Use of paeoniflorin-6'-o-benzenesulfonate for improving acinar atrophy

Abstract

The present application relates to the field of pharmacology, in particular to the use of paeoniflorin-6'-O-benzene sulfonate for improving acinar atrophy, maintaining the stability of gland functional units, and repairing gland secretion function. The paeoniflorin-6'-O-benzene sulfonate can effectively improve the acinar atrophy of diabetic animals, and the effect is significantly better than that of paeoniflorin, and can be used for preparing a medicine for treating xeroma.

Description

Technical Field

[0001] This invention relates to the field of pharmacology, specifically to the application of paeoniflorin-6'-O-benzenesulfonate in improving acinar atrophy. Background Technology

[0002] Diabetes mellitus is a chronic systemic disease primarily characterized by glucose metabolism disorders, accompanied by lipid and protein metabolism disorders, caused by an absolute or relative deficiency of insulin secretion. The typical symptoms of diabetes are "the three highs and one low" (excessive thirst, excessive hunger, excessive urination, and weight loss). Diabetic patients often experience impaired glandular secretion, leading to reduced saliva production, resulting in symptoms such as dry mouth, oral mucosal lesions, and oral thrush. As the disease progresses, severe cases may even develop into oral cancer.

[0003] The acini are the functional units of the submandibular gland that secrete saliva. In diabetic animal models, atrophy of the submandibular gland acinar tissue is observed, suggesting that acinar lesions are an important pathological manifestation affecting saliva secretion in diabetic patients and a significant cause of dry mouth symptoms. However, there are currently no marketed drugs specifically designed to improve acinar tissue atrophy or impaired glandular secretion function in diabetic patients. Clinically, drugs that stimulate glandular secretion, such as pilocarpine and cevimeline, may be used to treat dry mouth symptomatically, but these are off-label uses, and their efficacy is greatly affected by the degree of glandular remnant. If the glandular structure is significantly damaged and secretory function is severely impaired, even high-dose administration will not achieve the desired effect. Therefore, for diabetic patients, in addition to controlling blood sugar, improving acinar pathology and repairing glandular secretory function is also a crucial part of the disease treatment process.

[0004] Therefore, the present invention provides a benzenesulfonated paeoniflorin derivative, namely paeoniflorin-6'-O-benzenesulfonate, which can effectively improve acinar atrophy lesions and repair glandular secretory function, with significantly better therapeutic effects than paeoniflorin. Summary of the Invention

[0005] The purpose of this invention is to provide a new application of paeoniflorin-6'-O-benzenesulfonate in improving glandular atrophy, reducing damage to glandular functional units, and restoring glandular secretory function in diabetic patients.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0007] The application of paeoniflorin-6'-O-benzenesulfonate in the preparation of formulations for the treatment or adjunctive treatment of diabetes; said paeoniflorin-6'-O-benzenesulfonate has the following structural formula:

[0008]

[0009] Preferably, it is a formulation for the treatment or adjunctive treatment of diabetic patients with submandibular gland function units.

[0010] Preferably, it is used to prepare a formulation that improves acinar atrophy lesions.

[0011] Preferably, it is used to prepare a formulation that promotes saliva secretion in diabetic patients.

[0012] For symptoms of reduced saliva secretion caused by non-inflammatory diseases such as diabetes, this invention can effectively promote saliva secretion.

[0013] A formulation obtained through the above-described application.

[0014] Preferably, the formulation comprises a drug; the drug further comprises a pharmaceutically acceptable carrier.

[0015] Preferably, the route of administration of the drug includes one or more of oral administration, injection administration, transdermal administration, and mucosal administration.

[0016] Preferably, when the route of administration of the drug includes injection, the dose of paeoniflorin-6'-O-benzenesulfonate is 1 to 20 mg / kg.

[0017] Preferably, when the route of administration of the drug includes oral administration, the dose of paeoniflorin-6'-O-benzenesulfonate includes 20 to 100 mg / kg.

[0018] Preferably, the drug comprises one of the following: tablets, capsules, lozenges, granules, powders, pills, powders, ointments, pills, suspensions, solutions, emulsions, injections, suppositories, creams, sprays, drops, or patches.

[0019] Compared with the prior art, implementing the present invention has the following beneficial effects:

[0020] The application of paeoniflorin-6'-O-benzenesulfonate in improving acinar atrophy lesions is disclosed.

[0021] This invention discovers the effects of paeoniflorin-6'-O-benzenesulfonate in improving acinar atrophy caused by diabetes and in restoring salivary secretion function by improving acinar atrophy. Based on this discovery, this invention provides the application of paeoniflorin-6'-O-benzenesulfonate in the preparation of a drug for treating submandibular gland dysfunction and dryness symptoms caused by diabetes in diabetic patients. Experiments have demonstrated that paeoniflorin-6'-O-benzenesulfonate can significantly improve submandibular gland acinar atrophy and restore glandular secretion function in diabetic animals, with significantly better effects than paeoniflorin alone, and can be formulated into a drug for treating dryness symptoms. Attached Figure Description

[0022] Figure 1 This is a pathological examination image of the submandibular gland acini in the blank control group of this invention (scale bar: 200μm per unit length);

[0023] Figure 2 This is a pathological examination image of the submandibular gland acini in the control group of the model of this invention (scale bar: 200μm per unit length);

[0024] Figure 3 This is a pathological examination image of the submandibular gland acini in the paeoniflorin-6'-O-benzenesulfonate (14 mg / kg intramuscular injection) group of the present invention (scale bar: 200 μm per unit length);

[0025] Figure 4 This is a pathological examination image of the submandibular gland acini in the paeoniflorin-6'-O-benzenesulfonate (7mg / kg intramuscular injection) group of the present invention (scale bar: 200μm per unit length);

[0026] Figure 5 This is a pathological examination image of the submandibular gland acini in the paeoniflorin-6'-O-benzenesulfonate (3.5 mg / kg intramuscular injection) group of the present invention (scale bar: 200 μm per unit length);

[0027] Figure 6 This is a pathological examination image of the submandibular gland acini in the paeoniflorin-6'-O-benzenesulfonate (70 mg / kg orally) group of the present invention (scale bar: 200 μm per unit length);

[0028] Figure 7 This is a pathological examination image of the submandibular gland acini in the paeoniflorin (14 mg / kg intramuscular injection) group of the present invention (scale bar: 200 μm per unit length). Detailed Implementation

[0029] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments are not intended to limit the present invention. Modifications or substitutions made to the methods, steps, or conditions of the present invention without departing from the spirit and substance of the present invention are all within the scope of the present invention. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0030] Example 1

[0031] Eight-week-old non-obese diabetic mice were fed normally, and the mice were observed weekly for scratching and damage to the skin around the eyes and the whole body, as well as the condition of the eyelids and lips. After the mice were fed to 13 weeks of age, saliva secretion was measured. Mice with significantly reduced saliva secretion were randomly divided into groups, and ICR mice were used as blank controls.

[0032] Each group was administered the drug by gavage at a volume of 10 ml / kg or by intramuscular injection at a volume of 0.1 ml / animal for 21 consecutive days. The blank control group and the model control group were given the same volume of solvent (physiological saline solution containing 5% Solutol and 5% DMSO) orally, and saliva secretion was measured after the last administration.

[0033] After the last administration, mice were fasted but allowed to drink water for 8–12 hours. Mice in each group were weighed, sacrificed, and their submandibular glands were isolated, fixed in formalin, stained with hematoxylin and eosin (HE), and observed under a light microscope to check whether the acinar structure was clear, whether the acinar cells were swollen, and whether the acinars had atrophied.

[0034] Saliva secretion measurement: A 0.0125 mg / ml pilocarpine saline solution was administered intraperitoneally at a dose of 0.1 ml / 10 g. Five minutes after the injection, anesthesia was achieved by intramuscular injection of 12.5 mg / ml saliva extract at a dose of 0.01 ml / 10 g. After successful anesthesia, a pre-weighed cotton ball (dry weight range controlled between 0.25 and 0.35 g) was placed in the animal's cheek. After 10 minutes, the cotton ball was removed, and its wet weight was measured. Saliva secretion volume (mg) was calculated as follows: Saliva secretion volume (mg) = wet weight - dry weight.

[0035] The results of the acinar pathological grading evaluation are shown in Figures 1-7 As shown in Table 1. Among them, Figures 1-7 Pathological examination of submandibular gland acini in different groups (HE staining 100×).

[0036] Table 1. Results of Pathological Grading of Acinar Cells ( n = 9-10)

[0037]

[0038]

[0039] Note: (1) Compared with the model control group, *P<0.05; (2) Non-parametric tests were used for ordinal variables; (3) The severity of the lesion increased with the increase of the pathological grade.

[0040] Depend on Figures 1-7 It was found that the submandibular gland structure was clear in the blank control group, with neatly arranged acinar cells and no abnormal changes in interlobular ducts and blood vessels. Compared with the blank control group, the submandibular glands of the diabetic model control group animals showed obvious damage, with duct dilation around the acini and between the lobules, and a significant reduction in acinar volume, indicating severe acinar atrophy.

[0041] The submandibular glands of diabetic model animals showed significant lesions and severe acinar atrophy. Table 1 shows that, compared to the model control group, intramuscular administration of a high dose (14 mg / kg) of paeoniflorin-6'-O-benzenesulfonate significantly improved acinar atrophy and alleviated acinar lesions. The improvement in salivary secretion with different intramuscular doses showed a dose-response relationship. The medium- and low-dose groups, as well as the oral administration group, also showed a clear trend of improvement, with very few grade III lesions, indicating that paeoniflorin-6'-O-benzenesulfonate can effectively improve acinar atrophy and alleviate acinar lesions.

[0042] The results of the saliva secretion assay are shown in Table 2.

[0043] Table 2. Results of saliva secretion measurement ( n = 8-10)

[0044]

[0045] Note: Compared with the model control group, **P<0.01, ***P<0.001; compared with the high-dose intramuscular injection group of paeoniflorin-6'-O-benzenesulfonate, ^P<0.05

[0046] Table 2 shows that salivation secretion in the model animals decreased significantly. After 3 weeks of administration, salivation secretion increased significantly in all treatment groups. Among them, the high-dose (14 mg / kg) paeoniflorin-6'-O-benzenesulfonate intramuscular injection showed a particularly significant improvement in salivation secretion, with a significantly better effect than other groups. Moreover, the improvement in salivation secretion showed a certain dose-response relationship among different doses of intramuscular injection.

[0047] The acini are the functional units of the submandibular gland that secrete saliva, playing a crucial role in the saliva secretion process. Acinar atrophy leads to glandular structural damage and impaired secretory function. Therefore, improving the pathological state of the acini and ensuring glandular structural stability are essential for restoring saliva secretion function. As a significant cause of reduced saliva secretion, acinar atrophy may be observed in patients with dry mouth symptoms, presenting with non-inflammatory glandular atrophic changes with minimal inflammatory cell infiltration. Such patients may have atrophic sclerosis, diabetes, hepatitis C secondary to other diseases, or multiple concurrent conditions.

[0048] Dry mouth is a common symptom in patients with diseases such as diabetes, Sjögren's syndrome, and AIDS. The mechanisms underlying dry mouth vary depending on the disease. For example, in patients with inflammation, submandibular gland lymphocyte infiltration is frequently observed, leading to dry mouth. In this case, dry mouth is often closely related to anti-SSA / SSB antibody levels. However, dry mouth in diabetic patients is not caused by lymphocyte infiltration of the glands. Instead, it results from elevated blood glucose levels, leading to increased blood osmotic pressure, increased renal osmotic urine production, and decreased blood volume. This triggers a thirst response in the cerebral cortex, resulting in dry mouth. Therefore, the salivary glands of diabetic patients bear a heavier burden than those of healthy individuals. Over time, this can lead to glandular fatigue, glandular shrinkage, and atrophy of functional acini, resulting in reduced saliva flow. This affects the nutritional balance of tissues and ducts, causing abnormal protein and lipid metabolism, which further reduces saliva secretion, creating a vicious cycle.

[0049] In diabetic model animals, the degree of lymphocyte infiltration in the submandibular gland was relatively low, but the acinar atrophy was obvious. Paeoniflorin-6'-O-benzenesulfonate could significantly improve acinar atrophy and repair secretory function in model animals, but it did not show significant pathological improvement on lymphocyte infiltration, nor did it have a significant effect on the anti-SSA / SSB antibody level in model animals. This indicates that the mechanism by which this product repairs glandular secretion in diabetic model animals is not through anti-inflammatory action, but by improving acinar atrophy, promoting the glandular morphology to return to normal, thereby increasing glandular secretion. It can play a very good role in promoting saliva secretion in cases of reduced saliva secretion caused by non-inflammatory diseases.

[0050] Overall, paeoniflorin-6'-O-benzenesulfonate can effectively improve acinar atrophy, maintain glandular morphological stability, and repair salivary secretion function impairment caused by diabetes. No significant changes in blood glucose levels were observed before and after administration to animals, showing good potential for diabetes drug development.

[0051] The above-disclosed embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. Therefore, any equivalent variations made in accordance with the claims of the present invention are still within the scope of the present invention.

Claims

1. The application of paeoniflorin-6'-O-benzenesulfonate, characterized in that, For use in the preparation of formulations for the treatment or adjunctive treatment of diabetes; the paeoniflorin-6'-O-benzenesulfonate has the following structural formula:

2. The application as described in claim 1, characterized in that, Preparations for the treatment or adjunctive treatment of submandibular gland dysfunction caused by diabetes.

3. The application as described in claim 1, characterized in that, Used to prepare formulations that improve acinar atrophy.

4. The application as described in claim 1, characterized in that, Used to prepare formulations that promote saliva secretion in diabetic patients.

5. A formulation obtained by the application as described in claim 1.

6. The formulation as described in claim 5, characterized in that, The formulation includes a drug; the drug further contains a pharmaceutically acceptable carrier.

7. The formulation of claim 6, characterized in that, The drug can be administered via one or more of the following routes: oral administration, injection administration, transdermal administration, and mucosal administration.

8. The formulation as described in claim 7, characterized in that, When the drug is administered via injection, the dose of paeoniflorin-6'-O-benzenesulfonate ranges from 1 to 20 mg / kg.

9. The formulation as described in claim 7, characterized in that, When the drug is administered orally, the dose of paeoniflorin-6'-O-benzenesulfonate is 20 to 100 mg / kg.

10. The formulation of claim 6, characterized in that, The drug includes one of the following: tablets, capsules, lozenges, granules, powders, pills, powders, ointments, pills, suspensions, solutions, emulsions, injections, suppositories, creams, sprays, drops, or patches.

Images