[go: up one dir, main page]

WO2021262956A1 - Formulations topiques de gel et leur utilisation dans le traitement d'affections cutanées - Google Patents

Formulations topiques de gel et leur utilisation dans le traitement d'affections cutanées Download PDF

Info

Publication number
WO2021262956A1
WO2021262956A1 PCT/US2021/038858 US2021038858W WO2021262956A1 WO 2021262956 A1 WO2021262956 A1 WO 2021262956A1 US 2021038858 W US2021038858 W US 2021038858W WO 2021262956 A1 WO2021262956 A1 WO 2021262956A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
topical composition
peg
skin
concentration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2021/038858
Other languages
English (en)
Inventor
Martin Osterhout
Meera G. PATEL
James Lee
Adam Simpson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roivant Sciences GmbH
Original Assignee
Roivant Sciences GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Roivant Sciences GmbH filed Critical Roivant Sciences GmbH
Publication of WO2021262956A1 publication Critical patent/WO2021262956A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/39—Derivatives containing from 2 to 10 oxyalkylene groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/731—Cellulose; Quaternized cellulose derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • 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
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/008—Preparations for oily skin

Definitions

  • Embodiments herein are directed to topical compositions comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytoluene, and optionally PEG 300.
  • Some embodiments herein are directed to methods of treating skin conditions in a patient in need thereof comprising topically applying a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytoluene, and optionally PEG 300.
  • the skin condition is atopic dermatitis.
  • FIG. 1 depicts the drug level of methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid in homogenized skin 12 hours post dose.
  • FIG. 2 depicts the estimated free fraction of drug (methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid) concentration.
  • the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45% to 55%.
  • administering when used in conjunction with a composition means to administer a composition to a patient whereby it positively impacts the tissue to which it is targeted, e.g. the skin.
  • administering a composition may be accomplished by, for example, topical administration, or in combination with other known techniques.
  • Administering may be self-administration, wherein the subject in need of such treatment administers a composition or administering may be by a medical or other health care professional or a caretaker of the subject in need of such treatment.
  • animal includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals.
  • acne vulgaris includes acne vulgaris and cystic acne and is characterized by areas of skin with seborrhea, comedones (blackheads and whiteheads), papules (pinheads), nodules (large papules) and pimples.
  • Acne vulgaris is a disorder resulting from the action of hormones on the skin's oil glands (sebaceous glands), wherein the sebaceous glands of the skin produce excess sebum, and become enlarged and/or infected when the pore opening becomes plugged with a comedo (a mixture of keratin and sebum).
  • comedo a mixture of keratin and sebum
  • the symptoms of acne include plugged pores and outbreaks of inflamed lesions commonly called pimples.
  • BHT refers to butylated hydroxytoluene or dibutylhydroxytoluene.
  • the term “consists of’ or “consisting of’ means that the composition or method includes only the elements, steps, or ingredients specifically recited in the particular embodiment or claim.
  • the term “consisting essentially of’ or “consists essentially of’ means that the composition or method includes only the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention.
  • dermatitis is used to refer to a group of skin conditions which result in inflammation of the skin and is characterized by itchiness, red skin and a rash. Included in this group are atopic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, stasis dermatitis, seborrheic dermatitis, chronic dermatitis, and eczema.
  • terapéuticaally effective amount refers to an amount of a composition, of the embodiments described herein, necessary or sufficient to achieve the desired effect.
  • the desired effect may include, without limitation, medically therapeutic, cosmetically therapeutic and/or prophylactic treatment, as appropriate.
  • exfoliative keratolysis or “keratolysis exfoliative” refer to a skin condition which is characterized by dry skin and superficial, air-filled blisters. These blisters can be peeled off very easily and will leave reddish, tender areas.
  • “Follicular hyperkeratinization” plays a key role in the pathogenesis of acne, cells of the follicle become cohesive and do not shed normally onto the skin's surface and results in a microcomedone.
  • ichthyosis refers to a genetic skin disorder characterized by dry, thickened, and scaly skin.
  • compositions and methods may be utilized with or on a subject in need of such treatment, which may also be referred to as “in need thereof.”
  • in need thereof means that the subject has been identified as having a need for the particular method or treatment and that the treatment has been given to the subject for that particular purpose.
  • keratosis follicularis or “Darier's disease” refer to a genetic disorder characterized by dark crusty patches on the skin, sometimes containing pus.
  • the term “Labrafil M1944CS” refers to the compound described as oleoyl polyoxylglycerides, oleoyl polyoxyl-6 glycerides, or oleoyl macrogol-6 glycerides.
  • lichen simplex chronicus refers to a skin disorder characterized by chronic itching and scratching. The constant scratching causes thick, leathery, darkened, (lichenified) skin.
  • lichen planus refers to a disease characterized by itchy reddish- purple polygon-shaped skin lesions on the lower back, wrists, and ankles.
  • the term “methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid,” ⁇ 6005,” or “RVT-501” shall also refer to alternative names of the compound, including N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic methyl ester, methyl 4-[(3-[6,7- dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl)carbamoyl]benzoate, and methyl 4-[( ⁇ 3- [6,7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl ⁇ amino)carbonyl]benzoate.
  • the compound represented as RVT-501 or E6005 is methyl N-[3-(6,7-dimethoxy-2- methylamino
  • metabolite of E6005 refers to the metabolite of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid.
  • the compound of Mil is 4-((3-(6,7-dimethoxy-2- (methylamino)quinazolin-4-yl)phenyl)carbamoyl)benzoic acid and has the structure: [0030]
  • pharmaceutically acceptable and grammatical variations thereof, as they refer to carriers, diluents, excipients, and reagents or other ingredients of the composition, represent that the materials used in the final composition are not irritating or otherwise harmful to the patient in general and to the skin, in particular, and preferably are pleasant and well tolerated with respect to general appearance, pH, color, smell and texture (feel), that they are not, for example, unacceptably sticky (tacky), oily or drying, and that they do spread easily, absorb into the skin at an acceptable rate of absorption.
  • pityriasis rubra pilaris refers to a group of chronic disorders characterized by reddish orange, scaling plaques and keratotic follicular papules. Symptoms may include reddish-orange patches on the skin, severe flaking, uncomfortable itching, thickening of the skin on the feet and hands, and thickened bumps around hair follicles.
  • psoriasis refers to the autoimmune disease characterized by patches of abnormal skin which is red, itchy and scaly. There are five main types of psoriasis: plaque, guttate, inverse, pustular, and erythrodermic.
  • pruritus or “prurigo” refer to the severe itching of the skin due to a variety of ailments.
  • rosacea refers to a skin condition characterized by redness, pimples, swelling, and small, superficial dilated blood vessels.
  • saccharous adenomas refers to a small bump on the skin, when many small bumps appear it is referred to as “sebaceous hyperplasia.”
  • sebaceous gland includes unilobular or multilobular glands that secrete sebum. Sebaceous glands include pilosebaceous units, fordyce spots, Meibomian glands, glands of the Zeiss and Montgomery areolar tubercles.
  • disorder associated with sebaceous glands includes diseases, conditions and symptoms related to sebaceous gland.
  • Disorders associated with sebaceous glands include acne, seborrhea, sebaceoma, sebaceous carcinoma, seborrheic dermatitis, sebaceous cysts, sebaceous adenoma and sebaceous hyperplasia.
  • the term “seborrheic dermatitis” includes inflammatory skin disorders characterized by scaly, flaky, itchy, and red skin and includes seborrheic dermatitis caused by fungal, genetic, environmental, hormonal and immune function disorders.
  • the term “sebaceous cysts” include steatocystoma simplex (e.g., simple sebaceous duct cyst and solitary steatocystoma) and steatocystoma multiplex (e.g., epidermal polycystic disease and sebocystomatosis).
  • saccharous hyperplasia includes enlargement of the sebaceous glands.
  • skin refers to the organ of the body which protects the subject from environmental irritations, regulates the body’s temperature and allows for external sensations.
  • the “skin” is separated into three layers: the outermost layer called the epidermis which contains melanocytes; the dermis which contains connective tissue, hair follicles and sweat glands; and the deepest subcutaneous layer called the hypodermis which is made up of fat and connective tissue.
  • topically and “topical” refers to application of the compositions of the present invention to the surface of the skin and mucous membranes.
  • Topical application or “topical administration” refers to the delivery of a composition, for treating conditions of the epidermis or dermis, wherein the topical composition is applied to the skin and acts locally and does not have a systemic effect. Topical administration of a drug may often be advantageously applied in, for example, the treatment of various skin disorders.
  • topical formulations and “topical compositions” refer to formulations or compositions that may be applied to skin or mucous membranes. Topical formulations or compositions may, for example, be used to confer therapeutic benefit to a patient or cosmetic benefit to a consumer. Such topical formulations or compositions may be provided in the form of a cream, foam, gel, lotion, or ointment.
  • Transcutol P refers to the compound described as diethylene glycol monoethyl ether or 2-(2-ethoxyethoxy)ethanol.
  • treat refers to therapeutic treatment, cosmetic treatment and/or prophylactic or preventative measures, wherein the object is to prevent, reduce, eliminate or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results (e.g. decrease acne, comedones, pimples, or breakouts).
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of unwanted side effects.
  • wart refers to the small, rough, and hard growths that are similar in color to the rest of the skin caused by caused by infection with a type of human papillomavirus (HPV).
  • HPV human papillomavirus
  • vitriligo refers to a skin condition characterized by patches of the skin losing their pigment.
  • the patches of skin affected become white and usually have sharp margins.
  • the hair from the skin may also become white.
  • Methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid is a phosphodiesterase type 4 inhibitor.
  • Phosphodiesterase type 4 inhibitors commonly referred to as a PDE4 inhibitors, are drugs used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP).
  • PDE4 family of enzymes are the most prevalent PDE in immune cells.
  • Alopecia areata is a T-cell-mediated autoimmune disease and has been the focus of much research, many animals models have been developed which have illuminate autoimmune pathogenesis and immunotherapeutic strategies. Gilhar, et al. Autoimmun Rev. 2016 July; 15(7): 726-735. Currently, no treatments have been approved for AA and effective therapeutic options are limited.
  • Apremilast is an oral inhibitor of phosphodiesterase 4 that regulates production of pro- and anti-inflammatory cytokines. Pilot studies of apremilast have demonstrated that apremilast has a beneficial preventative effect by reducing the production of pro-inflammatory cytokines and retention of hair. Keren, et al.
  • PDE4 inhibitors such as methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid (RVT-501), can be effective to treat AA.
  • Vitiligo is a common pigment disorder characterized by acquired development of white macules on the skin due to the loss of functioning melanocytes in the skin, the hair, or both. Vitiligo is linked to a dysregulated immune system governed by a proinflammatory cytokine network, involving local and systemic chronic inflammatory processes. Melanocytes cultured from vitiligo patient skin samples have been shown to express high levels of cytokines including IL-6 and IL-17. The use of apremilast, an oral PDE4 inhibitory has shown to be helpful in the treatment of vitiligo. Huff and Gottwald, Case Reports in Dermatological Medicine, Volume 2017, 3 pages, https://doi.org/10.1155/2017/2386234.
  • PDE4 inhibitors such as methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid (RVT-501), can be effective to treat vitiligo.
  • the compound represented by the formula (I) is methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid (RVT-501) having the structure:
  • Optical Isomers Diastereomers— Geometric Isomers — Tautomers.
  • Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers.
  • Embodiments herein include all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. The formulas are shown without a definitive stereochemistry at certain positions. Embodiments herein include all stereoisomers of such formulas and pharmaceutically acceptable salts thereof.
  • Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a compound of the general formula may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • Embodiments described herein include all isomers of the compound of formula (I) disclosed herein, such as a geometric isomer, an optical isomer, a stereoisomer, or a tautomer, and an isomeric mixture.
  • Embodiments herein include both the racemic form and the optically active form.
  • Embodiments further include a single crystal form or a mixture thereof.
  • embodiments herein also include an amorphous form, an anhydrate, and a hydrate form of the compound.
  • embodiments herein also include metabolites, salts, hydrates, and pro-drugs of the compounds disclosed herein.
  • a salt of compounds described herein may include an inorganic acid salt, an organic acid salt, an inorganic basic salt, an organic basic salt, an acidic or basic amino acid salt or the like.
  • the inorganic acid salt may include hydrochloride, hydrobromide, sulfate, nitrate, phosphate or the like.
  • the salt may be selected from a hydrochloride, hydrobromide, sulfate, or phosphate.
  • the organic acid salt may include acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, or benzenesulfonate.
  • the salt may be methanesulfonate or p-toluenesulfonate.
  • the inorganic basic salt may include: alkaline metal salts such as a sodium salt or a potassium salt; alkaline-earth metal salts such as a calcium salt or a magnesium salt; aluminum salts; ammonium salts, or the like.
  • the organic basic salt may include a diethylamine salt, a diethanolamine salt, a meglumine salt, an N,N'-dibenzylethylenediamine salt, or the like.
  • the acidic amino acid salt may include aspartate and glutamate.
  • the basic amino acid salt may include an arginine salt, a lysine salt, an ornithine salt or the like.
  • the active ingredient is methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid (RVT-501):
  • Embodiments herein are directed to topical compositions comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytoluene, and optionally PEG 300.
  • methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is at a concentration of about 0.01% to about 5% by weight of the topical composition.
  • benzyl alcohol is at a concentration of about 0.1% to about 5% by weight of the topical composition.
  • PEG 400 is at a concentration of about 30% to about 80% by weight of the topical composition.
  • diethylene glycol monoethyl ether is at a concentration of about 10% to about 60% by weight of the topical composition.
  • oleoyl polyoxylglycerides is at a concentration of about 1% to about 5% by weight of the topical composition.
  • hydroxyl propylcellulose is at a concentration of about 0.5% to about 5% by weight of the topical composition.
  • butylated hydroxytoluene is at a concentration of about 0.01% to about 1.0% by weight of the topical composition.
  • PEG 300 is at a concentration of about 5% to about 65% by weight of the topical composition.
  • a topical composition comprises methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.7% by weight, PEG 400 at 76.51% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, and butylated hydroxytoluene at 0.1% by weight.
  • a topical composition comprises a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 65% by weight, di ethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 12.21% by weight.
  • a topical composition comprises a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 45% by weight, di ethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 32.12% by weight.
  • Embodiments herein are directed to a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid and pharmaceutically acceptable topical excipients, wherein, within about 12 hours following administration of the topical composition, the 90% confidence interval for the ratio of means (population geometric means based on log- transformed data) of the AUC of the topical composition is within 80-125% of the AUC of any one the foregoing topical compositions and the 90% confidence internal for the ratio of means of the Cmax of the topical composition is within 70-143% of the Cmax of the same foregoing topical composition.
  • Embodiments herein are directed to a topical composition
  • a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight and pharmaceutically acceptable topical excipients, wherein the skin concentration of methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is about 1 pg/g to about 100 pg/g within about 12 hours following administration of the topical composition.
  • Embodiments herein are directed to a topical composition
  • a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight and pharmaceutically acceptable topical excipients, wherein the skin concentration of methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is about 0.005 pM to about 1 pM within 12 hours of administration within about 12 hours following administration of the topical composition.
  • Embodiments herein are directed to a topical composition
  • a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight and pharmaceutically acceptable topical excipients, wherein about 10% to about 100% of cellular Phosphodiesterase 4 (PDE4) is inhibited within 12 hours following administration of the topical composition.
  • PDE4 Phosphodiesterase 4
  • the topical compositions of the present invention may be formulated by those skilled in the art as liquids, toners, solutions, sprays, emulsions, moisturizers, sunscreens, creams, lotions, masks, suspensions, triturates, gels, jellies, pastes, foams, ointments, shampoos, adhesives, serums, treated clothes or pads and the like.
  • the topical composition is formulated as eye drops, as ear drops, or as a composition which can be applied to the surface of the tooth.
  • the topical compositions may be applied to the skin by any means known in the art including, but not limited to, by an aerosol, spray, pump-pack, brush, swab, or other applicator.
  • the applicator may provide either a fixed or variable metered dose application such as a metered dose aerosol, a stored-energy metered dose pump or a manual metered dose pump.
  • the topical composition is formulated as to be applied to a site one time a day or multiple times per day.
  • Embodiments herein are directed to methods of treating a disease (as described herein) comprising administering a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight and pharmaceutically acceptable topical excipients, wherein the skin concentration of methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is about 1 pg/g to about 100 pg/g within about 12 hours following administration of the topical composition.
  • Embodiments herein are directed to methods of treating a disease (as described herein) comprising administering a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight and pharmaceutically acceptable topical excipients, wherein the skin concentration of methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is about 0.005 pM to about 1 pM within 12 hours of administration within about 12 hours following administration of the topical composition.
  • Embodiments herein are directed to methods of treating a disease (as described herein) comprising administering a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight and pharmaceutically acceptable topical excipients, wherein about 10% to about 100% of cellular Phosphodiesterase 4 (PDE4) is inhibited within 12 hours following administration of the topical composition.
  • Phosphodiesterase 4 Phosphodiesterase 4
  • Embodiments herein are directed to methods of a treating skin condition in a patient in need thereof comprising topically applying a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytoluene, and optionally PEG 300.
  • methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is at a concentration of about 0.01% to about 5% by weight of the topical composition.
  • benzyl alcohol is at a concentration of about 0.1% to about 5% by weight of the topical composition.
  • PEG 400 is at a concentration of about 30% to about 80% by weight of the topical composition.
  • diethylene glycol monoethyl ether is at a concentration of about 10% to about 60% by weight of the topical composition.
  • oleoyl polyoxylglycerides is at a concentration of about 1% to about 5% by weight of the topical composition.
  • hydroxyl propylcellulose is at a concentration of about 0.5% to about 5% by weight of the topical composition.
  • butylated hydroxytoluene is at a concentration of about 0.01% to about 1.0% by weight of the topical composition.
  • PEG 300 is at a concentration of about 5% to about 65% by weight of the topical composition.
  • a topical composition comprises methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.7% by weight, PEG 400 at 76.51% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, and butylated hydroxytoluene at 0.1% by weight.
  • a topical composition comprises a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 65% by weight, di ethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 12.21% by weight.
  • a topical composition comprises a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 45% by weight, di ethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 32.12% by weight.
  • the method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytoluene, and optionally PEG 300.
  • a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytoluene, and optionally PEG 300.
  • methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is at a concentration of about 0.01% to about 5% by weight of the topical composition.
  • benzyl alcohol is at a concentration of about 0.1% to about 5% by weight of the topical composition.
  • PEG 400 is at a concentration of about 30% to about 80% by weight of the topical composition.
  • diethylene glycol monoethyl ether is at a concentration of about 10% to about 60% by weight of the topical composition.
  • oleoyl polyoxylglycerides is at a concentration of about 1% to about 5% by weight of the topical composition.
  • hydroxyl propylcellulose is at a concentration of about 0.5% to about 5% by weight of the topical composition.
  • butylated hydroxytoluene is at a concentration of about 0.01% to about 1.0% by weight of the topical composition.
  • PEG 300 is at a concentration of about 5% to about 65% by weight of the topical composition.
  • the method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition wherein methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is at 1.0% by weight, benzyl alcohol is at 2.7% by weight, PEG 400 is at 76.51% by weight, di ethylene glycol monoethyl ether is at 15% by weight, oleoyl polyoxylglycerides is at 2.94% by weight, hydroxyl propylcellulose is at 1.75% by weight, and butylated hydroxytoluene is at 0.1% by weight.
  • the method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 65% by weight, di ethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 12.21% by weight.
  • a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight
  • the method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 45% by weight, di ethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 32.12% by weight.
  • a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight
  • the method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid and pharmaceutically acceptable topical excipients, wherein 90% confidence interval for the ratio of means (population geometric means based on log- transformed data) of the AUC of the topical composition is within 80-125% of the AUC of any one the foregoing topical compositions and the 90% confidence internal for the ratio of means of the Cma x of the topical composition is within 70-143% of the Cma x of the same foregoing topical composition.
  • the skin condition being treated in a patient in need thereof is selected from the group consisting of dermatitis, psoriasis, itchy skin, acne, inflammation and redness of the skin, disorders associated with sebaceous glands, oily skin, dry skin, rosacea, bums, disorders affecting the palms or soles, genetic disorders of the skin, warts, vitiligo, alopecia areata, and any combination thereof.
  • dermatitis is selected from the group consisting of atopic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, stasis dermatitis, seborrheic dermatitis, chronic dermatitis, eczema, and any combination thereof.
  • psoriasis is selected from the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and any combination thereof.
  • itchy skin is selected from the group consisting of pruritus, prurigo, pityriasis rubra pilaris, lichen simplex chronicus, lichen planus, and any combination thereof.
  • acne is selected from the group consisting of acne vulgaris, cystic acne, inflammatory acne, non-inflammatory acne, and any combination thereof.
  • inflammation and redness of the skin is selected from the group consisting of seborrheic dermatitis, urticaria eczema, hives, seborrheic eczema, and any combination thereof.
  • disorders associated with sebaceous glands is selected from the group consisting of acne, follicular hyperkeratinization, sebostasis, sebaceous adenomas, sebaceous hyperplasia, excess sebum production, seborrhea, sebaceoma, sebaceous carcinoma, seborrheic dermatitis, sebaceous cysts, and any combination thereof.
  • oily skin is seborrhea.
  • dry skin is selected from the group consisting of sebostasis, ichthyosis, xerosis, and any combination thereof.
  • bums is sunburn.
  • disorders affecting the palms or soles is selected from the group consisting of palmoplantar pustulosis, exfoliative keratolysis, and any combination thereof.
  • genetic disorders of the skin is Darier’s disease.
  • the method of treating atopic dermatitis in a patient in need thereof comprises topically applying a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytoluene, and optionally PEG 300.
  • a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytolu
  • methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is at a concentration of about 0.01% to about 5% by weight of the topical composition.
  • benzyl alcohol is at a concentration of about 0.1% to about 5% by weight of the topical composition.
  • PEG 400 is at a concentration of about 30% to about 80% by weight of the topical composition.
  • diethylene glycol monoethyl ether is at a concentration of about 10% to about 60% by weight of the topical composition.
  • oleoyl polyoxyl glycerides is at a concentration of about 1% to about 5% by weight of the topical composition.
  • hydroxyl propylcellulose is at a concentration of about 0.5% to about 5% by weight of the topical composition.
  • butylated hydroxytoluene is at a concentration of about 0.01% to about 1.0% by weight of the topical composition.
  • PEG 300 is at a concentration of about 5% to about 65% by weight of the topical composition.
  • a method of treating atopic dermatitis in a patient in need thereof comprises topically applying a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 65% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxyl glycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 12.21% by weight.
  • a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 65% by weight, diethylene
  • a method of treating atopic dermatitis in a patient in need thereof comprises topically applying a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 45% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxyl glycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 32.12% by weight.
  • a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 45% by weight, diethylene
  • the method of treating vitiligo in a patient in need thereof comprises topically applying a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytoluene, and optionally PEG 300.
  • methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is at a concentration of about 0.01% to about 5% by weight of the topical composition.
  • benzyl alcohol is at a concentration of about 0.1% to about 5% by weight of the topical composition.
  • PEG 400 is at a concentration of about 30% to about 80% by weight of the topical composition.
  • diethylene glycol monoethyl ether is at a concentration of about 10% to about 60% by weight of the topical composition.
  • oleoyl polyoxylglycerides is at a concentration of about 1% to about 5% by weight of the topical composition.
  • hydroxyl propylcellulose is at a concentration of about 0.5% to about 5% by weight of the topical composition.
  • butylated hydroxytoluene is at a concentration of about 0.01% to about 1.0% by weight of the topical composition.
  • PEG 300 is at a concentration of about 5% to about 65% by weight of the topical composition.
  • a method of treating vitiligo in a patient in need thereof comprises topically applying a topical composition comprising methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.7% by weight, PEG 400 at 76.51% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, and butylated hydroxytoluene at 0.1% by weight.
  • a topical composition comprising methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.7% by weight, PEG 400 at 76.51% by weight, diethylene glycol monoethyl ether at 15%
  • a method of treating vitiligo in a patient in need thereof comprises topically applying a topical composition comprising methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 65% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 12.21% by weight.
  • a topical composition comprising methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 65% by weight, diethylene glycol mono
  • a method of treating vitiligo in a patient in need thereof comprises topically applying a topical composition comprising methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 45% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 32.12% by weight.
  • a topical composition comprising methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 45% by weight, diethylene glycol mono
  • the method of treating alopecia areata in a patient in need thereof comprises topically applying a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytoluene, and optionally PEG 300.
  • a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, benzyl alcohol, PEG 400, diethylene glycol monoethyl ether, oleoyl polyoxylglycerides, hydroxyl propylcellulose, butylated hydroxytolu
  • methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid is at a concentration of about 0.01% to about 5% by weight of the topical composition.
  • benzyl alcohol is at a concentration of about 0.1% to about 5% by weight of the topical composition.
  • PEG 400 is at a concentration of about 30% to about 80% by weight of the topical composition.
  • diethylene glycol monoethyl ether is at a concentration of about 10% to about 60% by weight of the topical composition.
  • oleoyl polyoxylglycerides is at a concentration of about 1% to about 5% by weight of the topical composition.
  • hydroxyl propylcellulose is at a concentration of about 0.5% to about 5% by weight of the topical composition.
  • butylated hydroxytoluene is at a concentration of about 0.01% to about 1.0% by weight of the topical composition.
  • PEG 300 is at a concentration of about 5% to about 65% by weight of the topical composition.
  • a method of treating alopecia areata in a patient in need thereof comprises topically applying a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.7% by weight, PEG 400 at 76.51% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, and butylated hydroxytoluene at 0.1% by weight.
  • a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.7% by weight, PEG 400 at 76.51% by weight, diethylene glycol monoethyl ether
  • a method of treating alopecia areata in a patient in need thereof comprises topically applying a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 65% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxylglycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 12.21% by weight.
  • a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 65% by weight, diethylene glyco
  • a method of treating alopecia areata in a patient in need thereof comprises topically applying a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 45% by weight, diethylene glycol monoethyl ether at 15% by weight, oleoyl polyoxyl glycerides at 2.94% by weight, hydroxyl propylcellulose at 1.75% by weight, butylated hydroxytoluene at 0.1% by weight, and PEG 300 at 32.12% by weight.
  • a topical composition comprising methyl N-[3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid at 1.0% by weight, benzyl alcohol at 2.0% by weight, PEG 400 at 45% by weight, diethylene
  • the method is directed to applying a topical composition once per day. In embodiments described herein, the method is directed to applying a topical composition multiple times per day. In some embodiments, the topical composition is applied two times per day, three times per day, four times per day, or five times per day. In some embodiments, the topical composition is applied one time in the morning and one time in the evening. In some embodiments, the topical composition is applied every 12 hours, every 11 hours, every 10 hours, every 9 hours, every 8 hours, every 7 hours, every 6 hours, every 5 hours, every 4 hours, every 3 hours, every 2 hours, or every hour.
  • the method is directed to applying a topical composition to multiple sites on the skin of the body.
  • the topical composition may be applied over large areas of skin prophylactically or the topical composition may be applied to particular sites in need of treatment.
  • the topical composition is applied to the skin as a liquid, toner, solution, spray, emulsion, moisturizer, sunscreen, cream, lotion, mask, suspension, triturate, gel, jelly, paste, foam, ointment, shampoo, adhesive, serum, treated cloth or pad.
  • the topical composition is applied to the eyes as eye drops, placed in the ear canal as ear drops or to the surface of the tooth.
  • Embodiments herein are directed to methods of treating a condition in a patient comprising administering a topical composition comprising methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid, and analyzing the level of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid and a metabolite in the patient’s blood.
  • the metabolite is 4-((3-(6,7- dimethoxy-2-(methylamino)quinazolin-4-yl)phenyl)carbamoyl)benzoic acid.
  • Embodiments herein are directed to methods of treating a condition in a child comprising administering a topical composition comprising methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid, and analyzing the level of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid and a metabolite in the child’s blood.
  • the metabolite is 4-((3-(6,7-dimethoxy-2- (methylamino)quinazolin-4-yl)phenyl)carbamoyl)benzoic acid.
  • the child is less than 18 years old, less than 15 years old, less than 12 years old, less than 10 years old, less than 5 years old, less than 3 years old, less than 2 years old, or less than 1 year old. In embodiments, the child is an infant. In embodiments, the child weighs less than 50 pounds, less than 40 pounds, less than 30 pounds, less than 20 pounds, or less than 10 pounds.
  • Embodiments herein are directed to methods of monitoring levels of a drug and a metabolite in a patient’s blood during treatment comprising administering a topical composition of the drug, collecting the patient’s blood, and analyzing the level of the drug and a metabolite in the blood.
  • the drug is methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid.
  • the metabolite is 4-((3-(6,7-dimethoxy-2-(methylamino)quinazolin-4-yl)phenyl)carbamoyl)benzoic acid.
  • the level of drug and/or metabolite in the child or patient’s blood may determine a treatment recommendation, wherein a level of drug and/or metabolite in the patient’s blood is within an acceptable limit may result in the recommendation to continue drug treatment, whereas a level of drug and/or metabolite in the patient’s blood outside of an acceptable limit may result in the discontinuation of the drug treatment or a change in the amount of drug treatment applied.
  • Embodiments herein are directed to methods of treating a skin condition in a patient in need thereof comprising: a) topically applying a topical composition comprising a therapeutically effective amount of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid, b) collecting about 10 pL to about 1 mL of a blood sample from the patient, c) spotting the blood sample onto a dried blood spot card, and d) analyzing the blood sample for a level of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid and 4-((3-(6,7-dimethoxy-2-(methylamino)quinazolin-4- yl )phenyl )carb amoyl)b enzoi c aci d .
  • the patient is an infant or a child
  • the volume of blood collected is about 1 mL, about 500 pL, about 100 pL, about 50 pL, about 40 pL, about 30 pL, about 25 pL, about 20 pL, about 15 pL, or about 10 pL.
  • Embodiments herein are directed to methods of detecting methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid and 4-((3-(6,7- dimethoxy-2-(methylamino)quinazolin-4-yl)phenyl)carbamoyl)benzoic acid comprising: a) collecting about 10 pL to about 1 mL of a blood sample from a patient, b) spotting the blood sample onto a dried blood spot card, c) punching a about 3mm to about 10 mm disc out of the dried blood spot card and processing the blood sample, d) analyzing the processed blood sample using UPLC-MS/MS (Ultra Performance Liquid Chromatography- tandem Mass Spectrometry), and e) quantifying an amount of methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-y
  • the volume of blood collected is about 1 mL, about 500 pL, about 100 pL, about 50 pL, about 40 pL, about 30 pL, about 25 pL, about 20 pL, about 15 pL, or about 10 pL.
  • the disc punched out from the dried blood spot card is about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, or about 10 mm.
  • the amount of methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid quantified from the blood sample is from about 1 mg/mL to about 200 ng/mL. In embodiments, the amount of methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid quantified from the blood sample is 3 ng/mL. In embodiments, the amount of methyl N-[3-(6,7-dimethoxy-2- methylaminoquinazolin-4-yl)phenyl]terephthalamic acid quantified from the blood sample is 160 ng/mL.
  • the amount of 4-((3-(6,7-dimethoxy-2- (methylamino)quinazolin-4-yl)phenyl)carbamoyl)benzoic acid quantified from the blood sample is from about 1 mg/mL to about 200 ng/mL. In embodiments, the amount of 4-((3- (6,7-dimethoxy-2-(methylamino)quinazolin-4-yl)phenyl)carbamoyl)benzoic acid quantified from the blood sample is 3 ng/mL.
  • the amount of 4-((3-(6,7-dimethoxy-2- (methylamino)quinazolin-4-yl)phenyl)carbamoyl)benzoic acid quantified from the blood sample is 160 ng/mL.
  • Table 1 provides the compositions for gel formulations and the justifications for each ingredient.
  • the ratio of the PEG400 to Transcutol P increased the permeation of the RVT-501 into the skin. It appears this effect is less related to Transcutol P’s effects as a penetration enhancer and more to its effects as a solvent for RVT- 501. RVT-501 dissolves in both PEG400 and Transcutol P and prefers to stay dissolved in each individual solvent versus going into the skin. In one of the ratio’s tested, the two solvents appear to antagonize each other, shifting the thermodynamics in favor of increased skin penetration.
  • RVT-501 is highly soluble in Transcutol P and thus an interpretation of the unusual finding of seeing enhanced skin penetration at lower levels of this penetration enhancer could also be attributed to the Transcutol P “holding on” to the RVT-501 and hindering its release into the skin.
  • DPK dermatopharmacokinetic
  • target sites are the hair follicles and sebaceous glands.
  • the drug diffuses through the stratum corneum, epidermis, and dermis to reach the site of action.
  • the drug may also follow follicular pathways to reach the sites of action.
  • the extent of follicular penetration depends on the particle size of the active ingredient if it is in the form of a suspension. Under these circumstances, the DPK approach is still expected to be applicable because studies indicate a positive correlation between the stratum corneum and follicular concentrations.
  • the treatment areas are marked using a template without disturbing or injuring the stratum comeum/skin.
  • the size of the treatment area will depend on multiple factors including drug strength, analytical sensitivity, the extent of drug diffusion, and exposure time.
  • the stratum corneum is highly sensitive to certain environmental factors.
  • the treatment sites and arms should be randomized. Uptake, steady-state, and elimination phases, as described in more detail below, may be randomized between the right and left arms in a subject. Exposure time points in each phase may be randomized among various sites on each arm. The test and reference products for a particular exposure time point may be applied on sites to minimize differences.
  • Test and reference products should be applied concurrently on the same subjects according to a SOP that has been previously developed and validated.
  • the premarked sites are treated with predetermined amounts of the products (e.g., 5 mg/sq cm) and covered with a nonocclusive guard. Occlusion is used only if recommended in product labeling.
  • Removal of the drug product is performed according to SOPs at the designated time points, using multiple cotton swabs or Q-tips with care to avoid stratum corneum damage. In case of certain oily preparations such as ointments, washing the area with a mild soap may be needed before skin stripping. If washing is carried out, it should be part of an SOP.
  • the BA/BE study should include measurements of drug uptake into the stratum corneum and drug elimination from skin. Each of these elements is important to establish bioavailability and/or bioequivalence of two products, and each may be affected by the excipients present in the product. A minimum of eight sites should be employed to assess uptake/elimination from each product. The time to reach steady state in the stratum corneum should be used to determine timing of samples. For example, if the drug reaches steady-state in three hours, 0.25, 0.5, 1 and 3 hours posttreatment may be selected to determine uptake and 4, 6, 8 and 24 hours may be used to assess elimination. A zero time point (control site away from test sites) on each subject should be selected to provide baseline data.
  • test/reference drug products are studied on both forearms, randomly selected sites on one arm may be designated to measure drug uptake/steady-state. Sites on the contralateral arm may then be designated to measure drug elimination.
  • drug uptake both the excess drug removal and stratum corneum stripping times are the same so that the stratum corneum stripping immediately follows the removal of the excess drug.
  • elimination phase the excess drug is removed from the sites at the steady-state time point, and the stratum corneum is harvested at succeeding times over 24 hours to provide an estimate of an elimination phase.
  • Skin stripping proceeds first with the removal of the first 1-2 layers of stratum corneum with two adhesive tapes strip/disc applications, using a commercially available product (e.g., D-Squame, Transpore). These first two tape-strip(s) contain the generally unabsorbed, as opposed to penetrated or absorbed, drug and therefore should be analyzed separately from the rest of the tape-strips. The remaining stratum corneum layers from each site are stripped at the designated time intervals. This is achieved by stripping the site with an additional 10 adhesive tape-strips. All ten tape strips obtained from a given time point are combined and extracted, with drug content determined using a validated analytical method.
  • a commercially available product e.g., D-Squame, Transpore
  • the values are generally expressed as amounts/area (e.g., ng/cm 2 ) to maintain uniformity in reported values.
  • Data may be computed to obtain full drug concentration-time profiles, Cmax-ss, T max -ss, and AUCs for the test and reference products.
  • dOFM dermal open-flow microperfusion
  • a thin, hollow tube is inserted just under the skin surface, running through a section of the skin a few inches wide and then exiting.
  • a liquid similar to body fluid is injected into the tubing; a portion of the tube under the skin is porous, so any drug that has been applied and absorbed through the skin's outer layer enters the flowing liquid, which is then collected for analysis.
  • dOFM can reliably measure the changing amounts of drug in the skin after topical application of a dermatological drug product.
  • a randomized placebo-controlled pilot study will be performed to evaluate efficacy of RVT-501 in subjects with Alopecia Areata.
  • the primary outcome measure will be the percentage of patients achieving 50% or greater improvement in their severity of Alopecia Tool (SALT) score (SALT50) at week 24 compared to Baseline.
  • SALT Alopecia Tool
  • the secondary outcome measures will be: 1) the proportion of subjects achieving an alopecia areata Physician's Global Assessment (aaPGA) score of 3 or above at Weeks 24 (0, no regrowth; 1, ⁇ 25% of regrowth; 2, 25%-49% of regrowth; 3, 50%-74% of regrowth; 4, 75%-99% of re growth; 5, 100% of regrowth), 2) the proportion of subjects achieving an alopecia areata Physician's Global Assessment (aaPGA) score of 3 or above at Weeks 48 (0, no regrowth; 1, ⁇ 25% of regrowth; 2, 25%-49% of regrowth; 3, 50%-74% of regrowth; 4, 75%-99% of re growth; 5, 100% of regrowth), 3) the percentage change from Baseline in the Alopecia Areata Symptom Impact Scale (AASIS) at Weeks 24, 4) the percentage change from Baseline in the Alopecia Areata Symptom Impact Scale (AASIS) at Weeks 48, 5) the percentage change from baseline in the Alopecia Areata Quality
  • a randomized placebo-controlled pilot study or a split body study will be performed to evaluate efficacy of RVT-501 in subjects with vitiligo.
  • the primary outcome measure will be the proportion of responders to RVT-501 at week 32 compared to baseline or control body region at week 16.
  • BSA Body Surface Area
  • VASI score Vitiligo Area and Severity Index
  • the body is divided into five separate and mutually exclusive regions: hands, upper extremities (excluding hands), trunk, lower extremities (excluding feet), and feet.
  • the axillary region is included with the upper extremities while the buttocks and inguinal areas are included with the lower extremities.
  • the extent of residual depigmentation is expressed by the following percentages: 0, 10%, 25%, 50%, 75%, 90%, or 100%.
  • VETF score (Vitiligo European Task Force) score weekly up to 64 weeks.
  • the VETF is a validated scoring system that assesses 3 dimensions of the disease (extent, staging, and spreading/progression). (1) the extent of vitiligo will be estimated as the percentage of vitiligo involvement of 5 body sites. (2) Stage of vitiligo will be assessed as 0 (normal pigmentation), 1 (incomplete depigmentation), 2 (complete depigmentation), 3 (partial hair whitening [ ⁇ 30%]), and 4 (complete hair whitening).
  • VETF Extent or Staging or Spreading Sum of all specific values for that category from all body sites (% of Area affected for Extent; 0-20 for Staging; -5 to +5 for Spreading). [00133] 4) assessing the Dermatology Life Quality Index weekly up to 64 weeks.
  • the DLQI is a simple 10-question validated questionnaire that has been used in over 40 different skin conditions, and its use has been described in over 1000 publications including many multinational studies. The DLQI is the most frequently used instrument in studies of randomized controlled trials in dermatology.
  • VAS Visual Analogue Scale
  • Example 6 A dried blood spot assay with UPLC -MS/MS for the simultaneous determination of E6005. a phosphodiesterase 4 inhibitor and its metabolite in human blood
  • E6005 a novel phosphodiesterase 4 inhibitor
  • ER- 392710 Mil
  • E6005 and Mil in 25 pL blood spotted onto FTATM DMPK-C cards were extracted by simple protein precipitation with water/acetonitrile (1:1, v/v), and then chromatographed on a reversed phase column under gradient elution.
  • Phosphodiesterase 4 (PDE4) is expressed on various inflammatory cells and considered to play a critical role in the inflammatory disorders including atopic dermatitis.
  • E6005 potently inhibited human PDE4 with an IC50 of 2.8 nM and also demonstrated efficacy in mice and humans, thus E6005 is considered as a promising drug for the treatment of atopic dermatitis.
  • Atopic dermatitis is one of autoimmune diseases and a number of children and infants are suffering from. Although it is important to monitor drug concentrations in children and infants, the volume of blood sampling is limited.
  • DBS Dried blood spots
  • E6005 and Mil were synthesized at Eisai Co., Ltd. (Ibaraki, Japan).
  • Blank human whole blood with EDTA-2K as an anticoagulant was obtained from volunteers in Eisai Co., Ltd. with written consent.
  • Blank human plasma was prepared by centrifuging aliquots of whole blood obtained or commercially available one was purchased from Biopredic International (Saint Gregoire, France).
  • High-performance liquid chromatography (HPLC) grade acetonitrile, methanol, distilled water, and ammonium formate as well as a special grade formic acid were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other chemicals used were of analytical grade.
  • Silica-gel desiccant and polyethylene bag for storing DBS cards were purchased from Toyotakako Co., Ltd. (Aichi, Japan) and Asahi Kasei home products Co. (Tokyo, Japan), respectively.
  • Assay conditions The analytical conditions of E6005 and Mil in DBS were the same as those used for the validated assay in plasma. Briefly, an Acquity system (Waters, MA, USA) coupled with triple quadrupole mass spectrometer Quattro Premier (Waters) was used as an ultra-performance liquid chromatography (UPLC) with tandem mass spectrometry (ULPC-MS/MS).
  • UPLC ultra-performance liquid chromatography
  • ULPC-MS/MS tandem mass spectrometry
  • E6005, Mil, and IS were eluted with the mobile phase consisting of (A) water/acetonitrile/1 mol/L ammonium formate (950:50:5, v/v/v) and (B) water/acetonitrile/1 mol/L ammonium formate (100:900:5, v/v/v) and chromatographed on an Acquity UPLC BEH C18 column (2.1 mm x 100 mm, 1.7 pm, Waters) maintained at 40 °C.
  • the gradient program is as follows: a linear increase of mobile phase (B) from 5% to 95% for 4.0 min, then an isocratic elution of 95% (B) for 0.5 min, followed by having the system equilibrated with 5% (B) for 1.5 min.
  • the flow rate was 0.25 mL/min to 4.5 min then increased to 0.3 mL/min for equilibrium.
  • the optimized mass spectrometer conditions in the multiple reaction monitoring were 370 °C for desolvation temperature, 125 °C for source temperature, and 1.3 kV for capillary voltage, 65 V for cone voltage, and -55 eV for collision energy.
  • the mass transition m/z (precursor ion®product ion) 473.1 ⁇ -163.0, m/z 459.1 ⁇ -149.0, m/z 477.2®167.0, and m/z 463.2®153.0 were monitored for E6005, Mil, IS of E6005, and IS of Mil, respectively.
  • Quality control samples including the lower limit of quantification (LLOQ), low QC (LQC), middle QC (MQC), and high QC (HQC), were prepared at concentrations of 1, 3, 30, and 160 ng/mL blood with designated hematocrit values. Blood samples with varying hematocrits were prepared by mixing plasma and blood cells with the nominal ratios of 80:20 to 30:70 (v/v).
  • Accurate hematocrit values determined using a hematology analyzer were 19.3, 26.9, 36.2, 46.7, 49.1, 51.8, 57.5, and 63.6% for the nominal hematocrit of 20% (80:20), 30% (70:30), 40% (60:40), 50% (50:50), 53% (47:53), 56% (44:56), 60% (40:60), and 70% (30:70), (plasma/blood cells, v/v), respectively.
  • Aliquots (25 pL) of blood samples were spotted onto the center of circle of FTATM DMPK-C cards using a calibrated pipette to prepare DBS. The cards were allowed to dry at room temperature for at least 2 h.
  • QC samples used for the long-term stability assessment were stored at designated temperature in a sealed polyethylene bag containing Silica-gel desiccant.
  • Intra- and inter-batch reproducibility Inaccuracy and imprecision of E6005 and Ml 1 were determined using QC samples (LLOQ, LQC, MQC, and HQC) in the intra- and inter-assay batch. Five replicates per concentration were assessed for the intra-batch reproducibility, and intra-batch evaluation was repeated across three batches for the inter batch reproducibility. The acceptance criteria for inaccuracy and imprecision were within ⁇ 15% and 15%, respectively ( ⁇ 20% for inaccuracy and 20% for imprecision are allowed for the LLOQ samples).
  • Extraction recovery and matrix effect Extraction recovery of E6005 and Mil from DBS discs was assessed at three concentrations (3, 30, and 160 ng/mL, three replicate/concentration), while recovery of the IS from the system was determined at 60 ng/mL. Extraction recovery of the analytes was determined by dividing the peak area of the analytes spiked to blank blood prior to extraction by that spiked after extraction (reference samples) taking the differences in areas between discs for extraction and blood spots into account while extraction recovery of the IS was determined just by comparison of peak area between the extracted samples and reference ones without any correction. Blood spot areas were calculated by nr 2 , where r is radius of spots determined by a ruler.
  • Matrix factors were evaluated by dividing peak area of reference samples from six individuals by that of neat solution with identical concentrations. Matrix factors were determined for the analytes of interest (E6005 and Mil) at 3 ng/mL and the corresponding IS at 160 ng/mL. IS-corrected matrix factors of E6005 and Mil were calculated by dividing matrix factor of E6005 and Mil by that of the corresponding IS. The % RSD of the IS-corrected matrix factor should be within 15%.
  • Carryover Two types of carryover assessments should be evaluated in bioanalytical methods using DBS-based assays; one is carryover derived from repetitive sample injection via UPLC, a typical validation parameter in the method validation, and the other is DBS-specific spot-to-spot carryover mainly derived from punching devices by repetitive punching of discs.
  • the carryover in the UPLC was assessed by injecting blank samples just after upper limit of quantification (ULOQ) samples.
  • ULOQ upper limit of quantification
  • the other possible carryover caused by repetitive punching was investigated by punching discs with blank samples just after the ULOQ samples using a punching device without any wash. Peak areas of any interferences in blank samples should be less than 20% and 5% of the LLOQ sample for the analytes of interest and the IS, respectively.
  • Stability Following stability of E6005 and Mil in DBS was assessed at low and high concentrations using LQC and HQC samples (three replicates/concentration): bench-top stability for 7 days at room temperature, long-term frozen stability for 160 days at room temperature and below -15°C, and processed sample stability for 85 h at 4°C. To investigate impacts of high humidity on the stability, bench-top stability test was performed at room temperature with relative humidity of ca. 80%-84%. Samples were considered stable when % bias from the nominal concentrations was within ⁇ 15%.
  • shelf-life of refrigerated blood As it is sometimes a challenge that fresh blood samples are available to prepare calibration or QC samples, it is of interest to know whether or not refrigerated blood can be used.
  • the shelf-life of refrigerated blood was assessed by assaying QC samples at low (3 ng/mL) and high (160 ng/mL) concentrations in three replicates prepared from refrigerated blood for seven days against calibration samples prepared from fresh blood.
  • the refrigerated blood can be used when % bias from the nominal concentrations was within ⁇ 15%.
  • Clinical application A clinical study was performed in which E6005 ointment containing 0.05% or 0.2% was topically applied twice a day for two weeks to pediatric subjects. Blood samples were obtained at 1- and 2-week post-dose as well as subsequent 7-day follow-up period in collection tubes with K2-EDTA as an anticoagulant, thereafter put on ice as soon as possible to reduce possible conversion of E6005 to Mil. Details on sample handling at the clinics were clarified in a lab manual; a 25 pL aliquot blood sample was spotted onto the center of circle of DBS cards (four replicates per sample) at clinics, then dried at room temperature for at least 2 h.
  • DBS cards with desiccants were placed in zip lock bags and stored frozen below -20°C until shipment to a bioanalytical laboratory. Samples were stored below -15°C at the laboratory until they were subjected to sample processing for the determination of E6005 and Mil concentrations in DBS.
  • Blood spotting is one of the crucial steps in the DBS method to ensure accurate determination, thus in the method development, some abuses on blood spotting were investigated.
  • blood samples with drugs of interest were spotted by one drop per spot with a pipette.
  • DBS with the double drop of blood samples each 15 pL aliquots was processed and concentrations of E6005 and Mil were determined against calibration samples with single blood drop (30 pL aliquots) to ensure whether the RE (%) was within ⁇ 15%.
  • the RE (%) of double drop samples was -4.6% and 3.7% for E6005 and Mi l, respectively, suggesting minimal impacts of double drop of blood samples as long as the total volume is comparable.
  • the laboratory manual indicates that pipettes should be kept just above the DBS paper not touched when spotting, however blood spot may be performed with pipettes touched on cards; the % RE of E6005 and Mil was 4.3% and 9.7%, respectively, indicating minimal impacts by pipette’ touching on card when spotting.
  • Extraction procedure focused on selecting appropriate extraction solvents: acetonitrile, acetonitrile/water (8:2, v/v), acetonitrile/water (1:1, v/v), methanol, methanol/water (8:2, v/v), and methanol/water (1:1, v/v). Although minimal extraction was noted with acetonitrile, other solvents showed similar extraction efficiency. Less endogenous peaks in chromatograms led to the selection of 50% acetonitrile rather than pure organic solvents or higher organic solvent containing solvents.
  • Table 4 shows extraction recoveries of the analytes of interest and the IS. Extraction recoveries of E6005 and Mil at low, middle, and high concentrations were 79.2%-86.7% and 73.3%-87.5%, respectively, by taking the differences in disc areas between extracted and spotted into account. The recovery of the IS was 93.7% for E6005 and 96.9% for Mil. Extraction recoveries of E6005 and Mil were consistent across the concentrations tested. Relatively lower extraction of the analytes than the IS was attributable to differences in fortifying neat solution in the system, where the analytes were spotted onto cards before extraction while the IS was just fortified after extraction of the analytes.
  • Data represent the mean ⁇ standard deviation of three replicates for the analytes at each level and nine replicates for the IS.
  • Table 5 Matrix effects of E6005 and Mil in human dried blood spots from six individuals
  • E6005 to Mil Possible conversion of E6005 to Mil was evaluated by fortifying only E6005 in blood and formed Mil levels were assessed (Table 7).
  • the conversion of E6005 in the long-term stability test was slightly higher at room temperature (2.2%) compared to that stored below - 15°C (1.2%). However, the conversion was not so different between 7 and 160 days even when stored at room temperature (1.0% and 2.2% for 7 and 160 days, respectively).
  • the minimal conversion of E6005 to Mil was not clinically significant given minimal exposure of E6005 after dermal application (1.65 ng/mL at the maximum).
  • Quality control samples at low (3 ng/mL) and high (160 ng/mL) levels were assayed in triplicates and the relative error was calculated from the mean. Percent bias was calculated against nominal concentrations.
  • the blood-to- plasma partition (B/P) of E6005 and Mil was determined by assaying concentrations of E6005 and Ml 1 in whole blood samples and plasma samples prepared from blood samples by centrifugation.
  • the B/P of E6005 was 0.690 and 0.669 at 3 and 160 ng/mL, respectively, while that of Mil was 0.594 and 0.574 at 3 and 160 ng/mL, respectively, suggesting that no concentration-dependent B/P was observed.
  • the average B/P of two levels was 0.679 for E6005 and 0.584 for Mi l.
  • Safety Data 3 Subjects reported AEs; 5 Subjects reported No AEs. All AEs were Grade 1/Mild (Headache (2), sore throat (unrelated), upper respiratory infection, biopsy site pain, burning sensation at application site, 1 mild AE of burning sensation at application site (0.5% ointment), 1 report of barely perceptible skin irritation reported (1% gel) on Day 1 at 1 hour post application. All AEs were resolved.
  • RVT-501 concentrations were measurable in all 40 skin samples (10 subjects x 4 samples per subject). Mil metabolite concentrations were below the limit of quantification in all 40 skin samples.
  • FIG. 1 provides free fraction skin concentration (pg/g) at day 3 for the 1% RVT- 501 Gel and 0.5% RVT-501 Ointment, as well as at day 7 for the 1% RVT-501 Gel and 0.5% RVT-501 Ointment.
  • Table 8 provides mean, median and ratio data; data assumes a skin density of about 1 g/ml, molecular weight of RVT-501 is 472.5 pg/pmol, and human skin protein binding is 99.4%.
  • FIG. 2 provides free fraction skin concentration (mM) at day 3 for the 1% RVT-501 Gel and 0.5% RVT-501 Ointment, as well as at day 7 for the 1% RVT-501 Gel and 0.5% RVT-501 Ointment.
  • Table 9 provides median, ratio data, and percent inhibition for each assay. Table 9: Comparison of Free Fraction of RVT-501 to PDE4 IC50
  • PK data suggests that application of 1.0% RVT-501 Gel leads to approximately 2.0-fold to 4.1-fold higher skin RVT-501 concentrations than application of 0.5% RVT-501 Ointment when applied to healthy human skin.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Birds (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Selon certains modes de réalisation, la présente invention concerne des compositions topiques comprenant une quantité thérapeutiquement efficace d'acide téréphtalique de méthyle N-[3-(6,7-diméthoxy-2-méthylaminoquinazoline-4-yl)phényle], d'alcool benzylique, de PEG 400, d'éther mono-éthylénique de diéthylène glycol, d'oléoyl polyoxylglycérides, d'hydroxyl propylcellulose, d'hydroxytoluène butylé, et éventuellement de PEG 300. Les compositions topiques peuvent être utilisées pour traiter diverses affections cutanées, notamment la dermatite atopique, le vitiligo et l'alopécie circonscrite.
PCT/US2021/038858 2020-06-24 2021-06-24 Formulations topiques de gel et leur utilisation dans le traitement d'affections cutanées Ceased WO2021262956A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063043160P 2020-06-24 2020-06-24
US63/043,160 2020-06-24

Publications (1)

Publication Number Publication Date
WO2021262956A1 true WO2021262956A1 (fr) 2021-12-30

Family

ID=79281819

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/038858 Ceased WO2021262956A1 (fr) 2020-06-24 2021-06-24 Formulations topiques de gel et leur utilisation dans le traitement d'affections cutanées

Country Status (1)

Country Link
WO (1) WO2021262956A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115541778A (zh) * 2022-11-28 2022-12-30 山东省食品药品检验研究院 一种测定人血浆中阿普斯特浓度的检测方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8513269B2 (en) * 2007-08-17 2013-08-20 Eisai R&D Management Co., Ltd. Preparation for external use
WO2017021489A1 (fr) * 2015-08-05 2017-02-09 Atotech Deutschland Gmbh Appareil de réception de porte-substrat
WO2019113475A1 (fr) * 2017-12-07 2019-06-13 Dermavant Sciences GmbH Formulations topiques de pommade et leur utilisation dans le traitement d'affections cutanées
WO2019113519A1 (fr) * 2017-12-07 2019-06-13 Dermavant Sciences GmbH Formulations topiques d'onguent d'inhibiteur de pde-4 et leur utilisation dans le traitement d'affections cutanées
US20190216779A1 (en) * 2016-06-29 2019-07-18 Menlo Therapeutics Inc. Use of neurokinin-1 antagonists to treat a variety of pruritic conditions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8513269B2 (en) * 2007-08-17 2013-08-20 Eisai R&D Management Co., Ltd. Preparation for external use
WO2017021489A1 (fr) * 2015-08-05 2017-02-09 Atotech Deutschland Gmbh Appareil de réception de porte-substrat
US20190216779A1 (en) * 2016-06-29 2019-07-18 Menlo Therapeutics Inc. Use of neurokinin-1 antagonists to treat a variety of pruritic conditions
WO2019113475A1 (fr) * 2017-12-07 2019-06-13 Dermavant Sciences GmbH Formulations topiques de pommade et leur utilisation dans le traitement d'affections cutanées
WO2019113519A1 (fr) * 2017-12-07 2019-06-13 Dermavant Sciences GmbH Formulations topiques d'onguent d'inhibiteur de pde-4 et leur utilisation dans le traitement d'affections cutanées

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115541778A (zh) * 2022-11-28 2022-12-30 山东省食品药品检验研究院 一种测定人血浆中阿普斯特浓度的检测方法
CN115541778B (zh) * 2022-11-28 2023-08-15 山东省食品药品检验研究院 一种测定人血浆中阿普斯特浓度的检测方法

Similar Documents

Publication Publication Date Title
RU2332208C2 (ru) Применение 6-[3-(1-адамантил)-4-метоксифенил]-2-нафтойной кислоты для лечения дерматологических расстройств
CN110545807B (zh) 用于治疗皮炎和炎性皮肤病的大麻素制剂
US20210093637A1 (en) Topical ointment formulations of pde-4 inhibitor and their use in treating skin conditions
WO2021262956A1 (fr) Formulations topiques de gel et leur utilisation dans le traitement d'affections cutanées
JP6793543B2 (ja) 乳幼児の皮膚の状態の評価方法
Lodén et al. Bioequivalence determination of topical ketoprofen using a dermatopharmacokinetic approach and excised skin penetration
WO2019113475A1 (fr) Formulations topiques de pommade et leur utilisation dans le traitement d'affections cutanées
Moglia et al. Effects of topical treatment with fenretinide (4-HPR) and plasma vitamin A levels in patients with actinic keratoses
CN112020352A (zh) 用于痤疮的大麻素给药方案
US11642356B2 (en) Pharmaceutical compositions
US20210260055A1 (en) Topical formulations of dgat1 inhibitors and their methods of use
EP2243483A1 (fr) Compositions de sel d'amlodipine pour application topique à application topique
Parfitt Investigations of the assessment of bioequivalence of topical clotrimazole products using a dermatopharmacokinetic approach
Duszynska-Krupa The rational design of topical formulations
RU2624238C2 (ru) Лечение себореи
Tettey-Amlalo Application of Dermal Microdialysis and Tape Stripping Methods to Determine the Bioavailability And/or Bioequivalence of Topical Ketoprofen Formulations
Gee Understanding the in vivo dynamics of non-occlusive drug delivery systems
Bronaugh et al. Absorption of Dermatological Products
Chik Pharmacokinetic studies for the development of transdermal drug delivery systems

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21829545

Country of ref document: EP

Kind code of ref document: A1

WA Withdrawal of international application
NENP Non-entry into the national phase

Ref country code: DE