TWI474827B - Hypoglycemic activity of osthole - Google Patents

Description

Hypoglycemic activity of osthole

The present invention relates to a method for controlling blood glucose concentration and a method for preventing or treating diabetes and/or its complications. The invention further relates to an anti-diabetic formulation for controlling blood glucose concentration and/or for preventing or treating diabetes and/or its complications.

The following discussion is intended to facilitate an understanding of the invention and is not intended to be a

Diabetes mellitus (diabetes) is a syndrome of metabolic abnormalities that is often attributed to a combination of genetic and environmental factors that result in abnormally high blood glucose levels (hyperglycemia). Blood glucose levels are controlled by the complex interactions of various chemicals and hormones in the receptor, including the hormone insulin produced in the beta-cells of the pancreas. Diabetes refers to a group of diseases that cause high blood sugar levels due to defects in insulin secretion (type I diabetes) or defects in insulin action (type II diabetes). Both type 1 diabetes and type 2 diabetes can cause hyperglycemia, which usually causes acute symptoms of diabetes: polyuria, compensatory thirst and increased fluid intake, blurred vision, unclear weight loss, lethargy, And changes in energy metabolism.

Hyperglycemia can cause long-term microvascular and macrovascular complications such as nephropathy, neuropathy, retinopathy, and peripheral vascular disease. In addition, diabetes is a comorbid disease often associated with hyperlipidemia, atherosclerosis and hypertension. Hyperlipidemia is a major risk factor for cardiovascular disease due to atherosclerosis. Long-term complications of diabetes are generally associated with decreased life expectancy, neuropathy, and increased prevalence of blindness, kidney disease, and heart disease compared with non-diabetes.

Diabetes can be controlled by insulin and in some cases can be controlled by paying attention to the diet. However, blood glucose levels in patients undergoing insulin or diet therapy will still fluctuate (and sometimes fluctuate). In addition, in cases of severe diabetes, patients must continuously monitor their blood glucose levels to prevent related diseases. People with diabetes are forced to inject insulin so that they eventually cause bruising in certain areas. In addition, other medical complications caused by diabetes include, for example, atherosclerosis, hyperlipidemia, retinal damage, nerve damage, fatigue, and weakness.

Therefore, there is a need for a safe and effective treatment for diabetes that has minimal side effects and/or no invasive procedures (such as injections).

Fructus cnidii, or Cnidium fruit, snake chestnut, snake rice, Taiwan Chuanxiong, false pheasant and wild scorpion, is the dried fruit of Cnidium monnieri (L.) Cuss. It has long been used as a Chinese herbal medicine in China for the treatment of impotence, dampness, infertility, low back pain, parasitic diseases, eczema or pruritus, itchy skin, trichomoniasis, rectal prolapse, hemorrhoids and Similar symptoms. As far as its nature is concerned, the snake bed is solid, bitter and warm. Snake beds are mainly found in Hebei, Shandong, Zhejiang, Jiangsu, Sichuan and Taiwan. The known active ingredients of the snake bed include: L-pinene, L-camphene, bornyl isovalarate, isoborneol, osthole ), cnidimine (eduotin), cnidiadin, isopimpinelline, xanthotoxol, and the like.

Osthole is a coumarin compound called 7-methoxy-8-isopentenylcoumarin or 7-methoxy-8-(3-methyl-2-butenyl)-2H 1-benzobenzopyran-2-one having the following chemical structure:

TW564177B discloses a method for extracting osthole from a snake bed, an anti-vaginal trichomoniasis preparation containing osthole as a main component, and a method for measuring the activity against vaginal trichomoniasis containing an osthole preparation. Wei, Y. et al. disclose the use of fractional dissolution by high-speed countercurrent chromatography (HSCCC) to separate osthole and xanthohumol from Common Cnidium Fruit (see J. Chromatogr. A. 2004, 1033 (2): 373-377). CN101095669A discloses a lecithin complex of osthole, a preparation method thereof and application thereof for increasing the solubility of osthole.

Recent studies have shown that osthole has effects on the cardiovascular system, the nervous system, the immune system, and the metabolism of lipids and bones, such as: dilating blood vessels (see Chiou, WF, et al., "Vasorelaxing effect of coumarins from Cnidium monnieri on rabbit corpus Cavernnosum." Planta. Med. 2001, 67(3): 282-284); inhibits proliferation of vascular smooth muscle cells (see Guh, JH, et al., "Antiproliferative effect in rat vascular smooth muscle cells by osthole, isolated from Angelica pubescens . ". Eur J. Pharmacol 1996,298 ( 2):. 191-197); inhibition of ion current in the neuronal cells (see Wu, SN," Inhibitory effect of the plant-extract osthole on L-type calcium current in NG108-15 neuronal cells." Biochem. Pharmacol. 2002, 63(2): 199-206); anti-allergic (see Matsuda, H., et al., "Anti-allergic effects of cnidii monnieri fructus (dried fruits of Cnidium) Monnieri ) and its major component, osthole." Biol. Pharm. Bull. 2002, 25(6): 809-812); prevention of hepatitis (see Okamoto, T., et al., "Osthole prevention anti-Fas antibody-induced hepatitis In mice by aff Ecting the caspase-3-mediated apoptotic pathway." Biochem. Pharmacol. 2003, 65(4): 677-681); inhibiting the growth of tumor cells (see Chou, SY, "Antitumor effects of Osthole from Cnidium monnieri : an in vitro And in vivo study." Phytother. Res. 2007, 21(3): 226-230); lowering blood fat and lowering blood pressure (see Ogawa, H., et al., "Effects of osthol on blood pressure and lipid metabolism in stroke- Prone spontaneously hypertensive rats." J. Ethnopharmacol. 2007, 112(1): 26-31); inhibition of fatty liver induced by alcohol or fat-containing dairy products (see Sun, F., et al., "Inhibitory effect of osthole on Alcohol-induced fatty liver in mice." Dig. Liver Dis., available on March 11th , 2008; and Zhang, Y., et al., "Therapeutic effect of osthole on hyperlipidemic fatty liver in rats." Acta Pharmacol. Sin . 2007,28 (3): 398-403); and inhibition of osteoporosis (see Kuo, PL, et al., "Osthole-mediated cell differentiation through bone morphogenetic protein-2 / p38 and extracellular signal-regulated kinase 1/2 Pathway in human osteoblast cells." J. Pharmacol Exp. Ther. 2005, 314(3): 1290-1299; Zhang, Q., et al., "Coumarins from Cnidium monnieri and their antiosteoporotic activity." Planta. Med. 2007, 73(1): 13-19; And Li, XX, et al., "Effects of osthole on postmenopausal osteoporosis using ovariectomized rats; comparison to the effects of estradiol." Biol. Pharm. Bull. 2002, 25(6): 738-742). However, there is no report on the effect of osthole on the regulation of blood glucose concentration.

It is an object of the present invention to provide a method for controlling blood glucose concentration comprising administering a therapeutically effective amount of osthole or a pharmaceutically acceptable derivative thereof to an individual in need thereof, thereby reducing the individual Blood sugar concentration. In particular, elevated blood glucose levels are due to diabetes.

Another object of the present invention is to provide a method for preventing or treating diabetes and/or its complications, which comprises administering a therapeutically effective amount of osthole or a pharmaceutically acceptable derivative thereof. Individual.

The invention also relates to an anti-diabetic formulation comprising a therapeutically effective amount of osthole or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient.

The invention is described in detail in the following sections. Other features, objects, and advantages of the invention will be apparent from the embodiments and appended claims.

Unless otherwise defined herein, the scientific and technical terms used in connection with the present invention are intended to be understood by those of ordinary skill in the art. The meaning and scope of these terms should be obvious; however, if there is any potential ambiguity, the definitions provided herein take precedence over any dictionary or foreign definition.

As used in this disclosure, the following terms are understood to have the following meanings unless otherwise indicated: The term "individual" as used herein refers to any animal, preferably a mammal, and more preferably a human. Examples of individuals include humans, non-human primates, rodents, guinea pigs, rabbits, sheep, pigs, goats, cows, horses, dogs, and cats.

The term "osthole" as used herein denotes the name 7-methoxy-8-isopentenylcoumarin or 7-methoxy-8-(3-methyl-2-butenyl) a compound of -2H-1-benzopipene-2-one.

The term "pharmaceutically acceptable derivative" as used herein denotes a compound that is modified by osthole but has the same or better properties and efficacy than osthole. Preferably, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, solvate or prodrug of osthole. For example, the compound can be joined to other materials to increase its solubility.

The term "therapeutically effective amount" as used herein refers to an amount effective to achieve the desired therapeutic effect at the required dosage and for the necessary period of time. The therapeutically effective amount of the agent may vary depending on such factors as the individual's condition, physical condition, age, sex, species, and weight. The dosing regimen can be adjusted to induce the optimal therapeutic response. For example, depending on the urgency of the treatment situation, the dosage may be administered several times a day or proportionally.

The term "prevention" is art-recognized and when applied to a condition, includes administering an individual agent prior to the onset of the condition to reduce the frequency or severity of the onset of the medical condition in the individual, or delaying the individual. The onset of symptoms of a medical condition (as opposed to an individual who did not receive the agent).

The term "treating" as used herein refers to reversing, slowing, inhibiting the progression or amelioration of the condition or condition or one or more symptoms to which the term applies, or ameliorating the condition or condition or one or more symptoms thereof.

The term "carrier" or "excipient" as used herein refers to any of the following: it is not itself a therapeutic agent, but is used as an agent and/or diluent and/or adjuvant, or a vehicle to treat The agent is delivered to the individual, or added to the formulation to improve its handling or storage characteristics or to allow or promote the dosage unit of the composition to form discrete articles such as capsules or lozenges suitable for oral administration. Suitable carriers or excipients are well known to those of ordinary skill in the art of making pharmaceutical formulations or food products, such as, but not limited to, buffers, diluents, disintegrating agents, binders, adhesives, wetting agents, A polymer, a lubricant, a glidant, a substance added to mask or counteract an undesired taste or odor, a fragrance, a dye, a fragrance, and a substance added to improve the appearance of the composition. Acceptable carriers or excipients include: citrate buffers, phosphate buffers, acetate buffers, bicarbonate buffers, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid, and sodium sulphate Salts and calcium salts, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starch, gelatin, cellulosic materials (such as Alkanoic acid cellulose esters and cellulose alkyl esters), low melting point waxes, cocoa butter, amino acids, ureas, alcohols, ascorbic acid, phospholipids, proteins (eg serum albumin), ethylenediaminetetraacetic acid (EDTA) , dimethyl hydrazine (DMSO), sodium chloride or other salts, liposomes, mannitol, sorbitol, glycerol or powder, polymers (such as polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol), And other pharmaceutically acceptable materials. The carrier should not destroy the pharmacological activity of the therapeutic agent and should be non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the agent.

Unless the context requires otherwise, the singular terms shall include the plural, and the plural terms shall include the singular.

Use for treatment

The present invention relates to a surprising finding that osthole or a pharmaceutically acceptable derivative thereof has hypoglycemic activity and is therefore useful for controlling blood glucose concentration in an individual and treating diabetes and/or its complications.

In a preferred embodiment, the blood glucose concentration is elevated due to diabetes. In one embodiment, the diabetes is type I diabetes. In another embodiment, the diabetes is type II diabetes. In certain embodiments, the complication of diabetes is selected from the group consisting of hyperglycemia, abnormal glucose tolerance, insulin resistance, pancreatic β-cell deficiency, intestinal endocrine deficiencies, diabetes, metabolic acid Toxic, cataract, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis Hardening, stroke, high blood pressure, and obesity.

According to the method of the present invention, osthole or a pharmaceutically acceptable derivative thereof can be chemically synthesized or extracted from a plant containing osthole. Methods of synthesizing or isolating osthole or a pharmaceutically acceptable derivative thereof are known in the art (such as TW564177B and CN1089497A; the disclosures of each of which are hereby incorporated by reference in its entirety). In one embodiment of the invention, osthole or a pharmaceutically acceptable derivative thereof is from a Cnidium plant. Preferably, osthole or a pharmaceutically acceptable derivative thereof is from Cnidium monnieri (L.) Cuss. More preferably, osthole or a pharmaceutically acceptable derivative thereof is derived from a snake bed. In another embodiment of the invention, the amount of osthole in the extract containing the osthole plant is greater than 10%; more preferably greater than 50%; most preferably greater than 95%.

According to the method of the present invention, the therapeutically effective amount is from about 10 mg/kg/day to about 200 mg/kg/day; preferably from about 40 mg/kg/day to about 100 mg/kg/day; optimally about 50. Mg/kg/day.

In accordance with the methods of the present invention, osthole or a pharmaceutically acceptable derivative thereof can be administered topically or systemically by any method known in the art including, but not limited to, intramuscular, dermal Internal, intravenous, subcutaneous, intraperitoneal, intranasal, oral or other mucosal routes. Suitable routes, formulations, and immunization procedures can be determined by those skilled in the art. Osthole or a pharmaceutically acceptable derivative thereof may be administered by a suitable non-toxic pharmaceutical carrier or excipient, or may be in the form of a liquid solution, suspension, emulsion, syrup, lozenge, pill, capsule, continuous Release formulations, powders, granules, ampoules, injections, infusions or combinations thereof, or dietary products.

According to the method of the present invention, osthole or a pharmaceutically acceptable derivative thereof can be administered in combination with a second agent which can effectively control blood glucose concentration, thereby lowering the blood glucose concentration in the individual. Many agents are known in the art to effectively control blood glucose concentration, and examples of such agents include, but are not limited to, sulfonylureas (such as glipizide, glimepiride, and glibenclamide). Glyburide), biguanides (such as metformin), alpha-glucosidase inhibitors (such as acarbose and miglitol), meglitinides, Such as nateglinide and repaglinide, thiazolidinediones (such as pioglitazone and rosiglitazone), amylinomimetic (amyllinomimetic), such as pramling Pramlintide), GLP-1 analogues (such as exenatide), and DPP4 inhibitors (such as sitagliptin and vildagliptin) (see Langley, A. k) ., et al., "Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus." Pharmacotherapy 2007, 27(8): 1163-1180; and Doupis, J. and Veves, A., DPP4 inhibitors: a new approach In diabetes treatment. "Adv. Ther. 2008, 25(7): 627-643).

According to the method of the present invention, osthole or a pharmaceutically acceptable derivative thereof can be administered in combination with a second agent effective for preventing or treating diabetes. Many agents are known in the art to effectively prevent or treat diabetes, and examples of such agents include, but are not limited to, sulfonylureas (such as glipizide, glimepiride, and glibenclamide), biguanides (such as metformin), alpha-glucosidase inhibitors (such as acarbose and miglitol), grannate (such as nateglinide and repaglinide), thiazolidinediones (such as Pioglitazone and rosiglitazone), amylin inducible mimics (such as pramlintide), GLP-1 analogues (such as exenatide), and DPP4 inhibitors (such as sitagliptin and vildagliptin) (See Langley, A. k., et al., "Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus." Pharmacotherapy 2007, 27(8): 1163-1180; and Doupis, J. and Veves, A. "DPP4 inhibitors: a new approach in diabetes treatment." Adv. Ther. 2008, 25(7): 627-643).

Formulation

The invention also provides an anti-diabetic formulation comprising a therapeutically effective amount of osthole or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient. This therapeutically effective amount has been defined and described herein, and those skilled in the art should have no difficulty in selecting a suitable therapeutic route and dosage.

In a preferred embodiment, the formulation of the invention is a medicament. According to the invention, the medicament may be formulated in different ways according to the respective route of administration, such as: liquid solutions, suspensions, emulsions, syrups, troches, pills, capsules, sustained release formulations, powders, granules, ampoules, injections, Infusion, kit or combination thereof. The agent may also contain carriers or excipients, many of which are known to those of ordinary skill in the art, such as those disclosed above.

In a preferred embodiment, the formulation of the invention is a dietary product. According to the present invention, the dietary product may be a food, a health food, a food supplement, a medical food, a liquid, a beverage, a food, or a mixture thereof. The dietary product may also contain carriers or excipients, many of which are known to those of ordinary skill in the art, such as those disclosed above.

According to the present invention, the anti-diabetic formulation can be used in combination or further comprising an agent or a dietary product effective for preventing or treating diabetes.

The following examples are provided to assist those skilled in the art in practicing the invention.

Instance Example 1 Effect of intraperitoneal administration of osthole to diabetic mice

Six male db / db diabetic mice (6 weeks to 11 weeks old, purchased from the National Laboratory Animal Center (Taipei, Taiwan)) were fasted for more than 8 hours and venous blood was collected for measurement. Blood sugar concentration. The mice were divided into two groups according to their blood glucose concentration and body weight (control group and experimental group). Solvent DMSO was administered to mice in the control group by intraperitoneal administration. Osthole (50 mg/kg body weight) (purchased from Hangzhou Gosun Biotechnologies Co., Zhejiang, China) was administered to mice in the experimental group by intraperitoneal administration. The solvent and osthole were administered once daily for five weeks. Next, the mice were sacrificed for about 16 hours and sacrificed and blood samples were collected for measurement of blood glucose concentration. The measurement results of blood glucose concentration are shown in Fig. 1.

As shown in Fig. 1, the blood glucose concentrations of the mice in the control group (CTL) and the experimental group (Os 50) were about 360 mg/dL before the treatment. After two weeks of treatment, the blood glucose concentration of the mice in the control group was raised to 550 mg/dL, while the blood glucose concentration of the mice in the experimental group was maintained at about 360 mg/dL. These results demonstrate that intraperitoneal administration of osthole can effectively control and reduce blood glucose concentrations in db / db diabetic mice.

Example 2 Effect of oral administration of osthole to diabetic mice

Six male db / db diabetic mice (5 weeks to 7 weeks old, purchased from the National Laboratory Animal Center (Taipei, Taiwan)) were fasted for more than 8 hours and venous blood was collected for measurement of blood glucose concentration. The mice were divided into two groups according to their blood glucose concentration and body weight (control group and experimental group). Mice in the control group were fed from a gastric tube in phosphate buffered saline (PBS). Mice in the experimental group were fed from the stomach tube with osthole (50 mg/kg body weight). PBS and osthole were administered once daily for five weeks. Next, the mice were sacrificed for about 16 hours and sacrificed and blood samples were collected for measurement of blood glucose concentration. The measurement results of blood glucose concentration are shown in Fig. 2.

As shown in Fig. 2, the blood glucose concentrations of the mice in the control group (CTL) and the experimental group (Os 50) were about 200 mg/dL before the treatment. After three weeks of treatment, the blood glucose concentration of the mice in the control group was raised to 400 mg/dL; while the blood glucose concentration of the mice in the experimental group was maintained at about 210 mg/dL. These results demonstrate that oral administration of osthole can effectively control and reduce blood glucose concentrations in db / db diabetic mice.

Although the present invention has been described in connection with the specific embodiments set forth above, many alternatives and modifications and variations of the embodiments are apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are considered to be within the scope of the invention.

Figure 1 shows blood glucose concentrations before and after intraperitoneal administration of osthole and DMSO in db / db diabetic mice.

Figure 2 shows the blood glucose concentrations of db / db diabetic mice before and after oral administration of osthole and PBS.

(no component symbol description)

Claims (21)

A use of osthole for the manufacture of a medicament for controlling blood glucose concentration in a type II diabetic individual, wherein the osthole is chemically synthesized or at least 95% pure. The use of claim 1, wherein the agent comprises a therapeutically effective amount of osthole, and the therapeutically effective amount is from 10 mg/kg to 200 mg/kg. The use of claim 2, wherein the therapeutically effective amount is about 50 mg/kg. The use of any one of claims 1 to 3, wherein the agent is administered parenterally or orally. The use of any one of claims 1 to 3, wherein the individual is a mammal. The use of claim 5, wherein the mammal is a human. The use of any one of claims 1 to 3, wherein the blood glucose concentration is elevated due to diabetes. The use of any one of claims 1 to 3, wherein the agent is used in combination with a second agent that is effective to control blood glucose concentration. The use of any one of claims 1 to 3, wherein the osthole is from a Cnidium plant. The use of any one of claims 1 to 3, wherein the osthole is from a Cnidium monnieri (L.) Cuss. The use of any one of claims 1 to 3, wherein the osthole is from a Cnidium fruit. Use of osthole for the manufacture of a medicament for treating diabetes and/or its complications in a type II diabetic individual, wherein the osthole system Chemically synthesized or at least 95% pure. The use of claim 12, wherein the agent comprises a therapeutically effective amount of osthole or the pharmaceutically acceptable derivative thereof, and the therapeutically effective amount is from 10 mg/kg to 200 mg/kg. The use of claim 13, wherein the therapeutically effective amount is about 50 mg/kg. The use of any one of claims 12 to 14, wherein the agent is administered parenterally or orally. The use of any one of claims 12 to 14, wherein the individual is a mammal. The use of claim 16, wherein the mammal is a human. The use of any one of claims 12 to 14, wherein the agent is used in combination with a second agent effective for treating diabetes. The use of any one of claims 12 to 14, wherein the osthole is from a genus of the genus. The use of any one of claims 12 to 14, wherein the osthole is from a snake bed. The use of any one of claims 12 to 14, wherein the osthole is from a snake bed.