JP2003501385A - Anti-hyperlipidemic combination comprising HMG-COA reductase inhibitor and carnitines - Google Patents

Abstract

  (57) [Summary] Disclosed are pharmaceutical compositions containing lipid lowering agents, such as lovastatin, simvastatin, pravastatin and fluvastatin, and L-carnitine or alkanoyl L-carnitine. This pharmaceutical composition has substantially no toxicity or side effects of the lipid-lowering agent while maintaining the effectiveness of the lipid-lowering agent.

Description

Detailed Description of the Invention

The present invention relates to a pharmaceutical composition for treating a disease caused by deficient lipid metabolism.
In particular, the present invention relates to a pharmaceutical composition containing statin and L-carnitine or an alkanoyl derivative thereof, which is useful for preventing and treating statin-induced toxicity or side effects.

Patients with cardiovascular disorders involving impaired lipid metabolism are very numerous in developed countries.
In Italy, for example, over 40% of all deaths are due to this disease (Cap
ocaccia R., Farchi G., Prati S. et al .: La mortalita 'in Italia nell'anno
1989. Rapporto ISTISAN 1992/22). Recent epidemiologic studies have revealed the relationship between cholesterol and coronary heart disease. Epidemiological studies conclude that severe coronary atherosclerosis is closely associated with serum cholesterol levels (McGill HC Jr. et al .: The International Atherosclerosis P
Roject. Lab. Invest. 18: 463-653, 1968; Keys A .: Correlation between coronary heart disease and mortality in seven countries, Harvard University Press, Cambridge, 1980).

[0003] The first measure for hyperlipidemia is always to improve the diet and to get a proper diet. However, strict diet is often intolerable,
Also, due to the severity of hypercholesterolemia and genetic resistance, good results are not always obtained.

In such cases, it has proven necessary to rely on drug treatment with lipid-lowering drugs in order to reach the desired result, ie to restore blood triglyceride and cholesterol levels to normal. ing. This category includes drugs that primarily reduce cholesterol levels and drugs that primarily reduce triglyceride levels.

The former drug group includes statins, probucols and resins, and the latter drug group includes fibrate, nicotinic acid, and omega-3-series fatty acids.

Statins (simvastatin, lovastatin, pravastatin, fluvastatin, etc.) are inhibitors of hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins reduce cholesterol production in the liver by inhibiting this enzyme (Lancet 1994; 334: 1383-1389). To compensate for the decrease in intracellular cholesterol, hepatocytes produce receptors for the LDL and VLDL series of lipoproteins, which clear the blood of LDL and VLDL lipoproteins.

Furthermore, statins reduce the absorption of food-derived cholesterol in the small intestine and reduce the production of apoprotein B contained in low density lipoprotein (LDL). Although statins are well tolerated compared to other cholesterol lowering agents, they do have some disadvantages. The most common side effects from this drug are gastrointestinal disorders, skin redness and headaches.

Many patients receiving statins complain of sleep disorders (EJ Schaffer,
N Engl J Med, 319: 1222, 1988; Lancet, 339: 547, February 29, 1992), while 40
Transaminase activity (GOT and GP) in patients receiving mg / kg statin
A significant increase in T) and a significant increase in CK relative to the base value are observed (Schwe
iz Med Wochenschr 1991 Jun 29; 121 (26): 977-83).

In addition, patients receiving simvastatin have myopathy, rhabdomyolysis,
Has developed side effects associated with myalgia and increased serum CK and LDH activity (Dedl
ypere JP & Vermeulen A. (1991) Ann. Intern. Med. 114: 342; Bizzarro N.
et al. (1992) Clin. Chem. 38: 1504]. EP0383432 discloses the use of a combination of HMG-CoA reductase inhibitor and coenzyme Q10 for the treatment of skeletal muscle myopathy caused by statins.

Statins have been reported to result in a reduction in the number of deaths due to coronary heart disease, while increasing deaths due to other factors such as tumors or trauma are being treated Permitted in patients (Davey-Smith G., Song F., Sheldo
n TA, Lowering Cholesterol and Lethality: The Importance of Considering Initial Levels at Risk BMJ 1993; 306: 1367-1373; Ravnshov U .; Cholesterol Lowering Attempts in Coronary Heart Disease: Citation Frequency and Results. BMJ 1992; 305: 15-19). Treatment of young rats with multiple cholesterol-lowering agents (simvastatin, lovastatin, and pravastatin) showed signs of myopathy when high doses of simvastatin were used (Reijneveld JC et al., 1976 Pediatr. Res. .
39: 1028-1035). In addition, Bhuiyan et al. (Bhuiyan J. & Seccombe DW 1996 Lipid
s 31: 867-870) is the administration of lovastatin to rabbits to induce L in liver, heart and skeletal muscle.
-Showing that it leads to a significant decrease in carnitine.

The results of animal studies and human trials indicate that drug therapy with statins to lower cholesterol levels should be limited to a short duration for patients at high risk of heart disease. (JAMA, 1996; 275: 55-60).

The triglyceride and cholesterol lowering effects of many alkanoylcarnitines, especially acetyl L-carnitine, are also well known. U.S. Pat.No. 4,26
No. 8,524 is an abnormally high L in plasma of patients at risk of cardiovascular disorders
Disclosed is a method of selectively reducing the DL + VLDL: HDL ratio by increasing the level of high density lipoprotein (HDL). This is a method that involves daily administration of 5-50 mg / kg of alkanoylcarnitine or one of its pharmaceutically acceptable salts.

Applicant's International Patent Application WO 99/01126 discloses a method of treating dyslipidemia using alkanoyl L-carnitine in combination with statins. WO99 / 01126
Do not disclose that L-carnitine or alkanoyl L-carnitines have protective effects against statin-induced toxicity or side effects.

Unexpectedly, the combined use of L-carnitine or alkanoyl L-carnitine having a straight or branched chain alkanoyl group of 2 to 6 carbon atoms or one of its pharmaceutically acceptable salts with a statin Provides a protective effect against statin-induced toxicity or side effects.

As is well known, L-carnitine and alkanoyl L-carnitines have no side effects, and because of the protective action against statin-induced toxicity or side effects by these compounds, the dose (10- It is possible to administer a higher dose of statin than 20 mg / day).

The combined use according to the invention is particularly useful for treating patients at risk of hypercholesterolemia and / or hypertriglyceridemia of short-, medium- or long-term cardiovascular disease.

Due to the protective effect of L-carnitine or alkanoyl L-carnitines, the dose of L-carnitine or alkanoyl L-carnitine is 100-3000 m.
It has been found that it is possible to use g / day, in which case it is possible to use higher doses of statins than those normally used for the treatment of humans.

As used herein, the term “combined use” of the above compounds refers to (i) co-administration, ie
Administering L-carnitine or one of the above alkanoyl L-carnitines, or a pharmaceutically acceptable salt thereof, and a statin substantially simultaneously.
Or (ii) both including administering the composition containing the active ingredients in combination with suitable excipients as a mixture. The term "combination administration" means that L-carnitine or one of alkanoyl L-carnitines, or a pharmaceutically acceptable salt thereof, and a statin are contained in separate dosage forms, and that the physician in charge determines the symptoms of the patient. It means a package or product accompanied by instructions for simultaneous ingestion of active ingredients in combination based on the dose determined in accordance with.

The invention disclosed in this application provides for the combined administration of L-carnitine or one of the above alkanoyl L-carnitines, or a pharmaceutically acceptable salt thereof, with a statin, and a mixture of these two active ingredients. And both of them can be administered orally or parenterally.

The subject matter of the present invention disclosed in this application is a therapeutically effective amount of a statin, and a detoxifying effective amount of L-carnitine or an alkanoyl L-carnitine having a linear or branched alkanoyl group having 2 to 5 carbon atoms. , Or one of these pharmaceutically acceptable salts, which is a medicinal product for the treatment of a disease caused by abnormal lipid metabolism, wherein the medicinal product is characterized by low statin-induced toxicity or side effects. Including using.

A further subject of the present invention is a detoxifying effective amount of L-carnitine or alkanoyl L-carnitine having a linear or branched alkanoyl group having 2-5 carbon atoms or one of the pharmaceutically acceptable salts thereof. For the manufacture of a medicament useful in the treatment of statin-induced toxicity or side effects.

The present invention also provides statin-induced toxicity or side effects of L-carnitine or alkanoyl L-carnitine having a linear or branched alkanoyl group having 2 to 5 carbon atoms or one of pharmaceutically acceptable salts thereof. Including use in the manufacture of a medicament useful in the treatment of

The statin is preferably selected from the group consisting of lovastatin, simvastatin, pravastatin and flavastatin, preferably as alkanoyl L-carnitine acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine. , Isovaleryl L-carnitine, or one of their pharmaceutically acceptable salts.

More preferably, the statin is simvastatin and the alkanoyl L-carnitine is propionyl L-carnitine or one of its pharmaceutically acceptable salts. Even more preferably, the statin is simvastatin and the carnitine is L-.
Carnitine or one of its pharmaceutically acceptable salts.

What is meant by a “pharmaceutically acceptable salt” of alkanoyl L-carnitine is:
Any salt may be used as long as it is a salt of alkanoyl L-carnitine and an acid that does not cause toxicity or side effects. Such acids are well known to pharmacists and experts in the pharmaceutical industry.

Examples of pharmaceutically acceptable salts of alkanoyl L-carnitines include, but are not limited to, chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, maleate and acid. Mention may be made of maleates, mucates, acid oxalates, acid sulphates, glucose phosphates, tartrates and acid tartrates.

By using high concentrations of statins, the combination of the present invention allows for better treatment of diseases due to dyslipidemia and thus leads to higher treatment success. The combinations of the invention also contribute to the healing and prolongation of life of treated patients.
There are various factors that can help increase the success rate of treatment, but one of them is that there is no interruption of the treatment plan due to side effects of statins, so that the administration can be continued for a longer period.

The protective effect of L-carnitine or alkanoyl L-carnitine against the toxicity or side effect of statins was confirmed by the examples shown below. In the examples below, L-carnitine is the only example, but it should be understood that such a protective action is also present in the alkanoyl L-carnitines and their pharmaceutically acceptable salts.

Example 1 Male Wistar rats (23 days old, body weight 45-50 g) were used. The animals were housed in polycarbonate cages so that each cage contained 5 animals. A 12 hour light / dark cycle was performed at a constant temperature of 22 ± 2 ° C. and 55 ± 15% relative humidity. 4RF2 for bait
He was given a pellet diet of 1 (Mucedola) and was ready to drink tap water. The control group consisted of 14 animals, and the treatment group consisting of each dose of simvastatin and the simvastatin / L-carnitine group consisted of 10 animals each. It was administered according to the following schedule:

[0030] Control (no treatment); Simvastatin 70 mg / kg; Simvastatin 140 mg / kg; Simvastatin 210 mg / kg; Simvastatin 70 mg / kg + L-carnitine 400 mg / kg. Simvastatin 140 mg / kg + L-carnitine 400 mg / kg. Simvastatin 210 mg / kg + L-carnitine 400 mg / kg.

L-carnitine was orally administered via the gastrointestinal tract twice a day (2 × 200 mg),
Administered daily. When administered together with statin, the one dissolved in 0.5% carboxymethyl cellulose (CMC) was used, and when administered alone, it was dissolved in water and administered. Simvastatin was orally administered by dissolving it in 0.5% carboxy-methylcellulose (CMC) (10 mL / kg). The duration of treatment is 9 days.

Twenty-four hours after the last dose, the animals were anesthetized and blood samples were taken via the sublingual vein. The collected blood is centrifuged at 400 rpm for 30 minutes, and the obtained serum is used for plasma CK and GOT.
, GPT and cholesterol were measured. CK, GOT, GPT and cholesterol analyzes were performed using a Cobas Mira S automated analyzer (Roche) and Roche diagnostic kit. The plasma enzyme activity obtained showed a very skewed dispersion and was analyzed using the non-parametric Mann-Whitney U test. The test data are shown as median and associated range. The results obtained are shown in Table 1.

[0033]

[Table 1] Mann-Whitney U test significant difference *** = p <0.002; ** = p <0.02; * = p <0.05

The group treated with statin alone measured a significant difference from the control group. In the group administered with the combination of -statin and L-carnitine, a significant difference was calculated when compared with the group administered with statin alone.

The results shown in Table 1 show that plasma GOT (p <0.002), GPT (p <0.002) and CK (in the group administered with the highest dose (210 mg / kg) of simvastatin, as compared with the control group. p
A substantial and significant increase of <0.05) was observed. Treatment with a lower dose of simvastatin (140 mg / kg) increased all enzyme activities tested, with significant differences in GOT (p <0.002) and GPT (p <0.02). The lowest dose of simvastatin (70 mg / kg) treatment did not show an increase in any of the enzyme activities tested.

Cholesterol levels were only significantly reduced at the highest simvastatin dose tested. When L-carnitine was administered to the simvastatin treatment group, lower plasma CK activity was observed as compared to the simvastatin single administration group. Statistically, L-carnitine administration was significantly effective in offsetting plasma CK elevations due to simvastatin administration of 140 and 210 mg / kg (Table 1).

Treatment with the lowest dose of simvastatin (70 mg / kg) in combination with L-carnitine reduced plasma CK activity, although not statistically significantly, than administration of the same concentration of simvastatin alone. . The results of these tests show that L-carnitine and alkanoyl L-carnitines protect against toxic side effects of statins, and form the basis of the present invention.

The second example was performed in the same manner as in Example 1 except that L-carnitine was added to the drinking water of the animal, but the results comparable to Example 1 were obtained. Accordingly, the present invention provides that a combination administration of L-carnitine or one of its alkanoyl derivatives or a pharmaceutically acceptable salt thereof and a statin as defined above is carried out in the treatment of animals, for example livestock and especially pets. Is further included. In this embodiment, L-carnitine or its derivative is a solid such as fumarate, tartrate, or mucate, and even if it is used by dissolving it in drinking water, it is a concentrated solution to be diluted and administered. May be.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 39/02 A61P 39/02 43/00 111 43/00 111 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ , BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Alessandro Pesquera Italy, I-00122 Ostia Lido (Rome), Via・ Cesare Laurentii No. 12 (72) Inventor Paolo Carminati Italy, Lee 20121 Milan, Via Agnello No. 19 F term (reference) 4C084 AA19 MA02 NA06 NA07 ZA511 ZC022 ZC202 ZC331 ZC332 ZC372 ZC751 4C086 AA01 AA02 BA17 MA02 MA04 MA10 NA0 6 NA07 ZA51 ZC02 ZC20 ZC33 ZC37 ZC75 4C206 AA01 AA02 FA59 MA02 MA04 NA06 NA07 ZA51 ZC02 ZC20 ZC33 ZC37 ZC75

Claims (20)

[Claims] 1. A therapeutically effective preparation containing a detoxifying amount of L-carnitine or alkanoyl L-carnitine having a linear or branched alkanoyl group having 2 to 6 carbon atoms, or one of pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising an amount of a statin. 2. A medicament containing a statin containing a detoxifying amount of L-carnitine having a linear or branched alkanoyl group containing 2 to 6 carbon atoms, or one of pharmaceutically acceptable salts thereof. A pharmaceutical composition characterized in that the statin dose is an amount higher than that which is used for normal treatment and which causes side effects by its use. 3. The pharmaceutical composition according to claim 1 or 2, wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin, preferably simvastatin. 4. The composition of claim 3, wherein the statin is simvastatin. 5. Alkanoyl L-carnitine is acetyl L-carnitine,
The composition according to claim 1 or 2, which is selected from the group consisting of propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine, and isovaleryl L-carnitine. 6. The composition of claim 5, wherein the alkanoyl L-carnitine is propionyl L-carnitine. 7. The composition according to claim 1 or 2 and claim 3 or 4, which comprises L-carnitine. 8. A pharmaceutically acceptable salt of L-carnitine or alkanoyl L-carnitine is chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, maleate and acid maleate, mucate, A composition according to claim 1 or 2 selected from the group consisting of acid oxalates, acid sulphates, glucose phosphates, tartrates and acid tartrates. 9. A therapeutically effective amount of statin and a detoxifying amount of L-carnitine or 2
Production of a pharmaceutical composition of alkanoyl L-carnitine having a linear or branched alkanoyl group having 6 to 6 carbon atoms, or one of pharmaceutically acceptable salts thereof, which is useful for treating a disease caused by deficient lipid metabolism. Use characterized by low statin-induced side effects by the pharmaceutical composition. 10. A therapeutically effective amount of statin and a detoxifying amount of L-carnitine or an alkanoyl L- having a linear or branched alkanoyl group of 2 to 6 carbon atoms.
Use of carnitine, or one of their pharmaceutically acceptable salts, for the manufacture of a pharmaceutical composition useful in the treatment of statin-induced toxicity or side effects. 11. A statin-induced toxicity or side effect of L-carnitine or alkanoyl L-carnitine having a linear or branched alkanoyl group having 2 to 6 carbon atoms, or one of pharmaceutically acceptable salts thereof. Use for the manufacture of a pharmaceutical composition useful for the treatment of. 12. Use according to claim 9, 10 or 11, wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin, preferably simvastatin. 13. The alkanoyl L-carnitine is selected from the group consisting of acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine, and isovaleryl L-carnitine, preferably propionyl L-carnitine. The use according to claim 9, 10 or 11. 14. Use according to claim 9, 10 or 11, wherein the alkanoyl L-carnitine is propionyl L-carnitine. 15. The method of claim 9, 10 or 1 wherein L-carnitine is present.
Use according to 1. 16. A pharmaceutically acceptable salt of L-carnitine or alkanoyl L-carnitine is chloride, bromide, orotate, acid aspartate,
12. An acid citrate, an acid phosphate, a fumarate and an acid fumarate, a maleate and an acid maleate, a mucate, an acid oxalate, an acid sulfate, a glucose phosphate, a tartrate and an acid tartrate, according to claim 9, 10 or 11. use. 17. A therapeutically effective amount of a statin selected from the group consisting of lovastatin, simvastatin, pravastatin, and fluvastatin, and L-carnitine or an alkanoyl L having a straight or branched chain alkanoyl group of 2 to 6 carbon atoms. -The combined use of carnitine, or a detoxifying amount of one of these pharmaceutically acceptable salts, to reduce the statin-induced toxic effects while maintaining the therapeutic efficacy of statins. 18. The use according to claim 16, wherein the administration is continuous. 19. The use according to claim 16, wherein the administration is substantially simultaneous. 20. A product, which is attached to the pharmaceutical composition according to claim 1 or 2 with instructions for ingesting each drug at the same time or ingesting each drug based on a predetermined dose standard.