Composition comprising L-carnitine or acyl-L-carnitine in combination with an ACE-inhibitor for the treatment of cardiovascular disorders

Abstract: Compositions containing (a) L-carnitine, an acyl L-carnitine, or a pharmacologically acceptable salt thereof in combination with (b) an ACE-inhibitor are useful for treating cardiovascular disorders. Orally, parenterally, rectally or transdermally administrable pharmaceutical compositions in unit dosage form contain from about 0.5 to about 2 g of L-carnitine, or an equimolar amount of an acyl L-carnitine or a pharmacologically acceptable salt thereof, and, e.g., from about 5 to about 20 mg of the ACE-inhibitor lisinopril.

Description: The present invention relates to orally, parenterally, rectally, or transdermally administrable pharmaceutical compositions suitable for treating cardiovascular disorders, which comprise, as active ingredients, L-carnitine, an acyl L-carnitine, or a pharmacologically acceptable salt thereof and an ACE-inhibitor. Previous therapeutical uses of L-carnitine are already known. For instance, L-carnitine has been used in the cardiovascular field in the treatment of acute and chronic myocardial ischemia, angina pectoris, cardiac arrhythmias and cardiac insufficiency. In nephrology, L-carnitine has been administered to chronic uremic patients who are subjected to regular hemodialysis treatment with a view to counteracting muscular asthenia and the onset of muscular cramps. Further therapeutic uses are the restoration of the HDL/LDL+VLDL ratio to normal and in total parenteral nutrition. The use of L-carnitine for the treatment of certain myopathies and muscular dystrophies is also known. The ACE-inhibitors form a class of medicaments that has been recently introduced and are capable of preventing the conversion or angiotensin I into angiotensin II, with a consequent anti-hypertensive effect. Typical ACE-inhibitors include: captopril, enalapril, lisinopril, ramipril, fosinopril, zofenopril, pivopril, rentiapril, quinapril, indolapril, spirapril, pentopril, benazepril, libenzapril, cilazapril, delapril and perindopril. The main indications for which ACE-inhibitors are used are essential hypertension and renovascular hypertension. Recently, combination preparations of ACE-inhibitors with various types of other medicaments have been proposed for the treatment of diverse pathological conditions. Examples of such combination preparations and the relative therapeutic indications are set out in Table 1. Known combination preparations of ACE-inhibitors with other medicaments Medicaments Indications Reference Captopril + diltiazem hypertension US 4,871,731 ACE-inhibitors + calcium antagonists loss of cognitive functions, Alzheimer, senile dementia EP 0 344 995 ACE-inhibitors + thrombolitics myocardiac post-ischaemia disfunction EP 0 366 033 ACE-inhibitor + lithium depression US 4,912,096 ACE-inhibitors + calcium antagonists medicament addiction EP 381 075 ACE-inhibitors + calcium antagonists appetite suppression EP 381 074 ACE-inhibitor + flosequinam cardiopathies myocardiac infarction WO 90/10445 The combinations set out above, particularly if used in the cardiovascular field, do not appear to be wholly satisfactory in that it is foreseeable that the improved therapeutic activity would be accompanied by at least the sum of the side effects of the ACE-inhibitors themselves on the one hand and on the other hand the side effects of the medicaments combined with them. In particular, in the case of the compositions containing calcium antagonists, side effects caused by excessive peripheral vasodilatation with consequent tachycardial reflex effects are to be expected. With regard to the use of acyl carnitines in combination with other medicaments, US-A-4,537,772 discloses combinations of acyl carnitines (in which the acyl group can be saturated C 2 -C 20 acyl, C 2 -C 20 acyl with 1-6 double bonds, C 2 -C 20 hydroxyacyl with 1-3 hydroxyl groups, C 4 -C 20 ketoacyl, unsaturated C 5 -C 20 hydroxyacyl or C 5 -C 20 carbolkoxyacyl) and their pharmacologically acceptable salts in combination with various classes of medicaments, such as beta-lactamase antibiotics, aminoglycosidic antibiotics, antiviral agents, amino acids, relaxing agents for the smooth musculature, polypeptides, anti-inflammatory agents and diuretics. The only example supplied in US-A-4,537,772 of combination between an acyl carnitine and a medicament with cardiovascular anti-hypertensive action is a combination of palmitoyl carnitine chloride and methyl dopa. The effect foreseen in US-A-4,537,772 consists of improved gastrointestinal absorption (induced by the presence of the acyl carnitine) of a medicament which is poorly absorbed when administered on its own by the oral or rectal route. It is clear that there is no correlation between the use of acyl carnitines described in United States Patent No. 4,537,772 and that which forms the subject of the present invention. Thus, there remains a need for pharmaceutical compositions useful for treating cardiovascular disorders. Accordingly, it is one object of the present invention to provide novel pharmaceutical compositions for treating cardiovascular disorders. It is another object of the present invention to provide pharmaceutical compositions which exhibit a low tendency to case side effects. These and other objects, which will become apparent during the following detailed description, have been achieved by the inventor's discovery that the combination of (a) L-carnitine, an acyl L-carnitine, or a pharmacologically acceptable salt thereof with (b) an ACE-inhibitor offers significant advantages over previously available medicaments for treating cardiovascular disorders, such as ischemia, infarction, angina, hypertension, and congestive heart failure. Thus, in a first embodiment, the present invention provides pharmaceutical compositions comprising (a) L-carnitine, an acyl L-carnitine, or a pharmacologically acceptable salt thereof, and (b) an ACE-inhibitor as the active ingredients and a pharmacologically acceptable carrier or excipient. These compositions are suitable for oral, parenteral, rectal or topical (transdermal) administration. The acyl L-carnitine useful for the pharmaceutical compositions and methods of the present invention are those wherein the acyl group is a straight or branched-chain alkanoyl group having from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms. Particularly preferred are acetyl, propionyl, butyryl, valeryl and isovaleryl L-carnitines. Pharmaceutically acceptable salts of L-carnitine include all pharmaceutically acceptable salts which are prepared by the addition of an acid to L-carnitine, and which do not give rise to undesired toxic or side effects. The formation of pharmaceutically acceptable acid addition salts is well known in pharmaceutical technology. Examples of suitable salts include the chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate, acid fumarate, lactate, maleate, acid maleate, acid oxalate, acid sulphate, glucose phosphate, tartrate and acid tartrate salts. Other suitably acceptable salts which are nontoxic and provide substantially similar results to administration of L-carnitine and the above-identified pharmaceutical salts will be readily apparent to one having ordinary skill in the art and are considered to be equivalent to the salts enumerated above. For the sake of simplicity and clarity, hereinbelov reference viii be made to L-carnitine only, it being understood, however, that whatever is disclosed in connection with L-carnitine equally applies to the above-identified acyl L-carnitine and pharmacologically acceptable salts thereof. Suitable ACE-inhibitors include captopril, enalapril, lisinopril, ramipril, fosinopril, zofenopril, pivopril, rentiapril, quinapril, indolapril, spirapril, pentopril, benazepril, libenzapril, cilazapril, delapril and perindopril. The compositions of the invention suitably contain from 1 to 90% by weight, preferably 25 to 75% by weight, based on the total weight of the composition, of an ACE-inhibitor and from 1 to 90% by weight, preferably 25 to 75% by weight, based on the total weight of the composition, of L-carnitine. Unit dosage forms will preferably contain from 0.5 g to 2 g of L-carnitine, while the quantity of ACE-inhibitor will depend on the characteristics of this component. For example, with specific reference to ACE-inhibitors already approved for clinical use, ramipril may be present in quantities from 1 to 10 mg, enalapril from 5 to 50 mg, captopril from 10 to 100 mg, and lisinopril from 5 to 50 mg. The composition of the present invention may also be in the form of separate dosage units for simultaneous, separate or sequential use. In particular, compositions comprising about 1 g of L-carnitine and from 5 to 20 mg of lisinopril are preferred, for administration once per day. Using other ACE-inhibitors having different pharmacological characteristics (such as captopril), the compositions of the invention will preferably be administered two or more times per day, up to a daily dosage of 2-3 g of L-carnitine and 20-300 mg of ACE-inhibitor. Suitable forms of administration include capsules, tablets, syrups, granules, ampoules or phials, suppositories, or aqueous or oleous solutions. The compositions of the invention can be prepared by resorting to conventional processes and excipients, such as are described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., New York, USA, XVIII Ed., 1984. As noted above, the cardiovascular disorders which may be treated by the present method include ischemia, infarction, angina, hypertension, and congestive heart failure. The present composition may be used by oral, parenteral, rectal, or transdermal administration. Oral administration is obviously preferred for chronic pathologies, while the parenteral route may be preferable for acute pathologies, for example in the case of an infarction. Although the exact dosage ranges of (a) L-carnitine, acyl L-carnitine, or pharmacologically acceptable salt thereof and (b) the ACE-inhibitor will vary according to the exact condition being treated and the state of the patient being treated, typically, the composition will comprise 0.5 to 3g, preferably about 1 to 2g, of L-carnitine (or an equimolar amount of the acyl L-carnitine or salt thereof) daily and 1 to 500mg, preferably 5 to 100mg of the ACE-inhibitor daily. As discussed above, the dosage range of the ACE-inhibitor may be adjusted based on the exact identity of the ACE-inhibitor. EXAMPLES Set out below are the results of certain clinical trials which demonstrate the advantages obtained by the present invention. Clinical trails 25 patients suffering from congestive heart failure as a result of coronary pathologies or of ischemia of the myocardium, who had already been treated without appreciable therapeutic response with diuretics and an ACE-inhibitor (captopril) for periods longer than 30 days, were given lisinopril (4 mg) and L-carnitine (1 g) for 15 days. At the end of the treatment, 23 patients had a hemodynamic profile that was distinctly better, characterized by a reduction of systemic vascular resistance, an increase in contractility and cardiac output not accompanied by an increase in cardiac frequency, and a reduction in venous pressure. Only two patients did not show significant improvements but the preliminary data indicated that extension of the period of treatment would have produced beneficial effects even in these non-responders. In none of the patients were toxic effects or side effects noted that could be attributed to the pharmacological treatment. The results set out above show clearly that L-carnitine is able to contribute markedly to treatment with ACE-inhibitors of non-responder patients, without a need to increase the dosage. Compositions The following examples illustrate some typical compositions of the present invention. Example 1 : TABLETS Lisinopril 5 mg L-carnitine 100 mg microcrystalline cellulose 250 mg magnesium stearate 20 mg lactose 100 mg Example 2 : CAPSULES enalapril 10 mg L-carnitine 750 mg lactose 250 mg Example 3 : CAPSULES captopril 50 mg L-carnitine 1000 mg lactose 500 mg Example 4 : TABLETS ramipril 50 mg L-carnitine 350 mg starch 40 mg gelatin 10 mg microcrystalline cellulose 20 mg magnesium stearate 5 mg Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings.

Claims: A pharmaceutical composition, comprising: (a) L-carnitine, an acyl L-carnitine (wherein the acyl group is a straight or branched alkanoyl group having 2-8 carbon atoms), or a pharmacologically acceptable salt thereof; (b) an ACE-inhibitor; and (c) a pharmacologically acceptable excipient. The composition of Claim 1, wherein said acyl group is an alkanoyl group having 2-6 carbon atoms. The composition of Claim 1, wherein said acyl group is selected from the group consisting of acetyl, propionyl, butyryl, valeryl, and isovaleryl. The composition of Claim 1, wherein said ACE-inhibitor is selected from the group consisting of captopril, enalapril, lisinopril, ramipril, fosinopril, zofenopril, pivopril, rentiapril, quinapril, indolapril, spirapril, pentopril, benazepril, libenzapril, cilazapril, delapril, and perindopril. The composition of Claim 1, which in unit dosage form comprises: (a) from 0.5 to 2 g of L-carnitine or an equimolar amount of said acyl L-carnitine or said pharmacologically acceptable salt thereof; and (b) from 1 to 50 mg of said ACE-inhibitor. The composition of claim 1, which is in a form suitable for oral, parenteral, rectal, or transdermal administration. Use of L-carnitine or an acyl L-carnitine wherein the acyl group is a straight or branched alkanoyl having 2-8, preferably 2-6, carbon atoms or a pharmacologically acceptable salt thereof in combination with an ACE-inhibitor for preparing a medicament for treating cardiovascular disorders.

Inventors: CAVAZZA CLAUDIO, CAVAZZA, CLAUDIO
Applicants: SIGMA TAU IND FARMACEUTI, SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A.
Application year: 1993
Main classification: A61K38
IPC codes: A61K31, A61P9, A61K45, A61P43, A61K38