KR20230055994A - Use of 4-hexylresorcinol for treating diabetes or diabetes complication - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating diabetes or diabetic complications comprising 4-hexylresorcinol or a pharmaceutically acceptable salt thereof as an active ingredient. According to the present invention, since treatment with 4-hexylresorcinol inhibits weight loss and reduces blood glucose concentration, 4-hexylresorcinol can be usefully used to prevent, alleviate, or treat diabetes or diabetic complications.

Description

Use of 4-hexylresorcinol for treating diabetes or diabetes complication}

The present invention relates to the use of 4-hexylresorcinol in the treatment of diabetes or diabetic complications.

Diabetes mellitus is a type of metabolic disease in which insulin secretion is insufficient or normal functions are not performed, and is characterized by hyperglycemia in which the concentration of glucose in the blood increases. The number of people with diabetes has increased dramatically worldwide over the past 20 years, and the age of onset is getting younger because of lifestyle changes.

Diabetes can be divided into type 1 diabetes and type 2 diabetes according to its mechanism. Type 1 diabetes occurs when pancreatic beta cells are destroyed and no insulin is secreted from the pancreas. called diabetes mellitus Type 2 diabetes is characterized by high blood sugar levels due to lack of insulin secretion, insulin action, or both. If this hyperglycemic state persists or is not properly controlled, it causes complications such as cardiovascular disease, visual impairment, various forms of neuropathy and cognitive impairment, stroke and peripheral vascular disease.

Therefore, an effective approach to control blood glucose is required to prevent diabetes or diabetic complications and improve quality of life. Initial management often entails lifestyle interventions including diet and exercise, but in most cases drug therapy is also required as the disease progresses. However, drugs used to control blood sugar often cause metabolic side effects including weight gain and organ toxicity. Therefore, there is a need to develop alternative treatments that do not cause these side effects.

Accordingly, the inventors of the present invention completed the present invention by confirming that 4-hexylresorcinol has an effect of suppressing weight loss and reducing blood sugar as a result of efforts to discover substances for preventing or treating diabetes or diabetic complications without side effects. .

An object of the present invention is to provide a novel use of 4-hexylresorcinol for preventing, improving or treating diabetes or diabetic complications.

The present inventors confirmed that when 4-hexylresorcinol was treated in diabetic rats, weight loss was suppressed and blood glucose concentration decreased, thereby confirming that 4-hexylresorcinol was used for the treatment of diabetes or diabetic complications. It was confirmed that it can be used usefully and the present invention was completed.

Accordingly, the present invention provides a pharmaceutical composition for preventing or treating diabetes or diabetic complications comprising 4-hexylresorcinol or a pharmaceutically acceptable salt thereof as an active ingredient.

According to the present invention, since the treatment of 4-hexylresorcinol can suppress weight loss due to diabetes and reduce blood glucose concentration, 4-hexylresorcinol is useful for preventing, alleviating or treating diabetes or diabetic complications can make use of it.

1 confirms that weight loss is suppressed compared to a control group when 4-hexylresorcinol is treated in diabetic induced rats.
Figure 2 confirms that blood glucose concentration is reduced compared to the control group when treated with 4-hexylresorcinol in diabetic induced rats.
FIG. 3 confirms that, when normal rats were treated with 4-hexylresorcinol, blood glucose concentration during fasting was reduced compared to the control group.
Figure 4 confirms that when 4-hexylresorcinol was treated in diabetic rats, the concentration of glucagon in the kidneys was reduced compared to the control group by the decrease in red staining.
Figure 5 confirms that, when 4-hexylresorcinol was treated in diabetic rats, the concentration of glucagon in the salivary glands was reduced compared to the control group by reducing red staining.
Figure 6 shows that when 4-hexylresorcinol was treated in diabetic rats, the expression of TNF-α (tumor necrosis factor-α) in the kidney glomeruli (arrow) was reduced compared to the control group by reduced brown staining. it was confirmed
Figure 7 confirms the blood sugar lowering effect when 4-hexylresorcinol ointment is administered to diabetic induced rats.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating diabetes or diabetic complications comprising 4-hexylresorcinol or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, "4-hexylresorcinol" is a compound having the IUPAC name of 4-hexylbenzene-1,3-diol, represented by the following formula (1) is a compound represented by:

[Formula 1]

In the present invention, the 4-hexylresorcinol may be used interchangeably with "4-hexylbenzene-1,3-diol" or "4-HR".

In the present invention, the pharmaceutically acceptable salt of 4-hexylresorcinol is a concentration that has a relatively non-toxic and harmless effective effect on patients, and the side effects caused by this salt reduce the beneficial effect of 4-hexylresorcinol. It means an organic or inorganic addition salt that does not drop. For example, pharmaceutically acceptable salts may be acid addition salts formed using organic or inorganic acids, such as formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, and malic acid. , maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxyacetic acid, benzene sulfonic acid, p-toluenesulfonic acid, and methanesulfonic acid-based salts, and inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, and boric acid-based salts. Preferably, the pharmaceutically acceptable salt may be in the form of a citrate or hydrochloride salt. In addition, the pharmaceutically acceptable salt may be an alkali metal salt (sodium salt, potassium salt, etc.) and an alkaline earth metal salt (calcium salt, magnesium salt, etc.).

In the present invention, "diabetes" refers to a metabolic disease in which high blood sugar levels persist for a long period of time. In one embodiment of the present invention, the diabetes may be type 1 diabetes, type 2 diabetes, gestational diabetes, or steroid diabetes. Diabetes is a chronic wasting disease, and as the disease progresses, the patient may lose weight.

In the present invention, "diabetic complications" may refer to all complications that appear in various organs due to prolonged hyperglycemia due to diabetes. For example, complications such as diabetic retinopathy, cataract, renal failure, neuropathy, coronary artery disease, cerebrovascular disease, peripheral vascular disease, diabetic foot disease, sexual dysfunction, skin disease, hypertension, heart disease, and salivary adenitis are caused. It can be. In one embodiment of the present invention, the diabetic complication is from the group consisting of diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic ulcer, diabetic heart disease, diabetic osteoporosis and diabetic arteriosclerosis. It may be selected, but is not limited thereto.

According to the following examples, since 4-hexylresorcinol can suppress weight loss due to diabetes and reduce blood glucose concentration, it can be usefully used for the treatment of diabetes or diabetic complications. In addition, according to an embodiment of the present invention, since 4-hexylresorcinol can reduce the long-term accumulation of glucagon commonly observed in diabetes, it can be usefully used for the treatment of diabetes or diabetic complications.

In the present invention, the 4-hexylresorcinol (4-HR) may be included at a concentration of 0.1 μM to 1 mM. For example, 4-hexylresorcinol may be included in a concentration of 0.5 μM to 500 μM, 1 μM to 100 μM. In the above concentration range of 4-hexylresorcinol, weight loss due to diabetes is suppressed and the effect of reducing blood glucose concentration can be maximized.

The route of administration of the pharmaceutical composition containing 4-hexylresorcinol as an active ingredient may be administered through any general route as long as the drug can reach the target tissue, and may be administered to the subject through oral or parenteral route. can For example, intraperitoneal administration, intravenous administration, intraarterial administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration (including dermal application, instillation and inhalation), transdermal administration, intrathecal and epidural It may be administration, intranasal administration, intraocular administration, intrapulmonary administration, rectal administration, vaginal administration, etc., but is not limited thereto. In addition, the pharmaceutical composition containing 4-hexylresorcinol as an active ingredient may be in any convenient pharmaceutical product form, such as tablets, powders, granules, capsules, oral solutions, solutions, dispersions, suspensions, syrups, It can be administered as a spray, suppository, gel, emulsion, patch or the like.

The pharmaceutical composition of the present invention may further include pharmaceutically or physiologically acceptable carriers, excipients and diluents. In the present invention, the term "pharmaceutically acceptable carrier, excipient and diluent" refers to a carrier, excipient and diluent that does not stimulate living organisms and does not inhibit the biological activity and properties of the administered compound. Examples of suitable carriers, excipients and diluents that may be included in such compositions include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, glycerol, ethanol, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol. , starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, amorphous cellulose, hypromellose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc , magnesium stearate, mineral oil, and the like. When the composition is medicated, it may further include a conventional dispersing agent, filler, extender, binder, disintegrant, surfactant, anti-agglomerating agent, lubricant, wetting agent, flavoring agent, emulsifier, preservative, freeze-drying agent, and the like. The exact proportions of these excipients can be determined by the solubility and chemical properties of the active compound, the route of administration chosen, or standard pharmaceutical practice.

The composition of the present invention may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and sterile injection solutions according to conventional methods, respectively.

In the present invention, the pharmaceutical composition may be administered orally. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain at least one or more excipients such as starch, calcium carbonate, sucrose in the lecithin-like emulsifier. It can be prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium styrate and talc may also be used. Liquid formulations for oral administration may include suspensions, internal solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, and preservatives in addition to water and liquid paraffin, which are commonly used simple diluents. can be included Formulations for parenteral administration include sterilized aqueous solutions, water-insoluble agents, suspensions, emulsions, and lyophilized preparations. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous preparations and suspensions.

In the present invention, the pharmaceutical composition may be administered in the form of an injection. Injections may be formulated as intravenous or subcutaneous injections. In the case of a parenteral injection, it may contain components included in general injection compositions. For example, the injectable composition includes a liquid carrier such as sterile water, water for injection, or physiological saline. In addition, amino acids, sugars, lipids, vitamins, electrolytes, pH adjusting agents, stabilizers, osmotic pressure adjusting agents or solubilizing agents may be further included.

Various formulations for injection, parenteral administration, etc. can be prepared according to techniques known in the art or commonly used techniques. In addition, an effective amount of 4-hexylresorcinol may be formulated into a solution immediately before administration in saline or a buffer solution in a form suitable for intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, and the like.

Although not limited thereto, the pharmaceutical composition of the present invention may be in the form of a formulation for topical administration. For topical administration, the compounds may be formulated as lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickening, wetting and stabilizing agents may be included in the formulation. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like.

In addition, the present invention relates to the use of 4-hexylresorcinol or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prevention or treatment of diseases caused by diabetes, and a therapeutically effective amount of 4-hexylresorcinol or a pharmaceutical composition thereof. Provided is a method for preventing or treating a disease caused by diabetes comprising administering an acceptable salt to a subject in need thereof.

As used herein, the term "prevention" refers to any activity that suppresses or delays an immune disease by administration of the pharmaceutical composition according to the present invention, and the term "treatment" refers to any activity by administration of the pharmaceutical composition according to the present invention. It means any action that improves or benefits the symptoms of an immune disease. In the present invention, "subject" means a subject in need of prevention or treatment of a disease, and more specifically, any mammal in need of prevention or treatment of an immune disease, such as humans and primates, as well as It includes, but is not limited to, livestock such as cattle, pigs, sheep, horses, dogs and cats, but may preferably be human.

In the treatment method, the description of 4-hexylresorcinol, diabetes or diabetic complications can be applied as described above.

As used herein, "effective amount" means an amount necessary to delay or completely stop the onset or progression of a specific disease to be treated, and the effective amount of 4-hexylresorcinol contained in the pharmaceutical composition of the present invention is In diabetes or diabetic complications, it means the amount required to achieve the effect of suppressing weight loss and reducing blood sugar.

The pharmaceutical composition of the present invention may be applied differently depending on the purpose of administration and disease. The amount of active ingredient actually administered depends on various related factors, namely the disease to be treated, the severity of the disease, co-administration with other drugs, drug activity, drug sensitivity, patient's age, sex, weight, food, and administration time. , route of administration, and administration ratio of the composition may be appropriately selected by those skilled in the art. The composition may be administered once a day or in 1-3 divided doses, although the dosage and route of administration may be adjusted according to the type and severity of the disease.

The pharmaceutical composition containing 4-hexylresorcinol as an active ingredient of the present invention may be administered at a dose of 0.01 mg/kg to 1 g/kg, more preferably 0.1 mg/kg to 100 mg/kg, It may be administered in dosages of 1 mg/kg to 100 mg/kg, 10 mg/kg to 100 mg/kg, or 10 mg/kg to 50 mg/kg. On the other hand, the dosage may be appropriately adjusted according to the age, sex and condition of the patient.

Advantages and features of the present invention, and how to achieve them, will become clear with reference to the detailed description of the following embodiments. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various different forms, and only the present embodiments will complete the disclosure of the present invention and allow common knowledge in the art to which the present invention belongs. It is provided to fully inform the holder of the scope of the invention, and the present invention is only defined by the scope of the claims.

[Example]

Experimental Example 1: Confirmation of 4-hexylresorcinol's ability to inhibit weight loss

The animal experiment was conducted with the approval of Gangneung-Wonju National University IACUC (GWNU-2021-22, date of approval: November 23, 2021). 4-week-old mice with an average weight of 220 g were purchased and type 1 diabetes was induced by intravenous injection of streptozotocin (STZ). In order to confirm successful diabetes induction, fasting blood glucose was examined 3 days after STZ injection, and diabetes was induced in all rats by additional injection of STZ when blood glucose did not exceed 300 mg/dL. Diabetic rats were randomly divided into two groups, and in the experimental group, 12.8 mg/kg of 4-hexylresorcinol was administered by subcutaneous injection to the skin tissue of the back twice a week, while the control group did not contain 4-hexylresorcinol. Only the non-injected solvent was injected in the same way. After two injections of STZ, weight loss began in the diabetic rats, and weight changes were observed. As a result, the weight loss of the 4-hexylresorcinol-administered group was significantly less than that of the control group (FIG. 1).

Experimental Example 2 Confirmation of Decrease in Blood Glucose Concentration by 4-Hexylresorcinol Treatment

Diabetes was induced in rats in the same manner as in Experimental Example 1. After fasting for more than 12 hours in rats, fasting blood glucose was measured. Thereafter, glucose tolerance test was performed by measuring blood glucose after 1 hour and 2 hours after injecting glucose. As a result, compared to the control group, the rats periodically administered with 4-hexylresorcinol showed a greater decrease in blood glucose concentration (FIG. 2). Specifically, fasting blood glucose was also lower than that of the control group, and in particular, the decrease in blood glucose 2 hours after the glucose load was statistically significant compared to the control group (*P<0.05).

In addition, in order to confirm whether blood glucose reduction by 4-hexylresorcinol appears in normal rats as well as in diabetic induced rats, 4-hexylresorcinol was administered to normal rats and fasting blood glucose levels were measured. As a result, compared to the control group, normal rats periodically administered with 4-hexylresorcinol showed a greater reduction in blood glucose (FIG. 3).

Experimental Example 3 Confirmation of reduction of diabetic glomerulonephritis and salivary adenitis according to 4-hexylresorcinol treatment

Diabetes was induced in rats in the same manner as in Experimental Example 1. In diabetic rats, 4-hexylresorcinol was periodically administered to the experimental group and only the solvent was administered without 4-hexylresorcinol to the control group. After about 10 weeks, they were all sacrificed and the kidneys and salivary glands were removed, and through the PAS staining method, there was no difference between the two groups in the organ accumulation of glucagon, which is commonly observed in diabetes. I checked if there is. In addition, the difference in expression of TNF-α, which is increased during inflammation, was also examined. As a result, a small amount of glucacon accumulation occurred in the kidneys and salivary glands of rats periodically administered with 4-hexylresorcinol compared to the control group (FIGS. 4 and 5).

In addition, the expression of TNF-α (tumor necrosis factor-α) is increased in the glomeruli during glomerulonephritis of the kidney, and the expression of TNF-α is almost observed in rats periodically administered with 4-hexylresorcinol did not (Fig. 6).

Experimental Example 4: Checking the blood sugar lowering effect of 4-hexylresorcinol ointment

4-hexylresorcinol was purchased from Sigma (St. Louis, MO, USA) and used. A weight of 4-hexylresorcinol corresponding to 2% of the weight of the required ointment was prepared. Lanolin oil was used as an ointment base, which was also purchased from Sigma. Silk sericin protein extracted from Bombyx mori corresponding to 0.2% of the weight was mixed for efficient component absorption through the oral mucosa. After dissolving the prepared 4-hexylresorcinol and silk sericin in 100% ethanol solution, they were mixed with lanolin oil liquefied in a water bath at 60 °C and mixed with a homogenizer for 10 minutes. After slowly cooling the mixed ointment to room temperature, it was stored in a refrigerator at 4°C until use.

Diabetes was induced in rats in the same manner as in Experimental Example 1. All rats were anesthetized with isoflurane gas inhalation, and traumatic ulceration of the left buccal mucosa was induced using a Ø4.0 mm healing abutment heated to 120 °C. An experiment was conducted by applying the prepared ointment to an ulcer formed in the oral cavity of a rat. The experiment was divided into three groups. Oramedi was administered as a positive control group (n=14), and as a negative control group, only the ointment base lanolin oil was applied (n=8), and as an experimental group, 2% wt 4-hexylresorcinol was used as the main ingredient ointment was applied to the mouth (n=14). Ointment was applied every other day for 2 weeks before euthanasia, and blood glucose was measured by obtaining blood from the tail vein 2 weeks later. Blood glucose data obtained from the three groups were analyzed using analysis of variance (ANOVA) and compared, and a post-hoc test, Bonferroni, was performed if a statistically significant difference was found (P < 0.05).

As a result, it was observed that the blood sugar level in the experimental group was lowered statistically significantly compared to the other groups (FIG. 7). Specifically, the blood glucose level measured in the Oramedi group was 498.0 ± 59.8 mg/dL, in the group administered only with lanolin, the blood glucose level was 500.5 ± 26.9 mg/dL, and in the group administered with ointment containing 4-hexylresorcinol. , the blood glucose level was 412.9 ± 70.4 mg/dL. There was a statistically significant difference between the three groups in the ANOVA test (P=0.001). In multiple comparisons, blood sugar levels in the group administered with ointment containing 4-hexylresorcinol were significantly lower than those in the Oramedy group or the group administered only with lanolin (P=0.002 for oramedy, P=0.006 for lanolin only) ).

Claims (7)

A pharmaceutical composition for preventing or treating diabetes or diabetic complications, comprising 4-hexylresorcinol or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 1, wherein the diabetes is type 1 diabetes, type 2 diabetes, gestational diabetes, or steroid diabetes. The method of claim 1, wherein the diabetic complication is selected from the group consisting of diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic ulcer, diabetic heart disease, diabetic osteoporosis and diabetic arteriosclerosis. That is, the pharmaceutical composition. The pharmaceutical composition according to claim 1, wherein the composition reduces blood glucose concentration The pharmaceutical composition according to claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 1, wherein the composition is administered at a dosage of 0.1 mg/kg to 100 mg/kg. The pharmaceutical composition according to claim 1, wherein the composition is administered orally or parenterally.

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