External preparations for treating epilepsy or autism spectrum disorder

Abstract

[Problem] To provide a pharmaceutical agent for treating epilepsy, a pharmaceutical agent for treating an autism spectrum disorder, and / or a pharmaceutical agent for treating an anxiety disorder which have high safety and are easily administered. [Solution] An external preparation containing, as an active ingredient, at least one selected from the group consisting of sirolimus and a sirolimus derivative is easily administered, and has a high level of safety as a therapeutic agent for epilepsy, an autism spectrum disorder, and / or an anxiety disorder. A suitable active ingredient may include, for example, sirolimus, everolimus, temsirolimus, ridaforolimus, and zotarolimus.

Description

[Technical field]

[0001] The present invention relates to the treatment of epilepsy, the treatment of autism spectrum disorders, and the treatment of anxiety disorders. [Background technology]

[0002] The present inventors have discovered that skin lesions associated with tuberous sclerosis can be treated by using an external preparation containing sirolimus (rapamycin), and have developed it as a pharmaceutical product (Patent Document 1).

[0003] Epilepsy is a chronic brain disease that causes paroxysmal symptoms such as impaired consciousness and convulsions due to excessive electrical excitation of nerve cells in the brain. It has been reported that oral administration of sirolimus or everolimus may be effective for epilepsy (Non-Patent Documents 1 to 3), but since antiepileptic drugs need to be administered continuously, safer drugs are required. In addition, easy administration is also required to maintain good adherence and continue the drug.

[0004] Autism spectrum disorder refers to a concept almost identical to that of "pervasive developmental disorder," and includes autism, Asperger's syndrome, and the like. Experiments of intraperitoneal administration in mice have suggested the possibility that sirolimus may reverse autism (Non-Patent Document 4). The present inventors have also reported that oral administration of everolimus improves autism (Non-Patent Document 5). Since drugs for autism spectrum disorder must also be administered continuously, safer drugs are required. In addition, ease of administration is also required to maintain good adherence and continue the treatment. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2012 / 105521 [Non-patent literature]

[0006] [Non-Patent Document 1] French JA, et al., Lancet 2016 Oct 29;388(10056):2153-2163 [Non-Patent Document 2] Krueger DA, et al., Ann Neurol 2013;74:679-87 [Non-Patent Document 3] Cardamone M, et al., J Pediatr 2014; 164:1195-200 [Non-Patent Document 4] Sato A, et al., Nature Communications 2012; 3:1292 [Non-Patent Document 5] Ishii R, et al., Neuropsychiatric Electrophysiology 2015 1:6 Summary of the Invention [Problem to be solved by the invention]

[0007] An objective of the present invention is to provide an external preparation for treating epilepsy, an external preparation for treating autism spectrum disorder, and / or an external preparation for treating anxiety disorder that is highly safe and easy to administer. [Means for solving the problem]

[0008] The present inventors have found that epilepsy, autism spectrum disorder, and / or anxiety disorder can be treated by external application of sirolimus or a sirolimus derivative, and have completed the present invention. That is, the present invention includes the following aspects. 1. An external preparation for treating epilepsy containing as an active ingredient at least one selected from the group consisting of sirolimus and sirolimus derivatives. 2. The topical preparation described in the preceding item 1, wherein the sirolimus derivative is at least one selected from the group consisting of everolimus, temsirolimus, ridaforolimus and zotarolimus. 3. The external preparation described in the preceding item 1 or 2, wherein the epilepsy is epilepsy associated with tuberous sclerosis. 4. The external preparation according to any one of the preceding items 1 to 3, which is for administration to the head. 5. The topical preparation according to any one of claims 1 to 4, which contains a lower alcohol. 6. An external preparation for treating autism spectrum disorder, comprising as an active ingredient at least one selected from the group consisting of sirolimus and sirolimus derivatives. 7. The external preparation described in the preceding item 6, wherein the autism spectrum disorder is autism. 8. The external preparation according to the preceding item 6, wherein the autism spectrum disorder is impairment in establishing interpersonal relationships and / or fixation or obsession in autism spectrum disorder. 9. The external preparation described in the preceding item 6, wherein the autism spectrum disorder is autism spectrum disorder associated with tuberous sclerosis complex. 10. An external preparation for treating anxiety disorders, comprising as an active ingredient at least one selected from the group consisting of sirolimus and sirolimus derivatives. 11. The external preparation described in the preceding item 10, wherein the anxiety disorder is generalized anxiety disorder. 12. The external preparation described in the preceding item 10, wherein the anxiety disorder is an anxiety disorder associated with tuberous sclerosis complex. 13. A method for treating epilepsy comprising topically applying at least one selected from the group consisting of sirolimus and sirolimus derivatives. 14. Apply externally to the head using the method described in paragraph 13 above. 15. A method for treating an autism spectrum disorder, comprising topically applying at least one selected from the group consisting of sirolimus and sirolimus derivatives. 16. A method for treating an anxiety disorder comprising topically applying at least one selected from the group consisting of sirolimus and sirolimus derivatives. Effect of the Invention

[0009] The topical preparation of the present invention is effective in treating epilepsy symptoms by transdermal or transmucosal administration, and can suppress epileptic seizures and reduce the number of seizures.

[0010] The topical preparation of the present invention is effective in treating autism spectrum disorders by transdermal or transmucosal administration.

[0011] The topical preparation of the present invention is effective in treating anxiety disorders by transdermal or transmucosal administration.

[0012] The topical preparation of the present invention is a safe drug with less side effects and less impact on other organs and tissues because it exerts its effect without increasing the blood concentration. In addition, the method of applying or attaching to the skin or mucous membrane is a simple administration method, and the preparation is suitable for long-term continuous administration. In addition, it can be administered to patients and children who have difficulty with oral administration. It is a preparation that can be administered even when symptoms that are difficult to administer orally occur, such as during epileptic seizures. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is a photograph of mice with sirolimus gel or placebo applied to their shaved foreheads. [Diagram 2] Figure 2 shows the results of applying 5 mg (10 μg of sirolimus) of 0.2% by weight sirolimus gel or placebo (base only) once a day to model mice and control mice (normal mice), and measuring the number of epileptic seizures for 7 days (n=4 per group). Homo is a model mouse with tuberous sclerosis, and Ct is a control mouse (normal mouse). ** P<0.01, *** P<0.001 [Diagram 3] Figure 3 is a graph showing the results of intraperitoneal administration of sirolimus (3 mg / kg / day) or saline once a day for 7 days to model mice and control mice (normal mice) (n=6 per group). Homo is a model mouse with tuberous sclerosis, and Ct is a control mouse (normal mouse). * P<0.05, ** P<0.01 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention is not limited to the embodiments described below, and various modifications are possible within the scope of the claims. The embodiments and examples obtained by appropriately combining the technical means disclosed in the different embodiments and examples are also included in the technical scope of the present invention.

[0015] The external preparation for treating epilepsy, the external preparation for treating autism spectrum disorder, and the external preparation for treating anxiety disorder according to the present invention contain at least one selected from the group consisting of sirolimus and sirolimus derivatives as an active ingredient.

[0016] The sirolimus derivative is not particularly limited, but can be, for example, everolimus, temsirolimus, ridaforolimus and zotarolimus. These have a basic structure almost the same as that of sirolimus, and are known to have the same physiological activity as sirolimus. Therefore, these sirolimus derivatives can be used as an active ingredient according to one embodiment of the present invention, similar to sirolimus.

[0017] Sirolimus has already been used as an external therapeutic agent for skin lesions associated with tuberous sclerosis, and its safety and absorbability have been confirmed in clinical trials. Therefore, sirolimus is a more preferred active ingredient.

[0018] The external preparation for treating epilepsy, the external preparation for treating autism spectrum disorder, and the external preparation for treating anxiety disorder according to the present invention can be used to treat various symptoms developed in patients with the diseases.

[0019] As used herein, the term "treatment" includes, for example, the following concepts: (1) Preventing the onset of one or more symptoms of a disease or reducing the risk of onset. (2) Preventing or reducing the risk of recurrence of one or more symptoms associated with a disease. (3) Alleviating or improving one or more symptoms associated with a disease, or eliminating the symptoms. (4) Suppressing the aggravation or progression of one or more symptoms related to the disease. (5) reducing the rate of progression of one or more symptoms associated with the disease.

[0020] Epilepsy is a disease that causes repeated epileptic seizures, such as sudden loss of consciousness and unresponsiveness, and the symptoms of epileptic seizures vary depending on which area of ​​the brain is disturbed or excited by electrical signals. The topical preparation for treating epilepsy of the present invention can suppress epileptic seizures. There is no limitation on the epileptic seizures that can be treated by the present invention, and all epileptic seizures are included. Preferably, epileptic seizures in focal cortical dysplasia type II are treated. In addition, the preparation is effective in suppressing epileptic seizures associated with tuberous sclerosis.

[0021] The autism spectrum disorder in the present invention is almost the same as a pervasive developmental disorder. The autism spectrum disorder in the present invention includes autism, Asperger's syndrome, and other pervasive developmental disorders. Autism spectrum disorder has three symptoms (characteristics): impaired interpersonal relationships, impaired communication, and bias in interests and behavior (persistence, obsession, etc.). The topical preparation of the present invention is preferably for treating autism. The topical preparation of the present invention is also preferably for treating autism spectrum disorder associated with tuberous sclerosis. More preferably, the topical preparation of the present invention is for treating autism associated with tuberous sclerosis. The topical preparation of the present invention can also be preferably used for improving impaired construction of interpersonal relationships, reduced sociability, impaired communication, bias in interests and behavior, obsession, obsession, repetitive behavior, and / or sensory abnormalities in autism spectrum disorder. The topical preparation of the present invention is preferably used for treating disorders of interpersonal relationship construction and / or perseveration and fixation associated with autism spectrum disorder, and more preferably used for treating disorders of interpersonal relationship construction and / or perseveration and fixation associated with tuberous sclerosis.

[0022] The anxiety disorder in the present invention includes generalized anxiety disorder, anxiety disorder due to a general physical disease, etc. The topical preparation of the present invention is preferably for treating generalized anxiety disorder or anxiety disorder associated with a general physical disease. It can be preferably used for treating anxiety disorder associated with tuberous sclerosis.

[0023] The topical preparation for treating epilepsy and the topical preparation for treating autism spectrum disorder of the present invention are preferably topical preparations for administration to the head. The administration site of the topical preparation of the present invention is preferably the head. The head includes the face, parietal region, occipital region, temporal region, nasal cavity, oral cavity, etc., and the preferred administration site is the face. The preferred administration method is application or attachment to the face. The topical preparation of the present invention is preferably a topical preparation for administration to the face.

[0024] The topical agent of the present invention can be used for humans and non-human mammals. Examples of non-human mammals include mammals other than humans. Examples of mammals other than humans include even-toed ungulates such as cows, wild boars, pigs, sheep, and goats, odd-toed ungulates such as horses, rodents such as mice, rats, hamsters, and squirrels, lagomorphs such as rabbits, and carnivores such as dogs, cats, and ferrets. In addition, these non-human animals can be preferably livestock or companion animals (pets).

[0025] The administration route of the topical agent of the present invention is transdermal, transmucosal, etc. Therefore, the topical agent of the present invention may be a gel, an ointment, a cream, a patch, a nasal drop, a suppository, a cataplasm, a liniment, a lotion, an inhalant, a spray, etc. Gels are more preferable dosage forms because the active ingredient is more easily absorbed into the skin tissue than ointments, etc.

[0026] The topical preparation of the present invention can effectively treat epilepsy, autism spectrum disorder, and / or anxiety disorder by external application. It exerts a therapeutic effect without increasing the blood concentration of the drug, and is therefore a safe preparation with minimal effect on other organs and reduced side effects.

[0027] The amount of the active ingredient contained in the topical preparation of the present invention is not particularly limited. From the viewpoint of suppressing the migration of the active ingredient into the blood, suppressing systemic side effects, and obtaining a therapeutic effect, the following concentrations are suitable.

[0028] The lower limit of the concentration of the active ingredient may be 0.01 wt % or more, 0.02 wt % or more, 0.03 wt % or more, 0.04 wt % or more, 0.05 wt % or more, 0.06 wt % or more, 0.07 wt % or more, 0.08 wt % or more, 0.09 wt % or more, or 0.1 wt % or more, based on the total weight of the topical preparation.

[0029] The upper limit of the concentration of the active ingredient may be 2.0 wt% or less, 1.5 wt% or less, 1.0 wt% or less, 0.9 wt% or less, 0.8 wt% or less, 0.7 wt% or less, 0.6 wt% or less, 0.5 wt% or less, 0.4 wt% or less, 0.3 wt% or less, 0.25 wt% or less, or 0.2 wt% or less, based on the total weight of the topical preparation.

[0030] The concentration of the active ingredient is, for example, preferably 0.01 to 2.0% by weight, more preferably 0.03 to 1.0% by weight, more preferably 0.04 to 0.8% by weight, and even more preferably 0.05 to 0.4% by weight, based on the total weight of the topical preparation.

[0031] The daily dose of sirolimus or a sirolimus derivative per unit surface area of ​​a living body is not particularly limited.

[0032] For example, the lower limit of the dose is 0.0001 mg / cm per day. 2 More than 0.0002mg / cm 2 More than 0.0005mg / cm 2 More than 0.001mg / cm 2 More than 0.002 mg / cm 2 More than 0.003mg / cm 2 It could be more than that.

[0033] For example, the upper limit of the dose is 2 mg / cm per day. 2 Below 1mg / cm 2Below, 0.5mg / cm 2 Below, 0.05mg / cm 2 Below, 0.04mg / cm 2 Below, 0.03mg / cm 2 It can be the following:

[0034] The dosage is, for example, 0.0001 to 2 mg / cm 2 , preferably 0.0002 to 1 mg / cm 2 , more preferably 0.0005 to 0.5 mg / cm 2 , more preferably 0.001 to 0.05 mg / cm 2 The above-mentioned amount of sirolimus or a sirolimus derivative may be administered once a day or in divided doses a few times a day by application or the like. In other words, it is preferable that the topical preparation of the present invention is one that can achieve the above-mentioned dosage.

[0035] The topical preparation can be prepared according to a known method. For example, a gel can be prepared by gelling a solution containing sirolimus or a sirolimus derivative. An ointment can be prepared by mixing an ointment base with sirolimus or a sirolimus derivative. Gels, ointments and creams are specifically described below.

[0036] (A) Gel

[0037] When a solution containing sirolimus or a sirolimus derivative is to be gelled, the solution may be gelled using a gelling agent, such as carboxyvinyl polymer, carboxymethylcellulose, aluminum hydroxide, bentonite, etc.

[0038] The specific composition of the carboxyvinyl polymer is not particularly limited, and Carbopol (registered trademark), Hiviswako (registered trademark), Akpek (registered trademark), etc. can be used. Among these, Carbopol (registered trademark) 934P NF or Carbopol (registered trademark) 980 is preferred from the viewpoint of good texture when applied as an external preparation.

[0039] For example, when Carbopol (registered trademark) 934P NF or Carbopol (registered trademark) 980 is used, Carbopol (registered trademark) 934P NF or Carbopol (registered trademark) 980 is first added to a solution containing sirolimus or a sirolimus derivative. Furthermore, the pH of the solution is adjusted to neutral by adding a pH adjuster (e.g., triethanolamine, trishydroxymethylaminomethane). This can induce gelation of the solution.

[0040] The gel according to one embodiment of the present invention preferably contains alcohol. By containing alcohol, the active ingredient contained in the gel can be efficiently absorbed into the skin tissue. Preferred alcohols are lower alcohols, more preferably alcohols having 2 to 4 carbon atoms. More preferred examples of alcohols include ethanol and isopropanol. From the viewpoint of more efficiently and safely absorbing the active ingredient into the skin tissue, ethanol is particularly preferred.

[0041] The amount of the alcohol is not particularly limited, and may be an amount that can sufficiently dissolve sirolimus or a sirolimus derivative. For example, the weight of the alcohol may be 100 to 300 times, or 120 to 250 times, the weight of sirolimus or a sirolimus derivative. Based on the total weight of the external preparation, the amount of alcohol is preferably 20% by weight or more. More preferably, it is 30% by weight or more, and even more preferably, it is 40% by weight or more. If the amount of alcohol is 60% by weight or less, the alcohol will not evaporate excessively from the preparation, and the preparation with a stable active ingredient concentration can be preserved (stored). Therefore, the amount of alcohol is more preferably around 50% by weight (45 to 55%).

[0042] By containing an amount of alcohol that sufficiently dissolves the active ingredient, the active ingredient can be absorbed more efficiently into the skin tissue. As long as the amount of alcohol is 50% by weight or less, the active ingredient can be dissolved more thoroughly, and thus absorbed more efficiently into the skin tissue.

[0043] The amount of gelling agent contained in the gelling agent is not particularly limited, and may be an amount sufficient for gelling a solution containing sirolimus or a sirolimus derivative. The amount of gelling agent contained in the gelling agent may be, for example, 1.0% by weight or more based on the total weight of the gelling agent. More specifically, the amount may be 1.1 to 20% by weight, 1.2 to 15% by weight, 1.3 to 10% by weight, 1.4 to 5% by weight, or 1.5 to 2.5% by weight based on the total weight of the gelling agent.

[0044] The amount of pH adjuster (neutralizer) contained in the gel is not particularly limited and can be appropriately set depending on the amount of the solvent and gelling agent. The amount of pH adjuster contained in the gel can be, for example, 0.3 to 5.0% by weight, 0.4 to 2.5% by weight, or 0.5 to 1.0% by weight based on the total weight of the gel.

[0045] For example, when a gelling agent (such as Carbopol® 934P NF or Carbopol® 980) and a pH adjuster (such as triethanolamine, trishydroxymethylaminomethane) are used as gelation-inducing components, the amount of the gelling agent may be, for example, 1.6% by weight based on the total weight of the topical preparation, and the amount of the pH adjuster may be, for example, 0.4%, 0.6%, or 0.8% by weight based on the total weight of the topical preparation. Of course, the present invention is not limited to the above ratios.

[0046] The gel may contain other components in addition to the above-mentioned active ingredient, solvent (alcohol), gelling agent, and pH adjuster (neutralizer), such as water-soluble polymers, water, and medicinal ingredients other than sirolimus or sirolimus derivatives.

[0047] Examples of the water-soluble polymer include polyethylene glycol, starch, methyl cellulose, hydroxypropyl cellulose (HPC), polyvinyl alcohol, polyvinyl methyl ether, and polyvinylpyrrolidone.

[0048] The amount of the other components contained in the gel is not particularly limited, but may be, for example, 50% by weight or less, 40% by weight or less, 30% by weight or less, 20% by weight or less, or 10% by weight or less, based on the total weight of the gel.

[0049] The gel may be applied every day or once every 2 to 3 days. Daily application is preferred. When applied every day, application is preferably 1 to 3 times a day, and more preferably 2 to 3 times a day.

[0050] It is also preferable to adjust the concentration in the formulation and the number of administrations depending on the age, administration site, thickness of the skin, etc. For example, a gel with a concentration of 0.05 to 0.2% by weight can be applied 1 to 3 times a day to the thin skin and armpits of small children, etc. Also, a gel with a concentration of 0.2 to 0.8% by weight can be applied 1 to 2 times a day to the palms, soles, etc.

[0051] A more specific example of the composition of the gel is shown below, but the present invention is not limited to this composition. With the composition below, the desired effect can be obtained with a smaller amount of sirolimus or a sirolimus derivative, so that adverse effects on the living body can be reduced.

[0052] The gel may contain, in addition to sirolimus or a sirolimus derivative, a gelling agent (Carbopol (registered trademark) 934P NF, Carbopol (registered trademark) 980, etc.), water, alcohol (e.g., ethanol or isopropanol, etc., preferably ethanol), and a neutralizing agent (trishydroxymethylaminomethane, triethanolamine, etc.). In this case, the weight ratio of sirolimus or a sirolimus derivative, gelling agent, water, alcohol, and neutralizing agent may be, for example, as follows: The ratio of sirolimus or sirolimus derivative: gelling agent: water: alcohol: neutralizing agent may be (0.5-2): 16: 490: (450-500): 6. The ratio may be (0.5-2): 16: 490: (480-490): 6, or may be 2: 16: 490: 486: 6.

[0053] (B) Ointment

[0054] Examples of ointment bases include waxes (e.g., natural waxes such as white beeswax, lanolin, carnauba wax, and spermaceti; mineral waxes such as montan wax; and synthetic waxes), paraffins (e.g., liquid paraffin, solid paraffin), and petrolatum (e.g., white petrolatum, yellow petrolatum).

[0055] The amount of the base is not particularly limited, but may be, for example, 10% by weight or more, 20% by weight or more, 30% by weight or more, 40% by weight or more, 50% by weight or more, 60% by weight or more, 70% by weight or more, 80% by weight or more, or 90% by weight or more, based on the total weight of the ointment.

[0056] The ointment may contain ingredients other than sirolimus or a sirolimus derivative. Examples of the ingredients and contents of the other ingredients include those described above for the gel.

[0057] The ointment may contain propylene carbonate, solid paraffin, and white petrolatum in addition to sirolimus or a sirolimus derivative. The ointment may further contain liquid paraffin in addition to propylene carbonate, solid paraffin, and white petrolatum. The ointment may further contain white beeswax in addition to propylene carbonate, solid paraffin, white petrolatum, and liquid paraffin.

[0058] In this case, the weight ratio of sirolimus or sirolimus derivative, propylene carbonate, solid paraffin, white petrolatum, liquid paraffin and white beeswax may be sirolimus or sirolimus derivative:propylene carbonate:solid paraffin:white petrolatum:liquid paraffin:white beeswax=(0.3-10):(50-59.4):(30-45):(895):(0-10):(0-5), provided that in the above ratio, the total of the active ingredient, propylene carbonate, solid paraffin and liquid paraffin is 105.

[0059] More specifically, the ratios may be Ratio 1, Ratio 2, and Ratio 3 as described below.

[0060] (Ratio 1) Sirolimus or Sirolimus derivative: Propylene carbonate: Solid paraffin: White petrolatum: Liquid paraffin: White beeswax = 2:58:30:895:10:5

[0061] (Ratio 2) Sirolimus or Sirolimus derivative: Propylene carbonate: Solid paraffin: White petrolatum: Liquid paraffin: White beeswax = 2:58:45:895:0:0

[0062] (Ratio 3) Sirolimus or Sirolimus derivative: Propylene carbonate: Solid paraffin: White petrolatum: Liquid paraffin: White beeswax = 2:58:35:895:10:0

[0063] When comparing the above-mentioned ratios 1 and 2, the topical preparation made with ratio 1 has higher transparency and can reduce the amount of water present on the surface of the topical preparation compared to the topical preparation made with ratio 2.

[0064] When comparing the above-mentioned ratios 1 and 3, the topical preparation made with ratio 1 is smoother than the topical preparation made with ratio 3, and can reduce the amount of water present on the surface of the topical preparation.

[0065] The ointment may be applied daily or once every 2 to 3 days. Daily application is preferred. When applied daily, application is preferably 1 to 3 times a day, more preferably 2 to 3 times a day.

[0066] It is also preferable to adjust the concentration in the formulation and the number of administrations depending on the age, administration site, skin thickness, etc. For example, an ointment with a concentration of 0.05 to 0.2% can be applied 1 to 3 times a day to the thin skin and armpits of small children, etc. Also, an ointment with a concentration of 0.2 to 0.8% can be applied 1 to 2 times a day to the palms, soles, etc.

[0067] The ointment can be prepared according to a known method, and an example of the preparation method will be described below.

[0068] For example, it can be prepared using a homomixer (e.g., manufactured by Primix Corporation) or a universal mixer (e.g., manufactured by Dalton Corporation). When the base is solid at room temperature, the base is heated until it becomes liquid, and the liquid base is mixed with the solution in which the active ingredient is dissolved. More specifically, various ingredients that are solid at room temperature (e.g., waxes, paraffins, petrolatum, etc.) are heated to above their melting points (e.g., 70°C) to dissolve them, and the solution in which the active ingredient is dissolved is added to the dissolved matter and stirred. Thereafter, the mixture is cooled to around room temperature (e.g., 40°C) while stirring to produce an ointment.

[0069] As another method, the base is dissolved at 70°C to 80°C, and stirred in stirring mode at 800 rpm for 30 minutes, then at 1000 rpm for 5 minutes, and then at 2000 rpm for 1 minute (15°C) using a planetary centrifugal mixer (Thinky Corporation).Then, a solution in which the active ingredient is dissolved is added to the base, and the mixture is further stirred at 1000 rpm for 1 minute, then at 2000 rpm for 1 minute (without cooling), to prepare a better quality ointment in which very fine particles containing the active ingredient are dispersed.

[0070] When the other ingredients described above are to be contained in the ointment, a solution is prepared by dissolving the active ingredient and other ingredients in a desired solvent, a base is added to the solution, and the ointment can be prepared according to the above-mentioned method for the steps thereafter.

[0071] (C) Cream

[0072] The cream can be prepared by mixing a solution containing sirolimus or a sirolimus derivative with a base of the cream. Examples of the solution for dissolving sirolimus or a sirolimus derivative include alcohol and ethylene glycol ether. The cream of the present invention is preferably a cream that has low transfer of sirolimus or a sirolimus derivative into the blood, and preferably contains ethylene glycol ether. A preferred example of a diethylene glycol ether is diethylene glycol monoalkyl ether. The alkyl group of the diethylene glycol monoalkyl ether is preferably C 1 ~C 6 Examples of the alkyl groups include those shown below. Preferred are diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, and mixtures thereof. More preferred are diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof, and most preferred is diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol, TRANSCUTOL (registered trademark) P).

[0073] Sirolimus or a sirolimus derivative is soluble in diethylene glycol ether. Sirolimus is highly soluble in diethylene glycol monoethyl ether, and can be dissolved up to 2.02 W / V %.

[0074] Sirolimus or a sirolimus derivative can be formulated after being dissolved in diethylene glycol ether. A formulation using diethylene glycol ether can assist the skin penetration of sirolimus or a sirolimus derivative and retain the active ingredient in the skin tissue. A formulation using diethylene glycol monoethyl ether is particularly excellent in assisting the skin penetration of the active ingredient and retaining it in the skin tissue.

[0075] The amount of diethylene glycol ether contained in the cream may be an amount that allows sirolimus or a sirolimus derivative to be dissolved in the preparation, and is, for example, preferably 1 to 40% by weight, more preferably 2 to 30% by weight, more preferably 5 to 25% by weight, and more preferably 10 to 20% by weight, based on the total weight of the topical preparation.

[0076] The base of the cream contains an oily component, an aqueous component and a surfactant, and may further contain other additives.

[0077] Examples of the oily component include hydrocarbons, fatty acid esters, waxes, higher fatty acids, and higher alcohols. Hydrocarbons and higher alcohols are preferred.

[0078] Examples of the hydrocarbons include white petrolatum and liquid paraffin. White petrolatum is preferred. Examples of the higher alcohols include stearyl alcohol, cetanol, myristyl alcohol, lauryl alcohol, and oleyl alcohol. Stearyl alcohol is preferred. Examples of the fatty acid esters include isopropyl myristate. Examples of the waxes include beeswax and lanolin. Examples of the higher fatty acids include stearic acid.

[0079] The content of the oily component is, for example, preferably 20 to 60%, and more preferably 30 to 50%, based on the total weight of the topical preparation.

[0080] Examples of aqueous components contained in the cream include water, polyhydric alcohols, and lower alcohols, with water and polyhydric alcohols being preferred.

[0081] Examples of the polyhydric alcohol include glycerin, propylene glycol, and 1,3-butylene glycol. Propylene glycol is preferred. Examples of the lower alcohol include ethanol and isopropanol.

[0082] The content of the aqueous component including water contained in the cream is, for example, preferably 20 to 60%, and more preferably 30 to 50%, based on the total weight of the topical preparation.

[0083] The surfactant (emulsifier) ​​is not particularly limited, and any surfactant (emulsifier) ​​known to those skilled in the art can be used. Preferred surfactants (emulsifiers) include polyoxyethylene hydrogenated castor oil 60 and glycerin monostearate. The content of the surfactant is preferably, for example, 1 to 10%, more preferably 2 to 8%, based on the total weight of the topical preparation.

[0084] Examples of other additives include preservatives, antioxidants, pH adjusters, etc. Furthermore, the composition may contain a medicinal ingredient other than sirolimus or a sirolimus derivative.

[0085] A preferred composition of the cream, based on the total weight of the topical agent, is, for example, as follows: 0.01-2.0% by weight of sirolimus or sirolimus derivative, 1-40% by weight of diethylene glycol ether, 5-40% by weight of hydrocarbons, 5-30% by weight of higher alcohol, 1-30% by weight of polyhydric alcohol, 10-50% by weight of water.

[0086] A more preferred composition of the cream, based on the total weight of the topical agent, is, for example, as follows: 0.04-0.8% by weight of sirolimus or sirolimus derivative, 2-30% by weight of diethylene glycol ether, 10-30% by weight of hydrocarbons, 10-25% by weight of higher alcohol, 3-20% by weight of polyhydric alcohol, and 20-40% by weight of water.

[0087] The cream is administered, for example, by applying it to the affected area every day or once every 2 to 3 days. Daily application is preferred, 1 to 3 times a day is preferred, and 2 to 3 times a day is more preferred.

[0088] In addition, it is preferable to adjust the concentration of the active ingredient in the topical agent and the number of administrations depending on the age, administration site, thickness of the skin, etc. For example, for the thin skin or armpits of small children, a 0.05 to 0.2% topical agent can be applied 1 to 3 times a day. For the palms, soles, etc., a 0.2 to 0.8% topical agent can be applied 1 to 2 times a day.

[0089] Creams can be manufactured according to known methods. For example, the base ingredients are all dissolved and mixed in order at 70°C to 80°C, emulsified, and then cooled while mixing, to prepare a high-quality cream containing the active ingredient. For emulsification and mixing, it is efficient to use a planetary centrifugal mixer (manufactured by Thinky Corporation).

[0090] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. EXAMPLES

[0091] [Production Example: Preparation of Sirolimus-Containing Gel]

[0092] Gels containing sirolimus at various concentrations were prepared. Specifically, sirolimus was added to ethanol for dissolution, and then water for injection was added and mixed to prepare a mixed solution. Carbopol® 934P NF was added to the mixed solution and mixed to prepare a uniform suspension. Trishydroxymethylaminomethane, a neutralizing agent, was added to the suspension and mixed to prepare a gel.

[0093] The components other than sirolimus in 1 g of the gel were Carbopol (registered trademark) 934P NF 16 mg, water 490 mg, ethanol 480 to 490 mg, and trishydroxymethylaminomethane 6 mg.

[0094] More specifically, gels were prepared according to the compositions of Production Examples 1 to 5 below.

[0095] Preparation Example 1: Gel containing 0.4% by weight of sirolimus (total amount 100 g) Sirolimus 0.4g Ethanol 48.4g Water for injection 49g Carbopol(R) 934P NF 1.6g Tris(hydroxymethyl)aminomethane 0.6g

[0096] Preparation Example 2: Gel containing 0.8% by weight of sirolimus (total amount 100 g) Sirolimus 0.8g 48g ethanol Water for injection 49g Carbopol(R) 934P NF 1.6g Tris(hydroxymethyl)aminomethane 0.6g

[0097] Preparation Example 3: Gel containing 0.2% by weight of sirolimus (total amount 100 g) Sirolimus 0.2g Ethanol 48.6g Water for injection 49g Carbopol(R) 934P NF 1.6g Tris(hydroxymethyl)aminomethane 0.6g

[0098] Production Examples 4 to 5: In the same manner as in Production Examples 1 to 3, a gel containing 0.05% sirolimus (Production Example 4) and a gel containing 0.1% sirolimus (Production Example 5) were produced.

[0099] [Production Example: Preparation of Sirolimus-containing Cream]

[0100] Preparation Example 6: Cream containing 0.2% by weight of sirolimus (total amount 100 g) Sirolimus powder was obtained from Fujian Kerui Pharmaceutical Co., Ltd. Sirolimus powder was added to diethylene glycol monoethyl ether (TRANSCUTOL (registered trademark) P) and dissolved, and then mixed with a base (oil-in-water (O / W) emulsion) that had been mixed and prepared in advance to obtain a cream. The specific composition is shown below. Sirolimus 0.2g Diethylene glycol monoethyl ether 10g Hydrophilic cream 89.8g White Vaseline 22.45g Stearyl Alcohol 17.96g: Propylene glycol 10.78g Polyoxyethylene hydrogenated castor oil 60 3.59g Glyceryl monostearate 0.90g Methyl parabenzoate 0.09g Propyl parabenzoate 0.09g Purified water 33.94g

[0101] [Case]

[0102] Case 1 9-year-old female (with tuberous sclerosis and intractable epilepsy) The epileptic seizures occurred at a frequency of 8 to 10 times per month. When the patient started applying 0.2% sirolimus gel (preparation example 3) twice a day to the facial angiofibroma, the frequency of epileptic seizures decreased, and only three seizures occurred during the three-month application period. When the application was then discontinued, the frequency of seizures returned to almost the original frequency. When the patient started applying Lapalimus Gel (registered trademark) 0.2% (gel containing 0.2% sirolimus) twice a day again, no seizures occurred for two months after the application began. When the application was then discontinued, the frequency of seizures returned to almost the original frequency. When the patient started applying Lapalimus Gel (registered trademark) 0.2% again six months later, the frequency of seizures settled down to about four times a month. When the patient first applied the sirolimus gel, the blood concentration was measured (AP13200 LC-MS / MS system-SieX, measurement limit is 1.0 ng / ml) and found to be below the measurement limit. The external dose of sirolimus gel was about 10 g every two months, and the daily usage amount of sirolimus gel was about 0.17 g (0.3 mg as sirolimus).Rapalimus Gel (registered trademark) 0.2% is a sirolimus-containing gel developed by the present inventor in collaboration with Nobelpharma Co., Ltd., and contains 0.2% sirolimus in the gel, and contains carboxyvinyl polymer, ethanol, and triethanolamine as additives.

[0103] Case 2 13-year-old male (with tuberous sclerosis complex, autism, developmental disorder, and intractable epilepsy) When the patient started applying 0.1 g of Rapalimus® gel 0.2% twice a day to the face, the frequency of epileptic seizures, which had occurred almost daily, was reduced by half. In addition, the tendency to persistence improved.

[0104] Case 3 28-year-old male (tuberous sclerosis complex, developmental disorder) The patient had a significant developmental disorder (tendency towards autism), but after starting to use Rapalimus (registered trademark) gel 0.2% on the face, up to 0.15g at a time, twice a day, the patient became calmer, more cheerful, and less aggressive towards others. He also spoke less to himself.

[0105] Case 4 24-year-old female (tuberous sclerosis complex, developmental disorder, epilepsy, schizophrenia) After applying 0.15g of Rapalimus (registered trademark) gel 0.2% twice a day to the face, the number of epilepsy attacks decreased. In addition, the auditory and visual hallucinations that had not disappeared despite the use of various oral medications have disappeared. The patient has become less irritable, calmer, more cheerful, and easier to contact. Furthermore, although he had previously tended to stay indoors, he has started to go out alone.

[0106] Case 5 11 year old male (Tuberous sclerosis complex, developmental disorder) The patient had a pronounced developmental disorder and strong autistic symptoms, but after starting the treatment, his fixation tendencies improved and his repetitive behavior also improved.

[0107] [Pharmacological studies in mouse models]

[0108] Test Example 1 Number of epileptic seizures Model mice and control mice A mouse model of tuberous sclerosis (C57BL / 6J, Tsc2 flox / flox The model mouse (Mitf::Cre) was created by the present inventors. It is a conditional knockout mouse that expresses Cre recombinase in a melanocyte-specific Mitf promoter-dependent manner and has exons 3-5 of Tsc2 deleted (J Invest Dermatol. 2018; 138(3): 669-78). This model mouse is a model mouse of tuberous sclerosis that exhibits epilepsy, behavioral abnormalities, and vitiligo, and can also be used as a model mouse of epilepsy (PLoS One. 2020; 15(1)). As a control, C57BL / 6J,Tsc2 + / flox Mitf::Cre mice were used. These control mice did not exhibit abnormalities such as epilepsy and were indistinguishable from C57BL / 6J mice, and are therefore hereinafter referred to as normal mice.

[0109] The center of the forehead of both groups of mice was shaved under anesthesia. 0.2 wt% sirolimus gel prepared in Production Example 3 or placebo (base only) was applied once a day at 5 mg (10 μg of sirolimus) to the shaved forehead (Figure 1). The number of epileptic seizures in the mice to which sirolimus gel or placebo was applied was counted for 7 days. The number of epileptic seizures was investigated by handling three times per day. Handling consisted of transferring the mouse to another empty cage and restraining it for 2 minutes as when performing intraperitoneal injection, grabbing the tail and turning it upside down, etc. If a seizure occurred, the number of seizures was counted as 1. If a seizure occurred before handling, the number of seizures was also counted as 1. The results are shown in Table 1. The number of seizures was reduced by application of sirolimus gel.

[0110] [Table 1]

[0111] Test Example 2 Open field test As in Test Example 1, mice to which sirolimus gel or a placebo had been applied were subjected to an open field test on the eighth day (Day 8) after the start of application. Mice were placed in a circular open field (diameter 50 cm), and the time spent in the central area and other areas, the movement speed, and the movement distance were measured for 15 minutes. The central area was the central area with a diameter of 30 cm. The results are shown in Table 2. Border / Center is the ratio of the cumulative time spent outside the central area to the cumulative time spent in the central area, and indicates the proportion of time spent outside the central area (area at the edge of the field: Border), and a high value indicates a strong tendency toward anxiety. The test results showed that application of sirolimus gel reduced anxiety and suppressed the movement speed and movement distance.

[0112] [Table 2]

[0113] Test Example 3 Sirolimus Blood Concentration

[0114] 18 cm of the back of a hairless mouse (HR mouse, 8 weeks old, male) 2 (6 x 3 cm) of 0.05% sirolimus gel prepared in Production Example 4, 0.2% sirolimus gel prepared in Production Example 3, or 0.4% sirolimus gel prepared in Production Example 1 were applied in an amount of 125 mg, and blood was collected two hours later to measure the blood concentration (AP13200 LC-MS / MS System SIEXX, measurement limit 0.1 ng / ml). The blood concentration for each mouse is shown in Table 3. Despite the application of a large amount of sirolimus gel, there was almost no increase in the blood concentration.

[0115] [Table 3]

[0116] Test Example 4 Number of epileptic seizures (external application) As in Test Example 1, 0.2% by weight sirolimus gel or placebo (base only) was applied once a day at 5 mg (10 μg as sirolimus) to model mice and normal mice. The number of epileptic seizures in the mice to which sirolimus gel or placebo was applied was measured for 7 days in the same manner as in Test Example 1 (n=4 in each group). The number of seizures over 7 days is shown in Figure 2. The number of seizures was reduced by application of sirolimus.

[0117] Test Example 5 Number of epileptic seizures (intraperitoneal administration) Sirolimus (3 mg / kg / day) or placebo (physiological saline) was intraperitoneally administered once a day for seven days to model mice and normal mice similar to those in Test Example 1. The number of attacks was measured by observing the mice for two minutes, five times a day (n=6 per group). The results are shown in Figure 3. The number of attacks was reduced by intraperitoneal administration of sirolimus. The number of attacks in the seven days in the group that received intraperitoneal administration of sirolimus was about five, which was almost the same as the number of attacks when 5 mg (10 μg of sirolimus) of 0.2 wt% sirolimus gel was administered to the forehead once a day.

[0118] Test Example 6 Blood concentration after 7 consecutive days of administration Mice (C57BL / 6J, body weight 20 g) were intraperitoneally administered sirolimus (3 mg / kg / day) or placebo (physiological saline) once a day for 7 days. 24 hours after administration on the 7th day, blood was collected from each mouse and the sirolimus concentration in the blood was measured. The results are shown in Table 4.

[0119] [Table 4]

[0120] ICR mice (body weight approximately 37 g) were obtained (Japan SLC). 0.2% by weight sirolimus gel prepared in Production Example 3 or placebo (base only) was applied once a day to the shaved forehead at 5 mg (10 μg as sirolimus). 24 hours after administration on the 7th day, blood was collected from each mouse and the sirolimus concentration in the blood was measured. The results are shown in Table 5.

[0121] [Table 5]

[0122] The blood concentration was measured using the same method as in Test Example 3. The blood concentration after topical application to the skin was 1 / 26th of the mean blood concentration after systemic administration via intraperitoneal administration. The seizure suppression effect was almost the same, but it was revealed that the blood concentration was kept low by topical application. The mechanism of action for suppressing epileptic seizures by systemic administration and the mechanism for suppressing epileptic seizures by topical application may differ.

[0123] Test Example 7 Three-week consecutive administration Using the same model mice and normal mice aged 6 to 8 weeks as in Test Example 1, 0.2 wt% sirolimus gel prepared in Production Example 3 and placebo (base only) were applied for 3 weeks in the same manner as in Test Example 1. The average number of seizures per day for each week during the administration period is shown in Table 6. The method for measuring the number of seizures was the same as in Test Example 1. In the 0.2 wt% sirolimus gel treatment group, the number of epileptic seizures decreased from about the fourth day of the first week, and in the second and third weeks, the average number of seizures per week was 1 or less (0.143 per day).

[0124] [Table 6]

[0125] Test Case 8 Recurrence of attacks due to cessation of topical application Using the same model mouse (7 weeks old, body weight 21.55 g) as in Test Example 1 and normal mice, 0.2 wt% sirolimus gel was applied for 4 days (Days 1 to 4) in the same manner as in Test Example 1. Application was stopped from Day 5, and recurrence of attacks was observed. The method of measuring attacks was the same as in Test Example 1. On Day 18 (Day 18), recurrence occurred and one attack was observed. After Day 18, attacks were observed every day. The number of attacks on Day 1 and from Day 4 to Day 22 is shown in Table 6.

[0126] [Table 7]

[0127] From the above results, it has become clear that the topical preparation of the present invention exhibits therapeutic effects on epilepsy, autism spectrum disorder, and anxiety disorder without causing a substantial increase in blood concentration. [Industrial Applicability]

[0128] The topical preparation of the present invention will make a great contribution to future medical treatment.

Claims

1. A gel preparation for external use for treating epilepsy, autism spectrum disorder, or anxiety disorder, comprising at least one active ingredient selected from the group consisting of sirolimus, everolimus, temsirolimus, ridaforolimus, and zotarolimus.

2. The external preparation according to claim 1 , which is for administration to the head.

3. An external preparation as described in claim 1 or 2, containing ethanol.

4. An external preparation described in any one of claims 1 to 3 for treating epilepsy.

5. The external preparation according to claim 4, wherein the epilepsy is epilepsy associated with tuberous sclerosis.

6. An external preparation described in any one of claims 1 to 3 for treating autism spectrum disorder.

7. The external preparation according to claim 6, wherein the autism spectrum disorder is autism.

8. The external preparation according to claim 6, wherein the autism spectrum disorder is impairment in constructing interpersonal relationships and / or fixation or obsession in autism spectrum disorder.

9. The external preparation according to claim 6, wherein the autism spectrum disorder is autism spectrum disorder associated with tuberous sclerosis complex.

10. An external preparation described in any one of claims 1 to 3 for treating anxiety disorders.

11. The external preparation according to claim 10, wherein the anxiety disorder is generalized anxiety disorder.

12. The external preparation according to claim 10, wherein the anxiety disorder is anxiety disorder associated with tuberous sclerosis complex.

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