METHODS AND COMPOSITIONS FOR THE TREATMENT OF IMMUNOINFLAMMATORY DISORDERS

Background of the Invention 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

In a first aspect, 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. In certain embodiments 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. In other embodiments 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. In one particular embodiment, 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 another particular embodiment, 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.

In certain embodiments, 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 emulsifying agents used in the topical dosage forms of the invention can be any emulsifying agent described herein. In certain embodiments, 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, tocopherol esters, and sterol esters. The occlusive emollient agents used in the topical dosage forms of the invention can be any occlusive emollient agent described herein. In certain embodiments, 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.

In a related aspect, 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. In invention also features 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.

In the methods and kits of the invention, 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. In certain embodiments, the dermal immunoinflammatory disorder is an inflammatory dermatosis. In other embodiments, the dermal immunoinflammatory disorder is a proliferative skin disease.

As used herein, the term "treating" refers to administering a composition formulated for topical application for prophylactic and/or therapeutic purposes. To "prevent' ^" 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. To "treat" 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. Thus, in the claims and embodiments, treating is the administration to a subject either for therapeutic or prophylactic purposes.

By "subject" is meant 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.

By "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.

By "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. 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.

The term "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. As used herein, the term "inflammatory dermatoses" includes, for example, psoriasis, acute febrile neutrophilic dermatosis, eczema (e.g., asteatotic 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 dermatosis. As used herein, the term "proliferative skin disease" refers to a benign or malignant disease that is characterized by accelerated cell division in the epidermis or dermis. Examples of 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. As will be appreciated by one skilled in the art, 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.

As used herein, "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.

As used herein, a "lotion" is a liquid, often a suspension or dispersion, intended for external application to the body.

As used herein, a "cream" is a soft preparation. 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. Generally, preparations of this type are classified as ointments. Specifically, they belong to the emulsion-type bases.

As used herein, an "ointment" is a semisolid preparation for external application of such consistency that may be readily applied to the skin. Typically, 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.

The term "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. Representative 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.

Other features and advantages of the invention will be apparent from the following detailed description, the drawings, and the claims.

Brief Description of the Drawing Figure 1 is a flow chart depicting the manufacturing process for the creams of Example 1.

Detailed Description

The invention provides for compositions in topical dosage form containing loratadine and nortriptyline. The compositions are useful, for example, for the treatment of dermal immunoinflammatory disorders.

Loratadine

Loratadine (CLARITIN®) is a tricyclic piperidine that acts as a selective peripheral histamine Hl -receptor antagonist. As used herein, the term "loratadine" refers to the compound and pharmaceutically acceptable salts of the compound.

Loratadine

In any of the kits, compositions, and methods described herein, 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, temelastine, terfenadine, trimeprazine, tripelennamine, triprolidine, utrizine, and similar compounds (described, e.g., in U.S. Patent Nos. 3,956,296, 4,254,129, 4,254,130, 4,283,408, 4,362,736, 4,394,508, 4,285,957, 4,285,958, 4,440,933, 4,510,309, 4,550,116, 4,692,456, 4,742,175, 4,908,372, 5,204,249, 5,375,693, 5,578,610, 5,581,011, 5,589,487, 5,663,412, 5,994,549, 6,201,124, and 6,458,958). Loratadine, cetirizine, and fexofenadine are second-generation Hl -receptor antagonists that lack the sedating effects of many first generation Hl -receptor antagonists. Piperidine Hl -receptor antagonists include loratadine, cyproheptadine hydrochloride (PERIACTIN), and phenindiamine tartrate (NOLAHIST).

Nortriptyline

Antihistamines in combination with various antidepressants are more effective in suppressing TTSfFa in vitro than the agents alone. As used herein, the term "nortriptyline" refers to the compound and pharmaceutically acceptable salts of the compound.

Nortriptyline

In any of the kits, compositions, and methods described herein, 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,lϋ-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,4)diazepine; 4-(l IH- dibenz(b,e)azepin-6-y l)piperazine; 8-chloro- 11 -(4-methyl- 1 -piperazinyl)- 5H- dibenzo(b,e)( 1 ,4)diazepin-2-ol; 8-chloro- 11 -(4-methyl- 1 -piperazinyl)-5H- dibenzo(b,e)(l,4)diazepine monohydrochloride; 8-chloro-2-methox\-l l-(4- methyl- 1 -piperazinyl)- 5H-dibenzo(b,e)( 1 ,4)diazepine; (Z)-2-butenedioate; 7- hydroxyamoxapine; 8-hydroxyamoxapine; 8-hydroxyloxapine; Adinazolam; Amineptine; amitriptyline; amitriptylinoxide; amoxapine; butriptyline; clomipramine; clothiapine; clozapine; demexiptiline; desipramine; l l-(4- methyl- 1 -piperazinyl)-dibenz(b,f)( 1 ,4)oxazepine; 1 1 -(4-methyl- 1 -piperazinyl)- 2-nitro-dibenz(b,f)( 1 ,4)oxazepine; 2-chloro- 11 -(4-methyl- 1 -piperazinyl )- dibenz(b,f)(l,4)oxazepine monohydrochloride; 11 -(4-methyl- 1-piperazinyl)- dibenzo(b,f)(l,4)thiazepine; dibenzepin; dimetacrine; dothiepin; doxepin;

fluacizine; fluperlapine; imipramine; imipramine N-oxide; iprindole lofepramine; loxapine; loxapine hydrochloride; loxapine succinate; maprotiline; melitracen; metapramine; metiapine; metralindole; mianserin; mirtazapine; 8-chloro-6-(4-methyl- 1 -piperazinyl)-morphanthridine; N- acetylamoxapine; nomifensine; norclomipramine; norclozapine; nortriptyline; noxiptilin; octriptyline; opipramol; oxaprotiline; perlapine; pizotyline; propizepine; protriptyline; quetiapine; quinupramine; tianeptine; tomoxetine; and trimipramine. Others are described in U.S. Patent Nos. 4,933,438 and 4,931,435.

Therapy

The invention features methods, kits, and compositions for treating dermal immunoinflammatory disorders.

In particular embodiments of any of the methods of the invention, it may be desirable to administer to the patient other compounds, such as a corticosteroid, 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. 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. Such 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 TNFα. Agents that inhibit TNFα include

etanercept, adelimumab, infliximab, and CDP-870. In this example (that of agents blocking the effect of TNF α), 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.

Therapy according to the invention 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. Desirably, the methods, compositions, and kits of the invention are more effective than other methods, compositions, and kits. By "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.

Psoriasis

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, SCIO 469, doramapimod, RO 30201 195, SCIO 323, DPC 333, pranalcasan, mycophenolate, and merimepodib), non-steroidal immunophilin-dependent immunosuppressants (e.g., cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), vitamin D analogs (e.g., calcipotriene, calcipotriol), psoralens (e.g., methoxsalen), retinoids (e.g., acitretin, tazoretene), DMARDs (e.g., methotrexate), and anthralin. Thus, in one embodiment, the invention features the combination of loratadine, nortriptyline, and an antipsoriatic agent, and methods of treating psoriasis therewith.

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. For example, the creams of Example 1 can be applied to the site of discomfort on the subject. For example, 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. Examples of 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. Thus, 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).

Emulsifying Agents

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, and Coster Kl, Condea), PEG-2 stearate (Nikkol MYS-2, Nikko), PEG-2 oleate (Nikkol MYO-2, Nikko), PEG-4 laurate (Mapeg® 200 ML, PPG), PEG-4 oleate (Mapeg® 200 MO, PPG), PEG-4 stearate (Kessco® PEG 200 MS, Stepan), PEG-5 stearate (Nikkol TMGS-5, Nikko), PEG-5 oleate (Nikkol TMGO-5, Nikko), PEG-6 oleate (Algon OL 60, Auschem SpA), PEG-7 oleate (Algon OL 70, Auschem SpA), PEG-6 laurate (Kessco® PEG300 ML, Stepan), PEG-7 laurate (Lauridac 7, Condea), PEG-6 stearate (Kessco® PEG300 MS, Stepan), PEG-8 laurate (Mapeg® 400 ML, PPG), PEG-8 oleate (Mapeg® 400 MO, PPG), PEG-8 stearate (Mapeg® 400 MS, PPG), PEG-9 oleate (Emulgante A9, Condea), PEG-9 stearate (Cremophor S9, BASF), PEG-10 laurate (Nikkol MYL- 10, Nikko), PEG-10 oleate (Nikkol MYO-10, Nikko), PEG- 12 stearate (Nikkol MYS-10, Nikko), PEG- 12 laurate (Kessco® PEG 600 ML, Stepan), PEG- 12 oleate (Kessco® PEG 600 MO, Stepan), PEG- 12 ricinoleate (CAS # 9004-97-1), PEG- 12 stearate (Mapeg® 600 MS, PPG), PEG- 15 stearate (Nikkol TMGS- 15, Nikko), PEG-15 oleate (Nikkol TMGO-15, Nikko), PEG-20 laurate (Kessco® PEG 1000 ML, Stepan),

PEG-20 oleate (Kessco® PEG 1000 MO, Stepan), PEG-20 stearate (Mapeg® 1000 MS, PPG), PEG-25 stearate (Nikkol MYS-25, Nikko), PEG-32 laurate (Kessco® PEG 1540 ML, Stepan), PEG-32 oleate (Kessco® PEG 1540 MO, Stepan), PEG-32 stearate (Kessco® PEG 1540 MS, Stepan), PEG-30 stearate (Myrj 51), PEG-40 laurate (Crodet L40, Croda), PEG-40 oleate (Crodet O40, Croda), PEG-40 stearate (Emerest® 2715, Henkel), PEG-45 stearate (Nikkol MYS-45, Nikko), PEG-50 stearate (Myrj 53), PEG-55 stearate (Nikkol MYS- 55, Nikko), PEG-100 oleate (Crodet O- 100, Croda), PEG-100 stearate (Ariacel 165, ICI), PEG-200 oleate (Albunol 200 MO, Taiwan Surf.), PEG-400 oleate (LACTOMUL, Henkel), and PEG-600 oleate (Albunol 600 MO, Taiwan Surf.). Formulations of the invention may include one or more of the polyethoxylated fatty acids above.

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 (Kessco® PEG 600 DL, Stepan), PEG- 12 distearate (Kessco® PEG 600 DS, Stepan), PEG- 12 dioleate (Mapeg® 600 DO, PPG), PEG-20 dilaurate (Kessco® PEG 1000 DL, Stepan), PEG-20 dioleate (Kessco® PEG 1000 DO, Stepan), PEG-20 distearate (Kessco® PEG 1000 DS, Stepan), PEG-32 dilaurate (Kessco® PEG 1540 DL, Stepan), PEG-32 dioleate (Kessco® PEG 1540 DO, Stepan), PEG-32 distearate (Kessco® PEG 1540 DS, Stepan), PEG-400 dioleate (Cithrol 4DO series, Croda), and PEG-400 distearate Cithrol 4DS series, Croda). 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 fatty acid esters above.

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, Nikko), PEG-100 castor oil, PEG-200 castor oil (Eumulgin® PRT 200, Pulcra SA), PEG-5 hydrogenated castor oil (Nikkol HCO-5, Nikko), PEG-7 hydrogenated castor oil (Cremophor WO7,

BASF), PEG-IO hydrogenated castor oil (Nikkol HCO-10, Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, Nikko), PEG-25 hydrogenated castor oil (Simulsol® 1292, Seppic), PEG-30 hydrogenated castor oil (Nikkol HCO- 30, Nikko), PEG-40 hydrogenated castor oil (Cremophor RH 40, BASF), PEG- 45 hydrogenated castor oil (Cerex ELS 450, Auschem Spa), PEG-50 hydrogenated castor oil (Emalex HC-50, Nihon Emulsion), PEG-60 hydrogenated castor oil (Nikkol HCO-60, Nikko), PEG-80 hydrogenated castor oil (Nikkol HCO-80, Nikko), PEG-100 hydrogenated castor oil (Nikkol HCO- 100, Nikko), PEG-6 corn oil (Labrafil® M 2125 CS, Gattefosse), PEG-6 almond oil (Labrafil® M 1966 CS, Gattefosse), PEG-6 apricot kernel oil

(Labrafil® M 1944 CS, Gattefosse), PEG-6 olive oil (Labrafil® M 1980 CS, Gattefosse), PEG-6 peanut oil (Labrafil® M 1969 CS, Gattefosse), PEG-6 hydrogenated palm kernel oil (Labrafil® M 2130 BS, Gattefosse), PEG-6 palm kernel oil (Labrafil® M 2130 CS, Gattefosse), PEG-6 triolein (Labrafil® M 2735 CS, Gattefosse), PEG-8 corn oil (Labrafil® WL 2609 BS, Gattefosse), PEG-20 corn glycerides (Crovol M40, Croda), PEG-20 almond glycerides (Crovol A40, Croda), PEG-25 trioleate (TAGAT® TO, Goldschmidt), PEG-40 palm kernel oil (Crovol PK-70), PEG-60 corn glycerides (Crovol M70, Croda), PEG-60 almond glycerides (Crovol A70, Croda), PEG-4 caprylic/capric triglyceride (Labrafac® Hydro, Gattefosse), PEG-8 caprylic/capric glycerides (Labrasol, Gattefosse), PEG-6 caprvlic/capric glycerides (SOFTIGEN®767, HuIs), lauroyl macrogol-32 glyceride (GELUCIRE 44/14, Gattefosse), stearoyl macrogol glyceride (GELUCIRE 50/13, Gattefosse), mono, di, tri, tetra esters of vegetable oils and sorbitol (SorbitoGlyceride, Gattefosse), pentaerythrityl tetraisostearate (Crodamol PTIS, Croda), pentaerythrityl distearate (Albunol DS, Taiwan Surf.), pentaerythrityl tetraoleate (Liponate PO-4, Lipo Chem.), pentaerythrityl tetrastearate (Liponate PS-4, Lipo Chem.), pentaerythrityl tetracaprylate tetracaprate (Liponate PE-810, Lipo Chem.), and pentaerythrityl tetraoctanoate (Nikkol Pentarate 408, Nikko). Also included as oils in this category of surfactants are oil-soluble vitamins, such as vitamins A, D, E, K,

etc. Thus, 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 Decaglyn l-O, Nikko), polyglyceryl-10 stearate (Nikkol Decaglyn 1 -S, Nikko), polyglyceryl-6 ricinoleate (Nikkol Hexaglyn PR- 15, Nikko), polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN, Nikko), polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-O, Nikko), polyglyceryl-3 dioleate (Cremophor GO32, BASF), polyglyceryl-3 distearate (Cremophor GS32, BASF), polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-O, Nikko), polyglyceryl-6 dioleate (Caprol® 6G20, ABITEC), polyglyceryl-2 dioleate (Nikkol DGDO, Nikko), polyglyceryl-10 trioleate (Nikkol Decaglyn 3-O, Nikko), polyglyceryl-10 pentaoleate (Nikkol Decaglyn 5-O, Nikko), polyglyceryl-10 septaoleate (Nikkol Decaglyn 7-O, Nikko), polyglyceryl-10 tetraoleate (Caprol® 10G4O, ABITEC), polyglyceryl-10 decaisostearate (Nikkol Decaglyn 10-IS, Nikko), polyglyceryl-101 decaoleate (Drewpol 10-10-

O, Stepan), polyglyceryl- 10 mono, dioleate (Caprol® PGE 860, ABITEC), and polyglyceryl polyricinoleate (Polymuls, Henkel). Formulations of the invention may include one or more of the polyglycerized fatty acids above.

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, ABITEC), propylene glycol caprylate caprate (LABRAFAC PG, Gattefosse), propylene glycol dilaurate, propylene glycol distearate (Kessco® PGDS, Stepan), propylene glycol dicaprylate (Nikkol Sefsol 228, Nikko), and propylene glycol dicaprate (Nikkol PDD, Nikko). Formulations the invention may include one or more of the propylene glycol fatty acid esters above.

Mixtures of 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). Examples of 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 monolaurate (ALDO® MLD, Lonza), glycerol monopalmitate (Emalex GMS-P, Nihon), glycerol monostearate (Capmul® GMS, ABITEC), glyceryl mono- and dioleate (Capmul® GMO-K, ABITEC), glyceryl palmitic/stearic (CUTINA MD-A, ESTAGEL-G 18), glyceryl acetate (Lamegin® EE, Grunau GmbH), glyceryl laurate (Imwitor® 312, HuIs), glyceryl citrate/lactate/oleate/linoleate (Imwitor® 375, HuIs), glyceryl caprylate (Imwitor® 308, HuIs), glyceryl caprylate/caprate (Capmul® MCM, ABITEC), caprylic acid mono- and diglycerides (Imwitor® 988, HuIs), caprylic/capric glycerides (Imwitor® 742, HuIs), Mono-and diacetylated monoglycerides (Myvacet® 9-45, Eastman), glyceryl monostearate (Aldo® MS, Arlacel 129, ICI), lactic acid esters of mono and diglycerides (LAMEGTN GLP, Henkel), dicaproin (C6) (Larodan), dicaprin (ClO) (Larodan), dioctanoin (C8) (Larodan), dimyristin (C 14) (Larodan), dipalmitin (C 16) (Larodan), distearin (Larodan), glyceryl dilaurate (C 12) (Capmul® GDL, ABITEC), glyceryl dioleate (Capmul® GDO, ABITEC), glycerol esters of fatty acids (GELUCIRE 39/01, Gattefosse), dipalmitolein (C 16:1) (Larodan), 1,2 and 1,3- diolein (C 18:1) (Larodan), dielaidin (C 18:1) (Larodan), and dilinolein (Cl 8:2) (Larodan). Formulations of the invention may include one or more of the mono- and diglycerides above.

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 MSS, Condea), PEG-6 sorbitan monostearate (Nikkol TS 106, Nikko), PEG-20 sorbitan tristearate (Tween® 65, Atlas/ICI), PEG-6 sorbitan tetrastearate (Nikkol GS-6, Nikko), PEG-60 sorbitan tetrastearate (Nikkol GS-460, Nikko), PEG-5 sorbitan monooleate (Tween® 81, Atlas/ICI), PEG-6 sorbitan monooleate (Nikkol TO- 106, Nikko), PEG-20 sorbitan monooleate (Tween® 80, Atlas/ICI), PEG-40 sorbitan oleate (Emalex ET 8040, Nihon Emulsion), PEG-20 sorbitan trioleate (Tween® 85, Atlas/ICI), PEG-6 sorbitan tetraoleate (Nikkol GO-4, Nikko), PEG-30 sorbitan tetraoleate (Nikkol GO-430, Nikko), PEG-40 sorbitan tetraoleate (Nikkol GO-440, Nikko), PEG-20 sorbitan monoisostearate (Tween® 120, Atlas/ICI), PEG sorbitol hexaoleate (Atlas G- 1086, ICI), polysorbate 80 (Tween® 80, Pharma), polysorbate 85 (Tween® 85, Pharma), polysorbate 20 (Tween® 20, Pharma), polysorbate 40 (Tween® 40, Pharma), polysorbate 60 (Tween® 60, Pharma), and PEG-6 sorbitol hexastearate (Nikkol GS-6, Nikko). Formulations of the invention may include one or more of the polyethylene glycol sorbitan fatty acid esters above.

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), and 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. Examples of commercially available sugar esters 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. These 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. Examples of 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. Examples of 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 cholylsarcosinate, sodium N-methyl taurocholate, egg yolk phosphatides, hydrogenated soy lecithin, dimyristoyl lecithin, lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidic acid, phosphatidyl glycerol, phosphatidyl serine, diethanolamine, phospholipids, poly oxy ethylene- 10 oleyl ether phosphate, esterification products of fatty alcohols or fatty alcohol ethoxylates, with phosphoric acid or anhydride, ether carboxylates (by oxidation of terminal OH group of, fatty alcohol ethoxylates), succinylated monoglycerides, sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono/diacetylated tartaric acid esters of mono- and diglycerides, citric acid esters of mono-, diglycerides, glyceryl-lacto esters of fatty acids, acyl lactylates, lactylic esters of fatty acids, sodium stearoyl-2- lactylate, sodium stearoyl lactylate, alginate salts, propylene glycol alginate, ethoxylated alkyl sulfates, alkyl benzene sulfones, α-olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, sodium octyl sulfosuccinate, sodium undecylenamideo-MEA-sulfosuccinate, hexadecyl triammonium bromide, decyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyldimethylammonium salts, diisobutyl phenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts, betaines (trialkylglycine), lauryl betaine (N-lauryl,N.N-dimethylglycine), and ethoxylated amines

(polyoxyethylene- 15 coconut amine). For simplicity, typical counterions are provided above. It will be appreciated by one skilled in the art, however, that any bioacceptable counterion may be used. For example, although the fatty acids are shown as sodium salts, other cation counterions can also be used,

such as, for example, alkali metal cations or ammonium. Formulations of the invention may include one or more of the ionic surfactants above.

Tocopherol esters and sterol esters, as described in U.S. Patent Nos. 6,632,443 and 6,191,172, each of which is incorporated herein by reference, may be used as emulsifying agents for the formulations of the invention. These tocopherol and sterol esters are described by formula II:

{X-OOC-[(CH ₂ ) _n -COO] _m } _p -Y (II) wherein X is selected from α-tocopherol, β-tocopherol, γ-tocopherol, δ- 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.

The 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. For example, 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

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.

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

Example 1. Low Dose and High Dose Topical Creams

Two strengths of topical cream have been manufactured for use in clinical trials, one containing 0.1% nortriptyline HCl in combination with 0.1% loratadine (low dose topical cream), and the second containing 0.1% nortriptyline HCl in combination with 0.3% loratadine (high dose topical cream). This product is supplied as white to off-white cream with a net fill weight of approximately 85 g (± 5 g) in 125 mL brown glass jars or approximately 24 g (± 5 g) in 35 mL brown glass jars (see Table 1).

Table 1. Quantitative Composition of the Low Dose and High Dose Topical

Creams

% Weight/Weight low dose topical high dose topical cream (0.1% cream (0.1%

Component Function Nortriptyline HCI+ Nortriptyline HCI+ 0.1% Loratadine) 0.3% Loratadine)

Nortriptyline HCl 0.100 0.100 Active

Loratadine 0.100 0.300 Active

Macrogol cetostearyl ether 2.250 2.250 Emulsifier

Light liquid paraffin 6.000 6.000 Emollient

Cetostearyl alcohol 7.200 7.200 Emulsifier

White vaseline 15.000 15.000 Emollient

Phosphoric acid (85%) 0.002 0.002 pH Adjustment

Monosodium phosphate dihydrate 0.300 0.300 pH adjustment

Chlorocresol 0.120 0.120 Preservative

Aqueous phase

Water (purified, EP) 68 928 68.728 solvent

Abbreviations: EP = European Pharmacopeia

Batch Formulations

Clinical batches of topical cream were manufactured at the 15 kg scale. The batch formulas for the two dosage strengths are shown in Table 2.

Table 2. Composition of the Low Dose and High Dose Topical Creams

Low Dose Topical Cream ( High Dose Topical Cream

Component 0.1% Nortriptyline HCl + (0.1% Nortriptyline HCl + 0.1% Loratadine 0.3% Loratadine

Loratadine 0.0150 kg 0.0450 kg

Nortriptyline HCI 0.0150 kg 0.0150 kg

Macrogol cetostearyl ether 0.3375 kg 0.3375 kg

Light liquid paraffin 0.9000 kg 0.9000 kg

Cetostearyl alcohol 1.0800 kg 1.0800 kg

White vaseline 2.2500 kg 2.2500 kg

Phosphoric acid (85%) 0.0003 kg 0.0003 kg

Monosodium phosphate dihydrate 0.0450 kg 0.0450 kg

Chlorocresol 0.0180 kg 0.0180 kg

Water (purified) 10.3392 kg 10.3092 kg

Total 15.0000 kg 15.0000 kg

Manufacturing Process

The manufacturing and primary packaging processes for the topical creams are shown schematically in Figure 1, and described in greater detail below.

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.

While maintaining the temperature of both phases at 70°C, 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. While continuing to mix, 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). After approximately 10 minutes, 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.

Other Embodiments

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the

invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

What is claimed is: