WO2023088830A1 - Solid snedds based on salts of methacrylic copolymers - Google Patents

Solid snedds based on salts of methacrylic copolymers Download PDF

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Publication number
WO2023088830A1
WO2023088830A1 PCT/EP2022/081745 EP2022081745W WO2023088830A1 WO 2023088830 A1 WO2023088830 A1 WO 2023088830A1 EP 2022081745 W EP2022081745 W EP 2022081745W WO 2023088830 A1 WO2023088830 A1 WO 2023088830A1
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Prior art keywords
acid
drug delivery
delivery system
triglycerides
polyoxyl
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PCT/EP2022/081745
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French (fr)
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Fabian-Pascal SCHMIED
Christian MOERS
Alexander Bernhardt
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Evonik Operations Gmbh
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Publication of WO2023088830A1 publication Critical patent/WO2023088830A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention refers to a method of preparing a specific solid self-nanoemulsifying drug delivery system, which comprises adding the obtained self-nanoemulsifying drug delivery system to a salt of at least one methacrylic copolymer and of an inorganic acid or of an organic acid having a pK a value of 3.5 or lower and optionally at least one additive by hot melt extrusion, freeze drying, spray drying, adsorption, electrospinning, electrospraying, prilling by vibration, granulation or supercritical fluidization.
  • the present invention refers to the solid self-nanoemulsifying drug delivery system obtainable or obtained by the method of the present invention and this system for use as a pharmaceutical or nutraceutical product.
  • SNEDDS Self-nanoemulsifying drug delivery systems
  • the systems use the emulsion of poorly water-soluble active ingredients to improve drug solubilization.
  • two kinds of SNEDDS are known, liquid or semi-liquid SNEDDS and solid SNEDDS (S-SNEDDS). While the liquid or semi-liquid character of SNEDDS is often seen as a disadvantage in view of dosing for peroral applications and in view of their lack of storage stability, solid self-nanoemulsifying systems are preferred.
  • EP 2 101 729 B1 describes in this regard several ways for the conversion of microemulsions into the solid state. These are adsorption on colloidal silicon dioxide, stabilization of individual phases with colloidal silicon dioxide and hydrophobic colloidal silicon dioxide, incorporation in polyethylene glycol dispersions and spray drying.
  • S-SMEDDS solid self-microemulsifying drug delivery system
  • CN107308133 A discloses S-SMEDDS comprising curcumin containing SMEDDS employing AEROSIL® 200 as adsorbent.
  • the object of the present invention was to provide a pharmaceutical or nutraceutical composition, in particular a solid self-nanoemulsifying drug delivery system that is solid at more than 40° C, based on dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymers which can provide good stability and fast drug release characteristics.
  • the present invention refers to a method of preparing a solid self-nanoemulsifying drug delivery system comprising or consisting of the following steps: providing a self-nanoemulsifying drug delivery system by mixing
  • the present invention pertains to a solid self-nanoemulsifying drug delivery system obtainable or obtained by the method of the present invention.
  • the present invention refers to a solid self-nanoemulsifying drug delivery system according to the present invention for use as a pharmaceutical or nutraceutical product.
  • “One or more”, as used herein, relates to at least one and comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9 or more of the referenced species. Similarly, “at least one” means one or more, i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9 or more. "At least one”, as used herein in relation to any component, refers to the number of chemically different molecules, i.e. to the number of different types of the referenced species, but not to the total number of molecules.
  • At least one surfactant means that at least one type of molecule falling within the definition for a surfactant is used but that also two or more different types of surfactants falling within this definition can be present, but does not mean that only one or more molecules of one type of surfactant are present.
  • “Essentially free of’ according to the present invention with regard to compounds means that the compound can only be present in an amount, which does not influence the characteristics of the composition, in particular the respective compound is present in less than 3 wt.-%, preferably 1 wt.- %, more preferably 0.01 wt.-%, based on the total weight of the composition or is not present at all.
  • the weight average molecular weight Mw and the number average molecular weight Mn can be determined by GPC employing polystyrene standards or SEC.
  • For neutral or anionic (meth)acrylate (co)polymers the method described in M. Adler et. al. "Molar mass characterization of hydrophilic copolymers, 1 Size exclusion chromatography of neutral and anionic (meth)acrylate copolymers” e- Polymers, vol. 4, no. 1 , 2004 can be used.
  • For cationic (meth)acrylate (co)polymers the method described in N. Adler et. al. "Molar mass characterization of hydrophilic copolymers, 2 Size exclusion chromatography of cationic (meth)acrylate copolymers” e-Polymers, vol. 5, no. 1 , 2005 can be used.
  • the glass transition temperature T g may be determined by DSC (Differential Scanning Calorimetry) analysis according to DIN EN ISO 11357-2:2013 (measurement without addition of plasticizer at a residual monomer content (ReMo) of less than 3000 ppm, heating rate 10°C/min, nitrogen atmosphere).
  • the median of the particle size’s volume distribution Dv.so and Z-A verage particle size D z can be determined by dynamic light scattering (DLS) according to ISO 22412:2017 “Particle size analysis - Dynamic light scattering (DLS)”.
  • the polydispersity index (PDI) is determined from a two-parameter fit to the correlation data (the cumulants analysis). The calculations used for the determination of PDI are defined in the ISO standard documents 22412:2017.
  • the degree of neutralization for dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer after salt formation may be determined via direct titration by potentiometrical detection of the endpoint as explained in the experimental part (Methods).
  • the present invention refers to a method of preparing a solid self-nanoemulsifying drug delivery system comprising the following steps: providing a self-nanoemulsifying drug delivery system by mixing
  • any pharmaceutically or nutraceutically active ingredient or mixtures of pharmaceutically or nutraceutically active ingredients known to the skilled person may be incorporated in the pharmaceutical or nutraceutical compositions and S-SNEDDS.
  • the pharmaceutical or nutraceutical compositions of the present invention are very useful for poorly water-soluble pharmaceutically or nutraceutically active ingredients or for pharmaceutically or nutraceutical active ingredients which show a high drug loss after storage.
  • the pharmaceutically or nutraceutically active ingredient may be a drug poorly soluble, in particular poorly water-soluble, after peroral administration.
  • the pharmaceutically or nutraceutically active ingredient (i) may show a solubility of less than 0.1 mg of pharmaceutically or nutraceutically active ingredient, preferably of the pure pharmaceutically or nutraceutically active ingredient, in 1 ml water at 37 °C (as defined for poorly insoluble drugs in the USP).
  • the determination of the solubility of the pharmaceutically or nutraceutically active ingredient is well known to a person skilled in the art. For instance, an excess amount of the pharmaceutically or nutraceutically active ingredient is placed in a certain amount of water and mixed. The dissolved amount of the pharmaceutically or nutraceutically active ingredient is then determined by a suitable analytical method, for instance by spectrometry.
  • the at least one pharmaceutically active ingredient may be selected from acalabrutinib, albendazole, allendronic acid, aripiprazole, asenapine, atazanavir, atorvastatin, BETd-260 bleomycin, bosentan, BRD4 degrader AT1 , buprenorphine, budesonide, camostat, candesartan, carbamazepine, carvedilol, celecoxib, cilazapril, clarithromycin, clodronic acid, clopidogrel, curcumin, cytarabine, darunavir, dasatinib, deferasirox, dexamethasone, dexlansoprazole, diclofenac, diltiazem, docetaxel, doxorubicin, duloxetine, dutasteride, efavirenz, elbasvir, eprosartan, erlot
  • the at least one pharmaceutically or nutraceutically active ingredient is selected from resveratrol from grape products or pro-anthocyanins or anthocyanins, in particular from bilberries or black currants, soluble dietary fiber products, such as psyllium seed, broccoli (sulphane), and soy or clover (isoflavonoids), flavonoids, alpha-linoleic acid from flax seed, betacarotene from marigold petals or mixtures thereof.
  • the at least one pharmaceutically or nutraceutically active ingredient may be selected from celecoxib, efavirenz and fenofibrate or mixtures thereof, more preferably fenofibrate.
  • Any lipid component which can be used for pharmaceutical compositions is in general suitable.
  • the at least one lipid component is selected from C6-C12 fatty acid triglycerides; C13-C21 fatty acid triglycerides; propylene glycol dicaprylate I dicaprate; glyceryl tricaprylate / tricaprate; glyceryl triricinoleate; lauric acid triglycerides; glyceryl dibehenate; linoleic acid and oleic acid triglycerides; linoleic acid, oleic acid, and palmitic acid triglycerides; ethyl oleate; isopropyl myristate; monolinoleate triglycerides I diglycerides I monoglycerides; glyceryl tricaprylate / tricaprate / trilaurate; oleic acid; oleic acid and palmitic acid triglycerides; palmitic acid, oleic acid, and
  • the at least one lipid component (ii) may be selected from medium chain triglycerides (C6-C12 fatty acids), long chain triglycerides (C13-C21 fatty acids), propylene glycol dicaprylate / dicaprate (Captex® 200), glyceryl tricaprylate I tricaprate (Captex® 300), glyceryl triricinoleate (Castor oil), medium chain triglycerides (lauric acid) (Coconut oil), glyceryl dibehenate (Compritol® 888 ATO), triglycerides (linoleic acid, oleic acid) (Corn oil), triglycerides (linoleic acid, oleic acid, palmitic acid) (Cottonseed oil), ethyl oleate (CrodamolTM EO), glyceryl tricaprylate / tricaprate (CrodamolTM GTCC), isopropyl myristate
  • the at least one surfactant (iii), may comprise one or more surfactants
  • the at least one surfactant is preferably selected from polyoxyethylene (23) lauryl ether; polyoxyethylene (2) oleyl ether; glyceryl monooleate; caprylate and caprate monoglycerides/diglycerides; glyceryl monocaprylate; propylene glycol monocaprylate; polyoxyl-35 hydrogenated castor oil; polyoxyl-40 hydrogenated castor oil; lauroyl polyoxyl-32 glycerides; stearoyl polyoxyl-32 glycerides; polyoxyl-15 hydroxystearate; triblock copolymer of polyoxyethylene and polyoxypropylene; oleoyl polyoxyl-6 glycerides; linoleoyl polyoxyl-6 glycerides; lauroyl polyoxyl-6 glycerides; caprylocaproyl polyoxyl-8 glycerides; propylene glycol monolaurate; polyoxyl-40 stearate; diacetylene glycol monolaurate
  • a solvent may be employed. Any solvent which can be used for pharmaceutical compositions is in general suitable.
  • the at least one solvent (iv) can be selected from diethylene glycol monoethyl ether, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 6000, propane-1 ,2, 3-triol, (z)-octadec-9-enylamine, polypropylene glycol, propylene glycol, 2-pyrrolidone and tetraethylene glycol or any mixture thereof.
  • the self-nanoemulsifying drug delivery system may essentially free of solvent.
  • any additive which can be used for pharmaceutical compositions, different from (i) to (iv), is in general suitable.
  • the at least one additive can be the same or different. In one embodiment only additive (v) is present. In an alternative embodiment only the additive to the salt of the at least one methacrylic copolymer of the inorganic or organic acid is present. In one embodiment essentially no additive is present.
  • the at least one additive is preferably selected from antiadherents; binders; flavors; pigments; disintegrants; glidants; flow regulators; antioxidants; sweeteners; and antistatics; or mixtures thereof.
  • Suitable additives may be antiadherents, like magnesium stearate; fillers, like lactose, mannitol, starches, cellulose and their derivatives; binders, like polyacrylates, starches, guar, xanthan, alginate, carrageenan, pectin, tragacanth, polysaccharides and their derivatives; flavors, like mint, cherry, anise, vanilla, raspberry; colors, like natural colorants, azo and xanthene compounds; pigments, like titanium dioxides, iron oxides, magnesium oxide; disinteg rants, like starches, croscarmellose, crosslinked polyvinylpyrrolidone, sodium hydrogen carbonate preferably in combination with citric acid (for effervescent tablets); glidants, like silica gel, fumed silica, talc, magnesium carbonate, flow regulators, like highly dispersed silicon dioxide; antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium
  • S-SNEDDS Solid self-nanoemulsifying drug delivery systems
  • a self-nanoemulsifying drug delivery system forms and remains a nanoemulsion in contact with water or gastrointestinal fluids.
  • a skilled person in the field of nanoemulsions knows how to prepare the self-nanoemulsifying drug delivery system of the present invention with commonly known methods.
  • the Z-A verage size D z (Z-A verage particle size D z ) of the particles in the nanoemulsion may be between 1 and 1 ,000 nm, in many cases between 100 and 500 nm or from 10 to 100 nm.
  • the nanoemulsion formation may happen during manufacturing of a pharmaceutical composition or by a medical professional or in vivo.
  • the formation happens, when the emulsifying components and the pharmaceutically or nutraceutically active ingredient are added to an aqueous media, preferably water.
  • the formation is performed under stirring of the mixture and/or heating the mixture to 30 to 60 °C, preferably 45 to 55 °C, more preferably 50 °C. Stirring and/or heating can improve the provision of a homogenous mixture.
  • the emulsifying components of the self-nanoemulsifying drug delivery systems are usually comprising, or are consisting of, a lipid component, at least one surfactant and optionally a solvent and/or optionally an additive, i.e. components (ii) to (v).
  • a lipid component usually comprising, or are consisting of, a surfactant and optionally a solvent and/or optionally an additive, i.e. components (ii) to (v).
  • emulsifying components (ii) to (v) are mixed with a pharmaceutically or nutraceutically active ingredient (i) into a solution, which forms a self- nanoemulsifying drug delivery system (SNEDDS).
  • SNEDDS self- nanoemulsifying drug delivery system
  • (i) is present in 0.01 to 25 wt.-%, preferably 0.1 to 15 wt.-%;
  • (iii) is present in 5 to 60 wt.-%;
  • (iv) is present in 0 to 50, preferably 10 to 50 wt.-%; (v) is present in 0 to 25, preferably 0.1 to 5, wt.-%; based on the total weight of the self- nanoemulsifying drug delivery system.
  • the self-nanoemulsifying drug delivery system (SNEDDS) and a carrier in the present invention the salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pK a value of 3.5 or lower and optionally an additive, form after processing, for instance by hot melt extrusion, freeze drying, spray drying, adsorption, electrospinning, electrospraying, prilling by vibration, granulation or supercritical fluid technology the solid self-nanoemulsifying drug delivery system (S-SNEDDS).
  • the S-SNEDDS are obtained by hot melt extrusion.
  • the S-SNEDDS are obtained by freeze drying.
  • the self-nanoemulsifying drug delivery system is present in 1 to 30 wt.-%, based on the total weight of the solid self-nanoemulsifying drug delivery system and the mixture.
  • the S-SNEDDS of the present invention are obtained by hot melt extrusion at a temperature of 130 to 150 °C, preferably of 140 °C.
  • the components may be extruded within a twin-screw extruder.
  • the components may be extruded within a twin-screw extruder at a torque of about 30 to 100 Ncm.
  • the components may be extruded within a twin-screw extruder at a torque of about 45 to 85 Ncm.
  • the extruded mass may leave the extruder in the form of a strand, which may be comminuted by grinding and milling to a powder product.
  • the provided self-nanoemulsifying drug delivery system as explained above is applied on an aqueous solution comprising a salt of at least one methacrylic copolymer and of an inorganic acid or of an organic acid having a pK a value of 3.5 or lower and optionally at least one additive.
  • the methacrylic copolymer is a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer.
  • the 2-dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer may be obtained by radically polymerizing the monomers 2-dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a ratio of a) 30 to 70 wt.-% dimethylaminoethyl methacrylate; b) 15 to 35 wt.% butyl methacrylate; and c) 15 to 35 wt.-% methyl methacrylate; whereby the sum of a) to c) is 100 wt.-%; optionally in the presence of further additives and/or has a residual monomer content of not more than 0.5 % for each monomer and/or has a weight average molecular weight Mw of from 15,000 to 400,000 g/mol, preferably from 20,000 to 300,000 g/mol, more preferably from 25,000 to 200,000 g/mol ;
  • Suitable further additives are at least one initiator, preferably selected from di- (3,5,5)trimethylhexanoyl peroxide, tert-butyl peroxyneodecanoate, tert-butyl perbenzoate, tert-amyl peroxy-2-ethylhexanoate, bisdecanoyl peroxide, tert-butyl peroxy-2-ethylhexanoate, tert-butyl peroxy-2-ethylhexylcabonate, 1 ,1 ’-azobis(cyclohexanecarbonitrile), benzoyl peroxide, 2,2-di-(tert- butylperoxy)butane, dicumyl peroxide, di-tert-amyl peroxide, di-tert-butyl peroxide, lauroyl peroxide, tert-butylperoxy-3,5,5-trimethylhexanoate, 1 ,1-di
  • the at least one methacrylic acid-ethyl acrylate copolymer may be obtained by an emulsion polymerization process with an optional subsequent drying step.
  • the copolymers can be used in powder form, preferably having an average particle size D v ,5o in the range of from 1 to 1 ,000 pm, more preferably from 2 to 100 pm.
  • the powder can be obtained by milling and grinding.
  • EUDRAGIT® E is a commercially available methacrylic copolymer, i.e. a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer, and suitable to be used in the method according to the present invention. Its precise chemical designation is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1 :2:1.
  • the salt of the at least one methacrylic copolymer being a 2-dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, may be obtained by mixing the methacrylic copolymer being a 2-dimethylaminoethyl methacrylate- butyl methacrylate-methyl methacrylate copolymer with an inorganic acid or with an organic acid having a pK a value of 3.5 or lower and drying of the so obtained aqueous dispersion or aqueous solution.
  • the at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer is preferably poly(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1 :2:1 (commercially available under the trade name EUDRAGIT® E).
  • the salt of the at least one methacrylic copolymer may be obtained by radically polymerizing the monomers 2- dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a ratio of a) 30 to 70 wt.-% dimethylaminoethyl methacrylate; b) 15 to 35 wt.% butyl methacrylate; and c) 15 to 35 wt.-% methyl methacrylate; whereby the sum of a) to c) is 100 wt.-%; optionally in the presence of further additives; and/or has a residual monomer content of not more than 0.5 % for each monomer; and/or has a weight average molecular weight Mw of 15,000 to 400,000 g/
  • the inorganic acid is hydrochloric acid.
  • an organic acid having a pK a value of 3.5 or lower is chosen or is selected from maleic acid, tartaric acid, malic acid, fumaric acid and citric acid; or mixtures thereof.
  • the degree of neutralization of the methacrylic copolymer of the salt of the at least one methacrylic copolymer and of the inorganic or of the organic acid is more than 20 %.
  • the degree of neutralization of the methacrylic copolymer of the salt of the at least one methacrylic copolymer and of the inorganic or of the organic acid can be determined via direct titration by potentiometrical detection of the endpoint.
  • the glass transition temperature (T g ) of the salt of the at least one methacrylic copolymer and of the inorganic acid or of the organic acid is from 55 to 135 °C.
  • T g temperature ranges also encompass deviations of +/- 10 % having the same technical effect.
  • the solid self-nanoemulsifying drug delivery system (S-SNEDDS), of the present invention are suitable for use (method of use) as a medicament or nutraceutical product, which preferably enhances the solubility of the included pharmaceutically or nutraceutically active ingredient compared to the pharmaceutically or nutraceutically active ingredient alone in the treatment of a disease of a human or an animal subject.
  • the invention in particular pertains to:
  • a method of preparing a solid self-nanoemulsifying drug delivery system comprising the following steps: providing a self-nanoemulsifying drug delivery system by mixing
  • organic acid is selected from maleic acid, tartaric acid, malic acid, fumaric acid and citric acid or mixtures thereof.
  • the glass transition temperature (T g ) of the salt of the at least one methacrylic copolymer and of the inorganic acid or of the organic acid is 55 - 135 °C.
  • the at least one pharmaceutically or nutraceutically active ingredient has a solubility of less than 0.1 mg in 1 ml water at 37 °C and/or is selected from celecoxib, efavirenz and fenofibrate or mixtures thereof.
  • the at least one lipid component is selected from C6-C12 fatty acid triglycerides; C13-C21 fatty acid triglycerides; propylene glycol dicaprylate / dicaprate; glyceryl tricaprylate / tricaprate; glyceryl triricinoleate; lauric acid triglycerides; glyceryl dibehenate; linoleic acid and oleic acid triglycerides; linoleic acid, oleic acid, and palmitic acid triglycerides; ethyl oleate; isopropyl myristate; monolinoleate triglycerides I diglycerides I monoglycerides; glyceryl tricaprylate / tricaprate / trilaurate; oleic acid; oleic acid and palmitic acid triglycerides; palmitic acid,
  • the at least one surfactant is selected from polyoxyethylene (23) lauryl ether; polyoxyethylene (2) oleyl ether; glyceryl monooleate; caprylate and caprate monoglycerides/diglycerides; glyceryl monocaprylate; propylene glycol monocaprylate; polyoxyl-35 hydrogenated castor oil; polyoxyl-40 hydrogenated castor oil; lauroyl polyoxyl-32 glycerides; stearoyl polyoxyl-32 glycerides; polyoxyl-15 hydroxystearate; triblock copolymer of polyoxyethylene and polyoxypropylene; oleoyl polyoxyl-6 glycerides; linoleoyl polyoxyl-6 glycerides; lauroyl polyoxyl-6 glycerides; caprylocaproyl polyoxyl-8 glycerides; propylene glycol monolaurate; polyoxyl-40 stearate; di
  • the at least one solvent is selected from diethylene glycol monoethyl ether, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 6000, propane-1 ,2, 3-triol, (z)-octadec-9-enylamine, polypropylene glycol, propylene glycol, 2-pyrrolidone, tetraethylene glycol and diethylene glycol monoethyl ether, or any mixtures thereof.
  • the at least one additive is selected from antiadherents; binders; flavors; pigments; disintegrants; glidants; flow regulators; antioxidants; sweeteners; and antistatics; or mixtures thereof.
  • the self-nanoemulsifying drug delivery system is present in 1 to 30 wt.-%, based on the total weight of the solid self-nanoemulsifying drug delivery system and the mixture.
  • (i) is present in 0.01 to 25 wt.-%, preferably 0.1 to 15 wt.-%,
  • (v) is present in 0 to 25 wt.-%; based on the total weight of the self-nanoemulsifying drug delivery system.
  • a solid self-nanoemulsifying drug delivery system obtainable or obtained by the method of any of the preceding items.
  • the solid self-nanoemulsifying drug delivery system of item 14 for use as a pharmaceutical.
  • Fenofibrate (propan-2-yl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate) obtained from D.K. Pharma Chem PVT Ltd. (Maharashtra, India) was used as model compound.
  • Dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate (EUDRAGIT® E) is a commercially available product from Evonik Operations GmbH (Darmstadt, Germany).
  • Polyoxyethylene (80) sorbitan monooleate (Tween® 80), d-a-Tocopherol polyethylene glycol 1000 succinate (d-TPGS) and polyoxyethylene (23) lauryl ether (Brij® 35) were purchased from Sigma Aldrich Chemie GmbH (Steinheim, Germany).
  • Medium-chain triglycerides (Miglyol® 812) was obtained from Caesar & Loretz GmbH (Hilden, Germany). All other chemicals were of analytical grade and purchased commercially.
  • dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer e.g., E/hydrochloride, E/maleate, E/tartrate, E/fumarate, E/citrate, E/malate,
  • the corresponding aqueous acidic solution was added to the copolymer under vigorous magnetic stirring (1 ,000 rpm for 4 h) in order to neutralize the functional amino groups of the dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (salt formation).
  • the resulting aqueous dispersion or aqueous solution was subsequently spray dried using a Niro Minor spray dryer (GEA Group AG, Dusseldorf, Germany).
  • the dispersion was atomized into fine droplets using a two-fluid nozzle with a bore diameter of 0.5 mm.
  • Nitrogen was used as the atomizing and drying gas in this spray drying process at an inlet temperature of 70 - 120 °C depending on the composition.
  • the fine droplets were sprayed using a top-down spray drying process and the dry particles were collected in a vessel after their separation from the gas flow using a cyclone.
  • S-SNEDDS Solid-SNEDDS
  • ASD amorphous solid dispersion
  • HME hot-melt extrusion
  • a certain copolymer e.g., the dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate hydrochloride (E/HCI), or dimethylaminoethyl methacryl
  • the SNEDDS-polymer blend was processed via hot-melt extrusion technology using a co-rotating HAAKE MiniLab twin screw extruder from Thermo Fisher Scientific (Dreieich, Germany) that exhibited a conical screw design.
  • the hot-melt extrusion process was characterized by recording the applied screw speed, the torque and the process temperature.
  • the granule was ground (mesh size: 0.25 mm) using an Ultra Centrifugal Mill ZM 200 from Retsch GmbH (Haan, Germany).
  • the obtained powder was the dosage form of the manufactured S-SNEDDS that was used for all further studies.
  • a blend of polymer and drug substance (ASD) was prepared using a Turbular mixer from WAB Group (Nidderau-Heldenbergen, Germany) for approximately 10 min. The blend was then processed via the mentioned hot-melt extrusion process in order to assess the effect of S-SNEDDS referring to different characteristics in comparison to ASDs.
  • the copolymers dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate (EUDRAGIT® E) and dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate hydrochloride (E/HCI) or dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate tartrate (E/Tartrate) were applied.
  • EUDRAGIT® E dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate
  • E/HCI dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate hydrochloride
  • E/Tartrate dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate tartrate
  • a blend of the compounds 1 to 4 (Table 1) as well as the drug substance fenofibrate was prepared by mixing these substances in a beaker glass under moderate magnetic stirring for approximately 30 min. The blend was subjected to a temperature of 50 °C while stirring.
  • blends of an aqueous solution of a salt of a copolymer e.g., dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate hydrochloride copolymer (E/HCI) or dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate tartrate (E/Tartrate)
  • E/HCI dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate tartrate
  • EUDRAGIT® E dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer
  • the three homogeneous mixtures (50.0 g each) were divided in parts of 5.0 g each and transferred to separate glass vials for the freeze-drying process.
  • the freeze- drying process was started at 30 °C. Within the first hour, the mixture was cooled down to -40 °C and maintained at this temperature for another 3 h. After 4 h the pressure was reduced to a pressure level below 0.1 mbar. After 5 h the temperature was gradually increased during the process to a final temperature of 20 °C.
  • the entire freeze-drying process was conducted over a time period of 54 h using an Epsilon 2-6D (LSC) freeze dryer from Martin Christ Gefriertrocknungsanlagen GmbH (Osterode am Harz, Germany).
  • LSC Epsilon 2-6D
  • the generated S-SNEDDS and ASDs that were prepared via freeze drying resulted in white or off-white, flowable, small particles.
  • Dissolution experiments were performed according to USP 42-NF 37 (2019). Dissolution experiments were conducted with 25 mg drug substance or an equivalent amount of S-SNEDDS or ASD using USP apparatus II (DT 800 LH) from ERWEKA GmbH (Langen, Germany). The paddle speed was set to 100 rpm and all experiments were performed in 500 ml of 0.1 N hydrochloric acid at 37 ⁇ 0.5 °C. All samples were withdrawn by a fraction collector, equipped with cannula filters of 10 pm pore size and manually diluted 1 :1 (v/v) with acetonitrile before HPLC analysis. The dissolution tests were conducted over 120 min. HPLC method for analysing feno fibrate
  • HPLC high-performance liquid chromatography
  • DSC Differential scanning calorimetry
  • the copolymers were analysed via DSC to determine their glass transition temperature (T g ) and if the incorporated drug demonstrated an amorphous (glass transition) or crystalline (melting/crystallization peak) appearance.
  • the glass transition is a reversible transition from a hard and relatively brittle, frozen state to a molten or rather rubbery state within amorphous or partly amorphous materials.
  • the melting point of the pure drug substance as well as the glass transition temperature of the copolymers were investigated for identifying changes and/or shifts in the thermograms regarding crystalline and/or amorphous characteristics.
  • a sample of 5 - 10 mg each was weighed into a small, perforated aluminum pan with a lid that was cold sealed and exposed to a heating-cooling-heating cycle starting from 0 °C up to 200 °C while running the measurement continuously applying inert nitrogen atmosphere.
  • the constant heating/cooling rate was set to 10 °C/min.
  • the heat flow is plotted against the temperature using an endothermic presentation method.
  • the evaluation was based on the second heating cycle, and the indicated value is the mean value in the glass transition interval.
  • the analysis was conducted using a DSC 3+ (DSC-HC01) from Mettler Toledo (GieBen, Germany).
  • the dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer was always used as the basic compound for the salt formation when applying different acids.
  • the alkali value of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer was determined.
  • the alkali values of the generated salts of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer were specified.
  • the analysis of the samples (200 mg each) for the determination of the alkali values was conducted using a titrimetric method (direct titration) applying 0.1 N perchloric acid as the titrant.
  • the endpoint of the titration for the aqueous solutions of the samples was potentiometrically detected.
  • the degree of neutralization for dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer after salt formation was calculated using the ratio of the corresponding alkali values.
  • Table 1 Composition of SNEDDS-solution incorporating fenofibrate compound 1 compound 2 compound 3 compound 4 drug substance trade name Miglyol® 812 Brij® 35 Tween® 80 d-TPGS fenofibrate amount [%] 17.20 8.60 50.16 10.04 14.00
  • the composition of the analysed samples including the SNEDDS load and/or drug load as well as the process parameters regarding the hot-melt extrusion process or freeze-drying process were recorded and presented in Tables 2 and 3.
  • the dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (EUDRAGIT® E) was not suitable to be applied for S- SNEDDS manufacturing via HME as well as FD as the generated product was not solid and inhomogeneous.
  • the following data related to E/HCI or E/Tartrate were collected using E/HCI or E/Tartrate with a neutralization degree of 80 %.
  • Table 2 Composition & hot-melt extrusion process parameters of S-SNEDDS and ASD incorporating fenofibrate sample name total total extrusion torque screw
  • the AV c was the alkali value of the dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer after salt formation and the A l/ s was the alkali value of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer.
  • Table 7 The pK a of the acidic substances, the T g and degree of neutralization of the prepared salts of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer salt acid pK a of acid T g of salt [°C] degree of neutralization [%]

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Abstract

The present invention refers to a method of preparing a solid self-nanoemulsifying drug delivery system, which comprises adding the obtained self-nanoemulsifying drug delivery system to a salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower e.g. by hot melt extrusion or freeze drying. Furthermore, the present invention refers to the solid self-nanoemulsifying drug delivery system obtainable by the method of the present invention and its use as a medicament.

Description

Solid SNEDDS based on salts of methacrylic copolymers
Field of the invention
The present invention refers to a method of preparing a specific solid self-nanoemulsifying drug delivery system, which comprises adding the obtained self-nanoemulsifying drug delivery system to a salt of at least one methacrylic copolymer and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower and optionally at least one additive by hot melt extrusion, freeze drying, spray drying, adsorption, electrospinning, electrospraying, prilling by vibration, granulation or supercritical fluidization. Furthermore, the present invention refers to the solid self-nanoemulsifying drug delivery system obtainable or obtained by the method of the present invention and this system for use as a pharmaceutical or nutraceutical product.
Background
Self-nanoemulsifying drug delivery systems (SNEDDS) are well known in the field of pharmaceutical compositions. The systems use the emulsion of poorly water-soluble active ingredients to improve drug solubilization. In general, two kinds of SNEDDS are known, liquid or semi-liquid SNEDDS and solid SNEDDS (S-SNEDDS). While the liquid or semi-liquid character of SNEDDS is often seen as a disadvantage in view of dosing for peroral applications and in view of their lack of storage stability, solid self-nanoemulsifying systems are preferred.
General methods of providing solid self-nanoemulsifying drug delivery systems or in the neighboring field of self-microemulsifying drug delivery systems (SMEDDS) are for example disclosed in the following publications.
EP 2 101 729 B1 describes in this regard several ways for the conversion of microemulsions into the solid state. These are adsorption on colloidal silicon dioxide, stabilization of individual phases with colloidal silicon dioxide and hydrophobic colloidal silicon dioxide, incorporation in polyethylene glycol dispersions and spray drying.
Silva, D. Luis Antonio, et al. (International Journal of Pharmaceutics 541 (2018) 1 - 10) describe the preparation of a solid self-microemulsifying drug delivery system (S-SMEDDS) by hot melt extrusion. S-SMEDDS were prepared by blending carvedilol and a lipid mixture with hydroxyl propyl methyl cellulose acetate succinate (HPMCAS). Extrudates prepared at the lowest drug concentration and highest temperature and recirculation time promoted a complete and rapid drug release at pH 6.8.
CN107308133 A discloses S-SMEDDS comprising curcumin containing SMEDDS employing AEROSIL® 200 as adsorbent. The object of the present invention was to provide a pharmaceutical or nutraceutical composition, in particular a solid self-nanoemulsifying drug delivery system that is solid at more than 40° C, based on dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymers which can provide good stability and fast drug release characteristics.
Summary of the invention
Therefore, the present invention refers to a method of preparing a solid self-nanoemulsifying drug delivery system comprising or consisting of the following steps: providing a self-nanoemulsifying drug delivery system by mixing
(i) at least one pharmaceutically or nutraceutically active ingredient,
(ii) at least one lipid component,
(iii) at least one surfactant,
(iv) optionally at least one solvent and
(v) optionally at least one additive and then adding the obtained self-nanoemulsifying drug delivery system to a salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower and optionally at least one additive or to an aqueous dispersion of or to an aqueous solution of a salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylatemethyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower and optionally at least one additive by hot melt extrusion, freeze drying, spray drying, adsorption, electrospinning, electrospraying, prilling by vibration, granulation or supercritical fluidization to obtain the solid self-nanoemulsifying drug delivery system.
In a further aspect, the present invention pertains to a solid self-nanoemulsifying drug delivery system obtainable or obtained by the method of the present invention.
In a further aspect, the present invention refers to a solid self-nanoemulsifying drug delivery system according to the present invention for use as a pharmaceutical or nutraceutical product.
Description of the figures
Figure 1 shows the dissolution profiles of Solid-SNEDDS and amorphous solid dispersions (ASD) incorporating fenofibrate processed via hot-melt extrusion (HME) or freeze drying (FD) and fenofibrate drug substance in 500 ml 0.1 N hydrochloric acid at 37 ± 0.5 °C using USP apparatus II. Each value designates the mean ± standard deviation (S.D.) of n = 3.
Figure 2 shows the dissolution profiles of Solid-SNEDDS and amorphous solid dispersions (ASD) incorporating fenofibrate via hot-melt extrusion (HME) process or freeze drying (FD) in 500 ml 0.1 N hydrochloric acid at 37 ± 0.5 °C using USP apparatus II. Each value designates the mean ± standard deviation (S.D.) of n = 3.
Detailed description
Numerical ranges that are indicated in the format “from x to y” also include the stated values. If several preferred numerical ranges are indicated in this format, it is self-evident that all ranges that result from the combination of the various endpoints are also included. The numerical ranges also encompass deviations of +/- 10 % having the same technical effect.
"One or more", as used herein, relates to at least one and comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9 or more of the referenced species. Similarly, "at least one" means one or more, i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9 or more. "At least one", as used herein in relation to any component, refers to the number of chemically different molecules, i.e. to the number of different types of the referenced species, but not to the total number of molecules. For example, "at least one surfactant" means that at least one type of molecule falling within the definition for a surfactant is used but that also two or more different types of surfactants falling within this definition can be present, but does not mean that only one or more molecules of one type of surfactant are present.
All percentages given herein in relation to the compositions or formulations relate to wt.-% relative to the total weight of the respective composition, if not explicitly stated otherwise.
“Essentially free of’ according to the present invention with regard to compounds means that the compound can only be present in an amount, which does not influence the characteristics of the composition, in particular the respective compound is present in less than 3 wt.-%, preferably 1 wt.- %, more preferably 0.01 wt.-%, based on the total weight of the composition or is not present at all.
The weight average molecular weight Mw and the number average molecular weight Mn can be determined by GPC employing polystyrene standards or SEC. For neutral or anionic (meth)acrylate (co)polymers the method described in M. Adler et. al. "Molar mass characterization of hydrophilic copolymers, 1 Size exclusion chromatography of neutral and anionic (meth)acrylate copolymers" e- Polymers, vol. 4, no. 1 , 2004 can be used. For cationic (meth)acrylate (co)polymers the method described in N. Adler et. al. "Molar mass characterization of hydrophilic copolymers, 2 Size exclusion chromatography of cationic (meth)acrylate copolymers" e-Polymers, vol. 5, no. 1 , 2005 can be used.
The glass transition temperature Tg may be determined by DSC (Differential Scanning Calorimetry) analysis according to DIN EN ISO 11357-2:2013 (measurement without addition of plasticizer at a residual monomer content (ReMo) of less than 3000 ppm, heating rate 10°C/min, nitrogen atmosphere). The median of the particle size’s volume distribution Dv.so and Z-A verage particle size Dz can be determined by dynamic light scattering (DLS) according to ISO 22412:2017 “Particle size analysis - Dynamic light scattering (DLS)". The polydispersity index (PDI) is determined from a two-parameter fit to the correlation data (the cumulants analysis). The calculations used for the determination of PDI are defined in the ISO standard documents 22412:2017.
The degree of neutralization for dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer after salt formation may be determined via direct titration by potentiometrical detection of the endpoint as explained in the experimental part (Methods).
The present invention refers to a method of preparing a solid self-nanoemulsifying drug delivery system comprising the following steps: providing a self-nanoemulsifying drug delivery system by mixing
(i) at least one pharmaceutically or nutraceutically active ingredient,
(ii) at least one lipid component,
(iii) at least one surfactant,
(iv) optionally at least one solvent and
(v) optionally at least one additive and then adding the obtained self-nanoemulsifying drug delivery system to a salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pKa value of about 3.5 or lower and optionally at least one additive or to an aqueous dispersion of or to an aqueous solution of a salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower and optionally at least one additive by hot melt extrusion, freeze drying, spray drying, adsorption, electrospinning, electrospraying, prilling by vibration, granulation or supercritical fluidization to obtain the solid self-nanoemulsifying drug delivery system.
Pharmaceutically or nutraceutically active ingredient (i)
Any pharmaceutically or nutraceutically active ingredient or mixtures of pharmaceutically or nutraceutically active ingredients known to the skilled person may be incorporated in the pharmaceutical or nutraceutical compositions and S-SNEDDS. However, the pharmaceutical or nutraceutical compositions of the present invention are very useful for poorly water-soluble pharmaceutically or nutraceutically active ingredients or for pharmaceutically or nutraceutical active ingredients which show a high drug loss after storage. Preferably, the pharmaceutically or nutraceutically active ingredient may be a drug poorly soluble, in particular poorly water-soluble, after peroral administration. The pharmaceutically or nutraceutically active ingredient (i) may show a solubility of less than 0.1 mg of pharmaceutically or nutraceutically active ingredient, preferably of the pure pharmaceutically or nutraceutically active ingredient, in 1 ml water at 37 °C (as defined for poorly insoluble drugs in the USP). The determination of the solubility of the pharmaceutically or nutraceutically active ingredient is well known to a person skilled in the art. For instance, an excess amount of the pharmaceutically or nutraceutically active ingredient is placed in a certain amount of water and mixed. The dissolved amount of the pharmaceutically or nutraceutically active ingredient is then determined by a suitable analytical method, for instance by spectrometry.
In one embodiment the at least one pharmaceutically active ingredient may be selected from acalabrutinib, albendazole, allendronic acid, aripiprazole, asenapine, atazanavir, atorvastatin, BETd-260 bleomycin, bosentan, BRD4 degrader AT1 , buprenorphine, budesonide, camostat, candesartan, carbamazepine, carvedilol, celecoxib, cilazapril, clarithromycin, clodronic acid, clopidogrel, curcumin, cytarabine, darunavir, dasatinib, deferasirox, dexamethasone, dexlansoprazole, diclofenac, diltiazem, docetaxel, doxorubicin, duloxetine, dutasteride, efavirenz, elbasvir, eprosartan, erlotinib, estradiol, etidronic acid, etravirine, everolimus, ezetimibe, felodipine, fenofibrate, fluconazole, fluorouracil, foretinib-based PROTAC 7, glimepiride, grazoprevir, griseovulvin, hydrochlorothiazide, hydrocortisone, hydroxychloroquine, ibuprofen, imatinib, irbesartan, irinotecan, itraconazole, ivacaftor, ivermectin, ledipasvir, lamotrigine, linezolid, lisinopril, lopinavir, losartan, lumefantrine, mefloquine, mesalazine, methotrexate, metoprolol, modafinil, moexipril, morphine, mycophenolate, naloxone, nifedipine, nilotinib, nilvadipine, nitrendipine, olanzapine, olmesartan, omeprazole, ondansetron, paclitaxel, pamidronic acid, paracetamol, pemetrexed, perindopril, phenytoin, pibrentasvir, pioglitazone, prednisone, progesterone, quercetin, quetiapine, raloxifene, raltegravir, ramipril, rebamipide, remdesivir, rilpivirine, risedronic acid, risperidone, ritonavir, rivaroxaban, rivastigmine, rosuvastatin, selegiline, sevelamer, sibutramine, sildenafil, simvastatin, sirolimus, sitagliptin, sofosbuvir, sorafenib, spirapril, sunitinib, tacrolimus, tadalafil, tamoxifen, telaprevir, telmisartan, tenoxicam, terbutaline, ticagrelor, tiludronic acid, trandolapril, troglitazone, umifenovir, valsartan, velpatasvir, vemurafenib, verapamil, ziprasidone, zoledronic acid and ZXH-3-26, or, where applicable, from pharmaceutically acceptable salt forms thereof or mixtures thereof.
In another embodiment, the at least one pharmaceutically or nutraceutically active ingredient is selected from resveratrol from grape products or pro-anthocyanins or anthocyanins, in particular from bilberries or black currants, soluble dietary fiber products, such as psyllium seed, broccoli (sulphane), and soy or clover (isoflavonoids), flavonoids, alpha-linoleic acid from flax seed, betacarotene from marigold petals or mixtures thereof.
Preferably, the at least one pharmaceutically or nutraceutically active ingredient may be selected from celecoxib, efavirenz and fenofibrate or mixtures thereof, more preferably fenofibrate. Lipid component (ii)
Any lipid component which can be used for pharmaceutical compositions is in general suitable.
In the method according to the present invention the at least one lipid component is selected from C6-C12 fatty acid triglycerides; C13-C21 fatty acid triglycerides; propylene glycol dicaprylate I dicaprate; glyceryl tricaprylate / tricaprate; glyceryl triricinoleate; lauric acid triglycerides; glyceryl dibehenate; linoleic acid and oleic acid triglycerides; linoleic acid, oleic acid, and palmitic acid triglycerides; ethyl oleate; isopropyl myristate; monolinoleate triglycerides I diglycerides I monoglycerides; glyceryl tricaprylate / tricaprate / trilaurate; oleic acid; oleic acid and palmitic acid triglycerides; palmitic acid, oleic acid, and linoleic acid triglycerides; oleic acid, linoleic acid, and palmitic acid triglycerides; linoleic acid, oleic acid, and palmitic acid triglycerides; linoleic acid, oleic acid, alpha-linolenic acid, and palmitic acid triglycerides; linoleic acid, oleic acid, and stearic acid triglyceride; glyceryl triacetate; glyceryl tricaprylate; hard fat or any mixtures thereof.
The at least one lipid component (ii) may be selected from medium chain triglycerides (C6-C12 fatty acids), long chain triglycerides (C13-C21 fatty acids), propylene glycol dicaprylate / dicaprate (Captex® 200), glyceryl tricaprylate I tricaprate (Captex® 300), glyceryl triricinoleate (Castor oil), medium chain triglycerides (lauric acid) (Coconut oil), glyceryl dibehenate (Compritol® 888 ATO), triglycerides (linoleic acid, oleic acid) (Corn oil), triglycerides (linoleic acid, oleic acid, palmitic acid) (Cottonseed oil), ethyl oleate (Crodamol™ EO), glyceryl tricaprylate / tricaprate (Crodamol™ GTCC), isopropyl myristate (IPM-100), glyceryl tricaprylate / tricaprate (Labrafac™ CC), glyceryl tricaprylate / tricaprate (Labrafac™ lipophil WL 1349), propylene glycol dicaprylate I dicaprate (Labrafac™ PG), long chain triglycerides I diglycerides I monoglycerides (monolinoleate) (Maisine® CC), glyceryl tricaprylate / tricaprate / trilaurate (Miglyol® 812), oleic acid (Pamolyn™ 100 Oleic Acid), triglycerides (oleic acid, palmitic acid) (olive oil), triglycerides (palmitic acid, oleic acid, linoleic acid), triglycerides (oleic acid, linoleic acid, palmitic acid), triglycerides (linoleic acid, oleic acid, palmitic acid) (palm oil), triglycerides (linoleic acid, oleic acid, alpha-linolenic acid, palmitic acid) (sesame oil), triglycerides (linoleic acid, oleic acid, stearic acid) (soybean oil), glyceryl triacetate (Kollisolv® GTA), glyceryl tricaprylate (Tricaprylin®), hard fat (triglycerides / diglycerides) and hard fat (triglycerides) (Witepsol® H 35) or any mixture thereof.
Expressions in the above list with brackets indicate the main components of the lipid component (example: medium chain triglycerides (lauric acid)). Expressions in the above list with slashes indicate the components of the lipid component (example: glyceryl tricaprylate / tricaprate I trilaurate). Surfactant (iii)
Any surfactant which can be used for pharmaceutical compositions is in general suitable. The at least one surfactant (iii), may comprise one or more surfactants
In the method according to the present invention the at least one surfactant is preferably selected from polyoxyethylene (23) lauryl ether; polyoxyethylene (2) oleyl ether; glyceryl monooleate; caprylate and caprate monoglycerides/diglycerides; glyceryl monocaprylate; propylene glycol monocaprylate; polyoxyl-35 hydrogenated castor oil; polyoxyl-40 hydrogenated castor oil; lauroyl polyoxyl-32 glycerides; stearoyl polyoxyl-32 glycerides; polyoxyl-15 hydroxystearate; triblock copolymer of polyoxyethylene and polyoxypropylene; oleoyl polyoxyl-6 glycerides; linoleoyl polyoxyl-6 glycerides; lauroyl polyoxyl-6 glycerides; caprylocaproyl polyoxyl-8 glycerides; propylene glycol monolaurate; polyoxyl-40 stearate; diacetylated monoglyceride; polyglyceryl-3 dioleate; sorbitan monolaurate; sorbitan monooleate; sorbitan sesquioleate; sorbitan trioleate; glyceryl monostearate; d-a-tocopherol polyethylene glycol 1000 succinate; polyoxyethylene sorbitan monolaurate; polyoxyethylene sorbitan monostearate; and polyoxyethylene sorbitan monooleate or any mixtures thereof.
Solvent (iv)
In the method according to the present invention a solvent may be employed. Any solvent which can be used for pharmaceutical compositions is in general suitable. The at least one solvent (iv) can be selected from diethylene glycol monoethyl ether, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 6000, propane-1 ,2, 3-triol, (z)-octadec-9-enylamine, polypropylene glycol, propylene glycol, 2-pyrrolidone and tetraethylene glycol or any mixture thereof. In the method according to the present invention the self-nanoemulsifying drug delivery system may essentially free of solvent.
Additives (v)
Any additive which can be used for pharmaceutical compositions, different from (i) to (iv), is in general suitable. The at least one additive can be the same or different. In one embodiment only additive (v) is present. In an alternative embodiment only the additive to the salt of the at least one methacrylic copolymer of the inorganic or organic acid is present. In one embodiment essentially no additive is present.
In the method according to the present invention the at least one additive is preferably selected from antiadherents; binders; flavors; pigments; disintegrants; glidants; flow regulators; antioxidants; sweeteners; and antistatics; or mixtures thereof. Suitable additives may be antiadherents, like magnesium stearate; fillers, like lactose, mannitol, starches, cellulose and their derivatives; binders, like polyacrylates, starches, guar, xanthan, alginate, carrageenan, pectin, tragacanth, polysaccharides and their derivatives; flavors, like mint, cherry, anise, vanilla, raspberry; colors, like natural colorants, azo and xanthene compounds; pigments, like titanium dioxides, iron oxides, magnesium oxide; disinteg rants, like starches, croscarmellose, crosslinked polyvinylpyrrolidone, sodium hydrogen carbonate preferably in combination with citric acid (for effervescent tablets); glidants, like silica gel, fumed silica, talc, magnesium carbonate, flow regulators, like highly dispersed silicon dioxide; antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, butylated hydroxyanisole, butylated hydroxytoluene; sweeteners, like sucrose, sorbitol, saccharin sodium, cyclamate, aspartame; and antistatics, like alkyl sulfonates or quaternary ammonium compounds preferably combined with polystyrene; or mixtures thereof.
Solid self-nanoemulsifying drug delivery systems (S-SNEDDS)
A self-nanoemulsifying drug delivery system forms and remains a nanoemulsion in contact with water or gastrointestinal fluids. A skilled person in the field of nanoemulsions knows how to prepare the self-nanoemulsifying drug delivery system of the present invention with commonly known methods. The Z-A verage size Dz (Z-A verage particle size Dz) of the particles in the nanoemulsion may be between 1 and 1 ,000 nm, in many cases between 100 and 500 nm or from 10 to 100 nm. The nanoemulsion formation may happen during manufacturing of a pharmaceutical composition or by a medical professional or in vivo. The formation happens, when the emulsifying components and the pharmaceutically or nutraceutically active ingredient are added to an aqueous media, preferably water. In one embodiment, the formation is performed under stirring of the mixture and/or heating the mixture to 30 to 60 °C, preferably 45 to 55 °C, more preferably 50 °C. Stirring and/or heating can improve the provision of a homogenous mixture.
The emulsifying components of the self-nanoemulsifying drug delivery systems are usually comprising, or are consisting of, a lipid component, at least one surfactant and optionally a solvent and/or optionally an additive, i.e. components (ii) to (v). A skilled person in the field knows how to select the components and adjust the amounts of the components to the pharmaceutically or nutraceutically active ingredient to be delivered. Thus, emulsifying components (ii) to (v) are mixed with a pharmaceutically or nutraceutically active ingredient (i) into a solution, which forms a self- nanoemulsifying drug delivery system (SNEDDS).
In one embodiment of the present invention
(i) is present in 0.01 to 25 wt.-%, preferably 0.1 to 15 wt.-%;
(ii) is present in 5 to 40 wt.-%;
(iii) is present in 5 to 60 wt.-%;
(iv) is present in 0 to 50, preferably 10 to 50 wt.-%; (v) is present in 0 to 25, preferably 0.1 to 5, wt.-%; based on the total weight of the self- nanoemulsifying drug delivery system.
The self-nanoemulsifying drug delivery system (SNEDDS) and a carrier, in the present invention the salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower and optionally an additive, form after processing, for instance by hot melt extrusion, freeze drying, spray drying, adsorption, electrospinning, electrospraying, prilling by vibration, granulation or supercritical fluid technology the solid self-nanoemulsifying drug delivery system (S-SNEDDS). In an embodiment of the present invention, the S-SNEDDS are obtained by hot melt extrusion. In a further embodiment of the present invention, the S-SNEDDS are obtained by freeze drying.
In one embodiment the self-nanoemulsifying drug delivery system is present in 1 to 30 wt.-%, based on the total weight of the solid self-nanoemulsifying drug delivery system and the mixture.
For example, the S-SNEDDS of the present invention are obtained by hot melt extrusion at a temperature of 130 to 150 °C, preferably of 140 °C. In one embodiment, the components may be extruded within a twin-screw extruder. In one embodiment, the components may be extruded within a twin-screw extruder at a torque of about 30 to 100 Ncm. Preferably, the components may be extruded within a twin-screw extruder at a torque of about 45 to 85 Ncm. The extruded mass may leave the extruder in the form of a strand, which may be comminuted by grinding and milling to a powder product.
Methacrylic copolymer
In the method according to the present invention the provided self-nanoemulsifying drug delivery system as explained above is applied on an aqueous solution comprising a salt of at least one methacrylic copolymer and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower and optionally at least one additive.
The methacrylic copolymer is a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer.
The 2-dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer may be obtained by radically polymerizing the monomers 2-dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a ratio of a) 30 to 70 wt.-% dimethylaminoethyl methacrylate; b) 15 to 35 wt.% butyl methacrylate; and c) 15 to 35 wt.-% methyl methacrylate; whereby the sum of a) to c) is 100 wt.-%; optionally in the presence of further additives and/or has a residual monomer content of not more than 0.5 % for each monomer and/or has a weight average molecular weight Mw of from 15,000 to 400,000 g/mol, preferably from 20,000 to 300,000 g/mol, more preferably from 25,000 to 200,000 g/mol ; and/or is obtained by a solution polymerization process and by subsequent mixing the methacrylic copolymer with an inorganic acid or with an organic acid having a pKa value of 3.5 or lower and drying of the so obtained dispersion.
Suitable further additives are at least one initiator, preferably selected from di- (3,5,5)trimethylhexanoyl peroxide, tert-butyl peroxyneodecanoate, tert-butyl perbenzoate, tert-amyl peroxy-2-ethylhexanoate, bisdecanoyl peroxide, tert-butyl peroxy-2-ethylhexanoate, tert-butyl peroxy-2-ethylhexylcabonate, 1 ,1 ’-azobis(cyclohexanecarbonitrile), benzoyl peroxide, 2,2-di-(tert- butylperoxy)butane, dicumyl peroxide, di-tert-amyl peroxide, di-tert-butyl peroxide, lauroyl peroxide, tert-butylperoxy-3,5,5-trimethylhexanoate, 1 ,1-di-tert-butylperoxy-3,3,5-trimethylcyclohexane, 2-(1- cyan-1-methyl(ethyl)azocarboxamide, tert-butyl peroxyacetate, tert-butyl peroxypivalate or mixtures thereof, more preferably selected from tert-butyl peroxyneodecanoate and tert-butyl peroxypivalate or mixtures thereof; and/or at least one chain-transfer agent preferably selected from carbon tetrachloride, carbon tetrabromide, bromotrichloromethane, 4-methylbenzenethiol, isooctyl 3- mercaptopropionate, pentaphenylethane, tert-nonyl mercaptan, 4,4’-thiobisbenzenethiol and n- dodecyl mercaptan, more preferably the chain-transfer agent is n-dodecyl mercaptan, and/or at least one solvent. For the polymerization reaction, any solvent which is suitable for use in those reactions is generally suitable.
The at least one methacrylic acid-ethyl acrylate copolymer may be obtained by an emulsion polymerization process with an optional subsequent drying step.
The copolymers can be used in powder form, preferably having an average particle size Dv,5o in the range of from 1 to 1 ,000 pm, more preferably from 2 to 100 pm. The powder can be obtained by milling and grinding.
EUDRAGIT® E is a commercially available methacrylic copolymer, i.e. a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer, and suitable to be used in the method according to the present invention. Its precise chemical designation is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1 :2:1.
Salts of methacrylic copolymers
In the method according to the present invention the salt of the at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, may be obtained by mixing the methacrylic copolymer being a 2-dimethylaminoethyl methacrylate- butyl methacrylate-methyl methacrylate copolymer with an inorganic acid or with an organic acid having a pKa value of 3.5 or lower and drying of the so obtained aqueous dispersion or aqueous solution.
The at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer is preferably poly(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1 :2:1 (commercially available under the trade name EUDRAGIT® E).
In a further optional embodiment of the method according to the present invention the salt of the at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylatemethyl methacrylate copolymer, may be obtained by radically polymerizing the monomers 2- dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a ratio of a) 30 to 70 wt.-% dimethylaminoethyl methacrylate; b) 15 to 35 wt.% butyl methacrylate; and c) 15 to 35 wt.-% methyl methacrylate; whereby the sum of a) to c) is 100 wt.-%; optionally in the presence of further additives; and/or has a residual monomer content of not more than 0.5 % for each monomer; and/or has a weight average molecular weight Mw of 15,000 to 400,000 g/mol; and/or is obtained by a solution polymerization process and by subsequent mixing the methacrylic copolymer with an inorganic acid or with an organic acid having a pKa value of 3.5 or lower and drying of the so obtained dispersion.
In one embodiment of the method according to the present invention the inorganic acid is hydrochloric acid.
In a further embodiment of the method according to the present invention an organic acid having a pKa value of 3.5 or lower is chosen or is selected from maleic acid, tartaric acid, malic acid, fumaric acid and citric acid; or mixtures thereof.
In the method according to the present invention the degree of neutralization of the methacrylic copolymer of the salt of the at least one methacrylic copolymer and of the inorganic or of the organic acid is more than 20 %. The degree of neutralization of the methacrylic copolymer of the salt of the at least one methacrylic copolymer and of the inorganic or of the organic acid can be determined via direct titration by potentiometrical detection of the endpoint.
Preferably the glass transition temperature (Tg) of the salt of the at least one methacrylic copolymer and of the inorganic acid or of the organic acid is from 55 to 135 °C. These Tg temperature ranges also encompass deviations of +/- 10 % having the same technical effect. Use as a medicament
The solid self-nanoemulsifying drug delivery system (S-SNEDDS), of the present invention are suitable for use (method of use) as a medicament or nutraceutical product, which preferably enhances the solubility of the included pharmaceutically or nutraceutically active ingredient compared to the pharmaceutically or nutraceutically active ingredient alone in the treatment of a disease of a human or an animal subject.
The invention in particular pertains to:
1 . A method of preparing a solid self-nanoemulsifying drug delivery system comprising the following steps: providing a self-nanoemulsifying drug delivery system by mixing
(i) at least one pharmaceutically or nutraceutically active ingredient,
(ii) at least one lipid component,
(iii) at least one surfactant,
(iv) optionally at least one solvent and
(v) optionally at least one additive and then adding the obtained self-nanoemulsifying drug delivery system to a salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower and optionally at least one additive or to an aqueous dispersion of or to an aqueous solution of a salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylatemethyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower and optionally at least one additive by hot melt extrusion, freeze drying, spray drying, adsorption, electrospinning, electrospraying, prilling by vibration, granulation or supercritical fluidization to obtain the solid self-nanoemulsifying drug delivery system.
2. The method of item 1 , wherein the inorganic acid is hydrochloric acid.
3. The method of item 1 , wherein the organic acid is selected from maleic acid, tartaric acid, malic acid, fumaric acid and citric acid or mixtures thereof.
4. The method of any of the preceding items wherein the degree of neutralization of the methacrylic copolymer of the salt of the at least one methacrylic copolymer and of the inorganic or of the organic acid is more than 20 %.
5. The method of any of the preceding items wherein the glass transition temperature (Tg) of the salt of the at least one methacrylic copolymer and of the inorganic acid or of the organic acid is 55 - 135 °C. 6. The method of any of the preceding items, wherein the at least one pharmaceutically or nutraceutically active ingredient has a solubility of less than 0.1 mg in 1 ml water at 37 °C and/or is selected from celecoxib, efavirenz and fenofibrate or mixtures thereof.
7. The method of any of the preceding items, wherein the at least one lipid component is selected from C6-C12 fatty acid triglycerides; C13-C21 fatty acid triglycerides; propylene glycol dicaprylate / dicaprate; glyceryl tricaprylate / tricaprate; glyceryl triricinoleate; lauric acid triglycerides; glyceryl dibehenate; linoleic acid and oleic acid triglycerides; linoleic acid, oleic acid, and palmitic acid triglycerides; ethyl oleate; isopropyl myristate; monolinoleate triglycerides I diglycerides I monoglycerides; glyceryl tricaprylate / tricaprate / trilaurate; oleic acid; oleic acid and palmitic acid triglycerides; palmitic acid, oleic acid, and linoleic acid triglycerides; oleic acid, linoleic acid, and palmitic acid triglycerides; linoleic acid, oleic acid, and palmitic acid triglycerides; linoleic acid, oleic acid, alpha-linolenic acid, and palmitic acid triglycerides; linoleic acid, oleic acid, and stearic acid triglyceride; glyceryl triacetate; glyceryl tricaprylate; hard fat or any mixtures thereof.
8. The method of any of the preceding items, wherein the at least one surfactant is selected from polyoxyethylene (23) lauryl ether; polyoxyethylene (2) oleyl ether; glyceryl monooleate; caprylate and caprate monoglycerides/diglycerides; glyceryl monocaprylate; propylene glycol monocaprylate; polyoxyl-35 hydrogenated castor oil; polyoxyl-40 hydrogenated castor oil; lauroyl polyoxyl-32 glycerides; stearoyl polyoxyl-32 glycerides; polyoxyl-15 hydroxystearate; triblock copolymer of polyoxyethylene and polyoxypropylene; oleoyl polyoxyl-6 glycerides; linoleoyl polyoxyl-6 glycerides; lauroyl polyoxyl-6 glycerides; caprylocaproyl polyoxyl-8 glycerides; propylene glycol monolaurate; polyoxyl-40 stearate; diacetylated monoglyceride; polyglyceryl-3 dioleate; sorbitan monolaurate; sorbitan monooleate; sorbitan sesquioleate; sorbitan trioleate; glyceryl monostearate; d-a-tocopherol polyethylene glycol 1000 succinate; polyoxyethylene sorbitan monolaurate; polyoxyethylene sorbitan monostearate; and polyoxyethylene sorbitan monooleate or any mixtures thereof.
9. The method of any of the preceding items, wherein the at least one solvent is selected from diethylene glycol monoethyl ether, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 6000, propane-1 ,2, 3-triol, (z)-octadec-9-enylamine, polypropylene glycol, propylene glycol, 2-pyrrolidone, tetraethylene glycol and diethylene glycol monoethyl ether, or any mixtures thereof.
10. The method of any of the preceding items, wherein the at least one additive is selected from antiadherents; binders; flavors; pigments; disintegrants; glidants; flow regulators; antioxidants; sweeteners; and antistatics; or mixtures thereof. 11 . The method of any of the preceding items, wherein the self-nanoemulsifying drug delivery system is present in 1 to 30 wt.-%, based on the total weight of the solid self-nanoemulsifying drug delivery system and the mixture.
12. The method of any of the preceding items, wherein
(i) is present in 0.01 to 25 wt.-%, preferably 0.1 to 15 wt.-%,
(ii) is present in 5 to 40 wt.-%,
(iii) is present in 5 to 60 wt.-%,
(iv) is present in 10 to 50 wt.-%,
(v) is present in 0 to 25 wt.-%; based on the total weight of the self-nanoemulsifying drug delivery system.
13. A solid self-nanoemulsifying drug delivery system obtainable or obtained by the method of any of the preceding items.
14. The solid self-nanoemulsifying drug delivery system of item 13, wherein the solid self- nanoemulsifying drug delivery system is a nutraceutical product or a pharmaceutical.
15. The solid self-nanoemulsifying drug delivery system of item 14 for use as a pharmaceutical.
Examples
Materials & Methods
Materials
Fenofibrate (propan-2-yl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate) obtained from D.K. Pharma Chem PVT Ltd. (Maharashtra, India) was used as model compound. Dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate (EUDRAGIT® E) is a commercially available product from Evonik Operations GmbH (Darmstadt, Germany). Polyoxyethylene (80) sorbitan monooleate (Tween® 80), d-a-Tocopherol polyethylene glycol 1000 succinate (d-TPGS) and polyoxyethylene (23) lauryl ether (Brij® 35) were purchased from Sigma Aldrich Chemie GmbH (Steinheim, Germany). Medium-chain triglycerides (Miglyol® 812) was obtained from Caesar & Loretz GmbH (Hilden, Germany). All other chemicals were of analytical grade and purchased commercially. Methods
Preparation of salts of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer
For the preparation of salts of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (e.g., E/hydrochloride, E/maleate, E/tartrate, E/fumarate, E/citrate, E/malate, ), the corresponding aqueous acidic solution was added to the copolymer under vigorous magnetic stirring (1 ,000 rpm for 4 h) in order to neutralize the functional amino groups of the dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (salt formation). The resulting aqueous dispersion or aqueous solution was subsequently spray dried using a Niro Minor spray dryer (GEA Group AG, Dusseldorf, Germany). The dispersion was atomized into fine droplets using a two-fluid nozzle with a bore diameter of 0.5 mm. Nitrogen was used as the atomizing and drying gas in this spray drying process at an inlet temperature of 70 - 120 °C depending on the composition. The fine droplets were sprayed using a top-down spray drying process and the dry particles were collected in a vessel after their separation from the gas flow using a cyclone.
Preparation of Solid-SNEDDS (S-SNEDDS) and amorphous solid dispersion (ASD) via hot-melt extrusion (HME)
A blend of the compounds 1 to 4 (Table 1) as well as the pharmaceutically active ingredient fenofibrate, in the following referred to as drug as well, was prepared by mixing these substances in a glass beaker under moderate magnetic stirring for approximately 30 min. The blend was subjected to a temperature of 50 °C while stirring. The obtained SNEDDS-solution was added to a certain copolymer, (e.g., the dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate hydrochloride (E/HCI), or dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate tartrate (E/Tartrate)), considering a defined mixture ratio. The SNEDDS-polymer blend was processed via hot-melt extrusion technology using a co-rotating HAAKE MiniLab twin screw extruder from Thermo Fisher Scientific (Dreieich, Germany) that exhibited a conical screw design. The hot-melt extrusion process was characterized by recording the applied screw speed, the torque and the process temperature. The continuously generated strand, leaving the extruder at its nozzle (nozzle diameter of 3.0 mm), cooled down while it was transported using a conveying belt and was finally chopped into a coarse granule. The granule was ground (mesh size: 0.25 mm) using an Ultra Centrifugal Mill ZM 200 from Retsch GmbH (Haan, Germany). The obtained powder was the dosage form of the manufactured S-SNEDDS that was used for all further studies. In addition, a blend of polymer and drug substance (ASD) was prepared using a Turbular mixer from WAB Group (Nidderau-Heldenbergen, Germany) for approximately 10 min. The blend was then processed via the mentioned hot-melt extrusion process in order to assess the effect of S-SNEDDS referring to different characteristics in comparison to ASDs. For ASDs the copolymers dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate (EUDRAGIT® E) and dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate hydrochloride (E/HCI) or dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate tartrate (E/Tartrate) were applied.
Preparation of S-SNEDDS and ASD via freeze drying (FD)
A blend of the compounds 1 to 4 (Table 1) as well as the drug substance fenofibrate was prepared by mixing these substances in a beaker glass under moderate magnetic stirring for approximately 30 min. The blend was subjected to a temperature of 50 °C while stirring. 4.5 g of the obtained SNEDDS-solution (Table 1) was added to 45.5 g of an aqueous solution of the salt of a specific copolymer (e.g., dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate hydrochloride (E/HCI) solution (21 wt%) or dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate tartrate (E/Tartrate) solution (21 wt%)) under vigorous magnetic stirring (600 rpm) for 15 min applying a temperature of 50 °C. In addition, blends of an aqueous solution of a salt of a copolymer (e.g., dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate hydrochloride copolymer (E/HCI) or dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate tartrate (E/Tartrate)) as well as an aqueous dispersion of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (EUDRAGIT® E) with the drug substance fenofibrate were prepared applying the same drug load as used for the corresponding SNEDDS-copolymer mixture. The three homogeneous mixtures (50.0 g each) were divided in parts of 5.0 g each and transferred to separate glass vials for the freeze-drying process. The freeze- drying process was started at 30 °C. Within the first hour, the mixture was cooled down to -40 °C and maintained at this temperature for another 3 h. After 4 h the pressure was reduced to a pressure level below 0.1 mbar. After 5 h the temperature was gradually increased during the process to a final temperature of 20 °C. The entire freeze-drying process was conducted over a time period of 54 h using an Epsilon 2-6D (LSC) freeze dryer from Martin Christ Gefriertrocknungsanlagen GmbH (Osterode am Harz, Germany). The generated S-SNEDDS and ASDs that were prepared via freeze drying resulted in white or off-white, flowable, small particles.
Dissolution studies of S-SNEDDS, ASD and the drug substance fenofibrate
Dissolution experiments were performed according to USP 42-NF 37 (2019). Dissolution experiments were conducted with 25 mg drug substance or an equivalent amount of S-SNEDDS or ASD using USP apparatus II (DT 800 LH) from ERWEKA GmbH (Langen, Germany). The paddle speed was set to 100 rpm and all experiments were performed in 500 ml of 0.1 N hydrochloric acid at 37 ± 0.5 °C. All samples were withdrawn by a fraction collector, equipped with cannula filters of 10 pm pore size and manually diluted 1 :1 (v/v) with acetonitrile before HPLC analysis. The dissolution tests were conducted over 120 min. HPLC method for analysing feno fibrate
The high-performance liquid chromatography (HPLC) system (Agilent 1260 Infinity) was used for the quantification of fenofibrate consisted of a quaternary pump (G1311 B), autosampler (G1329B), column oven (G1316A) and UV detector (G1314C), all obtained from Agilent Technologies (Frankfurt am Main, Germany). Separation was achieved using a Symmetry 300 C18 (150 x 4.6 mm, 5 pm) column maintained at 22 °C. The mobile phase consisted of an acetonitrile: water mixture (70:30 v/v), adjusted to pH 2.50 with phosphoric acid. The flow rate was set to 2.0 ml/min. An injection volume of 20 pl was applied and fenofibrate was detected at 286 nm. In the concentration range of 0.12 - 532 pg/ml, the analytical curve was linear (r2 = 0.999995). The method was found to be accurate (100.2 - 100.5 %) and precise (CV 2.98 %) with a quantification limit of 0.05 pg/ml. Run time was defined to be 6 min. Selectivity was determined (formulation excipients) and no interference was observed in drug retention time. Moreover, the peak area did not change in the presence of all excipients used in the study.
Differential scanning calorimetry (DSC) analysis (DIN EN ISO 11357-2:2013)
The copolymers were analysed via DSC to determine their glass transition temperature (Tg) and if the incorporated drug demonstrated an amorphous (glass transition) or crystalline (melting/crystallization peak) appearance. The glass transition is a reversible transition from a hard and relatively brittle, frozen state to a molten or rather rubbery state within amorphous or partly amorphous materials. The melting point of the pure drug substance as well as the glass transition temperature of the copolymers were investigated for identifying changes and/or shifts in the thermograms regarding crystalline and/or amorphous characteristics. A sample of 5 - 10 mg each was weighed into a small, perforated aluminum pan with a lid that was cold sealed and exposed to a heating-cooling-heating cycle starting from 0 °C up to 200 °C while running the measurement continuously applying inert nitrogen atmosphere. The constant heating/cooling rate was set to 10 °C/min. In the resulting thermogram the heat flow is plotted against the temperature using an endothermic presentation method. The evaluation was based on the second heating cycle, and the indicated value is the mean value in the glass transition interval. The analysis was conducted using a DSC 3+ (DSC-HC01) from Mettler Toledo (GieBen, Germany).
Determination of alkali value and neutralization degree of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer after salt formation
The dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer was always used as the basic compound for the salt formation when applying different acids. First, the alkali value of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer was determined. Afterwards, the alkali values of the generated salts of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer were specified. The analysis of the samples (200 mg each) for the determination of the alkali values was conducted using a titrimetric method (direct titration) applying 0.1 N perchloric acid as the titrant. The endpoint of the titration for the aqueous solutions of the samples was potentiometrically detected. The degree of neutralization for dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer after salt formation was calculated using the ratio of the corresponding alkali values.
Results and Discussion
Table 1: Composition of SNEDDS-solution incorporating fenofibrate compound 1 compound 2 compound 3 compound 4 drug substance trade name Miglyol® 812 Brij® 35 Tween® 80 d-TPGS fenofibrate amount [%] 17.20 8.60 50.16 10.04 14.00
Composition & hot-melt extrusion process parameters of S-SNEDDS & ASD
The composition of the analysed samples including the SNEDDS load and/or drug load as well as the process parameters regarding the hot-melt extrusion process or freeze-drying process were recorded and presented in Tables 2 and 3. The dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (EUDRAGIT® E) was not suitable to be applied for S- SNEDDS manufacturing via HME as well as FD as the generated product was not solid and inhomogeneous. The EUDRAGIT® E copolymers’ low Tg did not allow sufficient processability. The following data related to E/HCI or E/Tartrate were collected using E/HCI or E/Tartrate with a neutralization degree of 80 %.
Table 2: Composition & hot-melt extrusion process parameters of S-SNEDDS and ASD incorporating fenofibrate sample name total total extrusion torque screw
SNEDDS drug temperature [°C] [Ncm] speed load [%] load [%] [rpm]
E/HCI SNEDDS 30 4.2 140 45 - 55 200
HME
E/Tartrate SNEDDS 30 4.2 160 90-110 200
HME
E/HCI HME (ASD) 0 4.2 150 170 - 190 200
E/Tartrate HME 4.2 160 85 200
(ASD)
EUDRAGIT® E HME 0 4.2 140 35 - 40 200
(ASD) Table 3: Composition & freeze-drying process parameters of S-SNEDDS and ASD incorporating fenofibrate sample name total total total process temperature range
SNEDDS drug time of freeze of freeze-drying load [%] load [%] drying [h] process [°C]
E/HCI SNEDDS FD 30 4.2 54 -40 - 30
E/Tartrate SNEDDS 30 4.2 54 -40 - 30
E/HCI FD (ASD) 0 4.2 54 -40 - 30
E/Tartrate (ASD) 0 4.2 54 -40 - 30
EUDRAGIT® E FD 0 4.2 54 -40 - 30
(ASD) Thermal characterization of the copolymers, S-SNEDDS & ASD via DSC analysis
All copolymers (Table 4), S-SNEDDS and ASD samples (Table 5) were analysed via the mentioned DSC method to determine the Tg of the different copolymers as well as the samples. The Tg of the manufactured S-SNEDDS and ASD was lower in comparison to the pure corresponding copolymer. The copolymers, the S-SNEDDS and the ASD demonstrated one Tg in the temperature range that was specified. Table 5 showed the Tg of the samples processed via HME and FD.
Table 4: Glass transition temperature (Tg) of the pure copolymers polymer Tg (polymer) [°C]
EUDRAGIT® E 42
E/HCI 114
E/Tartrate 80
Table 5: Glass transition temperature (Tg) of the S-SNEDDS & ASD sample name Tg (sample) [°C]
E/HCI SNEDDS HME 104
E/HCI HME (ASD) 97
E/Tartrate SNEDDS HME 73
E/Tartrate HME (ASD) 69
EUDRAGIT® E HME (ASD) 34
E/HCI SNEDDS FD 99
E/HCI FD (ASD) 110
E/Tartrate SNEDDS FD 69
E/Tartrate FD (ASD) 56
EUDRAGIT® E FD (ASD) 35 Dissolution studies
The highest, final level of drug release for the samples incorporating fenofibrate was achieved by the S-SNEDDS formulations applying the copolymer E/HCI (Table 6 and Figure 1). S-SNEDDS based on E/HCI processed by FD demonstrated a final drug release of about 88 %, while the S- SNEDDS manufactured by HME revealed 47 % of drug release after 120 min (Table 6 and Figure 1). The S-SNEDDS based on E/Tartrate demonstrated a final drug release of about 39%, and the drug release of E/Tartrate processed by HME demonstrated of about 26% (Table 6 and Figure 2). Basically, the drug release of S-SNEDDS based on E/HCI or E/Tartrate was substantially higher than the corresponding ASDs as well as the ASDs manufactured with EUDRAGIT® E regardless of their manufacturing process (Table 6, Figure 1 & 2). All samples showed an enhancement of solubility in comparison to the pure drug substance fenofibrate.
Table 6: Comparison of drug release after 120 min of dissolution testing regarding S-SNEDDS and ASD incorporating the drug substance fenofibrate sample name drug release after 120 min [%]
E/HCI SNEDDS HME 47.0 ± 0.5
E/HCI HME (ASD) 6.4 ± 0.4
E/Tartrate SNEDDS HME 25.9 ± 0.2
E/Tartrate HME (ASD) 6.3 ± 1 .4
EUDRAGIT® E HME (ASD) 6.3 ± 1.4
E/HCI SNEDDS FD 88.3 ± 0.1
E/HCI FD (ASD) 2.0 ± 0.1
E/Tartrate SNEDDS FD 38.8 ± 1 .3
E/Tartrate FD (ASD) 2.6 ± 0.0
EUDRAGIT® E FD (ASD) 2.1 ± 0.1
Fenofibrate drug substance 0.0 ± 0.0
Neutralization degree and Tg of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer after salt formation using different acids
Several other acids for preparing salts (E/salt) with the copolymer dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate have been evaluated. The specific salts of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer and their analysed parameters are shown in Table 7. The E/salts (Table 7) can be used to act as a carrier substance in S-SNEDDS formulations for solubility enhancement of poorly water-soluble drugs. The degree of neutralization was calculated using the following equation: Degree of neutralizat
= 100 100 (1)
Figure imgf000022_0001
The AVcwas the alkali value of the dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer after salt formation and the A l/s was the alkali value of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer.
Table 7: The pKa of the acidic substances, the Tg and degree of neutralization of the prepared salts of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer salt acid pKa of acid Tg of salt [°C] degree of neutralization [%]
E/hydrochloride hydrochloric - 8 131 98 acid
E/hydrochloride hydrochloric - 8 114 80 acid
E/maleate maleic acid 1.9, 6.5 67, 110 18
E/tartrate tartaric acid 2.9, 4.3 81 25
E/fumarate fumaric acid 3, 4.5 74, 106 22
E/citrate citric acid 3.1 , 4.8, 6.4 53 26
E/malate malic acid 3.4, 5.1 57 22
N/D = not determined

Claims

22 Claims
1 . A method of preparing a solid self-nanoemulsifying drug delivery system comprising the following steps: providing a self-nanoemulsifying drug delivery system by mixing
(i) at least one pharmaceutically or nutraceutically active ingredient,
(ii) at least one lipid component,
(iii) at least one surfactant,
(iv) optionally at least one solvent and
(v) optionally at least one additive and then adding the obtained self-nanoemulsifying drug delivery system to a salt of at least one methacrylic copolymer, being a 2-dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, and of an inorganic acid or of an organic acid having a pKa value of 3.5 or lower and optionally at least one additive by hot melt extrusion, freeze-drying, spray drying, adsorption, electrospinning, electrospraying, prilling by vibration, granulation or supercritical fluidization to obtain the solid self-nanoemulsifying drug delivery system.
2. The method of claim 1 , wherein the inorganic acid is hydrochloric acid.
3. The method of claim 1 , wherein the organic acid is selected from maleic acid, tartaric acid, malic acid, fumaric acid and citric acid or mixtures thereof.
4. The method of any of the preceding claims wherein the degree of neutralization of the methacrylic copolymer of the salt of the at least one methacrylic copolymer and of the inorganic or of the organic acid is more than 20 %.
5. The method of any of the preceding claims wherein the glass transition temperature (Tg) of the salt of the at least one methacrylic copolymer and of the inorganic acid or of the organic acid is 55 - 135 °C.
6. The method of any of the preceding claims, wherein the at least one pharmaceutically or nutraceutically active ingredient has a solubility of less than 0.1 mg in 1 ml water at 37 °C and/or is selected from celecoxib, efavirenz and fenofibrate or mixtures thereof.
7. The method of any of the preceding claims, wherein the at least one lipid component is selected from C6-C12 fatty acid triglycerides; C13-C21 fatty acid triglycerides; propylene glycol dicaprylate I dicaprate; glyceryl tricaprylate I tricaprate; glyceryl triricinoleate; lauric acid triglycerides; glyceryl dibehenate; linoleic acid and oleic acid triglycerides; linoleic acid, oleic acid, and palmitic acid triglycerides; ethyl oleate; isopropyl myristate; monolinoleate triglycerides I diglycerides / monoglycerides; glyceryl tricaprylate / tricaprate / trilaurate; oleic acid; oleic acid and palmitic acid triglycerides; palmitic acid, oleic acid, and linoleic acid triglycerides; oleic acid, linoleic acid, and palmitic acid triglycerides; linoleic acid, oleic acid, and palmitic acid triglycerides; linoleic acid, oleic acid, alpha-linolenic acid, and palmitic acid triglycerides; linoleic acid, oleic acid, and stearic acid triglyceride; glyceryl triacetate; glyceryl tricaprylate; hard fat or any mixtures thereof.
8. The method of any of the preceding claims, wherein the at least one surfactant is selected from polyoxyethylene (23) lauryl ether; polyoxyethylene (2) oleyl ether; glyceryl monooleate; caprylate and caprate monoglycerides/diglycerides; glyceryl monocaprylate; propylene glycol monocaprylate; polyoxyl-35 hydrogenated castor oil; polyoxyl-40 hydrogenated castor oil; lauroyl polyoxyl-32 glycerides; stearoyl polyoxyl-32 glycerides; polyoxyl-15 hydroxystearate; triblock copolymer of polyoxyethylene and polyoxypropylene; oleoyl polyoxyl-6 glycerides; linoleoyl polyoxyl-6 glycerides; lauroyl polyoxyl-6 glycerides; caprylocaproyl polyoxyl-8 glycerides; propylene glycol monolaurate; polyoxyl-40 stearate; diacetylated monoglyceride; polyglyceryl-3 dioleate; sorbitan monolaurate; sorbitan monooleate; sorbitan sesquioleate; sorbitan trioleate; glyceryl monostearate; d-a-tocopherol polyethylene glycol 1000 succinate; polyoxyethylene sorbitan monolaurate; polyoxyethylene sorbitan monostearate; and polyoxyethylene sorbitan monooleate or any mixtures thereof.
9. The method of any of the preceding claims, wherein the at least one solvent is selected from diethylene glycol monoethyl ether, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 6000, propane-1 ,2, 3-triol, (z)-octadec-9-enylamine, polypropylene glycol, propylene glycol, 2-pyrrolidone, tetraethylene glycol and diethylene glycol monoethyl ether, or any mixtures thereof.
10. The method of any of the preceding claims, wherein the at least one additive is selected from antiadherents; binders; flavors; pigments; disintegrants; glidants; flow regulators; antioxidants; sweeteners; and antistatics; or mixtures thereof.
11 . The method of any of the preceding claims, wherein the self-nanoemulsifying drug delivery system is present in 1 to 30 wt.-%, based on the total weight of the solid self-nanoemulsifying drug delivery system and the mixture.
12. The method of any of the preceding claims, wherein
(i) is present in 0.01 to 25 wt.-%,
(ii) is present in 5 to 40 wt.-%,
(iii) is present in 5 to 60 wt.-%,
(iv) is present in 10 to 50 wt.-%,
(v) is present in 0 to 25 wt.-%; based on the total weight of the self-nanoemulsifying drug delivery system.
13. A solid self-nanoemulsifying drug delivery system obtainable by the method of any of the preceding claims.
14. The solid self-nanoemulsifying drug delivery system of claim 13, wherein the solid self- nanoemulsifying drug delivery system is a nutraceutical product or a pharmaceutical.
15. The solid self-nanoemulsifying drug delivery system of claim 14 for use as a pharmaceutical.
PCT/EP2022/081745 2021-11-18 2022-11-14 Solid snedds based on salts of methacrylic copolymers WO2023088830A1 (en)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
EP2101729B1 (en) 2006-12-27 2011-03-30 LEK Pharmaceuticals d.d. Self-microemulsifying drug delivery systems
CN107308133A (en) 2016-04-27 2017-11-03 周意 Curcumin pharmaceutical preparation

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
EP2101729B1 (en) 2006-12-27 2011-03-30 LEK Pharmaceuticals d.d. Self-microemulsifying drug delivery systems
CN107308133A (en) 2016-04-27 2017-11-03 周意 Curcumin pharmaceutical preparation

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