Pharmaceutical composition for treating hashimoto thyroiditis

Abstract

The invention relates to a pharmaceutical composition for treating hashimoto thyroiditis, and further relates to application of the pharmaceutical composition. The pharmaceutical composition comprises crocin and oxymatrine as active pharmaceutical ingredients, has an obvious improvement effect on serum TPO-Ab, TG-Ab, TSH, FT4, IFN-gamma, TNF-alpha and IL-10 levels of rats suffering from hashimoto thyroiditis, and is obviously superior to crocin and oxymatrine with the same dosage; the crocin and the oxymatrine have a synergistic effect in treatment of hashimoto thyroiditis, and the combination of the crocin and the oxymatrine has enhanced safety and wider application scenarios.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition for treating Hashimoto's thyroiditis. Background Art

[0002] Hashimoto's thyroiditis (HT) is a common autoimmune thyroid disease (AITD) of the endocrine system, also known as chronic autoimmune thyroiditis. Epidemiological surveys have shown that Hashimoto's thyroiditis is the most common cause of hypothyroidism in iodine-sufficient areas. As the disease progresses, most patients with Hashimoto's thyroiditis will eventually develop symptoms related to hypothyroidism, such as fatigue, chills, and bradycardia. Severe cases may even develop myxedema and coma. In addition, Hashimoto's thyroiditis may increase the risk of cardiovascular disease, thyroid cancer, and other diseases. The diagnosis of Hashimoto's thyroiditis is mainly based on the positive test results of thyroid peroxidase antibodies (TPO-Ab) and / or thyroglobulin antibodies (TG-Ab) and histopathological features.

[0003] At present, the treatment of Hashimoto's thyroiditis mainly relies on drugs, among which Western medicine is widely used clinically because of its advantages such as rapid onset and good efficacy. The key to Western medicine treatment is to regulate thyroid hormone levels to improve thyroid function and delay the development of the disease. Among them, methimazole is an imidazole antithyroid drug commonly used for Hashimoto's thyroiditis. It can inhibit the production of peroxidase in the thyroid gland, prevent the oxidation of iodide in the thyroid gland, affect the coupling of tyrosine, thereby reducing the production of thyroid hormones and improving thyroid function; levothyroxine sodium is a thyroid hormone drug that can be used to supplement thyroid hormones. It can increase thyroid hormone levels and reduce thyroid antibody levels when used alone or in combination with Chinese patent medicine preparations; prednisone is an adrenal cortex hormone drug. Its main mechanism for treating thyroid inflammation is to regulate the body's immune function and inhibit local and systemic inflammatory responses. It can inhibit thyroid antibodies, antigen binding and The release of inflammatory factors ultimately exerts antiviral and anti-inflammatory effects and alleviates clinical symptoms; dexamethasone is a glucocorticoid drug with strong anti-inflammatory and immunosuppressive effects, which can reduce the titer of autoantibodies, hinder the formation of antigen-antibody complexes, and protect cell membranes; at the same time, dexamethasone can protect thyroid follicles, prevent antigens from damaging thyroid cells, and then improve thyroid function; cyclophosphamide is a powerful immunosuppressant that can reduce the level of thyroid-related autoantibodies, reduce the size of the thyroid gland, and prevent the occurrence of hypothyroidism; selenium yeast is a combination of selenium and yeast, and its therapeutic effect is better than levothyroxine sodium, and it is more conducive to reducing oxidative stress levels and improving patients' thyroid function.

[0004] However, Western medicine treatments have certain limitations and potential risks. For example, long-term oral administration of levothyroxine sodium tablets may lead to cardiovascular disease and other related complications. Traditional Chinese medicine treatment, Chinese patent medicine treatment, and acupuncture treatment are also effective treatments for Hashimoto's thyroiditis. After treatment, most patients have varying degrees of reduction in antibody indicators, and can reduce the occurrence of adverse drug reactions and clinical complications. Active monomers of traditional Chinese medicine are the active ingredients in traditional Chinese medicine. An increasing number of active monomers of traditional Chinese medicine have been found to have immunomodulatory activity, which can inhibit the production of cytokines and autoreactive antibodies. They also have stable efficacy, few toxic and side effects, and clear chemical drug structures. They are now used in combination with other drugs to treat autoimmune diseases. Studies have shown that a variety of active monomers of traditional Chinese medicine have ameliorative effects on autoimmune diseases such as Hashimoto's thyroiditis, such as crocin, calendula glycosides, mogrosides, ophiopogon saponins, huperzine A, and oxymatrine.

[0005] However, the therapeutic effect of a single active monomer of traditional Chinese medicine is also insufficient. The development of a combination of active monomers of traditional Chinese medicine with synergistic effects is currently a research hotspot for the treatment of Hashimoto's thyroiditis. Summary of the Invention

[0006] The object of the present invention is to provide a pharmaceutical composition that can effectively treat Hashimoto's thyroiditis.

[0007] In the first aspect, the present invention provides a pharmaceutical composition comprising crocin or a pharmaceutically acceptable salt thereof and oxymatrine or a pharmaceutically acceptable salt thereof, wherein the weight ratio of crocin or a pharmaceutically acceptable salt thereof to oxymatrine or a pharmaceutically acceptable salt thereof is 1-5:1-5 based on crocin and oxymatrine.

[0008] Preferably, the weight ratio of crocin or a pharmaceutically acceptable salt thereof and oxymatrine or a pharmaceutically acceptable salt thereof, calculated as crocin and oxymatrine, is 1:1, 1:2, 1:3, 1:4, 1:5, 2:1, 2:3, 2:5, 3:1, 3:2, 3:3, 3:4, 3:5, 4:1, 4:3, 4:5, 5:1, 5:2, 5:3, 5:4 or 3:5.

[0009] More preferably, the weight ratio of crocin or its pharmaceutically acceptable salt to oxymatrine or its pharmaceutically acceptable salt, calculated on the basis of crocin and oxymatrine, is 1:2-2:1.

[0010] Most preferably, the weight ratio of crocin or a pharmaceutically acceptable salt thereof to oxymatrine or a pharmaceutically acceptable salt thereof, calculated on the basis of crocin and oxymatrine, is 1:1.

[0011] In a second aspect, the present invention also provides use of the pharmaceutical composition in preparing a drug for treating thyroiditis.

[0012] Preferably, the thyroiditis includes acute thyroiditis, subacute thyroiditis, Hashimoto's thyroiditis, chronic fibrous thyroiditis, and painless thyroiditis.

[0013] In the present invention, the CAS registration number of the crocin is 42553-65-1; the pharmaceutically acceptable salt of the crocin includes a salt formed by crocin and a pharmaceutically acceptable acid or base.

[0014] In the present invention, the CAS registration number of the oxymatrine is 16837-52-8; the pharmaceutically acceptable salt of the oxymatrine includes a salt formed by paeonol and a pharmaceutically acceptable base.

[0015] Preferably, the crocin or a pharmaceutically acceptable salt thereof and oxymatrine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition or medicament of the present invention can be administered in the same or different pharmaceutical formulations. The pharmaceutical dosage forms of the crocin or a pharmaceutically acceptable salt thereof and oxymatrine or a pharmaceutically acceptable salt thereof can be the same or different. The crocin or a pharmaceutically acceptable salt thereof and oxymatrine or a pharmaceutically acceptable salt thereof can be administered simultaneously or sequentially.

[0016] In the medical uses described above, the administration time, number of administrations and frequency of administration of crocin or its pharmaceutically acceptable salt and oxymatrine or its pharmaceutically acceptable salt, etc., need to be determined according to the specific diagnosis results of the disease, which is within the technical scope mastered by those skilled in the art.

[0017] Preferably, the pharmaceutical composition or medicine of the present invention further comprises a pharmaceutically acceptable excipient.

[0018] As used herein, the term "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or carrier that is involved in the administration form or is compatible with the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when combined, such that interactions that would substantially reduce the therapeutic efficacy of the compound of the invention upon administration to a subject, as well as interactions that would render the pharmaceutical composition unpharmaceutically unacceptable, are avoided. Furthermore, the purity of each excipient must, of course, be sufficiently high to render it pharmaceutically acceptable.

[0019] The pharmaceutical compositions and medicaments of the present invention are generally formulated into dosage forms suitable for administration to a subject via a desired route of administration. For example, dosage forms include those (1) suitable for oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, slurries, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) suitable for parenteral administration, such as sterile solutions, suspensions; (3) suitable for transdermal administration, such as transdermal patches; (4) suitable for rectal administration, such as suppositories; (5) suitable for inhalation, such as dry powders, aerosols, suspensions, and solutions; and (6) suitable for topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0020] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, suitable pharmaceutically acceptable excipients can be selected based on the specific function they perform in the pharmaceutical composition or medicament. For example, certain pharmaceutically acceptable excipients can be selected based on their ability to facilitate the preparation of a uniform dosage form, certain pharmaceutically acceptable excipients can be selected based on their ability to facilitate the preparation of a stable dosage form, and certain pharmaceutically acceptable excipients can be selected based on their ability to facilitate the carriage or transport of the composition of the present invention from one organ or part of the body to another organ or part of the body after administration to a subject.

[0021] Suitable pharmaceutically acceptable excipients include the following excipient types: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavorings, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants and buffers. It will be understood by those skilled in the art that some pharmaceutically acceptable excipients can be used with more than one function and with alternative functions, depending on how much the excipient is present in the formulation and what other ingredients are present in the formulation.

[0022] Those skilled in the art with knowledge and skill in the art will be able to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. The pharmaceutical compositions or medicaments of the present invention are prepared using techniques and methods known to those skilled in the art.

[0023] For solid oral dosage forms, such as tablets or capsules, it comprises a safe and effective amount of pharmaceutical composition of the present invention or medicine and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, glucose, mannitol, sorbitol, starch (such as corn starch, potato starch and pregelatinized starch), cellulose and its derivatives (such as microcrystalline cellulose), calcium sulfate and calcium hydrogen phosphate. Oral solid dosage forms may also include a binder. Suitable binders include starch (such as corn starch, potato starch and pregelatinized starch), gelatin, gum arabic, sodium alginate, alginic acid, tragacanth gum, guar gum, polyvidone and cellulose and its derivatives (such as microcrystalline cellulose). Oral solid dosage forms may also include a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, cross-linked carboxymethyl cellulose, alginic acid and sodium carboxymethyl cellulose. Oral solid dosage forms may also include a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

[0024] Beneficial effects:

[0025] The present invention provides a pharmaceutical composition for treating Hashimoto's thyroiditis. The pharmaceutical composition contains crocin and oxymatrine as active pharmaceutical ingredients. The two have a synergistic effect in treating Hashimoto's thyroiditis, can greatly improve the treatment effect, thereby improving the efficacy and reducing the drug dosage, and has better safety and application scenarios. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The effects of different drugs on the levels of TPO-Ab, TG-Ab, TSH and FT4 in rat serum;

[0027] Figure 2 The effects of different drugs on the levels of IFN-γ, TNF-α and IL-10 in rat serum. DETAILED DESCRIPTION

[0028] The embodiments of the present invention are described in detail below. The embodiments are given to better illustrate the contents of the present invention and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0029] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0030] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0031] Example:

[0032] Twenty-one 6-week-old SPF female SD rats (body weight 180-200 g) were adaptively raised for one week and then randomly divided into a blank control group, a model group, a crocin group, an oxymatrine group, and a crocin + oxymatrine group, with 6 rats in each group. HT rat models were established according to the method of Li Xuying et al. (Journal of Jilin University (Medical Edition), 2019, 45(3): 558-565). Rats were allowed to drink iodine-rich water (0.6 mg / mL, solute is sodium iodide, solvent is distilled water) freely. In the third week, 200 μL of primary immune emulsion (1:1 Freund's complete adjuvant and 1 g / L antigen solution (solute is thyroglobulin, solvent is phosphate buffer)) were subcutaneously injected at multiple points on the back of the rats twice a week. Rats received a weekly subcutaneous injection of 200 μL of a booster emulsion (a 1:1 mixture of Freund's incomplete adjuvant and a 1 g / L antigen solution (thyroglobulin as the solute and phosphate buffered saline as the solvent)) at multiple points on their backs. The drug-treated groups were gavaged with the corresponding doses of drugs simultaneously with model establishment: 10 mg / kg / d for the crocin group, 10 mg / kg / d for the oxymatrine group, and 5 mg / kg / d for the crocin plus oxymatrine group. Rats in the blank control group received distilled water and a regular diet for 7 weeks.

[0033] Detection indicators: Serum TPO-Ab, TG-Ab, TSH and FT4 levels were detected by chemiluminescence method, and serum IFN-γ, TNF-α and IL-10 levels were detected by enzyme-linked immunosorbent assay (ELISA)

[0034] 1. Detect serum TG-Ab, TPO-Ab, TSH, and FT4 levels in each group of mice according to the assay kit instructions (purchased from Shanghai Yuanxin Biotechnology). Specific steps are as follows: Set up blank wells, standard wells, and sample wells, and add 100 μL of PBS, the standard, and the test sample to each well. Add the corresponding detection reagents in sequence and incubate according to the corresponding reaction conditions. Finally, measure the OD value of each well at a wavelength of 550 nm using a microplate reader.

[0035] 2. Detect the levels of IFN-γ, TNF-α, and IL-10 in the serum of each group of mice according to the instructions of the detection kit (purchased from Shanghai ELISA Biotechnology). The specific steps are as follows: set up standard and sample wells, add 100 μL of sample and standard of different concentrations to each well, incubate at 37°C for 2 hours, wash the plate three times with PBS, add the appropriate amount of enzyme-labeled antibody, incubate at 37°C for 1 hour, wash the plate three times with PBS, add colorimetric reagent for color development, and measure the OD value of each well at a wavelength of 450 nm using a microplate reader.

[0036] The results are as follows Figure 1 and 2As shown in the results, compared with the blank control group, the serum thyroid peroxidase antibody TPO-Ab, thyroglobulin antibody TG-Ab, thyroid stimulating hormone TSH, and free thyroxine FT4 levels of the model rats were significantly increased, indicating that the TH rat model was successfully established. Compared with the model group, the serum TPO-Ab, TG-Ab, TSH, and FT4 levels of the rats in the drug treatment group were significantly decreased, and the reduction in serum TPO-Ab, TG-Ab, TSH, and FT4 levels of the rats in the crocin + oxymatrine group was significantly better than that of the crocin group and the oxymatrine group at the same dose. In addition, the serum levels of proinflammatory cytokines IFN-γ and TNF-α in the model rats were significantly increased, while the level of regulatory cytokine IL-10 was significantly decreased. After drug treatment, the levels of IFN-γ and TNF-α decreased, while the level of IL-10 increased. The crocin + oxymatrine group had the best therapeutic effect, which was significantly better than the crocin group and the oxymatrine group at the same dose. The above results indicate that the combination of crocin and oxymatrine has a synergistic effect in the treatment of Hashimoto's thyroiditis.

[0037] Obviously, the above embodiments are merely examples for the purpose of illustrating the present invention and are not intended to limit the embodiments of the present invention. Those skilled in the art may make various modifications and variations to the present invention without departing from the spirit and scope of the present invention. Thus, to the extent such modifications and variations fall within the scope of the claims and their equivalents, the present invention is intended to encompass such modifications and variations.

Claims

1. A pharmaceutical composition comprising crocin or a pharmaceutically acceptable salt thereof and oxymatrine or a pharmaceutically acceptable salt thereof, wherein the weight ratio of crocin or a pharmaceutically acceptable salt thereof to oxymatrine or a pharmaceutically acceptable salt thereof is 1-5:1-5 based on the weight ratio of crocin to oxymatrine.

2. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of the crocin or a pharmaceutically acceptable salt thereof and oxymatrine or a pharmaceutically acceptable salt thereof, calculated on the basis of crocin and oxymatrine, is 1:1, 1:2, 1:3, 1:4, 1:5, 2:1, 2:3, 2:5, 3:1, 3:2, 3:3, 3:4, 3:5, 4:1, 4:3, 4:5, 5:1, 5:2, 5:3, 5:4 or 3:

5.

3. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of crocin or its pharmaceutically acceptable salt to oxymatrine or its pharmaceutically acceptable salt is 1:2-2:1 based on crocin and oxymatrine.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The dosage forms of the pharmaceutical composition include: (1) a dosage form suitable for oral administration; (2) a dosage form suitable for parenteral administration; (3) a dosage form suitable for transdermal administration; (4) a dosage form suitable for rectal administration; (5) a dosage form suitable for inhalation; and (6) a dosage form suitable for topical administration.

5. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a medicament for treating thyroiditis.

6. The use according to claim 5, characterized in that The thyroiditis includes acute thyroiditis, subacute thyroiditis, Hashimoto's thyroiditis, chronic fibrous thyroiditis, and painless thyroiditis.

7. The use according to claim 5, characterized in that The thyroiditis is Hashimoto's thyroiditis.

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