Topical formulations containing an mtor inhibitor

Abstract

A formulation of an mTOR inhibitor for topical administration with a longer shelf life. The formulation includes an mTOR inhibitor and a solvent capable of dissolving and stabilizing the inhibitor. The document also discloses the use of the formulation for the treatment of skin lesions and other diseases for topical administration.

Description

TECHNICAL FIELD

[0001] The present invention relates to a new formulation of mTOR inhibitors and a method of treating skin disorders. BACKGROUND

[0002] Sirolimus, also known as rapamycin, is the active ingredient of Rapamune® oral solution and tablets approved by Wyeth for the prevention of organ rejection in patients aged > 13 years receiving a kidney transplant. Sirolimus is an immunosuppressant agent that is suitable for preventing organ rejection in patients receiving a kidney transplant.

[0003] Everolimus is a semi-synthetic macrolide immunosuppressant derived from sirolimus. It is the active ingredient of Zortress® oral tablets approved by Novartis for the treatment of nephrotic syndrome in patients with focal segmental glomerulosclerosis (FSGS). Everolimus has never been approved for topical use.

[0004] Sirolimus and everolimus are poorly water-soluble. They are easily oxidized. They block the activation of T and B cells by inhibiting IL-2 and other cytokine receptor-dependent signal transduction mechanisms through their action on mTOR (mammalian target of rapamycin). As a serine-threonine kinase, mTOR is a downstream molecule of the PI3K-AKT pathway, which is involved in protein synthesis and cell cycle control. Sirolimus and everolimus have been shown to be inhibitors of tumor growth in xenograft models of various human cancer cell lines. Downregulation of p70 S6 kinase (S6K, a downstream kinase of mTOR involved in protein translation) in the xenograft models tested is directly correlated with their antitumor activity.

[0005] The immunosuppressive effect of everolimus was demonstrated in vitro by the blockade of mitogenic stimulated lymphocyte proliferation. In Europe, everolimus is used as an immunosuppressant in organ transplant patients to prevent rejection of the transplant. In addition, in vitro experiments showed a direct inhibitory effect of everolimus on the formation and activity of mouse and human osteoclasts, and to a lesser extent on the differentiation of osteoblasts.

[0006] Facial angiofibromas are disfiguring facial lesions present in up to 80% of patients with tuberous sclerosis complex (TSC). Lesions appear in early childhood and in some patients, lesions can coalesce and cause severe disfigurement. Typical facial angiofibromas are red to pink papules / nodules on a shiny, smooth surface when they first appear. They are usually, but not always, bilateral and symmetrically distributed in the central facial region, particularly in the nasolabial folds, and butterfly-shaped on the cheeks and chin.

[0007] Recent elucidation of the complex signaling relationship between the tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2) gene products and mTOR has led to a surge in research investigating the use of mTOR inhibitors, such as rapamycin and everolimus, in TSC. Most patients with TSC have mutations in either TSC1 or TSC2 that result in constitutive activation of mTOR. Because mTOR overactivity is the underlying mechanism of the disease, mTOR inhibitors have the potential to treat the underlying cause of TSC in patients.

[0008] Current treatment options for facial angiofibromas include destructive methods such as microdermabrasion, surgical excision, and laser therapy. General anesthesia may sometimes be required, depending on the individual's symptoms and ability to cope with surgery, particularly for those with TSC who have severe learning disabilities. While clinical case studies have shown efficacy for mTOR inhibitors in the treatment of facial angiofibromas, these studies typically used topical application of a powdered tablet. Summary of the Invention

[0009] This patent document provides a topical formulation of an mTOR inhibitor. This formulation is capable of penetrating the superficial dermis, delivering a therapeutically effective dose of the active ingredient. Furthermore, the active ingredient remains stable within the formulation over time, providing a convenient long-term treatment option. Furthermore, this invention significantly improves patient compliance and reduces the medical burden, as untreated skin lesions can progress to hospitalization or even require surgery.

[0010] This patent document also provides a topical composition or preparation of sirolimus or everolimus. The preparation can be an ointment, cream, solution, and suspension. In some embodiments, the preparation contains an effective dose of sirolimus or everolimus and a dermatological carrier. In some embodiments, the effective dose of the mTOR inhibitor in the preparation is 0.001% to 2% (by weight). The dermatological carrier is selected from an emollient, an emulsifier, a thickener, a preservative, a penetration enhancer, a buffer, and a solvent. In some embodiments, the emollient of the preparation is white petrolatum and mineral oil, the emulsifier is capryloylhexyl polyoxyethylene-8 glyceride, the thickener is glyceryl behenate, and the solvent is DMSO and propylene carbonate.

[0011] The present invention also provides a process for preparing a pharmaceutical ointment formulation, comprising (a) dissolving sirolimus or everolimus in one or more solvents; (b) providing an ointment base; and mixing the product of step (a) with the product of step (b).

[0012] The present invention also provides a method for treating TSC-related skin lesions, such as facial angiofibromas. The method comprises topically applying the formulation to the affected area once, twice, three times, four times daily, or as needed to provide a targeted, localized, effective concentration of the formulation. The formulation is not administered systemically, thereby reducing the typical side effects of systemic administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 HPLC chromatograms of sirolimus, Secco-rapamycin, and Isomer C in sirolimus ointment are shown. DETAILED DESCRIPTION

[0014] The present invention provides a pharmaceutical composition or formulation containing a suitable organic solvent for topical administration of a therapeutic agent. The formulation can be a solution, suspension, foam, spray, ointment, cream, or aerosol. Compared to traditional oral administration routes, the topical formulation disclosed herein bypasses the portal venous circulation and first-pass metabolism in the liver, significantly reducing potential side effects of systemic administration. Furthermore, the formulation effectively delivers the active ingredient to the affected area and eliminates issues associated with gastrointestinal irritation with oral administration. Furthermore, the stability of the active ingredient in the formulation can be maintained for an extended period of time.

[0015] Although the following text may refer to or illustrate specific embodiments of the formulations or methods for treating diseases or conditions, it is not intended to limit the scope of the embodiments or methods to such specific references or examples. Those skilled in the art may make various modifications based on practical and economic considerations, such as the ingredients in the formulation and their ratio in the solvent and the effective dose of the formulation for treating the disease.

[0016] Unless otherwise stated, the terms “a ” and “an ” It means "one or more" or "at least one". That is, with the indefinite article "a ” or "an ” The recitation of any element or component of the present invention does not exclude the possibility of more than one of that element or component being present.

[0017] As used herein, the term "about" refers to a reference number plus or minus 10% of the reference number.

[0018] As used herein, the term "subject" includes both humans and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cattle, horses, chickens, amphibians, and reptiles, but preferably mammals, such as non-human primates, sheep, dogs, cats, cattle, and horses. Preferred subjects include human patients in need of an enhanced immune response. The present method is particularly suitable for human patients with diseases that can be treated by enhancing the immune response.

[0019] " The terms "treat" or "treatment of a disease state" include: 1) preventing the disease state, i.e., preventing the clinical symptoms of the disease state in a subject who may be susceptible to or predisposed to the disease state but who does not yet develop or display symptoms of the disease state; 2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; or 3) or ameliorating the disease state, i.e., causing the disease state or its clinical symptoms to resolve temporarily or permanently.

[0020] As used herein, the term "effective dose" refers to the amount of an agent or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human being that is being sought by a researcher, clinician, or the like. Furthermore, the term "therapeutically effective dose" refers to any dose that cures, cures, prevents, or ameliorates a disease, disorder, or side effect, or reduces the rate of progression of a disease or disorder, as compared to a corresponding subject not receiving the dose. The term also includes doses within its scope that are effective to enhance normal physiological function. The specific dose can be readily determined by one of ordinary skill in the art using conventional methods.

[0021] As used herein, the term "preparation" or "composition" includes a product containing specified ingredients in predetermined amounts or proportions, as well as any product that is formed directly or indirectly by the combination of specified ingredients in specific amounts. The term is related to pharmaceutical compositions and includes products consisting of active ingredients and inert ingredients that constitute carriers, as well as any product that is produced directly or indirectly by the combination, complexation or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. In general, pharmaceutical preparations or compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or a fine solid carrier, or both, and then (if necessary) shaping the product into the desired form. In the pharmaceutical preparation or composition, the amount of active ingredient is sufficient to produce the desired effect on the disease process or condition. Therefore, the pharmaceutical preparations or compositions described herein include any preparation or composition made by mixing a compound of the present invention and a pharmaceutically acceptable carrier.

[0022] As used herein, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating, antibacterial and antifungal agent, isotonic and absorption delaying agent, and similar physiologically compatible substances. A "pharmaceutically acceptable carrier" does not cause adverse physiological effects upon administration to a subject. The carrier in a pharmaceutical composition must be "acceptable," that is, it must be compatible with and capable of stabilizing the active ingredient. One or more solubilizing agents may be used as a pharmaceutical carrier for delivering the active agent. Examples of pharmaceutically acceptable carriers include, but are not limited to, penetrants, emulsifiers, thickeners, emollients, biocompatible carriers, adjuvants, additives, and diluents to provide a composition that can be formulated. Other examples of carriers include colloidal silicon oxide, magnesium stearate, cellulose, and sodium lauryl sulfate. Other suitable pharmaceutical carriers and diluents, as well as pharmaceutical excipients for use with such carriers and diluents, are described in Remington's Pharmaceutical Sciences. Preferred carriers are suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., injection or infusion). The therapeutic compound may include one or more pharmaceutically acceptable salts.

[0023] A "pharmaceutically acceptable salt" is a salt of an active ingredient. This salt form retains the desired biological activity of the parent compound without any adverse toxicological effects. Pharmaceutically acceptable salts can be inorganic acid salts, organic acid salts, or metallic salts.

[0024] This patent document also provides a preparation for local delivery of therapeutic agents. The preparation generally includes a macrolide immunosuppressant or an mTOR inhibitor (approximately 0.01% to 15% by weight of the preparation) and a solvent (approximately 1% to 99% by weight of the preparation). The solvent is capable of dissolving the macrolide immunosuppressant, and the amount of macrolide immunosuppressant degraded in the preparation within 2 months is less than 4%. The preparation can be in a liquid or semi-solid state, with a longer shelf life, overcoming the instability of traditional dosage forms when exposed to solvents. Non-limiting macrolide immunosuppressants include tacrolimus, pimecrolimus, sirolimus, cytarabine, everolimus, and pharmaceutically acceptable salts thereof. The preparation can be a solution, foam, spray, gel, ointment, cream, or aerosol.

[0025] Sirolimus and everolimus are both mTOR inhibitors, each with three isomeric forms: isomers A, B, and C. Isomer B is the active form and converts to A or C in solution. Isomer C refers to the oxane isomer of sirolimus or everolimus. Seco-rapamycin is another isomer and degradation product that can be formed from isomer B of sirolimus.

[0026] Isomer B is the predominant isomer of sirolimus and contains an intramolecular kemikal group, forming a six-membered ring. Isomer C, which can be formed from isomer B, also contains an intramolecular kemikal group but has an adjacent keto group, thus forming a seven-membered ring (oxepane) in its structure. Sirolimus isomers B and C have the following structures:

[0027]

[0028] Isomer B of everolimus can also be converted to isomer C. The formulations disclosed herein minimize the conversion of sirolimus or everolimus to undesirable isomers (e.g., isomers A, C, and Secco-rapamycin) and maintain the therapeutically effective form of the agent for a longer period of time. In exemplary embodiments of the formulations described herein, although the undesirable isomer may be present in the formulation initially (hour 0), within about 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 1 year, 2 years, or 3 years, less than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.8%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the sirolimus or everolimus is converted from isomer B to isomer A, C, or Secco-rapamycin of sirolimus or everolimus under controlled room temperature or refrigerated conditions at 2-8°C. In some embodiments, less than about 0.1%, less than about 0.15%, less than about 0.2%, less than about 0.4%, less than about 0.5%, less than about 0.8%, or less than about 1% of sirolimus is converted or degraded from isomer B to secco-rapamycin within about 1 week, or 2 weeks from 0. In some embodiments, less than about 0.2%, less than about 0.4%, less than about 0.5%, less than about 0.6%, less than about 0.8%, or less than about 1% of sirolimus isomer B is converted to isomer C within about 2 weeks from 0. In some embodiments, less than about 0.2%, less than about 0.4%, less than about 0.5%, less than about 0.8%, less than about 1%, less than about 1.5%, less than about 2%, less than about 3%, or less than about 5% of sirolimus isomer B is converted to isomer C within about 4 weeks from 0.

[0029] In other examples of the presently disclosed formulations or methods, the amount of Isomer C or Cyclo-Lapachone is less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% of the total amount of Sirolimus or Everolimus over a period of about 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 year, 2 years, or 3 years at room temperature or refrigerated storage conditions (2-8°C). In some embodiments, the amount of Isomer C or Cyclo-Lapachone increases by less than 0.1%, 0.2%, 0.5%, 0.8%, 1%, 3%, 5%, or 10% over a period of 1 hour, 5 hours, 10 hours, 24 hours, 1 week, 2 weeks, 4 weeks, 2 months, 6 months, 12 months, 1 year, 2 years, or 3 years.

[0030] In some embodiments, the formulation can be a solution, foam, spray, gel, ointment, cream, or aerosol. Ointments are generally semisolid, contain little (e.g., less than 5%) or no water, but include hydrocarbons, waxes, or polyols as carriers. Creams are semisolid, contain water-in-oil or water-in-oil emulsions or aqueous microcrystalline dispersions. Gels are clear formulations containing a water or water-alcohol mixture of cellulose ethers, Carbromer, or other polymers. Foams are objects formed from gas pockets in a liquid or solid containing the active ingredient, are water-based and non-water-based spray formulations for topical use. Sprays are fine, jet-type liquid, coarser than vapor; produced by mixing a liquid from a fine opening in an atomizer with air, suitable for topical application. Aerosols are pressurized dosage forms containing a therapeutic active ingredient, release a fine dispersion of liquid and / or solid material in a gaseous medium upon actuation.

[0031] Topical formulations generally contain from about 0.01% to about 15% (including all subranges) by weight of the mTOR inhibitor and a dermatological carrier. In some embodiments, the mTOR inhibitor is present in the formulation at a weight ratio of about 0.01% to about 10%, 0.001% to about 5%, 0.001% to about 2%, 0.05% to about 5%, 0.05% to about 3%, 0.05% to about 2%, 0.05% to about 1.5%, 0.05% to about 1%, 0.1% to about 5%, from 0.1% to about 2%, from 0.1% to about 1%, 0.1% to about 0.5%, 0.3% to about 2%, 0.3% to about 1%, 0.3% to about 0.8%, 0.5% to about 2%, 0.5% to about 1%, about 0.05% to about 1%, about 0.1% to about 1%, about 0.1% to about 0.8%, about 0.1% to about 0.6%, about 0.1% to about 0.5%, about 0.2% to about 0.5%, or about 0.2% to about 0.4%. In some embodiments, the mTOR inhibitor is sirolimus or everolimus. In further exemplary embodiments, the formulation contains about 0.01%, 0.03%, 0.05%, 0.08%, 0.1%, 0.13%, 0.15%, 0.18%, 0.2%, 0.23%, 0.25%, 0.28%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0% by weight of sirolimus or everolimus, with Isomer B being the sole or predominant form.

[0032] In composition, the amount of solvent can be changed according to factors such as specific preparation and disease to be treated.Solvent not only plays the effect (so that preparation) of dissolving therapeutic agent (such as sirolimus or everolimus), but also can maintain the storage stability of therapeutic agent.In certain embodiments, the existence range of solvent (comprising all sub-ranges) is about 0.5%-50%.In certain embodiments, the scope of solvent in preparation is about 0.5%-20%, about 1% to about 10%, about 1% to about 8%, about 1% to about 5%, about 1% to about 3%, about 2% to about 10%, about 2% to about 8% or about 2% to about 5%.In further exemplary embodiments, solvent exists with about 0.5%, 1%, 1.5%, 2%, 2.5%, 5%, 7.5% or 10% weight. The solvent includes, but is not limited to, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), propylene glycol, propylene carbonate, octyldecyl polyoxyethylene-8 glyceride, and any combination of two or more thereof.

[0033] The ratio between the mTOR inhibitor and the solvent is from about 1:1 to about 1:100, about 1:10 to about 1:100, about 1:10 to about 1:80, about 1:10 to about 1:50, about 1:5 to about 1:20, about 1:5 to about 1:15, about 1:8 to about 1:25, about 1:10 to about 1:25, about 1:10 to about 1:15, about 1:20 to about 1:25, or about 1:10 to about 1:20. In some more exemplary embodiments, the ratio of the active ingredient mTOR inhibitor to the solvent is 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, and 1:25. In some embodiments, the mTOR inhibitor is sirolimus or everolimus, each in the form of isomer B as the active ingredient.

[0034] In some embodiments, the formulation or solvent contains less than 5%, less than 1%, less than 0.5%, less than 0.1%, less than 0.05%, less than 0.01% water. In some embodiments, the ratio of solvent to water in the formulation is greater than 5:1, 8:1, 10:1, 15:1, 20:1, or 30:1. In some embodiments, the ratio of sirolimus or everolimus to solvent is about 1:5 to 1:25, 1:8 to 1:20, or about 1:8 to 1:15.

[0035] In some embodiments of the topical formulations described herein, the mTOR inhibitor is isomer B of everolimus. In some embodiments, the solvent comprises one, two, three, or more of DMSO, NMP, dimethyl isosorbide (DMI), propylene glycol, glycerol, and propylene carbonate. In some embodiments, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% of the solvent is one of NMP, DMSO, propylene glycol, and propylene carbonate. In some embodiments, the solvent consists essentially of DMSO and propylene carbonate. In some embodiments, the solvent consists essentially of DMSO and NMP. In some embodiments, the solvent comprises a combination of propylene carbonate and DMSO. In some embodiments, the solvent comprises a combination of NMP and DMSO. In some embodiments, more than 70%, more than 80%, more than 90%, or more than 95% of the solvent is propylene carbonate. In some embodiments, more than 50%, more than 60%, more than 70%, more than 80%, more than 85%, more than 90%, more than 95%, or more than 99% of the solvent is NMP. In some embodiments, the ratio (weight ratio) of DMSO to propylene carbonate or DMSO to NMP in the solvent is about 5:1 to about 1:20, about 2:1 to about 1:10, about 1:1 to about 1:20, about 1:1 to about 1:15, about 1:1 to about 1:10, about 1:2 to about 1:10, about 1:4 to about 1:10, about 1:6 to about 1:10, about 1:8 to about 1:10, or about 1:7 to about 1:9. In some more exemplary embodiments, the ratio of DMSO to propylene carbonate or DMSO to NMP or the combination of DMSO and NMP with propylene carbonate in the solvent is about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, or 1:15.

[0036] In some embodiments of the topical formulations described herein, the mTOR inhibitor is isomer B of sirolimus. In some embodiments of the topical formulations described herein, the solvent comprises one, two, three, or more of DMSO, propylene glycol, NMP, dimethyl isosorbide (DMI), propylene glycol, glycerol, and propylene carbonate. In some embodiments, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% of the solvent is one of NMP, DMSO, and propylene carbonate. In some embodiments, the solvent consists essentially of DMSO and propylene carbonate. In some embodiments, the solvent consists essentially of DMSO and NMP. In some embodiments, the solvent comprises a combination of propylene carbonate and DMSO. In some embodiments, the solvent comprises a combination of NMP and DMSO. In some embodiments, more than 70%, more than 80%, more than 90%, or more than 95% of the solvent is propylene carbonate. In some embodiments, more than 50%, more than 60%, more than 70%, more than 80%, more than 85%, more than 90%, more than 95%, or more than 99% of the solvent is NMP. In some embodiments, more than 50%, more than 60%, more than 70%, more than 80%, more than 85%, more than 90%, more than 95% or more than 99% of the solvent is DMSO. In some embodiments, the ratio of DMSO to propylene carbonate or the ratio of DMSO to NMP in the solvent is about 5:1 to about 1:20, about 2:1 to about 1:10, about 1:1 to about 1:20, about 1:1 to about 1:15, about 1:1 to about 1:10, about 1:2 to about 1:10, about 1:4 to about 1:10, about 1:6 to about 1:10, about 1:8 to about 1:10, or about 1:7 to about 1:9. In some more exemplary embodiments, the ratio between DMSO and propylene carbonate or between DMSO and NMP in the solvent is about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0037] Preparation can comprise one or more pharmaceutically or dermatologically acceptable carriers, including surfactant, polymeric thickener, emollient, emulsifier, buffer, penetration enhancer and / or oily ointment base.Dermatological carrier is selected from emollient, emulsifier, thickener, preservative, penetration enhancer, buffer and solvent.In certain embodiments, the emollient of described composition is white vaseline.In certain embodiments, the emollient of described composition is mineral oil.In certain embodiments, the emollient of described composition is the combination of white vaseline and mineral oil.In certain embodiments, described surfactant or emulsifier is PEG-8 decyl or octyl polyoxyethylene-8 glyceride (Labrasol).In certain embodiments, thickener is glyceryl behenate (Compitrol 888ATO), and solvent is DMSO and propylene carbonate.

[0038] In some embodiments, the formulation contains a surfactant in an amount ranging from about 0.1% to about 10%, from about 1% to about 10%, from about 2% to about 8%, or from about 3% to about 6% by weight of the formulation. In some embodiments, the surfactant is capryloyl hexyl polyoxyethylene-8 glyceride.

[0039] In some embodiments, the formulation contains a thickening agent in an amount ranging from about 0.1% to about 10%, about 1% to about 10%, about 1% to about 8%, about 1% to about 5%, or about 1% to about 3% by weight of the formulation. In some embodiments, glyceryl behenate (Combitrol 888ATO).

[0040] Non-limiting examples of polymers having surfactant or emulsifying properties include, but are not limited to, hydrophobically modified polyacrylic acids available under the trade names Pemulen™ TR-1 and TR-2 from Lubrizol; water-soluble or water-swellable copolymers based on acrylamidoalkylsulfonic acid and cyclic N-vinylformamide available under the trade names AVC, manufactured by Clariant; a water-soluble or water-swellable copolymer based on acrylamidosulfonic acid and hydrophobically modified methacrylic acid, sold under the trade name Aristo HMB, manufactured by Clariant; and homopolymers of acrylamidosulfonic acid, tradename Granthix APP, manufactured by Grant Industries, Inc. Another class of polymeric emulsifiers worth noting includes hydrophobically modified, cross-linked anionic acrylic copolymers, including random polymers, but may also exist in other forms, such as block, star, graft, etc. In one embodiment, the hydrophobically modified, cross-linked anionic acrylic copolymer can be synthesized from at least one acidic monomer and at least one hydrophobic ethylenically unsaturated monomer. Suitable acidic monomers include those ethylenically unsaturated acid monomers that can be neutralized by a base. Suitable hydrophobic ethylenically unsaturated monomers include those containing hydrophobic chains with a carbon chain length of at least about 3 carbon atoms. Suitable emollients include vegetable oils, fats obtained from animals, semi-solid hydrocarbons obtained from petroleum, etc. Oily ointment bases include white ointment, yellow ointment, cetyl ester wax, paraffin, petroleum grease, white gypsum, white wax, yellow wax, etc. and mixtures thereof. Polymers having thickening properties include, but are not limited to, PEG-150 distearate, PEG-7 glyceryl cocoate, PEG 200 hydrogenated glyceryl palmitate, PEG-120 methyl glucose dioleate, carboxymethyl polymers, carboxyvinyl polymers, acrylates, Clo-C3O alkyl acrylate crosspolymer, and combinations thereof.

[0041] Penetration enhancers increase the permeability of the skin to increase the speed at which the drug penetrates the skin. Exemplary penetration enhancers include, but are not limited to, volatile organic solvents (such as ethanol), non-volatile organic solvents (amides, such as pyrrolidone; polyol ethers, such as glycol ethers; polyols, such as ethylene glycol; and derivatives thereof) and analogs and mixtures thereof. Skin penetration enhancers also include fatty acids, fatty acid esters, fatty alcohols, terpenes, ethylene glycol and glycol esters, 1,3-dioxolanes, macrocyclic ketones containing at least 12 carbon atoms, oxazolidinones and oxazolidinone derivatives, alkyl-2-(N,N-disubstituted amino)-alkanoates, (N,N-disubstituted amino)-alkanolalkanoates and mixtures thereof.

[0042] Emollients include, but are not limited to, mineral oil, dimethicone, glycerin, isopropyl palmitate, propylene glycol, paraffin, palm wax, cetyl alcohol, cetyl esters wax, cetyl alcohol, emulsifying wax, hydrated lanolin, lanolin, lanolin alcohol, microcrystalline wax, paraffin, stearic acid, stearyl alcohol, white wax, yellow wax, squalane, and any combination thereof.

[0043] In some embodiments, the surfactant is a polymer and is present in an amount ranging from about 0.1% to about 10% by weight of the formulation. In some embodiments, the thickener is a polymer and is present in an amount ranging from about 0.1% to 10% by weight of the formulation. In some embodiments, the ointment base is present in an amount ranging from about 20% to about 90% by weight of the formulation.

[0044] In some embodiments, the ointment is a topical preparation. In some embodiments, the preparation contains about 0.1% to about 0.5% of Isomer B of sirolimus, about 1% to about 10% or about 4% to about 5% of a solvent (primarily composed of DMSO and propylene carbonate in a ratio of about 1:5 to about 1:10 (e.g., about 1:8)), about 1% to about 10% (e.g., about 5%) of a surfactant (e.g., Labrasol), about 1% to about 10% (e.g., about 2%) of a thickener (e.g., Compritol 888ATO), and about 70% to about 80% of an ointment base.

[0045] The patent document also provides a process for preparing the aforementioned formulation. Developing this topical formulation requires the introduction of a suitable solvent and associated processing methods to dissolve and process the active pharmaceutical ingredient (API). APIs such as sirolimus and everolimus should have a high solubility in this solvent to facilitate further solution manufacturing. Furthermore, the processing method should not affect the stability of sirolimus and everolimus, thereby further ensuring quality, efficacy, and safety. The method generally includes:

[0046] (a) dissolving the mOTR inhibitor in a solvent to form a solution; and

[0047] (b) mixing the solution with one or more pharmaceutically acceptable carriers.

[0048] The ranges and compositions of the mOTR inhibitor, solvent and pharmaceutically acceptable carrier are as described above.

[0049] In some embodiments, one or more pharmaceutically acceptable carriers include an ointment base selected from white ointment, yellow ointment, hexadecyl ester wax, paraffin, vaseline, white latex, white wax, yellow wax, and any combination thereof. In some embodiments, one or more pharmaceutically acceptable carriers are prepared as a separate mixture or solution and then mixed with a solution of an mOTR inhibitor (such as sirolimus or everolimus). In some embodiments, the solvent is selected from N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), propylene glycol, dimethyl isosorbide (DMI), glycerol, and propylene carbonate, and any combination thereof.

[0050] The solvent used to dissolve the therapeutic agent (e.g., sirolimus or everolimus) can include one, two, three, or more organic components (e.g., DMSO, propylene carbonate). The agent can also be dissolved in one component and then the other component is added. The solution containing the inert carrier or component can be heated. The amount or ratio is the same as in the above-mentioned formula.

[0051] Exemplary embodiments are as follows:

[0052] 1. dissolving the active ingredient in a solvent to obtain solution I (the solvent comprises DMSO, NMP, propylene carbonate, or any combination thereof, such as a combination of DMSO and propylene carbonate or a combination of DMSO and NMP, in the proportions described above);

[0053] 2. Heat the remaining ingredients or carrier to above room temperature (e.g., 70°C to 90°C) to obtain Solution II, and then stir at 400 rpm for 10 minutes.

[0054] 3. Maintaining the same speed, let Solution II cool to 50-60°C, then add Solution I to Solution II and maintain the same speed at 50°C for 10 minutes.

[0055] 4. Stir the resulting solution at 300 rpm and cool to room temperature (optional).

[0056] 5. Pour the cooled solution into a test tube or bottle.

[0057] The active ingredients, solvents and other excipients are as described above. The present invention also provides a preparation prepared according to the method described herein.

[0058] This patent document also provides a method for treating skin diseases or conditions, such as skin lesions associated with tuberous sclerosis complex (TSC), in particular facial angiofibromas. Topical administration has many advantages over traditional routes of administration because of its large application area, ease of application, dynamicity, and non-invasiveness during treatment. First, topical administration bypasses the portal circulation, thereby bypassing the first-pass metabolism of the liver. Second, topical administration avoids the problem of changes in systemic absorption and metabolism. Third, topical administration has the potential to reduce gastrointestinal irritation associated with oral administration. In addition, topical administration also avoids the risks and patient non-compliance associated with parenteral treatment. In view of the potential disease mechanism and literature reports on the use of mTOR inhibitors such as rapamycin as topical drugs, the formulation of mTOR inhibitors disclosed herein is expected to provide excellent clinical benefits in the treatment of skin diseases or conditions (such as facial angiofibromas associated with TSC).

[0059] The method comprises topically applying a formulation disclosed herein to the area of ​​skin to be treated once or twice, or daily as needed, thereby providing a targeted, localized, effective concentration of the agent. The skin area can be any part of the subject's body, such as the face, trunk, and extremities. In some embodiments, the subject is a human. The exact dosage and frequency of administration may depend on the specific condition of the subject and the agent. A person skilled in the art can determine an appropriate dosing regimen based on the formulation disclosed herein and existing knowledge in relevant medical fields (e.g., the treatment of facial angiofibromas). The agent is not administered systemically, thereby reducing the typical side effects of systemic administration.

[0060] Local diseases or conditions that can be treated with the formulations disclosed herein include, but are not limited to, angiofibroma, atopic dermatitis, congenital cataract, anterior uveitis, port wine stains, oral mucosal disease caused by graft-versus-host disease, oral lichen planus, cutaneous T-cell lymphoma, non-melanoma skin cancer, Sturge-Weber syndrome, multiple endocrine neoplasia type 1 (MEN1), Birt-Hogg-Dub disease, and leukemia. é syndrome (BHDS), Crohn's disease, vitiligo, vulvar lichen, vernal keratoconjunctivitis, cutaneous lupus erythematosus, severe seborrheic dermatitis, psoriasis, allergic conjunctivitis, nodular urticaria, ulcerative colitis, tinea versicolor, psoriasis vulgaris, chronic hand dermatitis, Kaposi's sarcoma, and hemangioma.

[0061] For each of the above-mentioned diseases or conditions, the present preparation can be topically applied once, twice, three times, four times or as needed multiple times per day. Alternatively, the composition can be applied once every 2, 3, or 4 days, depending on the specific circumstances. The actual dosage and frequency of applying the composition can depend on the specific disease condition and can be determined by one of ordinary skill in the art (e.g., a dermatologist) without the need for undue experimentation. In an exemplary embodiment, sirolimus or everolimus can be administered in the above-mentioned composition at a dosage of about 0.01 g to about 10 g per day.

[0062] Examples

[0063] The following examples are intended to enable those skilled in the art to practice the present invention and are merely illustrative of the present invention. These examples should not be construed as limiting the scope of the present invention as defined in the claims.

[0064] Example 1 Ointment-formulation composition I

[0065] This example evaluates the solubility and stability of sirolimus and everolimus together or individually in various FDA-approved topical solvents and co-solvent systems, such as diethylene glycol monoethyl ether (Gattefosse P), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), ethanol, capryloylformyl polyoxy-8 glyceride (produced by Gattefosse ) and propylene carbonate.

[0066] In Transcutol P, the solubility of sirolimus is greater than 80 mg / ml at room temperature and under refrigeration, and the solubility of everolimus is greater than 100 mg / ml at room temperature and under refrigeration. In NMP, the solubility of sirolimus is greater than 100 mg / ml at room temperature and under refrigeration, and the solubility of everolimus is greater than 100 mg / ml at room temperature and under refrigeration. In DMSO, the solubility of sirolimus is greater than 100 mg / ml at room temperature, and the solubility of everolimus is greater than 200 mg / ml at room temperature. The melting point of DMSO is 19°C (66 ℉ ; 292K), so it can freeze under refrigeration. In propylene carbonate, the solubility of sirolimus is about 30mg / ml under room temperature and refrigeration, while the solubility of everolimus is greater than 100mg / ml under room temperature and refrigeration.

[0067] Table 1.

[0068]

[0069] The ointment composition of this embodiment is prepared in the following manner:

[0070] 1. Dissolve sirolimus in DMSO and propylene carbonate to form solution I;

[0071] 2. Heat mineral oil, white petrolatum, and Compritol 888ATO at 70°C to 75°C to form a solution. Stir at 400 rpm for 10 minutes to form Solution II.

[0072] 3. Maintaining the same speed, let Solution II cool to 50°C, then add Solution I to Solution II and maintain the same speed at 50°C for 10 minutes.

[0073] 4. Stir the resulting solution at 300 rpm and allow it to cool to room temperature;

[0074] 5. Pour the cooled solution into a test tube or bottle.

[0075] Example 2 Ointment-formulation composition II

[0076] Table 2.

[0077]

[0078] The preparation of the formulation in this example is substantially the same as that of the composition in Example 1, except that solution I is everolimus dissolved in DMSO.

[0079] Example 3 Ointment-formulation composition III

[0080] Table 3.

[0081]

[0082] The preparation of the formulation in this example is substantially the same as that of the composition in Example 1, except that Solution I is everolimus dissolved in propylene carbonate.

[0083] Example 4 Ointment-formulation composition IV

[0084] Table 4.

[0085]

[0086]

[0087] The preparation method of the formulation in this example is basically the same as that of the composition in Example 1.

[0088] Example 5 Ointment-formulation composition V

[0089] Table 5.

[0090]

[0091]

[0092] The preparation of the formulations in this example was essentially the same as for the composition of Example 1. The table shows the percentage of Isomer C in the total amount of everolimus at different time points.

[0093] Example 6 Concentration (%) of everolimus isomer C in stability study in different solvents

[0094] Table 6.

[0095]

[0096] The stability of everolimus at a concentration of 20 mg / ml in Transcutol P, NMP, DMSO and propylene carbonate at 40°C and the stability of everolimus at a concentration of 80 mg / ml in Transcutol P, NMP, DMSO, ethanol, Labrasol and propylene carbonate at 50°C was investigated. DMSO and propylene carbonate have a very good stabilizing effect on sirolimus and can be used together or separately as solubilizing agents. DMSO, NMP and propylene carbonate have a stabilizing effect on sirolimus and everolimus and can be used together or separately as solubilizing agents.

[0097] The concentration of everolimus in the solvent and co-solvent systems was 80 mg / ml. The solutions were stored in an oven at 50°C and samples were evaluated at time 0, 1 h, 2 h and 4 h.

[0098] All the solvent or co-solvent systems in Table 6 provide a relatively stable environment for everolimus, even at high temperatures and high concentrations compared to the solvents in Table 6. In DMSO, propylene carbonate and NMP, the detection of Isomer C of everolimus increased by less than 1.5% from 0 h to 4 h.

[0099] Example 7 Stability of sirolimus isomer C in different solvents at 40°C for 24 hours

[0100] Table 7.

[0101]

[0102] The concentration of sirolimus in the solvent and co-solvent systems was 20 mg / ml. The solutions were stored in an oven at 40°C and samples were evaluated by HPLC analysis at 0, 1, 4 and 24 hours. The table shows the percentage of Isomer C of sirolimus in the total amount of sirolimus at different time points.

[0103] Sirolimus is very stable in the solvents NMP, DMSO and propylene carbonate. Although there is a small amount of Isomer C at 0 h, less than 1.5% of sirolimus is converted to Isomer C in NMP, DMSO and propylene carbonate over 24 hours.

[0104] Example 8: Secco-rapamycin in various solvents at 40°C for 24 hours

[0105] Table 8

[0106]

[0107] ND not detected

[0108] Secco-rapamycin, the primary decomposition product of sirolimus and the ring-opened form of rapamycin (sirolimus), was also quantified in the solvent systems. Table 8 shows the concentration of Secco-rapamycin in the solvent and cosolvent systems. The table shows the percentage of Secco-rapamycin in the total amount of sirolimus at different time points. Initial concentrations of Secco-rapamycin were undetectable in the samples tested. Less than 0.5% of sirolimus was converted or degraded to Secco-rapamycin in propylene carbonate, DMSO, and NMP.

[0109] DMSO and propylene carbonate exhibit excellent stabilization effects on sirolimus. However, propylene carbonate has a relatively low solubility for sirolimus, while DMSO has a relatively low freezing point of 19°C, making these two solvents unsuitable as solvents for the active ingredient when used alone. Surprisingly, in the formulation described herein, the solvent system consisting of DMSO and propylene carbonate effectively solubilized the active ingredient and maintained its stability.

[0110] Example 9 Optimizing the Ratio of DMSO and Propylene Carbonate in Sirolimus Ointment by Evaluating the Effect of Isomer C and Seco-Rapamycin Concentration on Stability

[0111] Table 9.

[0112]

[0113]

[0114] The ratio of propylene carbonate to DMSO in the sirolimus ointment formulation was further evaluated, and the results are listed in Table 9. In the final formulation, the ratio of DMSO to propylene carbonate was 2.5%:2.5%; 1.0%:4.0%; 5.0%:5.0% and 0.5%:4.0% (w / w), and the API was dissolved in the above solvent systems and its stability was evaluated under different conditions over 10 weeks. The formulations with a DMSO:propylene carbonate ratio of 0.5%:4% (0928-1 and 0928-2) showed the best stability, with less than 0.5% of secco-rapamycin and less than 3% of isomer C after 10 weeks of storage at 25°C / 60%RH. The HPLC chromatogram of the sirolimus ointment shows the amount of sirolimus, secco-rapamycin and isomer C, as shown in Figure 9. Figure 1 shown.

[0115] It will be understood by those skilled in the art that the present invention is not limited to what has been particularly shown and described. The scope of the invention is defined by the claims appended hereto. The above description should be understood to represent only illustrative examples of embodiments. This description does not attempt to exhaustively list all possible variations. Alternative embodiments may not be proposed for a particular part of the invention, may result from a different combination of the described parts, or other undescribed alternative embodiments may be applicable to a certain part, which should not be construed as a negation of these alternative embodiments. It is understood that many of those undescribed embodiments are within the literal scope of the following claims, and others are equivalent.

Claims

1. A formulation for local delivery of a therapeutic agent, comprising: An mTOR inhibitor, the content of which in the preparation is 0.01% to 5% by weight, wherein The mTOR inhibitor is sirolimus, A solvent, the content of which in the formulation is 1% to 20% by weight, the solvent consisting of DMSO and propylene carbonate, wherein the ratio of DMSO to propylene carbonate is 1:5 to 1:10, and Surfactant capryloyl hexyl polyoxyethylene-8 glyceride, the amount of which is 1% to 10% by weight of the preparation, wherein the solvent is capable of dissolving the mTOR inhibitor, less than 2% of sirolimus is converted from isomer B to isomer C within 2 weeks, less than 5% of sirolimus is converted from isomer B to isomer C within 6 months, and less than 0.2% of sirolimus is degraded to secco-rapamycin within 2 weeks, The structural formula of isomer B is: The structural formula of isomer C is:

2. The formulation according to claim 1, wherein the weight range of the mTOR inhibitor is 0.05% to 3%.

3. The preparation according to claim 1, wherein the weight range of the solvent is 2% to 10%.

4. The preparation according to claim 1, wherein the ratio of sirolimus to solvent is 1:10 to 1:

25.

5. The preparation according to claim 1, further comprising one or more pharmaceutically acceptable carriers selected from the group consisting of thickeners, emollients, emulsifiers, buffers, penetration enhancers and ointment bases.

6. The preparation according to claim 5, wherein the thickener is glyceryl behenate and is used in an amount of 1% to 5% by weight of the preparation.

7. The formulation according to claim 5, wherein the thickener is diglyceride and is used in an amount of 1% to 10% by weight of the formulation.

8. The preparation according to claim 5, wherein the ointment base accounts for 20% to 90% by weight of the preparation.

9. The formulation of claim 5, wherein the emollient is selected from the group consisting of mineral oil, dimethicone, glycerin, isopropyl palmitate, propylene glycol, petrolatum, palm wax, cetyl alcohol, cetyl esters, emulsifying wax, lanolin, microcrystalline wax, paraffin, stearic acid, stearyl alcohol, white wax, yellow wax, squalane, and any combination thereof.

10. The preparation according to claim 1, which is in the form of a solution, foam, spray, gel, ointment, cream or aerosol.

11. The preparation according to claim 1, which is an ointment.

12. The preparation of claim 1 in the preparation of a medicament for treating a local disease in a subject use, in, The localized disease is selected from the group consisting of angiofibroma, atopic dermatitis, congenital cataract, anterior uveitis, cutaneous T-cell lymphoma, non-melanoma skin cancer, Sturge-Weber syndrome, Birt-Hogg-Dubé syndrome (BHDS), Crohn's disease, vitiligo, cutaneous lupus erythematosus, psoriasis, and hemangioma.

13. A method for preparing the preparation of claim 1, comprising: (a) dissolving an mTOR inhibitor in a solvent consisting of DMSO and propylene carbonate, wherein the ratio of DMSO to propylene carbonate is 1:5 to 1:10, to form a solution; and (b) mixing the solution with a surfactant and one or more pharmaceutically acceptable carriers.

14. The method of claim 13, wherein the one or more pharmaceutically acceptable carriers comprises an ointment base selected from cetyl esters wax, paraffin, petrolatum, white latex, white wax, yellow wax, and any combination thereof.

15. The method according to claim 14, wherein the obtained preparation is in the form of a white ointment or a yellow ointment.

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