GB2052976A - Pharmaceutical preparation containing carnitine for lowering the lipid level in the body - Google Patents

Abstract

A pharmaceutical preparation useful in reducing the level of lipo- proteins in the body in the treatment of hyperlipoproteinaemia contains an active dose of carnitine and conventional carriers and/or additives such as amino acids, sugars, vitamins/salts.

Description

SPECIFICATION Pharmaceutical preparation for lowering the lipid level in the body This invention relates to a pharmaceutical preparation for lowering the lipid level in the body, in particular an agent by which the level of lipoproteins in the seurm can be lowered.

At a rough estimate, ca. 20% of the population suffer from hyperlipoproteinaemia. A high proportion of these subjects are unaware of their condition. Together with nicotine abuse, this hyperlipoproteinaemia is a major risk factor in the development of arteriosclerosis which is liable to lead to strokes, disturbances in the blood supply to the extremities and disturbances in the blood supply to the heart and hence to cardiac infarction. Apart from the problem of cancer, the pathological conditions caused by hyperlipoproteinaemia at present constitutes one of the most pressing problems in medicine.

Lipoproteins serve as transport vehicles for the sparingly water soluble lipids, carrying triglycerides from the intestinal wail and liver to the sites and tissues where they are to be used.

These lipoproteins may be subdivided into four main groups according to their protein content and lipid content: 1. chylomicrons, 2. very low density lipoproteins (VLDL), 3. low density lipoproteins (LDL) and 4. high density lipoproteins (H DL).

These lipoproteins can be determined both quantitatively and qualitatively by electrophoresis.

The electrophoretically-determined lipid composition and total lipid content can give a ciear indication of incipient or already established hyperlipoproteinaemia.

The LDL and VLDL lipoprotein fractions are of pre-eminent important in the generation of cardio-vascular diseases whereby chylomicrons and HDLs have not hitherto been shown to produce any adverse effects and have even shown advantageous effects. While the chylomicron patricles transport the fats absorbed from the intestine, the very low density lipoproteins transport triglycerides endogenously synthesized in the liver to the peripheral tissues to be used or stored there. After release of the triglycerides, an increase in cholestorol and phospholipide content takes place and the small, cholestorol rich LDLs are formed. The last two lipoprotein particles mentioned constitute the main risk factor in the development of arteriosclerosis and cardiac infarction.If hyperlipidaemia and hyperlipoproteinaemia are to be effectively combatted, the concentrations of these lipid transport particles in the serum must be lowered to a level at which there is no acute risk of development of arteriosclerosis.

For the preventive treatment of patients who tend to develop arteriosclerosis at an early age, a combination of dietary and medical treatment is frequently proposed. Whereas the dietary treatment consists mainly in replacing saturated fatty acids in the diet by unsaturated fatty acids and reducing the total fat intake, the medical treatment has numerous variations.

The substances are used to accelerate lipoprotein catabolism are frequently substances which cannot be reabsorbed, such as ion exchangers, e.g. cholestyramine, neomycin and the like, as well as reabsorbable substances such as d-thyroxine. These substances act either by replacing the cholestrol which is responsible for the formation of deposits on the walls of the vessels (cholestyramine) or by promoting the oxidation of cholesterol to bile acids. The side effects produced by these preparations (constipation, nausea, deficiency symptons and increased incidence of cardiac complications) have led to their being discontinued, at least in the case of thyroxine.

Substances which inhibit lipoprotein production have also been used. Among the most common drugs belonging to this group of substances are nicotinic acid and clofibrate.

Substances of this type either reduce LDL synthesis (nicotinic acid) or control VLDL production (clofibrate). Therapeutic success is thus achieved mainly in conditions of raised triglyceride levels.

Preparations containing these substances also have serious side effects, inter alia nausea, gastrointestinal symptons such as upper abdominal pain, formation of gallstones, and the like.

This has recently led to the removal of clofibrate from the market.

At the same time, the requirement for certain essential fatty acids in the human diet must be met. A fat-free diet causes serious growth disturbances and other pathological changes, particularly in the hair and skin. Patients with post-traumatic and post-operative katabolism, in which a raised lipid level is ascertained at the beginning, show a serious loss of essential fatty acids within a few days. These essential fatty acids must be supplied either from the fat reservoir or from a suitable exogenous supply of fat. If the patient is to be nourished parenterally, administration is problematic since fats are not water-soluble and must therefore be infused in a suitably emulsified form. A balanced fat supply was found to be necessary under these conditions because the reservoir of body fats has not made sufficient fat available.

It is an object of the present invention to provide means for both lowering the serum lipid concentration and accelerating lipid breakdown.

It has now bsen found that the blood lipid level can be substantially lowered by means of carnitine. This substance, which corresponds to the following general formula

is known to be present in the body tissues but its function remained unknown for a long time until it was found to constitute an essential growth factor for mealworms. It was concluded from this observation that carnitine performs a specific function in cell growth. On this basis, it may be classified as an insect vitamin (BT).

It is also known for its transport properties, by means of which fatty acid-co A products are washed out of the tissues into the mitochondria. This effect is attributable to the action of an enzyme which catalyses the transfer of the fatty acid group from co A to carnatine. After this transfer, the fatty acid-carnitine product passes through the membrane to enter the mitochondria where it is again decomposed to form fatty acid-co A. This product is finally broken down in the mitochondria and metabolised.

It has now surprisingly been found that the exogenous addition of carnitine, either in parenteral solutions or in pharmaceutical preparations administered orally, is effective in lowering the serum lipid level. A marked reduction in the lipid in the serum may be observed both in patients suffering from hyperlipoproteinaemia and in patients having a raised lipid level in the post-traumatic phase. Furthermore, the transport of lipid from the lipid pool could obviously be accelerated since no drop in the essential fatty acid content in the serum can be observed in patients with post-traumatic katabolism, even after several days.

The carnitine used in the preparations of the invention, which is in its ordinary commercial form of water-soluble crystals, may be used in combination with a pharmaceutical vehicle to give solid or liquid preparations such as tablets, capsules, powders, pills, granules, syrups, elixirs, suppositories or sterile dispersions in water or vegetable oils for parenteral or other forms of administration either alone or in combination with other drugs, for example in parenteral feeding.

The powders are prepared by breaking down the active substance into suitably fine particles and mixing it in this form with a similarly finely-divided diluent. The diluent may be an edible carbohydrate material such as starch. A sweetener and flavouring are preferably also added.

Capsules can be prepared by making up a powder mixture as described above and filling it into preformed gelatine containers. A lubricant such as, for example, talc, magnesium stearate or calcium stearate is advantageously added to the powder mixture before it is filled into the capsules to aid the filling process.

Tablets may be prepared by making up a powder mixture, granulating it or suspending it to form a slurry, adding a lubricant and compressing the mixture to form tablets. The powder mixture can be prepared by mixing the finely-divided active substance with a diluent or a base such as, for example, starch, lactose, kaolin, dicalcium phosphate, calcium sulphate or the like.

The powder mixture may be granulated by moistening it with a binder such as a syrup, gelatine solution, methyl cellulose solution or acacia gum, and pressing it through a sieve. As an alternative to granulating it in the moist state, the powder mixture may be finely divided, i.e it may be passed through a tablet press and the large tablets obtained may then be crushed to form a granulate. To prevent the mixture sticking in the tablet press, the granulates can be lubricated by the addition of stearic acid, a stearate, talc or a mineral oil. The mixture containing lubricant is then pressed to form tablets. The tablets may advantageously be covered with a protective coating of shellac which acts as a seal, and then covered with sugar and methyl cellulose and finally glazed with a coating of carnauba wax.

Liquids for oral administration can be made up in a form which can be taken in single doses, such as syrups and elixirs, each teaspoonful of which contains a previously-determined quantity of the active substance to be administered.

A syrup may be prepared by dispersing the active substance in an aqueous sugar solution containing suitable flavourings. An elixir can be similarly prepared, using an aqueous alcoholic carrier agent. Elixirs are suitable for use as carrier materials if the composition contains a therapeutic agent which is not sufficiently water soluble.

The preparations according to the invention for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions and emulsions with or without the additions of local anaesthetics. These compositions may contain additives such as emulsifying and dispersing agents. They may be sterilized, for example by filtration through filters which are impervious to bacteria, by the addition of sterilizing agents to the preparations or by irradiation or heating.

They may also be prepared in the form of solid sterile preparations, for example by freeze drying, and these may then be dissolved in sterile water or some other sterile medium suitable for injection immediately before use.

Although sterile solutions of the new compositions may, of course, be administered parenterally, the solutions should be substantially isotonic when used in intravenous drips.

A suspension for parenteral administration may also be prepared by suspending the active substance in a suitable vegetable oil for parenteral administration, with or without the addition of auxiliary agents, and sterilizing the suspension after it has been introduced into ampoules.

For oral administration in veterinary medicine, the active substance is suitably prepared in the form of a premix to be added to feeds. The premix may contain the active substance in admixture with an edible pharmaceutical diluent such as starch, oatmeal, flour, calcium carbonate, talcum, dried fish meal or the like. The premix prepared in this manner is then suitably added to the normal feed so that the animal receives the medicament in the course of feeding.

Thevlerm "unit dose form" used in this description and the claims denotes physically separate units suitable as unit doses for human and animal subjects, each unit containing a predetermined quantity of the active constituent calculated to produce the desired therapeutic effect when used in combination with the necessary pharmaceutical diluents, vehicles or carriers. The characteristics of the new unit dose forms of the present invention inevitably depend on the following factors: (a) the unique characteristics of the active substance and the special therapeutic effect to be achieved and (b) the limitations in the techniques of preparing a mixture with such an active substance for therapeutic use in humand and animals.

Examples of suitable unit dose forms are: tablets, capsules, pills, powder packets, granulates, wafers, gelatine capsules, suppositories, parenteral solutions, separate multiple preparations of one of the forms mentioned above and other forms described here.

The quantity of active substance 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 dose to be administered lies within the range of from 1-120, preferably from 5-90, in particular from 8-70 mg/kg of body weight. The dose for humans is in the range of ca. 400 mg to 10 g per day, either as a single dose or sub-divided into three or four doses. The doses in veterinary medicine correspond to those used for humans, the quantities bearing the same relationship to the body weight of the animal as in adult humans.

The invention will now be described in more detail with the aid of the following examples.

Example 1 Tablets 20,000 notched tablets for oral administration, each containing 500 mg of carnitine, were prepared from the following constituents: Carnitine, ground to finest particles 10 kg starch 350 g talcum 250 g calcium stearate 35 g The carnitine ground to finest particles was granulated with a 4% (weight/volume) aqueous solution of methyl cellulose. A mixture of the remaining constituents is added to the dried granulate and the mixture finally obtained is pressed to form tablets of the appropriate weight.

Satisfactory clinical reactions were obtained in adult sufferers of hypolipoproteinaemia by the administration of 5 tablets per day, distributed uniformly over the day.

Example 2 Capsules 20,000 jointed hard gelatine capsules for oral administration, each containing 500 mg of carnitine, were prepared from the following constituents: Carnitine 10 kg lactose 1 kg starch 300 g talcum 65 g calcium stearate 25 g Carnitine ground to finest particles was mixed with the starch-lactose mixture and then with the talcum and calcium stearate. The final mixture obtained was filled into the capsules in the usual manner. One capsule was administered 3 hourly to control lipoproteinaemia. Capsules containing 100, 200, 300 and 400 mg of carnitine were also prepared by using 2 kg, 4 kg, 6 kg and 8 kg in the above formulation instead of 10 kg.

Example 3 Soft elastic capsules Unjointed soft elastic capsules for oral administration, each containing 200 mg of carnitine, were prepared by the usual method, the pulverulent active material being first dispersed in a sufficient quantity of corn oil so that it could be worked up into a suitable consistency for capsules.

Example 4 Aqueous preparation An aqueous preparation for oral administration containing 200 mg of carnitine in 5 ml was prepared from the following constituents: Carnitine 400 g Methylparabene 7.5 g propylparabene 2.5 g sodium saccharin 12.5 g sodium cyclamate 2.5 g glycerol 31 tragacanth powder 10 g orange oil flavouring 10 g orange dye 7.5 g de-ionised water to make up to 10 litres Example 5 Suspension for parenteral administration A sterile aqueous suspension suitable for intramuscular injection, containing 200 mg of carnitine per millilitre, was prepared from the following constituents: polyethylene glycol 3 g sodium chloride 0.9 g polysorbate 0.4 g sodium metabisulphite 0.1 g methylparabene 0.18 9 propylparabene 0.02 g cart tine 20 g water for injection to make up to 100 ml Example 6 Aqueous solution An aqueous solution for oral administration containing 500 mg of carnitine in 25 ml of solution was prepared from the following constituents: carnitine 100 g de-ionised water to make up to 1 litre Example 7 Solution for parenteral administration A sterile aqueous solution for intravenous or intra-muscular injection containing 100 mg of carnitine in 2 ml was prepared from the following constituents: carnitine 50 g chlorobutanol 3 g water for injection to make up to 1 litre Example 8 Parenteral solution 1-isoleucine 2.50 g/l 1-leucine 3.70 g/l 1-lysine 3.30 g/l 1-methionine 2.15 g/l 1-phenylalanine 2.55 g/l 1-threonine 2.20 g/l 1 -valine 3.10 g/l 1-arginine 6.00 g/l 1 -histidine 1.50 g/l aminoacetic acid 7.00 g/l 1-alanine 7.50 g/l 1-proline 7.50 gil sorbitol 150.00 g/l 1-malic acid 4.70 g/l carnitine 0.50 g/l 1-tryptophane 1.00 g/l riboflavine-5' phosphoric acid ester-N 0.002 g/l nicotinamide 0.015 g/l dexpanthenol 0.010 g/l pyridoxine hydrochloride 0.002 g/l Na+ 0.690 g/l K+ 0.782 g/l Mg+ + 0.122 g/l Cl- 2.127 g/l Example 9 Parenteral solution 1-isoleucine 5.00 g/l 1-leucine 7.40 g/l 1 -lysine 6.60 g/l 1 -methionine 4.30 9/ I 1-phenylalanine 5.10 g/l 1-threonine 4.40 g/l 1-tryptophane 2.00 g/l 1 -valine 6.20 9/1 1-arginine 12.00 g/l 1-histidine 3.00 g/l aminoacetic acid 14.00 g/l 1-alanine 15.00 9/l 1-proline 15.00 gil sorbitol 50.00 g/l xylitol 50.00 gil 1-malic acid 8.94 g/l carnitine 0.50 g/l sodium chloride 1.17 gil sodium dihydrogene phosphate 1.56 gil potassium chloride 1.49 gil magnesium chloride (6H20) 1.02 gil Example 10 Parenteral solution 1-arginine 28.9 9/1 1-malic acid 14.7 g/l sorbitol 50.0 g/l carnitine 0.9 g/l Na+ 37.0 mval/l 40.0 mval/l Cl- 40.0 mval/l malate- 27.0 mval/l asparagine- 10.0 mval/l riboflavine-5' phosphoric acid ester, Na salt 0.012 9/1 nicotinamide 0.100 g/l dexpanthenol 0.020 g/l pyridoxine hydrochloride 0.080 gil Example Ii Parenteral solution 1-isoleucine 4.67 g/l 1-leucine 7.06 g/l 1-lysine 5.97 g/l 1-methionine 4.10 g/l 1-phenylalanine 4.82 g/l 1-threonine 4.21 g/l 1-tryptophane 1.82 g/l 1-valine 5.92 g/l 1-arginine 10.64 g/l 1-histidine 2.88 g/l aminoacetic acid 15.95 g/l 1-alanine 15.00 gil 1-proline 15.00 g/l total amino acids 100.00 g/l 1-malic acid 8.08 gil carnitine 0.75 g/l electrolytes sodium chloride 1.753 gil potassium chloride 1.491 g/l magnesium chloride (6H20) 1.015 gil The following applies to the electrolytes:: Na+ 30.0 mmol/l 30.0 mval/l 0.690 g/l K+ 20.0 mmol/I =20.0 mval/l 0.782 g/l Mg++ 5.0 mmol/l= 10.0 mval/l 0.122 g/l Cl- 60.0 mmol/l=60.0 mval/l 2.127 g/l total nitrogen content 16.0 g/l Example 12 Solid diet mixture Protein (oligo-and polypeptides from high grade proteins) 12.30 g nitrogen 1.97 g fat (sunflower oil) 3.30 g a proportion of essential fatty acids 2.00 g carbohydrates (oligo and polysaccharides) 67.80 g carnitine 1.50 g vitamin supplements A (retinol acetate) 833 IU D3 (cholecalciferol-cholesterol) 67 IU E (d,1 -oe-tocopherol acetate) 5 IU K3 (menadione) 33.00 g B1 (thiamine nitrate) 0.27 mg B2 (riboflavin -5-phosphoric acid ester, sodium salt) 0.26 mg nicotinic acid (nicotinic acid amide) 3.20 mg B8 (pyridoxine hydrochloride) 0.28 mg B12 (cyanocobalamine) 1.00 pug pantothenic acid (Ca-d-pantothenate) 2.30 mg myoinositol 40.00 mg choline (calcium phosphoryl choline chloride.4 H20) O.11 g biotin 0.04 mg folic acid 0.10 mg C (ascorbic acid) 16.00 mg electrolytes Na+ '766 mg = 33.3 mval K+ ~520 mg = 13.3 mval Ca++ 234 mg = 11.7 mval Cl- 1064 mg = 30.0 mval P 250 mg Example 13 solid dietary mixture.

1-amino acids 7.824 g (alanine, arginine, asparagine, glutanine, glycocoll, histidine hydrochloride, isoleucine, leucine, lysine hydro chloride, methionine, monomagnesium-1 - glutamate, phenylalanine, proline, serine, threonine, tryptophane, tyrosine ethyl ester hydrochloride, valine) Neutral oil (MCT-medium chain triglycerides) 0.33 g sunflower oil 2.34 g a proportion of essential fatty acids 2.00 g carnitine 1.2 g carbohydrates (maltodextrine, cold swelling starch, saccharose) 74.0 g sodium chloride 146.0 mg calcium chloride 48.0 mg dipotassium hydrogen phosphate 726.0 mg calcium glycerophosphate 633.0 mg coper acetate (1 H20) 0.387 mg iron-ll-gluconate (2H2O) 28.8 mg potassium iodide 53.3 ,ug manganese acetate (4H2O) 3.33 mg zinc oxide 2.0 mg vitamins ascorbic acid (C) 16.00 mg biotin 40.00 ,ug calcium phosphoryl choline chloride (4H20) 295.00 mg folic acid 100.00 ,ug nicotinic acid amide 3.30 mg calcium-d-pantothenate 2.50 mg riboflavine-5'-phosphoric acid ester, sodium salt (B2) 333.30 g aneurine nitrate (B,) 333.30 'tg pyridoxine hydrochloride (B6) 333.30 y9 cyanocobalamine (vitamin B,2 cyanocomple) 1.00 ,ug vitamin A acetate, oily concentrate (1 g = 106 IU) 0.83 mg cu-tocopherol acetate (vitamin E acetate) 5.00 mg cholecalciferol cholesterol (D3 cholesterol) 3.5 ,ug myoinositol 40.0 mg

Claims (7)

1. A pharmaceutical preparation containing an active dose of carnitine and one or more conventional carriers and/or additives.

2. A pharmaceutical preparation according to Claim 1, in combination with amino acids for parenteral administration.

3. A pharmaceutical preparation according to either of the preceding claims, in combination with one or more electrolytes.

4. A pharmaceutical preparation according to any of the preceding claims, in combination with one or more sugars.

5. A pharmaceutical preparation according to any of the preceding claims, in combination with vitamins.

6. A pharmaceutica preparation according to any of the preceding claims, in a pulverulent form for dietary purposes.

7. A pharmaceutical preparation, substantially as herein described, with reference to any one of the Examples.