CN112353933A

CN112353933A - Medicine for preventing and/or treating hysteromyoma and preparation method thereof

Info

Publication number: CN112353933A
Application number: CN202011475273.3A
Authority: CN
Inventors: 孙淼; 毛新; 柏青松
Original assignee: Heilongjiang University of Chinese Medicine
Current assignee: Heilongjiang University of Chinese Medicine
Priority date: 2020-12-14
Filing date: 2020-12-14
Publication date: 2021-02-12
Anticipated expiration: 2040-12-14
Also published as: CN112353933B

Abstract

The invention relates to a medicament for preventing and/or treating hysteromyoma and a preparation method thereof, which is characterized by containing leuprorelin acetate as an active ingredient, wherein the preparation is a gel preparation. The gel preparation capable of being administered through vagina is beneficial to direct action of leuprorelin acetate on a pathological change part, slowly releases active ingredients, avoids fluctuation of hormone level, and improves the treatment effect of preventing and/or treating hysteromyoma.

Description

Medicine for preventing and/or treating hysteromyoma and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition for preventing and/or treating hysteromyoma and a preparation method thereof.

Background

Uterine fibroid is one of the most common benign tumors in female reproductive organs, and is also one of the most common tumors in human body, which is also called fibroid and uterine fibroid. The hysteromyoma is mainly formed by hyperplasia of uterine smooth muscle cells, and a small amount of fibrous connective tissue exists as a supporting tissue, so the hysteromyoma is known to be more definite and is called as the hysteromyoma for short.

Symptoms associated with uterine fibroids most often include severe menstrual bleeding or menostaxis, pelvic pressure and pelvic organ compression, back pain, and adverse reproductive consequences. Heavy menstrual bleeding; menorrhagia (more than 80mL per menstrual cycle); menstrual blood loss is inconvenient and may lead to iron deficiency anemia, which is the major cause of surgical intervention including hysterectomy. Other symptoms, particularly compression symptoms, depend to a large extent on the size, number and location of the tumor.

Although the pathogenesis has not been fully elucidated, it is known that the growth of uterine fibroids is largely dependent on estrogens and progestogens. After menopause, myomas tend to shrink due to reduced hormone production.

At present, the clinical treatment of hysteromyoma is mainly performed, the hysteromyoma is easy to relapse, 75-95% of hysteromyoma can relapse 2-3 years after the operation, and in order to prevent the relapse, a treatment scheme of completely cutting off the whole uterus is often adopted. Then, after hysterectomy, the whole blood circulation of the body and the female specific functions are changed, accompanied by mental shock, and finally may cause premature aging of the body and seriously affect the life of the couple, or even may lead to marital rupture. Removal of the uterus is a very rare option for patients with uterine fibroids. Therefore, new methods for better treating uterine fibroids and preventing recurrence of uterine fibroids are needed.

GnRH peptide agonists, such as leuprolide acetate, are commonly used to treat uterine fibroids, a benign sex hormone-dependent gynecological disease. However, conventional administration causes uneven release of GnRH peptide agonists and the initial increase in hormone by the GnRH agonist can lead to a temporary worsening of symptoms known as clinical episodes. Temporary symptomatic deterioration may include HMB deterioration. The effectiveness of GnRH agonist treatment does not begin to appear until about 3 to 4 weeks after the initial dose. Therefore, there is an urgent need in the art for a drug for preventing and/or treating uterine fibroids, which enables a relatively smooth and slow release of GnRH agonists.

Disclosure of Invention

The invention aims to solve the defects, provides the medicine for preventing and/or treating the hysteromyoma, can directly reach the focus by vaginal administration, and has the advantages of convenient use, direct medicine effect on the focus, small side effect, lasting medicinal effect, quick response, obvious curative effect and the like. Specifically, in order to achieve the purpose of the present invention, the following technical solutions are proposed:

the invention relates to a pharmaceutical preparation for preventing and/or treating hysteromyoma, which is characterized by containing GnRH peptide agonist as active ingredient, wherein the preparation is a gel preparation; preferably, the GnRH peptide agonist is leuprolide acetate.

In a preferred embodiment of the present invention, the gel formulation is prepared by dissolving leuprolide acetate, hydroxypropyl chitosan, chondroitin sulfate and polysuccinimide in deionized water.

In a preferred embodiment of the invention, the weight ratio of chondroitin sulfate to polysuccinimide is 5-8: 1. The present invention helps to reduce the irritativeness of polysuccinimide by an excess of chondroitin sulfate without affecting the gel properties.

In a preferred embodiment of the invention, the weight ratio of hydroxypropyl chitosan to polysuccinimide is 8-12: 1. The invention is beneficial to forming a stable gel preparation by reasonably setting the proportion of hydroxypropyl chitosan and succinimide.

In a preferred embodiment of the present invention, the leuprolide acetate is present in the gel formulation in an amount of 0.1 wt% to 0.2 wt%. The invention can reduce the administration dosage and improve the compliance of patients by setting the leuprorelin acetate with higher concentration. According to the invention, the upper limit of the content of the leuprorelin acetate is set, so that the impact on the estrogen level of a patient is avoided.

The invention also relates to application of the medicinal preparation in preparing a medicament for preventing and/or treating uterine fibroids.

In a preferred embodiment of the invention, the medicament is a vaginally administered medicament.

In another aspect, the invention also relates to the combination of the medicine and the cassia twig and tuckahoe pill. The invention is beneficial to improving the curative effect by combining western medicines and traditional Chinese medicines and combining the western medicines and the traditional Chinese medicines.

Advantageous effects

The invention provides the gel preparation which can be administrated through the vagina, which is beneficial to direct action of the leuprorelin acetate on the part of a patient, slow release of active ingredients, avoidance of fluctuation of hormone level and improvement of the treatment effect of preventing and/or treating hysteromyoma.

Drawings

Fig. 1 is a graph showing the release profile of leuprolide acetate in acidic buffer solution.

Detailed Description

In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.

Example 1: preparation of pharmaceutical preparations

(1) Weighing 0.1g of leuprorelin acetate, 5g of hydroxypropyl chitosan, 3g of chondroitin sulfate and 0.5g of polysuccinimide, dissolving in 50ml of deionized water to obtain an aqueous solution, and shearing at high speed for 30min to form the gel-like medicinal preparation.

(2) The viscosity and shear rate were measured for 5s using a coaxial cylinder system of a rheometer type RV-100 from Haake, Germany^-1The measurement temperature was 37 ℃ and the viscosity was 320 mPas.

Comparative example 1:

0.1g of leuprorelin acetate, 5g of hydroxypropyl chitosan and 3g of chondroitin sulfate are weighed and dissolved in 50ml of deionized water to obtain an aqueous solution, and the aqueous solution is sheared at a high speed for 60min, so that a gel-like medicinal preparation cannot be formed.

Comparative example 2:

weighing 0.1g of leuprorelin acetate, 5g of hydroxypropyl chitosan and 0.5g of polysuccinimide, dissolving in 50ml of deionized water to obtain an aqueous solution, and shearing at high speed for 30min to form the gel-like medicinal preparation. The preparation is tested by in vitro skin, causes red and swollen skin, and has higher irritation, while the red and swollen skin is not found in example 1.

Comparative example 3:

0.1g of leuprorelin acetate, 3g of chondroitin sulfate and 0.5g of polysuccinimide are weighed and dissolved in 50ml of deionized water to obtain an aqueous solution, and the aqueous solution is sheared at a high speed for 60min, so that a gel-like medicinal preparation cannot be formed.

Example 2: slow release effect test

10g of the gel preparation prepared in example 1 was placed in 100g of a disodium hydrogen phosphate-citric acid buffer solution (pH 4), and the concentration of leuprolide acetate in the buffer solution was measured on each of day 0, day 1, day 3, day 5 and day 7 by slowly shaking the container, and the results of the test are shown in FIG. 1, and it was confirmed from the results of the experiment that the gel preparation of example 1 slowly and uniformly released the active ingredient in the acidic buffer solution.

Example 3: clinical experiments

The medicine is clinically verified in a first hospital affiliated to the university of traditional Chinese medicine in Heilongjiang, and the working steps and experimental results are as follows:

1. case collection and diagnosis

60 patients with hysteromyoma are collected in an outpatient clinic and hospitalized among 10 months in 2019 to 2020, and are randomly divided into 30 cases of treatment groups and 30 cases of control groups, wherein the age is 37 to 52 years, the average age is 46.8 years, and the course of disease is 12.8 months. The comparative difference of the age and the disease course of the 2 groups has no statistical significance and is comparable.

Diagnostic criteria

According to the diagnosis standard of the national clinical professional conference of hysteromyoma: (1) increased menstrual flow and prolonged menstrual period. (2) The lower abdomen is wrapped with a block. (3) Frequent urination, difficulty in urination, constipation, etc. (4) Intermittent bleeding or purulent leucorrhea in the vagina. (5) Gynecological examination may reveal enlarged uterus or fibroid nodules may be reached. (6) B-mode ultrasound examination may show images of fibroids. (7) Pain: general patients have no abdominal pain, often have lower abdomen and fall, distending, soreness and pain of waist and back, etc., when the serosal sub-muscular tumor pedicle is twisted, acute abdominal pain myoma with red color change can occur, the abdominal pain is severe and accompanied with heat.

2. Test method

2.1 methods of treatment

The gel prepared in example 1 is administered every four weeks for 1g each time in a non-menstrual period for 6 months.

The control group was injected subcutaneously with 1.88mg of leuprolide acetate 1 time every 4 weeks.

3. Standard of therapeutic effect and therapeutic result

3.1 therapeutic criteria

And (3) clinical control: clinical symptoms disappear, and myoma disappears in ultrasonic examination;

the method has the following advantages: the clinical symptoms are improved, and the volume of the myoma is reduced in comparison with that after the myoma is treated by ultrasonic examination;

and (4) invalidation: the clinical symptoms are not improved, and the volume of the myoma is enlarged compared with that after the myoma is treated by ultrasonic examination;

3.2 the results of the treatment are shown in Table 1.

Table 1 two groups of therapeutic effects are compared table 2: the curative effect of the treatment group is compared with that of the control group

4. Side effects: during the treatment period, a dose-dependent inhibition of estradiol in the treated and control groups was observed. For the treatment group, the median estradiol level at the subjects visit per month was between 35.8 and 46.8pg/mL, with estradiol concentrations <20pg/mL for 15% to 24% of women. For the control group, the median estradiol level at the subjects visit per month was between 16.8 and 18.7pg/mL, with estradiol concentrations <20pg/mL for 71% to 81% of women. Thus, the pharmaceutical preparation of the invention can better control the estrogen level.

The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims

1. A pharmaceutical preparation for preventing and/or treating uterine fibroids, characterized by containing a GnRH peptide agonist as an active ingredient, said preparation being a gel preparation; preferably, the GnRH peptide agonist is leuprolide acetate.

2. The pharmaceutical formulation of claim 1, wherein the gel formulation is prepared by dissolving leuprolide acetate, hydroxypropyl chitosan, chondroitin sulfate, and polysuccinimide in deionized water.

3. The pharmaceutical formulation of claim 2, wherein the weight ratio of chondroitin sulfate to polysuccinimide is 5-8: 1.

4. A pharmaceutical formulation according to claim 2, wherein the weight ratio of hydroxypropyl chitosan to polysuccinimide is 8-12: 1.

5. The pharmaceutical formulation of claim 1, wherein the leuprolide acetate is present in the gel formulation in an amount of 0.1 wt% to 0.2 wt%.

6. Use of a pharmaceutical formulation according to any one of claims 1 to 5 for the preparation of a medicament for the prevention and/or treatment of uterine fibroids.

7. The use of claim 6, wherein said medicament is a vaginally administered medicament.

8. A pharmaceutical combination preparation comprising the pharmaceutical preparation of any one of claims 1 to 5 in combination with a cinnamomi poria pill.