Use of CFTR corrector in preparation of drug for treating hyperplasia of the mammary glands

Abstract

The present invention belongs to the biopharmaceutical field. Provided is the use of a CFTR corrector in the preparation of a drug for treating hyperplasia of the mammary glands. A non-clinical pharmacodynamic test has found that the tezacaftor compound as shown in formula I can significantly reduce the nipple diameter and height in rats, and uterus index of rats, alleviate hyperplasia of the mammary glands, and improve E2 and PROG content levels in serum in rat models of hyperplasia of the mammary glands; and has a good therapeutic effect in treating hyperplasia of the mammary glands. The compound has the potential of being used in the preparation of a drug for treating hyperplasia of the mammary glands.

Description

Application of a CFTR corrector in the preparation of a drug for treating mammary hyperplasia Technical Field

[0001] The present invention belongs to the field of biopharmaceuticals, and particularly relates to the use of a CFTR corrector in the preparation of a medicine for treating fibrocystic breast disease. Background Art

[0002] Hyperplasia of the mammary glands (HMG) is a benign breast disease (BBD) caused by abnormalities in the normal development and involution of the mammary gland. Essentially, it results from varying degrees of proliferation and incomplete involution of the mammary gland's parenchyma and stroma, leading to a disturbance in the normal mammary gland's architecture. Its pathological morphology is diverse and complex, resulting in a lack of standardized clinical nomenclature. Epidemiological studies show that HMG is a common and recurring disease in women, ranking first among breast diseases. Surveys indicate that its incidence has been increasing annually in recent years, with the age of patients becoming younger. According to experts, 70%-80% of women experience varying degrees of HMG. The etiology and pathogenesis of HMG remain unclear. Scholars generally agree that endocrine disorders are the primary cause, and their associated clinical manifestations are the outward manifestations of hormonal imbalances. These include: ① an imbalance in the ratio of estrogen to progesterone, leading to excessive mammary gland proliferation and incomplete involution; ② abnormal distribution and expression of estrogen receptors in various parts of the mammary gland; and ③ elevated prolactin levels, indirectly affecting mammary development and interfering with hypothalamic-pituitary function. Because this condition often persists and is prone to recurrence, it significantly impacts the physical and mental health of many women.

[0003] Currently, the first-line treatment for breast hyperplasia is traditional Chinese medicine (TCM), such as Rupi Sanjie Capsules, Rupi Xiao Tablets, Danlu Capsules, and Honghua Xiaoyao Tablets. Chemical drugs are generally used as second-line treatments when first-line drugs are ineffective, but they are scarce. Tamoxifen is currently the most commonly used, but its adverse reactions are more frequent and severe.

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

[0005] Summary of the Invention

[0006] In order to overcome the deficiencies of the prior art, the purpose of the present invention is to provide an application of a CFTR corrector in the preparation of a drug for treating fibrocystic breast disease, to invent a drug having a therapeutic effect on fibrocystic breast disease and a pharmaceutical composition thereof, which can be used for the clinical treatment of fibrocystic breast disease.

[0007] To solve the above problems, the present invention adopts the following technical solution: the use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating mammary hyperplasia,

[0008] The present invention relates to a compound represented by formula I, namely Tezacaftor, or a pharmaceutically acceptable salt and / or a solvate and / or a hydrate thereof, and a pharmaceutical composition containing the compound, for use in treating breast hyperplasia.

[0009] Preferably, the solvate of the compound represented by formula I and / or the solvate of its pharmaceutically acceptable salt is used in the preparation of a drug for treating breast hyperplasia.

[0010] Preferably, the hydrate of the compound represented by formula I and / or the hydrate of the pharmaceutically acceptable salt thereof is used in the preparation of a drug for treating breast hyperplasia.

[0011] The present invention also relates to a pharmaceutical composition comprising the compound represented by formula I or a pharmaceutically acceptable salt thereof and / or a solvate thereof and / or a hydrate thereof.

[0012] The pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient. Specifically, the pharmaceutical composition is a solid preparation, a liquid preparation, an oral preparation, an injection or a compound preparation.

[0013] 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, wherein oral administration is preferred.

[0014] When administered orally, the compound of Formula I, or its pharmaceutically acceptable salts and / or solvates and / or hydrates, can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or suspensions. Common carriers for tablets include lactose, corn starch, microcrystalline cellulose, and sodium carboxymethyl cellulose, and lubricants such as magnesium stearate may also be added. Common diluents for capsule formulations include lactose and dried corn starch. Suspension formulations typically combine the active ingredient with a suitable emulsifier and suspending agent. If desired, sweeteners, flavorings, or coloring agents may be added to these oral dosage forms.

[0015] When administered by injection, the compound represented by Formula I or its pharmaceutically acceptable salts and / or solvates and / or hydrates thereof can be prepared into the form of injection solutions or powder injections, wherein the carriers that can be used include but are not limited to water for injection, volume-increasing carrier materials, pH regulators, antioxidants, support agents, etc.

[0016] The beneficial effects of the technical solution of the present invention are as follows: Through innovative non-clinical pharmacodynamic studies, the present invention discovered that the compound represented by Formula I, Tizacator, significantly reduced nipple diameter, height, and uterine index in a rat model of mammary hyperplasia, alleviated mammary hyperplasia, and improved serum E2 and PROG levels, demonstrating excellent therapeutic efficacy in treating mammary hyperplasia. The compound has the potential to be used in the preparation of a medicament for treating mammary hyperplasia. In this invention, the therapeutic targets are mammals, including humans, canines, rodents, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1. Nipple size of rats in each group after 30 days of drug treatment;

[0018] Figure 2 Ovarian index and uterine index of rats in each group after 30 days of drug treatment;

[0019] Figure 3 Expression of estrogen and progesterone in the serum of rats in each group after 30 days of drug treatment;

[0020] Figure 4 Staining of mammary gland tissue sections of mice in each group after 30 days of drug treatment. DETAILED DESCRIPTION

[0021] The present invention will be further described in detail below with reference to the examples, but is not limited thereto.

[0022] A: Pharmacological and pharmacodynamic evaluation

[0023] Example 1: Pharmacodynamics of Tizacator in a rat model of mammary hyperplasia

[0024] Experimental Design: Twenty-four female SD rats, 7-8 weeks old, weighing 200-250g, were randomly divided into four groups: a blank control group, a model group, a tizacato-treated group (hereinafter referred to as the treatment group), and a tamoxifen-treated group (hereinafter referred to as the positive group). Rats in the model, treatment, and positive groups were induced to develop a model of mammary hyperplasia before drug administration: Estradiol benzoate injection (0.5 mg / kg / day) was injected into the medial hind leg muscle of the rats for 25 consecutive days. Starting on the 26th day, progesterone injection (5 mg / kg / day) was injected into the medial leg muscle for 5 consecutive days, for a total of 30 days.

[0025] Blank control group: Rats were injected with an equal volume of normal saline into the inner hind limb muscles once a day, alternating injections into the left and right hind limbs, for 30 consecutive days. Starting on the 31st day, normal saline was administered orally for 30 days.

[0026] Model group: On day 31, the mice were given solvent by gavage for 30 consecutive days, and samples were collected 0.5 h after the last administration.

[0027] Treatment group: On day 31, mice were given 40 mg / kg / d of tiazacator by oral gavage for 30 consecutive days, and samples were collected 0.5 h after the last administration.

[0028] Positive group: On day 31, rats were given tamoxifen 4 mg / kg / d by gavage for 30 consecutive days, and samples were collected 0.5 h after the last administration.

[0029] Detection indicators: ① nipple diameter and height detection, ② ovarian index and uterine index detection, ③ changes in the expression of E2 and PROG in serum, ④ the number of acinar cells in rat mammary lobules, acinar cavity diameter and duct diameter.

[0030] The animal groups and dosing regimens are summarized as follows:

[0031] Example 2: Evaluation of nipple size in rats with mammary hyperplasia treated with tiazacator

[0032] In the experiment of Example 1, the diameter and height of the rat nipples were measured 30 days after administration. The nipple size of rats in each group is shown in Figure 1. The nipple diameter and height data of 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 the treatment group and the positive drug group decreased, and the difference was statistically significant.

[0033] Table 1 Diameter of nipples of rats in each group (mm)

[0034] Table 2 Nipple height of rats in each group (mm)

[0035] One-way ANOVA was used to analyze the data of each group. Compared with the model group, * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

[0036] Example 3: Evaluation of ovarian index and uterine index in rats with mammary hyperplasia treated with tiazacator

[0037] In the experiment described in Example 1, the uterus, ovaries, and rat weights were measured 30 days after administration. Uterine index = uterine weight / rat weight, and uterine index = uterine weight / rat weight. A comparison of the ovarian and uterine indices of rats in each group is shown in Figure 2 , and the ovarian and uterine indices for each group are shown in Table 3 below. The results showed that compared to the model group, the ovarian and uterine indices of rats in the treatment and positive drug groups decreased, with statistically significant differences.

[0038] Table 3 Uterine index and ovarian index of rats in each group

[0039] One-way ANOVA was used to analyze the data of each group. Compared with the model group, * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

[0040] Example 4: Evaluation of E2 and PROG Expression in Serum of Rats with Mammary Hyperplasia Treated by Tizacator

[0041] In the experiment of Example 1, 30 days after administration, the expression of E2 and PROG in the serum of rats in each group was detected using a test kit. The comparison of the values ​​of these two items in each group is shown in Figure 3. The results showed that compared with the model group, the expression of E2 in the treatment group and the positive drug group was significantly decreased, and the expression of PROG was significantly increased, with significant differences in both indicators.

[0042] Example 5: Pathological analysis and evaluation of mammary glands in rats with mammary hyperplasia treated with tiazacator

[0043] In the experiment of Example 1, the mammary glands of rats in each group were sampled, dehydrated, embedded and sliced ​​30 days after administration. The mammary glands of rats in each group were stained with HE and analyzed pathologically. The HE staining results of the mammary glands of rats in each group are shown in Figure 4. After analysis of the slides, the pathological examination score table is shown in Table 4 below. The results showed that the mammary glands of the normal control group were normal, while the model group had obvious breast hyperplasia, manifested by an increase in the number of lobules and alveoli, dilation of ducts and alveoli, abundant secretions, and obvious interstitial hyperplasia. Compared with the model group, the breast hyperplasia phenomenon in the positive drug group and the treatment group was alleviated.

[0044] Table 4 Histopathological examination scores

[0045] Note: All morphological changes are marked as "1 point", "2 points", "3 points" and "4 points" according to their severity, representing mild, mild, moderate and severe, respectively. No lesion is marked as "0 point" and missing lesions are marked as "none".

[0046] Example 6: Analysis of the comprehensive efficacy of tiazacator in treating mammary hyperplasia in rats

[0047] According to the results and evaluation of the above-mentioned multiple indicators, after administering tiazacato to rats with hormone-induced breast hyperplasia model, the nipple diameter, height and uterine index of the model group rats can be significantly reduced, and breast hyperplasia can be alleviated. At the same time, the levels of E2 and PROG in serum are also significantly improved, and the differences are statistically significant, indicating that tiazacato can be used to treat breast hyperplasia.

[0048] B: Pharmaceutical Composition

[0049] Example 7: Preparation of a pharmaceutical composition containing tiazacator, prescription of oral tablets:

[0050] Preparation process:

[0051] (1) Weigh the prescribed amount of tizacator and microcrystalline cellulose and place them in a wet granulator and mix for 5 minutes;

[0052] (2) Add the prescribed amount of sodium lauryl sulfate to the above mixed powder and mix for 5 minutes;

[0053] (3) Weigh the prescribed amount of hydroxypropyl cellulose and dissolve it in 150 ml of water to prepare a 5% hydroxypropyl cellulose solution;

[0054] (4) Add the hydroxypropyl cellulose solution to the mixed powder and granulate it using a wet granulator for 10 minutes;

[0055] (5) The granulated powder was placed in a boiling dryer and dried for 20 min;

[0056] (6) Place the dried powder and the prescribed amount of cross-linked cellulose sodium and magnesium stearate into a mixer and mix for 5 minutes;

[0057] (7) Compressing the mixed powder into tablets weighing 200 mg to obtain bare tablets;

[0058] (8) The bare tablets are coated with a coating material. When the weight increases by 4%, the coating is stopped to obtain the finished product.

[0059] Example 8: Preparation of a pharmaceutical composition containing tizacator, formulation of lyophilized powder for injection:

[0060] Preparation process:

[0061] (1) Weigh the prescribed amount of tiazacator monohydrate, dissolve it in 1 ml of methanol, and stir at 450 rpm for 5 min.

[0062] (2) Weigh the prescribed amount of sulfobutyl-β-cyclodextrin and dissolve it in 2 ml of methanol and 1 ml of water until clear;

[0063] (3) The two solutions were mixed, stirred at 450 rpm for 2 h, and then sterilized through a 0.22 μm filter membrane;

[0064] (4) The above solution was vacuum dried in a water bath at 50°C and 60 rpm to obtain a solid;

[0065] The solid was reconstituted with 10 ml of water for injection and then freeze-dried in a freeze dryer to obtain the finished product.

[0066] All documents mentioned herein are incorporated by reference into this application to the same extent as if each document were individually incorporated by reference.

Claims

1. Use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating breast hyperplasia, 2. Use of a solvate of the compound represented by formula I as claimed in claim 1 and / or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hyperplasia of the breast.

3. Use of a hydrate of the compound represented by formula I as claimed in claim 1 and / or a hydrate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hyperplasia of the breast.

4. Use of a pharmaceutical composition in the preparation of a drug for treating breast hyperplasia, characterized in that: The pharmaceutical composition comprises the compound represented by formula I of claim 1 or its pharmaceutically acceptable salt and / or solvate and / or hydrate thereof, 5. The use according to claim 4, characterized in that: The pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

6. The use according to claim 4, characterized in that: The pharmaceutical composition is a solid preparation or a liquid preparation.

7. The use according to claim 4, characterized in that: The pharmaceutical composition is an oral preparation or an injection.

8. The use according to claim 4, characterized in that: The pharmaceutical composition is a compound preparation.

9. The use according to any one of claims 1 to 8, characterized in that: The application objects include humans, canines, rodents and other mammals.

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