(12) United States Patent
`Chen et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US0063834 71Bl
`US 6,383,471 Bl
`May 7, 2002
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(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? .................................................. 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
`
`4,388,307 A
`6/1983 Cavanak ..................... 424/177
`4,572,915 A
`2/1986 Crooks ....................... 514/458
`4,713,246 A
`12/1987 Begum et a!.
`.............. 424/455
`4,719,239 A
`1!1988 Muller eta!. ............... 514/785
`4,727,109 A
`2/1988 Schmidt et a!. ............. 424/455
`4,731,384 A
`3/1988 Dell eta!. .................. 514/658
`4,944,949 A
`7/1990 Story et a!. ................. 424/451
`5,071,643 A
`12/1991 Yu eta!. ..................... 514/570
`5,145,684 A
`9/1992 Liversidge eta!. ......... 424/489
`5,244,925 A
`9/1993 Wretlind eta!. ............ 514/777
`5,300,529 A
`4/1994 Narayanan .................. 514/788
`8/1994 Hauer et a!. ................ 424/455
`5,342,625 A
`11/1994 Yu et a!. ..................... 424/455
`5,360,615 A
`............... 424/450
`11/1994 Benita et a!.
`5,364,632 A
`12/1994 Morton eta!. .............. 514/786
`5,376,688 A
`11/1995 Argiriadi et a!. ............ 424/456
`5,468,502 A
`5,532,002 A
`7/1996 Story ......................... 424/456
`5,589,455 A
`12/1996 Woo ............................ 514/11
`5,614,491 A
`3/1997 Walch eta!. ................. 514/11
`5,616,330 A
`4/1997 Kaufman et a!.
`........... 424/400
`5,639,474 A
`6/1997 Woo ........................... 424/452
`5,639,724 A
`6/1997 Cavanak ...................... 514/11
`5,645,856 A
`7/1997 Lacy et a!.
`................. 424/455
`5,652,212 A
`7/1997 Cavanak eta!. .............. 514/11
`5,653,987 A
`8/1997 Modi et a!. ................. 424/400
`5,726,181 A
`3/1998 Hausheer eta!. ........... 514/283
`5,731,355 A
`3/1998 Jones eta!. ................. 514/731
`5,741,822 A
`4/1998 Yesair ........................ 514/784
`5,747,066 A
`5/1998 Pittrof et a!.
`............... 424/450
`5,766,629 A
`6/1998 Cho et a!. ................... 424/455
`5,773,029 A
`6/1998 Chiesi et a!.
`............... 424/488
`5,858,401 A
`1!1999 Bhalani et a!.
`............. 424/450
`01HER PUBLICATIONS
`Alvarez, F. 1. and Stella, V. J., "The Role of Calcium Ions
`and Bile Salts on the Pancreatic Lipase-Catalyzed Hydroly(cid:173)
`sis of Triglyceride Emulsions Stabilized with Lecithin",
`Pharmaceutical Research, 6(6), 449-457 (1989).
`Bates, T. R. and Sequeira, J. A, "Bioavailability of Micron(cid:173)
`ized Griseofulvin from Corn Oil-in-Water Emulsion, Aque(cid:173)
`ous Suspension, and Commercial Tablet Dosage Forms in
`Humans", Journal of Pharmaceutical Sciences, 64(5),
`793-797 (1975).
`
`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(cid:173)
`cal Properties on Dissolution of Drugs in the Gastrointesti(cid:173)
`nal Tract", Advanced Drug Delivery Reviews 25, 3-14
`(1997).
`Humberstone, A. 1. 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", J ourn(cid:173)
`ees Galeniques, 67-74, (1994).
`Johnson, L. R., "Gastrointestinal Physiology", Department
`of Physiology, University of Texas Medical School, Hous(cid:173)
`ton, Texas, 25-26, 93, 106, 133-134, 136-137 (1997).
`MacGregor, K. 1. et al., "Influence of Lipolysis on Drug
`Absorption From the Gastro-intestinal Tract", Advanced
`Drug Delivery Reviews 25, 33-46 (1997).
`Ponton, 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 Gattefosse,
`No. 90, 13-18 (1997).
`Winne, D., "Dependence oflntestinalAbsorption 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(cid:173)
`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(cid:173)
`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(cid:173)
`peutic agent, an ionizing agent, and a surfactant, and neu(cid:173)
`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, No Drawings
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1009, Pg. 1 of 30
`
`

`

`US 6,383,471 Bl
`
`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
`
`2
`system can be diethylene glycol monoethyl ether, glycerol
`caprylate/caprate, polyglycerol oleate, alpha-hydro-w(cid:173)
`hydroxypoly( oxyethylene )-poly( oxypropylene )-poly
`(oxyethylene) block copolymers, or mixtures of those corn-
`s 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
`10 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-
`15 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
`20 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(cid:173)
`trointestinal or intestinal fluids. This precipitation is particu(cid:173)
`larly disadvantageous, since the precipitated therapeutic
`25 agent is essentially unavailable for absorption, leading to
`difficulties in controlling dosages, and a need to administer
`large doses of the therapeutic agent to ensure that a thera(cid:173)
`peutically effective amount reaches the absorption site in a
`bioavailable form. Such difficulties necessarily result in
`30 increased costs, and compromised patient safety and thera(cid:173)
`peutic effectiveness.
`Thus, there is a need for versatile and effective pharma(cid:173)
`ceutical compositions that overcome these deficiencies in
`the prior art.
`
`35
`
`Hydrophobic therapeutic agents, i.e., therapeutic com(cid:173)
`pounds having poor solubility in aqueous solution, present
`difficult problems in formulating such compounds for effec(cid:173)
`tive administration to patients. A well-designed formulation
`must, at a minimum, be capable of presenting a therapeuti(cid:173)
`cally effective amount of the hydrophobic compound to the
`desired absorption site, in an absorbable form. Even this
`minimal functionality is difficult 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(cid:173)
`ery of such hydrophobic therapeutic agents must carry the
`hydrophobic compound through the aqueous environment,
`while maintaining the hydrophobic compound in an absorb(cid:173)
`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(cid:173)
`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- 40
`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 45
`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 ss
`enhanced solubility in the partially ionized form. The ref(cid:173)
`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- 60
`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(cid:173)
`ceutical solution of an acidic, basic or amphoteric pharma- 65
`ceutical agent. The solution includes a pharmaceutical agent,
`an ionizing species, and a solvent system. The solvent
`
`50
`
`SUMMARY OF THE INVENTION
`It is therefore an object of the present invention to provide
`pharmaceutical compositions capable of solubilizing thera(cid:173)
`peutically effective amounts of ionizable hydrophobic thera(cid:173)
`peutic agents.
`It is another object of the invention to provide ph arm a(cid:173)
`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 ph arm a(cid:173)
`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(cid:173)
`izable hydrophobic therapeutic agents.
`It is still another object of the invention to provide
`methods of treating an animal with pharmaceutical compo(cid:173)
`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(cid:173)
`bic therapeutic agents.
`In one embodiment, the invention is directed to a phar(cid:173)
`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(cid:173)
`tant. Optionally, the carrier also includes solubilizers, trig(cid:173)
`lycerides and neutralizing agents.
`In another embodiment, the invention is directed to a
`pharmaceutical composition including a hydrophobic thera-
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1009, Pg. 2 of 30
`
`

`

`US 6,383,471 Bl
`
`5
`
`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(cid:173)
`eride.
`In another embodiment, the invention is directed to a
`pharmaceutical composition including a hydrophobic thera(cid:173)
`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 10
`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(cid:173)
`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(cid:173)
`cosides; alkylmaltosides; alkylthioglucosides; lauryl mac(cid:173)
`rogolglycerides; polyoxyethylene alkyl ethers; fatty acids;
`lower alcohol fatty acid esters; polyoxyethylene alkylphe(cid:173)
`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 30
`glycerides; polyoxyethylene sterols, derivatives, and ana(cid:173)
`logues thereof; polyoxyethylene vegetable oils; polyoxyeth(cid:173)
`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 35
`sterols; sugar esters; sugar ethers; sucroglycerides; fatty acid
`salts; bile salts; phospholipids; phosphoric acid esters; car(cid:173)
`boxylates; sulfates; and sulfonates.
`In another embodiment, the present invention is directed
`to a pharmaceutical composition including a hydrophobic 40
`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(cid:173)
`factant includes at least one compound selected from the 45
`group consisting of alkylglucosides; alkylmaltosides; alky(cid:173)
`lthioglucosides; lauryl macrogolglycerides; fatty acids;
`lower alcohol fatty acid esters; polyoxyethylene alkylphe(cid:173)
`nols; polyethylene glycol fatty acids esters; polypropylene
`glycol fatty acid esters; glycerol fatty acid esters; acetylated 50
`glycerol fatty acid esters; polyethylene glycol glycerol fatty
`acid esters; polyglyceryl fatty acid esters; polyoxyethylene
`sorbitan fatty acid esters; polyoxyethylene glycerides; poly(cid:173)
`oxyethylene sterols, derivatives, and analogues thereof;
`polyoxyethylene vegetable oils; polyoxyethylene hydroge- 55
`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- 60
`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 65
`ethanol, isopropanol, butanol, benzyl alcohol, ethylene
`glycol, propylene glycol, butanediols and isomers thereof,
`
`4
`glycerol, pentaerythritol, sorbitol, mannitol, dimethyl
`isosorbide, polypropylene glycol, polyvinylalcohol, hydrox(cid:173)
`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(cid:173)
`bic therapeutic agent and a carrier which includes an ion(cid:173)
`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
`15 method of treating an animal with an ionizable hydrophobic
`therapeutic agent. The method includes the steps of provid(cid:173)
`ing a pharmaceutical composition having an ionizable
`hydrophobic therapeutic agent and a carrier which includes
`an ionizing agent and a surfactant; and administering the
`20 pharmaceutical composition to an animal.
`These and other objects and features of the present
`invention will become more fully apparent from the follow(cid:173)
`ing description and appended claims, or may be learned by
`25 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(cid:173)
`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(cid:173)
`ous dosage forms of the pharmaceutical composition.
`The present invention further provides a method of solu(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`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
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1009, Pg. 3 of 30
`
`

`

`US 6,383,471 Bl
`
`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(cid:173)
`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 Br0nsted-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(cid:173)
`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 Br0nsted-Lowry acid
`or Lewis acid, or as a Br0nsted-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(cid:173)
`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(cid:173)
`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(cid:173)
`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
`5 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
`10 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
`15 least one ionizable acidic functional group include, but are
`not limited to: acetazolamide, acetohexamide, acrivastine,
`alatrofioxacin, albuterol, alclofenac, aloxiprin, alprostadil,
`amodiaquine, amphotericin, amylobarbital, aspirin,
`atorvastatin, atovaquone, baclofen, barbital, benazepril,
`20 bezafibrate, bromfenac, bumetanide, butobarbital,
`candesartan, capsaicin, captopril, cefazolin, celecoxib,
`cephadrine, cephalexin, cerivastatin, cetrizine,
`chlorambucil, chlorothiazide, chlorpropamide,
`chlorthalidone, cinoxacin, ciprofioxacin, clinofibrate,
`25 cloxacillin, cromoglicate, cromolyn, dantrolene,
`dichlorophen, diclofenac, dicloxacillin, dicumarol,
`difiunisal, dimenhydrinate, divalproex, docusate,
`dronabinol, enoximone, enalapril, enoxacin, enrofioxacin,
`epalrestat, eposartan, essential fatty acids, estramustine,
`30 ethacrynic acid, ethotoin, etodolac, etoposide, fenbufen,
`fenoprofen, fexofenadine, fluconazole, fiurbiprofen,
`fiuvastatin, fosinopril, fosphenytoin, fumagillin, furosemide,
`gabapentin, gemfibrozil, gliclazide, glipizide,
`glybenclamide, glyburide, glimepiride, grepafioxacin,
`35 ibufenac, ibuprofen, imipenem, indomethacin, irbesartan,
`isotretinoin, ketoprofen, ketorolac, lamotrigine,
`levofioxacin, levothyroxine, lisinopril, lomefioxacin,
`losartan, lovastatin, meclofenamic acid, mefenamic acid,
`mesalamine, methotrexate, metolazone, montelukast, nalid-
`40 ixic acid, naproxen, natamycin, nimesulide, nitrofurantoin,
`non-essential fatty acids, norfioxacin, nystatin, ofioxacin,
`oxacillin, oxaprozin, oxyphenbutazone, penicillins,
`pentobarbital, perfioxacin, phenobarbital, phenytoin,
`pioglitazone, piroxicam, pramipexol, pranlukast,
`45 pr a vas ta tin, probenecid, pro bucol, prop ofo 1,
`propylthiouracil, quinapril, rabeprazole, repaglinide,
`rifampin, rifapentine, sparfioxacin, sulfabenzamide,
`sulfacetamide, sulfadiazine, sulfadoxine, sulfamerazine,
`sulfamethoxazole, sulfafurazole, sulfapyridine,
`50 sulfasalazine, sulindac, sulphasalazine, sulthiame,
`telmisartan, teniposide, terbutaline, tetrahydrocannabinol,
`tirofiban, tolazamide, tolbutamide, tolcapone, tolmetin,
`tretinoin, troglitazone, trovafioxacin, undecenoic acid,
`ursodeoxycholic acid, valproic acid, valsartan, vancomycin,
`55 verteporfin, vigabatrin, vitamin K-S (II) and zafirlukast.
`Among the above-listed hydrophobic therapeutic agents
`having at least one acidic functional group, preferred hydro(cid:173)
`phobic therapeutic agents are: acetohexamide, acrivastine,
`alatrofioxacin, albuterol, alclofenac, amodiaquine,
`60 amphotericin, aspirin, atorvastatin, atovaquone, baclofen,
`benazepril, bezafibrate, bromfenac, butobarbital,
`candesartan, capsaicin, captopril, celecoxib, cerivastatin,
`cetrizine, chlorambucil, chlorpropamide, chlorthalidone,
`clinofibrate, cinoxacin, ciprofioxacin, clinofibrate,
`65 cloxacillin, cromoglicate, cromolyn, dantrolene, diclofenac,
`dicumarol, divalproex, docusate, dronabinol, enalapril,
`enoxacin, eposartan, etodolac, etoposide, fenbufen,
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1009, Pg. 4 of 30
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`US 6,383,471 Bl
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`7
`fenoprofen, fexofenadine, fluconazole, flurbiprofen,
`fluvastatin, fosphenytoin, fumagillin, gabapentin,
`gemfibrozil, gliclazide, glipizide, glyburide, glimepiride,
`grepafloxacin, ibufenac, ibuprofen, imipenem,
`indomethacin, irbesartan, isotretinoin, ketoprofen, 5
`ketorolac, lamotrigine, levofloxacin, levothyroxine,
`lisinopril, lomefloxacin, losartan, lovastatin, mesalamine,
`methotrexate, montelukast, naproxen, nimesulide, non(cid:173)
`essential fatty acids, norfloxacin, ofloxacin, oxaprozin,
`phenytoin, pioglitazone, piroxicam, pramipexol, pravastatin, 10
`probucol, propofol, rabeprazole, repaglinide, rifampin,
`rifapentine, sparfloxacin, sulfadiazine, sulfamethoxazole,
`sulfasalazine, sulindac, sulphasalazine, telmisartan,
`teniposide, terbutaline, tetrahydrocannabinol, tirofiban,
`tolazamide, tolbutamide, tolcapone, tolmetin, tretinoin, 15
`troglitazone, trovafloxacin, undecenoic acid, valproic acid,
`valsartan, vancomycin, verteporfin, vigabatrin, vitamin K-S
`(II) and zafirlukast.
`Among the preferred hydrophobic therapeutic agents hav(cid:173)
`ing at least one ionizable acidic functional group, the more 20
`preferred hydrophobic therapeutic agents are: acrivastine,
`alatrofloxacin, albuterol, aldlofenac, aspirin, atorvastatin,
`atovaquone, baclofen, benazepril, bezafibrate, bromfenac,
`butobarbital, celecoxib, cerivastatin, cetrizine,
`chlorpropamide, ciprofloxacin, cromoglicate, cromolyn, 25
`dantrolene, diclofenac, dicumarol, divalproex, dronabinol,
`enoxacin, etodolac, etoposide, fenoprofen, fexofenadine,
`fluconazole, flurbiprofen, fluvastatin, fosphenytoin,
`gemfibrozil, glipizide, glyburide, glimepiride,
`grepafloxacin, ibufenac, ibuprofen, isotretinoin, ketoprofen, 30
`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, 35
`rifapentine, sulfamethoxazole, sulfasalazine, teniposide,
`tetrahydrocannabinol, tolcapone, tolmetin, tretinoin,
`troglitazone, trovafloxacin, valproic acid, vancomycin, vita(cid:173)
`min K-S (II) and zafirlukast.
`The most preferred hydrophobic therapeutic agents hav- 40
`ing at least one ionizable acidic functional group are:
`alclofenac, aspirin, atorvastatin, atovaquone, benazepril,
`bromfenac, celecoxib, cromoglicate, cromolyn, diclofenac,
`dronabinol, etodolac, fexofenadine, flurbiprofen,
`glimepiride, ibufenac, ibuprofen, isotretinoin, ketoprofen, 45
`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 50
`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, 55
`amodiaquine, amoxapine, amphetamine, amphotericin,
`amprenavir, amrinone, amsacrine, astemizole, atenolol,
`atropine, azathioprine, azelastine, azithromycin, baclofen,
`benethamine, benidipine, benzhexol,