Alginate-Based Modified Release Compositions

Abstract

The present invention relates to raft-forming pharmaceutical compositions suitable for modified release formulations, methods for their preparation, and use in the treatment of medical conditions such as gastroesophageal reflux disease.

Description

[Technical Field]

[0001] The present invention relates to raft-forming pharmaceutical compositions suitable for modified release formulations, methods for their preparation, and use in the treatment of medical conditions such as gastroesophageal reflux disease. [Background technology]

[0002] Modified-release dosage forms provide a means for less frequent administration, thereby improving patient compliance and ensuring effective and safe treatment with minimal side effects. Compared with immediate-release dosage forms, modified-release dosage forms can prolong the effect of the active ingredient after administration and reduce fluctuations in the plasma concentration of the drug over the entire administration interval, thereby eliminating or reducing sharp peaks. Due to their many advantages, developing such improved modified-release dosage forms is the goal of many skilled in the art.

[0003] The majority of modified-release dosage forms are tablets or pellets that contain a core that is either coated with a drug or contains a drug. In this case, the core is coated with a release-modifying polymer in which the drug may be dispersed. The release-modifying polymer gradually disintegrates, releasing the drug over time. Thus, the outermost layer of the composition effectively slows down the composition when it is exposed to an aqueous environment, i.e., the gastrointestinal tract, thereby regulating the diffusion of the drug across the coating layer. The net diffusion rate of the drug depends primarily on the ability of gastric fluid to penetrate the coating layer or matrix and the solubility of the drug itself.

[0004] WO 2020131780 relates to a sustained release composition for oral administration comprising a physiologically active ingredient mixed with methylcellulose, the methylcellulose having anhydroglucose units linked by 1 to 4 bonds, the hydroxy groups of the anhydroglucose units being substituted with methyl groups such that s23 / s26 is 0.27 or less, and the composition further comprising a liquid diluent in a weight ratio of liquid diluent to active ingredient in the range of 0:1 to 0.85:1.

[0005] WO 2020131784 relates to a sustained-release composition for oral administration comprising a physiologically active ingredient mixed with methylcellulose, the methylcellulose having anhydroglucose units linked by 1 to 4 bonds, the hydroxy groups of the anhydroglucose units being substituted with methyl groups such that s23 / s26 is greater than 0.27, and the concentration of methylcellulose is 0.1 to 10% of the active ingredient by dry weight.

[0006] WO2012128520 relates to a liquid composition for treating gastroesophageal diseases by oral administration.

[0007] There is a need for the development of more easily manufactured, less expensive and equally well suited modified release compositions, which the inventors of the present invention provide using alginate rafts. Summary of the Invention [Problem to be solved by the invention]

[0008] It is an object of embodiments of the present invention to provide pharmaceutical compositions suitable for modified release formulations, such as for oral administration.

[0009] Another object of embodiments of the present invention is to provide compositions suitable for use in raft composition pharmaceutical platforms.

[0010] In a broad aspect, the present invention relates to raft-forming pharmaceutical formulations. [Means for solving the problem]

[0011] Thus, in a first aspect, the present invention provides a binary pharmaceutical composition suitable for a modified release formulation, comprising compositions (I) and (II), wherein the first raft-forming composition (I) comprises: a) alginate in an amount of 2% (w / w) to 8% (w / w), b) a carbonate, such as an alkali metal carbonate, for example ammonium carbonate, ammonium bicarbonate, sodium carbonate or sodium bicarbonate, or calcium carbonate, c) a polyvalent ion, such as strontium ion or for example calcium ion, magnesium ion, aluminum ion, for example derived from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w), which crosslinks the alginate, d) i) a hydrocolloid, for example any one selected from the group consisting of guar gum, pectin and derivatives thereof, xanthan gum, arabinoxylan, cellulose and derivatives thereof, chitin, xylan, beta-glucan, gum arabic, hyaluronic acid, and gelatin, and ii) a pharmaceutically acceptable polyacrylic acid, for example carbomer, and e) water or any other pharmaceutically acceptable vehicle; and wherein the second composition (II) comprises or consists of: a) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose, and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof; b) an active pharmaceutical ingredient (API); and c) optionally, water or any other pharmaceutically acceptable vehicle; and wherein the first (I) composition and the second (II) composition are mixed prior to oral administration.

[0012] It will be appreciated that components b) and c) of the first raft-forming composition (I) described herein, i.e., the multivalent ions cross-linking the carbonate and alginate, respectively, can be the same compound, e.g., if the carbonate source for the flotation of the raft is, for example, calcium carbonate, then the calcium carbonate also provides the multivalent cross-linking ions.

[0013] In a second aspect, the present invention relates to a method for preparing a two-component pharmaceutical composition, the method comprising the step of mixing compositions (I) and (II), the first raft-forming composition (I) comprising: a) alginate in an amount of 2% (w / w) to 8% (w / w); b) a carbonate, such as an alkali metal carbonate, for example ammonium carbonate, ammonium bicarbonate, sodium carbonate or sodium bicarbonate, or calcium carbonate; c) a polyvalent ion, such as strontium ion or for example calcium ion, magnesium ion, aluminum ion, for example derived from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w), which crosslinks the alginate; d) a hydrocolloid, such as guar gum, pectin and its derivatives, xanthan gum, arabinoxylan, cellulose and its derivatives, chitin, xylan, beta-glucan, gum arabic, hyaluronic acid, and gelatin; and ii) at least one pharmaceutically acceptable viscosity imparting agent selected from pharmaceutically acceptable polyacrylic acids, e.g., carbopol, in an amount of about 0.01 (w / w) to 1.0% (w / w), and e) water or other pharmaceutically acceptable vehicle; and the second composition (II) comprises or consists of a) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC), e.g., sodium carboxymethylcellulose, and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof, b) an active pharmaceutical ingredient (API), and c) optionally, water or any other pharmaceutically acceptable vehicle.

[0014] In a third aspect, the present invention relates to the use of a two-component pharmaceutical composition consisting of compositions (I) and (II), wherein the first raft-forming composition (I) comprises: a) alginate in an amount of 2% (w / w) to 8% (w / w); b) a carbonate, such as an alkali metal carbonate, for example ammonium carbonate, ammonium bicarbonate, sodium carbonate or sodium bicarbonate, or calcium carbonate; c) a polyvalent ion, such as strontium ion or for example calcium ion, magnesium ion, aluminum ion, for example derived from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w), which cross-links the alginate; d) i) a hydrocolloid, for example any one selected from the group consisting of guar gum, pectin and derivatives thereof, xanthan gum, arabinoxylan, cellulose and derivatives thereof, chitin, xylan, beta-glucan, gum arabic, hyaluronic acid, and gelatin; and and ii) at least one pharmaceutically acceptable viscosity imparting agent selected from pharmaceutically acceptable polyacrylic acids, such as carbopol, in an amount of about 0.01 (w / w) to 1.0% (w / w), and e) water or other pharmaceutically acceptable vehicle, and the second composition (II) comprises or consists of a) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose, and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof, b) an active pharmaceutical ingredient (API), and c) optionally water or any other pharmaceutically acceptable vehicle, for use in the treatment of a medical condition for which the API is indicated.

[0015] In a further aspect, the present invention relates to a method for treating a medical condition for which an API is indicated, the method comprising administering to a subject in need thereof an effective amount of a binary pharmaceutical composition comprising compositions (I) and (II), wherein the first raft-forming composition (I) comprises: a) alginate in an amount of 2% (w / w) to 8% (w / w); b) a carbonate, such as an alkali metal carbonate, for example, ammonium carbonate, ammonium bicarbonate, sodium carbonate or sodium bicarbonate, or calcium carbonate; c) a multivalent ion, such as strontium ions or for example calcium ions, which cross-links the alginate, in an amount of about 1.1% (w / w) to 2.2% (w / w). , magnesium ions, aluminum ions, such as those derived from calcium carbonate, d) i) hydrocolloids, such as any one selected from the group consisting of guar gum, pectin and derivatives thereof, xanthan gum, arabinoxylan, cellulose and derivatives thereof, chitin, xylan, beta-glucan, gum arabic, hyaluronic acid, and gelatin, and ii) pharmaceutically acceptable polyacrylic acids, such as carbopol, in an amount of about 0.01 (w / w) to 1.0% (w / w), and e) water or other pharmaceutically acceptable vehicle, The second composition (II) relates to a method for treating a medical condition for which an API is indicated, comprising or consisting of: a) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose, and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof; b) an active pharmaceutical ingredient (API); and c) optionally, water or any other pharmaceutically acceptable vehicle.

[0016] It is understood that while the modified release alginate compositions of the present invention use alginate as a raft and as a means to suspend the composition in the gastric medium, thereby providing specific drug release in the stomach, both the raft and the cellulosic polymer function as controlled release polymers, providing sustained release of the active ingredient (API) in the gastric medium.

[0017] This provides a platform technology with great advantages and potential for maximum drug content release in the stomach. Controlled drug release can be achieved over a 6-24 hour period using this technology.

[0018] The composition comprising the active pharmaceutical ingredient may be formulated in any suitable manner, for example as granules in sachets, capsules, or tablets.

[0019] The portion of the formulation containing the active pharmaceutical ingredient may be mixed with a composition containing alginate.

[0020] Therefore, this concept provides a platform for achieving stomach-targeted drug release for a variety of APIs. DETAILED DESCRIPTION OF THE INVENTION

[0021] As described above, the present invention provides a two-component pharmaceutical composition suitable for modified release formulations, comprising compositions (I) and (II), wherein the first raft-forming composition (I) comprises: a) alginate in an amount of 2% (w / w) to 8% (w / w), b) carbonate, such as an alkali metal carbonate, for example ammonium carbonate, ammonium bicarbonate, sodium carbonate or sodium bicarbonate, or calcium carbonate, c) polyvalent ions, such as strontium ions or for example calcium ions, magnesium ions, aluminum ions, for example derived from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w), which crosslink the alginate, d) i) hydrocolloid, for example guar gum. and, e) water or other pharmaceutically acceptable vehicle, The second composition (II) comprises or consists of a) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose, and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof, b) an active pharmaceutical ingredient (API), and c) optionally, water or any other pharmaceutically acceptable vehicle, wherein the first (I) composition and the second (II) composition are mixed prior to oral administration.

[0022] As used herein, a modified release formulation refers to a pharmaceutical formulation that has a mechanism for delivering an API (as opposed to an immediate release dosage) either at a delay after its administration (delayed release dosage), or over an extended period of time (sustained release dosage), or to a specific target within the body (targeted release dosage), in this case preferably in the stomach.

[0023] In some embodiments, this second composition (II) is in the form of granules with a granule size in the range of 200 to 2000 μm, such as in the range of 250 to 1400 μm, for example in the range of 300 to 1000 μm.

[0024] In some embodiments, this second (II) composition is in the form of a granule, a sachet, a capsule, a tablet, or a liquid suspension.

[0025] In some embodiments, the composition is in the form of a liquid dispersion after mixing the first (I) composition and the second (II) composition.

[0026] In some embodiments, the API is a compound suitable for use in the local treatment of, for example, the gastrointestinal system, for example, for peptic ulcers and reflux esophagitis, such as ranitidine, amoxicillin, levofloxacin, metronidazole; drugs with low solubility at alkaline pH, such as ofloxacin and cinnarizine; compounds with a narrow absorption spectrum, such as riboflavin, cilostazol, and pregabalin; drugs that are poorly absorbed from the lower gastrointestinal tract, such as atenolol, lafutidine; drugs that are unstable at alkaline pH, such as verapamil and captopril; antidiabetic drugs, such as metformin; antihypertensive drugs, such as metoprolol hydrochloride, propranolol hydrochloride; proton pump inhibitors, such as omeprazole, pantoprazole; nonsteroidal anti-inflammatory analgesics, such as paracetamol, ibuprofen; hydrophilic compounds, such as niacinamide and metoclopramide HCl; or hydrophobic compounds.

[0027] In some embodiments, the cellulosic polymer is selected from hydroxypropyl methylcellulose acetate succinate, methylcellulose, and ethylcellulose.

[0028] 7. The binary pharmaceutical composition according to any one of claims 1 to 6, wherein the alginate is a salt of alginic acid, such as sodium alginate.

[0029] In some embodiments, the carbonate, eg, alkali metal carbonate, is sodium bicarbonate, or potassium bicarbonate or ammonium carbonate.

[0030] In some embodiments, the composition further comprises a preservative, such as propyl parahydroxybenzoate and / or methyl parahydroxybenzoate, and any salts thereof.

[0031] In some embodiments, the composition further comprises a flavoring compound and / or a sweetening compound, and / or a pH adjusting agent.

[0032] In some embodiments the alginate is present in an amount of at least 2.1% (w / w), such as at least 2.2% (w / w), for example at least 2.3% (w / w), such as at least 2.4% (w / w), for example at least 2.5% (w / w), such as at least 2.6% (w / w), for example at least 2.7% (w / w), such as at least 2.8% (w / w), for example at least 2.9% (w / w), such as at least 3.0% (w / w), for example at least 3.2% (w / w), such as at least 3.4% (w / w), for example at least 3.6% (w / w), such as at least 3.8% (w / w), for example at least 4.0% (w / w) relative to the first raft-forming composition (I).

[0033] In some embodiments, the alginate is present in an amount of 7.8% (w / w) or less, such as 7.6% (w / w) or less, for example 7.5% (w / w) or less, such as 7.4% (w / w) or less, for example 7.2% (w / w) or less, such as 7.0% (w / w) or less, for example 6.8% (w / w) or less, such as 6.6% (w / w) or less, for example 6.4% (w / w) or less, such as 6.2% (w / w) or less, for example 6.0% (w / w) or less, such as 5.8% (w / w) or less, e.g. For example, it may be present in an amount of 5.6% (w / w) or less, such as 5.4% (w / w) or less, for example 5.2% (w / w) or less, such as 5.0% (w / w) or less, for example 4.9% (w / w) or less, such as 4.8% (w / w) or less, for example 4.7% (w / w) or less, such as 4.6% (w / w) or less, for example 4.5% (w / w) or less, such as 4.4% (w / w) or less, for example 4.3% (w / w) or less, such as 4.2% (w / w) or less, for example 4.1% (w / w) or less, for example 4.0% (w / w) or less.

[0034] In some embodiments, the cellulose derivative polymer is methylcellulose, for example, at a concentration of 2% in water at 5° C. for 10 seconds. -1 It is a methylcellulose having a viscosity in the range of 15 mPa·s to 100,000 mPa·s when measured at a shear rate of 100,000 mPa·s.

[0035] In some embodiments, the cellulose derivative polymer is methylcellulose, for example, at a concentration of 2% in water at 5° C. for 10 seconds. -1 It is a methylcellulose having a viscosity in the range of 150 mPa·s to 100,000 mPa·s when measured at a shear rate of 100,000 mPa·s.

[0036] In some embodiments, the cellulose derivative polymer is methylcellulose having an s23 / s26 of 0.10 to 0.24, e.g., 0.14 to 0.23, where s23 is the mole fraction of anhydroglucose units in which only two hydroxy groups, at positions 2 and 3, of the anhydroglucose unit are substituted with methyl groups, and s26 is the mole fraction of anhydroglucose units in which only two hydroxy groups, at positions 2 and 6, of the anhydroglucose unit are substituted with methyl groups.

[0037] In some embodiments, the ratio between the API and the cellulosic polymer is in the range of 1:0.001 to 1:0.1, such as in the range of 1:0.002 to 1:0.09, for example 1:0.003 to 1:0.08, such as 1:0.004 to 1:0.07, for example 1:0.005 to 1:0.06, such as 1:0.006 to 1:0.05, for example 1:0.007 to 1:0.04, such as 1:0.008 to 1:0.03, for example 1:0.009 to 1:0.02, such as about 1:0.01.

[0038] In some embodiments, the cellulose derivative polymer is present in a proportion of at least 0.1% (w / w) relative to the second composition (II), such as at least 0.12% (w / w), at least 0.14% (w / w), at least 0.16% (w / w), at least 0.18% (w / w), at least 0.20% (w / w), at least 0.22% (w / w), at least 0.24% (w / w), at least 0.26% (w / w), at least Methylcellulose present in an amount of 0.28% (w / w), at least 0.30% (w / w), at least 0.32% (w / w), at least 0.34% (w / w), at least 0.36% (w / w), at least 0.38% (w / w), at least 0.40% (w / w), at least 0.42% (w / w), at least 0.46% (w / w), at least 0.48% (w / w), or at least 0.50% (w / w).

[0039] In some embodiments, the cellulose derivative polymer is present in an amount of 3% (w / w) or less, such as 3.0% (w / w) or less, for example, 2.9% (w / w) or less, 2.8% (w / w) or less, 2.6% (w / w) or less, 2.4% (w / w) or less, 2.2% (w / w) or less, 2.0% (w / w) or less, 1.9% (w / w) or less, 1.8% (w / w) or less, 1.7% (w / w) or less, relative to the second composition (II). methylcellulose present in an amount of less than 1.6% (w / w), less than 1.5% (w / w), less than 1.4% (w / w), less than 1.3% (w / w), less than 1.2% (w / w), less than 1.1% (w / w), less than 1.0% (w / w), less than 0.9% (w / w), less than 0.8% (w / w), less than 0.7% (w / w), less than 0.6% (w / w), or less than 0.5% (w / w).

[0040] In some embodiments, the cellulose derivative polymer is methylcellulose present in an amount of 0.1% (w / w) to 2.0% (w / w), such as in the range of 0.2% (w / w) to 1.8% (w / w), for example in the range of 0.3% (w / w) to 1.7% (w / w), such as in the range of 0.4% (w / w) to 1.6% (w / w), for example in the range of 0.5% (w / w) to 1.5% (w / w), such as in the range of 0.6% (w / w) to 1.4% (w / w), for example in the range of 0.7% (w / w) to 1.3% (w / w), relative to the second composition (II).

[0041] In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC), for example, HPMC having a viscosity in the range of 2500 mPa·s to 120,000 mPa·s when measured at 20° C., c=2% in water according to USP 37.

[0042] In some embodiments, the cellulose derivative polymer is hydroxypropyl methylcellulose (HPMC) present in an amount of at least 1% (w / w), such as at least 2% (w / w), at least 3% (w / w), at least 4% (w / w), at least 5% (w / w), or at least 6% (w / w) relative to the second composition (II).

[0043] In some embodiments, the cellulose derivative polymer is hydroxypropyl methylcellulose (HPMC) present in an amount of 22% (w / w) or less, such as 21% (w / w) or less, for example, 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, or 14% (w / w) or less, relative to the second composition (II).

[0044] In some embodiments, the cellulose derivative polymer is hydroxypropyl methylcellulose (HPMC) present in an amount of from 1% (w / w) to 20% (w / w), such as in the range of from 2% (w / w) to 18% (w / w), for example in the range of from 3% (w / w) to 18% (w / w), such as in the range of from 4% (w / w) to 18% (w / w), for example in the range of from 5% (w / w) to 18% (w / w), such as in the range of from 5% (w / w) to 17% (w / w), for example in the range of from 6% (w / w) to 17% (w / w), relative to the second composition (II).

[0045] In some embodiments, the cellulosic polymer is ethyl cellulose, for example, ethyl cellulose having a viscosity in the range of 3 mPa·s to 150 mPa·s when measured at 25° C. for a 5% solution measured with an Ubbelohde viscometer in a solvent of 80% toluene and 20% ethanol.

[0046] In some embodiments, the cellulose derivative polymer is ethylcellulose present in an amount of at least 1% (w / w), such as at least 2% (w / w), at least 3% (w / w), at least 4% (w / w), at least 5% (w / w), or at least 6% (w / w) relative to the second composition (II).

[0047] In some embodiments, the cellulose derivative polymer is ethylcellulose present in an amount of 22% (w / w) or less, such as 21% (w / w) or less, for example, 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, or 14% (w / w) or less, relative to the second composition (II).

[0048] In some embodiments, the cellulose derivative polymer is ethylcellulose present in an amount of from 1% (w / w) to 20% (w / w), such as in the range of from 2% (w / w) to 18% (w / w), for example in the range of from 3% (w / w) to 18% (w / w), such as in the range of from 4% (w / w) to 18% (w / w), for example in the range of from 5% (w / w) to 18% (w / w), such as in the range of from 5% (w / w) to 17% (w / w), for example in the range of from 6% (w / w) to 17% (w / w), relative to the second composition (II).

[0049] In some embodiments, the alkali metal carbonate, such as sodium carbonate or sodium bicarbonate, is present in an amount of 1.5 to 5% (w / w), such as in the range of 1.6 to 4.8% (w / w), for example in the range of 1.7 to 4.6% (w / w), for example in the range of 1.8 to 4.4% (w / w), such as in the range of 1.9 to 4.2% (w / w), for example in the range of 2.0 to 4.0% (w / w), such as in the range of 2.1 to 3.8% (w / w), for example in the range of 2.2 to 3.6% (w / w), such as in the range of 2.3 to 3.4% (w / w), for example in the range of 2.4 to 3.2% (w / w), such as in the range of 2.5 to 3.0% (w / w), for example in the range of 2.0 to 3.5% (w / w), relative to the first raft-forming composition (I).

[0050] In some embodiments, the multivalent ions cross-linking the alginate, such as strontium ions or for example calcium ions, magnesium ions, aluminum ions, for example those derived from calcium carbonate, are present in an amount of 0.8 to 4% (w / w) relative to the first raft-forming composition (I), such as in the range of 0.9 to 3.9% (w / w), for example in the range of 1.0 to 3.8% (w / w), such as in the range of 1.1 to 3.7% (w / w), for example in the range of 1.2 to 3.6% (w / w), for example in the range of 1.2 to 3.5% (w / w), such as in the range of 1.2 to 3.4% (w / w).

[0044] The compound is present in an amount in the range of 1.2 to 3.3% (w / w), for example in the range of 1.2 to 3.2% (w / w), for example in the range of 1.2 to 3.0% (w / w), such as in the range of 1.2 to 2.8% (w / w), for example in the range of 1.2 to 2.6% (w / w), for example in the range of 1.2 to 2.4% (w / w), such as in the range of 1.2 to 2.2% (w / w), for example in the range of 1.2 to 2.0% (w / w), for example in the range of 1.3 to 2.0% (w / w), such as in the range of 1.3 to 1.8% (w / w), for example in the range of 1.4 to 1.8% (w / w).

[0051] In some embodiments, the viscosity imparting agent, such as a hydrocolloid, is present in an amount of from 0.05% (w / w) to 1.0% (w / w), such as in the range of from 0.06% (w / w) to 0.8% (w / w), for example in the range of from 0.07% (w / w) to 0.7% (w / w), such as in the range of from 0.08% (w / w) to 0.6% (w / w), for example in the range of from 0.09% (w / w) to 0.5% (w / w), such as in the range of from 0.10% (w / w) to 0.40% (w / w), for example in the range of from 0.12% (w / w) to 0.35% (w / w).

[0052] In some embodiments, the viscosity imparting agent is a pharmaceutically acceptable polyacrylic acid, such as a carbomer, for example, carbomer type A.

[0053] In some embodiments, the first (I) composition and the second (II) composition are mixed into the final pharmaceutical composition.

[0054] Alginic acid and its salts. Alginate, derived primarily from brown seaweed, is a linear, unbranched biopolymer composed of (1-4) linked β-D-mannuronic acid (M) and α-L-guluronic acid (G) residues. Alginate is not a random copolymer, but consists of blocks of equal and alternating sequences of residues, e.g., MMMM, GGGG, and GMGM. In its extracted form, alginate rapidly absorbs water. The physical properties of alginate may depend on the relative proportions of M and G blocks. Gel formation at neutral pH requires a calcium source to provide calcium ions for interaction with the G blocks. The greater the proportion of these G blocks, the stronger the gel.

[0055] "Alginate" is a term usually used for salts of alginic acid, but it can also refer to all derivatives of alginic acid and alginic acid itself. Alginate exists in the cell walls of brown algae as calcium, magnesium, and sodium salts of alginic acid. Dry powdered sodium or potassium alginate can be obtained from this brown algae extraction process. The seaweed residue is then removed by filtration, and the remaining alginate can then be recovered from the aqueous solution.

[0056] Another method for recovering alginate from the initial extraction solution is to add calcium salts. This causes calcium alginate to form along with the fibrous tissue. It is insoluble in water and can be separated from the fibrous tissue. The separated calcium alginate is suspended in water and acid is added to convert it to alginic acid.

[0057] Alginates suitable for use in the practice of the present invention are typically 2 wt % at 20° C. using a rheometer apparatus with cup and bob geometry for 10 s -1The alginates will have a molecular weight such that they exhibit a viscosity in the range of 5 to 1,000 mPa·s, when measured using a shear rate of 1000 to 2000 mPa·s. In some embodiments, such alginates will exhibit a viscosity, when so measured, of between 6 and 600 mPa·s, such as between 7 and 500 mPa·s, or between 8 and 500 mPa·s. In other embodiments, such alginates will exhibit a viscosity, when so measured, of between 8 and 400 mPa·s, such as between 8 and 300 mPa·s, such as between 9 and 200 mPa·s, or between 10 and 100 mPa·s.

[0058] In some embodiments according to the present invention, a high G-type alginate is used. By high G-type alginate, it is meant that the alginate used in the practice of the present invention has an average of at least 50 percent adjacent G units. In some embodiments, the alginate will have an average of at least 52 percent adjacent G units, in other embodiments, such alginates will have an average of at least 55 percent or more adjacent G units, and in other embodiments, such alginates will have an average of at least 60, 65, or 70 percent or more adjacent G units, and therefore, a higher content of adjacent G units may result in improved product texture.

[0059] According to the present invention, the alginate, such as alginic acid or an alginate salt, is present in an amount of 2% (w / w) to 8% (w / w) based on the total weight of the final composition. In the present invention, alginate refers to any alginic acid or alginate salt, such as sodium alginate, magnesium alginate, potassium alginate, triethanolamine alginate, or propylene glycol monoglycolate.

[0060] As used herein, "alginate-crosslinking polyvalent ions" refers to any ions suitable for crosslinking alginate or forming a gel. Of course, this alginate gel formation can be achieved by many polyvalent ions, such as divalent alkaline earth cations (Mg2+, Ca2+, and Sr2+), divalent transition metal ions (Mn2+, Co2+, Cu2+, and Zn2+), and trivalent metal cations (Fe3+, Cr3+, Al3+, Ga3+, Sc3+, and La3+). In certain embodiments, the alginate-crosslinking polyvalent ions used are calcium ions, magnesium ions, or aluminum ions. In certain embodiments, the alginate-crosslinking polyvalent ions used are strontium ions.

[0061] Viscosity imparting agent Viscosifiers or viscosifying agents are known to those skilled in the art. Suitable viscosifying agents include hydrocolloids, such as guar gum, pectin and its derivatives, xanthan gum, arabinoxylan, cellulose and its derivatives, chitin, xylan, beta-glucan, gum arabic, hyaluronic acid, and gelatin, as well as pharmaceutically acceptable polyacrylic acids, such as carbomers, e.g., carbomer type A. For purposes of the present invention, viscosifying agents do not include alginates or cellulose derivative polymers, as specifically defined elsewhere. As used herein, polyacrylic acid (also referred to as carbomer) is a polymer having the formula (CH2-CHCO2H). This term refers to both homopolymers, copolymers, crosslinked polymers, and partially deprotonated derivatives thereof. In aqueous solution at neutral pH, polyacrylic acid is an anionic polymer. Carbomer codes (910, 934, 940, 941, and 934P) are indicators of the molecular weight and specific components of the polymer. For many applications, polyacrylic acid is used in the form of an alkali metal salt or ammonium salt, such as sodium polyacrylate. Suitable carbomers to be used in accordance with the present invention include Carbopol® Polymer 71G NF, 971P NF, 974P NF, and 934P NF (Lubrizol Life Science). Viscosifiers may also be referred to herein as stabilizers.

[0062] Cellulose Derivative Polymers Any suitable cellulosic polymer may be used in accordance with the present invention, and those skilled in the art will be aware of such suitable polymers.

[0063] Suitable film-forming polymers for use in accordance with the present invention include low-viscosity hydroxypropyl cellulose (HPC), ethyl cellulose (EC), methyl cellulose (MC), carboxymethyl cellulose (CMC), and hydroxypropyl methyl cellulose (HPMC), such as hypromellose 2910 (7-12% HP, 28-30% methoxy), hypromellose 2906 (4-7.5% HP, 27-30% methoxy), hypromellose 2208 (4-12% HP, 19-24% methoxy), and hypromellose 1828 (23-32% HP, 16.5-20% methoxy). Commercially available carboxymethyl celluloses (CMC) include TEXTURACEL™ from IFF, Celetec™ from CPKelco, Aqualon™ from Ashland, Rheoflo® from USK Kimya AS, and Akucell® from Nouryon (formerly AkzoNobel). Commercially available methylcellulose and hydroxypropyl methylcellulose include the Japanese Pharmacopoeia METOLOSE (trademark) series and the food additive METOLOSE series manufactured by Shin-Etsu Chemical Co., Ltd., the AnyCoat-C or AnyAddy (trademark) series manufactured by Lotte (formerly Samsung) Fine Chemicals Co., Ltd., the METHOCEL (trademark) series manufactured by International Flavors & Fragrances (IFF) (formerly DOW Chemical), and the Benecel (trademark) series manufactured by Ashland.

[0064] Methylcellulose is a type of cellulose derivative polymer suitable for the present invention. Methylcellulose has anhydroglucose units connected by one to four bonds. Each anhydroglucose unit contains hydroxyl groups at the 2-, 3-, and 6-positions. Partial or complete replacement of these hydroxyl groups with methoxyl groups results in methylcellulose. For example, treating cellulose fibers with a caustic solution followed by a methylating agent yields a cellulose ether substituted with one or more methoxyl groups. Unless further substituted with other alkyls, this cellulose ether is known as methylcellulose. Methylcellulose is characterized by the weight percent of methoxyl groups. By convention, the weight percent is the average weight percent based on the total weight of the cellulose repeat units, including all substituents. The methoxyl content is reported based on the mass of methoxyl groups (i.e., -OCH3). The determination of the % methoxyl in methylcellulose (MC) polymers is performed according to the United States Pharmacopeia (USP 37, "Methylcellulose," pp. 3776-3778). The % methoxyl can be converted to the degree of substitution (DS) for methyl substituents, i.e., DS(methyl). The DS(methyl) of methylcellulose, also known as DS(methoxyl), is the average number of OH groups replaced with methyl groups per anhydroglucose unit. Preferably, the methylcellulose has a % methoxyl of 18% or more, more preferably 25% or more. Preferably, component (b) has a % methoxyl of 50% or less, more preferably 40% or less, and even more preferably 35% or less. Even more preferably, the methylcellulose has a DS(methyl) of 1.55 or more, more preferably 1.65 or more, and most preferably 1.70 or more. The DS(methyl) is preferably 2.25 or less, more preferably 2.20 or less, and most preferably 2.10 or less. In some embodiments according to the present invention, a suitable characterization of methylcellulose is the index s23 / s26. The numbers 2, 3, and 6 refer to the carbon atoms of the defined anhydroglucose unit.

[0065] The parameter s23 is the mole fraction of anhydroglucose units in which only two hydroxy groups, at positions 2 and 3, are substituted with methyl groups, and the parameter s26 is the mole fraction of anhydroglucose units in which only two hydroxy groups, at positions 2 and 6, are substituted with methyl groups. In determining s23, the term "molar fraction of anhydroglucose units in which only two hydroxy groups, at positions 2 and 3, are substituted with methyl groups" means that the two hydroxy groups, at positions 2 and 3, are substituted with methyl groups and the hydroxy group at position 6 is unsubstituted. In determining s26, the term "molar fraction of anhydroglucose units in which only two hydroxy groups, at positions 2 and 6, are substituted with methyl groups" means that the two hydroxy groups, at positions 2 and 6, are substituted with methyl groups and the hydroxy group at position 3 is unsubstituted. The index s23 / s26 is determined by dividing s23 by s26. According to the present invention, in some embodiments, s23 / s26 is 0.24 or less, e.g., 0.23 or less. Furthermore, s23 / s26 can be 0.10 or more, e.g., 0.14 or more. Methylcellulose having such an s23 / s26 ratio can be produced as generally described in International Patent Application Publication No. WO 2013 / 059064. A specific process for producing methylcellulose having the above-described s23 / s26 ratio is described in WO 2017192445, and a commercial product having such an s23 / s26 ratio is Methocel™ Bind 112 manufactured by IFF.

[0066] Solutions for viscosity measurement of sodium carboxymethylcellulose (CMC, e.g., TEXTURACEL™ 20000PA07) are prepared by adding an appropriate amount of CMC powder to an appropriate amount of water while stirring with a laboratory overhead stirrer at ambient temperature for at least 1 hour to achieve a 1% concentration. Viscosity is measured at 20°C using a rheometer (e.g., Anton Paar MCR501) with a cup and bob geometry (e.g., CC-27). Viscosity ranges from 10 mPa·s to 15,000 mPa·s; in some embodiments, the viscosity measured will be between 15 and 12,000 mPa·s, e.g., between 20 and 11,000 mPa·s, or between 25 and 10,000 mPa·s.

[0067] Solutions for viscosity measurements of methylcellulose (MC, e.g., Methocel™ BIND 112) are prepared by adding an appropriate amount of MC powder to an appropriate amount of water at ambient temperature while stirring with a laboratory overhead stirrer to achieve a 2% concentration. The solution is then cooled to a temperature below 5°C and stirred for at least 3 hours. Viscosity is measured at 5°C using a rheometer (e.g., Anton Paar MCR501) with a cup-and-bob geometry (e.g., CC-27). Viscosity ranges from 15 mPa·s to 100,000 mPa·s; in some embodiments, the viscosity measured will be between 50 and 80,000 mPa·s, e.g., between 100 and 75,000 mPa·s, or between 150 and 70,000 mPa·s.

[0068] The preservative may be any suitable pharmaceutically acceptable compound known in the art, such as ethanol, benzethonium chloride, citric acid monohydrate, sodium salicylate, carbol, sodium benzoate, sodium dehydroacetate, oxyquinoline sulfate, potassium sorbate, benzalkonium chloride, benzeneconium chloride, honey, 2-propanol, formalin, 1,2-hydroxypropane, human serum albumin, potassium L-glutamate, N-cocoacyl-N-carboxymethyl-N-hydroxyethylethylenediamine sodium, thimerosal, boric acid, taurine, sodium edetate, N-hexadecylviridinium chloride, chloride), 4-chloro-3-methylphenol, m-cresol, cresol, phenylethanol, 1,2-benzisothiazolin-3-one, disodium sulfite, glycerol(II) sulfate, phosphoric acid, butyl glycidyl ether, dl-camphor, sodium citrate, chlorobutanol, 2-hydroxybenzoic acid, phenyl salicylate, thymol, paraform, benzyl alcohol, sodium tetraborate, L-menthol, carboxybenzene, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, It may be any one selected from the group consisting of methyl hydroxybenzoate, eucalyptus oil, chlorhexidine gluconate, butylhydroxytoluene, sorbic acid, borneol, β-naphthol, dehydroacetic acid, isobutyl p-hydroxybenzoate, colored balsam of Peru, benzoin, agar, 2-mercaptobenzimidazole, isopropyl p-hydroxybenzoate, n-dodecyltrimethylammonium chloride, tea tree oil, glyceryl caprate, polyglyceryl-2 laurate, polyglyceryl-10 laurate, ethylhexylglycerin, glyceryl caprylate, or a combination of two or more thereof.

[0069] Active Pharmaceutical Ingredients (API) An active pharmaceutical ingredient (also called a "drug") is a pharmacologically active substance used to treat humans, animals, or plants. Preferably, the drug is approved by the appropriate regulatory agency for the treatment of a condition occurring in humans or animals. Particularly preferred drugs include, for example, antifungals, antibiotics, anti-inflammatory drugs, antimigraine drugs, antihistamines, analgesics, antioxidants, nicotine, antipsychotic drugs, and lifestyle-enhancing drugs (e.g., erectile dysfunction drugs). More than one drug may be added to the compositions of the present invention.

[0070] Preferably, the drug is in its free base form if it is basic, or in its acid form if it is acidic. Preferably, the drug is a "low-solubility drug," meaning that the drug has an aqueous solubility of about 0.5 mg / mL or less at physiologically relevant pH (e.g., pH 1-8). As used herein, aqueous solubility (mg / mL) refers to the minimum value observed in any physiologically relevant aqueous solution (e.g., those with a pH value between 1 and 8), including USP gastric and intestinal simulating buffers.

[0071] Related categories of suitable APIs include compounds used for local therapeutic activities such as peptic ulcers and reflux esophagitis, such as ranitidine, amoxicillin, levofloxacin, and metronidazole. Drugs with low solubility at alkaline pH, such as ofloxacin and cinnarizine, drugs with narrow absorption bands, such as riboflavin, cilostazol, and pregabalin, and drugs poorly absorbed from the lower GIT, such as atenolol and lafutidine. Drugs that are unstable at alkaline pH, such as verapamil and captopril, antidiabetic drugs, such as metformin, antihypertensive drugs, such as metoprolol hydrochloride and propranolol hydrochloride, proton pump inhibitors, such as omeprazole and pantoprazole, and nonsteroidal anti-inflammatory analgesics, such as paracetamol and ibuprofen.

[0072] Experimental section The formulation of the final product requires two major steps: preparation of the alginate liquid, followed by preparation of the paracetamol modified release formulation. [Example]

[0073] Example 1: Paracetamol Granules 500 mg and Liquid Raft Composition Equipment used to manufacture the drug product 1.Overhead stirrer 2.Weighing balance

[0074] [Table 1]

[0075] Manufacturing Process: A) Preparation process of liquid alginate: 1. Add sodium bicarbonate, calcium carbonate, and sodium saccharin to purified water and dissolve. Add sodium alginate and stir the mixture for 30 minutes. 2. Add Carbopol to purified water with stirring until dissolved. Neutralize the polymer with sodium hydroxide dissolved in water. 3. Add Step 2 to Step 1 and mix the dispersion thoroughly. 4. Add methylparaben and propylparaben to the warm water and dissolve. Allow the solution to cool. 5. Add Step 4 to Step 3 and mix thoroughly with stirring. Stir the mixture for 30 minutes.

[0076] B) Paracetamol modified release preparations - Preparation of 2% METHOCEL Bind 112 gel METHOCEL™ Bind 112 is added to purified water (temperature 20-25°C) at room temperature while stirring with a laboratory overhead stirrer at 750 rpm. The solution is cooled to approximately 1.5°C. After reaching a temperature of 1.5°C, the solution is stirred at 750 rpm for 180 minutes.

[0077] Preparation of paracetamol modified-release granules Paracetamol (25 gm) was mixed with METHOCEL Bind 112 solution (12.5 gm) to obtain a paste. The paste was dried at 50°C and the mass was passed through a #18 mesh ASTM sieve to obtain granules. The granules retained on the #24 ASTM sieve were used for dissolution testing.

[0078] Dissolution test: Elution conditions: Medium: 900 mL of 0.1 N hydrochloric acid (pH 1.2) Device: USP Type II paddle RPM: 50 Temperature: 37℃

[0079] The medium was added to the dissolution bowl and allowed to reach a temperature of 37°C. Paracetamol granules (equivalent to 500 mg of paracetamol) were added to 67 mL of the liquid alginate solution and mixed for 5 minutes. The mixture was added to the dissolution bowl. Aliquots were removed at different time points and analyzed for drug release.

[0080] Example 2: High-Dose API

[0081] [Table 2]

[0082] The manufacturing process and dissolution method remain the same as described in Example 1, except that the paracetamol dose is changed to 1000 mg.

[0083] Example 3: Paracetamol granules 500 mg prepared using high viscosity hydroxypropyl methylcellulose (METHOCEL™ K100M Premium) and RAFT fluid

[0084] [Table 3]

[0085] The manufacturing process and dissolution method remain the same as described in Example 1, except for the method of preparation of the METHOCEL™ K100M Premium gel.

[0086] Preparation of METHOCEL™ K100M Premium gel - The polymer is added and dispersed in warm purified water. The dispersion is stirred at room temperature for 60 minutes.

[0087] Examples 4 to 6: Paracetamol granules (500 mg) prepared using cellulose of different chemical properties and RAFT solution

[0088] [Table 4]

[0089] The manufacturing process and dissolution method remain the same as those described in Example 1, except for the preparation method of the polymer gel.

[0090] Preparation of METHOCEL™ polymer gel - The polymer is added to and dispersed in warm purified water. The solution is stirred at room temperature for 60 minutes.

[0091] Preparation of ETHOCEL™ polymer gel - The polymer is slowly added to purified water and dispersed. The solution is stirred at room temperature for 60 minutes.

[0092] Example 7: Ibuprofen granules and modified RAFT fluid (reduced concentration of sodium alginate and xanthan gum as stabilizer)

[0093] [Table 5]

[0094] Manufacturing Process: A) Preparation process of liquid alginate: 1. Add sodium bicarbonate, calcium carbonate, and sodium saccharin to purified water and dissolve. Add sodium alginate and stir the mixture for 30 minutes. Add xanthan gum and stir the mixture again for 30 minutes. 2. Add sodium carboxymethylcellulose to purified water with stirring and dissolve. Stir the mixture for 30 minutes. 3. Add Step 2 to Step 1 and mix the dispersion thoroughly. 4. Add methylparaben and propylparaben to the warm water and dissolve. Allow the solution to cool. 5. Add Step 4 to Step 3 and mix thoroughly with stirring. Stir the mixture for 30 minutes.

[0095] For the preparation and dissolution method of ibuprofen granules, see Example 1 except that the API ibuprofen is added rather than paracetamol.

[0096] result: Drug release findings:

[0097] [Table 6]

Claims

1. A two-component pharmaceutical composition suitable for a modified release formulation, comprising compositions (I) and (II), wherein said first raft-forming composition (I) comprises: a) alginate in an amount of 2% (w / w) to 8% (w / w); b) carbonates, such as alkali metal carbonates, for example ammonium carbonate, ammonium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate, or calcium carbonate; c) polyvalent ions that cross-link the alginate, such as strontium ions or, for example, calcium ions, magnesium ions, aluminum ions, e.g., derived from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w); d) at least one pharmaceutically acceptable viscosity imparting agent in an amount of about 0.01 (w / w) to 1.0% (w / w) selected from i) hydrocolloids, such as any one selected from the group consisting of guar gum, pectin and its derivatives, xanthan gum, arabinoxylan, cellulose and its derivatives, chitin, xylan, beta-glucan, gum arabic, hyaluronic acid, and gelatin, and ii) a pharmaceutically acceptable polyacrylic acid, such as carbomer; and e) Water or other pharmaceutically acceptable vehicle comprising or consisting of the second composition (II) comprises or consists of a) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose, and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof, b) an active pharmaceutical ingredient (API), and c) optionally, water or any other pharmaceutically acceptable vehicle, and the first (I) composition and the second (II) composition are mixed prior to oral administration; Two-component pharmaceutical compositions.

2. 2. The binary pharmaceutical composition according to claim 1, wherein the second composition (II) is in the form of granules having a particle size of the granules in the range of 200 to 2000 μm, such as in the range of 250 to 1400 μm, for example in the range of 300 to 1000 μm.

3. 3. The binary pharmaceutical composition of claim 1 or 2, wherein the second (II) composition is in the form of granules, sachets, capsules, tablets, or liquid suspensions.

4. 4. The binary pharmaceutical composition according to any one of claims 1 to 3, wherein the first (I) composition and the second (II) composition, after mixing, are in the form of a liquid dispersion.

5. 5. The binary pharmaceutical composition according to any one of claims 1 to 4, wherein the API is, for example, a compound suitable for local therapeutic use in the gastrointestinal system, for example for peptic ulcer and reflux esophagitis, such as ranitidine, amoxicillin, levofloxacin, metronidazole; for example, drugs with low solubility at alkaline pH, such as ofloxacin and cinnarizine; compounds with a narrow absorption spectrum, such as riboflavin, cilostazol, and pregabalin; drugs that are poorly absorbed from the lower gastrointestinal tract, such as atenolol, lafutidine; drugs that are unstable at alkaline pH, such as verapamil and captopril; antidiabetic drugs, such as metformin; antihypertensive drugs, such as metoprolol hydrochloride, propranolol hydrochloride; proton pump inhibitors, such as omeprazole, pantoprazole; non-steroidal anti-inflammatory analgesics, such as paracetamol, ibuprofen; hydrophilic compounds, such as niacinamide and metoclopramide HCl; or hydrophobic compounds.

6. A binary pharmaceutical composition according to any one of claims 1 to 5, wherein the cellulose derivative polymer is selected from hydroxypropyl methylcellulose acetate succinate, methylcellulose and ethylcellulose.

7. A binary pharmaceutical composition according to any one of claims 1 to 6, wherein the alginate is a salt of alginic acid, such as sodium alginate.

8. 8. The binary pharmaceutical composition according to any one of claims 1 to 7, wherein the alkali metal carbonate is sodium bicarbonate or potassium bicarbonate.

9. A binary pharmaceutical composition according to any one of claims 1 to 8, further comprising a preservative, such as propyl parahydroxybenzoate and / or methyl parahydroxybenzoate, and any salts thereof.

10. A binary pharmaceutical composition according to any one of claims 1 to 9, further comprising a flavouring compound and / or a sweetening compound, and / or a pH adjusting agent.

11. 11. A binary pharmaceutical composition according to any one of claims 1 to 10, wherein the alginate is present in an amount of at least 2.1% (w / w), such as at least 2.2% (w / w), for example at least 2.3% (w / w), such as at least 2.4% (w / w), for example at least 2.5% (w / w), such as at least 2.6% (w / w), for example at least 2.7% (w / w), such as at least 2.8% (w / w), for example at least 2.9% (w / w), such as at least 3.0% (w / w), for example at least 3.2% (w / w), such as at least 3.4% (w / w), for example at least 3.6% (w / w), such as at least 3.8% (w / w), for example at least 4.0% (w / w) relative to the first raft-forming composition (I).

12. The alginate may be present in an amount of 7.8% (w / w) or less, such as 7.6% (w / w) or less, for example 7.5% (w / w) or less, for example 7.4% (w / w) or less, for example 7.2% (w / w) or less, such as 7.0% (w / w) or less, for example 6.8% (w / w) or less, for example 6.6% (w / w) or less, for example 6.4% (w / w) or less, for example 6.2% (w / w) or less, for example 6.0% (w / w) or less, for example 5.8% (w / w) or less, for example 5.6% (w / w) or less, for example 12. A binary pharmaceutical composition according to any one of claims 1 to 11, wherein the compound is present in an amount of 5.4% (w / w) or less, such as 5.2% (w / w) or less, for example 5.0% (w / w) or less, such as 4.9% (w / w) or less, for example 4.8% (w / w) or less, such as 4.7% (w / w) or less, for example 4.6% (w / w) or less, such as 4.5% (w / w) or less, for example 4.4% (w / w) or less, such as 4.3% (w / w) or less, for example 4.2% (w / w) or less, such as 4.1% (w / w) or less, for example 4.0% (w / w) or less.

13. The cellulose derivative polymer may be methylcellulose, for example, at a concentration of 2% in water at 5° C., for 10 seconds. －１ 13. The binary pharmaceutical composition according to any one of claims 1 to 12, wherein the methylcellulose has a viscosity in the range of 15 mPa·s to 100,000 mPa·s when measured at a shear rate of 100000 mPa·s.

14. 14. A binary pharmaceutical composition according to any one of claims 1 to 13, wherein the cellulose derivative polymer is methylcellulose having an s23 / s26 of 0.10 to 0.24, for example 0.14 to 0.23, where s23 is the molar fraction of anhydroglucose units in which only two hydroxy groups, at positions 2 and 3, of the anhydroglucose unit are substituted with methyl groups, and s26 is the molar fraction of anhydroglucose units in which only two hydroxy groups, at positions 2 and 6, of the anhydroglucose unit are substituted with methyl groups.

15. 15. A binary pharmaceutical composition according to claim 13 or 14, wherein the ratio between said API and said cellulose derivative polymer is in the range of 1:0.001 to 1:0.1, such as in the range of 1:0.002 to 1:0.09, for example 1:0.003 to 1:0.08, such as 1:0.004 to 1:0.07, for example 1:0.005 to 1:0.06, such as 1:0.006 to 1:0.05, for example 1:0.007 to 1:0.04, such as 1:0.008 to 1:0.03, for example 1:0.009 to 1:0.02, such as about 1:0.

01.

16. The cellulose derivative polymer may be present in an amount of at least 0.1% (w / w) relative to the second composition (II), for example at least 0.12% (w / w), at least 0.14% (w / w), at least 0.16% (w / w), at least 0.18% (w / w), at least 0.20% (w / w), at least 0.22% (w / w), at least 0.24% (w / w), at least 0.26% (w / w), at least 0.28% (w / w), at least 0.

16. A binary pharmaceutical composition according to any one of claims 13 to 15, wherein the methylcellulose is present in an amount of at least 30% (w / w), at least 0.32% (w / w), at least 0.34% (w / w), at least 0.36% (w / w), at least 0.38% (w / w), at least 0.40% (w / w), at least 0.42% (w / w), at least 0.46% (w / w), at least 0.48% (w / w), or at least 0.50% (w / w).

17. The cellulose derivative polymer is present in an amount of 3% (w / w) or less, for example, 3.0% (w / w) or less, for example, 2.9% (w / w) or less, 2.8% (w / w) or less, 2.6% (w / w) or less, 2.4% (w / w) or less, 2.2% (w / w) or less, 2.0% (w / w) or less, 1.9% (w / w) or less, 1.8% (w / w) or less, 1.7% (w / w) or less, or 1.6% (w / w) or less, relative to the second composition (II).

17. A binary pharmaceutical composition according to any one of claims 13 to 16, wherein the methylcellulose is present in an amount of 1.5% (w / w) or less, 1.4% (w / w) or less, 1.3% (w / w) or less, 1.2% (w / w) or less, 1.1% (w / w) or less, 1.0% (w / w) or less, 0.9% (w / w) or less, 0.8% (w / w) or less, 0.7% (w / w) or less, 0.6% (w / w) or less, or 0.5% (w / w) or less.

18. 18. A binary pharmaceutical composition according to any one of claims 1 to 17, wherein said cellulose derivative polymer is methylcellulose present in an amount of from 0.1% (w / w) to 2.0% (w / w), such as in the range of from 0.2% (w / w) to 1.8% (w / w), for example in the range of from 0.3% (w / w) to 1.7% (w / w), such as in the range of from 0.4% (w / w) to 1.6% (w / w), for example in the range of from 0.5% (w / w) to 1.5% (w / w), such as in the range of from 0.6% (w / w) to 1.4% (w / w), for example in the range of from 0.7% (w / w) to 1.3% (w / w), relative to said second composition (II).

19. 13. A binary pharmaceutical composition according to any one of claims 1 to 12, wherein the cellulose derivative polymer is hydroxypropyl methylcellulose (HPMC), for example HPMC having a viscosity in the range of 2500 mPa s to 120,000 mPa s when measured according to USP 37 at 20°C, c=2% in water.

20. 20. The binary pharmaceutical composition of claim 19, wherein the cellulose derivative polymer is hydroxypropylmethylcellulose (HPMC) present in an amount of at least 1% (w / w), such as at least 2% (w / w), at least 3% (w / w), at least 4% (w / w), at least 5% (w / w), or at least 6% (w / w) relative to the second composition (II).

21. 21. A binary pharmaceutical composition according to claim 19 or 20, wherein the cellulose derivative polymer is hydroxypropyl methylcellulose (HPMC) present in an amount of 22% (w / w) or less, such as 21% (w / w) or less, such as 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, or 14% (w / w) or less, relative to the second composition (II).

22. 22. A binary pharmaceutical composition according to any one of claims 19 to 21, wherein said cellulose derivative polymer is hydroxypropyl methylcellulose (HPMC) present in an amount of from 1% (w / w) to 20% (w / w), such as in the range of from 2% (w / w) to 18% (w / w), for example in the range of from 3% (w / w) to 18% (w / w), such as in the range of from 4% (w / w) to 18% (w / w), for example in the range of from 5% (w / w) to 18% (w / w), such as in the range of from 5% (w / w) to 17% (w / w), for example in the range of from 6% (w / w) to 17% (w / w), relative to said second composition (II).

23. 13. A binary pharmaceutical composition according to any one of claims 1 to 12, wherein the cellulose derivative polymer is ethylcellulose, for example ethylcellulose having a viscosity in the range of 3 mPa s to 150 mPa s when measured at 25°C for a 5% solution in a solvent of 80% toluene and 20% ethanol as measured with an Ubbelohde viscometer.

24. 24. The binary pharmaceutical composition of claim 23, wherein the cellulose derivative polymer is ethylcellulose present in an amount of at least 1% (w / w), such as at least 2% (w / w), at least 3% (w / w), at least 4% (w / w), at least 5% (w / w), or at least 6% (w / w) relative to the second composition (II).

25. 25. The binary pharmaceutical composition of claim 23 or 24, wherein the cellulose derivative polymer is ethylcellulose present in an amount of 22% (w / w) or less, such as 21% (w / w) or less, such as 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, or 14% (w / w) or less, relative to the second composition (II).

26. 26. A binary pharmaceutical composition according to any one of claims 23 to 25, wherein said cellulose derivative polymer is ethylcellulose present in an amount of from 1% (w / w) to 20% (w / w), such as in the range of from 2% (w / w) to 18% (w / w), for example in the range of from 3% (w / w) to 18% (w / w), such as in the range of from 4% (w / w) to 18% (w / w), for example in the range of from 5% (w / w) to 18% (w / w), such as in the range of from 5% (w / w) to 17% (w / w), for example in the range of from 6% (w / w) to 17% (w / w), relative to said second composition (II).

27. 27. A binary pharmaceutical composition according to any one of claims 1 to 26, wherein the alkali metal carbonate, such as sodium carbonate or sodium bicarbonate, is present in an amount of 1.5 to 5% (w / w), such as in the range of 1.6 to 4.8% (w / w), for example in the range of 1.7 to 4.6% (w / w), such as in the range of 1.8 to 4.4% (w / w), for example in the range of 1.9 to 4.2% (w / w), such as in the range of 2.0 to 4.0% (w / w), for example in the range of 2.1 to 3.8% (w / w), such as in the range of 2.2 to 3.6% (w / w), for example in the range of 2.3 to 3.4% (w / w), such as in the range of 2.4 to 3.2% (w / w), for example in the range of 2.5 to 3.0% (w / w), such as in the range of 2.0 to 3.5% (w / w), relative to the first raft-forming composition (I).

28. The polyvalent ions cross-linking the alginate, such as strontium ions or for example calcium ions, magnesium ions, aluminium ions, for example those derived from calcium carbonate, may be present in an amount of 0.8 to 4% (w / w) relative to the first raft-forming composition (I), such as in the range of 0.9 to 3.9% (w / w), for example in the range of 1.0 to 3.8% (w / w), for example in the range of 1.1 to 3.7% (w / w), such as in the range of 1.2 to 3.6% (w / w), for example in the range of 1.2 to 3.5% (w / w), for example in the range of 1.2 to 3.4% (w / w), for example in the range of 1.2 to 3.

28. A binary pharmaceutical composition according to any one of claims 1 to 27, wherein the composition is present in an amount in the range of 3% (w / w), such as in the range of 1.2 to 3.2% (w / w), for example in the range of 1.2 to 3.0% (w / w), such as in the range of 1.2 to 2.8% (w / w), for example in the range of 1.2 to 2.6% (w / w), such as in the range of 1.2 to 2.4% (w / w), for example in the range of 1.2 to 2.2% (w / w), such as in the range of 1.2 to 2.0% (w / w), for example in the range of 1.3 to 2.0% (w / w), such as in the range of 1.3 to 1.8% (w / w), for example in the range of 1.4 to 1.8% (w / w).

29. 29. A binary pharmaceutical composition according to any one of claims 1 to 28, wherein the viscosity imparting agent, such as a hydrocolloid, is present in an amount of from 0.05% (w / w) to 1.0% (w / w), such as in the range of from 0.06% (w / w) to 0.8% (w / w), for example in the range of from 0.07% (w / w) to 0.7% (w / w), such as in the range of from 0.08% (w / w) to 0.6% (w / w), for example in the range of from 0.09% (w / w) to 0.5% (w / w), such as in the range of from 0.10% (w / w) to 0.40% (w / w), for example in the range of from 0.12% (w / w) to 0.35% (w / w).

30. A binary pharmaceutical composition according to any one of claims 1 to 29, wherein the viscosity imparting agent is a pharmaceutically acceptable polyacrylic acid, such as a carbomer, such as carbomer type A.

31. The binary pharmaceutical composition according to any one of claims 1 to 30, wherein said first (I) composition and said second (II) composition are mixed to form a final pharmaceutical composition.

32. 1. A method for preparing a two-component pharmaceutical composition, said method comprising the steps of mixing compositions (I) and (II), said first raft-forming composition (I) comprising: a) alginate in an amount of 2% (w / w) to 8% (w / w); b) carbonates, such as alkali metal carbonates, for example ammonium carbonate, ammonium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate, or calcium carbonate; c) polyvalent ions that cross-link the alginate, such as strontium ions or, for example, calcium ions, magnesium ions, aluminum ions, e.g., derived from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w); d) at least one pharmaceutically acceptable viscosity imparting agent in an amount of about 0.01 (w / w) to 1.0% (w / w) selected from i) hydrocolloids, such as any one selected from the group consisting of guar gum, pectin and its derivatives, xanthan gum, arabinoxylan, cellulose and its derivatives, chitin, xylan, beta-glucan, gum arabic, hyaluronic acid, and gelatin, and ii) a pharmaceutically acceptable polyacrylic acid, such as carbopol; and e) Water or other pharmaceutically acceptable vehicle comprising or consisting of said second composition (II) comprises or consists of: a) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose, and methylcellulose (MC), hydroxypropylcellulose (HPC) and mixtures thereof; b) an active pharmaceutical ingredient (API); and c) optionally, water or any other pharmaceutically acceptable vehicle; Methods for preparing binary pharmaceutical compositions.

33. 33. The method of claim 32, further comprising either of the steps of: 1) forming a paste, drying, and then passing the semi-dry material through a passage to obtain the desired granule size; or 2) granulating the mixed powder with water or any other pharmaceutically acceptable vehicle to obtain granules having the desired granule size.

34. 1. Use of a two-component pharmaceutical composition comprising compositions (I) and (II), wherein said first raft-forming composition (I) comprises: a) alginate in an amount of 2% (w / w) to 8% (w / w); b) carbonates, such as alkali metal carbonates, for example ammonium carbonate, ammonium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate, or calcium carbonate; c) polyvalent ions that cross-link the alginate, such as strontium ions or, for example, calcium ions, magnesium ions, aluminum ions, e.g., derived from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w); d) at least one pharmaceutically acceptable viscosity imparting agent in an amount of about 0.01 (w / w) to 1.0% (w / w) selected from i) hydrocolloids, such as any one selected from the group consisting of guar gum, pectin and its derivatives, xanthan gum, arabinoxylan, cellulose and its derivatives, chitin, xylan, beta-glucan, gum arabic, hyaluronic acid, and gelatin, and ii) a pharmaceutically acceptable polyacrylic acid, such as carbopol; and e) Water or other pharmaceutically acceptable vehicle comprising or consisting of 1. Use of a two-component pharmaceutical composition for use in the treatment of a medical condition for which said API is indicated, wherein said second composition (II) comprises or consists of: a) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose, and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof; b) an active pharmaceutical ingredient (API); and c) optionally, water or any other pharmaceutically acceptable vehicle.

35. 1. A method for treating a medical condition for which an API is indicated, said method comprising administering to a subject in need thereof an effective amount of a binary pharmaceutical composition comprising compositions (I) and (II), said first raft-forming composition (I) comprising: a) alginate in an amount of 2% (w / w) to 8% (w / w); b) carbonates, such as alkali metal carbonates, for example ammonium carbonate, ammonium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate, or calcium carbonate; c) polyvalent ions that cross-link the alginate, such as strontium ions or, for example, calcium ions, magnesium ions, aluminum ions, e.g., derived from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w); d) at least one pharmaceutically acceptable viscosity imparting agent in an amount of about 0.01 (w / w) to 1.0% (w / w) selected from i) hydrocolloids, such as any one selected from the group consisting of guar gum, pectin and its derivatives, xanthan gum, arabinoxylan, cellulose and its derivatives, chitin, xylan, beta-glucan, gum arabic, hyaluronic acid, and gelatin, and ii) a pharmaceutically acceptable polyacrylic acid, such as carbopol; and e) Water or other pharmaceutically acceptable vehicle comprising or consisting of said second composition (II) comprises or consists of: a) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose, and methylcellulose (MC), hydroxypropylcellulose (HPC) and mixtures thereof; b) an active pharmaceutical ingredient (API); and c) optionally, water or any other pharmaceutically acceptable vehicle; A method for treating a medical condition for which the API is indicated.

Images