CH646056A5 - LIPID LOWERING AGENT. - Google Patents

Description

The invention relates to a pharmaceutical or dietetic agent.

According to rough estimates, about 20% of the population should suffer from hyperlipoproteinemia, with a large part not knowing about this. In addition to nicotine abuse, this hyperlipoproteinemia represents an essential risk factor for the development of arteriosclerosis, which can lead to strokes, circulatory disorders in the extremities and circulatory disorders in the heart and thus to a heart attack. In addition to the cancer problem, the conditions caused by hyperlipoproteinemia are currently among the most burning medical problems.

For the poorly water-soluble lipids, lipoproteins serve as transport vehicles with which the triglycerides are transported from the intestinal wall or from the liver to the places of consumption or deposition.

Depending on their protein and lipid content, these lipoproteins can be divided into four main groups:

1. chylomicrons,

2. very low density lipoproteins (VLDL),

3. Low density lipoproteins (LDL) and

4. High density lipoproteins (HDL).

These lipoproteins can be determined electrophoretically both quantitatively and qualitatively. A starting or already existing hyperlipoproteinemia can be clearly identified from the lipid composition and total lipid amount obtained in the electrophoresis.

The lipoprotein fractions LDL and VLDL are of paramount importance for the development of cardiovascular diseases, whereas the chylomicrons and HDL have so far not shown any adverse effects or even advantageous effects. While the chylomicron particles transport the fats absorbed from the intestine, the VLDLs carry triglycerides synthesized endogenously in the liver to the peripheral tissues, where they are used for extraction or storage. After the release of triglycerides, the small, high-cholesterol LDL are formed with the enrichment of cholesterol and phospholipids. These two last-mentioned lipid protein particles represent the main risk factors in the development of arteriosclerosis or heart attack. In order to effectively combat hyperlipidemia or hyperlipoproteinemia, the concentrations of these lipid transport particles in the serum must be reduced to such an extent that there is no acute risk of arteriosclerosis developing is.

A combination of dietary and medicinal treatment is often used for preventive treatment of patients who are prone to atherosclerosis2

beaten. While the dietary act mainly consists of replacing saturated acids with unsaturated acids and reducing overall fat consumption, there are numerous possible variations in drug treatment.

Non-resorbable substances, such as ion exchangers, for example cho-isestyramine, neomycin and the like, and resorbable substances, such as D-thyroxine, are frequently used as substances which lead to an acceleration of lipo-protein catabolism. These substances either exchange the cholesterol (cholestyramine) responsible for the deposition on the walls of the vessels or increase the oxidation of cholesterol to bile acids. The side effects occurring with these preparations (constipation, nausea, deficiency symptoms or increased incidence of cardial complications) led to withdrawal at least in thyroxine.

On the other hand, substances are also used which lead to an inhibition of lipoprotein production. The most common drugs in this group of substances include derivatives of nicotinic acid and clofibrate. Such substances either reduce LDL synthesis (nicotinic acid) or control VLDL production (clofibrate). Therapy successes occur especially in conditions with elevated triglyceride levels.

Preparations containing these substances also have considerable disadvantages, i.a. Nausea, gastrointestinal symptoms such as upper abdominal pain, gallstone formation and the like.

30 On the other hand, the need for certain essential fatty acids in human nutrition must be met. A fat-free diet leads to severe growth disorders and other pathological changes, especially on the hair and skin. Patients with 35 post-traumatic and post-operative catabolism, in whom increased lipid levels were initially detected, already show a strong drop in essential fatty acids within a few days. These essential fatty acids must either be supplied from the fat pool or by an appropriate exogenous fat supply. If the patient has to be fed parenterally, application is problematic in that fats do not dissolve in water and can therefore only be infused in a suitable fat emulsion. A balanced intake of fat was necessary, 45 because the fat pool in the body did not provide sufficient fat.

The invention is therefore based on the object of providing a means with which both the lipid concentration in the serum can be reduced, and thus an accelerated lipid breakdown can also be carried out.

This object is achieved by the characterizing feature of claim 1.

It has now been found that the use of carnitine can significantly lower the lipid level in the blood. This carnitine, which is the general formula

CH.

+ /

60 CH0-N-CHn-CH-CH0-C00

ô l di <L

65 is known to be present in the tissue. However, its function remained unknown for a long time until it was found that it is an essential growth factor for the mealworm. From this it was then concluded that one

646 056

4th

solutions, separate multiple preparations of the above form, as well as other forms described herein.

The amount of the active ingredient to be administered depends on the age and weight of the patient, the particular condition to be treated, the frequency of administration and the mode of administration. The dosage range ranges from 1-120, preferably 5-90, in particular 8-70 mg / kg body weight. The human dose is in the range of about 400 mg to 10 g daily as a single dose or divided into 3 or 4 doses. The dosages in veterinary medicine correspond to the dosages in humans, the amounts administered being in relation to the body weight of the animal in comparison to the adult human.

The invention is illustrated by the examples below.

Example 1 tablets

20,000 indented oral tablets, each containing 500 mg of carnitine, were made from the following ingredients:

Carnitine, ground to fine particles 10 kg

Thickness 350 g

Talc 250 g

Calcium stearate 35 g

The carnitine ground to very fine particles was granulated with a 4% (w / v) aqueous solution of methyl cellulose. A mixture of the remaining constituents is added to the dried granules and the final mixture is pressed into tablets of the appropriate weight. In adults with hyperlipoproteinemia, satisfactory clinical responses have been achieved with 5 tablets / day, with the tablets being distributed evenly throughout the day.

Example 2 capsules

20,000 two-piece oral hard gelatin capsules, each containing 500 mg of carnitine, were made from the following ingredients:

Carnitine 10 kg

Lactose 1 kg

Strength 300 g

Talc 65 g

Calcium stearate 25 g

The carnitine, which is ground to very fine particles, is mixed with the starch-lactose mixture and then with the talc and the calcium stearate. The final mixture is then filled into capsules in the usual way. One capsule is administered every 3 hours to regulate lipoproteinemia. Furthermore, capsules containing 100, 200, 300 and 400 mg of carnitine were prepared by using 2, 4.6 and 8 kg instead of the 10 kg used in the above preparation.

Example 3 Soft Elastic Capsules One-piece, soft, elastic oral capsules, each containing 200 mg of carnitine, were prepared in the usual manner, first dispersing the powdered active material in a sufficient amount of corn oil to process the material Make capsule shape editable.

Example 4 Aqueous Preparation An aqueous preparation for oral use, each containing 5 ml with an amount of 200 mg of carnitine, was prepared from the following ingredients:

Carnitine

400 g

Methyl paraben

7.5 g

Propyl paraben

2.5 g

Sodium saccharin

12.5 g

Sodium cyclamate

2.5 g

glycerin

3 1

Tragacant powder

10 g

Orange oil flavor

10 g

Orange dye

7.5 g

Deionized water to 10 1

Example 5

Suspension for parenteral administration A sterile aqueous suspension suitable for intramuscular injection and containing 200 mg carnitine per milliliter was prepared from the following ingredients:

Polyethylene glycol 3 g

Sodium chloride 0.9 g

25 polysorbate 0.4 g

Sodium metabisulfite 0.1 g

Methyl paraben 0.18 g

Propyl paraben 0.02 g

Carnitine 20 g 30 water for injection to 100 ml

Example 6 Aqueous Solution 35 An oral oral solution containing 500 mg of carnitine in 25 ml each was prepared from the following ingredients:

Carnitine 100 g

Deionized water to 1 1

40

Example 7

Parenteral administration solution A sterile aqueous solution for intravenous or intramuscular injection containing 100 mg of carnitine in 2 ml of 45 was prepared from the following ingredients:

Carnitine

50 g

Chlorobutanol

3 g

Water for injection to 1 1

Example 8

Parenteral solution

L-isoleucine

2.50 g / 1

L-leucine

3.70 g / 1

L-lysine

3.30 g / 1

L-methionine

2.15 g / 1

L-phenylalanine

2.55 g / 1

L-threonine

2.20 g / 1

L-valine

3.10 g / 1

L-arginine

6.00 g / 1

L-histidine

1.50 g / 1

Amino acetic acid

7.00 g / 1

L-alanine

7.50 g / 1

L-proline

7.50 g / 1

Sorbitol

150.00 g / 1

L-malic acid

4.70 g / 1

Carnitine

0.50 g / 1

L-tryptophan

1.00 g / 1

certain function for cell growth. In this respect, it can be classified under insect vitamins (Bx).

Furthermore, it is also known for its transport properties, by means of which fatty acid CoA products are channeled from the tissue into the mitochondria. This effect is due to the action of an enzyme that catalyzes the transfer of the fatty acid residue from the CoA to the carnitine. After the transfer, the fatty acid carnitine product enters the mitochondria through the membrane and is in turn decomposed there with the formation of fatty acid CoA. This product is ultimately split and implemented in the mitochondria.

Surprisingly, it has now been found

that the exogenous addition of carnitine either in parenteral solutions or in orally administered pharmaceutical preparations was able to effectively lower the lipid level in the serum. A significant decrease in serum lipids was observed in both patients suffering from hyperlipoproteinemia and in patients with elevated lipid levels in the post-traumatic phase. Furthermore, the transport of lipids from the lipid pool could obviously be accelerated, since there was no decrease in essential fatty acids in the serum in patients with post-traumatic catabolism even after several days.

The carnitine to be used according to the invention, which is in the form of water-soluble crystals and is commercially available, can be combined with a pharmaceutical carrier in solid or liquid dosage forms, such as tablets, capsules, powders, pills, granules, syrups, elixirs, suppositories or sterile dispersions Water or vegetable oils for parenteral or other administration may be used alone or in combination with other drugs, such as administered in parenteral nutrition ^

Powders are produced by comminuting the active ingredient to an appropriate fine particle size and mixing it with a similarly comminuted diluent. The diluent can be an edible carbohydrate material, for example starch. A sweetening agent and a flavoring agent are advantageously present.

Capsules are made by preparing a powder mixture as described above and pouring it into preformed gelatin shells. In the filling process, a lubricant, such as talc, magnesium stearate or calcium stearate, is advantageously added to the powder mixture before the filling process.

Tablets are made by making a powder mixture, granulating or slurrying it, adding a lubricant and pressing tablets. The powder mixture is produced by mixing the appropriately comminuted active ingredient with a diluent or a base, such as, for example, starch, lactose, kaolin, dibasic calcium phosphate, calcium sulfate and the like. The powder mixture can be granulated by moistening with a binder such as syrup, gelatin solution, methyl cellulose solution or acacia mucus and pressing through a sieve. As an alternative to granulating in the wet state, the powder mixture can also be comminuted, i.e. passed through a tablet machine and the large tablets obtained can be broken into granules. In order to prevent getting stuck in the tablet production form, the granules are further lubricated by adding stearic acid, a stearate salt, talc or a mineral oil. The lubricated mixture is then pressed into tablets. Advantage3 646056

Luckily, the tablet can be given a protective coating consisting of a shellac sealing coating, a sugar and methyl cellulose coating, and a carnauba wax gloss coating. Oral administration liquids are made in unit dosage forms such as syrups and elixirs, each of which Teaspoon of the composition contains a predetermined amount of the active ingredient for administration.

io A syrup is produced by dispersing the active ingredient in an aqueous sucrose solution which has been flavored accordingly. In the same way, an elixir is made using an aqueous alcoholic vehicle. Elixirs are advantageous as carrier materials if a therapeutic agent that is not sufficiently water-soluble is in the composition.

The preparations according to the invention for parenteral administration include sterile, aqueous and non-aqueous solutions, suspensions or emulsions with or without the addition of local anesthetics. These compositions can also contain additives, emulsifiers and dispersants. They can be sterilized, for example by filtration through bacteria-tight filters, by the addition of sterilizing agents to the preparations, by radiation or by heating. They can also be prepared in the form of sterile solid preparations, for example by lyophilization, which can then be dissolved in sterile water or another sterile injectable medium immediately before use.

Although it is of course possible to administer sterile solutions of the new compositions parenterally, these solutions should still be essentially isotonic when administered intravenously.

A suspension for parenteral administration can also be prepared by suspending the active ingredient in a vegetable oil suitable for parenteral administration with or without additional auxiliaries and sterilizing it after filling into ampoules. 40 For oral use in veterinary medicine, the active ingredient is expediently prepared in the form of a feed premix. The feed premix can contain the active ingredient in admixture with a measurable pharmaceutical diluent, such as, for example, starch, oat 4S flour, flour, calcium carbonate, talc, dried fish meal and the like. The premix prepared in this way is then expediently added to the normal feed, so that the animal receives the medicament in the course of feeding.

50 The term "unit dosage form" used in this specification refers to physically separate units that are suitable as unit dosages for humans and animals, each unit containing a predetermined amount of the active ingredient calculated to be 55 in association with the required pharmaceutical diluent, carrier or carrier material the desired therapeutic effect is achieved. The characteristics for the new unit dosage forms of the present invention inevitably depend on the following factors: 60 a) the unique properties of the active ingredient and the particular therapeutic effect which is to be achieved, and b) the limitations in the technique of producing a mixture with such Active ingredient for thera-6S use in humans and animals.

Examples of suitable unit dosage forms are tablets, capsules, pills, powder packs, granules, waffles, gelatin capsules, suppositories, parenteral solutions.

5

646056

Riboflavin-5'-phosphoric acid-Na

Nicotinamide

Dexpanthenol

Pyridoxine hydrochloride

Well +

K +

Mg ++

cr

Example 9 Parenteral solution

L-isoleucine

L-leucine

L-lysine

L-methionine

L-phenylalanine

L-threonine

L-tryptophan

L-valine

L-arginine

L-histidine

Amino acetic acid

L-alanine

L-proline

Sorbitol xylitol

L-malic acid

Carnitine

Sodium chloride

Sodium dihydrogen phosphate

Potassium chloride

Magnesium chloride (6H20)

Example 10 Parenteral solution

L-arginine

L-malic acid

Sorbitol

Carnitine

Well +

K +

cr

Malate "

Asparagine

Riboflavin-5'-phosphoric acid ester,

Na salt

Nicotinamide

Dexpanthenol

Pyridoxine hydrochloride

Example 11 Parenteral solution

L-isoleucine L-leucine L-lysine L-methionine L-phenylalanine L-threonine L-tryptophan L-valine L-arginine L-histidine aminoacetic acid L-alanine L-proline

Total amino acids L-malic acid

0.002 g / 1 0.015 g / 1 0.010 g / 1 0.002 g / 1 0.690 g / 1 0.782 g / 1 0.122 g / 1 2.127 g / 1

5.00 g / 1 7.40 g / 1 6.60 g / 1 4.30 g / 1 5.10 g / 1 4.40 g / 1 2.00 g / 1 6.20 g / 1 12. 00 g / 1 3.00 g / 1 14.00 g / 1 15.00 g / 1 15.00 g / 1 50.00 g / 1 50.00 g / 1 8.94 g / 1 0.50 g / 1 1.17 g / 1 1.56 g / 1 1.49 g / 1 1.02 g / 1

28.9 g / 1 14.7 g / 1 50.0 g / 1 0.9 g / 1. 37.0 mval / 1 40.0 mval / 1 40.0 mval / 1 27.0 mval / 1 10.0 mval / 1

0.012 g / l 0.100 g / 1 0.020 g / 1 0.080 g / 1

4.67 g / 1 7.06 g / 1 5.97 g / 1 4.10 g / 1 4.82 g / 1 4.21 g / 1 1.82 g / 1 5.92 g / 1 10, 64 g / 1 2.88 g / 1 15.95 g / 1 15.00 g / 1 15.00 g / 1 100.00 g / 1 8.08 g / 1

15

• Carnitine 0.75 g / 1 electrolyte

Sodium chloride 1.753 g / l

Potassium chloride 1.491 g / 1

Magnesium chloride (6H20) 1.015 g / 1 The following applies to the electrolytes:

Na + 30.0 mmol / 1 = 30.0 meq / 1 0.690 g / 1

K + 20.0 mmol / 1 = 20.0 meq / 1 0.782 g / 1

Mg + + 5.0 mmol / 1 = 10.0 meq / 1 0.122 g / 1

he 60.0 mmol / 1 = 60.0 meq / 1 2.127 g / 1

Total nitrogen content 16.0 g / 1

Example 12 Solid Diet Mix

Protein (oligo- and polypeptides

from high quality proteins)

12.30 g

nitrogen

1.97 g

20th

Fat (sunflower oil)

3.30 g

essential fatty acids

2.00 g

Carbohydrates (oligo- and polysaccharides)

67.80 g

Carnitine

1.50 g

Vitamin supplements

25th

A (retinol acetate)

833 IU

D3 (cholecalciferol cholesterol)

67 IU

E (D, L-a-tocopherol acetate)

5 IU

K3 (menadione)

33.00 Hg

Bj (thiamine nitrate)

0.27 mg

30th

B2 (riboflavin-5-phosphoric acid ester,

Sodium salt)

0.26 mg

Nicotinic acid (nicotinic acid amide)

3.20 mg

B6 (pyridoxine hydrochloride)

0.28 mg

Bj2 (cyanocobalamin)

1.00 ng

35

Pantothenic acid (Ca-D pantothenate)

2.30 mg

myo-inositol

40.00 mg

Choline (calcium phosphorylcholine

chorid-4H20)

0.11g

Biotin

0.04 mg

40

Folic acid

0.10mg

C (ascorbic acid)

16.00 mg

Electrolytes

Na + <766 mg

= 33.3 meq

K + <520 mg

= 13.3 meq

45

Ca ++ 234 mg

= 11.7 meq

Cl "^ 1064 mg

= 30.0 meq

P 250 mg

50

55

60

65

Example 13 Solid Diet Mix

L-amino acids 7.824 g

(Alanine, arginine, asparagine, glutanine,

Glycocoll, histidine hydrochloride,

Isoleucine, leucine, lysine hydrochloride,

Methionine, monomagnesium L-glutamate, phenylalanine, proline, serine,

Threonine, tryptophan, tyrosine ethyl ester hydrochloride, valine)

Neutral oil

(MCT medium chain triglycerides)

Sunflower oil contains essential fatty acids carnitine carbohydrates (maltodextrin, cold-swelling starch sucrose) 74.0

Sodium chloride 146.0

0.33 g 2.34 g 2.00 g 1.2 g mg

646 056

6

Calcium chloride

48.0 mg

Calcium D-pantothenate

2.50

mg

Dipotassium hydrogen phosphate

726.0 mg

Riboflavin-5'-phosphoric acid ester,

Calcium glycerophosphate

633.0 mg

Sodium salt (B2)

333.30

Ed

Copper acetate (1H20)

0.387 mg

Aneurine nitrate (Bj)

333.30

Ed

Iron II gluconate (2H20)

28.8 mg s pyridoxine hydrochloride (Be)

333.30

Ed

Potassium iodide

53.3 Hg

Cyanocobalamin

Manganese Acetate (4H20)

3.33 mg

(Vitamin B12 cyano complex)

1.00

Ed

zinc oxide

2.0 mg

Vitamin A acetate, high concentrate

Vitamins

(1 g = 10® IE)

0.83

mg

Ascorbic acid (C)

16.00 mg io a-tocopherol acetate

Biotin

40.00 Hg

(Vitamin E acetate)

5.00 mg

Calcium phosphorylchplin chloride (4H20)

295.00 mg

Cholecalciferol cholesterol

Folic acid

100.00 | ig

(D3 cholesterol)

3.5

Ed

Nicotinamide

3.30 mg myo-inositol

40.0

mg

15

20th

25th

30th

55

40

45

50

60

Claims (6)

646 056 PATENT CLAIMS 1. Pharmaceutical or dietetic agent containing carnitine in addition to carriers and additives. 2. Composition according to claim 1, characterized in that it contains amino acids for parenteral nutrition. 3. Agent according to one of the preceding claims, characterized in that it contains electrolytes. 4. Composition according to one of the preceding claims that it contains sugar. 5. Composition according to one of the preceding claims that it contains vitamins. 6. Agent according to one of the preceding claims that it is in powder form.