Novel alginate and cellulose derivative-based compositions for anti-reflux liquid formulations

Abstract

The present invention relates to a raft-forming pharmaceutical suspension suitable for the oral treatment of gastroesophageal reflux disease, a method for its preparation, and its use in the treatment of gastroesophageal reflux disease.

Description

Technical Field

[0001] The present invention relates to a raft-forming pharmaceutical suspension suitable for the oral treatment of gastroesophageal reflux disease, a method for its preparation, and its use in the treatment of gastroesophageal reflux disease.

Background Art

[0002] The human stomach is a complex system with various functions such as storing food, initiating the digestion of proteins, killing harmful bacteria, and moving food into the small intestine as a pasty substance called chyme.

[0003] When an individual ingests food, the swallowed food enters the stomach through the esophagus by wave-like contractions known as peristalsis. The lumen at the end of the esophagus is slightly narrowed due to the thickening of the circular muscle fibers in its wall: the lower esophageal or gastroesophageal sphincter. After the food enters the stomach, the contraction of the muscle fibers prevents the contents of the stomach from flowing back into the esophagus. The reflux may occur due to the pressure difference on both sides as a result of the respiratory movement.

[0004] Gastroesophageal reflux occurs when the esophageal sphincter opens spontaneously or cannot be closed for various periods, causing acidic gastric juice to rise from the stomach through the esophagus and sometimes up to the mouth. Gastroesophageal reflux disease occurs when reflux episodes occur for a long period. This disease or syndrome is caused by the incomplete closure of the cardiac sphincter at the uppermost part of the stomach, and the symptoms can range from a burning sensation to esophagitis, vagus nerve reflex, thickening in the esophageal region (hiatal hernia), and epithelial mutations (Barrett's esophagus). Gastroesophageal reflux disease can also promote esophageal cancer, or exacerbate or contribute to respiratory disorders (such as asthma, chronic cough, and pulmonary fibrosis). The reflux of acid from the stomach, when in contact with the inner layer of the esophagus, not only causes direct damage to the mucosa but also can cause a burning sensation in the chest and pharynx known as "heartburn". This disease can cause severe complications, especially chronic inflammatory conditions (reflux esophagitis), which can cause bleeding and mucosal changes that narrow the esophageal lumen over time, making swallowing difficult.

[0005] The alginate composition described in British Patent No. 1524740 forms the basis of a product called Gaviscon. In a strongly acidic environment such as the stomach, a thick neutral gel can be formed that floats in the gastric juice and forms a thick, high-density layer called a "raft", which acts as a plug for gastroesophageal reflux and suppresses acid reflux from the stomach into the esophagus.

[0006] WO 2012 / 128520 pamphlet relates to a liquid composition for treating gastroesophageal diseases by oral administration. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] It is an object of an embodiment of the present invention to provide a raft-forming pharmaceutical suspension suitable for the treatment of gastroesophageal reflux disease. MEANS FOR SOLVING THE PROBLEMS [[ID=Z19]]

[0008] In a broad aspect, the present invention relates to a raft-forming suspension containing a relatively small amount of alginate compared to conventional suspensions, having equivalent raft strength, and being suitable for the treatment of gastroesophageal reflux disease.

[0009] Thus, in a first aspect, the present invention is a raft-forming pharmaceutical suspension suitable for the treatment of gastroesophageal reflux disease by oral administration, a) an alginate in an amount of 2% (w / w) to 5% (w / w), and b) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof, c) a carbonate, such as an alkali metal carbonate, such as sodium carbonate or sodium bicarbonate or ammonium carbonate or calcium, d) An amount of divalent alginate cross-linking ions from about 1.1% (w / w) to 2.2% (w / w), such as ions of calcium, magnesium, aluminum, e.g., those derived from calcium carbonate, and e) i) A hydrophilic colloid 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) At least one thickening agent selected from pharmaceutically acceptable polyacrylic acids, such as carbomers, e.g., carbomer type A, and f) Water or another pharmaceutical vehicle and relates to a raft-forming pharmaceutical suspension comprising or consisting of these.

[0010] Components c) and d) of the suspension composition described herein, namely the carbonate and divalent alginate cross-linking ions respectively, can be the same compound. For example, it will be understood that this carbonate source for raft floating is, for example, calcium carbonate, and this calcium carbonate also provides divalent cross-linking ions.

[0011] In a second aspect, the present invention is a method for preparing a raft-forming suspension, comprising a) An amount of alginate from 2% (w / w) to 5% (w / w), and b) A cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), e.g., sodium carboxymethylcellulose and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof, and c) A carbonate, such as an alkali metal carbonate, e.g., sodium carbonate or sodium bicarbonate or ammonium carbonate or calcium, and d) An amount of divalent alginate cross-linking ions from about 1.1% (w / w) to 2.2% (w / w), such as ions of calcium, magnesium, aluminum, e.g., those derived from calcium carbonate, and e) i) Any one selected from the group consisting of hydrophilic colloids 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 thickening agent selected from pharmaceutically acceptable polyacrylic acids such as carbomers, such as carbomer A type, f) water or other pharmaceutical vehicle and a method comprising the step of mixing the components thereof.

[0012] In a third aspect, the present invention is for use in the treatment of gastroesophageal reflux disease a) alginate in an amount of 2% (w / w) to 5% (w / w), b) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose and methylcellulose (MC), hydroxypropylcellulose (HPC) and mixtures thereof, c) carbonates, such as alkali metal carbonates, such as sodium carbonate or sodium bicarbonate or ammonium carbonate or calcium, d) polyvalent alginate cross-linking ions in an amount of about 1.1% (w / w) to 2.2% (w / w), such as calcium, magnesium, aluminum ions, such as those derived from calcium carbonate, e) i) Any one selected from the group consisting of hydrophilic colloids 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 thickening agent selected from pharmaceutically acceptable polyacrylic acids such as carbomers, such as carbomer A type, f) water or other pharmaceutical vehicle and relates to the use of a raft-forming pharmaceutical suspension comprising.

Mode for Carrying Out the Invention

[0013] Alginic acid and its salts. Alginates, especially those derived from brown algae, are linear unbranched biopolymers composed of (1-4)-linked β-D-mannuronic acid (M) and α-L-guluronic acid (G) residues. Alginates are not random copolymers but consist of blocks of similar and alternating sequences of residues, such as MMMM, GGGG, and GMGM. In the extracted form, alginates rapidly absorb water. The physical properties of alginates can depend on the relative proportion of M blocks and G blocks. Gel formation at neutral pH requires a source of polyvalent ions, such as calcium, magnesium, aluminum, e.g., calcium ions, to interact with the G blocks. The greater the proportion of these G blocks, the greater the gel strength.

[0014] As used herein, "polyvalent alginate crosslinking ions" refers to any ions suitable for crosslinking or gel formation of alginates. It will be understood that this alginate gel formation can be provided by many polyvalent ions, including 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 some specific embodiments, the polyvalent alginate crosslinking ions used are calcium ions or magnesium ions or aluminum ions.

[0015] "Alginates" is a term commonly used for salts of alginic acid, but can also refer to all derivatives of alginic acid and alginic acid itself. Alginates are present in the cell walls of brown algae as calcium, magnesium, and sodium salts of alginic acid. Dry powdered sodium alginate or potassium alginate can be obtained from this extraction process of brown algae. The seaweed residue can then be removed by filtration, and the remaining alginate can then be recovered from the aqueous solution.

[0016] Another way to recover alginate from the initial extraction solution is to add a calcium salt. This causes calcium alginate to form with a fibrous texture that does not dissolve in water and can be separated from water. The separated calcium alginate is suspended in water and an acid is added to convert it to alginic acid.

[0017] Alginates suitable for use in the practice of the present invention typically have a molecular weight such that when measured at 20 °C and 2 wt% using a rheometer facility equipped with a cup and bob geometry at a shear rate of 10 s -1 , exhibit viscosities in the range of 5 - 1,000 mPa·s. In some embodiments, when measured in this way, such alginates exhibit viscosities of 6 - 600 mPa·s, such as 7 - 500 mPa·s or 8 - 500 mPa·s. In some other embodiments, when measured in this way, such alginates exhibit viscosities of 8 - 400 mPa·s, such as 8 - 300 mPa·s, such as 9 - 200 mPa·s or 10 - 100 mPa·s.

[0018] In some embodiments according to the present invention, high G-type alginates are used. High G-type alginates mean that the alginates used in the practice of the present invention have on average at least 50 percent adjacent G units. In some embodiments, the alginate has on average at least 52 percent adjacent G units, in other embodiments, such alginates have on average at least 55 percent or more adjacent G units, and in other embodiments, such alginates have on average at least 60, 65 or 70 percent or more adjacent G units. This is because such higher contents of adjacent G units can result in an improvement in the product texture.

[0019] The fine dispersion of alginic acid containing an appropriate ratio or amount of plasticizer has been found to be capable of forming an alginic acid film. This alginic film exhibits controlled drug permeation over time in the Franz cell diffusion test. A very thin film thickness (59 μm) is required for a hard but flexible film that provides controlled release, such as zero-order controlled release. In connection with the present invention, it will be understood that there is a significantly lower alginate concentration when compared to existing alginate raft-forming suspensions. The composition provides the desired raft properties using a significantly reduced amount of alginate (40% w / w compared to the amount used in the reference Gaviscon composition).

[0020] Furthermore, there is a reduction in the variability of raft strength. When the alginate is reduced and sodium carboxymethyl cellulose is added, the composition exhibits a reduction in the variability of raft strength (%RSD less than 15%) compared to the reference formulation (%RSD greater than 20%). This can provide consistency in raft strength performance in vivo.

[0021] According to the present invention, alginates such as alginic acid or salts of alginic acid are present in an amount of 2% (w / w) to 5% (w / w) based on the total weight of the composition. In the present invention, alginates refer to alginic acid or salts of alginic acid, such as sodium alginate, magnesium alginate, potassium alginate, triethanolamine alginate, or propylene glycol monoglycolate.

[0022] Thickening agent Thickening agents or viscosity-imparting agents are known to those skilled in the art. Suitable thickening agents include any one selected from the group consisting of hydrophilic colloids 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) pharmaceutically acceptable polyacrylic acids such as carbomers, such as Carbomer A type. For the purposes of the present invention, the thickening agent does not include alginates or cellulose derivative polymers specifically defined elsewhere.

[0023] Cellulose derivative polymer Any suitable cellulose derivative polymer can be used in accordance with the present invention. Those skilled in the art will know these suitable polymers. Suitable film-forming polymers used 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), hypromellose 1828 (23-32% HP, 16.5-20% methoxy).

[0024] Examples of commercially available carboxymethyl cellulose (CMC) include TEXTURACEL™ from IFF, Celetec™ from CPKelco, Aqualon™ from Ashland, Rheoflo® from USK Kimya A.S., and Akucell® (formerly AkzoNobel) from Nouryon. Examples of commercially available methyl cellulose and hydroxypropyl methyl cellulose include the Japanese Pharmacopoeia METOLOSE™ series and METOLOSE™ series for food additives from Shin-Etsu Chemical Co., Ltd., the AnyCoat-C or AnyAddy™ series from Lotte (formerly Samsung) Fine Chemicals Co., Ltd., the METHOCEL™ series from IFF (formerly DOW Chemical Company), and the Benecel™ series from Ashland.

[0025] The preservative can be any suitable compound known in the technical field of pharmaceutically acceptable compounds, such as any one selected from the group consisting of ethanol, benzethonium chloride, citric acid monohydrate, sodium salicylate, carbolic acid, sodium benzoate, sodium dehydroacetate, oxyquinoline sulfate, potassium sorbate, benzalkonium chloride, benzenconium chloride, honey, 2-propanol, formalin, 1,2-hydroxypropane, human serum albumin, potassium L-glutamate, N-coconut oil fatty acyl-N-carboxymethyl-N-hydroxyethyl ethylenediamine sodium, thimerosal, boric acid, taurine, sodium edetate, N-hexadecylpyridinium 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 para-hydroxybenzoate, butyl para-hydroxybenzoate, propyl para-hydroxybenzoate, methyl para-hydroxybenzoate, methyl paraoxybenzoate, eucalyptus oil, chlorhexidine gluconate, butylhydroxytoluene, sorbic acid, borneol, β-naphthol, dehydroacetic acid, isobutyl p-oxybenzoate, colored Peru balsam, benzoin, agar, 2-mercaptobenzimidazole, isopropyl p-oxybenzoate, n-dodecyltrimethylammonium chloride, tea tree oil, glyceryl caprylate, polyglyceryl-2 laurate, polyglyceryl-10 laurate, ethylhexylglycerin, glyceryl caprate, or any combination of two or more of these.

[0026] Methyl cellulose is one of the cellulose derivative polymers suitable for the present invention. Methyl cellulose has anhydroglucose units linked by 1-4 bonds. Each anhydroglucose unit contains hydroxyl groups at the 2nd, 3rd, and 6th positions. By partial or complete substitution of these hydroxyls with methoxyl groups, methyl cellulose is produced. For example, treatment of cellulose fibers with a caustic solution followed by a methylating agent results in a cellulose ether substituted with one or more methoxyl groups. If not further substituted with other alkyls, this cellulose ether is known as methyl cellulose. Methyl cellulose is characterized by the weight percentage of methoxyl groups. By convention, the weight percentage is the average weight percentage based on the total weight of the cellulose repeating unit including all substituents. The methoxyl content is recorded based on the mass of the methoxyl group (i.e., -OCH3). The determination of methoxyl (%) in the methyl cellulose (MC) polymer is carried out according to the United States Pharmacopeia (USP 37, “Methylcellulose”, pages 3776-3778). Methoxyl (%) can be converted to the degree of substitution (DS) for the methyl substituent, DS(methyl). The DS(methyl) of methyl cellulose, also referred to as DS(methoxyl), is the average number of OH groups substituted with methyl groups per anhydroglucose unit. Preferably, methyl cellulose has 18% or more, more preferably 25% or more of methoxyl (%). Preferably, component (b) has 50% or less, more preferably 40% or less, even more preferably 35% or less of methoxyl (%). Even more preferably, methyl cellulose has a DS(methyl) of 1.55 or more, more preferably 1.65 or more, and most preferably 1.70 or more. 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 proper characterization of methyl cellulose is the ratio s23 / s26. The numbers 2, 3, and 6 refer to the defined carbon atoms on the anhydroglucose unit.

[0027] Parameter s23 is the mole fraction of anhydroglucose units in which only the two hydroxy groups at the 2- and 3-positions of the anhydroglucose unit are substituted with methyl groups, and parameter s26 is the mole fraction of anhydroglucose units in which only the two hydroxy groups at the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups. For determining s23, the term "mole fraction of anhydroglucose units in which only the two hydroxy groups at the 2- and 3-positions of the anhydroglucose unit are substituted with methyl groups" means that the two hydroxy groups at the 2- and 3-positions are substituted with methyl groups and the hydroxy group at the 6-position is unsubstituted. For determining s26, the term "mole fraction of anhydroglucose units in which only the two hydroxy groups at the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups" means that the two hydroxy groups at the 2- and 6-positions are substituted with methyl groups and the hydroxy group at the 3-position is unsubstituted. The ratio s23 / s26 is determined by dividing s23 by s26.

[0028] According to the present invention, in some embodiments, s23 / s26 is 0.24 or less, for example 0.23 or less. Further, s23 / s26 can be 0.10 or more, for example 0.14 or more. Methylcellulose having such an s23 / s26 ratio can be produced as mostly described in the pamphlet of International Patent Application Publication No. WO 2013 / 059064. A specific process for producing methylcellulose having the above-described s23 / s26 ratio is described in the pamphlet of International Publication No. WO 2017 / 192445, and a commercially available product having such an s23 / s26 ratio is Methocel (trademark) Bind 112 from IFF.

[0029] The present invention also requires that the raft-forming suspension contains a carbonate source for raft floating, such as an alkali metal carbonate, such as an alkali metal hydrogen carbonate or an alkali metal carbonate, such as sodium carbonate or sodium hydrogen carbonate or ammonium carbonate or ammonium hydrogen carbonate, calcium carbonate or any other carbonate or hydrogen carbonate. The raft-forming suspension is also required to contain a polyvalent ion, such as calcium, magnesium, aluminum, for example, from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w) for alginate crosslinking.

[0030] A solution for measuring the viscosity of sodium carboxymethyl cellulose (CMC, for example, TEXTURACEL™ 20000 PA 07) is prepared by adding an appropriate amount of CMC powder to an appropriate amount of water to obtain a 1% concentration while stirring with an overhead laboratory stirrer at ambient temperature for at least 1 hour. The viscosity is examined at 20 °C using a rheometer (for example, Anton Paar MCR 501) equipped with a cup and bob geometry (for example, CC-27). The viscosity is in the range of 10 mPa·s to 15000 mPa·s, and in some embodiments, when measured in this way, exhibits a viscosity of 15 to 12000 mPa·s, for example, 20 to 11000 mPa·s or 25 to 10000 mPa·s.

[0031] A solution for measuring the viscosity of methylcellulose (MC, e.g., Methocel™ BIND 112) is prepared by adding an appropriate amount of MC powder to an appropriate amount of water while stirring with an overhead laboratory stirrer at ambient temperature to obtain a 2% concentration. Then, the solution is cooled to a temperature below 5°C and stirred for at least 3 hours. The viscosity is examined at 5°C using a rheometer (e.g., Anton Paar MCR 501) equipped with a cup and bob geometry (e.g., CC-27). The viscosity is in the range of from 15 mPa·s to 100,000 mPa·s, and in some embodiments, when measured in this way, exhibits a viscosity of from 50 to 80,000 mPa·s, such as from 100 to 75,000 mPa·s or from 150 to 70,000 mPa·s.

Example

[0032] Example 1 Apparatus used for manufacturing the formulation 1. Overhead stirrer 2. Weighing balance

[0033] Liquid alginate preparation: Composition 1:

[0034]

Table 1

[0035] Process: 1. Sodium bicarbonate, calcium carbonate, and sodium saccharin are added to purified water and dissolved. Sodium alginate is added thereto, and the mixture is stirred for 30 minutes. 2. Xanthan gum is added to Step 1. The mixture is stirred for 30 minutes. 3. Sodium carboxymethylcellulose is added to purified water with stirring to dissolve. 4. Step 3 is added to 2, and the dispersion is thoroughly mixed. 5. Methylparaben and propylparaben are added to warm water and dissolved. 6. Add Step 5 to 4 and mix well with stirring. Stir this mixture for 30 minutes.

[0036] Raft strength evaluation: Raft strength test assay: 1. Add 20 mL of the raft suspension to 150 mL of 0.1 M HCl maintained at 37 °C in a 250 mL round-bottom glass beaker having an inner diameter of 60 - 70 mm. A L-shaped stainless steel wire probe containing 316 gauge stainless steel with a diameter of 1 mm and having a 90 mm vertical arm and a 20 mm horizontal arm with a hook at the top was held vertically such that during the addition of the suspension, the vertical arm of the probe hung down the central axis of the beaker and the horizontal arm was at one-third from the bottom of the acid. 2. Maintain this beaker at 37 °C for 30 minutes. 3. After 30 minutes of raft formation, place the beaker on a TX Plus Texture Analyzer (TX plus type, manufactured by Stable Microsystem, UK) using a 5.0 kg load cell. 4. Hang the wire probe on the arm of the texture analyzer and pull it vertically through the raft at a speed of 5 mm / second. 5. Record the force (g) required to pull the wire probe through the raft using the texture analyzer. The variation in raft strength is expressed as the relative standard deviation (RSD) in percentage. This is calculated by multiplying the standard deviation by 100 and dividing by the mean of the raft strength values.

[0037] Raft volume and raft weight test: 1. Weigh the beaker beforehand (W1). Add 20 mL of the raft suspension to 150 mL of 0.1 M HCl maintained at 37 °C in a 250 mL round-bottom glass beaker. 2. Maintain this beaker at 37 °C for 30 minutes. 3. After 30 minutes of raft formation. 4. Mark on the outside of the beaker the position reached by the top of each raft. Weigh this beaker (W2). 5. Next, the supernatant was carefully decanted and removed, and the raft was taken out of the beaker by pouring it into a pre-weighed plastic weighing boat. 6. This was left standing for 30 seconds to drain off the excess supernatant, and the raft was weighed (W3). 7. Using a paper towel, the remaining liquid was removed from the inside of the beaker, and then the beaker was refilled with water up to the marked position and weighed (W4). 8. Next, the volume of each raft was calculated from the following formula: raft volume = (W4 - W1) - (W2 - W1 - W3) (where the raft volume is measured in ml). All weights are measured in g.

[0038] [Table 2]

[0039] The raft strength variation data for the reference product and the test compositions are listed below, which shows an improvement in the observed raft strength variation.

[0040] [Table 3]

[0041] Composition 2:

[0042] [Table 4]

[0043] Process: Preparation of METHOCEL™ Bind 112 gel: METHOCEL™ Bind 112 (methylcellulose) is added to purified water (temperature 20 - 25°C) with stirring using an overhead laboratory stirrer at room temperature. After complete dispersion, the solution is stirred at 750 rpm for 120 minutes under low temperature conditions (temperature below 5°C).

[0044] Preparation of raft composition 1. Sodium bicarbonate, calcium carbonate, and sodium saccharin are added to purified water and dissolved. Sodium alginate is added thereto, and the mixture is stirred for 30 minutes. 2. The prepared METHOCEL (trademark) Bind 112 gel is added to Step 2 under stirring. The mixture is stirred for 1 hour. 3. Xanthan gum is added, and the mixture is stirred for 30 minutes. 4. Methylparaben and propylparaben are added to warm water and dissolved. 5. Added from Step 4 to 3 and mixed well under stirring. The mixture is stirred for 30 minutes.

[0045] Raft strength evaluation: For the procedure, refer to the procedure listed in Composition 1.

[0046]

Table 5

[0047] The raft strength variation data of the reference product and the test composition are listed below, which shows an improvement in the observed raft strength variation.

[0048]

Table 6

Claims

1. A raft-forming pharmaceutical suspension suitable for the treatment of gastroesophageal reflux disease by oral administration, a) alginate in an amount of 2% (w / w) to 5% (w / w), b) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose and methylcellulose (MC), hydroxypropylcellulose (HPC), and mixtures thereof, c) a carbonate, such as an alkali metal carbonate, such as sodium carbonate or sodium bicarbonate or ammonium carbonate or calcium carbonate, d) polyvalent alginate cross-linking ions in an amount of about 1.1% (w / w) to 2.2% (w / w), such as calcium, magnesium, aluminum ions, such as those derived from calcium carbonate, e) i) a hydrophilic colloid, 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) at least one thickening agent selected from pharmaceutically acceptable polyacrylic acids, such as carbomer, such as carbomer type A, f) water or other pharmaceutical vehicles A raft-forming pharmaceutical suspension comprising or consisting of these.

2. The raft-forming pharmaceutical suspension according to claim 1, wherein the alginate is a salt of alginic acid such as sodium alginate.

3. The raft-forming pharmaceutical suspension according to claim 1 or 2, wherein the polyvalent ions are calcium ions such as those derived from calcium carbonate.

4. The raft-forming pharmaceutical suspension according to any one of claims 1 to 3, wherein the carbonate is an alkali metal carbonate such as sodium bicarbonate or potassium bicarbonate.

5. The raft-forming pharmaceutical suspension according to any one of claims 1 to 4, further comprising a preservative such as propyl p-hydroxybenzoate and / or methyl p-hydroxybenzoate.

6. The raft-forming pharmaceutical suspension according to any one of claims 1 to 5, further comprising a flavor and / or sweetening compound.

7. The alginate is present in an amount of at least 2.1% (w / w), for example at least 2.2% (w / w), for example at least 2.3% (w / w), for example at least 2.4% (w / w), for example at least 2.5% (w / w), for example at least 2.6% (w / w), for example at least 2.7% (w / w), for example at least 2.8% (w / w), for example at least 2.9% (w / w), for example at least 3.0% (w / w), for example at least 3.2% (w / w), in the raft-forming pharmaceutical suspension according to any one of claims 1 to 6.

8. The alginate is present in an amount of 5% (w / w) or less, for example 4.9% (w / w) or less, for example 4.8% (w / w) or less, for example 4.7% (w / w) or less, for example 4.6% (w / w) or less, for example 4.5% (w / w) or less, for example 4.4% (w / w) or less, for example 4.3% (w / w) or less, for example 4.2% (w / w) or less, for example 4.1% (w / w) or less, for example 4.0% (w / w) or less, for example 3.9% (w / w) or less, for example 3.8% (w / w) or less, for example 3.7% (w / w) or less, for example 3.6% (w / w) or less, for example 3.5% (w / w) or less, for example 3.4% (w / w) or less, for example 3.3% (w / w) or less, in the raft-forming pharmaceutical suspension according to any one of claims 1 to 7.

9. The cellulose derivative polymer is present in an amount of at least 0.1% (w / w), for example at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 or 1.8% (w / w), in the raft-forming pharmaceutical suspension according to any one of claims 1 to 8.

10. The cellulose derivative polymer is present in an amount of 2.0% (w / w) or less, for example 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6 or 0.5% (w / w) or less, in the raft-forming pharmaceutical suspension according to any one of claims 1 to 8.

11. The cellulose derivative polymer is carboxymethyl cellulose such as sodium carboxymethyl cellulose and is present in an amount of 0.1% (w / w) to 2.0% (w / w), in the raft-forming pharmaceutical suspension according to any one of claims 1 to 10.

12. The cellulose derivative polymer is, for example, carboxymethyl cellulose such as sodium carboxymethyl cellulose, present in an amount in the range of 0.1% (w / w) to 0.75% (w / w), for example, 0.2% (w / w) to 0.65% (w / w), for example, 0.3% (w / w) to 0.60% (w / w), for example, 0.4% (w / w) to 0.6% (w / w), the raft-forming pharmaceutical suspension according to any one of claims 1 to 11.

13. The cellulose derivative polymer has a viscosity in the range of 10 mPa·s to 15,000 mPa·s when measured at 20 °C at a concentration of 1% in water at a shear rate of 10 s －１ and is carboxymethyl cellulose such as sodium carboxymethyl cellulose, the raft-forming pharmaceutical suspension according to any one of claims 1 to 12.

14. The cellulose derivative polymer is, for example, methyl cellulose present in an amount in the range of 0.5% (w / w) to 2.0% (w / w), for example, 0.6% (w / w) to 1.8% (w / w), for example, 0.7% (w / w) to 1.7% (w / w), for example, 0.8% (w / w) to 1.8% (w / w), for example, 0.9% (w / w) to 1.9% (w / w), for example, 1.0% (w / w) to 1.8% (w / w), for example, 1.1% (w / w) to 1.7% (w / w), for example, 1.2% (w / w) to 1.6% (w / w), the raft-forming pharmaceutical suspension according to any one of claims 1 to 10.

15. The cellulose derivative polymer is 10s －１ 15. The raft-forming pharmaceutical suspension of claim 14, 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 at a concentration of 2% in water at 5°C.

16. The cellulose derivative polymer is methyl cellulose having an s23 / s26 of 0.10 to 0.24, for example, 0.14 to 0.23, where s23 is the mole fraction of anhydroglucose units in which only two hydroxy groups at the 2nd and 3rd positions 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 the 2nd and 6th positions of the anhydroglucose unit are substituted with methyl groups, the raft-forming pharmaceutical suspension according to claim 14 or 15.

17. The carbonate such as an alkali metal carbonate such as sodium carbonate or sodium hydrogen carbonate is present in an amount in the range of 1.5 to 5% (w / w), for example, 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), for example, in the range of 1.9 to 4.2% (w / w), for example, in the range of 2.0 to 4.0% (w / w), for example, in the range of 2.1 to 3.8% (w / w), for example, in the range of 2.2 to 3.6% (w / w), for example, in the range of 2.3 to 3.4% (w / w), for example, in the range of 2.4 to 3.2% (w / w), for example, in the range of 2.5 to 3.0% (w / w), for example, in the range of 2.0 to 3.5% (w / w), the raft-forming pharmaceutical suspension according to any one of claims 1 to 16.

18. The polyvalent alginate cross-linking ions such as those derived from calcium carbonate are present in an amount in the range of 0.8 to 4% (w / w), for example, 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), 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), for example, in the range of 1.2 to 3.4% (w / w), for example, 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), for example, 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), for example, 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), for example, in the range of 1.3 to 1.8% (w / w), for example, in the range of 1.4 to 1.8% (w / w), the raft-forming pharmaceutical suspension according to any one of claims 1 to 17.

19. The thickener is present in an amount in the range of 0.05% (w / w) to 1.0% (w / w), for example in the range of 0.06% (w / w) to 0.8% (w / w), for example in the range of 0.07% (w / w) to 0.7% (w / w), for example in the range of 0.08% (w / w) to 0.6% (w / w), for example in the range of 0.09% (w / w) to 0.5% (w / w), for example in the range of 0.10% (w / w) to 0.40% (w / w), for example in the range of 0.12% (w / w) to 0.35% (w / w), the raft-forming pharmaceutical suspension according to any one of claims 1 to 18.

20. The raft strength measured with a texture analyzer as described in the raft strength test assay is higher than 7.5 g, for example higher than 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0 or 13.5 g, the raft-forming pharmaceutical suspension according to any one of claims 1 to 19.

21. The variation in raft strength is a relative standard deviation (%RSD) of less than 20%, for example less than 18, 16, 14, 12, 10, 8 or 7 percent, the raft-forming pharmaceutical suspension according to any one of claims 1 to 20.

22. A method for preparing a raft-forming suspension, a) an alginate in an amount of 2% (w / w) to 5% (w / w), b) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), for example sodium carboxymethylcellulose and methylcellulose (MC), hydroxypropylcellulose (HPC) and mixtures thereof, c) a carbonate, for example an alkali metal carbonate, for example sodium carbonate or sodium bicarbonate or ammonium carbonate or calcium, d) a polyvalent alginate crosslinking ion in an amount of about 1.1% (w / w) to 2.2% (w / w), for example an ion of calcium, magnesium, aluminum, for example from calcium carbonate, e) i) Any one selected from the group consisting of hydrophilic colloids 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 thickening agent selected from pharmaceutically acceptable polyacrylic acids such as carbomers, for example carbomer type A, and f) water or other pharmaceutical vehicles A method comprising the step of mixing the components of.

23. For use in the treatment of gastroesophageal reflux disease, a) alginate in an amount of 2% (w / w) to 5% (w / w), b) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose and methylcellulose (MC), hydroxypropylcellulose (HPC) and mixtures thereof, c) carbonates, such as alkali metal carbonates, such as sodium carbonate or sodium bicarbonate or ammonium carbonate or calcium carbonate, d) polyvalent alginate cross-linking ions in an amount of about 1.1% (w / w) to 2.2% (w / w), such as calcium, magnesium, aluminum ions, such as those derived from calcium carbonate, e) i) Any one selected from the group consisting of hydrophilic colloids 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 thickening agent selected from pharmaceutically acceptable polyacrylic acids such as carbomers, for example carbomer type A, and f) water or other pharmaceutical vehicles Use of a raft-forming pharmaceutical suspension comprising.

24. A method for the treatment of gastroesophageal reflux disease, comprising administering to a subject in need thereof an effective amount of a raft-forming suspension, said raft-forming suspension comprising a) alginate in an amount of 2% (w / w) to 5% (w / w), b) a cellulose derivative polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose and methylcellulose (MC), hydroxypropylcellulose (HPC) and mixtures thereof, c) a carbonate, such as an alkali metal carbonate, such as sodium carbonate or sodium bicarbonate or ammonium carbonate or calcium carbonate, and d) polyvalent alginate cross-linking ions in an amount of about 1.1% (w / w) to 2.2% (w / w), such as calcium, magnesium, aluminum ions, such as those derived from calcium carbonate, and e) i) a hydrophilic colloid 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) at least one thickening agent selected from pharmaceutically acceptable polyacrylic acids, such as carbomers, such as Carbomer A type, and f) water or another pharmaceutical vehicle A method comprising or consisting of these.

25. The suspension is as described in any one of claims 1 to 21, a method of preparation, use or treatment as described in any one of claims 22 to 24.

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