Delayed release compositions resistant to mediate state

Abstract

The present invention relates to a pharmaceutical composition for coating pharmaceutical dosage forms and for BCS IIamp; compositions comprising anionic acrylic polymers with enhanced solubility of class IV actives. The composition comprises: i. 25 to 95 wt%, based on the total weight of the composition, of an anionic (meth) acrylic copolymer; and ii. 5 to 75 wt%, based on the total weight of the anionic (meth) acrylic copolymer in the composition, of at least one poloxamer wherein the anionic (meth) acrylic copolymer has reacted with ammonia or an organic base such that 0.1 to 25 mol% 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 a composition for coating a pharmaceutical dosage form, which comprises an anionic acrylic polymer, and a composition for enhancing the solubility of active pharmaceutical ingredients (APIs) of class II & IV according to the Biopharmaceutical Classification System (BCS). Background Art

[0002] The pH of the normal human stomach can range from about 1 - 3, however, it is usually closer to 2. Pharmaceutical dosage forms usually contain a coating that prevents the release of the drug in the gastric environment. However, the integrity of such a coating can be problematic when food is present in the stomach, since the pH may thereby increase to 4 - 5. After the food has left the stomach, bicarbonate ions are secreted to neutralize and alkalinize the mixture. This results in the coating failure and the inability to provide protection for the dosage form. In addition, it is generally desired that dosage forms containing low solubility (BCS class II and IV) APIs achieve faster dissolution and absorption from the intestinal environment shortly after passing through the gastric pH (i.e., above pH 5).

[0003] Known techniques for solubility enhancement of poorly soluble APIs are hot melt extrusion, spray drying and using pH - dependent polymers. However, processing pH - dependent polymers together with poorly soluble APIs does not significantly enhance solubility, especially it does not provide immediate solubility of the poorly soluble API under pH conditions such as pH 5.5. However, this results in slower dissolution and delayed action of the API from such dosage forms.

[0004] US 6420473 B1 discloses a non - toxic edible enteric film coating for pharmaceutical tablets, which comprises a) an acrylic polymer, wherein the polymer comprises i) 20 to 85% by weight of at least one acrylic alkyl ester or methacrylic alkyl ester structural moiety, and ii) 80 to 15% by weight of at least one vinyl or vinylidene structural moiety having a carboxylic acid group capable of forming a salt. However, this enteric coating cannot provide tolerance up to pH 5.0.

[0005] US10758489 B2 discloses an acidified film coating composition containing a polymer and an acidic component, which is used on an orally ingestible substrate such as a tablet, etc. The acidified coating composition can be applied as an aqueous dispersion to an enteric - coated substrate to improve the anti - disintegration property against an aqueous medium up to pH 5.0. In order to achieve the anti - disintegration property up to pH 5.0, this document discloses a double - coating system for the core substrate. The coating formulation also includes a high percentage of talc, however, this is not desirable because it is believed to be harmful to human health.

[0006] Accordingly, the prior art discloses technical solutions with drawbacks, such as the use of undesirable components such as talc, the need for two layers to achieve anti-disintegrability up to pH 5.0, long processing times, and impaired process efficiency.

[0007] The prior art cannot provide a coating without using talc. In addition, the prior art also cannot provide a single-layer enteric coating that can provide anti-disintegrability for a pharmaceutical dosage form at a pH up to 5.0. In particular, the prior art does not disclose an enteric coating composition in powder form that can be easily dispersed in an aqueous medium and provide a single-layer enteric coating for a pharmaceutical dosage form. Such a composition will not only reduce processing time but also improve process efficiency. Summary of the Invention

[0008] Accordingly, one object of the present invention is to provide a powder composition for enteric coating of a pharmaceutical dosage form that can be used without adding 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 for a pharmaceutical dosage form. A further object of the present invention is to provide a single-layer enteric coating for a pharmaceutical dosage form 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 BCS Class II and IV drugs / APIs (poorly soluble molecules) at pH ≥ 5. Overview of the Invention

[0010] It has been found that a powder composition comprising an anionic (meth)acrylic copolymer in salt form and a poloxamer allows for the provision of a composition for coating a pharmaceutical dosage form. Such a composition can be used without adding talc and / or glidants. The powder composition can also be dispersed in an aqueous medium and used as a single-layer enteric coating for a pharmaceutical dosage form. In addition, it has been found that a single-layer enteric coating having a composition comprising i) an anionic (meth)acrylic copolymer in salt form and ii) a poloxamer provides disintegration stability up to pH 5.0 for a pharmaceutical dosage form. Furthermore, a co-processed composition comprising an anionic (meth)acrylic copolymer in salt form, a poloxamer, and a BCS II or IV API allows for the provision of a significant solubility enhancement at pH ≥ 5.0. Such co-processed mixtures can be easily incorporated into pharmaceutically or nutritionally acceptable dosage forms.

[0011] Accordingly, in a first aspect, the present invention relates to a powder composition comprising:

[0012] i. 25 to 95% by weight of an anionic (meth)acrylic copolymer, based on the total weight of the composition; and

[0013] ii. At least one poloxamer in an amount of 5 to 75% by weight, based on the total weight of the anionic (meth)acrylic copolymer in the composition,

[0014] wherein the anionic (meth)acrylic copolymer is polymerized from the following monomers

[0015] a1. At least one C1-C4-alkyl acrylate and / or C1-C4-alkyl methacrylate in an amount of 25 to 95% by weight, based on the total weight of the monomers, and

[0016] a2. Acrylic acid and / or methacrylic acid in an amount of 5 to 75% by weight, based on the total weight of the monomers, and

[0017] the anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that after the reaction, 0.1 to 25 mol% of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0018] In a second aspect, the invention relates to an aqueous dispersion comprising the composition according to the first aspect.

[0019] In a third aspect, the invention relates to a method of coating a pharmaceutical dosage form with an enteric coating, which comprises the following steps:

[0020] i. Providing the aqueous dispersion according to the second aspect,

[0021] ii. Coating the pharmaceutical dosage form with the aqueous dispersion of step i. to obtain a coated pharmaceutical dosage form, and

[0022] iii. Optionally, curing / drying the coated pharmaceutical dosage form of step ii. to obtain an enteric-coated pharmaceutical dosage form.

[0023] In a fourth aspect, the invention relates to an enteric-coated pharmaceutical dosage form obtained according to the third aspect.

[0024] In a fifth aspect, the invention relates to a method of increasing the solubility of BCS Class II and Class IV APIs; wherein the method comprises the following steps:

[0025] i. Providing a BCS Class II or Class IV API,

[0026] ii. Combining the API of step i. with the composition according to the first aspect to obtain a mixture, and

[0027] iii. Co-processing the mixture obtained in step ii. to form a homogeneous mixture. DETAILED DESCRIPTION OF THE INVENTION

[0029] Within the meaning of the present invention, the terms "solidification" and "drying" are used interchangeably. The terms "solidification" and "drying" are defined as treating the pharmaceutical dosage form obtained after spray drying and coated with the anionic (meth)acrylic copolymer in the form of the composition or salt at the required temperature for the required time.

[0030] The "stability" of the formulations within the scope of the present invention can be determined by estimating the release and / or degradation of the drug at a specific pH over a defined period of time.

[0031] The present invention relates to a powder composition comprising:

[0032] i. 25 to 95% by weight, based on the total weight of the composition, of an anionic (meth)acrylic copolymer; and

[0033] ii. 5 to 75% by weight, based on the total weight of the anionic (meth)acrylic copolymer in the composition, of at least one poloxamer,

[0034] wherein the anionic (meth)acrylic copolymer is polymerized from the following monomers

[0035] a1. 25 to 95% by weight, based on the total weight of the monomers, of at least one C1-C4-alkyl acrylate and / or C1-C4-alkyl methacrylate, and

[0036] a2. 5 to 75% by weight, based on the total weight of the monomers, of acrylic acid and / or methacrylic acid, and

[0037] wherein the anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that 0.1 to 25 mol% of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0038] 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.

[0039] An advantage of the above composition is that it can be easily dispersed in water and coated on the pharmaceutical dosage form. The pharmaceutical dosage form coated with the above composition provides not only stability in the gastric environment but also stability at a pH up to 5.0. A further advantage of the composition is that a single coating layer is sufficient to provide stability at a pH up to 5.0. It has been found that the use of ammonia or an organic base is superior to inorganic bases such as NaOH, KOH, Na2CO3, etc. for reacting 0.1 to 25 mol% of the anionic groups of the anionic (meth)acrylic copolymer into salt form, since the product obtained by using ammonia or an organic base provides stability in the gastric environment.

[0040] In one embodiment, an anionic (meth)acrylic copolymer has been reacted with ammonia such that 2.0 to 7.0 mol% of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form. It is particularly advantageous to use ammonia to react with the anionic (meth)acrylic copolymer because it provides improved stability at pH values up to 5.0 compared to organic bases.

[0041] The amount of ammonia or organic base required to neutralize 0.25 to 25 mol% 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 that has reacted with the anionic (meth)acrylic copolymer can be determined using different methods. One such method is to measure the acid value of the anionic acrylic polymer before and after reaction with ammonia or organic base. The acid value of a compound / polymer can be determined according to the 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:

[0042]

[0043] AV = acid value

[0044] N = required neutralization mol%

[0045] MW1 = molecular weight of KOH

[0046] MW2 = molecular weight of the neutralizing agent

[0047] Q = amount of polymer dispersion

[0048] Anionic (meth)acrylic copolymer

[0049] The composition comprises from 25 to 95% by weight, based on the total weight of the composition, of an anionic (meth)acrylic copolymer. In one embodiment, the composition comprises from 55 to 90% by weight, based on the total weight of the composition, of an anionic (meth)acrylic copolymer. The anionic (meth)acrylic copolymer is obtained by polymerizing from 25 to 95% by weight, based on the total weight of the monomers, of at least one C1-C4-alkyl ester of acrylic acid and / or of methacrylic acid and from 5 to 75% by weight, based on the total weight of the monomers, of acrylic acid and / or methacrylic acid. In another embodiment, the anionic (meth)acrylic copolymer is obtained by polymerizing from 40 to 60% by weight, based on the total weight of the monomers, of at least one C1-C4-alkyl ester of acrylic acid and / or of methacrylic acid and from 60 to 40% by weight, based on the total weight of the monomers, of acrylic acid or methacrylic acid. In yet another embodiment, the anionic (meth)acrylic copolymer is obtained by polymerizing from 40 to 60% by weight, based on the total weight of the monomers, of ethyl acrylate and from 60 to 40% by weight, based on the total weight of the monomers, of methacrylic acid.

[0050] In another embodiment, the C1-C4-alkyl ester of acrylic acid and / or the C1-C4-alkyl ester of 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 C1-C4-alkyl ester of methacrylic acid is selected from methyl acrylate, ethyl acrylate, methyl methacrylate or a mixture of two or more thereof.

[0051] In another embodiment, the anionic (meth)acrylic copolymer has from 40 to 60% by weight, based on the total weight of the monomers, of methacrylic acid.

[0052] Suitable anionic (meth)acrylic copolymers are available under the trade names L30-D55, L 100-55, L 100, S100 and FS30D.

[0053] L 30-D55 and L 100-55 are well-known commercially available (meth)acrylate copolymer products for pharmaceutical applications. L 30-D55 is available as a 30% aqueous dispersion, L 100-55 is sold in powder form. L 30-D55 and L 100-55 contains 46 to 50.6% by weight of methacrylic acid and 49.4 to 54% by weight of ethyl acrylate, each based on the total weight of the monomers.

[0054] L 100 is a well-known commercially available (meth)acrylate copolymer obtained by polymerizing approximately 50% by weight of methyl methacrylate and approximately 50% by weight of methacrylic acid.

[0055] S100 is a well-known commercially available (meth)acrylate copolymer obtained by polymerizing approximately 70% by weight of methyl methacrylate and approximately 30% by weight of methacrylic acid.

[0056] FS30D is a well-known commercially available (meth)acrylate copolymer obtained by polymerizing approximately 10% by weight of methacrylic acid, approximately 65% by weight of methyl acrylate, and approximately 25% by weight of methyl methacrylate.

[0057] Poloxamer

[0058] The term "poloxamer" refers to a non-toxic non-ionic triblock copolymer consisting of a central hydrophobic polypropylene oxide (poly(propylene oxide)) chain flanked by two hydrophilic polyethylene oxide (poly(ethylene oxide)) chains. Poloxamers are represented by the following general chemical formula:

[0059] HO(C2H4O) a’ -[C3H6O] b -(C2H4O) a H

[0060] where a and a' can be the same or different and are each integers such that the hydrophilic portion represented by (C2H4O) (i.e., the polyethylene oxide portion of the copolymer) constitutes approximately 60% to 90% by weight of the copolymer, and b is an integer such that the hydrophobic portion represented by (C3H6O) (i.e., the polypropylene oxide portion of the copolymer) constitutes approximately 10% to 40% by weight of the copolymer. In another preferred embodiment, "a" and "a'" are independently integers in the range of 64 to 141; and "b" is an integer in the range of 27 to 56. Poloxamers include poloxamer 188 (e.g., sold under the trademarks F-68, Flocor TM , Poloxamers 188, 237, 338, and 407 (those for sale). The nomenclature of polyoxyethylene / polyoxypropylene copolymers refers to their monomeric 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 percentage of the hydrophilic polyoxyethylene content. For example, Poloxamer 188 describes a polymer containing a polyoxypropylene hydrophobic moiety of approximately 1,800 Da and having a hydrophilic polyoxyethylene content of approximately 80% of the total molecular weight. Poloxamers are synthesized in two steps, first constructing the polyoxypropylene core and then adding polyoxyethylene to the capped ends of the polyoxypropylene core. Due to the variation in polymerization rates during the two steps, Poloxamers can contain heterogeneous polymer species of different molecular weights. The distribution of the polymer species can be characterized using standard techniques, including but not limited to gel permeation chromatography (GPC).

[0061] In another embodiment of the present invention, the Poloxamer is selected from Poloxamer 188, Poloxamer 237, Poloxamer 338, Poloxamer 407, or a mixture thereof, preferably Poloxamer 237 and Poloxamer 407.

[0062] The amount of Poloxamer in the composition is based on the weight of the dry anionic (meth)acrylic acid copolymer in the composition.

[0063] Redispersible powder of anionic (meth)acrylic acid copolymer in salt form

[0064] The anionic (meth)acrylic acid copolymer in salt form obtained after reaction with ammonia or an organic base is in powder form after removal of the solvent. This powder can be redispersed in water to obtain a dispersion of the anionic (meth)acrylic acid copolymer in salt form.

[0065] The method for preparing an anionic (meth)acrylic acid copolymer in salt form comprises the following steps:

[0066] i. Adding ammonia or an organic base to an aqueous dispersion / suspension of the anionic (meth)acrylic acid copolymer and reacting it to obtain the anionic (meth)acrylic acid copolymer in salt form, and

[0067] ii. Removing water from step i. to obtain the solid anionic (meth)acrylic acid copolymer in salt form.

[0068] The method may further comprise the step of:

[0069] iii. Drying the solid anionic (meth)acrylic acid copolymer in salt form obtained in step ii.

[0070] In this method, only a part of the anionic (meth)acrylic acid copolymer can be converted into its salt form. The anionic (meth)acrylic acid copolymer in the salt form thus obtained can be further mixed with the remaining anionic (meth)acrylic acid copolymer. It is further advantageous to use ammonia or an organic base to neutralize the methacrylic acid copolymer in two or more steps, wherein in the first step, the methacrylic acid groups in a partial amount of the methacrylic acid copolymer are neutralized with the total amount of the base. Then, the remaining amount of the methacrylic acid copolymer is mixed with the above-mentioned dispersion so that the overall neutralization level of the methacrylic acid groups in the methacrylic acid copolymer reaches a range of 0.1 to 25 mol%, preferably the overall neutralization level of the methacrylic acid groups in the methacrylic acid copolymer reaches a range of 2 to 7 mol%.

[0071] Methods such as evaporation, spray drying or freeze drying can be used to remove the water from step ii. The preferred methods for removing water are spray drying or freeze drying. The product obtained after removing water is in the form of a powder and contains a certain amount of moisture. Therefore, the product obtained after removing water is optionally dried. The drying in step iii. is carried out at a temperature in the range of 35 to 75 °C for a time of 5 to 2880 minutes.

[0072] The advantage of drying the anionic (meth)acrylic acid copolymer in the salt form at this stage is that the drying time of the final pharmaceutical dosage form coated with the formulation according to the invention can be significantly reduced. This improves the efficiency of the method. The drying of the anionic (meth)acrylic acid copolymer in the salt form can be based on an exposure factor in the range of 1.4 to 5, wherein the exposure factor is determined according to the following formula:

[0073] E = Log[(C - 40) x log(m x 30)]

[0074] where "C" is the solid anionic (meth)acrylic acid copolymer obtained in step ii. exposed for "m" minutes at this temperature in °C. The optimal range of the exposure factor is 1.5 to 2.1.

[0075] The aqueous dispersion of the composition

[0076] A further embodiment of the invention relates to an aqueous dispersion comprising:

[0077] i. 25 to 95% by weight of an anionic (meth)acrylic acid copolymer based on the total weight of the composition; and

[0078] ii. 5 to 75% by weight of at least one poloxamer based on the total weight of the anionic (meth)acrylic acid copolymer in the composition,

[0079] wherein the anionic (meth)acrylic copolymer is obtained by polymerizing the following monomers

[0080] a1. 25 to 95% by weight, based on the total weight of the monomers, of at least one C1-C4-alkyl ester of acrylic acid and / or C1-C4-alkyl ester of methacrylic acid, and

[0081] a2. 5 to 75% by weight, based on the total weight of the monomers, of acrylic acid and / or methacrylic acid, and

[0082] wherein the anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that 0.1 to 25 mol% of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0083] The aqueous dispersion may further comprise at least one component selected from plasticizers, surfactants, emulsifiers, pigments, flow aids, anti-caking / anti-sticking agents, auxiliary film formers or mixtures thereof. The advantage of such an aqueous dispersion is that a pharmaceutical dosage form can be easily coated to form an enteric coating.

[0084] The plasticizer is selected from trialkyl citrates, triacetin, triethyl acetylcitrate, dibutyl sebacate, diethyl phthalate, polyethylene glycols having a molecular weight in the range of 200 to 8000, glycerol, castor oil, copolymers of propylene oxide and ethylene oxide or mixtures thereof. Based on the total weight of the components of the coating composition in dry form, the plasticizer constitutes from 0% to about 50% by weight. In another embodiment, based on the total weight of the components of the coating composition in dry form, the plasticizer constitutes from 2% to about 20% by weight.

[0085] The surfactant is selected from sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, polysorbate 80, Tween 80 or mixtures thereof. Preferably, based on the total weight of the components of the coating composition in dry form, the aqueous dispersion comprises at least one surfactant in the range of 0.1% to about 15% by weight.

[0086] The emulsifier is selected from the class of alkoxylates, polyglycerols, polysorbates, betaines, glycolipids or mixtures thereof.

[0087] The pigment is 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 can be used together to produce different shades of color.

[0088] The glidant is selected from silica, such as fumed silica. The glidant imparts fluidity to the powdery composition during dry mixing and subsequent transfer from the blender to the storage container.

[0089] The anti-sticking agent / anti-caking agent is selected from talc, carnauba wax, hydrogenated castor oil, magnesium stearate or calcium stearate, ground silica, kaolin, or a nonionic emulsifier with an HLB value between 2 and 8, sodium stearoyl fumarate, or a mixture thereof.

[0090] The auxiliary film-forming agent is selected from xanthan gum, sodium alginate, propylene glycol alginate, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (CMC sodium), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose acetyl succinate (HPMCA), hydroxypropyl methylcellulose phthalate (HPMCP), starch derivatives, natural polysaccharides and their derivatives, methacrylates such as L 100, S100, FS 30D, konjac flour, carrageenan, or a mixture thereof.

[0091] The advantage of the powder composition according to the present invention is that the composition can be easily dispersed to obtain an aqueous dispersion, which can be used as such for coating pharmaceutical dosage forms. An aqueous dispersion containing the composition according to the present invention is prepared by a method comprising at least the following steps:

[0092] i. Providing the powder composition according to the present invention,

[0093] ii. Optionally adding at least one component selected from plasticizers, surfactants, emulsifiers, pigments, glidants, anti-caking agents, auxiliary film-forming agents, anti-sticking agents, or a mixture thereof / mixing with the powder composition in step i. to obtain a mixture,

[0094] iii. Blending the composition in step i. or the mixture obtained in step ii. with stirring and adding it to water to obtain an aqueous dispersion.

[0095] Enteric-coated pharmaceutical dosage form

[0096] The enteric-coated pharmaceutical dosage form according to the present invention can be (coated) tablets, minitablets, pellets, granules, hard capsules, soft capsules filled with pellets or powders or granules, or capsules filled with oil, coated pellets, powders, or granules.

[0097] An aqueous dispersion containing the composition according to the present invention is suitable for coating pharmaceutical dosage forms.

[0098] Coating a pharmaceutical dosage form with an aqueous dispersion, which comprises the following steps:

[0099] i. Providing an aqueous dispersion as described above comprising the composition according to the invention,

[0100] ii. Coating the pharmaceutical dosage form with the aqueous dispersion of step i. to obtain a coated pharmaceutical dosage form.

[0101] The method may further comprise step iii. of drying the coated pharmaceutical dosage form of step ii. to obtain an enteric-coated pharmaceutical dosage form. The advantage of this additional drying step is the improved stability of the coated pharmaceutical dosage form at pH 5.

[0102] The drying in step iii. is carried out at a temperature in the range of 35 to 80 °C, preferably at 40 °C to 65 °C for a time of 5 minutes to 2880 minutes.

[0103] 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:

[0104] E = Log[(C - 40) x log(m x 30)]

[0105] where "C" is the temperature in °C at which the coated pharmaceutical dosage form of step ii. is exposed for a time of "m" minutes.

[0106] In another embodiment, the pharmaceutical dosage form comprises at least one pharmaceutically active ingredient selected from antimicrobial agents, hormones, enzymes, enzyme inhibitors, receptor agonists & antagonists, oral vaccines, proteins, peptides, and combinations thereof, or combinations of two or more of them.

[0107] Examples of pharmaceutically active ingredients may be selected from dexlansoprazole, lansoprazole, omeprazole, diclofenac, minoprazole, pantoprazole, rabeprazole, erythromycin, ampicillin, doxycycline, fluoxetine, ketoprofen, hydromorphone hydrochloride, tramadol, hydromorphone hydrochloride, sulfasalazine, mesalazine, didanosine, mycophenolate mofetil, heparin, human interleukin-10, human growth hormone, IgG antibodies, including their salts, derivatives, polymorphs, isomorphs or any kind of mixtures or combinations thereof. In the context of the present invention, the term "coated tablet" is understood to include tablets containing pellets or compressed tablets. Such tablets may have a size of approximately 5 to 25 mm. Generally, a defined number of small pellets containing the active ingredient are compressed together with a binder excipient therein to obtain a tablet form. After oral ingestion and contact with body fluids, the tablet form is disrupted and the pellets are released. Compressed tablets combine the advantages of a single-dose form for ingestion with the advantages of multiple forms, such as dose accuracy.

[0108] In the context of the present invention, the term "mini-tablet" is intended to be understood as referring to a tablet that is smaller than a conventional tablet and may have dimensions of approximately 1 to 5 mm. Similar to pellets, mini-tablets are a single dosage form for multi-dose use. Compared to pellets that may have the same dimensions, mini-tablets generally have the advantage of a more regular surface, which can be coated more precisely and uniformly. Mini-tablets can be provided encapsulated in a capsule such as a gelatin capsule. Such a capsule breaks down after oral ingestion and upon contact with gastric or intestinal fluids, and releases the mini-tablet. Another application of mini-tablets is the individual fine-tuning of the dose of the active ingredient. In this case, the patient can directly ingest a defined number of mini-tablets, which is matched to the severity of the disease to be cured and also to their individual body weight. Mini-tablets are different from the compressed tablets containing pellets as described above.

[0109] In the context of the present invention, the term "pellet" or "granule" is used to denote the core for coating, or the core in a compressed tablet, or the core filled into a capsule after coating. Such pellets or granules may have dimensions (average diameter) in the range of 50 to 1000 microns, and such pellets or granules can be produced using processes such as high-shear and low-shear granulation, extrusion and spheronization, prilling, active layering, compaction, agglomeration, and fluidized bed processes.

[0110] In the context of the present invention, the term "coated pellet" is used to denote a pellet to be filled in a capsule, such as a gelatin or HPMC capsule. Capsules containing pellets can also be coated with the coating composition according to the present invention.

[0111] Compositions and methods for enhancing the solubility of BCS Class II and IV drug molecules (poorly soluble APIs):

[0112] The present invention also relates to a composition for enhancing the solubility of Class II and IV APIs according to the biopharmaceutics classification system. In particular, the solubility of the drug at pH ≥ 5 is increased. This results in improved absorption and bioavailability of the poorly soluble drug molecule. The composition comprises:

[0113] i. at least one drug molecule of Class II or IV according to the BCS; and

[0114] ii. a composition according to the first aspect as defined above.

[0115] The above composition may further comprise one or more pharmaceutically or nutritionally acceptable excipients.

[0116] The term "solubility" generally refers to a quantitative term related to the property of a solid, liquid or gas chemical substance, called a "solute", to dissolve in a solid, liquid or gaseous "solvent". Solubility is expressed as a "solubility level", which represents the amount of the substance that dissolves in a given amount of solvent. Generally, a substance is said to be slightly soluble / poorly soluble if less than 0.1 g dissolves in 100 ml of solvent. Solubility can be measured experimentally. A related term used is "dissolution rate", which represents the solubility measured relative to the time period over which the substance dissolves in a given amount of solvent at a specific pH and temperature.

[0117] The API of the composition according to the present invention is selected from aceclofenac, acimenide, atorvastatin calcium, azithromycin, bicalutamide, budesonide, bicalutamide, cefuroxime, carbamazepine, cinnarizine, chlorzoxanozone, clonazepam, clopidogrel, clonzapine, daclatasvir, danazol, darunavir, dexlansoprazole, dextromethorphan hydrobromide, diacerien, diclofenac sodium, diazepam, dolutegravir sodium, efavirenz, enzalutamide, eplerenone, etoricoxib, ezetimibe, felodipine, fenofibrate, flubendazole, gefitinib, abdine, griseofulvin, glibenclamide, ibrutinib, ibuprofen, indinavir sulfate, itraconazole, ketoprofen, ketoconazole, indomethacin, ivermectin, lopanoic acid, lanroprazole, mebendazole, montelukast sodium, naproxen, nicardipine, nifedipine, nitrofurantoin, obeticholic acid, olanzapine, omeprazole, oxcarbazepine, oxfendazole, ozanimod, palbociclib isethionate, paliperidone palmitate, pemitinib, phenytoin sodium, posaconazole, pralatinib, racecadotril, rifampicin, risperidone, rosuvastatin, sertraline, sildenafil, spironolactone, sulfamethoxazole sulfamethaxazole, tamoxifen citrate, telmisartan, terbinafine hydrochloride, trimethoprim, testosterone undecanoate, valsartan, venetoclax, vericipam, abiraterone acetate, acetazolamide, albendazole, aprepitant, avacopan, afatinib, bifonazole, ciprofloxacin, digoxin, docetaxel, erythromycin succinate, haloperidol, hydrochlorothiazide, mesalazine, paclitaxel, pernamod, relugolix, ritonavir, saquinavir, sulfasalazine, tivozanib, verapamil hydrochloride or a mixture thereof.

[0118] In another embodiment, the present invention relates to a method for increasing the solubility of a poorly soluble molecule according to the BCS at pH ≥ 5, comprising the following steps:

[0119] i. providing a class II or IV drug molecule according to the BCS;

[0120] ii. Add the composition according to the first aspect and as defined above to obtain a mixture; and

[0121] iii. Co-process the mixture obtained in step ii. to form a homogeneous mixture.

[0122] The method may further comprise the step of adding one or more pharmaceutically or nutritionally acceptable excipients before the co-processing step iii.

[0123] According to the present invention, different "co-processing" techniques can be used. The co-processing techniques are selected from co-extrusion, co-crystallization, co-solvency, nanotechnology, kneading, co-precipitation, complexation, freeze-drying, microwave radiation, microemulsion, self-emulsifying drug delivery, solid solution, solid dispersion, fusion, dry or wet granulation, solvent evaporation, agglomeration, melt solvent method, spray drying, hot melt extrusion, melt granulation, spray congealing, co-grinding, co-screening, dropping method, blending, supercritical fluid process, liquisolid technology, soluFlo technology, technology, technology or compaction.

[0124] The preferred method of co-processing is co-extrusion.

[0125] Item:

[0126] 1. A powder composition comprising:

[0127] i. 25 to 95% by weight of an anionic (meth)acrylic acid copolymer based on the total weight of the composition; and

[0128] ii. 5 to 75% by weight of at least one poloxamer based on the total weight of the anionic (meth)acrylic acid copolymer in the composition,

[0129] wherein the anionic (meth)acrylic acid copolymer is obtained by polymerizing the following monomers

[0130] a1. 25 to 95% by weight of at least one C1-C4-alkyl ester of acrylic acid and / or C1-C4-alkyl ester of methacrylic acid based on the total weight of the monomers, and

[0131] a2. 5 to 75% by weight of acrylic acid and / or methacrylic acid based on the total weight of the monomers, and

[0132] wherein the anionic (meth)acrylic acid copolymer has been reacted with ammonia or an organic base such that 0.1 to 25 mol% of the anionic groups of the anionic (meth)acrylic acid copolymer are present in salt form.

[0133] 2. The powder composition according to item 1, wherein the anionic (meth)acrylic copolymer is obtained by polymerizing the following monomers

[0134] a1. At least one C1-C4-alkyl ester of acrylic acid and / or C1-C4-alkyl ester of methacrylic acid, 40 to 60% by weight based on the total weight of the monomers, and

[0135] a2. Acrylic acid or methacrylic acid, 60 to 40% by weight based on the total weight of the monomers.

[0136] 3. The powder composition according to item 1, wherein the anionic (meth)acrylic copolymer is obtained by polymerizing the following monomers

[0137] a1. Ethyl acrylate, 25 to 95% by weight based on the total weight of the monomers, and

[0138] a2. Methacrylic acid, 5 to 75% by weight based on the total weight of the monomers.

[0139] 4. The powder composition according to any one of items 1 to 3, wherein the anionic (meth)acrylic copolymer is obtained by polymerizing the following monomers

[0140] a1. Ethyl acrylate, 40 to 60% by weight based on the total weight of the monomers, and

[0141] a2. Methacrylic acid, 60 to 40% by weight based on the total weight of the monomers.

[0142] 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 a mixture thereof.

[0143] 6. The powder composition according to any one of items 1 to 5, wherein the anionic (meth)acrylic copolymer is present in an amount of 55 to 90% by weight based on the total weight of the composition.

[0144] 7. The powder composition according to any one of items 1 to 6, wherein the poloxamer is present in an amount of 10 to 25% by weight based on the total weight of the anionic (meth)acrylic copolymer in the composition.

[0145] 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 mol% of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

[0146] 9. An aqueous dispersion comprising the composition according to any one of items 1 to 8.

[0147] 10. The aqueous dispersion according to item 9, which further comprises at least one component selected from plasticizers, surfactants, emulsifiers, pigments, glidants, anti-agglomerants, auxiliary film-forming agents, anti-sticking agents, or mixtures thereof.

[0148] 11. A method for preparing an aqueous dispersion according to any one of items 9 to 10, which comprises at least the following steps:

[0149] i. Providing a powder composition according to any one of items 1 to 8,

[0150] ii. Optionally adding at least one component according to item 10 to the powder composition of step i. to obtain a mixture,

[0151] iii. Blending the composition of step i. or the mixture obtained in step ii. with stirring and adding it to water to obtain an aqueous dispersion.

[0152] 12. A method for coating an enteric coating on a pharmaceutical dosage form, which comprises at least the following steps:

[0153] i. Providing an aqueous dispersion according to any one of items 9 to 10,

[0154] ii. Coating the pharmaceutical dosage form with the aqueous dispersion of step i. to obtain a coated pharmaceutical dosage form, and

[0155] iii. Optionally, drying the coated pharmaceutical dosage form of step ii. to obtain an enteric-coated pharmaceutical dosage form.

[0156] 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.

[0157] 14. The method according to any one of items 12 to 13, wherein the drying in step iii. is carried out for a time of 5 to 2880 minutes.

[0158] 15. The method according to any one of items 12 to 14, wherein the drying in step iii. is based on an exposure factor in the range of 1.4 to 5.0, wherein the exposure factor is determined according to the following formula:

[0159] E = Log[(C - 40) x log(m x 30)]

[0160] wherein "C" is the exposure time of the solid anionic (meth)acrylic copolymer at the temperature in °C for "m" minutes.

[0161] 16. An enteric-coated pharmaceutical dosage form, which is obtained according to any one of items 12 to 14.

[0162] 17. A method for preparing an anionic (meth)acrylic copolymer in the form of a salt, which comprises the following steps:

[0163] i. adding ammonia or an organic base to an aqueous dispersion / suspension of an anionic (meth)acrylic copolymer and reacting it to obtain an anionic (meth)acrylic copolymer in the form of a salt, and

[0164] ii. removing water from step i. to obtain a solid anionic (meth)acrylic copolymer in the form of a salt.

[0165] 18. The method according to item 17, wherein in step i., a part of the anionic (meth)acrylic copolymer is converted into its salt form and further mixed with the remaining anionic (meth)acrylic copolymer in one or more steps.

[0166] 19. The method according to items 17 to 18, which further comprises:

[0167] iii. drying the solid anionic (meth)acrylic copolymer in the form of a salt.

[0168] 20. The method according to item 19, wherein the drying in step iii. is carried out at a temperature in the range of 35 to 75 °C for a time of 5 to 2880 minutes.

[0169] 21. The method according to any one of items 19 to 20, wherein the drying in step iii. is based on an exposure factor in the range of 1.4 to 5, wherein the exposure factor is determined according to the following formula:

[0170] E = Log[(C - 40) x log(m x 30)]

[0171] wherein "C" is the solid anionic (meth)acrylic copolymer in the form of a salt exposed for a time of "m" minutes at the temperature in °C.

[0172] 22. The method according to item 21, wherein the solid anionic (meth)acrylic copolymer in the form of a salt is cured / dried based on an exposure factor in the range of 1.4 to 2.1.

[0173] 23. A composition, which comprises:

[0174] i. a drug molecule of class II or class IV according to BCS; and

[0175] ii. a composition according to any one of items 1 to 8,

[0176] iii. optionally, adding one or more pharmaceutically or nutritionally acceptable excipients.

[0177] 24. A method for increasing the solubility of a sparingly soluble drug molecule at pH 5.5, comprising the following steps:

[0178] i. Providing a drug molecule according to Class II or Class IV of the BCS;

[0179] ii. Adding a composition according to any one of items 1 to 8 to obtain a mixture;

[0180] iii. Optionally adding one or more pharmaceutically or nutritionally acceptable excipients to the mixture of step ii.,

[0181] iv. Co-processing the mixture obtained in step ii. or step iii. to obtain a homogeneous mixture.

[0182] 25. The method according to item 24, wherein the co-processing is co-extrusion.

[0183] 26. The method according to any one of items 24 to 25, further comprising the step of formulating the homogeneous mixture obtained in step iv. into a pharmaceutically acceptable dosage form. Detailed Description

[0184] Examples

[0185] A. Materials

[0186] L 30D-55 is an aqueous dispersion containing 30 wt% of L 100-55.

[0187]

[0188] Diclofenac sodium was obtained from Aarti Drugs Limited, India.

[0189] Omeprazole magnesium pellets were obtained from Lee Pharma, India.

[0190] Magnesium oxide was obtained from Merck.

[0191] Tween 80 was obtained from Loba Chemie.

[0192] Sodium lauryl sulfate was obtained from Indo Overseas.

[0193] Sodium laurate was obtained from TCI.

[0194] Hydroxypropyl methylcellulose 3 cps was obtained from JRS Pharma.

[0195] Talc was obtained from Neelkanth Finechem LLP.

[0196] Microcrystalline cellulose 101 was obtained from JRS Pharma.

[0197] Croscarmellose sodium was obtained from FMC.

[0198] Poloxamer P 188 and Poloxamer P 407 are commercially available from BASF SE and Sigma Aldrich under the trade names P 188 and P407.

[0199] The equipment used for spray drying was a single-nozzle type laboratory-scale spray dryer supplied by Büchi.

[0200] The post-drying equipment was GPCG 1.1 (Glatt-Powder-Coater-Granulator).

[0201] B. Preparation of core pellets:

[0202] Omeprazole magnesium pellets, diclofenac sodium pellets, and theophylline pellets were used as drug dosage forms. The formulations used for preparing the core pellets are summarized in Table 1.

[0203] Table 1: Formulations

[0204]

[0205] * Theoretical analysis in the final formulation

[0206] B1. Method for preparing barrier-coated omeprazole magnesium pellets - Example 1

[0207] i. Hydroxypropyl methylcellulose 3 cps was added to the required amount of water under constant stirring to obtain a clear solution.

[0208] ii. Talc was added to the solution from step i. under constant stirring to obtain a homogeneous dispersion.

[0209] iii. The homogeneous dispersion from step ii. was passed through an ASTM #60 sieve.

[0210] The homogeneous dispersion obtained in step iii. was used for coating the omeprazole pellets in the GPCG 1.1 (Glatt-Powder-Coater-Granulator) to obtain barrier-coated omeprazole pellets.

[0211] Table 2: Coating parameters for Example 1

[0212] Equipment GPCG 1.1 Core weight (g) 1100 Nozzle (mm) 0.8 Product temperature (°C) 34-39 Spray rate (g / min) 3-6 Atomization (bar) 1.1 Solids build up (%) 15

[0213] B2. Method for preparing diclofenac sodium pellets - Example 2

[0214] i. All components are sieved through an ASTM #40 sieve and granulated with water in a planetary mixer.

[0215] ii. The granulated blend from step i. is extruded using a domed extruder with a 1 mm sieve size to obtain an extrudate.

[0216] iii. The extrudate from step ii. is rounded at 1700 rpm for 2 minutes to form pellets.

[0217] iv. The pellets formed in step iii. are dried in a fluidized bed dryer at 60 °C for 30 minutes to obtain dried pellets.

[0218] v. The dried pellets obtained in step iv. are sieved, and the fraction obtained from an ASTM #18 / 25 sieve is used for the coating test.

[0219] C. Preparation of partially neutralized anionic (meth)acrylic acid copolymers

[0220] Table 3 provides the formulations (Examples 4 - 10) for the preparation of partially neutralized anionic (meth)acrylic acid copolymers.

[0221] Table 3:

[0222]

[0223] * 30% solids dispersion

[0224] q.s. sufficient quantity

[0225] C1. Preparation of partially neutralized spray - dried polymer (Example 4):

[0226] i. 1N ammonia solution is added with stirring to the L 30D - 55 dispersion and stirred for an additional 30 minutes.

[0227] ii. The dispersion from step i. is passed through an ASTM #60 sieve.

[0228] iii. The dispersion obtained in step ii. is spray - dried to obtain an ammonia - neutralized anionic (meth)acrylic acid copolymer.

[0229] iv. The ammonia - neutralized anionic (meth)acrylic acid copolymer obtained in step iii. is optionally dried at a temperature in the range of 35 to 75 °C for a time of 5 to 2880 minutes.

[0230] The spray - dried powder of the ammonia - neutralized anionic (meth)acrylic acid copolymer, or the dried spray - dried powder, is further used for the preparation of the coating composition.

[0231] Preparation of partially neutralized spray-dried polymers (Examples 5-6):

[0232] i. A 10% solution of sodium hydroxide / tris(2-amino-2-hydroxymethyl-propane-1,3-diol) was added to the L 30D-55 dispersion with stirring and stirred for an additional 30 minutes to obtain a dispersion.

[0233] ii. The dispersion obtained in step i. was passed through an ASTM #60 sieve.

[0234] iii. The dispersion obtained in step ii. was spray-dried to obtain an anionically (meth)acrylic copolymer neutralized with sodium hydroxide or tris(2-amino-2-hydroxymethyl-propane-1,3-diol).

[0235] iv. The anionically (meth)acrylic copolymer neutralized with sodium hydroxide or tris(2-amino-2-hydroxymethyl-propane-1,3-diol) obtained in step iii. was optionally dried at a temperature in the range of 35 to 75 °C for a time of 5 to 2880 minutes.

[0236] The spray-dried powder of the anionically (meth)acrylic copolymer neutralized with sodium hydroxide or tris(2-amino-2-hydroxymethyl-propane-1,3-diol), or the dried spray-dried powder was further used to prepare a coating composition.

[0237] Preparation of partially neutralized spray-dried polymers (Example 7):

[0238] i. Magnesium oxide, Tween 80 and poloxamer 188 were added to the required amount of water and homogenized to obtain a homogenized mixture.

[0239] ii. The homogenized mixture obtained in step i. was added to the L30D-55 dispersion with stirring and stirred for an additional 30 minutes to obtain a dispersion.

[0240] iii. The dispersion obtained in step ii. was passed through an ASTM #60 sieve.

[0241] iv. The dispersion obtained in step iii. was spray-dried using the following parameters to obtain a neutralized anionically (meth)acrylic copolymer.

[0242] v. The neutralized anionically (meth)acrylic copolymer obtained in step iv. was optionally dried at a temperature in the range of 35 to 75 °C for a time of 5 to 2880 minutes.

[0243] Spray-dried powder of an anion (meth)acrylic copolymer neutralized with magnesium oxide, or the dried spray-dried powder is further used to prepare a coating composition.

[0244] C4. Preparation of neutralized spray-dried polymer batches for coating tests (Example 8)

[0245] i. 300 g L100-55 and 1300 g of water were neutralized to 5 mol% with 85.53 g of 1N ammonia solution using a overhead stirrer at 1200 rpm (the beaker used to dispense the ammonia solution was also rinsed with 50 g of water and added to the dispersion) and stirred for 45 minutes, then the dispersion was filtered through #60.

[0246] ii. The dispersion was spray-dried using the following parameters.

[0247] The spray-dried powder of the ammonia-neutralized anion (meth)acrylic copolymer is further used to prepare a coating composition.

[0248] C5. Preparation of neutralized spray-dried polymer batches for coating tests (Example 9)

[0249] i. 600 g L100 and 1500 g of water were neutralized to 10 mol% with 342.19 g of 1N ammonia solution using a overhead stirrer at 1200 rpm (the beaker used to dispense the ammonia solution was also rinsed with 50 g of water and added to the dispersion) and stirred for 45 minutes, then the dispersion was filtered through #60.

[0250] ii. The dispersion was spray-dried using the following parameters.

[0251] The spray-dried powder of the ammonia-neutralized anion (meth)acrylic copolymer is further used to prepare a coating composition.

[0252] C6. Preparation of neutralized spray-dried polymer batches for coating tests (Example 10)

[0253] i. 350 g of Aqaot AS-LF and 2400 g of water were neutralized to 25 mol% with 136.55 g of 1N ammonia solution using a overhead stirrer at 1200 rpm for 45 minutes, then the dispersion was filtered through #60.

[0254] ii. The dispersion was spray-dried using the following parameters.

[0255] The spray-dried powder of the ammonia-neutralized Aqaot AS-LF is further used to prepare a coating composition.

[0256] Table 4: Spray drying parameters:

[0257] Experiment number 4 5 6 7 8 9 10 Inlet temperature (°C) 85-92 88-89 85-91 75-82 80-90 90 90-92 Spray rpm 15-22 17-19 15-22 10-20 20-25 25 20-25 Atomization (bar) 7 7 7 7 7 7 7 Suction device 85-96 85-95 85-91 92-100 90 90 90 Outlet temperature (°C) 50-56 51-53 48-58 49-51 52-60 53-55 50-58

[0258] D. Coating experiments

[0259] D1. Preparation of coated pharmaceutical dosage forms

[0260] Table 5 summarizes the formulations for the enteric coatings used to barrier coat omeprazole pellets and the coating examples using theophylline and diclofenac pellets (Comparative Examples C1 - C4, C10 - C11 and Examples I1 - I7, I13 - I16 according to the invention).

[0261]

[0262]

[0263] D1.1 Preparation of coating solution for barrier coating omeprazole pellets (C1):

[0264] i. Disperse L 100 - 55 in water under stirring,

[0265] ii. Add sodium laurate and poloxamer 188 to the dispersion in step i. under stirring and continue stirring at a speed of 1500 - 2000 rpm for 90 minutes to obtain a mixed dispersion.

[0266] iii. Pass the mixed dispersion obtained in step ii. through an ASTM #60 sieve and use it for coating the barrier - coated omeprazole pellets.

[0267] D1.2 Preparation of coating solution for barrier coating omeprazole pellets (C2):

[0268] i. Disperse the neutralized spray - dried polymer of Example 7 in water under stirring.

[0269] ii. Pass the dispersion obtained in step i. through an ASTM #60 sieve and use it for coating the barrier - coated omeprazole pellets.

[0270] D1.3 Preparation of coating dispersion for barrier coating omeprazole pellets (C3 - C4 and I1 - I9):

[0271] i. Blend the neutralized spray - dried polymer, poloxamer 407 and sodium dodecyl sulfate to obtain a mixture.

[0272] ii. Disperse the mixture obtained in step i. in water under stirring and continue stirring at a speed of 1500 rpm - 2000 rpm for 45 minutes to obtain a dispersion.

[0273] iii. Pass the dispersion obtained in step ii. through an ASTM #60 sieve and use it for coating the enteric-coated omeprazole pellets.

[0274] D1.4 Preparation of coating dispersion for coating enteric-coated omeprazole pellets (I13 and C10):

[0275] i. Blend the neutralized spray-dried polymer, poloxamer 407, and sodium lauryl sulfate to obtain a mixture.

[0276] ii. Disperse the mixture obtained in step i. in water with stirring and continue stirring at a speed of 1500 rpm - 2000 rpm for 45 minutes to obtain a dispersion.

[0277] iii. Pass the dispersion obtained in step ii. through an ASTM #60 sieve and use it for coating the enteric-coated omeprazole pellets.

[0278] D1.5 Preparation of coating dispersion for coating diclofenac pellets (I14):

[0279] i. Blend the neutralized spray-dried polymer, Kolliphor 407, talc, and triethyl citrate to obtain a mixture.

[0280] ii. Add the mixture from step i. to pure water with stirring and stir at 1600 RPM for 45 minutes to form a homogeneous dispersion.

[0281] iii. Pass the dispersion obtained in step ii. through an ASTM #60 sieve and use it for coating the diclofenac sodium pellets.

[0282] D1.6 Preparation of coating solution for pellet coating: I15 - I16, C11

[0283] i. Blend the neutralized spray-dried polymer, poloxamer 188 / micronized poloxamer 407 / PEG 6000, and sodium lauryl sulfate to obtain a mixture.

[0284] ii. Disperse the mixture obtained in step i. in water with stirring and continue stirring at a speed of 1500 rpm for 45 minutes to obtain a dispersion.

[0285] iii. Pass the dispersion obtained in step ii. through an ASTM #60 sieve and use it for coating the enteric-coated omeprazole pellets.

[0286] D2. Coating of enteric-coated omeprazole / diclofenac pellets:

[0287] The enteric-coated omeprazole pellets are coated with the coating solution / dispersion prepared above using the following parameters. The coated pharmaceutical dosage forms are used to test their stability.

[0288] Table 6:

[0289]

[0290] D3. Stability study of the coated pharmaceutical dosage forms

[0291] The stability of the enteric-coated omeprazole pellets is evaluated in 0.1 N HCl and at pH 5.0 for 2 hours each. The release curves of omeprazole are measured, and the results for Comparative Examples C1 to C4, C10 - C11 are listed in Table 7.

[0292] Table 7:

[0293]

[0294] ND* - Not Done

[0295] Enteric-coated omeprazole pellets that exhibit less than 5.0% release of the core component in 0.1 N HCl and less than 25% release of the core component at pH 5 for 2 hours are considered stable products and are protected at pH 5.0. It is evident from Table 7 that Comparative Examples C1 to C4, and C10 - C11 are unstable at pH 5 for 2 hours.

[0296] The stability of enteric-coated omeprazole pellets coated with the composition according to the invention is evaluated. This evaluation also includes the drying effect at different cumulative percentages of solids in the coating solution. The release curves of omeprazole / theophylline / diclofenac sodium are measured, and the results for Examples I1 - I9 and I13 - I16 are listed in Table 8.

[0297]

[0298] A. Drying effect (I10) of the neutralized spray-dried polymer of Example 4 before coating on the pellets of Example 1:

[0299] The neutralized spray-dried polymer obtained in Example 4 is dried using the following parameters. The average post-drying temperature is 60 °C for 24 hours. The exposure factor based on the above parameters is 1.98.

[0300] The dried powder obtained above is used for coating the enteric-coated omeprazole pellets. The formulation for obtaining the dispersion used for coating the enteric-coated omeprazole pellets is given in Table 9, and the method for coating the pellets is given below.

[0301] Table 9:

[0302] Composition Constitution (% w / w) Neutralized spray-dried polymer of Example 4 83.33 Poloxamer 407 (Kolliphor P 407) 16.67 Water (q.s. % w / w solids) q.s. to 20 w / w solids Total 100 Solids build up (%) 50

[0303] A1. Preparation of the Coating Dispersion for Experiment

[0304] i. The dried and 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.

[0305] ii. The dispersion from step i was passed through an ASTM #60 sieve and further used for coating the enteric-coated omeprazole pellets.

[0306] A2. Coating of Enteric-Coated Omeprazole Pellets

[0307] The enteric-coated omeprazole pellets were coated with the coating dispersion obtained above using GPCG 1.1 with the following parameters.

[0308] Table 10:

[0309]

[0310] The stability of the coated pellets at pH 5 was evaluated without any further drying, and the results are summarized in Table 11.

[0311] Table 11

[0312]

[0313] As is evident from Table 11, the drying / curing of the neutralized spray-dried copolymer can provide 2-hour stability at pH 5.0 for the enteric-coated omeprazole pellets without drying the final dosage form. This not only provides flexibility to the process but also improves the efficiency of the process.

[0314] Example 12 (I12) of the present invention was carried out to show the effectiveness of the coating composition even under different neutralization sequences. This was used for coating the pellets.

[0315] Table 12: Formulation for Generating the Neutralized Spray-Dried Polymer (I12)

[0316]

[0317] * 30% solids dispersion

[0318] A3. Preparation of the Neutralized Spray-Dried Polymer

[0319] i. 350 grams The L30D-55 dispersion is diluted with 300 g of water and then neutralized to 20 mol% with 1N ammonia solution while stirring constantly at 1500 rpm for 15 minutes.

[0320] ii. Then the neutralized dispersion from step i. is added to 1650 g of the L30D-55 dispersion while stirring at 1500 - 2000 rpm.

[0321] iii. The dispersion obtained in step ii. is passed through an ASTM #60 sieve and spray-dried using the following parameters to obtain the neutralized copolymer.

[0322] The spray-drying parameters used are as follows:

[0323] Table 13: Spray-drying parameters:

[0324] Experiment number I12 Inlet temperature (°C) 90-93 Spray rpm 24 Atomization (bar) 7 Suction device 90 Outlet temperature (°C) 50

[0325] The coating compositions are prepared and processed with a solids content accumulation of 40% in a similar manner to Examples I1 to I9 of the present invention. The compositions thus obtained are used for coating omeprazole pellets for barrier coating. The coating parameters are similar to those in Table 6, I1 - I9. The stability of the final pellets at pH 5 is evaluated, and the results are summarized in Table 14.

[0326] Table 14:

[0327]

[0328] As is evident from Table 14, neutralizing a portion of the anionic (meth)acrylic copolymer and mixing it with the remaining copolymer to obtain the anionic (meth)acrylic copolymer in salt form does not affect the coating performance. This method can be used to improve process efficiency.

[0329] B. Effect of coating compositions without surfactants:

[0330] B1. Preparation of the dispersion

[0331] Table 15 summarizes the formulation for enteric coating of omeprazole pellets for barrier coating (Comparative Example I17)

[0332] Table 15: Formulation for enteric coating of pellets I17 for barrier coating

[0333] Composition Constitution (% w / w) Core Example 1 Experiment number I17 Neutralized spray-dried polymer of I12 83.33 Poloxamer 407 16.67 Water (q.s. % w / w solids) q.s. to 20 Total 100

[0334] For pellet coating: Preparation of the coating solution for I17

[0335] i. The neutralized spray-dried polymer and poloxamer 407 are blended to obtain a mixture.

[0336] ii. Disperse the mixture obtained in step i in water under stirring and continue stirring at a speed of 1500 rpm - 2000 rpm for 45 minutes to obtain a dispersion.

[0337] iii. Pass the dispersion obtained in step ii through an ASTM #60 sieve and use it for coating the enteric-coated omeprazole pellets.

[0338] B2 Coating of enteric-coated omeprazole pellets:

[0339] The enteric-coated omeprazole pellets are coated with the coating solution / dispersion prepared above using the following parameters. The coated drug dosage forms are used to test their stability.

[0340] Table 16:

[0341]

[0342] Evaluate the stability of the coated pellets at pH 5, and the results are summarized in Table 17.

[0343] Table 17:

[0344]

[0345] It is obvious from Table 17 that the presence of the surfactant is not essential for the performance of the coating composition at pH 5.

[0346] C. Solubility enhancement of poorly soluble active ingredients:

[0347] Test the solubility enhancement of the compositions according to the present invention at pH ≥ 5. Table 18 summarizes the formulations used to evaluate the solubility enhancement of poorly soluble APIs.

[0348] Table 18:

[0349]

[0350] Weigh the above ingredients, pass through ASTM #40 and blend. The blended composition is further processed in a hot melt extrusion (HME) procedure, and its parameters are given in Table 16 below. Cool and grind the extrudate to form a powder and pass through ASTM #45.

[0351] Table 19: HME parameters for I11, C8 - C9

[0352]

[0353] Measure the solubility enhancement of the poorly soluble API at pH 5.5 according to the dissolution method given below.

[0354] Dissolution parameters are:

[0355]

[0356] Procedure:

[0357] Weigh a sample equivalent to 43 mg and transfer it to the dissolution vessel, and perform the dissolution test according to the parameters given above. After discarding the first 2 mL of filtrate, filter the sample solution through a 0.45 μm PVDF syringe filter.

[0358] Perform chromatographic analysis on the sample according to the USP method for Fenofibrate tablets as published in USP42-NF 37 (official as of May 1, 2019).

[0359] Measure the solubility enhancement of the composition of the present invention, and the results are listed in Table 20.

[0360] Table 20:

[0361]

[0362] It is evident from Table 20 that the poorly soluble active ingredient co-processed with the composition according to the present invention exhibits nearly 100% dissolution enhancement at pH 5.5 compared to the comparative examples of Fenofibrate API, C8, and C9.

Claims

1. A powder composition comprising: i. 25 to 95% by weight of an anionic (meth)acrylic copolymer, based on the total weight of the composition; and 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, wherein the anionic (meth)acrylic copolymer is polymerized from the following monomers a1. 25 to 95% by weight of at least one C1-C4 alkyl ester of acrylic acid and / or C1-C4 alkyl ester of methacrylic acid, based on the total weight of the monomers, and a2. 5 to 75% by weight of acrylic acid and / or methacrylic acid, based on the total weight of the monomers, and wherein the anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that 0.1 to 25 mol% of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

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

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

4. The powder composition according to any one of claims 1 to 3, wherein the poloxamer is selected from poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 or a mixture thereof.

5. The powder composition according to any one of claims 1 to 4, wherein the anionic (meth)acrylic copolymer is present in an amount of 55 to 90% by weight, based on the total weight of the composition.

6. The powder composition according to any one of claims 1 to 5, wherein the poloxamer is present in an amount of 10 to 25% by weight, based on the total weight of the anionic (meth)acrylic copolymer in the composition.

7. The powder composition according to any one of claims 1 to 6, wherein the anionic (meth)acrylic copolymer has been reacted with ammonia or an organic base such that 2 to 7 mol% of the anionic groups of the anionic (meth)acrylic copolymer are present in salt form.

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

9. The aqueous dispersion according to claim 8, wherein the aqueous dispersion further comprises at least one component selected from plasticizers, surfactants, emulsifiers, pigments, glidants, anti-caking agents, auxiliary film-forming agents, anti-sticking agents or mixtures thereof.

10. A method for coating an enteric coating on a pharmaceutical dosage form, comprising the following steps: i. Providing the aqueous dispersion according to any one of claims 8 to 9, and ii. Coating the pharmaceutical dosage form with the aqueous dispersion of step i. to obtain a coated pharmaceutical dosage form.

11. The method according to claim 10, wherein the method further comprises step iii. of drying the coated pharmaceutical dosage form obtained in step ii. to form an enteric-coated pharmaceutical dosage form.

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

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

14. A method for enhancing the solubility of a Class II or Class IV drug molecule according to the BCS, comprising the following steps: i. Providing a Class II or Class IV drug molecule according to the BCS; ii. Mixing the composition according to 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., and iv. Co-processing the mixture obtained in step ii. or iii. to form a homogeneous mixture.

15. The method according to claim 14, wherein the method further comprises the step of formulating the homogeneous mixture obtained in step iv. into a pharmaceutically acceptable dosage form.

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