A traditional Chinese medicine compound for delaying female ovary aging, and a preparation method and application thereof

Abstract

The application discloses a traditional Chinese medicine compound for delaying female ovary aging and a preparation method and application thereof. The traditional Chinese medicine compound is composed of four traditional Chinese medicines of rhizoma polygonati nudi, radix astragali, poria and pericarpium citri reticulatae. The traditional Chinese medicine compound can obviously improve estrous cycle disorder, balance hormone level, ovary structure and follicle quantity of mice, can be used for delaying ovary aging, has an effect superior to that of single medicine rhizoma polygonati nudi, radix astragali or poria, and a combination of rhizoma polygonati nudi and radix astragali, has no influence on the weight of mice, is high in safety, and provides a new treatment strategy and drug selection for clinically preventing and treating ovary aging.

Description

Technical Field

[0001] This invention belongs to the field of natural medicine technology, specifically relating to a traditional Chinese medicine compound for delaying ovarian aging in women, its preparation method, and its application. Background Technology

[0002] Ovarian aging is a natural physiological process that occurs in women as they age. The function of the reproductive system declines irreversibly with age, manifested as a continuous decline in the number and quality of oocytes, menstrual disorders, decreased or lost fertility, accompanied by perimenopausal symptoms such as hot flashes and insomnia, and a continuous shrinkage of ovarian volume, which seriously affects women's quality of life.

[0003] Genetics, immunity, iatrogenic factors, environment, lifestyle, psychology, and age are all important factors contributing to ovarian aging. Ovarian aging is primarily characterized by a significant decrease in hormone levels such as anti-Müllerian hormone (AMH) and estradiol (E2), while levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increase. Currently, there are no definitive drugs to combat ovarian aging; clinically, hormone replacement therapy is often used to alleviate related symptoms, but long-term use can lead to risks such as cardiovascular disease.

[0004] Therefore, finding effective ways to delay ovarian aging is crucial. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a traditional Chinese medicine compound for delaying ovarian aging in women, its preparation method and application, wherein the traditional Chinese medicine compound can effectively improve the disorder of the estrous cycle and the disorder of ovarian endocrine function, thereby effectively improving the symptoms of ovarian aging.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] On the one hand, the present invention provides a traditional Chinese medicine compound for delaying ovarian aging, which contains the following components: Polygonatum sibiricum, Astragalus membranaceus, Poria cocos and Citrus reticulata peel.

[0008] Preferably, the traditional Chinese medicine compound for delaying ovarian aging includes the following components in parts by weight: 5-30 parts of Polygonatum sibiricum, 5-50 parts of Astragalus membranaceus, 5-30 parts of Poria cocos, and 1-20 parts of Citrus reticulata peel.

[0009] More preferably, the traditional Chinese medicine compound for delaying ovarian aging includes the following components in parts by weight: 15 parts of Polygonatum sibiricum, 20 parts of Astragalus membranaceus, 10 parts of Poria cocos, and 5 parts of Citrus reticulata peel.

[0010] On the other hand, the present invention also provides a method for preparing the above-mentioned traditional Chinese medicine compound for delaying ovarian aging, comprising the following steps: extracting the above-mentioned traditional Chinese medicine materials by two-stage decoction, combining the decoctions and concentrating them, and freeze-drying them to obtain the final product.

[0011] Preferably, the preparation method includes the following steps: take the raw materials of traditional Chinese medicine in the prescribed amount, use the decoction method, use water as solvent, add 10 times the amount of water for the first time, soak for 0.5 hours, and then decoct for 1 hour; add 8 times the amount of water for the second time, decoct for 0.5 hours, combine the two decoctions, and concentrate the decoction to 0.644 g / mL or 0.193 g / mL; freeze-dry the concentrate to obtain the traditional Chinese medicine compound.

[0012] On the other hand, the present invention also provides the application of the above-mentioned traditional Chinese medicine compound in the preparation of products that delay ovarian aging.

[0013] Preferably, the product includes pharmaceuticals.

[0014] Preferably, the product is a solid dosage form or a liquid dosage form.

[0015] Preferably, the solid dosage form includes powder, granules, tablets, or capsules.

[0016] Preferably, the liquid formulation includes a solution, a suspension, or an emulsion.

[0017] On the other hand, the present invention also provides a product for delaying ovarian aging, which comprises an effective amount of a traditional Chinese medicine compound as an active ingredient and pharmaceutically acceptable excipients.

[0018] The traditional Chinese medicine compound affects the expression of serum AMH, FSH, LH, and E2, thereby delaying ovarian aging.

[0019] The traditional Chinese medicine compound of this invention has the effects of tonifying the kidney and replenishing essence, invigorating qi and strengthening the spleen, and regulating qi and harmonizing the middle jiao. Among them, the wine-processed Polygonatum mainly enters the kidney meridian, tonifies the kidney and replenishes essence, and nourishes the innate foundation, serving as the principal drug; Astragalus mainly enters the spleen meridian, replenishes qi and generates blood, and assists the principal drug in enhancing its tonifying power, serving as the assistant drug; Poria strengthens the spleen and eliminates dampness, calms the mind and soothes the nerves, and both assists Astragalus in enhancing the generation of qi and blood, and prevents the wine-processed Polygonatum from being too greasy and hindering the stomach, serving as the adjuvant drug; Tangerine peel is pungent and warm, regulates qi, guides the medicine into the spleen meridian, promotes the absorption of the whole formula, and harmonizes the medicines, serving as the adjuvant and guiding drug.

[0020] The wine-processed Polygonatum tonifies the kidneys and replenishes essence, while Astragalus tonifies the spleen and benefits qi, taking into account both innate and acquired constitution. Poria promotes diuresis and Citrus reticulata promotes qi circulation, ensuring smooth flow of qi and blood. The whole formula works together to nourish both innate and acquired constitution, tonifying while promoting circulation, nourishing without stagnation.

[0021] This invention discovers that a traditional Chinese medicine compound (Qi Huang Yang Kun Fang) composed of four herbs—Polygonatum sibiricum, Astragalus membranaceus, Poria cocos, and Citrus reticulata peel—can significantly improve estrous cycle disorders and balance hormone levels in mice. It can be used to prevent premature ovarian failure, and its effect is superior to that of single herbs such as Polygonatum sibiricum, Astragalus membranaceus, or Poria cocos, as well as the combination of Polygonatum sibiricum and Astragalus membranaceus. Moreover, it has no effect on the weight of mice and has high safety, providing a new treatment strategy and drug option for the clinical prevention and treatment of ovarian aging. Attached Figure Description

[0022] Figure 1 Changes in body weight and estrous cycle in mice after administration of Qihuang Yangkun Formula (Formulas 1-3) (±s, n=10)

[0023] Figure 2 Changes in body weight in mice after experimental drug administration ( ±s, n=10). Compared with 2m mice, ** P<0.01.

[0024] Figure 3 This study investigated changes in the estrous cycle in mice after experimental drug administration.

[0025] Figure 4 The effects of drug administration on serum AMH, E2, LH, and FSH levels in mice were investigated. ±s, n=6). Compared with the 2m normal group mice, ** P<0.01; compared with the 9m model group mice, # P<0.05, ## P<0.01; compared with the 12m model group mice, & P<0.05, && P<0.01; compared with the 9m+HJHQ group, a P<0.05, aa P<0.01; compared with the 12m+HJHQ group, $ P<0.05, $$ P<0.01.

[0026] Figure 5 This is a pathological image of a mouse ovary. Detailed Implementation

[0027] The following embodiments are further illustrations of the present invention, but not limitations thereof.

[0028] Example 1: Preparation of Qihuang Yangkun Formula

[0029] Astragalus and Astragalus Nourishing the Body Formula (Formulas 1-3) consists of the ingredients in the weight proportions shown in the table below:

[0030] Astragalus and Astragalus Nourishing the Body Formula Wine-processed Polygonatum Astragalus Poria Dried tangerine peel Formula 1 15 20 10 5 Formula 2 5 50 5 20 Formula 3 30 5 30 1

[0031] Preparation method of Formula 1: Weigh 15 parts of wine-processed Rhizoma Polygonati, 20 parts of Radix Astragali, 10 parts of Poria and 5 parts of Pericarpium Citri Reticulatae, adopt the decoction method with water as the solvent, add 10 times the amount of water for the first time, soak for 0.5 h, then decoct for 1 h; add 8 times the amount of water for the second time, decoct for 0.5 h, combine the two decoction solutions, concentrate the medicinal solution to 0.644 g / mL or 0.193 g / mL; freeze-dry the concentrated solution to obtain the Qihuang Yangkun Formula.

[0032] Formula 2 and Formula 3 are prepared with reference to the above preparation method.

[0033] Preparation of Rhizoma Polygonati extract: Weigh 15 parts of wine-processed Rhizoma Polygonati, and prepare it with reference to the above preparation method to obtain the Rhizoma Polygonati extract.

[0034] Preparation of Radix Astragali extract: Weigh 20 parts of Radix Astragali, and prepare it with reference to the above preparation method to obtain the Radix Astragali extract.

[0035] Preparation of Poria extract: Weigh 10 parts of Poria, and prepare it with reference to the above preparation method to obtain the Poria extract.

[0036] Preparation of Rhizoma Polygonati and Radix Astragali extract: Weigh 15 parts of wine-processed Rhizoma Polygonati and 20 parts of Radix Astragali, and prepare it with reference to the above preparation method to obtain the Rhizoma Polygonati and Radix Astragali extract.

[0037] Example 2: Experimental verification of Qihuang Yangkun Formula (Formulas 1-3)

[0038] 1. Laboratory animals

[0039] SPF-grade C57BL / 6J female mice weighing 24-28 g, provided by Hunan Silaike Jingda Laboratory Animal Co., Ltd., with the Laboratory Animal Production License No.: (SCXK (Xiang) 2021-0002). The mice are housed in the animal room of the Laboratory Animal Center of the First Affiliated Hospital of Guangzhou University of Chinese Medicine for adaptive observation, with the Laboratory Animal Use License No.: (SCXK (Yue) 2023-0092). The indoor environment is 22~26℃, the relative humidity is 50~70%, with 12 h light / 12 h dark alternating light and dark, the working illuminance is 200-300 Lux, and the animal illuminance is 15-20 Lux. The mice have free access to food and water.

[0040] 2. Experimental method

[0041] The mouse model selected in the present invention is a natural aging animal model. The animals are randomly grouped by body weight: 2-month-old (2m) normal group, 9-month-old (9m) model group, 9-month-old Qihuang Yangkun Formula (Formula 1) group, 9-month-old Qihuang Yangkun Formula (Formula 2) group, and 9-month-old Qihuang Yangkun Formula (Formula 3) group, with 6 mice in each group.

[0042] Vaginal smears were examined in mice to observe changes in their estrous cycle. When mice exhibited estrous cycle disorder or prolonged estrous cycles, the aging model was considered successful, and gavage administration was initiated. The normal and model groups were administered pure water by gavage. The Astragalus and Astragalus Nourishing Kun Formula (Formula 1) group was administered Astragalus and Astragalus Nourishing Kun Formula liquid at a dose of 7.50 g crude drug / kg; the Astragalus and Astragalus Nourishing Kun Formula (Formula 2) group was administered Astragalus and Astragalus Nourishing Kun Formula liquid at a dose of 10.51 g crude drug / kg; and the Astragalus and Astragalus Nourishing Kun Formula (Formula 3) group was administered Astragalus and Astragalus Nourishing Kun Formula liquid at a dose of 9.91 g crude drug / kg. The gavage volume was 0.1 mL / 10 g, administered once daily for 28 days.

[0043] 3. Data Processing

[0044] Experimental data were statistically analyzed using SPSS 20.0 software. All normally distributed data were expressed as mean ± standard deviation (SD). Data are expressed as mean ± standard deviation (±s), and one-way ANOVA is performed. When variances are homogeneous, the Bonferroni test is used for pairwise comparisons of means between groups; when variances are unequal, Dunnett's T3 test is used. For ordinal data, the rank-sum test is used for comparisons between groups. A p-value < 0.05 is considered statistically significant.

[0045] 4. Experimental Results

[0046] Regularity of the estrous cycle is an important indicator of reproductive performance in female mammals. To evaluate the effect of Qihuang Yangkun Formula (QHYKF) on the estrous cycle in aged mice, changes in the estrous cycle (one cycle lasts 4-5 days) were observed. Representative vaginal cytological images of four different estrous cycle stages are shown below. Figure 1 As shown in Figure A.

[0047] Figure 1 BC results showed that 20% of mice in the 2m group had irregular estrous cycles, while 60% of mice in the 9m model group had estrous cycle disorders, with most remaining in the estrus or estrus phase. Compared with the 9m model group, 90% of mice in the Qihuang Yangkun Formula 1 group, 50% in the Qihuang Yangkun Formula 2 group, and 70% in the Qihuang Yangkun Formula 3 group had regular estrous cycles.

[0048] The above results indicate that Qihuang Yangkun Formula can improve estrous cycle disorders in aged mice, and Formula 1 has better efficacy.

[0049] Example 3: Verification of the effect of Qihuang Yangkun Formula in delaying ovarian aging

[0050] 1. Laboratory animals

[0051] SPF grade C57BL / 6J mice, 24-28g, female, provided by Hunan SJA Laboratory Animal Co., Ltd., with the experimental animal production license number: (SCXK (Xiang) 2021-0002). The mice were housed in the animal room of the Laboratory Animal Center of the First Affiliated Hospital of Guangzhou University of Chinese Medicine for adaptive observation, with the experimental animal use license number: (SCXK (Yue) 2023-0092). The indoor environment is 20~26℃, the relative humidity is 40~70%, with a 12h light / 12h dark alternating cycle, the working illumination is 200-300Lux, and the animal illumination is 15-20Lux. The mice had free access to food and water.

[0052] 2. Experimental instruments

[0053] Electronic balance (Changshu Shuangjie Testing Instrument Factory); 1 / 10000 analytical balance (Mettler-Toledo Instruments Co., Ltd.); biological microscope (Chongqing Aote Optical Instrument Co., Ltd.); tissue dehydrator (Leica Instruments Co., Ltd.); paraffin embedding machine (Thermo Fisher Scientific, USA); rotary microtome (Leica Instruments Co., Ltd.).

[0054] 3. Experimental methods

[0055] C57 mice were randomly grouped by body weight: 2-month-old (2m) normal group, 9-month-old (9m) model group, 9-month-old Polygonati Rhizoma (9m+HJ) group, 9-month-old Astragali Radix (9m+HQ) group, 9-month-old Poria (9m+FL) group, 9-month-old Polygonati Rhizoma-Astragali Radix (9m+HJHQ) group, 9-month-old Qihuang Yangkun Formula (9m+QHYKF) group, 12-month-old (12m) model group, 12-month-old Polygonati Rhizoma (12m+HJ) group, 12-month-old Astragali Radix (12m+HQ) group, 12-month-old Poria (12m+FL) group, 12-month-old Polygonati Rhizoma-Astragali Radix (12m+HJHQ) group, 12-month-old Qihuang Yangkun Formula (12m+QHYKF) group, with 10 mice in each group.

[0056] Among them, the 9-month-old Polygonati Rhizoma group, 9-month-old Astragali Radix group, 9-month-old Poria group, 9-month-old Polygonati Rhizoma-Astragali Radix group, and 9-month-old Qihuang Yangkun Formula group were respectively administered by gavage with the Polygonati Rhizoma extract, Astragali Radix extract, Poria extract, Polygonati Rhizoma-Astragali Radix extract and Qihuang Yangkun Formula (Formula 1) prepared in Example 1 to the 9-month-old mice. The 12-month-old Polygonati Rhizoma group, 12-month-old Astragali Radix group, 12-month-old Poria group, 12-month-old Polygonati Rhizoma-Astragali Radix group, and 12-month-old Qihuang Yangkun Formula group were respectively administered by gavage with the Polygonati Rhizoma extract, Astragali Radix extract, Poria extract, Polygonati Rhizoma-Astragali Radix extract and Qihuang Yangkun Formula (Formula 1) prepared in Example 1 to the 12-month-old mice.

[0057] The normal and model groups were administered pure water by gavage. The Astragalus and Astragalus Nourishing the Kun Formula group was administered Astragalus and Astragalus Nourishing the Kun Formula liquid by gavage at a dose of 6.44 g crude drug / kg; the Polygonatum group was administered Polygonatum liquid by gavage at a dose of 1.93 g crude drug / kg; the Astragalus group was administered Astragalus liquid by gavage at a dose of 2.57 g crude drug / kg; the Poria group was administered Poria liquid by gavage at a dose of 1.29 g crude drug / kg; and the Polygonatum and Astragalus group was administered Polygonatum and Astragalus liquid by gavage at a dose of 4.51 g crude drug / kg. The gavage volume was 0.1 mL / 10 g, administered once daily for 28 days. On the last day of administration, the mice were anesthetized with isoflurane, and blood was collected from the abdominal aorta. The serum levels of AMH (anti-Müllerian hormone), FSH (follicle-stimulating hormone), LH (luteinizing hormone), and E2 (estradiol) were detected by ELISA, and the pathological changes of the mouse ovaries were detected by HE staining.

[0058] 4. Data Processing

[0059] Experimental data were statistically analyzed using SPSS 20.0 software. All normally distributed data were expressed as mean ± standard deviation (SD). Data are expressed as mean ± standard deviation (±s), and one-way ANOVA is performed. When variances are homogeneous, the Bonferroni test is used for pairwise comparisons of means between groups; when variances are unequal, Dunnett's T3 test is used. For ordinal data, the rank-sum test is used for comparisons between groups. A p-value < 0.05 is considered statistically significant.

[0060] 5. Experimental Results

[0061] (1) Astragalus and Astragalus Nourishing Formula had no effect on the body weight of mice.

[0062] After 28 days of drug administration, compared with 2m mice, the body weight of mice in the 9m and 12m model groups was significantly increased (P<0.01); compared with the 9m and 12m model groups, there was no effect on body weight in any of the drug administration groups. Results are shown below. Figure 2 .

[0063] (2) Effects of Qihuang Yangkun Formula on the Estrogenic Cycle of Aged Rats

[0064] Figure 3The results showed that 20% of mice in the 2m group had irregular estrous cycles, 50% of mice in the 9m model group had disordered estrous cycles, and 60% of mice in the 12m model group had disordered estrous cycles, with most remaining in the estrus or estrus phase. Compared with the 9m model group, 80% of mice treated with Polygonatum sibiricum (HJ) had regular estrous cycles, 70% treated with Astragalus membranaceus (HQ) had regular estrous cycles, 40% treated with Poria cocos (FL) had regular estrous cycles, 90% treated with Polygonatum sibiricum and Astragalus membranaceus (HJHQ) had regular estrous cycles, and all mice treated with Qihuang Yangkun Formula (QHYKF) showed regular changes in their estrous cycles. Compared with the 12m model group mice, 70% of mice treated with Polygonatum sibiricum (HJ) showed regular estrous cycles, 60% treated with Astragalus membranaceus (HQ) showed regular estrous cycles, 50% treated with Poria cocos (FL) showed regular estrous cycles, 80% treated with Polygonatum sibiricum and Astragalus membranaceus (HJHQ) showed regular estrous cycles, and 90% treated with Qihuang Yangkun Formula (QHYKF) showed regular estrous cycles. These results indicate that Qihuang Yangkun Formula can better improve estrous cycle disorders in aged mice.

[0065] (3) Effects of Qihuang Yangkun Formula on serum AMH, E2, LH and FSH

[0066] Compared with the 2m group mice, the serum LH and FSH levels of the 9m model group mice were significantly increased (P<0.01), while the AMH and E2 levels were significantly decreased (P<0.01). Compared with the 9m model group mice, the serum AMH and E2 levels of mice were significantly increased (P<0.01) and the LH and FSH levels were significantly decreased (P<0.01) after administration of Polygonatum sibiricum (HJ); the serum AMH and E2 levels of mice were significantly increased (P<0.05) and the LH and FSH levels were significantly decreased (P<0.05) after administration of Astragalus membranaceus (HQ); the serum AMH and E2 levels of mice were significantly increased (P<0.01) and the LH and FSH levels were significantly decreased (P<0.01) after administration of Poria cocos (FL); the serum AMH and E2 levels of mice were significantly increased (P<0.01) and the LH and FSH levels were significantly decreased (P<0.01) after administration of Qihuang Yangkun Formula (QHYKF); and the serum AMH and E2 levels of mice were significantly increased (P<0.01) and the LH and FSH levels were significantly decreased (P<0.01) after administration of Qihuang Yangkun Formula (QHYKF). Compared with the 9m+HQHJ group, the 9m+QHYKF group showed significantly increased AMH and E2 levels (P<0.01 or P<0.05), and extremely significantly decreased LH and FSH levels (P<0.01 or P<0.05). Results are shown in [link to results]. Figure 4 .

[0067] Compared with the 2m group mice, the serum LH and FSH levels of the 12m model group mice were significantly increased (P<0.01), while the AMH and E2 levels were significantly decreased (P<0.01). Compared with the 12m model group mice, the serum AMH and E2 levels of mice were significantly increased (P<0.01 or P<0.05) and the LH and FSH levels were extremely significantly decreased (P<0.01) after administration of Polygonatum sibiricum (HJ); the serum E2 level of mice was significantly increased (P<0.01) and the LH and FSH levels were extremely significantly decreased (P<0.01 or P<0.05) after administration of Poria cocos (FL); the serum AMH, E2, LH, and FSH levels of mice were not significantly improved after administration of Poria cocos (HJHQ); the serum AMH and E2 levels of mice were extremely significantly increased (P<0.01) and the LH and FSH levels were extremely significantly decreased (P<0.01) after administration of Astragalus and Astragalus Decoction (QHYKF); and the serum AMH and E2 levels of mice were extremely significantly increased (P<0.01) and the LH and FSH levels were significantly decreased (P<0.01) after administration of Astragalus and Astragalus Decoction (QHYKF). Compared with the 12m+HQHJ group, the 12m+QHYKF group showed significantly increased AMH and E2 levels (P<0.01 or P<0.05), and significantly decreased LH and FSH levels (P<0.05). Results are shown below. Figure 4 .

[0068] (4) Effects of Qihuang Yangkun Formula on Ovarian Pathology in Mice

[0069] like Figure 5 Pathological images of mouse ovaries show that the ovaries of 2m mice have clear structures and regular morphology, with relatively intact follicle morphology and structure, and normal follicle number distribution. Compared with 2m mice, the ovaries of 9m and 12m model mice are significantly smaller in volume, structurally disordered, and have a reduced number of follicles. Compared with the 9m and 12m groups, the ovarian structure of mice in all groups improved after drug administration, and the number of follicles increased. Among them, the group treated with Qihuang Yangkun Formula (QHYKF) showed the best improvement.

[0070] In conclusion, Qihuang Yangkun Formula can significantly improve estrous cycle disorders, balance hormone levels, ovarian structure and follicle number in mice, and has no effect on mouse weight, demonstrating high safety.

[0071] The above detailed description is a specific description of the embodiments of the present invention. These embodiments are not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included in the patent scope of this case.

Claims

1. A traditional Chinese medicine compound for delaying ovarian aging, characterized in that, The traditional Chinese medicine compound consists of the following components in parts by weight: 5-30 parts of Polygonatum sibiricum, 5-50 parts of Astragalus membranaceus, 5-30 parts of Poria cocos, and 1-20 parts of Citrus reticulata peel.

2. The traditional Chinese medicine compound for delaying ovarian aging according to claim 1, characterized in that, The traditional Chinese medicine compound consists of the following components in parts by weight: 15 parts of Polygonatum sibiricum, 20 parts of Astragalus membranaceus, 10 parts of Poria cocos, and 5 parts of Citrus reticulata peel.

3. A method for preparing a traditional Chinese medicine compound for delaying ovarian aging as described in claim 1 or 2, characterized in that, The process includes the following steps: extracting the traditional Chinese medicine described in claim 1 or 2 using a two-stage decoction method, combining the decoctions and concentrating them, then freeze-drying them to obtain the final product.

4. The application of the traditional Chinese medicine compound according to claim 1 or 2 in the preparation of products that delay ovarian aging.

5. The application according to claim 4, characterized in that, The product in question is a pharmaceutical product.

6. The application according to claim 5, characterized in that, The product is a solid dosage form or a liquid dosage form.

7. The application according to claim 6, characterized in that, The solid dosage form is a powder, granule, tablet, or capsule.

8. The application according to claim 6, characterized in that, The liquid formulation is a solution, suspension, or emulsion.

9. A product for delaying ovarian aging, characterized in that, It consists of a traditional Chinese medicine compound as described in claim 1 or 2, in an effective amount as the active ingredient, and pharmaceutically acceptable excipients.

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