阅读说明：本技术 一种控制血糖波动的药物组合物 (Pharmaceutical composition for controlling blood sugar fluctuation ) 是由 谢和兵 吕伟红 顾书华 于 2020-04-02 设计创作，主要内容包括：本发明公开了一种控制血糖波动的药物组合物,该组合物由左卡尼汀、左卡尼汀衍生物、左卡尼汀或其衍生物的可药用盐以及及代谢调节药物、胰岛素及其类似物、磺酰脲类促泌剂、二甲双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮类衍生物促敏剂、苯茴酸类衍生物促泌剂、胰高血糖素样肽-1(GLP-1)受体激动剂、二肽基肽酶4(DPP-4)抑制剂、胰淀粉样多肽类似物中的一种或几种组成,具有控制血糖波动的作用。(The invention discloses a pharmaceutical composition for controlling blood sugar fluctuation, which consists of one or more of levocarnitine, levocarnitine derivatives, pharmaceutically acceptable salts of levocarnitine or derivatives thereof, metabolism regulating drugs, insulin and analogues thereof, sulfonylurea secretagogues, metformin, alpha-glucosidase inhibitors, thiazolidinedione derivative sensitizers, anthranilic acid derivative secretagogues, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and amylin analogues, and has the function of controlling blood sugar fluctuation.)

1. A medicament for controlling blood sugar, which is characterized by comprising one or more of levocarnitine, levocarnitine derivatives, levocarnitine or pharmaceutically acceptable salts of the derivatives of the levocarnitine.

2. The glycemic control drug of claim 1, wherein the levocarnitine derivative comprises formyl levocarnitine, acetyl levocarnitine, propionyl levocarnitine, butyryl levocarnitine; the pharmaceutically acceptable salts of the levocarnitine comprise hydrochloride, hydrobromide, iodohydrorate, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, pantothenate, methanesulfonate and p-toluenesulfonate.

3. A pharmaceutical composition for controlling blood glucose, comprising the blood glucose controlling drug according to any one of claims 1-2, and one or more of metabolic regulation drugs, insulin and its analogs, sulfonylurea secretagogues, metformin, α -glucosidase inhibitors, thiazolidinedione derivative sensitizers, anthranilic acid derivative secretagogues, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and amylin analogs.

4. The glycemic control pharmaceutical composition of claim 3, wherein the metabolic regulating drug comprises trimetazidine, trimetazidine dihydrochloride, vinpocetine, creatinine glucose, coenzyme A, an energy cocktail, sodium fructose diphosphate; the insulin analogues comprise insulin lispro, insulin aspart, insulin glargine and insulin detemir; the sulfonylurea secretagogue comprises glipizide, gliclazide and glimepiride; the metformin comprises metformin and phenformin; the alpha-glucosidase inhibitor comprises sugar-100, acarbose and voglibose; the thiazolidinedione derivative sensitivity promoter comprises rosiglitazone and pioglitazone; the anthranilic acid derivative secretagogue comprises repaglinide and nateglinide; the glucagon-like peptide-1 (GLP-1) receptor agonist includes exenatide, liraglutide; the dipeptidyl peptidase 4 (DPP-4) inhibitor comprises sitagliptin, saxagliptin, vildagliptin; the amylin peptide analog comprises pramlintide.

5. Use of the glycemic control drug of any one of claims 1-2 or the glycemic control pharmaceutical composition of any one of claims 3-4 in the manufacture of a medicament for controlling glycemic volatility.

6. The use according to claim 5, wherein said blood glucose excursions include blood glucose excursions due to defective insulin secretion or action; stress blood glucose fluctuations caused by surgery, trauma, severe illness, etc.; blood glucose excursions caused by injection of insulin or insulin analogs or oral hypoglycemic agents; blood glucose excursions of diabetic ketoacidosis; blood glucose excursions of the hypertonic hyperglycemic syndrome; hunger, exercise, alcohol, stress induced blood glucose fluctuations.

7. Use according to claim 5 or 6, wherein the pharmaceutical composition is administered orally, by injection or topically.

8. The oral administration forms comprise tablets, granules, capsules, oral solutions, syrups, inhalants and sprays; the injection administration forms comprise freeze-dried powder injection, suspension for injection, emulsion for injection and solution injection; the topical administration forms comprise aerosol, ointment, lotion, suppository, patch, liniment, eye drop, and vaginal effervescent tablet.

Technical Field

The invention relates to the field of medicines, in particular to a pharmaceutical composition for controlling blood sugar fluctuation and application thereof in preparing medicines for preventing and treating blood sugar fluctuation.

Background

It is known that diabetes is a group of metabolic diseases characterized by chronic hyperglycemia caused by various causes, and long-term carbohydrate, fat and protein metabolic disorders can cause multi-system damage, resulting in chronic progressive lesions, hypofunction and failure of tissues and organs such as eyes, kidneys, nerves, hearts, blood vessels and the like; severe conditions or stress are those in which acute severe metabolic disorders may occur, such as diabetic ketoacidosis, hyperosmolar hyperglycemia syndrome.

Hypoglycemic agents, especially insulin preparations and sulfonylurea and non-sulfonylurea insulinotropic agents, often cause excessive reduction of blood glucose, causing hypoglycemia and large blood glucose fluctuations. Hypoglycemia is a group of syndromes caused by various causes and mainly characterized by low blood sugar concentration, sympathetic nerve excitation and brain cell sugar deficiency, and comprises drug hypoglycemia, hunger hypoglycemia, motor hypoglycemia, alcohol hypoglycemia, reactive hypoglycemia and the like. Repeated severe hypoglycemic episodes and long duration can cause irreversible brain damage. For mild to moderate hypoglycemia, oral administration of sugar water or food, etc. can alleviate it, but for reactive hypoglycemia often the symptoms are not relieved by food, but by increasing the food rich in fat and protein.

The risk of large blood glucose excursions is greater than that of simple hyperglycemia. Scientific research proves that the cell tissues of the human body have certain adaptability under the relatively stable hyperglycemia environment. However, when the fluctuation of blood sugar level is large, the adaptability of cell tissue is worse, which can cause damage and death of vascular endothelial cells, and promote the early occurrence of vascular complications. Clinical researches also find that repeated fluctuation of blood sugar easily causes frequent hypoglycemia in the treatment process, so that the excitability of sympathetic nerves is abnormally increased, and the incidence rate and the death rate of cardiovascular and cerebrovascular diseases are increased. Generally, the greater the blood glucose excursions, the higher the incidence of chronic complications.

At present, the method for controlling blood sugar fluctuation mainly comprises combined, continuous and reasonable medication, strengthens the control of diet by moving, controlling and adjusting the emotion and the life rule of the user, and does not have the medicine for specifically and purposely controlling the blood sugar fluctuation to be sold on the market.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims at providing a blood sugar control drug, aims at providing a blood sugar control drug composition containing the blood sugar control drug, and aims at providing an application of the blood sugar control drug or the blood sugar control drug composition in preparing a blood sugar fluctuation control drug.

Technical scheme of the invention

The blood sugar controlling medicine comprises one or more of levocarnitine, levocarnitine derivatives, levocarnitine and pharmaceutically acceptable salts of the derivatives of the levocarnitine, wherein the levocarnitine derivatives comprise formyl levocarnitine, acetyl levocarnitine, propionyl levocarnitine and butyryl levocarnitine; the pharmaceutically acceptable salts of the levocarnitine comprise hydrochloride, hydrobromide, iodohydrorate, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, pantothenate, methanesulfonate and p-toluenesulfonate.

Levocarnitine is an essential natural substance in the body of mammals in energy metabolism, and its main function is to promote lipid metabolism. It can bring long-chain fatty acid into mitochondrial matrix, promote its oxidative decomposition, provide energy for cell, and output short-chain fatty acid produced in mitochondria. The supplement of L-carnitine can relieve fat metabolism disorder and dysfunction of tissues such as skeletal muscle and cardiac muscle caused by carnitine deficiency in vivo. The composition is clinically used for preventing and treating the levocarnitine deficiency, is suitable for a series of complicating symptoms caused by secondary carnitine deficiency, and has clinical manifestations such as cardiomyopathy, skeletal myopathy, arrhythmia, hyperlipidemia, hypotension, muscle spasm in dialysis and the like. In addition, the levocarnitine has an obvious protective effect on ischemia and hypoxia injuries of important tissues such as brain, heart, liver, kidney and the like of a human body, has wide application in the field of treatment of cardiovascular and cerebrovascular diseases, has few adverse reactions and high safety, and has a large number of clinical application reports of treating chronic renal failure, myocarditis, heart failure, angina pectoris, myocardial infarction, fatigue resistance, exercise endurance improvement, oxidation resistance, cancer resistance and the like.

The pharmaceutical composition for controlling blood sugar comprises one or more of the blood sugar controlling drugs, metabolism regulating drugs, insulin and analogues thereof, sulfonylurea secretagogues, metformin, alpha-glucosidase inhibitors, thiazolidinedione derivative sensitizers, anthranilic acid derivative secretagogues, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and amylin analogues.

The metabolism regulating medicine comprises trimetazidine, trimetazidine hydrochloride, vinpocetine, creatinine glucose, coenzyme A, an energy mixture and fructose diphosphate sodium; the insulin analogues comprise insulin lispro, insulin aspart, insulin glargine and insulin detemir; the sulfonylurea secretagogue comprises glipizide, gliclazide and glimepiride; the metformin comprises metformin and phenformin; the alpha-glucosidase inhibitor comprises sugar-100, acarbose and voglibose; the thiazolidinedione derivative sensitivity promoter comprises rosiglitazone and pioglitazone; the anthranilic acid derivative secretagogue comprises repaglinide and nateglinide; the glucagon-like peptide-1 (GLP-1) receptor agonist includes exenatide, liraglutide; the dipeptidyl peptidase 4 (DPP-4) inhibitor comprises sitagliptin, saxagliptin, vildagliptin; the amylin peptide analog comprises pramlintide.

The application of the blood sugar controlling medicine or the blood sugar controlling medicine composition in preparing the medicine for controlling blood sugar fluctuation.

The blood glucose fluctuations include blood glucose fluctuations due to defective insulin secretion or action; stress blood glucose fluctuations caused by surgery, trauma, severe illness, etc.; blood glucose excursions caused by injection of insulin or insulin analogs or oral hypoglycemic agents; blood glucose excursions of diabetic ketoacidosis; blood glucose excursions of the hypertonic hyperglycemic syndrome; hunger, exercise, alcohol, stress induced blood glucose fluctuations.

The pharmaceutical composition is administered in an oral administration form, an injection administration form or a topical administration form. The oral administration forms comprise tablets, granules, capsules, oral solutions, syrups, inhalants and sprays; the injection administration forms comprise freeze-dried powder injection, suspension for injection, emulsion for injection and solution injection; the topical administration forms comprise aerosol, ointment, lotion, suppository, patch, liniment, eye drop, and vaginal effervescent tablet.

The dosage of each drug component in the drug composition refers to the dosage recorded in the drug use instruction of the single preparation products on the market, and the preferable weight ratio range or specific ratio of each drug component can be screened out through limited scientific experiments.

The specific implementation mode is as follows:

the following examples are intended only to illustrate the invention in order to facilitate the understanding of the invention by a person skilled in the art, but are not intended to limit the invention in any way.

Example 1: influence on stress rise of blood sugar caused by high altitude anoxia

Male SD rats 72, randomly divided into: plain control group, plateau control group, levocarnitine 200mg/kg, 400mg/kg, 600mg/kg groups, levocarnitine 600mg + trimetazidine 3mg/kg, each group consisting of 12. Feeding rats of plain control group in normal plain environment, and placing rats in low-pressure and low-oxygen animal experiment cabin for 1 hr after the last administration of plain environment of other groups^-1Reducing the pressure, increasing the pressure to a simulated altitude of 6000m, intracabin intragastric gavage administration for 2d, reducing the simulated altitude to 5000m during administration, keeping water and fasting for the last 12h in the cabin, keeping the simulated altitude of 5000m 2h after the last administration, carrying out anesthesia according to 1.5g/kg intraperitoneal injection of 10% urethane, fixing the supine position, and unhairing for later use. Arterial blood was taken and blood glucose, serum urea nitrogen and myocardial damage index were measured.

The results show that: when rats simulate the altitude of 6000m and lack oxygen for 48 hours, the blood sugar is obviously increased. The blood sugar of the administration group is obviously reduced, has obvious difference compared with the model group, has no obvious difference with the normal group, and is close to the normal value in numerical view.

In addition, BUN, CK-MB and LDH all have a reduction trend, which indicates that the levocarnitine has the effect of protecting liver and kidney and myocardial hypoxia injury.

(influence on biochemical indexes after 48 hours of hypoxia exposure of rats with simulated altitude 6000m±s)

*P<0.05，**P<0.01 vsPlateau control group

Example 2: effect on exercise-induced hypoglycemia

40 Kunming mice are randomly divided into blank control group, levocarnitine 300mg/kg group, levocarnitine 600mg/kg group and Kunming mouse 900mg/kg group. The administration is carried out by intragastric administration of 10ml/kg 2 times a day for 7 days. Starting on day 6 to day 7, fasting was 12 hours. After 30 min, the mice swim for 30 min with 3% of load, and blood is taken after 5min of rest, and the blood sugar and the blood lactic acid content are measured.

The results show that: blood sugar of mice is obviously reduced after fasting exercise, compared with a blank control group, the blood sugar of a levocarnitine dried group is obviously increased, and the blood lactic acid content is obviously reduced.

Group of	Blood sugar (mmol/L)	Blood lactic acid (mmol/L)
			Blank control group	3.12±0.54	2.32±0.49
Levocarnitine low dose group	5.72±0.43**	2.28±0.69
			Levocarnitine medium dose group	6.01±0.55**	1.72±0.82*
High dose group of levocarnitine	6.53±0.72**	1.62±0.23*

P < 0.05, P < 0.01, compared to the blank control group

Example 3: effect on blood glucose excursions in high-glucose model rats

30 SD rats are randomly divided into a normal group, a model group and a levocarnitine group, and each group comprises 10 rats. Preparing an animal high-sugar model: after feeding the rats with the high-fat and high-sugar feed for 6 weeks, the rats are fasted for 12 hours and injected with STZ intraperitoneally at a dose of 30 mg/kg. The random blood sugar is more than 16.7 mmol/L and is stable for 1 week. The levocarnitine group was administered by gavage at 400mg/kg, and the normal group and the model group were administered with the same volume of physiological saline 1 time a day for 4 consecutive weeks.

Observation indexes are as follows:

1. abdominal glucose tolerance (IPGTT), area under the curve (AUCg)

Carrying out IPGTT experiment according to IPGTT operation method established by American society for animal models with diabetes complications (AMDCC). The method comprises the steps of strictly fasting rats for 12 hours before measurement and giving sufficient drinking water, weighing the body mass of the rats by using balance before the measurement, taking blood from tail tips, measuring fast fasting blood glucose, starting timing after intraperitoneal injection by using 25% glucose solution according to the dose of 2.5 g/kg, measuring the blood glucose level by using glucose oxidase at 0 min, 30 min, 60 min and 120 min, drawing an experimental blood glucose graph of IPGTT according to the blood glucose, and calculating GAUC. GAUC = (G0 + G120)/2 + G30 + G60.

2. Fluctuating blood glucose levels

During the experiment, the body mass is measured at a fixed time of 1 d every week, and the tail breakage is detected for 4 times of rapid random blood sugar. The blood glucose level Standard Deviation (SDBG), Mean Amplitude of Glucose Excursion (MAGE), maximum amplitude of glucose excursion (LAGE), M-value were calculated.

SDBG=(BG is the blood glucose level, N is the number of blood glucose measurements, μ is the daily average blood glucose). Represents the standard deviation of the mean blood glucose within 1 day. The dispersion of the blood glucose fluctuation can be prompted.

LAGE = maximum blood glucose level-minimum blood glucose level within a day. Represents the maximum fluctuation amplitude of the blood sugar of the rat in 1 day.

MAGE = Σ (λ/x) (λ is the difference between the maximum and minimum values of each blood glucose fluctuation, x is the number of effective fluctuations). Showing fluctuating blood glucose levels.

M value = Σ | 10 × LOG10 (BG/5) |³(BG is blood glucose level, N is number of blood glucose measurements). The dispersion of daily blood glucose excursions in the rat is shown.

The results show that: compared with the model group, the levocarnitine can obviously reduce IPGTT of the rat with high glucose, AUGg level and blood glucose fluctuation.

1. Comparison of IPGTT (mmol/L) results for various groups of rats

Group of	0min	15min	30min	60min	120min
						Normal group	4.86±0.33	10.78±1.52	12.20±3.15	9.46±1.15	8.16±0.43
Model set	8.28±1.01	22.28±2.15	29.81±1.21	32.16±3.23	30.53±1.42
						Levocarnitine group	8.16±0.54	16.52±1.15*	24.42±2.76*	23.15±1.23*	15.46±2.17*

P < 0.05 in comparison with model group

2. Groups of rats GAUG comparison (mmol/L-min)

Group of	GAUG（mmol/L·min）
		Normal group	34.86±3.36
Model set	98.21±11.52
		Levocarnitine group	65.16±10.54*

P < 0.05 in comparison with model group

3. Blood glucose fluctuation index of rats in each group

Example 4: influence of levocarnitine and insulin on blood glucose fluctuation after blood glucose reaches standard

20 type 2 diabetic patients were collected and randomized into observation and control groups, 10 in each group. All patients received health education and lifestyle intervention after admission, and the standard nutritional meals were unified. The observation group was treated with 1g/d of L-carnitine in combination with insulin pump, and the control group was treated with insulin pump only. And adjusting the insulin dosage in time according to the blood sugar condition until the blood sugar reaches the standard. After the blood sugar reaches the standard, the blood sugar content in 24 hours is monitored by adopting a dynamic blood sugar monitoring (CGMS) instrument.

The results show that: compared with the single insulin, the combination of the levocarnitine and the insulin can effectively reduce the blood sugar fluctuation.

Two groups of blood sugar fluctuation indexes are compared

Index (I)	Control group	Observation group
			MBG（mmol/L）	8.12±1.05	6.50±0.74
MAGE（mmol/L）	5.24±1.64	3.45±0.88
			SDBG（mmol/L）	2.61±0.50	1.67±1.16
LAGE（mmol/L）	8.72±1.25	6.37±1.31
			MODD（mmol/L）	1.76±0.43	1.01±0.41
GAUC	6.65±0.83	5.46±0.78

Example 5: acetyl levocarnitine injection

Prescription: acetyl L-carnitine 1000g

0.5g disodium edetate

Appropriate amount of hydrochloric acid

Adding water for injection to 1000ml

The process comprises the following steps: adding 80% of injection water according to the prescription amount into a preparation container, adding acetyl levocarnitine for dissolving, adding prepared edetate disodium and hydrochloric acid solution, stirring uniformly, adjusting the pH value of the liquid medicine to be 6.0-6.2, adding the injection water to the full amount, adding 0.1% of activated carbon for decoloring, filtering by using a sintered glass filter and a membrane filter, filling and sealing under nitrogen gas flow, and finally sterilizing by circulating steam at 100 ℃ for 15 min.

Example 6: compound (levocarnitine and metformin) tablet

Prescription: 1000g of L-carnitine

1250g of metformin hydrochloride

Lactose 2000g

Microcrystalline cellulose 600g

80g of hypromellose

Dried starch 20g

Proper amount of magnesium stearate

Making into 5000 pieces

The process comprises the following steps: sieving levocarnitine and metformin hydrochloride with a 80-mesh sieve, mixing with microcrystalline cellulose and lactose, adding hypromellose to prepare a soft material, granulating with a 14-mesh sieve, drying at 70-80 ℃, grading with a 12-mesh sieve, adding dried starch and magnesium stearate, mixing uniformly, and tabletting to obtain the finished product.

Example 7: compound tablet (levocarnitine and trimetazidine dihydrochloride)

Prescription: 1000g of L-carnitine

Trimetazidine hydrochloride 5g

Lactose 200g

Starch 100g

10% starch slurry 100g

Crosslinked Povidone 20g

Magnesium stearate 15g

Making into 2000 pieces

The process comprises the following steps: sieving levocarnitine and trimetazidine hydrochloride with a 80-mesh sieve, mixing with starch and lactose, adding starch slurry to prepare a soft material, granulating with a 14-mesh sieve, drying at 70-80 ℃, grading with a 12-mesh sieve, adding crospovidone and magnesium stearate, mixing uniformly, and tabletting to obtain the compound preparation.

Example 8: compound tablet (acetyl levocarnitine, vinpocetine and acarbose)

Prescription: acetyl L-carnitine 400g

Vinpocetine 5g

Acarbose 25g

Lactose 150g

Microcrystalline cellulose 50g

10% starch slurry 100g

50g of dry starch

Proper amount of magnesium stearate

Making into 1000 pieces

The process comprises the following steps: sieving levocarnitine, vinpocetine and acarbose with a 80-mesh sieve, mixing with microcrystalline cellulose and lactose, adding starch slurry to prepare a soft material, granulating with a 14-mesh sieve, drying at 70-80 ℃, grading with a 12-mesh sieve, adding dry starch and magnesium stearate, mixing, and tabletting.

Example 9: compound (levocarnitine, rosiglitazone and gliclazide) capsule

Prescription: l-carnitine 3000 g

10 g of rosiglitazone

Gliclazide 200g

Gelatin 800 g

Glycerol 80g

1000g of water

Proper amount of cod liver oil

The process comprises the following steps: dissolving levocarnitine, rosiglitazone and gliclazide in cod liver oil (solid fat is removed at about 0 deg.C), and suspending to obtain medicinal liquid; heating glycerol and water to 80 deg.C, adding gelatin, stirring for dissolving, keeping the temperature for 2 hr, removing floating foam, filtering, adding drop pill machine for dropping, collecting condensed capsule with liquid paraffin as cooling liquid, wiping off the adhered cooling liquid with gauze, blowing cold air at room temperature for 4 hr, drying at 30 deg.C for 2 hr, washing with petroleum ether twice (3 min each time), removing liquid paraffin on the outer layer of the capsule, washing with 95% ethanol for petroleum ether, drying at 30 deg.C for 2 hr, screening, testing quality, and packaging.