Use of a CFTR corrector in the preparation of a medicament for treating breast hyperplasia

Abstract

The application provides application of a CFTR corrector in preparation of a drug for treating mammary gland hyperplasia, and belongs to the field of biopharmacy.The application creatively finds, through non-clinical pharmacodynamics test, that a compound represented by formula I, tizacatol, can significantly reduce the nipple diameter, height and uterus index of a mammary gland hyperplasia rat model, relieve mammary gland hyperplasia, and improve the content level of E2 and PROG in serum, and has a good treatment effect in treating mammary gland hyperplasia, and has the potential of being applied in preparation of a drug for treating mammary gland hyperplasia.

Description

Technical Field

[0001] This invention belongs to the field of biopharmaceuticals, specifically relating to the application of a CFTR corrector in the preparation of a drug for treating breast hyperplasia. Background Technology

[0002] Hyperplasia of the mammary glands (HMG) is a benign breast disease (BBD) caused by abnormalities in the normal development and regression of the mammary glands. Essentially, it is a disorder of the normal breast structure due to varying degrees of hyperplasia and incomplete involution of the mammary gland matrix and stroma. Its pathological morphology is diverse and complex, hence the lack of a unified clinical nomenclature. Epidemiological data shows that HMG is one of the most common and frequently occurring diseases in women, ranking first among breast diseases. Surveys indicate that the incidence of this disease has been increasing year by year in recent years, and the age of patients is becoming increasingly younger. According to experts, 70%-80% of women have varying degrees of HMG. Currently, the etiology and pathogenesis of HMG are not fully understood. Scholars generally agree that endocrine disorders are the main cause, and the related clinical manifestations are external manifestations of hormonal imbalances. This includes: ① an imbalance in the ratio of estrogen to progesterone leading to excessive proliferation and incomplete involution of mammary glands; ② abnormal distribution and expression of estrogen receptors in different parts of the mammary gland; ③ elevated prolactin levels indirectly affecting related mammary gland development and interfering with the function of the hypothalamus-pituitary-gonadal axis. Furthermore, because this disease is often chronic and prone to recurrence, it greatly impacts the physical and mental health of many women.

[0003] For breast hyperplasia, the first-line treatment in clinical practice is currently traditional Chinese medicine, such as Rupisanjie Capsules, Rupixiao Tablets, Danlu Capsules, and Honghua Xiaoyao Tablets. Chemical drugs are generally used as second-line drugs when first-line treatment is ineffective, but there are few types available. Currently, tamoxifen is the most commonly used in clinical practice, but tamoxifen has a high incidence and relatively serious adverse reactions.

[0004] Therefore, there is an urgent need to discover chemical drugs with better efficacy and fewer side effects for the treatment of breast hyperplasia. Summary of the Invention

[0005] In order to overcome the shortcomings of the prior art, the purpose of this invention is to provide an application of CFTR corrector in the preparation of a drug for treating breast hyperplasia, and to invent a drug and drug composition that have a therapeutic effect on breast hyperplasia, which can be used for the clinical treatment of breast hyperplasia.

[0006] To solve the above problems, the technical solution adopted by the present invention is as follows: the use of the compound represented by Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast hyperplasia.

[0007]

[0008]

[0009] The application involves the use of the compound represented by Formula I, tezacaftor, or a pharmaceutically acceptable salt and / or solvate and / or hydrate thereof, and a pharmaceutical composition containing the above compound for the treatment of breast hyperplasia.

[0010] The preferred use of solvates of the compounds represented by Formula I and / or solvates of their pharmaceutically acceptable salts in the preparation of medicaments for treating breast hyperplasia.

[0011] The preferred use of the hydrates of the compounds represented by Formula I and / or the hydrates of their pharmaceutically acceptable salts in the preparation of medicaments for treating breast hyperplasia.

[0012] The present invention also relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and / or a solvate thereof and / or a hydrate thereof.

[0013] The pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient, specifically, the pharmaceutical composition being a solid dosage form, liquid dosage form, oral dosage form, injection dosage form, or combination dosage form.

[0014] According to the present invention, the pharmaceutical composition can be administered in any of the following ways: oral administration, parenteral administration such as subcutaneous, intravenous, or intramuscular injection. Oral administration is preferred.

[0015] When administered orally, the compound represented by Formula I or its pharmaceutically acceptable salts and / or solvates and / or hydrates thereof may be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or suspensions. Tablets typically use carriers including lactose, corn starch, microcrystalline cellulose, and sodium carboxymethyl cellulose, and lubricants such as magnesium stearate may also be added. Capsule formulations typically use diluents including lactose and dried corn starch. Suspension formulations typically involve mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, sweeteners, flavorings, or colorings may also be added to the above oral dosage forms.

[0016] When administered by injection, the compound represented by Formula I or its pharmaceutically acceptable salt and / or both solvates and / or both hydrates may be formulated as an injection solution or a powder for injection, wherein the carriers that may be used include, but are not limited to, water for injection, compatibilizing carrier materials, pH adjusters, antioxidants, proppants, etc.

[0017] The beneficial effects of adopting the technical solution of this invention are as follows: This invention creatively discovers through non-clinical pharmacodynamic experiments that the compound tizacateldophor shown in Formula I can significantly reduce nipple diameter, height, and uterine index in a rat model of mammary hyperplasia, alleviate mammary hyperplasia, and improve serum E2 and PROG levels, demonstrating a good therapeutic effect in treating mammary hyperplasia. It has the potential for application in the preparation of drugs for treating mammary hyperplasia. In this invention, the target of drug treatment is mammals, including humans, canines, rodents, etc. Attached Figure Description

[0018] Figure 1 Nipple size in rats of different groups after 30 days of drug treatment;

[0019] Figure 2 Ovarian and uterine indices of rats in each group after 30 days of drug treatment;

[0020] Figure 3 Serum estrogen and progesterone levels in rats of different groups after 30 days of drug treatment;

[0021] Figure 4 Staining of mammary tissue sections from mice in each group after 30 days of drug treatment. Detailed Implementation

[0022] The present invention will be further described in detail below with reference to embodiments, but is not limited thereto.

[0023] A: Pharmacological and pharmacodynamic evaluation

[0024] Example 1: Pharmacodynamic study of tezacotto in a rat model of mammary hyperplasia

[0025] Experimental Design: Twenty-four female SD rats, aged 7-8 weeks and weighing 200-250g, were randomly divided into four groups: a blank control group, a model group, a tizacalotoxin treatment group (hereinafter referred to as the treatment group), and a tamoxifen treatment group (hereinafter referred to as the positive group). Before drug administration, rats in the model group, treatment group, and positive group underwent mammary hyperplasia modeling: estradiol benzoate injection (0.5 mg / kg / d) was injected intramuscularly into the medial hind leg for 25 consecutive days. Starting from day 26, progesterone injection (5 mg / kg / d) was injected intramuscularly into the medial hind leg for 5 consecutive days, for a total of 30 days of modeling.

[0026] Control group: Rats were injected intramuscularly with an equal volume of physiological saline once daily, alternating between the left and right hind limbs, for 30 consecutive days. Starting on day 31, they were administered physiological saline by gavage for another 30 days.

[0027] Model group: On day 31, the patient was given the solvent by gavage. The administration was continued for 30 days, and samples were collected 0.5 hours after the last administration.

[0028] Treatment group: On day 31, tezacotto 40 mg / kg / d was administered by gavage for 30 consecutive days, and samples were collected 0.5 hours after the last administration.

[0029] Positive group: On day 31, tamoxifen 4 mg / kg / d was administered by gavage for 30 consecutive days. Samples were collected 0.5 hours after the last administration.

[0030] Detection indicators: ① Nipple diameter and height, ② Ovarian index and uterine index, ③ Changes in the expression of E2 and PROG in serum, ④ Number of lobular acini, acini lumen diameter and duct diameter in rat mammary glands.

[0031] The animal grouping and dosing regimens are summarized below:

[0032]

[0033] Example 2: Evaluation of nipple size in rats with mammary hyperplasia treated with tezacotto

[0034] In the experiment of Example 1, the diameter and height of the rat nipples were measured 30 days after drug administration. See the attached images for details of the nipple size in each group. Figure 1 The nipple diameter and height data for each group are shown in Tables 1 and 2 below. The results showed that, compared with the model group, the nipple diameter and height of rats in both the treatment group and the positive control group decreased, and the differences were statistically significant.

[0035] Table 1. Nipple diameter (mm) of rats in each group

[0036]

[0037] Table 2. Nipple height (mm) in rats of different groups

[0038]

[0039] In the experiment, one-way ANOVA was used to perform statistical analysis on each group. Compared with the model group, * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001.

[0040] Example 3: Evaluation of ovarian and uterine indices in rats with mammary hyperplasia treated with tezacotto

[0041] In Example 1, the uterus, ovaries, and rat weights were measured 30 days after drug administration. The uterine index was calculated as uterine weight / rat weight. For a detailed comparison of ovarian and uterine indices in each group, please refer to [link to example 1]. Figure 2The ovarian and uterine indices for each group are shown in Table 3 below. The results showed that, compared with the model group, both the treatment group and the positive drug group exhibited a decrease in ovarian and uterine indices, with statistically significant differences.

[0042] Table 3. Uterine index and ovarian index of rats in each group

[0043]

[0044] In the experiment, one-way ANOVA was used to perform statistical analysis on each group. Compared with the model group, * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001.

[0045] Example 4: Evaluation of serum E2 and PROG expression in rats with mammary hyperplasia treated with tezacotto

[0046] In Example 1, the expression of E2 and PROG in the serum of rats in each group was detected using a kit 30 days after drug administration. For a detailed comparison of these two values ​​among the groups, please refer to [link to example 1]. Figure 3 The results showed that, compared with the model group, E2 expression was significantly decreased and PROG expression was significantly increased in both the treatment group and the positive drug group, with significant differences in both indicators.

[0047] Example 5: Pathological analysis and evaluation of mammary glands in rats with mammary hyperplasia treated with tezacotto

[0048] In Example 1, mammary glands of rats in each group were collected, dehydrated, embedded, and sectioned 30 days after drug administration. HE staining and pathological analysis were performed. The HE staining results of mammary glands in each group are shown below. Figure 4 The pathological examination scoring table is shown in Table 4 below, based on the analysis of the slides. The results showed no abnormalities in the breast tissue of the normal control group, while the model group exhibited significant breast hyperplasia, characterized by an increased number of lobules and alveoli, dilation of ducts and alveoli, abundant secretions, and significant stroma hyperplasia. Compared with the model group, the breast hyperplasia was reduced in the positive control group and the treatment group.

[0049] Table 4. Histopathological examination scores

[0050]

[0051]

[0052] Note: All morphological changes are marked with "1 point", "2 points", "3 points" and "4 points" according to their severity, representing mild, moderate and severe, respectively. No lesion is marked with "0 points" and missing is marked with "none".

[0053] Example 6: Comprehensive Efficacy Analysis of Tezaccato in Treating Rats with Mammary Hyperplasia

[0054] Based on the results and evaluation of the above indicators, administration of tezacotto to rats with hormone-induced mammary hyperplasia significantly reduced nipple diameter, height, and uterine index, alleviating mammary hyperplasia. At the same time, serum E2 and PROG levels were also significantly improved, with statistically significant differences, indicating that tezacotto can be used to treat mammary hyperplasia.

[0055] B: Pharmaceutical Composition

[0056] Example 7: Preparation of a pharmaceutical composition containing tizacaloerol, formulation for oral tablets:

[0057]

[0058] Preparation process:

[0059] (1) Weigh out the prescribed amounts of tizacalo and microcrystalline cellulose, and mix them in a wet granulator for 5 minutes.

[0060] (2) Add the prescribed amount of sodium dodecyl sulfate to the above powder mixture and mix for 5 minutes;

[0061] (3) Weigh the prescribed amount of hydroxypropyl cellulose and dissolve it in 150ml of water to prepare a 5% hydroxypropyl cellulose solution;

[0062] (4) Add the hydroxypropyl cellulose solution to the mixed powder and granulate using a wet granulation machine for 10 min;

[0063] (5) Place the granulated powder into a fluidized bed dryer and dry for 20 minutes;

[0064] (6) Place the dried powder and the prescribed amounts of cross-linked cellulose sodium and magnesium stearate into a mixer and mix for 5 minutes;

[0065] (7) Compress the above mixed powder into tablets at a weight of 200 mg to obtain bare tablets;

[0066] (8) Coat the bare film with coating material, and stop coating after the weight increases by 4% to obtain the finished product.

[0067] Example 8: Preparation of a pharmaceutical composition containing tizacalotoxin, and a formulation for lyophilized powder for injection:

[0068]

[0069]

[0070] Preparation process:

[0071] (1) Weigh out the prescribed amount of tezacotto monohydrate and dissolve it in 1 ml of methanol. Stir at 450 rpm for 5 min.

[0072] (2) Weigh out the prescribed amount of sulfobutyl-β-cyclodextrin and dissolve it in 2 ml of methanol and 1 ml of water until clear;

[0073] (3) Mix the two solutions and stir at 450 rpm for 2 hours, then filter through a 0.22 μm filter membrane for sterilization;

[0074] (4) The above solution was dried under vacuum at 50°C water bath and 60 rpm to obtain a solid.

[0075] The solid was reconstituted with 10 ml of water for injection and then freeze-dried in a freeze dryer to obtain the finished product.

[0076] All references to this invention are incorporated herein by reference as if each reference were individually incorporated herein by reference.

Claims

1. The use of the compound represented by Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast hyperplasia. Ⅰ。 2. The use of a pharmaceutical composition in the preparation of a medicament for treating breast hyperplasia, characterized in that, The pharmaceutical composition described herein comprises a compound of formula I or a pharmaceutically acceptable salt thereof. Ⅰ。 3. The application according to claim 2, characterized in that, The pharmaceutical composition described therein also contains a pharmaceutically acceptable carrier.

4. The application according to claim 2, characterized in that, The pharmaceutical composition described therein also contains pharmaceutically acceptable excipients.

5. The application according to claim 2, characterized in that, The pharmaceutical composition described therein is a solid dosage form or a liquid dosage form.

6. The application according to claim 2, characterized in that, The pharmaceutical composition described herein is an oral preparation or an injectable preparation.

7. The application according to claim 2, characterized in that, The pharmaceutical composition described therein is a compound preparation.

8. The application according to any one of claims 1-7, characterized in that, The application targets include humans, canines, rodents, and other mammals.

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