Pharm/Biotech
Resources

Outsourcing Guide

Cont. Education

Software/Reports

Training Courses

Web Seminars

Jobs

Buyer's Guide

Home Page

Pharm Patents /
Licensing

Pharm News

Federal Register

Pharm Stocks

FDA Links

FDA Warning Letters

FDA Doc/cGMP

Pharm/Biotech Events

Consultants

Advertiser Info

Newsletter Subscription

Web Links

Suggestions

Site Map
 

 

 

 

Title:  Methods and compositions for treating pain of the mucous membrane

United States Patent:  6,509,028

Issued:  January 21, 2003

Inventors:  Williams; Robert O. (Austin, TX); Zhang; Feng (Austin, TX); Koleng; John J. (Austin, TX); Pasternak; Gavril W. (New York, NY); Kolesnikov; Yuri A. (Tenafly, NJ)

Assignee:  EpiCept Corporation (Englewood Cliffs, NJ)

Appl. No.:  172455

Filed:  June 17, 2002

Abstract

Compositions useful for long-lasting pain relief from mucosal damage, such as mucosal inflamation, abrasions, ulcerations, lesions, trauma and incisions, without significant systemic absorption. The compositions of the invention are particularly suitable for application to the mucous membrane of the nasal cavity and buccal cavity. To relieve pain, the compositions or the invention are topically applied directly to the affected area.

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 compositions 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 forming 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 (.mu.), kappa (.kappa.), and delta (.delta.) 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 reference. The opioid can be any opioid receptor agonist or antagonist known or to be developed. Preferred opioids interact with the .mu.-opioid receptor, the .kappa.-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, 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 naltrexone or pharmaceutically-acceptable salts thereof, or mixtures 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 (.alpha.-Neoendorphin), Tyr-Gly-Gly-Phe-Leu-Arg-Lsy-Tyr-Pro (.beta.-Neoendorphin), Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Ly s-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (.beta.h -Endorphin), [D-Ala2,MePhe4 Gly(ol)5 ]enkephalin (DAMGO), [D-Pen2, D-Pen5 ]enkephalin (DPDPE), [D-Ser2, Leu5 ]enkephalin-Thr6 (DSLET), [D-Ala2, D-Leu5 ]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-Ala2 Glu4 ]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, ropivacaine, salicyl alcohol, tetracaine, tolycaine, 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 associated 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.RTM., and Celebrex.RTM.. Furthermore, in order to improve the effectiveness and tolerance of the present topically-effective therapy, local anesthetics with different pharmacodynamics and pharmacokinetics may be combined in a composition of the invention. 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 therapeutic 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 systemically.

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 J. Colloid Interface Sci. 59:398). Mucoadhesive substances often form viscous aqueous solutions. The composition itself does not need to be mucoadhesive, as long as it can form a mucoadhesive gel upon on the contact with the mucous membrane. For example, gellan gum itself is a very weak mucoadhesive. 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, mucoadhesives possess binding properties that may be distinguished from non-mucoadhesives by comparing the degree of adhesion to a mucosal surface. For example, comparison of a potential mucoadhesive with a control emulsion of comparable viscosity prepared without mucoadhesive properties, 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, preferably 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. Substances 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. 36:295, 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 25oC. 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 invention 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; cellulose 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 containing 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 International Journal of Pharmaceutical Compounding 1:71); poly(vinyl alcohol); polyacrylamide; hydrolyzed polyacrylamide; 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.RTM. 400, 410, or 430 commercially available from 3V Inc. Weehawkin, N.J.); Orabase.RTM. (i.e., a mixture of gelatine, pectin and sodium carboxymethyl cellulose in a plasticized hydrocarbon gel, commercially available from Hoyt laboratories, Needhm, Mass.); Carafate.RTM. (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.

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 represented by formula I, are shown in Table 1 below.

 

    TABLE 1
                                           approximate approximate approximate
    Name          Trade Name               value of x  value of y  value of z
    Poloxamer 101 Pluronic .RTM. L-31           2          16           2
    Poloxamer 105 Pluronic L-35                11          16          11
    Poloxamer 108 Pluronic F-38                46          16          46
    Poloxamer 122 Calgene Nonionic .RTM. 1042-L      5          21           5
    Poloxamer 123 Pluronic L-43                 7          21           7
    Poloxamer 124 Pluronic L-44                11          21          11
    Poloxamer 181 Pluronic L-61                 3          30           3
    Poloxamer 182 Pluronic L-62                 8          30           8
    Poloxamer 183 Calgene Nonionic 1063-L      10          30          10
    Poloxamer 184 Pluronic L-64                13          30          13
    Poloxamer 185 Pluronic P-65                19          30          19
    Poloxamer 188 Pluronic F-68                75          30          75
    Poloxamer 212 Calgene Nonionic 1072-L       8          35           8
    Poloxamer 215 Calgene Nonionic 1075-P      24          35          24
    Poloxamer 217 Pluronic F-77                52          35          52
    Poloxamer 23l Pluronic L-81                 6          39           6
    Poloxamer 234 Pluronic P-84                22          39          22
    Poloxamer 235 Pluronic P-85                27          39          27
    Poloxamer 237 Pluronic F-87                62          39          62
    Poloxamer 238 Pluronic F-88                97          39          97
    Poloxamer 282 Pluronic L-92                10          47          10
    Poloxamer 284 Calgene Nonionic 1094-P      21          47          21
    Poloxamer 288 Pluronic F-98                122         47          122
    Poloxamer 331 Pluronic L-101                7          54           7
    Poloxamer 333 Puronic P-103                20          54          20
    Poloxamer 334 Pluronic P-104               31          54          31
    Poloxamer 335 Pluronic P-105               38          54          38
    Poloxamer 338 Pluronic F-108               128         54          128
    Poloxamer 401 Pluronic L-121                6          67           6
    Poloxamer 403 Pluronic P-123               21          67          21
    Poloxamer 407 Pluronic F-127               98          67          98

The most preferred mucoadhesive for use with the invention 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 compositions 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 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., acids, such as acetic, boric, citric, lactic, phosphoric, hydrochloric; 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 include, but are not limited to, antibiotics, analgesics, antifungal 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, solubilizing 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, arbekacin, bambermycins, butirosin, dibekacin, neomycin, neomycin undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, and spectinomycin; amphenicol antibiotics, such as azidamfenicol, chloramphenicol, florfenicol, and thiamphenicol; ansamycin antibiotics, such as rifamide and rifampin; carbacephems, such as loracarbef; carbapenems, such as biapenem and imipenem; cephalosporins, such as cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefozopran, cefpimizole, cefpiramide, and cefpirome; cephamycins, such as cefbuperazone, cefmetazole, cefminox; monobactams, such as aztreonam, carumonam, and tigemonam; oxacephems, such as flomoxef, and moxalactam; penicillins, such as amdinocillin, amdinocillin pivoxil, amoxicillin, bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium, epicillin, fenbenicillin, floxacillin, penamccillin, penethamate hydriodide, penicillin o-benethamine, penicillin 0, penicillin V, penicillin V benzathine, penicillin V hydrabamine, penimepicycline, and phencihicillin potassium; lincosamides, such as clindamycin, and lincomycin; macrolides, such as azithromycin, carbomycin, clarithomycin, dirithromycin, erythromycin, erythromycin acistrate; polypeptides, such as amphomycin, bacitracin, capreomycin, colistin, enduracidin, and enviomycin; tetracyclines, such as apicycline, chlortetracycline, clomocycline, and demeclocycline; 2,4-diaminopyrimidines, such as brodimoprim; nitrofurans, such as furaltadone, and furazolium chloride; quinolones and analogs, such as cinoxacin, ciprofloxacin, clinafloxacin, flumequine, and grepagloxacin; sulfonamides, such as acetyl sulfamethoxypyrazine, benzylsulfamide, noprylsulfamide, phthalylsulfacetamide, sulfachrysoidine, and sulfacytine; sulfones, such as diathymosulfone, glucosulfone sodium, and solasulfone; and others, such as cycloserine, mupirocin, tuberin.

Examples of suitable analgesics include, but are not limited to, aceclofenac, acetaminophen, acetaminosalol, acetanilide, acetylsalicylsalicylic acid, alclofenac, alminoprofen, aloxiprin, aluminum bis(acetylsalicylate), aminochlorthenoxazin, 2-amino-4-picoline, aminopropylon, aminopyrine, ammonium salicylate, amtohnetin guacil, antipyrine, antipyrine salicylate, antrafenine, apazone, aspirin, benorylate, benoxaprofen, benzpiperylon, benzydamine, bermoprofen, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bucetin, bufexamac, bumadizon, butacetin, calcium acetylsalicylate, carbamazepine, carbiphene, carsalam, chlorthenoxazin(e), choline salicylate, cinchophen, ciramadol, clometacin, clonixin, cropropamide, crotethamide, dexoxadrol difenamizole, difiunisal, dihydroxyaluminum acetylsalicy, late, dipyrocetyl, dipyrone, emorfazone, enfenamic acid, epirizole, etersalate, ethenzamide, ethoxazene, etodolac, felbinac, fenoprofen, floctafenine, flufenamic acid, fluoresone, flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid, glafenine, ibufenac, imidazole salicylate, indomethacin, indoprofen, isofezolac, isoladol, isonixin, ketoprofen, ketorolac, p-lactophcnetide, lefetamine, lomoxicam, loxoprofen, lysine acerylsalicylate, magnesium acetylsalicylate, methotrimeprazine, metofoline, mofezolac, morazone, morpholine salicylate naproxen, nefopam, nifenazone, 5'-nitro-2'-propoxyacetanilide, parsalmide, perisoxal, phenacetin, phenazopyridine hydrochloride, phenocoll, phenopyrazone, phenyl acetylsalicylate, phenyl salicylate, phenyramidol, pipebuzone, piperylone, propacetamol, propyphenazone, ramifenazone, rimazolium metilsulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, salverine, simetride, sodium salicylate, suprofen, talniflumate, tenoxicam, terofenamate, tetrandrine, tinoridine, tolfenamic acid, tramadol, tropesin, viminol, xenbucin, and zomepirac.

Examples of suitable antifungal agents include, but are not limited to, polyenes, such as amphotericin b, candicidin, mepartricin, natamycin, and nystatin; allylamines, such as butenafine, and naftifine; imidazoles, such as bifonazole, butoconazole, chlordantoin, flutrimazole, isoconazole, ketoconazole, and lanoconazole; thiocarbamates, such as tolciclate, tolindate, and tolnaftate; triazoles, such as fluconazole, itraconazole, saperconazole, and terconazole; and others, such as bromosalicylchloranilide, buclosamide, calcium propionate, chlorphenesin, and ciclopirox; and others, such as azaserine, griseofulvin, oligomycins, neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin, viridin.

Examples of suitable non-steroidal anti-inflammatory agents include, but are not limited to, aminoarylcarboxylic acid derivatives, such as enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, and tolfenamic acid; arylacetic acid derivatives, such as aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac isoxepac, lonazolac, metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, tropesin, and zomepirac; arylbutyric acid derivatives, such as bumadizon, butibufen, fenbufen, xenbucin; arylcarboxylic acids, such as clidanac, ketorolac, tinoridine; arylpropionic acid derivatives, such as alminoprofen, benoxaprofin, bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid, ximoprofen, and zaltoprofen; pyrazoles, such as difenamizole, and epirozole; pyrazolones, such as apazone, benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone, and thiazolinobutazone; salicylic acid derivatives, such as acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphtyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, sulfasalazine; thiazinecarboxamides, such as ampiroxicam, droxicam, isoxicam, lomoxicam, piroxicam, and tenoxicam; and others, such as .epsilon.-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutytic acid, amixetrine, bendazac, benzydamine, .alpha.-bisabolol, bucololome, difenpiramide, ditazol, emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline, perisoxal, proquazone, superoxide dismutase, tenidap, and zilenton.

Examples of suitable antitussive agents include, but are not limited to, alloclamide, amicibone, benproperine, benzonatate, bibenzonium bromide, bromoform, butamirate, butethamate, caramiphen ethanedisulfonate, carbetapentane, chlophedianol, clobutinol, cloperastine, codeine, codeine methyl bromide, codeine n-oxide, codeine phosphate, codeine sulfate, cyclexanone, dimethoxanate, dropropizine, drotebanol, eprazinone, ethyl dibunate, ethylmorphine, fominoben, guaiapate, hydrocodone, isoaminile, levopropoxyphene, morclofone, narceine, mormethadone, noscapine, oxeladin, oxolamine, pholcodine, picoperine, pipazethate, piperidione, prenoxdiazine hydrochloride, racemethorphan, sodium dibunate, tipepidine, and zipeprol.

Example of suitable expectorants include, but are not limited to, ambroxol, ammonium bicarabonate, ammonium carbonate, bromhexine, calcium iodide, carbocysteine, guaiacol, guaiacol benzoate, guaiacolcarbonate, guaiacol phosphate, guaifenesin, guaithylline, hydriodic acid, iodinated glycerol, potassium guaiacolsulfonate, potassium iodide, sodium citrate, sodium iodide, storax, terebene, terpin, and trifolium.

Suitable glucocorticoids include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, flucortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, and triamcinolone hexacetonide.

Suitable vitamins include, but are not limited to calcipotriene, calcitriol, ergosterol, 1.alpha.-hydroxycholecalciferol, vitamin D2+, vitamin D3+, ascorbic acid, calcium ascorbate, nicotinamide ascorbate, sodium ascorbate, .alpha.-carotene, .beta.-carotene, .delta.-carotene, vitamin A, cobamamide, folic acid, hydroxocobalamin, sodium folate, vitamin B12, menadiol, menadione, menadoxime, menaquinones, phylloquinone, vitamin K5+, inositol, .alpha.tocopherol, .gamma.-tocopherol, .gamma.-tocopherol, vitamin E, vitamin E acetate, and vitamin U.

Examples of suitable anti-oxidants include, but are not limited to, ascorbic acid, sodium ascorbate, sodium bisulfite, sodium thiosulfate, 8-hydroxy quinoline, and N-acetyl cysterine.

Examples of suitable flavoring agents include, but are not limited to, oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate.

Examples of suitable sweetening agents include, but not limited to, sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenyl alanine, methyl ester), and saccharine.

The compositions of the present invention optionally can include an iso-osmotic agent which functions to prevent irritation of the mucosa by the composition. Examples of pharmaceutically-acceptable iso-osmotic agents which can be used include sodium chloride, dextrose, and calcium chloride.

Preferably, the amount of local anesthetic in the composition is within the range of from about 0.005 percent to about 2 percent of the total weight of the composition, more preferably, of from about 0.01 percent to about 0.5 percent of the total weight of the composition.

For treatment of oral mucositis, a preferred concentration of local anesthetic is from about 0.02 percent to about 0.1 percent of the total weight of the composition, more preferably, about 0.04 percent to about 0.08 percent. For treatment of more painful conditions, such as dental surgery (e.g., tooth extraction or root canal), a preferred concentration of local anesthetic is from about 0.1 percent to about 0.4 percent of the total weight of the composition, more preferably, about 0.2 percent to about 0.3 percent.

Preferably, the amount of opioid in the composition is within the range of from about 0.005 percent to about 3 percent of the total weight of the composition, more preferably, of from about 0.01 percent to about 2 percent, still more preferably, of from about 0.05 percent to about 1 percent of the total weight of the composition. For treatment of oral mucositis, a preferred concentration of opioid is from about 0.1 percent to about 0.3 percent of the total weight of the composition. For treatment of more painful conditions, such as dental surgery, a preferred concentration of opioid is from about 0.3 percent to about 0.8 percent of the total weight of the composition, more preferably, about 0.4 percent to about 0.5 percent.

Preferably, the amount of mucoadhesive in the composition is within the range of from about 0.1 percent to about 40 percent of the total weight of the composition, more preferably, of from about 10 percent to about 30 percent, and optimally, of from about 15 percent to about 25 percent of the total weight of the composition.

Preferably, the amount of water in the composition is within the range of from about 95 percent to about 10 percent of the total weight of the composition, more preferably, of from about 90 percent to about 50 percent, and optimally, of from about 85 percent to about 75 percent of the total weight of the composition.

When a chelating agent is used, preferably, it is present in an amount within the range of from about 0.005 percent to about 1 percent of the total weight of the composition, more preferably, of from about 0.01 percent to about 0.5 percent, still more preferably, of from about 0.05 percent to about 0.2 percent of the composition.

When a preservative is used, preferably, it is present in an amount within the range of from about 0.0001 percent to about 0.2 percent of the total weight of the composition, more preferably, of from about 0.0005 percent to about 0.1 percent, and optimally, of from about 0.001 percent to about 0.05 percent of the total weight of the composition.

To relieve pain from mucositis, the compositions or the invention are topically applied directly to the affected area. The compositions of the invention can be applied to the affected area of the mucous membrane in any conventional manner well known in the art, for example, as a mist via an aerosol applicator, by cannula, via a patch, by a dropper, or by an applicator stick, preferably as a mist, more preferably as a metered-dose mist. A mist can be sprayed onto the area to be treated via an aerosol container, pressurized or non-pressurized, preferably a non-pressurized pump. For more specific applications, a cannula can be used. The cannula can be attached to a pressurized or non-pressurized pump, preferably a non-pressurized pump.

A suitable non-pressurized pump for application of compositions of the invention can comprise a container, a valve, an actuator, and optionally a dip tube. The non-pressurized pump's container can be metal, such as a tin plated steel or aluminum, glass, or plastic. The valve's primary purpose is to regulate the flow of product from the container. It provides a means of discharging the desired amount. Suitable spray valves are described in Remington's Pharmaceutical Sciences 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, Pa., 1990 pp. 1703-1704, incorporated herein by reference. The actuator provides a means for releasing the contents from a pressurized container. Suitable actuators are described in Remington's Pharmaceutical Sciences 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, Pa., 1990 pp. 1704-1705, incorporated herein by reference.

Preferably, the metered pump is a VP 7 Screw-On Pump (90 .mu.l, 18/415) commercially available from Valois of America, Inc. (Greenwich, Conn.). The VP 7 screw-on pump is manufactured from polyethylene and polypropylene. It is designed in a way such that the hydraulically opening clapper eliminates the use of any elastomeric gaskets in contact with the product. The pump has an annular dosing chamber, which fills only at the full return of the actuator to ensure full dosing and precision.

The preferred actuator is the 132C-BL GP4 BL long throat actuator commercially available from Valois Pharmaceuticals, Inc. Preferably, the actuator is manufactured from polyethylene and polypropylene and, preferably, contains a captive insert to provide a well-atomized spray pattern. The captive insert also reduces the dead volume in the actuator.

When a cannula is used, for application to a specific area rather than as a spray, the preferred actuator is a stainless-steel cannula of about 73 mm in length, for example, the 215 stainless-steel cannula commercially available from Valois Pharmaceuticals, Inc. Polyethylene or polypropylene cannulas can also be used.

The compositions of the invention can also be delivered to the buccal or nasal cavity via a patch that is applied adjacent to the area of skin to be treated. As used herein a "patch" comprises at least a composition of the invention and a covering layer, such that, the patch can be placed over the area to be treated. Preferably, the patch is designed to maximize local delivery and to minimize absorption into the circulatory system, reduce lag time, promote uniform absorption, and reduce mechanical rub-off. Suitable patches are described in Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc. p. 249-297, incorporated herein by reference. Suitable patches for buccal delivery of compositions of the invention is disclosed in U.S. Pat. Nos. 5,713,852 and 4,900,552, both of which are incorporated herein by reference.

The amount of the composition of the invention applied to the buccal or nasal passages will vary depending on the particular mucoadhesive, local anesthetic, and opioid used; the nature and severity of the mucosal lesion or inflamation being treated, and the subject. The composition should be applied to the affected area as recommended by a physician, preferably, as needed by the patient to relieve pain. For example, a dose of about 0.05 mg to about 4 mg morphine sulfate and 0.02 mg to about 3 mg of lidocaine hydrochloride in about 0.5 g to about 3 g of composition can be delivered to the affected area. When applying as a spray, a dose of about 2 mg morphine sulfate and about 1 mg lidocaine hydrochloride in about 1.5 g of composition can be delivered to the affected area. For more precise applications by cannula, a dose of about 2 mg morphine sulfate and about 1 mg lidocaine hydrochloride in about 0.4 g of composition can be delivered to the affected area.

In a preferred embodiment of administration, the dose is delivered with a spray actuator in about 8 to about 20 separate spray shots, more preferably about 16 spray shots, wherein each spray shot weighs about 50 mg to about 150 mg, more preferably about 100 mg. In another preferred embodiment of administration, the dose is delivered via cannula in about 4 spray shots, wherein each spray shot weighs about 100 mg.

Although the present invention has been described in considerable detail with reference to certain preferred embodiments, other embodiments are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiments contained herein.

Claim 1 of 31 Claims

What is claimed is:

1. A composition comprising a mucoadhesive, a local anesthetic or a pharmaceutically-acceptable salt thereof, and an opioid or a pharmaceutically-acceptable salt thereof, wherein the mucoadhesive is a block copolymer of ethylene oxide and propylene oxide.

 


____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

[ Outsourcing Guide ] [ Cont. Education ] [ Software/Reports ] [ Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ]

[ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ]
[ Pharm Stocks ] [ FDA Links ] [ FDA Warning Letters ] [ FDA Doc/cGMP ]
[ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ]
[ Site Map ]