic, is placed on the cornea. Allow sufficient time (approximately 1 minute) for it to anesthetize the cornea before placing the probe on the eye. The eye is gently opened by the person doing the tonometer reading.
• the probe is placed on the cornea at the point of greatest curvature and a stable reading is obtained.
• the probe is held parallel to the floor and perpendicular to the line of the rabbit's sight. The reading is repeated until a reasonable reading can be obtained.
• the piston should be between the red and black lines or at the black line on the probe.
• the effects of Brimonidine-linoleic acid ion pair complex is shown on Table 2. It appears that the complex is able to reduce intraocular pressure in a rabbit's eye for at least 6 hours. For example, 6 hours after the administration at times 0 hr, 24hr, 48hr, 72 hr, and 96 hr, the intraocular pressure remained below the initial time. However, it also appears that the effect of the complex is less than 18 hrs. For example, 18 hrs after administration of the complex at time 6 hr, the intraocular pressure returned to about the same initial level.
• Example 4 The following composition is prepared by mixing together the specified amounts of the ingredients.
• composition is formulated for and is effective for the treatment of disorders of the eye.
• composition is prepared by mixing together the specified amounts of the ingredients.
• composition is formulated for and is effective for the treatment of disorders of the eye.
• composition is prepared by mixing together the specified amounts of the ingredients.
• composition is formulated for and is effective for the treatment of disorders of the eye.
• composition is prepared by mixing together the specified amounts of the ingredients.
• composition is formulated for and is effective for the treatment of disorders of the eye.
• composition is prepared by mixing together the specified amounts of the ingredients .
• composition is formulated for and is effective for the treatment of disorders of the eye.
• composition is prepared by mixing together the specified amount of the ingredients.
• composition is formulated for and is effective for the treatment of disorders of the eye.
• composition is prepared by mixing together the specified amount of the ingredients.
• composition is prepared by mixing together the specified amount of the ingredients.
• This composition is formulated for and is effective for the treatment of disorders of the eye.
• This composition exemplifies a linolenic acid to brimonidine molar ratio of 2.0 resulting in a ratio of electrical charge from the linolenic acid to electrical charge from the brimonidine of 1.0.
• Example 12 The following composition is prepared by mixing together the specified amount of the ingredients .
• This composition is formulated for and is effective for the treatment of disorders of the eye.
• This composition exemplifies a linolenic acid to brimonidine molar ratio of 2.2 resulting in a ratio of electrical charge from the linolenic acid to electrical charge from the brimonidine of 1.1.
• composition is prepared by mixing together the specified amount of the ingredients .
• This composition is formulated for and is effective for the treatment of disorders of the eye.
• This composition exemplifies a linolenic acid to brimonidine molar ratio of 2.4 resulting in a ratio of electrical charge from the linolenic acid to electrical charge from the brimonidine of 1.2.
• the roilowing composition is prepared by mixing together the specified amount, of the ingredients. Ingredient Amount.
• Linolenic Acid 1.64 mg l.Q molar Phosphate Buffer (pH 7.5) • 0.1 ml Polysorbate 80 90 mg
• This composition is formulated for and is effective for the treatment of disorders of the eye.
• This composition exemplifies a linolenic acid to brimonidine is molar ratio of 2.6 resulting in a ratio of electrical charge from the linolenic acid to electrical charge from the brimonidine of 1.3.

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