Methacrylate copolymers and compositions comprising the same

Abstract

The present invention relates to a methacrylic acid copolymer comprising units derived from at least one alkyl methacrylate and methacrylamide, wherein the units derived from methacrylamide are present in at least 34 wt.-% based on the total weight of the copolymer. Furthermore, the present invention relates to a process for the preparation of these methacrylic acid copolymers. Furthermore, the present invention relates to pharmaceutical compositions, nutritional compositions, coated pharmaceutical or nutritional dosage forms and nanoparticles or microparticles comprising the methacrylic acid copolymers of the present invention. Finally, the present invention relates to the use of the methacrylic acid copolymers of the present invention as coatings, carriers and matrices for amorphous solid dispersions.

Description

Technical Field

[0001] This invention relates to a novel methacrylic acid copolymer comprising units derived from at least one alkyl methacrylate and units derived from methacrylamide, wherein the methacrylamide-derived units are present in at least 34% by weight based on the total weight of the copolymer. Furthermore, this invention relates to methods for preparing these novel methacrylic acid copolymers. Additionally, this invention relates to pharmaceutical compositions, nutritional compositions, coated pharmaceutical or nutritional dosage forms, and nanoparticles or microparticles comprising the methacrylic acid copolymers described herein. Finally, this invention relates to the use of the methacrylic acid copolymers of this invention as coatings, as carriers, and as matrices for amorphous solid dispersions. Background Technology

[0002] In the fields of pharmaceutical compositions, nutritional compositions, and nanoparticles, the use of methacrylic acid copolymers to modify drug / nutrient release properties and affect the stability of compositions / particles is well known.

[0003] For example, this (meth)acrylic acid copolymer can be traded under the name E purchased it from Evonik Industries AG. Its use in pharmaceutical compositions is disclosed, for example, in US 6,391,338 B1, which describes the use of substantially water-insoluble active ingredients such as ibuprofen, itraconazole, and nifedipine through the active ingredient and E-type polymers are flash-flowed or extruded to improve solubility or increase bioavailability. During processing, the active ingredient can be converted to a higher-energy state (solid dispersion) and then released as dissolved nanoparticles.

[0004] However, there remains a need for novel methacrylic acid copolymers suitable for pharmaceutical and nutritional compositions that can provide similar or improved properties to such compositions compared to known methacrylic acid copolymers in the art. Specifically, there is a need for methacrylic acid copolymers that can provide stable pharmaceutical compositions, are easier / better to process, and can provide improved dosing characteristics.

[0005] The inventors of this invention have unexpectedly discovered that this objective can be achieved by a novel methacrylic acid copolymer comprising units derived from at least one alkyl methacrylate and units derived from methacrylamide, wherein the units derived from methacrylamide are present in an amount of at least 34% by weight based on the total weight of the copolymer of this invention.

[0006] Unbound by any theory, it is believed that a considerable number of units derived from methacrylamide, particularly those derived from dimethylaminopropylmethacrylamide (DMAPMA), lead to commercially available... E PO and E 100 polymer has similar or even better effects.

[0007] Caizhen Liang et al. (Colloids and Surfaces A: Physiochem. Eng. Aspects 513 (2017) 136-145) obtained a polymer similar to the novel polymer of the present invention in a very different field, which contains units derived from DMAPMA, a fact not considered by those skilled in the art of pharmaceutical and nutritional compositions. This publication describes the effect of acrylamide copolymers on the stability and rheological properties of yellow iron oxide dispersions. The polymerization reaction of a dimethylaminopropylmethacrylamide (DMAPMA)-butyl methacrylate (BMA)-methyl methacrylate (MMA) copolymer is described, wherein the molar ratio of monomers in the initial monomer feed is 2:1:1, corresponding to approximately 59 wt% DMAPMA, 24 wt% BMA, and 17 wt% MMA. Polymerization was carried out in tetrahydrofuran as a solvent in the presence of azobis(isobutyronitrile)AIBN as an initiator and 2-{[(butylthioalkyl)thiocarbonyl]thioalkyl}propionic acid (IBCP) as a chain transfer agent. Table 2 of this literature shows that the polymerization conditions resulted in very low monomer conversion rates for both DMAPMA and BMA. Without being bound by any theory, it is assumed that this is primarily due to the use of the chain transfer agent IBCP and the RAFT polymerization technique, which, in addition to affecting chain length, may also influence the activity of specific monomer radicals. The average conversion rates for DMAPMA were only 23%, for BMA 67%, and for MMA 94%. Therefore, it can be calculated that the monomer units in the DMAPMA-BMA-MMA copolymer of Caizhen Liang et al. are approximately 29 wt% DMAPMA polymerization units, 36 wt% BMA polymerization units, and 35 wt% MMA polymerization units. Summary of the Invention

[0008] Therefore, in a first aspect, the present invention relates to a methacrylic acid copolymer comprising units derived from at least one alkyl methacrylate and units derived from methacrylamide, wherein the units derived from methacrylamide are present in an amount of at least 34% by weight based on the total weight of the copolymer.

[0009] In a second aspect, the present invention relates to a method for preparing the methacrylic acid copolymer of the present invention, comprising the following steps:

[0010] Free radical polymerization is carried out on a monomer mixture comprising or consisting of at least one initiator, at least one chain transfer agent, and optionally at least one solvent:

[0011] 40 to 60% by weight of methacrylamide, alkyl methacrylamide or aminoalkyl methacrylamide, and

[0012] 40 to 60% by weight of at least one alkyl methacrylate

[0013] The total amount of monomers is 100% by weight.

[0014] In a third aspect, the present invention relates to a pharmaceutical composition comprising at least one methacrylic acid copolymer according to the invention and at least one pharmaceutically active ingredient.

[0015] In a fourth aspect, the present invention relates to a nutritional composition comprising at least one methacrylic acid copolymer according to the invention and at least one nutritionally active ingredient.

[0016] In a fifth aspect, the present invention relates to a coated pharmaceutical or nutritional dosage form, wherein the coating comprises at least one methacrylic acid copolymer of the present invention.

[0017] In a sixth aspect, the present invention relates to nanoparticles or microparticles comprising at least one methacrylic acid copolymer according to the invention.

[0018] Finally, in a seventh aspect, the present invention relates to the use of at least one methacrylic acid copolymer according to the invention as a coating, as a carrier, or as a matrix for an amorphous solid dispersion.

[0019] These and other aspects, embodiments, features, and advantages of the invention will become apparent to those skilled in the art from the following detailed description and claims. Any feature from one aspect of the invention can be used in any other aspect of the invention. Furthermore, it will be readily understood that the embodiments contained herein are intended to describe and illustrate, and not to limit, the invention, and in particular, the invention is not limited to these embodiments.

[0020] Numerical ranges expressed in the form of "from x to y" also include the values ​​mentioned. If several preferred numerical ranges are specified in this format, it goes without saying that all ranges generated by various combinations of endpoints are also included.

[0021] As used herein, “one or more” refers to at least one and includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or more of the mentioned classes. Similarly, “at least one” means one or more, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 or more. As used herein, “at least one” in relation to any component means the number of chemically distinct molecules, i.e., the number of different types of the referred class, not the total number of molecules. For example, “at least one copolymer” means the use of at least one type of molecule that conforms to the definition of a copolymer, but two or more different types of copolymers that conform to the definition may also exist, but it does not mean that only one or more molecules of one type of copolymer exist.

[0022] Unless otherwise expressly stated, all percentages given herein regarding compositions or formulations are by weight relative to the total weight of the respective composition.

[0023] According to the present invention, "substantially free" in relation to a compound or group means that the compound or group is present only in an amount that does not affect the properties of the composition, in particular, the corresponding compound or group is present in an amount of less than 3% by weight, preferably 1% by weight, more preferably 0.01% by weight, or not present at all, based on the total weight of the composition.

[0024] According to the present invention, the polymer is understood to comprise units obtained by polymerizing a specific monomer, which is then included in the polymer as those units, by the characteristic of "units derived from the polymer". For example, units derived from methacrylamide refer to monomers using methacrylamide groups suitable for polymerization. This characteristic includes methacrylamide and other monomers containing methacrylamide groups, such as dimethylaminopropyl methacrylamide.

[0025] Weight-average molecular weight M w Number-average molecular weight M n The determination can be performed by GPC or SEC (gel permeation chromatography or size exclusion chromatography) (see, for example, HFMark et al., Encyclopaedia of Polymer Science and Engineering, 2nd Edition, Vol. 10, pages 1 ff., J. Wiley, 1989), preferably using polymethyl methacrylate standards.

[0026] Glass transition temperature T g It can be determined by DSC (differential scanning calorimetry) according to DIN EN ISO 11357-2:2013 (measured under nitrogen atmosphere with residual monomer content (ReMo) less than 100 ppm, heating rate 20 °C / min, and no plasticizer added).

[0027] Z-average particle size D z The polydispersity index (PDI) can be determined by dynamic light scattering (DLS) according to ISO 22412:2017 (published February 2017). The PDI is determined by fitting correlation data (cumulative difference analysis) using two parameters. The calculations used to determine the PDI are defined in ISO standard document 22412:2017.

[0028] The amount of polymerized monomer units in the copolymer and the resulting monomer conversion rate are preferably determined by 1H-NMR spectroscopy. This method is well known to those skilled in the art, for example, in US 8,399,523 B2. Figure 2 As described in Table 1, deuterated MeOH was used. d4 of 1H NMR spectrum of E PO.

[0029] The amount of monomer units polymerized can also be indirectly determined by the residual monomer content (ReMo) in the final copolymer formulation, prior to the removal of volatile substances, for example, before drying (HPLC analysis of dimethylaminopropylmethacrylamide and GC analysis of butyl methacrylate and methyl methacrylate), followed by calculation. This method is well known to those skilled in the art (see, for example, WO 2012 / 048740 A1, page 20).

[0030] Further methods are disclosed in the following description and examples sections. Attached Figure Description

[0031] Figure 1 Dissolution profiles of fenofibrate and its amorphous solid dispersion (hereinafter also referred to as ASD) in 500 ml of 0.1 N HCl in USP Unit II. Each value represents the mean ± standard deviation, hereinafter referred to as SD (n = 3).

[0032] Figure 2 Dissolution profiles of fenofibrate and fenofibrate active pharmaceutical ingredient (ASD) (after 3 months of storage) in 500 ml of 0.1 N HCl in USP Unit II. Each value represents the mean ± SD (n = 3).

[0033] Figure 3 Dissolution curves of coated dihydroxypropyltheophylline beads in 250 ml of artificial saliva dissolution medium (pH 6.8) in USP device II. Each value represents the mean ± SD (n = 3). Detailed Implementation

[0034] This invention relates to a methacrylic acid copolymer comprising or composed of units derived from:

[0035] At least one alkyl methacrylate, preferably at least one C methacrylate 1-5 Alkyl esters, more preferably at least two methacrylates C 1-5 Alkyl esters; methyl methacrylate and butyl methacrylate are most preferred.

[0036] and units derived from methacrylamide, preferably derived from alkyl methacrylamide or aminoalkyl methacrylamide, more preferably derived from C 1-5 Alkyl methylacrylamide or dimethylamino C 1-5 Alkyl methyl acrylamide or diethylamino C 1-5 Alkylmethylacrylamide, preferably derived from dimethylaminopropylmethylacrylamide,

[0037] The unit is derived from methacrylamide, preferably from alkyl methacrylamide or aminoalkyl methacrylamide, and more preferably from C 1-5 Alkyl methylacrylamide or dimethylamino C 1-5 Alkyl methyl acrylamide or diethylamino C 1-5 The unit of alkylmethylacrylamide,

[0038] The most preferred unit is derived from dimethylaminopropylmethacrylamide, and is present in an amount of at least 34% by weight, preferably 35 to 55% by weight, and more preferably 45 to 50% by weight, based on the total weight of the copolymer.

[0039] In one embodiment, the weight-average molecular weight M of the methacrylic acid copolymer w The weight-average molecular weight M is 15,000 to 500,000, preferably 50,000 to 350,000 g / mol or 30,000 to 300,000 g / mol or 40,000 to 200,000, more preferably 75,000 to 305,000 g / mol, and most preferably 150,000 to 260,000 g / mol. In one embodiment, the weight-average molecular weight M w The values ​​range from 45,000 to 95,000 g / mol.

[0040] In one embodiment, the number-average molecular weight M of the methacrylic acid copolymer nThe number average molecular weight is from 10,000 to 150,000, preferably from 15,000 to 100,000 g / mol, more preferably from 25,000 to 85,000 g / mol, most preferably from 35,000 to 75,000 g / mol, and particularly from 40,000 to 65,000 g / mol. In one embodiment, the number average molecular weight M is... n It ranges from 16,000 to 25,000 g / mol.

[0041] In one embodiment, the polydispersity of the methacrylic acid copolymer is 2.0 to 10.0, preferably 2.0 to 5.0, more preferably 2.7 to 4.5, and most preferably 2.7 to 4.0, 3.0 to 5.0, or 3.5 to 4.5.

[0042] In one embodiment, the glass transition temperature T of the methacrylic acid copolymer g The temperature is 60 to 100°C, preferably 65 to 95°C, and more preferably 70 to 90°C.

[0043] In one embodiment, the methacrylic acid copolymer is substantially free of reactive groups, such as epoxy groups, that can be further polymerized.

[0044] In a preferred embodiment, the methacrylic acid copolymer is a dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer.

[0045] In one embodiment, the methacrylic acid copolymer is in powder form, preferably with an average particle size D. z The particle size is 1 to 1,000 μm, more preferably 100 to 500 μm. The powder can be obtained by grinding and milling.

[0046] The preferred copolymer is a dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer, polymerized from 40 to 60 wt%, preferably 45 to 55 wt%, of dimethylaminopropylmethacrylamide and 15 to 35 wt%, preferably 20 to 30 wt%, of butyl methacrylate and 15 to 35 wt%, preferably 20 to 30 wt%, of methyl methacrylate, wherein the total amount of monomers is 100 wt%; wherein, based on the total weight of the copolymer, the amount of polymeric units of dimethylaminopropylmethacrylamide in the copolymer is at least 34 wt%, preferably 35 to 55 wt%, more preferably 45 to 50 wt%. Preferably, the copolymer contains the following amounts of polymeric units: 45 to 55 wt% of dimethylaminopropylmethacrylamide, 23 to 28 wt% of butyl methacrylate, and 23 to 28 wt% of methyl methacrylate.

[0047] Furthermore, the present invention relates to a method for preparing the methacrylic acid copolymer according to the present invention, comprising or consisting of the following steps:

[0048] Free radical polymerization is carried out on a monomer mixture comprising or consisting of at least one initiator, at least one chain transfer agent, and optionally at least one solvent:

[0049] 40 to 60% by weight of methacrylamide, alkylmethacrylamide or aminoalkylmethacrylamide, preferably C 1-5 Alkyl methylacrylamide or dimethylamino C 1-5 Alkylmethylacrylamide or diethylamino C 1-5 Alkyl methylacrylamide, more preferably dimethylaminopropyl methylacrylamide; and

[0050] 40 to 60 wt% of at least one alkyl methacrylate, preferably C methacrylate 1-5 Alkyl esters, more preferably 10 to 35% by weight of butyl methacrylate; and

[0051] 15 to 40% by weight of methyl methacrylate,

[0052] The total amount of monomers is 100% by weight.

[0053] The at least one initiator is preferably selected from: azobisisobutyronitrile, 2,2'-azobis(2-methylpropionitrile), 1,1'-azobis(cyclohexaneformitrile), 2,2'-azobis(2-methylpropanediamine) dihydrochloride, ethyl α-bromoisobutyrate, 1,1,1-tris(2-bromoisobutyryloxymethyl)ethane, 2-(2-bromoisobutyryloxy)ethyl methacrylate, bis[2-(2-bromoisobutyryloxy)undecyl]disulfide, 2-bromoisobutyric acid hydroxysuccinimide, 2-bromoisobutyric acid 3-butynediate, 2-bromoisobutyric acid propynediate, camphor Brain quinone, 3-bromopropionitrile, 2-bromopropionitrile, dichlorophenylmethane, α,α-dichlorotoluene, 2-chloropropionitrile, 2-azidoethyl 2-bromoisobutyrate, 2-bromoisobutyric anhydride, benzyl bromide, cumene hydroperoxide, α-bromoisobutyryl bromide, 4-(chloromethyl)benzoyl chloride, (1-bromoethyl)benzene, ethyl 2-chloropropionate, 2-chloropropionic acid, n-(bromomethyl)phthalimide, methyl α-bromophenylacetate, methyl dichloroacetate, diethyl 2-bromo-2-methylmalonate, 4-isopropylbenzenesulfonyl chloride, tert-butyl α-bromoisobutyrate, 4-tert-butyl-n,n-dimethyl Benzyl aniline, dimethyl 2,6-dibromoheptanoate, 2-chloropropionyl chloride, diethyl meso-2,5-dibromohexanoate, hexamethylphosphoramide, ethyl α-bromophenylacetate, ethyl 2-bromoisobutyrate, trichloromethanesulfonyl chloride, 1,1,1-tris(4-chlorosulfonylphenyl)ethane, methanesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, di-(3,5,5)trimethylhexanoyl peroxide, tert-butyl peroxynedecanoate, tert-butyl peroxybenzoate, tert-amyl peroxy-2-ethylhexanoate, didecyl peroxide, tert-butyl peroxy-2-ethylhexanoate, tert-ethylhexyl peroxy tert-butyl carbonate, benzoyl peroxide, 2,2-di-(tert-butylperoxy)butane, dicumyl peroxide, di-tert-pentyl peroxide, di-tert-butyl peroxide, lauroyl peroxide, tert-butylperoxy-3,5,5-trimethylhexanoate, 1,1-di-tert-butylperoxy-3,3,5-trimethylcyclohexane, 2-(1-cyano-1-methylethyl)azocarboxamide, tert-butyl peroxyacetate, tert-butyl peroxyneopentaate or mixtures thereof, more preferably selected from tert-butyl peroxyneopentaate and tert-butyl peroxyneopentaate or mixtures thereof, and

[0054] The at least one chain transfer agent is preferably selected from: chloroform, thiocholesterol, propyne acrylate, poly(n,n)-dimethylacrylamide, methyl 4-pentenoate, methyl 2-(bromomethyl)acrylate, L-cysteine, ethylene, methane, ethane, propane, trimethylamine, dimethylamine, chloroform, methanol, pentaerythritol tetra(3-mercaptopropionate), trimethylolpropane tri(3-mercaptopropionate), 4-methylbenzenethiol, carbon tetrachloride, carbon tetrabromide, isooctyl 3-mercaptopropionate, pentaphenylethane, tert-nonylthiol, 4,4'-thiodiphenylthiol and n-dodecylthiol or mixtures thereof, preferably n-dodecylthiol.

[0055] Those skilled in the art of polymer science know how to perform free radical polymerization and can employ appropriate processing parameters, such as temperature or reaction time. It should be noted that free radical polymerization is fundamentally different from the highly specific RAFT polymerization, which requires a particular RAFT chain transfer agent.

[0056] In one embodiment, the solvent is selected from n-propanol, isopropanol, dichloromethane, ethyl acetate, methanol, ethanol, n-butanol, benzyl alcohol, chloroform, isopropyl acetate, methyl acetate, dimethyl sulfoxide, toluene, methyl ethyl ketone, dimethyl carbonate, hexane, heptane, methyl tert-butyl ether, acetone, dimethylformamide, n-methylformamide, tetrahydrofuran, acetonitrile, n,n-methylformamide, acetic anhydride, pyridine, 1,4-dioxane, diethyl ether, benzene, piperidine, carbon disulfide, carbon tetrachloride, triethylamine, 1,3-dimethyl-2-oxo-hexahydropyrimidine, hexamethylphosphoramide, morpholine, and cyclohexane, or mixtures thereof. In a preferred embodiment, the solvent is n-propanol, isopropanol, or mixtures thereof.

[0057] In one embodiment, the reaction is carried out in an inert atmosphere, preferably under argon or nitrogen, more preferably under nitrogen.

[0058] In one embodiment, the reaction is carried out under heating, preferably at a temperature of 60 to 90°C.

[0059] In one embodiment, the reaction takes place for 180 to 420 minutes, preferably 240 to 360 minutes.

[0060] In one embodiment, two initiators are used, wherein the second initiator is added 2 hours after the start of free radical polymerization, preferably 3 hours after the start, preferably at 70 to 90°C, more preferably at 80 to 85°C.

[0061] In one embodiment, the initiator, preferably a first initiator, and at least one solvent are added to the monomer mixture at a continuous flow rate of 1 to 10 g / min, preferably 3 to 5 g / min.

[0062] In one embodiment, at least one chain transfer agent is added to a mixture at a temperature of 50 to 70°C, preferably 60 to 65°C, preferably before the addition of the (first) initiator.

[0063] In one implementation, the reaction is carried out under stirring.

[0064] In the method, the monomer conversion rates of the monomers are preferably 85% by weight or more for dimethylaminopropylmethacrylamide, 95% by weight or more for butyl methacrylate, and 95% by weight or more for methyl methacrylate.

[0065] When the initial amount of dimethylaminopropylmethacrylamide in the monomer feed is known, the amount (by weight) of dimethylaminopropylmethacrylamide polymeric units in the copolymer can be determined by analyzing the total and individual residual monomer content (ReMo), and then calculated accordingly. The total and individual residual monomer content can be determined by high-performance liquid chromatography (HPLC). The determination of the total and individual residual monomer content by HPLC is well known to those skilled in the art.

[0066] Monomers dimethylaminopropylmethacrylamide, butyl methacrylate, and methyl methacrylate typically undergo free radical polymerization at different conversions in the reaction. The slight differences depend on the polymerization conditions. The monomer conversions of butyl methacrylate and methyl methacrylate are quite high compared to the initial monomer feed, and are in the same range as about 95 wt% or more, exceeding 95 wt% up to 99.9 wt% of the polymerizable monomers. The monomer conversion of dimethylaminopropylmethacrylamide is slightly lower than that of butyl methacrylate and methyl methacrylate, at about 85 wt% or more, up to 95 wt% of the polymerizable monomers compared to the initial monomer feed. This means that when the weight ratio of dimethylaminopropylmethacrylamide:butyl methacrylate:methyl methacrylate in the initial monomer feed is, for example, 50:25:25, the proportion of polymerizable units in the copolymer may differ, for example, 47:26:27. The conversion also depends slightly on the polymerization conditions, such as temperature and reaction duration, as well as the choice of polymerization initiator and chain transfer agent.

[0067] An exemplary method for preparing a dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer is described below. Dimethylaminopropylmethacrylamide monomers (e.g., 500.0 g), butyl methacrylate (e.g., 250.0 g), and methyl methacrylate (e.g., 250.0 g) are added to a mixing apparatus, such as a 3,000 ml round-bottom flask equipped with a magnetic rod, a reflux condenser, and a nitrogen inlet. The reaction vessel is placed in a preheated water bath at 70 to 90°C, for example, 82°C. When the internal temperature reaches approximately 60 to 70°C, for example, 65°C, n-dodecyl mercaptan (e.g., 3.0 g, 5.0 g, 9.0 g, or 15.0 g) is added to control the molecular weight of the polymer during preparation. Simultaneously, a solution of 0.1 to 1 wt% (based on the weight of monomers) of tert-butyl peroxyneoplastate (e.g., 6.0 g) and 80 to 120 wt% (based on the weight of monomers) of n-propanol (e.g., 1,000 g) is added, for example, at a continuous flow rate of 2 to 10 g / min, for example, 5 g / min, to initiate free radical polymerization. After approximately 2 to 4 hours, for example, 3 hours, at a temperature between 80 and 85°C, a second initiator, such as tert-butyl peroxyneoplastate (e.g., 0.5 g), is added to complete the reaction, for example, for 60 to 120 minutes, for example, 90 minutes. The mixture can be cooled and transferred to an oven at 30 to 50°C, such as 40°C, to remove n-propanol, for example, for more than 48 hours. Deionized water can be used as the purification medium to purify the polymer to remove residual monomers and residual organic solvents, and then it can be dried, for example, at 50°C for more than 10 days. The dried coarse polymer (e.g., sieve size: 0.25 mm) can be ground and pulverized using an Ultra Centrifugal Mill ZM 200 from Retsch GmbH (Haan, Germany).

[0068] Furthermore, the present invention relates to a pharmaceutical composition comprising at least one methacrylic acid copolymer according to the present invention and at least one pharmaceutically active ingredient, wherein the pharmaceutical composition is preferably an amorphous solid dispersion.

[0069] Any pharmaceutical active ingredient or mixture of pharmaceutical active ingredients known to those skilled in the art can be added to the pharmaceutical composition. However, the pharmaceutical compositions of the present invention are particularly suitable for pharmaceutical active ingredients with poor water solubility or those with high loss of drug release after storage. Preferably, the pharmaceutical active ingredient may be a drug with poor water solubility after oral administration.

[0070] The active pharmaceutical ingredient (API) is characterized by a solubility of less than 0.1 mg of API in 1 ml of water at 37°C, preferably a pure API (as defined in the USP as a poorly soluble drug). The determination of the solubility of the API is well known to those skilled in the art. For example, an excess of the API is placed in a certain volume of water and mixed. The amount of API dissolved is then determined by a suitable analytical method, such as spectrometry.

[0071] 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, carmostat, candesartan, carbamazepine, carvedilol, celecoxib, cilazapril, clarithromycin, clodronicacid, and clopidogrel. idogrel, curcumin, cytarabine, darunavir, dasatinib, deferasirox, dexamethasone, dexlansoprazole, diclofenac, diltiazem, docetaxel, doxorubicin, duloxetine, dutasteride, efavirenz, elbasvir, eprosartan, erlotinib, estradiol, etidronic acid acid), etravirine, everolimus, ezetimibe, felodipine, fenofibrate, fluconazole, fluorouracil, PROTAC 7 (based on foretinib), glimepiride, grazoprevir, griseovulvin, hydrochlorothiazide, hydrocortisone, hydroxychloroquine, ibuprofen, imatinib.Irbesartan, irinotecan, itraconazole, ivacaftor, ivermectin, ledipasvir, lamotrigine, linezolid, lisinopril, lopinavir, losartan, mefloquine, mesalazine, methotrexate, metoprolol Prolol, Modafinil, Moexipril, Morphine, Mycophenolate, Naloxone, Nifedipine, Nilotinib, Nivadipine, Nirendipine, Olanzapine, Olmesartan, Omeprazole, Ondansetron, Paclitaxel, Pamidronic acid Acetaminophen (paracetamol), pemetrexed, perindopril, phenytoin, pibrentasvir, pioglitazone, prednisone, progesterone, quetiapine, raloxifene, raltegravir, ramipril, rebamipide, remdesivir, rilpivirine, risedronic acid (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 (acid) and ZXH-3-26, or, where applicable, from their pharmaceutically acceptable salt forms or mixtures thereof.

[0072] Preferably, the at least one active pharmaceutical ingredient may be selected from celecoxib, efavirenz, and fenofibrate, or a mixture thereof.

[0073] Based on the total weight of the composition, the at least one pharmaceutically active ingredient may be present in an amount of 0.1 to 50% by weight, preferably 5 to 50% by weight, or 10 to 25% by weight.

[0074] The pharmaceutical composition may also contain at least one additive. Any additive that can be used in a pharmaceutical composition is generally suitable.

[0075] In a preferred embodiment, the additives are present in less than 50% by weight, preferably less than 20% by weight, and more preferably less than 10% by weight, based on the total weight of the composition.

[0076] The additives are preferably selected from anti-adhesion agents, such as magnesium stearate; fillers, such as lactose, mannitol, starch, cellulose and their derivatives; binders, such as polyacrylates, starch, guar gum, xanthan gum, alginate, carrageenan, pectin, tragacanth gum, polysaccharides and their derivatives; flavoring agents, such as mint, cherry, fennel, vanilla, raspberry; colorings, such as natural colorants, azo and oxalool compounds; pigments, such as titanium dioxide, iron oxide, magnesium oxide; and disintegrants, such as starch, croscarmellose, and croscarmellose. Alkane, sodium bicarbonate, preferably in combination with citric acid (for effervescent tablets); flow aids, such as silica, fumed silica, talc, magnesium carbonate; flow conditioners, such as highly dispersed silica; antioxidants, such as vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, butylated hydroxyanisole, butylated hydroxytoluene; sweeteners, such as sucrose, sorbitol, sodium saccharin, cyclamate, aspartame; and antistatic agents, such as alkyl sulfonates or quaternary ammonium compounds, preferably in combination with polystyrene; or mixtures thereof.

[0077] The pharmaceutical formulation may exist in the form of tablets, oral dispersible tablets, pills, microspheres, capsules, sugar-coated pills, and granules.

[0078] In a preferred embodiment, the pharmaceutical composition is an amorphous solid dispersion or comprises an amorphous solid dispersion. Amorphous solid dispersions are known to those skilled in the art and are disclosed, for example, in US 6,391,338 B1. The composition and method of manufacturing the composition described in this reference are incorporated herein by reference, whereby the water-soluble polymer of the reference is replaced by the methacrylic acid copolymer according to the invention.

[0079] Amorphous solid dispersions are common in the field of pharmaceutical compositions. Amorphous solid dispersions can be obtained, for example, by hot melt extrusion, spray drying, adsorption, electrospinning, electrospraying, vibration granulation, pelletizing, or supercritical fluidization. Hot melt extrusion is preferred in this invention.

[0080] Amorphous solid dispersions obtained by hot melt extrusion, i.e. extrudates, can be further processed into pharmaceutical formulations.

[0081] This drug formulation can be available in the form of tablets, oral dispersible tablets, microspheres, capsules, sugar-coated pills, and granules.

[0082] To prepare the extrudate, the pharmaceutical active ingredient is mixed with at least one methacrylic acid copolymer according to the invention. Optionally, at least one plasticizer may be present. The mixture is introduced into an extruder and processed there into a homogeneous melt.

[0083] Technicians in the field of hot melt extrusion know how to perform hot melt extrusion and can select appropriate temperatures, extrusion speeds, and torques.

[0084] The resulting extrudates are typically bundles of varying lengths, which are randomly broken after cooling away from the extruder. These extrudates can be ground using a milling machine (e.g., a centrifugal mill) to obtain a classification of particle sizes. Depending on the grinding process, particles of different sizes can be produced. Typically, D... z The range is from 1 to 1000 μm. D is measured by laser diffraction according to DIN ISO 13320:2020-01. z .

[0085] The obtained extrudate can be further processed into a drug, particularly a solid dosage form, in a manner known in the art.

[0086] According to the invention, solid dosage forms, such as microspheres, pills, capsules, and tablets, are preferred. These dosage forms may be coated or uncoated. Tablets can be prepared, for example, by dry pressing or direct compression pulverization, particularly by grinding, an amorphous solid dispersion. Rapid-release and sustained-release dosage forms can be produced.

[0087] For example, microspheres can be prepared by cutting the extrudate strip as it leaves the extruder and then cooling it. In particular, a micro-pelletizer attached to the extruder is suitable for this purpose. For example, for the production of granules, a granulator attached to the extruder and cooling belt is suitable, which cuts the solidified strip extrudate into granules.

[0088] For the preparation of capsules, an amorphous solid dispersion can be ground and optionally mixed with other additives such as fillers and flow control agents, and then filled into capsules such as gelatin capsules.

[0089] Amorphous solid dispersions are formulated into tablets using conventional pharmaceutical excipients. Suitable excipients include, for example, fillers, binders, disintegrants, flow conditioners, flow aids, and flavoring agents.

[0090] In addition to the amorphous solid dispersion, the pharmaceutical formulation according to the invention may contain, for example, 0 to 90% by weight of excipients, based on the total weight of the formulation.

[0091] The content of the disintegrant can be in the range of 1 to 40% by weight, preferably 20 to 30% by weight, based on the total weight of the formulation, depending on the disintegrant, filler and other additives used.

[0092] The content of the gliding agent is preferably in the range of 0.1% to 4% by weight, more preferably 0.5% by weight, based on the total weight of the formulation.

[0093] As fillers, one or more compounds can be used, such as microcrystalline cellulose, starch, cellulose powder, lactose, especially spray-dried lactose, glucose, mannitol and sorbitol.

[0094] Suitable disintegrants are starch, especially corn starch, alginate and its salts and derivatives, such as calcium alginate and sodium alginate, sodium carboxymethyl cellulose, polyacrylic acid, croscarmellose, croscarmellose sodium, croscarmellose sodium starch, low-substituted sodium carboxymethyl cellulose, sodium bicarbonate and magnesium peroxide or mixtures thereof.

[0095] Suitable gliding agents include, for example, magnesium stearate, calcium behenate, glyceryl monostearate, stearic acid, hydrogenated vegetable fat, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, and talc or mixtures thereof.

[0096] As a flow control agent, fumed silica is suitable.

[0097] It can be used to coat pharmaceutical compositions or pharmaceutical formulations.

[0098] There is no particular limit to the weight of the tablets; a typical tablet is 100 to 800 mg, for example, 300 to 400 mg.

[0099] Furthermore, the present invention relates to a nutritional composition comprising at least one methacrylic acid copolymer according to the present invention and at least one nutritionally active ingredient.

[0100] Examples of nutritional supplements include resveratrol from grape products as an antioxidant, soluble dietary fiber products such as psyllium husk used to lower high cholesterol, broccoli (thiocyanates) as a cancer protectant, and soybeans or clover (isoflavones) for improving arterial health. Other examples of nutritional supplements include flavonoids, amino acids, antioxidants, pyrroloquinoline quinones, omega-3 fatty acids, vitamins, alpha-linolenic acid from flaxseed, beta-carotene from calendula petals, or anthocyanins from berries.

[0101] Preferred nutritional compositions may have the same composition as the pharmaceutical compositions and formulations described above, except that at least one pharmaceutical active ingredient is replaced by at least one nutritional active ingredient.

[0102] In another aspect, the present invention relates to coated pharmaceutical or nutritional dosage forms, wherein the coating comprises at least one methacrylic acid copolymer according to the present invention, and wherein the coated pharmaceutical dosage form is preferably a pill, tablet or capsule.

[0103] Example coated capsules and coating methods are disclosed, for example, in WO 2019096833 A1, where the polymer is replaced by a methacrylic acid copolymer according to the invention. Example coating compositions and methods of manufacturing thereof are disclosed in US 4,452,862, where the polymer is replaced by a methacrylic acid copolymer according to the invention.

[0104] Any known drug or nutritional composition core is generally suitable.

[0105] In one embodiment, the core is a dihydroxypropyltheophylline microsphere.

[0106] Typically, a coating comprising at least one methacrylic acid copolymer according to the invention may further comprise common compounds used for coating, such as plasticizers, preferably triethyl citrate, and flow aids, such as talc.

[0107] In one embodiment, the coating is applied by spraying, preferably by bottom spraying.

[0108] Furthermore, the present invention relates to nanoparticles or microparticles comprising at least one methacrylic acid copolymer according to the present invention, preferably as a carrier.

[0109] The type of nanoparticles or microparticles is generally not limited, as long as at least one methacrylic acid copolymer according to the present invention can be used.

[0110] In one embodiment, the nanoparticles or microparticles further comprise a bioactive ingredient. Such nanoparticles or microparticles can be obtained, for example, by solvent emulsification, a method comprising an organic phase (OP) and an aqueous phase (AP) to form an emulsion, wherein, in the case of an oil-in-water emulsion (O / W), the organic phase (OP) comprises a bioactive ingredient dissolved or dispersed therein.

[0111] In the case of water-in-oil emulsions (W1 / O), the aqueous phase (AP) contains the bioactive components dissolved or dispersed therein.

[0112] The method includes the following steps:

[0113] a) Providing an organic phase (OP) comprising a partially water-miscible organic solvent or solvent mixture (S1), wherein the organic phase (OP) is saturated with an aqueous phase (AP) and wherein the organic phase (OP) comprises a methacrylic acid copolymer according to the invention and optionally a bioactive component dissolved or dispersed therein.

[0114] b) Provides an aqueous phase (AP) comprising an aqueous solvent or solvent mixture (S2), comprising water and pharmaceutically acceptable salts dissolved therein, wherein the saline phase is further saturated with an organic phase (OP) solvent or solvent mixture (S1), and comprises an emulsion stabilizer and optionally a bioactive ingredient dissolved or dispersed therein.

[0115] c) Mixing the organic phase (OP) and the aqueous phase (AP) to obtain an oil-in-water emulsion (O / W) or a water-in-oil emulsion (W1 / O),

[0116] d) In the case of a water-in-oil emulsion (W1 / O), add an excess of another aqueous phase (AP) to obtain a water-in-oil emulsion (W1 / O / W2).

[0117] e) Removing the organic solvent or solvent mixture (S1) from the oil-in-water emulsion (O / W) from step c) or from the water-in-oil-in-water emulsion (W1 / O / W2) from step d) by evaporation and / or extraction to promote the formation of nanoparticles or microparticles comprising the methacrylic acid copolymer and bioactive ingredients according to the invention in the remaining aqueous suspension.

[0118] f) Separate nanoparticles or microparticles from the aqueous suspension.

[0119] In one embodiment of the method, nanoparticles or microparticles are separated from the aqueous suspension in step f) by filtration or centrifugation, washing and / or evaporation and / or drying.

[0120] In one embodiment of the method, the particle size D of the nanoparticles or microparticles 50 In the range of approximately 500 nm to 1000 μm.

[0121] In one embodiment of the method, the bioactive ingredient is selected from BCS-II and BCS-IV.

[0122] In one embodiment of the method, the bioactive ingredient is selected from albendazole, allendronic acid, aripiprazole, asenapine, atazanavir, atorvastatin, bleomycin, bosentan, buprenorphine, budesonide, candesartan, carbamazepine, carvedilol, celecoxib, cilazapril, clarithromycin, and clodronic acid. , clopidogrel, curcumin, cytarabine, darunavir, dasatinib, deferasirox, dexamethasone, dexlansoprazole, diclofenac, diltiazem, docetaxel, doxorubicin, duloxetine, dutasteride, efavirenz, elbasvir, eprosartan, erlotinib, estradiol, etidronic acid acid), etravirine, everolimus, ezetimibe, fenofibrate, fluconazole, fluorouracil, glimepiride, grazoprevir, griseovulvin, hydrocortisone, ibuprofen, imatinib, irbesartan, irinotecan, itraconazole, ivacaftor, ledipasvir, lamotrigine, linezolid, lisinopril,Lopinavir, Losartan, Mesalazine, Methotrexate, Metoprolol, Modafinil, Moexipril, Morphine, Mycophenolate Moxonazole, Naloxone, Nifedipine, Nilotinib, Nilvadipine, Nirendipine, Olanzapine, Olmesartan, Omeprazole, Ondansetron, Paclitaxel, Pamidronic Acid Acetaminophen (paracetamol), pemetrexed, perindopril, pioglitazone, prednisone, progesterone, quetiapine, raloxifene, raltegravir, ramipril, rebamipide, risedronic acid (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, valsartan, velpatasvir.Vemurafenib, verapamil, ziprasidone, zoledronic acid, or, where applicable, from their pharmaceutically acceptable salt forms.

[0123] In another embodiment, the bioactive ingredient is the aforementioned pharmaceutical active ingredient or the aforementioned nutritional active ingredient.

[0124] In one embodiment of the method, the aqueous phase (AP) contains about 1 to 50% by weight of a pharmaceutically acceptable salt.

[0125] In one embodiment of the method, the pharmaceutically acceptable salt is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, magnesium chloride, magnesium sulfate, calcium chloride, sodium acetate, potassium acetate, magnesium acetate, ammonium acetate, ammonium sulfate, and ammonium chloride, or any mixture thereof.

[0126] In one embodiment of the method, the solvent or solvent mixture (S1) has a miscibility of 0.1 to 35% by weight in water at 25°C.

[0127] In one embodiment of the method, the solvent or solvent mixture (S1) is selected from n-butanol, n-butyl acetate, isobutyl acetate, dichloromethane, chloroform, benzyl alcohol, methyl ethyl ketone, diethyl ketone, methyl acetone, methyl isopropyl ketone, methyl tert-butyl ether, diethyl ether, diisopropyl ether, dimethyl carbonate, diethyl carbonate, isopropyl acetate, propyl acetate, methyl acetate, methyl formate, butyl formate, isobutyl formate, ethyl formate, methyl benzoate, diethyl malonate, and dimethyl malonate. Methyl isobutyl ketone, 2-methyl-1-propanol, methyl butyrate, ethyl butyrate, isopropyl butyrate, methyl benzoate, methyltetrahydrofuran, 2,2-dimethyltetrahydrofuran, 2,2,5,5-tetramethyltetrahydrofuran and 2,5-dimethylfuran, 3-methoxy-3-methyl-1-butanol, 1-methoxy-2-propyl acetate, 1-methoxypropyl acetate, 3-methoxy-1-butanol, acetaldehyde dimethyl acetal, acetaldehyde diethyl acetal, and mixtures of two or more thereof.

[0128] In one embodiment of the method, the mixing in step c) is performed using a static mixer, a stirred or pulsed extraction column, a bead-filled column, a Pall- or Raschig-ring filled column, a Sulzer or Raschig metal-filled column, a rotor-stator mixing system, a baffle reactor, an oscillating baffle reactor, a continuous baffle reactor, a laminar jet breaker, a cross-flow membrane emulsifier, a premixed membrane emulsifier, a vortex membrane emulsifier, a microflow device (operating on the principles of co-flow, tangential cross-flow, or flow focusing), or a microstructured membrane emulsifier.

[0129] In one embodiment of the method, the aqueous phase (AP) contains about 0.001 to 5% by weight of an emulsion stabilizer, preferably selected from polyvinyl alcohol and polysorbate.

[0130] Finally, the present invention relates to the use of at least one methacrylic acid copolymer according to any one of the present invention as a coating, as a carrier, or as a matrix for an amorphous solid dispersion.

[0131] This invention specifically relates to:

[0132] 1. A methacrylic acid copolymer, comprising or composed of units derived from the following

[0133] At least one alkyl methacrylate,

[0134] Preferably at least one C 1-5 Alkyl methacrylate;

[0135] More preferably, methyl methacrylate and butyl methacrylate;

[0136] and units derived from methacrylamide,

[0137] This unit is preferably derived from alkyl methylacrylamide or aminoalkyl methylacrylamide.

[0138] More preferably derived from C 1-5 Alkyl methylacrylamide or dimethylamino C 1-5 Alkyl methyl acrylamide or diethylamino C 1-5 Alkylmethylacrylamide,

[0139] The most preferred derivative is dimethylaminopropylmethacrylamide, wherein the units derived from methacrylamide, preferably dimethylaminopropylmethacrylamide, are present in an amount of at least 34% by weight or 40% by weight, preferably 35 to 55% by weight or 40 to 55% by weight, more preferably 45 to 50% by weight, based on the total weight of the copolymer.

[0140] 2. The methacrylic acid copolymer according to claim 1, wherein the methacrylic acid copolymer has

[0141] i) a weight-average molecular weight M of 15,000 to 500,000 g / mol, preferably 30,000 to 300,000 g / mol, more preferably 40,000 to 200,000 g / mol. w ; and / or

[0142] ii) A number-average molecular weight M of 10,000 to 150,000 g / mol, preferably 15,000 to 100,000 g / mol, more preferably 18,000 to 85,000 g / mol.n ; and / or

[0143] iii) Polydispersity of 2.0 to 10.0, preferably 2.0 to 5.0, more preferably 3.5 to 4.5; and / or

[0144] iv) A glass transition temperature T of 60 to 100°C, preferably 65 to 95°C, more preferably 75 to 90°C g .

[0145] 3. The methacrylic acid copolymer according to claim 1 or 2, wherein the methacrylic acid copolymer is a dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer.

[0146] 4. A method for preparing the methacrylic acid copolymer according to any one of claims 1 to 3, comprising or consisting of the following steps:

[0147] Free radical polymerization is carried out on a monomer mixture comprising or consisting of the following monomers in the presence of at least one initiator, at least one chain transfer agent, and optionally at least one solvent:

[0148] 40 to 60% by weight, preferably 45 to 55% by weight, of methacrylamide, alkylmethacrylamide or aminoalkylmethacrylamide, preferably C 1-5 Alkyl methylacrylamide or dimethylamino C 1-5 Alkyl methyl acrylamide or diethylamino C 1-5 Alkyl methylacrylamide, more preferably dimethylaminopropyl methylacrylamide;

[0149] and

[0150] 40 to 60% by weight of at least one alkyl methacrylate, preferably C-methacrylate. 1-5 Alkyl esters, more preferably 10 to 35% by weight of butyl methacrylate; and 15 to 40% by weight of methyl methacrylate,

[0151] The total amount of the monomers mentioned herein is 100% by weight.

[0152] The at least one initiator is preferably selected from: 2,2'-azobis(2-methylpropionitrile), 1,1'-azobis(cyclohexaneformitrile), 2,2'-azobis(2-methylpropanediamine) dihydrochloride, ethyl α-bromoisobutyrate, 1,1,1-tris(2-bromoisobutyryloxymethyl)ethane, ethyl 2-(2-bromoisobutyryloxy)methacrylate, bis[2-(2-bromoisobutyryloxy)undecyl]disulfide, 2-bromoisobutyric acid hydroxysuccinimide, 3-butynedilicate 2-bromoisobutyric acid, propynedilicate 2-bromoisobutyric acid, camphorquinone, 3- Bromopropionitrile, 2-bromopropionitrile, dichlorophenylmethane, α,α-dichlorotoluene, 2-chloropropionitrile, 2-bromoisobutyric acid 2-ethyl azide, 2-bromoisobutyric anhydride, benzyl bromide, cumene hydroperoxide, α-bromoisobutyryl bromide, 4-(chloromethyl)benzoyl chloride, (1-bromoethyl)benzene, ethyl 2-chloropropionate, 2-chloropropionic acid, n-(bromomethyl)phthalimide, methyl α-bromophenylacetate, methyl dichloroacetate, diethyl 2-bromo-2-methylmalonate, 4-isopropylbenzenesulfonyl chloride, tert-butyl α-bromoisobutyrate, 4-tert-butyl-n,n-dimethylaniline Dimethyl 2,6-dibromoheptanoate, 2-chloropropionyl chloride, diethyl meso-2,5-dibromohexanoate, hexamethylphosphoramide, ethyl α-bromophenylacetate, ethyl 2-bromoisobutyrate, trichloromethanesulfonyl chloride, 1,1,1-tris(4-chlorosulfonylphenyl)ethane, methanesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, di-(3,5,5)trimethylhexanoyl peroxide, tert-butyl neodecanoate, tert-butyl benzoate peroxide, tert-amyl peroxy-2-ethylhexanoate, didecyl peroxide, tert-butyl peroxy-2-ethylhexanoate, tert-ethylhexyl peroxide tert-butyl carbonate, benzoyl peroxide, 2,2-di-(tert-butylperoxy)butane, dicumyl peroxide, di-tert-pentyl peroxide, di-tert-butyl peroxide, lauroyl peroxide, tert-butyl peroxy-3,5,5-trimethylhexanoate, 1,1-di-tert-butylperoxy-3,3,5-trimethylcyclohexane, 2-(1-cyano-1-methylethyl)azocarboxamide, tert-butyl peroxyacetate, tert-butyl peroxyneoplastate or mixtures thereof, more preferably selected from tert-butyl peroxyneoplastate and tert-butyl peroxyneoplastate or mixtures thereof;

[0153] The at least one chain transfer agent is preferably selected from: chloroform, thiocholesterol, propyne acrylate, poly(n,n)-dimethylacrylamide, methyl 4-pentenoate, methyl 2-(bromomethyl)acrylate, L-cysteine, ethylene, methane, ethane, propane, trimethylamine, dimethylamine, chloroform, methanol, pentaerythritol tetra(3-mercaptopropionate), trimethylolpropane tri(3-mercaptopropionate), 4-methylbenzenethiol, carbon tetrachloride, carbon tetrabromide, isooctyl 3-mercaptopropionate, pentaphenylethane, tert-nonylthiol, 4,4'-thiodiphenylthiol and n-dodecylthiol or mixtures thereof, preferably n-dodecylthiol.

[0154] 5. A pharmaceutical composition comprising at least one methacrylic acid copolymer according to any one of claims 1 to 3 and at least one pharmaceutically active ingredient, wherein the pharmaceutical composition is or preferably comprises an amorphous solid dispersion.

[0155] 6. A nutritional composition comprising at least one methacrylic acid copolymer according to any one of claims 1 to 3 and at least one nutritionally active ingredient.

[0156] 7. A coated pharmaceutical or nutritional dosage form, wherein the coating comprises at least one methacrylic acid copolymer according to any one of claims 1 to 3, wherein the coated pharmaceutical dosage form is preferably a pill, tablet, granule, microsphere, or capsule.

[0157] 8. Nanoparticles or microparticles comprising at least one methacrylic acid copolymer according to any one of claims 1 to 3, preferably as a carrier.

[0158] 9. Use of at least one methacrylic acid copolymer according to any one of claims 1 to 3 as a coating, as a carrier, or as a matrix for an amorphous solid dispersion.

[0159] Example

[0160] Materials and methods

[0161] Material

[0162] Fenofibrate (propyl-2-yl-2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionate, obtained from DKPharma Chem PVT Ltd. (Maharashtra, India) and dihydroxypropyltheophylline (7-(2,3-dihydroxypropyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), obtained from NBS Biologicals (Huntingdon, United Kingdom), were used as model compounds. A novel dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer (2:1:1) (E-173kDa, E-254kDa, E-281kDa, E-305kDa) is an internal research product of Evonik Nutrition & Care GmbH (Darmstadt, Germany). Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. Polyvinylpyrrolidone-polyvinyl acetate copolymer ( VA 64) and polyvinylpyrrolidone (VA 64) 17PF) purchased from BASF SE (Ludwigshafen, Germany). Hydroxypropyl methylcellulose acetate succinate ( AS-MMP was generously donated by Shin-Etsu Chemical Co., Ltd. (Tokio, Japan). Hydroxypropyl methylcellulose ( HPMC 100LV is supplied by Dow Chemical Company (Schwalbach am Taunus, Germany). Dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate (from the same polymer) E PO (powder form) E 100 (granules) is a commercially available product from Evonik Nutrition & Care GmbH (Darmstadt, Germany). Triethyl citrate, isopropanol, acetone, sodium chloride, potassium chloride, potassium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, calcium chloride, and magnesium chloride were purchased from Merck KGaA (Darmstadt, Germany). Talc was supplied by Imerys SA (Paris, France). All other chemicals were analytical grade and commercially purchased.

[0163] method

[0164] Examples 1 to 4

[0165] Preparation of a novel dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer (2∶1∶1 (weight ratio))

[0166] To prepare a dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer, monomers dimethylaminopropylmethacrylamide (500.0 g), butyl methacrylate (250.0 g), and methyl methacrylate (250.0 g) were added to a 3,000 ml round-bottom flask equipped with a magnetic rod, a reflux condenser, and a nitrogen inlet. The reaction vessel was placed in a preheated water bath at 82°C. When the internal temperature reached 65°C, n-dodecyl mercaptan (3.0 g, 5.0 g, 9.0 g, or 15.0 g) was immediately added to control the molecular weight of the polymer during the reaction. Simultaneously, a solution of tert-butyl peroxyneodecanate (6.0 g) and n-propanol (1,000 g) was added at a continuous flow rate of 5 g / min to initiate free radical polymerization. After reacting at 80°C to 85°C for approximately 3 hours, the second initiator, tert-butyl peroxyneodecanate (0.5 g), completed the reaction within an additional 90 minutes. The mixture was cooled and transferred to an oven at 40°C to remove n-propanol over 48 hours. The polymer was purified using deionized water and then dried at 50°C for more than 10 days. The dried coarse polymer (sieve size: 0.25 mm) was milled using an UltraCentrifugal Mill ZM 200 from Retsch GmbH (Haan, Germany).

[0167] Four copolymers with different weight-average molecular weights of 173 kDa, 254 kDa, 281 kDa and 305 kDa were obtained, and are referred to below as polymers E-173 kDa, E-254 kDa, E-281 kDa and E-305 kDa, respectively.

[0168] Residual monomer (ReMo) analysis and monomer conversion rate

[0169] Residual monomers in the dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer were analyzed by HPLC for dimethylaminopropylmethacrylamide and by GC for butyl methacrylate and methyl methacrylate prior to drying. Based on the results of the residual monomer analysis (6.16% by weight for dimethylaminopropylmethacrylamide, 0.002% by weight for butyl methacrylate, and 0.035% by weight for methyl methacrylate), with a monomer ratio of 2:1:1 (dimethylaminopropylmethacrylamide:butyl methacrylate:methyl methacrylate), the average monomer conversion rates were calculated to be 87.68% for dimethylaminopropylmethacrylamide, 99.99% for butyl methacrylate, and 99.86% for methyl methacrylate. This resulted in the final polymer composition containing 46.74 wt% dimethylaminopropylmethacrylamide, 26.65 wt% butyl methacrylate, and 26.61 wt% methyl methacrylate based on the total weight of the copolymer.

[0170] Gel permeation chromatography (GPC)

[0171] The molecular weight distribution of dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer was determined using an Agilent 1100 Series GPC-SEC analytical system from Agilent Technologies (Frankfurt am Main, Germany), comprising a pump (G1310A), autosampler (G1313A), column oven (G1316A), RI detector (G1362A), and control module (G1323B). Separation was achieved using a pre-set GRAM column (8 × 50 mm, 10 μm) and three additional GRAM columns (8 × 300 mm, 10 μm), all maintained at 60 °C. The eluent consisted of n,n-dimethylacetamide:lithium bromide:tris(hydroxymethyl)aminomethane (TRIS):water (1000:2:2:10 w / w), with a flow rate of 1 ml / min and an injection volume of 100 μl. The RI detector was maintained at 40°C, and a polymethyl methacrylate solution (1 g / L) was used as a standard. The number-average molecular weight (Mn), weight-average molecular weight (Mw), and polydispersity index (PDI) of the dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer were determined (Table 9).

[0172] Amorphous solid dispersions (ASDs) were prepared by hot melt extrusion.

[0173] stoichiometric blends of the polymer and a specific drug were prepared by mixing these materials in a screw-capped glass vial for approximately 10 minutes using a Turbular mixer from WAB Group (Nidderau-Heldenbergen, Germany) (Table 3). The polymer-drug blends were processed using a hot-melt extrusion process with a conical screw design from the Thermo Fisher Scientific (Dreieich, Germany) HAAKE MiniLab twin-screw extruder to obtain an amorphous solids dispersion (ASD). The hot-melt extrusion process was characterized by recording the applied screw speed, torque, and processing temperature (Table 3). The continuously produced filament exited the extruder at the nozzle, cooled while being conveyed by a conveyor belt, and was finally shredded into coarse particles. These particles were ground using an UltraCentrifugal Mill ZM 200 from Retsch GmbH (Haan, Germany) (sieve size: 0.25 mm). The resulting powder was a dosage form for further research.

[0174] ASD Dissolution Study

[0175] Dissolution experiments were performed according to USP 42-NF 37 (2019). Dissolution experiments were conducted using a USP Instrument II (DT 800LH) from ERWEKA GmbH (Heusenstamm, Germany), with 25 mg of the active pharmaceutical ingredient or an equivalent volume of ASD. The screw speed was set to 100 rpm, and all experiments were performed in 500 ml of 0.1 N hydrochloric acid. Dissolution tests were conducted over 120 minutes.

[0176] HPLC method for analyzing fenofibrate

[0177] Celecoxib was quantitatively analyzed using an Agilent 1260 Infinity high-performance liquid chromatography (HPLC) system, consisting of a quaternary pump (G1311B), an autosampler (G1329B), a column oven (G1316A), and a UV detector (G1314C), all sourced from Agilent Technologies (Frankfurt am Main, Germany). Separation was achieved using a Symmetry 300 C18 (150 × 4.6 mm, 5 μm) 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. The injection volume was 20 μL, and fenofibrate was detected at 286 nm. The analysis was linear (r0) over a concentration range of 0.13 to 526 μg / mL. 2 =0.999992). The method was found to be accurate (101.2–101.4%) and precise (CV 2.42%), with a limit of quantitation of 0.05 μg / ml. The run time was limited to 6 minutes. Selectivity (formulation excipients) was determined, and no interference was observed in drug retention time. Furthermore, no change in peak area was observed in the presence of all excipients used in the study.

[0178] Differential scanning calorimetry (DSC) analysis (DIN EN ISO 11357-2:2013)

[0179] Thermal analysis of ASD was performed using DSC to determine whether the added drug exhibited an amorphous (glass transition) or crystalline (melting / crystallization peak) appearance. The glass transition is a reversible change in amorphous or partially amorphous materials from a hard and relatively brittle frozen state to a molten state, or more precisely, a rubbery state. The melting point of the pure drug substance and the glass transition temperature of the polymer were investigated to identify variations and / or shifts in the thermal spectrum of ASD regarding crystalline and / or amorphous characteristics. Samples of 5 to 10 mg were weighed into a covered, perforated aluminum dish, which was cooled and sealed and exposed to a heating-cooling-heating cycle from 0 °C to 200 °C, with continuous measurements performed under an inert nitrogen atmosphere. A constant heating / cooling rate was set at 10 °C / min. The heat flow versus temperature was plotted in the resulting thermal spectrum using endothermic representation. Evaluation was based on a second heating cycle, with the indicated value being the average value of the glass transition range. Analysis was performed using DSC3+ (DSC-HC01) from Mettler Toledo (Giebeen, Germany).

[0180] Coating of dihydroxypropyltheophylline beads

[0181] An organic solution / dispersion for coating dihydroxypropyl theophylline microspheres was prepared using a solvent mixture of acetone:isopropanol:water (38.86:58.28:2.86 w / w), wherein the microspheres were made from a copolymer of dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate or dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate. The coating consisted of E 100, triethyl citrate plasticizer, and talc powder flow aid (in amounts given in Table 7). Dihydroxypropyl theophylline pellets were placed in the coating, and the organic solution / dispersion was atomized at the nozzle outlet via a peristaltic pump during the treatment. The coating treatment was characterized by recording the product bed and exhaust temperatures, as well as the relative humidity of the exhaust (Table 7). Furthermore, fixed parameters for the coating treatment included a nozzle diameter of 0.8 mm and a constant air volume of 20 m³. 3 The parameters were: flow rate / h, pipe inner diameter 1.0 mm, flow rate 1.4 g / min, spray pressure 0.7 bar, supply air temperature 25℃, relative humidity 26%, and product container volume of the fluidized bed system 0.3 L. The OYSTAR HüttlinMycrolab fluidized bed system from Hüttlin GmbH (Schopfheim, Germany) was used for coating treatment, employing bottom spray technology.

[0182] Solubility Study of Coated Dihydroxypropyl Theophylline Beads

[0183] Dissolution experiments were performed according to USP 42-NF 37 (2019). Dissolution experiments were conducted using a USP Instrument II (DT 700B) from ERWEKA GmbH (Heusenstamm, Germany), with 15 mg of the active pharmaceutical ingredient or an equivalent volume of coated dihydroxypropyltheophylline beads. The screw speed was set to 100 rpm, and all experiments were performed in microcapsules in 250 ml of artificial saliva dissolution medium (pH 6.8). The composition of the artificial saliva (pH 6.8) is shown in Table 1. Dissolution tests were performed for 10 minutes.

[0184] Table 1: Composition of artificial saliva-dissolving medium (pH 6.8), according to Pimparade, MB., Morott, JT., Park, JB., Kulkarni, VI., Majumdar, S., Murthy, SN., Lian, Z., Pinto, E., Bi, V., Durig, T., Murthy, R., Shivakumar, HN., Vanaja, K., Kumar, PC., Repka, MA (2015). "Development of taste-masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro-in vivo evaluations, International Journal of Pharmaceutics 487(1-2): 167-176.

[0185]

[0186]

[0187] Before adding calcium chloride and magnesium chloride, the artificial saliva dissolution medium (pH 6.8) is adjusted to pH 6.8 using phosphoric acid. Adding these salts does not change the final pH value.

[0188] Analysis of the UV / Vis spectrum of dihydroxypropyltheophylline

[0189] Dihydroxypropyltheophylline samples were analyzed at 274 nm using a Lambda25 UV / VIS spectrophotometer from PerkinElmer LAS GmbH (Rodgau, Germany) at a wavelength of 274 nm with artificial saliva-dissolving medium (pH 6.8) as a blank sample. The calculations were based on a two-point calibration of dihydroxypropyltheophylline.

[0190] Water vapor permeability test of polymer films (gravimetric analysis) (DIN 53122-1:2001)

[0191] To determine water vapor transmission rate (WVTR) using gravimetric analysis, a polymer film is first prepared. The polymer is dissolved in a solvent mixture containing acetone:isopropanol:water (38.86:58.28:2.86 w / w) under vigorous magnetic stirring. To remove any remaining undissolved solid particles or small agglomerates, approximately 25% by weight of the polymer solution is filtered through a 100 μm sieve and allowed to stand for about 30 minutes to allow air bubbles to escape. A condenser is used to aspirate a 16 × 14 cm glass plate, and the filtered polymer solution is then pulled onto the glass plate using a spatula. After solvent evaporation over 24 hours, a polymer film with a thickness of 25 μm ± 5 μm is formed. Circular sample surfaces with a diameter of 35 mm are punched from the dried polymer film to form test cells for the water vapor permeability test. Before use, the test cells are filled with silica gel and pre-dried at 140°C for 24 hours, then cooled in a desiccator to ensure consistent quality. The polymer film sample was placed between the upper (20 mm high) and lower (48 mm high) ground-edge glass slides (20 mm inner diameter, 36 mm outer diameter) of the test cell and placed in a special glass test desiccator. The test desiccator, including the lid, had a measuring height of 390 mm and a bottom circular surface diameter of 340 mm. It was filled with a supersaturated potassium chloride solution to approximately 20 mm height and equipped with a perforated ceramic plate (126 holes with a diameter of 4 mm). A moisture meter, thermometer, and a stirring motor with a blade stirrer for air circulation were also installed in the test desiccator. The temperature of the evaporation chamber in the closed test desiccator was 23 ± 2 °C, and the relative humidity was 85 ± 3%. The initial weight of the test cell containing the polymer film was determined, and the test cell was placed in the test desiccator. The first 2 hours of the water vapor permeability test were used for warming up and impregnating the polymer film. The mass of the test cell measured after 2 hours was used as a blank value for the measurement after 24 hours. The water vapor transmission rate (WVTR) calculated by gravimetric analysis was expressed in g / (m³). 2 *d) represents.

[0192] Liquidity measurement

[0193] The flowability of the polymers was analyzed using a BEP2 flowability tester from Copley Scientific (Nottingham, United Kingdom). This device measured the time required for 100g of polymer to flow through a 10mm nozzle and determined the stacking angle. High flow rate and low angle indicate good flowability of the polymer. For better comparability, all polymers undergoing flowability testing were reduced to approximately 250μm (d) beforehand using an Ultra Centrifugal Mill ZM 200 from Retsch GmbH (Haan, Germany). 50 ) particle size.

[0194] Particle size distribution analysis

[0195] Using the Mastersizer 3000 from Malvern Panalytical Ltd. (Malvern, United Kingdom), laser diffraction was employed to analyze samples with different molecular weights (M... W The particle size distribution of dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer (DMA) and dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer was studied. The particles were suspended in Milli-Q water, and measurements were taken immediately when the masking range reached 5-10%. Particle size distribution can also be measured according to ISO DIN 13320:2020-01.

[0196] Stability Study

[0197] ASD was stored for 6 months in a controlled environment chamber from Binder GmbH (Tuttlingen, Germany) under constant and controlled conditions (30°C / 65% RH). Samples were stored in 30 ml amber glass vials, sealed with screw caps. Samples were removed after 3 and 6 months, and the results of appearance, drug release, and DSC were compared with the data from the time of sample manufacturing.

[0198] Results and discussion

[0199] result

[0200] Table 2: Considering different molecular weights (M) W Flow data for dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer and dimethylaminopropyl methacrylamide-butyl methacrylate-methyl methacrylate copolymer. Each value represents the mean ± SD (n = 3).

[0201]

[0202]

[0203] *Particle size is approximately 250 μm (d 50 )

[0204] The flowability of the dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer improved with increasing molecular weight (Table 2). Dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate ( E 100) indicates that no product flows through the nozzle of the flowability tester specified in the method.

[0205] Composition and hot melt extrusion processing parameters of ASD

[0206] Table 3: Composition and hot melt extrusion processing parameters of ASD with added fenofibrate

[0207]

[0208] Thermal properties of pure polymer and ASD were characterized by DSC analysis.

[0209] All samples (Table 4) were analyzed immediately after treatment using the DSC method described above, and showed an amorphous appearance (no crystalline peaks). Compared to pure polymers, ASD's T... g Typically lower.

[0210] Table 4: Glass transition temperatures (T) of pure polymers with added fenofibrate and ASD g )

[0211]

[0212] Dissolution study

[0213] E-173kDa achieved the highest final level of ASD drug release incorporating fenofibrate. Figure 1 The E-173kDa ASD was stable throughout the entire 120-minute dissolution experiment and showed no drug precipitation. Compared to ASDs using other polymers incorporated with fenofibrate, the E-173kDa ASD exhibited a significantly higher level of drug release (approximately 30%) after 120 minutes. and E PO identified the initial burst release of fenofibrate, which then precipitated after 5 to 10 minutes of testing. Figure 1 ).

[0214] Stability Study

[0215] Appearance

[0216] After storage for 3 months under defined and constant conditions (30°C / 65% RH), almost all ASD samples showed no significant agglomeration and could be easily re-dispersed. Only E PO could not be re-dispersed and showed large, sticky clumps.

[0217] Dissolution study (after 3 months of storage)

[0218] The above method was used to perform a solubility test on ASDs in the active pharmaceutical ingredient fenofibrate, and the percentage of drug released after 120 minutes was determined. Figure 2 Depending on the polymer, varying degrees of reduction in drug release could be detected compared to the sample at the time of manufacture (Table 5). For most polymers, no reduction in the release of the active pharmaceutical ingredient fenofibrate was observed. However, for… VA64 and AS-MMP exhibits a very high relative loss of drug release. Compared to dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymers (E-173kDa and E-254kDa), Eudragit E PO shows a higher relative loss of drug release after 3 months of storage.

[0219] Table 5: Comparison of drug release for ASD when fenofibrate was added during manufacturing and after 3 months of storage.

[0220]

[0221] Water vapor permeability test

[0222] Table 6: Considering different molecular weights (M) W Water vapor transmission rate (WVTR) of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymers and dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymers. Each value represents the mean ± SD (n = 2).

[0223]

[0224]

[0225] Under the same test conditions, compared with dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate ( Compared to E 100, the dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer, especially E-254kDa, exhibits a lower water vapor transmission rate (WVTR) (Table 6). The data from the water vapor permeability tests suggest that the dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer exhibits similar moisture-proof potential to dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate.

[0226]

[0227] Dihydroxypropyltheophylline microspheres coated with polymer E-305kDa showed the lowest dihydroxypropyltheophylline release (1.5%) over a 10-minute period in artificial saliva culture medium. Compared to E-305kDa and E-173kDa, E100 coating showed approximately 5% dihydroxypropyltheophylline release over a 10-minute period, with higher polymer content observed after coating. For this experiment, higher polymer content in the coating resulted in a greater delay in drug release. Considering that E-173kDa releases approximately 35% dihydroxypropyltheophylline over 10 minutes, it is reasonable to hypothesize that the molecular weight of the polymer significantly affects the resistance of the polymer coating. The very low drug release in artificial saliva-dissolving medium (pH 6.8) resulted in good taste-masking properties.

[0228] Residual monomer (ReMo) analysis and monomer conversion rate

[0229] Based on the results of residual monomer analysis (average values ​​in Table 8) (by weight, dimethylaminopropylmethacrylamide 6.16%, butyl methacrylate 0.002%, and methyl methacrylate 0.035%), and considering a monomer ratio of 2:1:1 (dimethylaminopropylmethacrylamide: butyl methacrylate: methyl methacrylate), the average monomer conversion rates were calculated to be 87.68% for dimethylaminopropylmethacrylamide, 99.99% for butyl methacrylate, and 99.86% for methyl methacrylate. This resulted in the final polymer composition containing 46.74 wt% dimethylaminopropylmethacrylamide, 26.65 wt% butyl methacrylate, and 26.61 wt% methyl methacrylate.

[0230] Table 8: Residual monomer content, monomer conversion rate, and final polymer composition of dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer

[0231]

[0232]

[0233] *DMAPMA = Dimethylaminopropylmethacrylamide, BMA = Butyl methacrylate, MMA = Methyl methacrylate

[0234] Gel permeation chromatography (GPC)

[0235] The described GPC method was used to determine the number-average molecular weight (Mn), weight-average molecular weight (Mw), and polydispersity index (PDI) of dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymers synthesized using four different concentrations of the chain transfer agent n-dodecyl mercaptan. The results are shown in Table 9.

[0236] Table 9: M of the dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer by GPC analysis n M w and PDI

[0237]

[0238] Examples 5 to 8

[0239] Similar to the methods disclosed in Examples 1 to 4 above, further novel methacrylic acid copolymers were prepared. Examples 5 to 8 were prepared using the same monomers, chemical reaction conditions, chain transfer agent (CTA), and free radical initiator and setup as described in Examples 1 to 4. The difference from Examples 1 to 4 is that Examples 5 to 8 were synthesized using isopropanol instead of n-propanol. Using isopropanol as a solvent generally results in lower M compared to experiments using n-propanol. w Furthermore, for Example 8, a diluted neodecanoate peroxide solution (0.3% in isopropanol) was applied using a higher flow rate of approximately 9.3 g / min, and the variation in monomer ratio (4:1:3 by weight of dimethylaminopropylmethacrylamide: butyl methacrylate: methyl methacrylate) was tested.

[0240] Examples 5 through 7 exhibited the same monomer ratios as Examples 1 through 4. For example, compared to Examples 6 and 7, Example 5 had a lower CTA content, resulting in a higher M w .

[0241]

Claims

1. A methacrylic acid copolymer, comprising units derived from at least one alkyl methacrylate and units derived from methacrylamide, The methacrylamide-derived units are present in at least 40% by weight, based on the total weight of the copolymer. The methacrylic acid copolymer is a dimethylaminopropylmethacrylamide-butyl methacrylate-methyl methacrylate copolymer.

2. The methacrylic acid copolymer according to claim 1, wherein the methacrylic acid copolymer has i) Weight-average molecular weight M ranging from 15,000 to 350,000 g / mol w ; and / or ii) Number-average molecular weight M of 10,000 to 150,000 g / mol n ; The weight-average molecular weight M w and the number-average molecular weight M n Determined through GPC or SEC analysis; and / or iii) Polydispersity of 2.0 to 10.0, wherein the polydispersity is determined according to ISO standard 22412:2017; and / or iv) Glass transition temperature of 60 to 100 °C T g The Tg was determined by DSC analysis according to DIN EN ISO 11357-2:2013.

3. A method for preparing a methacrylic acid copolymer, comprising the following steps: A mixture of monomers comprising the following components is subjected to free radical polymerization in the presence of at least one initiator, at least one chain transfer agent, and optionally at least one solvent: 40 to 60% by weight of dimethylaminoC 1-5 Alkylmethylacrylamide or diethylamino C 1-5 Alkyl methylacrylamide; and 40 to 60% by weight of at least one alkyl methacrylate, The total amount of the monomers is 100 by weight.

4. A pharmaceutical composition comprising at least one methacrylic acid copolymer according to any one of claims 1 to 2 and at least one pharmaceutically active ingredient.

5. A nutritional composition comprising at least one methacrylic acid copolymer according to any one of claims 1 to 2 and at least one nutritionally active ingredient.

6. A coated pharmaceutical or nutritional dosage form, wherein the coating comprises at least one methacrylic acid copolymer according to any one of claims 1 to 2.

7. Nanoparticles or microparticles comprising at least one methacrylic acid copolymer according to any one of claims 1 to 2.

8. Use of at least one methacrylic acid copolymer according to any one of claims 1 to 2 as a coating, as a carrier, or as a matrix for an amorphous solid dispersion.

9. A methacrylic acid copolymer prepared by the following method, comprising the following steps: A mixture of monomers comprising the following components is subjected to free radical polymerization in the presence of at least one initiator, at least one chain transfer agent, and optionally at least one solvent: 40 to 60% by weight of dimethylaminoC 1-5 Alkylmethylacrylamide or diethylamino C 1-5 Alkyl methylacrylamide; and 40 to 60% by weight of at least one alkyl methacrylate, The total amount of the monomers is 100% by weight; and The methacrylamide-derived units are present at least 34% by weight, based on the total weight of the copolymer.

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