Delayed-release compositions resistant to fed-state gastric conditions - Patent Application 20070122997

Abstract

The present invention relates to a composition comprising an anionic acrylic polymer for coating pharmaceutical dosage forms and for enhancing the solubility of BCS Class II and IV active substances. i. 25 to 95 wt. % of an anionic (meth)acrylic copolymer, based on the total weight of the composition; ii. 5 to 75% by weight of at least one poloxamer, based on the total weight of the anionic (meth)acrylic copolymer in the composition; The anionic (meth)acrylic copolymer is reacted with ammonia or an organic base so that 0.1 to 25 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in the form of a salt.

Description

[Technical Field]

[0001] The present invention relates to compositions comprising anionic acrylic polymers for coating pharmaceutical dosage forms and compositions for enhancing the solubility of active pharmaceutical ingredients (APIs) in Class II and IV according to the Biopharmaceutical Classification System (BCS).

[0002] Background technology The normal human stomach has a pH that can range from approximately 1 to 3, but is usually closer to 2. Pharmaceutical dosage forms typically contain a coating that prevents drug release in the gastric environment. However, the integrity of this coating can be challenged when food is present in the stomach, as the pH can rise to 4 to 5. After food exits, gastric bicarbonate ions are secreted, neutralizing and alkalizing the mixture. This can damage the coating, rendering it unable to protect the dosage form. Furthermore, it is generally desirable for dosage forms containing poorly soluble (BCS Class II and IV) APIs to achieve even faster dissolution and absorption from the intestinal environment immediately after exceeding the gastric pH (i.e., above pH 5).

[0003] Known techniques for enhancing the solubility of poorly soluble APIs include hot melt extrusion, spray drying, and the use of pH-dependent polymers. However, processing a poorly soluble API with a pH-dependent polymer does not significantly enhance the solubility, and specifically does not result in immediate solubility of the poorly soluble API under pH conditions such as pH 5.5. On the other hand, this slows down the solubilization of the API from such dosage forms, delaying the effect of the API.

[0004] U.S. Patent No. 6,420,473 discloses a non-toxic, edible enteric film coating for pharmaceutical tablets, comprising an acrylic polymer containing i) 20 to 85% by weight of at least one alkyl acrylate or alkyl methacrylate moiety, and ii) 80 to 15% by weight of at least one vinyl or vinylidene moiety having a carboxylic acid group capable of salt formation. However, this enteric coating cannot provide resistance up to pH 5.0.

[0005] U.S. Patent No. 10,758,489 discloses an acidified film coating composition containing a polymer and an acidic component for use on orally ingestible substrates such as tablets. This acidified coating composition can be applied as an aqueous dispersion to an enteric coated substrate to enhance disintegration resistance in aqueous media up to pH 5.0. To achieve disintegration resistance up to pH 5.0, this document discloses a double coating system for the core substrate. This coating formulation also contains a high proportion of talc, which is undesirable because it is considered harmful to human health.

[0006] Therefore, the technical solutions disclosed in the prior art suffer from drawbacks such as the use of undesirable ingredients such as talc, the need for two layers for disintegration resistance up to pH 5.0, long processing times, and impaired process efficiency.

[0007] The prior art has failed to provide a coating without using talc. Furthermore, the prior art has failed to provide a single-layer enteric coating that can provide resistance to disintegration of pharmaceutical dosage forms up to pH 5.0. In particular, the prior art has failed to disclose a powder-form enteric coating composition that can be easily dispersed in an aqueous medium and provide a single-layer enteric coating on pharmaceutical dosage forms. Such a composition not only shortens processing time but also improves process efficiency.

[0008] Therefore, it is an object of the present invention to provide a powder composition for enteric coating of pharmaceutical dosage forms that can be used without the addition of talc and / or glidants. Another object of the present invention is to provide a composition for enteric coating that can be easily dispersed in an aqueous medium and used as a single-layer enteric coating of pharmaceutical dosage forms. A further object of the present invention is to provide a single-layer enteric coating for pharmaceutical dosage forms that can provide disintegration stability up to pH 5.0. Yet another object of the present invention is to provide a composition and method for enhancing the solubility of Class II and Class IV drugs / APIs (poorly soluble molecules) with BCS at pH ≥ 5.

[0009] Summary of the Invention It has been discovered that a powder composition comprising an anionic (meth)acrylic copolymer in salt form and a poloxamer can provide a composition for coating pharmaceutical dosage forms. This composition can be used without the addition of talc and / or a glidant. This powder composition can also be dispersed in an aqueous medium and used as a single-layer enteric coating for pharmaceutical dosage forms. Furthermore, it has been discovered that a single-layer enteric coating comprising i) an anionic (meth)acrylic copolymer in salt form and ii) a poloxamer provides a pharmaceutical dosage form with disintegration stability up to pH 5.0. Furthermore, a co-processed composition comprising an anionic (meth)acrylic copolymer in salt form, a poloxamer, and a BCS II or IV API can provide significant solubility enhancement at pH ≥ 5.0. Such a co-processed mixture can be easily incorporated into pharmaceutically or nutritionally acceptable dosage forms.

[0010] Thus, in a first aspect, the present invention provides a method for producing a medicament for the treatment of a medicament comprising: i. 25 to 95 wt. % of an anionic (meth)acrylic copolymer, based on the total weight of the composition; ii. 5-75 wt. % of at least one poloxamer, based on the total weight of the anionic (meth)acrylic copolymer in the composition, The anionic (meth)acrylic copolymer a1. 25 to 95 wt. % of at least one C1-C4-alkyl ester of acrylic acid and / or methacrylic acid, based on the total weight of the monomers; and a2. Polymerized from 5 to 75% by weight of acrylic acid and / or methacrylic acid based on the total weight of the monomers; The present invention relates to a powder composition in which an anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that, after the reaction, 0.1 to 25 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0011] In a second aspect, the present invention relates to an aqueous dispersion comprising a composition according to the first aspect.

[0012] In a third aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: i. providing an aqueous dispersion according to the second aspect; ii. coating a pharmaceutical dosage form with the aqueous dispersion of step i. to obtain a coated pharmaceutical dosage form; iii. optionally curing / drying the coated pharmaceutical dosage form of step ii to obtain an enteric coated pharmaceutical dosage form.

[0013] In a fourth aspect, the present invention relates to an enteric coated pharmaceutical dosage form obtained according to the third aspect.

[0014] In a fifth aspect, the present invention provides a method for producing a pharmaceutical composition comprising: i. Providing a Class II or Class IV API by a BCS; ii. combining the API of step i. with a composition according to the first aspect to obtain a mixture; iii. co-processing the mixture obtained in step ii. to form a homogenous mixture.

[0015] MODE FOR CARRYING OUT THE INVENTION The terms curing and drying may be used interchangeably within the meaning of the present invention and are defined as treating the composition obtained after spray drying or the pharmaceutical dosage form after coating with the anionic (meth)acrylic copolymer in salt form at a desired temperature for a desired time.

[0016] The "stability" of a formulation within the present invention can be derived by estimating the drug released and / or degraded at a particular pH within a defined time period.

[0017] The present invention provides i. 25 to 95 wt. % of an anionic (meth)acrylic copolymer, based on the total weight of the composition; ii. 5-75 wt. % of at least one poloxamer, based on the total weight of the anionic (meth)acrylic copolymer in the composition, The anionic (meth)acrylic copolymer a1. 25 to 95 wt. % of at least one C1-C4-alkyl ester of acrylic acid and / or methacrylic acid, based on the total weight of the monomers; and a2. Polymerized from 5 to 75% by weight of acrylic acid and / or methacrylic acid based on the total weight of the monomers; The present invention relates to a powder composition in which an anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that 0.1 to 25 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0018] Preferred organic bases are selected from tris(2-amino-2-hydroxymethyl-propane-1,3-diol), histidine, arginine, lysine, polyhistidine, polyarginine, polylysine, phospholipids, ribonucleosides, deoxyribonucleosides or mixtures thereof.

[0019] The advantage of the composition is that it can be easily dispersed in water and coated onto a pharmaceutical dosage form. Pharmaceutical dosage forms coated with the composition are stable not only in the gastric environment but also at pH levels up to 5.0. A further advantage of the composition is that a single coating layer is sufficient to provide stability at pH levels up to 5.0. The use of ammonia or an organic base has been found to be more advantageous than inorganic bases such as NaOH, KOH, and Na2CO3 for providing stability in the gastric environment, by reacting 0.1 to 25 mole percent of the anionic groups of the anionic (meth)acrylic copolymer into a salt form as the product obtained by using ammonia or an organic base.

[0020] In one embodiment, the anionic (meth)acrylic copolymer is reacted with ammonia such that 2.0 to 7.0 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in the salt form. The use of ammonia in the reaction with the anionic (meth)acrylic copolymer is particularly advantageous because it provides improved stability at pHs up to 5.0 compared to organic bases.

[0021] The amount of ammonia or organic base required to neutralize 0.25 to 25 mole percent of the carboxylic acid groups in the anionic (meth)acrylic copolymer can be calculated based on the molecular weight and percentage of methacrylic acid present in the polymer. The percentage of ammonia or organic base reacted with the anionic (meth)acrylic copolymer can be determined using various methods. One such method is by determining the acid number of the anionic acrylic polymer before and after reaction with ammonia or organic base. The acid number of the compound / polymer can be determined according to European Pharmacopoeia 01 / 2016:20220. The amount of ammonia or organic base required to neutralize the anionic (meth)acrylic copolymer is calculated according to the following formula:

number

[0022] Anionic (meth)acrylic copolymer The composition comprises 25 to 95 wt. % of the anionic (meth)acrylic copolymer, based on the total weight of the composition. In one embodiment, the composition comprises 55 to 90 wt. % of the anionic (meth)acrylic copolymer, based on the total weight of the composition. The anionic (meth)acrylic copolymer is obtained by polymerizing 25 to 95 wt. % of at least one C1-C4-alkyl ester of acrylic acid and / or methacrylic acid, based on the total weight of monomers, and 5 to 75 wt. % of acrylic acid and / or methacrylic acid, based on the total weight of monomers. In another embodiment, the anionic (meth)acrylic copolymer is polymerized from 40 to 60 wt. % of at least one C1-C4-alkyl ester of acrylic acid and / or methacrylic acid, based on the total weight of monomers, and 60 to 40 wt. % of acrylic acid or methacrylic acid, based on the total weight of monomers. In yet another embodiment, the anionic (meth)acrylic copolymer is polymerized from 40 to 60 weight percent ethyl acrylate, based on the total weight of monomers, and 60 to 40 weight percent methacrylic acid, based on the total weight of monomers.

[0023] In another embodiment, the C1-C4-alkyl ester of acrylic acid and / or methacrylic acid is selected from methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, isopropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, or a mixture of two or more thereof. In yet another embodiment, the at least one C1-C4-alkyl ester of acrylic acid or methacrylic acid is selected from methyl acrylate, ethyl acrylate, methyl methacrylate, or a mixture of two or more thereof.

[0024] In another embodiment, the anionic (meth)acrylic copolymer has 40 to 60 weight percent methacrylic acid, based on the total weight of the monomers.

[0025] Suitable anionic (meth)acrylic copolymers are commercially available under the trade names EUDRAGIT® L 30-D55, EUDRAGIT® L 100-55, EUDRAGIT® L 100, EUDRAGIT® S 100 and EUDRAGIT® FS 30D.

[0026] EUDRAGIT® L 30-D55 and EUDRAGIT® L 100-55 are well-known, commercially available (meth)acrylate copolymer products for pharmaceutical applications. EUDRAGIT® L 30-D55 is available as a 30% aqueous dispersion, while EUDRAGIT® L 100-55 is sold in powder form. EUDRAGIT® L 30-D55 and EUDRAGIT® L 100-55 each contain 46-50.6% by weight methacrylic acid and 49.4-54% by weight ethyl acrylate, based on the total weight of monomers.

[0027] EUDRAGIT® L 100 is a well-known commercially available (meth)acrylate copolymer polymerized from about 50% by weight methyl methacrylate and about 50% by weight methacrylic acid.

[0028] EUDRAGIT® S 100 is a well-known commercially available (meth)acrylate copolymer polymerized from about 70% by weight methyl methacrylate and about 30% by weight methacrylic acid.

[0029] EUDRAGIT® FS30D is a well-known commercially available (meth)acrylate copolymer polymerized from about 10% by weight methacrylic acid, about 65% by weight methyl acrylate, and about 25% by weight methyl methacrylate.

[0030] Poloxamer The term "poloxamer" refers to a non-toxic, non-ionic triblock copolymer composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Poloxamers are represented by the following general chemical formula: HO(C2H4O) a’ -[C3H6O] b -(C2H4O) a H wherein a and a' may be the same or different and each is an integer such that the hydrophilic portion constitutes approximately 60% to 90% by weight of the copolymer (i.e., the polyoxyethylene portion of the copolymer), and b is an integer such that the hydrophobic portion constitutes approximately 10% to 40% by weight of the copolymer (i.e., the polyoxypropylene portion of the copolymer). In another preferred embodiment, "a" and "a'" are independent of each other and are integers ranging from 64 to 141, and "b" is an integer ranging from 27 to 56. Poloxamers include poloxamer 188 (e.g., trademarks Pluronic® F-68, Flocor™, Kolliphor®, Lutrol®), poloxamer 237, poloxamer 338, and poloxamer 407. The names of polyoxyethylene / polyoxypropylene copolymers refer to their monomer composition. The first two digits of the poloxamer number multiplied by 100 give the approximate molecular weight of the hydrophobic polyoxypropylene block. The last digit multiplied by 10 gives the approximate weight percent of the hydrophilic polyoxyethylene content. For example, Poloxamer 188 represents a polymer containing approximately 1,800 Da of polyoxypropylene hydrophobic material, with the hydrophilic polyoxyethylene content being approximately 80% of the total molecular weight. Poloxamers are synthesized in two steps by first constructing the polyoxypropylene core and then adding polyoxyethylene to the end of the polyoxypropylene core. Due to variations in polymerization rates during both steps, poloxamers may contain heterogeneous polymer species of various molecular weights. The distribution of polymer species can be characterized using standard techniques, including, but not limited to, gel permeation chromatography (GPC).

[0031] In another embodiment of the invention, the poloxamer is selected from poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 or mixtures thereof, preferably poloxamer 237 and poloxamer 407.

[0032] The amount of poloxamer in the composition is based on the weight of the dry anionic (meth)acrylic copolymer in the composition.

[0033] Redispersible powder of anionic (meth)acrylic copolymer in salt form The anionic (meth)acrylic copolymer in salt form obtained after reaction with ammonia or an organic base is in powder form after removal of the solvent, which can be redispersed in water to obtain a dispersion of the anionic (meth)acrylic copolymer in salt form.

[0034] The process for preparing an anionic (meth)acrylic copolymer present in salt form comprises the following steps: i. adding ammonia or an organic base to an aqueous dispersion / suspension of an anionic (meth)acrylic copolymer and reacting to obtain the anionic (meth)acrylic copolymer in salt form; and ii. Removing the water from step i. to obtain a solid anionic (meth)acrylic copolymer in salt form. The process may further comprise the steps of iii. Drying the solid anionic (meth)acrylic copolymer in salt form obtained in step ii.

[0035] In this process, only a portion of the anionic (meth)acrylic copolymer may be converted to its salt form. The resulting anionic (meth)acrylic copolymer in salt form may be further mixed with the remaining anionic (meth)acrylic copolymer. It is more advantageous to neutralize the methacrylic copolymer in two or more steps using ammonia or an organic base, where in the first step, a partial amount of the methacrylic acid groups in the methacrylic acid copolymer are neutralized with the entire amount of the base. The remaining amount of the methacrylic acid copolymer is then mixed with the dispersion to achieve an overall neutralization level of the methacrylic acid groups in the methacrylic acid copolymer in the range of 0.1 to 25 mole percent, preferably 2 to 7 mole percent.

[0036] The water from step ii. can be removed using methods such as evaporation, spray drying, or freeze drying. Preferred methods for removing water are spray drying or freeze drying. The product obtained after removing water is in powder form containing some amount of moisture. Therefore, the product obtained after removing water is optionally dried. The drying in step iii. is carried out at a temperature ranging from 35 to 75°C for a time ranging from 5 to 2880 minutes.

[0037] The advantage of drying the anionic (meth)acrylic copolymer in salt form at this stage is that the drying time of the final pharmaceutical dosage form coated with the formulation according to the present invention can be significantly reduced, thereby improving the efficiency of the process. Drying of the anionic (meth)acrylic copolymer in salt form can be based on an exposure factor in the range of 1.4 to 5, which is determined according to the following formula: E=Log[(C-40)×log(m x30)] where "C" is the temperature (°C) to which the solid anionic (meth)acrylic copolymer obtained in step ii. is exposed for a time period of "m" minutes. The optimum range of the exposure factor is 1.5 to 2.1.

[0038] Aqueous dispersion of the composition A further embodiment of the present invention comprises: i. 25 to 95 wt. % of an anionic (meth)acrylic copolymer, based on the total weight of the composition; ii. 5 to 75% by weight of at least one poloxamer, based on the total weight of the anionic (meth)acrylic copolymer in the composition, The anionic (meth)acrylic copolymer a1. 25 to 95 wt. % of at least one C1-C4-alkyl ester of acrylic acid and / or methacrylic acid, based on the total weight of the monomers; and a2. Polymerized from 5 to 75% by weight of acrylic acid and / or methacrylic acid based on the total weight of the monomers; The present invention relates to an aqueous dispersion in which an anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that 0.1 to 25 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0039] The aqueous dispersion may further comprise at least one ingredient selected from a plasticizer, a surfactant, an emulsifier, a pigment, a flow aid, a deflocculating agent / detackifier, a secondary film former, or mixtures thereof. An advantage of this aqueous dispersion is that it can be easily coated onto a pharmaceutical dosage form to form an enteric coating.

[0040] The plasticizer is selected from trialkyl citrate, glyceryl triacetate, acetyl triethyl citrate, dibutyl sebacate, diethyl phthalate, polyethylene glycol having a molecular weight ranging from 200 to 8000, glycerol, castor oil, copolymers of propylene oxide and ethylene oxide, or mixtures thereof. The plasticizer comprises 0% to about 50% by weight, based on the total weight of the components of the coating composition in dry form. In another embodiment, the plasticizer comprises 2% to about 20% by weight, based on the total weight of the components of the coating composition in dry form.

[0041] The surfactant is selected from sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate 80, Tween 80, or mixtures thereof. Preferably, the aqueous dispersion comprises at least one surfactant in the range of 0.1% to about 15% by weight, based on the total weight of the components of the coating composition in dry form.

[0042] The emulsifiers are selected from the categories of alkoxylates, polyglycerols, polysorbates, betaines, glycolipids or mixtures thereof.

[0043] The pigments are selected from FD&C or D&C lakes, titanium dioxide, iron oxides, riboflavin, carmine 40, curcumin, annatto, other non-synthetic colorants, insoluble dyes, pearlescent pigments based on mica and / or titanium dioxide, or mixtures thereof. The type and amount of pigment used depends on the desired color. Multiple pigments may be used together to create a variety of different shades.

[0044] The flow aid is selected from silica, such as fumed silica. The flow aid imparts flowability to the powdered composition during dry blending and subsequent transfer from the blender to a storage container.

[0045] The detackifying / anti-agglomerating agent is selected from talc, carnauba wax, hydrogenated castor oil, mg stearate or calcium stearate, ground silica, kaolin, or a non-ionic emulsifier having an HLB value of 2 to 8, sodium stearyl fumarate, or mixtures thereof.

[0046] The secondary film former is selected from cellulose derivatives such as xanthan gum, sodium alginate, propylene glycol alginate, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (sodium CMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose acetylsuccinate (HPMCA), hydroxypropyl methylcellulose phthalate (HPMCP), starch derivatives, natural polysaccharides and their derivatives, methacrylates such as EUDRAGIT® L 100, EUDRAGIT® S 100, EUDRAGIT® FS 30 D, konjac flour, carrageenan, or mixtures thereof.

[0047] An advantage of the powder composition according to the invention is that the composition can be easily dispersed to obtain an aqueous dispersion that can be used directly to coat pharmaceutical dosage forms. The aqueous dispersion comprising the composition according to the invention is prepared by a process that includes at least the following steps: i. providing a powder composition according to the present invention; ii. optionally adding / mixing at least one ingredient selected from plasticizers, surfactants, emulsifiers, pigments, flow aids, anti-agglomerating agents, secondary film formers, detackifying agents or mixtures thereof with the powder composition of step i. to obtain a mixture; iii. Blending and adding the composition of step i, or the mixture obtained in step ii, to water under stirring to obtain an aqueous dispersion.

[0048] Enteric coated pharmaceutical dosage forms The enteric coated pharmaceutical dosage form according to the invention may be a (coated) tablet, a minitablet, a pellet, a granule, a hard shell capsule, a soft shell capsule filled with pellets or powder or granules, or a capsule filled with oil, coated pellets, powder or granules.

[0049] Aqueous dispersions comprising compositions according to the present invention are suitable for coating pharmaceutical dosage forms.

[0050] The pharmaceutical dosage form is coated with an aqueous dispersion comprising the following steps: i. providing an aqueous dispersion comprising a composition according to the present invention as described above; ii. Coating a pharmaceutical dosage form with the aqueous dispersion of step i to obtain a coated pharmaceutical dosage form.

[0051] The process may further comprise step iii) of drying the coated pharmaceutical dosage form of step ii) to obtain an enteric coated pharmaceutical dosage form. An advantage of the additional drying step is improved stability of the coated pharmaceutical dosage form at pH 5.

[0052] The drying in step iii is carried out at a temperature in the range of 35 to 80°C, preferably the drying is carried out at 40 to 65°C for a period in the range of 5 to 2880 minutes.

[0053] In another embodiment, the drying in step iii is based on an exposure factor in the range of 1.4 to 5.0, preferably in the range of 1.5 to 2.1. The exposure factor is determined according to the following formula: E=Log[(C-40)×log(m x30)] where "C" is the temperature (°C) to which the coated pharmaceutical dosage form of step ii is exposed for a period of "m" minutes.

[0054] In another embodiment, the pharmaceutical dosage form comprises at least one active pharmaceutical ingredient selected from antimicrobial agents, hormones, enzymes, enzyme inhibitors, receptor agonists and receptor antagonists, oral vaccines, proteins, peptides and combinations thereof, or combinations of two or more thereof.

[0055] Examples of active pharmaceutical ingredients may be selected from Dexlansoprazole, Lansoprazole, Omeprazole, Diclofenac, Minoprazole, Pantoprazole, Rabeprazole, Erythromycin, Ampicillin, Doxycycline, Fluoxetine, Ketoprofen, Oxymorphone Hydrochloride, Tramadol, Hydromorphone Hydrochloride, Sulfazsalazine, Mesalamine, Didanosine, Mycophenolate Mofetil, Heparin, Human Interleukin-10, Human Growth Hormone, IgG antibodies (including salts, derivatives, polymorphs, congeners, or any kind of mixtures thereof), or combinations thereof.

[0056] In the context of this invention, the term "coated tablets" is understood to include pellet-containing tablets or compressed tablets. Such tablets may range in size from approximately 5 to 25 mm. Typically, a number of small, defined active ingredient-containing pellets are compressed with a binder excipient to produce a tablet form. Upon oral ingestion and contact with body fluids, the tablet form is destroyed and the pellets disintegrate. Compressed tablets combine the advantages of a single-dose form for ingestion with the advantages of a multiple-dose form, such as dosing accuracy.

[0057] In the context of the present invention, the term minitablets is understood to refer to tablets that are smaller than conventional tablets and may have a size of approximately 1 to 5 mm. Minitablets, like pellets, are single dosage forms used in multiple doses. Compared to pellets, which may be the same size, minitablets typically have the advantage of having a more regular surface that allows for more accurate and more uniform coating. Minitablets may be enclosed in capsules, such as gelatin capsules. Such capsules disintegrate after oral ingestion, and upon contact with gastric or intestinal fluids, the minitablets disintegrate. Another use of minitablets is for individual fine-tuning of the active ingredient dosage. In this case, patients may directly ingest a prescribed number of minitablets that are tailored to their individual weight as well as the severity of their condition, from death to recovery. Minitablets differ from pellet-containing compressed tablets, as described above.

[0058] In the context of the present invention, the term pellets or granules is used to refer to cores for coating, or cores in compressed tablets, or cores to be filled into capsules after coating. Such pellets or granules may have a size (average diameter) ranging from 50 to 1000 micrometers and may be produced using processes such as high-shear and low-shear granulation, extrusion and spheronization, prilling, active layer formation, compression, agglomeration, and fluidized bed processes.

[0059] In the context of the present invention, the term coated pellets is used to denote pellets that are filled into capsules, for example gelatin or HPMC capsules. The capsules containing the pellets may also be coated with a coating composition according to the present invention.

[0060] Compositions and methods for enhancing the solubility of BCS class II and class IV drug molecules (poorly soluble APIs): The present invention also relates to a composition for enhancing the solubility of Class II and IV APIs according to the biopharmaceutical classification system. In particular, the solubility of the drug is increased at pH ≥ 5. This improves the absorption and bioavailability of poorly soluble drug molecules. The composition comprises: i. at least one drug molecule from class II or IV by BCS, and ii. A composition according to the first aspect, as defined hereinabove.

[0061] The composition may further comprise one or more pharmaceutically or nutritionally acceptable excipients.

[0062] The term "solubility" generally refers to a quantitative term relating to the property of a solid, liquid, or gaseous chemical substance, called a "solute," to dissolve in a solid, liquid, or gaseous "solvent." Solubility is expressed in terms of the "solubility level," which describes the amount of said substance that dissolves in a given amount of solvent. Generally, a substance is said to be sparingly / poorly soluble if less than 0.1 g dissolves in 100 ml of solvent. Solubility can be measured experimentally. A correlation term used is the "dissolution rate," which describes the solubility measured against the time it takes for the substance to dissolve in a given amount of solvent at a particular pH and temperature.

[0063] The API of the composition according to the present invention is aceclofenac, asiminib, atorvastatin calcium, azithromycin, bicalutamide, budesonide, bicalutamide, cefuroxime, carbamazepine, cinnarizin, chlorzoxanozone, clonazepam, clopidogrel, clonzapine, daclatasvir, danazol, darunavir, dexlansoprazole, dextromethorphan hydrobromide, diacerien, diclofenac sodium, diazepam, dolutegravir sodium, efavirenz, phenanthrene ... Virenz, enzalutamide, eplerenone, etoricoxib, ezetimibe, felodipine, fenofibrate, flubendazole, gefitinib, griseofulvin, glibenclamide, ibrutinib, ibuprofen, indinavir sulfate, itraconazole, ketoprofen, ketoconazole, indomethacin, ivermectin, iopanoic acid, lanroprazole, mebendazole, montelukast sodium, naproxen, nicardipine, nifedipine, nitrofurantoin, obeticholic acid , olanzapine, omeprazole, oxcarbazepine, oxfendazole, ozanimod, palbociclib isethionate, paliperidone palmitate, pemigatinib, phenytoin sodium, posaconazole, pralsetinib, racecadotril, rifampicin, risperidone, rosuvastatin, sertraline, sildenafil, spironolactone, sulfamethaxazole, tamoxifen citrate, telmisartan, terbinafine HCl, trimethoprim, undeca testosterone phosphate, valsartan, venetoclax, vericuguat, abiraterone acetate, acetazolamide, albendazole, aprepitant, avacopan, avapritinib, bifonazole, ciprofloxacin, digoxin, docetaxel, erythromycin succinate, haloperidol, hydrochlorothiazide, mesalamine, paclitaxel, ponesimod, relugolix, ritonavir, saquinavir, sulfasalazine, tivozanib, verapamil HCl or mixtures thereof.

[0064] In another embodiment, the present invention relates to a method for increasing the solubility of poorly soluble molecules with BCS at pH≧5, comprising the steps of: i. providing a Class II or IV drug molecule by BCS; ii. adding a composition as defined hereinabove according to the first aspect to obtain a mixture, and iii. Co-processing the mixture obtained in step ii. to form a homogeneous mixture.

[0065] The process may further comprise the step of adding one or more pharmaceutically or nutritionally acceptable excipients prior to the co-processing step iii.

[0066] According to the present invention, various "co-processing" techniques can be used, selected from co-extrusion, co-crystallization, co-dissolution, nanotechnology, kneading, co-precipitation, complexation, freeze-drying, microwave irradiation, microemulsion, self-emulsifying drug delivery, solid solutions, solid dispersions, fusion, dry or wet granulation, solvent evaporation, coacervation, fused solvent method, spray drying, hot melt extrusion, melt granulation, spray congealing, co-milling, co-sieving, trickling, blending, supercritical fluid processing, liquisolid technology, soluFlo technology, formEZE® technology, soluFlo® technology or compression.

[0067] The preferred method of co-processing is co-extrusion.

[0068] item: 1.i. 25 to 95 wt. % of an anionic (meth)acrylic copolymer, based on the total weight of the composition; ii. 5 to 75% by weight of at least one poloxamer, based on the total weight of the anionic (meth)acrylic copolymer in the composition; A powder composition comprising: The anionic (meth)acrylic copolymer a1. 25 to 95 wt. % of at least one C1-C4-alkyl ester of acrylic acid and / or methacrylic acid, based on the total weight of the monomers; and a2. Polymerized from 5 to 75% by weight of acrylic acid and / or methacrylic acid based on the total weight of the monomers; A powder composition in which an anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that 0.1 to 25 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0069] 2. The anionic (meth)acrylic copolymer is a1. 40 to 60 wt. % of at least one C1-C4-alkyl ester of acrylic acid and / or methacrylic acid, based on the total weight of the monomers; and a2. The powder composition according to item 1, polymerized from 60 to 40% by weight of acrylic acid or methacrylic acid, based on the total weight of the monomers.

[0070] 3. The anionic (meth)acrylic copolymer is a1. 25 to 95% by weight of ethyl acrylate based on the total weight of the monomers, and a2. The powder composition according to item 1, polymerized from 5 to 75% by weight of methacrylic acid based on the total weight of the monomers.

[0071] 4. The anionic (meth)acrylic copolymer is a1. 40 to 60% by weight of ethyl acrylate based on the total weight of the monomers, and a2. A powder composition according to any one of items 1 to 3, polymerized from 60 to 40% by weight of methacrylic acid, based on the total weight of the monomers.

[0072] 5. The powder composition according to any one of items 1 to 4, wherein the poloxamer is selected from poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 or mixtures thereof.

[0073] 6. The powder composition according to any one of items 1 to 5, wherein the anionic (meth)acrylic copolymer is present in an amount ranging from 55 to 90% by weight, based on the total weight of the composition.

[0074] 7. The powder composition according to any one of items 1 to 6, wherein the poloxamer is present in an amount ranging from 10 to 25% by weight, based on the total weight of the anionic (meth)acrylic copolymer in the composition.

[0075] 8. The powder composition according to any one of items 1 to 7, wherein the anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that 2 to 7 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0076] 9. An aqueous dispersion comprising a composition according to any one of items 1 to 8.

[0077] 10. The aqueous dispersion according to item 9, further comprising at least one component selected from a plasticizer, a surfactant, an emulsifier, a pigment, a flow aid, an anti-flocculant, a secondary film former, a detackifying agent or a mixture thereof.

[0078] 11.i. Providing a powder composition according to any one of items 1 to 8; ii. optionally adding at least one component according to item 10 to the powder composition of step i. to obtain a mixture; iii. blending and adding the composition of step i. or the mixture obtained in step ii. to water under stirring to obtain an aqueous dispersion; 11. A method for preparing an aqueous dispersion according to any one of items 9 to 10, comprising at least

[0079] 12.i. Providing an aqueous dispersion according to any one of items 9 to 10; ii. coating a pharmaceutical dosage form with the aqueous dispersion of step i. to obtain a coated pharmaceutical dosage form; iii. optionally drying the coated pharmaceutical dosage form of step ii to obtain an enteric coated pharmaceutical dosage form; 1. A method for coating an enteric coat onto a pharmaceutical dosage form, comprising at least:

[0080] 13. The method according to item 12, wherein the drying in step iii. is carried out at a temperature in the range of 35 to 80°C.

[0081] 14. The method according to any one of items 12 to 13, wherein the drying in step iii. is carried out for a time period ranging from 5 to 2880 minutes.

[0082] 15. The drying in step iii. is based on an exposure factor in the range of 1.4 to 5.0, and the exposure factor is determined according to the following formula: E=Log[(C-40)×log(m x30)] 15. The method according to any one of items 12 to 14, wherein "C" is the temperature (°C) to which the solid anionic (meth)acrylic copolymer is exposed for a time period of "m" minutes.

[0083] 16. An enteric coated pharmaceutical dosage form obtained according to any one of items 12 to 14.

[0084] 17.i. adding ammonia or an organic base to an aqueous dispersion / suspension of an anionic (meth)acrylic copolymer and reacting to obtain the anionic (meth)acrylic copolymer in salt form; ii. removing the water from step i. to obtain a solid anionic (meth)acrylic copolymer in salt form; 1. A process for preparing an anionic (meth)acrylic copolymer present in salt form, comprising:

[0085] 18. The process according to item 17, wherein a portion of the anionic (meth)acrylic copolymer is converted to its salt form in step i. and further mixed with the remaining anionic (meth)acrylic copolymer in one or more steps.

[0086] 19.iii. Drying the solid anionic (meth)acrylic copolymer in salt form; The process according to items 17 to 18, further comprising:

[0087] 20. The method according to item 19, wherein the drying in step iii. is carried out at a temperature ranging from 35 to 75°C for a time ranging from 5 to 2880 minutes.

[0088] 21. The drying in step iii. is based on an exposure factor in the range of 1.4 to 5, and the exposure factor is determined according to the following formula: E=Log[(C-40)×log(m x30)] 21. The method according to any one of items 19 to 20, wherein "C" is the temperature (°C) to which the solid anionic (meth)acrylic copolymer in salt form is exposed for a time of "m" minutes.

[0089] 22. The process according to item 21, wherein the solid anionic (meth)acrylic copolymer in salt form is cured / dried based on an exposure factor in the range of 1.4 to 2.1.

[0090] 23.i. Class II or Class IV drug molecules by BCS and ii. a composition according to any one of items 1 to 8; and iii. optionally, one or more pharmaceutically or nutritionally acceptable excipients A composition comprising:

[0091] 24. i. Providing a Class II or Class IV drug molecule by BCS; ii. adding a composition according to any one of items 1 to 8 to obtain a mixture; iii. optionally adding one or more pharmaceutically or nutritionally acceptable excipients to the mixture of step ii.; iv. co-processing the mixture obtained in step ii. or step iii. to obtain a homogeneous mixture; A method for increasing the solubility of a poorly soluble drug molecule at pH 5.5, comprising:

[0092] 25. The method according to item 24, wherein the co-processing is co-extrusion.

[0093] 26. The method according to any one of items 24 to 25, further comprising formulating the homogenous mixture obtained in step iv. into a pharmaceutically acceptable dosage form.

[0094] Example A. Material EUDRAGIT® L 30 D-55 is an aqueous dispersion containing 30% by weight of EUDRAGIT® L 100-55. [Table 1]

[0095] Diclofenac sodium is obtained from Aarti Drugs Limited, India.

[0096] Omeprazole magnesium pellets are obtained from Lee Pharma, India.

[0097] Magnesium oxide is obtained from Merck.

[0098] Tween 80 is obtained from Loba Chemie.

[0099] Sodium lauryl sulfate is obtained from Indo Overseas.

[0100] Sodium laurate is obtained from TCI.

[0101] Hydroxypropyl methylcellulose 3 cps is obtained from JRS Pharma.

[0102] Talc is obtained from Neelkanth Finechem LLP.

[0103] Microcrystalline cellulose 101 is obtained from JRS Pharma.

[0104] Croscarmellose sodium is obtained from FMC.

[0105] Poloxamer P 188 and Poloxamer P407 are commercially available under the trade names Kolliphor® P 188 and Kolliphor® P407 by BASF SE and Sigma Aldrich.

[0106] The equipment used for spray drying was a single nozzle lab scale spray dryer supplied by Buchi.

[0107] Post-drying equipment GPCG 1.1 (Glatt-Powder-Coater-Granulator).

[0108] B. Core Pellets Preparation: Omeprazole magnesium pellets, diclofenac sodium pellets, and theophylline pellets were used as pharmaceutical dosage forms. The formulations for preparing the core pellets are summarized in Table 1. [Table 2]

[0109] B1. Preparation Process of Barrier Coated Omeprazole Magnesium Pellets Example 1 i. With constant stirring, 3 cps of hydroxypropyl methylcellulose was added to the required amount of water to obtain a clear solution. ii. With constant stirring, talc was added to the solution of step i. to obtain a homogeneous dispersion. iii. The homogeneous dispersion of step ii was passed through an ASTM #60 sieve.

[0110] The homogeneous dispersion obtained in step iii. was used to coat omeprazole pellets in a GPCG 1.1 (Glatt-Powder-Coater-Granulator) to obtain barrier-coated omeprazole pellets. [Table 3]

[0111] B2. Preparation Process of Diclofenac Sodium Pellets Example 2 i. All ingredients were sieved through an ASTM #40 sieve and granulated with water in a planetary mixer. ii. The granulated blend of step i was extruded using a dome type extruder with a screen size of 1 mm to obtain extrudates. iii. The extrudate of step ii. was spheronized at 1700 rpm for 2 minutes to form pellets. iv. The pellets formed in step iii. were dried in a fluidized bed dryer at 60° C. for 30 minutes to obtain dried pellets. v. The dried pellets obtained in step iv. were sieved and the fraction obtained through the ASTM #18 / 25 sieve was used for coating testing.

[0112] C. Preparation of Partially Neutralized Anionic (Meth)acrylic Copolymers Table 3 shows formulations for preparing partially neutralized anionic (meth)acrylic copolymers (Examples 4-10). [Table 4]

[0113] C1. Preparation of Partially Neutralized Spray-Dried Polymer (Example 4): i. The 1N ammonia solution was added to the EUDRAGIT® L 30 D-55 dispersion while stirring and stirred for an additional 30 minutes. ii. The dispersion from step i. was passed through an ASTM #60 sieve. iii. The dispersion obtained in step ii was spray dried to obtain an ammonia-neutralized anionic (meth)acrylic copolymer. iv. Optionally, the ammonia-neutralized anionic (meth)acrylic copolymer obtained in step iii. was dried at a temperature ranging from 35 to 75° C. for a time period ranging from 5 to 2880 minutes.

[0114] Spray-dried or dry spray-dried powders of ammonia-neutralized anionic (meth)acrylic copolymers were further used in preparing coating compositions.

[0115] C2. Preparation of Partially Neutralized Spray-Dried Polymers (Examples 5-6): i. While stirring, a 10% solution of sodium hydroxide / tris(2-amino-2-hydroxymethyl-propane-1,3-diol) was added to the EUDRAGIT® L 30 D-55 dispersion and stirred for an additional 30 minutes to obtain a dispersion. ii. The dispersion obtained in step i. was passed through an ASTM #60 sieve. iii. The dispersion obtained in step ii. was spray dried to obtain a sodium hydroxide or tris(2-amino-2-hydroxymethyl-propane-1,3-diol) neutralized anionic (meth)acrylic copolymer. iv. Optionally, dry the sodium hydroxide or tris(2-amino-2-hydroxymethyl-propane-1,3-diol) neutralized anionic (meth)acrylic copolymer obtained in step iii. at a temperature ranging from 35 to 75° C. for a time period ranging from 5 to 2880 minutes.

[0116] Spray-dried or dry spray-dried powders of anionic (meth)acrylic copolymers neutralized with sodium hydroxide or tris(2-amino-2-hydroxymethyl-propane-1,3-diol) were further used to prepare coating compositions.

[0117] C3. Preparation of Partially Neutralized Spray-Dried Polymer (Example 7): i. Magnesium oxide, Tween 80 and Poloxamer 188 were added to the required amount of water and homogenized to obtain a homogenized mixture. ii. While stirring, the homogenized mixture from step i. was added to the EUDRAGIT® L 30D-55 dispersion and stirred for an additional 30 minutes to obtain a dispersion. iii. The dispersion obtained in step ii. was passed through an ASTM #60 sieve. iv. The dispersion obtained in step iii. was spray dried to obtain a neutralized anionic (meth)acrylic copolymer using the following parameters: v. The neutralized anionic (meth)acrylic copolymer obtained in step iv. was optionally dried at a temperature ranging from 35 to 75° C. for a time period ranging from 5 to 2880 minutes.

[0118] Spray-dried or dry spray-dried powders of anionic (meth)acrylic copolymers neutralized with magnesium oxide were further used to prepare coating compositions.

[0119] C4. Preparation of Neutralized Spray-Dried Polymer Product for Coating Testing (Example 8) i. Using an overhead stirrer at a speed of 1200 rpm, 300 gm of EUDRAGIT® L100-55 and 1300 gm of water were neutralized with 85.53 gm of 1N ammonia solution to 5% molar (the beaker used to dispense the ammonia solution was also rinsed with 50 g of water and added to the dispersion), stirred for 45 minutes, and then the dispersion was strained through a #60 filter. ii. The dispersion was subjected to spray drying using the following parameters:

[0120] The spray-dried powder of ammonia-neutralized anionic (meth)acrylic copolymer was further used in the preparation of coating compositions.

[0121] C5. Preparation of Neutralized Spray-Dried Polymer Product for Coating Testing (Example 9) i. Using an overhead stirrer at a speed of 1200 rpm, 600 gm of EUDRAGIT® L100 and 1500 gm of water were neutralized with 342.19 gm of 1N ammonia solution to 10% molar (the beaker used to dispense the ammonia solution was also rinsed with 50 g of water and added to the dispersion), stirred for 45 minutes, and then the dispersion was strained through a #60 filter. ii. The dispersion was subjected to spray drying using the following parameters:

[0122] The spray-dried powder of ammonia-neutralized anionic (meth)acrylic copolymer was further used in the preparation of coating compositions.

[0123] C6. Preparation of Neutralized Spray-Dried Polymer Product for Coating Testing (Example 10) i. 350 gm of Aqaot AS-LF and 2400 gm of water were neutralized to 25% molar with 136.55 gm of 1N ammonia solution for 45 minutes using an overhead stirrer at a speed of 1200 rpm, and then the dispersion was filtered through #60. ii. The dispersion was subjected to spray drying using the following parameters:

[0124] A spray-dried powder of ammonia-neutralized Aqaot AS-LF was further used in the preparation of coating compositions. [Table 5]

[0125] D. Coating experiment D1. Preparation of coated pharmaceutical dosage forms Table 5 summarizes the formulations used for the enteric coating of barrier-coated omeprazole pellets and the coating examples using theophylline pellets and diclofenac pellets (Comparative Examples C1-C4, C10-C11, and Examples I1-I7, I13-I16 according to the invention). [Table 6]

[0126] D1.1 Preparation of coating solution for coating barrier coated omeprazole pellets (C1): i. With stirring, EUDRAGIT® L 100-55 was dispersed in water. ii. Sodium laurate and poloxamer 188 were added to the dispersion liquid of step i. while stirring, and stirring was continued at a speed of 1500 to 2000 rpm for 90 minutes to obtain a mixed dispersion liquid. iii. The mixed dispersion obtained in step ii. was passed through an ASTM #60 sieve and used to coat barrier coated omeprazole pellets.

[0127] D1.2 Preparation of coating solution for coating barrier coated omeprazole pellets (C2): i. With stirring, the neutralized spray dried polymer of Example 7 was dispersed in water. ii. The dispersion obtained in step i. was passed through an ASTM #60 sieve and used to coat barrier coated omeprazole pellets.

[0128] D1.3 Preparation of coating dispersions for coating barrier coated omeprazole pellets (C3-C4, and I1-I9): i. Neutralized spray dried polymer, poloxamer 407 and sodium lauryl sulfate were blended to obtain a mixture. ii. The mixture obtained in step i. was dispersed in water while stirring, and stirring was continued at a speed of 1500 rpm to 2000 rpm for 45 minutes to obtain a dispersion liquid. iii. The dispersion obtained in step ii. was passed through an ASTM #60 sieve and used to coat barrier coated omeprazole pellets.

[0129] D1.4 Preparation of coating dispersions for coating barrier coated omeprazole pellets (I13 and C10): i. Neutralized spray dried polymer, poloxamer 407 and sodium lauryl sulfate were blended to obtain a mixture. ii. The mixture obtained in step i was dispersed in water while stirring, and stirring was continued at a speed of 1500 rpm to 2000 rpm for 45 minutes to obtain a dispersion liquid. iii. The dispersion obtained in step ii was passed through an ASTM #60 sieve and used to coat barrier coated omeprazole pellets.

[0130] D1.5 Preparation of coating dispersion for coating diclofenac pellets (I14): i. Neutralized spray dried polymer, Kolliphor 407, talc, triethyl citrate were blended to obtain a mixture. ii. While stirring, the mixture from step i was added to purified water and stirred for 45 minutes at 1600 RPM to form a uniform dispersion. iii. The dispersion obtained in step ii was passed through an ASTM #60 sieve and used to coat diclofenac sodium pellets.

[0131] D1.6 Preparation of coating solutions for pellet coating: I15-I16, C11 i. Neutralized spray dried polymer, Poloxamer 188 / Poloxamer 407, Micronized / PEG 6000 and Sodium Lauryl Sulfate were blended to obtain a mixture. ii. The mixture obtained in step i was dispersed in water while stirring, and stirring was continued at a speed of 1500 rpm for 45 minutes to obtain a dispersion. iii. The dispersion obtained in step ii was passed through an ASTM #60 sieve and used to coat barrier coated omeprazole pellets.

[0132] D2. Barrier Coating Coating of Omeprazole / Diclofenac Pellets: Barrier coated omeprazole pellets were coated with the coating solution / dispersion prepared above using the following parameters: The coated pharmaceutical dosage forms were used to test their stability. [Table 7]

[0133] D3. Stability testing of coated pharmaceutical dosage forms The coated barrier-coated omeprazole pellets were evaluated for stability in 0.1 N HCl and at pH 5.0 over a 2-hour period. The release profile of omeprazole was measured. The results for Comparative Examples C1-C4 and C10-C11 are summarized in Table 7. [Table 8]

[0134] Barrier coated omeprazole pellets that exhibit less than 5.0% release of the core components over 2 hours in 0.1 N HCl and less than 25% release of the core components over 2 hours at pH 5 are considered stable products with protection at pH 5.0. From Table 7, it is clear that Comparative Examples C1-C4, and C10-C11 are not stable at pH 5 for 2 hours.

[0135] The stability of barrier-coated omeprazole pellets coated with compositions according to the present invention was evaluated. The evaluation included the drying effect of different solids accumulation rates in the coating solution. The release profile of omeprazole / theophylline / diclofenac sodium was measured. The results for Examples I1-I9 and I13-I16 are summarized in Table 8. [Table 9]

[0136] From Table 8 it is clear that barrier coated omeprazole pellets coated with the composition according to the present invention are stable not only at gastric pH but also at pHs up to 5.

[0137] A. Effect of Drying Neutralized Spray-Dried Polymer of Example 4 Before Coating on Pellets of Example 1 (I10): The following parameters were used to dry the neutralized spray-dried polymer obtained in Example 4. The average post-drying temperature was 60° C. for 24 hours. The exposure factor based on the above parameters was 1.98.

[0138] The dry powder obtained above was used to coat barrier-coated omeprazole pellets. The formulation for obtaining the dispersion for coating the barrier-coated omeprazole pellets is shown in Table 9, and the process for coating the pellets is shown below. [Table 10]

[0139] A1. Preparation of experimental coating dispersions i. The dry neutralized spray dried polymer of Example 4 and Poloxamer 407 were blended and added to the required amount of water with stirring, and the dispersion was further stirred at high speed for 45 minutes. ii. The dispersion of step i was passed through an ASTM #60 sieve and further used for coating barrier coated omeprazole pellets.

[0140] A2. Barrier Coating Coating of Omeprazole Pellets Barrier coated omeprazole pellets were coated with the above obtained coating dispersion using GPCG 1.1 with the following parameters: [Table 11]

[0141] Without further drying, the coated pellets were evaluated for stability at pH 5. The results are summarized in Table 11. [Table 12]

[0142] From Table 11, it is clear that drying / curing the neutralized spray-dried copolymer was able to provide stability to the barrier-coated omeprazole pellets at pH 5.0 for 2 hours without drying the final dosage form, which not only provides process flexibility but also improves process efficiency.

[0143] Inventive Example 12 (I12) was conducted to demonstrate the effectiveness of the coating composition, even with a different neutralization order, which was used to coat pellets. [Table 13]

[0144] A3. Preparation of Neutralized Spray-Dried Polymer i. 350 g of EUDRAGIT® L30D-55 dispersion was diluted with 300 g of water and then neutralized to 20% molar with 1 N ammonia solution with constant stirring at 1500 rpm for 15 minutes. ii. The neutralized dispersion from step i. was then added to 1650 g of EUDRAGIT® L30D-55 dispersion while stirring at 1500-2000 rpm. iii. The dispersion obtained in step ii. was passed through an ASTM #60 sieve and spray dried using the following parameters to obtain a neutralized copolymer.

[0145] The spray drying parameters used were as follows: [Table 14]

[0146] Coating compositions were prepared and processed similarly to inventive Examples I1-I9 with a solids load of 40%. The resulting compositions were used to coat barrier-coated omeprazole pellets. Coating parameters were similar to I1-I9 in Table 6. The final pellets were evaluated for stability at pH 5. The results are summarized in Table 14. [Table 15]

[0147] From Table 14, it is clear that neutralizing a portion of the anionic (meth)acrylic copolymer and mixing it with the remaining copolymer to obtain the salt form of the anionic (meth)acrylic copolymer does not affect the performance of the coating, and this method is useful for improving process efficiency.

[0148] B. Effect of coating composition without surfactant: B1. Preparation of dispersion Table 15 summarizes the formulation (Comparative Example 117 used for enteric coating of barrier coated omeprazole pellets). [Table 16]

[0149] Preparation of coating solution for pellet coating: I17 i. Neutralized spray dried polymer, Poloxamer 407 was blended to obtain a mixture. ii. The mixture obtained in step i was dispersed in water while stirring, and stirring was continued at a speed of 1500 rpm to 2000 rpm for 45 minutes to obtain a dispersion liquid. iii. The dispersion obtained in step ii was passed through an ASTM #60 sieve and used to coat barrier coated omeprazole pellets.

[0150] B2 Barrier Coating Omeprazole Pellets Coating: Barrier coated omeprazole pellets were coated with the coating solution / dispersion prepared above using the following parameters: The coated pharmaceutical dosage forms were used to test their stability. [Table 17]

[0151] The coated pellets were evaluated for stability at pH 5. The results are summarized in Table 17. [Table 18]

[0152] From Table 17 it is clear that the presence of a surfactant is not essential to the performance of the coating composition at pH 5.

[0153] C. Solubility enhancement of poorly soluble active ingredients: Compositions according to the present invention were tested for solubility enhancement at pH > 5. Table 18 summarizes the formulations used to evaluate solubility enhancement of poorly soluble APIs. [Table 19]

[0154] The above ingredients were weighed, run through ASTM #40, and blended. The blended composition was further processed by a hot melt extrusion (HME) procedure, the parameters of which are shown in Table 16 below. The extrudate was cooled, crushed to form a powder, and run through ASTM #45. [Table 20]

[0155] The solubility enhancement of a poorly soluble API at pH 5.5 was measured according to the dissolution method shown below.

[0156] The solubility parameters are as follows: [Table 21]

[0157] procedure: A sample equivalent to 43 mg was weighed and transferred to a dissolution jar and subjected to the dissolution test according to the parameters described above. After discarding the first 2 mL of filtrate, the sample solution was filtered through a 0.45 μm PVDF syringe filter.

[0158] Samples were analyzed by chromatography according to the USP method for fenofibrate tablets published in USP42-NF37 (official since May 1, 2019).

[0159] The solubility enhancement of the compositions of the present invention was measured and the results are summarized in Table 20. [Table 22]

[0160] It is clear from Table 20 that the poorly soluble active ingredient co-processed with the composition according to the present invention showed nearly 100% enhancement of dissolution at pH 5.5 compared to the comparative fenofibrate APIs, C8 and C9.

Claims

1. i. 25 to 95 wt % of an anionic (meth)acrylic copolymer, based on the total weight of the composition; ii. 5 to 75% by weight of at least one poloxamer, based on the total weight of the anionic (meth)acrylic copolymer in the composition; A powder composition comprising: The anionic (meth)acrylic copolymer is a1. 25 to 95% by weight of at least one C of acrylic acid and / or methacrylic acid based on the total weight of the monomers １ -C ４ alkyl esters, and a2. Polymerized from 5 to 75% by weight of acrylic acid and / or methacrylic acid based on the total weight of the monomers; A powder composition wherein the anionic (meth)acrylic copolymer is reacted with ammonia or an organic base such that 0.1 to 25 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

2. The anionic (meth)acrylic copolymer is a1. 40 to 60% by weight of at least one C of acrylic acid and / or methacrylic acid based on the total weight of the monomers １ -C ４ alkyl esters, and a2. The powder composition of claim 1, polymerized from 60 to 40% by weight of acrylic acid or methacrylic acid based on the total weight of the monomers.

3. The anionic (meth)acrylic copolymer is a1. 40 to 60 wt. % of ethyl acrylate, based on the total weight of the monomers, and a2. The powder composition of claim 2, polymerized from 60 to 40% by weight of methacrylic acid based on the total weight of the monomers.

4. 4. The powder composition of claim 1, wherein the poloxamer is selected from poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, or mixtures thereof.

5. 5. The powder composition of claim 1, wherein the anionic (meth)acrylic copolymer is present in an amount ranging from 55 to 90 wt. %, based on the total weight of the composition.

6. 6. The powder composition of claim 1, wherein the poloxamer is present in an amount ranging from 10 to 25% by weight, based on the total weight of the anionic (meth)acrylic copolymer in the composition.

7. 7. The powder composition of claim 1, wherein the anionic (meth)acrylic copolymer is reacted with ammonia or an organic base such that 2 to 7 mole percent of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

8. An aqueous dispersion comprising the composition of any one of claims 1 to 7.

9. 10. The aqueous dispersion of claim 8, further comprising at least one component selected from a plasticizer, a surfactant, an emulsifier, a pigment, a flow aid, a deflocculating agent, a secondary film former, a detackifying agent, or a mixture thereof.

10. i. Providing an aqueous dispersion according to claim 8 or 9; ii. Coating a pharmaceutical dosage form with the aqueous dispersion of step i to obtain a coated pharmaceutical dosage form; 1. A method for coating an enteric coat onto a pharmaceutical dosage form, comprising:

11. 11. The method of claim 10, further comprising step iii) of drying the coated pharmaceutical dosage form obtained in step ii) to form an enteric coated pharmaceutical dosage form.

12. 12. The method of claim 11, wherein the drying in step iii is carried out at a temperature in the range of 35 to 80°C.

13. 13. The method of any one of claims 10 to 12, wherein the drying in step iii is carried out for a time in the range of from 5 to 2880 minutes.

14. i. providing a Class II or Class IV drug molecule by BCS; ii. Mixing the composition of any one of claims 1 to 7 with the drug molecule of step i to obtain a mixture; iii. Optionally, adding one or more pharmaceutically or nutritionally acceptable excipients to the mixture of step ii; iv. co-processing the mixture obtained in step ii or iii to form a homogeneous mixture; A method for increasing the solubility of a class II or class IV drug molecule by a BCS, comprising:

15. 15. The method of claim 14, further comprising formulating the homogenous mixture obtained in step iv into a pharmaceutically acceptable dosage form.

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