Pediatric suspension formulation

Abstract

To provide a pediatric suspension formulation.SOLUTION: The present disclosure relates to storage-stable proton pump inhibitor (PPI) systems comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, which are constituted with water prior to administration. The present disclosure also relates to oral pharmaceutical suspensions comprising water, a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, and one or more buffering agents.SELECTED DRAWING: None

Description

[Background technology]

[0001] Omeprazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole, inhibits gastric acid secretion. Omeprazole belongs to the substituted benzimidazoles, a class of antisecretory compounds that do not exhibit anticholinergic or H2 histamine antagonistic properties. Drugs in this class of compounds inhibit the release of H2 at the secretory surface of gastric cells. + / K + They suppress gastric acid secretion by specifically inhibiting the ATPase enzyme system and are called proton pump inhibitors.

[0002] Proton pump inhibitors such as omeprazole are acid labile and therefore rapidly degraded in acidic media such as the contents of the stomach, but have acceptable stability under alkaline conditions. Absorption of orally administered proton pump inhibitors such as omeprazole occurs in the small intestine.

[0003] To solve the problem of omeprazole stability in acidic conditions, some commercially available omeprazole dosage forms incorporate omeprazole as enteric-coated granules or pellets in a delayed-release solid oral dosage form. Examples of such dosage forms include, for example, Losec® and Losec MUPS®, which both contain enteric-coated pellets of omeprazole in a hard resistant capsule and a gastroresistant tablet, respectively.

[0004] Pediatric subjects commonly encounter difficulties in being administered solid oral dosage forms such as tablets or capsules.

[0005] Currently, no oral liquid dosage forms of omeprazole are approved in Europe. In the United States, omeprazole powder for oral suspension is sold under the trade name Zegerid®, a white flavored powder packaged in single-dose packets that are reconstituted with water before administration. Each packet contains either 20 mg or 40 mg of omeprazole, 1680 mg of sodium bicarbonate, and the following excipients: xylitol, sucrose, sucralose, xanthan gum, and flavoring. A single dose of Zegerid® powder for oral suspension contains 460 mg of sodium (Na + In the United States, it also contains omeprazole powder and FIRST-PPI (proton pump inhibitor) suspension. A FIRST®-Omeprazole Compounding Kit is available, consisting of a suspension containing artificial strawberry flavor, benzyl alcohol, FD&C Red No. 40, Magnasweet 100 (ammonium glycyrrhizinate), poloxamer 188, propylene glycol, purified water, simethicone emulsion, sodium bicarbonate, sodium citrate (dihydrate), sucralose, and xanthan gum. When compounded, the final product provides a homogenous suspension containing 2 mg / ml omeprazole in the FIRST®-PPI suspension. These omeprazole suspension formulations contain a high amount of sodium, making them intolerable to pediatric subjects.

[0006] There is a need for a liquid oral omeprazole formulation specifically designed for pediatric subjects. Summary of the Invention [Means for solving the problem]

[0007] The present disclosure relates to a storage-stable proton pump inhibitor (PPI) system comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, which is reconstituted with water prior to administration and contains sodium at an acceptable level for use in the treatment of pediatric subjects upon reconstitution with water. The storage-stable PPI system is particularly suitable for use in multi-dose dosage forms. The present disclosure also relates to an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, and one or more buffering agents. The oral pharmaceutical suspension of the present disclosure has a buffering capacity acceptable for pediatric subjects. In some embodiments, the buffering capacity of the oral pharmaceutical suspension described herein is about 2 mEq / ml of oral suspension.

[0008] In one aspect, the present disclosure provides a storage-stable omeprazole system, the system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the system comprising a water content of about 2.5% or less, the system containing no sodium from a sodium-containing buffer, or sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and the storage-stable omeprazole system is reconstituted with water prior to administration. In some embodiments of this aspect, the sodium and potassium are present in a weight ratio of about 1:3.2. In some embodiments, the system has a water content of about 0.5% to about 1.5%.

[0009] In some embodiments, the storage-stable omeprazole system further comprises a pharmaceutically acceptable desiccant, hi some embodiments, the pharmaceutically acceptable desiccant is sodium alginate.

[0010] In another aspect, the present disclosure provides a storage-stable omeprazole system, the system comprising: (i) (a) a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the first mixture comprising about 2.5% or less moisture; and (ii) a second mixture comprising a second buffer, the second mixture comprising about 2.5% or less moisture; the first and second mixtures being stored separately from each other and mixed together at or immediately before reconstitution with water; the system containing no sodium from the sodium-containing buffer or sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments, the sodium and potassium are present in a weight ratio of about 1:3.2. In some embodiments, the first mixture further comprises (b) a first desiccant. In some embodiments, the first mixture further comprises (c) a first buffering agent. In some embodiments, the first mixture further comprises both (b) a first desiccant and (c) a first buffering agent. In some embodiments, the second mixture further comprises a second desiccant.

[0011] In another aspect, the present disclosure provides a storage-stable omeprazole system formulated in a drug delivery device suitable for multiple-dose administration of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system comprises a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the system comprises a water percentage of about 2.5% or less, the system does not contain sodium from a sodium-containing buffer or the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable omeprazole system is reconstituted with water prior to administration.

[0012] In another aspect, the present disclosure provides a storage-stable omeprazole powder system, the system comprising: (i) a first powder mix comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) sodium alginate, and (c) a first buffering agent; and (ii) a second powder mix comprising sodium alginate and a second buffering agent, wherein the first and second powder mixes are stored separately from one another and mixed together at or immediately before reconstitution with water, the system containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments, the sodium and potassium are present in a weight ratio of about 1:3.2.

[0013] In another aspect, the present disclosure provides an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed therein, and one or more buffering agents, wherein the suspension does not contain sodium from a sodium-containing buffer or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0014] In some embodiments, the oral pharmaceutical suspension comprises water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffering agents, wherein the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0015] In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof in the storage-stable omeprazole system or oral pharmaceutical suspension described herein is micronized. In some embodiments, the storage-stable omeprazole system or oral pharmaceutical suspension described herein contains a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the storage-stable omeprazole system, or specifically the storage-stable omeprazole powder system, is provided in a drug delivery device suitable for multiple-dose administration of omeprazole or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the storage-stable omeprazole systems described herein remain stable for at least 2 years at 25° C. / 60% relative humidity.

[0017] In some embodiments, the oral pharmaceutical suspension of the present disclosure comprises a first and a second C 最大 and the first and second T 最大 after oral administration in a subject in need thereof.

[0018] In another aspect, the present disclosure provides a method for inhibiting gastric acid secretion in a subject in need thereof. In certain embodiments, the method comprises administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffering agents, wherein the suspension does not contain sodium from a sodium-containing buffer or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments, the method comprises administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffering agents, wherein the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments, the subject is a child. In some embodiments, the suspension comprises from about 1 mg / ml to about 10 mg / ml of omeprazole or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the present disclosure provides a method for preparing an oral pharmaceutical suspension. Typically, the method includes: (a) combining a first mixture containing a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the first mixture containing about 2.5% or less water, with a second mixture containing a second buffer, the second mixture containing about 2.5% or less water, to obtain a combined mixture, wherein the combined mixture does not contain sodium from a sodium-containing buffer or the combined mixture contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4; and adding water to the combined mixture. In some embodiments, the second mixture further contains a second desiccant. In some embodiments, the method includes: (a) combining a first mixture containing a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the first mixture containing about 2.5% or less moisture, with a second mixture containing a second desiccant and a second buffer to obtain a combined mixture, the combined mixture containing sodium and potassium in a ratio of about 1:2.6 to about 1:3.4; and adding water to the combined mixture. In some embodiments, the first mixture further includes (b) a first desiccant. In some embodiments, the first mixture further includes (c) a first buffer. In some embodiments, the first mixture further includes both (b) the first desiccant and (c) the first buffer.

[0020] In another aspect, the disclosure provides a method of inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed therein, and one or more buffering agents, wherein the suspension does not contain sodium from a sodium-containing buffer or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, wherein the oral pharmaceutical suspension comprises: (a) a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof; The present invention provides a method for preparing a granular ... In some embodiments, the method is a method of inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed therein, and one or more buffering agents, wherein the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, the oral pharmaceutical suspension being prepared by (a) combining a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the first mixture containing no more than about 2.5% water, with a second mixture comprising a second desiccant and a second buffering agent to obtain a combined mixture, the combined mixture containing sodium and potassium in a ratio of about 1:2.6 to about 1:3.4; and adding water to the combined mixture. In some embodiments, the first mixture further comprises (c) a first buffering agent. In some embodiments, the first mixture further comprises both (b) a first desiccant and (c) a first buffer.

[0021] Additional embodiments and advantages described herein will be set forth in part in the description that follows and may arise from the description or may be learned by the practice described herein. The described embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0022] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief explanation of the drawings]

[0023] [Figure 1] 1 shows a delivery device suitable for use with the storage-stable system of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0024] The headings provided herein are not limitations of the various embodiments described herein, but may be defined by reference to the specification as a whole. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present disclosure will be limited only by the appended claims.

[0025] definition For convenience, the meanings of some terms and phrases used in the specification, examples, and appended claims are provided below. Unless otherwise specified or implicit from the context, the following terms and phrases include the meanings provided below. Since the scope of the present technology is limited only by the claims, definitions are provided to help describe particular embodiments and are not intended to limit the claimed technology. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this technology belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided herein shall prevail.

[0026] The articles "a," "an," and "the" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0027] As used herein, the term "about" means ±10% of the stated value, unless otherwise indicated.

[0028] The term "at least" before a number or number series is understood to include the number adjacent to the term "at least" and all subsequent numbers or integers that may be logically included, as is clear from the context. When "at least" is present before a number series or range, it is understood that "at least" can modify each of the numbers in the series or range.

[0029] The term "less than" before a number or number series is understood to include the number adjacent to the term "less than" and all preceding digits or integers that may be logically included, as is clear from the context. When "less than" is before a number series or range, it is understood that the "less than" can modify each of the numbers in the series or range.

[0030] As used herein, "comprises," "comprising," "having" Terms such as "having," "including," and "containing" and "comprises," which are open-ended terms meaning "including, but not limited to." To the extent that a given embodiment disclosed herein "comprises" certain elements, it is to be understood that the present disclosure also specifically contemplates, discloses embodiments "consisting essentially of," and "consisting of" those elements.

[0031] The terms "treat," "treating," and "treatment" refer to any indicator of successful treatment or amelioration, including any objective or subjective parameter, such as remission, remission, reduction of symptoms, or making the injury, disease, or condition more tolerable to the patient, slowing the rate of regression or decline, or improving the patient's physical or mental well-being. Treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, or psychiatric evaluation.

[0032] An "effective" amount or a "therapeutically effective amount" or a "pharmaceutically effective amount" of a drug or pharmacologically active agent means a non-toxic but sufficient amount of the drug or agent to provide the desired effect. The "effective" amount will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agent, etc. Thus, it is not always possible to specify an exact "effective amount." However, an appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0033] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable inorganic and organic acids.

[0034] As used herein, the terms "desiccant," "primary desiccant," and "secondary desiccant" refer to pharmaceutically acceptable hygroscopic materials that help maintain a dry state. These desiccants remove humidity from the air; they adsorb water, thereby creating and maintaining a dry, moisture-free environment. Suitable pharmaceutically acceptable desiccants include, for example, sodium alginate, starch, and the like.

[0035] The term "buffering agent" or "buffer" refers to omeprazole. "Bases containing benzoyl peroxidase" refers to any pharmaceutically acceptable weak or strong base and mixtures thereof that, when formulated or delivered before, during, and / or after a proton pump inhibitor such as benzoyl peroxidase, function to substantially prevent or inhibit acid degradation of the proton pump inhibitor by stomach acid and to maintain oral bioavailability of the proton pump inhibitor.

[0036] The term "percent moisture" refers to a value measured using the Loss on Drying (LOD) method, which involves heating a sample (e.g., sodium alginate or omeprazole) at 90°C for 5 minutes and determining the % weight loss.

[0037] As used herein, the term "multi-dose" means that after constitution with water, the omeprazole powder system can be administered in multiple doses over a period of time, for example, more than 7 days, more than 14 days, or more than 28 days.

[0038] As used herein, the term "stability" or "storage stability" refers to the ability to withstand temperatures of at least 6 months at 40°C and 75% relative humidity (RH), or at 25°C and 60% relative humidity, to the extent necessary for sale and use of the omeprazole powder system described herein. This refers to the chemical stability such that upon storage at room temperature for at least 2 years, not more than 5% w / w of all related substances, e.g., omeprazole degradants, are formed.

[0039] As used herein, the phrase "low viscosity grade sodium alginate" refers to sodium alginate having a solution viscosity of less than about 100 millipascal seconds (mPa.s) in a 3% aqueous solution. Suitable low viscosity grade sodium alginates include, for example, Manucol® LB (by FMC Biopolymer).

[0040] The term "GERD (gastro-esophageal reflux disease)" refers to gastroesophageal reflux disease, a condition in which acid from the stomach leaks into the esophagus (the tube that connects the throat to the stomach), causing pain, inflammation, and heartburn. In children, symptoms of the condition can include stomach contents returning to the mouth (regurgitation), feeling sick (vomiting), and poor weight gain.

[0041] The term "PICS (Protection In Situ Constitution System)" refers to a system that protects in situ structures. PICS refers to a configuration system. The PICS system is a bottle with a one-piece cap, as shown in Figure 1. The omeprazole (or any PPI)-containing mixture is in dry form within the cap until the point of configuration. A diluent phase, such as the second mixture described below, is contained in the bottle. At the time of configuration, the drug-loaded mixture is released from the cap into the diluent phase (or second mixture) by twisting the cap, after which water is added for configuration.

[0042] As used herein, the term "child" is a human being between the stages of birth and adolescence.

[0043] The term "puberty" refers to the process of physical changes that occur when a child's body grows into an adult body capable of sexual reproduction. On average, girls begin puberty at about 10-11 years of age and finish at about 15-17 years of age, while boys begin puberty at about 11-12 years of age and finish at about 16-17 years of age.

[0044] As used herein, the term "infant" is synonymous with baby, i.e., "very young human child." The term "infant" typically applies to young children under the age of 1 year.

[0045] As used herein, the term "infant" refers to a child between the ages of 12 and 36 months.

[0046] As used herein, the term "pre-adolescent" refers to a person between the ages of 10 and 13.

[0047] As used herein, the term "adolescent" refers to a person between the ages of 10 and 19.

[0048] The storage-stable systems described herein Proton pump inhibitors, such as omeprazole, are widely used to treat gastric acid-mediated disorders in patients, but their chemical instability in acidic media prevents the formulation of simple aqueous dosage forms for therapy. The present disclosure provides a storage-stable PPI system that, upon reconstitution with water, provides an oral pharmaceutical PPI suspension for administering an effective amount of a PPI (e.g., omeprazole or a pharmaceutically acceptable salt thereof) to a subject in need thereof, while having a sodium level acceptable for administration to pediatric subjects. The oral pharmaceutical suspensions of the present disclosure have an acceptable buffering capacity for pediatric subjects. In some embodiments, the buffering capacity of the oral pharmaceutical suspensions described herein is about 2 mEq / ml of oral suspension. This is achieved, for example, by using a balanced buffering system based on sodium bicarbonate and potassium bicarbonate. In some embodiments, the buffering capacity of the oral pharmaceutical suspensions described herein is about 0.5 mEq / ml to about 4 mEq / ml of oral suspension. In some embodiments, the buffer capacity of the oral pharmaceutical suspensions described herein is from about 1.6 mEq / ml to about 2.3 mEq / ml of oral suspension.

[0049] In one aspect, the present disclosure provides a storage-stable PPI system (e.g., a storage-stable omeprazole system), the system comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, the system comprising a water content of about 2.5% or less, the system containing no sodium from a sodium-containing buffer, or sodium and potassium in a weight ratio of about 1:100 to about 100:1, and the storage-stable PPI system being reconstituted with water prior to administration. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:2 to about 1:5.

[0050] In some embodiments, the storage-stable PPI system (such as a storage-stable omeprazole system) may be selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, sodium tetraborate, sodium acetate, disodium hydrogen phthalate, sodium hydrogen phthalate, and tartaric acid. hydrogen It does not contain sodium from sodium-containing buffers such as sodium tartrate, disodium succinate, etc.

[0051] In some embodiments, a storage-stable PPI system (e.g., a storage-stable omeprazole system) comprises a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, wherein the system comprises a water content of about 2.5% or less, and wherein the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable PPI system is reconstituted with water prior to administration. In some embodiments of this aspect, the sodium and potassium are present in a weight ratio of about 1:3.2.

[0052] In some embodiments, the storage-stable PPI system (e.g., a storage-stable omeprazole system) has a moisture content of about 0.5% to about 1.5%. In some embodiments, the storage-stable PPI system (e.g., a storage-stable omeprazole system) has a moisture content of about 1% or less.

[0053] Suitable PPIs (proton pump inhibitors) that can be used in the storage-stable PPI systems described herein include, for example, omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, dexlansoprazole, rapeprazole, dontoprazole, tenatoprazole, habaprazole, thiazolinone ... Examples of benzodiazepines include benzodiazepines, ... In some embodiments, the PPI is selected from the group consisting of omeprazole, esomeprazole, lansoprazole, pantoprazole, dexrazoprazole, rabeprazole, and pharmaceutically acceptable salts thereof. In some embodiments, the PPI is omeprazole or esomeprazole, or a pharmaceutically acceptable salt thereof. Examples of suitable pharmaceutically acceptable salts of PPIs include sodium, magnesium, calcium, and potassium salts, such as omeprazole sodium, omeprazole magnesium, omeprazole calcium, omeprazole potassium, esomeprazole sodium, esomeprazole magnesium, esomeprazole calcium, and esomeprazole potassium.

[0054] In some embodiments, the PPI is omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the PPI is omeprazole (i.e., the neutral form of omeprazole without salt-forming cations). In some embodiments, the PPI is esomeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the PPI is esomeprazole (i.e., the neutral form of esomeprazole without salt-forming cations).

[0055] In some embodiments, the storage-stable PPI system further comprises a desiccant. Suitable desiccants include any desiccants that are pharmaceutically acceptable and that exclude humidity from the air and absorb water, thereby creating and maintaining a dry, moisture-free environment for the PPI. Suitable pharmaceutically acceptable desiccants include, for example, sodium alginate, starch, etc. In some embodiments, the desiccant is sodium alginate. The desiccant may comprise one pharmaceutically acceptable desiccant or a mixture of two or more pharmaceutically acceptable desiccants.

[0056] In some embodiments, the sodium alginate present in the storage-stable PPI systems described herein is dry, i.e., the sodium alginate contains less than about 2% moisture. In some embodiments, the storage-stable PPI systems comprise dry sodium alginate having a moisture content of about 0.5% to about 1.5%.

[0057] In some embodiments, the sodium alginate present in the storage-stable PPI system described herein, such as the storage-stable omeprazole system, is a low-viscosity grade of sodium alginate. A suitable low-viscosity grade of sodium alginate has a solution viscosity of less than about 100 millipascal seconds (mPa.s) in a 3% aqueous solution. An example of a suitable low-viscosity grade of sodium alginate is Manucol® LB (by FMC Biopolymer).

[0058] In some embodiments, the storage-stable PPI systems described herein, such as the storage-stable omeprazole systems, contain one or more buffering agents. In some embodiments, the storage-stable PPI systems described herein contain one, two, three, or four buffering agents. In some embodiments, the storage-stable PPI systems described herein contain one buffering agent. In some embodiments, the storage-stable PPI systems described herein contain two or three buffering agents. In some embodiments, the storage-stable PPI systems described herein contain two buffering agents.

[0059] The storage-stable PPI systems described herein, such as the storage-stable omeprazole system, can include any suitable buffering agent that functions to substantially prevent or inhibit acid degradation of the PPI (e.g., omeprazole or a pharmaceutically acceptable salt thereof) by gastric acid sufficient to maintain the bioavailability of the administered PPI. In some embodiments, the one or more buffering agents are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. In some embodiments, the one or more buffering agents are each independently selected from the group consisting of sodium or potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates.

[0060] In some embodiments, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) may be prepared using a combination of sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, sodium tetraborate, sodium acetate, disodium hydrogen phthalate, sodium hydrogen phthalate, tartaric acid, or the like. hydrogenIn some embodiments, the storage-stable PPI system (such as the storage-stable omeprazole system) described herein comprises at least one buffering agent selected from potassium carbonate, potassium bicarbonate, potassium dihydrogen phosphate, potassium hydrogen phosphate, tripotassium phosphate, potassium dihydrogen citrate, dipotassium hydrogen citrate, tripotassium citrate, potassium tetraborate, potassium acetate, dipotassium hydrogen phthalate, potassium hydrogen phthalate, tartrate, or the like. hydrogen Potassium, tartrate two The buffer comprises at least one buffer selected from potassium, and potassium succinate.

[0061] In some embodiments, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) can be selected from the group consisting of potassium carbonate, potassium bicarbonate, potassium dihydrogen phosphate, potassium hydrogen phosphate, tripotassium phosphate, potassium dihydrogen citrate, dipotassium hydrogen citrate, tripotassium citrate, potassium tetraborate, potassium acetate, dipotassium hydrogen phthalate, potassium hydrogen phthalate, and tartaric acid. hydrogen Potassium, tartrate two In some embodiments, the buffer comprises up to one buffer selected from potassium bicarbonate, potassium iodide, and potassium succinate.

[0062] In some embodiments, the storage-stable PPI systems described herein (e.g., storage-stable omeprazole systems) contain two or more buffering agents selected from sodium and potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. In some embodiments, the storage-stable PPI systems described herein contain both sodium bicarbonate and potassium bicarbonate. In some embodiments, the sodium bicarbonate and potassium bicarbonate are present in the system in a weight ratio of about 1:100 to about 100:1. In some embodiments, the sodium bicarbonate and potassium bicarbonate are present in the system in a weight ratio of about 1:50 to about 50:1. In some embodiments, the sodium bicarbonate and potassium bicarbonate are present in the system in a weight ratio of about 1:10 to about 10:1. In some embodiments, the sodium bicarbonate and potassium bicarbonate are present in the system in a weight ratio of about 1:2 to about 1:5. In some embodiments, the sodium bicarbonate and potassium bicarbonate are present in the system in a weight ratio of about 1:2.5 to about 1:3.4, hi some embodiments, the sodium bicarbonate and potassium bicarbonate are present in a weight ratio of about 1:2.7.

[0063] The one or more buffering agents present in the storage-stable PPI systems (such as storage-stable omeprazole systems) described herein are present in an amount sufficient to increase the gastric pH to a pH that prevents at least partial degradation of the PPI (such as omeprazole or a pharmaceutically acceptable salt thereof) in gastric fluid.

[0064] In some embodiments, the one or more buffering agents provide a buffering capacity of about 0.5 to about 4 mEq / ml of a dose of a structured storage-stable PPI system described herein with water. In some embodiments, the one or more buffering agents provide a buffering capacity of about 1.6 to about 2.3 mEq / ml of a dose of a structured storage-stable PPI system described herein with water. In some embodiments, the one or more buffering agents provide a buffering capacity of about 2 mEq / ml of a dose of a structured storage-stable PPI system described herein with water.

[0065] In some embodiments, the one or more buffering agents provide a buffering capacity of about 0.5 to about 4 mEq / ml of a dose of the structured storage-stable omeprazole system described herein with water. In some embodiments, the one or more buffering agents provide a buffering capacity of about 1.6 to about 2.3 mEq / ml of a dose of the structured storage-stable omeprazole system described herein with water. In some embodiments, the one or more buffering agents provide a buffering capacity of about 2 mEq / ml of a dose of the structured storage-stable omeprazole system described herein with water.

[0066] The storage-stable PPI system (such as a storage-stable omeprazole system) described herein can be prepared in any suitable multiparticulate dosage form that provides an oral suspension when dispersed in water. Suitable dosage forms include, but are not limited to, powders, pellets, granules, seeds, beads, spheroids, microspheres, or mixtures thereof. In some embodiments, the storage-stable PPI system (such as a storage-stable omeprazole system) described herein is in the form of a powder or pellets. Suitable powders, pellets, granules, seeds, beads, spheroids, microspheres, and mixtures thereof can be prepared by conventional pharmacological techniques known in the art.

[0067] In some embodiments, the storage-stable PPI system (e.g., a storage-stable omeprazole system) described herein comprises: (i) (a) a first mixture comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), the first mixture comprising about 2.5% or less of water; and (ii) a second mixture comprising a second buffer, the second mixture comprising about 2.5% or less of water; the first and second mixtures are stored separately from each other and mixed together upon or immediately prior to reconstitution with water; the system either contains no sodium from the sodium-containing buffer or contains sodium and potassium in a weight ratio of about 1:100 to about 100:1. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:2 to about 1:5.

[0068] In some embodiments, the storage-stable PPI system (e.g., a storage-stable omeprazole system) described herein includes: (i) a first mixture containing a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), the first mixture containing about 2.5% or less water; and (ii) a second mixture containing a second buffer, the second mixture containing about 2.5% or less water, the first and second mixtures being stored separately from each other and mixed together upon or immediately prior to reconstitution with water, the system either containing no sodium from the sodium-containing buffer or containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments, the sodium and potassium are present in a weight ratio of about 1:3.2.

[0069] In some embodiments, the storage-stable PPI system (such as a storage-stable omeprazole system) does not contain sodium from a sodium-containing buffer.

[0070] In some embodiments, the first mixture further comprises (b) a first desiccant, and / or the second mixture further comprises a second desiccant.

[0071] In some embodiments, the storage-stable PPI system (e.g., a storage-stable omeprazole system) described herein comprises: (i) (a) a first mixture comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), the first mixture comprising about 2.5% or less moisture, and (ii) a second mixture comprising a second desiccant and a second buffer, the first and second mixtures being stored separately from each other and mixed together upon or immediately prior to reconstitution with water, the system comprising sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments of this aspect, the storage-stable PPI system (e.g., a storage-stable omeprazole system) described herein comprises sodium and potassium in a weight ratio of about 1:3.2.

[0072] In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.5% to about 1.5%. In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.6% to about 1.1%. In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.5% to about 0.9%. In some embodiments, the first mixture has a moisture content of about 0.5% to about 1.5%, and the second mixture has a moisture content of about 1.5% or less. In some embodiments, the second mixture has a moisture content of about 0.5% or less.

[0073] In some embodiments, the first mixture further comprises (b) a first desiccant.

[0074] In some embodiments, the first mixture further comprises (c) a first buffering agent.

[0075] In some embodiments, the storage-stable PPI system described herein (such as a storage-stable omeprazole system) comprises: (i) a first mixture comprising (a) a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), (b) a first desiccant, and (c) a first buffer, the first mixture comprising about 2.5% or less moisture, and (ii) a second mixture comprising a second desiccant and a second buffer, the first and second mixtures being stored separately from each other and mixed together upon or immediately prior to reconstitution with water, the system comprising sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments of this aspect, the storage-stable PPI system described herein (such as a storage-stable omeprazole system) comprises sodium and potassium in a weight ratio of about 1:3.2. In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.5% to about 1.5%. In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.6% to about 1.1%. In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.5% to about 0.9%. In some embodiments, the first mixture has a moisture content of about 0.5% to about 1.5%, and the second mixture has a moisture content of about 1.5% or less. In some embodiments, the second mixture has a moisture content of about 0.5% or less.

[0076] The first and second desiccants may comprise any pharmaceutically acceptable desiccants defined above, or a mixture of two or more pharmaceutically acceptable desiccants. The first and second desiccants may be the same or different. In some embodiments, the first desiccant is the same as the second desiccant. In some embodiments, the first and second desiccant are different. In some embodiments, the first and second desiccant are sodium alginate. In some embodiments, the sodium alginate is dry, i.e., the sodium alginate contains less than about 2% moisture. In some embodiments, the dry sodium alginate has a moisture content of about 0.5% to about 1.5%.

[0077] In some embodiments, the first mixture and the second mixture can be independently in the form of a powder, pellets, granules, seeds, beads, spheroids, microspheres, or mixtures thereof. In some embodiments, the first mixture and the second mixture are each independently in the form of a powder or pellets. In other embodiments, the first mixture and the second mixture can both be in the form of a powder.

[0078] In some embodiments, the PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, present in the storage-stable systems described herein is micronized.

[0079] In some embodiments, the PPI or pharmaceutically acceptable salt thereof is present in the storage-stable system described herein and is a mixture of micronized and non-micronized PPI or a pharmaceutically acceptable salt thereof. In some embodiments of this aspect, the PPI or pharmaceutically acceptable salt thereof comprises about 30% to about 70% by weight of micronized PPI or a pharmaceutically acceptable salt thereof, with the remainder being non-micronized. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a 1:1 mixture, by weight, of micronized and non-micronized PPI or a pharmaceutically acceptable salt thereof. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of micronized and non-micronized PPI or a pharmaceutically acceptable salt thereof. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized PPI or pharmaceutically acceptable salt thereof in a ratio of about 1:2.3 by weight (i.e., about a 30:70 mixture). In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized PPI or pharmaceutically acceptable salt thereof in a ratio of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized PPI or pharmaceutically acceptable salt thereof in a ratio of about 1:1.5 by weight (i.e., about a 40:60 mixture).

[0080] In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is present in the storage-stable omeprazole system described herein and is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof comprises about 30% to about 70% by weight of micronized omeprazole or a pharmaceutically acceptable salt thereof, with the remainder being non-micronized. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:2.3 by weight (i.e., about a 30:70 mixture). In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:1.5 by weight (i.e., about a 40:60 mixture).

[0081] In some embodiments, the first and second buffering agents are present in amounts sufficient to increase the gastric pH to a pH that prevents at least partial degradation of the PPI, or a pharmaceutically acceptable salt of omeprazole, in the gastric fluid.

[0082] In some embodiments, the first and second buffering agents provide a buffering capacity of about 0.5 to about 4 mEq / ml of a dose of the configured storage-stable PPI system described herein with water. In some embodiments, the first and second buffering agents provide a buffering capacity of about 1.6 to about 2.3 mEq / ml of a dose of the configured storage-stable PPI system described herein with water. In some embodiments, the first and second buffering agents provide a buffering capacity of about 2 mEq / ml of a dose of the configured storage-stable PPI system described herein with water. In some embodiments, the first and second buffering agents provide a buffering capacity of about 2.1 mEq / ml of a dose of the configured storage-stable PPI system described herein with water.

[0083] In some embodiments, the first and second buffering agents provide a buffering capacity of about 0.5 to about 4 mEq / ml of a dose of the configured storage-stable omeprazole system described herein with water. In some embodiments, the first and second buffering agents provide a buffering capacity of about 1.6 to about 2.3 mEq / ml of a dose of the configured storage-stable omeprazole system described herein with water. In some embodiments, the first and second buffering agents provide a buffering capacity of about 2 mEq / ml of a dose of the configured storage-stable omeprazole system described herein with water. In some embodiments, the first and second buffering agents provide a buffering capacity of about 2.1 mEq / ml of a dose of the configured storage-stable omeprazole system described herein with water.

[0084] In some embodiments, the first buffer and the second buffer each independently comprise one buffer or a mixture of two or more buffers. In some embodiments, the first buffer and the second buffer each independently comprise one, two, three, or four buffers. In some embodiments, the first buffer and the second buffer each independently comprise one, two, or three buffers. In some embodiments, the first buffer and the second buffer each independently comprise one buffer or two buffers.

[0085] In some embodiments, the first buffering agent and the second buffering agent are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and mixtures thereof. In some embodiments, the first buffering agent and the second buffering agent are each independently selected from sodium or potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and mixtures thereof.

[0086] In some embodiments, the first buffering agent is sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, sodium tetraborate, sodium acetate, disodium hydrogen phthalate, sodium hydrogen phthalate, tartaric acid hydrogen The preferred salts of the hydroxybenzoates are selected from the group consisting of sodium, disodium tartrate, sodium succinate, and mixtures thereof.

[0087] In some embodiments, the second buffering agent is selected from sodium or potassium carbonate, bicarbonate, phosphate, citrate, borate, acetate, phthalate, tartrate, succinate, and mixtures thereof.

[0088] In some embodiments, the first buffering agent and the second buffering agent are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof. In some embodiments, the first buffering agent is sodium bicarbonate. In some embodiments, the second buffering agent is a mixture of sodium bicarbonate and potassium bicarbonate. In some embodiments, the second mixture comprises about 11% by weight sodium bicarbonate and about 89% by weight potassium bicarbonate.

[0089] In some embodiments, the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:100 to about 100:1. In some embodiments, the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.5 to about 1:3.4. In some embodiments, the sodium bicarbonate and potassium bicarbonate are present in a weight ratio of about 1:2.7.

[0090] In some embodiments, the first buffering agent and the second buffering agent are each independently selected from the group consisting of potassium carbonate, potassium bicarbonate, potassium dihydrogen phosphate, potassium hydrogen phosphate, tripotassium phosphate, potassium hydrogen citrate, dipotassium hydrogen citrate, tripotassium citrate, potassium tetraborate, potassium acetate, dipotassium hydrogen phthalate, potassium hydrogen phthalate, tartaric acid hydrogen In some embodiments, the first buffering agent and the second buffering agent are selected from potassium bicarbonate, dipotassium tartrate, potassium succinate, and mixtures thereof.

[0091] The storage-stable PPI systems (such as the storage-stable omeprazole systems) described herein can further comprise one or more pharmaceutically acceptable excipients, including sweeteners, flavoring agents, preservatives, thickeners, suspending agents, opacifiers, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, diluents, and antifoaming agents.

[0092] Suitable sweeteners include, for example, mannitol, sucrose, fructose, dextrose, isomalt, maltitol, sorbitol, sucralose, acesulfame K, aspartame, cyclamate, saccharin, stevia, sucralose, sodium saccharin, xylitol, or a combination thereof. In some embodiments described herein, the sweetener is mannitol, sucralose, or maltitol, or a mixture thereof.

[0093] Suitable flavorings include, for example, the following flavors: mint, vanilla, banana, apple, orange, pear, peach, strawberry, raspberry, chocolate, lemon, lime, butterscotch, caramel, cherry, and cinnamon, or mixtures thereof. In some embodiments described herein, the flavoring is mint flavor, vanilla flavor, or mixtures thereof.

[0094] Suitable preservatives include those suitable for use in pharmaceutical formulations, including antimicrobial preservatives. Suitable antimicrobial preservatives include, for example, sodium benzoate, potassium benzoate, calcium benzoate, methylparaben sodium, ethylparaben sodium, and mixtures thereof. In some embodiments described herein, the preservative is sodium benzoate, methylparaben sodium, or a mixture thereof. In some embodiments, the preservative is a mixture of sodium benzoate and methylparaben sodium.

[0095] Suitable thickening agents (or thickeners) have other properties, The viscosity of the liquid can be increased without substantially changing the viscosity, and includes substances suitable for oral pharmaceutical formulations. Examples of suitable thickening agents include sodium alginate, xanthan gum, guar gum, and locust bean gum. In some embodiments, the thickening agent is sodium alginate, xanthan gum, or a mixture thereof.

[0096] Suitable opacifying agents include pharmaceutically acceptable substances added to materials to make the subsequent system opaque, such as titanium dioxide (TiO2).

[0097] In some embodiments, the shelf-stable PPI systems described herein (such as shelf-stable omeprazole systems) further comprise a sweetener, a flavoring agent, a preservative, or a mixture thereof.

[0098] In some embodiments, the second mixture in the shelf-stable PPI systems described herein (such as the shelf-stable omeprazole system) further comprises a sweetener and a preservative.

[0099] In some embodiments, the storage-stable PPI system (e.g., a storage-stable omeprazole system) described herein is provided in a drug delivery device suitable for multiple dose administration of the PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof). In certain embodiments, the delivery device is as described in U.S. Patent Nos. 9,051,100, 10,238,803, or U.S. Patent Application Publication No. 2014 / 0311929, the contents of which are incorporated by reference in their entireties.

[0100] In some embodiments, the delivery device is a PICS system. In some aspects, the PICS system is as shown in FIG.

[0101] In some embodiments, the drug delivery device comprises two chambers. In some embodiments, the two chambers of the drug delivery device can be integrated. In some embodiments, the second chamber of the drug delivery device can be a container body (such as a bottle), and the first chamber can contain the multiparticulate material and can be a cap that fits into the opening of the container body.

[0102] In some embodiments, the drug delivery device further comprises means for releasing the contents of the first chamber into the second chamber without removing the cap from the drug delivery device.

[0103] In some embodiments, the storage-stable PPI system (e.g., a storage-stable omeprazole system) described herein is provided in a container body including a cap, wherein (i) the container body contains a second mixture and has a container opening formed at its upper end, (ii) the cap has a cylindrical storage portion containing the first mixture and a cap portion sealing the upper end of the storage portion, and (iii) the cap is attached to the container opening of the container body, and when the cap is twisted, the first mixture is released into the container body. In some embodiments, the container body is an amber polyethylene terephthalate bottle, and the cap is a polypropylene tamper-evident cap.

[0104] In certain embodiments, the storage-stable PPI system (e.g., a storage-stable omeprazole system) described herein is formulated in a drug delivery device suitable for multiple-dose administration of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), wherein the system comprises a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), the system comprises a water content of about 2.5% or less, the system does not contain sodium from a sodium-containing buffer, or the system contains sodium and potassium in a weight ratio of about 1:100 to about 100:1, and the storage-stable omeprazole system is reconstituted with water prior to administration. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:2 to about 1:5. In certain embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments of this aspect, the sodium and potassium are present in a weight ratio of about 1:3.2. In some embodiments, the storage-stable PPI system (such as a storage-stable omeprazole system) does not contain sodium from a sodium-containing buffer.

[0105] In some embodiments, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) remain stable for at least 2 years at 25° C. / 60% relative humidity.

[0106] In some embodiments, the present disclosure provides a storage-stable omeprazole powder system, the system comprising: (i) a first powder mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) sodium alginate, and (c) a first buffering agent; and (ii) a second powder mixture comprising sodium alginate and a second buffering agent, wherein the first powder mixture and the second powder mixture are stored separately from one another and mixed together at or immediately before reconstitution with water, and the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0107] In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is micronized. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof comprises about 30 to about 70% micronized omeprazole or a pharmaceutically acceptable salt thereof, with the remainder of the omeprazole or pharmaceutically acceptable salt thereof being non-micronized. In some embodiments, the omeprazole is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of micronized and non-micronized omeprazole or pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of about 1:2.3 by weight of micronized and non-micronized omeprazole or pharmaceutically acceptable salt thereof (i.e., a mixture of about 30:70). In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of non-micronized and micronized omeprazole or pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is about a 1:1.5 mixture by weight of micronized and non-micronized omeprazole or pharmaceutically acceptable salt thereof (i.e., about a 40:60 mixture).

[0108] The first powder mixture can be prepared, for example, by wet granulating a mixture of omeprazole or a pharmaceutically acceptable salt thereof, sodium alginate, and a first buffer, drying the granules, and milling the dried granules. In some embodiments, the first powder mixture further comprises dry sodium alginate. Suitable methods for preparing the first powder mixture are described, for example, in U.S. Patent No. 8,093,271, the contents of which are incorporated by reference in their entirety.

[0109] In some embodiments, about 20 to about 30% of the sodium alginate present in the first powder mixture is uniformly distributed on the surface of the first buffer. In some embodiments, about 20 to about 25% of the sodium alginate present in the first powder mixture is uniformly distributed on the surface of the first buffer. In some embodiments, the sodium alginate in the first powder mixture that is not distributed on the surface of the first buffer is dry, i.e., contains less than about 2% moisture. In some embodiments, the sodium alginate present in the second powder mixture is dry.

[0110] In some embodiments, the dry sodium alginate has a moisture content of about 0.5% to about 1.5%. In some embodiments, the sodium alginate is a low viscosity grade sodium alginate as defined above.

[0111] The first buffering agent and the second buffering agent are present in an amount sufficient to increase the gastric pH to a pH that prevents at least partial degradation of omeprazole or a pharmaceutically acceptable salt thereof in the gastric fluid. In some aspects, the first and second buffering agents provide a buffering capacity of about 0.5 to about 4 mEq / ml of the configured storage-stable omeprazole powder system described herein with water. In some aspects, the first and second buffering agents provide a buffering capacity of about 1.6 to about 2.3 mEq / ml of the configured storage-stable omeprazole powder system described herein with water. In some embodiments, the first and second buffering agents provide a buffering capacity of about 2 mEq / ml of the configured storage-stable omeprazole powder system described herein with water.

[0112] In some embodiments, the first and second buffering agents present in the storage-stable omeprazole powder system are each independently selected from the group consisting of alkali or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and mixtures thereof. In some embodiments, the first and second buffering agents are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0113] In some embodiments, the first buffering agent in the storage-stable omeprazole powder system is sodium bicarbonate.

[0114] In some embodiments, the second buffering agent in the storage-stable omeprazole powder system is a mixture of sodium bicarbonate and potassium bicarbonate.

[0115] In some embodiments, the first buffer in the storage-stable omeprazole powder system is sodium bicarbonate and the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate, hi some embodiments, the second buffer is a mixture of about 11% by weight sodium bicarbonate and about 89% by weight potassium bicarbonate.

[0116] In some embodiments, the first and second powder mixtures in the storage-stable omeprazole powder system comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.5 to about 1:3.4, hi some embodiments, the sodium bicarbonate and potassium bicarbonate are present in a weight ratio of about 1:2.7.

[0117] In some embodiments, the first buffering agent in the storage-stable omeprazole powder system is potassium bicarbonate and the second buffering agent is potassium bicarbonate.

[0118] In some embodiments, the second powder blend of the shelf-stable omeprazole powder system further comprises a sweetener and a preservative. Suitable sweeteners and preservatives as described above.

[0119] In some embodiments, the storage-stable omeprazole powder system is provided in a drug delivery device suitable for administering multiple doses of omeprazole.

[0120] In certain embodiments of this aspect, the drug delivery device includes a first chamber containing the first powder mixture and a second chamber containing the second powder mixture. In certain embodiments, the first chamber and the second chamber can be integrated. In some embodiments, the second chamber of the drug delivery device can be a container body (such as a bottle) containing the second powder mixture, and the first chamber can be a cap containing the first powder mixture attached to an opening of the container body.

[0121] The drug delivery device may further comprise means for releasing the first powder mixture into the second chamber without removing the cap from the drug delivery device.

[0122] In certain embodiments, the storage-stable omeprazole powder system is provided in a delivery device that is a container body with a cap. In some embodiments, (i) the container body contains a second powder mixture and has a container opening formed at its upper end, (ii) the cap has a cylindrical storage portion containing the first powder mixture and a cap portion sealing the upper end of the storage portion, and (iii) the cap is attached to the container opening of the container body, and when the cap is twisted, the first powder mixture is released into the container body. In certain embodiments, the container body is an amber polyethylene terephthalate bottle, and the cap is a polypropylene tamper-evident cap.

[0123] In certain embodiments, the storage-stable omeprazole powder system of the present disclosure remains stable for at least 6 months at 40°C / 75% relative humidity. In some embodiments, the storage-stable omeprazole powder system remains stable for at least 1 year at 30°C / 65% relative humidity. In some embodiments, the storage-stable omeprazole powder system remains stable for at least 2 years at 25°C / 60% relative humidity.

[0124] In some embodiments, the storage-stable PPI systems described herein (e.g., storage-stable omeprazole systems) are enclosed in a sealed aluminum foil pouch to minimize moisture ingress during storage of the unstructured system. In some embodiments, the aluminum foil pouch can reduce moisture-related degradation of the PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof) during storage of the storage-stable PPI systems described herein (e.g., storage-stable omeprazole systems). In some embodiments, the aluminum foil pouch has an internal polymer coating. The aluminum foil pouch can be sealed using a Hawo Heat Sealer (temperature setting: 150°C, hold time: 1-2 seconds).

[0125] Oral Pharmaceutical Suspension The present disclosure also provides oral pharmaceutical suspensions for providing a pharmaceutically effective amount of a PPI, or a pharmaceutically acceptable salt thereof, to a subject, particularly a pediatric subject, in need thereof. The oral pharmaceutical suspensions described herein contain sodium at levels acceptable for use in the treatment of pediatric subjects. The oral pharmaceutical suspensions are particularly suitable for use in multi-dose dosage forms, which can provide a uniform dosage of the PPI or a pharmaceutically acceptable salt thereof.

[0126] In one aspect, the present disclosure provides an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof) dispersed in the water, and one of a number of buffering agents. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:100 to about 100:1. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:2 to about 1:5. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In certain embodiments, sodium and potassium are present in the oral pharmaceutical suspension in a weight ratio of about 1:3.2.

[0127] In some embodiments, the oral pharmaceutical suspension comprises sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, sodium tetraborate, sodium acetate, disodium hydrogen phthalate, sodium hydrogen phthalate, tartaric acid hydrogen It does not contain sodium from sodium-containing buffers such as sodium tartrate, disodium succinate, etc.

[0128] In some embodiments, the oral pharmaceutical suspensions described herein further comprise a stabilizer or a thickener, or both. Suitable thickeners and stabilizers include gelling agents that stabilize liquid dosage forms such as suspensions. In certain embodiments, the thickener or stabilizer is sodium alginate. In certain embodiments, the sodium alginate present is a low viscosity grade of sodium alginate as described above.

[0129] In certain embodiments, about 1 ml of oral pharmaceutical suspension contains about 1 mg to about 10 mg of a PPI or a pharmaceutically acceptable salt thereof. In certain embodiments, about 1 ml of oral pharmaceutical suspension contains about 1 mg to about 10 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0130] In certain embodiments, about 1 ml of oral pharmaceutical suspension contains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of PPI or a pharmaceutically acceptable salt thereof. In certain embodiments, about 1 ml of oral pharmaceutical suspension contains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0131] In certain embodiments, about 1 ml of oral pharmaceutical suspension contains about 2 mg or about 4 mg of a PPI or a pharmaceutically acceptable salt thereof. In certain embodiments, about 1 ml of oral pharmaceutical suspension contains about 2 mg or about 4 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the oral pharmaceutical suspensions described herein comprise one, two, three, or four buffering agents. In some embodiments, the oral pharmaceutical suspensions described herein comprise one buffering agent. In some embodiments, the oral pharmaceutical suspensions described herein comprise two or three buffering agents. In some embodiments, the oral pharmaceutical suspensions described herein comprise two buffering agents.

[0133] Oral pharmaceutical suspensions described herein, such as those containing omeprazole or a pharmaceutically acceptable salt thereof, can contain any suitable buffering agent that functions to substantially prevent or inhibit acid degradation of the PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole, a pharmaceutically acceptable salt thereof) by gastric acid sufficient to maintain the bioavailability of the administered PPI. In some embodiments, one or more buffering agents are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. In some embodiments, one or more buffering agents are each independently selected from the group consisting of sodium or potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates.

[0134] In some embodiments, the oral pharmaceutical suspensions described herein (e.g., suspensions comprising omeprazole or a salt thereof) may be prepared using any of the following: sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, sodium tetraborate, sodium acetate, disodium hydrogen phthalate, sodium hydrogen phthalate, tartaric acid, hydrogen In some embodiments, the oral pharmaceutical suspensions described herein comprise at least one buffering agent selected from potassium carbonate, potassium bicarbonate, potassium dihydrogen phosphate, potassium hydrogen phosphate, tripotassium phosphate, potassium dihydrogen citrate, dipotassium hydrogen citrate, tripotassium citrate, potassium tetraborate, potassium acetate, dipotassium hydrogen phthalate, potassium hydrogen phthalate, tartrate. hydrogen Potassium, tartrate two The buffer comprises at least one buffer selected from potassium, and potassium succinate.

[0135] In some embodiments, the oral pharmaceutical suspensions described herein (e.g., suspensions comprising omeprazole or a pharmaceutically acceptable salt thereof) may contain potassium carbonate, potassium bicarbonate, potassium dihydrogen phosphate, potassium hydrogen phosphate, tripotassium phosphate, potassium dihydrogen citrate, dipotassium hydrogen citrate, tripotassium citrate, potassium tetraborate, potassium acetate, dipotassium hydrogen phthalate, potassium hydrogen phthalate, tartaric acid, or the like. hydrogen Potassium, tartrate two In some embodiments, the buffer comprises up to one buffer selected from potassium bicarbonate, potassium iodide, and potassium succinate.

[0136] In some embodiments, the oral pharmaceutical suspensions described herein (such as those comprising omeprazole or a pharmaceutically acceptable salt thereof) comprise two or more buffering agents selected from sodium and potassium carbonate, bicarbonate, phosphate, citrate, borate, acetate, phthalate, tartrate, and succinate. In some embodiments, the oral pharmaceutical suspensions described herein comprise two buffering agents. In some embodiments, the oral pharmaceutical suspensions described herein comprise both sodium bicarbonate and potassium bicarbonate.

[0137] In some embodiments, the sodium bicarbonate and potassium bicarbonate are present in the oral pharmaceutical suspension in a weight ratio of about 1:2.5 to about 1:3.4 per ml of suspension, hi some embodiments, the sodium bicarbonate and potassium bicarbonate are present in a weight ratio of about 1:2.7 per ml of suspension.

[0138] In certain embodiments, the oral pharmaceutical suspensions described herein contain sodium and potassium in a weight ratio of about 1:100 to about 100:1. In certain embodiments, the oral pharmaceutical suspensions described herein contain sodium and potassium in a weight ratio of about 1:50 to about 50:1. In certain embodiments, the oral pharmaceutical suspensions described herein contain sodium and potassium in a weight ratio of about 1:10 to about 10:1. In certain embodiments, the oral pharmaceutical suspensions described herein contain sodium and potassium in a weight ratio of about 1:2 to about 1:5.

[0139] In certain embodiments, the oral pharmaceutical suspensions described herein contain sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In certain embodiments, the sodium and potassium are present in the oral pharmaceutical suspension in a weight ratio of about 1:3.2.

[0140] The one or more buffering agents present in the oral pharmaceutical suspensions described herein are present in an amount sufficient to increase the gastric pH to a pH that prevents at least partial degradation of the PPI (e.g., omeprazole or a pharmaceutically acceptable salt thereof) in the gastric fluid.

[0141] In certain embodiments, the one or more buffering agents present in the oral pharmaceutical suspension provide a buffering capacity of about 0.5 to about 4 mEq / ml of suspension. In certain embodiments, the one or more buffering agents present in the oral pharmaceutical suspension provide a buffering capacity of about 1.6 to about 2.3 mEq / ml of suspension. In certain embodiments, the one or more buffering agents present in the oral pharmaceutical suspension provide a buffering capacity of about 2 mEq / ml of suspension.

[0142] In certain embodiments, the oral pharmaceutical suspensions described herein contain low levels of sodium, making the suspensions suitable for administration to pediatric subjects. In some aspects, the oral pharmaceutical suspensions described herein contain about 50 mg to about 150 mg of sodium per 5 ml of suspension. In certain embodiments, about 70 mg to about 100 mg of sodium is present in 5 ml of suspension. In some embodiments, the oral pharmaceutical suspensions described herein contain about 86 mg of sodium per 5 ml of suspension. This 5 ml dose corresponds to 4.3% of the WHO recommended maximum daily dietary intake of sodium for adults.

[0143] In some embodiments, the PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, present in the oral pharmaceutical suspensions described herein is micronized.

[0144] In some embodiments, the PPI or pharmaceutically acceptable salt thereof is present in the oral pharmaceutical suspensions described herein as a mixture of micronized and non-micronized PPI or pharmaceutically acceptable salt thereof. In some embodiments of this aspect, the PPI or pharmaceutically acceptable salt thereof comprises about 30% to about 70% by weight of micronized PPI or pharmaceutically acceptable salt, with the remainder being non-micronized. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a 1:1 mixture, by weight, of micronized and non-micronized PPI or pharmaceutically acceptable salt thereof. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9, by weight, of micronized and non-micronized PPI or pharmaceutically acceptable salt thereof. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized PPI or pharmaceutically acceptable salt thereof in a ratio of about 1:2.3 by weight (i.e., about a 30:70 mixture). In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized PPI or pharmaceutically acceptable salt thereof in a ratio of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized PPI or pharmaceutically acceptable salt thereof in a ratio of about 1:1.5 by weight (i.e., about a 40:60 mixture).

[0145] In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is present in the oral pharmaceutical suspensions described herein as a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof comprises about 30% to about 70% by weight of micronized omeprazole or a pharmaceutically acceptable salt thereof, with the remainder being non-micronized. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:2.3 by weight (i.e., about a 30:70 mixture). In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:1.5 by weight (i.e., about a 40:60 mixture).

[0146] In certain embodiments, the oral pharmaceutical suspension comprises a first and a second C 最大 and the first and second T 最大 after oral administration in a subject in need thereof.

[0147] In certain embodiments, a 5 ml volume of the oral pharmaceutical suspension described herein comprises about 10 mg or about 20 mg of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), about 200 mg to about 300 mg of sodium bicarbonate, about 600 mg to about 720 mg of potassium bicarbonate, and about 100 mg to about 150 mg of sodium alginate. In some embodiments, the 5 ml oral pharmaceutical suspension further comprises about 10 mg to about 15 mg of methylparaben sodium salt and about 15 mg to about 30 mg of sodium benzoate.

[0148] In certain embodiments, a 5 ml dose of the oral pharmaceutical suspension described herein comprises about 10 mg or about 20 mg of omeprazole, or a pharmaceutically acceptable salt thereof, about 256 mg of sodium bicarbonate, about 695 mg of potassium bicarbonate, and about 125 mg of sodium alginate.

[0149] In some embodiments, 5 ml of oral pharmaceutical suspension further comprises about 11.45 mg of methylparaben sodium salt and about 25 mg of sodium benzoate.

[0150] The oral pharmaceutical suspensions described herein (such as suspensions containing omeprazole or a pharmaceutically acceptable salt thereof) can further comprise one or more pharmaceutically acceptable excipients, including sweeteners, flavoring agents, preservatives, thickeners, suspending agents, opacifiers, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, diluents, and antifoaming agents.

[0151] Suitable sweeteners include, for example, mannitol, sucrose, fructose, dextrose, isomalt, maltitol, sorbitol, sucralose, acesulfame K, aspartame, cyclamate, saccharin, stevia, sucralose, sodium saccharin, xylitol, or a combination thereof. In some embodiments described herein, the sweetener is mannitol, sucralose, or maltitol, or a mixture thereof.

[0152] Suitable flavoring agents include, for example, the following flavors or mixtures thereof: mint, vanilla, banana, apple, orange, pear, peach, strawberry, raspberry, chocolate, lemon, lime, butterscotch, caramel, cherry, and cinnamon. In some aspects described herein, the flavoring agent is mint flavor, vanilla flavor, or mixtures thereof.

[0153] Suitable preservatives include those suitable for use in pharmaceutical formulations, including antimicrobial preservatives. Suitable antimicrobial preservatives include, for example, sodium benzoate, potassium benzoate, calcium benzoate, methylparaben sodium, ethylparaben sodium, and mixtures thereof. In some aspects described herein, the preservative is sodium benzoate, methylparaben sodium, or a mixture thereof. In some embodiments, the preservative is a mixture of sodium benzoate and methylparaben sodium.

[0154] Suitable thickening agents (or thickeners) have other properties, The viscosity of the liquid can be increased without substantially changing the viscosity, and includes substances suitable for oral pharmaceutical formulations. Examples of suitable thickening agents include sodium alginate, xanthan gum, guar gum, and locust bean gum. In some embodiments, the thickening agent is sodium alginate, xanthan gum, or a mixture thereof.

[0155] Suitable opacifying agents include pharmaceutically acceptable substances added to materials to make the subsequent system opaque, such as titanium dioxide (TiO2).

[0156] In some embodiments, the oral pharmaceutical suspensions described herein further comprise a sweetener, a flavoring agent, a preservative, or a mixture thereof.

[0157] The oral pharmaceutical suspensions described herein remain stable for at least one month after reconstitution with water. The suspensions should generally be stored in a refrigerator (2°C to 8°C). For up to two days, the suspensions may be stored below 25°C.

[0158] In some embodiments, after storage for 3 months at 40°C and 75% relative humidity (RH) prior to constitution with water, the total amount of impurities (i.e., degradants of the PPI, such as omeprazole) formed in the oral pharmaceutical suspensions described herein on the day of constitution with water (i.e., day 0) is 0.16% w / w or less. In some embodiments, the total amount of impurities formed in the oral pharmaceutical suspensions on day 0 is 0.11% w / w or less.

[0159] In some embodiments, the total amount of impurities formed in the oral pharmaceutical suspensions described herein after storage for 28 days at 2°C-8°C after constitution with water (i.e., day 28) and after storage for 3 months at 40°C and 75% RH before constitution with water is 0.28% w / w or less. In some embodiments, the total amount of impurities formed in the oral pharmaceutical suspensions at 2°C-8°C after 28 days is 0.23% w / w or less.

[0160] In some embodiments, the total amount of impurities formed in the oral pharmaceutical suspensions described herein after storage for 56 days at 2°C-8°C after constitution with water (i.e., day 56) and after storage for 3 months at 40°C and 75% RH before constitution with water is 0.38% w / w or less. In some embodiments, the total amount of impurities formed in the oral pharmaceutical suspensions at 2°C-8°C after 56 days is 0.33% w / w or less.

[0161] In some embodiments, sodium methyl parahydroxybenzoate is used as a preservative in the storage-stable PPI systems (e.g., storage-stable omeprazole systems) and oral pharmaceutical suspensions described herein. In some embodiments, after storage at 40°C and 75% RH for 3 months prior to reconstitution with water, the amount of sodium methyl parahydroxybenzoate present in the oral pharmaceutical suspensions described herein on the day of reconstitution with water (i.e., day 0) is at least 94.5% w / w of the total amount originally present in the storage-stable PPI systems (e.g., storage-stable omeprazole systems) described herein. In some embodiments, the amount of sodium methyl parahydroxybenzoate present in the oral pharmaceutical suspensions on day 0 is at least 95.9% w / w of the total amount originally present in the storage-stable PPI systems (e.g., storage-stable omeprazole systems) described herein.

[0162] In some embodiments, after 28 days of storage at 2°C-8°C after constitution with water (i.e., day 28), and after 3 months of storage at 40°C and 75% RH before constitution with water, the amount of sodium methyl parahydroxybenzoate present in the oral pharmaceutical suspension described herein is at least 92% w / w of the total amount originally present in the storage-stable PPI system described herein (e.g., the storage-stable omeprazole system). In some embodiments, the amount of sodium methyl parahydroxybenzoate present in the oral pharmaceutical suspension on day 28 is at least 94% w / w of the total amount originally present in the storage-stable PPI system described herein (e.g., the storage-stable omeprazole system).

[0163] In some embodiments, after 56 days of storage at 2°C-8°C after constitution with water (i.e., day 56), and after 3 months of storage at 40°C and 75% RH before constitution with water, the amount of sodium methyl parahydroxybenzoate present in the oral pharmaceutical suspension described herein is at least 84% w / w of the total amount originally present in the storage-stable PPI system described herein (e.g., the storage-stable omeprazole system). In some embodiments, the amount of sodium methyl parahydroxybenzoate present in the oral pharmaceutical suspension on day 56 is at least 86.1% w / w of the total amount originally present in the storage-stable PPI system described herein (e.g., the storage-stable omeprazole system).

[0164] In some embodiments, the oral pharmaceutical suspensions described herein are provided in a drug delivery device suitable for multiple dose administration of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof. Suitable drug delivery devices are, for example, as described above in connection with the storage-stable systems described herein. Treatment method

[0165] Omeprazole and other benzimidazole proton pump inhibitors are well-known active agents for the treatment of acid-related disorders.

[0166] In one aspect, the present disclosure provides a method of inhibiting gastric acid secretion in a subject, the method comprising administering to a subject in need thereof an effective amount of the oral pharmaceutical suspension of the present disclosure described above.

[0167] In certain aspects, the disclosure provides a method for inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffering agents, wherein the suspension contains no sodium from a sodium-containing buffer or contains sodium and potassium in a weight ratio of about 1:100 to about 100:1.

[0168] In certain embodiments, the present disclosure provides a method of inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed therein, and one or more buffering agents, wherein the suspension contains no sodium from a sodium-containing buffer or contains sodium and potassium in a weight ratio of about 1:100 to about 100:1.

[0169] In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:2 to about 1:5.

[0170] In certain aspects, the present disclosure provides a method for inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffering agents, wherein the oral pharmaceutical suspension contains no sodium from a sodium-containing buffer or contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0171] In certain embodiments, the disclosure provides a method of inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed therein, and one or more buffering agents, wherein the suspension contains no sodium from a sodium-containing buffer or contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0172] In some embodiments, the oral pharmaceutical suspension comprises sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, sodium tetraborate, sodium acetate, disodium hydrogen phthalate, sodium hydrogen phthalate, tartaric acid hydrogen It does not contain sodium from sodium-containing buffers such as sodium tartrate, disodium succinate, etc.

[0173] In certain embodiments, the subject is a child, hi some embodiments, the child is an infant, a toddler, a pre-adolescent, or an adolescent.

[0174] In some embodiments, the method comprises administering to a subject an oral pharmaceutical suspension described herein, wherein about 1 ml of the suspension contains about 1 mg to about 10 mg of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof). In some embodiments, about 1 ml of the suspension contains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof). In some embodiments, about 1 ml of the suspension contains about 2 mg of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof). In some embodiments, about 1 ml of the suspension contains about 4 mg of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof).

[0175] The oral pharmaceutical suspensions described herein, particularly those containing omeprazole or a pharmaceutically acceptable salt thereof, are useful for treating, for example, duodenal ulcers, gastric ulcers, NSAID-associated gastric and duodenal ulcers, reflux esophagitis, and symptomatic gastroesophageal reflux disease (GERD).

[0176] In one aspect, the disclosure also provides a method of inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof) dispersed in the water, and one or more buffering agents, wherein the suspension does not contain sodium from a sodium-containing buffer or the suspension contains sodium and potassium in a weight ratio of about 1:100 to about 100:1, and the oral pharmaceutical suspension comprises: (a) a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof); The oral pharmaceutical suspension is prepared by combining a first mixture containing a sodium-containing buffer (e.g., a pharmaceutically acceptable salt thereof), the first mixture containing about 2.5% or less of water, with a second mixture containing a second buffer, the second mixture containing about 2.5% or less of water, to obtain a combined mixture, wherein the combined mixture does not contain sodium from the sodium-containing buffer or the combined mixture contains sodium and potassium in a weight ratio of about 1:100 to about 100:1; and adding water to the combined mixture. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:2 to about 1:5. In certain embodiments, the oral pharmaceutical suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments, the second mixture further comprises a second desiccant.

[0177] In certain embodiments, a method for inhibiting gastric acid secretion comprises administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof) dispersed in the water, and one or more buffering agents, wherein the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. The oral pharmaceutical suspension is prepared by: (a) combining a first mixture comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), the first mixture containing about 2.5% or less water, with a second mixture comprising a second desiccant and a second buffering agent to obtain a combined mixture, the combined mixture containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4; and adding water to the combined mixture.

[0178] Dosage and Administration In some embodiments, an effective amount of the oral pharmaceutical suspensions described herein is administered without food on an empty stomach, preferably at least 30 minutes before a meal. A glass of water may be drunk after taking the dose. The oral pharmaceutical suspensions described herein may also be administered via nasogastric via a percutaneous endoscopic gastrostomy (NG) or percutaneous endoscopic gastrostomy (PEG) tube and administered to the subject.

[0179] In some embodiments, an oral pharmaceutical suspension containing about 2 mg / ml of a PPI or a pharmaceutically acceptable salt (such as omeprazole or a pharmaceutically acceptable salt) is suitable for administering a dose of less than about 15 mg.

[0180] In some embodiments, an oral pharmaceutical suspension containing about 4 mg / ml of a PPI or a pharmaceutically acceptable salt (such as omeprazole or a pharmaceutically acceptable salt) is suitable for administering a dose of about 20 mg or about 40 mg.

[0181] A suitable dose for an adult is about 10 mg to about 40 mg once daily. In some embodiments, the adult dose is about 10 mg, about 20 mg, about 30 mg, or about 40 mg once daily.

[0182] Doses for children are generally based on their weight.

[0183] In some embodiments, a suitable dose of omeprazole or a salt thereof administered in an oral pharmaceutical suspension to a child 1 month to 1 year of age is about 1 mg / kg once daily.

[0184] In some embodiments, a suitable dose of omeprazole or a salt thereof administered in an oral pharmaceutical suspension to a child over 1 year of age weighing about 10-20 kg is about 10 mg once daily, which can be increased to 20 mg once daily.

[0185] In some embodiments, a suitable dose of omeprazole or a salt thereof in an oral pharmaceutical suspension for a child over 2 years of age and weighing more than about 20 kg is about 20 mg once daily, which can be increased to 40 mg once daily.

[0186] In some embodiments, the oral pharmaceutical suspensions of the present disclosure may be used in combination with another pharmaceutical agent indicated for the treatment or prevention of gastrointestinal disorders, such as, for example, antibacterial agents, prokinetic agents, H2 antagonists, and antacids, or sucralfate, which are commonly administered to minimize pain and / or complications associated with gastrointestinal disorders. How to prepare a suspension

[0187] In one aspect, the present disclosure provides a method for preparing an oral pharmaceutical suspension described herein. The method includes: (a) combining a first mixture containing a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), the first mixture containing about 2.5% or less water, with a second mixture containing a second buffer, the second mixture containing about 2.5% or less water, to obtain a combined mixture, wherein the combined mixture does not contain sodium from a sodium-containing buffer or the combined mixture contains sodium and potassium in a weight ratio of about 1:100 to about 100:1; and adding water to the combined mixture. In certain embodiments, the combined mixture contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In certain embodiments, the combined mixture contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In certain embodiments, the combined mixture contains sodium and potassium in a weight ratio of about 1:2 to about 1:5. In certain embodiments, the combined mixture contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments, the combined mixture contains sodium and potassium in a weight ratio of about 1:3.2. In some embodiments, the combined mixture does not contain sodium from a sodium-containing buffer. In some embodiments, the first mixture and the second mixture independently have a water content of about 0.5% to about 1.5%. In some embodiments, the first mixture further comprises (b) a first desiccant, and / or the second mixture further comprises a second desiccant.

[0188] In some embodiments, the present disclosure provides a method for preparing an oral pharmaceutical suspension, comprising: (a) combining a first mixture containing a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof), the first mixture containing about 2.5% or less water, with a second mixture containing a second desiccant and a second buffer to obtain a combined mixture, the combined mixture containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4; and adding water to the combined mixture. In some embodiments, the sodium and potassium are present in a weight ratio of about 1:3.2. In some embodiments, the first mixture has a water content of about 0.5% to about 1.5%.

[0189] In some embodiments, the first mixture further comprises (b) a first desiccant.

[0190] In some embodiments, the first desiccant and the second desiccant are sodium alginate.

[0191] In some embodiments, the first mixture further comprises (c) a first buffering agent.

[0192] In some embodiments, the first mixture and the second mixture can each independently be in the form of a powder, pellets, granules, seeds, beads, spheroids, microspheres, or a mixture thereof.

[0193] In some embodiments, the PPI or its pharmaceutically acceptable salt (e.g., omeprazole or its pharmaceutically acceptable salt) present in the oral pharmaceutical suspension described herein can be micronized before preparing the oral suspension. Methods known in the art can be used to micronize omeprazole or its salt. For example, conventional micronization techniques based on friction to reduce particle size, such as milling, grinding, and the like, can be used. A typical industrial mill usually consists of a cylindrical metal drum containing steel balls. As the drum rotates, the spheres inside collide with solid particles, thus crushing them into smaller diameters. In the case of grinding, solid particles are formed when the grinding units of the device rub against each other, while solid particles are trapped between them. Methods such as crushing and cutting can also be used to reduce particle diameter. Crushing uses a hammer-like tool to break solids into smaller particles by impact. Cutting uses sharp blades to cut coarse solid pieces into smaller ones. In addition, more advanced micronization methods using supercritical fluids in the micronization process can be used. These methods use supercritical fluids to induce a state of supersaturation, which leads to the precipitation of individual particles. Suitable techniques include the RESS process (Rapid Expansion of Supercritical Solutions), the SAS method (Supercritical Anti-Solvent), and the PGSS method (Gas Saturated Solution). These latest techniques allow for greater process tunability. Parameters such as relative pressure and temperature, solute concentration, and antisolvent to solvent ratio can be varied to adjust for the desired particle size. Supercritical fluid methods offer finer control over particle diameter, particle size distribution, and morphology consistency.

[0194] In some embodiments, a micronized PPI or pharmaceutically acceptable salt thereof suitable for use in the oral suspensions described herein is a composition in which 90% or more of the particles have a particle size of 20 micrometers or less (i.e., 20 μm or less). In some embodiments, the oral pharmaceutical suspensions described herein comprise a micronized PPI or pharmaceutically acceptable salt thereof. In some embodiments, 90% or more of the particles in the micronized PPI or salt thereof have a particle size of 20 micrometers or less.

[0195] In some embodiments, micronized omeprazole or a pharmaceutically acceptable salt thereof suitable for use in the oral suspensions described herein is a composition in which 90% or more of the particles have a particle size of 20 micrometers or less (i.e., 20 μm or less). In some embodiments, the oral pharmaceutical suspensions described herein comprise micronized omeprazole. In some embodiments, 90% or more of the particles in the micronized omeprazole have a particle size of 20 micrometers or less.

[0196] In some embodiments, the non-micronized omeprazole is a composition in which 95% or more of the particles have a particle size of 425 micrometers or less and 30% or more of the particles have a particle size of 75 micrometers or less.

[0197] The PPIs and their salts can be prepared by any suitable method known in the art.

[0198] In particular, omeprazole and its salts can be prepared by any suitable method known in the art.

[0199] In some embodiments, the PPI or pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof) used in the methods described herein is micronized.

[0200] In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized PPI or a pharmaceutically acceptable salt thereof. In some embodiments, the PPI comprises about 30 to about 70% micronized PPI or a pharmaceutically acceptable salt thereof, with the remainder of the PPI or pharmaceutically acceptable salt thereof being non-micronized. In some embodiments, the PPI is a 1:1 mixture, by weight, of micronized and non-micronized PPI or a pharmaceutically acceptable salt thereof. In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9, by weight, of micronized and non-micronized PPI or a pharmaceutically acceptable salt thereof. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized PPI or pharmaceutically acceptable salt thereof in a ratio of about 1:2.3 by weight (i.e., about a 30:70 mixture). In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized PPI or pharmaceutically acceptable salt thereof in a ratio of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight. In some embodiments, the PPI or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized PPI or pharmaceutically acceptable salt thereof in a ratio of about 1:1.5 by weight (i.e., about a 40:60 mixture).

[0201] In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole comprises about 30 to about 70% micronized omeprazole or a pharmaceutically acceptable salt thereof, with the remainder of the omeprazole or pharmaceutically acceptable salt thereof being non-micronized. In some embodiments, the omeprazole is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or a pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9, by weight, of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:2.3 by weight (i.e., about a 30:70 mixture). In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight. In some embodiments, the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:1.5 by weight (i.e., about a 40:60 mixture).

[0202] The first and second buffering agents used in the present methods are present in amounts sufficient to increase the gastric pH to a pH that prevents at least partial degradation of omeprazole in the gastric fluid. In some embodiments, the first and second buffering agents together provide a buffering capacity of the suspension of about 0.5 mEq / ml to about 4 mEq / ml dose. In some embodiments, the first and second buffering agents together provide a buffering capacity of the suspension of about 1.6 mEq / ml to about 2.3 mEq / ml dose. In some embodiments, the first and second buffering agents together provide a buffering capacity of the suspension of about 2 mEq / ml dose.

[0203] In some embodiments, the first buffering agent and the second buffering agent are each independently selected from the group consisting of alkali or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and succinates. In some embodiments, the first buffering agent and the second buffering agent are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0204] In some embodiments, the first buffer is sodium bicarbonate. In other aspects, the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate. In some embodiments, the second buffer comprises about 11% by weight sodium bicarbonate and about 89% by weight potassium bicarbonate.

[0205] In some embodiments, the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0206] In some embodiments, the first buffering agent and the second buffering agent are potassium bicarbonate.

[0207] In some embodiments, the second mixture further comprises a sweetener and a preservative.

[0208] In some embodiments, the method further comprises providing the oral pharmaceutical suspension in a drug delivery device suitable for multiple dose administration of the PPI or a pharmaceutically acceptable salt thereof (e.g., omeprazole or a pharmaceutically acceptable salt thereof). Suitable drug delivery devices are, for example, as described above in connection with the storage-stable systems described herein.

[0209] The present disclosure also provides the following specific embodiments.

[0210] Embodiment 1. A storage-stable omeprazole system, the system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the system comprising a water percentage of about 2.5% or less, the system containing no sodium from a sodium-containing buffer or the system containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable omeprazole system is reconstituted with water prior to administration.

[0211] Embodiment 2. The storage-stable omeprazole system of embodiment 1, wherein the sodium and potassium are present in a weight ratio of about 1:3.2.

[0212] Embodiment 3. The storage-stable omeprazole system of embodiment 1 or 2, wherein the system has a water content of about 0.5% to about 1.5%.

[0213] Embodiment 4. The storage-stable omeprazole system of any one of embodiments 1-3, further comprising a pharmaceutically acceptable desiccant.

[0214] Embodiment 5. The storage-stable omeprazole system of embodiment 4, wherein the pharmaceutically acceptable desiccant is sodium alginate.

[0215] Embodiment 6. The storage-stable omeprazole system according to embodiment 5, wherein the sodium alginate is dry.

[0216] Embodiment 7. The storage-stable omeprazole system of embodiment 6, wherein the dry sodium alginate has a moisture content of about 0.5% to about 1.5%.

[0217] Embodiment 8. A storage-stable omeprazole system according to any one of embodiments 5 to 7, wherein the sodium alginate is a low viscosity grade of sodium alginate.

[0218] Embodiment 9. A storage-stable omeprazole system according to any one of the preceding claims, wherein the system comprises one or more buffering agents, each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates.

[0219] Embodiment 10. A storage-stable omeprazole system according to any one of embodiments 1 and 3-9, wherein the system comprises one buffering agent which is potassium bicarbonate.

[0220] Embodiment 11. A storage-stable omeprazole system according to embodiment 9, wherein the system comprises two or more buffering agents selected from sodium and potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates.

[0221] Embodiment 12. A storage-stable omeprazole system according to embodiment 9 or 11, comprising sodium bicarbonate and potassium bicarbonate.

[0222] Embodiment 13. The storage-stable omeprazole system of embodiment 12, wherein the sodium bicarbonate and potassium bicarbonate are present in a weight ratio of about 1:2.7.

[0223] Embodiment 14. A storage-stable omeprazole system according to any one of embodiments 1 to 13, wherein the system is in the form of a powder, pellets, granules, seeds, beads, spheroids, microspheres, or a mixture thereof.

[0224] Embodiment 15. A storage-stable omeprazole system comprising: (i) (a) a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture comprises a moisture content of about 2.5% or less; and (ii) a second mixture comprising a second buffer, wherein the second mixture comprises a moisture content of about 2.5% or less, wherein the first and second mixtures are stored separately from one another and mixed together at or immediately before reconstitution with water, wherein the system does not contain sodium from a sodium-containing buffer or the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0225] Embodiment 16. The storage-stable omeprazole system of embodiment 15, wherein the sodium and potassium are present in a weight ratio of about 1:3.2.

[0226] Embodiment 17. The storage-stable omeprazole system of embodiment 15 or 16, wherein the first mixture and / or the second mixture has a water content of about 0.5% to about 1.5%.

[0227] Embodiment 18. The storage-stable omeprazole system of any one of embodiments 15 to 17, wherein the first mixture further comprises (b) a first desiccant and / or the second mixture further comprises a second desiccant.

[0228] Embodiment 19. The storage-stable omeprazole system of any one of embodiments 15 to 18, wherein the first desiccant and the second desiccant are sodium alginate.

[0229] Embodiment 20. The storage-stable omeprazole system of any one of embodiments 15 to 19, wherein the first mixture further comprises (c) a first buffering agent.

[0230] Embodiment 21. The storage-stable omeprazole system of any one of embodiments 15 to 20, wherein the first mixture and the second mixture are each independently in the form of a powder, pellets, granules, seeds, beads, spheroids, microspheres, or a mixture thereof.

[0231] Embodiment 22. A storage-stable omeprazole system according to any one of embodiments 1 to 21, wherein the omeprazole or a pharmaceutically acceptable salt thereof is micronized.

[0232] Embodiment 23. A storage-stable omeprazole system according to any one of embodiments 1 to 21, wherein the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0233] Embodiment 24. The storage-stable omeprazole system of embodiment 23, wherein the omeprazole or pharmaceutically acceptable salt thereof comprises about 30 to about 70% micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder of the omeprazole or a pharmaceutically acceptable salt thereof is non-micronized.

[0234] Embodiment 25. The storage-stable omeprazole system according to embodiment 24, wherein the omeprazole or pharmaceutically acceptable salt thereof is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or pharmaceutically acceptable salt thereof.

[0235] Embodiment 26. The storage-stable omeprazole system of any one of embodiments 15 to 25, wherein the first buffering agent and the second buffering agent are present in amounts sufficient to increase the gastric fluid pH to a pH that prevents at least partial degradation of the omeprazole in the gastric fluid.

[0236] Embodiment 27. The storage-stable omeprazole system of any one of embodiments 20 to 26, wherein the first buffering agent and the second buffering agent together provide a buffering capacity of about a 2 mEq / ml dose of the constituted powder with water.

[0237] Embodiment 28. The storage-stable omeprazole system of any one of embodiments 15 to 27, wherein the first buffering agent and the second buffering agent are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and mixtures thereof.

[0238] Embodiment 29. The storage-stable omeprazole system of any one of embodiments 14 to 28, wherein the first buffering agent and the second buffering agent are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0239] Embodiment 30. The storage-stable omeprazole system of any one of embodiments 20 to 29, wherein the first buffering agent is sodium bicarbonate.

[0240] Embodiment 31. The storage-stable omeprazole system of any one of embodiments 15 to 29, wherein the second buffering agent is a mixture of sodium bicarbonate and potassium bicarbonate.

[0241] Embodiment 32. The storage-stable omeprazole system of embodiment 31, wherein the second buffering agent comprises about 11% by weight sodium bicarbonate and about 89% by weight potassium bicarbonate.

[0242] Embodiment 33. The storage-stable omeprazole system of any one of embodiments 15 to 31, wherein the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0243] Embodiment 34. The storage-stable omeprazole system of any one of embodiments 15 to 29, wherein the first buffering agent and the second buffering agent are potassium bicarbonate.

[0244] Embodiment 35. The storage-stable omeprazole system according to any one of embodiments 15 to 32 and 34, wherein the second mixture further comprises a sweetener and a preservative.

[0245] Embodiment 36. The storage-stable omeprazole system of any one of embodiments 1 to 35, wherein the storage-stable omeprazole system is provided in a drug delivery device suitable for administering multiple doses of omeprazole or a pharmaceutically acceptable salt thereof.

[0246] Embodiment 37. The storage-stable omeprazole system of embodiment 36, wherein the drug delivery device comprises two chambers.

[0247] Embodiment 38. The storage-stable omeprazole system of embodiment 37, wherein the drug delivery device further comprises means for releasing the contents of the first chamber into the second chamber without removing the cap from the drug delivery device.

[0248] Embodiment 39. The storage-stable omeprazole powder system according to any one of embodiments 15 to 38, wherein the storage-stable omeprazole system is provided in a container body including a cap, (i) the container body contains the second mixture and has a container opening formed at its upper end, (ii) the cap has a cylindrical storage portion containing the first mixture and a cap portion sealing the upper end of the storage portion, and (iii) the cap is attached within the container opening of the container body, and when the cap is twisted, the first mixture is released into the container body.

[0249] Embodiment 40. The storage-stable omeprazole system according to embodiment 39, wherein the container body is an amber polyethylene terephthalate bottle and the cap is a polypropylene tamper-evident cap.

[0250] Embodiment 41. A storage-stable omeprazole system according to any one of embodiments 1 to 40, wherein the powder system remains stable at 25°C / 60% relative humidity for at least 2 years.

[0251] Embodiment 42. A storage-stable omeprazole system formulated in a drug delivery device suitable for multiple-dose administration of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system comprises a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the system comprises a water percentage of about 2.5% or less, the system does not contain sodium from a sodium-containing buffer, or the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable omeprazole system is reconstituted with water prior to administration.

[0252] Embodiment 43. The storage-stable omeprazole system of any one of embodiments 1 to 42, wherein the storage-stable omeprazole system is enclosed in a sealed aluminum foil pouch.

[0253] Embodiment 44. A storage-stable omeprazole powder system, the system comprising: (i) a first powder mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) sodium alginate, and (c) a first buffering agent; and (ii) a second powder mixture comprising sodium alginate and a second buffering agent, wherein the first powder mixture and the second powder mixture are stored separately from one another and mixed together at or immediately before constitution with water, and wherein the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0254] Embodiment 45. A storage-stable omeprazole powder system according to embodiment 44, wherein the omeprazole or a pharmaceutically acceptable salt thereof is micronized.

[0255] Embodiment 46. A storage-stable omeprazole powder system according to embodiment 44 or 45, wherein the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0256] Embodiment 47. The storage-stable omeprazole powder system of embodiment 46, wherein the omeprazole or pharmaceutically acceptable salt thereof comprises about 30 to about 70% micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder of the omeprazole or a pharmaceutically acceptable salt thereof is non-micronized.

[0257] Embodiment 48. A storage-stable omeprazole powder system according to embodiment 46, wherein the omeprazole is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0258] Embodiment 49. A storage-stable omeprazole powder system according to any one of embodiments 44 to 48, wherein the omeprazole, or a pharmaceutically acceptable salt thereof, and about 20 to about 30% of the sodium alginate present in the first powder mixture are homogeneously distributed on the surface of the first buffer.

[0259] Embodiment 50. The storage-stable omeprazole powder system of embodiment 49, wherein the omeprazole, or a pharmaceutically acceptable salt thereof, and about 20 to about 25% of the sodium alginate present in the first powder mixture are homogeneously distributed on the surface of the first buffer.

[0260] Embodiment 51. A storage-stable omeprazole powder system according to embodiment 49 or 50, wherein the sodium alginate that is not distributed on the surface of the first buffer in the first powder mixture is dry.

[0261] Embodiment 52. A storage-stable omeprazole powder system according to any one of embodiments 44 to 51, wherein the sodium alginate present in the second powder mixture is dry.

[0262] Embodiment 53. A storage-stable omeprazole powder system according to embodiment 51 or 52, wherein the dry sodium alginate has a moisture content of about 0.5% to about 1.5%.

[0263] Embodiment 54. A storage-stable omeprazole powder system according to any one of embodiments 44 to 53, wherein the sodium alginate is a low viscosity grade of sodium alginate.

[0264] Embodiment 55. The storage-stable omeprazole powder system of any one of embodiments 44 to 54, wherein the first and second buffering agents are present in amounts sufficient to increase the gastric fluid pH to a pH that prevents at least partial degradation of the omeprazole or pharmaceutically acceptable salt thereof in the gastric fluid.

[0265] Embodiment 56. A storage-stable omeprazole powder system according to any one of embodiments 44 to 55, wherein the first and second buffering agents together provide a buffering capacity of the constituted powder of about a 2 mEq / ml dose with water.

[0266] Embodiment 57. The storage-stable omeprazole powder system of any one of embodiments 44 to 56, wherein the first and second buffering agents are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and mixtures thereof.

[0267] Embodiment 58. A storage-stable omeprazole powder system according to any one of embodiments 44 to 57, wherein the first and second buffering agents are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0268] Embodiment 59. A storage-stable omeprazole powder system according to any one of embodiments 44 to 58, wherein the first buffering agent is sodium bicarbonate.

[0269] Embodiment 60. A storage-stable omeprazole powder system according to any one of embodiments 44 to 59, wherein the second buffering agent is a mixture of sodium bicarbonate and potassium bicarbonate.

[0270] Embodiment 61. A storage-stable omeprazole powder system according to embodiment 60, wherein the mixture comprises about 11% by weight of sodium bicarbonate and about 89% by weight of potassium bicarbonate.

[0271] Embodiment 62. A storage-stable omeprazole powder system according to any one of embodiments 44 to 61, wherein the first powder mixture and the second powder mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0272] Embodiment 63. A storage-stable omeprazole powder system according to any one of embodiments 44 to 62, wherein the second powder mixture further comprises a sweetener and a preservative.

[0273] Embodiment 64. The storage-stable omeprazole powder system of any one of embodiments 44 to 63, wherein the storage-stable omeprazole powder system is provided in a drug delivery device suitable for administering multiple doses of omeprazole.

[0274] Embodiment 65. The storage-stable omeprazole powder system of embodiment 64, wherein the drug delivery device comprises a first chamber containing a first powder mixture and a second chamber containing a second powder mixture.

[0275] Embodiment 66. The storage-stable omeprazole powder system of embodiment 65, wherein the drug delivery device further comprises a means for releasing the first powder mixture into the second chamber without removing the cap from the drug delivery device.

[0276] Embodiment 67. The storage-stable omeprazole powder system according to any one of embodiments 44 to 66, wherein the storage-stable omeprazole powder system is provided in a container body including a cap, (i) the container body contains a second powder mixture and has a container opening formed at its upper end, (ii) the cap has a cylindrical storage portion containing the first powder mixture and a cap portion sealing the upper end of the storage portion, and (iii) the cap is attached within the container opening of the container body, and when the cap is twisted, the first powder mixture is released into the container body.

[0277] Embodiment 68. A storage-stable omeprazole powder system according to embodiment 67, wherein the container body is an amber polyethylene terephthalate bottle and the cap is a polypropylene tamper-evident cap.

[0278] Embodiment 69. A storage-stable omeprazole powder system according to any one of embodiments 44 to 68, wherein the powder system remains stable at 25°C / 60% relative humidity for at least 2 years.

[0279] Embodiment 70. A storage-stable omeprazole powder system according to any one of embodiments 44 to 69, wherein the storage-stable omeprazole system is enclosed in a sealed aluminum foil pouch.

[0280] Embodiment 71. An oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed therein, and one or more buffering agents, wherein the suspension does not contain sodium from a sodium-containing buffer, or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0281] Embodiment 72. The oral pharmaceutical suspension of embodiment 71, further comprising sodium alginate.

[0282] Embodiment 73. An oral pharmaceutical suspension according to embodiment 71 or 72, wherein about 1 ml of the suspension contains from about 1 mg to about 10 mg of omeprazole, or a pharmaceutically acceptable salt thereof.

[0283] Embodiment 74. An oral pharmaceutical suspension according to embodiment 73, wherein about 1 ml of the suspension contains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of omeprazole, or a pharmaceutically acceptable salt thereof.

[0284] Embodiment 75. An oral pharmaceutical suspension according to embodiment 74, wherein about 1 ml of the suspension contains about 2 mg or about 4 mg of omeprazole, or a pharmaceutically acceptable salt thereof.

[0285] Embodiment 76. An oral pharmaceutical suspension according to any one of embodiments 71 to 75, wherein the one or more buffering agents provide a buffering capacity of about 2 mEq per ml of suspension.

[0286] Embodiment 77. An oral pharmaceutical suspension according to any one of embodiments 71 to 76, wherein the one or more buffering agents are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates.

[0287] Embodiment 78. An oral pharmaceutical suspension according to any one of embodiments 71 to 77, comprising one buffering agent.

[0288] Embodiment 79. An oral pharmaceutical suspension according to embodiment 78, wherein one buffering agent is potassium bicarbonate.

[0289] Embodiment 80. An oral pharmaceutical suspension according to any one of embodiments 71 to 77, comprising a mixture of two buffering agents.

[0290] Embodiment 81. The oral pharmaceutical suspension of embodiment 80, comprising a mixture of sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0291] Embodiment 82. An oral pharmaceutical suspension according to any one of embodiments 71-77 and 80-81, wherein the suspension comprises about 86 mg of sodium per 5 ml of suspension.

[0292] Embodiment 83. An oral pharmaceutical suspension according to any one of embodiments 71-77 and 80-82, wherein the sodium and potassium are present in a weight ratio of about 1:3.2.

[0293] Embodiment 84. The suspension comprises a first and a second C 最大 and the first and second T 最大84. The oral pharmaceutical suspension of any one of embodiments 71-83, wherein the suspension provides, after oral administration in a subject in need thereof, a biphasic pharmacokinetic profile having:

[0294] Embodiment 8: An oral pharmaceutical suspension according to any one of embodiments 66 to 77, wherein a 5.5 ml dose comprises about 10 mg or about 20 mg of omeprazole or a pharmaceutically acceptable salt thereof, about 256 mg of sodium bicarbonate, about 695 mg of potassium bicarbonate, and about 125 mg of sodium alginate.

[0295] Embodiment 86. The oral pharmaceutical suspension of embodiment 78, further comprising about 11.45 mg of methylparaben sodium salt and about 25 mg of sodium benzoate.

[0296] Embodiment 87. An oral pharmaceutical suspension according to any one of embodiments 71 to 86, wherein the omeprazole or pharmaceutically acceptable salt thereof is micronized.

[0297] Embodiment 88. An oral pharmaceutical suspension according to any one of embodiments 71 to 86, wherein the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0298] Embodiment 89. The oral pharmaceutical suspension of embodiment 88, wherein the omeprazole or pharmaceutically acceptable salt thereof comprises about 30 to about 70% micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder of the omeprazole or a pharmaceutically acceptable salt thereof is non-micronized.

[0299] Embodiment 90. An oral pharmaceutical suspension according to embodiment 88, wherein the omeprazole is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0300] Embodiment 91. An oral pharmaceutical suspension according to any one of embodiments 71 to 90, wherein the suspension is provided in a drug delivery device suitable for administering multiple doses of omeprazole.

[0301] Embodiment 92. A method for inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of the oral pharmaceutical suspension of any one of embodiments 71 to 91.

[0302] Embodiment 93. The method of embodiment 92, wherein the subject is a child.

[0303] Embodiment 94. The method of embodiment 93, wherein the child is an infant, toddler, pre-adolescent, or adolescent.

[0304] Embodiment 95. The method of any one of embodiments 92 to 94, wherein about 1 ml of the suspension contains about 1 mg to about 10 mg of omeprazole, or a pharmaceutically acceptable salt thereof.

[0305] Embodiment 96. The method of any one of embodiments 92 to 95, wherein 1 ml of the suspension contains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of omeprazole, or a pharmaceutically acceptable salt thereof.

[0306] Embodiment 97. The method of any one of embodiments 92 to 96, wherein 1 ml of suspension contains about 2 mg of omeprazole, or a pharmaceutically acceptable salt thereof.

[0307] Embodiment 98. The method of any one of embodiments 92 to 96, wherein 1 ml of suspension contains about 4 mg of omeprazole, or a pharmaceutically acceptable salt thereof.

[0308] Embodiment 99. A method for preparing an oral pharmaceutical suspension, comprising: (i)(a) combining a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the first mixture comprising a moisture content of about 2.5% or less, with a second mixture comprising a second buffer, the second mixture comprising a moisture content of about 2.5% or less, to obtain a combined mixture, wherein the combined mixture does not contain sodium from a sodium-containing buffer or the combined mixture contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4; and adding water to the combined mixture.

[0309] Embodiment 100. The method of embodiment 99, wherein the sodium and potassium are present in a weight ratio of about 1:3.2.

[0310] Embodiment 101. The method of embodiment 99 or 100, wherein the first mixture has a water content of about 0.5% to about 1.5%.

[0311] Embodiment 102. The method of any one of embodiments 99-101, wherein the first mixture further comprises (b) a first desiccant, and / or the second mixture further comprises a second desiccant.

[0312] Embodiment 103. The method of any one of embodiments 99 to 102, wherein the first desiccant and the second desiccant are sodium alginate.

[0313] Embodiment 104. The method of any one of embodiments 99-103, wherein the first mixture further comprises (c) a first buffering agent.

[0314] Embodiment 105. The method of any one of embodiments 99 to 104, wherein the first mixture and the second mixture are each independently in the form of a powder, pellets, granules, seeds, beads, spheroids, microspheres, or a mixture thereof.

[0315] Embodiment 106. The method of any one of embodiments 99 to 105, wherein the omeprazole or pharmaceutically acceptable salt thereof is micronized.

[0316] Embodiment 107. The method of any one of embodiments 99 to 105, wherein the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole, or a pharmaceutically acceptable salt thereof.

[0317] Embodiment 108. The method of embodiment 107, wherein the omeprazole comprises about 30 to about 70% micronized omeprazole, or a pharmaceutically acceptable salt thereof, and the remainder of the omeprazole or a pharmaceutically acceptable salt thereof is non-micronized.

[0318] Embodiment 109. The method of embodiment 107, wherein the omeprazole is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0319] Embodiment 110. The method of any one of embodiments 99-109, wherein the first buffering agent and the second buffering agent are present in amounts sufficient to increase the gastric fluid pH to a pH that prevents at least partial degradation of omeprazole in the gastric fluid.

[0320] Embodiment 111. The method of any one of embodiments 104 to 110, wherein the first buffer and the second buffer together provide a buffering capacity of about a 2 mEq / ml dose of the suspension.

[0321] Embodiment 112. The method of any one of embodiments 99-111, wherein the first buffering agent and the second buffering agent are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates.

[0322] Embodiment 113. The method of any one of embodiments 99-112, wherein the first buffering agent and the second buffering agent are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0323] Embodiment 114. The method of any one of embodiments 104 to 113, wherein the first buffering agent is sodium bicarbonate.

[0324] Embodiment 115. The method of any one of embodiments 99-113, wherein the second buffering agent is a mixture of sodium bicarbonate and potassium bicarbonate.

[0325] Embodiment 116. The method of embodiment 115, wherein the mixture comprises about 11% by weight sodium bicarbonate and about 89% by weight potassium bicarbonate.

[0326] Embodiment 117. The method of any one of embodiments 99 to 116, wherein the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0327] Embodiment 118. The method of any one of embodiments 99 and 101-113, wherein the first buffering agent and the second buffering agent are potassium bicarbonate.

[0328] Embodiment 119. The method of any one of embodiments 99 to 118, wherein the second mixture further comprises a sweetener and a preservative.

[0329] Embodiment 120. The method of any one of embodiments 99 to 119, wherein the oral pharmaceutical suspension is provided in a drug delivery device suitable for multi-dose administration of omeprazole.

[0330] Embodiment 121. A method for inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffering agents, wherein the suspension does not contain sodium from a sodium-containing buffer, or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and wherein the oral pharmaceutical suspension is prepared by the method of any one of embodiments 99 to 120.

[0331] Embodiment 122. An oral pharmaceutical suspension according to any one of embodiments 71 to 90, wherein the suspension remains stable for at least 1 month at 2°C to 8°C after constitution with water.

[0332] The present disclosure also provides the following specific embodiments.

[0333] Embodiment I. A storage-stable omeprazole system, the system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the system comprising a water percentage of about 2.5% or less, the system containing no sodium from a sodium-containing buffer or the system containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable omeprazole system is reconstituted with water prior to administration.

[0334] Embodiment II. A storage-stable omeprazole system according to embodiment I, wherein the system comprises one or more buffering agents, each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates.

[0335] Embodiment III. The storage-stable omeprazole system of embodiment I comprising: (i)(a) a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture comprises a moisture content of about 2.5% or less; and (ii) a second mixture comprising a second buffer, wherein the second mixture comprises a moisture content of about 2.5% or less, wherein the first and second mixtures are stored separately from one another and mixed together at or immediately before reconstitution with water, wherein the system does not contain sodium from a sodium-containing buffer or the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0336] Embodiment IV. A storage-stable omeprazole powder system, the system comprising: (i) a first powder mix comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) sodium alginate, and (c) a first buffering agent; and (ii) a second powder mix comprising sodium alginate and a second buffering agent, wherein the first powder mix and the second powder mix are stored separately from one another and mixed together at or immediately before constitution with water, and wherein the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0337] Embodiment V. A storage-stable omeprazole system or a storage-stable omeprazole-based powder system according to any one of Embodiments I-IV, wherein the omeprazole or pharmaceutically acceptable salt thereof is micronized.

[0338] Embodiment VI. A storage-stable omeprazole system or storage-stable omeprazole powder system according to any one of Embodiments I-IV, wherein the omeprazole or pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0339] Embodiment VII. The storage-stable omeprazole system or storage-stable omeprazole powder system of any one of the preceding claims, wherein the storage-stable omeprazole system or omeprazole powder system is provided in a drug delivery device suitable for administering multiple doses of omeprazole or a pharmaceutically acceptable salt thereof.

[0340] Embodiment VIII. The storage-stable omeprazole powder system of embodiment IV or VII, wherein the storage-stable omeprazole powder system is provided in a container body including a cap, (i) the container body contains a second powder mixture and has a container opening formed at its upper end, (ii) the cap comprises a cylindrical storage portion containing the first powder mixture and a cap portion sealing the upper end of the storage portion, and (iii) the cap is attached within the container opening of the container body, and when the cap is twisted, the first powder mixture is released into the container body.

[0341] Embodiment IX. The storage-stable omeprazole system or storage-stable omeprazole powder system of any one of the preceding claims, wherein the omeprazole system or omeprazole powder system remains stable at 25°C / 60% relative humidity for at least 2 years.

[0342] Embodiment X. An oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed therein, and one or more buffering agents, wherein the suspension does not contain sodium from a sodium-containing buffer or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0343] Embodiment XI. An oral pharmaceutical suspension according to embodiment X, wherein about 1 ml of the suspension contains from about 1 mg to about 10 mg of omeprazole, or a pharmaceutically acceptable salt thereof.

[0344] Embodiment XII. An oral pharmaceutical suspension of embodiment X or XI, wherein the suspension remains stable for at least 1 month at 2°C to 8°C after constitution with water.

[0345] Embodiment XIII. A method of inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of the oral pharmaceutical suspension of any one of Embodiments X-XII.

[0346] Embodiment XIV. A method of administering an oral pharmaceutical suspension to a subject in need of inhibition of gastric acid secretion, the method comprising: 1) preparing the oral pharmaceutical suspension by combining a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture comprises a water percentage of about 2.5% or less, with a second mixture comprising a second buffer, wherein the second mixture comprises a water percentage of about 2.5% or less, to obtain a combined mixture, wherein the combined mixture does not contain sodium from a sodium-containing buffer or wherein the combined mixture contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4; and adding water to the combined mixture; and 2) administering an effective amount of the oral pharmaceutical suspension to a subject in need thereof.

[0347] Embodiment XV. The method of embodiment XIII or XIV, wherein the subject is a child. [Example]

[0348] The formulations described herein will now be further described in detail with reference to the following examples. These examples are for illustrative purposes only and should not be construed as limiting the embodiments described herein. Rather, the embodiments should be construed as encompassing any and all variations that become apparent as a result of the teachings provided herein. Example 1 Exemplary Formulations and Manufacturing Details of Omeprazole 2 mg / ml and 4 mg / ml Oral Suspension and Shelf-Stable Omeprazole Powder Systems

[0349] In Table 1 below, granule compositions are used to prepare examples of the first mixture present in the storage-stable omeprazole powder system described herein. [Table 1-1] [Table 1-2] [Table 1-3] Example 2 Exemplary Formulations of Omeprazole 2 mg / ml and 4 mg / ml Oral Suspension [Table 2] Example 3 Exemplary Chemical Compositions of Omeprazole Oral Suspension [Table 3] Example 4

[0350] This example demonstrates the benefits of the storage-stable omeprazole powder system of the present disclosure on the stability of a constituted omeprazole oral suspension according to the present disclosure.

[0351] Omeprazole 2 mg / ml oral suspensions of Examples J, K, and L were prepared having identical constituted suspension compositions, but with the following differences:

[0352] Example J is an aluminum (titanium) foil packaged two-chamber dosage form according to the present disclosure, comprising a cap containing a first powder mixture fastened onto a bottle containing a second powder mixture;

[0353] Example K is a comparative example of a foil-packaged two-chamber dosage form including a cap containing a first powder mixture fastened onto a bottle containing a second powder mixture constituted with water;

[0354] Example L is a comparative example of a foil-packaged single-chamber dosage form that includes a capped bottle containing a powder mixture of a first powder mixture and a second powder mixture.

[0355] A detailed description of the manufacturing, packaging, and composition of the prepared omeprazole 2 mg / ml suspensions of Examples J, K, and L is provided below. [Table 4-1-1] [Table 4-1-2] [Table 4-1-3]

[0356] A summary of the formulation and characterization details of the omeprazole 2 mg / ml oral suspensions of Examples J, K, and L is provided in Table 4. [Table 4-2-1] [Table 4-2-2]

[0357] A summary of the stability study results for omeprazole 2 mg / ml oral suspension of Examples J, K, and L is provided in Table 5. [Table 5] Example 5 Exemplary Chemical Compositions of Omeprazole Oral Suspensions Prepared Using Micronized Omeprazole

[0358] A detailed description of the manufacturing, packaging, and composition of the prepared omeprazole 4 mg / ml suspension of Example M is provided below. [Table 9-1] [Table 9-2]

[0359] A summary of the formulation and characterization details of Example M omeprazole 4 mg / ml oral suspension is provided in Table 6. [Table 6]

[0360] A summary of the stability study results for Example M omeprazole 4 mg / ml oral suspension is provided in Table 7. [Table 7] Example 6 Exemplary Chemical Compositions of Omeprazole Oral Suspensions Prepared Using a Mixture of Micronized and Non-Micronized Omeprazole

[0361] A detailed description of the manufacturing, packaging, and composition of the prepared omeprazole 4 mg / ml suspensions of Examples N and O is provided below. [Table 10-1] [Table 10-2]

[0362] A summary of the formulation and characterization details of the omeprazole 4 mg / ml oral suspensions of Examples N and O is provided in Table 8. [Table 8-1] [Table 8-2]

[0363] Having now fully described this disclosure, it will be understood by those skilled in the art that the same may be practiced within a wide equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof.

[0364] Other embodiments described herein will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0365] All patents, patent applications, and publications cited herein are hereby fully incorporated by reference in their entirety. The present invention provides, for example, the following items. (Item 1) 1. A storage-stable omeprazole system, the system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the system comprising a water percentage of about 2.5% or less, the system containing no sodium from a sodium-containing buffer, or the system containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable omeprazole system is reconstituted with water prior to administration. (Item 2) 2. The storage-stable omeprazole system according to item 1, wherein the sodium and potassium are present in a weight ratio of about 1:3.2. (Item 3) 3. The storage-stable omeprazole system according to item 1 or 2, wherein the system has a water content of about 0.5% to about 1.5%. (Item 4) 4. The storage-stable omeprazole system according to any one of items 1 to 3, further comprising a pharmaceutically acceptable desiccant. (Item 5) 5. The storage-stable omeprazole system according to item 4, wherein the pharmaceutically acceptable desiccant is sodium alginate. (Item 6) 6. The storage-stable omeprazole system according to item 5, wherein the sodium alginate is dry. (Item 7) 7. The storage-stable omeprazole system according to item 6, wherein the dry sodium alginate has a moisture content of about 0.5% to about 1.5%. (Item 8) 8. The storage-stable omeprazole system according to any one of items 5 to 7, wherein the sodium alginate is a low viscosity grade sodium alginate. (Item 9) 9. The storage-stable omeprazole system according to any one of items 1 to 8, wherein the system comprises one or more buffering agents each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. (Item 10) 10. The storage-stable omeprazole system according to any one of items 1 and 3 to 9, wherein the system comprises one buffering agent which is potassium bicarbonate. (Item 11) 10. The storage-stable omeprazole system according to item 9, wherein the system comprises two or more buffering agents selected from sodium and potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. (Item 12) 12. The storage-stable omeprazole system according to item 9 or 11, comprising sodium bicarbonate and potassium bicarbonate. (Item 13) 13. The storage-stable omeprazole system according to item 12, wherein the sodium bicarbonate and potassium bicarbonate are present in a weight ratio of about 1:2.7. (Item 14) 14. The storage-stable omeprazole system according to any one of items 1 to 13, wherein the system is in the form of a powder, pellets, granules, seeds, beads, spheroids, microspheres, or a mixture thereof. (Item 15) 1. A storage-stable omeprazole system, comprising: (i)(a) a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the first mixture comprising a moisture content of about 2.5% or less; and (ii) a second mixture comprising a second buffer, the second mixture comprising a moisture content of about 2.5% or less; wherein the first and second mixtures are stored separately from each other and are mixed together at or immediately before reconstitution with water; and wherein the system does not contain sodium from a sodium-containing buffer or the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. (Item 16) 16. The storage-stable omeprazole system according to item 15, wherein the sodium and potassium are present in a weight ratio of about 1:3.2. (Item 17) 17. The storage-stable omeprazole system according to item 15 or 16, wherein the first mixture and / or the second mixture has a water content of about 0.5% to about 1.5%. (Item 18) 18. The storage-stable omeprazole system according to any one of items 15 to 17, wherein the first mixture further comprises (b) a first desiccant and / or the second mixture further comprises a second desiccant. (Item 19) 19. The storage-stable omeprazole system according to any one of items 15 to 18, wherein the first desiccant and the second desiccant are sodium alginate. (Item 20) 20. The storage-stable omeprazole system according to any one of items 15 to 19, wherein the first mixture further comprises (c) a first buffering agent. (Item 21) 21. The storage-stable omeprazole system according to any one of items 15 to 20, wherein the first mixture and the second mixture are each independently in the form of a powder, pellets, granules, seeds, beads, spheroids, microspheres, or a mixture thereof. (Item 22) 22. The storage-stable omeprazole system according to any one of items 1 to 21, wherein the omeprazole or the pharmaceutically acceptable salt thereof is micronized. (Item 23) 22. The storage-stable omeprazole system according to any one of items 1 to 21, wherein the omeprazole or the pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or the pharmaceutically acceptable salt thereof. (Item 24) 24. The storage-stable omeprazole system according to item 23, wherein the omeprazole or the pharmaceutically acceptable salt thereof comprises about 30 to about 70% micronized omeprazole or the pharmaceutically acceptable salt thereof, the remainder of the omeprazole or the pharmaceutically acceptable salt thereof being non-micronized. (Item 25) 25. The storage-stable omeprazole system according to item 24, wherein the omeprazole or the pharmaceutically acceptable salt thereof is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or the pharmaceutically acceptable salt thereof. (Item 26) 26. The storage-stable omeprazole system according to any one of items 15 to 25, wherein the first buffering agent and the second buffering agent are present in an amount sufficient to increase the gastric fluid pH to a pH that prevents at least partial degradation of the omeprazole in gastric fluid. (Item 27) 27. The storage-stable omeprazole system according to any one of items 20 to 26, wherein the first buffering agent and the second buffering agent together provide a buffering capacity of about a 2 mEq / ml dose of the constituted powder with water. (Item 28) 28. The storage-stable omeprazole system according to any one of items 15 to 27, wherein the first buffering agent and the second buffering agent are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and mixtures thereof. (Item 29) 29. The storage-stable omeprazole system according to any one of items 14 to 28, wherein the first buffering agent and the second buffering agent are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof. (Item 30) 30. The storage-stable omeprazole system according to any one of items 20 to 29, wherein the first buffering agent is sodium bicarbonate. (Item 31) 30. The storage-stable omeprazole system according to any one of items 15 to 29, wherein the second buffering agent is a mixture of sodium bicarbonate and potassium bicarbonate. (Item 32) 32. The storage-stable omeprazole system according to item 31, wherein the second buffering agent comprises about 11% by weight sodium bicarbonate and about 89% by weight potassium bicarbonate. (Item 33) 32. The storage-stable omeprazole system according to any one of items 15 to 31, wherein the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7. (Item 34) 30. The storage-stable omeprazole system according to any one of items 15 to 29, wherein the first buffering agent and the second buffering agent are potassium bicarbonate. (Item 35) 35. The storage-stable omeprazole system according to any one of items 15 to 32 and 34, wherein the second mixture further comprises a sweetener and a preservative. (Item 36) 36. The storage-stable omeprazole system according to any one of items 1 to 35, wherein the storage-stable omeprazole system is provided in a drug delivery device suitable for administration of multiple doses of omeprazole or the pharmaceutically acceptable salt thereof. (Item 37) 37. The storage-stable omeprazole system according to item 36, wherein the drug delivery device comprises two chambers. (Item 38) 38. The storage-stable omeprazole system of claim 37, wherein the drug delivery device further comprises means for releasing the contents of the first chamber into the second chamber without removing a cap from the drug delivery device. (Item 39) 39. The storage-stable omeprazole system according to any one of items 15 to 38, wherein the storage-stable omeprazole system is provided in a container body including a cap, (i) the container body contains the second mixture and has a container opening formed at an upper end thereof, (ii) the cap comprises a cylindrical storage portion containing the first mixture and a cap portion sealing an upper end of the storage portion, and (iii) the cap is attached within the container opening of the container body, and when the cap is twisted, the first mixture is released into the container body. (Item 40) 40. The storage-stable omeprazole system according to item 39, wherein the container body is an amber polyethylene terephthalate bottle and the cap is a polypropylene tamper-evident cap. (Item 41) 41. The storage-stable omeprazole system according to any one of items 1 to 40, wherein the powder system remains stable at 25°C / 60% relative humidity for at least 2 years. (Item 42) 1. A storage-stable omeprazole system formulated in a drug delivery device suitable for multiple dose administration of omeprazole or a pharmaceutically acceptable salt thereof, the system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the system comprising a water percentage of about 2.5% or less, the system containing no sodium from a sodium-containing buffer or the system containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable omeprazole system is reconstituted with water prior to administration. (Item 43) 43. The storage-stable omeprazole system according to any one of items 1 to 42, wherein the storage-stable omeprazole system is enclosed in a sealed aluminum foil pouch. (Item 44) 1. A storage-stable omeprazole powder system, the system comprising: (i) a first powder mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) sodium alginate, and (c) a first buffering agent; and (ii) a second powder mixture comprising sodium alginate and a second buffering agent, the first powder mixture and the second powder mixture being stored separately from one another and mixed together at or just before constitution with water, the system containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. (Item 45) 45. The storage-stable omeprazole powder system according to item 44, wherein the omeprazole or the pharmaceutically acceptable salt thereof is micronized. (Item 46) 46. ​​The storage-stable omeprazole powder system according to item 44 or 45, wherein the omeprazole or the pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or the pharmaceutically acceptable salt thereof. (Item 47) 47. The storage-stable omeprazole powder system according to item 46, wherein the omeprazole or the pharmaceutically acceptable salt thereof comprises about 30 to about 70% micronized omeprazole or the pharmaceutically acceptable salt thereof, the remainder of the omeprazole or the pharmaceutically acceptable salt thereof being non-micronized. (Item 48) 47. The storage-stable omeprazole powder system according to item 46, wherein the omeprazole is a 1:1 mixture by weight of micronized and non-micronized omeprazole or said pharmaceutically acceptable salt thereof. (Item 49) 49. The storage-stable omeprazole powder system according to any one of items 44 to 48, wherein the omeprazole or the pharmaceutically acceptable salt thereof and about 20 to about 30% of the sodium alginate present in the first powder mixture are homogeneously distributed on the surface of the first buffer. (Item 50) Item 51. The storage-stable omeprazole powder system according to Item 49, wherein the omeprazole or the pharmaceutically acceptable salt thereof and about 20 to about 25% of the sodium alginate present in the first powder mixture are homogeneously distributed on the surface of the first buffer. 51. The storage-stable omeprazole powder system according to item 49 or 50, wherein the sodium alginate that is not distributed on the surface of the first buffer agent in the first powder mixture is dry. (Item 52) 52. The storage-stable omeprazole powder system according to any one of items 44 to 51, wherein the sodium alginate present in the second powder mixture is dry. (Item 53) 53. The storage-stable omeprazole powder system according to item 51 or 52, wherein the dry sodium alginate has a moisture content of about 0.5% to about 1.5%. (Item 54) 54. The storage-stable omeprazole powder system according to any one of items 44 to 53, wherein the sodium alginate is a low viscosity grade sodium alginate. (Item 55) 55. The storage-stable omeprazole powder system according to any one of items 44 to 54, wherein the first and second buffering agents are present in amounts sufficient to increase the gastric fluid pH to a pH that prevents at least partial degradation of the omeprazole or the pharmaceutically acceptable salt thereof in gastric fluid. (Item 56) 56. The storage-stable omeprazole powder system according to any one of items 44 to 55, wherein the first and second buffering agents together provide a buffering capacity of the constituted powder of about a 2 mEq / ml dose with water. (Item 57) 57. The storage-stable omeprazole powder system according to any one of items 44 to 56, wherein the first and second buffering agents are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and mixtures thereof. (Item 58) 58. The storage-stable omeprazole powder system according to any one of items 44 to 57, wherein the first and second buffering agents are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof. (Item 59) 59. The storage-stable omeprazole powder system according to any one of items 44 to 58, wherein the first buffering agent is sodium bicarbonate. (Item 60) 60. The storage-stable omeprazole powder system according to any one of items 44 to 59, wherein the second buffering agent is a mixture of sodium bicarbonate and potassium bicarbonate. (Item 61) 61. The storage-stable omeprazole powder system according to item 60, wherein the mixture comprises about 11% by weight of sodium bicarbonate and about 89% by weight of potassium bicarbonate. (Item 62) 62. The storage-stable omeprazole powder system according to any one of items 44 to 61, wherein the first powder mixture and the second powder mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7. (Item 63) 63. The storage-stable omeprazole powder system according to any one of items 44 to 62, wherein the second powder mixture further comprises a sweetener and a preservative. (Item 64) 64. The storage-stable omeprazole powder system according to any one of items 44 to 63, wherein the storage-stable omeprazole powder system is provided in a drug delivery device suitable for multi-dose administration of omeprazole. (Item 65) 65. The storage-stable omeprazole powder system of claim 64, wherein the drug delivery device comprises a first chamber containing the first powder mixture and a second chamber containing the second powder mixture. (Item 66) 66. The storage-stable omeprazole powder system according to item 65, wherein the drug delivery device further comprises means for releasing the first powder mixture into the second chamber without removing a cap from the drug delivery device. (Item 67) 67. The storage-stable omeprazole powder system according to any one of items 44 to 66, wherein the storage-stable omeprazole powder system is provided in a container body including a cap, (i) the container body contains the second powder mixture and has a container opening formed at an upper end thereof, (ii) the cap comprises a cylindrical storage portion containing the first powder mixture and a cap portion sealing an upper end of the storage portion, and (iii) the cap is attached within the container opening of the container body, and when the cap is twisted, the first powder mixture is released into the container body. (Item 68) Item 68. The storage-stable omeprazole powder system according to item 67, wherein the container body is an amber polyethylene terephthalate bottle and the cap is a polypropylene tamper-evident cap. (Item 69) 69. The storage-stable omeprazole powder system according to any one of items 44 to 68, wherein the powder system remains stable at 25°C / 60% relative humidity for at least 2 years. (Item 70) 70. The storage-stable omeprazole powder system according to any one of items 44 to 69, wherein the storage-stable omeprazole system is enclosed in a sealed aluminum foil pouch. (Item 71) 1. An oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in said water, and one or more buffering agents, wherein said suspension does not contain sodium from a sodium-containing buffer or said suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. (Item 72) 72. The oral pharmaceutical suspension of item 71, further comprising sodium alginate. (Item 73) 73. The oral pharmaceutical suspension according to item 71 or 72, wherein about 1 ml of the suspension contains about 1 mg to about 10 mg of omeprazole, or the pharmaceutically acceptable salt thereof. (Item 74) 74. The oral pharmaceutical suspension of item 73, wherein about 1 ml of the suspension contains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of omeprazole or the pharmaceutically acceptable salt thereof. (Item 75) 75. The oral pharmaceutical suspension of item 74, wherein about 1 ml of the suspension contains about 2 mg or about 4 mg of omeprazole, or the pharmaceutically acceptable salt thereof. (Item 76) 76. The oral pharmaceutical suspension of any one of items 71 to 75, wherein the one or more buffering agents provide a buffering capacity of about 2 mEq / ml of the suspension. (Item 77) 77. The oral pharmaceutical suspension of any one of items 71 to 76, wherein the one or more buffering agents are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. (Item 78) 78. The oral pharmaceutical suspension according to any one of items 71 to 77, comprising one buffering agent. (Item 79) 79. The oral pharmaceutical suspension of item 78, wherein the one buffering agent is potassium bicarbonate. (Item 80) 78. The oral pharmaceutical suspension according to any one of items 71 to 77, comprising a mixture of two buffering agents. (Item 81) 81. The oral pharmaceutical suspension according to item 80, comprising a mixture of sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7. (Item 82) 82. An oral pharmaceutical suspension according to any one of items 71 to 77 and 80 to 81, wherein the suspension comprises about 86 mg of sodium per 5 ml of the suspension. (Item 83) 83. The oral pharmaceutical suspension of any one of items 71 to 77 and 80 to 82, wherein the sodium and potassium are present in a weight ratio of about 1:3.2. (Item 84) The suspension is a first and a second C 最大and the first and second T 最大 84. The oral pharmaceutical suspension of any one of items 71 to 83, wherein the suspension provides, after oral administration in a subject in need thereof, a biphasic pharmacokinetic profile having (Item 85) 78. The oral pharmaceutical suspension according to any one of items 66 to 77, wherein a 5 ml dose comprises about 10 mg or about 20 mg of omeprazole or its pharmaceutically acceptable salt, about 256 mg of sodium bicarbonate, about 695 mg of potassium bicarbonate, and about 125 mg of sodium alginate. (Item 86) 79. The oral pharmaceutical suspension of item 78, further comprising about 11.45 mg of methylparaben sodium salt and about 25 mg of sodium benzoate. (Item 87) 87. The oral pharmaceutical suspension of any one of items 71 to 86, wherein the omeprazole or the pharmaceutically acceptable salt thereof is micronized. (Item 88) 87. The oral pharmaceutical suspension according to any one of items 71 to 86, wherein the omeprazole or the pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole, or the pharmaceutically acceptable salt thereof. (Item 89) 89. The oral pharmaceutical suspension according to item 88, wherein the omeprazole or the pharmaceutically acceptable salt thereof comprises about 30 to about 70% micronized omeprazole or the pharmaceutically acceptable salt thereof, the remainder of the omeprazole or the pharmaceutically acceptable salt thereof being non-micronized. (Item 90) 89. The oral pharmaceutical suspension of item 88, wherein the omeprazole is a 1:1 mixture by weight of micronized and non-micronized omeprazole or the pharmaceutically acceptable salt thereof. (Item 91) 91. The oral pharmaceutical suspension of any one of items 71 to 90, wherein the suspension is provided in a drug delivery device suitable for multi-dose administration of omeprazole. (Item 92) 92. A method for inhibiting gastric acid secretion, comprising administering an effective amount of the oral pharmaceutical suspension according to any one of items 71 to 91 to a subject in need thereof. (Item 93) Item 93. The method of item 92, wherein the subject is a child. (Item 94) Item 94. The method of item 93, wherein the child is an infant, toddler, pre-adolescent, or adolescent. (Item 95) 95. The method according to any one of items 92 to 94, wherein about 1 ml of the suspension contains about 1 mg to about 10 mg of omeprazole, or the pharmaceutically acceptable salt thereof. (Item 96) 96. The method of any one of items 92 to 95, wherein 1 ml of the suspension contains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of omeprazole, or the pharmaceutically acceptable salt thereof. (Item 97) 97. The method according to any one of items 92 to 96, wherein 1 ml of the suspension contains about 2 mg of omeprazole, or the pharmaceutically acceptable salt thereof. (Item 98) 97. The method according to any one of items 92 to 96, wherein 1 ml of the suspension contains about 4 mg of omeprazole, or the pharmaceutically acceptable salt thereof. (Item 99) 1. A method for preparing an oral pharmaceutical suspension, comprising: (a) combining a first mixture containing a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the first mixture containing about 2.5% or less water, with a second mixture containing a second buffer, the second mixture containing about 2.5% or less water, to obtain a combined mixture, wherein the combined mixture does not contain sodium from a sodium-containing buffer or the combined mixture contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4; and adding water to the combined mixture. (Item 100) 99. The method of claim 98, wherein the sodium and potassium are present in a weight ratio of about 1:3.2. (Item 101) Item 99. The method according to item 90, wherein the first mixture has a water content of about 0.5% to about 1.5%. (Item 102) 102. The method of any one of items 99 to 101, wherein the first mixture further comprises (b) a first desiccant, and / or the second mixture further comprises a second desiccant. (Item 103) 103. The method according to any one of items 99 to 102, wherein the first desiccant and the second desiccant are sodium alginate. (Item 104) 104. The method according to any one of items 99 to 103, wherein the first mixture further comprises (c) a first buffering agent. (Item 105) 105. The method of any one of items 99 to 104, wherein the first mixture and the second mixture are each independently in the form of a powder, pellets, granules, seeds, beads, spheroids, microspheres, or a mixture thereof. (Item 106) 106. The method according to any one of items 99 to 105, wherein the omeprazole or the pharmaceutically acceptable salt thereof is micronized. (Item 107) 106. The method according to any one of items 99 to 105, wherein the omeprazole or the pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole, or the pharmaceutically acceptable salt thereof. (Item 108) Item 108. The method of item 107, wherein the omeprazole comprises about 30 to about 70% micronized omeprazole or the pharmaceutically acceptable salt thereof, and the remainder of the omeprazole or the pharmaceutically acceptable salt thereof is non-micronized. (Item 109) 108. The method of claim 107, wherein the omeprazole is a 1:1 mixture, by weight, of micronized and non-micronized omeprazole or the pharmaceutically acceptable salt thereof. (Item 110) 100. The method of any one of items 99 to 109, wherein the first buffering agent and the second buffering agent are present in amounts sufficient to increase gastric fluid pH to a pH that prevents at least partial degradation of the omeprazole in gastric fluid. (Item 111) 111. The method of any one of items 104 to 110, wherein the first buffer and the second buffer together provide a buffering capacity of about 2 mEq / ml of the suspension. (Item 112) 112. The method of any one of items 99 to 111, wherein the first buffering agent and the second buffering agent are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. (Item 113) 113. The method of any one of items 99 to 112, wherein the first buffering agent and the second buffering agent are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof. (Item 114) 114. The method according to any one of items 104 to 113, wherein the first buffering agent is sodium bicarbonate. (Item 115) 114. The method according to any one of items 99 to 113, wherein the second buffering agent is a mixture of sodium bicarbonate and potassium bicarbonate. (Item 116) Item 116. The method of item 115, wherein the mixture comprises about 11% by weight sodium bicarbonate and about 89% by weight potassium bicarbonate. (Item 117) 117. The method of any one of items 99 to 116, wherein the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7. (Item 118) 114. The method according to any one of items 99 and 101 to 113, wherein the first buffering agent and the second buffering agent are potassium bicarbonate. (Item 119) 119. The method according to any one of items 99 to 118, wherein the second mixture further comprises a sweetener and a preservative. (Item 120) 119. The method of any one of items 99 to 119, wherein the oral pharmaceutical suspension is provided in a drug delivery device suitable for multi-dose administration of omeprazole. (Item 121) 121. A method of inhibiting gastric acid secretion, comprising administering to a subject in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffering agents, wherein the suspension does not contain sodium from a sodium-containing buffer or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and the oral pharmaceutical suspension is prepared by the method of any one of items 99 to 120. (Item 122) 91. The oral pharmaceutical suspension of any one of items 71 to 90, wherein the suspension remains stable for at least 1 month at 2°C to 8°C after constitution with water.

Claims

[Claim 1] The invention described in the present specification.

Images