`Chen et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,383,471 B1
`May 7, 2002
`
`US006383471B1
`
`Charman, W. N., Porter, C.J.H., Mithani, S., and Bressman,
`J .B., “Physicochemical and Physiological Mechanisms for
`the Effects of Food on Drug Absorption: The Role of Lipids
`and pH”, Journal of Pharmceutical Sciences, 86(3),
`269-282 (1997).
`Gennaro, A. R., Remington’s Pharmaceutical Sciences,
`Chapter 20, 293-300 (1985).
`Horter, D. and Dressman, J.B., “Influence of Physicochemi-
`cal Properties on Dissolution of Drugs in the Gastrointesti-
`nal Tract”, Advanced Drug Delivery Reviews 25, 3-14
`(1997).
`Humberstone, A. J . and Charman, W. N. “Lipid-based
`Vehicles for the Oral Delivery of Poorly Water Soluble
`Drugs”,Advanced Drug Delivery Reviews, 103-128 (1997).
`Hutchison, K., “Digestible Emulsions and Microemulsions
`for Optimum Oral Delivery of Hydrophobic Drugs”, Journ-
`ées Galéniques, 67-74, (1994).
`Johnson, L. R., “Gastrointestinal Physiology”, Department
`of Physiology, University of Texas Medical School, Hous-
`ton, Texas, 25-26, 93, 106, 133-134, 136-137 (1997).
`MacGregor, K. J. et al., “Influence of Lipolysis on Drug
`Absorption From the Gastro-intestinal Tract”, Advanced
`Drug Delivery Reviews 25, 33-46 (1997).
`Pouton, C. W., “Formulation of Self-Emulsifying Drug
`Delivery Systems”, Advanced Drug Delivery Reviews 25,
`47-58 (1997).
`Reymond, J . and Sucker, H., “In Vitro Model for Ciclosporin
`Intestinal Absorption in Lipid Vehicles”, Pharmaceutical
`Research, 5(10), 677-679.
`Tarr, D. T. and Yalkowsky, S. H. “Enhanced Intestinal
`Absorption of Cyclosporine in Rats Through the Reduction
`of Emulsion Droplet Size”, Pharmaceutical Research, 6(1),
`40-43 (1989).
`Wilson, C. G., O’Mahony, B., “The Behaviour of Fats and
`Oils in the Upper G.I. Tract”, Bulletin Technique Gattefossé,
`No. 90, 13-18 (1997).
`Winne, D., “Dependence of Intestinal Absorption in Vivo on
`the Unstirred Layer”, Archives of Pharmacology, 304,
`175-181 (1978).
`Zhi, J., Rakhit, A., and Patel, I. H., “Effects of Dietary Fat
`on Drug Absorption”, Clinical Pharmacology and Thera-
`peutics, 58(5), 487-491 (1995).
`
`Primary Examiner—Raj Bawa
`(74) Attorney, Agent, or Firm—Dianne E. Reed; Reed &
`Associates
`
`(57)
`
`ABSTRACT
`
`The present invention is directed to a pharmaceutical com-
`position including a hydrophobic therapeutic agent having at
`least one ionizable functional group, and a carrier. The
`carrier includes an ionizing agent capable of ionizing the
`functional group, a surfactant, and optionally solubilizers,
`triglycerides, and neutralizing agents. The invention further
`relates to a method of preparing such compositions by
`providing a composition of an ionizable hydrophobic thera-
`peutic agent, an ionizing agent, and a surfactant, and neu-
`tralizing a portion of the ionizing agent with a neutralizing
`agent. The compositions of the invention are particularly
`suitable for use in oral dosage forms.
`
`114 Claims, N0 Drawings
`
`(54) COMPOSITIONS AND METHODS FOR
`IMPROVED DELIVERY OF IONIZABLE
`HYDROPHOBIC THERAPEUTIC AGENTS
`
`(75)
`
`Inventors: Feng-Jing Chen; Mahesh V. Patel,
`both of Salt Lake City, UT (US)
`
`(73) Assignee: Lipocine, Inc., Salt Lake City, UT (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/287,043
`
`(22) Filed:
`
`Apr. 6, 1999
`
`Int. Cl.7 ................................................ .. A61K 9/12
`(51)
`(52) U.S. Cl.
`......................... .. 424/45; 424/401; 424/46;
`424/451; 424/436; 514/944
`(58) Field of Search .......................... .. 424/401, 45, 46,
`424/451, 436; 514/944
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`6/1983 Cavanak ................... .. 424/177
`4,388,307 A
`2/1986 Crooks ........ ..
`514/458
`4,572,915 A
`12/1987 Begum et al.
`424/455
`4,713,246 A
`1/1988 Muller et al.
`............. .. 514/785
`4,719,239 A
`2/1988 Schmidt et al.
`........... .. 424/455
`4,727,109 A
`3/1988 Dell et al.
`...... ..
`514/658
`4,731,384 A
`7/1990 Story et al.
`424/451
`4,944,949 A
`12/1991 Yu et al.
`............. ..
`514/570
`5,071,643 A
`9/1992 Liversidge et al.
`424/489
`5,145,684 A
`9/1993 Wretlind et al.
`.... ..
`514/777
`5,244,925 A
`4/1994 Narayanan ...... ..
`514/788
`5,300,529 A
`8/1994 Hauer et al.
`424/455
`5,342,625 A
`11/1994 Yu et al.
`......... ..
`424/455
`5,360,615 A
`11/1994 Benita et al.
`424/450
`5,364,632 A
`12/1994 Morton et al.
`514/786
`5,376,688 A
`..
`11/1995 Argiriadi et al.
`424/456
`5,468,502 A
`7/1996 Story ............. ..
`424/456
`5,532,002 A
`12/1996 W00 ................. .. 514/11
`5,589,455 A
`3/1997 Walch et al.
`. . . . .
`. . . .. 514/11
`5,614,491 A
`4/1997 Kaufman et al.
`.
`424/400
`5,616,330 A
`6/1997 Woo ............... ..
`424/452
`5,639,474 A
`6/1997 Cavanak ..
`514/11
`5,639,724 A
`..... ..
`7/1997 Lacy et al.
`424/455
`5,645,856 A
`7/1997 Cavanak et al.
`..
`514/11
`5,652,212 A
`8/1997 Modi et al.
`..... ..
`424/400
`5,653,987 A
`3/1998 Hausheer et al.
`.
`514/283
`5,726,181 A
`3/1998 Jones et al.
`..... ..
`514/731
`5,731,355 A
`4/1998 Yesair
`......... ..
`514/784
`5,741,822 A
`5/1998 Pittrof et al.
`424/450
`5,747,066 A
`6/1998 Cho et al.
`....... ..
`424/455
`5,766,629 A
`6/1998 Chiesi et al.
`424/488
`5,773,029 A
`1/1999 Bhalani et al.
`........... .. 424/450
`5,858,401 A
`OTHER PUBLICATIONS
`
`
`
`Alvarez, F. J. and Stella, V. J ., “The Role of Calcium Ions
`and Bile Salts on the Pancreatic Lipase—Catalyzed Hydroly-
`sis of Triglyceride Emulsions Stabilized with Lecithin”,
`Pharmaceutical Research, 6(6), 449-457 (1989).
`Bates, T. R. and Sequeira, J. A., “Bioavailability of Micron-
`ized Griseofulvin from Corn Oil-in-Water Emulsion, Aque-
`ous Suspension, and Commercial Tablet Dosage Forms in
`Humans”, Journal of Pharmaceutical Sciences, 64(5),
`793-797 (1975).
`
`|PR2015-01099 |PR2015-01097
`|PR2015-01100 |PR2015-01105
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`Lupin EX 1105
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`US 6,383,471 B1
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`1
`COMPOSITIONS AND METHODS FOR
`IMPROVED DELIVERY OF IONIZABLE
`HYDROPHOBIC THERAPEUTIC AGENTS
`
`FIELD OF THE INVENTION
`
`The present invention relates to drug delivery systems,
`and in particular to pharmaceutical compositions for the
`improved delivery of ionizable hydrophobic compounds and
`methods therefor.
`
`BACKGROUND
`
`therapeutic com-
`i.e.,
`Hydrophobic therapeutic agents,
`pounds having poor solubility in aqueous solution, present
`diflicult problems in formulating such compounds for effec-
`tive administration to patients. A well-designed formulation
`must, at a minimum, be capable of presenting a therapeuti-
`cally effective amount of the hydrophobic compound to the
`desired absorption site, in an absorbable form. Even this
`minimal functionality is diflicult to achieve when delivery of
`the hydrophobic therapeutic agent requires interaction with
`aqueous physiological environments, such as gastric fluids
`and intestinal fluids. Pharmaceutical compositions for deliv-
`ery of such hydrophobic therapeutic agents must carry the
`hydrophobic compound through the aqueous environment,
`while maintaining the hydrophobic compound in an absorb-
`able form, and avoiding the use of physiologically harmful
`solvents or excipients.
`A number of approaches to formulating hydrophobic
`therapeutic agents for oral or parenteral delivery are known.
`Such approaches include,
`for example,
`formulations in
`which the hydrophobic therapeutic agent is present in an
`oil-in-water emulsion, a microemulsion, or a solution of
`micelles, liposomes, or other multi-lamellar carrier particles.
`While such approaches may be appropriate for some ioniz-
`able as well as non-ionizable hydrophobic therapeutic
`agents, they fail to take advantage of the unique acid-base
`chemical properties, and associated solubility properties, of
`ionizable compounds.
`In particular, unlike non-ionizable hydrophobic therapeu-
`tic agents, ionizable hydrophobic therapeutic agents can be
`rendered soluble in aqueous solution if the pH of the solution
`is adjusted to ionize the therapeutic agent. Such an approach
`is well known in the art. For example, U.S. Pat. No.
`5,773,029 is directed to a pharmaceutical composition of an
`acidic drug, wherein the solubility of the acidic drug is
`enhanced by simultaneous salt formation with an organic or
`inorganic base and complexation with a cyclodextrin. The
`resultant drug/cyclodextrin/base complexes reportedly are
`readily soluble in water in high concentrations.
`U.S. Pat. No. 5,360,615 discloses a pharmaceutical carrier
`system for an acidic, basic or amphoteric pharmaceutical
`agent in which the pharmaceutical agent is partially ionized
`by an acid or base in a polyethylene glycol-based solvent
`system. The pharmaceutical agent reportedly shows
`enhanced solubility in the partially ionized form. The ref-
`erence also discloses that addition of glycerin, propylene
`glycol and/or polyvinylpyrrolidone further enhances the
`solubility of the pharmaceutical agent in the polyethylene
`glycol base. However, the invention is limited to polyeth-
`ylene glycol-based solvent systems and a narrow range of
`ionizing agent concentration, and there is no disclosure of
`other solvent systems. Thus, its utility is severely limited.
`Similarly, U.S. Pat. No. 5,376,688 discloses a pharma-
`ceutical solution of an acidic, basic or amphoteric pharma-
`ceutical agent. The solution includes a pharmaceutical agent,
`an ionizing species, and a solvent system. The solvent
`
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`system can be diethylene glycol monoethyl ether, glycerol
`caprylate/caprate, polyglycerol oleate, alpha-hydro-w-
`hydroxypoly(oxyethylene)-poly(oxypropylene)-poly
`(oxyethylene) block copolymers, or mixtures of those com-
`ponents. The solvent system can also be a mixture of
`polyethylene glycol and a polyoxyethylene sorbitan ester.
`Optional components include water, glycerin, propylene
`glycol, and polyvinylpyrrolidone. However, the invention is
`limited to these particular compounds and a narrow range of
`ionizing agent concentration, rendering its utility severely
`limited. Moreover, some of the solvent system components
`show poor or questionable biocompatibility, and thus would
`be impractical for drug delivery to a patient.
`A further problem with conventional approaches to solu-
`bilizing ionizable hydrophobic therapeutic agents is the
`difficulty in maintaining the solubilized therapeutic agent in
`solubilized form. Thus, for example, while ionizing an
`acidic therapeutic agent with a base may increase its
`solubility, the therapeutic agent is prone to precipitation in
`the gastrointestinal tract due to the acidic pH conditions
`encountered upon administration to a patient, and the
`approximately 10 to 100-fold dilution expected in gas-
`trointestinal or intestinal fluids. This precipitation is particu-
`larly disadvantageous, since the precipitated therapeutic
`agent is essentially unavailable for absorption, leading to
`difliculties in controlling dosages, and a need to administer
`large doses of the therapeutic agent to ensure that a thera-
`peutically effective amount reaches the absorption site in a
`bioavailable form. Such difficulties necessarily result
`in
`increased costs, and compromised patient safety and thera-
`peutic effectiveness.
`Thus, there is a need for versatile and effective pharma-
`ceutical compositions that overcome these deficiencies in
`the prior art.
`SUMMARY OF THE INVENTION
`
`It is therefore an object of the present invention to provide
`pharmaceutical compositions capable of solubilizing thera-
`peutically effective amounts of ionizable hydrophobic thera-
`peutic agents.
`It is another object of the invention to provide pharma-
`ceutical compositions capable of maintaining a solubilized
`ionizable hydrophobic therapeutic agent in solubilized form
`upon administration to a patient.
`It is another object of the invention to provide pharma-
`ceutical compositions of ionizable hydrophobic therapeutic
`agents with improved delivery of the therapeutic agent to the
`absorption site.
`It is a further object of the invention to provide improved
`methods of preparing pharmaceutical compositions of ion-
`izable hydrophobic therapeutic agents.
`It
`is still another object of the invention to provide
`methods of treating an animal with pharmaceutical compo-
`sitions of ionizable hydrophobic therapeutic agents.
`In accordance with these and other objects and features,
`the present invention provides pharmaceutical compositions
`and methods for improved delivery of ionizable hydropho-
`bic therapeutic agents.
`In one embodiment, the invention is directed to a phar-
`maceutical composition including an ionizable hydrophobic
`therapeutic agent and a carrier. The carrier includes an
`ionizing agent to ionize the therapeutic agent, and a surfac-
`tant. Optionally, the carrier also includes solubilizers, trig-
`lycerides and neutralizing agents.
`In another embodiment,
`the invention is directed to a
`pharmaceutical composition including a hydrophobic thera-
`
`Page 2
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`US 6,383,471 B1
`
`3
`peutic agent having at least one ionizable functional group,
`and a carrier. The carrier includes an ionizing agent capable
`of ionizing the functional group, a surfactant, and a triglyc-
`eride.
`
`the invention is directed to a
`In another embodiment,
`pharmaceutical composition including a hydrophobic thera-
`peutic agent having at least one ionizable functional group
`and a carrier, wherein the carrier includes an ionizing agent
`capable of ionizing the ionizable functional group and
`present in a pre-reaction amount of greater than about 1.5
`mole equivalents per mole of ionizable functional group,
`and a surfactant. In a further aspect of this embodiment, the
`composition further includes a neutralizing agent capable of
`neutralizing a portion of the ionizing agent.
`In another embodiment,
`the invention is directed to a
`pharmaceutical composition including a hydrophobic thera-
`peutic agent having at least one ionizable functional group,
`and a carrier, wherein the carrier includes an ionizing agent
`capable of ionizing the ionizable functional group, a
`surfactant, and a solubilizer present in an amount of greater
`than about 10% by weight, based on the total weight of the
`composition. In this embodiment, the surfactant includes at
`least one compound from the group consisting of alkylglu-
`cosides; alkylmaltosides; alkylthioglucosides;
`lauryl mac-
`rogolglycerides; polyoxyethylene alkyl ethers; fatty acids;
`lower alcohol fatty acid esters; polyoxyethylene alkylphe-
`nols; polyethylene glycol fatty acids esters; polypropylene
`glycol fatty acid esters; glycerol fatty acid esters; acetylated
`glycerol fatty acid esters; polyethylene glycol glycerol fatty
`acid esters; polyglyceryl fatty acid esters; polyoxyethylene
`glycerides; polyoxyethylene sterols, derivatives, and ana-
`logues thereof; polyoxyethylene vegetable oils; polyoxyeth-
`ylene hydrogenated vegetable oils; reaction mixtures of
`polyols and at least one member of the group consisting of
`fatty acids, vegetable oils, hydrogenated vegetable oils, and
`sterols; sugar esters; sugar ethers; sucroglycerides; fatty acid
`salts; bile salts; phospholipids; phosphoric acid esters; car-
`boxylates; sulfates; and sulfonates.
`In another embodiment, the present invention is directed
`to a pharmaceutical composition including a hydrophobic
`therapeutic agent having at least one ionizable functional
`group and a carrier, wherein the carrier includes an ionizing
`agent capable of ionizing the ionizable functional group, a
`surfactant, and a solubilizer. In this embodiment, the sur-
`factant includes at least one compound selected from the
`group consisting of alkylglucosides; alkylmaltosides; alky-
`lthioglucosides;
`lauryl macrogolglycerides;
`fatty acids;
`lower alcohol fatty acid esters; polyoxyethylene alkylphe-
`nols; polyethylene glycol fatty acids esters; polypropylene
`glycol fatty acid esters; glycerol fatty acid esters; acetylated
`glycerol fatty acid esters; polyethylene glycol glycerol fatty
`acid esters; polyglyceryl fatty acid esters; polyoxyethylene
`sorbitan fatty acid esters; polyoxyethylene glycerides; poly-
`oxyethylene sterols, derivatives, and analogues thereof;
`polyoxyethylene vegetable oils; polyoxyethylene hydroge-
`nated vegetable oils; reaction mixtures of polyols and at
`least one member of the group consisting of fatty acids,
`vegetable oils, hydrogenated vegetable oils, and sterols;
`sugar esters; sugar ethers; sucroglycerides; fatty acid salts;
`bile salts; phospholipids; phosphoric acid esters; carboxy-
`lates; sulfates; and sulfonates.
`The solubilizer in this embodiment includes at least one
`compound selected from the group consisting of alcohols,
`polyols, amides, esters, and propylene glycol ethers,
`the
`alcohol or polyol being selected from the group consisting of
`ethanol,
`isopropanol, butanol, benzyl alcohol, ethylene
`glycol, propylene glycol, butanediols and isomers thereof,
`
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`glycerol, pentaerythritol, sorbitol, mannitol, dimethyl
`isosorbide, polypropylene glycol, polyvinylalcohol, hydrox-
`ypropyl methylcellulose and other cellulose derivatives,
`maltodextrins, and cyclodextrins and cyclodextrin deriva-
`tives.
`
`In another embodiment, the present invention provides a
`method of preparing a pharmaceutical composition of an
`ionizable hydrophobic therapeutic agent.
`In this
`embodiment, the method includes the steps of: providing a
`pharmaceutical composition having an ionizable hydropho-
`bic therapeutic agent and a carrier which includes an ion-
`izing agent and a surfactant; and providing a neutralizing
`agent to neutralize at least a portion of the ionizing agent.
`In another embodiment, the present invention provides a
`method of treating an animal with an ionizable hydrophobic
`therapeutic agent. The method includes the steps of provid-
`ing a pharmaceutical composition having an ionizable
`hydrophobic therapeutic agent and a carrier which includes
`an ionizing agent and a surfactant; and administering the
`pharmaceutical composition to an animal.
`These and other objects and features of the present
`invention will become more fully apparent from the follow-
`ing description and appended claims, or may be learned by
`the practice of the invention as set forth hereinafter.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`The present invention overcomes the problems described
`above characteristic of conventional formulations, by pro-
`viding pharmaceutical compositions including an ionizable
`hydrophobic therapeutic agent and a carrier. The carrier
`includes a surfactant, and an ionizing agent capable of
`ionizing the ionizable hydrophobic therapeutic agent.
`Optional components include one or more additional
`surfactants, solubilizers, triglycerides, neutralizing agents,
`and various additives. The carrier is able to solubilize the
`
`ionizable hydrophobic therapeutic agent and maintain the
`therapeutic agent in solubilized form for improved delivery
`to the absorption site The invention also encompasses vari-
`ous dosage forms of the pharmaceutical composition.
`The present invention further provides a method of solu-
`bilizing ionizable hydrophobic therapeutic agents for
`improved performance in pharmaceutical compositions. The
`method includes the steps of providing a pharmaceutical
`composition as described above, and providing a neutraliz-
`ing agent to neutralize a portion of the ionizing agent.
`1. Ionizable Hydrophobic Therapeutic Agents
`Ionizable hydrophobic therapeutic agents suitable for use
`in the pharmaceutical compositions of the present invention
`are not particularly limited, as the carrier is surprisingly
`capable of solubilizing and delivering a wide variety of
`ionizable hydrophobic therapeutic agents. Ionizable hydro-
`phobic therapeutic agents are compounds with little or no
`water solubility at neutral pH. Intrinsic water solubilities
`(i.e., water solubility of the unionized form) for the ionizable
`hydrophobic therapeutic agents usable in the present inven-
`tion are less than about 1% by weight, and typically less than
`about 0.1% or 0.01% by weight. Such therapeutic agents can
`be any agents having therapeutic or other value when
`administered to an animal, particularly to a mammal, such as
`drugs, nutrients, and cosmetics (cosmeceuticals). It should
`be understood that while the invention is described with
`
`particular reference to its value in oral dosage form, the
`invention is not so limited. Thus, ionizable hydrophobic
`drugs, nutrients or cosmetics which derive their therapeutic
`or other value from, for example, topical or transdermal
`
`Page 3
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`
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`US 6,383,471 B1
`
`5
`administration, are still considered to be suitable for use in
`the present invention.
`It is a particular feature of the present invention that a
`wide variety of therapeutic agents can be effectively incor-
`porated in and delivered by the present pharmaceutical
`compositions. The essential feature of a suitable therapeutic
`agent is the presence of at least one ionizable functional
`group. Ionizable functional groups can be acidic groups, or
`basic groups, with “acidic” and “basic” referring to acidic or
`basic behavior in a Br(25nsted-Lowry or Lewis acid/base
`sense. Acidic functional groups are those groups that can be
`deprotonated by a suitable base to yield the corresponding
`anionic group (the conjugate base), or groups that can accept
`an electron pair. Basic functional groups are those groups
`that can be protonated by a suitable acid to yield the
`corresponding cationic group (the conjugate acid), or can
`donate an electron pair. It should be appreciated that the
`suitability of a therapeutic agent for use in the methods and
`compositions of the present invention is not determined by
`its therapeutic class, but is instead determined by the acid-
`base properties of its acidic or basic functional groups.
`The terms “acid” and “base” as used herein refer to the
`
`ability of a functional group to act as a Brqfinsted-Lowry acid
`or Lewis acid, or as a Br(25nsted-Lowry base or Lewis base,
`in the presence of an appropriate ionizing agent. For
`simplicity,
`the acidic and basic properties of functional
`groups,
`ionizing agents, and neutralizing agents are
`described herein with particular reference to Br0nsted-
`Lowry properties, but the corresponding Lewis acid/base
`properties are also included within the scope of these terms.
`This usage should be contrasted with the terminology
`typically used in describing whether a compound is “acidic”
`or “basic” based on the pKa of the compound in deionized
`water. For example, the equivalent pKa of a functional group
`need not be less than 7 to be considered “acidic”, since even
`functional groups with a large pKa can be “acidic” if they
`can be deprotonated by a strong base. Similarly, a functional
`group with an equivalent pKa of less than 7 may still be
`considered “basic” if it can be protonated by a stronger acid.
`Thus, it is the ability of a particular functional group to be
`ionized (protonated or deprotonated) by a suitable ionizing
`agent (acid or base) that determines whether a functional
`group is acidic or basic, rather than the particular pKa
`associated with that group or with the compound as a whole.
`As a specific example,
`itraconazole is a hydrophobic
`therapeutic agent having a pKa of 3.7, and a pKb of 10.3.
`Thus, itraconazole can be protonated by an acid having a
`pKa less than 3.7, or deprotonated by a base having a pKb
`less than 10.3.
`
`Suitable therapeutic agents contain at least one ionizable
`functional group. Of course, many suitable therapeutic
`agents contain a plurality of such groups, and a single
`therapeutic agent may contain one or more acidic functional
`groups as well as one or more basic functional groups. Such
`therapeutic agents are also within tile scope of the present
`invention.
`
`Acidic functional groups include, but are not limited to,
`carboxylic acids,
`imidazolidinediones,
`thiazolidinediones,
`pyrimidinetriones, hydroxyheteroaromatics, phenols, phos-
`phoric acids, sulfuric acids, sulfonic acids, sulfonamides,
`aminosulfones, sulfonylureas, tetrazoles and thiols.
`In order to avoid particularly cumbersome terminology,
`the functional groups, whether acidic or basic, are referred
`to by naming the corresponding free compound. For
`example, referring to a functional group, the term “amino-
`sulfone” is used, rather than the more technically precise
`term “aminosulfonyl”. This usage is common in the art, and
`is well understood by one skilled in the art.
`
`6
`Basic functional groups include, but are not limited to,
`aliphatic amines, aromatic amines, C-substituted aromatic
`amines, N-substituted aromatic amines, heterocyclic
`amines, C-substituted heterocyclic amines and N-substituted
`heterocyclic amines.
`Examples of aromatic amines and substituted aromatic
`amines include, but are not
`limited to, aniline,
`N-methylaniline and p-toluidine.
`Examples of heterocyclic and substituted heterocyclic
`amines include, but are not limited to, pyrrole, pyrazole,
`imidazole,
`indole, pyridine, pyridazine, pyrimidine,
`quinoline, piperidine, pyrrolidine, morpholine,
`thiazole,
`purine and triazole.
`Specific examples of suitable therapeutic agents having at
`least one ionizable acidic functional group include, but are
`not limited to: acetazolamide, acetohexamide, acrivastine,
`alatrofloxacin, albuterol, alclofenac, aloxiprin, alprostadil,
`amodiaquine, amphotericin, amylobarbital, aspirin,
`atorvastatin, atovaquone, baclofen, barbital, benazepril,
`bezafibrate, bromfenac, bumetanide, butobarbital,
`candesartan, capsaicin, captopril, cefazolin, celecoxib,
`cephadrine, cephalexin, cerivastatin, cetrizine,
`chlorambucil, chlorothiazide, chlorpropamide,
`chlorthalidone, cinoxacin, ciprofloxacin, clinofibrate,
`cloxacillin, cromoglicate, cromolyn, dantrolene,
`dichlorophen, diclofenac, dicloxacillin, dicumarol,
`diflunisal, dimenhydrinate, divalproex, docusate,
`dronabinol, enoximone, enalapril, enoxacin, enrofloxacin,
`epalrestat, eposartan, essential
`fatty acids, estramustine,
`ethacrynic acid, ethotoin, etodolac, etoposide, fenbufen,
`fenoprofen,
`fexofenadine,
`fluconazole,
`flurbiprofen,
`fluvastatin, fosinopril, fosphenytoin, fumagillin, furosemide,
`gabapentin, gemfibrozil, gliclazide, glipizide,
`glybenclamide, glyburide, glimepiride, grepafloxacin,
`ibufenac,
`ibuprofen,
`imipenem,
`indomethacin,
`irbesartan,
`isotretinoin, ketoprofen, ketorolac,
`lamotrigine,
`levofloxacin,
`levothyroxine,
`lisinopril,
`lomefloxacin,
`losartan,
`lovastatin, meclofenamic acid, mefenamic acid,
`mesalamine, methotrexate, metolazone, montelukast, nalid-
`ixic acid, naproxen, natamycin, nimesulide, nitrofurantoin,
`non-essential fatty acids, norfloxacin, nystatin, ofloxacin,
`oxacillin, oxaprozin, oxyphcnbutazonc, pcnicillins,
`pentobarbital, perfloxacin, phenobarbital, phenytoin,
`pioglitazone, piroxicam, pramipexol, pranlukast,
`pravastatin, probenecid, probucol, propofol,
`propylthiouracil, quinapril,
`rabeprazole,
`repaglinide,
`rifampin,
`rifapentine, sparfloxacin, sulfabenzamide,
`sulfacetamide, sulfadiazine, sulfadoxine, sulfamerazine,
`sulfamethoxazole, sulfafurazole, sulfapyridine,
`sulfasalazine, sulindac, sulphasalazine, sulthiame,
`telmisartan,
`teniposide,
`terbutaline,
`tetrahydrocannabinol,
`tirofiban,
`tolazamide,
`tolbutamide,
`tolcapone,
`tolmetin,
`tretinoin,
`troglitazone,
`trovafloxacin, undecenoic acid,
`ursodeoxycholic acid, valproic acid, valsartan, vancomycin,
`verteporfin, vigabatrin, vitamin K-S (II) and zafirlukast.
`Among the above-listed hydrophobic therapeutic agents
`having at least one acidic functional group, preferred hydro-
`phobic therapeutic agents are: acetohexamide, acrivastine,
`alatrofloxacin, albuterol, alclofenac, amodiaquine,
`amphotericin, aspirin, atorvastatin, atovaquone, baclofen,
`benazepril, bezafibrate, bromfenac, butobarbital,
`candesartan, capsaicin, captopril, celecoxib, cerivastatin,
`cetrizine, chlorambucil, chlorpropamide, chlorthalidone,
`clinofibrate, cinoxacin, ciprofloxacin, clinofibrate,
`cloxacillin, cromoglicate, cromolyn, dantrolene, diclofenac,
`dicumarol, divalproex, docusate, dronabinol, enalapril,
`enoxacin, eposartan, etodolac, etoposide,
`fenbufen,
`
`10
`
`15
`
`20
`
`25
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`30
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`35
`
`40
`
`45
`
`50
`
`55
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`60
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`65
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`US 6,383,471 B1
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`7
`flurbiprofen,
`fluconazole,
`fexofenadine,
`fenoprofen,
`fumagillin, gabapentin,
`fosphenytoin,
`fluvastatin,
`gemfibrozil, gliclazide, glipizide, glyburide, glimepiride,
`grepafloxacin,
`ibufenac,
`ibuprofen,
`imipenem,
`indomethacin,
`irbesartan,
`isotretinoin, ketoprofen,
`ketorolac,
`lamotrigine,
`levofloxacin,
`levothyroxine,
`lisinopril,
`lomefloxacin,
`losartan,
`lovastatin, mesalamine,
`methotrexate, montelukast, naproxen, nimesulide, non-
`essential fatty acids, norfloxacin, ofloxacin, oxaprozin,
`phenytoin, pioglitazone, piroxicam, pramipexol, pravastatin,
`probucol, propofol,
`rabeprazole,
`repaglinide,
`rifampin,
`rifapentine, sparfloxacin, sulfadiazine, sulfamethoxazole,
`sulfasalazine, sulindac, sulphasalazine,
`telmisartan,
`teniposide,
`terbutaline,
`tetrahydrocannabinol,
`tirofiban,
`tolazamide,
`tolbutamide,
`tolcapone,
`tolmetin,
`tretinoin,
`troglitazone, trovafloxacin, undecenoic acid, valproic acid,
`valsartan, vancomycin, verteporfin, vigabatrin, vitamin K-S
`(II) and zafirlukast.
`Among the preferred hydrophobic therapeutic agents hav-
`ing at least one ionizable acidic functional group, the more
`preferred hydrophobic therapeutic agents are: acrivastine,
`alatrofloxacin, albuterol, aldlofenac, aspirin, atorvastatin,
`atovaquone, baclofen, benazepril, bezafibrate, bromfenac,
`butobarbital, celecoxib, cerivastatin, cetrizine,
`chlorpropamide, ciprofloxacin, cromoglicate, cromolyn,
`dantrolene, diclofenac, dicumarol, divalproex, dronabinol,
`enoxacin, etodolac, etoposide, fenoprofen, fexofenadine,
`fluconazole,
`flurbiprofen,
`fluvastatin,
`fosphenytoin,
`gemfibrozil, glipizide, glyburide, glimepiride,
`grepafloxacin, ibufenac, ibuprofen, isotretinoin, ketoprofen,
`ketorolac,
`lamotrigine,
`levofloxacin,
`levothyroxine,
`lomefloxacin,
`lovastatin, methotrexate, montelukast,
`naproxen, nimesulide, non-essential fatty acids, norfloxacin,
`ofloxacin, oxaprozin, phenytoin, pioglitazone, piroxicam,
`pravastatin, probucol, rabeprazole, repaglinide, rifampin,
`rifapentine, sulfamethoxazole, sulfasalazine,
`teniposide,
`tetrahydrocannabinol,
`tolcapone,
`tolmetin,
`tretinoin,
`troglitazone, trovafloxacin, valproic acid, vancomycin, vita-
`min K-S (II) and zafirlukast.
`The most preferred hydrophobic therapeutic agents hav-
`ing at
`least one ionizable acidic functional group are:
`alclofcnac, aspirin, atorvastatin, atovaquonc, bcnazcpril,
`bromfenac, celecoxib, cromoglicate, cromolyn, diclofenac,
`dronabinol, etodolac,
`fexofenadine,
`flurbiprofen,
`glimepiride, ibufenac, ibuprofen, isotretinoin, ketoprofen,
`ketorolac,
`levothyroxine, naproxen, non-essential
`fatty
`acids, oxaprozin, phenytoin, pioglitazone,
`rabeprazole,
`repaglinide,
`teniposide,
`tetrahydrocannabinol,
`tolmetin,
`tretinoin, troglitazone, trovafloxacin and vitamin K-S (II).
`Specific examples of suitable hydrophobic therapeutic
`agents having at least one ionizable basic functional group
`include, but are not
`limited to: abacavir, acebutolol,
`acrivastine, alatrofloxacin, albuterol, albendazole,
`alprazolam, alprenolol, amantadine, amiloride,
`aminoglutethimide, amiodarone, amitriptyline, amlodipine,
`amodiaquine, amoxapine, amphetamine, amphotericin,
`amprenavir, amrinone, amsacrine, astemizole, atenolol,
`atropine, azathioprine, azelastine, azithromycin, baclofen,
`benethamine, benidipine, benzhexol, benznidazole,
`benztropine, biperiden, bisacodyl, bisanthrene,
`bromazepam, bromocriptine, bromperidol,
`brompheniramine, brotizolam, bupropion, butenafine,
`butoconazole, cambendazole, camptothecin, carbinoxamine,
`cephadrine, cephalexin, cetrizine, cinnarizine, chlorambucil,
`chlorpheniramine, chlorproguanil, chlordiazepoxide,
`chlorpromazine, chlorprothixene, chloroquine, cimetidine,
`ciprofloxacin, cisapride, citalopram, clarithromycin,
`
`8
`clemastine, clemizole, clenbuterol, clofazimine,
`clomiphene, clonazepam, clopidogrel, clozapine,
`clotiazepam, clotrimazole, codeine, cyclizine,
`cyproheptadine, dacarbazine, darodipine, decoquinate,
`delavirdine, demeclo-cycline, dexamphetamine,
`dexchlorpheniramine, dexfenfluramine, diamorphine,
`diazepam, diethylpropion, dihydrocodeine,
`dihydroergotamine, diltiazem, dimenhydrinate,
`diphenhydramine, diphenoxylate, diphenyl-imidazole,
`diphenylpyraline, dipyridamole, dirithromycin,
`disopyramide, dolasetron, domperidone, donepezil,
`doxazosin, doxycycline, droperidol, econazole, efavirenz,
`ellipticine, enalapril, enoxacin, enrofloxacin, eperisone,
`ephedrine, ergotamine, erythromycin, ethambutol,
`ethionamide, ethopropazine, etoperidone,
`famotidine,
`felodipine,
`fenbendazole,
`fenfluramine,
`fenoldopam,
`fentanyl, fexofenadine, flecainide, flucytosine, flunarizine,
`flunitrazepam,
`fluopromazine,
`fluoxetine,
`fluphenthixol,
`fluphenthixol decanoate,
`fluphenazine,
`fluphenazine
`decanoate,
`flurazepam,
`flurithromycin,
`frovatriptan,
`gabapentin, granisetron, grepafloxacin, guanabenz,
`halofantrine, haloperidol, hyoscyamine,
`imipenem,
`indinavir,