WO2010048264A2 - Procédés et compositions pour le traitement de troubles immuno-inflammatoires - Google Patents

Procédés et compositions pour le traitement de troubles immuno-inflammatoires Download PDF

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Publication number
WO2010048264A2
WO2010048264A2 PCT/US2009/061446 US2009061446W WO2010048264A2 WO 2010048264 A2 WO2010048264 A2 WO 2010048264A2 US 2009061446 W US2009061446 W US 2009061446W WO 2010048264 A2 WO2010048264 A2 WO 2010048264A2
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peg
fatty acid
dosage form
esters
topical dosage
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PCT/US2009/061446
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English (en)
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WO2010048264A3 (fr
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Mahesh V. Padval
Todd W. Chappell
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Combinatorx, Incorporated
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Publication of WO2010048264A2 publication Critical patent/WO2010048264A2/fr
Publication of WO2010048264A3 publication Critical patent/WO2010048264A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the invention relates to the treatment of dermal immunoinflammatory disorders.
  • Immunoinflammatory conditions are characterized by the inappropriate activation of the body's immune defenses. Rather than targeting infectious invaders, the immune response targets and damages the body's own tissues or transplanted tissues.
  • the tissue targeted by the immune system varies with the disorder. For example, in multiple sclerosis, the immune response is directed against the neuronal tissue, while in Crohn's disease the digestive tract is targeted.
  • Immunoinflammatory disorders affect millions of individuals and include conditions such as asthma, allergic intraocular inflammatory diseases, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anaemia, inflammatory dermatoses, inflammatory bowel or gastrointestinal disorders (e.g., Crohn's disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pmritis/inflammation, psoriasis, rheumatoid arthritis, cirrhosis, and systemic lupus erythematosus.
  • Current treatment regimens for dermal immunoinflammatory disorders typically rely on immunosuppressive agents. The effectiveness of these agents can vary and their use is often accompanied by adverse side effects. Thus, improved therapeutic agents and methods for the treatment of dermal immunoinflammatory disorders are needed. Summary of the Invention
  • the invention features a composition in topical dosage form including from 0.05 to 1.0 % (w/w) loratadine and from 0.05 to 1.0% (w/w) nortriptyline.
  • the w/w ratio of the loratadine to the nortriptyline in the in topical dosage form can be from 1 :5 to 5:1, 1:4 to 4:1, 1 :3 to 3:1, 1 :2 to 2:1, 2:1 to 1 :1, 3: 1 to 1 :1, 4:1 to 1 : 1, 4: 1 to 1 :2, 3.5:1 to 1 :2, 3.5:1 to 2:1 , 3:1 to 1 :2, 2.5:1 to 1 :2, 1.5:1 to 1 :2, or 1.5:1 to 1 :1.5.
  • the topical dosage form includes from 0.05 to 1.0 %, 0.05 to 0.8 %, 0.05 to 0.5 %, 0.08 to 0.8 %, 0.08 to 0.5 %, 0.08 to 0.2 %, 0.08 to 0.15 %, 0.08 to 0.12 %, 0.2 to 0.5 %, 0.2 to 0.4 %, or 0.25 to 0.35 % (w/w) loratadine.
  • the topical dosage form includes from 0.05 to 1.0 %, 0.05 to 0.8 %, 0.05 to 0.5 %, 0.08 to 0.8 %, 0.08 to 0.5 %, 0.08 to 0.2 %, 0.08 to 0.15 %, or 0.08 to 0.12 % (w/w) nortriptyline.
  • the topical dosage form includes from 0.08 to 0.12 % (w/w) loratadine and from 0.08 to 0.12% (w/w) nortriptyline.
  • the topical dosage form includes from 0.28 to 0.32 % (w/w) loratadine and from 0.08 to 0.12% (w/w) nortriptyline.
  • the topical dosage form can be any form described herein including, without limitation, a cream, lotion, spray, stick, ointment, soap, paste, body wash, shampoo, foam, or mask.
  • the topical dosage form includes from 5 to 15 % (w/w) one or more emulsifying agents; from 15 to 30 % (w/w) one or more occlusive emollient agents; and from 60 to 80 % (w/w) water.
  • the topical dosage forms of the invention can include from 5 to 25 %, 5 to 20 %, 5 to 15 %, 5 to 10 %, 7.5 to 25 %, 7.5 to 20 %, 7.5 to 15 %, 7.5 to 12 %, 8.5 to 12 %, or 8.5 to 1 1 % (w/w) one or more emulsifying agents.
  • the topical dosage forms of the invention can include from 10 to 50 %, 10 to 40 %, 10 to 30 %, 15 to 30 %, 15 to 40 %, 15 to 25 %, 18 to 25 %, or 19 to 23 % (w/w) one or more occlusive emollient agents.
  • the topical dosage forms of the invention can include from 40 to 90 %, 50 to 90 %, 60 to 90 %, 60 to 80 %, 65 to 75 %, or 66 to 72 % (w/w) water.
  • the topical dosage form includes one or more emulsifying agents selected from polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono-ester and di-ester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, fatty alcohols, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters-glycerol esters, mono- and diglycerides, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, lower alcohol fatty acid esters, ionic surfactants,
  • the occlusive emollient agents used in the topical dosage forms of the invention can be any occlusive emollient agent described herein.
  • the topical dosage form includes one or more occlusive emollient agents selected from beeswax, carnauba wax, ozokerite, paraffin, lanolin, dimethiconol behenate, petrolatum, isopropyl palmitate, mineral oil, petroleum jelly, and dimethicone.
  • the invention features a method for treating a dermal immunoinflammatory disorder in a subject in need thereof by administering to the subject a topical dosage form of the invention in an amount sufficient to treat the disorder.
  • a kit including (i) a topical dosage form of the invention; and (ii) instructions for administering the a topical dosage form of the invention to a subject for the treatment of a dermal immunoinflammatory disorder.
  • the dermal immunoinflammatory disorder can be any dermal immunoinflammatory disorder described herein including, without limitation, psoriasis, eczema, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, epidermolytic hyperkeratosis, premalignant keratosis, acne, and seborrheic dermatitis.
  • the dermal immunoinflammatory disorder is an inflammatory dermatosis.
  • the dermal immunoinflammatory disorder is a proliferative skin disease.
  • treating refers to administering a composition formulated for topical application for prophylactic and/or therapeutic purposes.
  • a disease or condition refers to prophylactic treatment of a patient who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease or condition.
  • a disease or use for “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease to improve the patient's condition.
  • treating is the administration to a subject either for therapeutic or prophylactic purposes.
  • subject any animal (e.g., a human).
  • Other animals that can be treated using the methods, compositions, and kits of the invention include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds.
  • an amount sufficient is meant the amount of a topical dosage form of the invention required to treat or prevent a dermal immunoinflammatory disorder in a clinically relevant manner.
  • a sufficient amount of topical dosage form used to practice the present invention for therapeutic treatment of conditions caused by or contributing to a dermal immunoinflammatory disorder varies depending upon the topical formulation used, the age, body weight, and general health of the patient. Ultimately, the prescribers will decide the appropriate amount and dosage regimen.
  • composition, or kit exhibits greater efficacy, is less toxic, safer, more convenient, better tolerated, or less expensive, or provides more treatment satisfaction than another method, composition, or kit with which it is being compared. Efficacy may be measured by a skilled practitioner using any standard method that is appropriate for a given indication.
  • the topical dosage forms of the invention can be more effective topical dosage forms.
  • dermal immunoinflammatory disorder encompasses a variety of conditions, including proliferative skin diseases, and inflammatory dermatoses. Dermal immunoinflammatory disorders result in the destruction of healthy dermal tissue by an inflammatory process, dysregulation of the immune system, and/or unwanted proliferation of cells.
  • the term "inflammatory dermatoses” includes, for example, psoriasis, acute febrile neutrophilic dermatosis, eczema (e.g., histotic eczema, dyshidrotic eczema, vesicular palmoplanar eczema), balanitis circumscripta plasmacellularis, balanoposthitis, Behcet's disease, erythema annulare centrifugum, erythema dyschromicum perstans, erythema multiforme, granuloma annulare, lichen nitidus, lichen planus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen spinulosus, nummular dermatitis, pyoderma gangrenosum, sarcoidosis, subcorneal pustular dermatosis, urticaria, and transient acantholytic dermato
  • proliferative skin disease refers to a benign or malignant disease that is characterized by accelerated cell division in the epidermis or dermis.
  • proliferative skin diseases are psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant keratosis, acne, and seborrheic dermatitis.
  • a particular disease, disorder, or condition may be characterized as being both a proliferative skin disease and an inflammatory dermatosis.
  • An example of such a disease is psoriasis.
  • topical dosage form refers to fluid or semisolid formulations for application to the skin of a subject, such as a cream, lotion, spray, stick, ointment, soap, paste, body wash, shampoo, foam, or mask.
  • a “lotion” is a liquid, often a suspension or dispersion, intended for external application to the body.
  • creams are soft preparations.
  • Creams of the oil-in- water (O/W) type include preparations, such as foundation creams, hand creams, and the like.
  • Creams of the water- in-oil (W/O) type include cold creams, emollient creams, and the like.
  • Pharmaceutically, creams are solid emulsions containing suspensions or solutions of active components for external application.
  • preparations of this type are classified as ointments. Specifically, they belong to the emulsion-type bases.
  • an "ointment” is a semisolid preparation for external application of such consistency that may be readily applied to the skin.
  • an ointment is a composition that softens, but not necessarily melt, when applied to the body and serves as a vehicle for the topical application of active components, as well as functioning as a protective/emollient for the skin.
  • Ointments may contain oleaginous mixtures or emulsions of fatty or wax-like materials with comparatively high proportions of water, such as water-in-oil (W/O) or oil-in-water (O/W) emulsions, depending primarily on the selection of the emulsifying agent.
  • Semisolid emulsions are also referred to as creams. Creams and ointments containing large amounts of insoluble powders are pastes. Pastes are usually stiffer and more absorptive than creams and ointments.
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include acetate, ascorbate, aspartate, benzoate, citrate, digluconate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, lactate, malate, maleate, malonate, mesylate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, valerate salts, and the like.
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • compositions in topical dosage form containing loratadine and nortriptyline are useful, for example, for the treatment of dermal immunoinflammatory disorders.
  • Loratadine (CLARITIN®) is a tricyclic piperidine that acts as a selective peripheral histamine Hl -receptor antagonist.
  • loratadine refers to the compound and pharmaceutically acceptable salts of the compound.
  • loratadine can be substituted by structural and functional analogs of loratadine, such as piperidines, tricyclic piperidines, and histamine Hl -receptor antagonists.
  • Loratadine functional and/or structural analogs include other Hl- receptor antagonists, such as AHR-11325, acrivastine, antazoline, astemizole, azatadine, azelastine, bromopheniramine, carebastine, cetirizine, chlorpheniramine, chlorcyclizine, clemastine, cyproheptadine, descarboethoxyloratadine, desloratadine, dexchlorpheniramine, dimenhydrinate, diphenylpyraline, diphenhydramine, ebastine, fexofenadine, hydroxyzine ketotifen, lodoxamide, levocabastine, methdilazine, mequitazine, oxatomide, pheniramine pyrilamine, promethazine, pyrilamine, setastine, tazifylline, warmthlastine, terfenadine, trimeprazine, tripele
  • Antihistamines in combination with various antidepressants are more effective in suppressing TTSfFa in vitro than the agents alone.
  • the term "nortriptyline” refers to the compound and pharmaceutically acceptable salts of the compound.
  • nortriptyline can be substituted by structural and functional analogs of nortriptyline, such as 10-(4-methylpiperazin-l-yl)pyrido(4,3- b)(l,4)benzothiazepine; 11 -(4-methyl- l-piperazinyl)-5H- dibenzo(b,e)(l,4)diazepine; 5,l ⁇ -dihydro-7-chloro-10-(2-(morpholino)ethyl)- 1 lH-dibenzo(b,e)(l,4)diazepin-l l-one; 2-(2-(7-hydroxy-4- dibenzo(b,l)(l,4)thiazepine-l l-yl-l-piperazinyl)ethoxy)ethanol; 2-chloro-l 1- (4-methyl-l-piperazinyl)-5H-dibenzo(b,e)(l,
  • the invention features methods, kits, and compositions for treating dermal immunoinflammatory disorders.
  • NSAID e.g., naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid, fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, and tolmetin), COX-2 inhibitor (e.g., rofecoxib, celecoxib, valdecoxib, and lumiracoxib), glucocorticoid receptor modulator, or DMARD.
  • COX-2 inhibitor e.g., rofecoxib, celecoxib, valdecoxib, and lumiracoxib
  • glucocorticoid receptor modulator e.g.,
  • Combination therapies of the invention are especially useful for the treatment of immunoinflammatory disorders in combination with other agents either biologies or small molecules - that modulate the immune response to positively affect disease.
  • agents include those that deplete key inflammatory cells, influence cell adhesion, or influence cytokines involved in immune response.
  • This last category includes both agents that mimic or increase the action of anti-inflammatory cytokines such as IL-IO, as well as agents inhibit the activity of pro-inflammatory cytokines such as IL-6, IL-I, IL-2, IL-12, IL-15 or TNF ⁇ .
  • Agents that inhibit TNF ⁇ include etanercept, adelimumab, infliximab, and CDP-870.
  • the combination therapy reduces the production of cytokines, etanercept or infliximab act on the remaining fraction of inflammatory cytokines, providing enhanced treatment.
  • Small molecule immunodulators include, e.g., p38 MAP kinase inhibitors such as VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, TACE inhibitors such as DPC 333, ICE inhibitors such as pranalcasan, and IMPDH inhibitors such as mycophenolate and merimepodib.
  • Treatment may be performed alone or in conjunction with another therapy and may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital. Treatment optionally begins at a hospital so that the doctor can observe the therapy's effects closely and make any adjustments that are needed, or it may begin on an outpatient basis.
  • the duration of the therapy depends on the type of disease or disorder being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient responds to the treatment. Additionally, a person having a greater risk of developing an inflammatory disease (e.g., a person who is undergoing age-related hormonal changes) may receive treatment to inhibit or delay the onset of symptoms.
  • the methods, compositions, and kits of the invention are more effective than other methods, compositions, and kits.
  • “more effective” is meant that a method, composition, or kit exhibits greater efficacy, is less toxic, safer, more convenient, better tolerated, or less expensive, or provides more treatment satisfaction than another method, composition, or kit with which it is being compared.
  • the methods, compositions, and kits of the invention may be used for the treatment of psoriasis. If desired, one or more antipsoriatic agents typically used to treat psoriasis may be included with the methods, compositions, and kits of the invention.
  • Such agents include biologies (e.g., alefacept, inflixamab, adelimumab, efalizumab, etanercept, and CDP-870), corticosteroids (e.g., alclometasone dipropionate, amcinonide, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoximetasone, dexamethasone, diflorasone diacetate, flucinolone acetonide, flumethasone, fluocinonide, flurandrenolide, halcinonide, halobetasol propionate, hydrocortisone butyrate, hydrocortisone valerate, methylprednisolone, mometasone furoate, prednisolone, and triamcinolone acetonide), small molecule immunomodulators (e.g., VX 702, SC
  • Topical Formulations For compositions adapted for topical use, a topical vehicle containing from between 0.01% to 5% (w/w) each of loratadine and nortriptyline, preferably from between 0.05% to 1% (w/w), more preferably from between 0.08% to 0.6% (w/w) active agents.
  • the topical dosage form can be applied one to four times daily, or as needed.
  • the creams of Example 1 can be applied to the site of discomfort on the subject.
  • a cream may be applied directly to skin afflicted with psoriasis or eczema.
  • the loratadine and nortriptyline may each be, independently, formulated and administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry.
  • acid addition salts include organic acids such as acetic, lactic, pamoic, nialeic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like.
  • Metal complexes include zinc, iron, and the like.
  • the loratadine and nortriptyline are admixed with a suitable carrier substance, and are generally present in an amount of 0.05-3% by weight of the total weight of the composition and preferably including one or more emulsifying agents and one or more occlusive emollient agents.
  • the composition may be in form of, e.g., suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, sprays, or aerosols.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A.R. Gennaro, 2000, Lippincott Williams & Wilkins, Philadelphia, PA. and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-2002, Marcel Dekker, New York).
  • the formulations of the invention can include one or more emulsifying agents.
  • Emulsifying agents that may be used in the formulations of the invention include, without limitation, compounds belonging to the following classes: polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono-ester and di-ester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transcstcrification products, fatty alcohols, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters and glycerol esters, mono- and diglycerides, sterol and sterol derivatives.
  • polyethylene glycol sorbitan fatty acid esters polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene- polyoxypropylene block copolymers, sorbitan fatty acid esters, lower alcohol fatty acid esters, ionic surfactants, tocopherol esters, and sterol esters.
  • Commercially available examples for each class of emulsifying agent are provided below.
  • Polyethoxylated fatty acids may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available polyethoxylated fatty acid monoester surfactants include: PEG 4-100 monolaurate (Crodet L series, Croda), PEG 4-100 monooleate (Crodet O series, Croda), PEG 4-100 monostearate (Crodet S series, Croda, and Myrj Series, Atlas/ICI), PEG 400 distearate (Cithrol 4DS series, Croda), PEG 100, 200, or 300 monolaurate (Cithrol ML series, Croda), PEG 100, 200, or 300 monooleate (Cithrol MO series, Croda), PEG 400 dioleate (Cithrol 4DO series, Croda), PEG 400-1000 monostearate (Cithrol MS series, Croda), PEG-I stearate (Nikkol MYS-IEX, Nikko
  • Polyethylene glycol fatty acid diesters may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available polyethylene glycol fatty acid diesters include: PEG-4 dilaurate (Mapeg® 200 DL, PPG), PEG-4 dioleate (Mapeg® 200 DO, PPG), PEG-4 distearate (Kessco® 200 DS, Stepan), PEG-6 dilaurate (Kessco® PEG 300 DL, Stepan), PEG-6 dioleate (Kessco® PEG 300 DO, Stepan), PEG-6 distearate (Kessco® PEG 300 DS, Stepan), PEG-8 dilaurate (Mapeg® 400 DL, PPG), PEG-8 dioleate (Mapeg® 400 DO, PPG), PEG-8 distearate (Mapeg® 400 DS, PPG), PEG-10 dipalmitate (Polyaldo 2PKFG), PEG-12 dilaurate (
  • Formulations of the invention may include one or more of the polyethylene glycol fatty acid diesters above.
  • PEG-fatty acid mono- and di-ester mixtures may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available PEG-fatty acid mono- and di-ester mixtures include: PEG 4-150 mono, dilaurate (Kessco® PEG 200-6000 mono, Dilaurate, Stepan), PEG 4- 150 mono, dioleate (Kessco® PEG 200-6000 mono, Dioleate, Stepan), and PEG 4-150 mono, distearate (Kessco® 200-6000 mono, Distearate, Stepan).
  • Formulations of the invention may include one or more of the PEG-fatty acid mono- and di-ester mixtures above.
  • Polyethylene glycol glycerol fatty acid esters may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available polyethylene glycol glycerol fatty acid esters include: PEG-20 glyceryl laurate (Tagat® L, Goldschmidt), PEG-30 glyceryl laurate (Tagat® L2, Goldschmidt), PEG- 15 glyceryl laurate (Glycerox L series, Croda), PEG-40 glyceryl laurate (Glycerox L series, Croda), PEG-20 glyceryl stearate (Capmul® EMG, ABITEC), and Aldo® MS-20 KFG, Lonza), PEG-20 glyceryl oleate (Tagat® O, Goldschmidt), and PEG-30 glyceryl oleate (Tagat® O2, Goldschmidt).
  • Formulations of the invention may include one or more of the polyethylene glycol glycerol
  • Alcohol-oil transesterification products may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available alcohol-oil transesterification products include: PEG-3 castor oil (Nikkol CO-3, Nikko), PEG-5, 9, and 16 castor oil (ACCONON CA series, ABITEC), PEG-20 castor oil, (Emalex C-20, Nihon Emulsion), PEG-23 castor oil (Emulgante EL23), PEG-30 castor oil (Incrocas 30, Croda), PEG-35 castor oil (Incrocas-35, Croda), PEG-38 castor oil (Emulgante EL 65, Condea), PEG- 40 castor oil (Emalex C-40, Nihon Emulsion), PEG-50 castor oil (Emalex C- 50, Nihon Emulsion), PEG-56 castor oil (Eumulgin® PRT 56, Pulcra SA), PEG-60 castor oil (Nikkol CO-60TX,
  • oils in this category of surfactants are oil-soluble vitamins, such as vitamins A, D, E, K, etc.
  • derivatives of these vitamins such as tocopheryl PEG-1000 succinate (TPGS, available from Eastman) are also suitable surfactants.
  • Formulations of the invention may include one or more of the alcohol-oil transesterification products above.
  • Fatty alcohols may be used as emulsifying agents for the formulations of the invention. Examples of commercially available fatty alcohols include: benzyl alcohol, butyl alcohol, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, lanolin alcohols, octyldodecanol, oleyl alcohol, and stearyl alcohol.
  • Formulations of the invention may include one or more of the fatty alcohols above.
  • Polyglycerized fatty acids may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available polyglycerized fatty acids include: polyglyceryl-2 stearate (Nikkol DGMS, Nikko), polyglyceryl-2 oleate (Nikkol DGMO, Nikko), polyglyceryl-2 isostearate (Nikkol DGMIS, Nikko), polyglyceryl-3 oleate (Caprol® 3GO, ABITEC), polyglyceryl-4 oleate (Nikkol Tetraglyn l-O, Nikko), polyglyceryl- 4 stearate (Nikkol Tetraglyn 1-S, Nikko), polyglyceryl-6 oleate (Drewpol 6-1- O, Stepan), polyglyceryl-10 laurate (Nikkol Decaglyn 1-L, Nikko), polyglyceryl-10 oleate (Nikkol Deca
  • Propylene glycol fatty acid esters may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available propylene glycol fatty acid esters include: propylene glycol monocaprylate (Capryol 90, Gattefosse), propylene glycol monolaurate (Lauroglycol 90, Gattefosse), propylene glycol oleate (Lutrol OP2000, BASF), propylene glycol myristate (Mirpyl), propylene glycol monostearate (LIPO PGMS, Lipo Chem.), propylene glycol hydroxystearate, propylene glycol ricinoleate (PROPYMULS, Henkel), propylene glycol isostearate, propylene glycol monooleate (Myverol P-O6, Eastman), propylene glycol dicaprylate dicaprate (Captex® 200, ABITEC), propylene glycol dioctanoate (Captex® 800, A
  • propylene glycol esters and glycerol esters may be used as emulsifying agents for the formulations of the invention.
  • One preferred mixture is composed of the oleic acid esters of propylene glycol and glycerol (Arlacel 186).
  • these surfactants include: oleic (ATMOS 300, ARLACEL 186, ICI), stearic (ATMOS 150).
  • Formulations of the invention may include one or more of the mixtures of propylene glycol esters and glycerol esters above.
  • Mono- and diglycerides may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available mono- and diglycerides include: monopalmitolein (C16: l) (Larodan), monoelaidin (Cl 8:1) (Larodan), monocaproin (C6) (Larodan), monocaprylin (Larodan), monocaprin (Larodan), monolaurin (Larodan), glyceryl monomyristate (C 14) (Nikkol MGM, Nikko), glyceryl monooleate (C18: l) (PECEOL, Gattefosse), glyceryl monooleate (Myverol, Eastman), glycerol monooleate/linoleate (OLICINE, Gattefosse), glycerol monolinoleate (Maisine, Gattefosse), glyceryl ricinoleate (Softigen® 701, HuIs), glyceryl mono
  • Sterol and sterol derivatives may be used as emulsifying agents for the formulations of the invention.
  • examples of commercially available sterol and sterol derivatives include: cholesterol, sitosterol, lanosterol, PEG-24 cholesterol ether (Solulan C-24, Amerchol), PEG-30 cholestanol (Phytosterol GENEROL series, Henkel), PEG-25 phytosterol (Nikkol BPSH-25, Nikko), PEG-5 soyasterol (Nikkol BPS-5, Nikko), PEG-IO soyasterol (Nikkol BPS-IO, Nikko), PEG-20 soyasterol (Nikkol BPS-20, Nikko), and PEG-30 soyasterol (Nikkol BPS-30, Nikko).
  • Formulations of the invention may include one or more of the sterol and sterol derivatives above.
  • Polyethylene glycol sorbitan fatty acid esters may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available polyethylene glycol sorbitan fatty acid esters include: PEG-IO sorbitan laurate (Liposorb L-IO, Lipo Chem.), PEG-20 sorbitan monolaurate (Tween® 20, Atlas/ICI), PEG-4 sorbitan monolaurate (Tween® 21, Atlas/ICI), PEG-80 sorbitan monolaurate (Hodag PSML-80, Calgene), PEG-6 sorbitan monolaurate (Nikkol GL-I, Nikko), PEG-20 sorbitan monopalmitate (Tween® 40, Atlas/ICI), PEG-20 sorbitan monostearate (Tween® 60, Atlas/ICI), PEG-4 sorbitan monostearate (Tween® 61, Atlas/ICI), PEG-8 sorbitan monostearate (DACOL
  • Polyethylene glycol alkyls may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially available polyethylene glycol alkyl ethers include: PEG-2 oleyl ether, oleth-2 (Brij 92/93, Atlas/ICI), PEG-3 oleyl ether, oleth-3 (Volpo 3, Croda), PEG-5 oleyl ether, oleth-5 (Volpo 5, Croda).
  • PEG-IO oleyl ether, oleth-10 Volpo 10, Croda
  • PEG-20 oleyl ether, oleth-20 Volpo 20, Croda
  • PEG-4 lauryl ether, laureth-4 Brij 30, Atlas/ICI
  • PEG-9 lauryl ether PEG-23 lauryl ether, laureth-23 (Brij 35, Atlas/ICI)
  • PEG-2 cetyl ether Brij 52, ICI
  • PEG-IO cetyl ether Brij 56, ICI
  • PEG-20 cetyl ether BriJ 58, ICI
  • PEG-2 stearyl ether Brij 72, ICI
  • PEG-IO stearyl ether Brij 76, ICI
  • PEG-20 stearyl ether Brij 78, ICI
  • PEG-100 stearyl ether Brij 700, ICI
  • Formulations of the invention may include one or more of the polyethylene glycol alkyl ethers above, or alkyl ethers of a mixture of polyethylene glycols, such as macrogol cetostearyl ether.
  • Sugar esters may be used as emulsifying agents for the formulations of the invention.
  • sugar esters examples include: sucrose distearate (SUCRO ESTER 7, Gattefosse), sucrose distearate/monostearate (SUCRO ESTER 1 1 , Gattefosse), sucrose dipalmitate, sucrose monostearate (Crodesta F- 160, Croda), sucrose monopalmitate (SUCRO ESTER 15, Gattefosse), and sucrose monolaurate (Saccharose monolaurate 1695, Mitsubisbi-Kasei).
  • Formulations of the invention may include one or more of the sugar esters above.
  • Polyethylene glycol alkyl phenols may be used as emulsifying agents for the formulations of the invention.
  • examples of commercially available polyethylene glycol alkyl phenols include: PEG- 10- 100 nonylphenol series (Triton X series, Rohm & Haas) and PEG- 15- 100 octylphenol ether series (Triton N-series, Rohm & Haas).
  • Formulations of the invention may include one or more of the polyethylene glycol alkyl phenols above.
  • Polyoxyethylene-polyoxypropylene block copolymers may be used as emulsifying agents for the formulations of the invention.
  • surfactants are available under various trade names, including one or more of Synperonic PE series (ICI), Pluronic® series (BASF), Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac.
  • the generic term for these polymers is "poloxamer” (CAS 9003-1 1-6).
  • These polymers have the formula I: HO(C 2 H 4 O) 3 (C 3 H 6 O) 13 (C 2 H 4 O) 3 H (I) where "a” and "b” denote the number of polyoxyethylene and polyoxypropylene units, respectively.
  • Formulations of the invention may include one or more of the polyoxyethylene-polyoxypropylene block copolymers above.
  • Polyoxyethylenes such as PEG 300, PEG 400, and PEG 600, may be used as emulsifying agents for the formulations of the invention.
  • Sorbitan fatty acid esters may be used as emulsifying agents for the formulations of the invention.
  • Examples of commercially sorbitan fatty acid esters include: sorbitan monolaurate (Span-20, Atlas/ICI), sorbitan monopalmitate (Span-40, Atlas/ICI), sorbitan monooleate (Span-80, Atlas/ICI), sorbitan monostearate (Span-60, Atlas/ICI), sorbitan trioleate (Span-85, Atlas/ICI), sorbitan sesquioleate (Arlacel-C, ICI), sorbitan tristearate (Span-65, Atlas/ICI), sorbitan monoisostearate (Crill 6, Croda), and sorbitan sesquistearate (Nikkol SS- 15, Nikko).
  • Formulations of the invention may include one or more of the sorbitan fatty acid esters above.
  • Esters of lower alcohols (C2 to C4) and fatty acids (C8 to C 18) are suitable surfactants for use in the invention.
  • these surfactants include: ethyl oleate (Crodamol EO, Croda), isopropyl myristate (Crodamol IPM, Croda), isopropyl palmitate (Crodamol IPP, Croda), ethyl linoleate (Nikkol VF-E, Nikko), and isopropyl linoleate (Nikkol VF-IP, Nikko).
  • Formulations of the invention may include one or more of the lower alcohol fatty acid esters above.
  • Ionic surfactants may be used as emulsifying agents for the formulations of the invention.
  • useful ionic surfactants include: sodium caproate, sodium caprylate, sodium capratc, sodium laurate, sodium myristate, sodium myristolate, sodium palmitate, sodium palmitoleate, sodium oleate, sodium ricinoleate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl sulfate (dodecyl), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium glyco cheno deoxycholate, sodium cholylsarco
  • Formulations of the invention may include one or more of the ionic surfactants above.
  • Tocopherol esters and sterol esters may be used as emulsifying agents for the formulations of the invention. These tocopherol and sterol esters are described by formula II:
  • X is selected from ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ - tocopherol, cholesterol, 7-dehydrocholesterol, campesterol, sitosterol, ergosterol, and stigmasterol;
  • p is 1 or 2;
  • m is 0 or 1;
  • n is an integer from 0 to 18; and
  • Y is a hydrophilic moiety selected from polyalcohols, polyethers, and derivatives thereof.
  • emulsifying agents present in the formulations of the invention are present in amounts such that the loratadine and nortriptyline are evenly dispersed throughout the carrier and does not undergo phase separation over the course of months, or even years.
  • the relative amounts of surfactants required are readily determined by observing the resistance of a particular formulation to phase separation.
  • a formulation of the invention can include from 3% to 20% by weight, preferably 5% to 15% by weight, of one or more emulsifying agents.
  • Occlusive emollient agents are substances that soften and soothe the skin. They are used to correct dryness and scaling of the skin by providing a layer of oil on the surface of the skin to slow water loss and thus increase the moisture content of the stratum corneum. Oils that can be useful as occlusive emollient agents in the formulations of the invention include beeswax, carnauba wax, ozokerite, paraffin, lanolin, dimethiconol behenate, petrolatum, isopropyl palmitate, mineral oil, petroleum jelly, and dimethicone. The formulations of the invention can include from 0.5% to 40% by weight, preferably 10% to 25% by weight, of one or more occlusive emollient agents.
  • EP European Pharmacopeia
  • Macrogol cetostearyl ether, light liquid paraffin, cetostearyl alcohol and white vaseline were mixed to obtain the non-aqueous phase of the formulation.
  • the combined ingredients were heated to 70 0 C while mixing in a Brogli mixer (mixer speed 7450 revolutions per minute (rpm) and scraper speed 46 rpm) until all excipients were fully melted to a homogenous clear liquid.
  • the aqueous phase consisting of purified water, phosphoric acid (85%) and monosodium phosphate dihydrate, was mixed using a homogenizer (mixer speed 7450 rpm) in a suitably sized stainless steel tank; the pH of the solution is determined and recorded.
  • the solution is heated to 70°C and chlorocresol is added to the solution while mixing at the same speed.
  • the aqueous solution was added to the non-aqueous phase in the Brogli mixer.
  • the tank was rinsed thoroughly to ensure the transfer of all ingredients.
  • a vacuum of - 0.4 bar was applied to the vessel and the mixture is homogenized (mixer speed 7450 rpm) under agitation (scraper speed 46 rpm) for approximately 10 minutes at 70°C.
  • the mixture was gradually cooled to approximately 55-60°C under a vacuum of -0.4 bar.
  • Nortriptyline HCl was added to the emulsion and homogenization was continued under vacuum for 10 minutes (mixer speed 7450 rpm and scraper speed 46 rpm).
  • loratadine was added to the emulsion and homogenization was continued under vacuum for an additional 10 minutes (mixer speed 7450 rpm and scraper speed 46 rpm).
  • the cream was gradually cooled to about 25-30 0 C with continuous mixing with the scraper (46 rpm). A visual inspection was performed to ensure dispersion of nortriptyline HCl and loratadine in the cream.

Abstract

L'invention porte sur un procédé de traitement d'un patient diagnostiqué avec, ou à risque de développer, un trouble immuno-inflammatoire dermique par administration topique au patient de loratadine et de nortriptyline. L'invention porte également sur des formes posologiques topiques contenant de la loratadine et de la nortriptyline.
PCT/US2009/061446 2008-10-23 2009-10-21 Procédés et compositions pour le traitement de troubles immuno-inflammatoires WO2010048264A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2549987C1 (ru) * 2014-06-17 2015-05-10 Государственное бюджетное образовательное учреждение высшего профессионального образования "Башкирский государственный медицинский университет" Министерства здравоохранения Российской Федерации Средство для ускорения заживления ран и регенерации тканей
GB2540764A (en) * 2015-07-24 2017-02-01 Fontus Health Ltd Topical composition
WO2019043064A1 (fr) * 2017-08-30 2019-03-07 Blaess Markus Composition pour le traitement topique de maladies inflammatoires de la peau et des muqueuses non provoquées par des micro-organismes

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Publication number Priority date Publication date Assignee Title
WO2003006026A1 (fr) * 2001-07-09 2003-01-23 Combinatorx, Incorporated Combinaisons pour le traitement de troubles inflammatoires
US20050192261A1 (en) * 2003-09-15 2005-09-01 Jost-Price Edward R. Methods and reagents for the treatment of immunoinflammatory disorders
WO2007056457A2 (fr) * 2005-11-09 2007-05-18 Combinatorx, Incorporated Procedes, compositions et kits pour le traitement de pathologies

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003006026A1 (fr) * 2001-07-09 2003-01-23 Combinatorx, Incorporated Combinaisons pour le traitement de troubles inflammatoires
US20050192261A1 (en) * 2003-09-15 2005-09-01 Jost-Price Edward R. Methods and reagents for the treatment of immunoinflammatory disorders
WO2007056457A2 (fr) * 2005-11-09 2007-05-18 Combinatorx, Incorporated Procedes, compositions et kits pour le traitement de pathologies

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2549987C1 (ru) * 2014-06-17 2015-05-10 Государственное бюджетное образовательное учреждение высшего профессионального образования "Башкирский государственный медицинский университет" Министерства здравоохранения Российской Федерации Средство для ускорения заживления ран и регенерации тканей
GB2540764A (en) * 2015-07-24 2017-02-01 Fontus Health Ltd Topical composition
WO2019043064A1 (fr) * 2017-08-30 2019-03-07 Blaess Markus Composition pour le traitement topique de maladies inflammatoires de la peau et des muqueuses non provoquées par des micro-organismes

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