Pharmaceutical combination kit for controlling blood sugar

Abstract

The invention relates to a pharmaceutical composition kit for controlling blood sugar. The pharmaceutical composition kit comprises an oral insulin enteric capsule and a ketoester oral liquid or a ketoester capsule. The insulin enteric capsule is orally taken before sleep, so that fasting blood-glucose at night and in the morning can be well controlled. The ketoester oral liquid is taken before meals in daytime, so that a human body enters a ketogenic state, the blood sugar is reduced, and the postprandial blood sugar peak can be avoided. The combination of the two medicines can realize better control of human blood sugar. Furthermore, ketone ester can enhance insulin sensitivity and enhance the heart function of the diabetic patient. The kit is low in cost and good in sugar control effect, and is an ideal sugar control scheme for diabetics at present.

Description

Drug combination kit for controlling blood sugar Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a drug combination kit for controlling blood sugar and treating diabetes. Technical Background

[0002] Insulin is widely used for blood sugar control in diabetic patients. In particular, the recent development of recombinant human insulin and its mutants, as well as various insulin modifications, including long-acting, ultra-long-acting, and ultra-short-acting insulin, have become increasingly effective means of blood sugar control for diabetics. Currently, the majority of pharmaceutical insulins on the market are injectable, which carries numerous side effects. Among the top ten medications causing adverse events, insulin ranks first, at 8%. Insulin injections often cause the following major side effects: hypoglycemia, heart rate effects, weight gain, subcutaneous thickening at the injection site, and insulin allergic reactions. Long-term insulin injections are also associated with an increased incidence of rectal and colon cancers and hypertension in patients with type 2 diabetes.

[0003] Due to the inconvenience and side effects of injectable formulations, people have been hoping for oral formulations for 100 years. Numerous scientists and biopharmaceutical companies have been working tirelessly to develop oral formulations, but most have failed. In recent years, the oral formulation developed by Israel's Oramed was considered the most promising for commercialization, but it failed in Phase III clinical trials in January 2023. Tianhui Biopharmaceuticals, a domestic company, used similar technology and announced a successful Phase III clinical trial in April 2023. When the drug is applied for marketing, it will become the first commercially available oral insulin drug, bringing hope to mankind.

[0004] The success of Tianhui Bio's technical solution stems primarily from a different clinical approach from Oramed's. Tianhui Bio's clinical approach targets patients with a BMI of 18.5-30 who have not responded to one or two chemical hypoglycemic drugs. The patient dose is 16mg per pill, one to three tablets, taken daily before meals.

[0005] Oramed's clinical program is to take one 8mg tablet per day before bedtime. The selected patients are those who have not responded well to 2-3 chemical hypoglycemic drugs and whose BMI index is 25-40. Analysis shows that the domestic clinical program can be successful because the selected patients have relatively mild conditions. Under the same circumstances, low weight also means mild conditions. Considering that most type 2 diabetes is caused by obesity, the therapeutic effect of Tianhui Bio's oral dosage form on patients with severe conditions still needs further clinical verification. The problem is that the dosage of insulin is large and the cost is high. After commercialization, only people with higher incomes can use it. Intestinal cells have IGF receptors. Although the affinity with insulin is very weak, long-term use of large doses may cause adverse effects on intestinal cells, which needs further clinical verification.

[0006] Under normal physiological conditions, insulin is secreted from the pancreas, then enters the portal vein of the liver, passes through the liver, and finally circulates throughout the body. Even without food, the pancreas secretes basal insulin to maintain blood sugar stability. After a meal, blood sugar spikes occur. To lower postprandial blood sugar, the pancreas also produces a corresponding peak in insulin secretion. Because insulin passes through the liver, an insulin gradient exists between its secretion and distribution throughout the body, resulting in a very low amount of insulin reaching the periphery. Compared to injectable formulations, the drug enters the body, reaches high concentrations in the periphery, and then travels through the liver to exert its effects, leading to clinical side effects. Oral enteric-coated insulin capsules allow insulin to be absorbed through the intestines, enter the portal vein of the liver, and finally be distributed throughout the body. This somewhat mimics the insulin secretion process in the body, avoiding the side effects of insulin injections. Oramed's clinical approach uses regular recombinant insulin, which is cost-effective, scientifically administered at bedtime, and maintains fasting blood sugar levels, resulting in more consistent absorption. Clinical results have shown excellent control of nighttime and morning fasting blood sugar levels, but have struggled to control postprandial blood sugar spikes, leading to clinical failure. In China's Tianhui Biopharmaceuticals' clinical plan, the drug has good absorption consistency when taken on an empty stomach in the morning. Before lunch and dinner, due to certain differences in the types and quantities of food consumed each day, the consistency of absorption is more difficult to control. However, by using large doses, better postprandial blood sugar control can be achieved, so it passed the Phase III clinical trial.

[0007] The traditional ketogenic diet is a low-carb diet, typically consisting of no more than 5% carbohydrates, 20-30% protein, and 70-80% fat per meal. It was initially used to treat intractable epilepsy and, before the advent of insulin, was also used for advanced diabetes, extending life expectancy by 2-3 years. However, low-carb diets can cause many side effects and generally require short-term adherence under the guidance of a doctor or nutritionist. Long-term adherence is difficult for most people. More recently, exogenous ketones have gained popularity, as they can induce ketosis without requiring dietary changes. An early exogenous ketone, sodium 3-hydroxybutyrate, suffers from poor ketosis, a short-lived effect, and excessive consumption can lead to electrolyte imbalances. MCT oil, another exogenous ketone with a longer-term effect, also has limited effectiveness, with diarrhea occurring in 50% of people.

[0008] Ketone esters are a new type of exogenous ketone. They were launched in the US as a dietary supplement in 2016 under the trade name KE4. Another brand, HVMN, was launched in the US in 2017. In 2020, they were launched in Europe as deltaG ketones. These ketone esters are available as oral solutions, with a strong ketogenic effect, reaching approximately 3mM, and a long-lasting effect of 4-6 hours. They are currently the world's most potent exogenous ketones and have numerous benefits, including anti-aging, anti-inflammatory, anti-cancer, neurodegeneration prevention, blood sugar reduction, and enhanced insulin sensitivity. Most importantly, ketone esters can prevent postprandial blood sugar spikes. The Buck Institute in the US is conducting anti-aging research, and clinical trials are also underway in the US for type I and II diabetes, as well as for cognitive enhancement in people over 50. Recently, the University of Oxford in the UK reported that 28 consecutive days of ketone ester consumption in type II diabetics who were using chemical medications to control blood sugar and not taking insulin resulted in a 13.4% decrease in fructosamine, representing blood sugar levels over the past month, and an 8.3% decrease in glycated hemoglobin, representing blood sugar levels over the past three months. This suggests that ketone ester consumption significantly improves blood sugar levels in diabetics, using a mechanism distinct from that of insulin.

[0009] Summary of the Invention

[0010] Based on the aforementioned progress in oral insulin development and a theoretical analysis of the strengths and weaknesses of both marketed and unsuccessful oral insulin formulations, the inventors have proposed a more advantageous drug combination, assembled into a kit. This kit includes oral insulin capsules and ketone ester oral liquid or ketone ester soft capsules, and is expected to better achieve blood sugar control in diabetic patients.

[0011] In one aspect, the present invention provides a drug combination kit for controlling blood sugar in diabetic patients, the kit comprising oral insulin capsules and ketone ester oral liquid or ketone ester soft capsules.

[0012] According to the present invention, the dosage of oral insulin capsules is 2-20 mg, preferably 4-16 mg, and more preferably 6-10 mg. The dosage of ketone ester oral liquid is 2-50 g, preferably 5-25 g, and more preferably 10-15 g. Alternatively, the dosage of ketone ester soft capsules is 0.5-5 g, and preferably 3-4 g. "Dose" herein refers to the dosage of the active ingredient. For example, the dosage of an oral insulin capsule is the dosage of insulin in the capsule. Similarly, the dosage of a ketone ester oral liquid or ketone ester soft capsule is the dosage of the ketone ester in the oral liquid or soft capsule. Unless otherwise specified, "dose" herein refers to the "unit dose." Generally, ketone esters are formulated as solutions of approximately 50% (w / v), or solutions with lower concentrations, such as 40%, 30%, 20%, or 10%. Gastric-soluble soft capsules are primarily made of gelatin, typically using sorbitol or mannitol as plasticizers and methylparaben or ethylparaben as preservatives, resulting in a soft, smooth texture. Ketone ester solutions have a less pleasant taste. To enhance patient compliance, the present invention uses gastric-soluble soft capsules to improve the taste. The dosage of each soft capsule (i.e., unit dose) is preferably around 3g, which is easier to swallow. For patients with swallowing difficulties, ketone ester oral solution can be used.

[0013] According to the present invention, insulin includes natural insulin extracted from animal tissues, recombinant human insulin or insulin derivatives, such as detemir insulin, glargine insulin, degludec insulin, OI338GT insulin, icodec insulin, etc. (although used as injections, it is also possible to prepare it into capsules).

[0014] According to the present invention, ketoester refers to (R)-3-hydroxybutyric acid-(R)-1,3-butanediol ester, and also includes its functional analogs or ketogenic substitutes, such as diester derivatives, dihexanoyl (R)-1,3-butanediol. Mixing ketoesters with other ketogenic substances can also achieve a better ketogenic effect, such as KE1, which is a mixture of ketoesters and sodium 3-hydroxybutyrate. The "ketoesters" of the present invention also include mixtures of ketoesters and other ketogenic substances (for example, pharmaceutically acceptable salts of 3-hydroxybutyric acid).

[0015] In another aspect, the present invention also provides a method for controlling blood sugar in a diabetic patient, comprising administering the kit of the present invention to a patient in need thereof.

[0016] According to the present invention, oral insulin enteric-coated capsules are taken before bedtime, and ketone ester oral solution or ketone ester soft capsules are taken before meals during the day (e.g., at least 0.5-1 hour, such as 1.0 hour, 2.0 hours, 3.0 hours, and up to 4.0 hours).

[0017] The specific steps of the sugar control method of the present invention are:

[0018] 1. Take one insulin capsule (8 mg or less) before bedtime;

[0019] 2. Eat a ketogenic meal for breakfast, or consume about 12.5g of ketone esters, and then eat normally half an hour later;

[0020] 3. Eat a balanced diet at lunch and consume 12.5g of ketone ester 0.5-1 hour before meals;

[0021] 4. Eat a balanced dinner and consume 12.5g of ketone ester 0.5-1 hour before the meal.

[0022] Ketone esters can help prevent post-meal blood sugar spikes. Combined with insulin capsules, they complement the shortcomings of Oramed's clinical glucose control program, achieving better glucose control. Ketone esters are used to achieve ketosis, and the amount consumed varies greatly from person to person. Each person's intake needs to be adjusted based on blood ketone levels.

[0023] Using this combination regimen to control blood sugar in diabetic patients has the following benefits:

[0024] 1. Compared with Tianhui Bio's successful oral insulin dosage form, it significantly reduces insulin usage and cost.

[0025] 2. It can avoid the adverse side effects that may be caused by the activation of IGF receptors in intestinal cells by the use of large amounts of insulin in Tianhui Biological's dosage form.

[0026] 3. Compared with Tianhui Bio's oral insulin which only provides insulin, edible ketone esters can enhance insulin sensitivity and improve diabetic conditions.

[0027] 4.60-70% of diabetics die from heart disease. Ketone esters are energy suppliers that are more advantageously used by the brain and heart. Taking them can enhance the heart function of diabetics and reduce their mortality rate.

[0028] 5. The combination drug of the kit can achieve better effects (eg, synergistic effects) than oral administration of insulin capsules or edible ketone esters alone. DETAILED DESCRIPTION

[0029] Considering that the majority of diabetic patients currently have type 2 diabetes, and that the majority of type 2 diabetes is caused by obesity, patients treated with insulin typically experience pancreatic damage, leading to insufficient insulin secretion or severe insulin resistance in their cells. To test the efficacy of the drug combination, the inventors used an animal model of type 2 diabetes caused by obesity-induced insulin resistance and pancreatic damage.

[0030] 1. Establishment of Animal Model

[0031] Aging (Albany NY). 2021 Mar 15; 13(5): 7691–7706 Studies have shown that diabetes is associated with aging. The results of diabetic model experiments using animals of different ages vary greatly. Using older animals for experiments is more in line with the actual situation. The inventors selected 12-month-old male SPD rats (weighing 540 to 560 grams) for the experiment. They were fed a high-sugar and high-fat diet (10% lard, 2.5% cholesterol, 1.0% porcine bile salt, 20% sucrose and 66.5% conventional feed). After one month, insulin resistance was induced. STZ was then injected intravenously to cause certain damage to pancreatic beta cells. The rats were fed a high-sugar and high-fat diet for another 12 weeks. Finally, animals with fasting blood glucose greater than 10 mmol / L were selected. Fasting blood glucose was measured every 3 days for 3 consecutive measurements. Rats with stable fasting blood glucose greater than 10 mmol / L were selected. Each group consisted of five animals, and a standard diet (18.0% fat, 24.0% protein, 58.0% glycogen) was maintained during the drug intervention period. Considering the lifespan of glycated hemoglobin (HbA1c) is three months, to ensure the accuracy of HbA1c measurements after drug intervention, the duration of drug intervention was set at three months. The diabetic animal model established in this manner resembles the condition of most type II diabetic patients currently treated with insulin. Data from the experimental animals were analyzed for significance using a one-way ANOVA test, with a P value less than 0.05. ** indicates a significant difference, and no * indicates no significant difference.

[0032] 2. Preparation of Oral Insulin Capsules and Ketone Ester Oral Solution

[0033] Oral insulin capsules were prepared using the method and proportions of Oramed's patent US10058593B2. The proportions were 8 mg of conventional recombinant islets, 150 mg of EDTA, 150,000 units of aprotinin, and 150 mg of trypsin. The mixture was shaken and mixed with unsaturated fish oil. The capsules were then filled in extra-long No. 9 enteric-coated capsules, each containing 5 units of insulin, equivalent to 0.125 mg of insulin (40 units / mg of insulin). The blank capsules in the control group contained the same ingredients and proportions, except that the insulin was replaced with an equal amount of bovine serum albumin. The ketone ester was diluted to a 50% concentration with flavored water, while the control group used flavored water. Gastric gavage was used.

[0034] 3. Determination of oral insulin dosage

[0035] Referring to the literature published in Biomaterials, 2010, pp. 6849-6858, each animal was administered oral insulin at doses of 5, 10, and 15 units. No food was provided after 5 PM, and oral insulin capsules were administered once daily at 10 PM. After three months of administration, blood was drawn from the tail for fasting blood glucose and glycated hemoglobin measurements, and the averaged results were used. The results (see Table 1 and Figure 1) showed that the effect of 5 units was significantly different from that of 10 and 15 units, but the difference between 10 and 15 units was negligible. Therefore, 10 units of oral insulin was used in the following experiments.

[0036] Table 1. Effects of different amounts of oral insulin on blood glucose and glycosylated hemoglobin

[0037] 4. 50% Ketone Ester Feeding Test

[0038] The animals were fed a 50% ketone ester solution three times a day: at 8:00 AM, 12:00 PM, and 5:00 PM. The total daily dosage was determined based on BMC Anesthesiol. 2023;23:p43, with either 3 or 5 g / kg / day. Results (see Table 2 and Figure 2) showed no significant difference between the two dosages. The following experiments used 3 g / kg / day of the 50% ketone ester solution.

[0039] Table 2. Effects of consuming different amounts of ketone esters on blood glucose and glycosylated hemoglobin

[0040] 5. Oral insulin capsule and ketone ester combination drug trial

[0041] Methods 3 and 4 above were combined to test the efficacy of an oral insulin plus ketone ester combination, using canagliflozin, currently used clinically, as a control. The results (see Table 3 and Figure 3) showed no significant difference between the combination and canagliflozin.

[0042] Table 3. Effects of feeding combination drugs and the hypoglycemic drug canagliflozin on fasting blood glucose and glycosylated hemoglobin

[0043] *The fasting blood glucose and glycosylated hemoglobin values ​​of normal rats were 5.65+ / -0.63mmol / L and 3.83+ / -0.49%, respectively.

[0044] 6. Synergistic effects of oral insulin capsules and ketone esters

[0045] Oral insulin utilization is generally 10-15%, and insulin accounts for the majority of the cost of combination medications. The inventors further explored whether combining oral insulin with ketone esters could further reduce the dosage of oral insulin. The experimental results (see Table 4 and Figure 4) showed that even when the dosage of oral insulin in the combination medication was reduced by half, there was no significant difference in efficacy. The inventors believe that ketone esters enhance cellular sensitivity to insulin, indicating a synergistic effect between oral insulin and ketone esters.

[0046] Table 4. Effects of Combination Drugs on Fasting Blood Glucose and HbA1c After Feeding Reduced Doses of Oral Insulin Capsules

[0047] The above implementation steps describe the present invention in detail. However, it should be noted that the above implementation steps are merely illustrative of the method disclosed herein. Without departing from the spirit and substance of the present invention, those skilled in the art may devise various alternatives and improvements to the present invention, all of which are to be understood as falling within the scope of protection of the present invention.

Claims

1. A drug combination kit for controlling blood sugar in diabetic patients, the kit comprising oral insulin capsules and ketone ester oral liquid or ketone ester soft capsules.

2. The kit of claim 1, wherein the dosage of the oral insulin capsule is 2-20 mg, preferably 4-16 mg, more preferably 6-10 mg, and the dosage of the ketone ester oral solution is 2-50 g, preferably 5-25 g, more preferably 10-15 g, or the dosage of the ketone ester soft capsule is 0.5-5 g, preferably 3-4 g.

3. The kit of claim 1 or 2, wherein the insulin comprises natural insulin, recombinant insulin or an insulin derivative (e.g., insulin detemir, insulin glargine, insulin degludec, OI338GT insulin and insulin icodec).

4. The kit of claim 1 or 2, wherein the ketoester comprises (R)-3-hydroxybutyric acid-(R)-1,3-butanediol ester, its functional analogs or ketogenic substitutes (e.g., dihexanoyl (R)-1,3-butanediol), and a mixture of ketoesters and other ketogenic substances (e.g., a mixture of ketoesters and pharmaceutically acceptable salts of 3-hydroxybutyric acid).

5. A method for controlling blood sugar in a diabetic patient, comprising administering the kit according to any one of claims 1 to 4 to a patient in need thereof.

6. The method of claim 5, wherein the oral insulin enteric-coated capsules are taken before bedtime, and the ketone ester oral solution or ketone ester soft capsules are taken before meals during the day (e.g., at least 0.5-1.0 hours).

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