(12) United States Patent
`Williams et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,509,028 B2
`Jan. 21, 2003
`
`US006509028B2
`
`(54) METHODS AND COMPOSITIONS FOR
`TREATING PAIN OF THE MUCOUS
`MEMBRANE
`
`(75)
`
`Inventors: Robert O. Williams, Austin, TX (US);
`Feng Zhang, Austin, TX (US); John J,
`Kmeng, Austin, TX (Us); Gavrj] W_
`Pasternak, New York, NY (US); Yuri
`A_ Kmesnjkovt Tenafly, NJ (Us)
`
`(73) Assignee: EpiCept Corporation, Englewood
`Cliffs, NJ (US)
`
`( * ) N0t1C€1
`
`the term Of this
`t0 any d1SC1a1H1€f,
`S1lbj€Ct
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 10/172,455
`(22)
`1311993
`J1111- 17: 2002
`(65)
`Prior Publication Data
`US 2002/0192288 A1 Dec. 19, 2002
`_
`_
`Related U'S' Apphcatlon Data
`(63) Continuation of application No. 09/888,466, filed on Jun.
`25, 2001, now abandoned.
`(60)
`Provisional application No. 60/222,164, filed on Jun. 26,
`2000.
`
`(51)
`
`Int. Cl.7 ........................... A61F 13/00, A61K 9/70,
`A61K 9/14
`..................... .. 424/434, 424/443, 424/486;
`514/817; 514/818
`
`(52) U.s. Cl.
`
`(58) Field of Search ................................. 424/489, 434,
`424/435, 443, 444, 445, 446, 447, 448,
`449; 514/716’ 626’ 772’ 817’ 818’ 900
`,
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`rain
`1:(§’tt;:‘t‘:’:rgF‘°it1(fit;ttQ1_9(?(}I;t:‘1.?1j;e1°§’t‘§fV“tt{‘tft‘:a::St¥;%t:fSBtg;
`Oral Use’”, J. Pharm. Pharma(g:ol. 43:457-464.
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`tl.,1998,“It
`t'
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`',
`'
`“
`.
`.
`.
`1,
`.
`Stein et al., 1997, Peripheral morphine analgesia , Pain.
`71(2)¢119-21
`t
`t
`Primary Examm€V—Th11rmaH K Page
`Assistant Examiner—Blessing Fubara
`(74) Attorney, Agent, or Firm—Pennie & Edmonds LLP
`
`(57)
`
`ABSTRACT
`
`.
`.
`.
`.
`.
`long-lasting pain relief from
`for
`Compositions useful
`mucosal damage, such as mucosal inflamation, abrasions,
`ulcerations, lesions, trauma and incisions, without signifi-
`cant systemic absorption. The compositions of the invention
`are particularly suitable for application to the mucous mem-
`brane of the nasal cavity and buccal cavity. To relieve pain,
`tihe compostiltionfi or dthe invention are topically applied
`irect y to t e a ecte
`area.
`
`31 Claims, No Drawings
`Petitioner |nnoPharma EX 1088
`
`|PR2015—00902
`
`|PR2015—00903
`
`Page 1
`
`

`
`US 6,509,028 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`5,744,458
`5,747,060
`5,760,023
`5,798,093
`5,811,078
`5,814,330
`5,817,625
`5,834,478
`5,846,971
`5,849,322
`5,849,761
`5,849,762
`5,855,907
`5,866,143
`5,876,744
`5,885,597
`5,900,247
`5,906,810
`
`>>>>>>>>>>>>>>>>>>
`
`4/1998
`5/1998
`6/1998
`8/1998
`9/1998
`9/1998
`10/1998
`11/1998
`12/1998
`12/1998
`12/1998
`12/1998
`1/1999
`2/1999
`3/1999
`3/1999
`5/1999
`5/1999
`
`Kruse et al.
`Sackler et al.
`Farrar et al.
`Farrar et al.
`Maycock et al.
`Putteman et al.
`Haley
`Ito
`Sangekar et al.
`Ebert et al.
`Yaksh
`Farrar et al.
`Peyman
`Elkhoury
`Della Valle et al.
`Botknecht et al.
`Rault et al.
`Turner
`
`5,908,846
`5,922,340
`5,942,243
`5,942,251
`5,948,430
`5,955,097
`5,958,379
`5,972,906
`5,972,932
`5,976,573
`5,989,535
`5,993,846
`6,031,007
`5,662,924
`5,667,773
`5,667,805
`5,686,112
`5,713,852
`
`>>>>>>>>>>>>>>>>>>
`
`6/1999
`7/1999
`8/1999
`8/1999
`9/1999
`9/1999
`9/1999
`10/1999
`* 10/1999
`11/1999
`11/1999
`11/1999
`2/2000
`9/1997
`9/1997
`9/1997
`11/1997
`2/1998
`
`*
`
`Bundgaard et al.
`Berde et al.
`Shah
`Merkus
`Zerbe et al.
`Tapolsky et al.
`Regenold et al.
`Asculai et al.
`Benvenga et al.
`Kim
`Nayak
`Friedman et al.
`Brodin et al.
`Rhodes
`Farrar et al.
`Merrill et al.
`Liedtke
`Anthony et al.
`
`* cited by examiner
`
`........ .. 514/220
`
`......... .. 514/716
`
`Page 2
`
`Page 2
`
`

`
`US 6,509,028 B2
`
`1
`METHODS AND COMPOSITIONS FOR
`TREATING PAIN OF THE MUCOUS
`MEMBRANE
`
`This is a continuation of application Ser. No. 09/888,466,
`filed Jun. 25, 2000, now Abandon.
`This application claims the benefit of U.S. Provisional
`patent application Ser. No. 60/222,164, filed Jun. 26, 2000,
`hereby incorporated by reference herein in its entirety.
`
`FIELD OF THE INVENTION
`
`The invention relates to methods and compositions for
`treating the pain associated with mucosal damage, such as
`inflamation, abrasions, ulcerations, lesions, incisions, and
`trauma.
`
`BACKGROUND OF THE INVENTION
`
`The term mucous membrane refers to the moist linings of
`the buccal cavity, nasal cavity, gastrointestinal tract, respi-
`ratory tract, conjunctiva, vagina, colon, urinary bladder, and
`urethra (Forstner et al., 1973 J. Cell. Sci. 12:585; Peppas et
`al., 1985 J. Control. Release 2:257; Lehr et al., 1992 J.
`Control Release 18:249; Spiro, 1970 Ann. Rev. Biochem.
`392599; Lebat-Robert et al., 1979 Path. Biol. 24:241). The
`normally smooth, moist, and pink buccal mucosa is very
`sensitive and inflamation or ulceration (oral mucositis)
`causes severe pain. Dental surgery, such as root canal and
`tooth extraction can also severely damage the buccal mucosa
`causing severe pain. Moreover, oral mucositis and dental
`surgery can induce secondary conditions, such as weight
`loss and dehydration from reluctance to eat or drink, infec-
`tion (bacterial, fungal, and viral), fever, nausea, and diar-
`rhea.
`
`Oral mucositis has a variety of causes, for example,
`bacterial infections, such as streptococci; viral infections,
`such as herpes simplex virus; fungal infections; side effects
`of systemic diseases; vitamin deficiency; iron deficiency;
`cheek biting; mouth breathing; jagged teeth; orthodontic
`appliances; ill-fitting dentures; excessive use of alcohol or
`tobacco;
`thermally-hot foods; spicy foods; and as a side
`effect of medication. Severely-painful oral mucositis is a
`symptom endured by almost all chemotherapy patients.
`Mucositis symptoms peak 7 to 10 days following
`chemotherapy, and gradually recede over the following two
`weeks. For a discussion of the causes and symptoms of
`mucositis, see The Merck Manuel, Fifteenth Edition, Merck
`Sharp & Dohme Research Laboratories, Rahway, N.J.,
`(1987) pp. 2322-2320.
`Topical application of local anesthetics can provide some
`relief of oral-mucositis and dental-surgery pain but absorp-
`tion through the mucous membranes occurs rapidly, and
`pharmaceuticals applied to the mucous membrane for their
`local effect sometimes cause systemic toxicity (Goodman
`and Gilman’s The Pharmacological Basis of Therapeutics
`9th ed. J. G. Harman and L. E. Limird Eds., McGraw-Hill
`New York 1996 p. 8) especially with the higher doses
`required for adequate pain relief. Systemic absorption is
`even more likely when the mucous membrane is ulcerated or
`inflamed. Thus, with traditional anesthetic compositions for
`mucositis, e.g., 2 percent
`lidocaine oral
`rinse or 5%
`lidocaine ointment, systemic toxicity limits the dosage and
`so adequate pain relief is difficult to achieve. Other less toxic
`pain relieving compositions, such as rinses comprising
`hydrogen peroxide and sodium bicarbonate are less effective
`at reducing pain. An additional problem with oral rinses is,
`that following application,
`the action of swallowing and
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`saliva reduces the concentration of active agent on the
`affected area, thus oral rinses comprising local anesthetics
`have a low duration of activity.
`In summation, a long-lasting, non-toxic anesthetic com-
`position effective for amelioration of the severe pain induced
`by mucosal damage, such as mucositis and dental surgery, is
`needed.
`
`SUMMARY OF THE INVENTION
`
`In one aspect, the invention provides compositions and
`methods that provide long-lasting local anesthesia and effec-
`tive pain relief. The compositions of the invention can be
`topically applied to the affected area, for example, via a
`dose-metered applicator adapted for spraying or adapted for
`use with a cannula. When topically applied, the composi-
`tions of the invention provide a powerful local-anesthetizing
`effect, in spite of low anesthetic concentration. Hence, the
`compositions of the invention provide significant pain relief
`with low systemic absorption and, therefore, low systemic
`toxicity. The compositions of the invention, in addition to
`the ability to remain on the affected area for extended
`periods, hydrate and soothe.
`In one embodiment, the compositions of the invention can
`be topically applied directly to the affected area to alleviate
`pain in a subject on any area of a subject’s body.
`In another embodiment, the compositions of the invention
`are useful for topical application to a subject’s mucous
`membrane, to induce a long-lasting local-anesthetic effect,
`thereby relieving pain from mucositis, such as mucosal
`inflamation, abrasions, ulcerations, and lesions, without sig-
`nificant systemic absorption.
`the compositions of the
`In yet another embodiment,
`invention are useful for topical application to the site of
`dental surgery, such as root-canal or
`tooth-extraction
`surgery,
`to induce a long-lasting local-anesthetic effect,
`thereby relieving the surgical pain, without significant sys-
`temic absorption.
`In one more embodiment, the invention relates to com-
`positions comprising a mucoadhesive, a local anesthetic or
`a pharmaceutically-acceptable salt thereof, and an opioid or
`a pharmaceutically-acceptable salt thereof. In a preferred
`embodiment, the compositions contain water and are sterile.
`In a more preferred embodiment, the compositions of the
`invention, further comprise a chelating agent and a preser-
`vative.
`
`In another embodiment, the invention relates to a con-
`tainer adapted for
`topical application and containing a
`pharmaceutically-acceptable composition comprising a
`mucoadhesive, a local anesthetic or a pharmaceutically-
`acceptable salt thereof, and an opioid or a pharmaceutically-
`acceptable salt thereof. Preferably, the container is adapted
`for dose-metered application, such as a dose-metered pump
`for use with a spray applicator or cannula.
`In still another embodiment,
`the invention relates to a
`method of inducing local anesthesia in a subject’s mucosal
`membrane by topically applying a pharmaceutically-
`acceptable composition comprising a local anesthetic or a
`pharmaceutically-acceptable salt thereof and an opioid or a
`pharmaceutically-acceptable salt
`thereof to the subject’s
`mucosal membrane. Preferably, the composition is applied
`to an area within the subject’s buccal or nasal cavity.
`Preferably, the composition further comprises a mucoadhe-
`s1ve.
`
`the invention relates to a
`In yet another embodiment,
`method of inducing local anesthesia in a subject by topically
`
`Page 3
`
`Page 3
`
`

`
`US 6,509,028 B2
`
`3
`applying a composition comprising a mucoadhesive, a local
`anesthetic or a pharmaceutically-acceptable salt thereof, and
`an opioid or a pharmaceutically-acceptable salt thereof to a
`subject. Preferably, the composition is applied to a mucosal
`surface of the subject, for example, an area within the
`subject’s buccal or nasal cavity.
`These and other features, aspects, and advantages of the
`invention will become better understood with reference to
`
`5
`
`the following detailed description, examples, and appended
`claims.
`
`10
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The phrase “pharmaceutically-acceptable salt(s),” as used
`herein includes but is not limited to salts of acidic or basic
`
`groups that may be present in compounds used in the present
`compositions. Compounds included in the present compo-
`sitions that are basic in nature are capable of forming a wide
`variety of salts with various inorganic and organic acids. The
`acids that may be used to prepare pharmaceutically-
`acceptable acid addition salts of such basic compounds are
`those that form non-toxic acid addition salts,
`i.e., salts
`containing pharmacologically acceptable anions, including,
`but not limited to, sulfuric, citric, maleic, acetic, oxalic,
`hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
`bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
`lactate, salicylate, citrate, acid citrate,
`tartrate, oleate,
`tannate, pantothenate, bitartrate, ascorbate, succinate,
`maleate, gentisinate,
`fumarate, gluconate, glucaronate,
`saccharate, formate, benzoate, glutamate, methanesulfonate,
`ethanesulfonate, benzenesulfonate, p-toluenesulfonate and
`pamoate (i.e., 1,1‘-methylene-bis-(2-hydroxy-3-
`naphthoate)) salts.
`Compounds included in the present compositions that
`include an amino moiety may form pharmaceutically-
`acceptable salts with various amino acids, in addition to the
`acids mentioned above. Compounds, included in the present
`compositions, that are acidic in nature are capable of form-
`ing base salts with various pharmacologically acceptable
`cations. Examples of such salts include alkali metal or
`alkaline earth metal salts and, particularly, calcium,
`magnesium, sodium, lithium, zinc, potassium, and iron salts.
`For a review on pharmaceutically-acceptable salts see Berge
`et al., 1977 J. Pharm. Sci., 66:1, incorporated herein by
`reference.
`
`As used herein the term “opioid” means all agonists and
`antagonists of opioid receptors, such as mu (,u), kappa (K),
`and delta (5) opioid receptors and subtypes thereof. For a
`discussion of opioid receptors and subtypes see Goodman
`and Gilman’s The Pharmacological Basis of Therapeutics
`9th ed. J. G. Harman and L. E. Limird Eds., McGraw-Hill
`New York:1996 pp. 521-555, incorporated herein by refer-
`ence. The opioid can be any opioid receptor agonist or
`antagonist known or to be developed. Preferred opioids
`interact with the it-opioid receptor, the K-opioid receptor, or
`both. Preferably, the opioid is an opioid-receptor agonist.
`Examples of suitable opioids for use with the invention
`include, but are not
`limited to, alfentanil, allylprodine,
`alphaprodine, anileridine, benzylmorphine, benzitramide,
`nor-binaltorphimine, bremazocine, buprenorphine,
`butorphanol, clonitazene, codeine, CTOP, DAMGO,
`desomorphine, dextromoramide, dezocine, diampromide,
`dihydrocodeine, dihydrocodeine enol acetate,
`dihydromorphine, dimenoxadol, dimepheptanol,
`dimethylthiambutene, dioxaphetyl butyrate, dipipanone,
`diprenorphine, DPDPE, eptazocine, ethoheptazine,
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`ethylketocyclazocine, ethylmethylthiambutene, etonitazene,
`etorphine,
`fentanyl, hydrocodone, hydromorphone,
`hydroxypethidine,
`isomethadone, ketobemidone,
`levorphanol,
`lofentanil,
`loperamide, meperidine,
`meptazinol, metazocaine, methadone, metopon, morphine,
`myrophine, nalbuphine, naltrindole, benzoylhydrazone,
`naltrexone, narceine, nicomorphine, norlevorphanol,
`normethadone, normorphine, norpipanone, opium,
`oxycodone, oxymorphone, papaveretum, papaverine,
`pentazocine, phenadoxone, phenazocine, phenoperidine,
`piminodine, pirtramide, proheptazine, promedol, propiram,
`propoxyphene, remifentanil, spiradoline, sufentanil, tilidine,
`U50,488, and U69,593, amiphenazole, cyclazocine,
`levallorphan, nalmefene, nalorphine, naloxone, and naltrex-
`one or pharmaceutically-acceptable salts thereof, or mix-
`tures thereof.
`
`Examples of peptide opioids include, but are not limited
`to, Tyr-Gly-Gly-Phe-Leu ([Leu5]enkephalin), Tyr-Gly-Gly-
`Phe-Met
`([Met5]enkephalin), Tyr-Gly-Gly-Phe-Leu-Arg-
`Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln
`(DynorphinA), Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-
`Lys-Val-Val-Thr (Dynorphin B), Tyr-Gly-Gly-Phe-Leu-Arg-
`Lys-Tyr-Pro-Lys (ot-Neoendorphin), Tyr-Gly-Gly-Phe-Leu-
`Arg-Lsy-Tyr-Pro ([3-Neoendorphin), Tyr-Gly-Gly-Phe-Met-
`Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-
`Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu
`([3,;-Endorphin),
`[D-Ala2,MePhe4Gly(ol)5]enkephalin
`(DAMGO), [D-Pen2’D-Pen5]enkephalin (DPDPE), [D-Serz’
`Leu5]enkephalin-Thr6 (DSLET),
`[D-Ala2’D-Leus]
`enkephalin (DADL), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-
`Thr-NH2(CTOP),
`[D-Ala2,N-MePhe4,Met(O)5-ol]
`enkephalin (FK-33824), Tyr-D-Ala-Phe-Asp-Val-Val-Gly-
`NH2 ([D-Ala2]Deltorphin 1), Tyr-D-Ala-Phe-Glu-Val-Val-
`Gly-NH2 ([D-Ala2Glu4]Deltorphin (Deltorphin II)), Tyr-
`Pro-Phe-Pro-NH2 (Morphiceptin), Tyr-Pro-MePhe-D-Pro-
`NH2 (PL-017), [D-Ala2,Leu5,Cys6]enkephalin (DALCE) or
`pharmaceutically-acceptable salts thereof, or mixtures
`thereof Preferred opioids include morphine, loperamide and
`loperamide derivatives such as those disclosed in U.S. Pat.
`Nos. 5,763,445; 5,981,513; 5,869,521; 5,744,458; 5,760,
`023; 5,798,093; 5,849,762; 5,811,078; 6,004,964; 5,962,
`477; 5,688,955; 5,888,494; 5,646,151; and 5,667,773 (all of
`which patents are incorporated by reference herein), or
`pharmaceutically-acceptable salts thereof, or mixtures
`thereof. The most preferred opioid is morphine or a
`pharmaceutically-acceptable salt thereof.
`As used herein, the term “local anesthetic” means any
`drug that provides local numbness or analgesia or any drug
`that provides a regional blockage of nociceptive pathways
`(afferent and/or efferent) and that is not an agonist or an
`antagonist of an opioid receptors. The local anesthetic can be
`any local anesthetic known or to be developed. Examples of
`local anesthetics suitable for use with the invention include:
`
`ambucaine, amolanone, amylcaine, benoxinate, benzocaine,
`betoxycaine, biphenamine, bupivacaine, butacaine,
`butamben, butanilicaine, butethamine, butoxycaine,
`carticaine, chloroprocaine, cocaethylene, cocaine,
`cyclomethycaine, dibucaine, dimethisoquin, dimethocaine,
`diperodon, dyclonine, ecogonidine, ecogonine, euprocin,
`fenalcomine, formocaine, hexylcaine, hydroxyteteracaine,
`isobutyl p-aminobenzoate,
`leucinocaine,
`levoxadrol,
`lidocaine, mepivacaine, meprylcaine, metabutoxycaine,
`methyl chloride, myrtecaine, naepaine, octacaine,
`orthocaine, oxethazaine, parenthoxycaine, phenacaine,
`phenol, piperocaine, piridocaine, polidocanol, pramoxine,
`prilocaine, procaine, propanocaine, proparacaine,
`propipocaine, propoxycaine, pseudococaine, pyrrocaine,
`
`Page 4
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`
`US 6,509,028 B2
`
`5
`tolycaine,
`tetracaine,
`ropivacaine, salicyl alcohol,
`trimecaine, zolamine, or pharmaceutically-acceptable salts
`thereof, or mixtures thereof.
`The amide and ester type local anesthetics are preferred.
`Amide type local anesthetics are characterized by an amide
`functionality, While ester type local anesthetics contain an
`ester functionality. Preferred amide type local anesthetics,
`include lidocaine, bupivacaine, prilocaine, mepivacaine,
`etidocaine, ropivacaine, dibucaine, and pharmaceutically-
`acceptable salts thereof and mixtures thereof. Preferred ester
`type local anesthetics include tetracaine, procaine,
`benzocaine, chloroprocaine, and pharmaceutically-
`acceptable salts thereof and mixtures thereof. The most
`preferred local anesthetic is lidocaine. The meaning of “local
`anesthetic” also encompasses drugs not traditionally asso-
`ciated with local anesthetic properties but which have a
`local-anesthetic effect, for example, non-narcotic analgesics,
`such as, acetylsalicylic acid, ketoprofen, piroxicam,
`diclofenac,
`indomethacin, ketorolac, Vioxx®, and Cele-
`brex®. Furthermore, in order to improve the effectiveness
`and tolerance of the present topically-effective therapy, local
`anesthetics with different pharmacodynamics and pharma-
`cokinetics may be combined in a composition of the inven-
`tion. A preferred combination of local anesthetics is
`lidocaine and prilocaine and another preferred combination
`is lidocaine and tetracaine.
`
`As used herein, the term “local delivery” of a therapeutic,
`means topical application of the therapeutic to a subject,
`Whereafter a therapeutically-effective amount of the thera-
`peutic is absorbed in the immediate application area,
`preferably, Without significant absorption into the blood
`stream.
`
`As used herein, a “therapeutically-effective amount” of
`the compositions of the invention means the amount
`required to induce a local-anesthetic effect or numbness
`sufficient
`to ameliorate pain induced by ulceration,
`inflamation, or lesions of the buccal or nasal membrane or
`other mucous membranes or
`the pain associated with
`mucosal
`trauma, such as dental surgery. Preferably,
`the
`active agents of the composition are not absorbed systemi-
`cally.
`As used herein, the term “subject” means any animal,
`preferably a mammal, more preferably a human.
`As used herein the term “mucoadhesive” means a natural
`
`or synthetic substance, e.g., gels, pastes, macromolecules,
`polymers, and oligomers, or mixtures thereof,
`that can
`adhere to a subject’s mucous membrane for a period of time
`sufficient
`to locally deliver a therapeutically-effective
`amount of a composition of the invention to a subject.
`Adhesion of mucoadhesives to the mucous membrane
`
`occurs primarily via secondary chemical bonds, such as
`hydrogen bonding and Van der Waal forces (Tabor et al.,
`1977 J. Colloid Interface Sci. 58:2 and Good 1977]. Colloid
`Interface Sci. 592398). Mucoadhesive substances often form
`viscous aqueous solutions. The composition itself does not
`need to be mucoadhesive, as long as it can form a mucoad-
`hesive gel upon on the contact with the mucous membrane.
`For example, gellan gum itself is a very Weak mucoadhe-
`sive. On contact with the buccal membrane, gellan gum can
`interact with the ions in the mucous membrane and form an
`
`adhesive gel layer. According to the invention, mucoadhe-
`sives possess binding properties that may be distinguished
`from non-mucoadhesives by comparing the degree of adhe-
`sion to a mucosal surface. For example, comparison of a
`potential mucoadhesive with a control emulsion of compa-
`rable viscosity prepared Without mucoadhesive properties,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`e.g., a starch solution. At similar viscosities, the emulsion
`prepared with the mucoadhesive will bind to the mucosal
`surface more strongly than will the control emulsion, pref-
`erably at least 25% greater mucosal binding than the control
`emulsion, more preferably at least 50% greater, still more
`preferably at least 100% greater mucosal binding. Either
`mechanical binding to mucous membrane per se or the
`degree of biological effect of a drug delivered may be used
`as a measurement parameter for mucoadhesion. This test
`may be used to distinguish preferred mucoadhesives. Sub-
`stances can be screened for their ability to be used as
`mucoadhesives for local delivery of compositions of the
`invention according to the methodology described in Smart
`et al., 1982 J. Pharm. Pharmacol. 34:70P and Smart et al.,
`1984 J. Pharm. Pharmacol. 36295, which methodology
`comprises estimating values of adhesive strength between
`the substance and the mucous membrane. Preferably, the
`mucoadhesive is Water soluble, such that at least 1% by
`Weight of the mucoadhesive is soluble in Water at 25° C. In
`a preferred embodiment,
`the mucoadhesive will exhibit
`non-Newtonian fluid properties, i.e., the viscosity decreases
`with increasing shear forces. Accordingly, the viscosity of
`the composition can be modulated by altering the shear
`forces present when the composition is applied to a surface.
`A composition with non-Newtonian fluid properties,
`becomes less viscous when shaken or atomized, then, upon
`standing, returns to its original viscosity.
`Examples of mucoadhesives for use in the present inven-
`tion include, but are not limited to, pectin, alginic acid,
`chitosan, hyaluronic acid, polysorbates, such as polysorbate-
`20,
`-21,
`-40,
`-60,
`-61,
`-65,
`-80,
`-81,
`-85; poly
`(ethyleneglycol), such as PEG-7, -14, -16, -18, -55, -90,
`-100, -135, -180, -4, -240, -6, -8, -9, -10, -12, -20, or -32;
`oligosaccharides and polysaccharides, such as gellan,
`carrageenan, xanthan gum, gum Arabic, and dextran; cellu-
`lose esters and cellulose ethers; modified cellulose
`polymers,
`such as carboxymethylcellulose,
`hydroxyethylcellulose, hydroxypropyl methylcellulose,
`hydroxyethyl ethylcellulose; polyether polymers and
`oligomers, such as polyoxyethylene; condensation products
`of poly(ethyleneoxide) with various reactive hydrogen con-
`taining compounds having long hydrophobic chains (e.g.
`aliphatic chains of about 12 to 20 carbon atoms), for
`example, condensation products of poly(ethylene oxide)
`with fatty acids, fatty alcohols, fatty amides, polyhydric
`alcohols; polyether compounds, such as poly(methyl vinyl
`ether), polyoxypropylene of less than 10 repeating units;
`polyether compounds, such as block copolymers of ethylene
`oxide and propylene oxide; mixtures of block copolymers of
`ethylene oxide and propylene oxide with other excipients,
`for example, pluronic lethicin organogel (see 1997 Interna-
`tionalJournal ofPharmaceutical Compounding 1:71); poly
`(vinyl alcohol); polyacrylamide; hydrolyzed polyacryla-
`mide; poly(vinyl pyrrolidone); poly(methacrylic acid); poly
`(acrylic acid) or cosslinked polyacrylic acid, such as
`carbomer, i.e., a homopolymer of acrylic acid crosslinked
`with either an allyl ether of pentaerythritol, an allyl ether of
`sucrose, or an allyl ether of propylene (e.g., Acrisint® 400,
`410, or 430 commercially available from 3V Inc.
`Weehawkin, N.J.); Orabase® (i.e., a mixture of gelatine,
`pectin and sodium carboxymethyl cellulose in a plasticized
`hydrocarbon gel, commercially available from Hoyt
`laboratories, Needhm, Mass.); Carafate® (sulfated sucrose
`and aluminum hydroxide, commercially available from
`Marion Laboratories, Inc., Kansas City, Mont.). The block
`copolymers of ethylene oxide and propylene oxide are
`particularly preferred. Preferred block copolymers of ethyl-
`
`Page 5
`
`Page 5
`
`

`
`US 6,509,028 B2
`
`7
`ene oxide and propylene oxide are represented by formula I
`below:
`
`Ho—ecH2CH2o
`
`X
`
`CHCHZO
`
`CH2CH2OfiZ—H
`
`CH3
`
`Wherein X is an integer having an average value within the
`range of from about 2 to about 128; y is an integer having
`an average value within the range of from about 14 to about
`80; and Z is an integer having an average value within the
`range of from about 2 to about 128. Preferably, X and y are
`about equal. More preferred block copolymers of ethylene
`oxide and propylene oxide, falling within the genus repre-
`sented by formula I, are shown in Table 1 below.
`
`10
`
`15
`
`8
`anti-microbial agents such as chlorhexidine, chlorocresol,
`and polymyxin.
`Suitable chelating agents include, but are not limited to,
`deferoxamine, ditiocarb sodium, edetate calcium disodium,
`edetate disodium, edetate sodium, edetate trisodium,
`penicillamine, pentetate calcium trisodium, pentetic acid,
`succimer, trientin.
`Preferably, the pH of the composition is within the range
`of from about 2 to about 9, more preferably, about 3 to about
`7, even more preferably about 4 to about 5, and optimally
`about 4.5. Under acidic conditions, protonation permits
`H-bonding between the polymer and the mucin network,
`resulting in enhanced retention of the polymer in contact
`with a mucosal surface. The pH can be adjusted by adding
`an aqueous acid or base, dropwise to the composition until
`the desired pH is obtained. Any physiologically acceptable
`pH adjusting acids, bases or buffers are acceptable, e.g.,
`
`TABLE 1
`
`Trade Name
`Name
`Po oxamer 101 P uronic ® L-31
`Po oxamer 105 P uronic L-35
`P0 oxamer 108 P uronic F-38
`P0 oxamer 122 Calgene Nonionic ® 1042-L
`Po oxamer 123 P uronic L-43
`Po oxamer 124 P uronic L-44
`P0 oxamer 181 P uronic L-61
`Po oxamer 182 P uronic L-62
`Po oxamer 183 Calgene Nonionic 1063-L
`P0 oxamer 184 P uronic L-64
`P0 oxamer 185 P uronic P-65
`P0 oxamer 188 P uronic F-68
`P0 oxamer 212 Calgene Nonionic 1072-L
`Po oxamer 215 Calgene Nonionic 1075-P
`P0 oxamer 217 P uronic F-77
`P0 oxamer 231
`P uronic L-81
`Po oxamer 234 P uronic P-84
`P0 oxamer 235 P uronic P-85
`P0 oxamer 237 P uronic F-87
`P0 oxamer 238 P uronic F-88
`P0 oxamer 282 P uronic L-92
`P0 oxamer 284 Calgene Nonionic 1094-P
`P0 oxamer 288 P uronic F-98
`P0 oxamer 331 P uronic L-101
`Po oxamer 333 Puronic P-103
`P0 oxamer 334 P uronic P-104
`P0 oxamer 335 P uronic P-105
`P0 oxamer 338 P uronic F-108
`P0 oxamer 401 P uronic L-121
`Po oxamer 403 P uronic P-123
`P0 oxamer 407 P uronic F-127
`
`approximate
`value of x
`2
`11
`46
`5
`7
`11
`3
`8
`10
`13
`19
`75
`8
`24
`52
`6
`22
`27
`62
`97
`10
`21
`122
`7
`20
`31
`38
`128
`6
`21
`98
`
`approximate
`value of y
`16
`16
`16
`21
`21
`21
`30
`30
`30
`30
`30
`30
`35
`35
`35
`39
`39
`39
`39
`39
`47
`47
`47
`54
`54
`54
`54
`54
`67
`67
`67
`
`approximate
`value of z
`2
`11
`46
`5
`7
`11
`3
`8
`10
`13
`19
`75
`8
`24
`52
`6
`22
`27
`62
`97
`10
`21
`122
`7
`20
`31
`38
`128
`6
`21
`98
`
`The most preferred mucoadhesive for use with the inven-
`tion is poloxamer 407. The block copolymers of ethylene
`oxide and propylene oxide sold under the trade name
`Pluronic are commercially available, e.g., BASF
`(Washington, N.J The block copolymers of ethylene oxide
`and propylene oxide sold under the trade name Calgene are
`commercially available, e.g., Calgene Chemical,
`Inc.
`Skokie, Ill.
`Preferably, when administered to a subject, the composi-
`tions of the invention are sterile.
`
`Suitable preservatives include, but are not limited to,
`quaternary ammonium compounds, such as benzalkonium
`chloride, benzethonium chloride, cetrimide, dequalinium
`chloride, and cetylpyridinium chloride; mercurial agents,
`such as phenylmercuric nitrate, phenylmercuric acetate, and
`thimerosal; alcoholic agents, for example, chlorobutanol,
`phenylethyl alcohol, and benzyl alcohol; antibacterial esters,
`for example, esters of para-hydroxybenzoic acid; and other
`
`50
`
`55
`
`60
`
`65
`
`acids, such as acetic, boric, citric, lactic, phosphoric, hydro-
`chloric; bases, such as sodium hydroxide, sodium
`phosphate, sodium borate, sodium citrate, sodium acetate,
`sodium lactate, THAM (trishydroxymethylaminomethane);
`and buffers such as citrate/dextrose, sodium bicarbonate,
`ammonium chloride and mixtures thereof, preferably, 0.1
`normal hydrochloric acid for a pH of less than 7 and 0.1
`normal aqueous sodium hydroxide for a pH of greater than
`7.
`
`The composition of the invention can also comprise
`NMDA receptor antagonists including, but not limited to,
`dextromethorphan, dextrorphan, ketamine, pyroloquinolin
`quinone, cis-4-(phosphonomethyl)-2-piperidine carboxylic
`acid, MK801, memantine, D-methadone, or
`pharmaceutically-acceptable salts thereof.
`The compositions of the invention can also include other
`excipients and pharmaceuticals. Examples of excipients that
`can be included in the topical compositions of the invention
`
`Page 6
`
`Page 6
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`

`
`US 6,509,028 B2
`
`9
`include, but are not limited to, antibiotics, analgesics, anti-
`fungal agents, non-steroidal anti-inflammatory agents, anti-
`tussive agents, expectorants, glucocorticoids, vitamins, anti-
`oxidants, flavoring agents, sweetening agents, iso-osmotic
`agents, moisturizers, emollients, buffering agents, solubiliz-
`ing agents, penetration agents, protectants, surfactants, and
`propellants, and other conventional systemic or topical pain
`relief therapies, analgesics, and pharmaceuticals.
`Examples of suitable antibiotics include, but are not
`limited to, aminoglycoside antibiotics; such as apramycin,
`a