Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • 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
  • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
• • 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
  • A61P3/06—Antihyperlipidemics
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
  • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

• This invention relates to complexes between anilide derivatives of polycarbon chain and cyclodextrins, as well as pharmaceutical compositions containing them.
• the polycarbonate anilide derivatives are more particularly dodecylthio-phenylacetanilide derivatives such as (S) -2 ', 3', 5'-trimethyl-4'-hydroxy- ⁇ - dodecylthio-phenylacetanilide (laboratory code: F12511) or its related derivatives.
• ACAT Acyl Cholesterol Acyl Transferase
• dyslipidemias such as hypercholesterolemia
• atherosclerosis they are presented as molecules of choice for the treatment of dyslipidemias, such as hypercholesterolemia, and the prevention of atherosclerosis.
• 25 F12511 is a non-salified molecule, of the crude formula C29 H 3 NO2S and of molecular weight 479.73 g. Its developed formula is:
• This molecule is practically insoluble in water and the solvents usually used in galenical formulation and physiologically compatible with essentially oral or parenteral administration.
• hydrophilic solvents such as ethanol or macrogol 400 cannot be used pure; unfortunately an addition of water very quickly decreases the solubility of F12511 as evidenced by the result obtained with 95% ethyl alcohol where the solubility at saturation is no more than 2 mg / ml.
• the use of surfactants in aqueous solution does not allow better results to be obtained.
• the amount of F12511 dissolved after 2 hours of stirring in a 5% aqueous solution of sodium lauryl sulfate is approximately 10 ⁇ g / ml, at 25 ° C.
• Cyclodextrins were discovered approximately one hundred years ago (Pr D. DUCHENE, F. GLOMOT and Dr C. NAUTION Cyclodextrins and their industrial uses (Editions de Santé, 1987) Chapter 6: Pharmaceutical applications of cyclodextrins, p. 213) . At first, only small quantities of relatively impure cyclodextrins were isolated, but their high production cost prevented their industrial use.
• Cyclodextrins come from the enzymatic degradation of starch, the two main constituents of which are: branched amylopectin and straight chain amylose.
• dextrins The partial breakdown products of these two macromolecules are called dextrins.
• cyclodextrins cyclic dextrins
• cyclodextrins cyclic oligosaccharide compounds which, depending on the reaction conditions, mainly comprise 6, 7 or 8 glucose units linked by links - (1, 4): this is called ⁇ -, ⁇ - and ⁇ - cyclodextrin.
• Native cyclodextrin molecules form toroidal structures, the exterior of which is hydrophilic and the interior hydrophobic. Their solubility in water are respectively, at 25 ° C:
• ⁇ - cyclodextrin 14.2 g% ml
• ⁇ - cyclodextrin 1.8 g% ml
• ⁇ - cyclodextrin 23.2 g% ml.
• Cyclodextrin derivatives have been prepared to increase this solubility in water. Hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin have a solubility greater than 50 g% ml. Certain methylated derivatives have a solubility also greater than 50 g% ml such as heptakis (2,6-di-O-methyl) - ⁇ -cyclodextrin or DIMEB, or even greater than 200 g% ml such as the methylated derivative in a randomized manner ⁇ -cyclodextrin or RAMEB.
• solubility depends on the degree of substitution of the cyclodextrin derivative considered.
• the present invention relates to complexes of anilide derivatives with polycarbon chain and of cyclodextrins, more particularly of dodecylthio-phenylacetanilides derivatives such as (S) -2 ', 3', 5'-trimethyl ⁇ 4'-hydroxy- ⁇ -dodecylthio-phenylacetanilide (F12511) or its related derivatives and of cyclodextrins, more precisely of ⁇ -, ⁇ -, ⁇ - cyclodextrins and their derivatives such as hydroxypropyl, tallow obutyl ether or methylated derivatives.
• These complexes are inclusion complexes or complexes formed by multiple interactions, and more generally by surface interactions observable in solid dispersions.
• the complexes which are the subject of the invention formed from anilide derivatives with a polycarbon chain which inhibit ACAT and from cyclodextrins have a solubility in aqueous medium considerably greater than that of the anilide derivative with a polycarbon chain alone.
• micellization capacity of the anilide derivatives with polycarbon chain ACAT inhibitors by surfactants such as sodium lauryl sulfate is unexpectedly multiplied by a significant factor in the presence of these complexes.
• Polycarbonate anilide derivatives are amorphous or crystalline. In the latter case, it may be a single crystal form or a mixture of different crystal forms.
• cyclodexti'ine complexes can be used. They differ in the nature of the reaction medium: semi-solid, solid or liquid.
• Type 1 In the case of semi-solid preparations, the active ingredient / cyclodextrin complexation is carried out by kneading (or “kneading") in the pasty state, in the presence of a small amount of liquid, of water in the most common case, but also ethanol, or water / ethanol mixtures, or any other suitable hydrophilic co-solvent.
• the process can be discontinuous (e.g. mixing in a suitable mixer), or continuous (e.g. extrusion).
• the mixing is carried out in a BRABENDER type mixer.
• the tank of the latter is provided with arms of geometry called "Z", driven at 30 revolutions.min ' 1 .
• a mixture of 24.2 mmol of ⁇ -cyclodextrin and 9.3 ml of purified water is introduced into the mixer tank and kneaded until a homogeneous dough is obtained.
• 5.7 g of F12511 (12.1 mmol) are gradually added and kneaded between 30 ° C and 55 ° C until complete disappearance of the endothermic peak characteristic of the solid / liquid transition of F12511.
• the product obtained is calibrated on a FREWITT oscillating device and dried under vacuum at 40 ° C for 12 hours.
• thermograms are shown in Figure 1.
• the thermogram of F12511 (a) shows three main characteristic endothermic events.
• the endothermic peak centered on 102 ° C of ⁇ -cyclodextrin (b) corresponds to the evaporation of water.
• the thermogram of the simple physical mixture F12511: ⁇ -cyclodextrin, dry, with the molar ratio (1: 2) (c) is the simple superposition of the thermograms of pure compounds.
• the F12511 ⁇ -cyclodextrin system at molar ratio (1: 2) after mixing (d) has a single endothermic peak centered on 112 ° C, the endothermic events characteristic of F12511 having completely disappeared.
• the infrared spectra are produced according to the dispersion method in KBr using an IRTF Nicolet 310 spectrometer.
• FIG. 2 shows the IR spectra of the different systems, F12511 (a), ⁇ -cyclodextrin (b).
• the spectrum of the simple physical mixture F12511: ⁇ -cyclodextrin, dry, with the molar ratio (1: 2) (c) is the simple superposition of the spectra of pure compounds.
• ⁇ -cyclodextrin (: 2) is 560 ⁇ g / ml instead of 11 ⁇ g / ml for the F12511 alone.
• cyclodextrin molar ratio used is an important factor which conditions the degree of interaction between the two entities, as demonstrated by the following examples 2 and 3:
• Example 3 The mixing is carried out under the same conditions as in Example 1. Only the quantities of F12511 and of ⁇ -cyclodextrin, calculated to obtain a molar ratio 1: 1, vary. The differential thermal analysis carried out on the product obtained indicates a percentage d interaction close to 60%. The amount of F12511 solubilized in an aqueous solution of sodium lauryl sulfate at 5% is then only 385 ⁇ g / ml after 2 hours of stirring.
• Example 3 The amount of F12511 solubilized in an aqueous solution of sodium lauryl sulfate at 5% is then only 385 ⁇ g / ml after 2 hours of stirring.
• the mixing is carried out under the same conditions as in Example 1. Only the quantities of F12511 and of ⁇ -cyclodextrin vary, calculated to obtain a molar ratio 1: 1.5. The differential thermal analysis carried out on the product obtained indicates a percentage of interaction close to 80%. The quantity of F12511 solubilized in an aqueous solution of sodium lauryl sulfate at 5% is then only 495 ⁇ g / ml after 2 hours of stirring.
• Example 1 to 3 the method for preparing the complexes is carried out by pre-pasting ⁇ -cyclodextrin with purified water followed by the addition of F12511.
• Other preparation methods are possible.
• an alternative process can consist of a premix F12511 and ⁇ -cyclodextrin followed by the addition of purified water.
• the mixing is carried out in a mortar.
• F12511 methyl- ⁇ -cyclodextrin
• 1: 1, 1: 2 and 1: 3 in the presence of water.
• the mass of F12511 treated is of the order of 500 mg.
• After drying in an oven at 120 ° C for 30 minutes, the final products are characterized by differential thermal analysis, on a METTLER TOLEDO STAR $ System device.
• Figure 3 indicates that despite the drying carried out, residual water remains present in the 3 compositions.
• the polymorphism peak of F12511 is observed at 110 ° C but the melting peak is absent. Alone, an endothermic massif then exothermic ending at 150 ° C is highlighted. Exploitation of the thermogram is difficult.
• Example 1 relates to the preparation in the presence of water of an F12511: ⁇ -cyclodextrin complex, at a 1: 2 molar ratio, from a total mixture mass of approximately 40 g.
• Type 2 In a solid medium, the active principle and the cyclodextrin are mixed in the pulverulent state and co-ground.
• Co-grinding is carried out in an ANGOUMAU type D impact mill: 1 g of equimolar mixture consisting of 0.57 mmol of F12511 and 0.57 mmol of ⁇ -cyclodextrin is introduced into a 65 cm 3 steel pot containing a aluminum ball 20 mm in diameter and mass 10 g. The pot is subjected to a vertical movement back and forth, at the frequency of 730 cycles per minute. The mixture is co-ground until the endothermic peak characteristic of the solid / liquid transition of F12511 disappears completely.
• the differential thermal analysis is carried out by heating from 30 ° C to 280 ° C at 10 ° C. min- 1 under nitrogen using a Perkin Elmer DSC 7 device.
• the thermograms are shown in Figure 6.
• the thermogram of F12511 (a) shows three main characteristic endothermic events. Peak endothermic centered on 105 ° C of ⁇ -cyclodextrin (b) corresponds to the evaporation of water.
• the thermogram of simple dry physical mixing, in equimolar proportions F12511: ⁇ -cyclodextrin (c) is the simple superposition of the thermograms of pure compounds.
• the co-ground equimolar mixture (d) has a single endothermic peak centered on 70 ° C., the endothermic events characteristic of F12511 having completely disappeared.
• the infrared spectra are produced according to the dispersion method in KBr using an IRTF Nicolet 310 spectrometer.
• FIG. 7 presents the IR spectra of the different systems: F12511 (a), ⁇ -cylodextrin (b).
• the spectrum of the equimolar physical mixture FI 2511: ⁇ -cylo ⁇ extrin (c) is the simple superposition of the spectra of pure compounds.
• Co-grinding is carried out under the same conditions as in Example 6.
• the mixture F12511: ⁇ -cyclodextrin used corresponds to the molar ratio (1: 2). It consists of 0.32 mmol of F12511 and 0.64 mmol of ⁇ -cyclodextrin.
• the F12511 ⁇ -cyclodextrin complexes derived from the preparations described in examples 6 and 7 above were dissolved in an aqueous solution of sodium lauryl sulfate at 5%: after 2 hours of stirring, the amounts of dissolved F12511 are 420 and 210 ⁇ g / ml for the F12511: ⁇ -cyclodextrin molar ratios 1: 1 and 1: 2.
• Examples 6 and 7 illustrate the preparation by co-grinding on a laboratory scale of complexes F12511: ⁇ -cyclodextrin, with respective molar ratios of 1: 1 and 1: 2 for a total mass of 1 g.
• FIG. 8 shows the change in the percentage of complexation of F12511 during co-grinding: the transformation is complete for the sample taken after 36 h of treatment.
• shredders can also be used, in particular the Hybridizer system from the company NARA which uses the technology of modification of the surface of the powders ("high energy impact” or “particle design mill”) and which offers the advantage of a very short process time.
• Co-grinding is carried out in a Hybridizer system model NHS-0. 20 g of mixture consisting of 6.33 mmol of F12511 and 12.66 mmol of ⁇ -cyclodextrin are introduced and co-ground at a speed of rotation of 16,200 revolutions.min- 1 . After only 5 minutes of process, the product obtained already shows, by differential thermal analysis, an interaction percentage of 75%.
• the amount of F12511 solubilized from this co-ground product is 105 ⁇ g / ml.
• Type 3 In semi-solid or solid medium:
• the complexation of anilide derivatives with polycarbon chain by cyclodextrins occurs from the moment when energy is supplied to the simple physical mixing of the two components, whether or not with water, whether this energy either mechanical, and / or thermal, and / or developed by high pressures, as confirmed by the example below which illustrates the combined action of soft mechanical energy with high temperatures and high pressures.
• Carbon dioxide is introduced into the autoclave and pressurized to 300 bars.
• the differential thermal analysis reveals a degree of complexation F 2511: ⁇ -cyclodextrin greater than 75%.
• Type 4 The principle of the method of preparation in a liquid medium is to bring into contact, in the molecular state, the active principle and the cyclodextrin, then to isolate the complex formed for example by the use of solvents or non-solvents appropriate.
• a mixture of 200 ml of water containing 1.47 mmol of ⁇ -cyclodextrin and 400 ml of tetrahydrofuran containing 2.94 mmol of F12511 is stirred by magnetic stirring, at 370 rpm, for one day, at a temperature of 40 ° C. After 3 days of storage at + 5 ° C, a precipitate has formed, which is collected by filtration and dried: the amount of product recovered is 549.4 mg; it contains F12511 complexed by ⁇ -cyclodextrin.
• the complexes are also recovered by co-crystallization, evaporation, lyophilization or nebulization.
• dodecylthio-phenylacetanilide derivatives such as (S) -2 ', 3', 5'- trimethyl-4'-hydroxy- ⁇ -dodecylthio-phenylacetanilide or its related derivatives and native
• the saturation solubility in water of F12511 is less than 50 ng / ml, this value in fact representing the analytical detection limit of the molecule in saturated solution.
• ⁇ -cyclodextrin therefore makes it possible to multiply the quantity of F12511 solubilized in water by a factor of at least 20 to 40 times. Furthermore, the behavior of this same complex F12511: ⁇ -cyclodextrin (1: 2) in an aqueous solution of sodium lauryl sulphate at 5% reveals a micellization capacity of the surfactant multiplied up to 260 times compared to the result obtained for F12511 alone, as shown in the table below and Figure 9.
• micellization capacity of F12511 by sodium lauryl sulfate can be multiplied up to 400 times compared to the result obtained for F12511 alone.
• the molar ratios of the two entities are variable: they are advantageously between 1: 5 and 5: 1, more precisely between 1: 1 and 1: 3 and more particularly equal to 1: 2.
• the method of preparation of the complex is mixing in an aqueous medium.
• hydrophilic agents such as, by way of nonlimiting examples, cellulosic polymers (ex: hydroxypropylmethylcellulose or hydroxyethylcellulose or also carboxymethylcellulose), derivatives of the polyvinylpyrrolidone (ex: crospovidone) or surfactants (ex: polysorbates), capable of increasing the hydrophilicity of the preparation, is part of the invention and can further improve the rate of dissolution of the complexes formed or the stability of these complexes .
• hydrophilic agents such as, by way of nonlimiting examples, cellulosic polymers (ex: hydroxypropylmethylcellulose or hydroxyethylcellulose or also carboxymethylcellulose), derivatives of the polyvinylpyrrolidone (ex: crospovidone) or surfactants (ex: polysorbates), capable of increasing the hydrophilicity of the preparation, is part of the invention and can further improve the rate of dissolution of the complexes formed or the stability of these complexes .
• hydrophilic, polymer and / or surfactant compounds are used during the complexation even of the anilide derivatives with polycarbon chain and of the cyclodextrins or their derivatives, or else included as ingredients in the formula for the corresponding pharmaceutical compositions.
• the second table presents the percentages of complexation of F12511 determined by differential thermal analysis, as well as the quantities of F12511 solubilized, from these complexes, in water at 37 ° C., after 2 hours of stirring.
• Wthe solubility of F12511 in water being less than 50.10 " 6 mg / ml, a result of 57.8 ⁇ g / ml represents an increase in solubility by a multiplying factor of at least 1000 times.
• anilide derivatives with a polycarbon chain more specifically dodecylthio-phenylacetanilide derivatives such as (S) -2 ', 3', 5'-trimethyl-4'-hydroxy- ⁇ - dodecylthio-phenylacetanilide or its related derivatives, whose particles have a high specific surface of between 0.5 and 100 m 2 / and more particularly 5 and 50 m 2 / g, also forms part of the invention.
• compositions containing the complexes of polycarbon chain anilide derivatives and cyclodextrins more particularly of dodecylthio-phenylacetanilides derivatives such as (S) -2 ', 3', 5'-trimethyl-4'-hydroxy- ⁇ - dodecylthio-phenylacetanilide (F12511) or its related derivatives and cyclodextrins, more precisely ⁇ -, ⁇ , ⁇ -cyclodextrins and their derivatives such as hydroxypropyl, sulfobutyl ether or methylated derivatives also form part of the invention.
• dodecylthio-phenylacetanilides derivatives such as (S) -2 ', 3', 5'-trimethyl-4'-hydroxy- ⁇ - dodecylthio-phenylacetanilide (F12511) or its related derivatives and cyclodextrins, more precisely ⁇ -, ⁇ , ⁇ -cyclod
• the capsules were administered as one capsule orally to 6 male dogs. Average plasma concentrations are shown in Figure 11.
• compositions which are the subject of the invention allow the treatment of dyslipidemias, such as hypercholesterolemia and the prevention of atherosclerosis.

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