Composition containing L-carnitine or its derivatives and application thereof

Abstract

The invention relates to the use of L-carnitine or its derivatives in preparing a medicine for treating constipation. The L-carnitine derivatives are selected from acetyl-L-carnitine, propionyl-L-carnitine, and their pharmaceutically acceptable salts and pharmaceutically acceptable salts of L-carnitine. The medicine comprises an oral preparation and an injection.

Description

Technical Field

[0001] The invention relates to the field of drug application, and in particular to the application of a drug containing L-carnitine or its derivatives in the preparation of a drug for treating constipation. Background Art

[0002] Constipation refers to the state of having difficulty in defecation, including two situations: dry stool that is difficult to pass and wet stool that is also difficult to pass. Generally, constipation refers to having less than 2-3 bowel movements per week (food residues that cannot be passed within 48 hours).

[0003] Normal people's bowel habits vary greatly, which is related to individual differences, living habits, and especially eating habits. Generally speaking, normal people defecate 1-2 times a day, and some defecate once every 2-3 days (as long as there is no difficulty in defecation or other discomfort, it is normal), but most people (about more than 60%) defecate once a day.

[0004] Constipation is one of the common diseases of the digestive system. In the past, it was not taken seriously by people. In many medical books, it was only introduced as a symptom of internal organs. In terms of treatment, it was limited to "treating the head for a headache and the foot for a foot pain", so the effect was not good.

[0005] With the development of basic medical research and diagnosis and treatment technology, the medical concept and diagnosis and treatment level of constipation have made great breakthroughs. However, the treatment of constipation is still mainly based on drug therapy. Surgery and treatment with instruments are limited to patients who are critically ill or weak and cannot defecate on their own. The drugs are mainly laxatives, supplemented by prokinetic drugs. Laxatives are the following 4 types:

[0006] 1. Bulk laxatives: This type of laxative can increase the volume of stool to enhance the stimulation of intestinal receptors by stool. Commonly used laxatives include sodium carboxymethylcellulose, lactulose, sorbitol, mannitol, polyethylene glycol 4000 and saline laxatives (magnesium sulfate and sodium sulfate, etc.). Lactulose and polyethylene glycol 4000 are also called osmotic laxatives. After use, they can increase the local osmotic pressure of the intestinal cavity, reduce water absorption, and increase the volume of stool.

[0007] 2. Lubricating laxatives: These laxatives are not absorbed in the intestines, but they can hinder the absorption of water, so they often play a role in lubricating the intestinal wall and softening the stool (also known as stool softeners). Commonly used ones include liquid paraffin, glycerin and vegetable oils. Since long-term use of these laxatives can lead to the absorption of vitamins A, D, K and calcium and phosphorus, they are not suitable for long-term use.

[0008] 3. Stimulant laxatives: Also known as contact laxatives, this type of laxative has a strong cathartic effect because it irritates the intestinal mucosa and affects the absorption of water and electrolytes in the intestine. Plant-based laxatives such as rhubarb, senna leaves and aloe contain anthraquinone glycosides, which only play a cathartic role when anthraquinone glycosides are decomposed into anthraquinones by bacteria in the intestine. Long-term use of highly irritating laxatives can cause patients to become dependent on the drugs. In addition, long-term use can also lead to melanosis coli. Since salt laxatives such as magnesium sulfate have a strong irritating effect on the intestine, they can also be included in this category.

[0009] 4. Local irritant laxatives: After glycerin / sodium chloride (suppositories), glycerin suppositories, etc. are inserted into the anus, they can make the patient feel the urge to defecate and induce a defecation reflex. They are called anal local laxatives and are better for patients with chronic outlet obstruction constipation.

[0010] The above drugs are mainly cathartic agents and have certain side effects. Patients usually experience diarrhea after taking them, and become constipated again after stopping the medication. Patients with constipation usually become dependent on them, and long-term repeated use can cause great physical and mental harm.

[0011] The present invention aims to find a medicine for treating constipation which will not cause persistent diarrhea and will not produce dependence. Summary of the invention

[0012] The invention provides a medicine capable of effectively treating constipation. The medicine is prepared from an active ingredient, levocarnitine or its derivatives and a pharmaceutically acceptable carrier, and has the characteristics of safety, effectiveness and small side effects.

[0013] L-Carnitine (L-carnitine) is a component of food and widely exists in nature. The human body can also synthesize L-carnitine. There are about 20 grams of L-carnitine in an adult, which is mainly distributed in the myocardium and skeletal muscles. L-Carnitine and its derivatives are well-known compounds and have been used clinically to treat carnitine deficiency caused by various reasons. It is recognized as a safe food by the US FDA. In my country, L-Carnitine is also included in the national standards as food and medicine. L-Carnitine has been used clinically to treat carnitine deficiency caused by various reasons. It has been deeply studied and applied in the treatment of carnitine deficiency and ischemic heart disease in patients with renal dialysis. However, there are no reports on its use alone to treat constipation. After long-term research, our unit found that L-Carnitine has the effect of treating constipation and does not have the side effects of other drugs for treating constipation. It is expected to become a new drug for treating constipation, benefiting a large number of patients and having positive significance for society.

[0014] The first object of the present invention is to disclose a medicine for treating constipation; the second object of the present invention is to disclose a pharmaceutical preparation for treating constipation; the third object of the present invention is to disclose the application of L-carnitine and its derivatives in treating constipation.

[0015] The L-carnitine derivative in the medicine of the present invention is selected from acetyl-L-carnitine, propionyl-L-carnitine, and their pharmaceutically acceptable salts and pharmaceutically acceptable salts of L-carnitine. Preferred are L-carnitine, acetyl-L-carnitine and their pharmaceutically acceptable salts. Particularly preferred are L-carnitine and its pharmaceutically acceptable salts.

[0016] The L-carnitine derivative in the medicine of the present invention is selected from acetyl-L-carnitine, propionyl-L-carnitine, and their pharmaceutically acceptable salts and pharmaceutically acceptable salts of L-carnitine. Preferred are L-carnitine, acetyl-L-carnitine and their pharmaceutically acceptable salts. Particularly preferred are L-carnitine and its pharmaceutically acceptable salts.

[0017] The pharmaceutically acceptable salts described in the present invention include hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, acetates, maleates, fumarates, citrates, citrates, oxalates, succinates, tartrates, malates, mandelates, trifluoroacetates, pantothenates, methanesulfonates, and p-toluenesulfonates.

[0018] We prepared various constipation animal models in different ways, and then administered various doses of L-carnitine to observe the efficacy of L-carnitine in treating constipation (see the examples for details).

[0019] The test results show that L-carnitine has different degrees of efficacy on various constipation models, and within the appropriate dosage range it can treat constipation without causing diarrhea and without causing dependence.

[0020] In fact, using the pharmacological and biochemical knowledge we already know, constipation is secondary to the body's metabolic disorder, and is also a risk factor for important organs of the body, such as cardiovascular accidents. Therefore, when the body is in metabolic disorder, the level of circulating fatty acids in the body increases, coupled with the reduction of glucose transporters and the downregulation of insulin receptors, the energy metabolism of important organs such as the myocardium is disordered; in order to regulate the balance, the body consumes a large amount of endogenous carnitine. Therefore, exogenous supplementation of L-carnitine promotes fatty acid oxidation, regulates the acyl ratio in mitochondria, discharges excessive or irrational acyl groups in the body, and eliminates the metabolic toxicity caused by acyl accumulation in the body; promotes the oxidation of acetoacetate, plays a role in the elimination and utilization of ketone bodies; prevents the toxicity of excessive ammonia in animals, and can be used as a biological antioxidant to scavenge free radicals, maintain membrane stability, and improve the immunity and disease resistance and stress resistance of animals, etc., to achieve the effect of treating constipation. The drug of the present invention can be administered to mammals, including humans, alone or preferably mixed with a pharmaceutically acceptable carrier, excipient or diluent according to standard pharmaceutical specifications. Therefore, another aspect of the present invention provides a pharmaceutical preparation for treating constipation, which contains the above-mentioned L-carnitine or its derivatives or pharmaceutically acceptable salts thereof as an active ingredient and one or more pharmaceutically acceptable carriers.

[0021] The pharmaceutical preparation of the present invention can be administered orally or parenterally. Parenteral administration mainly includes intravenous injection, such as injection and lyophilized powder injection.

[0022] The pharmaceutical preparation of the present invention may be in a form suitable for oral use, such as tablets, sustained-release tablets, capsules, solutions, suspensions or syrups; preferably solutions, suspensions, syrups, tablets and capsules.

[0023] The preparations of the present invention for oral use can be prepared according to any known method for preparing oral pharmaceutical compositions in the art, and such compositions may contain one or more substances selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide pharmaceutically beautiful and palatable preparations.

[0024] Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets in admixture therewith. These excipients may be: inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.

[0025] Tablets may be uncoated or may be coated by techniques well known in the art to mask the unpleasant taste of the drug or to delay its disintegration and absorption in the gastrointestinal tract and thereby maintain a sustained action over a longer period of time. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose or time delay materials such as ethylcellulose, cellulose acetate butyrate may be used.

[0026] The oral preparation of the present invention can also be provided in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate and kaolin, or in the form of soft gelatin capsules, in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily medium such as peanut oil, liquid paraffin or olive oil.

[0027] The oral liquid of the present invention contains active substances and excipients or dispersants suitable for preparing aqueous suspensions mixed therewith. The excipients include: suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic. The dispersant can be a natural phospholipid such as lecithin, or a condensation product of an alkylene oxide and a fatty acid, such as polyoxyethylene stearate, or a condensation product of an alkylene oxide and a long-chain aliphatic alcohol such as heptadecaethyleneoxycetanol, or a condensation product of an alkylene oxide and a partial ester derived from fat and hexitol, such as polyoxyethylene sorbitol monooleate.

[0028] The aqueous suspensions of the invention may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, for example sucrose, saccharin or aspartame.

[0029] The syrup of the present invention can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain buffers, preservatives, flavoring agents and coloring agents and antioxidants. The pharmaceutical preparation of the present invention may be a sterile injection aqueous solution or a lyophilized powder injection in the form of an injection. The carrier or solvent that can be used includes water, Ringer's solution, isotonic sodium chloride solution, hydrochloric acid, hydrolyzed gelatin, mannitol, calcium gluconate, etc. The medicine described in the present invention is an oral preparation and an injection, wherein the oral dosage form includes a solution, a suspension, a syrup, a tablet and a capsule; the injection includes an injection solution and a lyophilized powder injection.

[0030] The preparation process of the injection solution in the medicine of the present invention comprises the following steps:

[0031] Dissolve, add water for injection solvent to prepare 20-70% (w / v) L-carnitine solution;

[0032] Adjust the pH by adding hydrochloric acid to adjust the concentrated solution to pH 5.5-6.5;

[0033] To decolorize and remove pyrogens, add 0.1%-0.4% of the volume of L-carnitine solution in activated carbon for injection, stir and decolorize in a water bath at 20℃-100℃ for 5-60 minutes;

[0034] Decarbonization and fine filtration, 4-stage filtration: (1) Filtration with gauze wrapped around a titanium rod for decarbonization; (2) Filtration with a 0.8 μm filter element and microporous filter; (3) Filtration with a 0.45 μm filter element and microporous filter; (4) Filtration with a 0.22 μm filter element and microporous filter to obtain a clear fine filtrate;

[0035] Dilution: Add water for injection to dilute the concentrated solution to 20% or 40% (w / v) L-carnitine solution;

[0036] Adjust the pH by adding hydrochloric acid to adjust the pH of the diluted solution to 5.5-6.5;

[0037] Filling: Fill the L-carnitine solution with nitrogen into 5mL, 10mL, 20mL colorless or colored ampoule bottles to form L-carnitine injection;

[0038] Sterilization: Sterilize the L-carnitine injection by moist heat at 121°C for 30 minutes.

[0039] Packaging: plastic core plus hard paper box packaging, 1 piece / box or 5 pieces / box or 10 pieces / box.

[0040] The present invention has found that the stability of the L-carnitine aqueous solution is only related to the pH of the solution. It is more stable when it is slightly acidic, and decomposition reaction will occur when it is slightly alkaline. Therefore, as long as the pH of the solution is kept slightly acidic during the preparation process and the product, the stability of the injection can be guaranteed, which can not only ensure the simplification of the prescription, but also meet the stability requirements, which is also the key point of the injection preparation process. The dissolution step in the injection preparation process adopts a concentrated or diluted preparation process. When the L-carnitine content in the product solution is high, such as preparing an injection with a L-carnitine content of 40%, a diluted preparation process is adopted. When the L-carnitine content in the product solution is low, such as preparing an injection with a L-carnitine content of 20% or even lower, a concentrated preparation process is adopted. Generally, a 50%-70% L-carnitine solution is prepared first, and then diluted to a specified low solubility after decolorization, so that the amount of activated carbon used and the decolorization and decarbonization time can be reduced. The concentration of the concentrated solution is generally controlled below 70%. The reason is that the higher the solubility of the solution, the greater the viscosity of the solution. When the solubility of the solution is high, reaching 70% or above, it is difficult to filter the solution. The pH of the solution in the injection preparation process is adjusted to ensure that the solution remains acidic during the entire preparation process. It is generally controlled at around 6.0. After dilution, since the pH of the injection water is neutral, the pH of the solution may rise, and the pH needs to be adjusted again by a pH adjuster. Hydrochloric acid is generally used, including 36% concentrated hydrochloric acid or lower concentration dilute hydrochloric acid. The pH adjuster generally needs to be decolorized and pyrogen-free.

[0041] When the pharmaceutical preparation of the present invention is administered to the human body, the daily dose is usually determined by the prescribing physician, and the dosage generally changes with the age, body weight, sex and reaction of individual patients and the severity of the patient's symptoms. Usually, the oral dosage for adults is 1-500 mg active ingredient / kg body weight every day, preferably 5-300 mg active ingredient / kg body weight every day, and particularly preferably 20-200 mg active ingredient / kg body weight every day. The injection dosage is 5-300 mg active ingredient / kg body weight every day, preferably 10-200 mg active ingredient / kg body weight every day, and particularly preferably 50-200 mg active ingredient / kg body weight every day. DETAILED DESCRIPTION

[0042] The following examples are only used to further explain the present invention, rather than to limit the scope of the present invention.

[0043] Example 1: A temporary functional constipation model in mice was established using compound diphenoxylate to study the laxative effect of L-carnitine on the constipation model mice.

[0044] Material

[0045] 1.1 Drugs: Test drug: L-carnitine. Modeling drug: Compound diphenoxylate.

[0046] Experimental animals: 75 healthy male ICR mice weighing 20±2g were selected.

[0047] Reagents

[0048] Preparation of ink: Accurately weigh 100 g of gum arabic, add 800 ml of water, boil until the solution becomes transparent, weigh 50 g of activated carbon (powdered) and add it to the above solution and boil it 3 times. After the solution cools, add water to make up to 1,000 ml, store in a refrigerator at 4°C, and shake well before use.

[0049] Preparation of compound diphenoxylate suspension: Before use, take 50 mg (20 tablets) of compound diphenoxylate tablets, grind them into powder in a mortar, add water to 100 ml, and prepare 10 mg / (kg·bw) compound diphenoxylate suspension for oral administration.

[0050] Preparation of L-carnitine aqueous solution: Preparation of L-carnitine solution: Weigh an appropriate amount of L-carnitine and dissolve it in distilled water to prepare 90 mg / ml, 45 mg / ml, and 27.5 mg / ml L-carnitine solutions for intragastric administration.

[0051] Experimental methods

[0052] 2.1 Animal grouping and administration: The experimental animals were randomly grouped according to body weight. A negative control, a model control and three experimental dose groups (450 mg / kg, 900 mg / kg and 1800 mg / kg) were set up, with 15 animals in each group. The drug was administered by gavage at 20 ml / kg body weight, and the negative control and model control groups were given an equal volume of normal saline for 10 consecutive days.

[0053] Model establishment: Mice were administered for 10 days. All mice were fasted but not watered for 16 h. Except for the blank control group, which was given the same volume of distilled water, all other groups were gavaged with compound diphenoxylate 10 mg / (kg·bw). 0.5 h after compound diphenoxylate was administered, each administration group was given ink containing the corresponding test drug (containing 5% activated carbon powder and 10% gum arabic), and the blank control group and model control group were gavaged with the same volume of ink. In the experiment, mice were housed in single cages and fed with normal water and food. The time of the first black stool, the number of stools and weight within 5 h were recorded for each mouse.

[0054] Statistical analysis of experimental data: The data of each group were expressed as mean ± standard deviation ( ± s The difference between the means of each group was expressed as t test.

[0055] Experimental Results

[0056] 3.1 Effect of L-carnitine on the first black stool in mice: A model control group was established after oral administration of 10 mg / (kg·bw) compound diphenoxylate. The time of first black stool was (258.3±31.3) min, which was significantly different from the time of first black stool in the negative control (180.8±41.9) min (P<0.01), indicating that the compound diphenoxylate constipation model in mice was established. Compared with the model control group, the first defecation time of the medium dose group 900 mg / kg and the high dose group of the L-carnitine administration group was 196.7±23.3 min and 188.5±30.9 min, respectively, which was significantly different from the model control group (258.3±31.3 min) (P<0.01). The defecation time was negatively correlated with the dose. The larger the dose of L-carnitine, the shorter the defecation time, indicating that L-carnitine can shorten the time of first black stool in constipation model mice.

[0057] Table 1 Effect of L-carnitine on the time of first black stool excretion in mice (x± s,n=15 )

[0058]

[0059] Note: Compared with the model group, *P<0.05; **P<0.01.

[0060] Effect of L-carnitine on the number of fecal particles in mice: Compared with the negative control group and the model control group, the number of fecal particles in mice was significantly different (P<0.01), indicating that the compound diphenoxylate-induced constipation model in mice was established. Compared with the model control group, the number of fecal particles in mice in the L-carnitine administration group was significantly different (P<0.05). The number of fecal particles in mice in the administration group was positively correlated with the dose. The higher the dose, the more fecal particles. Compared with the model control group, the high-dose group of L-carnitine (1800 mg / kg) showed that the high-dose group could significantly increase the number of fecal particles in constipation model mice (P<0.01).

[0061] Table 2 Effect of recurrent diphenoxylate on the number of fecal particles in mice (x± s,n=15 )

[0062]

[0063] Note: Compared with the model control group, *P<0.05; **P<0.01.

[0064] 3.3 Effect of L-carnitine on the quality of mouse defecation: There was a significant difference in the quality of mouse defecation between the negative control group and the model control group (P<0.05), indicating that the model of mouse constipation defecation quality was successfully established. There was a significant difference in the quality of mouse defecation between the L-carnitine administration group and the model control group (P<0.01), indicating that L-carnitine can increase the defecation quality of constipation model mice.

[0065] Table 3 Effects of L-carnitine on defecation quality of mice (x± s,n=15 )

[0066]

[0067] Note: Compared with the model group, **P<0.01.

[0068] Conclusion: L-carnitine can shorten the time of the first black stool in constipation model mice, increase the number of stool particles and the quality of stool in constipation model mice, especially in the case of medium and high doses. It can be seen that L-carnitine has a better effect in treating constipation, indicating that the effect of L-carnitine in treating constipation is positively correlated with dose.

[0069] Example 2: A dryness-induced constipation model was prepared by feeding rice and depriving water for 3 days to observe the effect of L-carnitine on the laxative function of dryness-induced dehydration-induced constipation.

[0070] Material

[0071] 1.1 Animals Kunming mice, half male and half female, weighing (20±2) g; Wistar rats, half male and half female, weighing (220±20) g. They were raised at room temperature (22±2)℃ and humidity 40%-60%RH and were acclimatized for 1 week before the experiment.

[0072] Drugs and Reagents L-Carnitine (for oral administration of mice): dilute with distilled water to 90mg / ml, 45mg / ml, 27.5mg / ml before use. L-Carnitine (for oral administration of rats): dilute with distilled water to 120mg / ml, 60mg / ml, 30mg / ml before use. All reagents used are analytical grade.

[0073] method

[0074] 2.1 Preparation of dryness and dehydration constipation model Feed rice and deprive water (including all moisture in vegetables) for 3 consecutive days. At this time, the animals appear shriveled, thin, lose weight, have yellow urine, and dry stool (small feces particles, beaded or round).

[0075] Effect of L-carnitine on defecation function of mice with dry-type constipation Fifty healthy mice were randomly divided into five groups. They were negative control group, model control group, low-dose L-carnitine (450 mg / kg) group, medium-dose (900 mg / kg) group, and high-dose (1800 mg / kg) group, with 10 mice in each group. The model group and L-carnitine group were used to prepare the mouse dry-type constipation model according to the method in 2.1. The negative control group and the model control group were given normal saline, and the other groups were given the corresponding drugs by gavage at 20 ml / kg body weight. The time of the first bowel movement after administration and the total number of feces within 5 hours were carefully recorded.

[0076] Effect of L-carnitine on colonic motility in rats with dry-type constipation Fifty rats were randomly divided into five groups, namely negative control group, model control group, low-dose L-carnitine (300 mg / kg) group, medium-dose (600 mg / kg) group, and high-dose (1200 mg / kg) group, with 10 rats in each group. The model group and L-carnitine group were used to prepare the rat dry-type constipation model according to the method in 2.1. The negative control group and the model control group were given normal saline, and the other groups were given corresponding drugs by gavage at 10 ml / kg body weight. Immediately after gavage, ether was lightly anesthetized, and the ileocecal region was found by opening the abdomen. All rats in each group were injected with 20 ml / kg of 50% ink saline solution from the ileocecal region. Double lines were used to make ligatures in the ileum segment near the ileocecal region, and the ileum was cut between the two lines, and the time was immediately counted. The intestinal tube was put back into the abdominal cavity and the incision was sutured. The rats were killed 2 hours later, and the abdomen was immediately opened to remove the colon from the anus to the cecum. The colon was placed on a glass plate moistened with water and straightened. The total length of the colon and the distance of ink advancement were measured with a ruler.

[0077] The statistical data were expressed as mean ± standard deviation (x ± s The difference between the means of each group was expressed as t test.

[0078] Experimental Results

[0079] 3.1 Effect of L-carnitine on defecation function in mice with dry-type constipation

[0080] The first defecation time of the model control group was 56.1±4.2 min, and the total number of feces within 5 hours was 3.2±1.9, which was significantly different from the first defecation time of the negative control group (27.8±46.6 min, and the total number of feces within 5 hours was 8.0±1.5) (P<0.01), indicating that the membrane was successfully formed; each drug-treated group was significantly different from the model group (P<0.01 or P<0.05), among which the effect of L-carnitine 900mg / kg and 1800mg / kg groups was the most obvious (P<0.01), indicating that L-carnitine can significantly shorten the first defecation time of mice with dry constipation and increase the total number of feces within 5 hours, and has a strong defecation-promoting effect. The results are shown in Table 4.

[0081] Table 4 Effects of L-carnitine on defecation function of mice with dryness-induced constipation (x± s , n =10)

[0082]

[0083] Note: Compared with the model group, *P<0.05; **P<0.01; ***P<0.001.

[0084] Effects of L-carnitine on large intestinal motility in rats with dry-type constipation

[0085] The propulsion rate of the model control group (19.2±5.2%) was significantly lower than that of the negative control group (22.4±5.0%) (P<0.05), indicating that the model was successfully established. Compared with the model control group, the medium-dose group (300 mg / kg) and high-dose group (600 mg / kg) of L-carnitine had significant differences in the peristalsis and propulsion rate of the rat large intestine (P<0.001 or P<0.01). It can be seen that L-carnitine can directly act on the smooth muscle of the large intestine and significantly enhance the propulsion of the large intestine. The results are shown in Table 5.

[0086] Table 5 Effects of L-carnitine on large intestinal motility in rats with dry constipation (x± s , n =10)

[0087]

[0088] Note: Compared with the model group, **P<0.01; ***P<0.001.

[0089] Conclusion: L-carnitine can enhance the propulsive function of the large intestine and improve the defecation function of dry constipation.

[0090] Example 3: Mr. Chao, male, 82 years old, constipated for 10 years, with an interval of 5-10 days between bowel movements, using enema for each bowel movement, and each bowel movement lasting more than 2 hours. The patient weighed 50 kg and took L-carnitine oral solution (each vial containing 1 g of L-carnitine) at a dosage of 60 mg active ingredient / kg body weight per day, 1 vial each time, three times a day. After taking the medicine for 2 days, he had a bowel movement with a stool quality close to normal. After taking the medicine for 6 days, he could have a normal bowel movement without using enema, with an interval of 1-2 days between bowel movements, and each bowel movement lasting about 15 minutes, with a normal stool quality.

[0091] Example 4: Mr. Xie, male, 53 years old, hyperlipidemia, constipation history for 2 years, he had hemorrhoid surgery, bowel movement interval of about one week, each defecation 1-2 hours, hard stool. The patient weighed 60 kg, and took L-carnitine sustained-release tablets (each tablet containing 0.5g of L-carnitine) at a dosage of 200mg active ingredient / kg body weight per day, 8 tablets each time, three times a day, defecation after 2 days of medication, continued to take the medicine for one week, defecation was normal, 1-2 times a day, and stopped taking the medicine for another week. Follow-up after 1 month showed that the patient had normal defecation and normal stool quality.

[0092] Example 5: Ms. Ding, female, 48 years old, diabetic constipation, 3 years of diabetes, combined with a history of constipation for 2 and a half years, bowel movement interval of about one week, abdominal distension, difficulty in defecation, dry stool; had taken a variety of laxatives, had problems with diarrhea and recurrence after drug withdrawal, and the patient is currently anxious, insomnia, and poor complexion. The patient weighs 50 kg, and is given L-carnitine injection (each containing 1g of L-carnitine) at a dosage of 20mg active ingredient / kg body weight per day, 1 bottle each time, once a day, defecation after 3 days of medication, dry stool improved, the patient's complexion returned to normal, and the mental state was better. After one week of continuous medication, the patient's constipation condition improved significantly, defecation 1-2 times a day, normal stool, the patient reported improved sleep, abdominal distension disappeared, and a happy mood.

[0093] Example 6: Ms. Li, female, 28 years old, constipated for half a year, bowel movement interval of about one week, difficult defecation, feeling of defecation but unable to defecate normally, small amount of defecation, feeling of incomplete defecation, abdominal pain and bloating. The patient weighed 50 kg, and took L-carnitine sustained-release granules (each bag containing 1g of L-carnitine) at a dosage of 120mg active ingredient / kg body weight per day, 2 bags each time, three times a day, defecation after 2 days of medication, continued to take the medicine for 1 week, defecation was normal, once a day, follow-up after 1 month of discontinuation of medication, the patient's defecation was normal.

[0094] Example 7: Preparation of L-carnitine injection

[0095] prescription:

[0096] L-Carnitine 20000g

[0097] Hydrochloric acid

[0098] Add water for injection to 100000mL

[0099] Preparation process:

[0100] 1) Dissolve: weigh L-carnitine and add water for injection to dissolve it to prepare a 20% (w / v) L-carnitine solution;

[0101] 2) Adjust the pH by adding hydrochloric acid to adjust the solution to pH 5.8;

[0102] 3) Decolorization and pyrogen removal: add 0.2% (w / v) activated carbon for needles, stir and decolorize in a 60°C water bath for 30 minutes;

[0103] 4) Decarbonization and fine filtration, using four-stage filtration, (1) decarbonization by filtering with gauze wrapped around a titanium rod; (2) filtering with a 0.8 μm filter element and microporous filter; (3) filtering with a 0.45 μm filter element and microporous filter; (4) filtering with a 0.22 μm filter element and microporous filter to obtain a clarified fine filtrate;

[0104] 5) Filling: fill the L-carnitine solution with nitrogen and fill it into a 5 mL colorless ampoule to form the L-carnitine injection;

[0105] 6) Sterilization: sterilize the L-carnitine injection by moist heat sterilization at 121°C for 30 minutes.

[0106] 7) Packaging: plastic core plus hard paper box packaging, 1 piece / box, 5 pieces / box, or 10 pieces / box.

[0107] Example 8: Preparation of L-carnitine injection

[0108] prescription:

[0109] L-Carnitine 20000g

[0110] Hydrochloric acid

[0111] Add water for injection to 100000mL

[0112] Preparation process:

[0113] 1) Dissolve: weigh L-carnitine and add water for injection to dissolve it to prepare a 60% (w / v) L-carnitine solution;

[0114] 2) Adjust the pH by adding hydrochloric acid to adjust the solution to pH 6.0;

[0115] 3) Decolorization and pyrogen removal: add 0.4% (w / v) activated carbon for needles, stir and decolorize in a 60°C water bath for 40 minutes;

[0116] 4) Decarbonization and fine filtration, using four-stage filtration, (1) decarbonization by filtering with gauze wrapped around a titanium rod; (2) filtering with a 0.8 μm filter element and microporous filter; (3) filtering with a 0.45 μm filter element and microporous filter; (4) filtering with a 0.22 μm filter element and microporous filter to obtain a clarified fine filtrate;

[0117] 5) Dilution: add water for injection to dilute the concentrated solution to 20% (w / v) L-carnitine solution;

[0118] 6) Adjust the pH by adding hydrochloric acid to adjust the pH of the diluted solution to 6.2;

[0119] 7) Filling: fill the L-carnitine solution with nitrogen and fill it into a 10 mL colorless ampoule to form the L-carnitine injection;

[0120] 8) Sterilization: sterilize the L-carnitine injection by moist heat at 121°C for 30 minutes.

[0121] 9) Packaging: plastic core plus hard paper box packaging, 1 piece / box, 5 pieces / box, or 10 pieces / box.

[0122] Example 9: Preparation of L-carnitine injection

[0123] prescription:

[0124] L-Carnitine 40000g

[0125] Hydrochloric acid

[0126] Add water for injection to 100000mL

[0127] Preparation process:

[0128] 1) Dissolve: weigh L-carnitine and add water for injection to dissolve it to prepare a 40% (w / v) L-carnitine solution;

[0129] 2) Adjust the pH by adding hydrochloric acid to adjust the solution to pH 6.1;

[0130] 3) Decolorization and pyrogen removal: add 0.3% (w / v) activated carbon for needles, stir and decolorize in a water bath at 80°C for 30 minutes;

[0131] 4) Decarbonization and fine filtration, using four-stage filtration, (1) decarbonization by filtering with gauze wrapped around a titanium rod; (2) filtering with a 0.8 μm filter element and microporous filter; (3) filtering with a 0.45 μm filter element and microporous filter; (4) filtering with a 0.22 μm filter element and microporous filter to obtain a clarified fine filtrate;

[0132] 5) Filling: fill the L-carnitine solution with nitrogen and fill it into a 5 mL colorless ampoule to form the L-carnitine injection;

[0133] 6) Sterilization: sterilize the L-carnitine injection by moist heat sterilization at 121°C for 30 minutes.

[0134] 7) Packaging: plastic core plus hard paper box packaging, 1 piece / box, 5 pieces / box, or 10 pieces / box.

[0135] Example 10: Preparation of L-carnitine injection

[0136] prescription:

[0137] L-Carnitine 20000g

[0138] Hydrochloric acid

[0139] Add water for injection to 200000mL

[0140] Preparation process:

[0141] 1) Dissolve: weigh L-carnitine and add water for injection to dissolve it to prepare a 10% (w / v) L-carnitine solution;

[0142] 2) Adjust the pH by adding hydrochloric acid to adjust the solution to pH 5.9;

[0143] 3) Decolorization and pyrogen removal: add 0.1% (w / v) activated carbon for needles, stir and decolorize in a 70°C water bath for 10 minutes;

[0144] 4) Decarbonization and fine filtration, using four-stage filtration, (1) decarbonization by filtering with gauze wrapped around a titanium rod; (2) filtering with a 0.8 μm filter element and microporous filter; (3) filtering with a 0.45 μm filter element and microporous filter; (4) filtering with a 0.22 μm filter element and microporous filter to obtain a clarified fine filtrate;

[0145] 5) Filling: fill the L-carnitine solution with nitrogen and fill it into a 20 mL colorless ampoule to form the L-carnitine injection;

[0146] 6) Sterilization: sterilize the L-carnitine injection by moist heat sterilization at 121°C for 30 minutes.

[0147] 7) Packaging: plastic core plus hard paper box packaging, 1 piece / box, 5 pieces / box, or 10 pieces / box.

[0148] Example 11: Preparation of L-carnitine injection

[0149] prescription:

[0150] L-Carnitine 20000g

[0151] Hydrochloric acid

[0152] Add water for injection to 100000mL

[0153] Preparation process:

[0154] 1) Dissolve: weigh L-carnitine and add water for injection to dissolve it to prepare a 50% (w / v) L-carnitine solution;

[0155] 2) Adjust the pH by adding hydrochloric acid to adjust the solution to pH 6.2;

[0156] 3) Decolorization and pyrogen removal: add 0.3% (w / v) activated carbon for needles, stir and decolorize in a 30°C water bath for 60 minutes;

[0157] 4) Decarbonization and fine filtration, using four-stage filtration, (1) decarbonization by filtering with gauze wrapped around a titanium rod; (2) filtering with a 0.8 μm filter element and microporous filter; (3) filtering with a 0.45 μm filter element and microporous filter; (4) filtering with a 0.22 μm filter element and microporous filter to obtain a clarified fine filtrate;

[0158] 5) Dilution: add water for injection to dilute the concentrated solution to 20% (w / v) L-carnitine solution;

[0159] 6) Adjust the pH by adding hydrochloric acid to adjust the pH of the diluted solution to 6.0;

[0160] 7) Filling: fill the L-carnitine solution with nitrogen and fill it into a 5 mL brown ampoule to make L-carnitine injection;

[0161] 8) Sterilization: sterilize the L-carnitine injection by moist heat at 121°C for 30 minutes.

[0162] 9) Packaging: plastic core plus hard paper box packaging, 1 piece / box, 5 pieces / box, or 10 pieces / box.

Claims

1. Use of L-carnitine or its derivatives in the preparation of a medicine for treating constipation; the L-carnitine derivative is selected from pharmaceutically acceptable salts of L-carnitine.

2. The method of claim 1, wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, pantothenate, methanesulfonate, or p-toluenesulfonate.

3. The use of claim 1, wherein the medicine is in the form of oral preparations and injections, wherein the oral preparations are solutions, suspensions, syrups, tablets and capsules; and the injections are injection solutions and freeze-dried powder injections.

4. The use according to claim 3, characterized in that The preparation process of the injection comprises the following steps: weighing L-carnitine, adding injection water solvent to dissolve and prepare a 10-70% L-carnitine concentrated solution; adding hydrochloric acid to adjust the pH value of the concentrated solution to 5.5-6.5; adding activated carbon for injection at a volume of 0.1%-0.4% of the L-carnitine concentrated solution, stirring in a water bath at 30°C-80°C for decolorization for 10-60 minutes to remove pyrogens; using a titanium rod wrapped in gauze for filtration and decarbonization, 0.8μm filter element microporous filter filtration, 0.45μm filter element microporous filter filtration, and 0.22μm filter element microporous filter filtration for four-stage filtration and decarbonization fine filtration; adding injection water to dilute the concentrated solution to 20% or 40% L-carnitine solution; adding hydrochloric acid to adjust the pH value of the solution to 5.5-6.5; filling the L-carnitine solution with nitrogen and sealing it in an ampoule to prepare the L-carnitine injection; wet heat sterilization, and packaging.

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