`

`Patent Application Publication Aug. 16, 2007 Sheet 1 of 4
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`US 2007/0190019 A1
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`Figure 1
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`US 2007/0190019 AI
`
`Aug. 16, 2007
`
`1
`
`COMPOSITIONS AND METHODS FOR TOPICAL
`ADMINISTRATION
`
`[0020] a. from about 20 to about 50 wt. %water, based on
`the total weight of cream base composition;
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`
`[0001] This application claims the benefit of priority from
`U.S. Provisional Ser. No. 60/480,230, filed Jun. 23, 2003.
`This application, in its entirety, is incorporated herein.
`
`[0002] The present invention relates generally to compo(cid:173)
`sitions for administration of active agents through the skin
`and other membranes and methods of using the same and to
`methods for administering active agents using these com(cid:173)
`positions.
`
`[0003] The present invention relates to compositions
`effective for the topical administration across skin and other
`membranes of active agents and to the methods for treating
`and/or preventing symptoms and/or disorders associated
`with disease or hormonal imbalances.
`
`[0004] One embodiment of the present invention provides
`for a vanishing cream base composition suitable for topical
`application of an active agent to an animal or plant com(cid:173)
`prising:
`
`[0005] a. from about 20 to about 70 wt. %water, based on
`the total weight of cream base composition;
`
`[0006] b. at least about 10 wt. %, based on the total weight
`of cream base, of at least one alcohol;
`
`[0007] c. at least one polymeric thickening agent, option(cid:173)
`ally having a nitrogen containing acrylic unit;
`
`[0008] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound; and
`
`[0009] e. an emulsifying agent;
`
`[0010] wherein said cream base is stable upon storage at
`ambient conditions, and clarifies at a temperature greater
`than 30° C.
`
`[0011] Another embodiment of the present invention pro(cid:173)
`vides for a vanishing cream composition suitable for topical
`application of an active agent to an animal or plant com(cid:173)
`prising:
`
`[0021] b. at least about 30 wt. %, based on the total weight
`of cream base, of at least one alcohol;
`
`[0022] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0023] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound;
`
`[0024] e. an emulsifying agent;
`
`[0025] wherein said cream base is stable upon storage at
`ambient conditions, and clarifies at a temperature greater
`than 30° C.
`
`[0026] Another embodiment of the present invention pro(cid:173)
`vides a vanishing cream base composition suitable for
`topical application of an ionic active agent to an animal or
`plant comprising:
`
`[0027] a. at least about 55 wt. %water, based on the total
`weight of cream base composition;
`
`[0028] b. at least about 15 wt. %, based on the total weight
`of cream base, of at least one alcohol;
`
`[0029] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0030] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound; and
`
`[0031] e. an emulsifying agent;
`
`[0032] wherein said cream base is stable upon storage at
`ambient conditions, and clarifies at a temperature greater
`than 30° C.
`
`[0033] Another embodiment of the present invention pro(cid:173)
`vides a vanishing cream composition suitable for topical
`application to an animal or plant comprising:
`
`[0034] a. from about 20 to about 50 wt. %water, based on
`the total weight of cream base composition;
`
`[0035] b. at least about 30 wt. %, based on the total weight
`of cream base, of at least one alcohol;
`
`[0012] a. from about 20 to about 70 wt. %water, based on
`the total weight of cream base composition;
`
`[0036] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0013] b. at least about 10 wt. %, based on the total weight
`of cream base, of at least one alcohol;
`
`[0037] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound;
`
`[0014] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0015] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound;
`
`[0016] e. an emulsifying agent; and
`
`[0017]
`
`f. an active agent;
`
`[0018] wherein said cream base is stable upon storage at
`ambient conditions, and clarifies at a temperature greater
`than 30° C.
`
`[0019] Another embodiment of the present invention pro(cid:173)
`vides a vanishing cream base composition suitable for
`topical application of a non-ionic active agent to an animal
`or plant comprising:
`
`[0038] e. a non-ionic active agent; and
`
`[0039]
`
`f. an emulsifYing agent;
`
`[0040] wherein said cream base is stable upon storage at
`ambient conditions, and clarifies at a temperature greater
`than 30° C.
`
`[0041] Another embodiment of the present invention pro(cid:173)
`vides for a vanishing cream composition suitable for topical
`application of an ionic active agent to an animal or plant
`comprising:
`
`[0042] a. at least about 55 wt. %water, based on the total
`weight of cream base composition;
`
`[0043] b. at least about 15 wt. %, based on the total weight
`of cream base, of at least one alcohol;
`
`6
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`US 2007/0190019 AI
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`Aug. 16, 2007
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`2
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`[0044] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0045] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound;
`
`[0046] e. an emulsifying agent; and
`
`[0047]
`
`f. an ionic active agent;
`
`[0048] wherein said cream base is stable upon storage at
`ambient conditions, and clarifies at a temperature greater
`than 30° C.
`
`[0049] Still another embodiment of the present invention
`provides a method offorming a vanishing cream suitable for
`administering a non-ionic active agent to an animal or plant
`comprising, mixing:
`
`[0050] a. from about 20 to about 50 wt. %water, based on
`the total weight of cream base composition;
`
`[0051] b. at least about 30 wt. %, based on the total weight
`of cream base, of at least one alcohol;
`
`[0052] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0053] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound;
`
`[0054] e. an emulsifying agent; and
`
`[0055]
`
`f. a non-ionic active agent.
`
`[0056] Another embodiment of the present invention pro(cid:173)
`vides a method of forming a vanishing cream suitable for
`administering a ionic active agent to animal or plant com(cid:173)
`prising, mixing:
`
`[0057] a. from about 20 to about 50 wt. %water, based on
`the total weight of cream base composition;
`
`[0058] b. at least about 30 wt. %, based on the total weight
`of cream base, of at least one alcohol;
`
`[0059] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0060] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound;
`
`[0061] e. an emulsifying agent; and
`
`[0062]
`
`f. an ionic active agent.
`
`[0063] Another embodiment of the present invention pro(cid:173)
`vides for a vanishing cream composition suitable for topical
`application to an animal comprising:
`
`[0064] a. from about 25 to 50 wt. % water, based on the
`total weight of cream base composition;
`
`[0065] b. from about 25 to about 45 wt. %, based on the
`total weight of cream base, of at least one alcohol;
`
`[0066] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0067] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound;
`
`[0068] e. an emulsifying agent; and
`
`[0069]
`one;
`
`f. from about 0.5 wt. %to about 5 wt. % testoster(cid:173)
`
`[0070] wherein said cream base is stable upon storage at
`ambient conditions, and clarifies at a temperature greater
`than 30° C.
`
`[0071] Another embodiment of the present invention pro(cid:173)
`vides a vanishing cream composition suitable for topical
`application to an animal comprising:
`
`[0072] a. from about 40 to about 50 wt. %water, based on
`the total weight of cream base composition;
`
`[0073] b. from about 35 to about 50 wt. %, based on the
`total weight of cream base, of at least one alcohol;
`
`[0074] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0075] d. a penetration enhancing effective amount of a
`skin penetration enhancing_ compound;
`
`[0076] e. an emulsifying agent; and
`
`f. from about 0.5 wt. % to about 5 wt. % prostag(cid:173)
`[0077]
`landin E1;
`
`[0078] wherein said cream base is stable upon storage at
`ambient conditions, and clarifies at a temperature greater
`than 30° C.
`
`[0079] Another embodiment of the present invention pro(cid:173)
`vides a vanishing cream composition suitable for topical
`application to an animal comprising:
`
`[0080] a. from 0 to about 20 wt.% water, based on the total
`weight of cream base composition;
`
`[0081] b. at least 60 wt. %, based on the total weight of
`cream base, of at least one alcohol;
`
`[0082] c. at least one polymeric thickening agent compris(cid:173)
`ing a nitrogen containing acrylic unit;
`
`[0083] d. a penetration enhancing effective amount of a
`skin penetration enhancing compound;
`
`[0084] e. an emulsifying agent; and
`
`f. from about 1 wt. % to about 5 wt. % hydro(cid:173)
`[0085]
`quinone;
`
`[0086] wherein said cream base is stable upon storage at
`ambient conditions, and clarifies at a temperature greater
`than 30° C.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0087] FIG. 1 shows a schematic representation of the
`diffusion cells used in Example 1.
`
`[0088] FIGS. 2A and 2B show graphs illustrating average
`flux (FIG. 2A) and cumulative delivery (FIG. 2B) of PGE 1
`across human skin vs. time for formulation number 11 in
`Table 1, against a clear gel control of 1% PGEv 5%
`SEPA-0009, 1% Klucel HF, 65.1% ethanol, and 27.9%
`water.
`
`[0089] FIGS. 3A and 3B show graphs illustrating average
`flux (FIG. 3A) and cumulative delivery (FIG. 3B) of PGE 1
`across human skin vs. time for formulations 11 and 13 in
`Table 1, against a clear gel control of 1% PGEv 5%
`SEPA-0009, 1% Klucel HF, 65.1% ethanol, and 27.9%
`water.
`
`7
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`US 2007/0190019 AI
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`Aug. 16, 2007
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`3
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`[0090] FIGS. 4A and 4B show graphs illustrating average
`flux (FIG. 4A) and cumulative delivery (FIG. 4B) of PGE,
`across human skin vs. time for formulations 11, 13 and 16
`in Table 1, against a clear gel control of 1% PGE1, 5%
`SEPA-0009, 1% Klucel HF, 65.1% ethanol, and 27.9%
`water.
`
`1. Active Agents
`
`[0091] As used herein, the term "active agent" means any
`chemical or biological material suitable for administration,
`that produces a desired biological, pharmacological, or
`physiological effect in an animal or plant to which the agent
`is administered. Such effects may include, but are not limited
`to (1) having a prophylactic effect on the animal or plant,
`such as preventing an undesired biological effect, for
`example, as in preventing an infection; (2) alleviating a
`condition caused by a disease of the animal or plant, for
`example, alleviating pain or inflammation caused as a result
`of disease; and/or (3) either alleviating, reducing, or com(cid:173)
`pletely eliminating a disease from the animal or plant. The
`effect may be local, such as providing for a local anesthetic
`effect, or it may be systemic. Active agents are present in a
`pharmaceutically effective amount. The term "animal" as
`use herein is understood to also include human beings as
`well as other mammals.
`
`[0092] Active agents that may be used in the compositions
`of the present invention include any locally or systemically
`active agents which are compatible with the compositions of
`the present invention and which can be delivered through the
`skin or other membrane to achieve a desired effect. In
`addition to pharmaceuticals, the present invention may also
`include other active agents, such as cosmetic agents. Rep(cid:173)
`resentative active agents (grouped by therapeutic class)
`include but are not limited to:
`
`Alimentary System
`
`[0093] Antidiarrhoeals such as diphenoxylate, loperamide
`and hyoscyamine.
`
`Cardiovascular System
`
`[0094] Antihypertensives such as hydralazine, minoxidil,
`captopril, enalapril, clonidine, prazosin, debrisoquine, dia(cid:173)
`zoxide, guanethidne, methyldopa, reserpine, trimetaphan.
`
`[0095] Calcium channel blockers such as diltiazem, felo(cid:173)
`dopine, amlodipine, nitrendipine, nifedipine and verapamil.
`
`[0096] Antiarrhyrthmics such as amiodarone, flecainide,
`disopyramide, procainamide, mexiletene and quinidine.
`
`[0097] Antiangina agents such as glyceryl trinitrate, eryth(cid:173)
`ritol tetranitrate, pentaerythritol tetranitrate, mannitol hex(cid:173)
`anitrate, perhexilene, isosorbide dinitrate and nicorandil.
`
`[0098] Beta-adrenergic blocking agents such as alpre(cid:173)
`nolol, atenolol, bupranolol, carteolol, labetalol, metoprolol,
`nadolol, nadoxolol, oxprenolol, pindolol, propranolol,
`sotalol, timolol and timolol maleate.
`
`[0099] Cardiotonic glycosides such as digoxin and other
`cardiac glycosides and theophylline derivatives.
`
`[0101] Vasodilators such as cyclandelate, isoxsuprine,
`papaverine, dipyrimadole, isosorbide dinitrate, phentola(cid:173)
`mine, nicotinyl alcohol, co-dergocrine, nicotinic acid, glyc(cid:173)
`eryl trinitrate, pentaerythritol tetranitrate and xanthinol.
`
`[0102] Antimigraine preparations such as ergotamine,
`dihydroergotamine, methysergide, pizotifen and sumatrip(cid:173)
`tan.
`
`Drugs Affecting Blood and Haemopoietic Tissues
`
`[0103] Anticoagulants and thrombolytic agents such as
`warfarin, dicoumarol, low molecular weight heparins such
`as enoxaparin; streptokinase and its active derivatives. Hae(cid:173)
`mostatic agents such as aprotinin, tranexamic acid and
`protamine.
`
`Central Nervous System
`
`[0104] Analgesics, antipyretics including the opiod anal(cid:173)
`gesics such as buprenorphine, dextromoramide, dextropro(cid:173)
`poxyphene, fentanyl, alfentanil, sufentanil, hydromorphone,
`methadone, morphine, oxycodone, papaveretum, pentazo(cid:173)
`cine, pethidine, phenoperidine, codeine and dihydrocodeine.
`Others include acetylsalicylic acid (aspirin), paracetamol,
`and phenazone.
`
`[0105] Hypnotics and sedatives such as the barbiturates,
`amylobarbitone, butobarbitone and pentobarbitone and
`other hypnotics and sedatives such as choral hydrate, chlo(cid:173)
`rmethiazole, hydroxyzine and meprobamate.
`
`[0106] Antianxiety agents such as the benzodiazepines,
`alprazolam, bromazepam, chlordiazepoxide, clobazam,
`chlorazepate,
`diazepam,
`flunitrazepam,
`flurazepam,
`lorazepam, nitrazepam, oxazepam, temazepam and triaz(cid:173)
`olam.
`
`[0107] Neuroleptic and antipsychotic drugs such as the
`phenothiazines, chlorpromazine, fluphenazine, pericyazine,
`perphenazine, promazine, thiopropazate, thioridazine and
`trifluoperazine and the butyrophenone, droperidol and halo(cid:173)
`peridol and the other antipsychotic drugs such as pimozide,
`thiothixene and lithium.
`
`[0108] Antidepressants such as the tricyclic antidepres(cid:173)
`sants amitryptyline, clomipramine, desipramine, dothiepin,
`doxepin, imipramine, nortriptyline, opipramol, protriptyline
`and trimipramine and the tetracyclic antidepressants such as
`mianserin and the monoamine oxidase inhibitors such as
`isocarboxazid, phenelizine, tranylcypromine and moclobe(cid:173)
`mide and selective serotonin re-uptake inhibitors such as
`fluoxetine, paroxetine, citalopram, fluvoxamine and sertra(cid:173)
`line.
`
`[0109] CNS stimulants such as caffeine.
`
`[0110] Anti-alzheimer's agents such as tacrine.
`
`[0111] Antiparkinson agents such as amantadine, benser(cid:173)
`azide, carbidopa, levodopa, benztropine, biperiden, ben(cid:173)
`zhexol, procyclidine and dopamine-2 agonists such as S(-)-
`2-(N -propyl-N-2-thienylethylamino )-5 -hydroxytetralin
`(N-0923).
`
`[0100] Adrenergic stimulants such as adrenaline, ephe(cid:173)
`drine, fenoterol, isoprenaline, orciprenaline, rimeterol, salb(cid:173)
`utamol, salmeterol, terbutaline, dobutamine, phenylephrine,
`phenylpropanolamine, pseudoephedrine and dopamine.
`
`[0112] Anticonvulsants such as phenytoin, valproic acid,
`primidone, phenobarbitone, methylphenobarbitone and car(cid:173)
`bamazepine, ethosuximide, methsuximide, phensuximide,
`sulthiame and clonazepam.
`
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`Aug. 16, 2007
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`4
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`[0113] Antiemetics, antinauseants such as the phenothiaz(cid:173)
`ines, prochloperazine, thiethylperazine and 5HT-3 receptor
`antagonists such as ondansetron and granisetron and others
`such as dimenhydrinate, diphenhydramine, metoclopramide,
`domperidone, hyoscine, hyoscine hydrobromide, hyoscine
`hydrochloride, clebopride and brompride.
`
`Musculoskeletal System
`
`[0114] Non-steroidal anti-inflammatory agents including
`their racemic mixtures or individual enantiomers where
`applicable, such as ibuprofen, flurbiprofen, ketoprofen,
`aclofenac, diclofenac, aloxiprin, aproxen, aspirin, diflunisal,
`fenoprofen, indomethacin, mefenamic acid, naproxen, phe(cid:173)
`nylbutazone, piroxicam, salicylamide, salicylic acid, sulin(cid:173)
`dac, desoxysulindac, tenoxicam, tramadol and ketoralac.
`Non-steroidal antiinflammatory agents may also include
`salicylamide, salicylic acid, flufenisal, salsalate, triethano(cid:173)
`lamine salicylate, aminopyrine, antipyrine, oxyphenbuta(cid:173)
`zone, apazone, cintazone, flufenamic acid, clonixeril,
`clonixin, meclofenamic acid, flunixin, coichicine, demecol(cid:173)
`cine, allopurinol, oxypurinol, benzydamine hydrochloride,
`dimefadane, indoxole, intrazole, mimbane hydrochloride,
`paranylene hydrochloride,
`tetrydamine, benzindopyrine
`hydrochloide, fluprofen, ibufenac, naproxol, fenbufen, cin(cid:173)
`chophen, diflumidone sodium, fenamole, flutiazin, metaza(cid:173)
`mide, letimide hydrochloride, nexeridine hydrochloride,
`octazamide, molinazole, neocinchophen, nimazole, prox(cid:173)
`azole citrate, tesicam, tesimide, tolmetin, and triflumidate.
`
`fluocortolone, halcinonide, halopredone, hydrocortisone,
`hydrocortisone 17 -valerate, hydrocortisone 17 -butyrate,
`hydrocortisone 21-acetate methylprednisolone, predniso(cid:173)
`lone, prednisolone 21-phosphate, prednisone, triamcino(cid:173)
`lone, triamcinolone acetonide.
`
`[0124] Further examples of steroidal antiinflammatory
`agents include cortodoxone, fluoracetonide, fludrocortisone,
`difluorsone
`diacetate,
`flurandrenolone
`acetonide,
`medrysone, amcinafel, amcinafide, betamethasone and its
`other esters, chloroprednisone, clorcortelone, descinolone,
`desonide, dichlorisone, difluprednate, flucloronide, flu(cid:173)
`methasone, flunisolide, flucortolone, fluoromethalone, flu(cid:173)
`perolone, fluprednisolone, meprednisone, methylmepred(cid:173)
`nisolone, paramethasone, cortisone acetate, hydrocortisone,
`cyclopentylpropionate, cortodoxone, flucetonide, fludrocor(cid:173)
`tisone acetate,
`flurandrenolone acetonide, medrysone,
`amcinafal, amcinafide, betamethasone, betamethasone ben(cid:173)
`zoate, chloroprednisone acetate, clocortolone acetate, desci(cid:173)
`nolone acetonide, desoximetasone, dichlorisone acetate, dif(cid:173)
`luprednate, flucloronide, flumethasone pivalate, flunisolide
`acetate,
`fluperolone acetate,
`fluprednisolone valerate,
`paramethasone acetate, prednisolamate, prednival, triamci(cid:173)
`nolone hexacetonide, cortivazol, formocortal and nivazol.
`
`[0125] Pituitary hormones and their active derivatives or
`analogs such as corticotrophin, thyrotropin, follicle stimu(cid:173)
`lating hormone (FSH), luteinising hormone (LH) and gona(cid:173)
`dotrophin releasing hormone (GnRH).
`
`[0115] Antirheumatoid agents such as penicillamine,
`aurothioglucose, sodium aurothiomalate, methotrexate and
`auranofin.
`
`[0126] Hypoglycemic agents such as insulin, chlorpropa(cid:173)
`mide, glibenclamide, gliclazide, glipizide, tolazamide, tolb(cid:173)
`utamide and metformin.
`
`[0116] Muscle relaxants such as baclofen, diazepam,
`cyclobenzaprine hydrochloride, dantrolene, methocarbamol,
`orphenadrine and quinine.
`
`[0117] Agents used in gout and hyperuricaemia such as
`allopurinol, colchicine, probenecid and sulphinpyrazone.
`
`Hormones and Steroids
`
`[0118] Oestrogens such as oestradiol, oestriol, oestrone,
`ethinyloestradiol, mestranol, stilboestrol, dienoestrol, epi(cid:173)
`oestriol, estropipate and zeranol.
`
`[0119] Progesterone and other progestagens such as ally(cid:173)
`loestrenol, dydrgesterone,
`lynoestrenol, norgestrel, nor(cid:173)
`ethyndrel, norethisterone, norethisterone acetate, gestodene,
`levonorgestrel, medroxyprogesterone and megestrol.
`
`[0120] Antiandrogens such as cyproterone acetate and
`danazol.
`
`[0121] Antioestrogens such as tamoxifen and epitiostanol
`and the aromatase inhibitors, exemestane and 4-hydroxy(cid:173)
`androstenedione and its derivatives. Androgens and anabolic
`agents such as testosterone, methyltestosterone, clostebol
`acetate, drostanolone, furazabol, nandrolone oxandrolone,
`stanozolol, trenbolone acetate, dihydro-testosterone, 17-.al(cid:173)
`pha.-methyl-19-nortestosterone and fluoxymesterone.
`
`[0127] Thyroid hormones such as calcitonin, thyroxine
`and liothyronine and antithyroid agents such as carbimazole
`and propylthiouracil.
`
`[0128] Other miscellaneous hormone agents such as oct(cid:173)
`reotide.
`
`[0129] Pituitary inhibitors such as bromocriptine.
`
`[0130] Ovulation inducers such as clomiphene.
`
`Genitourinary System
`
`[0131] Diuretics such as the thiazides, related diuretics
`and loop diuretics, bendrofluazide, chlorothiazide, chlortha(cid:173)
`lidone, dopamine, cyclopenthiazide, hydrochlorothiazide,
`indapamide, mefruside, methycholthiazide, metolazone,
`quinethazone, bumetanide, ethacrynic acid and frusemide
`and potassium sparing diuretics, spironolactone, amiloride
`and triamterene.
`
`[0132] Antidiuretics such as desmopressin, lypressin and
`vasopressin including their active derivatives or analogs.
`
`[0133] Obstetric drugs including agents acting on the
`uterus such as ergometrine, oxytocin and gemeprost.
`
`[0134] Prostaglandins such as alprostadil (PGE1), prosta(cid:173)
`cyclin (PGI2), dinoprost (prostaglandin F2-alpha) and miso(cid:173)
`prostol.
`
`[0122] 5-alpha reductase inhibitors such as finasteride,
`turosteride, LY-191704 and MK-306.
`
`Antimicrobials
`
`[0123] Corticosteroids such as betamethasone, betametha(cid:173)
`sone valerate, cortisone, dexamethasone, dexamethasone
`21-phosphate, fludrocortisone, flumethasone, fluocinonide,
`fluocinonide desonide, fluocinolone, fluocinolone acetonide,
`
`[0135] Antimicrobials including the cephalosporins such
`as cephalexin, cefoxytin and cephalothin.
`
`[0136] Penicillins such as amoxycillin, amoxycillin with
`clavulanic acid, ampicillin, bacampicillin, benzathine peni-
`
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`5
`
`cillin, benzylpenicillin, carbenicillin, cloxacillin, methicil(cid:173)
`lin, phenethicillin, phenoxymethylpenicillin, flucloxacillin,
`mezlocillin, piperacillin, ticarcillin and azlocillin.
`
`[0137] Tetracyclines such as minocycline, chlortetracy(cid:173)
`cline, tetracycline, demeclocycline, doxycycline, methacy(cid:173)
`cline and oxytetracycline and other tetracycline-type antibi(cid:173)
`otics.
`
`[0138] Aminoglycosides such as amikacin, gentamicin,
`kanamycin, neomycin, netilmicin and tobramycin. Antifun(cid:173)
`gals such as amorolfine, isoconazole, clotrimazole, econa(cid:173)
`zole, miconazole, nystatin, terbinafine, bifonazole, ampho(cid:173)
`tencm, griseofulvin, ketoconazole,
`fluconazole
`and
`flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate,
`triacetin, zinc, pyrithione and sodium pyrithione.
`[0139] Quinolones such as nalidixic acid, cinoxacin,
`ciprofloxacin, enoxacin and norfloxacin. Sulphonamides
`such as phthalylsulphthiazole, sulfadoxine, sulphadiazine,
`sulphamethizole and sulphamethoxazole.
`
`[0140] Sulphones such as dapsone.
`
`[0141] Other miscellaneous antibiotics such as chloram(cid:173)
`phenicol, clindamycin, erythromycin, erythromycin ethyl
`carbonate, erythromycin estolate, erythromycin glucepate,
`erythromycin ethy !succinate, erythromycin !acto bionate,
`roxithromycin, lincomycin, natamycin, nitrofurantoin, spec(cid:173)
`tinomycin, vancomycin, aztreonam, colistin IV, metronida(cid:173)
`zole, tinidazole, fusidic acid and trimethoprim; 2-thiopyri(cid:173)
`dine N-oxide; halogen compounds, particularly iodine and
`iodine compounds such as
`iodine-PVP complex and
`diiodohydroxyquin; hexachlorophene; chlorhexidine; chlo(cid:173)
`roamine compounds; benzoylperoxide.
`
`[0142] Antituberculosis drugs such as ethambutol, iso(cid:173)
`niazid, pyrazinamide, rifampicin and clofazimine. Antima(cid:173)
`larials such as primaquine, pyrimethamine, chloroquine,
`hydroxychloroquine, quinine, mefloquine and halofantrine.
`
`[0143] Antiviral agents such as acyclovir and acyclovir
`prodrugs, famciclovir, zidovudine, didanosine, stavudine,
`lamivudine, zalcitabine, saquinavir,
`indinavir, ritonavir,
`n-docosanol, tromantadine and idoxuridine.
`
`[0144] Anthelmintics such as mebendazole, thiabenda(cid:173)
`zole, niclosamide, praziquantel, pyrantel embonate and
`diethylcarbamazine.
`
`[0145] Cytotoxic agents such as plicamycin, cyclophos(cid:173)
`phamide, dacarbazine, fluorouracil and its prodrugs [de(cid:173)
`scribed,for example, in International Journal of Pharma(cid:173)
`ceutics 111, 223-233 (1994)], methotrexate, procarbazine,
`6-mercaptopurine and mucophenolic acid.
`
`Metabolism
`
`[0146] Anorectic and weight reducing agents including
`dexfenfluramine, fenfluramine, diethylpropion, mazindol
`and phentermine.
`
`[0147] Agents used in hypercalcaemia such as calcitriol,
`dihydrotachysterol and their active derivatives or analogs.
`
`Respiratory System
`
`[0148] Antitussives such as ethylmorphine, dextrometho(cid:173)
`rphan and pholcodine.
`
`[0149] Expectorants such as acetylcysteine, bromhexine,
`emetine, guaiphenesin, ipecacuanha and saponins.
`
`[0150] Decongestants such as phenylephrine, phenylpro(cid:173)
`panolamine and pseudoephedrine.
`
`[0151] Antiasthmatic agents such as terbutaline.
`
`[0152] Bronchospasm relaxants such as ephedrine, fenot(cid:173)
`erol, orciprenaline, rimiterol, salbutamol, sodium cromogly(cid:173)
`cate, cromoglycic acid and its prodrugs [described, for
`example, in International Journal of Pharmaceutics 7,
`63-7 5 (1980) ], terbutaline, ipratropium bromide, salmeterol
`and theophylline and theophylline derivatives.
`
`Allergy and Immune System
`
`[0153] Antihistamines such as meclozine, cyclizine, chlo(cid:173)
`rcyclizine, hydroxyzine, brompheniramine,
`chlorphe(cid:173)
`niramine,
`clemastine,
`cyproheptadine,
`dexchlorphe(cid:173)
`niramine, diphenhydramine, diphenylamine, doxylamine,
`mebhydrolin, pheniramine, tripolidine, azatadine, diphe(cid:173)
`nylpyraline, methdilazine, terfenadine, astemizole, lorati(cid:173)
`dine and cetirizine.
`
`[0154] Local anaesthetics such as bupivacaine, ame(cid:173)
`thocaine, lignocaine, cinchocaine, dibucaine, mepivacaine,
`prilocaine and etidocaine.
`
`[0155] Stratum corneum lipids, such as ceramides, cho(cid:173)
`lesterol and free fatty acids, for improved skin barrier repair.
`See: Man, eta!., J. Invest. Dermatol., 106(5), 1096 (1996).
`
`[0156] Neuromuscular blocking agents such suxametho(cid:173)
`nium, alcuronium, pancuronium, atracurium, gallamine,
`tubocurarine and vecuronium.
`
`[0157] Smoking cessation agents such as nicotine, bupro(cid:173)
`pion and ibogaine.
`
`[0158]
`Insecticides and other pesticides which are suitable
`for local or systemic application to plants.
`
`[0159] Dermatological agents, such as vitamins A and E,
`vitamin E acetate and vitamin E sorbate.
`
`[0160] Allergens for desensitisation such as house dust
`mite allergen.
`
`[0161] Nutritional agents, such as vitamins, essential
`amino acids and essential fats.
`
`[0162] Keratolytics such as the alpha-hydroxy acids, gly(cid:173)
`collic acid and salicylic acid.
`
`[0163] Psychicenergisers, such as 3-(2-aminopropyl)in(cid:173)
`dole, 3-(2-aminobutyl)indole, and the like.
`[0164] Anti-acne agents such as containing isotretinoin,
`tretinoin and benzoyl peroxide.
`
`[0165] Anti-psoriasis agents such as containing etretinate,
`cyclosporin and calcipotriol.
`
`[0166] Anti-itch agents such as capsaicin and its deriva(cid:173)
`tives such as nonivamide
`
`[0167]
`(1994)].
`
`[Tsai, et a!., Drug. Dev. Ind Pharm., 20( 4), 719
`
`[0168] Anticholinergic agents, which are effective for the
`inhibition of axillary sweating and for the control of prickly
`heat. The antiperspirrant activity of agents such as methat(cid:173)
`ropine nitrate, propantheline bromide, scopolamine, meth(cid:173)
`scopolamine bromide, and the new class of soft antiperspi(cid:173)
`rants,
`quaternary
`acyloxymethyl
`ammonium
`salts
`[described, for example, by Bodor, eta!., J. Med. Chern. 23,
`
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`6
`
`474 (1980) and also in United Kingdom Specification No.
`2010270, published Jun. 27, 1979].
`
`[0169] Physiologically active peptides and proteins. Spe(cid:173)
`cific-examples of peptides and proteins include, human
`growth hormone, LHRH, LHRH analogs such as goserelin,
`buserelin, gonadorelin, napharelin and leuprolide, GHRH,
`GHRF, insulin, insultropin, calcitonin, octreotide, endor(cid:173)
`phin, TRH, NT-36 (chemical name: [[(s)4-oxo-2-azetidinyl]
`carbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary hor(cid:173)
`mones (e.g., HGH, HMG, desmopressin acetate, etc), fol(cid:173)
`licle luteoids, alpha-ANF, growth factors such as growth
`factor releasing factor (GFRF), beta-MSH, somatostatin,
`bradykinin, somatotropin, platelet-derived growth factor,
`asparaginase, bleomycin sulfate, chymopapain cholecysto(cid:173)
`kinin, chorionic gonadotropin, corticotropin (ACTH), eryth(cid:173)
`ropoietin, epoprostenol (platelet aggregation inhibitor), glu(cid:173)
`cagon, HCG,
`hirulog,
`hyaluronidase,
`interferon,
`interleukins, menotropins (urofollitropin (FSH) and LH),
`oxytocin, streptokinase, tissue plasminogen activator, uroki(cid:173)
`nase, vasopressin, desmopressin, ACTH analogs, ANP, ANP
`clearance inhibitors, angiotensin II antagonists, antidiuretic
`hormone agonists, bradykinin antagonists, CD4, ceredase,
`CSI's , eukephalins, FAB fragments, IgE peptide suppres(cid:173)
`sors, IGF-1, neurotrophic factors, colony stimulating fac(cid:173)
`tors, parathyroid hormone and agonists, parathyroid hor(cid:173)
`mone antagonists, prostaglandin antagonists, pentigetide,
`protein C, protein S, renin inhibitors, thymosin alpha-!,
`thrombolytics, TNF, vaccines, vasopressin antagonists ana(cid:173)
`logs, alpha-! antitrypsin (recombinant), and TGF-beta.
`
`[0170] The active agents of the present invention may be
`either ionic or non-ionic.
`
`[0171] These active agents may be used as such or in the
`form of salts, esters or prodrugs. Prodrugs include esters,
`amides, or other derivatives of active agents which may
`generate the active agent in vivo upon administration. Dif(cid:173)
`ferent drugs may have multiple physiological, pharmaco(cid:173)
`logical or cosmetic effects, which, as known to those skilled
`in the art, may vary as a function of concentration.
`
`[0172] The active agents may be present in the composi(cid:173)
`tions in pharmacologically, pharmaceutically or cosmeti(cid:173)
`cally effective amounts and will depend on such factors as
`the disease or condition being treated, the age of the patient
`and other factors well understood by those skilled in the art.
`Generally, amounts of active agent may range from about
`0.01 wt. % to about 15 wt. % relative to the weight of the
`total composition, such as from about 0.1 wt. % to about
`12% wt, such as from about 0.5 wt.% to about 5 wt. %, or
`from about 1 wt. % to about 10 wt. %, or from about 1 wt.
`% to about 5 wt. %, for example, from about 1.5 wt. % to
`about 3 wt. % by weight of the composition.
`
`2. Cream Base Formulations
`
`[0173] The present invention also provides cream base
`formulations for delivering one or more active agents to a
`plant or animal. Such cream compositions resist separation
`under ambient conditions, and maintain a pleasant consis(cid:173)
`tency for application. Such cream base formulations may
`deliver a non-ionic active agent, an ionic active agent, or a
`mixture of ionic and non-ionic active agents.
`
`[0174] Traditionally, cosmetic or pharmaceutical creams
`were limited to oil-in-water emulsions which contain