Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to a composition for the prevention and/or treatment of diseases due to the presence of free radicals, and more specifically to a combination of carnitine with polyphenols, including hydroxytyrosol.
• alkanoyl-L-camitines ubiquitous, naturally occurring compounds, the greatest concentrations of which are in skeletal muscle and myocardium
• muscular and functional deficits which can be restored to normal by the administration of these compounds.
• Acetyl-L-carnitine is observed in the brain and in peripheral nervous tissue, where its presence is necessary for normal nerve conduction. The production of energy by camitines
• Acetyl-L-carnitine protects cerebral tissue against oxidative phenomena.
• Carnitine is necessary for normal growth. Reduced carnitine levels have been detected during aging. During the metabolic processes associated with aging, increased oxidative processes are detected together with a related increase in free radicals, the presence of which mediates the onset of diabetic lesions.
• Impaired mitochondrial activity leads to an increase in oxidants, which the cell defenses are no longer able to combat effectively.
• the increase in peroxides, hydroxides and singlet oxygen produced by aerobic metabolism leads to damage to macromolecules (DNA, proteins and lipids), which in turn contributes to the onset of degenerative diseases, including diabetes.
• the reduced mitochondrial activity which comes with aging is also accompanied by a reduction in cardiolipin, a diphosphatidyl-glycerol derivative which is part of the structure of the mitochondrial membrane and plays an important role in maintaining mitochondrial activity,
• Mitochondrial activity including the
• fatty acid ⁇ -oxidation processes can be enhanced by the administration of acetyl-L-carnitine, which can restore normal cardiolipin concentrations in the mitochondria.
• antioxidants have been shown to regulate glucose utilization and insulin activity. Lipid peroxidation, which is increased in diabetic neuropathy, can be controlled and reduced, both at cerebral level and at the level of the sciatic nerve and the ocular lens, by the administration of antioxidants. Moreover, antioxidants inhibit the aldose reductase activated by hyperglycemia. Therefore, antioxidants may be an important in diabetic therapy. An antioxidant effect has been shown to protect against brain damage induced by ischemia and has a postulated therapeutic role in Parkinson's disease and AIDS.
• Antioxidants may work either directly or indirectly, via restoration of glutathione
• ⁇ -lipoic acid directly affects carbohydrate
• ROS reactive oxygen species
• lipoic acid are ⁇ lower than normal values, and the administration of ⁇ -lipoic acid may restore
• AGEs Advanced Glycosylation End products
• end products of glycosylation include glucose and albumin, glucose and collagen, and glucose and hemoglobin.
• AGEs affect tissues and cells in a large proportion of diabetic diseases at nervous, muscular and endothelial level. In fact, AGEs enhance the synthesis of the components of the extracellular matrix; increase endothelial permeability and the formation of immune complexes and cytokines; and cause neuronal and retinal ischemia, myelin accumulation and myelin degeneration. A number of these compounds are formed in both diabetes and aging.
• ⁇ -Lipoic acid also inhibits or limits glycosylation or glucose oxidation reactions.
• a composition comprises acetyl-L-carnitine, or a pharmacologically acceptable salt thereof, and a mixture of polyphenols containing hydroxytyrosol in an effective weight ratio.
• the carnitine is selected from the group consisting of L-camitine, propionyl-L-carnitine, valeryl-L-carnitine, isovaleryl-L-carnitine and their pharmacologically acceptable salts or mixtures thereof.
• the composition has a weight ratio of carnitine:hydroxytyrosol which is from 100:1 to 1 :10.
• Pharmacologically acceptable salts of acetyl-L-carnitine or alkanoyl-L-carnitine are selected from the group consisting of chloride, bromide, iodide, aspartate, acid aspartate, citrate, acid citrate, tartrate, phosphate, acid phosphate, fiimarate, acid fiimarate, glycerophosphate, glucose phosphate, lactate, maleate, acid maleate, orotate, acid oxalate, sulphate, acid sulphate, trichloroacetate, trifluoroacetate and methane sulfonate.
• the composition further comprises vitamins, coenzymes, mineral substances or other antioxidants.
• the composition can be an orally administered form, such as a dietary supplement.
• the composition can be orally, parenterally, rectally or transdermaHy administered as a medicament.
• the composition can be in solid, semi-solid or liquid form.
• the composition can be in the form of tablets, lozenges, pills, capsules, granulates, syrups, injection or drops.
• Another embodiment of the invention is a -method of preventing tissue damage brought about by the presence of free radicals due to environmental pollution, for preventing brain or myocardial lesions induced by free radicals following cerebral or myocardial ischemia and attendant reperfusion, for preventing diabetic or toxic neuropathies, or for metabolic disorders in glucose utilization.
• the method comprises administering to a subject in need of same a composition which comprises acetyl-L-carnitine or a pharmacologically acceptable salt thereof and also a carnitine selected from the group consisting of L-camitine, propionyl-L- carnitine, valeryl-L-carnitine, isovaleryl-L-carnitine or their pharmacologically acceptable salts or mixtures thereof; and a mixture of polyphenols containing hydroxytyrosol.
• a composition which comprises acetyl-L-carnitine or a pharmacologically acceptable salt thereof and also a carnitine selected from the group consisting of L-camitine, propionyl-L- carnitine, valeryl-L-carnitine, isovaleryl-L-carnitine or their pharmacologically acceptable salts or mixtures thereof; and a mixture of polyphenols containing hydroxytyrosol.
• Another embodiment is a method of treating a disease brought about by the presence of free radicals due to environmental pollution, brain or myocardial lesions induced by free radicals following cerebral or myocardial ischemia and attendant reperfusion, atherosclerosis lesions and tissue proliferative processes, diabetic or toxic neuropathies, and of metabolic disorders in glucose utilization.
• This method comprises administering to a subject in need of same a composition comprising acetyl-L-carnitine, or a pharmacologically acceptable salt thereof, and optionally also a carnitine selected from the group consisting of L-carnitine, propionyl L-camitine, valeryl L-camitine, isovaleryl L-camitine or their pharmacologically acceptable salts or mixtures thereof; and a mixture of polyphenols containing hydroxytyrosol.
• Carnitine and hydroxytyrosol are administered in a weight ratio of from 100:1 to 1:10.
• oleuropein and hydroxytyrosol are the natural polyphenols from olives that provide the highest level of free radical protection ever reported for any natural antioxidant compound. Hydroxytyrosol is also known as 3,4-dihydroxyphenylalanine. D'Angelo, et al. (DMD 29:1492-1498, 2001), determined that hydroxytyrosol is the major component of olive oil fractions. Phenolic compounds, including hydroxytyrosol, are known to have powerful antioxidant properties.
• hydroxytyrosol has the ' ability to scavenge peroxynitrite, which is both a reactive nitrogen species (R ⁇ S) and a reactive oxygen species (ROS) (de la Puerta, et al., Life Sci 69:1213-22, 2001).
• R ⁇ S reactive nitrogen species
• ROS reactive oxygen species
• Nisioli and Galli listed some of the biological activities of olive oil polyphenols as a) inhibition of low density lipoprotein oxidation, b) inhibition of platelet aggregation, c) scavenging of superoxide and other ROS, d) inhibition of peroxynitrite-induced D ⁇ A damage and tyrosine nitration, e) increased nitric oxide production by lipase-challenged macrophages, f) hypotensive action and g) increased TAG.
• the vegetation water can be acidified to between pH of 2.0 and 4.0 to convert oleuropein to hydroxytyrosol (U.S. Pat. No. 6,165,475).
• the weight ratio of hydroxytyrosol to oleuropein is preferably between 1:1 and 400:1, more preferably between about 3:1 and about 200:1 and most preferably between about 5:1 and 100:1.
• the extracts may also be formulated to contain various weight ratios of hydroxytyrosol and tyrosol of between about 10:1 and about 50:1, and preferably between about 15:1 and about 30:1.
• the polyphenols are provided as about 0.05-20 mg/kg hydroxytyrosol in about 1-
• polyphenols Preferably there is about 0.15-10 mg/kg hydroxytyrosol in 10-100 mg/kg polyphenols. More preferably there is about 0.2-5 mg/kg hydroxytyrosol in about 15-50 mg/kg polyphenols. Most preferably, there is about 0.3-0.4 mg/kg hydroxytyrosol in about 15- 25 mg/kg polyphenols.
• the polyphenols and carnitine(s) can be administered orally or parenterally.
• Oral dosage forms can be in a solid or liquid form.
• Such dosage forms can be formulated from purified polyphenols, or they can be formulated from aqueous or aqueous-alcoholic extracts.
• aqueous or aqueous alcoholic (e.g., water-methanol or water-ethanol) extracts can be spray-dried to provide a dry powder that can be formulated into oral dosage forms with other pharmaceutically acceptable carriers.
• the solid oral dosage form compositions are prepared in a manner well known in the " pharmaceutical arts, and comprise polyphenols and camitine(s) in combination with at least one pharmaceutically acceptable carrier.
• the polyphenols either in substantially pure form or as a component of a raw distillate or extract
• the carrier can be in solid form, semi-solid or liquid material that acts as a vehicle, carrier or medium for the active ingredient.
• the carrier can be in the form of a capsule or other container to facilitate oral administration.
• the solid oral dosage forms for administration in accordance with the present invention can be in the form of tablets, pills, powders, or soft or hard gelatin capsules. '
• Polyphenols and camitine(s) can be formulated with other common pharmaceutically acceptable excipients, including lactose, dextrose, sucrose, sorbitol, mannitol, starches, gums, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, methyl cellulose, water, alcohol and the like.
• the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and . suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents or flavoring agents.
• the polyphenols and/or camitine(s) can be formulated to provide quick, sustained or delayed release of the active ingredient after administration to a subject.
• the polyphenols and/or camitine(s) can be in liquid form wherein the pharmaceutically acceptable carrier is water or an aqueous-alcoholic (e.g., ethanol) medium.
• the pharmaceutically acceptable carrier is water or an aqueous-alcoholic (e.g., ethanol) medium.
• Parenteral formulations of polyphenols and camitines are prepared using standard techniques in the art. They are commonly prepared as sterile injectable solutions, using a parenterally acceptable carrier such as isotonic saline prior to administration to a subject.
• pharmacologically acceptable salt of L-camitine or alkanoyl-L- carnitine is any salt of these active ingredients with an acid that does not give rise to unwanted . toxic or side effects.
• Non-limiting examples of suitable salts are the following: chloride; bromide; iodide; aspartate, acid aspartate; citrate, acid, citrate; tartrate; phosphate, acid phosphate; fumarate, acid fiimarate; glycerophosphate, glucose phosphate; lactate; maleate, acid maleate; orotate; oxalate, acid oxalate; sulphate, acid sulphate, trichloroacetate, trifluoroacetate and methane sulphonate.
• a list of FDA-approved pharmacologically acceptable salts is given in Int J of Pharm, 33:(1986), 201-217; this publication is incorporated herein by reference.
• the composition according to the invention may also comprise vitamins, coenzymes, minerals substances and antioxidants.
• Example 1 Toxicological Tests
• camitines and hydroxytyrosol are well known for their low toxicity and good tolerability. These favorable toxicological characteristics of camitines and hydroxytyrosol have been confirmed. In rats and mice, in fact, it proved possible to administer amounts of up to 250 mg/kg of acetyl-L-camitine or 1 g /kg of polyphenols including hydroxytyrosol parenterally.
• Safety and toxicity studies at 0.5, 1 and 2 g/kg of hydroxytyrosol and other phenolic compounds indicated no clinical or pathological toxicity in mice (Primeca Redfield Study).
• Example 2 ⁇ europrotective Activity Tests in Experimental Cerebral Ischemia
• MCA middle cerebral artery
• endothelin-1 120 pmol in 3 nl
• a microcannula placed stereotactically in the piriform cortex at the level of the MCA.
• Occlusion of the MCA is induced, and the resulting ischemia is to be checked three days after this procedure after sacrificing the rats with transcardiac perfusion of a solution of paraformaldehyde (4% in PBS).
• the volume of the infarcted area is calculated according to the method described by Park (Park, C, Ann Neurol, 24:543-51, 1988). The results of these tests are intended to determine whether acetyl-L-camitine, the carnitine mixture, and hydroxytyrosol are capable of reducing the ischemic area; but it is expected that the greatest and most significant result would occur with a combination of these products and, in particular, with a combination of acetyl L- carnitine and hydroxytyrosol.
• Controlling serum glucose is one of the most important means of preventing diseases related to diabetes.
• experimental diabetes is induced in rats; and tests are then performed to establish whether the induced hyperglycemia could be reduced by the administration of acetyl L-camitine, or carnitine mixture, or hydroxytyrosol, or combinations of these products (Table 2).
• the hyperglycemia is induced by subcutaneous injection of alloxan
• test substances Treatment with the test substances is given orally for a period of three weeks. At the end of this period, serum glucose is measured in the various groups of rats, both hyperglycemic and treated.
• results obtained are intended to show whether both camitines and hydroxytyrosol alone or in combination are capable of lowering the high initial serum glucose values.
• Example 4 Tests of Sorbitol Content in Ocular Lens and Sciatic Nerve of the Diabetic Rat [0041] One of the most frequent causes of lesions induced by diabetic hyperglycemia is the intracellular accumulation of sorbitol, with consequent reduction of osmotic capacity and cell integrity. [0042] . This has been attributed as a cause of the ocular and peripheral nerve conditions.
• Tests are conducted in a group of rats in which diabetes is induced, for example, by means of the intravenous administration of 50 mg/kg of streptozotocin.
• serum glucose is tested; and those rats are considered diabetic with serum glucose values above 450 mg/dl.
• the diabetic rats then receive intraperitoneal injections for eight consecutive days of the following: acetyl-L-camitine (100 mg/kg); or carnitine mixture (acetyl-L-camitine-t-propionyl-L- carmtine+isovaleryl-L-carmtine in a 1:1 weight ratio to one another) (100 mg/kg); or hydroxytyrosol (5 mg/kg), either alone or in various combinations (Table 3).
• the sorbitol concentration in the sciatic nerve and the ocular lens of diabetic rats is measured. A decrease in the sorbitol concentration is interpreted as less nerve and lens diabetic damage.
• Rats with induced diabetes whose sciatic nerve has been cut are known to present inferior regenerative activity to that of normal rats. These tests are conducted to investigate whether regeneration of the sciatic nerve in diabetic rats may be accelerated by treatment with acetyl-L-carnitine, carnitine mixture, or hydroxytyrosol, or combinations of these products. The technique used in these tests is the one described by Fernandez (Fernandez, E., Int J Gin Pharmacol Res, 10:85, 1990). [0045] Diabetes (serum glucose above 450 mg/dl) is induced in a group of rats by subcutaneous injection of 100 mg/kg of alloxan.
• Acetyl-L-camitine, carnitine mixture and hydroxytyrosol are administered with the diet in such a way that the daily intake was 200 mg/kg of acetyl-L-camitine, 200 mg/kg of carnitine mixture (acetyl-L-camitine + propionyl-L-carnitine + isovaleryl-L-camitine in a 1:1 weight ratio to one another) and 5 mg/kg of hydroxytyrosol (Table 4).
• the compounds are administered a week before cutting the sciatic nerve and for thirty days after cutting.
• the sciatic nerve is cut under anesthesia and after exposing 1 cm of it at the level of the sciatic foramen.
• the border of the lesion is marked with an epineural suture.
• the tissue of the tibial nerve one of the main divisions of the sciatic nerve, is examined, after sacrificing the animals.
• Four cross-sections of the tibial nerve measuring approximately 4 mm in length are thus subjected to morphological and morphometric examination by means of a semiautomatic image analyzer (such as the Zeiss Videoplan Image Analyser).
• the number of regenerating axons and their density per 100 nm 2 are counted, as well as the degenerate elements. This is used to assess the diabetes-induced degeneration of the tibial nerve elements, which may be corrected by treatment with acetyl-L-carnitine, carnitine mixture, and hydroxytyrosol.
• the muscle is stimulated via the sciatic nerve by means of two electrodes inserted at a distance of 10 mm from the nerve and connected to a stimulator.
• a bipolar electrode is placed at the distal end of the gastrocnemius.
• the electromyogram is displayed on an oscilloscope.
• the NMCV is measured in m/sec and derives from dividing the distance between the stimulation electrodes by the mean difference in latency between the start of the ECG potentials evoked in the two sites.
• the MCF is expressed mmm.
• Example 7 Motor Co-ordination Abnormality Test
• the composition according to the invention described herein is suitable for preventing toxic and metabolic damage which gives rise to neuronal lesions of an acute or chronic nature.
• it can be used in the treatment of toxic neuropathies, especially diabetic peripheral neuropathies.
• this composition is also indicated in the prevention or treatment of abnormalities of toxic or anoxic nature and related to the release of free radicals in the brain, liver, heart or other organs and tissues.
• IGF-I pathological abnormalities related to aging, such as neuro-degenerative disorders, may also obtain satisfactory benefit from its use.

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