(19) United States
`(12) Patent Application Publication (10) Pub. N0.: US 2006/0046962 A1
`(43) Pub. Date:
`Mar. 2, 2006
`Meezan et al.
`
`US 20060046962A1
`
`(54) ABSORPTION ENHANCERS FOR DRUG
`ADMINISTRATION
`
`(75) Inventors: Elias Meezan, Birmingham, AL (US);
`Dennis J. Pillion, Hoover, AL (US);
`Edward T. Maggio, San Diego, CA
`(Us)
`Correspondence Address:
`DLA PIPER RUDNICK GRAY CARY US, LLP
`4365 EXECUTIVE DRIVE
`SUITE 1100
`SAN DIEGO, CA 92121-2133 (US)
`
`(73) Assignee: Aegis Therapeutics LLC, San Diego,
`CA
`
`(21) Appl. No.:
`
`11/127,786
`
`(22) Filed:
`
`May 11, 2005
`
`Related US. Application Data
`
`(60) Provisional application No. 60/649,958, ?led on Feb.
`3, 2005. Provisional application No. 60/ 637,284, ?led
`
`on Dec. 17, 2004. Provisional application No. 60/632,
`038, ?led on Nov. 30, 2004. Provisional application
`No. 60/609,890, ?led on Sep. 14, 2004. Provisional
`application No. 60/604,296, ?led on Aug. 25, 2004.
`
`Publication Classi?cation
`
`(51) Int. Cl.
`(2006.01)
`A61K 38/17
`(2006.01)
`A61K 31/70
`(52) Us. 01. ............................................... ..514/12; 514/25
`
`(57)
`
`ABSTRACT
`
`A composition including a surfactant and at least one alkyl
`glycoside and/or saccharide alkyl ester and a drug. The
`surfactant composition(s) When admixed With a drug is
`non-toxic and non-irritating, While stabilizing and increasing
`the bioavailability of the drug. The invention also provides
`compositions that enhance absorption of drugs via the oral,
`ocular, nasal, nasolacrimal, inhalation or pulmonary, oral
`cavity (sublingual or Buccal cell) or CSF delivery route of
`a patient, including but not limited to insulin, glucagon and
`eXendin-4.
`
`AQUESTIVE EXHIBIT 1011 page 0001
`
`

`

`Patent Application Publication Mar. 2, 2006 Sheet 1 of 3
`
`US 2006/0046962 A1
`
`' c I‘ I ‘152.09% _
`
`
`
`
`
`
`
`
`
`E’ I 5
`
`I'm-(1% -
`
`501.0%
`
`_.
`
`<8
`%
`g
`
`2
`
`m
`
`.w
`
`.
`
`..
`
`_,
`
`40;0%
`
`+/-~s%
`
`+/-~8% _
`__
`
`-
`
`v
`26.0%
`
`0.3% to 30%
`
`0.0%-
`"
`
`..===' it
`Mijnlnix'l?
`
`—'
`(10%
`
`—
`0.125%
`0.250%
`Alkyl glycoside Concentration
`
`FIG. 1
`
`AQUESTIVE EXHIBIT 1011 page 0002
`
`

`

`Patent Application Publication Mar. 2, 2006 Sheet 2 0f 3
`
`US 2006/0046962 A1
`
`
`
`
`
`Blood Glucose [mga'dljl
`
`.
`.
`mum D 3 B
`
`+ insu'iinfintmvsil A
`a‘
`insulin
`
`,
`
`Jasmin Q3 Lil/(125% lntravail A
`
`700
`
`60%) -
`
`S09 '
`
`409 -
`
`3GB '
`
`D
`
`60
`
`1 an
`I 26
`Time (min)
`
`240
`
`300
`
`FIG. 2
`
`AQUESTIVE EXHIBIT 1011 page 0003
`
`

`

`Patent Application Publication Mar. 2, 2006 Sheet 3 0f 3
`
`US 2006/0046962 A1
`
`
`
`
`
`QUEEV 3956 “52m
`
`40G
`
`100
`
`126
`180
`Time (min)
`
`2150
`
`380
`
`FIG. 3
`
`AQUESTIVE EXHIBIT 1011 page 0004
`
`

`

`US 2006/0046962 A1
`
`Mar. 2, 2006
`
`ABSORPTION ENHANCERS FOR DRUG
`ADMINISTRATION
`
`CROSS REFERENCE TO RELATED
`APPLICATION(S)
`[0001] This application claims the bene?t of priority under
`35 USC. § 119(e) of US. application Ser. No. 60/649,958
`?led Feb. 3, 2005, noW pending; the bene?t under 35 USC
`§ 119(e) of US. application Ser. No. 60/637,284 ?led Dec.
`17, 2004, noW pending; the bene?t under 35 USC § 119(e)
`of US. application Ser. No. 60/632,038 ?led Nov. 30, 2004,
`noW pending; the bene?t under 35 USC § 119(e) of US.
`application Ser. No. 60/609,890 ?led Sep. 14, 2004, noW
`pending; and the bene?t under 35 USC § 119(e) of US.
`application Ser. No. 60/604,296 ?led Aug. 25, 2004, noW
`pending. The disclosure of each of the prior applications is
`considered part of and is incorporated by reference in the
`disclosure of this application.
`
`FIELD OF THE INVENTION
`[0002] The invention relates generally to non-irritating,
`non-toxic compositions providing enhanced bioavailability
`and more speci?cally to alkyl glycoside or saccharide alkyl
`ester compositions for delivery of therapeutic agents to a
`subject.
`
`BACKGROUND INFORMATION
`
`[0003] Therapeutic agents are often combined With vari
`ous surfactants. Yet, surfactants are frequently irritating to
`the skin and other tissues, including mucosal membranes
`such as those found in the nose, mouth, eye, vagina, rectum,
`esophagus, intestinal tract, and the like. Many surfactants
`also cause proteins to denature, thus destroying their bio
`logical activity. Another serious limitation to the develop
`ment and use of such agents is the ability to deliver them
`safely, non-invasively, ef?ciently and stably to the site of
`action. Therefore, an ideal enhancing surfactant Will stabi
`liZe the therapeutic agent, be non-toxic and non-irritable to
`the skin or mucosal surfaces, and enhance the passage or
`absorption of the therapeutic agent through various mem
`brane barriers Without damaging the structural integrity and
`biological function of the membrane and increase bioavail
`ability of the agent.
`
`SUMMARY OF THE INVENTION
`
`[0004] The present invention is based, in part, on the
`development of a therapeutic composition containing a drug
`enhancing agent useful for increasing the absorption and
`bioavailability of the drug, While at the same time avoiding
`various adverse toxic effects of drug. In particular, the drug
`enhancing agents of the invention contain a non-toxic sur
`factant consisting of at least an alkyl glycoside and/or
`saccharide alkyl ester. One advantage of the therapeutic
`compositions of the invention is that they permit adminis
`tration and delivery of the therapeutic agents With high
`bioavailabilities at concentrations of enhancing agents that
`are dramatically beloW their so-called “no observable
`adverse effect levels” (their NOAEL’s). Accordingly, the
`present invention provides compositions, including alkyl
`glycosides and/or saccharide alkyl esters and a therapeutic
`agent (e.g. small molecule organic drug molecules, loW
`molecular Weight peptides such as Exenatide, GLP-1 and the
`like, proteins, and non-peptide therapeutic polymers such as
`
`loW molecular Weight heparin and inhibitory RNA), meth
`ods of administering and using the compositions eg via the
`oral, ocular, nasal, nasolacrimal, inhalation or pulmonary,
`oral cavity (sublingual or Buccal cell) or cerebral spinal ?uid
`(CSF) delivery route, and methods of ameliorating a disease
`state in a subject by administration of such compositions
`
`[0005] In one aspect, the present invention relates to a
`surfactant composition having at least one alkyl glycoside
`and/or at least one saccharide alkyl ester, and When admixed,
`mixed or blended With a therapeutic agent, a drug, or
`biologically active compound, the surfactant stabiliZes the
`biological activity and increases the bioavailability of the
`drug.
`[0006] Accordingly, in one aspect, the invention provides
`a therapeutic composition having at least one biologically
`active compound and at least one surfactant, Wherein the
`surfactant further consists of at least one alkyl glycoside
`and/or saccharide alkyl ester or sucrose ester and Wherein
`the therapeutic composition stabiliZes the biologically active
`compound for at least about 6 months, or more, and from
`about 4° C. to about 25° C.
`
`[0007] The invention also provides a method of adminis
`tering a therapeutic composition having a surfactant includ
`ing at least one alkyl glycoside and/or saccharide alkyl ester
`admixed, mixed, or blended With at least one therapeutic
`agent, or a drug, or biologically active compound, and
`administered or delivered to a subject, Wherein the alkyl has
`from about 10 to 24, 10 to 20, 10 to 16, or 10 to 14 carbon
`atoms, Wherein the surfactant increases the stability and
`bioavailability of the therapeutic agent.
`
`[0008] In yet another aspect, the invention provides a
`method of increasing absorption of a loW molecular Weight
`compound into the circulatory system of a subject by
`administering the compound via the oral, ocular, nasal,
`nasolacrimal, inhalation or pulmonary, oral cavity (sublin
`gual or Buccal cell), or CSF delivery route When admixed,
`mixed or blended With an absorption increasing amount of
`a suitable surfactant, Wherein the surfactant is a nontoxic and
`nonionic hydrophobic alkyl joined by a linkage to a hydro
`philic saccharide. Such loW molecular Weight compounds
`include but are not limited to, nicotine, interferon, PYY,
`GLP-1, synthetic exendin-4, parathyroid hormone, human
`groWth hormone, or a small organic molecule.
`
`[0009] The present invention also provides a method of
`treating diabetes including administering to a subject in need
`thereof via the oral, ocular, nasal, nasolacrimal, inhalation or
`pulmonary, or oral cavity (sublingual or Buccal cell), a blood
`glucose reducing amount of a therapeutic composition, for
`example, an incretin mimetic agent or a functional equiva
`lent thereof, and an absorption increasing amount of a
`suitable nontoxic, nonionic alkyl glycoside having a hydro
`phobic alkyl group joined by a linkage to a hydrophilic
`saccharide, thereby increasing the absorption of incretin
`mimetic agent or insulin and loWering the level of blood
`glucose and treating diabetes in the subject.
`
`[0010] The present invention also provides a method of
`treating congestive heart failure in a subject including
`administering to the subject in need thereof via the oral,
`ocular, nasal, nasolacrimal, or inhalation delivery route, a
`therapeutically effective amount of a composition compris
`ing a GLP-1 peptide or a functional equivalent thereof, and
`
`AQUESTIVE EXHIBIT 1011 page 0005
`
`

`

`US 2006/0046962 A1
`
`Mar. 2, 2006
`
`an absorption increasing amount of a suitable nontoxic,
`nonionic alkyl glycoside having a hydrophobic alkyl joined
`by a linkage to a hydrophilic saccharide, thereby treating the
`subject.
`[0011] In another aspect, the invention provides a method
`of treating obesity or diabetes associated With obesity in a
`subject comprising administering to a subject in need thereof
`via the oral, ocular, nasal, nasolacrimal, inhalation or CSF
`delivery route, a therapeutically effective amount of a com
`position comprising a PYY peptide or a functional equiva
`lent thereof, and an absorption increasing amount of a
`suitable nontoxic, nonionic alkyl glycoside having a hydro
`phobic alkyl joined by a linkage to a hydrophilic saccharide,
`thereby treating the subject.
`[0012] In another aspect, the invention provides a method
`of increasing absorption of a loW molecular Weight thera
`peutic compound into the circulatory system of a subject by
`administering via the oral, ocular, nasal, nasolacrimal, inha
`lation or CSF delivery route the compound and an absorp
`tion increasing amount of a suitable nontoxic, nonionic alkyl
`glycoside having a hydrophobic alkyl group joined by a
`linkage to a hydrophilic saccharide, Wherein the compound
`is from about 1-30 kD, With the proviso that the compound
`is not insulin, calcitonin, or glucagon When the route of
`administration is oral, ocular, nasal, or nasolacrimal.
`[0013] The present invention also provides a method of
`increasing absorption of a loW molecular Weight therapeutic
`compound into the circulatory system of a subject by
`administering via the oral, ocular, nasal, nasolacrimal, inha
`lation or pulmonary, oral cavity (sublingual or Buccal cell)
`or CSF delivery route the compound and an absorption
`increasing amount of a suitable nontoxic, nonionic alkyl
`glycoside having a hydrophobic alkyl joined by a linkage to
`a hydrophilic saccharide, Wherein the compound is from
`about 1-30 kilo Daltons (kD), With the proviso that the
`subject does not have diabetes When delivery is via the oral,
`ocular, nasal or nasolacrimal routes.
`
`[0014] In one aspect of the invention, there is provided a
`pharmaceutical composition having a suitable nontoxic,
`nonionic alkyl glycoside having a hydrophobic alkyl group
`joined by a linkage to a hydrophilic saccharide in combi
`nation With a therapeutically effective amount of Exenatide
`(exendin-4) in a pharmaceutically acceptable carrier.
`[0015] In one aspect, the invention provides a pharmaceu
`tical composition having a suitable nontoxic, nonionic alkyl
`glycoside having a hydrophobic alkyl group joined by a
`linkage to a hydrophilic saccharide in combination With a
`therapeutically effective amount of GLP-1 in a pharmaceu
`tically acceptable carrier.
`
`[0016] In one aspect, the invention provides a pharmaceu
`tical composition having a suitable nontoxic, nonionic alkyl
`glycoside having a hydrophobic alkyl group joined by a
`linkage to a hydrophilic saccharide in combination With a
`therapeutically effective amount of nicotine in a pharma
`ceutically acceptable carrier.
`
`[0017] In one aspect, the invention provides a pharmaceu
`tical composition comprising a suitable nontoxic, nonionic
`alkyl glycoside having a hydrophobic alkyl group joined by
`a linkage to a hydrophilic saccharide in combination With a
`therapeutically effective amount of interferon in a pharma
`ceutically acceptable carrier.
`
`[0018] In one aspect, the invention provides pharmaceu
`tical composition having a suitable nontoxic, nonionic alkyl
`glycoside having a hydrophobic alkyl group joined by a
`linkage to a hydrophilic saccharide in combination With a
`therapeutically effective amount of PYY in a pharmaceuti
`cally acceptable carrier.
`[0019] In one aspect, the invention provides a pharmaceu
`tical composition having a suitable nontoxic, nonionic alkyl
`glycoside having a hydrophobic alkyl group joined by a
`linkage to a hydrophilic saccharide in combination With a
`therapeutically effective amount of parathyroid hormone in
`a pharmaceutically acceptable carrier.
`
`[0020] In one aspect, the invention provides a pharmaceu
`tical composition having a suitable nontoxic, nonionic alkyl
`glycoside having a hydrophobic alkyl group joined by a
`linkage to a hydrophilic saccharide in combination With a
`therapeutically effective amount of a peptide having a
`molecular Weight of about 1-75 kD in a pharmaceutically
`acceptable carrier, With the proviso that the peptide is not
`insulin, calcitonin, and glucagon.
`[0021] In one aspect, the invention provides a pharmaceu
`tical composition having a suitable nontoxic, nonionic alkyl
`glycoside having a hydrophobic alkyl group joined by a
`linkage to a hydrophilic saccharide in combination With a
`therapeutically effective amount erythropoietin in a pharma
`ceutically acceptable carrier.
`[0022] In one aspect, the invention provides a method of
`increasing absorption of a compound into the CSF of a
`subject having administered intranasally the compound and
`an absorption increasing amount of a suitable nontoxic,
`nonionic alkyl glycoside having a hydrophobic alkyl group
`joined by a linkage to a hydrophilic saccharide.
`
`[0023] In yet another aspect, the invention provides a
`pharmaceutical composition having a suitable nontoxic,
`nonionic alkyl glycoside having a hydrophobic alkyl group
`joined by a linkage to a hydrophilic saccharide in combi
`nation With a mucosal delivery-enhancing agent selected
`from:
`[0024]
`[0025]
`[0026]
`[0027]
`[0028]
`[0029]
`(f) a ciliostatic agent;
`[0030] (g) a membrane penetration-enhancing agent
`selected from:
`
`(a) an aggregation inhibitory agent;
`(b) a charge-modifying agent;
`(c) a pH control agent;
`(d) a degradative enZyme inhibitory agent;
`(e) a mucolytic or mucus clearing agent;
`
`a surfactant; (ii) a bile salt; (ii) a phospholipid
`[0031]
`additive, mixed micelle, liposome, or carrier; (iii) an
`alcohol; (iv) an enamine; (v) an NO donor compound;
`(vi) a long-chain amphipathic molecule; (vii) a small
`hydrophobic penetration enhancer; (viii) sodium or a
`salicylic acid derivative;
`a glycerol ester of
`acetoacetic acid;
`a cyclodextrin or beta-cyclodex
`trin derivative;
`a medium-chain fatty acid; (xii) a
`chelating agent; (xiii) an amino acid or salt thereof;
`(xiv) an N-acetylamino acid or salt thereof; (xv) an
`enZyme degradative to a selected membrane compo
`nent;
`an inhibitor of fatty acid synthesis;
`an
`
`AQUESTIVE EXHIBIT 1011 page 0006
`
`

`

`US 2006/0046962 A1
`
`Mar. 2, 2006
`
`any combi
`inhibitor of cholesterol synthesis; and
`nation of the membrane penetration enhancing agents
`recited in (i)-(x);
`[0032] (h) a modulatory agent of epithelial junction physi
`0logy;
`a vasodilator agent;
`[0033]
`a selective transport-enhancing agent; and
`[0034]
`[0035] (k) a stabilizing delivery vehicle, carrier, mucoad
`hesive, support or complex-forming species With Which the
`compound is effectively combined, associated, contained,
`encapsulated or bound resulting in stabiliZation of the com
`pound for enhanced nasal mucosal delivery, Wherein the
`formulation of the compound With the intranasal delivery
`enhancing agents provides for increased bioavailability of
`the compound in a blood plasma of a subject.
`
`[0036] In one aspect, the invention provides a method of
`increasing absorption of a loW molecular Weight compound
`into the circulatory system of a subject by administering, via
`the oral, ocular, nasal, nasolacrimal, inhalation or pulmo
`nary, oral cavity (sublingual or Buccal cell) or CSF delivery
`route (a) the compound; (b) an absorption increasing amount
`of a suitable nontoxic, nonionic alkyl glycoside having a
`hydrophobic alkyl group joined by a linkage to a hydrophilic
`saccharide; and (c) a mucosal delivery-enhancing agent.
`[0037] In one aspect, the invention provides a method of
`controlling caloric intake by administering a composition
`having a therapeutic effective amount of exendin-4, or
`related GLP-l peptide, With an effective amount of Intravail
`alkyl saccharide.
`[0038] In another aspect, the invention provides a method
`of controlling blood glucose levels in a subject by admin
`istering to a subject a composition comprising a therapeutic
`effective amount of exendin-4, or related GLP-l peptide,
`With an effective amount of Intravail alkyl saccharide.
`
`[0039] Still, in another aspect, the invention provides a
`controlled release dosage composition comprising:
`[0040] (a) a core comprising:
`
`[0041]
`at least one therapeutic agent or drug;
`[0042] (ii) at least one alkyl glycoside and/or saccharide
`alkyl ester; and
`[0043] (b) at least one membrane coating surrounding the
`core, Wherein the coating is impermeable, permeable, semi
`permeable or porous and becomes more permeable upon
`sustained contact With contents of the gastrointestinal tract.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0044] FIG. 1 is a graph shoWing the intranasal percent
`bioavailability compared to intravenous injection and the
`subject-to-subject coef?cients of variation for MIACAL
`CIN® (salmon calcitonin) With and Without alkyl glycoside.
`[0045] FIG. 2 is a graph shoWing the effect of intranasal
`administration of insulin/0.25% TDM (?lled circles) and
`intranasal administration of insulin alone (open circles) in
`reducing blood glucose levels.
`[0046] FIG. 3 is a graph shoWing the effect of intranasal
`(closed triangles) and intraperitoneal (IP) injection (closed
`circles) administration of exendin-4/0.25% TDM and IP
`
`injection of saline alone, minus TDM (open circles) in
`reducing blood glucose levels folloWing oral administration
`of glucose (i.e., in a so-called “glucose tolerance test”).
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0047] The present invention may be understood more
`readily by reference to the folloWing detailed description of
`speci?c embodiments and the Examples included therein.
`
`[0048] The present invention is based on the discovery
`that therapeutic compositions comprising of least one drug
`and at least one surfactant, Wherein the surfactant is com
`prised of at least one alkyl glycoside and/or at least one
`saccharide alkyl ester are stable, non-toxic, non-irritating,
`anti-bacterial compositions that increase bioavailability of
`the drug and have no observable adverse effects When
`administered to a subject.
`
`[0049] A “therapeutic composition” can consist of an
`admixture With an organic or inorganic carrier or excipient,
`and can be compounded, for example, With the usual non
`toxic, pharmaceutically acceptable carriers for tablets, pel
`lets, capsules, suppositories, solutions, emulsions, suspen
`sions, or other form suitable for use. The carriers, in addition
`to those disclosed above, can include glucose, lactose,
`mannose, gum acacia, gelatin, mannitol, starch paste, mag
`nesium trisilicate, talc, corn starch, keratin, colloidal silica,
`potato starch, urea, medium chain length triglycerides, dex
`trans, and other carriers suitable for use in manufacturing
`preparations, in solid, semisolid, or liquid form. In addition,
`auxiliary stabiliZing, thickening or coloring agents can be
`used, for example a stabiliZing dry agent such as triulose.
`[0050] A “drug” is any therapeutic compound, or mol
`ecule, or therapeutic agent, or biologically active compound,
`including but not limited to nucleic acids, small molecules,
`proteins, polypeptides or peptides, etc. The term “nucleic
`acids” also denotes DNA, cDNA, RNA, siRNA, RNAi, etc.
`Which encode translated and untranslated regions or inhibits
`translated or untranslated regions of structural genes encod
`ing a peptide or protein of the invention. For example, a
`nucleic acid of the invention can include 5‘ and 3‘ untrans
`lated regulatory nucleotide sequences as Well as translated
`sequences associated With the structural gene, e.g. GLP-l.
`
`[0051] Apeptide of the invention may be any medically or
`diagnostically useful peptide or protein of small to medium
`size (ie up to about 15 kD, 30 kD, 40 kD, 50 kD, 60 kD,
`70 kD, 80 kD, 90 kD, 100 kD, for example). The mecha
`nisms of improved polypeptide absorption are described in
`US. Pat. No. 5,661,130 Which is hereby incorporated by
`reference in its entirety. Invention compositions can be
`mixed With all such peptides, although the degree to Which
`the peptide bene?ts are improved may vary according to the
`molecular Weight and the physical and chemical properties
`of the peptide, and the particular surfactant used. Examples
`of polypeptides include vasopressin, vasopressin polypep
`tide
`analogs, desmopressin, glucagon, corticotropin
`(ACTH), gonadotropin, calcitonin, C-peptide of insulin,
`parathyroid hormone (PTH), groWth hormone (HG), human
`groWth hormone (hGH), groWth hormone releasing hormone
`(GHRH), oxytocin, corticotropin releasing hormone (CRH),
`somatostatin or somatostatin polypeptide analogs, gonadot
`ropin agonist or gonadotrophin agonist polypeptide analogs,
`human atrial natriuretic peptide (ANP), human thyroxine
`
`AQUESTIVE EXHIBIT 1011 page 0007
`
`

`

`US 2006/0046962 A1
`
`Mar. 2, 2006
`
`releasing hormone (TRH), follicle stimulating hormone
`(FSH), prolactin, insulin, insulin like growth factor-I (IGF-I)
`somatomedin-C (SM-C), calcitonin, leptin and the leptin
`derived short peptide OB-3, melatonin, GLP-1 or Glucagon
`like peptide-1,, GiP, neuropeptide pituitary adenylate
`cyclase, GM-1 ganglioside, nerve groWth factor (NGF),
`nafarelin, D-tryp6)-LHRH, FGF, VEGF antagonists, leupro
`lide, interferon (e.g., ot,[3, y) loW molecular Weight heparin,
`PYY, LHRH antagonists, Keratinocyte GroWth Factor
`(KGF), Glial-Derived Neurotrophic Factor (GDNF), ghre
`lin, and ghrelin antagonists. Further, in some aspects, the
`peptide or protein is selected from a groWth factor, inter
`leukin, polypeptide vaccine, enZyme, endorphin, glycopro
`tein, lipoprotein, or a polypeptide involved in the blood
`coagulation cascade.
`[0052] Other drugs or therapeutic compounds, molecules
`and/or agents include compounds or molecules of the central
`nervous system affecting neurotransmitters or neural ion
`channels (i.e. antidepressants (bupropion)), selective sero
`tonin 2c receptor agonists, anti-seiZure agents (topiramate,
`Zonisamide), some dopamine antagonists, and cannab
`inoid-1 receptor antagonists (rimonabant)); leptin/insulin/
`central nervous system pathWay agents (i.e. leptin ana
`logues, leptin transport and/or leptin receptor promoters,
`ciliary neurotrophic factor (Axokine), neuropeptide Y and
`agouti-related peptide antagonists, proopiomelanocortin,
`cocaine and amphetamine regulated transcript promoters,
`alpha-melanocyte-stimulating hormone analogues, melano
`cortin-4 receptor agonists, protein-tyrosine phosphatase-1B
`inhibitors, peroXisome proliferator activated receptor
`gamma receptor antagonists, short-acting bromocriptine
`(ergoset), somatostatin agonists (octreotide), and adiponec
`tin); gastrointestinal-neural pathWay agents (i.e. agents that
`increase glucagon-like peptide-1 activity (eXtendin-4, lira
`glutide, dipeptidyl peptidase IV inhibitors), protein YY3-36,
`ghrelin, ghrelin antagonists, amylin analogues (pramlint
`ide)); and compounds or molecules that may increase resting
`metabolic rate “selective” beta-3 stimulators/agonist, mela
`nin concentrating hormone antagonists, phytostanol ana
`logues, functional oils, P57, amylase inhibitors, groWth
`hormone fragments, synthetic analogues of dehydroepi
`androsterone sulfate, antagonists of adipocyte 11B-hydroX
`ysteroid dehydrogenase type 1 activity, corticotropin-releas
`ing hormone agonists, inhibitors of fatty acid synthesis,
`carboXypeptidase inhibitors, and gastrointestinal lipase
`inhibitors (ATL962).
`[0053] The therapeutic composition of the invention
`includes a drug and a drug absorption enhancing agent, for
`eXample, a surfactant. The term “surfactant” is any surface
`active agent that modi?es interfacial tension of Water. Typi
`cally, surfactants have one lipophilic and one hydrophilic
`group in the molecule. Broadly, the group includes soaps,
`detergents, emulsi?ers, dispersing and Wetting agents, and
`several groups of antiseptics. More speci?cally, surfactants
`include stearyltriethanolamine, sodium lauryl sulfate, laury
`laminopropionic acid, lecithin, benZalkonium chloride, ben
`Zethonium chloride and glycerin monostearate; and hydro
`philic
`polymers
`such
`as
`polyvinyl
`alcohol,
`polyvinylpyrrolidone,
`carboXymethylcellulose
`sodium,
`methylcellulose, hydroXymethylcellulose, hydroXyethylcel
`lulose and hydroXypropylcellulose.
`
`[0054] Preferably, the surfactant of the invention consists
`of at least one suitable alkyl glycoside. As used herein,
`
`“alkyl glycoside” refers to any sugar joined by a linkage to
`any hydrophobic alkyl, as is knoWn in the art. Any “suitable”
`alkyl glycoside means one that ful?lls the limiting charac
`teristics of the invention, i.e., that the alkyl glycoside be
`nontoXic and nonionic, and that it increases the absorption of
`a compound When it is administered With the compound via
`the ocular, nasal, nasolacrimal, inhalation or pulmonary, oral
`cavity (sublingual or Buccal cell), or CSF delivery route.
`Suitable compounds can be determined using the methods
`set forth herein.
`
`[0055] Alkyl glycosides of the invention can be synthe
`siZed by knoWn procedures, i.e., chemically, as described,
`e.g., in Rosevear et al., Biochemistry 19:4108-4115 (1980)
`or KoeltZoW and Urfer, J. Am. Oil Chem. Soc, 61:1651
`1655 (1984), US. Pat. No. 3,219,656 and US. Pat. No.
`3,839,318 or enZymatically, as described, e.g., in Li et al.,].
`Biol. Chem., 266:10723-10726 (1991) or Gopalan et al., J.
`Biol. Chem. 267:9629-9638 (1992).
`
`[0056] Alkyl glycosides of the present invention can
`include, but are not limited to: alkyl glycosides, such as
`octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetrade
`cyl-, pentadecyl-,heXadecyl-, heptadecyl-, and octadecyl-ot
`or [3-D-maltoside, -glucoside or -sucroside (synthesiZed
`according to KoeltZoW and Urfer; Anatrace Inc., Maumee,
`Ohio; Calbiochem, San Diego, Calif.; Fluka Chemie, SWit
`Zerland); alkyl thiomaltosides, such as heptyl, octyl, dode
`cyl-, tridecyI-, and tetradecyl-[3-D-thiomaltoside (synthe
`siZed according to Defaye, J. and Pederson, C., “Hydrogen
`Fluoride, Solvent and Reagent for Carbohydrate Conversion
`Technology” in Carbohydrates as Organic RaW Materials,
`247-265
`W. Lichtenthaler, ed.) VCH Publishers, NeW
`York (1991); Ferenci, T., J. Bacteriol, 144:7-11 (1980));
`alkyl thioglucosides, such as heptyl- or octyl 1-thio ot- or
`[3-D-glucopyranoside (Anatrace, Inc., Maumee, Ohio; see
`Saito, S. and Tsuchiya, T. Chem. Pharm. Bull. 33:503-508
`(1985)); alkyl thiosucroses (synthesiZed according to, for
`eXample, Binder, T. P. and Robyt, J. F., Carbohydr. Res.
`140:9-20 (1985)); alkyl maltotriosides (synthesiZed accord
`ing to KoeltZoW and Urfer); long chain aliphatic carbonic
`acid amides of sucrose [3-amino-alkyl ethers; (synthesiZed
`according to Austrian Patent 382,381 (1987); Chem. Abstr.,
`108:114719 (1988) and Gruber and Greber pp. 95-116);
`derivatives of palatinose and isomaltamine linked by amide
`linkage to an alkyl chain (synthesiZed according to KunZ,
`M., “Sucrose-based Hydrophilic Building Blocks as Inter
`mediates for the Synthesis of Surfactants and Polymers” in
`Carbohydrates as Organic RaW Materials, 127-153); deriva
`tives of isomaltamine linked by urea to an alkyl chain
`(synthesiZed according to KunZ); long chain aliphatic car
`bonic acid ureides of sucrose [3-amino-alkyl ethers (synthe
`siZed according to Gruber and Greber, pp. 95-116); and long
`chain aliphatic carbonic acid amides of sucrose [3-amino
`alkyl ethers (synthesiZed according to Austrian Patent 382,
`381 (1987), Chem. Abstr., 108114719 (1988) and Gruber
`and Greber, pp. 95-116).
`[0057] Surfactants of the invention consisting of an alkyl
`glycoside and/or a sucrose ester have characteristic hydro
`phile-lipophile balance (HLB) numbers, Which can be cal
`culated or determined empirically (Schick, M. J. Nonionic
`Surfactants, p. 607 (NeW York: Marcel Dekker, Inc. (1967)).
`The HLB number is a direct re?ection of the hydrophilic
`character of the surfactant, i.e., the larger the HLB number,
`the more hydrophilic the compound. HLB numbers can be
`
`AQUESTIVE EXHIBIT 1011 page 0008
`
`

`

`US 2006/0046962 A1
`
`Mar. 2, 2006
`
`calculated by the formula: (20 times MW hydrophilic com
`ponent)/(MW hydrophobic component+MW hydrophilic
`component), Where MW=molecular Weight (Rosen, M. J .,
`Surfactants and Interfacial Phenomena, pp.242-245, John
`Wiley, NeW York (1978)). The HLB number is a direct
`expression of the hydrophilic character of the surfactant, i.e.,
`the larger the HLB number, the more hydrophilic the com
`pound. A preferred surfactant has an HLB number of from
`about 10 to 20 and an even more preferred range of from
`about 11 to 15.
`
`[0058] As described above, the hydrophobic alkyl can thus
`be chosen of any desired siZe, depending on the hydropho
`bicity desired and the hydrophilicity of the saccharide moi
`ety. For example, one preferred range of alkyl chains is from
`about 9 to about 24 carbon atoms. An even more preferred
`range is from about 9 to about 16 or about 14 carbon atoms.
`Similarly, some preferred glycosides include maltose,
`sucrose, and glucose linked by glycosidic linkage to an alkyl
`chain of 9, 10, 12, 13, 14, 16, 18, 20, 22, or 24 carbon atoms,
`e.g., nonyl-, decyl-, dodecyl- and tetradecyl sucroside, glu
`coside, and maltoside, etc. These compositions are nontoxic,
`since they are degraded to an alcohol and an oligosaccha
`ride, and amphipathic.
`
`[0059] The surfactants of the invention can also include a
`saccharide. As use herein, a “saccharide” is inclusive of
`monosaccharides, oligosaccharides or polysaccharides in
`straight chain or ring forms, or a combination thereof to
`form a saccharide chain. Oligosaccharides are saccharides
`having tWo or more monosaccharide residues. The saccha
`ride can be chosen, for example, from any currently com
`mercially available saccharide species or can be synthesiZed.
`Some examples of the many possible saccharides to use
`include glucose, maltose, maltotriose, maltotetraose, sucrose
`and trehalose. Preferable saccharides include maltose,
`sucrose and glucose.
`
`[0060] The surfactants of the invention can likeWise con
`sist of a sucrose ester. As used herein, “sucrose esters” are
`sucrose esters of fatty acids and is a complex of sucrose and
`fatty acid. Sucrose esters can take many forms because of
`the eight hydroxyl groups in sucrose available for reaction
`and the many fatty acid groups, from acetate on up to larger,
`more bulky fatty acids that can be reacted With sucrose. This
`?exibility means that many products and functionalities can
`be tailored, based on the fatty acid moiety used. Sucrose
`esters have food and non-food uses, especially as surfactants
`and emulsi?ers, With groWing applications in pharmaceuti
`cals, cosmetics, detergents and food additives. They are
`biodegradable, non-toxic and mild to the skin.
`
`[0061] The surfactants of the invention have a hydropho
`bic alkyl group linked to a hydrophobic saccharide. The
`linkage betWeen the hydrophobic alkyl group and the hydro
`philic saccharide can include, among o