TWI227672B - Solutions for medical use containing L-carnitine and its alkanoyl derivatives as osmotic agents - Google Patents

Abstract

The use of L-carnitine and its alkanoyl derivatives, optionally in the form of a pharmaceutically acceptable salt, as osmotic agents in the preparation of solutions for medical use, particularly for peritoneal dialysis, is described. Solution for medical use characterized in that the osmotic agent is L-carnitine, and/or one or more alkanoyl derivatives of L-carnitine, in which the alkanoyl is a straight or branched aliphatic group with 2 to 8 carbon atoms, optionally in the form of a salt with a pharmaceutically acceptable acid.

Description

1227672 A7 B7 V. Description of the invention (1) (Please read the notes on the back before filling out this page) The description of this invention is about the use of L-carnitine and its alkyl fluorenyl derivatives Accepted salt form) as a penetrant in medical (especially peritoneal dialysis) solutions. Background of the Invention Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics Patients at the end of kidney disease (ESR D) must receive dialysis treatment or a kidney transplant. These two treatments are extremely necessary in terms of the patient's quality of life and social costs. Dialysis treatment can be found, for example: Pastan S. and Bailey J. in the New England Journal of Medicine, 14 May 1 998, pp. 1 428-1 436, which is incorporated herein by reference in its entirety. Dialysis treatment includes two types of treatment, peritoneal dialysis and hemodialysis. The main differences between the two types of dialysis treatment are, for example, hemodialysis, which is expensive to treat, requires specialized departments, expensive equipment and qualified personnel, and the patient is in good health. On the other hand, the advantages of larger peritoneal dialysis are simple, and patients can be treated by themselves. In Italy, for example, 15% of dialysis patients are treated with peritoneal dialysis, the same in the United States (16%), the percentage of peritoneal dialysis patients is higher in Canada (38%) and the United Kingdom (52%), and as high as in Mexico 90%. These different ratios are also because peritoneal dialysis is cheaper than hemodialysis, and hemodialysis is not affordable in all national health care systems. However, since the dialysis course can be designed by individuals according to their daily habits, peritoneal dialysis can undoubtedly make the patient's life style more comfortable. In addition, the robot can perform the analysis at night. However, these two types of dialysis are difficult to decide; for example, because the size of the paper is suitable for the Chinese National Standard (CNS) A4 (210 X 297 mm) 1227672 Λ7 B7 V. Description of the invention (2) (Please read first Note on the back, please fill out this page again) 'Patients with insufficient visceral function or unstable angina cannot withstand any changes in blood flow and / or arterial blood pressure during hemodialysis, so it is more suitable for abdominal fe dialysis (see above) . Assume that an ESRD patient is beginning a peritoneal dialysis procedure 'through hemodialysis, and finally reaches the state required for kidney transplantation. Peritoneal dialysis is not without its disadvantages and adverse side effects. Such disadvantages can be divided into two distinct categories, namely adverse clinical effects and technical issues. The purpose of this invention is to compensate for such disadvantages and adverse clinical effects. During a typical peritoneal dialysis procedure, a plastic catheter is implanted into the peritoneal cavity and leads to the subcutaneous tissue. The dialysis solution contains physiological amounts of sodium, calcium, magnesium, a physiologically compatible buffer solution, and a non-toxic osmotic agent. Its solution has high osmotic properties similar to blood. The solution was injected into the peritoneal cavity through the catheter for several hours. In the meantime, the peritoneal cell membrane is replaced by diffusion exchange solutes in order to obtain fresh fluid. Assuming that kidney function decreases in the first few years of dialysis, the dose of dialysis fluid to be exchanged needs to be increased over time. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Peritonitis is the most common severe eruption. Other types of cyanosis are amino acid and albumin loss, dialysis solution incompatibility, peritoneal cavity volume effect, metabolic problems, pathological effects on the digestive tract, hypo appetite, and others (see C, M. Min. And Gokal and NP Mallick, Lancet, 1999; 353; 823-28). The biggest problem with peritoneal dialysis is choosing the right osmotic agent. The ideal peritoneal dialysis solution includes:-to provide nutritional requirements and avoid adverse metabolic effects;-to ensure minimal absorption of penetrants, which must be non-toxic under any circumstances. This paper applies Chinese National Standard (CNS) A4 specifications ( (210 X 297 mm) -5- A227672 λ7 _ B7 V. Solution of the invention description (3); ~ Can bridge ortho acid poisoning, and has physiological P Η; (Please read the precautions on the back before filling this page) ~ In addition to considering the techniques involved (eg: pyrogenic 'metal-free and synthetic material residues), this solution must be able to inhibit bacterial and fungal growth, must not damage the immune system and must be inert to the peritoneal cell membrane substance. A typical peritoneal dialysis solution contains various concentrations of glucose as an osmotic agent, as well as various amounts of lactate (partly due to patient tolerance issues and therefore replaces acetate), sodium, potassium, and calcium. The buffer system has also been studied in an attempt to solve the problems of sterilization and solution stability. With regard to sterilization characteristics, this is an important technical issue; in fact, it is generally used for thermal sterilization of medical solutions, which will cause degradation of glucose and result in secondary derivatives such as aldehydes and 5-hydroxy-methylfurfural. )toxicity. Traditionally, the thermal sterilization of a solution containing glucose (also known as glucose) is performed at ρ Η 5.0 to 5 · 5 to precisely avoid caramelization of grape sugar. Patients using acidic ρ Η solution will lead to further problems ’such as: abdominal pain and hardening of peritoneal cell membranes, thus reducing the exclusion of clothing printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. (Schmidt et a 1., Arch. Int. Med., 141; 20 1265 > 1266) 1981). The description of the present invention also provides a solution related to this complex problem in the use of glucose as a osmotic peritoneal dialysis solution. Glucose is widely used because it is readily available and inexpensive. It is a very safe substance, but when used at high concentrations, the ultrafiltration time is shortened and metabolic complications occur due to rapid absorption. For example, the paper size applies the Chinese National Standard (CNS) A4 (210 X 297) (Mm) -6- 1227672 A7 B7 5. Description of the Invention (4) (Please read the precautions on the back before filling out this page) Such as: hyperinsulinemia, hyperlipidemia, and weight gain. In addition, high osmotic pressure and low ρΗ can damage mesothelial and macrophages. In addition, matrix protein glycosylation can further cause peritoneal damage. It has also been reported that it inhibits the phagocytosis, bactericidal activity, and L TB 4 synthesis of peripheral neutrophils. Continuous ambulatory peritoneal dialysis (c A P D) 'can be performed for 6 hours or more, and the glucose concentration must be very high to maintain the ultrafiltration capacity. The biocompatibility of peritoneal dialysis solution can be found in the review article of C.J. Holmes in Peritoneal Dialysis International, Vol. 13, PP. 88-94, 1993. In order to overcome this problem, glucose is used as a osmotic agent in peritoneal dialysis. The latest technology in this technical range includes two types of solutions: 1) The use of low molecular weight osmotic agents can maintain ultrafiltration with minimal metabolic effects. Do not change the expression of ultrafiltration; 2) Use a high molecular weight penetrant to act on these two factors. Of the various low molecular weight agents, only glycerol and amino acid mixtures serve this specific clinical purpose. In Italy, for example, a 1.1% polyamine based acid solution printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, Baxter is sold under the trade names of Nutnneal® PD2 and PD4. Such alternative glucose is not without problems; other sugars with metabolic effects: For example, if sugar can cause hypertriglyceridemia and high osmotic pressure, sorbitol can cause high osmotic pressure and accumulation; xylitol can cause Lactic acidosis and high osmotic pressure; glycerol can be tolerated, but the ultrafiltration volume period is shortened and can cause high osmotic pressure, and adverse effects on phage cells have also been reported (de Fijter CWH et al., Advances m ContinuousAmbulatorial This paper Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 1227672 A7 ___ B7 V. Description of invention (5) (Please read the precautions on the back before filling this page)

Peritoneal Dialysis, Toronto, Peritoneal Dialysis Publicauon, 1991, 154-7). Although amino acids can be used in malnourished patients, increasing nitrogen loading can cause acidosis, which is contraindicated in patients with uremia. On the other hand, high-volume penetrants have several disadvantages, such as the possibility of causing catfish immunity, absorption, intraperitoneal bleeding (in mice), and ultrafiltration (such as the use of polydextrose (MW 6 0-2 0 0 k D a )), Cardiovascular instability, peritoneal damage and bleeding (such as the use of polyanions and cations (MW 40-90 kDa)), prolonged half-life; immunity, allergenicity, and high solution viscosity (such as the use of gelatin ( MW 20-390 kDa)) and maltose retention (for example using glucose polymers). Unfortunately, the adverse side effects of the 'peritoneal dialysis solution come not only from the selected penetrant, but also from other components of the solution. Lactate is necessary for sterilization (for example, when combined with a low p p solution), it can inhibit various peripheral functions and the activity of peritoneal white blood cells, and inhibit the production of IL-6 and T N F α by monocytes. The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed a review of penetrants. Gokal concluded in 1990 that no penetrant could replace glucose (Coles GA, Davies M, Williams JD (eds): CAPD: Host Defence, Nutrition and Ultrafiltration. Contrib. Nephrol., Basel, Karger, 1 990, vol. 85, pp. 126-133). In the search for an alternative to osmotic agents for glucose, the so-called `` ideal rhenium '' solution was found or at least approached. In many patent documents, it is necessary to mention the patent of JP 110771286, the application of Dingkou 11111001001, describing that this paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -8- Economy Printed by the Consumers' Cooperative of the Ministry of Intellectual Property Bureau l227672 r- B7 i. The solution of invention (6) The penetrant is composed of a mixture of glucose and maltose, with a molar ratio of 1: 〇.〇E 5-5 and penetrating The pressure is ^ 2 0 0-6 0 0 HI 〇s ΓΙ 1 / kg = -p Η 6.〇-7. 5:, which has strong water removal characteristics and reduces glucose absorption. For obese and diabetic patients, the same company provides N-acetamidine (L-amino acid), N-acetamyl-D-glucosamine, glucuronic acid and / or ascorbic acid (patent JP 1 1 0 7 1 2 7 3). Hexavalent aliphatic cyclic alcohol saccharide mixtures, hexanoic acid, and sucrose are described in Patent JP 1 1049671, filed by Baxterlnt. Inc. Patent application WO 0 910 1 1 4 4 is filed by Allied Therapeutics Ltd. and describes synthetic hydrogenated di- and trisaccharides. The patent MX 9 6 0 1 8 5 5 was filed by Trevino and used polydextrose 60. Baxter's patent JP 10094598 uses non-reducing oligosaccharides or polysaccharides containing 3 to 12 residues. Patent application W 0 9 8 0 1 1 4 1, filed by Bieffe Medital SpA, describes the use of glucosaminoglycans without anticoagulant or bleeding activity. US patents: US 5629025, US 5589197 and US 5 6 1025, applied by Baxter International Inc., describe a low sodium content peritoneal dialysis solution, which contains at least one amino acid or polypeptide, or polydextrose As a penetrant. University of Missouri provides chemically cross-linked gelatin as a penetrant, partially or completely replacing glucose (US 4 60 4 3 7 9). Starch hydrolysates are described in U.S. 5 8 3706, and are applied by Roquette Freres. Patent JP 73 2 3 084 by Monshita Roussel KK and this paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)

-9- 1227672 A7 B7 V. Description of the invention (7)

Application by Ajinomoto Co. Inc. describes the use of trehalose to prepare a neutral solution instead of glucose. See also US Pat. No. 4,761,237. (Please read the precautions on the back before filling out this page) Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs to discuss in detail the low molecular weight penetrants mentioned in the present invention. Poor patients have the advantage of providing nutritional support. Baxter International Inc., in its US patent U S 5 7 7 6 5 0 3, provides a very complex mixture of amino acids, which is useless except expensive. The US patent US 578 0 4 38, filed by Giltech Limited, describes a stable solution whose penetrant consists of a peptide mixture derived from the hydrolysis of casein or lactoprotein. The US patent US 5 8 6 9 4 4 4, filed by Research Corporation Technologies, further discusses glucose alternatives, and indicates the use of amino acid low molecular weight penetrants. However, although it has nutritional advantages, it has the disadvantages of high price and increased nitrogen load in the blood. Therefore, in the cited patent, he used oligopeptides (300-200 Da) derived from the hydrolysis of high-quality proteins (such as lactone) by enzymes, which have the dual advantages of dialysis and nutritional functions. However, in this patent, the hydrolysis and separation processes must be carefully controlled to avoid local molecular weight components, possible antigens or allergens. The biggest problem with the protein sources used today (including collagen) is that milk (but not casein) and other proteins are contaminated with protein infectin (BSE, scrapie). After the above description, the inventors have realized that it is indeed very difficult to ensure the quality of the hydrolysis process. Other features of peritoneal dialysis are in DE 1 9 7 4 8 2 9 0, WO 991 7 62, JP 1 033 0 27 0. This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -10- 1227672 A7 ___ B7 V. Description of the invention (8) w 0 9 8 5 2 5 9 9, w 〇 9 8 5 0 0 6 0 'CA 2219822, W9919772 and (Please read the precautions on the back before (Fill in this page) US 58278 2 0 has been described. All references cited herein are incorporated by reference. Summary of the invention It has been found that L-carnitine or a lower carbon number alkyl derivative thereof, or a combination of L-carnitine and a lower carbon number alkyl derivative thereof can be used as an osmotic agent to prepare a peritoneal dialysis solution, And penetrants for general medical solutions. One of the subject matter of the present invention is to describe the use of L-carnitine and its lower carbon number alkyl derivatives (lower number alkyl derivatives are linear or branched fats of 2 to 8 carbon atoms) Group hydrazone residues), as the osmotic agent for medical solutions in the form of pharmaceutically acceptable salts, as needed, especially for the preparation of peritoneal dialysis solutions. One of the other subjects of the present invention is a medical solution using L-carnitine or one of its alkanoyl derivatives (as defined above) (optionally with one or more other known penetrants) as the penetrant. . The consumer cooperation of the Intellectual Property Bureau of the Ministry of Economic Affairs, the social printing of L-carnitine and its lower carbon number alkyl derivatives have various therapeutic uses. In particular, U.S. Patent No. 4,327,167 (filed by the same applicant) describes the use of alkanoylcarnitine as defined above as a method of treatment for patients with chronic uremia in general dialysis. Various physiological saline solutions containing alkanoyl carnitine for hemodialysis are also described. Patent EP 0 793962 (filed by the same applicant) describes the use of propionyl L-carnitine to prepare drugs for the selective treatment of chronic occlusive atherosclerosis (cUudicatio intermUtens.). Patent _ This long scale applies Chinese National Standard (CNS) A4 specification (210 X 297 public love) -η-1227672 A7 B7 V. Description of invention (9) 1 τ 1 1 5 5 7 7 2 (Applied by the same applicant ), Describing the use of alkyl sulfonyl L-carnitine to treat myocardial hypoxia, ischemia, arrhythmia syndromes, and heart failure. Patent US 4 2 5 5 4 4 9 (applied by the same applicant) describes the use of L-carnitine to treat dyslipidemia. The patent application WO 109 0 603 (applied by the same applicant) describes the use of L-carnitine and a combination of its alkyl derivative and polycosanols to treat disorders of blood lipid metabolism. L-carnitine and alkylfluorenyl derivatives can be combined with many other active ingredients, such as: r-linoleic acid (see WO 9 8 4 1 1 1 3), to treat and prevent side effects of diabetes, especially peripheral nerves Degeneration. US patent US 4272549 teaches patients with uremia during general hemodialysis treatment to use a specific combination of oral and intravenous L-carnitine administration to combat post-dialysis syndrome. The US patent US 4 2 3 7 1 6 7 teaches the use of a specific combination of oral and intra-venous L-carnitine administration in the treatment of uremia patients in general hemodialysis to combat post-dialysis syndrome.

Patent application WO99 0 7419 (filed by Gupta), describing a dialysis composition containing an effective amount of at least one selected from the group consisting of folic acid, vitamin B 6, thiamine, vitamin B 1 2, and use as needed Vitamin C and / or carnitine vitamins. The purpose of these preparations is to supplement the vitamins that patients have lost due to hemodialysis or peritoneal dialysis. The description also indicates an effective amount. L-carnitine below 50 micromoles / liter prevents vitamin and carnitine deficiency during dialysis in dialysis patients. The preferred concentration is between 50 and 300 micromoles / liter. Therefore, the paper size described in Gupta solution is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public love) (Please read the precautions on the back before filling this page) t Order -------- ---- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-12-12672672 A7 B7 V. Description of the invention (10)-The amount of carnitine is lower than the L-carnitine content as a penetrant There are several advantages to using L-carnitine or its alkanoyl derivatives as defined above. Replacing glucose with L-carnitine or its alkyl derivative may eliminate the above-mentioned adverse side effects. In addition, carnitine (the L-botulinum test or its alkanoyl derivative as defined in the description of the present invention) is compatible with bicarbonate buffer solution, so the use of typical glucose solutions below physiological pΗ (eg, pH 5.0 or 5.5). The advantage of carnitine, especially L-carnitine, ethynyl L-carnitine and propionyl L-carnitine, over other known penetrants is that carnitine is non-toxic 2. Well-tolerated substances have no adverse side effects at the dosages described below. Unlike amino acids, carnitine is not involved in protein metabolism 'so it does not increase the amount of nitrogen in uremia patients. Unlike other high-molecular-weight penetrants, the advantages are immediately visible. Carnitine is a natural substance in organisms, especially mammals, including humans. Based on this point of view ', possible concerns about non-naturally occurring synthetic organics can be eliminated. In addition, the use of carnitine as an osmotic agent can provide L-carnitine lost by dialysis patients as a result of dialysis. Data on the carnitine content of patients undergoing c A P D can be found in Kidney Int. 1 996: an; 49 (1): 158-62 and Pent. Dial. Int. 1993; 13 Suppl 2. A further advantage described by the present invention is that using carnitine as a penetrating agent can not only supplement the loss of carnitine ', but also have a therapeutic effect on diseases related to renal insufficiency, such as the diseases described in the aforementioned patents. The present invention will be explained in detail using examples. The special paper size related to the field of the invention applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public love) I 丨 Mm (Please read the precautions on the back before filling this page)

• —Order- ·· -------- Line J Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -13- A7

1227672 V. Description of the invention (11) A family can easily appreciate the subject matter described in the present invention and its individual superior classes. The detailed description of the present invention. A lower carbon alkyl group refers to a fluorenyl group of 2 to 8 carbon atoms. Compared with @f, it is 2 to 6, for example: ethenyl, propionyl, butylamyl, isobutyryl, pentamyl, isopentyl, 2-methylbutynyl, 2, 2-dimethylpropionyl , Hexyl, heptyl, octyl, and all possible isomers. The present invention describes the use of carnitine as a salt. Where appropriate, their medically acceptable salts can also be used. L-Botox or Ortho-B-Carnitine derivatives. Pharmaceutically acceptable salts are acid salts that are non-toxic or have no side effects. Such acids are well known to pharmacists and medical technologists. The pharmaceutically acceptable salts of OL-carnitine or alkyl l-carnitine Examples (but not absolute) are: chloride, bromide , Lactate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, maleate and acid maleate Salt, acid oxalate, acid sulfate, glucose phosphate, tartrate, and acid tartrate. Preferred salts are fumarate, aspartate, citrate and maleate. The peritoneal dialysis solution described in the present invention also includes the form of a ready-to-use solution containing the permeant according to the present invention and the form of a concentrate diluted before use. Dosage, pharmacology, and treatment are generally determined by the physician based on his knowledge of the patient, the patient's symptoms, and the condition of the disease. The first preferred feature described in the present invention is the use of L-carnitine (this paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ---- 丨 丨; ----- -Wei (please read the precautions on the back before filling this page) ---; 丨 order- · -------- line 丨 j Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-14 Printed by the Consumer Consumption Cooperative of the Property Bureau 1227672 A7 B7 V. Description of the invention (2) Internal salt). A second preferred feature is carnitine in the form of fumarate. Although there is no theoretical basis, the applicant of the present invention believes that the advantages of fumarate can especially provide the energy required for dialysis patients. Fumarate is an energy substrate and can be used to treat ischemic organs. The applicant has shown the efficacy of L-carnitine fumarate in the treatment of organ ischemia, especially ischemic heart disease, which is described in patent application 99RM0003328, which is incorporated herein by reference in its entirety. A third feature described in the present invention is the use of a combination of L-carnitine and acetamidine L-carnitine. An added advantage of this combination is the provision of patient ethionyl L-carnitine supplements. In explaining the possible application of the present invention, the so-called carnitine refers to L-carnitine, which is an internal salt, or a salt formed with a pharmaceutically acceptable acid as described above or alone or with an alkyl alkane derivative One of them acts as an internal salt, or forms a salt with a pharmaceutically acceptable acid, or one of its alkyl derivatives is used as an internal salt, or forms a salt with a pharmaceutically acceptable acid. The first feature of the present invention is to use carnitine as a penetrant to replace glucose. The concentration of carnitine should be sufficient for use as an osmotic agent, up to the maximum physiologically tolerable concentration of radon. Therefore, the concentration of carnitine will (for example) allow the present invention to achieve satisfactory results in practical applications. In particular, satisfactory results can be considered as the therapeutic effect of peritoneal dialysis. Unless otherwise specified, concentration units are weight / volume (w / v). Concentration examples are about 0.5 to about 10%, preferably about 0.7 to this paper size applicable to China National Standard (CNS) A4 (210 X 297 mm) --- ml ----- sickle --------- Order (please read the precautions on the back before filling this page) Line 丨 · -15- A7 1227672 B7-~ ___ V. Description of the invention (13) About 7%, better introduction At about 1 to 5%. In a typical specific application of the present invention, the concentration of carnitine is equal to the concentration of glucose used in general commercial formulations, that is, between 1.5 and 4.25%. (Please read the precautions on the back before filling this page.) Experts in this field should be able to determine the effective concentration based on the type of solution used. The concentrations in the examples started at about 0.5%. If necessary, a botulism test can partially replace glucose. The botulinum test and the glucose concentration can be freely varied 'are subject to the condition that the present invention has a satisfactory effect when used. An example of a glucose combination is 4.0% glucose-0.25% carbohydrate test '1.0% glucose-0.5% botulinum test; 0.5% glucose-1.0% carnitine; 0 · 25% glucose — 4.0% meat test. A combination of 0. 5% glucose and 1.0% botulism is preferred. Carnitine penetrants and other known penetrants can also be combined in other subject matter of the present invention; for example, a preferred combination is an amino acid, such as an existing formula in the market, or a dipeptide of the above patent and / Or polypeptide. A particularly preferred subject matter is the use of the double-bag carnitine described in the patent DE 197 48 290, which uses bicarbonate as a buffer solution. The solution (described in W 0 9 9 07 4 1 9) can also increase the dose of carnitine, especially the L-carnitine printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, which is as effective as the concentration of penetrant. In another possible subject matter, the penetrant according to the present invention may be used in combination with the penetrant described in the US patent, US 5 8 2 7 8 2 0, issued to Baxter I n t e r n a t i ο n a i I n c. The penetrant used in accordance with the present invention can also be combined with a high molecular weight penetrant (especially an icodextnn) described in the above-mentioned documents. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). ) -16- 1227672 A 'A / ___ _ B7 ~~-One --------- V. Description of the invention (M) In the specific subject matter of the present invention, peritoneal dialysis solution can be added to those commonly used in this technique. Surfactant. For example, palmitoyl L-carnitine. One of the specific subjects of the present invention is a medical solution in which the penetrant is L-carnitine and / or its alkyl fluorenyl derivative, in which the alkyl fluorenyl is linear or branched having 2 to 8 carbon atoms Aliphatic residues, if necessary, in the form of pharmaceutically acceptable salts. A particular subject of the invention is a peritoneal dialysis solution. Such features can be applied industrially. The solution of the present invention can be contained in a suitable container for peritoneal dialysis, and is generally a double-bag type of suitable materials compatible with medicine. Containers for peritoneal dialysis are well known to those skilled in the art and do not require any particular description. The reader is already contained in a specific document and is general knowledge related to the scope of the present invention. The embodiment is a double bag type with single or multiple compartments, such as a double compartment, or a separate double bag type containing different solutions. It can be mixed with an automatic device when used. A peritoneal dialysis container containing a solution according to the invention is also within the scope of this patent application. The present invention uses experimental tests to illustrate the preferred subject matter related to the present invention. Professionals who are generally familiar with the art can easily modify the framework of the present invention with their general knowledge, even experiments and error methods. Such modifications are within the scope of the present invention. Study on in vitro delivery In vitro liquid delivery is performed using semi-permeable tubes containing cellulose membranes containing various dialysis solutions. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) «! 1 · (Please read the precautions on the back before filling this page) Order ·· --------- II I-- -Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-17- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1227672 Α7 ___ Β7 V. Description of the invention (〗 5) The concentration of carnitine in the buffer solution is 0.5, 1 · 0 And a 1.5% bicarbonate buffer solution (30 millimolar concentration) and Na C 1 (100 millimolar concentration) pH 7.2. A 1.5% glucose solution was used as the reference solution. Buffer solution composition: sodium 134 millimoles / liter, calcium 175 millimoles / liter, magnesium 0.5 millimoles / liter. The glucose-containing solution was buffered with p-5.5 with 35 mmol / L of L-lactate. The solution containing carnitine instead of glucose was buffered with 34 mmol / l bicarbonate to ρ Η 7.0-7 · 6. 10 ml of each dialysis solution was placed in a dialysis tube, and the dialysis tube was suspended in a 1-liter graduated cylinder containing 0.9% Na C 1 solution. At a rate of 500 ml / m i η directly flowing along the main axis of the dialysis tube, a physiological saline bath was recovered by infusion pump. After removing the liquid adhering to the membrane wall with absorbent paper, the amount of liquid recovered in the tube was measured by the specific gravity method. The dialysis tube is then returned to the graduated cylinder and the next weight measurement is taken after 15, 30, 45, 60, 90, 120, 18, 24, 30 and 360 minutes. Table 1 is the weight increase of the recovered liquid at different times of the dialysis solution. This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) H ϋ n I— nnn In ϋ ϋ 111 ϋ · tM! Nnn an n a fl .nnnnnn ϋ I ϋ (Please read the note on the back first Please fill in this page for matters) -18- 1227672 A7

V. Description of the invention (16) <· Contains 10 ml of liquid containing different concentrations of carnitine or glucose. Time 1 Temple ° _ Carnitine 0.5% Carnitine 1.0% Botox 15% Grape bran 1 S% 15 "grams liquid) 0.02 + 0.01 (gram liquid 0.07 + 0.02 (gram liquid) 0.10 ± 0.01 Ft3J UJJ V mouth 丄 · ”/ 0 * (g liquid) 0 09 ± 0 09 30 0.06 + 0,01 0.13 + 0.02 0.26 ± 0.03 0 · 19 ± 0.03 45 0.10+ 0.03 0.20 + 0.03 0.30 ± 0.02 0.27 ± 0.02 _ 60 〇 .12 ± 0.02 0,22 soil 0.03 0.35 + 0.04 0.31 + 0.04 __90 〇17 ± 0.03 0.33 + 0.03 0.48 + 0.04 0.41 + 0.04 120 0.19 + 0.02 0.36 ± 0_03 0.54 soil 0.04 0.47 ± 0.04 180 0.21 + 0.03 0.42 + 0.04 0.66 + 0.04 0.54 + 0.04 240 0.27 + 0.02 0.49 + 0.03 0.77 soil 0.05 0.59 ± 0.04 300 0.29 + 0.02 0.51 + 0.03 0.77 + 0.04 0.63 + 0.05 360 0.27 + 0.03 0.48 ± 0.04 0.74 soil 0.05 0 · 62 ± 0 · 〇4 (Please read the notes on the back before filling out this page) The number printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs is the average of 3 different experiments (11 == 3) ± S. D. Dialysis tube weight It increased with time as a function of different concentrations of carnitine. All concentrations reached the plateau phase after 240 minutes of measurement. The potential is similar to the sample containing 1.5% carnitine. In vivo experiments Peritoneal dialysis experiments were performed with male Sprague-Dawley mice (500-600 g, Charles Rlver). Animals are injected intraperitoneally with inactin (100). This paper size is in accordance with the Chinese National Standard (CNS) A4 (210 X 297 mm) -19-1227672 Α7 B7 5. Description of the invention (17) mg / kg) were anesthetized and placed on the operating table at a controlled temperature. The animals were tracheostomy, and a PE 500 medical silicone tube was inserted from the left jugular vein. The animals were anesthetized for 30 minutes at 2.3 ml / At a rate of h, physiological saline solution was injected during the experiment. After anesthesia for 1 h, preheat to 37 ° C. Inject the dialysis solution (15 ml) into the peritoneal cavity with a 15-gauge Teflon needle cannula. The weight of the injected liquid was determined by the weight of the electronic syringe before and after the injection of the syringe. At the end of each analysis period (2, 4 and 6 h), an incision was made in the abdomen of the rat with a cus sec t 〇r, and all the fluid in the peritoneum was withdrawn using a 1 ml injection syringe. After removing the surface fluid, carefully move the intestines in the abdominal cavity to collect fluid remaining in the back wall. The recovered liquid was placed in a beaker and weighed. The change in weight compared to the time point of 0 represents the liquid recovery of the solution injected into the peritoneum. A series of in vivo experiments were performed in accordance with the above experimental model to evaluate the transport capacity of various carnitine-containing dialysates. The data are based on the initial and final weights to calculate the percentage increase in liquid volume recovered from the peritoneum of each animal over different analysis times. Table 2 contains data obtained from experiments performed with dialysis fluids with different glucose concentrations (1.5, 2.5, and 4.25%). The data of such hypertonic solutions is the data of the control group, because it is a commonly used solution in clinical practice. Size of this paper · Specifications of the towels ⑵〇X 297mm)-------- 0 (Please read the precautions on the back before filling this page) Order -T -------- line 丨Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -20-1227672 A7 ____B7___ V. Description of the invention (18) Table 2 15 Percentage change of liquid volume recovery in 5 ml of mouse peritoneal dialysis with a solution containing different glucose concentrations. Solution volume increase% volume increase% volume increase% _ (2M __ (6) glucose 1.5% 2 1.1 ± 1.5 21.5 ± 1.9 21.7 ± 1.6 glucose 2.5% 35.2 ± 1.4 35.9 ± 1.3 36.8 ± 1.5 glucose 4.25% 59.8 ± 1.6 60.5 ± 1.7 5 9.1 ± 1.6 Please read the precautions on the back before filling in this page) ··-The results printed by the Consumers' Association of the Ministry of Economic Affairs and Intellectual Property of Japan are averaged (n = 3). SD indicates that all glucose concentrations are within 2 h. Will cause an increase in the volume of fluid in the abdominal cavity. In fact, the fluid volume of the peritoneum was still fixed at 4 and 6 h. The same experiments were performed with the same carnitine concentration. The results are shown in Table 3. Table 3. Percentage change in fluid volume recovery in 5 ml of a solution containing different concentrations of carnitine for rat peritoneal dialysis. Solution volume increase% (2h) Volume increase% (4h) Volume increase% (6) Order -------- I ----- Carnitine 1.5% Carnitine 2.5% Carnitine 4.2 5% 2 5 .8 ± 1. 3 38.1 ± 1.4 6 1. 5 ± 1. 5 22.5 ± 1.6 37.3 soil 1.4 64. 1 soil 1. 8 25.3 ± 1.4 38.5 ± 1.6 62.3 soil 1.9 This paper size applies to Chinese national standards (CNS) A4 specification (210 X 297 mm) -21-A7 B7 1227672 V. Description of the invention (〖9) Results are averaged (n = 3) ± SD, which means that carnitine is also a good penetrant (at least and As good as glucose). The percentage increase in fluid volume in the abdominal cavity is slightly greater than glucose. The liquid recovery of the botulinum test solution is also very fast, and the peak activity is reached within 2 hours, and the volume will not be further increased in the subsequent observation time (4 '6 ti). Peritoneal dialysis in vivo confirmed the activity of carnitine as an osmotic agent, followed by a series of experiments using a mixture of carnitine and glucose or amino acids (a a) to maintain a total percentage of osmolyte equal to 1.5%. The results are shown in Table 4. Table 5. Using an amino acid composition from another perspective. The amino acid solution composition is the most suitable composition for reducing metabolic acidosis when using this solution. Table 4 Percentage change in fluid volume recovery of 15 ml of a solution containing different concentrations of carnitine, glucose, and amino acid (a a) mixture for peritoneal dialysis in mice. ___ ^ _ Solution volume increase% Volume increase% Volume increase% I € (Please read the precautions on the back before filling out this page) Line 丨 · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (2h) (4h) (6) Carnitine 1.5% 25.8 _ι_ 1.3 22.5 ± 1.6 25, 3 soil 1.4 Glucose 1.5% 21.1 soil 1.5 21.5 soil 1.9 21.7 soil 1.6 Car + Glul.0 + 0.5% 25.6 1 1.6 28.4 soil 1.6 27.6 soil 1.5 Car + aa0 .5 + l .0% 24.6 soil 1.2 26.4 1 1.3 25.3 people 1.2 Car + aa0.8 + 0.7% 23.1 soil 1.5 24.5 soil 1.4 26.0 soil 1.5 Car + aal .0 + 0.5% 25.9 people 1.5 28.4 people 1, 5 33.8 ± 1.4 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -22- 1227672 A7 __ B7 V. Description of the invention (20) Results average (η 2 3) Soil S · D · It means that the liquid recovered within the first 2 hours is similar to all the measured solutions between 21.7 and 25.9%. In addition, all solutions remained fixed (4 and 6 h), but solutions containing c a r + a a (1, 0 + 0 · 5%) continued to increase. % ------------------ Order (please read the precautions on the back before filling this page) Line 丨 · Printed on this paper by the Intellectual Property Bureau of the Ministry of Economic Affairs and the Consumer Cooperative Shen Guo National Standard (CNS) A4 Specification (210 x 297 mm) -23- 1227672 A7 B7 V. Description of Invention (21) Table 5 Amino Acid Concentration of Solution Containing AA Composition (mg% Intellectual Property Bureau, Ministry of Economic Affairs) Employee Consumer Cooperative Co., Ltd. printed leucine valerate &gt; threonine isoleucine and levulinic acid HC; 1 histamine methionine phenylalanine f tryptophan &gt; alanine proline Glycine Glycerine Serine Tyrosine Aspartate: Phenylalanine glutamate / Tyrosine Production / Neutralizing Acid Basic / Total 7 4-1 〇004 7 6 1 — 5 5 -5 2- 3 2- 4 2- 4 3 〇-6 4 8-2 0- 5 5-5 5- 7 1 9 2 8 3 7 8 4 8 6 2 3〇1〇6 5 11 5 5 7 2 3 5 .〇4-0.7 The following examples further illustrate the present invention (please read the precautions on the back before filling this page)

This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -24- A7 1227672 ___B7 V. Description of the invention (22) Example 1 Sodium peritoneal dialysis solution 1 3 4.0 mmol / L calcium 175 millimoles per liter of magnesium 〇5 millimoles per liter of chlorine 1 305 millimoles per liter of bicarbonate t 3 40,000 millimoles per liter of L — botulinum test 1 1 • 5% implemented Example 2 Peritoneal dialysis solution sodium f 13 4 .0 mmol / L calcium · 1. 75 mmol / L magnesium 0.5 mmol / L chlorine 100.3 mmol / L bicarbonate V 3 4 • 〇mmol / L L-Carnitine 2.5% ------------- # (Please read the notes on the back before filling this page) Order-* — line! · Example 3 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics peritoneal 丨 dialysis solution: liquid sodium 1 3 4 • 〇mmol / liter of calcium 175 mmol / liter of magnesium 0 5 mmol / liter of chlorine 1 〇3 5 millimoles / litre bicarbonate 3 400 millimoles / litre L — Botox 4 2 5% This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1227672 A7 B7 V. Description of the invention (23) Example 4 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 4 peritoneal dialysis solution sodium 13 4 .0 mmol / l calcium 1.75 mmol / liter magnesium 0.5 mg / mol Litre of chlorine 10.3 mmol / L of lactate 3 50 mmol / L of L-carnitine &gt; 1.0% glucose 0.5% Example 5 Sodium ^ membrane dialysis solution f 13 4 .0 millimoles / liter of calcium 1.75 millimoles / liter of magnesium 0, 5 millimoles / liter of chlorine% 10.3 millimoles / liter of bicarbonate 34 400 millimoles / liter L Monocarnitine 1.0% amino acid mixture as shown in Table 5 is 0.5 step Example 6 double double bag type peritoneal analysis solution A packet sodium .〇 193 mmol / l calcium 1.7 5 mmol / l magnesium square .5 mmol / l chloride 〇3 1 .5 mmol / l - Shushu! ----- * _! (Please read the notes on the back before filling out this page)-§J »1 — — — — — —— I — — — — 1ΙΙΗΙΙ_ This paper size applies Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) -26- 1227672 Canton A / B7 Printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (24) Lactate glucose second packet of bicarbonate L-carnitine Example 7 sodium potassium calcium magnesium chloride bicarbonate

L 〇〇〇mmole / L 5-4.0% 34.0 moles / L 4.0-0.5% peritoneal dialysis solution Botox test Example Sodium potassium calcium magnesium chlorolactate 134.0 mM / Liter 2.0 mol / liter 1.75 mol / liter 0.5 mol / liter 105.5 mol / liter 34.0 mol / liter. 5-4. Peritoneal dialysis solution L-carnitine (please read the precautions on the back before filling out this page) 〇 05% 4 .0 mol / L 0 mol / L 7 5 mol / L 5 mol / L 5 5 millimoles / liter. 0 millimoles / liter. 5 — 4.0% This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) line. 丨 # · -27- 1227672 V. Description of the invention ( 25) Glucose 4. 0-0.5%! 1 | "——f (Please read the notes on the back before filling this page) —Order ~--Line 丨-Printed by the Consumers’ Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs System ____U___

L-! I 1 i I This paper size is applicable to China National Standard (CNS) A4 (210 χ 297 mm) -28-

Claims (1)

1227672 8 8 8 8 ABCD Excuse me, please ask; whether the original substance is changed after the revision of this case? 0 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6. Scope of patent application Annex A: Patent application No. 88 1 19898 Chinese amendment of patent scope Revision June 1 · A solution for peritoneal dialysis, characterized in that the penetrant is L-carnitine, and / or one or more L-carnitine alkylfluorenyl derivatives, wherein the alkylsulfonyl group contains 2 to A linear or branched aliphatic of 8 carbon atoms, which may optionally form a salt form with a pharmaceutically acceptable acid, in an amount from about 0.5% w / v to about 10% w / v. 2. The solution according to item 1 in the scope of the patent application, wherein the penetrant is a combination of 1-carnitine and at least one of its alkanoyl derivatives, wherein the alkanoyl group is a straight or branched chain containing 2 to 8 carbon atoms Aliphatic, which can form salt forms with pharmaceutically acceptable acids, if desired. 3. The solution in item 2 of the patent scope as claimed in § 靑, in which the acid-based derivative of the hospital is ethynyl L-carnitine, which can form a salt form with a pharmaceutically acceptable acid if necessary . 4. The solution according to item 1 of the scope of patent application, wherein the pharmaceutically acceptable salt is selected from the group consisting of fumarate, aspartate, citrate and maleate. 5. The solution according to item 2 of the patent application, wherein the pharmaceutically acceptable salt is selected from the group consisting of fumarate, aspartate, citrate and maleate. 6. The solution according to any one of the claims 1 to 15 of the scope of patent application, which is in the form of a concentrated solution. 7 · If the solution in any one of the items 1 to 5 of the scope of the patent application, the paper size is applicable to the Chinese National Standard (CNS) A4 specifications (210X297):-(Please read the precautions on the back before filling this page) 1227672 A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 々 The scope of patent application for this penetrant is 1.5% w / v of L-carnitine. 8. The solution of any one of items 115 to 15 of the scope of the patent application, wherein the penetrant is composed of L-carnitine and other penetrants. 9. A solution for peritoneal dialysis, wherein the osmotic agent is L-carnitine at a concentration of from about 0.7 to about 7% w / v. 10. A solution for peritoneal dialysis, wherein the osmotic agent is L-carnitine at a concentration between about 1 and about 5% w / v. 1 1. A solution for peritoneal dialysis, wherein the penetrant is L-carnitine at a concentration of about 1.5% w / v. 1 2. A solution for peritoneal dialysis, wherein the penetrant is L-carnitine at a concentration of about 2.5% w / v. 1 3. A solution for peritoneal dialysis, in which the penetrant is L-carnitine, with a concentration of about 4.25% w / v. 14. A solution for peritoneal dialysis, wherein the osmotic agent is a combination of L-carnitine at a concentration of 1.0% w / v and glucose at a concentration of 0.5% w / v. 15. A solution for peritoneal dialysis, wherein the osmotic agent is a combination of L-carnitine and an amino acid mixture at a concentration of 1.0% w / v. 16. A solution for peritoneal dialysis, wherein the penetrant is a combination of L-carnitine at a concentration of 0.8% w / v and an amino acid mixture at a concentration of 0.7% w / v. 17. — A solution for peritoneal dialysis, in which the penetrant is 1.0% w / v of L-carnitine and the concentration is 0.5%. The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm). )-^-(Please read the notes on the back before filling this page), τ 1227672 A8 B8 C8 D8 • Combination of amino acid mixtures with patent application scope W / V. 18. The solution according to any one of items 15 to 17 of the scope of the patent application, wherein the combination of the amino acid mixture is as follows: Amino acid concentration (mg%) Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Laminated valine, threonine, isoleucine, lysine, HCI Acid glutamate phenylalanine / tyrosine production / neutralizing acid basic / total 7 4-112 10 0-15 4 7-71 6 1-92 5 5-83 5 2-78 3 2-48 4 2-62 2 0-30 6 8-103 4 3-65 6 0-113 3 6-55 4 8-72 2 5 5 (Please read the notes on the back before filling this page) 3 5 _ 3 — 3 2 2 4-0 7 This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) -3- 1227672 A8 B8 C8 D8, patent application perimeter 1 9. If the scope of application for patents No. 1 5 and 9 1 The solution according to any one of 17 items, which comprises palmitoyl L-carnitine as a surfactant. 20. The solution according to item 6 of the patent application scope, which comprises palmitoyl L-carnitine as a surfactant. 2 1. The solution according to item 7 of the scope of patent application, which comprises palmitoyl L-carnitine as a surfactant. 2 2. The solution according to item 8 of the scope of patent application, which comprises palmitoyl-L-carnitine as a surfactant. 2 3. The solution according to item 18 of the scope of patent application, which comprises palmitoyl-L-carnitine as a surfactant. 24. The solution according to any one of claims 1 to 5 and 9 to 17 of the scope of patent application, which is contained in a container for peritoneal dialysis. (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper applies the Chinese National Standard (CNS) Α4 specification (210 × 297 mm) -4-