(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2008/0275030 A1
`
` Gizurarson et al. (43) Pub. Date: NOV. 6, 2008
`
`
`US 20080275030A1
`
`(54) METHODS AND COMPOSITIONS FOR THE
`DELIVERY OF A THERAPEUTIC AGENT
`
`(30)
`
`Foreign Application Priority Data
`
`(76)
`
`Inventors:
`
`Sveinbj orn Gizurarson, Reykjavik
`(IS); James Arp, Lexington, KY
`(US); Raouf Ghaderi, Franklin
`Park, NJ (US); Michael E. Lusty,
`Summit, NJ (US); Gregory G.
`Plucinski, Nicholasville, KY (US);
`Mehdi Yale“: COIHmblas SC (US)
`
`Correspondence Address:
`GOODWIN PROCTER LLP
`PATENT ADMINISTRATOR
`EXCHANGE PLACE
`BOSTON, MA 02109-2881 (US)
`
`(21) APP1~ N05
`
`12/0163724
`
`(22)
`
`Filed:
`
`Jan. 18, 2008
`
`Jan. 19, 2007
`
`(IS) ..................................... 8593/2007
`
`.
`.
`.
`.
`Publication Class1ficat10n
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 47/30
`(2006.01)
`A61K 31/5513
`(2006.01)
`A61K 31/5517
`(52) us. Cl. ....................... 514/220; 514/772.3; 514/221
`
`ABSTRACT
`(57)
`The present invention provides a liquid pharmaceutical com-
`position comprising a therapeutic agent and an alkoxy-poly-
`ethylene glycol, for example, methoxy-polyethylene glycol,
`for administration of the therapeutic agent to the mammal.
`The compositions can be applied to a membrane, for example,
`a nasal membrane during intranasal administration. The
`invention also provides methods of administering such com-
`positions to a mammal.
`
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`US 2008/0275030 A1
`
`Nov. 6, 2008
`
`METHODS AND COMPOSITIONS FOR THE
`DELIVERY OF A THERAPEUTIC AGENT
`
`RELATED APPLICATIONS
`
`[0001] This application claims the benefit of and priority to
`Icelandic Patent Application Serial No. 8593/2007, filed Jan.
`19, 2007, the entire disclosure of which is incorporated by
`reference herein for all purposes.
`
`FIELD OF THE INVENTION
`
`[0002] This invention relates generally to compositions for
`the delivery ofa therapeutic agent and to related methods, and
`more particularly relates to compositions containing one or
`more alkoxy-polyethylene glycols for the delivery of a thera-
`peutic agent and to related methods.
`
`BACKGROUND
`
`[0003] The administration of a therapeutic agent by inj ec-
`tion (e.g., intravenous, intramuscular or subcutaneous inj ec-
`tion) typically is regarded as the most convenient way of
`administration when the purpose is to achieve a rapid and
`strong systemic effect, for example, within 3-10 minutes,
`when the agent is not absorbed by the gastrointestinal tract, or
`when the agent is inactivated in the gastrointestinal tract or by
`first-pass hepatic metabolism. However, administration by
`injection presents a range of disadvantages. For example,
`sterile syringes must be used and inj ections cannot be admin-
`istered by untrained personnel. Furthermore, this mode of
`administration may cause pain and/or irritation, especially in
`the case of repeated injections at the same site.
`[0004] Mucosal administration, such as, intranasal, buccal,
`sublingual, rectal and pulmonal administration, is receiving
`particular interest as it avoids many of the disadvantages of
`injecting a therapeutic agent while, at the same time, still
`providing a strong and rapid systemic effect. In order to be an
`attractive alternative to injection, mucosal administration, for
`example, intranasal administration, should neither cause sig-
`nificant pain, discomfort or irritation nor cause any irrevers-
`ible damage to the mucosal surface. However, in the case of
`acute health threatening indications, a relatively high local
`irritation to the mucosa may be acceptable.
`[0005]
`In mucosal administration, such as during nasal,
`buccal or rectal administration, the therapeutic agent should
`be applied to the mucosa in a vehicle that permits it to pen-
`etrate, or be absorbed through, the mucosa. In order to pen-
`etrate the mucus, the vehicle should be biocompatible with
`mucus and hence have a certain degree of hydrophilicity.
`However, the vehicle should preferably also possess lipo-
`philic properties to dissolve a clinically relevant amount of
`the therapeutic agent of interest.
`[0006] The extensive network ofblood capillaries under the
`mucosal surface, especially in the nasal mucosa, is well suited
`to provide a rapid and effective systemic absorption of drugs,
`vaccines andbiologicals. Moreover, the nasal epithelial mem-
`brane in effect contains a single layer ofepithelial cells (pseu-
`dostratified epithelium) and, therefore, is more suited for drug
`administration than other mucosal surfaces having squamous
`epithelial layers, such as, the mouth and vagina.
`[0007]
`It has been hypothesized that the usefulness ofnasal
`administration can be limited if the therapeutic agent has
`limited solubility in water (Proctor, D. F. (1985) Nasal Physi-
`ology in Intranasal Drug Administrations, in Chien, Y. W.
`(Ed) TRANSNASAL SYSTEMIC MEDICATIONs, FUNDAMEN-
`TALS, DEVELOPMENTAL CONCEPTS AND BIOMEDICAL ASSESS-
`MENTS, ELSEVIER Science Publishers, Amsterdam, pp. 101-
`
`105). As a result, this hypothesis, if correct, may limit the
`delivery of certain therapeutic agents that are sparingly
`soluble in water.
`
`To facilitate delivery to the nasal cavity, an effective
`[0008]
`amount ofthe therapeutic agent should be dissolved in a small
`volume, for example, less than about 1000 ILL, preferably less
`than 300 ILL, and more preferably less than 150 ILL. Larger
`volumes drain out anteriorly through the nostrils or posteri-
`orly toward the pharynx where excess liquid is swallowed. As
`a result, if large volumes are administered, a portion of the
`therapeutic agent can be lost from the absorption site, and it
`can be difficult if not impossible to reproducibly administer
`the correct dose of the therapeutic agent.
`[0009] A variety of delivery systems have been developed
`for the nasal administration of therapeutic agents. Lau and
`Slattery studied the absorption characteristics of diazepam
`and lorazepam following their intranasal administration for
`the treatment of epilepticus (Lau, S. W. J. & Slattery, J. T.
`(1989), Absorption ofDiazepam and Lorazepam Following
`IntranasalAdministration, INT. J. PHARM., 54, 171-174). In
`order to solubilize the therapeutic agent, a non-ionic surfac-
`tantipolyoxyethylated castor oiliwas selected as the least
`irritating solvent of several solvents studied, including poly-
`ethylene glycol 400 (PEG 400). Diazepam absorption was
`84% and 72%, respectively, in two adults measured over a
`period of 60 hours. However, the peak concentration was not
`observed until 1.4 hours after the nasal administration and
`was only about 27% with reference to intravenous adminis-
`tration, suggesting that most ofthe absorption had takenplace
`after the test substance passed down to pharynx and swal-
`lowed. Similar results were obtained for lorazepam but with
`an even longer time to peak (2.3 hours). The authors con-
`cluded that the intranasal route of administration had limited
`potential for the acute treatment of epileptic seizures.
`[0010] Wilton et al. attempted to administer midazolam to
`45 children to achieve pre-anesthetic sedation (Wilton et al.
`(1988) Preanaesthetic Sedation ofPreschool Children Using
`Intranasal Midazolam, ANESTHESIOLOGY, 69, 972-975).
`However, the volumes used were impractical and exceeded
`the maximal volume required for efiicient administration.
`This resulted in coughing and sneezing with expulsion of at
`least part of the dose.
`[0011] Morimoto et al. studied a gel preparation for nasal
`application in rats of nifedipine containing the gelling agent
`carbopol (polyacrylic acid) in PEG 400, for achieving pro-
`longed action and high bioavailability ofthe therapeutic agent
`(Morimoto et al. (1 987) Nasal Absorption ofNifedipinefrom
`Gel Preparations in Rats, CHEMICAL AND PHARMACEUTICAL
`BULLETINS, 35, No. 7, 3041-3044). A mixture of equal
`amounts of carbopol and PEG 400 was preferred. It was
`shown that nasal application provided higher bioavailability
`of nifedipine than after peroral administration, but the peak
`plasma concentration was not observed until 30 minutes after
`administration.
`
`[0012] Danish Patent Application No. 2586/87 discloses a
`pharmaceutical composition comprising an anti-inflamma-
`tory steroid, water, 2 to 10% (v/v) propylene glycol, 10 to
`25% (v/v) PEG 400, and 1 to 4% (v/v) Tween 20.
`[0013] US. Pat. No. 4,153,689 discloses a stable aqueous
`solution of insulin intended for intranasal administration. The
`solutions had a pH not more than 4.7, and contained from 0.1
`to 20% by weight of a stabilizing agent including (a) one or
`more non-ionic surface active agents whose hydrophile-lipo-
`phile balance value was in the range of 9 to 22, and/or (b)
`polyethylene glycol whose molecular weight was in the range
`of from 200 to 7500. Exemplary non-ionic surface active
`agents included polyoxyethylene fatty acid ester, a polyoxy-
`
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`ethylene higher alcohol ether, a polyoxyethylene alkylphenyl
`ether, or a polyoxyethylene alkylphenyl ether, or a polyoxy-
`ethylene hydrogenated castor oil.
`[0014]
`International Patent Publication No. DK-2075/90
`discloses the nasal administration of therapeutic agents, for
`example, benzodiazepines,
`in compositions containing
`n-glycofurol, a derivative of polyethyleneglycol, for mucosal
`administration. The application discloses the nasal adminis-
`tration of therapeutic agents, for example, benzodiazepines,
`in formulations containing at least 30% n-ethyleneglycols
`ranging from 1-8 ethylene glycol, for example, polyethylene
`glycol 200 (PEG 200).
`[0015] US. Pat. No. 5,693,608 discloses a method of
`administering a therapeutic agent Via the nasal mucosa of a
`mammal, where the agent is dissolved or suspended in an
`n-ethyleneglycol containing vehicle where the n-ethyleneg-
`lycol
`is represented by the formula, H(OCH2CH2)POH,
`wherein p is a number from 1 to 8.
`[0016] Notwithstanding, there is still a need for composi-
`tions deliverable through mucosal membranes that produce
`therapeutic plasma concentrations of the therapeutic agent as
`fast as or nearly as fast as by intravenous administration but
`without causing irritation and/or unacceptable damage to the
`mucosal membrane.
`
`SUMMARY OF THE INVENTION
`
`[0017] The invention is based, in part, upon the discovery
`that the inclusion of one or more alkoxy-polyethylene glycols
`in a formulation provides certain advantages when the result-
`ing composition is to be applied, for example, to a mucosal
`surface. For example,
`it has been discovered that when
`alkoxy-polyethylene glycol is used in such formulations, the
`therapeutic agent can be still be solubilized (which is espe-
`cially useful for poorly soluble therapeutic agents) but the
`resulting formulations are less viscous and cause less irrita-
`tion to mucosal membranes because the amount of other
`potentially viscous and irritable excipients, for example,
`polyethylene glycol or propylene glucol, can be reduced or
`eliminated altogether. As a result, the lower viscosity formu-
`lations, when converted into droplets, for example, by a nasal
`sprayer during intranasal delivery, can produce a spray pat-
`tern optimized for delivering the therapeutic agent to the
`mucosal membrane. In addition, formulations containing
`alkoxy-polyethylene glycols create less irritation (burning
`sensation) when applied to a mucosal surface, for example, a
`nasal membrane following nasal administration. In addition,
`when administered intranasally,
`the compositions of the
`invention minimize undesirable after taste (for example, a
`petroleum-like after taste) that can be associated with certain
`other excipients.
`[0018]
`In one aspect, the invention provides a liquid phar-
`maceutical composition comprising a therapeutic agent and
`an alkoxy-polyethylene glycol represented by Formula I:
`R407(CH2CH2O),,7H
`
`(1)
`
`R is methyl, ethyl, n-propyl, isopropyl, or cyclopro-
`
`wherein,
`[0019]
`pyl; and
`n, which is the average number of oxyethylene
`[0020]
`repeating units, is a number in the range of from about 1 to
`about 25.
`
`In another aspect, the invention provides a liquid
`[0021]
`formulation for solubilizing a poorly soluble therapeutic
`agent, for example, a poorly soluble organic therapeutic
`agent. The composition comprises a poorly soluble therapeu-
`
`tic agent and an alkoxy-polyethylene glycol represented by
`Formula I:
`
`R407(CH2CH2O),,7H
`
`(1)
`
`wherein,
`[0022] R is (C1-C6)alkyl; and
`[0023]
`n, which is the average number of oxyethylene
`repeating units, is a number in the range of from about 1 to
`about 25.
`In another aspect, the invention provides methods of
`[0024]
`delivering a therapeutic agent of interest to a mammal, for
`example, a human, using an alkoxy-polyethylene glycol con-
`taining composition described herein. The composition is
`particularly useful when the composition is applied to a
`mucosal membrane, for example, a nasal membrane during
`intranasal drug delivery.
`[0025] These and other aspects and advantages of the
`invention will become apparent upon consideration of the
`following detailed description and claims.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0026] The invention is based, in part, upon the discovery
`that the inclusion of one or more alkoxy-polyethylene glycols
`into formulations provides certain advantages over other
`excipients when the formulations are applied, for example, to
`a mucosal surface. For example, it has been discovered that
`when an alkoxy-polyethylene glycol is used in such a formu-
`lation, the therapeutic agent (for example, a poorly soluble
`therapeutic agent) canbe solubilized more easily and in larger
`amounts than when other excipients, for example, polyethyl-
`ene glycol (more particularly PEG 400), are used. However,
`the resulting formulations are less viscous and cause less
`irritation to mucosal membranes as the amount of other vis-
`cous and irritable excipients can be reduced or eliminated
`altogether. As a result, the lower viscosity formulations, when
`converted into droplets, for example, by a nasal sprayer dur-
`ing intranasal delivery, produce a spray pattern optimized for
`delivering the therapeutic agent to the muco sal membrane. In
`addition, formulations containing one or more alkoxy-poly-
`ethylene glycols cause less irritation (for example, a burning
`sensation) when applied to a mucosal surface, for example, a
`nasal membrane during intranasal administration. In addi-
`tion, when administered intranasally, the compositions of the
`invention have less undesirable after taste (for example, a
`petroleum-like after taste) than when other excipients, for
`example, propylene glycol, are used.
`[0027] Under certain circumstances, the alkoxy-group also
`increases the bioadhesion of the composition to the site of
`administration on the mucosal surface thereby prolonging the
`duration ofthe composition at the site of administration. This
`can increase the amount oftherapeutic agent that is ultimately
`absorbed.
`
`I Formulations
`
`In one aspect, the invention provides a liquid phar-
`[0028]
`maceutical composition comprising a therapeutic agent and
`an alkoxy-polyethylene glycol represented by Formula I:
`R407(CH2CH2O),,7H
`
`(1)
`
`R is methyl, ethyl, n-propyl, isopropyl, or cyclopro-
`
`wherein,
`[0029]
`pyl; and
`n is the average number of oxyethylene repeating
`[0030]
`units and is a number in the range of from about 1 to about 25.
`[0031]
`In another aspect, the invention provides a liquid
`formulation for solubilizing a poorly soluble therapeutic
`agent. The liquid pharmaceutical composition comprises a
`
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`
`poorly soluble therapeutic agent, for example, a poorly
`soluble organic therapeutic agent, and an alkoxy-polyethyl-
`ene glycol represented by Formula I:
`R407(CH2CH2O),,7H
`
`(1)
`
`wherein,
`[0032] R is (C1-C6)alkyl; and
`[0033]
`n is the average number of oxyethylene repeating
`units and is a number in the range of from about 1 to about 25.
`The formulations typically are in liquid form at 20° C., 25° C.,
`30° C., 35° C., or 40° C. Certain formulations preferably are
`liquid formulations at 37° C.
`[0034] The term “poorly soluble therapeutic agent” refers
`to a compound having biological activity and a solubility in
`water ofless than about 1 mg/mL at pH 7 and 20° C. In certain
`embodiments, the poorly soluble therapeutic agent is an
`organic compound that has a molecular weight of less than
`1500 g/mol, and preferably less than 500 g/mol. In certain
`embodiments, the poorly soluble therapeutic agent is a com-
`pound, for example, an organic compound, having an aque-
`ous solubility of less than about 0.5 mg/mL, less than about
`0.3 mg/mL, or less than about 0.1 mg/mL, at pH 7 and 20° C.
`[0035]
`In addition, the term “alkyl” is art-recognized, and
`includes saturated aliphatic groups, including straight-chain
`alkyl groups, branched-chain alkyl groups, cycloalkyl (alicy-
`clic) groups, alkyl
`substituted cycloalkyl groups, and
`cycloalkyl substituted alkyl groups. The term “(C1 -C6)alkyl”
`refers to an alkyl group having between 1 and 6 carbon atoms.
`Representative alkyl groups include methyl, ethyl, n-propyl,
`isopropyl, n-butyl, sec-butyl,
`isobutyl,
`tert-butyl, pentyl,
`hexyl,
`cyclopropyl,
`cyclobutyl,
`cyclopropylmethylene,
`cyclopentyl,
`cyclobutylmethylene,
`cyclobutylethylene,
`cyclohexyl, cyclopropylpropylene, cyclobutylethylene, and
`cyclopentylmethylene. The term cyclopropylmethylene, for
`example, is art-recognized and refers to a radical having the
`following formula:
`
`W.
`
`In certain embodiments, the alkoxy-polyethylene
`[0036]
`glycol can comprise from about 0.1% (v/v) to about 80%
`(v/v), or from about 0.5% (v/v) to about 70% (v/v), of the
`composition. In certain other embodiments, the alkoxy-poly-
`ethylene glycol can comprise from about 5% (v/v) to about
`80% (v/v), or from about 30% (v/v) to about 75% (v/v) or
`from about 40% (v/v) to about 70% (v/v), ofthe composition.
`For certain hydrophilic drugs, the alkoxy-polyethylene glycol
`can comprise from about 0.1% (v/v) to about 80% (v/v), or
`from about 0.5% (v/v) to about 70% (v/v), or from about 1%
`(v/v) to about 60% of the composition. For certain lipophilic
`drugs, the alkoxy-polyethylene glycol can comprise from
`about 1% (v/v) to about 80% (v/v), or from about 2% (v/v) to
`about 65% (v/v), or from about 5% (v/v) to about 50% of the
`composition. Furthermore, the therapeutic agent can com-
`prise from about 0.001% (w/v) to about 20% (w/v) of the
`composition, or from about 0.1% (w/v) to about 10% (w/v) of
`the composition.
`[0037] The pharmaceutical composition can have a pH in
`the range of from about 4.5 to about 8.5, or from about 4.5 to
`about 7.5, or from about 4.5 to about 6.5, or from about 5.5 to
`about 8.5, or from about 6.5 to about 8.5, or from about 5.5 to
`about 7.5.
`[0038] As discussed, one of the advantages of using an
`alkoxy-polyethylene glycol is that it can be used in place of or
`
`can be used to reduce the amount of other excipients, for
`example, certain polyethylene glycols and propylrnr glycol,
`so as to reduce the viscosity of the resulting formulation. By
`reducing the viscosity of the resulting formation it is possible
`to create sprays that have more uniform spray characteristics
`(for example, more uniform droplet sizes and/orplume geom-
`etries) for the intranasal administration of therapeutic agent.
`The resulting pharmaceutical composition at a temperature of
`20° C. has a viscosity in the range of about 1.5 CF to about 60
`CR or from about 2 CF to about 50 CR or from about 3 CF to
`about 40 CF, or from about 4 CF to about 30 CR or from about
`5 CF to about 25 CF.
`[0039] Exemplary alkoxy-polyethylene glycols, therapeu-
`tic agents, and other excipients useful in creating composi-
`tions of the invention are described in the following sections.
`[0040] A. Alkoxy-polyethylene Glycol
`[0041] Useful alkoxy-polyethylene glycol excipients use-
`ful in the practice ofthe invention are represented by Formula
`(1)1
`
`R407(CH2CH2O),,7H
`
`(1)
`
`wherein, n, as the average number of oxyethylene repeating
`units, is a number in the range of from about 1 to about 25.
`Accordingly, n can be a number about 1, 2, 3, 4, 5, 6, 7, 8, 9,
`10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.
`In certain embodiments, n is an number in the range of from
`about 2 to about 15, or from about 2 to about 14, or from about
`2 to about 13, or from about 2 to about 12, or from about 2 to
`about 1 1, or from about 2 to about 10, or from about 3 to about
`15, or from about 3 to about 14, or from about 3 to about 13,
`or from about 3 to about 12, or from about 3 to about 11, or
`from about 3 to about 10.
`
`In certain embodiments, R is (C1-C6)alkyl. For
`[0042]
`example, as discussed above, R can be methyl, ethyl, n-pro-
`pyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl,
`hexyl,
`cyclopropyl,
`cyclobutyl,
`cyclopropylmethylene,
`cyclopentyl,
`cyclobutylmethylene,
`cyclobutylethylene,
`cyclohexyl, cyclopropylpropylene, cyclobutylethylene, or
`cyclopentylmethylene. In certain embodiments, R is selected
`from the group consisting of methyl, ethyl, n-propyl, isopro-
`pyl, and cyclopropyl.
`[0043]
`In a preferred embodiment, the alkoxy-polyethyl-
`ene glycol is methoxy-polyethylene glycol where R is methyl
`and n is an number from about 1 to about 25, or from about 2
`to about 12, or from about 3 to about 10.
`[0044] Useful methoxy-polyethylene glycols include, for
`example, methoxy-diethyleneglyol (m2EG), methoxy-trieth-
`ylene glycol (m3 EG), methoxy-tetraethylene glycol (m4EG),
`methoxy-pentaethylene glycol (m5EG), methoxy-hexaethyl-
`ene glycol (m6EG), methoxy-heptaethylene glycol (m7EG),
`methoxy-octaethylene glycol (m8EG), methoxy-nonaethyl-
`ene glycol (m9EG), methoxy-decaethylene glycol (m10EG),
`methoxy-undecaethylene glycol (m1 lEG), methoxy-dode-
`caethylene glycol (m12EG), methoxy-tridecaethylene glycol
`(m13EG) and methoxy-tetradecaethylene glycol (m14EG).
`The ethylene glycols may be used in the form of the single
`compounds or as a mixture of two or more methoxy-n-ethyl-
`ene glycols.
`[0045]
`In certain embodiments, the alkoxy-polyethylene
`glycol is methoxy-polyethylene glycol 350 (mPEG 350) or is
`methoxy-polyethylene glycol 550 (mPEG 550) or is meth-
`oxy-polyethylene glycol 750 (mPEG 750). The term “mPEG
`350” is understood to mean methoxy polyethylene glycol
`having an average molecular weight of about 350, and in
`certain embodiments “n,” as denoted in Formula I, is 7.2. The
`term “mPEG550” is understood to mean methoxy polyethyl-
`ene glycol having an average molecular weight of about 550,
`and in certain embodiments “n,” as denoted in Formula I, is
`
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`11.8. The term “mPEG750” is understood to mean methoxy
`polyethylene glycol having an average molecular weight of
`about 750, and in certain embodiments “n,” as denoted in
`Formula I, is 16.3.
`[0046] Certain, preferred alkoxy-polyethylene glycols
`include CarbowaxTM mPEG 350, CarbowaxTM mPEG 550 or
`CarbowaxTM mPEG 750, which are available commercially
`from Dow Chemical Company. Both mPEG350 and
`mPEG550 are colorless liquids that are miscible with water,
`alcohols, such as methanol, ethanol, n-propanol, glycerol and
`various oils in all proportions, and have a boiling point about
`155° C. It is understood that alkoxy-polyethylene glycols are
`known by other names, where, for example, methoxy-poly-
`ethylene glycol is also known as mono-methyl polyethylene
`glycol and poly(ethylene glycol) methyl ether.
`[0047] By using one or more of the alkoxy-polyethylene
`glycols described herein, the resulting pharmaceutical com-
`positions can be optimized, for example, with respect to bio-
`adhesion, viscosity and sprayability. For example, mPEG
`350, at an equivalent concentration as PEG 200, can still
`solubilize a therapeutic agent but the resulting composition
`has a lower viscosity. As a result, this substitution has a
`surprisingly positive effect on the sprayability compared with
`lower molecular weight PEG 200, which is important where
`the formulation is to be sprayed.
`[0048] B. Therapeutic Agent
`[0049] The pharmaceutical composition of the invention
`may comprise one or more therapeutic agents (also referred to
`as biologically active substances) selected from the group
`consisting of hydrophobic therapeutic agents, hydrophilic
`therapeutic agents, and combinations thereof.
`[0050] The alkoxy-polyethylene glycol excipients are sur-
`prisingly capable of solubilizing and delivering a wide variety
`of hydrophilic and hydrophobic therapeutic agents. The
`hydrophobic drugs have little or no water solubility. It is
`understood that the excipients described herein can be used to
`solubilize therapeutic agents that have a solubility in water of
`less than about 1.0 mg/mL, less than about 0.5 mg/mL, less
`than about 0.3 mg/mL, or less than about 0.1 mg/mL, or less
`than about 0.01 mg/mL, at pH 7 and 200 C. Such therapeutic
`agents can be any agents having therapeutic or other value
`when administered to a mammal, for example, a human, and
`can include organic molecules (for example, small molecule
`drugs having a molecular weight of less than 1,500 g/mol., or
`less than 500 g/mol.), proteins, peptides, immungens (e.g.
`vaccines, cytokines, etc.), nutrients, and cosmetics (cosme-
`ceuticals).
`[0051]
`In certain embodiments, the therapeutic agent is an
`analgesic agent, an anti-inflammatory agent, an anti-arrhyth-
`mic agent, an anti-asthma agent, an anti-bacterial agent, an
`anti-viral agent, an anti-coagulant, an anti-depressant, an
`anti-diabetic, an anti-epileptic, an anti-fungal agent, an anti-
`hypertensive agent, an anti-malarial, an anti-migraine agent,
`an anti-muscarinic agent, an anti-neoplastic agent, an immu-
`no suppres sant, an anti -protozoal agent, an anti-thyroid agent,
`an anxiolytic agent, a sedative, a hypnotic agent, a neuroleptic
`agent, a beta-Blocker, a cardiac inotropic agent, a corticos-
`teroid, a diuretic agent, an anti-Parkinsonian agent, a gas-
`trointestinal agent, an anti-histamine, a histamine-receptor
`antagonist, a lipid regulating agent, a muscle relaxant, nitrate
`and other anti-anginal agent, a nutritional agent, an opioid
`analgesic, sex hormone, stimulant, cytokine, peptidomi-
`metic, peptide, protein,
`toxoid, sera, antibody, vaccine,
`nucleoside, nucleotide, nucleic acid and peptidyl-nucleic
`acid.
`
`Specific non-limiting examples of hydrophobic
`[0052]
`therapeutic agents that can be used in the pharmaceutical
`
`compositions of the present invention include the following
`representative compounds, as well as their pharmaceutically
`acceptable salts, isomers, esters, ethers and other derivatives
`including, for example: (1) analgesics and anti-inflammatory
`agents, such as, aloxiprin, auranofin, azapropazone, benory-
`late, capsaicin, celecoxib, diclofenac, diflunisal, etodolac,
`fenbufen,
`fenoprofen calcium,
`flurbiprofen,
`ibuprofen,
`indomethacin, ketoprofen, ketorolac, leflunomide, meclofe-
`namic
`acid, mefenamic
`acid, nabumetone, naproxen,
`oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam,
`refocoxib,
`sulindac,
`tetrahydrocannabinol,
`tramadol and
`tromethamine; (2) anti-arrhythmic agents, such as, amio-
`darone HCl, disopyramide, flecainide acetate and quinidine
`sulfate; (3) anti-asthma agents, such as, zileuton, zafirlukast,
`montelukast, and albuterol; (4) anti-bacterial agents, such as,
`baclofen, benzathine penicillin, cinoxacin, clarithromycin,
`clofazimine, cloxacillin, demeclocycline, dirithromycin,
`doxycycline, erythromycin, ethionamide, furazolidone, gre-
`pafloxacin, imipenem, levofloxacin, lorefloxacin, moxifloxa-
`cin HCl, nalidixic acid, nitrofurantoin, norfloxacin, ofloxa-
`cin,
`rifampicin,
`rifabutine,
`rifapentine,
`sparfloxacin,
`spiramycin, sulphabenzamide, sulphadoxine, sulphamera-
`Zine, sulphacetamide, sulphadiazine, sulphafurazole, sulpha-
`methoxazole, sulphapyridine, tetracycline, trimethoprim and
`trovafloxacin;
`(5) anti-viral agents,
`such as, abacavir,
`amprenavir, delavirdine, efavirenz,
`indinavir,
`lamivudine,
`nelfinavir, nevirapine, ritonavir, saquinavir, and stavudine;
`(6) anti-coagulants, such as, cilostazol, clopidogrel, dicuma-
`rol, dipyridamole, nicoumalone, oprelvekin, phenindione,
`ticlopidine, and tirofiban; (7) anti-depressants, such as amox-
`apine, bupropion, citalopram, clomipramine, maprotiline
`HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl, ser-
`traline HCl, trazodone HCl, trimipramine maleate, and ven-
`lafaxine HCl; (8) anti-diabetics, such as, acetohexamide,
`chlorpropamide, glibenclamide, gliclazide, glipizide, glime-
`piride, miglitol, pioglitazone,
`repaglinide,
`rosiglitazone,
`tolazamide, tolbutamide and troglitazone; (9) anti-epileptics,
`such as, beclamide, carbamazepine, clonazepam, ethotoin,
`felbamate,
`fosphenytoin sodium,
`lamotrigine, methoin,
`methsuximide, methylphenobarbitone,
`oxcarbazepine,
`paramethadione, phenacemide, phenobarbitone, phenyloin,
`phensuximide, primidone, sulthiame, tiagabine HCl, topira-
`mate, valproic acid, and vigabatrin; (10) anti-fungal agents,
`such as, amphotericin, butenafine HCl, butoconazole nitrate,
`clotrimazole, econazole nitrate,
`fluconazole,
`flucytosine,
`griseofulvin, itraconazole, ketoconazole, miconazole, nata-
`mycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine
`HCl, terconazole, tioconazole and undecenoic acid; (1 1) anti-
`hypertensive agents, such as, amlodipine, benidipine, ben-
`ezepril, candesartan, captopril, darodipine, dilitazem HCl,
`diazoxide, doxazosin HCl, elanapril, eposartan,
`losartan
`mesylate,
`felodipine,
`fenoldopam,
`fosenopril, guanabenz
`acetate, irbesartan, isradipine, lisinopril, minoxidil, nicar-
`dipine HCl, nifedipine, nimodipine, nisoldipine, phenoxy-
`benzamine HCl, prazosin HCl, quinapril, reserpine, terazosin
`HCl, telmisartan, and valsartan; (12) anti-malarials, such as,
`amodiaquine, chloroquine, chlorproguanil HCl, halofantrine
`HCl, mefloquine HCl, proguanil HCl, pyrimethamine and
`quinine sulfate; (13) anti-migraine agents, such as, dihydro-
`ergotamine mesylate,
`ergotamine tartrate,
`frovatriptan,
`methysergide maleate, naratriptan HCl, pizotyline malate,
`rizatriptan benzoate, sumatriptan succinate, and zolmitriptan;
`(14) anti-muscarinic agents, such as, atropine, benzhexol
`HCl, biperiden, ethopropazine HCl, hyoscyamine, oxyphen-
`cyclimine HCl and tropicamide; (15) anti-neoplastic agents
`and immunosuppressants, such as, aminoglutethimide, amsa-
`crine, azathioprine, bicalutamide, bisantrene, busulfan,
`
`AQUESTIVE EXHIBIT 1070 Page 0005
`AQUESTIVE EXHIBIT 1070 Page 0005
`
`

`

`US 2008/0275030 A1
`
`NOV. 6, 2008
`
`camptothecin, chlorambucil, cyclosporin, dacarbazine, ellip-
`ticine, estramustine, etoposide, irinotecan, lomustine, mel-
`phalan, mercaptopurine, mitomycin, mitotane, mitoxantrone,
`mofetil mycophenolate, nilutamide, paclitaxel, procarbazine
`HCl, sirolimus, tacrolimus, tamoxifen citrate, teniposide, tes-
`tolactone, topotecan HCl, and toremifene citrate; (16) anti-
`protozoal agents, such as, at0Vaquone, benznidazole, clio-
`quinol, decoquinate, diiodohydroxyquinoline, diloxanide
`furoate, dinitolmide, furazolidone, metronidazole, nimora-
`Zole, nitrofurazone, omidazole and tinidazole; (17) anti-thy-
`roid agents, such as, carbimazole, paracalcitol, and propylth-
`iouracil; anti-tussiVes, such as, benzonatate; (18) anxiolytics,
`sedatives, hypnotics and neuroleptics, such as, alprazolam,
`amylobarbitone, barbitone, bentazepam, bromazepam, bro-
`mperidol, brotizolam, butobarbitone, carbromal, chlordiaz-
`epoxide, chlormethiazole, chlorpromazine, chlorprothixene,
`clonazepam, clobazam, clotiazepam, clozapine, diazepam,
`droperidol, ethinamate, flunanisone, flunitrazepam, triflupro-
`mazine, fluphenthixol decanoate, fluphenazine decanoate,
`flurazepam,
`gabapentin,
`haloperidol,
`lorazepam,
`lormetazepam, medazepam, meprobamate, mesoridazine,
`methaqualone, methylphenidate, midazolam, molindone,
`nitrazepam, olanzapine, oxazepam, pentobarbitone, per-
`phenazine pimozide, prochlorperazine, pseudoephedrine,
`quetiapine, rispiridone, sertindole, sulpiride,
`temazepam,
`thioridazine, triazolam, zolpidem, and zopiclone; (19) beta-
`Blockers, such as, acebutolol, alprenolol, labetalol, meto-
`prolol, nadolol, oxprenolol, pindolol and propranolol; (20)
`cardiac inotropic agents,
`such as, amrinone, digitoxin,
`digoxin, enoximone, lanatoside C and medigoxin; (21) a cor-
`ticosteroid, such as, beclomethasone, betamethasone, budes-
`onide, cortisone acetate, desoxymethasone, dexamethasone,
`fludrocortisone acetate, flunisolide, fluocortolone, flutica-
`sone propionate, hydrocortisone, methylprednisolone, pred-
`nisolone, prednisone and triamcinolone; (22) diuretics, such
`as, acetazolamide, amiloride, bendroflumethiazide, bumet-
`anide,
`chlorothiazide,
`chlorthalidone,
`ethacrynic
`acid,
`frusemide, metolazone, spironolactone and triamterene; (23)
`anti-Parkinsonian agents, such as, bromocriptine mesy