Amorphous Form of Ternary Complex of Drug, Protein and Water-Soluble Polymer

Abstract

The present invention relates to ternary complex amorphous forms that contain drug compounds, nutraceuticals or dietary supplements in combination with proteins and water-soluble polymers.Complex amorphous forms are combinations of three or more components that form a homogeneous amorphous system in which the components are homogeneously mixed at the molecular level.The ternary complex amorphous forms of the present invention provide increased solubility and dissolution rate of drug compounds, nutraceuticals and dietary supplements.This therefore increases the bioavailability of these compounds.

Description

[Technical field]

[0001] The present invention relates to a ternary complex amorphous form that includes a drug compound, nutraceutical or dietary supplement in combination with a protein and a water-soluble polymer. Such a ternary complex amorphous form provides increased solubility and dissolution rate of the drug compound, nutraceutical or dietary supplement, which therefore increases the bioavailability of these compounds. [Background technology]

[0002] It is known in the art that the solubility and dissolution of otherwise poorly soluble drug, nutraceutical or dietary supplement molecules can be increased by forming complex amorphous forms of these molecules with water soluble polymers.

[0003] More recently, complex amorphous forms of APIs and proteins have been shown to increase the solubility and dissolution rate of the API more than water-soluble polymers (WO 2018 / 113890 and WO 2021 / 110983), with the increase being more or less pronounced depending on the API in question.

[0004] Surprisingly, it has now been found that the solubility and dissolution rate can be increased even further by preparing an amorphous form of a ternary complex of a drug, nutraceutical or dietary supplement compound together with a protein and a water soluble polymer. Summary of the Invention [Means for solving the problem]

[0005] In one aspect, the present invention relates to amorphous forms of complexes of drugs, nutraceuticals or dietary supplements with proteins and water soluble polymers.

[0006] These ternary complex amorphous forms have been found to provide unexpectedly high solubility for compounds with very low aqueous solubility compared to binary complex amorphous forms containing either proteins or water-soluble polymers.

[0007] In another aspect, the present invention relates to a method for preparing the complex amorphous form according to the present invention, wherein the drug, nutraceutical or dietary supplement, protein and water soluble polymer are subjected together to spray drying, solvent evaporation, freeze drying, precipitation from supercritical fluids, melt quenching, hot melt extrusion, electrospinning, 2D printing, 3D printing and any comminution process such as wet milling, ball milling and cryogenic grinding.

[0008] In a further aspect, the invention relates to the use of a protein and a water soluble polymer to prepare a complex amorphous form with a drug, nutraceutical or dietary supplement. [Brief description of the drawings]

[0009] [Figure 1] XRPD diffractograms of binary and ternary complex amorphous forms of Compound A at a drug load of 25% (w / w) (a), binary and ternary complex amorphous forms of Compound B at a drug load of 23% (w / w) (b), binary and ternary blends of abiraterone acetate at drug loads of 40% and 56% (w / w) (c), binary and ternary blends of ibrutinib at a drug load of 50% (w / w) (d), binary blends of cannabidiol BSPG at drug loads of 20% and 30% (w / w) and ternary blends of cannabidiol BSPG at a drug load of 30% (w / w) (e). [Diagram 2] Powder dissolution of binary and ternary complex amorphous forms of Compound A at 25% (w / w) drug loading in FaSSGF (a) and FaSSIF-V2 (b). [Diagram 3] Powder dissolution of binary and ternary complex amorphous forms of Compound B at 23% (w / w) drug loading in FaSSIF-V1. [Figure 4]Powder dissolution of binary and ternary complex amorphous forms of abiraterone acetate at drug loadings of 40% and 56% (w / w) in FaSSIF-V1. [Diagram 5] Powder dissolution of binary and ternary complex amorphous forms of ibrutinib at 50% (w / w) drug loading in FaSSIF-V2. [Figure 6] Powder dissolution of crystalline cannabidiol BSPG, binary complex amorphous form of cannabidiol BSPG at 20% and 30% (w / w) drug loading and ternary complex amorphous form of cannabidiol BSPG at 30% (w / w) drug loading in FaSSIF-V2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] definition In the context of the present invention, the term "complex amorphous" refers to a combination of three or more components that form a homogeneous amorphous system in which the components are homogeneously mixed in a single phase or in two phases. X-ray powder diffraction (XRPD) can be used in conjunction with differential scanning calorimetry (DSC) to reveal, for example, the absence of Bragg peaks and one or two glass transition temperatures, i.e., less than the three Ts that would be observed if no mixing was performed at the molecular level. g By measuring the appearance of g This refers to a form having the following structure:

[0011] In the context of the present invention, the term "purity" in relation to a complex amorphous form of a protein such as β-lactoglobulin is defined as the percentage (w / w) of the total amount of protein contained in the complex amorphous form. When the complex amorphous form is included in a pharmaceutical composition, any additional proteins, such as gelatin, that may be included as excipients in the pharmaceutical formulation are not included in the calculation of the purity of β-lactoglobulin contained in the complex amorphous form. Furthermore, when an additional protein is included as an excipient in the pharmaceutical composition, said additional protein may generate an additional glass transition temperature (if amorphous) or melting point (if crystalline) in addition to the glass transition temperature of the complex amorphous form.

[0012] In the context of the present invention, the term "dietary supplement" refers to a food or portion of a food that is not registered or does not require registration as a drug or medicine and that may provide a medical or health benefit, including the prevention and treatment of disease. The term "dietary supplement" is defined by the FDA as "vitamins; minerals; herbs or other botanicals; amino acids; dietary substances for use by humans to supplement the diet by increasing total dietary intake; or concentrates, metabolites, components, extracts, or combinations of the above." Thus, "dietary supplements" constitute a part of "dietary supplements."

[0013] In the context of the present invention, the term "drug, nutraceutical or dietary supplement compound" is intended to refer to a product that contains an active pharmaceutical ingredient, a veterinary drug or a dietary ingredient, such as vitamins, minerals, amino acids and herbs or botanicals and other substances that can be used to supplement the diet. In one embodiment, the term "drug, nutraceutical or dietary supplement compound" refers to an active pharmaceutical ingredient. In the context of the present invention, reference to "a" drug, nutraceutical or dietary supplement compound may refer to one or more drug or dietary supplement compounds.

[0014] In the context of the present invention, the term "protein" refers to a synthetic, recombinant or naturally occurring polypeptide, preferably comprising at least 40 amino acids. The term "protein" also includes modified proteins, such as protein hydrolysates or modifications obtained by phosphorylation, glycosylation, lipidation, ubiquitination, carbonylation, nitrosylation, methylation, acetylation, palmitoylation, amidation, oxidation, nitration, formylation, sulfation, hydroxylation, myristoylation. When referring to a "water-soluble polymer" in the context of the present invention, reference is made to a polymer that is not peptidic, i.e. in which less than 10%, such as less than 5%, such as less than 1%, more particularly 0%, of the monomers used to form the polymer are amino acids.

[0015] (Complex) Amorphous form In one aspect, the present invention relates to an amorphous form of a complex of a drug, nutraceutical or dietary supplement with a protein and a water-soluble polymer. The complex amorphous form of the present invention may have one or two phases. In one embodiment, it has a single phase.

[0016] The complexed amorphous form of the present invention may contain 1-99% (w / w) of a drug, nutraceutical or dietary supplement, for example 5-95% (w / w) of a drug, nutraceutical or dietary supplement. In one embodiment, the complexed amorphous form comprises 10-90% (w / w) of a drug, nutraceutical or dietary supplement and 10-90% (w / w) of a protein and a water-soluble polymer. In a further embodiment, the complexed amorphous form comprises 20-90% (w / w) of a drug, nutraceutical or dietary supplement and 10-80% (w / w) of a protein and a water-soluble polymer. In yet another embodiment, the complexed amorphous form comprises 30-85% (w / w) of a drug, nutraceutical or dietary supplement and 15-70% (w / w) of a protein and a water-soluble polymer. In another embodiment, the complex amorphous form comprises 50-85% (w / w) of the drug, nutraceutical or dietary supplement and 15-50% (w / w) of the protein and water-soluble polymer. In a further embodiment, the complex amorphous form comprises 55-75% (w / w) of the drug, nutraceutical or dietary supplement and 25-45% (w / w) of the protein and water-soluble polymer. In yet another embodiment, the complex amorphous form comprises 30% (w / w) of the drug, nutraceutical or dietary supplement and 70% (w / w) of the protein and water-soluble polymer. In yet another embodiment, the complex amorphous form comprises 50% (w / w) of the drug, nutraceutical or dietary supplement and 50% (w / w) of the protein and water-soluble polymer. In yet another embodiment, the complex amorphous form comprises 60% (w / w) of the drug, nutraceutical or dietary supplement and 40% (w / w) of the protein and water-soluble polymer. In yet another embodiment, the complex amorphous form comprises 70% (w / w) drug, nutraceutical or dietary supplement and 30% (w / w) protein and water soluble polymer.

[0017] It has been found that lower drug loadings provide particularly good dissolution of drug molecules with low solubility, especially drug molecules with very low solubility. Thus, in one embodiment, the complex amorphous form comprises 5-35% (w / w) of drug, nutraceutical or dietary supplement, and 65-95% (w / w) of protein and water-soluble polymer. In a further embodiment, the complex amorphous form comprises 10-30% (w / w) of drug, nutraceutical or dietary supplement, and 70-90% (w / w) of protein and water-soluble polymer. In yet another embodiment, the complex amorphous form comprises 12-25% (w / w) of drug, nutraceutical or dietary supplement, and 75-88% (w / w) of protein and water-soluble polymer. In yet another embodiment, the complex amorphous form comprises 15-20% (w / w) of drug, nutraceutical or dietary supplement, and 80-85% (w / w) of protein and water-soluble polymer.

[0018] The relative amounts of protein and water-soluble polymer may be adjusted as necessary to prepare a complex amorphous form having a desired level of solubility. In one embodiment, the weight ratio between the protein and the water-soluble polymer ranges from 10:1 to 1:10. In another embodiment, the weight ratio between the protein and the water-soluble polymer ranges from 5:1 to 1:5. In yet another embodiment, the weight ratio between the protein and the water-soluble polymer ranges from 5:1 to 1:3. In yet another embodiment, the weight ratio between the protein and the water-soluble polymer ranges from 4:1 to 1:2. In yet another embodiment, the weight ratio between the protein and the water-soluble polymer ranges from 3:1 to 2:3. In a further embodiment, the weight ratio between the protein and the water-soluble polymer ranges from 2:1 to 1:1.

[0019] In a further aspect, the invention relates to the use of a protein and a water soluble polymer to prepare a complex amorphous form with a drug, nutraceutical or dietary supplement.

[0020] The complex amorphous form may be prepared according to the general methods disclosed in the examples of the present invention or in WO 2018 / 113890. Thus, in one aspect, the present invention relates to a method for preparing the complex amorphous form of the present invention, which is selected from spray drying, solvent evaporation, freeze drying, precipitation from supercritical fluids, melt quenching, hot melt extrusion, electrospinning, 2D printing, 3D printing and any comminution process, such as wet milling, ball milling and cryogenic grinding, together with a drug, nutraceutical or dietary supplement and β-lactoglobulin.

[0021] protein Proteins (peptide-based polymers) have been shown to increase the solubility of poorly soluble pharmaceutical ingredients when prepared with the active pharmaceutical ingredient as a complex amorphous form (WO 2017 / 186889, WO 2018 / 113890 and WO 2021 / 110983). In one embodiment, the protein is selected from the group consisting of whey protein isolate, soy protein, soy protein hydrolysate, pea protein, corn protein, wheat protein, hemp protein, rye protein, oat protein, peanut protein, barley protein, myoglobin, lysozyme, egg protein isolate, egg white protein isolate, egg white protein hydrolysate, ovalbumin, casein, beta-lactoglobulin, alpha-lactalbumin, lactoferrin, gelatin, albumin, serum albumin, bovine serum albumin, human serum albumin, egg albumin, fish albumin, keratin, elastin, collagen, immunoglobulin G, rice protein isolate, rice protein hydrolysate, yeast protein hydrolysate, and mixtures thereof. In another embodiment, the protein is beta-lactoglobulin.

[0022] In particular, it has been found that high purity β-lactoglobulin contributes to a complex amorphous form with high solubility. Thus, in one embodiment, the purity of β-lactoglobulin is at least 92% (w / w) of the total amount of protein. In a further embodiment of the invention, the purity of β-lactoglobulin is at least 94% (w / w) of the total amount of protein. In another embodiment of the invention, the purity of β-lactoglobulin is at least 95% (w / w) of the total amount of protein. In yet another embodiment of the invention, the purity of β-lactoglobulin is at least 96% (w / w) of the total amount of protein. In yet another embodiment, the purity of β-lactoglobulin is at least 97% (w / w) of the total amount of protein. In a further embodiment of the invention, the purity of β-lactoglobulin is at least 98% (w / w) of the total amount of protein.

[0023] Water-soluble polymers Several polymeric excipients are known in the art to increase the dissolution rate of an active pharmaceutical ingredient and / or increase the aqueous solubility of the active ingredient when formulated in tablets, capsules, etc. Water-soluble polymers are soluble in aqueous media at least in a portion of the pH range 1-14 at 25° C. Thus, water-soluble polymers include types of polymers that are soluble only at certain pH levels, e.g., polymers that are soluble at acidic pH but not at neutral pH. Water-soluble polymers suitable for use in the present invention are known in the art. Water-soluble polymers suitable for use in the present invention may be cellulosic or non-cellulosic. The polymers may be neutral or ionic in aqueous solution.

[0024] A suitable class of water-soluble polymers includes polymers that are "amphiphilic" in nature, meaning that the polymer has hydrophobic and hydrophilic portions. The hydrophobic portion may contain groups such as aliphatic or aromatic hydrocarbon groups. The hydrophilic portion may contain either ionic or non-ionic groups capable of hydrogen bonding, such as hydroxyl, carboxylic acid, ester, amine or amide.

[0025] One class of water-soluble polymers suitable for use in the present invention includes neutral non-cellulosic polymers. Exemplary polymers include vinyl polymers and copolymers having hydroxyl, alkylacyloxy, or cyclic amide substituents; polyvinyl alcohols having at least a portion of their repeat units in the non-hydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinylpyrrolidone; polyoxyethylene-polyoxypropylene copolymers, also known as poloxamers; and polyethylene polyvinyl alcohol copolymers.

[0026] Another class of water-soluble polymer suitable for use in the present invention comprises ionic non-cellulosic polymers.Exemplary polymers include carboxylic acid functionalized vinyl polymers, such as carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates, such as EUDRAGITS® manufactured by Evonik (Darmstadt, Germany), amine functionalized polyacrylates and polymethacrylates; and carboxylic acid functionalized starches, such as starch glycolates.

[0027] Amphiphilic non-cellulosic water-soluble polymers are copolymers of relatively hydrophilic and relatively hydrophobic monomers. Examples include acrylate and methacrylate copolymers and polyoxyethylene-polyoxypropylene copolymers. Exemplary commercial grades of such copolymers include EUDRAGITS, which are copolymers of methacrylate and acrylate, and PLURONICS, which are polyoxyethylene-polyoxypropylene copolymers, supplied by BASF.

[0028] A further class of water-soluble polymers suitable for use in the present invention includes cellulosic polymers that can be ionic or neutral. Neutral amphiphilic cellulosic water-soluble polymers include polymers in which the parent cellulosic polymer is substituted with at least one relatively hydrophobic substituent at any or all of the three hydroxyl groups present on each saccharide repeat unit. The hydrophobic substituent can be essentially any substituent that, when substituted to a high enough level or degree of substitution, can render the cellulosic polymer essentially insoluble in aqueous solution. Examples of hydrophobic substituents include ether-linked alkyl groups such as methyl, ethyl, propyl, butyl; or ester-linked alkyl groups such as acetate, propionate, butyrate; and ether- and / or ester-linked aryl groups such as phenyl, benzoate or phenylate. The hydrophilic regions of the polymer can be either the relatively unsubstituted portions or the regions substituted with hydrophilic substituents, since the unsubstituted hydroxyls themselves are relatively hydrophilic. Hydrophilic substituents include ether- or ester-linked non-ionic groups, such as hydroxyalkyl substituents hydroxyethyl, hydroxypropyl, and alkyl ether groups such as ethoxyethoxy or methoxyethoxy. Particularly preferred hydrophilic substituents are those which are ether- or ester-linked ionic groups, such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates or sulfonates.

[0029] One class of cellulosic water-soluble polymers includes neutral polymers, which means that the polymer is substantially non-ionic in aqueous solution. Such polymers contain non-ionic substituents that can be ether- or ester-linked. Exemplary ether-linked non-ionic substituents include alkyl groups such as methyl, ethyl, propyl, butyl; and hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl. Exemplary ester-linked non-ionic substituents include alkyl groups such as acetate, propionate, butyrate. Exemplary neutral polymers that can be used as water-soluble polymers include hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose.

[0030] In one embodiment, the water soluble polymer is selected from PVP (polyvinylpyrrolidone), PVAc (polyvinyl acetate), PVOH (polyvinyl alcohol), PVAP (polyvinyl acetate phthalate), poloxamer type polymers (e.g., Poloxamer 188), PEG, MC, HPMC, HPC, HEC, HPMCAS, HPMCP, chitosan, polymethacrylate-based copolymers (e.g., Eudragit type polymers), polyacrylic acid polymers (e.g., Carbomer or Carbopol 940), carboxymethyl cellulose acetate butyrate and other cellulose derivatives, modified starch and other polysaccharides, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (Soluplus) and different PPVVA grades (e.g., PPVVA 64) and any mixtures thereof.

[0031] In further embodiments, the water soluble polymer is selected from polyvinylpyrrolidone, poloxamer type polymers, polymethacrylate based copolymers, polystyrene sulfonate, and any mixture thereof, hi yet other embodiments, the water soluble polymer is polystyrene sulfonate.

[0032] Drugs, nutraceuticals or dietary supplement compounds The drug, nutraceutical or dietary supplement compound used in the method of the present invention can in principle be any pharma- ceutically active ingredient, nutraceutical or dietary supplement compound suitable for human consumption. Typically, such compounds have low solubility in water. This can be problematic, especially for drug compounds that require reproducibility in terms of bioavailability. Thus, the present invention is particularly useful for drug compounds. Thus, in one embodiment, the drug, nutraceutical or dietary supplement compound is a drug compound. In a further embodiment, the drug compound is classified into BCS class II or IV. These classes of drug compounds are referred to as "low solubility and high permeability" and "low solubility and low permeability", respectively. In another embodiment, the drug, nutraceutical or nutraceutical compound is abiraterone, abiraterone acetate, aceclofenac, acetazolamide, acetylsalicylic acid, aclidinium bromide, acyclovir, afamelanotide acetate, albendazole, albuterol sulfate, aliskiren fumarate, allopurinol, alprostadil, amantadine hydrochloride, aminolevulinic acid hydrochloride, amiodarone hydrochloride, amoxicillin, amprenavir, anagrelide hydrochloride, anidulafungin, apalutamide, apixaban, apremilast, aprepitant, aripiprazole, atorvastatin, azelaic acid, azithromycin, benidipine, bazedoxifene acetate, bedaquiline fumarate, benzonatate, bexarotene, bicalutamide, binimethymidine ... Nibs, bisacodyl, brivaracetam, budesonide, candesartan, carbamazepine, cabergoline, cannabidiol, cannabinoids, carfilzomib, carisoprodol, carvedilol, cefdinir, cefditoren, cefixime, cefotiam, cefpodoxime, cefuroxime axetil, celecoxib, clarithromycin, chloroquine, chlorpromazine, ciclesonide, cilexetil, cilostazol, ciprofloxacin, cladribine, clarithromycin, clofazimine, clonazepam, clopidogrel, clozapine, cobicistat, colistin methanesulfonate sodium, curcumin, cyclosporine, cyproterone, dabrafenib mesylate, dapagliflozin, dapsone, daptomycin, dasabuvir, dasatinib,Deferasirox, delafloxacin meglumine, dexamethasone, dexamethylphenidate hydrochloride, diazepam, diclofenac, diloxanide, docetaxel, dolutegravir sodium, doxycycline, dutasteride, duvelisib, ebastine, efavirenz, eluxadrine, elvitegravir, empagliflozin, enasidenib mesylate, enzalutamide, epalrestat, eprosartan, erythromycin, eslicarbazepine acetate, essential fatty acids, estradiol, estrone sulfate, ethyl icosapentate, etoposide , etravirine, everolimus, ezetimibe, famotidine, fenofibrate, flibanserin, fluocinonide, flurbiprofen, fluticasone furoate, fluticasone propionate, folic acid, formoterol fumarate, furosemide, gefitinib, glatiramer acetate, glibenclamide, gliclazide, glimepiride, glipizide, glycopyrrolate, griseofulvin, haloperidol, hydrochlorothiazide, hydrocortisone, hydroxyzine, ibuprofen, ibrutinib, ethyl icosapentate, imatinib , indinavir, irbesartan, irinotecan, isotretinoin, itraconazole, ivacaftor, ivermectin, ketoprofen, L-carbocysteine, lamotrigine, lenalidomide, lesinurad, letermovir, levabuterol tartrate, levodopa, levonorgestrel, linezolid, lopinavir, loratadine, lorazepam, lovastatin, lubiprostone, manidipine, mebendazole, medroxyprogesterone, mefloquine, megestrol acetate, melatonin, meloxicam, melphalan, menatetrenone, mercaptopurine, Mesalamine, metaxalone, methylphenidate, metoclopramide, metoprolol, metronidazole, midostaurin, modafinil, mometasone furoate, morphine sulfate, mosapride, mycamine, nabilone, nabumetone, nalidixic acid, naproxen sodium, nelfinavir, nepafenac, nevirapine, neratinib, nicergoline, niclosamide, nifedipine, nilotinib, nilotinib hydrochloride monohydrate, nilvadipine, nimesulide, nimodipine, nintedanib, nitisinone, nitrofurantoin, norethindrone acetate, nystatin,Olanzapine, olaparib, olmesartan, omadacycline, opicapone, orlistat, ospemifene, oxcarbazepine, oxycodone, paclitaxel, paliperidone palmitate, palonosetron hydrochloride, paricalcitol, pazopanib hydrochloride, perampanel, phenobarbital, phenytoin, pioglitazone, pitavastatin, posaconazole, pranlukast, praziquantel, prednisolone acetate, prednisone, progesterone, pyrantel, pyrimethase amine, quetiapine, quinine, raloxifene, rebamipide, regorafenib, retinol, ribociclib succinate, rifampicin, rifaximin, rilpivirine, rimegepant, riociguat, risperidone, ritonavir, rivaroxaban, rofecoxib, rolapitant hydrochloride, roxithromycin, rucaparib, safinamide mesylate, saquinavir, sennoside A, sertraline, sevelamer carbonate, sildenafil, simeprevir, simvastatin, sirolimus, sofosbuvir , sonidegibranate, sorafenib tosylate, spironolactone, sufentanil citrate, sugammadex sodium, sulfadiazine, sulfamethoxazole, sulfasalazine, sultamicillin, sulpiride, sunitinib malate, suvorexant, tacrolimus, tadalafil, tafamidis, tafamidis meglumine, tamoxifen, tasimelteon, tecobirimat, telaprevir, telmisartan, telotristat ethyl, teprenone, teriflunomide, theophylline, , ticlopidine, tipranavir, tocopherol nicotinate, tolterodine tartrate, topotecan hydrochloride, tosufloxacin, tretinoin, triflusal, trimethoprim, umeclidinium bromide, uridine triacetate, ursodeoxycholic acid, valproic acid, valsartan, vandetanib, vemurafenib, venetoclax, vitamin A, vitamin D, verapamil, voriconazole, warfarin, ziprasidone hydrochloride, and zaltoprofen.

[0033] Increased solubility The amorphous form of the complex of the present invention increases the solubility of a drug, nutraceutical or dietary supplement, increasing it with increased solubility compared to the amorphous form of the binary complex of the prior art. Thus, in one embodiment, the solubility of a drug, nutraceutical or dietary supplement in the amorphous form of a complex with a protein and a water-soluble polymer is increased compared to the solubility of the drug, nutraceutical or dietary supplement in the amorphous form of the binary complex with the same protein.

[0034] In a further embodiment, the solubility of a drug, nutraceutical or dietary supplement in an amorphous form complexed with a protein and a water soluble polymer is increased compared to the solubility of the drug, nutraceutical or dietary supplement in an amorphous form binary complexed with the same water soluble polymer.

[0035] In another embodiment, the increase in solubility compared to the binary complex amorphous form is at least 50%. In yet another embodiment, the increase is at least 70%. In yet another embodiment, the increase is at least 100%.

[0036] General matters It is to be understood that any features and / or embodiments described above in relation to the compounds according to the invention apply by analogy to the methods described herein.

[0037] The following figures and examples are provided below to illustrate the present invention, they are intended to be illustrative and are not to be construed as limiting in any way. EXAMPLES

[0038] material For the experiments described below, compound A (Mw=418.4 g / mol, melting point (Tm)=125° C., logP=3.998, pKa=5.41), compound B (Mw=385.4 g / mol, Tm=208° C.), abiraterone acetate (Mw=391.6 g / mol, Tm=147° C., logP=5.12, pKa=5.19), ibrutinib (Mw=440.5 g / mol, Tm=149-158° C., pKa=3.74), cannabidiol (BSPG Laboratories, Sandwich, Kent, UK) (containing a standard 98%-102% pure CBD isolate with an impurity profile of <0.15% and zero THC with an LOD of 0.000004%) (Brains Bio, BSPG Laboratories, Sandwich, Kent, UK). β-lactoglobulin (BLG) with a purity percentage of >98% in the protein fraction ((Mw=314 g / mol, Tm=67.5° C., pKa=9.7), polyvinylpyrrolidine K25 (PVP K25, Kollidon® 25, BASF, Ludwigshafen, Germany), methacrylic acid-ethyl acrylate copolymer (1:1) type A (Eudragit® L100-55, Evonik, Darmstadt, Germany), polystyrene sulfonate (PSS, Sigma Aldrich, St. Louis, MO, USA), microcrystalline cellulose (MCC, Avicel PH 102, DuPont Nutrition, Ireland), poloxamer 407 (Kolliphor® P 407, BASF, Ludwigshafen, Germany) was used.

[0039] method X-ray powder diffraction (XRPD) for solid state investigations The solid state of the prepared formulations was investigated using an X'Pert PANanalytical PRO X-ray diffractometer (PANanalytical, Almelo, the Netherlands) with Cu Kα radiation (λ = 1.54187 Å). Samples were scanned in reflection mode from 5° to 30° 2θ with a scan rate of 0.067° 2θ / s and a step size of 0.026° 2θ. The accelerating voltage and current were 45 kV and 40 mA, respectively.

[0040] Modulated temperature differential scanning calorimetry (mDSC) for the measurement of glass transition temperature (Tg) mDSC thermograms of the samples were collected using a Discovery DSC (TA instruments, New Castle, USA) under nitrogen gas flow of 50 mL / min. Samples were analyzed at a basic modulated temperature amplitude of 0.2120°C and a heating rate of 2°C / min with a period of 40 seconds. For cannabidiol samples were heated from -40°C to 150°C, and for all other compounds samples were heated from 0°C to 250°C. A total of 4-8 mg of sample powder was loaded into an aluminum Tzero pan and sealed with an aluminum Tzero lid. The glass transition temperature (Tg) was determined as the midpoint from the reverse heat flow signal.

[0041] Example 1 - Preparation of binary and ternary complex amorphous forms of Compound A Preparation method The binary complex amorphous form at 25% drug loading was prepared using vibratory ball milling (MixerMill MM400, Retsch GmbH & Co., Haan, Germany) at 30 Hz in a cold room at 4° C. Masses of 125 mg of Compound A and 375 mg of BLG were weighed into a 25 mL grinding jar and grinding was carried out with two 12 mm stainless steel balls for 60 minutes.

[0042] Ternary complex amorphous form at 25% drug loading was also prepared using vibratory ball milling at 30 Hz in a cold room at 4° C. Masses of 100 mg Compound A, 150 mg PVPK25 and 150 mg BLG were weighed into a 25 mL grinding jar and grinding was carried out using two 12 mm stainless steel balls for 120 minutes.

[0043] Dissolution Methods - Dissolution of Binary and Ternary Complex Amorphous Forms of Compound A in FaSSGF and FaSSIF-V2 Powder dissolution of binary and ternary complex amorphous forms of Compound A was measured at room temperature in fasted-state simulated gastric fluid (FaSSGF, Biorelevant) and fasted-state simulated intestinal fluid V2 (FaSSIF-V2, Biorelevant) as dissolution media. A sample equivalent to 20 mg of Compound A was added to an Erlenmeyer flask containing 20 mL of dissolution medium while stirring at a speed of 200 rpm.

[0044] A volume of 2 mL of dissolution medium was removed from the dissolution vessel at 5, 10, 20, 40, 60, 90 and 120 minutes and immediately replaced with 2 mL of fresh dissolution medium. The dissolution samples were filtered through a 0.45 μm filter, diluted with acetonitrile, and then filtered again through a 0.45 μm filter. Finally, the samples were analyzed for drug content using high performance liquid chromatography (HPLC). The dissolution profiles were plotted as cumulative concentrations.

[0045] result The appearance of an amorphous halo (Figure 1a) indicated successful amorphization for both the binary and ternary composite amorphous forms. The appearance of a single Tg in the mDSC thermogram of the ternary composite amorphous form (Table 1) suggested that it was a homogeneous single-phase composite amorphous system.

[0046] As shown in Figure 2, in FaSSGF, the ternary complex amorphous form initially released approximately 650 μg / mL of compound A (5 min) and then precipitated until compound A reached a concentration level of approximately 110 μg / mL. In comparison, the binary complex amorphous form only reached a lower concentration of approximately 6–10 μg / mL during the entire dissolution period.

[0047] In FaSSIF-V2, the ternary complex amorphous form initially released approximately 380 μg / mL of compound A (5 min), followed by precipitation of compound A until it reached a concentration level of approximately 83 μg / mL. In comparison, the binary complex amorphous form similarly only reached a low concentration of 15-25 μg / mL during the entire dissolution period. These results demonstrated that the ternary complex amorphous form formulated with BLG and PVPK25 significantly increased the dissolution rate and solubility of compound A compared to the binary complex amorphous form.

[0048] Example 2 - Preparation of binary and ternary complex amorphous forms of Compound B Preparation method Binary and ternary complex amorphous forms at 23% drug loading were prepared by spray drying using a ProCepT spray dryer (ProCepT, Zelzate, Belgium) equipped with an expansion column and a large cyclone. For binary complex amorphous forms, compound B and BLG were dissolved in formic acid at a solid concentration of 5%. For ternary complex amorphous forms, compound B, BLG and Eudragit L100-55 (compound B:BLG:EudL ratio: 23:54:23, w / w / w) were dissolved in formic acid at a solid concentration of 6.5%. The spray drying process was carried out under the following process settings: inlet temperature of 110°C, 0.4 m 3 / min inlet gas flow, cyclone gas flow of 300 L / min, nozzle gas flow of 6 L / min and a feed rate of about 2.5 g / min. The column outlet temperature was recorded to be about 67°C.

[0049] Dissolution Methods - Dissolution of Binary and Ternary Complex Amorphous Forms of Compound B in FaSSIF-V1 Powder dissolution of binary and ternary complex amorphous forms of Compound B was measured at room temperature in fasted state simulated intestinal fluid V1 (FaSSIF-V1, Biorelevant) as dissolution medium. Samples corresponding to 10 mg of Compound B were added into an Erlenmeyer flask containing 10 mL of dissolution medium, with stirring at a speed of 200 rpm. Volumes of 1 mL of dissolution medium were removed from the dissolution vessel at 5, 10, 20, 40, 80 and 120 minutes. Dissolution samples were filtered through a 0.22 μm filter, diluted with acetonitrile, and then filtered again through a 0.22 μm filter. Finally, samples were analyzed for drug content using HPLC. Dissolution profiles were presented as concentrations at each time point.

[0050] result The appearance of an amorphous halo (Figure 1b) indicated successful amorphization for both the binary and ternary complex amorphous forms. g The appearance of (Table 1) suggested that the ternary complex amorphous morphology resulted in a two-phase complex amorphous system.

[0051] As shown in Figure 3, the ternary complex amorphous form of Compound B initially released about 166 μg / mL of Compound B (5 min), followed by a slight decrease in concentration to about 136 μg / mL after 120 min. In comparison, the binary complex amorphous form of Compound B initially released about 38 μg / mL of Compound B (5 min), followed by significant precipitation of Compound B until the concentration level was about 15 μg / mL. This study demonstrated that the ternary complex amorphous form formulated with BLG and Eudragit L100-55 increased the solubility and prevented the precipitation of Compound B.

[0052] Example 3 - Preparation of binary and ternary complex amorphous forms of abiraterone acetate Preparation method Binary and ternary complex amorphous forms at 40% (w / w) and 56% (w / w) drug loading were prepared by spray drying using a ProCepT spray dryer equipped with an expansion column and a large cyclone. For the binary formulation at 40% (w / w) drug loading, abiraterone acetate and BLG were dissolved in 50% (v / v) aqueous 1-propanol at a solid concentration of 4%. For the binary complex amorphous form at 56% (w / w) drug loading, abiraterone acetate and BLG were dissolved in 57% (v / v) aqueous 1-propanol at a solid concentration of 3.5%. For the ternary complex amorphous form at drug loadings of 40% (w / w) and 56% (w / w), abiraterone acetate was dissolved in a mixture of 1-propanol, water and formic acid (10:10:2, v / v / v) at a solid concentration of 4.5% along with BLG and Eudragit L100-55 (BLG:Eudragit L100-55) in a 1:1 weight ratio. The spray drying process was carried out under the following process settings: inlet temperature of 100°C, 0.4 m 3 / min inlet gas flow, cyclone gas flow of 300 L / min, nozzle gas flow of 6 L / min and a feed rate of about 4 g / min. The column outlet temperature was recorded to be about 58°C.

[0053] Dissolution Methods - Dissolution of Binary and Ternary Complex Amorphous Forms of Abiraterone Acetate in FaSSIF-V1 Powder dissolution of binary and ternary complex amorphous forms of abiraterone acetate was measured at room temperature in fasted state simulated intestinal fluid V1 (FaSSIF-V1, Biorelevant) as the dissolution medium. A sample equivalent to 20 mg of abiraterone acetate was added into an Erlenmeyer flask containing 20 mL of dissolution medium while stirring at a speed of 200 rpm.

[0054] A volume of 2 mL of dissolution medium was removed from the dissolution vessel at 5, 10, 20, 40, 60, 90 and 120 minutes and immediately replaced with 2 mL of fresh dissolution medium. The dissolution samples were filtered through a 0.45 μm filter, diluted with acetonitrile, and then filtered again through a 0.45 μm filter. Finally, the samples were analyzed for drug content using high performance liquid chromatography (HPLC). The dissolution profiles were plotted as cumulative concentrations.

[0055] result The appearance of an amorphous halo (Figure 1c) indicated successful amorphization for the ternary composite amorphous forms. The appearance of a single Tg in the mDSC thermograms of the ternary blends (Table 1) suggested that both blends yielded homogeneous single-phase composite amorphous systems. However, the binary composite amorphous forms showed remaining crystalline diffractions in the diffractograms, indicating that they were not completely amorphous.

[0056] As shown in Figure 4, the ternary complex amorphous form at 40% drug loading released about 115 μg / mL of abiraterone acetate (120 min), and the ternary complex amorphous form at 56% drug loading released about 85 μg / mL of abiraterone acetate (120 min). In comparison, the binary formulation at 40% drug loading released about 85 μg / mL of abiraterone acetate (60 min), after which abiraterone acetate precipitated to a concentration level of about 70 μg / mL after 120 min. The binary formulation at 56% drug loading released only about 57 μg / mL of abiraterone acetate (120 min). These results demonstrated that the ternary complex amorphous form containing BLG and Eudragit L100-55 significantly increased the dissolution rate and solubility of abiraterone acetate compared to the binary formulation.

[0057] Example 4 - Preparation of binary and ternary complex amorphous forms of ibrutinib Preparation method Binary and ternary complex amorphous forms at 50% drug loading were prepared by spray drying using a ProCepT spray dryer (ProCepT, Zelzate, Belgium) equipped with an expansion column and a large cyclone. For binary complex amorphous forms, ibrutinib was dissolved in a mixture of methanol and water (74:26, v / v) with BLG or polystyrene sulfonate (PSS) at a solid concentration of 2.6%. For ternary complex amorphous forms, ibrutinib was dissolved in a mixture of methanol and water (74:26, v / v) with BLG and PSS (BLG:PSS) at a weight ratio of 1:1 at a solid concentration of 2.6%. The spray drying process was carried out under the following process settings: inlet temperature of 120°C, 0.4 m 3 / min inlet gas flow, cyclone gas flow of 300 L / min, nozzle gas flow of 6 L / min and a feed rate of about 4 g / min. The column outlet temperature was recorded to be about 64°C.

[0058] Dissolution Methods - Dissolution of Binary and Ternary Complex Amorphous Forms of Ibrutinib in FaSSIF-V2 Powder dissolution of binary and ternary complex amorphous forms of ibrutinib was measured at room temperature in fasted state simulated intestinal fluid V2 (FaSSIF-V2, Biorelevant) as dissolution medium. Samples equivalent to 20 mg of ibrutinib were added into an Erlenmeyer flask containing 20 mL of dissolution medium with stirring at a speed of 250 rpm. A volume of 2 mL of dissolution medium was removed from the dissolution vessel at 5, 10, 20, 40, 60, 90 and 120 minutes. The dissolution samples were centrifuged at 14600 rpm for 3 minutes and the supernatant was collected and diluted with acetonitrile. The samples were then filtered through a 0.45 μm filter and analyzed for drug content using HPLC. The dissolution profile was presented as the concentration at each time point.

[0059] result The appearance of an amorphous halo (Figure 1d) indicated successful amorphization for both the binary and ternary composite amorphous forms. The appearance of a single Tg in the mDSC thermogram of the ternary blend (Table 1) suggested that the blend resulted in a homogeneous single-phase composite amorphous system.

[0060] As shown in Figure 5, the ternary complex amorphous form of ibrutinib initially released about 181 μg / mL of ibrutinib (5 min), which then decreased to about 127 μg / mL after 120 min. In comparison, the binary complex amorphous form with PSS only released about 117 μg / mL of ibrutinib (5 min), which then decreased to about 80 μg / mL (120 min), and the binary complex amorphous form with BLG only released 67 μg / mL during the entire dissolution period. This study demonstrated that the ternary complex amorphous form formulated with BLG and PSS increased the solubility of ibrutinib compared to the binary formulation.

[0061] Example 5 - Preparation of binary and ternary complex amorphous forms of cannabidiol Preparation method Binary and ternary complex amorphous forms were prepared by spray drying using a ProCepT spray dryer (ProCepT, Zelzate, Belgium) equipped with an expansion column and a large cyclone. Cannabidiol and BLG were dissolved in a mixture of methanol and water at a solid concentration of 3-4% with or without poloxamer 407. Additionally, ternary complex amorphous forms containing insoluble microcrystalline cellulose (MCC) were spray dried from the same solutions as the ternary formulations, except by further dispersing MCC in the solution containing cannabidiol, BLG, and poloxamer 407. Binary formulations containing BLG were prepared at drug loadings of 20 and 30%. A ternary formulation was prepared at a drug loading of 30% and is abbreviated as cannabidiol_30% DL. In the case of the ternary blend with additional MCC, the ratio between cannabidiol BSPG, BLG and poloxamer 407 was 30:55:15, whereas with dispersed MCC the ratio between the components was 23:42:12:23. The ratios for the ternary blend remained the same, so this blend is abbreviated as cannabidiol_30% DL (MCC). The spray drying process was carried out under the following process settings: inlet temperature of 100°C, 0.4 m 3 / min inlet gas flow, cyclone gas flow of 300 L / min, nozzle gas flow of 6 L / min and a feed rate of approximately 4 g / min.

[0062] Dissolution Methods - Dissolution of Binary and Ternary Complex Amorphous Forms of Cannabidiol BSPG in FaSSIF-V2 Powder dissolution of binary and ternary complex amorphous forms of cannabidiol was measured at 37°C in fasted state simulated intestinal fluid V2 (FaSSIF-V2, Biorelevant) as dissolution medium. Samples corresponding to 10 mg of cannabidiol were added into a USP II setup in an ERWEKA DT 70 dissolution tester (ERWEKA, Langen, Germany) containing 100 mL of dissolution medium while stirring with a small paddle at a speed of 100 rpm. A volume of 2 mL of dissolution medium was removed from the dissolution vessel at 5, 10, 20 and 40 minutes. The dissolution samples were centrifuged at 14500 rpm for 3 minutes and the supernatant was collected and diluted with methanol. Afterwards, the samples were filtered through a 0.45 μm filter and analyzed for drug content using HPLC. The dissolution profile was presented as the concentration at each time point.

[0063] result The appearance of an amorphous halo (Figure 1e) indicated successful amorphization for the ternary complex amorphous form. The appearance of a single Tg in the mDSC thermograms of the ternary blends (Table 1) suggested that both blends resulted in homogeneous single-phase complex amorphous systems. However, the binary complex amorphous forms at 20% and 30% drug loading showed residual crystalline diffractions in the diffractograms, indicating that they were not completely amorphous.

[0064] As shown in Figure 6, the ternary complex amorphous form of cannabidiol at 30% drug loading with and without MCC released about 98 μg / mL and 80 μg / mL of cannabidiol, respectively (40 min). In comparison, the binary complex amorphous form at 30% drug loading and even lower drug loading (20%) released only about 31 μg / mL of cannabidiol (5 min), which then decreased to a concentration of about 24 μg / mL (40 min). This study demonstrated that the ternary complex amorphous form formulated with BLG and poloxamer 407 increased the solubility of cannabidiol compared to the binary formulation.

[0065] Example 6 - Preparation of binary and ternary complex amorphous forms of Olaparib A ternary olaparib formulation comprising olaparib, BLG and Eudragit L in a weight ratio of 60:25:15 may be prepared by dissolving olaparib, BLG and Eudragit L in a mixture of ethanol and water or a mixture of ethanol, water and formic acid, and then spray drying the resulting solution as described above to produce the ternary complex amorphous form of olaparib in BLG and Eudragit L.

[0066] [Table 1]

Claims

1. 1. A complex amorphous form of a drug, nutraceutical or dietary supplement with a protein and a water soluble polymer, wherein the protein is beta-lactoglobulin.

2. 2. The complex amorphous form of claim 1, wherein the purity of the β-lactoglobulin is at least 92% (w / w) of the total amount of protein in the complex amorphous form.

3. 3. The complex amorphous form of claim 1 or 2, wherein the water soluble polymer is selected from HPMCAS, PVPVA, PVP, PVAc, PVOH, PVAP (polyvinyl acetate phthalate), poloxamer type polymers (e.g., Poloxamer 188), PEG, MC, HPMC, HPC, HEC, HPMCAS, HPMCP, chitosan, polymethacrylate based copolymers (e.g., Eudragit type polymers), polyacrylic acid polymers (e.g., Carbomer or Carbopol 940), carboxymethyl cellulose acetate butyrate and other cellulose derivatives, modified starch and other polysaccharides, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), polystyrene sulfonate (PSS), and any mixture thereof.

4. 4. The complex amorphous form of claim 3, wherein the water-soluble polymer is selected from polyvinylpyrrolidone, poloxamer-type polymers, polymethacrylate-based copolymers, polystyrene sulfonate, and any mixture thereof.

5. 3. The complex amorphous form of claim 1 or 2, wherein the drug, nutraceutical or dietary supplement compound is a drug compound.

6. 6. The complex amorphous form of claim 5, wherein the drug compound is classified as BCS Class II or IV.

7. 3. A method for preparing the complex amorphous form of claim 1 or 2, wherein the drug, nutraceutical or dietary supplement, protein and water-soluble polymer are subjected together to spray drying, solvent evaporation, freeze drying, precipitation from supercritical fluids, melt quenching, hot melt extrusion, electrospinning, 2D printing, 3D printing and any comminution process such as wet milling, ball milling and cryogenic grinding.

8. 1. Use of a protein and a water-soluble polymer to prepare a complex amorphous form with a drug, nutraceutical or dietary supplement, wherein the protein is β-lactoglobulin.

9. 1. A complex amorphous form of a drug, nutraceutical or dietary supplement with a protein and a water-soluble polymer, wherein the water-soluble polymer is selected from polyvinylpyrrolidone, poloxamer-type polymers, polymethacrylate-based copolymers, polystyrene sulfonate and any mixture thereof.

10. 10. The complex amorphous form of claim 9, wherein the water-soluble polymer is polystyrene sulfonate.

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