Novel liquid anti-reflux formulation compositions based on alginate and cellulose derivatives

Abstract

The invention relates to a suspension formed by a drug raft suitable for oral treatment of gastroesophageal reflux diseases, a preparation method of the suspension and application of the suspension in treatment of the gastroesophageal reflux diseases.

Description

Technical Field

[0001] The invention relates to a drug raft-forming suspension suitable for oral treatment of gastroesophageal reflux disease, a preparation method thereof and use thereof in treating gastroesophageal reflux disease. Background Art

[0002] The human stomach is a complex system with different functions, such as storing food, initiating the digestion of proteins, killing harmful bacteria, and transporting food to the small intestine in a mushy substance called chyme.

[0003] When an individual ingests food, the swallowed food is moved through the esophagus into the stomach by wave-like contractions (called peristalsis). The lumen of the terminal part of the esophagus is slightly narrowed due to thickening of circular muscle fibers in its wall (the lower esophageal or gastroesophageal sphincter). After food enters the stomach, contractions of the muscle fibers prevent the stomach contents from flowing back into the esophagus. Reflux occurs because of the difference in pressure on each side caused by breathing movements.

[0004] Gastroesophageal reflux occurs when the esophageal sphincter opens spontaneously or fails to close for varying periods of time, causing acidic gastric juices to rise from the stomach into the esophagus and sometimes even into the mouth along with food. When reflux episodes persist for a longer period of time, gastroesophageal reflux disease develops. The disease or syndrome is caused by incomplete closure of the cardiac sphincter at the top of the stomach, and symptoms can range from burning sensations to esophagitis, nerve reflexes on the vagus nerve, thickening of the esophageal area (hiatal hernia), and epithelial mutations (Barrett's esophagus). Gastroesophageal reflux disease may also lead to esophageal cancer or may worsen or cause breathing disorders (such as asthma, chronic cough, and pulmonary fibrosis). When stomach acid refluxes into the lining of the esophagus, it not only directly damages the mucosa, but also causes a burning sensation in the chest and throat, the so-called "heartburn." The disease can cause serious complications, especially a chronic inflammatory state (reflux esophagitis), which over time can lead to bleeding and mucosal changes, narrowing of the esophageal lumen, and can make swallowing difficult.

[0005] The alginate composition described in GB 1524740 forms the basis of the product Gaviscon. In a strongly acidic environment like the stomach, thick neutral gels are formed that are able to float in gastric juice and form a thick dense layer, called a "raft", which acts as a plug for gastroesophageal reflux and inhibits the reflux of gastric acid into the esophagus.

[0006] WO 2012128520 relates to a liquid composition for treating gastroesophageal diseases by oral administration. Summary of the invention

[0007] It is an object of embodiments of the present invention to provide a drug raft-forming suspension suitable for treating gastroesophageal reflux disease.

[0008] In broad terms, the present invention relates to raft-forming suspensions comprising relatively small amounts of alginate compared to conventional suspensions, which suspensions have comparable raft strength and are useful for treating gastroesophageal reflux disease.

[0009] Thus, in a first aspect, the present invention relates to a pharmaceutical raft-forming suspension suitable for treating gastroesophageal reflux disease by oral administration, the pharmaceutical raft-forming suspension comprising or consisting of:

[0010] a) alginate in an amount of 2% (w / w) to 5% (w / w);

[0011] b) a cellulose derivative polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) such as sodium carboxymethyl cellulose, and methyl cellulose (MC), hydroxypropyl cellulose (HPC); and mixtures thereof;

[0012] c) carbonates, for example alkali metal carbonates, such as sodium carbonate or sodium bicarbonate; or ammonium carbonate or calcium carbonate;

[0013] d) polyvalent alginate cross-linking ions, such as calcium, magnesium, aluminum ions, for example from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w);

[0014] e) at least one viscosity increasing agent selected from: i) hydrocolloids, for example 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) pharmaceutically acceptable polyacrylic acid, for example carbomer, for example carbomer type A; and

[0015] f) Water or other pharmaceutical vehicles.

[0016] It will be appreciated that components c) and d) of the suspension compositions described herein (i.e. carbonate and multivalent alginate crosslinking ions respectively) may be the same compound, for example where the carbonate source for raft flotation is, for example, calcium carbonate; the calcium carbonate also providing the multivalent crosslinking ions.

[0017] In a second aspect, the present invention relates to a method for preparing a raft-forming suspension, the method comprising the following steps:

[0018] Combine the following ingredients:

[0019] a) alginate in an amount of 2% (w / w) to 5% (w / w);

[0020] b) a cellulose derivative polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) such as sodium carboxymethyl cellulose, and methyl cellulose (MC), hydroxypropyl cellulose (HPC); and mixtures thereof;

[0021] c) carbonates, for example alkali metal carbonates, such as sodium carbonate or sodium bicarbonate; or ammonium carbonate or calcium carbonate;

[0022] d) polyvalent alginate cross-linking ions, such as calcium, magnesium, aluminum ions, for example from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w);

[0023] e) at least one viscosity increasing agent selected from: i) hydrocolloids, for example 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) pharmaceutically acceptable polyacrylic acid, for example carbomer, for example carbomer type A; and

[0024] f) Water or other pharmaceutical vehicles.

[0025] In a third aspect, the present invention relates to the use of a drug raft-forming suspension for use in treating gastroesophageal reflux disease, the drug raft-forming suspension comprising

[0026] a) alginate in an amount of 2% (w / w) to 5% (w / w);

[0027] b) a cellulose derivative polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) such as sodium carboxymethyl cellulose, and methyl cellulose (MC), hydroxypropyl cellulose (HPC); and mixtures thereof;

[0028] c) carbonates, for example alkali metal carbonates, such as sodium carbonate or sodium bicarbonate; or ammonium carbonate or calcium carbonate;

[0029] d) polyvalent alginate cross-linking ions, such as calcium, magnesium, aluminum ions, for example from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w);

[0030] e) at least one viscosity increasing agent selected from: i) hydrocolloids, for example 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) pharmaceutically acceptable polyacrylic acid, for example carbomer, for example carbomer type A; and

[0031] f) Water or other pharmaceutical vehicles. DETAILED DESCRIPTION

[0032] Alginic acid and its salts.

[0033] Alginate, especially derived from brown seaweed, is a linear unbranched biopolymer composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G) residues connected by (1-4)-bonds. Alginate is not a random copolymer, but is composed of blocks of similar and alternating residue sequences, such as MMMM, GGGG and GMGM. Alginate in the form of extraction absorbs water rapidly. The physical properties of alginate may depend on the relative proportions of M blocks and G blocks. Gel formation at neutral pH requires multivalent ions (such as calcium, magnesium, aluminum, such as from a calcium source) to provide calcium ions to interact with G-blocks. The larger the ratio of these G-blocks, the greater the gel strength.

[0034] As used herein, "multivalent alginate cross-linking ions" refer to any ions suitable for alginate cross-linking or gel formation. It should be understood that the alginate gel formation can be provided by many multivalent 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 multivalent alginate cross-linking ions used are calcium ions or magnesium ions or aluminum ions.

[0035] "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; alginates are present in the cell walls of brown algae in the form of calcium, magnesium and sodium salts of alginic acid. Dry powdered sodium or potassium alginate can be obtained from this brown algae extraction process. The alginic residue is then removed by filtration, and the remaining alginate can then be recovered from the aqueous solution.

[0036] Another method of recovering alginate from the initial extraction solution is to add calcium salts. This results in the calcium alginate forming a fibrous texture; it is insoluble in water and can be separated from the water. The separated calcium alginate is suspended in water and acid is added to convert it into alginic acid.

[0037] Alginates suitable for use in the practice of the present invention will typically have a molecular weight such that when subjected to flow at 20°C using a rheometer apparatus equipped with cup and bob geometry for 10 s -1When measured at a shear rate of 2 wt %, these alginates exhibit a viscosity in the range of 5-1,000 mPa·s. In some embodiments, when measured in this way, such alginates will exhibit a viscosity between 6 and 600 mPa·s, for example, between 7 and 500 mPa·s or between 8 and 500 mPa·s. In some other embodiments, when measured in this way, such alginates will exhibit a viscosity between 8 and 400 mPa·s, for example, between 8 and 300 mPa·s, for example, between 9 and 200 mPa·s or between 10 and 100 mPa·s.

[0038] In some embodiments according to the present invention, high G-type alginate is used. High G-type alginate means that one or more alginates used in the practice of the present invention have an average of at least 50% adjacent G units. In some embodiments, the alginate will have an average of at least 52% adjacent G units; in other embodiments, such alginate will have an average of at least 55% or more adjacent G units, and in other embodiments, such alginate will have an average of at least 60%, 65% or 70% or more adjacent G units, so a higher adjacent G unit content can improve the product texture.

[0039] It has been found that alginic acid microdispersions containing the correct ratio or amount of plasticizer are capable of forming alginic acid films. In Franz cell diffusion tests, the alginate films showed controlled drug permeation over time. The strong but flexible film only requires a very low film thickness (59 μm) to provide controlled release, such as zero-order controlled release. It should be understood that in the context of the present invention, the concentration of alginate present is significantly lower than that of existing alginate raft-forming suspensions: the composition provides the desired raft characteristics with a significantly reduced amount of alginate (40% w / w compared to the amount used in the reference Gaviscon composition).

[0040] Furthermore, raft strength variability was reduced: by reducing alginate and adding sodium carboxymethylcellulose, the composition showed reduced raft strength variability (%RSD below 15%) compared to the reference formulation (%RSD above 20%). This may provide consistency in in vivo raft strength performance.

[0041] According to the present invention, alginate, such as alginic acid or alginate salt, is present in an amount of 2% (w / w) to 5% (w / w) based on the total weight of the composition. In the present invention, alginate refers to any alginic acid or alginate, such as sodium alginate, magnesium alginate, potassium alginate, triethanolamine alginate or propylene glycol monoglycolate.

[0042] Thickener

[0043] Viscosifiers or viscosifying agents are known to those skilled in the art. Suitable viscosifiers include hydrocolloids, for example any one selected from the group consisting of guar gum, pectin and its derivatives, xanthan gum, arabinoxylan, cellulose and its derivatives, chitin, xylan, β-glucan, gum arabic, hyaluronic acid and gelatin; and ii) pharmaceutically acceptable polyacrylic acids, such as carbomers, such as carbomer type A. For the purposes of the present invention, viscosifiers do not include alginate or cellulose derivative polymers, as specifically defined elsewhere.

[0044] Cellulose derivative polymers

[0045] Any suitable cellulose derivative polymer may be used according to the present invention. Those skilled in the art will be aware of such suitable polymers.

[0046] 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).

[0047] Commercially available carboxymethyl cellulose (CMC) includes TEXTURACEL from International Flavors & Fragrances (IFF) of the United States. TM , Celetec from CPKelco TM , Aqualon from Ashland TM , from USK Kimya A.S. and from Nouryon (formerly AkzoNobel) Commercially available methylcellulose and hydroxypropyl methylcellulose include the Japanese Pharmacopoeia METOLOSE (trademark) series and the METOLOSE series for food additives from Shin-Etsu Chemical Co., Ltd., the AnyCoat-C or AnyAddy (trademark) series from Lotte (formerly Samsung) Fine Chemicals, the METHOCEL (trademark) series from International Flavors & Fragrances (formerly DOW Chemical Company), and the Benecel (trademark) series from Ashland.

[0048] The preservative may be any suitable compound known in the art among pharmaceutically acceptable compounds, for example, any one selected from the group consisting of ethanol, benzethonium chloride, citric acid monohydrate, sodium salicylate, carbolic acid, sodium benzoate, sodium dehydroacetate, hydroxyquinoline sulfate, potassium sorbate, benzalkonium chloride, benzeneconium chloride, honey, 2-propanol, formalin, 1,2-hydroxypropane, human serum albumin, potassium L-glutamate, sodium N-coconut oil fatty acid acyl-N-carboxymethyl-N-hydroxyethylethylenediamine, thimerosal, boric acid, taurine, sodium edetate, N-hexadecyl green pyridinium chloride, 4-chloro-3-methylphenol, m-cresol, cresol, phenethyl alcohol, 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, paraformaldehyde, benzyl alcohol, sodium tetraborate, L-menthol, carboxybenzene, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, methyl parahydroxybenzoate paraoxybenzoate), eucalyptus oil, chlorhexidine gluconate, butylhydroxytoluene, sorbic acid, borneol, β-naphthol, dehydroacetic acid, isobutylparaben, Peruvian color balsam, benzoin, agar, 2-mercaptobenzimidazole, isopropylparaben, n-dodecyltrimonium chloride tea tree oil, glyceryl caprate, polyglyceryl-2 laurate, polyglyceryl-10 laurate, ethylhexylglycerin, glyceryl caprylate, or a combination of two or more thereof.

[0049] Methylcellulose is a cellulose derivative polymer suitable for the present invention. Methylcellulose has anhydroglucose units connected by 1-4 bonds. Each anhydroglucose unit contains hydroxyl groups at the 2-position, 3-position and 6-position. Partial or complete substitution of these hydroxyl groups with methoxy groups produces methylcellulose. For example, cellulose fibers are treated with a caustic solution and then treated with a methylating agent to produce a cellulose ether substituted with one or more methoxy groups. If not further substituted with other alkyl groups, such a cellulose ether is called methylcellulose. Methylcellulose is characterized by the weight percentage of methoxy groups. By convention, the weight percentage is the average weight percentage based on the total weight of the cellulose repeating units (including all substituents). The content of methoxy groups is reported based on the mass of methoxy groups (i.e., -OCH3). The determination of methoxy% in methylcellulose (MC) polymers is carried out according to the United States Pharmacopoeia (USP 37, "Methylcellulose", pages 3776-3778). Methoxy% can be converted into the degree of substitution (DS) of the methyl substituent, DS (methyl). The DS(methyl) of methylcellulose, also known as DS(methoxy), is the average number of OH groups substituted by methyl groups per anhydroglucose unit. Preferably, the methoxy % of methylcellulose is 18% or more; more preferably 25% or more. Preferably, the methoxy % of component (b) is 50% or less; more preferably 40% or less; and even more preferably 35% or less. Even more preferably, the DS(methyl) of methylcellulose is 1.55 or higher; more preferably, 1.65 or higher; and most preferably 1.70 or higher. DS(methyl) is preferably 2.25 or lower; more preferably 2.20 or lower; and most preferably 2.10 or lower. In some embodiments according to the present invention, the relevant characterization of methylcellulose is the quotient s23 / s26. The numbers 2, 3 and 6 refer to the carbon atoms on the defined anhydroglucose units.

[0050] The parameter s23 is the mole fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 3 of the anhydroglucose unit are substituted with methyl groups, and the parameter s26 is the mole fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 6 of the anhydroglucose unit are substituted with methyl groups. For determining s23, the term "the mole fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 3 of the anhydroglucose unit are substituted with methyl groups" means that the two hydroxyl groups at positions 2 and 3 are substituted with methyl groups, and the 6 position is an unsubstituted hydroxyl group. For determining s26, the term "the mole fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 6 of the anhydroglucose unit are substituted with methyl groups" means that the two hydroxyl groups at positions 2 and 6 are substituted with methyl groups, and the 3 position is an unsubstituted hydroxyl group. The quotient s23 / s26 is determined by dividing s23 by s26. According to the present invention, in some embodiments, s23 / s26 is 0.24 or less, such as 0.23 or less. In addition, s23 / s26 can be 0.10 or greater, such as 0.14 or greater. 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 s23 / s26 ratio is described in WO 2017192445, and a commercial product having such an s23 / s26 ratio is Methocel from International Flavors & Fragrances, Inc. TM Bind 112.

[0051] The present invention also requires that the raft forming suspension contains a carbonate source for raft flotation, such as an alkali metal carbonate, such as an alkali metal bicarbonate or an alkali metal carbonate, such as sodium carbonate or sodium bicarbonate, or ammonium carbonate, or ammonium bicarbonate, calcium carbonate, or any other carbonate or bicarbonate. It is also required that the raft forming suspension contains multivalent ions for alginate cross-linking, such as calcium, magnesium, aluminum, such as from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w).

[0052] For sodium carboxymethylcellulose (CMC, such as TEXTURACEL TMThe solution for viscosity measurement of 20000Pa 07) is prepared by adding an appropriate amount of CMC powder to an appropriate amount of water to reach a concentration of 1% while stirring with an overhead laboratory stirrer at ambient temperature for at least 1 hour. The viscosity is studied at 20°C using a rheometer (e.g., Anton Paar MCR 501) equipped with cup and bob geometry (e.g., CC-27). The viscosity range is 10mPa·s to 15000mPa·s; in some embodiments, when so measured, a viscosity between 15 and 12000mPa·s, such as between 20 and 11000mPa·s or between 25 and 10000mPa·s will be exhibited.

[0053] For methylcellulose (MC, such as Methocel TM BIND 112) is prepared by adding an appropriate amount of MC powder to an appropriate amount of water to reach a concentration of 2% while stirring with an overhead laboratory stirrer at ambient temperature; the solution is then cooled to a temperature below 5°C and stirred for at least 3 hours. The viscosity is studied 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 range is 15 mPa·s to 100,000 mPa·s; in some embodiments, when so measured, a viscosity between 50 and 80,000 mPa·s, such as between 100 and 75,000 mPa·s or between 150 and 70,000 mPa·s will be exhibited.

[0054] Experimental Section

[0055] Example 1

[0056] Equipment for the manufacture of preparations

[0057] 1. Overhead stirrer

[0058] 2. Weighing scale

[0059] Liquid alginate preparation:

[0060] Composition 1:

[0061]

[0062] method:

[0063] 1. Sodium bicarbonate, calcium carbonate and sodium saccharin were added to purified water and dissolved. Sodium alginate was added thereto and the mixture was stirred for 30 minutes.

[0064] 2. Add xanthan gum in step 1. Stir the mixture for 30 min.

[0065] 3. Add sodium carboxymethyl cellulose to purified water while stirring and allow to dissolve.

[0066] 4. Add step 3 to step 2 and mix the dispersion thoroughly.

[0067] 5. Add methylparaben and propylparaben to hot water and allow to dissolve.

[0068] 6. Add step 5 to step 4 while stirring and mix well. Stir the mixture for 30 minutes.

[0069] Raft strength assessment:

[0070] Raft strength test determination:

[0071] 1. Add 20 mL of the raft suspension to 150 ml of 0.1 M HCl maintained at 37° C. in a 250 ml low profile glass beaker with an inner diameter of 60 to 70 mm. While adding the suspension, keep an L-shaped stainless steel wire probe made of 1 mm diameter 316 stainless steel with a 90 mm vertical arm (with a hook on the top) and a 20 mm horizontal arm upright so that the vertical arm of the probe hangs on the central axis of the beaker and the horizontal arm is located in the lower third of the acid.

[0072] 2. Keep the beaker at 37°C for 30 min.

[0073] 3. After 30 min of raft formation, the beaker was placed on a TX Plus texture analyzer (Model-TX plus, manufactured by Stable Microsystems, UK) using a 5.0 kg load cell.

[0074] 4. Hook the stainless steel wire probe onto the texture analyzer arm and pull it vertically upward through the raft at a rate of 5 mm / s.

[0075] 5. The force (g) required to pull the stainless steel wire probe upward through the raft was recorded by the texture analyzer. The variability of the raft strength was expressed as the relative standard deviation (RSD) expressed as a percentage. The calculation method was to multiply the standard deviation by 100 and then divide it by the mean of the raft strength values.

[0076] Raft volume and raft weight test:

[0077] 1. Pre-weigh beaker (W1). Add 20 mL of raft suspension to 150 ml of 0.1 M HCl maintained at 37°C in a 250 ml low profile glass beaker.

[0078] 2. Keep the beaker at 37°C for 30 min.

[0079] 3. 30 minutes after the raft is formed,

[0080] 4. Mark on the outside of the beaker where the top of each raft reaches. Weigh the beaker (W2).

[0081] 5. The raft was then removed from the beaker by carefully decanting the lower liquid and pouring the raft into a pre-tared plastic weigh boat.

[0082] 6. Let it stand for 30 seconds, drain the excess lower liquid, and then weigh the raft (W3).

[0083] 7. Use a paper towel to remove the remaining liquid inside the beaker, then fill it up to the marked position with water and weigh it (W4).

[0084] 8. The volume of each raft was then calculated according to the following formula: Raft Volume = (W4-W1)-(W2-W1-W3), where the raft volume is measured in ml. All weights are measured in g.

[0085]

[0086] (n=3)

[0087] The raft strength variation data for the reference product and the test composition are listed below and show that the raft strength variation observations were improved.

[0088]

[0089] (n=3)

[0090] Composition 2:

[0091]

[0092]

[0093] method:

[0094] METHOCEL TM Preparation of Bind 112 gel:

[0095] At room temperature, METHOCEL TM Bind 112 (methylcellulose) was added to purified water (temperature 20-25°C) while stirring with an overhead laboratory stirrer. After complete dispersion, the solution was stirred at 750 rpm for 120 min under cold conditions (temperature below 5°C).

[0096] Preparation of raft composition

[0097] 1. Sodium bicarbonate, calcium carbonate and sodium saccharin were added to purified water and dissolved. Sodium alginate was added thereto and the mixture was stirred for 30 min.

[0098] 2. While stirring, add the prepared METHOCEL TM Add Bind 112 gel to step 2. Stir the mixture for 1 hour.

[0099] 3. Add xanthan gum and stir the mixture for 30min.

[0100] 4. Add methylparaben and propylparaben to hot water and allow to dissolve.

[0101] 5. While stirring, add step 4 to step 3 and mix well. Stir the mixture for 30min.

[0102] Raft strength assessment:

[0103] Procedure See the procedure listed in Composition 1

[0104]

[0105]

[0106] (n=3)

[0107] The raft strength variation data for the reference product and the test composition are listed below and show that the raft strength variation observations were improved.

[0108]

[0109] (n=3)

Claims

1. A drug raft-forming suspension suitable for treating gastroesophageal reflux disease by oral administration, the drug raft-forming suspension comprising or consisting of: a) alginate in an amount of 2% (w / w) to 5% (w / w); b) a cellulose derivative polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) such as sodium carboxymethyl cellulose, and methyl cellulose (MC), hydroxypropyl cellulose (HPC); and mixtures thereof; c) carbonates, for example alkali metal carbonates, such as sodium carbonate or sodium bicarbonate; or ammonium carbonate or calcium carbonate; d) polyvalent alginate cross-linking ions, such as calcium, magnesium, aluminum ions, for example from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w); e) at least one viscosity increasing agent selected from: i) hydrocolloids, for example 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) pharmaceutically acceptable polyacrylic acid, for example carbomer, for example carbomer type A; and f) Water or other pharmaceutical vehicles. 2 . The drug raft-forming suspension according to claim 1 , wherein the alginate is a salt of alginic acid, such as sodium alginate.

3. The drug raft forming suspension according to claim 1 or 2, wherein the multivalent ions are calcium ions, for example from calcium carbonate.

4. The drug raft-forming 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 drug raft-forming suspension according to any one of claims 1 to 4, further comprising a preservative, such as propylparaben and / or methylparaben.

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

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

8. The drug raft-forming suspension according to any one of claims 1 to 7, wherein the alginate is present in an amount of no more than 5% (w / w), such as no more than 4.9% (w / w), such as no more than 4.8% (w / w), such as no more than 4.7% (w / w), such as no more than 4.6% (w / w), such as no more than 4.5% (w / w), such as no more than 4.4% (w / w), such as no more than 4.3% (w / w), such as no more than 4.2% (w / w), such as no more than 4.1% (w / w), such as no more than 4.0% (w / w), such as no more than 3.9% (w / w), such as no more than 3.8% (w / w), such as no more than 3.7% (w / w), such as no more than 3.6% (w / w), such as no more than 3.5% (w / w), such as no more than 3.4% (w / w), such as no more than 3.3% (w / w).

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

10. The drug raft-forming suspension according to any one of claims 1 to 8, wherein the cellulose-derived polymer is present in an amount of no more than 2.0% (w / w), such as no more than 1.9% (w / w), 1.8% (w / w), 1.7% (w / w), 1.6% (w / w), 1.5% (w / w), 1.4% (w / w), 1.3% (w / w), 1.2% (w / w), 1.1% (w / w), 1.0% (w / w), 0.9% (w / w), 0.8% (w / w), 0.7% (w / w), 0.6% (w / w) or 0.5% (w / w).

11. The drug raft-forming suspension according to any one of claims 1 to 10, wherein the cellulose-derived polymer is carboxymethylcellulose, such as sodium carboxymethylcellulose, which is present in an amount of 0.1% (w / w) to 2.0% (w / w).

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

13. The drug raft-forming suspension according to any one of claims 1 to 12, wherein the cellulose derivative polymer is carboxymethyl cellulose, such as sodium carboxymethyl cellulose having a viscosity ranging from 10 mPa·smPa·smPa·smPa·s to 15000 mPa·smPa·smPa·smPa·s, such as sodium carboxymethyl cellulose having a viscosity ranging from 10 mPa·smPa·smPa·smPa·smPa·s at 20°C, at a concentration of 1%, at a temperature of 10 s -1 The shear rate is measured.

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

15. The drug raft-forming suspension according to claim 14, wherein the cellulose derivative polymer is methylcellulose having a viscosity ranging from 15 mPa·smPa·smPa·smPa·smPa·s to 100000 mPa·sm ... -1 The shear rate is measured.

16. The drug raft-forming suspension according to claim 14 or 15, wherein the cellulose derivative polymer is methyl cellulose, and the s23 / s26 of the methyl cellulose is 0.10 to 0.24, such as 0.14 to 0.23, wherein s23 is the mole fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 3 of the anhydroglucose units are substituted with methyl groups, and wherein s26 is the mole fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 6 of the anhydroglucose units are substituted with methyl groups.

17. The drug raft forming suspension according to any one of claims 1 to 16, wherein the carbonate, such as an alkali metal carbonate, such as sodium carbonate or sodium bicarbonate, is present in an amount of 1.5% (w / w)-5% (w / w), such as in the range of 1.6% (w / w)-4.8% (w / w), such as in the range of 1.7% (w / w)-4.6% (w / w), such as in the range of 1.8% (w / w)-4.4% (w / w), such as in the range of 1.9% (w / w)-4.2% (w / w). , for example in the range of 2.0% (w / w)-4.0% (w / w), for example in the range of 2.1% (w / w)-3.8% (w / w), for example in the range of 2.2% (w / w)-3.6% (w / w), for example in the range of 2.3% (w / w)-3.4% (w / w), for example in the range of 2.4% (w / w)-3.2% (w / w), for example in the range of 2.5% (w / w)-3.0% (w / w), for example in the range of 2.0% (w / w)-3.5% (w / w).

18. A drug raft forming suspension according to any one of claims 1 to 17, wherein the multivalent alginate cross-linking ions, e.g. from calcium carbonate, are present in an amount of 0.8% (w / w) - 4% (w / w), e.g. in the range of 0.9% (w / w) - 3.9% (w / w), e.g. in the range of 1.0% (w / w) - 3.8% (w / w), e.g. in the range of 1.1% (w / w) - 3.7% (w / w), e.g. in the range of 1.2% (w / w) - 3.6% (w / w), e.g. in the range of 1.2% (w / w) - 3.5% (w / w), e.g. in the range of 1.2% (w / w) - 3.4% (w / w), e.g. in the range of 1.2% (w / w) - 3.3% (w / w), e.g. In the range of 1.2% (w / w)-3.2% (w / w), for example in the range of 1.2% (w / w)-3.0% (w / w), for example in the range of 1.2% (w / w)-2.8% (w / w), for example in the range of 1.2% (w / w)-2.6% (w / w), for example in the range of 1.2% (w / w)-2.4% (w / w), for example in the range of 1.2% (w / w)-2.2% (w / w), for example in the range of 1.2% (w / w)-2.0% (w / w), for example in the range of 1.3% (w / w)-2.0% (w / w), for example in the range of 1.3% (w / w)-1.8% (w / w), for example in the range of 1.4% (w / w)-1.8% (w / w).

19. The drug raft-forming suspension according to any one of claims 1 to 18, wherein the viscosity enhancing agent is present in an amount of 0.05% (w / w) - 1.0% (w / w), such as in the range of 0.06% (w / w) - 0.8% (w / w), such as in the range of 0.07% (w / w) - 0.7% (w / w), such as in the range of 0.08% (w / w) - 0.6% (w / w), such as in the range of 0.09% (w / w) - 0.5% (w / w), such as in the range of 0.10% (w / w) - 0.40% (w / w), such as in the range of 0.12% (w / w) - 0.35% (w / w).

20. The pharmaceutical raft-forming suspension according to any one of claims 1-19, wherein the raft strength measured on a texture analyzer as described in the Raft Strength Test Assay is higher than 7.5 g, such as 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.

21. The drug raft-forming suspension of any one of claims 1-20, wherein the raft strength variability is less than 20%, such as less than 18%, 16%, 14%, 12%, 10%, 8% or 7% relative standard deviation (%RSD).

22. A method for preparing a raft-forming suspension, the method comprising the steps of: Combine the following ingredients: a) alginate in an amount of 2% (w / w) to 5% (w / w); b) a cellulose derivative polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) such as sodium carboxymethyl cellulose, and methyl cellulose (MC), hydroxypropyl cellulose (HPC); and mixtures thereof; c) carbonates, for example alkali metal carbonates, such as sodium carbonate or sodium bicarbonate; or ammonium carbonate or calcium carbonate; d) polyvalent alginate cross-linking ions, such as calcium, magnesium, aluminum ions, for example from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w); e) at least one viscosity increasing agent selected from: i) hydrocolloids, for example 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) pharmaceutically acceptable polyacrylic acid, for example carbomer, for example carbomer type A; and f) Water or other pharmaceutical vehicles.

23. Use of a drug raft-forming suspension for use in treating gastroesophageal reflux disease, the drug 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 hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) such as sodium carboxymethyl cellulose, and methyl cellulose (MC), hydroxypropyl cellulose (HPC); and mixtures thereof; c) carbonates, for example alkali metal carbonates, such as sodium carbonate or sodium bicarbonate; or ammonium carbonate or calcium carbonate; d) polyvalent alginate cross-linking ions, such as calcium, magnesium, aluminum ions, for example from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w); e) at least one viscosity increasing agent selected from: i) hydrocolloids, for example 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) pharmaceutically acceptable polyacrylic acid, for example carbomer, for example carbomer type A; and f) Water or other pharmaceutical vehicles.

24. A method for treating gastroesophageal reflux disease, the method comprising administering to a subject in need thereof an effective amount of a raft-forming suspension, the raft-forming suspension comprising or consisting of: a) alginate in an amount of 2% (w / w) to 5% (w / w); b) a cellulose derivative polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) such as sodium carboxymethyl cellulose, and methyl cellulose (MC), hydroxypropyl cellulose (HPC); and mixtures thereof; c) carbonates, for example alkali metal carbonates, such as sodium carbonate or sodium bicarbonate; or ammonium carbonate or calcium carbonate; d) polyvalent alginate cross-linking ions, such as calcium, magnesium, aluminum ions, for example from calcium carbonate, in an amount of about 1.1% (w / w) to 2.2% (w / w); e) at least one viscosity increasing agent selected from: i) hydrocolloids, for example 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) pharmaceutically acceptable polyacrylic acid, for example carbomer, for example carbomer type A; and f) Water or other pharmaceutical vehicles.

25. The method of preparation, use or treatment according to any one of claims 22 to 24, wherein the suspension is as defined in any one of claims 1 to 21.

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