Pediatric suspension formulation

Abstract

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 constituted with water prior to administration. The present disclosure also relates to an oral pharmaceutical suspension 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.

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 benzimidazole class, which is a class of antisecretory compounds that do not exhibit anticholinergic or H2 histamine antagonistic effects. Drugs in this class inhibit H2 histamine secretion on the secretory surface of gastric cells. + / K + These drugs suppress gastric acid secretion by inhibiting specific ATPase enzyme systems and are called proton pump inhibitors.

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

[0003] To address the stability issues of omeprazole under acidic conditions, several omeprazole dosage forms available on the market 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®, both of which contain enteric-coated pellets of omeprazole in hard-resistant capsules and gastric-resistant tablets, respectively.

[0004] In general, children often encounter difficulties when being administered solid oral dosage forms such as tablets or capsules.

[0005] Currently, an oral liquid dosage form of omeprazole is not 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 composed of 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 is 460 mg of sodium (Na) + It contains ). In addition, in the United States, the FIRST®-Omeprazole Compounding Kit is available, consisting of omeprazole powder and FIRST-PPI (proton pump inhibitor) suspension. This suspension contains 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 homogeneous suspension containing 2 mg / ml of omeprazole in the FIRST®-PPI suspension. These omeprazole suspension formulations contain high amounts of sodium that would make them unacceptable for pediatric use.

[0006] There is a particular need for a liquid oral omeprazole formulation designed for pediatric use. [Overview of the Initiative] [Means for solving the problem]

[0007] This 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, when combined with water before administration, contains sodium at an acceptable level for use in the treatment of pediatric subjects. The storage-stable PPI system is particularly suitable for use in high-dose dosage forms. This 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 buffers. The oral pharmaceutical suspension of this disclosure has an acceptable level of buffering capacity for pediatric subjects. In some embodiments, the buffering capacity of the oral pharmaceutical suspension described herein is approximately 2 mEq / ml of oral suspension.

[0008] In one embodiment, the present disclosure provides a storage-stable omeprazole system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system contains a water content of about 2.5% or less, the system does not contain 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, and further comprises a storage-stable omeprazole system composed of water before administration. In some embodiments of this embodiment, 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. In some embodiments, the pharmaceutically acceptable desiccant is sodium alginate.

[0010] In another embodiment, the present disclosure provides 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 water content of about 2.5% or less; and (ii) a second mixture comprising a second buffer, wherein the second mixture comprises a water 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 mixing with water, and the system is free of 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. In some embodiments, 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 buffer. In some embodiments, the first mixture further comprises both (b) a first desiccant and (c) a first buffer. In some embodiments, the second mixture further comprises a second desiccant.

[0011] In another embodiment, the Disclosure provides a storage-stable omeprazole system formulated in a drug delivery device suitable for high-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 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 1:2.6 to about 1:3.4, and further, the storage-stable omeprazole system is composed of water before administration.

[0012] In another embodiment, the Disclosure provides a storage-stable omeprazole powder 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 buffer; and (ii) a second powder mixture comprising sodium alginate and a second buffer, wherein the first and second powder mixtures are stored separately from each other and are mixed together at or immediately before mixing with water, and the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments, sodium and potassium are present in a weight ratio of about 1:3.2.

[0013] In another embodiment, the Disclosure provides 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 buffers, wherein the suspension is either sodium-free from a sodium-containing buffer or 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 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 a 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 high-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 two years at 25°C / 60% relative humidity.

[0017] In some embodiments, the oral pharmaceutical suspension of the present disclosure is first and second C 最大 and the first and second T 最大 This provides a biphasic pharmacokinetic profile with the characteristics described above, after oral administration, in subjects requiring it.

[0018] In another embodiment, the Disclosure provides a method for inhibiting gastric acid secretion in subjects requiring it. In certain embodiments, the method involves administering to a subject requiring it an effective amount of oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffers, 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 involves administering to a subject requiring it an effective amount of oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffers, 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 contains about 1 mg / ml to about 10 mg / ml of omeprazole or a pharmaceutically acceptable salt thereof.

[0019] In another embodiment, the present disclosure provides a method for preparing an oral pharmaceutical suspension. Typically, the method comprises (a) combining a first mixture containing a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains no more than about 2.5% water, with a second mixture containing a second buffer, wherein the second mixture contains no more than about 2.5% 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 comprises a second desiccant. In some embodiments, the method comprises: (a) a first mixture containing a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, and containing no more than about 2.5% water; and a second mixture containing a second desiccant and a second buffer, to obtain a combined mixture, wherein the combined mixture contains 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 (b) a first desiccant. In some embodiments, the first mixture further comprises (c) a first buffer. In some embodiments, the first mixture further comprises both (b) a first desiccant and (c) a first buffer.

[0020] In another aspect, the Disclosure relates to a method for inhibiting gastric acid secretion, comprising administering to a subject in need 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 buffers, wherein the suspension is sodium-free 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 a first mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, The present invention provides a method for obtaining a combined mixture by combining a first mixture, wherein the first mixture contains a moisture content of about 2.5% or less, with a second mixture containing a second buffer, wherein the second mixture contains a moisture content of about 2.5% or less, and 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 1:2.6 to about 1:3.4, and is prepared by adding water to the combined mixture. In some embodiments, the second mixture further comprises a second desiccant. In some embodiments, the method is a method for inhibiting gastric acid secretion, comprising administering an effective amount of oral pharmaceutical suspension prepared by (a) a first mixture containing a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, dispersed in water, and one or more buffers, wherein the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and administering an effective amount of oral pharmaceutical suspension prepared by (a) a first mixture containing a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains a water content of about 2.5% or less, and a second mixture containing a second desiccant and a second buffer to obtain a combined mixture, wherein the combined mixture contains sodium and potassium in a ratio of about 1:2.6 to about 1:3.4, to a subject requiring it, and adding water to the combined mixture. In some embodiments, the first mixture further comprises (c) a first buffer. In some embodiments, the first mixture further comprises both (b) a first desiccant and (c) a first buffer.

[0021] The additional embodiments and advantages described in this specification are, in part, set forth in the following description, or may arise from the description, or may be learned by practice of the embodiments described herein. The 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 Description of the Drawings

[0023] [Figure 1] Shows a delivery device suitable for use in the storage stability system of the present disclosure.

Modes for Carrying Out the Invention

[0024] The headings provided herein are not limitations on the various aspects described herein and may be defined by reference to the entire specification. It should also be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting since the scope of the present disclosure is limited only by the appended claims.

[0025] Definitions For the sake of simplicity, the meanings of some terms and phrases used in this specification, the examples, and the 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 assist in explaining specific embodiments and are not intended to limit the claimed technology. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs. If there is an apparent inconsistency between the use of a term in the art and its definition provided in this specification, the definition provided in this specification shall prevail.

[0026] The articles "a", "an", and "the" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects 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 specified value, unless otherwise indicated.

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

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

[0030] As used herein, terms such as “comprises,” “comprising,” “having,” “including,” and “containing” are open-ended terms meaning “including, but not limited to.” To the extent that a given embodiment disclosed herein “includes” certain elements, this disclosure should be understood to also disclose embodiments that are specifically contemplated, “essentially” derived from, and “consist of” those elements.

[0031] The terms “to treat,” “to treat,” and “treatment” refer to any indicator of the success of treatment or improvement, including any objective or subjective parameters, such as remission, remission, reduction of symptoms, or making the injury, disease, or condition more tolerable to the patient, slowing the rate of decline or reduction, or improving the patient’s physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, or psychiatric assessment.

[0032] The “effective” dose, “therapeutic effective dose,” or “pharmaceutical effective dose” of a drug or pharmacologically active agent means a quantity of the drug or agent that is non-toxic but sufficient to provide the desired effect. The “effective” dose will vary depending on the subject, depending on the individual’s age and general condition, the specific active agent or agent, etc. Therefore, it is not always possible to specify an exact “effective dose.” However, an appropriate “effective” dose for any individual can be determined by a person skilled in the art using routine experiments.

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

[0034] As used herein, the terms “desiccant,” “first desiccant,” and “second desiccant” refer to pharmaceutically acceptable hygroscopic materials that help maintain a dry state. These desiccants remove moisture from the air, adsorbing moisture and thereby creating and maintaining a dry, moisture-free environment. Suitable pharmaceutically acceptable desiccants include, for example, sodium alginate and starch.

[0035] The terms “buffering agent” or “buffer” mean any pharmaceutically acceptable weak base or strong base and mixture thereof that, when formulated or delivered before, during, and / or after a proton pump inhibitor such as omeprazole, function to substantially prevent or inhibit the acid degradation of the proton pump inhibitor by gastric acid and to maintain the oral bioavailability of the proton pump inhibitor.

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

[0037] As used herein, the term “multiple doses” means that, after being composed with water, the omeprazole powder system may 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 terms “stability” or “storage stability” refer to the chemical stability to which no more than 5% w / w of all related substances, such as omeprazole degradation products, are formed when the omeprazole powder system described herein is stored for at least 6 months at 40°C and 75% relative humidity (RH), or for at least 2 years at 25°C and 60% relative humidity, to the extent necessary for the sale and use of the omeprazole powder system described herein.

[0039] As used herein, the term "low viscosity grade sodium alginate" refers to sodium alginate having a solution viscosity of less than approximately 100 millipascal seconds (mPa·s) in a 3% aqueous solution. A suitable low viscosity grade sodium alginate is, for example, Manucol® LB (by FMC Biopolymer).

[0040] The term "GERD (gastro-esophageal reflux disease)" refers to gastroesophageal reflux disease. This is a condition in which stomach acid leaks into the esophagus (the tube connecting the throat to the stomach), causing pain, inflammation, and heartburn. In children, symptoms of the condition may include the return of stomach contents to the mouth (reflux), nausea (vomiting), and poor weight gain.

[0041] The term "PICS (Protection In Situ Constitution System)" refers to a protective in-situ constitution system. A PICS system is a bottle with a one-piece cap, as shown in Figure 1. The omeprazole (or any PPI)-containing mixture is in a dry state inside the cap until the point of composition. A diluent phase, such as a second mixture described below, is contained in the bottle. At the point of composition, the drug-loaded mixture is released from the cap into the diluent phase (or second mixture) by twisting the cap, and then water is added for composition.

[0042] As used herein, the term “child” refers to a human being in the stage between birth and adolescence.

[0043] The term "puberty" refers to the process of physical changes in a child's body as it grows and develops into an adult body capable of sexual reproduction. On average, girls begin puberty at around 10-11 years old and end it at around 15-17 years old, while boys begin puberty at around 11-12 years old and end it at around 16-17 years old.

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

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

[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 “youth” refers to a person between the ages of 10 and 19.

[0048] Storage stability system described herein Proton pump inhibitors such as omeprazole are widely used to treat gastric acid-mediated disorders in patients; however, their chemical instability in acidic media prevents the formulation of simple aqueous dosage forms for therapy. This disclosure provides a storage-stable PPI system that, when combined with water, provides an effective amount of PPI (such as omeprazole or a pharmaceutically acceptable salt thereof) to subjects requiring it, while having a sodium level acceptable for administration to pediatric subjects. The oral pharmaceutical suspensions of this 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 by using a balanced buffering system, for example, 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 buffering capacity of the oral pharmaceutical suspension described herein is approximately 1.6 mEq / ml to approximately 2.3 mEq / ml.

[0049] In one embodiment, the present disclosure provides a storage-stable PPI system (such as a storage-stable omeprazole system) wherein the system comprises a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof, such as 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 contains sodium and potassium in a weight ratio of about 1:100 to about 100:1, and further comprises a storage-stable PPI system composed of water before 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, storage-stable PPIs (such as storage-stable omeprazoles) do not contain sodium from sodium-containing buffers such as 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, sodium tartrate, disodium tartrate, and sodium succinate.

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

[0052] In some embodiments, the storage-stable PPI system (such as the storage-stable omeprazole system) has a water content of approximately 0.5% to approximately 1.5%. In some embodiments, the storage-stable PPI system (such as the storage-stable omeprazole system) has a water content of approximately 1% or less.

[0053] Suitable proton pump inhibitors (PPIs) that can be used in the storage-stable PPI systems described herein include, for example, omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, dexlansoprazole, rapeprazole, dontoprazole, tenatoprazole, haberprazole, lansoprazole, pariprazole, and reminoprazole, as well as pharmaceutically acceptable salts thereof. 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. Suitable examples of pharmaceutically acceptable PPI salts include sodium, magnesium, calcium, and potassium salts such as omeprazole sodium salt, omeprazole magnesium salt, omeprazole calcium salt, omeprazole potassium salt, esomeprazole sodium salt, esomeprazole magnesium salt, esomeprazole calcium salt, and esomeprazole potassium salt.

[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 desiccant that is pharmaceutically acceptable and plays a role in removing moisture from the air, adsorbing moisture, and thereby creating and maintaining a dry, moisture-free environment for the PPI. Suitable pharmaceutically acceptable desiccants include, for example, sodium alginate and starch. 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 system described herein is dry, i.e., the sodium alginate contains less than about 2% moisture. In some embodiments, the storage-stable PPI system contains 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 systems described herein, such as storage-stable omeprazole systems, is a low-viscosity grade sodium alginate. A suitable low-viscosity grade 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 sodium alginate is Manucol® LB (by FMC Biopolymer).

[0058] In some embodiments, the storage-stable PPI systems described herein, such as storage-stable omeprazole systems, include one or more buffers. In some embodiments, the storage-stable PPI systems described herein include one, two, three, or four buffers. In some embodiments, the storage-stable PPI systems described herein include one buffer. In some embodiments, the storage-stable PPI systems described herein include two or three buffers. In some embodiments, the storage-stable PPI systems described herein include two buffers.

[0059] Storage-stable PPI systems described herein, such as storage-stable omeprazole systems, may include any suitable buffer that functions to substantially prevent or inhibit the acid degradation of the PPI (such as omeprazole or a pharmaceutically acceptable salt thereof) by gastric acid in a manner sufficient to maintain the bioavailability of the administered PPI. In some embodiments, one or more buffers are 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 buffers are 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 (such as storage-stable omeprazole systems) described herein include at least one buffer selected from 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, sodium tartrate, disodium tartrate, and sodium succinate. In some embodiments, the storage-stable PPI systems (such as storage-stable omeprazole systems) described herein include at least one buffer selected from potassium carbonate, potassium bicarbonate, potassium dihydrogen phosphate, potassium hydrogen phosphate, trisodium phosphate, potassium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, potassium tetraborate, potassium acetate, disodium hydrogen phthalate, potassium hydrogen phthalate, disodium tartrate, potassium tartrate, and potassium succinate.

[0061] In some embodiments, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) include one or fewer buffers 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, dipotassium tartrate, potassium tartrate, and potassium succinate. In some embodiments, one buffer is potassium bicarbonate.

[0062] In some embodiments, the storage-stable PPI system described herein (such as the storage-stable omeprazole system) comprises two or more buffers selected from sodium and potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. In some embodiments, the storage-stable PPI system described herein comprises both sodium bicarbonate and potassium bicarbonate. In some embodiments, 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, 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, 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, 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, sodium bicarbonate and potassium bicarbonate are present in the system in a weight ratio of about 1:2.5 to about 1:3.4. In some embodiments, sodium bicarbonate and potassium bicarbonate are present in a weight ratio of about 1:2.7.

[0063] 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 raise the gastric juice pH to a level that prevents the degradation of at least a portion of the PPI (such as omeprazole or a pharmaceutically acceptable salt thereof) in the gastric juice.

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

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

[0066] The storage-stable PPI systems (such as storage-stable omeprazole systems) described herein can be prepared in any suitable multi-particulate 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 systems (such as storage-stable omeprazole systems) described herein are in the form of powders 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 described herein (such as a storage-stable omeprazole system) comprises (i) (a) a first mixture comprising a therapeutically effective amount of PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), wherein the first mixture contains no more than about 2.5% water; and (ii) a second mixture comprising a second buffer, wherein the second mixture contains no more than about 2.5% water, wherein the first and second mixtures are stored separately from each other and are mixed together at or immediately before mixing with water, and the system 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 described herein (such as a storage-stable omeprazole system) provides a storage-stable PPI system comprising: (i) (a) a first mixture comprising a therapeutically effective amount of PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), wherein the first mixture comprises a water content of about 2.5% or less; and (ii) a second mixture comprising a second buffer, wherein the second mixture comprises a water content of about 2.5% or less, wherein the first mixture and the second mixture are stored separately from each other and are mixed together at the time of or immediately before mixing with water, and the system comprises a second mixture which does not contain 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. In some embodiments, sodium and potassium are present in a weight ratio of about 1:3.2.

[0069] In some embodiments, storage-stable PPI systems (such as storage-stable omeprazole systems) do not contain sodium from sodium-containing buffers.

[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 described herein (such as a storage-stable omeprazole system) comprises (i) a first mixture comprising (a) a therapeutically effective amount of PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), wherein the first mixture contains a water content of about 2.5% or less; and (ii) a second mixture comprising a second desiccant and a second buffer, wherein the first mixture and the second mixture are stored separately from each other and are mixed together at or immediately before mixing with water, and the 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 storage-stable PPI system described herein (such as a storage-stable omeprazole system) contains 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 water content of about 0.5% to about 1.5%. In some embodiments, the first mixture and the second mixture each independently have a water content of about 0.6% to about 1.1%. In some embodiments, the first mixture and the second mixture each independently have a water content of about 0.5% to about 0.9%. In some embodiments, the first mixture has a water content of about 0.5% to about 1.5%, and the second mixture has a water content of about 1.5% or less. In some embodiments, the second mixture has a water content of about 0.5% or less.

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

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

[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 (such as omeprazole or a pharmaceutically acceptable salt thereof), (b) a first desiccant, and (c) a first buffer, wherein the first mixture contains no more than about 2.5% water; and (ii) a second mixture comprising a second desiccant and a second buffer, wherein the first mixture and the second mixture are stored separately from each other and are mixed together at or immediately before mixing with water, and the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4. In some embodiments of this embodiment, the storage-stable PPI system described herein (such as a storage-stable omeprazole system) contains 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 water content of about 0.5% to about 1.5%. In some embodiments, the first mixture and the second mixture each independently have a water content of about 0.6% to about 1.1%. In some embodiments, the first mixture and the second mixture each independently have a water content of about 0.5% to about 0.9%. In some embodiments, the first mixture has a water content of about 0.5% to about 1.5%, and the second mixture has a water content of about 1.5% or less. In some embodiments, the second mixture has a water content of about 0.5% or less.

[0076] The first and second desiccants may include any pharmaceutically acceptable desiccants as 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 desiccants are different. In some embodiments, the first and second desiccants 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 and second mixtures may independently be in the form of powder, pellets, granules, seeds, beads, spheroids, microspheres, or mixtures thereof. In some embodiments, the first and second mixtures may independently be in the form of powder or pellets. In other embodiments, both the first and second mixtures may be in the form of powder.

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

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

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

[0081] In some embodiments, the first and second buffers are present in amounts sufficient to raise the gastric juice pH to a level that prevents the degradation of at least some of the pharmaceutically acceptable salts of the PPI or omeprazole in the gastric juice.

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

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

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

[0085] In some embodiments, the first buffer and the second buffer 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 buffer and the second buffer 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 buffer is selected from 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, sodium tartrate, disodium tartrate, sodium succinate, and mixtures thereof.

[0087] In some embodiments, the second buffer is selected from sodium or potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and mixtures thereof.

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

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

[0090] In some embodiments, the first buffer and the second buffer are each independently selected from 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, potassium tartrate, dipotassium succinate, and mixtures thereof. In some embodiments, the first buffer and the second buffer are potassium bicarbonate.

[0091] The storage-stable PPIs described herein (such as storage-stable omeprazoles) may further comprise one or more pharmaceutically acceptable excipients, including sweeteners, flavorings, preservatives, thickeners, suspending agents, opaque agents, 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 combinations 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: 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-flavored, vanilla-flavored, or a mixture 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, sodium methylparaben, sodium ethylparaben, and mixtures thereof. In some embodiments described herein, the preservative is sodium benzoate, sodium methylparaben, or a mixture thereof. In some embodiments, the preservative is a mixture of sodium benzoate and sodium methylparaben.

[0095] Suitable thickening agents (or thickeners) include substances that can increase the viscosity of a liquid without substantially altering other properties and are suitable for oral pharmaceutical formulations. Examples of suitable thickening agents include, for example, 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 such as titanium dioxide (TiO2) that are added to materials to make the following systems opaque.

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

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

[0099] In some embodiments, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) are provided within a drug delivery device suitable for high-dose administration of PPIs or pharmaceutically acceptable salts thereof (such as omeprazole or pharmaceutically acceptable salts thereof). In certain embodiments, the delivery device is as described in U.S. Patent No. 9,051,100, No. 10,238,803, or U.S. Patent Application Publication No. 2014 / 0311929, the contents of which are fully incorporated by reference.

[0100] In some embodiments, the delivery device is a PICS system. In some embodiments, the PICS system is as shown in Figure 1.

[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 may be a container body (such as a bottle), and the first chamber may be a cap capable of containing particulate material and fitted into the opening of the container body.

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

[0103] In some embodiments, the storage-stable PPI system described herein (such as a storage-stable omeprazole system) is provided in a container body including a cap, (i) the container body contains a second mixture and has a container opening formed at its upper end, (ii) the cap comprises a cylindrical storage portion containing a first mixture and a cap portion sealing the upper end of the storage portion, and (iii) the cap is fitted into the container opening of the container body, and when the cap is screwed on, 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 described herein (such as a storage-stable omeprazole system) is formulated in a drug delivery device suitable for high-dose administration of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), the system comprises a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), the system contains 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 furthermore, the storage-stable omeprazole system is composed of water before 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, sodium and potassium are present in a weight ratio of about 1:3.2. In some embodiments, the storage-stable PPI system (such as the 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 two years at 25°C / 60% relative humidity.

[0106] In some embodiments, the Disclosure provides a storage-stable omeprazole powder 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 buffer; and (ii) a second powder mixture comprising sodium alginate and a second buffer, wherein the first and second powder mixtures are stored separately from each other and are mixed together at or immediately before mixing 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, omeprazole or a pharmaceutically acceptable salt thereof is micronized. In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and unmicronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof contains about 30 to about 70% micronized omeprazole or a pharmaceutically acceptable salt thereof, with the remainder of the omeprazole or a pharmaceutically acceptable salt thereof being unmicronized. In some embodiments, omeprazole is a 1:1 mixture by weight of micronized and unmicronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt in a weight ratio of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9. In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt in a weight ratio of about 1:2.3 (i.e., a mixture of about 30:70). In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized omeprazole or a pharmaceutically acceptable salt in a weight ratio of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9. In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and unmicronized omeprazole or a pharmaceutically acceptable salt thereof in a ratio of about 1:1.5 (i.e., about 40:60) by weight.

[0108] The first powder mixture can be prepared, for example, by wet granulation of a mixture of omeprazole or a pharmaceutically acceptable salt thereof, sodium alginate, and the first buffer, drying the granules, and grinding the dried granules. In some embodiments, the first powder mixture further comprises dried sodium alginate. A preferred method for preparing the first powder mixture is described, for example, in U.S. Patent No. 8,093,271, the contents of which are fully incorporated by reference.

[0109] In some embodiments, about 20-30% of the sodium alginate present in the first powder mixture is homogeneously distributed on the surface of the first buffer. In some embodiments, about 20-25% of the sodium alginate present in the first powder mixture is homogeneously 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 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 water content of about 0.5% to about 1.5%. In some embodiments, the sodium alginate is the low viscosity grade of sodium alginate as defined above.

[0111] The first and second buffers are present in amounts sufficient to raise the gastric juice pH to a level that prevents at least partial degradation of omeprazole or a pharmaceutically acceptable salt thereof in the gastric juice. In some embodiments, the first and second buffers provide a buffering capacity of about 0.5 to about 4 mEq / ml for the configured storage-stable omeprazole powder system described herein, having water. In some embodiments, the first and second buffers provide a buffering capacity of about 1.6 to about 2.3 mEq / ml for the configured storage-stable omeprazole powder system described herein, having water. In some embodiments, the first and second buffers provide a buffering capacity of about 2 mEq / ml for the configured storage-stable omeprazole powder system described herein, having water.

[0112] In some embodiments, the first and second buffers present in the storage-stable omeprazole powder system 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 and second buffers are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

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

[0114] In some embodiments, the second buffer 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. In some embodiments, the second buffer is a mixture of about 11% by weight of sodium bicarbonate and about 89% by weight of potassium bicarbonate.

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

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

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

[0119] In some embodiments, a storage-stable omeprazole powder system is provided within a drug delivery device suitable for high-dose administration of omeprazole.

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

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

[0122] In certain embodiments, the storage-stable omeprazole powder system is provided in a delivery device which 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 comprises a cylindrical storage portion containing a first powder mixture and a cap portion that seals the upper end of the storage portion; and (iii) the cap is fitted into the container opening of the container body, and when the cap is screwed on, 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 (such as storage-stable omeprazole systems) are sealed in a sealed aluminum foil pouch to minimize moisture ingress during non-constitutive storage. In some embodiments, the aluminum foil pouch can reduce moisture-related degradation of the PPI or its pharmaceutically acceptable salt (such as omeprazole or its pharmaceutically acceptable salt) during storage of the storage-stable PPI systems described herein (such as 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, holding time 1-2 seconds).

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

[0126] In one embodiment, the disclosure provides an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof dispersed in water (such as omeprazole or a pharmaceutically acceptable salt thereof), and one of several buffers. 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 does not contain sodium from sodium-containing buffers such as 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, sodium tartrate, disodium tartrate, and sodium succinate.

[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 the low-viscosity grade of sodium alginate described above.

[0129] In certain embodiments, about 1 ml of oral pharmaceutical suspension contains about 1 mg to about 10 mg of 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 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 suspension described herein comprises one, two, three, or four buffering agents. In some embodiments, the oral pharmaceutical suspension described herein comprises one buffering agent. In some embodiments, the oral pharmaceutical suspension described herein comprises two or three buffering agents. In some embodiments, the oral pharmaceutical suspension described herein comprises two buffering agents.

[0133] The oral pharmaceutical suspensions described herein, such as those containing omeprazole or a pharmaceutically acceptable salt thereof, may contain any suitable buffer that functions to substantially prevent or inhibit the acid degradation of the PPI or a pharmaceutically acceptable salt thereof (such as omeprazole, a pharmaceutically acceptable salt) by gastric acid in a manner sufficient to maintain the bioavailability of the administered PPI. In some embodiments, one or more buffers are 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 buffers are 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 (such as suspensions containing omeprazole or a salt thereof) include at least one buffer selected from 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, sodium tartrate, disodium tartrate, and sodium succinate. In some embodiments, the oral pharmaceutical suspensions described herein include at least one buffer selected from potassium carbonate, potassium bicarbonate, potassium dihydrogen phosphate, potassium hydrogen phosphate, trisodium phosphate, potassium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate, potassium tetraborate, potassium acetate, disodium hydrogen phthalate, potassium hydrogen phthalate, disodium tartrate, potassium tartrate, and potassium succinate.

[0135] In some embodiments, the oral pharmaceutical suspensions described herein (such as suspensions containing omeprazole or a pharmaceutically acceptable salt thereof) include one or fewer buffers 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, dipotassium tartrate, potassium tartrate, and potassium succinate. In some embodiments, one buffer is potassium bicarbonate.

[0136] In some embodiments, the oral pharmaceutical suspension described herein (such as one containing omeprazole or a pharmaceutically acceptable salt thereof) comprises two or more buffers selected from sodium and potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. In some embodiments, the oral pharmaceutical suspension described herein comprises two buffers. In some embodiments, the oral pharmaceutical suspension described herein comprises both sodium bicarbonate and potassium bicarbonate.

[0137] In some embodiments, 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 1 ml of suspension. In some embodiments, sodium bicarbonate and potassium bicarbonate are present in a weight ratio of about 1:2.7 per 1 ml of suspension.

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

[0139] In certain embodiments, the oral pharmaceutical suspension described herein 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.

[0140] One or more buffering agents present in the oral pharmaceutical suspension described herein are present in an amount sufficient to raise the gastric juice pH to a level that prevents the degradation of at least some of the PPIs (such as omeprazole or a pharmaceutically acceptable salt thereof) in the gastric juice.

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

[0142] In certain embodiments, the oral pharmaceutical suspensions described herein contain low levels of sodium so that the suspensions are suitable for administration to pediatric subjects. In some embodiments, 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 pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, present in the oral pharmaceutical suspension described herein is micronized.

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

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

[0146] In certain embodiments, the oral pharmaceutical suspension comprises first and second C 最大 and the first and second T 最大 This provides a biphasic pharmacokinetic profile with the characteristics described above, after oral administration, in subjects requiring it.

[0147] In certain embodiments, a 5 ml volume of the oral pharmaceutical suspension described herein contains about 10 mg or about 20 mg of a PPI or a pharmaceutically acceptable salt thereof (such as 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, a 5 ml oral pharmaceutical suspension further contains about 10 mg to about 15 mg of sodium methylparaben 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 contains 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, a 5 ml oral pharmaceutical suspension further comprises about 11.45 mg of sodium methylparaben 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) may further contain one or more pharmaceutically acceptable excipients, including sweeteners, flavorings, preservatives, thickeners, suspending agents, emulsions, 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 combinations thereof. In some embodiments described herein, the sweetener is mannitol, sucralose, or maltitol, or a mixture thereof.

[0152] Suitable flavorings include, for example, the following flavorings (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-flavored, vanilla-flavored, or a mixture 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, sodium methylparaben, sodium ethylparaben, and mixtures thereof. In some embodiments described herein, the preservative is sodium benzoate, sodium methylparaben, or a mixture thereof. In some embodiments, the preservative is a mixture of sodium benzoate and sodium methylparaben.

[0154] Suitable thickening agents (or thickeners) include substances that can increase the viscosity of a liquid without substantially altering other properties and are suitable for oral pharmaceutical formulations. Examples of suitable thickening agents include, for example, 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 such as titanium dioxide (TiO2) that are added to materials to make the following systems opaque.

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

[0157] The oral drug suspensions described herein remain stable for at least one month after being mixed 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 at 40°C and 75% relative humidity (RH) for 3 months before composition with water, the total amount of impurities (i.e., degradation products of PPIs such as omeprazole) formed in the oral pharmaceutical suspension described herein on the day of composition 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 suspension on day 0 is 0.11% w / w or less.

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

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

[0161] In some embodiments, sodium methylp-hydroxybenzoate is used as a preservative in storage-stable PPI systems (such as storage-stable omeprazole systems) and oral pharmaceutical suspensions described herein. In some embodiments, after being stored at 40°C and 75% RH for 3 months before composition with water, the amount of sodium methylp-hydroxybenzoate present in the oral pharmaceutical suspension described herein on the day of composition with water (i.e., day 0) is at least 94.5% w / w of the total amount originally present in the storage-stable PPI system (such as storage-stable omeprazole systems) described herein. In some embodiments, the amount of sodium methylp-hydroxybenzoate present in the oral pharmaceutical suspension on day 0 is at least 95.9% w / w of the total amount initially present in the storage-stable PPI system (such as storage-stable omeprazole systems) described herein.

[0162] In some embodiments, after being stored at 2°C to 8°C for 28 days after composition with water (i.e., on day 28), and after being stored at 40°C and 75% RH for 3 months prior to composition with water, the amount of sodium methylp-hydroxybenzoate present in the oral pharmaceutical suspension described herein after storage is at least 92% w / w of the total amount originally present in the storage-stable PPI system (such as a storage-stable omeprazole system) described herein. In some embodiments, the amount of sodium methylp-hydroxybenzoate present in the oral pharmaceutical suspension on day 28 is at least 94% w / w of the total amount initially present in the storage-stable PPI system (such as a storage-stable omeprazole system) described herein.

[0163] In some embodiments, after being stored at 2°C to 8°C for 56 days after composition with water (i.e., on day 56), and after being stored at 40°C and 75% RH for 3 months prior to composition with water, the amount of sodium methylp-hydroxybenzoate 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 (such as a storage-stable omeprazole system) described herein. In some embodiments, the amount of sodium methylp-hydroxybenzoate present in the oral pharmaceutical suspension on day 56 is at least 86.1% w / w of the total amount initially present in the storage-stable PPI system (such as a storage-stable omeprazole system) described herein.

[0164] In some embodiments, the oral pharmaceutical suspension described herein is provided in a drug delivery device suitable for high-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, those described above in relation to the storage stability system described herein. Treatment method

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

[0166] In one embodiment, the present disclosure provides a method for inhibiting gastric acid secretion in a subject. The method comprises administering an effective amount of the oral pharmaceutical suspension of the present disclosure to a subject in need.

[0167] In certain embodiments, the Disclosure provides a method for inhibiting gastric acid secretion, comprising administering an effective amount of an oral pharmaceutical suspension to a subject in need thereof, the oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffers, wherein the suspension is sodium-free 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 Disclosure provides a method for inhibiting gastric acid secretion, comprising administering an effective amount of an oral pharmaceutical suspension to a subject in need thereof, the oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffers, wherein the suspension is sodium-free 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 embodiments, the Disclosure provides a method for inhibiting gastric acid secretion, comprising administering an effective amount of an oral pharmaceutical suspension to a subject in need thereof, wherein the oral pharmaceutical suspension comprises water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffers, wherein the oral pharmaceutical suspension is sodium-free 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 for inhibiting gastric acid secretion, comprising administering an effective amount of an oral pharmaceutical suspension to a subject in need thereof, the oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffers, wherein the suspension is sodium-free 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 does not contain sodium from sodium-containing buffers such as 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, sodium tartrate, disodium tartrate, and sodium succinate.

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

[0174] In some embodiments, the method involves administering an oral pharmaceutical suspension described herein to a subject, where about 1 ml of the suspension contains about 1 mg to about 10 mg of a PPI or a pharmaceutically acceptable salt thereof (such as 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 (such as 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 (such as 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 (such as omeprazole or a pharmaceutically acceptable salt thereof).

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

[0176] In one embodiment, the Disclosure also provides a method for inhibiting gastric acid secretion, comprising administering to a subject in need 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 water (such as omeprazole or a pharmaceutically acceptable salt thereof), and one or more buffers, 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 preparation involves combining a first mixture containing a pharmaceutically acceptable salt (such as), wherein the first mixture contains no more than 2.5% water, with a second mixture containing a second buffer, wherein the second mixture contains no more than 2.5% water, to obtain a combined mixture in which 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 then 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 an effective amount of an oral pharmaceutical suspension to a subject in need, the suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof dispersed in water (such as omeprazole or a pharmaceutically acceptable salt thereof), and one or more buffers, wherein 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 (a) combining a first mixture comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), wherein the first mixture comprises a water content of about 2.5% or less, with a second mixture comprising a second desiccant and a second buffer, wherein the combined mixture contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and by adding water to the combined mixture.

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

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

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

[0181] The appropriate dose for adults is approximately 10 mg to 40 mg once daily. In some embodiments, the adult dose is approximately 10 mg, 20 mg, 30 mg, or 40 mg once daily.

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

[0183] In some embodiments, a preferred dose of omeprazole or its salt administered as an oral drug suspension to children aged 1 month to 1 year is approximately 1 mg / kg once daily.

[0184] In some embodiments, a preferred dose of omeprazole or a salt thereof administered in an oral pharmaceutical suspension to a child over 1 year of age with a body weight of approximately 10-20 kg is approximately 10 mg once daily. In some embodiments, this dose can be increased to 20 mg once daily.

[0185] In some embodiments, a preferred dose of omeprazole or a salt thereof in an oral pharmaceutical suspension administered to a child over 2 years of age and weighing over approximately 20 kg is approximately 20 mg once daily. In some embodiments, this dose 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 other pharmaceutical agents indicated for the treatment or prevention of gastrointestinal disorders, such as antibacterial agents, motility enhancers, H2 antagonists, and antacids, or sucralfate (these are commonly administered to minimize pain and / or complications associated with gastrointestinal disorders). Method for preparing a suspension

[0187] In one embodiment, the present disclosure provides a method for preparing an oral pharmaceutical suspension as described herein. The method comprises (a) combining a first mixture containing a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), wherein the first mixture contains no more than about 2.5% water, with a second mixture containing a second buffer, wherein the second mixture contains no more than about 2.5% 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 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 Disclosure provides a method for preparing an oral pharmaceutical suspension, comprising: (a) a first mixture comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), wherein the first mixture comprises a water content of about 2.5% or less; and a second mixture comprising a second desiccant and a second buffer, wherein the combined mixture comprises 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, 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) the first desiccant.

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

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

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

[0193] In some embodiments, PPIs or pharmaceutically acceptable salts thereof (such as omeprazole or a pharmaceutically acceptable salt thereof) present in the oral pharmaceutical suspension described herein may be pulverized before the preparation of the oral suspension. Methods known in the art can be used to pulverize omeprazole or a salt thereof. Conventional friction-based pulverization techniques for reducing particle size can be used, such as crushing, bashing, and grinding. A typical industrial mill consists of a cylindrical metal drum, usually containing steel balls. As the drum rotates, the spheres inside collide with solid particles, thus crushing them toward smaller diameters. In the case of grinding, solid particles are formed as 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 the solid into smaller particles by impact. Cutting uses a sharp blade to cut coarse solid pieces into smaller ones. In addition, modern pulverization methods using supercritical fluids in the pulverization process can be used. These methods induce a supersaturated state using supercritical fluids, which leads to the precipitation of individual particles. Preferred techniques include the RESS process (Rapid Expansion of Supercritical Solutions), the SAS method (Supercritical Anti-Solvent), and the PGSS method (Particles from Gas Saturated Solutions). These modern techniques allow for greater process tunability. Parameters such as relative pressure and temperature, solute concentration, and poor solvent-to-solvent ratio can be varied to adjust for the desired particle size. Supercritical fluid methods result in finer control over particle diameter, particle size distribution, and morphological consistency.

[0194] In some embodiments, the micronized PPI or a pharmaceutically acceptable salt thereof suitable for use in the oral suspension 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 suspension described herein comprises a micronized PPI or a pharmaceutically acceptable salt thereof. In some embodiments, 90% or more of the particles in the micronized PPI or a salt thereof have a particle size of 20 micrometers or less.

[0195] In some embodiments, the micronized omeprazole or a pharmaceutically acceptable salt thereof suitable for use in the oral suspension 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 suspension described herein comprises 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] PPIs and their salts can be prepared by any suitable method known in the art.

[0198] Specifically, 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 (such as omeprazole or a pharmaceutically acceptable salt thereof) used in the methods described herein is micronized.

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

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

[0202] The first and second buffers used in this method are present in an amount sufficient to raise the gastric juice pH to a level that prevents the degradation of at least a portion of the omeprazole in the gastric juice. In some embodiments, the first and second buffers together provide a buffering capacity for a suspension dose of about 0.5 mEq / ml to about 4 mEq / ml. In some embodiments, the first and second buffers together provide a buffering capacity for a suspension dose of about 1.6 mEq / ml to about 2.3 mEq / ml. In some embodiments, the first and second buffers together provide a buffering capacity for a suspension dose of about 2 mEq / ml.

[0203] In some embodiments, the first buffer and the second buffer 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 succinates. In some embodiments, the first buffer and the second buffer 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 embodiments, the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate. In some embodiments, the second buffer contains about 11% by weight of sodium bicarbonate and about 89% by weight of potassium bicarbonate.

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

[0206] In some embodiments, the first buffer and the second buffer 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 an oral pharmaceutical suspension in a drug delivery device suitable for high-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, those described above in relation to the storage stability systems described herein.

[0209] This disclosure also provides the following specific embodiments:

[0210] Embodiment 1. A storage-stable omeprazole system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system contains 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 1:2.6 to about 1:3.4, and further comprising a storage-stable omeprazole system composed of water before administration.

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

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

[0213] Embodiment 4. A storage-stable omeprazole system according to any one of Embodiments 1 to 3, further comprising a pharmaceutically acceptable desiccant.

[0214] Embodiment 5. The storage-stable omeprazole derivative according to 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 dried.

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

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

[0218] Embodiment 9. A storage-stable omeprazole system according to any one of the preceding claims, wherein the system independently comprises one or more buffers 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 to 9, wherein the system contains one buffering agent, which is potassium bicarbonate.

[0220] Embodiment 11. The 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 according to Embodiment 12, wherein sodium bicarbonate and potassium bicarbonate are present in a weight ratio of approximately 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 contains a water content of about 2.5% or less; and (ii) a second mixture comprising a second buffer, wherein the second mixture contains a water content of about 2.5% or less, wherein the first mixture and the second mixture are stored separately from each other and are mixed together at or immediately before mixing with water, wherein the system does not contain sodium from the 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 according to Embodiment 15, wherein sodium and potassium are present in a weight ratio of approximately 1:3.2.

[0226] Embodiment 17. The storage-stable omeprazole system according to 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. A storage-stable omeprazole system according to any one of Embodiments 15 to 17, wherein the first mixture further comprises (b) the first desiccant, and / or the second mixture further comprises the second desiccant.

[0228] Embodiment 19. The storage-stable omeprazole system according to 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 according to any one of Embodiments 15 to 19, wherein the first mixture further comprises (c) the first buffer.

[0230] Embodiment 21. A storage-stable omeprazole system according to 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 mixtures thereof.

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

[0232] Embodiment 23. The storage-stable omeprazole system according to any one of Embodiments 1 to 21, wherein omeprazole or a 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 according to Embodiment 23, wherein the omeprazole or a 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 not micronized.

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

[0235] Embodiment 26. The storage-stable omeprazole system according to any one of Embodiments 15 to 25, wherein the first buffer and the second buffer are present in amounts sufficient to raise the gastric juice pH to a level that prevents the degradation of at least a portion of the omeprazole in the gastric juice.

[0236] Embodiment 27. A storage-stable omeprazole system according to any one of Embodiments 20 to 26, wherein the first buffer and the second buffer together provide a buffering capacity for a powder configured at a dose of approximately 2 mEq / ml containing water.

[0237] Embodiment 28. A storage-stable omeprazole system according to any one of Embodiments 15 to 27, wherein the first buffer and the second buffer 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. A storage-stable omeprazole system according to any one of Embodiments 14 to 28, wherein the first buffer and the second buffer are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

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

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

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

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

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

[0244] Embodiment 35. A 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. A storage-stable omeprazole system according to any one of Embodiments 1 to 35, wherein the storage-stable omeprazole system is provided in a drug delivery device suitable for high-dose administration of omeprazole or a pharmaceutically acceptable salt thereof.

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

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

[0248] Embodiment 39. A 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 a second mixture and has a container opening formed at its upper end, (ii) the cap comprises a cylindrical storage portion containing a first mixture and a cap portion that seals the upper end of the storage portion, and (iii) the cap is attached inside the container opening of the container body, and when the cap is screwed on, 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 for at least two years at 25°C / 60% relative humidity.

[0251] Embodiment 42. A storage-stable omeprazole system formulated in a drug delivery device suitable for high-dose administration of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system contains a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the system contains 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 1:2.6 to about 1:3.4, and furthermore, the storage-stable omeprazole system is composed of water before administration.

[0252] Embodiment 43. The storage-stable omeprazole system according to 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 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 buffer; and (ii) a second powder mixture comprising sodium alginate and a second buffer, wherein the first and second powder mixtures are stored separately from each other and are mixed together at or immediately before mixing with water, and the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

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

[0255] Embodiment 46. The storage-stable omeprazole powder system according to Embodiment 44 or 45, wherein omeprazole or a 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 according to 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 pharmaceutically acceptable salt thereof is not micronized.

[0257] Embodiment 48. The 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 omeprazole or a pharmaceutically acceptable salt thereof, and about 20 to about 30% of 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 according to Embodiment 49, wherein omeprazole or a pharmaceutically acceptable salt thereof, and about 20 to about 25% sodium alginate present in the first powder mixture are homogeneously distributed on the surface of the first buffer.

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

[0261] Embodiment 52. The 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. The storage-stable omeprazole powder system according to Embodiment 51 or 52, wherein the dried sodium alginate has a water content of about 0.5% to about 1.5%.

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

[0264] Embodiment 55. A storage-stable omeprazole powder system according to any one of Embodiments 44 to 54, wherein the first and second buffers are present in an amount sufficient to raise the gastric juice pH to a level that prevents the degradation of at least a portion of omeprazole or a pharmaceutically acceptable salt thereof in the gastric juice.

[0265] Embodiment 56. A storage-stable omeprazole powder system according to any one of Embodiments 44 to 55, wherein the first and second buffers together provide a buffering capacity for a configured powder in a dose of approximately 2 mEq / ml containing water.

[0266] Embodiment 57. A storage-stable omeprazole powder system according to any one of Embodiments 44 to 56, wherein the first and second buffers 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 buffers are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0268] Embodiment 59. The 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. The storage-stable omeprazole powder system according to any one of Embodiments 44 to 59, wherein the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate.

[0270] Embodiment 61. The storage-stable omeprazole powder system according to Embodiment 60, wherein the mixture contains 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 contain sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0272] Embodiment 63. The 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. A storage-stable omeprazole powder system according to any one of Embodiments 44 to 63, wherein the storage-stable omeprazole powder system is provided in a drug delivery device suitable for high-dose administration of omeprazole.

[0274] Embodiment 65. The storage-stable omeprazole powder system according to 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 according to Embodiment 65, further comprising means for discharging a first powder mixture into a second chamber without removing a cap from the drug delivery device.

[0276] Embodiment 67. A 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 comprises a cylindrical storage portion containing a first powder mixture and a cap portion that seals the upper end of the storage portion, and (iii) the cap is attached inside the container opening of the container body, and when the cap is screwed on, the first powder mixture is released into the container body.

[0277] Embodiment 68. The 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 for at least two years at 25°C / 60% relative humidity.

[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 in water, and one or more buffers, 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 according to Embodiment 71, further comprising sodium alginate.

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

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

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

[0285] Embodiment 76. The oral pharmaceutical suspension according to any one of Embodiments 71 to 75, wherein one or more buffering agents provide a buffering capacity of about 2 mEq per 1 ml of the suspension.

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

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

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

[0289] Embodiment 80.The 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 according to Embodiment 80, comprising a mixture of sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0291] Embodiment 8_2. The oral pharmaceutical suspension according to any one of Embodiments 71 to 77 and 80 to 81, wherein the suspension contains about 86 mg of sodium per 5 ml of the suspension.

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

[0293] Embodiment 84. The suspension is the first and second C 最大 as well as the first and second T 最大The oral pharmaceutical suspension according to any one of embodiments 71 to 83, which provides a biphasic pharmacokinetic profile having it after oral administration to a subject who needs it.

[0294] The oral pharmaceutical suspension according to any one of embodiments 66 to 77, wherein the dose of embodiment 85.5 ml contains 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 according to embodiment 78, which further contains about 11.45 mg of sodium methylparaben and about 25 mg of sodium benzoate.

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

[0297] Embodiment 88. The oral pharmaceutical suspension according to any one of embodiments 71 to 86, wherein omeprazole or a 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 according to embodiment 88, wherein omeprazole or a pharmaceutically acceptable salt thereof contains about 30 to about 70% of micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder of omeprazole or a pharmaceutically acceptable salt thereof is non-micronized.

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

[0300] <00009​​

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

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

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

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

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

[0307] The method according to any one of Embodiments 92 to 96, wherein 8.1 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) combining (a) a first mixture containing a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the first mixture containing a proportion of water of about 2.5% or less, with (b) a second mixture containing a second buffering agent, the second mixture containing a proportion of water of about 2.5% or less, to obtain a combined mixture, wherein the combined mixture does not contain sodium from a sodium-containing buffering agent 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 according to Embodiment 99, wherein sodium and potassium are present in a weight ratio of about 1:3.2

[0310] Embodiment 101. The method according to 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 according to any one of Embodiments 99 to 101, wherein the first mixture further contains (b) a first desiccant and / or the second mixture further contains a second desiccant

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

[0313] Embodiment 104. The method according to any one of Embodiments 99 to 103, wherein the first mixture further contains (c) a first buffering agent

[0314] Embodiment 105. The method according to any one of Embodiments 99 to 104, wherein the first mixture and the second mixture are each independently in the form of a powder, pellet, granule, seed, bead, spheroid, microsphere, or a mixture thereof

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

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

[0317] Embodiment 108. The method according to 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 pharmaceutically acceptable salt thereof is not micronized.

[0318] Embodiment 109. The method according to Embodiment 107, wherein 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 according to any one of Embodiments 99 to 109, wherein the first buffer and the second buffer are present in amounts sufficient to raise the gastric juice pH to a pH that prevents the degradation of at least a portion of the omeprazole in the gastric juice.

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

[0321] Embodiment 112. The method according to any one of Embodiments 99 to 111, wherein the first buffer and the second buffer 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 according to any one of Embodiments 99 to 112, wherein the first buffer and the second buffer are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

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

[0324] Embodiment 115. The method according to any one of Embodiments 99 to 113, wherein the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate.

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

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

[0327] Embodiment 118. The method according to any one of Embodiments 99 and 101-113, wherein the first buffer and the second buffer are potassium bicarbonate.

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

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

[0330] Embodiment 121. A method for inhibiting gastric acid secretion, comprising administering to a subject in need 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 buffers, 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 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 at 2°C to 8°C for at least one month after being mixed with water.

[0332] This disclosure also provides the following specific embodiments:

[0333] Embodiment I. A storage-stable omeprazole system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system contains 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 1:2.6 to about 1:3.4, and further comprising a storage-stable omeprazole system composed of water before administration.

[0334] Embodiment II. The storage-stable omeprazole system according to Embodiment I, wherein each system independently comprises one or more buffers 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. (i)(a) a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains a water content of about 2.5% or less; and (ii) a second mixture comprising a second buffer, wherein the second mixture contains a water content of about 2.5% or less, wherein the first mixture and the second mixture are stored separately from each other and are mixed together at or immediately before mixing with water, and the system does not contain sodium from the sodium-containing buffer, or the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, the storage-stable omeprazole system according to Embodiment I.

[0336] Embodiment IV. A storage-stable omeprazole powder 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 buffer; and (ii) a second powder mixture comprising sodium alginate and a second buffer, wherein the first and second powder mixtures are stored separately from each other and are mixed together at or immediately before mixing with water, and 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 storage-stable omeprazole system powder according to any one of Embodiments I to IV, wherein omeprazole or a 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 to IV, wherein omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0339] Embodiment VII. A storage-stable omeprazole system or storage-stable omeprazole powder system according to any one of the preceding claims, wherein the storage-stable omeprazole system or storage-stable omeprazole powder system is provided in a drug delivery device suitable for high-dose administration of omeprazole or a pharmaceutically acceptable salt thereof.

[0340] Embodiment VIII. A storage-stable omeprazole system or storage-stable omeprazole system powder system according to Embodiment IV or VII, wherein the storage-stable omeprazole system 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 a first powder mixture and a cap portion that seals the upper end of the storage portion, and (iii) the cap is attached inside the container opening of the container body, and when the cap is screwed on, the first powder mixture is released into the container body.

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

[0342] Embodiment X. 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 buffers, 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 approximately 1 ml of the suspension contains approximately 1 mg to approximately 10 mg of omeprazole, or a pharmaceutically acceptable salt thereof.

[0344] Embodiment XII. An oral pharmaceutical suspension according to Embodiment X or XI, wherein the suspension remains stable at 2°C to 8°C for at least one month after being mixed with water.

[0345] Embodiment XIII. A method for inhibiting gastric acid secretion, comprising administering an effective amount of an oral pharmaceutical suspension described in any one of Embodiments X to XII to a subject requiring such suspension.

[0346] Embodiment XIV. A method for administering an oral pharmaceutical suspension to a subject requiring inhibition of gastric acid secretion, the method comprising: 1) preparing an oral pharmaceutical suspension comprising: 1) combining a first mixture containing a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains a water content of about 2.5% or less; and a second mixture containing a second buffer, wherein the second mixture contains a water content of about 2.5% or less; and adding water to the 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 2) administering an effective amount of the oral pharmaceutical suspension to a subject requiring it.

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

[0348] The formulations described herein will now be described in more 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 to these examples. Rather, the embodiments should be construed as encompassing all possible modifications that become apparent as a result of the teachings provided herein. Example 1 Exemplary formulations of omeprazole 2 mg / ml and 4 mg / ml oral suspensions and storage-stable omeprazole powder, as well as manufacturing details.

[0349] Table 1 below shows the granular compositions used in the preparation 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 oral suspensions of omeprazole 2 mg / ml and 4 mg / ml [Table 2] Example 3 Exemplary chemical compositions of omeprazole oral suspension [Table 3] Example 4

[0350] This example demonstrates the advantage of the storage stability omeprazole powder system of the present disclosure over the stability of the omeprazole oral suspension configured according to the present disclosure.

[0351] Omeprazole 2 mg / ml oral suspensions were prepared for Examples J, K, and L, each having the same suspension composition, but they differed in the following ways.

[0352] Example J is a two-chambered, aluminum foil-packaged dosage form according to the present disclosure, comprising a cap for containing the first powder mixture, which is fastened on a bottle containing the second powder mixture.

[0353] Example K is a comparative example of two chamber dosage forms in aluminum foil packaging, which include a cap for containing a first powder mixture, fastened on a bottle containing a second powder mixture composed of water.

[0354] Example L is a comparative example of a single-chamber dosage form in aluminum foil packaging, which includes a capped bottle containing a powder mixture of the first powder mixture and the second powder mixture.

[0355] The preparation, packaging, and composition of the 2 mg / ml omeprazole suspensions prepared in Examples J, K, and L are described below. [Table 4-1-1] [Table 4-1-2] [Table 4-1-3]

[0356] Table 4 provides a detailed summary of the formulations and characterizations of the omeprazole 2 mg / ml oral suspensions for Examples J, K, and L. [Table 4-2-1] [Table 4-2-2]

[0357] Table 5 provides a summary of the results of the stability tests for omeprazole 2 mg / ml oral suspensions of Example J, Example K, and Example L. [Table 5] Example 5 Exemplary chemical composition of an omeprazole oral suspension prepared using micronized omeprazole

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

[0359] Table 6 provides a detailed summary of the formulation and characterization of the omeprazole 4 mg / ml oral suspension of Example M. [Table 6]

[0360] A summary of the stability test results for Example M with omeprazole 4 mg / ml oral suspension is provided in Table 7. [Table 7] Example 6 Exemplary chemical composition of an omeprazole oral suspension prepared using a mixture of micronized and non-micronized omeprazole

[0361] The following provides a detailed description of the preparation, packaging, and composition of the omeprazole 4 mg / ml suspensions prepared in Examples N and O. [Table 10-1] [Table 10-2]

[0362] Table 8 provides a detailed summary of the formulations and characterizations of the omeprazole 4 mg / ml oral suspensions of Examples N and O. [Table 8-1] [Table 8-2]

[0363] Having described the present disclosure in its entirety, it will be understood by those skilled in the art that the same can be carried out within a broad and equivalent range of conditions, formulations, and other parameters without affecting the scope of the present invention or any embodiment thereof.

[0364] Other embodiments described herein will be apparent to those skilled in the art by considering the specification and practice of the invention disclosed herein. This specification is intended to be considered illustrative only, and the true scope and spirit of the invention are intended to be shown by the following claims.

[0365] All patents, patent applications, and publications cited herein are incorporated herein in their entirety by reference.

Claims

1. A storage-stable omeprazole combination, the combination comprising: (i) a first mixture consisting of (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) a first desiccant, (c) optionally a first buffer, and (d) optionally a sweetener, the first mixture having a moisture content of about 2.5% or less; and (ii) a second mixture comprising a second buffer, the second mixture containing neither omeprazole nor a pharmaceutically acceptable salt thereof, and the second mixture having a moisture content of about 2.5% or less. and a second mixture, wherein the first mixture and the second mixture are stored separately from one another and mixed together at or just before constitution with water, the combination containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and the first and second buffering agents are each independently selected from the group consisting of sodium or potassium carbonate, bicarbonate, phosphate, citrate, borate, acetate, phthalate, tartrate, succinate, and mixtures thereof.

2. A storage-stable omeprazole combination as described in claim 1, wherein the second mixture further comprises a second desiccant.

3. 3. The storage-stable omeprazole combination of claim 1 or 2, wherein the first mixture further comprises (c) a first buffering agent.

4. The storage-stable omeprazole combination according to any one of claims 1 to 3, wherein the first mixture further comprises (d) a sweetener.

5. 5. The storage-stable omeprazole combination of claim 4, wherein the sweetener is mannitol, sucralose, or maltitol, or a mixture thereof.

6. 6. The storage-stable omeprazole combination according to any one of claims 1 to 5, wherein the storage-stable omeprazole combination is provided in a drug delivery device suitable for administration of multiple doses of omeprazole or the pharmaceutically acceptable salt thereof.

7. 7. The storage-stable omeprazole combination according to any one of claims 1 to 6, wherein the storage-stable omeprazole combination 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 comprises 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.

8. 1. A storage-stable omeprazole powder combination, the combination comprising: (i) a first powder mix consisting of (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) sodium alginate, (c) a first buffering agent, and (d) optionally a sweetener; and (ii) a second powder mix comprising sodium alginate and a second buffering agent, the second powder mix containing no omeprazole or a pharmaceutically acceptable salt thereof, wherein the first powder mix and the first powder mix are mixed together.

1. A storage-stable omeprazole powder combination, wherein the second powder mixtures are stored separately from one another and mixed together at or just before constitution with water, the combination containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and the first and second buffering agents are each independently selected from the group consisting of sodium and potassium carbonate, bicarbonate, phosphate, citrate, borate, acetate, phthalate, tartrate, succinate, and mixtures thereof.

9. 9. The storage-stable omeprazole combination or storage-stable omeprazole powder combination according to any one of claims 1 to 8, wherein the omeprazole or the pharmaceutically acceptable salt thereof is micronized.

10. 9. The storage-stable omeprazole combination or storage-stable omeprazole powder combination according to any one of claims 1 to 8, wherein the omeprazole or the pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or the pharmaceutically acceptable salt thereof.

11. 11. The storage-stable omeprazole combination or storage-stable omeprazole powder combination of any one of claims 1 to 10, wherein the first and second buffering agents together provide a buffering capacity of about 2 mEq / ml of the constituted powder dose with water.

12. 12. The storage-stable omeprazole combination or storage-stable omeprazole powder combination of any one of claims 1 to 11, wherein the first and second buffering agents are each independently 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, sodium hydrogen tartrate, disodium tartrate, sodium succinate, 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, potassium hydrogen tartrate, dipotassium tartrate, potassium succinate, and mixtures thereof.

13. 13. The storage-stable omeprazole combination or storage-stable omeprazole powder combination of any one of claims 1 to 12, wherein the first and second buffering agents are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

14. 14. The storage-stable omeprazole powder combination of any one of claims 8 to 13, wherein the first mixture further comprises (d) a sweetener.

15. 15. The storage-stable omeprazole powder combination of claim 14, wherein the sweetener is mannitol, sucralose, or maltitol, or a mixture thereof.

16. 16. The storage-stable omeprazole powder combination of any one of claims 8 to 15, wherein the storage-stable omeprazole powder combination is provided in a drug delivery device suitable for administering multiple doses of omeprazole.

17. 17. The storage-stable omeprazole powder combination of any one of claims 8 to 16, wherein the storage-stable omeprazole powder combination is provided in a container body including a cap, wherein (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.

18. 18. The storage-stable omeprazole combination or storage-stable omeprazole powder combination of any one of claims 1 to 17, wherein the omeprazole combination or omeprazole powder combination remains stable at 25°C / 60% relative humidity for at least 2 years.

19. 20. An oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of the storage-stable omeprazole combination of any one of claims 1 to 7, 9 to 13 or 18 dispersed therein, wherein the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.

4.

20. 20. An oral pharmaceutical suspension comprising water and a pharmaceutically effective amount of the storage-stable omeprazole powder combination of any one of claims 8 to 18 dispersed in the water, wherein the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.

4.

21. 21. The oral pharmaceutical suspension of claim 19 or 20, wherein about 1 ml of the suspension contains about 1 mg to about 10 mg of omeprazole, or the pharmaceutically acceptable salt thereof, or 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.

22. 22. The oral pharmaceutical suspension of any one of claims 19 to 21, wherein said oral pharmaceutical suspension is for inhibiting gastric acid secretion in a subject.

23. 23. The oral pharmaceutical suspension of claim 22, wherein the subject is a child.

24. 1. A method for preparing an oral pharmaceutical suspension, comprising: (i) a first mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) a first desiccant, (c) optionally a first buffer, and (d) optionally a sweetener, wherein the first mixture has a moisture content of about 2.5% or less; and (ii) a second mixture comprising a second buffer, wherein the second mixture does not contain omeprazole or a pharmaceutically acceptable salt thereof, and the second mixture has a moisture content of about 2.5% or less. with a mixture of the above to obtain a combined mixture, 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, wherein the first and second buffering agents are each independently selected from the group consisting of sodium and potassium carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, succinates, and mixtures thereof.

25. 25. The method of claim 24, wherein the oral pharmaceutical suspension is prepared for inhibiting gastric acid secretion, the 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, the suspension containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.

4.

26. 24. An oral pharmaceutical suspension according to any one of claims 19 to 23, wherein the suspension remains stable for at least 1 month at 2°C to 8°C after constitution with water.

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