Topical ointment formulations of PDE-4 inhibitors and their use in treating skin conditions
阅读说明：本技术 Pde-4抑制剂的局部用软膏剂制剂及其在治疗皮肤病况中的应用 (Topical ointment formulations of PDE-4 inhibitors and their use in treating skin conditions ) 是由 J·李 A·辛普森 于 2018-12-07 设计创作，主要内容包括：本文实施方案针对局部用组合物,该局部用组合物包括治疗有效量的甲基N-[3-(6,7-二甲氧基-2-甲基氨基喹唑啉-4-基)苯基]对氨羰基苯甲酸、PEG 400、PEG 4000、白凡士林、维生素E、单硬脂酸甘油酯/甘油酯、肉豆蔻酸异丙酯和水。局部用组合物可以用于治疗多种皮肤病况(包含特应性皮炎)。被治疗的患者包含小儿、青少年和成人。(Embodiments herein are directed to topical compositions comprising therapeutically effective amounts of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, PEG400, PEG4000, white petrolatum, vitamin E, glyceryl monostearate/glyceride, isopropyl myristate, and water. The topical composition may be used to treat a variety of skin conditions, including atopic dermatitis. Patients to be treated include children, adolescents and adults.)
1. A method of treating a skin condition in a patient in need thereof, the method comprising topically applying a topical composition comprising a therapeutically effective amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, PEG400, PEG4000, white petrolatum, vitamin E, glyceryl monostearate/glyceride, isopropyl myristate, and water.
2. The method of claim 1, wherein the concentration of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid is from about 0.01% to about 5% by weight of the topical composition.
3. The method of claim 1, wherein the concentration of PEG400 is about 25% to about 75% by weight of the topical composition.
4. The method of claim 1, wherein the concentration of PEG4000 is about 15% to about 35% by weight of the topical composition.
5. The method of claim 1, wherein the concentration of white petrolatum is about 1% to about 10% by weight of the topical composition.
6. The method of claim 1, wherein the concentration of vitamin E is from about 0.01% to about 5% by weight of the topical composition.
7. The method of claim 1 wherein the concentration of glyceryl monostearate/glyceryl ester is from about 2% to about 15% by weight of the topical composition.
8. The method of claim 1, wherein the concentration of isopropyl myristate is from about 2% to about 25% by weight of the topical composition.
9. The method of claim 1, wherein the concentration of water is from about 0.1% to about 10% by weight of the topical composition.
10. The method of claim 1, wherein methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid is 0.2 wt%, PEG400 is 50.5 wt%, PEG4000 is 25.0 wt%, white petrolatum is 4.4 wt%, vitamin E is 0.1 wt%, glycerol monostearate/glyceride is 8.0 wt%, isopropyl myristate is 10.0 wt%, and water is 2.0 wt%.
11. The method of claim 1, wherein methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid is 0.5 wt%, PEG400 is 50.5 wt%, PEG4000 is 25.0 wt%, white petrolatum is 4.4 wt%, vitamin E is 0.1 wt%, glycerol monostearate/glyceride is 8.0 wt%, isopropyl myristate is 11.0 wt%, and water is 2.0 wt%.
12. The method of claim 1, wherein the skin condition is selected from the group consisting of dermatitis; psoriasis; itching of the skin; acne; inflammation and redness of the skin; disorders associated with sebaceous glands; oily skin; dry skin; rosacea; burns; disorders affecting the palm or the foot; genetic disorders of the skin; warts; and any combination thereof.
13. The method of claim 12, wherein 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.
14. The method of claim 12, wherein psoriasis is selected from the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and any combination thereof.
15. The method of claim 12, wherein the skin itch is selected from the group consisting of itch, prurigo, pityriasis rubra pilaris, lichen simplex chronicus, lichen planus, and any combination thereof.
16. The method of claim 12, wherein acne is selected from the group consisting of acne vulgaris, cystic acne, inflammatory acne, noninflammatory acne, and any combination thereof.
17. The method of claim 12, wherein the inflammation and redness of the skin is selected from the group consisting of seborrheic dermatitis, urticaria eczema, urticaria, seborrheic eczema, and any combination thereof.
18. The method of claim 12, wherein the sebaceous gland-associated disorder is selected from the group consisting of acne, follicular hyperkeratosis, sebaceous hyperplasia, sebaceous gland adenoma, sebaceous gland hyperplasia, excessive sebum production, seborrhea, sebaceous adenoma, sebaceous adenocarcinoma, seborrheic dermatitis, sebaceous cysts, and any combination thereof.
19. The method of claim 12, wherein the oily skin is seborrhea.
20. The method of claim 12, wherein skin dryness is selected from the group consisting of sebum enlargement, ichthyosis, xerosis, and any combination thereof.
21. The method of claim 12, wherein the burn is sunburn.
22. The method of claim 12, wherein the disorder affecting the palm or the foot is selected from the group consisting of palmoplantar pustulosis, exfoliative keratolysis, and any combination thereof.
23. The method of claim 12, wherein the genetic disorder of skin is darriella disease.
24. The method of claim 1, wherein the patient is a juvenile.
25. The method of claim 1, wherein the skin condition is atopic dermatitis.
Drawings
For a fuller understanding of the nature and advantages of the present invention, reference should be made to the following detailed description taken together with the accompanying figures wherein:
fig. 1 illustrates the average amount (μ g) of the compound of formula (I) of the embodiments herein collected from the stratum corneum of each donor 24 hours after application of the topical formulation of the embodiments herein.
Fig. 2 illustrates the average amount (μ g) of the compound of formula (I) of the embodiments herein collected from the epidermis of each donor 24 hours after application of the topical formulation of the embodiments herein.
Fig. 3 illustrates the average amount (μ g) of the compound of formula (I) of the embodiments herein collected from the dermis of each donor 24 hours after application of the topical formulation of the embodiments herein.
Fig. 4 illustrates a timeline of the scheme used in example 2.
Figure 5 illustrates hematoxylin and eosin staining of normal skin versus skin with atopic dermatitis lesions. Note DNCB-induced epidermal hyperplasia, hyperkeratosis, ulceration and immune cell infiltration in the skin.
Figure 6 illustrates hematoxylin and eosin staining of skin sections treated prophylactically (left) or therapeutically (right) for atopic dermatitis skin lesions at 40 x magnification.
Figure 7 illustrates selected cytokine data from both prophylactic (top) and therapeutic (bottom) studies. Characteristic cytokines are IL-6 (left), IL-17 (center) and TNF- α (right). Data was collected from skin samples on
Figure 8 illustrates scratch assay results in both prophylactic (top) and therapeutic (bottom) studies.
Figure 9 provides responses in IGA at week 4 in the ITT population (0/1+2 score improvement).
Figure 10 provides responses in IGA at week 4 in the PPS population (0/1+2 score improvement).
Fig. 11 provides the response in the IGA at week 4 in the ITT population (0/1).
Fig. 12 provides the response in the IGA at week 4 in the PPS population (0/1).
Figure 13 provides the kinetics of IGA response (0/1+2 score improvement) in the ITT population.
Figure 14 provides the IGA response (0/1+2 score improvement) kinetics in the PPS population.
Figure 15 shows% improvement in EASI from baseline and week 4 in the ITT population.
FIG. 16 provides data for the EASI 50/EASI 75/EASI 90 responders at week 4 in the ITT population.
Figure 17 provides data for EASI 50/75/90 responders at week 4 in the PPS population.
Figure 18 shows improvement of NRS (scrapie) from baseline in ITT population.
Figure 19 shows improvement in NRS (scrapie) from baseline at week 4 in the ITT population.
Figure 20 shows the improvement of NRS (scrapie) from baseline at week 4 in the PPS population.
Figure 21 shows the% improvement in BSA from baseline and the% improvement in BSA at week 4 in the ITT population.
Detailed Description
The invention is not limited to the particular methodology, compositions, or methodologies described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope of the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
As used herein, the term "about" means plus or minus 10% of the numerical value of the number it is using. Thus, about 50% means in the range of 45% to 51%.
When used in conjunction with a composition, "administering" means administering the composition to the patient, whereby the composition positively affects the tissue (e.g., skin) to which it is targeted. The act of "applying" the composition may be accomplished, for example, by topical application or in combination with other known techniques. Administration may be self-administration, wherein the subject in need of such treatment is administered the composition, or may be administered by a medical professional or other health care professional, or a caregiver of the subject in need of such treatment.
As used herein, the term "adolescent" is a human from about 12 years of age to less than 17 years of age.
The terms "patient" and "subject" are interchangeable, and can be taken to mean any person that can be treated with a compound of the invention. In some embodiments, the patient or subject is an adult, adolescent, child, or infant. In some embodiments, the patient or subject is an adult of 18 years of age or older. In some embodiments, the patient or subject is an adolescent age of 12-17 years. In some embodiments, the patient or subject is a pediatric individual with an age of 2-11 years.
As used herein, the terms "comprising," "including," "comprises," "including," and "comprising" are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
As used herein, the term "consisting of … … (consistency of)" or "consisting of … … (consistency of)" means that the composition or method includes only the elements, steps, or ingredients specifically recited in a particular embodiment or claim.
As used herein, the terms "consisting essentially of … … (or" consisting essentially of … …) "mean that the composition or method contains only the specified materials or steps and those materials or steps that do not materially affect the basic and novel characteristics of the claimed invention.
The language "consisting of … …" or "consisting essentially of … …" (rather than "comprising") may be used to further define particular embodiments disclosed herein in the claims. In other words, although embodiments described herein use the phrases "comprising" or "including," any embodiment described herein may be replaced with "consisting of … … (consistent of)"/"consisting of … … (consistent of)" or "consisting essentially of … … (consistent of)" or "consisting essentially of … … (consistent of)".
The term "dermatitis" is used to refer to a group of skin conditions that cause inflammation of the skin and are characterized by itching, redness of the skin, and rash. The group comprises atopic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, stasis dermatitis, seborrheic dermatitis, chronic dermatitis and eczema.
The term "therapeutically effective amount" refers to an amount of a composition of the embodiments described herein that is necessary or sufficient to achieve a desired effect. For example, in some embodiments, the desired effect may include, but is not limited to, medical therapeutic treatment, cosmetic therapeutic treatment, and/or prophylactic treatment (as appropriate).
The term "exfoliative keratolysis" or "exfoliative keratolysis" refers to a skin condition characterized by dry skin and superficial gas pockets. These blisters can be peeled off very easily and will leave a reddish tender area.
"follicular hyperkeratosis" plays a key role in the pathogenesis of acne, the cells of the hair follicle becoming adherent, failing to normally shed onto the surface of the skin, and causing microcomedones.
The term "GeleolTM"refers to glycerol monostearate (glyceryl monostearate) or glycerol monostearate/glycerol ester.
The term "ichthyosis" refers to an inherited skin disorder characterized by dry, thickened and scaly skin.
In each of the embodiments disclosed herein, the compositions and methods can be used with or for a subject in need of such treatment (which can also be referred to as "in need"). As used herein, the phrase "in need of" means that the subject has been identified as in need of a particular method or treatment, and means that the subject has been administered treatment for that particular purpose.
The term "keratosis follicularis" or "darrieus's disease" refers to an inherited disorder characterized by a dark scleroderma plaque (sometimes containing pus) on the skin.
The term "lichen simplex chronicus" refers to skin disorders characterized by chronic itching and scratching. Continued scratching caused thick, leathery, darkened (lichenized) skin.
The term "lichen planus" refers to a disease characterized by itchy red-purple polygonal shaped skin lesions on the lower back, wrists and ankles.
As used herein, the term "methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid", "E6005" or "RVT-501" shall also refer to alternative names for compounds, the compound comprises methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoate, 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-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid having the following structure:
as used herein, the term "pharmaceutically acceptable" and grammatical variations thereof, when referring to carriers (carriers), diluents, excipients, and agents or other ingredients of a composition, means that the materials used in the final composition are non-irritating or otherwise harmful to the patient as a whole and particularly to the skin, and are preferably pleasant and well tolerated in terms of overall appearance, pH, color, odor, and texture (feel), means that the materials used in the final composition are not, for example, unacceptably viscous (tacky), oily, or dry, and means that the materials used in the final composition do spread easily, absorb into the skin at an acceptable absorption rate.
As used herein, the term "metabolite of E6005", "ER-392710" or "M11" refers to a metabolite of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid. The compound of M11 is 4- ((3- (6, 7-dimethoxy-2- (methylamino) quinazolin-4-yl) phenyl) carbamoyl) benzoic acid, and has the following structure:
the term "pityriasis rubra pilaris" refers to a group of chronic disorders characterized by red-orange scaling plaques and keratinizing follicular papules. Symptoms may include red-orange patches on the skin, severe flaking, uncomfortable itching, thickened skin on the feet and hands, and thickened bumps around hair follicles.
The term "psoriasis" refers to an autoimmune disease characterized by patches of red, itchy, and scaly abnormal skin. There are five main types of psoriasis: plaque type, blob type, reversal type, pustule type, and erythrodermic type.
The term "itching" or "prurigo" refers to severe itching of the skin due to various ailments.
The term "palmoplantar pustulosis" refers to a chronic pustular condition affecting the palms and the soles.
The term "rosacea" refers to a condition of the skin characterized by redness, blisters, swelling, and small superficial dilated blood vessels.
The term "sebaceous gland adenoma" refers to a small bulge on the skin, when numerous small bulges are present, called "sebaceous gland hyperplasia".
The term "sebaceous gland" encompasses a unilobular or multilobular gland that secretes sebum. Sebaceous glands comprise fur fat units, Fondas spot (force spot), Meibomian gland (Meibomian gland), Zeiss gland (gland of the Zeiss) and Montgomery areola tuberosity (Montgomery areola tuberocle).
The phrase "sebaceous gland-associated disorders" encompasses diseases, conditions and symptoms associated with sebaceous glands. Disorders associated with sebaceous glands include acne, seborrhea, sebaceous adenomas, sebaceous adenocarcinoma, seborrheic dermatitis, sebaceous cysts, sebaceous adenomas, and sebaceous hyperplasia.
The term "seborrhea" encompasses oily skin.
The term "seborrheic dermatitis" encompasses inflammatory skin disorders characterized by scaly, flaky, itchy, and red skin, and encompasses seborrheic dermatitis caused by fungal disorders, genetic disorders, environmental disorders, hormonal disorders, and immune dysfunction.
The term "sebaceous cyst" encompasses simple sebaceous cysts (e.g., simple ductal sebaceous cysts and solitary sebaceous cysts) and multiple sebaceous cysts (e.g., epidermal polycystic disease and sebaceous cyst disease).
The term "sebaceous gland hyperplasia" encompasses an enlargement of the sebaceous glands.
As used herein, the term "skin" refers to a body organ that protects a subject from environmental stimuli, regulates the temperature of the body, and allows for external sensations. The "skin" is divided into three layers: the outermost layer, called the epidermis, which contains melanocytes; dermis containing connective tissue, hair follicles and sweat glands; and the deepest subcutaneous layer, called the hypodermis, which is composed of fat and connective tissue.
As used herein, the terms "topical" and "local" apply the compositions of the present invention to the surface of the skin and mucosa.
"topical application" or "topical administration" refers to the delivery of a composition for treating a condition of the epidermis or dermis, wherein the topical composition is applied to the skin, acts locally, and has no systemic effect. Topical administration of drugs can often be advantageously applied, for example, in the treatment of various skin disorders.
As used herein, the terms "topical formulation" and "topical composition" refer to a formulation or composition that can be applied to the skin or mucous membranes. For example, topical formulations or topical compositions may be used to impart therapeutic benefits to patients or to impart cosmetic benefits to consumers. Such topical formulations or topical compositions may be provided in the form of creams, foams, gels, lotions, or ointments.
As used herein, the terms "treatment," "treating," or "treating" refer to therapeutic treatment, cosmetic treatment, and/or a measure of disease prevention or prophylactic measure, wherein the object is to prevent, reduce, eliminate, or slow down (lessen) an undesired physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome (e.g., reduce acne, comedo, pimples, or rash). For purposes of this disclosure, beneficial or desired clinical results include (but are not limited to) alleviation of symptoms; reduction in the extent of a condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset of the condition, disorder or disease or slowing of progression of the condition, disorder or disease; alleviation of a condition, disorder or disease state; and alleviation (whether partial or complete) of the condition, disorder or disease, whether detectable or undetectable, or amelioration (enhancement) or amelioration of the condition, disorder or disease. Treatment involves eliciting a clinically significant response without excessive levels of deleterious side effects.
The term "wart" refers to a small, rough and hard growth of similar color to the rest of the skin caused by infection with one type of Human Papillomavirus (HPV). There are many types (including verruca vulgaris, verruca plantaris, verruca filiformis, and genital warts).
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (e.g., molecular weight, reaction conditions, and so forth) used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.
Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
The grouping of alternative elements or embodiments of the invention disclosed herein is not to be construed as limiting. Each group member may be referenced or claimed individually or in any combination with other members of the group or other elements found herein. It is contemplated that one or more members of a group may be included in a group or deleted from a group for convenience and/or patentability reasons.
A compound of formula (I)
In some embodiments, the compound represented by formula (I) is methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid (RVT-501) having the following structure:
this compound and methods of making such compounds are further described in U.S. patent nos. 7,939,540 and 8,530,654, each of which is hereby incorporated by reference in its entirety.
Optical isomers-diastereoisomers-geometric isomers-tautomers. The compounds described herein may contain asymmetric centers and, thus, may exist as enantiomers. In case the compound according to the invention has two or more asymmetric centers, it may additionally exist as diastereoisomers. Embodiments herein encompass all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. The formula shown has no defined stereochemistry at certain positions. The embodiments herein encompass all stereoisomers of such formula and pharmaceutically acceptable salts thereof. The diastereomeric pair of stereoisomers may be separated from a suitable solvent, for example, by fractional crystallization, and the enantiomeric pair thus obtained may be separated into the individual stereoisomers by conventional means (e.g., by using an optically active acid or an optically active base as a resolving agent or on a chiral HPLC column). Furthermore, any enantiomer or diastereomer of a compound of this formula may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration. Embodiments described herein encompass all isomers (e.g., geometric, optical, stereoisomers, or tautomers, as well as isomeric mixtures) of the compounds of formula (I) disclosed herein. Embodiments herein encompass both racemic and optically active forms. Embodiments also include single crystal forms or mixtures thereof. In addition, embodiments herein also encompass amorphous, anhydrate, and hydrate forms of the compound. In addition, embodiments herein also include metabolites, salts, hydrates, and prodrugs of the compounds disclosed herein.
In some embodiments, salts of compounds described herein can comprise inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic amino acid salts, basic amino acid salts, or the like. In some embodiments, the inorganic acid salt may comprise a hydrochloride, hydrobromide, sulfate, nitrate, phosphate, or the like. In some embodiments, the salt may be selected from a hydrochloride, hydrobromide, sulfate, or phosphate salt. In some embodiments, the organic acid salt may comprise an acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, mesylate, esylate, p-toluenesulfonate, or benzenesulfonate salt. In some embodiments, the salt may be a mesylate salt or a p-toluenesulfonate salt.
In some embodiments, the inorganic basic salt may comprise: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; an aluminum salt; ammonium salts, and the like. In some embodiments, the organic basic salt may comprise diethylamine salt, diethanolamine salt, meglumine salt, N' -dibenzylethylenediamine salt, and the like.
In some embodiments, the acidic amino acid salt may comprise aspartate and glutamate. In some embodiments, the basic amino acid salt may comprise an arginine salt, a lysine salt, an ornithine salt, and the like.
Topical formulations
In some embodiments, the active ingredient is methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid (RVT-501):
embodiments herein are directed to topical compositions comprising therapeutically effective amounts of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, PEG400, PEG4000, white petrolatum, vitamin E, glyceryl monostearate/glyceride, isopropyl myristate, and water. In some embodiments, the concentration of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid is from about 0.01% to about 5% by weight of the topical composition. In some embodiments, the concentration of PEG400 is about 25% to about 75% by weight of the topical composition. In some embodiments, the concentration of PEG4000 is from about 15% to about 35% by weight of the topical composition. In some embodiments, the concentration of white petrolatum is about 1% to about 10% by weight of the topical composition. In some embodiments, the concentration of vitamin E is from about 0.01% to about 5% by weight of the topical composition. In some embodiments, the concentration of glyceryl monostearate/glyceryl ester is from about 2% to about 15% by weight of the topical composition. In some embodiments, the concentration of isopropyl myristate is from about 2% to about 25% by weight of the topical composition. In some embodiments, the concentration of water is from about 0.1% to about 10% by weight of the topical composition.
In certain embodiments, the topical composition includes 0.2% by weight methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, 50.5% by weight PEG400, 25.0% by weight PEG4000, 4.4% by weight white petrolatum, 0.1% by weight vitamin E, 8.0% by weight glyceryl monostearate, 10.0% by weight isopropyl myristate, and 2.0% by weight water.
In certain embodiments, the topical composition comprises 0.5% by weight methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, 50.5% by weight PEG400, 25.0% by weight PEG4000, 4.4% by weight white petrolatum, 0.1% by weight vitamin E, 8.0% by weight glyceryl monostearate, 10.0% by weight isopropyl myristate, and 2.0% by weight water.
The embodiments herein are directed to topical compositions comprising a therapeutically effective amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl]P-aminocarbonylbenzoic acid and a pharmaceutically acceptable topical excipient, wherein the 90% confidence interval for the ratio of the mean of the AUC of the topical composition (the overall geometric mean based on log transformed data) is within 80% -125% of the AUC of any of the foregoing topical compositions, and the C of the topical composition is within the range of 80% -125% of the AUC of any of the foregoing topical compositionsmaxHas a 90% confidence interval in the ratio of the mean values of (A) in C of the same aforementioned topical compositionmaxWithin 70% -143%.
One skilled in the art can formulate the topical compositions of the present invention into liquids, skin creams (toners), solutions, sprays, emulsions, moisturizers, sunscreens, creams, lotions, masks, suspensions, triturates, gels, pastes, foams, ointments, shampoos, adhesives, slurries, treated cloths or pads, and the like. In some embodiments, the topical composition is formulated as eye drops, ear drops, or a composition that can be applied to the surface of the teeth.
In the embodiments described herein, the topical composition can be applied to the skin by any means known in the art, including (but not limited to) by a nebulizer, a pump set, a brush, a swab, or other applicator. The applicator may provide for the application of a fixed or variable metered dose, such as a metered dose nebulizer, an energy storage metered dose pump, or a manual metered dose pump.
In embodiments described herein, the topical composition is formulated for application to a site once a day or multiple times a day.
Method of use of topical formulations
Embodiments described herein are directed to methods of treating mild to moderate atopic dermatitis in a patient in need thereof, the method comprising topically applying a topical composition comprising a therapeutically effective amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, PEG400, PEG4000, white petrolatum, vitamin E, glyceryl monostearate/glyceride, isopropyl myristate, and water. In embodiments described herein, the patients may be different patient populations, wherein the patients may be pediatric, adolescent, or adult. In the embodiments described herein, the therapeutically effective amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid is 0.2% or 0.5%. In embodiments described herein, the topical composition is applied once daily or twice daily. According to example 2: treatment of atopic dermatitis, example 3:
Embodiments herein are directed to methods of treating a skin condition in a patient in need thereof, the method comprising topically applying a topical composition comprising a therapeutically effective amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, PEG400, PEG4000, white petrolatum, vitamin E, glyceryl monostearate/glyceride, isopropyl myristate, and water. In certain embodiments, the patient is a juvenile.
In some embodiments, the concentration of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid is from about 0.01% to about 5% by weight of the topical composition. In some embodiments, the concentration of PEG400 is about 25% to about 75% by weight of the topical composition. In some embodiments, the concentration of PEG4000 is from about 15% to about 35% by weight of the topical composition. In some embodiments, the concentration of white petrolatum is about 1% to about 10% by weight of the topical composition. In some embodiments, the concentration of vitamin E is from about 0.01% to about 5% by weight of the topical composition. In some embodiments, the concentration of glyceryl monostearate/glyceryl ester is from about 2% to about 15% by weight of the topical composition. In some embodiments, the concentration of isopropyl myristate is from about 2% to about 25% by weight of the topical composition. In some embodiments, the concentration of water is from about 0.1% to about 10% by weight of the topical composition.
In certain embodiments, a method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition comprising 0.2% by weight of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, 50.5% by weight of PEG400, 25.0% by weight of PEG4000, 4.4% by weight of white petrolatum, 0.1% by weight of vitamin E, 8.0% by weight of glyceryl monostearate/glyceride, 10.0% by weight of isopropyl myristate, and 2.0% by weight of water.
In certain embodiments, a method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition comprising 0.5% by weight methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, 50.5% by weight PEG400, 25.0% by weight PEG4000, 4.4% by weight white petrolatum, 0.1% by weight vitamin E, 8.0% by weight glyceryl monostearate, 10.0% by weight isopropyl myristate, and 2.0% by weight water.
The embodiments herein are directed to topical compositions comprising a therapeutically effective amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl]P-aminocarbonylbenzoic acid and a pharmaceutically acceptable topical excipient, wherein the 90% confidence interval for the ratio of the mean of the AUC of the topical composition (the overall geometric mean based on log transformed data) is within 80% -125% of the AUC of any of the foregoing topical compositions, and the C of the topical composition is within the range of 80% -125% of the AUC of any of the foregoing topical compositionsmaxHas a 90% confidence interval in the ratio of the mean values of (A) in C of the same aforementioned topical compositionmaxWithin 70% -143%.
In certain embodiments, the skin condition treated in a patient in need thereof is selected from the group consisting of dermatitis; psoriasis; itching of the skin; acne; inflammation and redness of the skin; disorders associated with sebaceous glands; oily skin; dry skin; rosacea; burns; disorders affecting the palm or the foot; genetic disorders of the skin; warts; and any combination thereof. In some embodiments, the 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. In some embodiments, the psoriasis is selected from the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and any combination thereof. In some embodiments, the skin itch is selected from the group consisting of itch, prurigo, pityriasis rubra pilaris, lichen simplex chronicus, lichen planus, and any combination thereof. In some embodiments, the acne is selected from the group consisting of acne vulgaris, cystic acne, inflammatory acne, noninflammatory acne, and any combination thereof. In some embodiments, the inflammation and redness of the skin is selected from the group consisting of seborrheic dermatitis, urticaria eczema, urticaria, seborrheic eczema, and any combination thereof. In some embodiments, the disorder associated with sebaceous glands is selected from the group consisting of acne, follicular hyperkeratosis, sebaceous hyperplasia (sebostatis), sebaceous adenoma, sebaceous hyperplasia, excessive sebum production, seborrhea, sebaceous adenoma, sebaceous adenocarcinoma, seborrheic dermatitis, sebaceous cysts, and any combination thereof. In some embodiments, the oily skin is seborrhea. In some embodiments, the skin is selected from the group consisting of sebum enlargement, ichthyosis, xerosis, and any combination thereof. In some embodiments, the burn is sunburn. In some embodiments, the disorder affecting the palm or the foot is selected from the group consisting of palmoplantar pustulosis, exfoliative keratolysis, and any combination thereof. In some embodiments, the genetic disorder of the skin is darriella disease.
In some embodiments, a 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 ] p-aminocarbonylbenzoic acid, PEG400, PEG4000, white petrolatum, vitamin E, glyceryl monostearate/glyceride, isopropyl myristate, and water. In certain embodiments, the patient is a juvenile.
In some embodiments, the concentration of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid is from about 0.01% to about 5% by weight of the topical composition. In some embodiments, the concentration of PEG400 is about 25% to about 75% by weight of the topical composition. In some embodiments, the concentration of PEG4000 is from about 15% to about 35% by weight of the topical composition. In some embodiments, the concentration of white petrolatum is about 1% to about 10% by weight of the topical composition. In some embodiments, the concentration of vitamin E is from about 0.01% to about 5% by weight of the topical composition. In some embodiments, the concentration of glyceryl monostearate/glyceryl ester is from about 2% to about 15% by weight of the topical composition. In some embodiments, the concentration of isopropyl myristate is from about 2% to about 25% by weight of the topical composition. In some embodiments, the concentration of water is from about 0.1% to about 10% by weight of the topical composition.
In certain embodiments, a method of treating atopic dermatitis in a patient in need thereof comprises topically applying a topical composition comprising 0.2% by weight of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, 50.5% by weight of PEG400, 25.0% by weight of PEG4000, 4.4% by weight of white petrolatum, 0.1% by weight of vitamin E, 8.0% by weight of glyceryl monostearate/glyceride, 10.0% by weight of isopropyl myristate, and 2.0% by weight of water.
In certain embodiments, a method of treating atopic dermatitis in a patient in need thereof comprises topically applying a topical composition comprising 0.5% by weight of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, 50.5% by weight of PEG400, 25.0% by weight of PEG4000, 4.4% by weight of white petrolatum, 0.1% by weight of vitamin E, 8.0% by weight of glyceryl monostearate/glyceride, 10.0% by weight of isopropyl myristate, and 2.0% by weight of water.
In embodiments described herein, the methods are directed to applying the topical composition once per day. In embodiments described herein, the method is directed to applying the topical composition multiple times per day. In some embodiments, the topical composition is applied twice daily, three times daily, four times daily, or five times daily. In some embodiments, the topical composition is applied once in the morning and once 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 1 hour.
In embodiments described herein, the method is directed to applying the topical composition to multiple sites on the skin of the body. For example, the topical composition may be applied prophylactically to a large area of skin, or the topical composition may be applied to a specific site in need of treatment. In some embodiments, the topical composition is applied to the skin as a liquid, skin cream, solution, spray, emulsion, moisturizer, sunscreen, cream, lotion, mask, suspension, triturate, gel, paste, foam, ointment, shampoo, adhesive, serum, treated cloth, or pad. In some embodiments, the topical composition is applied to the eye as eye drops, placed in the ear canal as ear drops, or applied to the surface of the teeth.
Method for detecting serum level of methyl N- [3- (6, 7-dimethoxy-2-methylamino quinazoline-4-yl) phenyl ] p-aminocarbonylbenzoic acid and metabolite thereof
Embodiments herein are directed to methods of treating a condition in a patient, the methods comprising administering a topical composition comprising methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, and analyzing the blood of the patient for the levels of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid and metabolites. In an embodiment, 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, the methods comprising administering a topical composition comprising methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, and analyzing the blood of the child for the levels of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid and metabolites. In an embodiment, the metabolite is 4- ((3- (6, 7-dimethoxy-2- (methylamino) quinazolin-4-yl) phenyl) carbamoyl) benzoic acid.
In embodiments, 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 the levels of drugs and metabolites in the blood of a patient during treatment, the methods comprising administering a topical composition of the drug, collecting the blood of the patient, and analyzing the levels of the drug and metabolites in the blood. In an embodiment, the drug is methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid. In an embodiment, the metabolite is 4- ((3- (6, 7-dimethoxy-2- (methylamino) quinazolin-4-yl) phenyl) carbamoyl) benzoic acid.
In embodiments, the level of the drug and/or metabolite in the blood of the child or patient may determine a treatment recommendation, wherein a level of the drug and/or metabolite in the blood of the patient within acceptable limits may result in a recommendation to continue the drug treatment, and a level of the drug and/or metabolite in the blood of the patient beyond acceptable limits may result in 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, the method comprising: a) topically applying a topical composition comprising a therapeutically effective amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid, b) collecting a blood sample from the patient from about 10 μ L to about 1mL, c) spotting the blood sample onto a dried blood spot card, and d) analyzing the blood sample for the level of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid and 4- ((3- (6, 7-dimethoxy-2- (methylamino) quinazolin-4-yl) phenyl) carbamoyl) benzoic acid.
In embodiments, the patient is an infant or child and the volume of blood collected is about 1mL, about 500 μ L, about 100 μ L, about 50 μ L, about 40 μ L, about 30 μ L, about 25 μ L, about 20 μ L, about 15 μ L, or about 10 μ L.
Embodiments herein are directed to methods of detecting methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid and 4- ((3- (6, 7-dimethoxy-2- (methylamino) quinazolin-4-yl) phenyl) carbamoyl) benzoic acid, the method comprising: a) collecting a blood sample of about 10 μ L to about 1mL from a patient, b) spotting the blood sample onto a dry plaque card, c) punching a disc of about 3mm to about 10mm from the dry plaque 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 the amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid and 4- ((3- (6, 7-dimethoxy-2- (methylamino) quinazolin-4-yl) phenyl) carbamoyl) benzoic acid in the blood sample.
In embodiments, the volume of blood collected is about 1mL, about 500 μ L, about 100 μ L, about 50 μ L, about 40 μ L, about 30 μ L, about 25 μ L, about 20 μ L, about 15 μ L, or about 10 μ L.
In embodiments, the disc punched from the dried blood spot card is about 3mm, about 4mm, about 5mm, about 6mm, about 7mm, about 8mm, about 9mm, or about 10 mm.
In embodiments, the amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic acid quantitated from the blood sample is from about 1mg/mL to about 200 ng/mL. In embodiments, the amount of methyl N- [3- (6, 7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl ] p-aminocarbonylbenzoic 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 ] p-aminocarbonylbenzoic acid quantified from the blood sample is 160 ng/mL.
In embodiments, the amount of 4- ((3- (6, 7-dimethoxy-2- (methylamino) quinazolin-4-yl) phenyl) carbamoyl) benzoic acid quantified from a blood sample is from about 1mg/mL to about 200 ng/mL. In an embodiment, the amount of 4- ((3- (6, 7-dimethoxy-2- (methylamino) quinazolin-4-yl) phenyl) carbamoyl) benzoic acid quantified from a blood sample is 3 ng/mL. In an embodiment, the amount of 4- ((3- (6, 7-dimethoxy-2- (methylamino) quinazolin-4-yl) phenyl) carbamoyl) benzoic acid quantified from a blood sample is 160 ng/mL.
Examples
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