CN106983738B

CN106983738B - Application of thyroid hormone and pharmaceutically acceptable salt or prodrug thereof in preparation of medicines for treating and/or preventing skin diseases

Info

Publication number: CN106983738B
Application number: CN201710239511.2A
Authority: CN
Inventors: 余国营
Original assignee: Shenzhen City Run Giti Technology Co Ltd
Current assignee: Shanghai YueShun Management Consulting Co.,Ltd.
Priority date: 2017-04-13
Filing date: 2017-04-13
Publication date: 2020-03-10
Anticipated expiration: 2037-04-13
Also published as: CN106983738A

Abstract

The invention provides a new application of thyroid hormone and pharmaceutically acceptable salts or prodrugs thereof, and the thyroid hormone and the pharmaceutically acceptable salts or prodrugs thereof are used for treating skin diseases. The thyroid hormone and the pharmaceutically acceptable salt or prodrug thereof can effectively protect epithelial cells, regulate synthesis, storage and distribution of proteins on the surfaces of the epithelial cells, promote maturation, differentiation and cell integrity of the epithelial cells, promote recovery of damaged mitochondria in the epithelial cells, enhance biosynthesis of the mitochondria, thereby being beneficial to repair of damaged skin tissues, preventing and reversing skin fibrosis, regulating immune response and achieving the effect of treating skin diseases such as scleroderma.

Description

Application of thyroid hormone and pharmaceutically acceptable salt or prodrug thereof in preparation of medicines for treating and/or preventing skin diseases

Technical Field

The invention relates to a new application of thyroid hormone and pharmaceutically acceptable salts or prodrugs thereof, in particular to an application of thyroid hormone and pharmaceutically acceptable salts or prodrugs thereof in preparing medicines for treating and/or preventing skin diseases.

Background

Scleroderma (Scleroderma) is a systemic autoimmune disease characterized by localized or diffuse skin thickening and fibrosis, which can affect multiple systems such as heart, lung, kidney, digestive tract, etc., and is classified into two types, localized and systemic, according to the degree of skin lesions and the affected parts. Localized scleroderma manifests itself primarily as skin sclerosis; systemic scleroderma, also known as systemic sclerosis. The pathological changes are characterized by skin fiber hyperplasia and skin-like changes of blood vessels and onions, which finally cause skin sclerosis and blood vessel ischemia, and besides skin diseases, the pathological changes also can affect internal organs (such as heart, lung, digestive tract and the like). The basic pathological changes are fibrosis and atrophy of connective tissue and vaso-occlusive vasculitis.

The cause of scleroderma is unknown and may be related to a combination of genetic, immunological, environmental, vascular and metabolic changes in collagen. Although some cases of scleroderma may be stopped from developing or alleviated by treatment, there is currently no specific treatment. Therefore, development of new methods for preventing and treating scleroderma is urgently needed.

Hormone derivatives are a class of compounds that play a significant biological role in a variety of basic metabolic transformations. Among the compounds, thyroid hormones such as thyroxine ((S) -2-amino-3- [4- (4-hydroxy-3, 5-diiodophenoxy) -3, 5-diiodophenyl ] propanoic acid, often abbreviated as T4, and triiodothyronine (abbreviated as T3), represent important key molecules involved in controlling the rate of various metabolic processes in vivo. Thyroid hormones are widely used in the treatment of several pathologies involving thyroid disorders. However, no report has been made so far on the use of thyroid hormone and its pharmaceutically acceptable salts or prodrugs for the treatment and/or prevention of skin diseases.

Disclosure of Invention

In order to solve the problems, the invention provides a new application of thyroid hormone and pharmaceutically acceptable salts or prodrugs thereof, namely an application in preparing medicines for treating and/or preventing skin diseases.

The invention provides the application of thyroid hormone and pharmaceutically acceptable salts or prodrugs thereof in preparing medicines for treating and/or preventing skin diseases.

Wherein the skin disease comprises scleroderma.

Wherein the skin disease comprises at least one of scleroderma, linear scleroderma with parafacial atrophy, CRES syndrome, acral scleroderma, eosinophilic fasciitis, chronic radiodermatitis, lymphedema sclerosis, neonatal sclerosis, varicose syndrome, scleromyxoedema, scleroatrophic lichen, scleroatrophic syndrome, and fibrotic basal cell carcinoma.

Wherein the thyroid hormone and its pharmaceutically acceptable salt or prodrug comprises thyroid hormone T3 and/or T4 and its pharmaceutically acceptable salt or prodrug.

Wherein the thyroid hormone and the pharmaceutically acceptable salts or prodrugs thereof are used as single active ingredients or are combined with other pharmaceutically acceptable active ingredients to prepare the medicament.

Wherein the drug is used in combination with other active agents, including nintedanib.

Wherein the administration mode of the medicine comprises local administration, digestive tract administration or non-digestive tract administration.

Wherein the administration mode of the medicine comprises epidermal administration.

Wherein the dosage of the thyroid hormone and the pharmaceutically acceptable salt or prodrug thereof is 0.1-5000 micrograms/kg body weight per day.

The embodiment of the invention provides a new application of thyroid hormone and pharmaceutically acceptable salts or prodrugs thereof, the thyroid hormone and the pharmaceutically acceptable salts or prodrugs thereof can effectively protect epithelial cells, regulate the synthesis, storage and distribution of proteins on the surfaces of the epithelial cells, promote the maturation, differentiation and cell integrity of the epithelial cells, promote the recovery of damaged mitochondria in the epithelial cells and enhance the biosynthesis of the mitochondria, thereby being beneficial to the repair of damaged skin tissues, preventing and reversing skin fibrosis, regulating immune response and achieving the effect of treating scleroderma.

In a second aspect, the invention provides a kit comprising instructions and a medicament as described in the first aspect above.

Drawings

FIG. 1 is a flow chart of the experimental design of the present invention;

FIG. 2 is a photograph of a tissue section of a mouse under different treatment conditions;

FIG. 3 is a graph of the relative expression intensity of col1a1 after treatment with thyroxine for bleomycin-induced dermal fibrosis;

FIG. 4 is a histogram of epidermal thickness, dermal thickness and number of blood vessels after treatment with bleomycin-induced skin fibrosis with thyroxine;

FIG. 5 is a representation of (a) Meisen trichrome (massson) stained skin tissue under different treatment conditions; (b) histogram of skin hydroxyproline relative content; (c) histogram of relative change in skin thickness; (d) histogram of relative change in collagen I gene expression levels. (n-16, p < 0.0001).

Detailed Description

While the following is a description of the preferred embodiments of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

Unless specifically stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although descriptions of methods and materials may be used in the description of the invention.

As used herein, "a" or "an" is used to refer to one or more than one (such as at least one). For example, "an ingredient" means one ingredient or more than one ingredient.

In this context, measurement means such as amount, duration, and the like are meant to include variations of 20% or 10%, or more precisely 5% or 1%, more precisely up to 0.1% at certain values, which are more suitable for the methods described in the article.

"alleviating" a disease or disorder refers to a patient having a reduced severity of symptoms of the problem, a reduced frequency of onset, or both.

By "co-administration" is meant, in one aspect, the simultaneous administration of the test drug or saline control (reference group) to the subject along with another drug, where the co-administration is separate from the actual administration, except that the drugs are used in combination in the treatment. The co-administered drugs may be in various forms or mixtures, such as solids, liquids, gels, or solutions.

As used herein, "combination" or "pharmaceutical combination" refers to a mixture of more than one drug used in the present invention, using a pharmaceutically acceptable carrier. The drug combination helps the drug to reach the focus of the patient or experimental animal more easily. The various techniques described in clauses include, but are not limited to, intravenous administration, oral administration, aerosol inhalation, parenteral, ophthalmic, nasal, pulmonary, and topical administration.

By "disease" herein is meant that the health status of the experimental animal is unable to maintain homeostasis, so that the disease is not improved herein and the health status of the animal continues to deteriorate.

By "disorder" herein is meant that the health status of the experimental animal is able to maintain homeostasis, but if the health status of the experimental animal is worse than if the animal is not "disordered". If left untreated, a "disorder" does not necessarily result in the development of a disease state in the experimental animal.

As used herein, "effective dose," "pharmaceutically effective dose," and "therapeutically effective dose" refer to a non-toxic but sufficient dose to elicit the desired biological result. These results include a reduction or alleviation of the characteristics, symptoms, causes of disease, or a good direction of development of other biological systems. Appropriate therapeutic doses for an individual can be derived from normal ranges of routine experimental data.

Herein, "scleroderma" or "skin fibrosis" refers to a group of diseases characterized by the formation or progression in the skin of excess fibrous connective tissue (fibrosis). Scleroderma patients have changes of skin hardening, thickening and atrophy, which can be classified into two types, local and systemic, according to the degree of skin lesions and affected parts. Localized scleroderma can be further classified according to the form and distribution of skin lesions: trichoderma, lamellar scleroderma, zonal scleroderma, and generalized scleroderma. Systemic scleroderma can be further classified into the following categories, according to the extent, degree, rate of progression, prognosis, etc.: limb scleroderma and diffuse scleroderma.

As used herein, "patient", "subject" and "individual" are used interchangeably, as are experimental animals and experimental cells, both in vivo and in vitro. In non-limiting examples, patients, subjects and individuals refer to humans.

As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not itself interfere with the biological activity of the drug, and which is relatively non-toxic, e.g., the material can be injected into an individual without causing an adverse biological response or a serious response to the drug it carries.

Herein, "pharmaceutically acceptable carrier" refers to pharmaceutically acceptable materials, tissues and or vehicles, such as liquids, solid fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, solvents or encapsulating materials, which serve to transport the active ingredients of the present invention so that they can exert their intended effect in a patient. Generally, transport is from one organ, or part of the body, to another organ, or another part of the body. Each carrier must be compatible with the ingredients of the respective formulation, including the active ingredients of the invention, so that it does not adversely affect the patient. Pharmaceutically acceptable carriers for these materials include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and pharmaceutically acceptable salts or prodrugs thereof, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; a surfactant; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; a phosphate buffer solution; and other non-toxic pharmaceutically formulation compatible materials.

As used herein, "pharmaceutically acceptable carrier" also includes all surface coatings, antibacterial and antifungal agents, absorption delaying agents, and analogs compatible with the activity of the compounds useful in the present invention, which are physiologically acceptable to the patient.

Supplementary active compounds can also be incorporated into the active ingredient combination.

The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable effective salt component of the present invention. Other ingredients also include pharmaceutical compositions, which are described and used in the practice of this invention, for example, in Remington pharmaceutical sciences (Genaro, Ed., Mack Publishing Co.,1985, Easton, Pa.), incorporated herein by reference.

As used herein, the phrase "pharmaceutically acceptable salt" refers to a salt of a compound prepared from a pharmaceutically acceptable non-toxic acid, which may be administered to a patient, including inorganic acids, organic acids, solvates, hydrates or clathrates.

As used herein, "prevention" means that the subject who has not developed the disease after administration of the drug is able to avoid or delay the onset of symptoms associated with the disease or condition.

Herein, "T3" refers to (S) -triiodothyronine, iodothyronine, (S) -2-amino-3- [4- (4-hydroxy-3-iodophenoxy) -3, 5-diiodophenyl ] propanoic acid or salts or solvates thereof. Specifically, the chemical formula of T3 is shown as the following formula (I).

Herein, "T4" (S) -thyroxine, (S) -2-amino-3- [4- (4-hydroxy-3, 5-diiodophenoxy) -3, 5-diiodophenyl ] propanoic acid or salts or solvates thereof. Specifically, the chemical formula of T4 is shown in the following formula (ii).

"therapeutic" refers to treatment of a subject who has developed a pathological condition for the purpose of reducing or eliminating symptoms.

"treatment" or "course of treatment" is defined herein as the use of a therapeutic agent, such as a compound of the invention (alone or in combination with other agents), in a patient, or in the extraction of isolated tissue or cell lines from a patient (e.g., for diagnosis or in vitro culture). The patient has the condition, symptom of the condition, or the likelihood of developing the condition considered herein, for the purpose of curing, treating, alleviating, altering, diminishing, increasing, or affecting the condition considered herein and or the likelihood of developing the symptom of the condition. These treatments can be tailored under appropriate circumstances based on the latest knowledge of different pharmacogenomics.

Throughout this patent document, various aspects of the invention may be presented in a range of formats. It is noted that the description in the range format is merely for convenience and brevity and is not intended to limit the scope of the present invention in any way. Accordingly, the description of a range should be considered to have disclosed in detail all the possible subranges and individual numerical values within the range. For example, description of a range such as 1 to 6 should be considered to have specifically disclosed sub-ranges, e.g., 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, from 3 to 6, etc., as well as individual numbers within that range, e.g., 1,2,2.7,3,4,5,5.1,5.3,5.5, and 6. This applies to the width of the range.

In a first aspect, the embodiments of the present invention provide an application of thyroid hormone and its pharmaceutically acceptable salts or prodrugs in preparing a medicament for treating and/or preventing skin diseases.

In an embodiment of the invention, the skin disease comprises scleroderma. Specifically, the skin disease includes at least one of a hard spot, linear scleroderma with facial hemiatrophy, CRES syndrome, acral scleroderma, eosinophilic fasciitis, chronic radiodermatitis, lymphedema sclerosis, neonatal sclerosis, varicose syndrome, scleromyxoedema, scleroatrophic lichen, scleroatrophic syndrome, and fibrotic basal cell carcinoma.

In an embodiment of the invention, the thyroid hormones and pharmaceutically acceptable salts or prodrugs thereof include thyroid hormones T3 and/or T4 and pharmaceutically acceptable salts or prodrugs thereof. Optionally, the thyroid hormone and pharmaceutically acceptable salts or prodrugs thereof include sodium salts of thyroid hormone T3 and/or T4. Specifically, the thyroid hormone and the pharmaceutically acceptable salt or prodrug thereof comprise thyroxine sodium.

In an embodiment of the present invention, the thyroid hormone and its pharmaceutically acceptable salts or prodrugs are used as a single active ingredient or are combined with other pharmaceutically acceptable active ingredients to prepare the drug.

In the embodiment of the invention, the thyroid hormone and the pharmaceutically acceptable salt or prodrug thereof can form a composition with a pharmaceutically acceptable carrier to prepare the medicament. In one embodiment, the pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a drug of the present invention and a pharmaceutically acceptable carrier. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of lecithin as the carrier, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferred to include isotonic substances, for example, sugars, sodium chloride or polyalcohols such as mannitol and sorbitol in the composition.

In an embodiment of the present invention, the thyroid hormone and the pharmaceutically acceptable salt or prodrug thereof and an oleaginous base form a composition to prepare the ointment-like medicament, and the thyroid hormone and the pharmaceutically acceptable salt or prodrug thereof are dispersed in the oleaginous base in a solid state or an oily state. Optionally, the oleaginous base is selected from at least one of hydrocarbons, fatty acid esters and animal and vegetable oils. Further alternatively, the hydrocarbon may include gelled hydrocarbon (liquid paraffin containing polyethylene having a molecular weight of 3500 or more, preferably liquid paraffin containing 2 to 8% of polyethylene having a molecular weight of 3500-35000), heavy liquid paraffin, light liquid paraffin, white petrolatum, yellow petrolatum, squalene, etc., the fatty acid ester may include synthetic oil such as medium-chain fatty acid triglyceride and hardened fat, olive oil, soybean oil, peanut oil, safflower oil, rice bran oil, sesame oil, camellia oil, corn oil, cottonseed oil, vegetable oil such as coconut oil, lard oil, tallow, etc., and hardened oil thereof, and the wax may include natural wax such as beeswax, carnauba wax, etc., petroleum wax such as paraffin, microcrystalline wax, etc., mineral wax such as montan wax, etc., synthetic wax, etc. In addition, several of these substances may be used in combination. Specifically, the oleaginous base is selected from at least one of white vaseline, a combination of white vaseline and light liquid paraffin, a combination of white vaseline and squalane, and a combination of white vaseline and methyl polysiloxane. Optionally, the content of thyroid hormone and its pharmaceutically acceptable salt or prodrug in the ointment is 20 μ g/ml-60 μ g/ml, optionally 40 μ g/ml.

The ointment of the present invention may contain a surfactant in order to improve the affinity of the ointment with the skin. Examples of the surfactant include a nonionic surfactant and/or an anionic surfactant. Examples of the nonionic surfactant include polyoxyethylene polyoxypropylene glycols, fatty alcohols, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and the like, examples of the anionic surfactant include fatty acids, sulfuric acid esters, polyacrylates, carboxyvinyl polymers, cellulose derivatives, alkali salts thereof, and the like, and nonionic surfactants are preferred, and when a surfactant is used, the content thereof is usually 50% or less, preferably 30% or less, usually 2 to 50%, preferably 5 to 30%, for example, in the ointment.

The emulsion can be formed by further containing water besides the surfactant. The emulsion may be in the form of W/O or O/W, but the oleaginous base is preferably in the form of W/O which is easily contacted with the skin. In the case of using water, the content of water is usually 50% or less, preferably 30% or less, usually, for example, 5 to 50%, preferably 10 to 30% in the ointment.

Other additives such as antioxidants such as phenols and preservatives such as benzoic acids may also be added to the ointment of the present invention. In the case of adding these additives, the content of the additives is usually 0.01 to 1% in the ointment.

The ointment of the invention can be directly applied to the affected part, and can also be prepared into patches such as cataplasm, plaster and the like coated with the ointment.

The oily ointment of the present invention can be prepared by a conventional method. That is, thyroid hormone and a pharmaceutically acceptable salt or prodrug thereof are mixed with the oleaginous base and, if necessary, a surfactant, water and other additives, uniformly dispersed, and heated under a high viscosity. In the case of water, water is added last and mixed. The thyroid hormone and the pharmaceutically acceptable salt or prodrug thereof may be pulverized before mixing, or may be pulverized in a mixing and dispersing step. When the particle size of the thyroid hormone and the pharmaceutically acceptable salt or prodrug thereof is large, the thyroid hormone and the pharmaceutically acceptable salt or prodrug thereof can also be mixed after being crushed together with liquid hydrocarbon. The average particle size of thyroid hormone and its pharmaceutically acceptable salt or prodrug in the ointment is 60 μm or less, preferably 30 μm or less, and at least 80% of the number of particles is preferably in the range of 1 to 100 μm, particularly preferably in the range of 2 to 50 μm, as measured by particle size measurement using a microscope.

In one embodiment, the medicament of the present invention is packaged directly with a pharmaceutical composition comprising a container containing a therapeutically effective amount of the medicament, alone or in combination with another pharmaceutical substance; the description herein describes methods of use for treating, preventing or alleviating the symptoms of a disease or disorder with a drug.

The formulations may be employed in admixture with conventional excipients, i.e. pharmaceutically suitable organic or inorganic carrier materials suitable for any suitable mode of administration known in the art. The pharmaceutical preparations can be handled aseptically and, if desired, mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts of osmotic pressure-influencing buffers, colorants, flavoring and/or aromatic substances and the like. It may also be used in combination with other active ingredients, such as analgesics, as desired.

In an embodiment of the invention, the combination of the agents of the invention with at least one other agent is more effective in the treatment and prevention of scleroderma. Other drugs may be included in the invention or, for example, commercially available, known drugs that can prevent or alleviate the symptoms of the fibrotic skin disease. Optionally, the drug is used in combination with other active agents, including nintedanib.

In an embodiment of the invention, the mode of administration of the drug comprises topical administration, administration to the alimentary canal or administration to the non-alimentary canal. Topical administration means applying directly to the affected body area, such as topically (i.e., applying to the affected area). And (4) administration in the digestive tract, including oral administration. Parenteral administration includes arterial, intravenous, intramuscular, intracardiac, subcutaneous, or transdermal administration. Optionally, the administration of the medicament comprises topically applying to the affected area, orally administering, or injecting.

The pharmaceutical preparation of the present invention can be prepared using known methods. Such a formulation may be administered directly to a subject, for example, where the material is suitable for a subject. Each formulation may also contain one or more dispersing or wetting agents, suspending agents and preservatives. The formulation ingredients may also include additional excipients such as fillers and sweeteners, flavoring agents or coloring agents.

The dosage regimen may affect the effective amount of the constituent ingredients. The therapeutic formulations of the present invention may be administered to a subject either before or after the onset of disease. Furthermore, several divided doses as well as staggered doses may be administered daily or sequentially, or the doses may be continuously infused, or may be bolus injections. Also, the dosage of the therapeutic agent may be proportionally increased or decreased depending on the exigencies of the therapeutic or prophylactic situation. The dosage regimen may be adjusted to provide the best therapeutic effect.

Administration of the agents of the present invention to a patient, preferably a mammal, more preferably a human, can be performed using known dosing procedures, with the dosages and treatment times for the diseases or disorders set forth in the present invention. The effective therapeutic dose in this study needs to be adjusted according to various factors, including the stage of development of the disease and disorder of the patient, age, sex, body weight; and also the activity of therapeutic agents. For example, several divided doses may be administered daily, or the dose may be reduced proportionally to the exigencies of the therapeutic situation. One non-limiting example is a therapeutically effective dose of the present invention in the range of about 0.1 to about 5000 micrograms/kg body weight per day.

Researchers will be able to study the relevant factors and determine an effective dose of a therapeutic drug without undue experimentation. In practice, the amount of the active ingredient of the present invention to be administered may vary from patient to patient, because each patient reflects a drug and has a different threshold for drug toxicity.

The therapeutically effective dose of the present invention and the dose to be administered to the patient are adjusted depending on the age, sex and weight of the patient, the current conditions of administration and the progression of the disease. A physician, such as a physician or veterinarian, has the ability to make a prescription decision for a patient for a desired active ingredient. For example, a physician or veterinarian may initiate treatment using lower than recommended doses and then gradually increase the dose to achieve the desired therapeutic effect.

A suitable dosage range in the present invention may be from 0.1. mu.g to 5000. mu.g, alternatively from 1. mu.g to 500. mu.g, alternatively from 5. mu.g to 250. mu.g per day. This dose may be administered once or in multiple doses, which may be administered from 1 to 4 times a day. When administered multiple times, the dosage for each may be the same or different. For example, a1 μ g dose per day may be administered in two 0.5 μ g intervals of 12 hours.

In certain embodiments, the present invention is administered in an amount of 1 μ g to 5000 μ g. In certain embodiments, the invention is administered in an amount of less than 1000 μ g, or less than 500 μ g, or less than 200 μ g, or less than 50 μ g. Likewise, in certain embodiments, the dose of additional agent of the invention is less than 1000 μ g, or less than 800 μ g, or less than 600 μ g, or less than 500 μ g, or less than 400 μ g or less than 300 μ g, or less than 200 μ g, or less than 100 μ g, or less than 50 μ g, or less than 40 μ g, or less than 30 μ g, or less than 25 μ g, or less than 20 μ g, or less than 15 μ g, or less than 10 μ g, or less than 5 μ g, or less than 2 μ g, or less than 1 μ g, or less than 0.5 μ g, or any intermediate value therein.

In one embodiment, the study drug is administered to the patient from once to more than five times a day. In another embodiment, the frequency of drug administration in this study may be, but is not limited to, once daily, once every two days, once every three days, up to once weekly, once every two weeks. It is apparent that the frequency of administration of the various combinations currently varies depending on, but not limited to, age, whether the disease or disorder is being treated, sex, health, and other factors. Thus, the invention should not be construed as limited to any particular dosage regimen and the precise dosage and composition to be administered to any patient will be determined by physical determination taking into account all other factors of the patient.

It is understood that the daily administration of the drug may be, but is not limited to, once a day, once every two days, once every three days, once every four days, once every five days. For example, 5. mu.g is administered every two days, and the first 5. mu.g, the second 5. mu.g, the fifth 5. mu.g, and the subsequent steps may be performed in this order from Monday.

In the case of improvement in the patient's condition, the drug of the present invention may be administered continuously, at the discretion of the physician; alternatively, the dose of drug administered is temporarily reduced or temporarily suspended for a period of time (such as a "drug holiday"). The length of the drug holiday can be from 2 days to 1 year, including 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days. The dose reduction in the drug holiday is in the range of 10% to 100%, and may include 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once the patient develops symptoms, maintenance therapy doses may be administered. Alternatively, the dose or frequency, or both, may be reduced if the patient's physical function is improved in the case of disease or disorder. In one embodiment, the patient requires long periods of intermittent intelligence due to recurrent symptoms and/or infection.

The methods of use of the medicaments of the present invention can be formulated per unit dose. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for the subject to be treated, each unit containing a precalculated amount of active material, calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier. The unit dosage form may be administered once a day or more than once a day (e.g., once to four times a day). When multiple doses are administered per day, the unit doses may be the same or different at each time.

Toxicity and therapeutic efficacy can be determined selectively, and results from cytological and animal studies include, but are not limited to, LD50 (a dose lethal to 50% of the experimental population) and ED50 (a dose effective in 50% of the experimental population). The ratio of toxicity to efficacy is the therapeutic index, which is the ratio of LD50 to ED 50. The range of doses for use in humans can be inferred from cytologically and zoologically acquired data. The dose of each drug is preferably near ED50 in the systemic circulation and is minimally toxic. The dosage may vary depending on the administration mode and the route of use depending on the range.

In a second aspect of an embodiment of the invention there is provided a kit comprising instructions and a medicament as described in the first aspect above.

In embodiments of the invention, the instructions describe instructions, routes of administration, frequency, etc. for treating and/or preventing a skin disorder.

Example 1:

preparation of thyroxine ointment:

and uniformly mixing the thyroid hormone or the sodium salt thereof with vaseline to form thyroid hormone ointment with the concentration of the thyroid hormone or the sodium salt thereof being 40 mu g/ml.

The following description of the embodiments of the present invention is provided with reference to the accompanying drawings.

FIG. 1 is a flow chart of experimental design, in which C57BL mice induced skin fibrosis by subcutaneous injection of bleomycin at 2.5U/kg, and after four weeks, the affected parts were coated with thyroid hormone (30ng/kg) and vaseline (control) three times a day. After four weeks, skin samples were collected for scleroderma index detection. Wherein one group was harvested every week for collagen expression testing. Wherein the numbers "48" and "510" in the figure represent the sample numbers.

FIG. 2 is a fibrous view of a tissue section. Skin fibrosis (HES), collagen accumulation, elastic fibers and nucleic acid distribution were shown, respectively. Line one, before bleomycin treatment, line two, after bleomycin treatment, line three, after bleomycin induced fibrosis, and after 4 weeks of treatment with thyroid hormone T3. It can be seen from the figure that bleomycin treatment induced skin fibrosis as evidenced by thinning of the skin, decreased normal papillary infiltration, appearance of fibrotic foci and increased collagen accumulation compared to normal controls.

FIG. 3 shows the therapeutic effect of thyroxine on bleomycin-induced skin fibrosis. C57BL mice were injected subcutaneously with 2.5U/kg bleomycin to induce skin fibrosis for four weeks, and then applied thyroid hormone ointment (40. mu.g/ml) three times a day, and skin samples were collected weekly for fibrosis analysis. It can be seen from the figure that bleomycin treatment induced collagen type I gene expression and mRNA levels were significantly increased, while thyroxine T3 treatment inhibited the expression of the gene, slowing and reversing the progression of skin fibrosis, and thus was therapeutic.

Figure 4 shows the therapeutic effect of thyroxine on bleomycin-induced skin fibrosis. C57BL mice were injected subcutaneously with 2.5U/kg bleomycin to induce skin fibrosis for four weeks, then applied thyroid hormone ointment (40. mu.g/ml) three times a day, and skin samples were collected after four weeks for fibrosis analysis. From the figure, bleomycin can induce the thinning of epidermis, thickening of dermis and reduction of blood vessel number, and the treatment of thyroxine T3 can increase the number of subcutaneous blood vessels, thus being beneficial to injury repair.

FIG. 5 shows that thyroxine can prevent and treat bleomycin-induced scleroderma. a represents a representative image of Meisen trichrome-stained skin tissue; b represents a histogram of the relative content of hydroxyproline in the skin; c represents a histogram of relative change in skin thickness; d represents histogram of relative change of collagen I gene expression level. (n-16, p <0.0001), group A was a saline control group, group B was a bleomycin (2.5U/kg) administration group, group C was a bleomycin (2.5U/kg) and nintedanib (administration amount of 50mg/kg), group D was a bleomycin (2.5U/kg) and T4 (administration amount of 40mg/kg), and group E was a bleomycin (2.5U/kg) and T3 (administration amount of 40. mu.g/kg). It can be seen from the figure that thyroxine treatment can inhibit bleomycin-induced collagen accumulation, reduce hydroxyproline accumulation, inhibit collagen gene expression, promote skin injury repair, and restore the native structure.

Studies have shown that lack of thyroid hormone exacerbates skin fibrosis, and topical application of thyroid hormone ointment can reduce the progression of disease in animal models of skin damage and fibrosis. These results are given to patients with thyroid hormones who are likely to be effective in treating skin lesions and scleroderma. The results show that targeted administration of thyroid hormones and their pharmaceutically acceptable salts or prodrugs in damaged skin can be effective in reducing or completely preventing the fibrotic process.

As reported herein, the zoological studies include that in bleomycin-induced skin injury models in mice, multiple administrations of T4 or T3 to damaged skin tissue at different time points of disease progression are beneficial for disease healing. In a prevention experiment, the administration of T4 after the 3 rd to 7 th days after the induction of bleomycin can effectively inhibit skin fibrosis and promote wound healing. In the treatment experiment, T4 and T3 were administered daily after bleomycin induced scleroderma (28 days on), and samples were taken two weeks later to find significant effects on scleroderma. Thyroid hormones, particularly T3, have a better therapeutic effect than the FDA approved drug nintedanib.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. Use of thyroid hormone and its pharmaceutically acceptable salts for the manufacture of a medicament for the treatment and/or prevention of a skin disorder, the thyroid hormone and its pharmaceutically acceptable salts constituting a composition with an oleaginous base for the manufacture of the medicament, the thyroid hormone and its pharmaceutically acceptable salts being dispersed in the oleaginous base in a solid state, the oleaginous base being selected from at least one of hydrocarbons, fatty acid esters and animal and vegetable oils, the medicament having a thyroid hormone and its pharmaceutically acceptable salts content of from 20 μ g/ml to 60 μ g/ml, the medicament being in the form of a paste, the medicament being administered epicutaneously, the skin disorder being scleroderma, the thyroid hormone being thyroid hormone T3 and/or T4.

2. The use as claimed in claim 1 wherein the thyroid hormone and its pharmaceutically acceptable salts are used as the sole active ingredient in the manufacture of the medicament.

3. The use of claim 1, wherein the medicament is used in combination with another active agent, wherein the other active agent is nintedanib.

4. The use of claim 1, wherein the thyroid hormone and its pharmaceutically acceptable salts are used in an amount of 0.1 to 5000 μ g/kg body weight per day.

5. A kit, comprising instructions and a drug for treating and/or preventing a skin disorder, wherein the drug is prepared from a composition comprising a thyroid hormone and a pharmaceutically acceptable salt thereof dispersed in a solid state in an oleaginous base selected from at least one of hydrocarbons, fatty acid esters and animal and vegetable oils, and the content of the thyroid hormone and the pharmaceutically acceptable salt thereof in the drug is 20 μ g/ml to 60 μ g/ml, the drug is in the form of a ointment, the drug is administered epicutaneously, the skin disorder is scleroderma, and the thyroid hormone is thyroid hormone T3 and/or T4.