Classifications

• • 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
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/724—Cyclodextrins
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/40—Cyclodextrins; Derivatives thereof
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
• • 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
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to a new hydroxypropyl ⁇ -cyclodextrin (HRbO ⁇ ) as well as to a new process useful for its preparation.
• the invention also relates to the use of this HRbO ⁇ as an excipient.
• the invention also relates to an HRbO ⁇ , for its use as a medicament, and more particularly for the treatment or prevention of diseases or conditions linked to an overload, and / or to storage, and / or to the accumulation of cholesterol in tissues, as well as their consequences, such as certain affections of the central nervous system or the cardiovascular system.
• Cyclodextrins are cyclic oligosaccharides resulting from the enzymatic degradation of starch.
• the three most common natural cyclodextrins consist of 6, 7 or 8 aD-glucopyranose units in a chair configuration linked together by a-1, 4 bonds. They are more commonly called a, b, or y cyclodextrin, respectively.
• Their three-dimensional structure appears in the form of a truncated cone outside which are the hydroxyl groups representing the highly hydrophilic part of the cyclodextrins.
• the interior of the cone or the cavity of the cyclodextrins is formed by the hydrogen atoms carried by the carbons C 3 and C 5 as well as by the oxygen atoms participating in the glycosidic bond, thus giving them a nonpolar character.
• Cyclodextrins having a hydrophilic outer part and a hydrophobic cavity are generally used for their capacity to encapsulate lipophilic compounds or groups, and therefore, for their role as protector and solubilizer for these lipophilic compounds or carriers of lipophilic groups. They are thus found conventionally in the food industry, but also in galenics where they are used as an excipient in pharmaceutical formulations.
• the anhydroglucose units of the cyclodextrins each comprise 3 reactive hydroxyl groups, which are carried by the carbons C2, C3 and C6.
• Hydroxypropyl-beta-cyclodextrin in particular is widely used in galenics, for the oral or parenteral delivery of active ingredients.
• I ⁇ RbO ⁇ is obtained by reaction of a b-cyclodextrin with propylene oxide in basic medium, then the reaction is neutralized by adding hydrochloric acid.
• the crude reaction product is then purified in order to reduce the impurities, that is to say typically:
• reagents such as residual b-cyclodextrin (unsubstituted);
• reaction co-products such as salts, propylene glycol (propane 1,2 diol), - dipropylene glycol;
• This purification is ensured by means of one or more treatments such as filtration, discoloration, demineralization, washing with ethanol, extraction with acetone, dialysis.
• I ⁇ Rb ⁇ could have a positive effect on certain diseases of the central nervous system (CNS), for example on certain orphan diseases such as Niemann-Pick type C disease.
• CNS central nervous system
• the intrathecal route is preferred , and the safety requirements are very high.
• I ⁇ RbO ⁇ should have an average degree of molar substitution (MS) at most equal to 0.71, preferably in a range of 0.50 to 0.71, and have as few impurities as possible.
• MS average degree of molar substitution
• b-CD residual b-cyclodextrin
• the reaction by-products such as, for example, propylene glycol or dipropylene glycol. This causes a re-increase in the proportion of b-CD, since the elimination of these other co-products decreases the total dry mass of I ⁇ RbO ⁇ .
• the propylene glycol content is, for example, typically at least 5.0% by dry weight.
• the present invention aims to provide an HRbO ⁇ having an improved quality, in particular for its use as an excipient or as a pharmaceutical active ingredient.
• the present invention also aims to provide an HRbO ⁇ which is particularly effective, in particular with regard to the solubilization or stabilization of assets, in particular pharmaceutical active ingredients.
• the present invention also aims to provide a HRbO ⁇ of MS at most equal to 0.71 having reduced contents of residual b-CD, which in contrast to those of the prior art, can be free of undesirable organic solvents such as methanol, ethanol, acetone, acetonitrile, chloroform.
• I ⁇ RbBO ⁇ having a MS at most equal to 0.71, and a b-CD content at most 0.3% (sec / dry), preferably less than or equal to 0.2% (dry / dry).
• I ⁇ RbBO ⁇ according to the invention can have remarkable application properties, in particular as regards the stabilization of pharmaceutically active proteins.
• This HRbO ⁇ can advantageously be free from organic solvents which conventionally result from methods of purifying the latter, unlike the HRbO ⁇ used in patent application WO 2016/201 137.
• I ⁇ RbO ⁇ of the invention can be advantageously obtained according to a new process carried out in an aqueous medium.
• the solution lies in the hydroxypropylation step more than in the purification steps.
• the Applicant has shown that the judicious choice of the hydroxypropylation parameters made it possible to achieve I ⁇ RbO ⁇ of the invention.
• I_ ⁇ RbO ⁇ thus obtained has an MS not exceeding 0.71, and in particular in a range from 0.50 to 0.71. Its b-CD content is reduced, and does not exceed 0.3%, preferably 0.2%. Byproducts of undesirable reactions such as propylene glycol and dipropylene glycol can also be reduced.
• the present invention thus has for first object a hydroxypropyl-beta-cyclodextrin (HRbO ⁇ ) characterized:
• b-in that it has a b-cyclodextrin (b-CD) content less than or equal to 0.3%, preferably less than or equal to 0.2% by dry weight.
• b-CD b-cyclodextrin
• the present invention also relates to a process for the preparation of h ⁇ CD, which is particularly useful for the preparation of an HRbO ⁇ of the invention, characterized in that it comprises:
• the temperature of the solution obtained in step (a), before introduction of the propylene oxide is chosen from a range from 80 ° C to 120 ° C;
• the propylene oxide: anhydroglucose molar ratio used is chosen from a range going from 0.70: 1.00 to 0.86: 1.00;
• the rate of addition of propylene oxide is chosen from a range going from 0.15 to 0.30 kg / h / kg of b-CD;
• the present invention also relates to an HRbO ⁇ capable of being obtained according to the process for preparing h ⁇ CD of the invention.
• the present invention also relates to the use of an HRbO ⁇ according to the invention as a medicament, and / or as an excipient, and / or for encapsulating a substance, and / or solubilizing a substance in an aqueous medium, and / or for improving stability chemical of a substance, and / or to improve the delivery of a substance to and through biological membranes, and / or to increase the physical stability of a substance, and / or to formulate a substance in a form liquid to a powder form, and / or to prevent interactions of one substance with another substance, and / or to reduce local irritation after topical or oral administration of a substance, and / or to prevent absorption of a substance in certain tissues such as the skin, and / or to obtain a prolonged release of a substance, and / or to mask the taste of a substance, in particular its bitterness, and / or to mask the odor of a substance, and / or for modifi er the bioavailability of a substance.
• FIG. 1 presents the Monograph of Hydroxypropyl betadex (HRbO ⁇ ) from USP 41 N F 36, and is an integral part of the description of the patent application.
• FIG. 2 presents the Monograph of Flydroxypropyl betadex (HIRbO ⁇ ) from USP 41 N F 36, and is an integral part of the description of the patent application.
• FIG. 3 presents the Monograph of Flydroxypropyl betadex (HIRbO ⁇ ) from USP 41 N F 36, and is an integral part of the description of the patent application.
• the subject of the present invention is a hydroxypropyl-beta-cyclodextrin (FIP CD) characterized in that it has an average degree of molar substitution (MS) less than or equal to 0.71, a content in b-cyclodextrin (b-CD) less than or equal to 0.3% by dry weight.
• FEP CD hydroxypropyl-beta-cyclodextrin
• HRbO ⁇ conventionally covers a mixture of molecules of F ⁇ CD, as well as substances resulting from its preparation process.
• I ⁇ RbO ⁇ generally corresponds to a mixture of molecules of F ⁇ CD having different profiles and substitution patterns, and therefore which are structurally different.
• I_ ⁇ RbO ⁇ of the invention is firstly characterized by its average degree of molar substitution (MS), which is less than or equal to 0.71.
• this MS is chosen from a range from 0.50 to 0.71. It is preferably still less than or equal to 0.70, preferably less than or equal to 0.69.
• this MS is at least equal to 0.58, that is to say chosen from a range going from 0.58 to 0.71.
• This MS is also generally at least equal to 0.60, or even at least equal to 0.65. It is typically equal to 0.66, or equal to 0.67, or equal to 0.68 or equal to 0.69.
• the “average degree of molar substitution (MS)” corresponds to the average number of hydroxypropyl groups, per anhydroglucose unit.
• MS is different from the average degree of molecular substitution (DS) which corresponds to the average number of hydroxypropyl groups per molecule of cyclodextrin, and which is therefore a function of the number of anhydroglucose units constituting the starting cyclodextrin.
• the DS is equal to 7 times the MS, the b-cyclodextrins being made up of 7 anhydroglucose units.
• the MS can be conventionally determined by a person skilled in the art by nuclear magnetic resonance of the proton (NMR), preferably according to the "Hydroxypropyl Betadex” method; Molar substitution "from USP 41 NF 36 reproduced in the appendix.
• this mixture conventionally contains residual native beta-cyclodextrin (b-CD) molecules, that is to say not hydroxypropylated, but which are advantageously reduced in I ⁇ RbO ⁇ of the invention.
• b-CD beta-cyclodextrin
• I ⁇ RbO ⁇ of the invention has a b-CD content less than or equal to 0.3%, preferably less than or equal to 0.2%, preferably less than or equal to 0.1%, this percentage being expressed in dry weight of b-CD, relative to the total dry weight of I ⁇ RbO ⁇ .
• This residual b-CD content can be conventionally determined by a person skilled in the art by high performance liquid chromatography (HPLC), preferably according to a procedure in accordance with the method of USP 41 NF 36 ("Flydroxypropyl Betadex; limit of betadex, propylene glycol, and other related substances ”) reproduced in the annex.
• HPLC high performance liquid chromatography
• substitution patterns of I ⁇ Rb ⁇ according to the invention are such that:
• -at minimum equal to: 1.0%, or even 2.0%;
• I ⁇ RbO ⁇ in accordance with the invention comprises less than 5.0% of substitutions other than those listed above, for example 3,6-OHP substitutions, preferably less than 4.0%, preferably less than 3 , 0%, preferably less than 2.0%, preferably less than 1.0%, preferably less than 0.5%. More preferably, I ⁇ RbO ⁇ of the invention does not include other types of substitutions than those listed above. By “no other types of substitutions”, it is meant that the anhydroglucose units comprising such substitutions are not detectable, in particular by the so-called “Hakomori” method, said method comprising subjecting I ⁇ RbO ⁇ to the following successive stages: permethylation, hydrolysis , reduction, peracetylation.
• substitution patterns of I ⁇ RbO ⁇ according to the invention are such as:
• o at most equal to: 80%, even 78%, even 77%, even 78%; and or,
• o at least equal to: 15%, even 20%, even 22%, even 23%; and / or, o at most equal to: 40%, preferably 35%, preferably 30%, preferably 28%, preferably 26%, preferably 25%; and or
• o at least equal to: 1%, even 2%; and or, o at most equal to: 5%, preferably 4%, preferably 3%, even 2%; and or,
• o at least equal to: 2.0, preferably 3.0, preferably 4.0, preferably 5.0; and or,
• o at most equal to: 10.0, even 8.0, even 7.5; and or,
• o at least equal to: 1.5, preferably 2.0, preferably 2.1, preferably 2.2; and or,
• o at most equal to: 3.0, even 2.5.
• substitution patterns can be determined by a person skilled in the art, for example according to a method analogous to the so-called “Hakomori” method, typically by subjecting I ⁇ RbO ⁇ to the following successive steps: permethylation, hydrolysis, reduction, peracetylation.
• the extract is washed with water (20 mL) and evaporated.
• the residue is treated with water (25 mL) and extracted three times with ether (75 mL total).
• the extract is washed with water and then evaporated.
• the residue is dissolved in ether (100 mL), then stirred for 30 minutes in the presence of neutral alumina, filtered, then evaporated, until typically 3.7 g are obtained.
• the permethylated product 3 mg of the permethylated product is dissolved in aqueous trifluoroacetic acid (0.5 mL), then stored in a screw-top tube at 100 ° C overnight, and concentrated by rinsing with air.
• the chloroform phase is concentrated and the residue is analyzed by gas chromatography and gas-liquid chromatography coupled to mass spectrometry (GLC-MS).
• Gas-liquid chromatography is carried out for example on equipment of the Hewlett Packard 5830 A type equipped with a flame ionization detector, using hydrogen as the carrier gas.
• Gas-liquid chromatography coupled to mass spectrometry is carried out for example on a system of the Hewlett Packard 5790-5970 type, using helium as the carrier gas.
• a capillary column (length 25 m, internal diameter 0.20 mm) made of silica glass (crosslinked 5% methylphenylsilicone), for example of the Hewlett Packard Ultra 2 type, is used.
• the temperature is programmed as follows: 8 minutes at 185 ° C., -> 250 ° C. at 5 ° C per minute, 250 ° C. for 10 minutes.
• the inventors have found that the performance of I ⁇ RbO ⁇ is increased when I ⁇ RbO ⁇ exhibits particular substitution patterns. More specifically, the inventors have shown that the stabilization of proteins, in particular proteins of therapeutic interest (hormones, antibodies, etc.), is improved.
• I ⁇ RbO ⁇ in accordance with the invention has the following organic solvent contents:
• -less than 2000 ppm of d-limonene preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm;
• -less than 2000 ppm ethanol preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm ;
• ppm of methanol preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm;
• acetonitrile preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm;
• -less than 2000 ppm of acetone preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm ;
• ppm of chloroform preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm;
• organic solvent contents can be conventionally determined by a person skilled in the art by gas chromatography with detection by mass spectrometry (GC / MS), preferably by carrying out the analyzes by Headspace GC / MS.
• GC / MS gas chromatography with detection by mass spectrometry
• the HP CD in accordance with the invention does not contain detectable amounts of d-limonene, and / or ethanol, and / or methanol, and / or acetonitrile, and / or acetone and / or chloroform.
• the HP CD in accordance with the invention also has the following organic solvent contents:
• -less than 2000 ppm of p-xylene preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm; and or
• less than 2000 ppm of toluene preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm; and / or less than 2000 ppm of l-menthol, preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm; and or
• ppm of trichlorethylene preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm, preferably less than 5 ppm, preferably less than 1 ppm;
• I ⁇ RbO ⁇ in accordance with the invention has a total content of so-called class 1 organic solvents according to the “ ⁇ 467> Residual solvents” section of the general chapter of USP 41 NF 36 of less than 2000 ppm, preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm.
• I ⁇ RbO ⁇ in accordance with the invention has a total content of so-called class 2 organic solvents according to the “ ⁇ 467> Residual solvents” section of the general chapter of USP 41 NF 36 of less than 2000 ppm, preferably less than 1000 ppm, preferably less than 500 ppm, preferably less than 200 ppm, preferably less than 100 ppm, preferably less than 50 ppm, preferably less than 10 ppm.
• I ⁇ RbO ⁇ can be defined by the fact that it is capable of being obtained, or obtained, by a hydroxypropylation and purification process excluding the use of organic solvents, that is to say entirely carried out in an aqueous medium.
• I ⁇ RbO ⁇ has the following substitution profile, as determined by ionization by electrospray - Mass spectrometry (Electrospray ionization - Mass spectrometry (ESI-MS)):
• signal corresponding to the molecules of h ⁇ CD having a degree of substitution equal to 7 (HP7): in a range of 10 to 30%, preferably 15 to 25%, preferably 17 to 25%; and or signal corresponding to the HP CD molecules having a degree of substitution equal to 8 (HP8): in a range of 5 to 20%, preferably 5 to 15%, preferably 6 to 13%; and or
• HP10 -signal corresponding to the HP CD molecules having a degree of substitution equal to 10 (HP10): less than 5%, preferably less than 2%, preferably less than or equal to 1%, preferably equal to 1%; and or
• I ⁇ RbO ⁇ has a propylene glycol content less than or equal to 5.00%, this percentage being expressed in dry weight of propylene glycol relative to the total dry weight of I ⁇ RbO ⁇ .
• This propylene glycol content is preferably less than or equal to 2.50%, preferably less than or equal to 1.00%, preferably less than or equal to 0.50%, preferably less than or equal to 0.10%, preferably less than or equal to 0.05%.
• This propylene glycol content can be conventionally determined by a person skilled in the art by high performance liquid chromatography (HPLC), preferably according to a procedure in accordance with the method of USP 41 NF 36 reproduced in appendix ("Hydroxypropyl Betadex monograph; limit of betadex, propylene glycol, and other related substances").
• HPLC high performance liquid chromatography
• I ⁇ Rb ⁇ has a chloride content of less than or equal to 1000 ppm, this content being expressed in dry weight of chloride ions relative to the total dry weight of I ⁇ Rb ⁇ .
• this chloride content is less than or equal to 500 ppm, preferably less than or equal to 100 ppm, preferably less than or equal to 50 ppm, preferably less than 50 ppm.
• This chloride content can be conventionally determined by a person skilled in the art by potentiometric titration of an h ⁇ CD solution using a silver nitrate solution of known concentration.
• This pulverulent form is advantageous in particular with regard to the storage and transport of HPpCD.
• this pulverulent HP CD is in the form of an atomized product, that is to say in the form of a powder obtained by spray drying of a solution of HP CD.
• the HPpCD according to the invention has a pH in a range from 5.0 to 7.5; said pH being measured on the basis of a solution of HP CD consisting of 2 g of dry HP CD, 98 g of distilled water and 0.3 ml of a potassium chloride solution at 225 g / L .
• the HPpCD according to the invention has a conductivity less than or equal to 200 pS / cm, said conductivity being measured on the basis of a 10% dry distilled water solution of HP CD.
• this conductivity is less than or equal to 100 pS / cm, preferably less than or equal to 50 pS / cm, preferably less than or equal to 25 pS / cm, preferably less than or equal to 10 pS / cm.
• This conductivity is for example in a range from 1 to 10 pS / cm, or even from 2 to 5 pS / cm.
• the present invention also relates to a process for the preparation of P ⁇ CD, which is particularly useful for the preparation of an HRb ⁇ as described above, characterized in that it comprises:
• the propylene oxide: anhydroglucose molar ratio used is chosen from a range going from 0.70: 1.00 to 0.86: 1.00;
• the rate of addition of propylene oxide is chosen from a range going from 0.15 to 0.30 kg / h / kg of b-CD; a purification step (c) characterized in that it does not use organic solvents;
• the amount of soda in the solution of step (a) is chosen from a range going from 0.5 to 3.6% by dry weight of soda, relative to the dry weight of b-CD. More preferably, this amount of soda is greater than or equal to 1.0%, preferably greater than or equal to 1.2%, preferably greater than or equal to 1.3%, preferably greater than or equal to 1.4% , preferably greater than or equal to 1.5%, or even greater than or equal to 1.6%, or even greater than or equal to 1.7%, or even greater than or equal to 1.8%, or even greater than or equal to 1.9 %, or even greater than or equal to 2.0%, or even greater than or equal to 2.1%, or even greater than or equal to 2.2%, or even greater than or equal to 2.3%, or even greater than or equal to 2.4 % or even greater than or equal to 2.5%, or even or equal to 2.6%, or even greater than or equal to 2.7%, or even greater than or equal to 2.8%, or even greater than or equal to 2.9% .
• this quantity of soda is less than or equal to 3.5%, preferably less than or equal to 3.4%, preferably less than or equal to 3.3%, preferably less than or equal to 3.2%, preferably less than or equal to 3.1%, preferably less than or equal to 3.0%, preferably less than or equal to 2.9%.
• the temperature of the aqueous solution of b-CD, before introduction of the propylene oxide is greater than or equal to 85 ° C., preferably greater than or equal to 90 ° C.
• This temperature is also preferably less than or equal to 110 ° C., preferably less than or equal to 100 ° C. It is for example chosen from a range from 90 to 100 ° C, preferably from 94 to 96 ° C. It is for example equal to approximately 95 ° C.
• the rate of addition of propylene oxide is chosen from a range going from 0.20 to 0.30 kg / h / kg of b-CD, preferably going from 0.20 to 0.25 kg / h / kg of b-CD, preferably ranging from 0.21 to 0.23 kg / h / kg of b-CD, for example equal to 0.22 kg / h / kg from b-CD.
• I ⁇ RbO ⁇ obtained in step (b) can undergo one or more treatments, typically chosen from filtration, nanofiltration, treatment with activated carbon, demineralization.
• this purification comprises the following treatments, preferably carried out in this order:
• step (b.3) of membrane purification is carried out by nanofiltration, preferably by means of a nanofiltration module equipped with a membrane having a cutoff threshold of less than 800 Da or a higher nominal retention rate at 65% CaCI2, at a pressure below 35 bars and at a temperature above 45 ° C.
• the purification also comprises a step (b.4) of demineralization advantageously comprising a step of passing over cation exchange column, then on anion exchange column.
• the demineralization also comprises a passage over a mixed bed.
• step (b.4) is carried out so that the resistivity of the output product is greater than 500,000 Q.cm.
• the treatments (b.1) and (b.2) are carried out again after the membrane purification (b.3), or possibly after the demineralization treatment (b.4) when it is carried out.
• the method of the invention comprises, after the purification, a step of drying the hydroxypropylated and optionally purified product.
• This drying step can be carried out by any technique known to a person skilled in the art, typically by evaporation or by atomization, preferably by atomization.
• This atomization can be a single-effect or multiple-effect atomization.
• the atomizer is coupled with a fluidized bed, possibly integrated into the atomization tower, which makes it possible to agglomerate the particles formed by atomization. This latter process is particularly advantageous if it is desired to obtain powders of greater average diameter, and as a function of the desired flow for the resulting powder.
• the invention relates firstly to an HP CD in accordance with the invention for its use as a medicine.
• this use is for the treatment or prevention of a condition or disease related to overload, and / or storage, and / or accumulation of cholesterol in the tissues, as well as their consequences.
• This includes for example cardiovascular diseases, vascular diseases, occlusive peripheral arterial diseases such as atherosclerosis or complications related to atheroma, central nervous system diseases such as Alzheimer's disease, Parkinson's disease, glomerulosclerosis segmental and focal, and lysosomal diseases affecting the central nervous system such as, for example, Niemann-Pick disease, such as Niemann-Pick type A disease, Niemann-Pick type B disease, or Niemann-Pick disease type C.
• ischemia for example myocardial ischemia, coronary heart diseases, l angina pectoris, acute coronary syndrome, myocardial infarction, mesenteric infarction, stroke, aneurysm or arteriopathy of the lower limbs.
• the HRbO ⁇ s of the invention are for use in the treatment of Niemann-Pick type C disease or in the treatment of segmental and focal glomerulosclerosis.
• the HRbO ⁇ of the invention are intended to be administered to humans or to animals, preferably to humans.
• the present invention also relates to the use of an HRbO ⁇ according to the present invention for the manufacture of a medicament, in particular intended for the treatment and / or prevention of the aforementioned conditions and pathologies. It also relates to a method of treatment and / or prevention of the aforementioned conditions and pathologies in a subject, comprising the administration of a therapeutically effective amount of an HRbO ⁇ according to the invention.
• the HP CD according to the invention also has other possible applications, in particular chosen from those usually encountered for this type of product.
• lipophilic compounds or carriers of at least one lipophilic group can, for example, be chosen from compounds which are sparingly soluble, very sparingly soluble, or even practically insoluble in water, at room temperature (15-25 ° C.).
• “poorly water-soluble compound” it is conventionally understood that a volume of water of 100 to 1000 ml is necessary to dissolve 1 gram of said compound.
• this volume of water is more than 1,000 ml_ and goes up to 10,000 ml_.
• this volume of water is more than 10,000 ml_.
• FIG 1, 2, 3 see [FIG 1, 2, 3], and in particular the definition given in the European Pharmacopoeia of reference “1.4. Monographs, 07/2014: 10,000 ”.
• the active agents useful for the invention can be chemical molecules, but also so-called “biological” active agents, as is the case for example of the active principles based on or derived from proteins, nucleic acids - like those derived from DNA or RNA - from cells or viruses.
• biological active agents as is the case for example of the active principles based on or derived from proteins, nucleic acids - like those derived from DNA or RNA - from cells or viruses.
• preferred active agents according to the invention are therapeutically active proteins, for example antibodies or hormones.
• These other substances can also be chosen from the usual compounds, depending on the use and / or the galenical form desired, as long as the latter do not contravene the properties sought in the present invention.
• These other substances can for example be chosen from binders, (super) disintegrants, lubricants.
• the content of reducing sugars was determined by the Bertrand method, by precipitation with cuprous oxide in a reducing medium, filtration through sintered glass and weighing of the residue.
• the pH in solution was determined by measuring the potential difference between two immersed electrodes, at 20-25 ° C.
• the HP CD solution consisted of 2 g dry HP CD, 98 g of distilled water with a resistivity greater than 500,000 ohms. cm, and 0.3 mL of a 225 g / L potassium chloride solution.
• the chloride content (Cl-) was determined by potentiometric titration of a solution of HP CD, using a silver nitrate solution of known concentration. 5. The maximum absorbance of 230 to 400 nm was determined on the basis of a solution in distilled water at 2.50 g dry of HP CD per 100 ml of solution, using a cell having an optical path length 10 mm.
• the conductivity was determined at 25 ° C according to a procedure in accordance with the method described in USP 41 NF 36 reproduced in the Appendix ("Hydroxypropyl betadex monograph; conductivity" ,, based on a solution of 100 ml_ , at 10% of HP CD prepared in distilled water having a resistivity greater than 500,000 ohms cm
• the resistivity R of the solution thus obtained was measured by electronic conductivity meter, and the conductivity calculated from the latter (1 / R).
• the substitution profile was determined by electrostatic ionization - Elestrospray ionization - Mass psectrometry (ESI-MS).
• ESI-MS electrostatic ionization - Elestrospray ionization - Mass psectrometry
• the electrospray ionization (ESI) parameters were as follows: spraying voltage: 5 kV; nebulizer gas: 9, auxiliary gas: 2; sweep gas: 0; capillary voltage: 23 V; capillary temperature: 275 ° C; tube lens: 80 V.
• the mass spectrometry parameters were as follows: full scan; scanning ranges: 50-200 m / z; mass range: normal, scanning rate: improved; acquisition time: 1 min.
• HPX the ion current extracted for each ion
• XIC the ion current extracted for each ion
• the sodium adduct was the most intense h ⁇ CD ion
• the area under the curve of the corresponding peak for each HPX was integrated and related to the sum of the areas of HPX ions taken into account for the characterization (intensity greater than that of the background noise), in order to express it as a percentage.
• MS and b-CD values were measured for different commercial HRbO ⁇ (Mes.). Supplier specifications have also been provided for information (Spec.) When available.
• the purpose of this section is to present the influence of the hydroxypropylation parameters on the characteristics of the HRbO ⁇ obtained.
• HP CD was then purified and dried by the following techniques, in an aqueous medium, that is to say without using organic solvents:
• the bleaching step with activated carbon was carried out in batch, with stirring for a minimum of 1 h at 70 ° C ⁇ 5 ° C.
• the medium was then filtered on a cricket filter and then on a 0.22 ⁇ m cartridge filter.
• the membrane purification step was in particular carried out using a nanofiltration module equipped with a membrane having a cutoff threshold of 800 Da, at a pressure below 35 bars and at a temperature above 45 ° C. .
• the propylene glycol content of the retentate was checked by HPLC assay. The operation was stopped as soon as a propylene glycol content of less than 0.5% by weight on dry product was reached.
• the HP CD thus obtained was then dried under reduced pressure on a rotary evaporator so as to have a dry matter content by weight greater than 95%.
• a comparative HP CD (CP-1) was prepared as follows: 656 g of commercial b-cyclodextrin (b-CD) (corresponding to 594.4 g of anhydrous b-CD) were dissolved in an alkaline medium, with stirring and in an autoclave under an inert atmosphere. A solution comprising 52% of b-CD by dry weight relative to the total weight of solution, and 2.9% of sodium hydroxide relative to the dry weight of bq ⁇ was thus obtained. The reaction medium was maintained for 30 minutes at a temperature [T] of 75 ° C.
• b-CD commercial b-cyclodextrin
• An HRbO ⁇ according to the invention (IN-2) was prepared as follows: 1305 g of commercial b-cyclodextrin (b-CD) (corresponding to 1204 g of anhydrous b-CD) were dissolved in an alkaline medium, under stirring and in an autoclave under an inert atmosphere. A solution comprising 52% of b-CD by dry weight relative to the total weight of solution, and 2.9% of sodium hydroxide relative to the dry weight of bq ⁇ was thus obtained.
• b-CD commercial b-cyclodextrin
• the reaction medium was maintained for 30 minutes at a temperature [T] of 95 ° C., then 367 g of propylene oxide were added at a flow rate [D] of 0.22 kg / h / kg of dry b-CD, ie in a propylene oxide: anhydroglucose [PO: G] molar ratio of 0.85: 1.00. After the end of the introduction of propylene oxide, the reaction medium was kept stirring for 4 hours and then neutralized with hydrochloric acid.
• uHRbO ⁇ obtained was then purified and dried by submission to the following stages, in an aqueous medium, that is to say without using organic solvents:
• the bleaching step was carried out by treatment with active charcoal for 1 h at 70 ° C.
• the medium was then filtered through a bag filter and then a cartridge filter 1 ⁇ m then 0.22 ⁇ m.
• the membrane purification step was carried out using a nanofiltration module equipped with a membrane having a cutoff threshold of less than 800 Da, at a pressure of less than 35 bars and at a temperature of more than 45 ° C. .
• the propanediol content of the retentate was checked by HPLC assay. The nanofiltration operation was stopped as soon as a propanediol content of less than 0.1% by weight on dry product was reached.
• the demineralization step was in particular carried out by passage over a cationic ion exchange column, then anionic column and finally over a mixed bed in order to obtain an output resistivity greater than 500,000 Q.cm.
• the second step bleaching was carried out in batch by treatment with active carbon with stirring at 70 ° C for 1 h minimum.
• the HP CD solution was then filtered on a bag filter and then cartridge filters from 1 ⁇ m to 0.22 ⁇ m.
• the HP CD was then obtained in pulverulent form by spray drying of the HP CD solution.
• the inventors determined the substitution patterns for HP CD according to the invention, comparative HP CDs, as well as commercial CD CDs. Several batches were tested for HPBCD IN-2.
• C2 / C3 substitution ratio C2 / C3 ((2 OHP + 2,3-di-OHP + 2,6-di- OHP + 2,3,6-tri-OHP) / (3 OHP + 2,3 -di-OHP + 3,3'-di-OHP + 2,3,6-tri-OHP)
• substitution patterns such as those of I ⁇ RbO ⁇ of the invention seem to confer particular properties, in particular better efficiency in the stabilization of substances, in particular of active ingredients. pharmaceuticals, and more specifically biological active ingredients such as proteins active.
• HRbO ⁇ which had substitution motifs such as those of I ⁇ RbO ⁇ of the invention, compared to that obtained with CAVASOL® W7 products.

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