Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
• • 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
  • 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
  • A61P5/00—Drugs for disorders of the endocrine system

Definitions

• the subject of the invention is the synthesis, manufacture and use of associated drugs, preferably (but not exclusively) having a complementary and / or synergistic action.
• pharmacological action is meant the pharmacological action of two different compounds making it possible to act on the same pathology by two respectively different pharmacological mechanisms, for example, the combined use of two antidiabetics such as a biguanine and a sulfonylurea, or allowing to act on a main pathology and on an associated pathology, for example diabetes and a cardiovascular pathology.
• the pharmacological action of two different compounds is also understood, making it possible to act simultaneously by two respectively different mechanisms on two pathologies systematically associated in humans, or on a pathology and on the side effects due to the treatment of said pathology.
• the purpose of a drug combination according to the invention is to enable dual therapy in a single dose and by the use of a single compound.
• “Synergistic action” means the pharmacological action of two compounds consisting in potentiating the potential action of at least one of said compounds, for example potentiating the action of a biguanine by the action of a transporter, as described and proposed below by way of example.
• excipients allowing, in spite of the simultaneous administration, the sequenced or simultaneous release of the two active ingredients in the proportions fixed by the pharmacopoeia, is therefore essential, because these excipients will condition the release of the active ingredients and their respective bioavailability.
• This choice of excipients is quickly extremely delicate when one wishes to formulate two active principles, because the number of parameters, physicochemical and physiological to be considered, is too large. Faced with these difficulties, when two active ingredients have to be administered simultaneously, the solution of administering active ingredients in two separate dosage forms and in two separate doses is most often adopted.
• bioavailability and the synergy and / or complementarity of in-vivo action are then dependent on the simultaneous or successive intake of the two dosage forms, and are therefore difficult to predict and measure, and moreover dependent on the patient's compliance.
• an active compound capable of releasing in vivo for example in the intestine, the liver, the plasma or other target organs, two different active principles , in sequence or simultaneously, makes it possible to solve such problems of co-administration of different active ingredients, regardless of the half-lives of the active ingredients used.
• the present invention provides the use as a medicament of an active compound of general formula A '- V - C, capable of restoring at least entity A by in-vivo cleavage of the corresponding bond between A' and V , being specified that:
• V is a biogenic vectorization compound, of general formula X-R-Y, in which:
• R represents an aliphatic, cyclic or alicyclic hydrocarbon chain of 2 to 10 carbon atoms, saturated or not, optionally substituted by C1 to C5 alkyl groups, and / or hydroxyl groups,
• X and Y are each a free acid, amino or alcohol function.
• a and C are two different active principles respectively, one of which comprises a chemical function complementary to the function X, capable of reacting with the latter to give a cleavable bond in vivo, ionic A '- V or covalent A' - V, and which the other includes a chemical function complementary to the Y function, capable of reacting with the latter to give a bond, ionic V - C or covalent V - C.
• the V - C or V - C bond is cleavable in vivo, and said active compound is capable of also restoring the entities V and C by said cleavage in vivo.
• An active compound according to the present invention can for example be obtained by reaction between them of the entities A, V and C respectively, to obtain in bonded form respectively the radicals A ', V and C II it is understood that A and C are two active principles respectively different, for example capable of acting in synergy, in complement or in combination, that is to say that at least one of these active principles, for example A, is a pharmacologically active product, material or compound per se, and that, for example B is a pharmacologically active product, material, or compound, or acting by potentiating the effects of A.
• This potentiation may be due to sensitization of the receptors of A, vectorization of A with improvement of the bioavailability, or even a suppression of the inactivation of A.
• active principles A and C can possibly be already used in simple association, either in the same pharmaceutical presentation, either in simultaneous or combined prescription.
• V must comprise a function reacting with A and a function reacting with C.
• a and C each comprise an acid function
• V is a diamine, a dialcohol or an alcoholamine, so as to respectively form an amide, an ester or a salt.
• a and C each have an amino function
• V is a diacid so as to form an amide or a salt.
• a and C each have an alcohol function
• V is a diacid so as to form a diester. According to the principle of the invention, all the compositions are possible.
• V is for example an alcoholamine, to act with the acid function of A to give an amide, an ester or a salt, and with the alcohol function of C to give an ester.
• covalent bonds is meant here chemical bonds capable of being formed by reaction of so-called complementary chemical functions, between the biogenic vectoring compound V and the active principles A and C.
• ionic bonds we mean here connections by electrostatic force, capable of being formed by the action of so-called complementary chemical functions, between the biogenic vectoring compound V and the active principle A or C, therefore connections of the acid salt, amino salt, alcoholate and acid / base, regardless of the molar proportion existing between compound V and the active ingredient A or C, belonging to the complex formed by said ionic bonds.
• cleavable bond in-vivo means any bond allowing the release and restitution of the active principles A and C, and of the biogenic compound V of vectorization, in-vivo, by rupture of the ionic or covalent bonds between the complementary chemical functions of A and V, and C and V.
• the cleavable covalent bonds are cleaved by the action of enzymes present in the in-vivo medium of the release site. These covalent bonds being amide bonds or ester bonds, the enzymes involved in this cleavage are amidases, esterases and hydrolases. These enzymes are present in particular in the digestive tract (oral administration), predominantly in the liver, in the blood, and potentially present in the target organs.
• amidases which hydrolyze the bond -CO-NH- are found in the liver, they are not very active; whence a prolonged effect expected with the compound according to the invention carrying such a bond.
• these amidases some are known, these are endopeptidases which hydrolyze gamma-amino or gamma-acid bonds.
• V can indeed be according to the invention a gamma-amino acid, with a second acid or amino function in the gamma position (case of glutamic acid or lysine for example).
• esterases which hydrolyze the bond -CO-O- are very numerous in the living organism. They are however ubiquitous and very little specific to a substrate; hence a high reaction rate, with rapid release of the constituents A, V, C of the active compound according to the present invention.
• the most specific of a substrate are called this substrate, and as such, mention may be made, for example, of cholinesterases or procaine esterases.
• Hydrolases also hydrolyze esters and all large molecules supplied to the body in the form of food. These hydrolases are numerous and ubiquitous as well. They are nonetheless specific to the biogenic vectorization compound V used.
• proteolytic enzymes such as pepsin, trypsin, catalases, endo- and exo-peptidases. Also useful are amylases and osidases, and finally lipases and beta-oxygenases for the destruction of lipids.
• biogenic vectoring compound comprises one or more bonds which they are capable of cleaving.
• lipase acts if the biogenic vectoring compound is a long-chain diacid (8 to 10 carbon atoms, comparing it to a fatty acid), and the A - V or V - C bond is obtained by condensation with a secondary alcohol function of A or C.
• the cleavable ionic bonds are cleaved according to their place of release, for example intestine, liver, plasma, or target organ, it being understood that the acid, amino, or alcoholate salts are generally ionized at the pH of the media of living organisms. Generally the pH is between 2 and 8, and is for example 2 for the stomach, and 6 for example for the intestine. There is therefore an ionization of the active compound according to the invention, depending on the type of salt used, and a dissociation of said active compound, when the latter comprises at least one ionic bond.
• the salt is chosen according to its dissociation constant, and the pH of the in-vivo release site. For example, for dissociation in the stomach, a weak acid and strong base salt is chosen.
• biogenic vectorization compound and in particular the choice of its free functions X and Y is made according to the nature of the chemical functions, free and complementary, present in or on the active principles A and C intended to be vectorized, it is that is to say linked by covalent or ionic bond to this biogenic vectorization compound, but also according to the cleavage and liberation sites chosen.
• This biogenic vectorization compound is a product of natural or non-natural origin, and / or metabolizable and / or biodegradable and / or non-toxic with respect to humans or animals, at physiological dose.
• This biogenic vectorization compound will be chosen from biologically proven and described compounds, for example gamma-amino acids involved in protein synthesis, di-acids involved in the Kreps cycle, ethanolamines constituting cell membranes, metabolizable and non-toxic, and likely to be integrated, themselves or their metabolites in the major biological cycles of life. Mention may be made, for example, as a biogenic vectorization compound, of succinic acid which is found in the Kreps cycle, or methyl succinic acid which is biodegraded into succinic acid.
• Any active principle is a chemical, biochemical, biological, natural molecule or obtained by the hand of the man, for example by synthesis or by recombinant way.
• This molecule has a demonstrated biological activity to cure, or prevent, any organic or functional disease or disorder in humans or animals.
• This activity has for example an effect proportional to the dose, or a dualism of action, this biological activity being objectively demonstrated or demonstrable.
• pharmacologically and therapeutically active substances already known as such or to come.
• the different active ingredients A and C capable of acting in synergy and / or in addition, are preferably chosen from active ingredients having substantially equal half-lives, belonging to the same therapeutic class, and acting on the same pathology by two different mechanisms of action, or belonging to different therapeutic classes and making it possible to treat systematically associated polypathologies, for example a main pathology treated with a first active principle, and a secondary pathology treated with a second active principle, said secondary pathology being caused by the administration of the first active ingredient.
• the pharmacological actions of the active ingredients selected are therefore for example either complementary or synergistic. If the actions are synergistic, or if there is potentiation for example, the reduction in doses will allow the reduction of side effects.
• These active principles are chosen, in particular: according to their capacity to act in synergy and / or in complement, according to their capacity to bind to a biogenic vectoring compound, and according to their biochemical or metabolic capacity to be released in-vivo, by cleavage of the bonds binding them to the selected biogenic vectorization compound, by enzymatic action or as a function of the pH in-vivo in the release site.
• the links retained between the biogenic vectoring compound and the active principles A and B depend on the possible metabolisms at the gastrointestinal and hepatic level.
• salts can be dissociated in the digestive tract
• hydrolysis can be delayed by gastro-resistant dosage forms.
• the esters are hydrolyzed in an acid medium, or hydrolyzed by the esterases of the gastric juices, the hydrolysis can also be delayed by gastro-resistant dosage forms.
• Amides are hydrolyzed by hepatic amidases, the kinetics of these hydrolyses being generally slow.
• biogenic vectorization compound as a function of the complementary chemical functions of the active principles selected A and C, and of the qualities of the biogenic vectorization compound: said selected biogenic compound is metabolizable, and / or biodegradable, and / or non-toxic, - human or animal physiological dose. It is chosen from biologically assimilable compounds, described or proven. - validation of the possibility of synthesis of the AVC candidate compounds and,
• the acid, amino or alcohols functions suitable for implementing the invention are those which are not hindered in their reactivity by problems of steric hindrance for example, or by the proximity of substituents modifying the electro-activity of these chemical functions.
• the synthetic routes used are, for example, those generally used for the formation of double salts, diesters, diamides, salt-esters, salt-amides, or amide-esters, that is to say general methods of synthesis with protection / deprotection as a function of the chemical functions present, and of their respective reactivities.
• reaction sequence is then preferably and for example the following:
• tests to assess the ability to cleave in vivo the A'— V and V - C bonds and to the corresponding release of the active ingredients A and C can be performed. These tests consist, for example, in observing the release of the active ingredients in an intestinal juice, or the study of hepatic metabolism on primary culture of rat hepatocyte. These two tests are described below.
• In-vitro cleavage test in an intestinal juice An intestinal juice preparation containing trypsin, peptidases, lipase, amylase and all other enzymes of the exocrine pancreas is used. This test is previously validated with standard compounds.
• the compound A'V'C in known quantity (of the order of the microgram) is placed in the presence of a known quantity of intestinal juice (the trypsin and lipase contents of which are controlled).
• the reaction mixture is maintained at 37 ° C for one hour. This time is compatible with intestinal transit. Samples are taken every 1 5 min, and products A and C are detected and their concentration is measured by HPLC coupled to a UV detector, or a mass spectrometer if it is not possible to use UV .
• the columns used depend on the nature of A and C, but are generally ion exchange columns, due to the presence of released acid, amino or alcohol forms. After calibration, the total amount of A or C released in 1 hour is determined, and the intermediate points make it possible to calculate the dissociation constants Km and the speed Vmax of the enzymes for the active compound A'V'C used. This test can be coupled with a determination of the release of A, C and V in the gastric juice, using exactly the same principle but by replacing the intestinal juice by gastric juice.
• the possible toxicity of the biogenic vectorization compound, V is related to that of the active compound A'V'C according to the invention. As this active compound is metabolized into A, C and V, and since V is a substance by definition biological, the toxicity of the compound according to the invention must be compared to the sum of the toxicities due to the administration of the active principle
• Hepatocytes are isolated in situ by a collagenase infusion. They are then placed in a Williams medium supplemented with fetal calf serum, cortisol and glutamine, at a rate of 1 million cells per well. Increasing and toxic concentrations of A and C and A'— V— C are added to each well.
• Samples are taken after 6h, 12h, 24h, 48h and 96h and the viability of the cells is determined by a methylene blue test, by the expression of albumin, by hepatocyte apoptosis, and by the measurement of the activity of P450 cytocromes.
• the viability of the cells by the methylene blue test gives results similar to those obtained with an LD 50.
• albumin makes it possible to know the limits of tolerance of the hepatocyte to any toxic substance (toxicity in the long term). Indeed, one of the main roles of the hepatocyte is to synthesize proteins. During a toxic effect, this expression of the synthesis and the release of albumin is altered.
• Measuring the activity of cytocromes P 450 documents the phenomena of induction and inhibition of these enzymes, often encountered with pharmacologically active products. A series of tests makes it possible to determine the activity of the isoforms of cytocromes P 450.
• active compounds of general formula A '- V— C allowing, by cleavage in vivo, the simultaneous administration of two active principles A and C with complementary action and with antibiotic action, is carried out by reacting with a compound biogenic vectorization V, for example a sulfonamide such as sulfamethoxazole and trimethoprim.
• a compound biogenic vectorization V for example a sulfonamide such as sulfamethoxazole and trimethoprim.
• active compounds of general formula A 'TM V' TM C allowing, by cleavage in vivo, the simultaneous administration of two active principles A and C with complementary action and with antiulcer action, is carried out by reacting with a biogenic vectorization compound V, for example ranitidine and azole.
• a biogenic vectorization compound V for example ranitidine and azole.
• active compounds of general formula A 'TM V' TM C allowing by cleavage in vivo the simultaneous administration of two active principles A and C with complementary action and with anti- Rheumatic fever, for the treatment of arthritis, is performed by reacting with a biogenic vectoring compound V, for example a nonsteroidal anti-inflammatory drug and penicillamine.
• a biogenic vectoring compound V for example a nonsteroidal anti-inflammatory drug and penicillamine.
• active compounds of general formula A'— V 'TM C allowing by cleavage in vivo the simultaneous administration of two active principles A and C with synergistic action, one of which is an antidiabetic, is carried out by reacting with the biogenic vectoring compound, for example metformin and arginine, which by its role of transporter allows the potentiation of the action of metformin.
• the biogenic vectoring compound for example metformin and arginine
• active compounds of general formula A 'TM V' ⁇ C allowing by cleavage in vivo the simultaneous administration of two active ingredients with combined action, is carried out by reacting with the biogenic vectoring compound, by example an antihypertensive such as an ACE inhibitor, for example quinapril, benazepril and captopril, and a diuretic such as hydrochlorothiazide, in the treatment of hypertension, or, for example an anti-ulcer like ranitidine, and an antibiotic like metronidazole, in the treatment of gastric intestinal ulcer with helicobacter infection.
• an antihypertensive such as an ACE inhibitor, for example quinapril, benazepril and captopril
• a diuretic such as hydrochlorothiazide
• active compounds of general formula A 'TM V' ⁇ C allowing by cleavage in vivo the simultaneous administration of two active principles with complementary action, by action on the side effects systematically associated with a therapeutic treatment, is carried out by reacting with a biogenic vectoring compound, for example a non-steroidal anti-inflammatory such as diclofenac or naproxen, and an anti-ulcer such as cimetidine.
• a biogenic vectoring compound for example a non-steroidal anti-inflammatory such as diclofenac or naproxen, and an anti-ulcer such as cimetidine.
• an active compound which can be used as a medicament in the treatment of diabetes, and capable of restoring by cleavage in vivo of metformin (first active principle) and of arginine (second active principle) is produced using as a biogenic vectorization compound succinic acid to synthesize arginine hemisuccinimide-metformin hemisuccinate.
• the process for the preparation of this active compound comprises the following steps:
• metformin active ingredient A
• arginine active ingredient C
• biogenic comoose V consisting of acid succinic; the latter reacts, on the one hand covalently with an amino function of arginine and on the other hand ionically (salification reaction) with an amino function of metformin.
• the reaction liquid is kept under vigorous stirring for one hour, heating slowly for a complete distillation of the ether. Evaporated to dryness and the residue is taken up in a minimum of distilled water (20 ml), and acidified with dilute hydrochloric acid. By concentration (light heating under partial vacuum), white crystals of arginine hemisuccinimide are obtained.
• concentration light heating under partial vacuum
• white crystals of arginine hemisuccinimide are obtained.
• the NMR spectrum, the centesimal analysis and the purity of the product are verified by thin layer chromatography. We in particular, checks the presence of the amino acid residue of arginine by the reaction with ninhydrin and the presence of the free carboxyl of succinic acid by titrimetry.
• the yield is quantitative.
• metformin hydrochloride 10 grams are added to 40 ml of a 5N sodium hydroxide solution. The reaction mixture is heated for two hours at 40 ° C. After evaporation under vacuum at 40 ° C, the viscous residue is taken up in 100 ml of absolute ethanol. Filtration removes impurities and an insoluble residue of sodium chloride remains. Metformin base is in alcoholic solution and by evaporation it is isolated in the form of a viscous powder. The NMR spectrum confirms the structure of metformin. The absence of chloride is checked with silver nitrate.
• metformin that is to say the N, N-dimethylimidodicarbonimide diamide
• MERCK Index the number 5792 and characterized under the number Chemical Abstracts 657-24-9.
• metformin base is added mole to mole. Immediate dissolution is obtained.
• the water is completely evaporated at 60 ° C under vacuum. The residue is redissolved in distilled water and crystallizes during concentration in vacuo.
• Translucent crystals are obtained which are soluble in water and insoluble in organic solvents.
• the melting point is 1 88-1 89 ° C.
• This test is carried out according to the in vitro method in intestinal juice, described previously according to the in vitro toxicity test described. An immediate release of metformin is observed without modifying the hemisuccinimide-arginine part. A second test is carried out on a culture of rat hepatocytes, according to the method described above. A slow release of arginine is observed over 24 hours.
• arginine hemisuccinimide-metformin hemisuccinate and a metformin hydrochloride / arginine hydrochloride association: a) A pharmacokinetic study carried out in two groups of 20 rats each, receiving orally, respectively 50 mg / kg of metformin hydrochloride, and 50 mg / kg of arginine hemisuccinimide- metformin hemisuccinate made it possible to calculate the different kinetic parameters . Arginine hemisuccinimide-metformin hemisuccinate releases metformin and in both groups, plasma metformin levels are determined.
• the concentration peak is observed in 90 minutes and is found to be 3.9 ⁇ g / ml.
• the bioavailable fraction is 60% and the half-life is on average 2.5 hours.
• the administration of 50 mg / kg of arginine hemisuccinimide- metformin hemisuccinate corresponds to approximately 25 mg / kg of metformin hydrochloride or half a dose.
• the concentration peak is observed at 60 minutes and it is found to be 2.9 ⁇ g / ml of metformin.
• the bioavailable fraction is 75% and the half-life is 2.6 hours.
• the first model consists of treating rats with streptozotocin (50 mg / kg PI), a compound which induces an increase in blood sugar which goes from 5.5 mM to 12-14 mM in 21 days.
• streptozotocin 50 mg / kg PI
• metformin 30 mg / kg
• the arginine hemisuccinimide-metformin hemisuccinate decreases more significantly the hyperglycemia which goes from 1 2.66 to 7.56 mM.
• the difference between the two treatments is significant despite the lower dose of metformin.
• the second model is performed with the administration of fructose to
• Arginine hemisuccinimide-metformin hemisuccinate is found to be significantly more active than metformin alone at a dose equivalent to metformin base.
• arginine hemisuccinimide-metformin hemisuccinate reproduces at least the effects of the two active ingredients on microcirculation, namely the vasodilatory action of arginine and the action on vasomotion metformin.

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