A pharmaceutical composition for treating polycystic ovary syndrome and use thereof

Abstract

The application provides a pharmaceutical composition for treating polycystic ovary syndrome and application thereof. The pharmaceutical composition comprises curcumin and paeonol, and the two are used together to achieve synergistic effect, greatly improve the effect of preventing and treating polycystic ovary syndrome, and improve drug efficacy and safety.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, and in particular, the present application relates to a pharmaceutical composition for treating polycystic ovarian syndrome and its use. BACKGROUND

[0002] Polycystic ovarian syndrome (PCOS) is also known as Stein-Leventhal syndrome, which is an endocrine disease characterized by high androgen, persistent anovulation and polycystic changes in the ovary, often accompanied by insulin resistance and obesity. The main clinical symptoms are infertility, irregular menstrual cycle, hirsutism and / or acne. For women, PCOS is also an important risk factor for type II diabetes, cardiovascular disease, gestational diabetes and endometrial cancer. The cause of the disease is not clear, but research evidence shows that the interaction of genetics, environment and lifestyle factors can lead to the occurrence of the disease.

[0003] The cause of PCOS is not clear and the clinical manifestations are diverse, so there is no unified treatment plan and specially approved treatment drug at present. The clinical treatment is mainly symptomatic treatment, that is, different treatment methods are used according to the different treatment needs of patients. In the drug treatment method, efforts are generally made on the treatment of high androgen, the improvement of insulin resistance and the treatment of anti-inflammatory and lipid regulation. Typical treatment drugs include spironolactone, metformin, thiazolidinedione drugs, flunixin, dexamethasone, etc. In addition, a variety of Chinese medicine monomers have been reported in the literature to have certain therapeutic effects on PCOS, such as berberine, tanshinone, cryptotanshinone, glycyrrhetinic acid, pachymic acid, silymarin, resveratrol, curcumin, ginsenoside, paeoniflorin, quercetin, puerarin, glycyrrhizin, genistein, etc. The toxicity of Chinese medicine monomers is low, but there are deficiencies in drug efficacy, so more new products for preventing and treating polycystic ovarian syndrome need to be developed. SUMMARY

[0004] Therefore, the present application provides a pharmaceutical composition for treating polycystic ovarian syndrome, which has improved effects of preventing and treating polycystic ovarian syndrome.

[0005] In one aspect of the present application, the present application provides a pharmaceutical composition comprising curcumin and paeoniflorin.

[0006] In a preferred embodiment, the weight ratio of curcumin and paeoniflorin is (1-5):(5-1).

[0007] In a preferred embodiment, the weight ratio of curcumin and paeoniflorin is (1-3):(3-1).

[0008] In a preferred embodiment, the weight ratio of curcumin and paeoniflorin is 1:1.

[0009] In a preferred embodiment, the pharmaceutical composition according to the present application further comprises one or more pharmaceutically acceptable excipients.

[0010] Preferably, the pharmaceutically acceptable excipients in the pharmaceutical composition comprise one or more of carriers, excipients, diluents, lubricants, wetting agents, emulsifiers, preservatives, antioxidants, buffers, bacteriostatic agents, suspending agents, fillers, binders, humectants, disintegrants, absorption enhancers, surfactants, suspending agents, solubilizers, thickening agents, stabilizers, sweeteners.

[0011] The pharmaceutical composition is presented in unit dosage form such as tablets, pills, capsules, powders, granules, suspensions, oral liquids, aerosols or liquid sprays, drops, or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration or for administration by inhalation or jet; preferably the pharmaceutical dosage form is an oral formulation.

[0012] The oral formulation of the pharmaceutical composition according to the present application can comprise any of the conventionally used oral forms including tablets, pills, capsules, granules, suspensions, powders, oral liquids.

[0013] Capsules can contain mixtures of the active compound with inert fillers and / or diluents such as, for example, pharmaceutically acceptable starches (for example, corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (both crystal and microcrystalline), flours, gelatins, gums, and the like.

[0014] Useful tablet formulations can be prepared by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinyl pyrrolidine, gelatin, alginic acid, acacia, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch and powdered sugar. Surface modifying agents include non-ionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, Cetostearl alcohol, Cetomacrogol emulsifying wax, sorbitan esters, colloidol silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminate silicate and triethanolamine. Oral formulations herein can employ standard delayed- or sustained-release formulations to alter the absorption of the active compounds. The oral formulations can also include administering the active ingredients in water or fruit juice in which appropriate solubilizers or emulsifiers can be present.

[0015] In certain instances, the pharmaceutical composition can also be applied directly to the airways in the form of an aerosol.

[0016] The pharmaceutical compositions of the present application can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0017] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0018] In the present application, transdermal administration is understood to include all administration on the surface of the skin and body linings (including epithelial and mucosal tissue) of the body. Such administration can be carried out using the present compounds or pharmaceutically acceptable salts thereof in the form of lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

[0019] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as, for example, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, or the like. The active ingredient in the pharmaceutical composition of the present application should be present in an amount of from 0.01 to 99% by weight, preferably from 0.1 to 50% by weight, of the entire composition.

[0020] For adult patients, the compound of the present application can be administered orally or non-orally in an amount of 0.001-500 mg per administration, once a day or divided into several times. It should be noted that the administration amount can be appropriately increased or decreased according to the type of disease, age, body weight, symptoms, and the like of the patient.

[0021] Another aspect of the present application provides the use of the pharmaceutical composition in the preparation of a medicament for the treatment of polycystic ovary syndrome.

[0022] beneficial effects

[0023] The present application provides a pharmaceutical composition for treating polycystic ovary syndrome, which comprises curcumin and paeoniflorin. Curcumin and paeoniflorin can treat polycystic ovary syndrome to some extent, and the present application finds that the two have a synergistic effect when used together, can greatly improve the effect of preventing and treating polycystic ovary syndrome, and can reduce the amount of drug used and improve its safety. DETAILED DESCRIPTION

[0024] The present application is described in more detail below to facilitate understanding of the present application.

[0025] The experimental methods in the following examples are all conventional methods unless otherwise specified. If a specific technique or condition is not specified in the examples, it is performed according to the technique or condition described in the literature in the art or according to the product manual.

[0026] Example 1: Treatment effect of the pharmaceutical composition of the present application on dehydroepiandrosterone (DHEA)-induced PCOS model

[0027] Seventy 25-day-old female ICR mice were selected and raised at 22°C with a light cycle of 14 hours (06:00-20:00) and a dark cycle of 10 hours (20:00-06:00 of the next day). The mice were allowed to eat and drink freely. The mice were randomly divided into an experimental group (60 mice) and a normal group (10 mice). The mice in the experimental group were subcutaneously injected with 0.6 mg / kg of (the solvent was 10% 95% ethanol in sesame oil) once a day for 20 consecutive days to establish a PCOS mouse model. The mice in the normal group were subcutaneously injected with 10% 95% ethanol in sesame oil once a day for 20 consecutive days. After 20 days, 10 days of vaginal exfoliative cells in the experimental group were examined. Rats with persistent keratinization of vaginal epithelial cells were used as DHEA-induced rat PCOS animal models. Forty rats were divided into a model group, a curcumin group, a paeoniflorin group, and a curcumin+paeoniflorin group, with 10 rats in each group. The rats in the drug groups were orally administered with the drugs at the dosages shown in the following table for 28 days. The rats in the normal group and the model group were only given a placebo.

[0028] Table 1: Drug information table

[0029] curcumin 20 mg·kg -1 ·d -1 of curcumin paeoniflorin 20 mg·kg -1 ·d -1 of paeoniflorin curcumin + paeoniflorin 10 mg·kg -1 ·d -1 of curcumin + 10 mg·kg -1 ·d -1 of paeoniflorin

[0030] After the administration was completed, the blood of the mice in each group was collected by eyeball blood collection. The blood was allowed to stand at 4°C for 1 h, centrifuged at 3000 g for 10 min, and the serum was collected and stored at -20°C. The serum hormones were detected by enzyme-linked immunosorbent assay (ELISA). The serum testosterone (T), estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-Mullerian hormone (AMH) enzyme-linked immunosorbent assay (ELISA) detection kits were purchased from Novertaine Company, USA. Statistical analysis was performed using SPSS 26.0 software. The data are represented as mean ± standard deviation (x ± s). P<0.05 was considered statistically significant. The results are shown in Table 2 below.

[0031] Table 2: Serum hormone levels of rats (n=10)

[0032]

[0033]

[0034] Note: compared with the normal group, *P<0.05; compared with the model group, a P<0.05; compared with the curcumin group, b P<0.05; compared with paeoniflorin, c P<0.05

[0035] After blood collection, the bilateral ovaries of the rats in each group were surgically removed, and the wet weight was measured to calculate the ovarian coefficient. Ovarian coefficient = ovarian mass (g) / body weight (g). Statistical analysis was performed using SPSS 26.0 software. The data are represented as mean ± standard deviation Significant difference, P < 0.05. The results are shown in Table 3 below.

[0036] Table 3: Ovary coefficient of rats (n = 10)

[0037]

[0038] Note: compared with the normal group, *P < 0.05; compared with the model group, a P < 0.05; compared with the curcumin group, b P < 0.05; compared with the paeonol group, c P < 0.05

[0039] Morphological and pathological observation of the ovaries of the weighed rats: in the ovarian sections of the model rats, there were fewer normally developed follicles, and instead, there were cystic, anovocyte vacuoles with increased volume. Basically, no normally developed follicles and corpus luteum were observed. The granulosa cell layer of the follicle was significantly reduced and arranged loosely. Occasionally, there were obvious atretic follicles. In the ovaries of the curcumin + paeonol group rats, developed follicles and corpus luteum were observed. The granulosa cells were increased compared with the model group, but there were also a small amount of anovocyte vacuoles. The above results suggest that the pharmaceutical composition of curcumin + paeonol has a significant improvement effect on the pathological ovarian morphology of PCOS.

[0040] From the test results, compared with the normal group of rats, the serum T, LH, AMH levels of the model group of rats were significantly increased, while the E2 and FSH levels were significantly reduced. At the same time, the ovarian wet weight increased, cystic dilatation of the follicle occurred, the granulosa cell layer decreased, which was consistent with the overall symptoms of PCOS, indicating that the model group was successfully modeled. The curcumin and paeonol at the dose had a general effect on the prevention and treatment of PCOS, but compared with the use of the two alone, the combination of the two could more significantly alleviate the increase of T, LH, AMH and ovarian coefficient and the decrease of E2 and FSH, and the differences were statistically significant. And it reduced the cystic dilatation of the follicle, and increased the granulosa cell layer and corpus luteum. This shows that curcumin and paeonol have a synergistic effect on the treatment of PCOS.

[0041] Example 2: tablet composition

[0042] Formulation prescription:

[0043]

[0044]

[0045] The preparation process is:

[0046] 1. Curcumin and paeonol are sieved through a 100-mesh sieve, and other excipients are sieved through an 80-mesh sieve.

[0047] 2. Weigh the prescribed amount of curcumin, paeonol and aspartame, essence, and mix well.

[0048] 3. Weigh the prescribed amount of mannitol, lactose, microcrystalline cellulose, citric acid, and mix well.

[0049] 4. Add the mixture obtained in 3 to the mixture obtained in 2, and mix well.

[0050] 5. Add 70% ethanol aqueous solution to make soft material, pass through a 20 mesh sieve to granulate, and dry the obtained granules at 50°C, with the moisture controlled at 2-3%.

[0051] 6. Pass the dried granules through a 20 mesh sieve to granulate, add the prescribed amount of magnesium stearate, mix well, detect the content of the intermediate, calculate the tablet weight, and press into tablets to obtain the product.

[0052] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, without departing from the method of the present application, a number of improvements and supplements can be made, which should also be considered as the protection scope of the present application.

Claims

1. A pharmaceutical composition for treating polycystic ovary syndrome, the active ingredients of which consist of curcumin and paeoniflorin, the weight ratio of curcumin and paeoniflorin being 1:

1.

2. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

3. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition is presented in unit dosage form, which is a tablet, a pill, a capsule, a powder, a granule, a suspension, an oral liquid agent, a liquid spray, a drop or a suppository.

4. Use of the pharmaceutical composition according to any one of claims 1 to 3 for the manufacture of a medicament for treating polycystic ovary syndrome.

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