Pediatric suspension preparations

Abstract

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, the system being prepared with water prior to administration. This disclosure also relates to an oral drug 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 buffers.

Description

Background Technology

[0001] Omeprazole, or 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H-benzimidazole, inhibits gastric acid secretion. Omeprazole belongs to a class of antisecretory compounds, specifically substituted benzimidazoles, which do not exhibit anticholinergic or H2 histamine antagonist properties. These compounds work by specifically inhibiting H2 secretion at the surface of gastric cells. + / K + The ATPase system inhibits gastric acid secretion, and this is called a proton pump inhibitor.

[0002] Proton pump inhibitors (such as omeprazole) are unstable in acidic environments and therefore degrade rapidly in acidic media such as gastric contents, but they exhibit 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, some commercially available omeprazole formulations incorporate omeprazole as enteric-coated granules or pellets into sustained-release solid oral dosage forms. Examples of such formulations include, for instance... Losec They are enteric-coated pellets containing omeprazole, respectively, in hard, gastric-resistant capsules and gastric-resistant tablets.

[0004] Pediatric subjects often encounter difficulties when administering solid oral dosage forms such as tablets or capsules.

[0005] Currently, oral solution formulations of omeprazole have not been approved in Europe. In the United States, omeprazole powder for oral suspension is marketed under the brand name... Sold as a white flavored powder, packaged in single-dose packets and prepared with water before application. Each packet contains 20 mg or 40 mg of omeprazole and 1680 mg of sodium bicarbonate, along with the following excipients: xylitol, sucrose, sucralose, xanthan gum, and flavoring agents. For oral suspension use. One dose of the powder contains 460 mg of sodium (Na) + It is also available in the United States. - Omeprazole compound kit, which consists of omeprazole powder and FIRST-PPI (proton pump inhibitor) suspension containing artificial strawberry flavoring, benzyl alcohol, FD&C Red No. 40, Magnasweet 100 (ammonium glycyrrhizate), poloxamer 188, propylene glycol, purified water, dimethyl silicone oil emulsion, sodium bicarbonate, sodium citrate (dihydrate), sucralose, and xanthan gum. When compounded, the final product is provided in... -PPI suspensions contain a homogeneous suspension of 2 mg / ml omeprazole. These omeprazole suspension formulations contain a high amount of sodium, making them unacceptable for pediatric subjects.

[0006] A liquid oral omeprazole formulation specifically designed for pediatric subjects is required. Summary of the Invention

[0007] This disclosure relates to storage-stable proton pump inhibitor (PPI) systems comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), which, when formulated with water, contain acceptable levels of sodium for the treatment of pediatric subjects. These storage-stable PPI systems are particularly suitable for multi-dose formulations. This disclosure also relates to oral drug suspensions comprising water and 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 drug suspensions of this disclosure have acceptable levels of buffering capacity for pediatric subjects. In some aspects, the buffering capacity of the oral drug suspensions described herein is approximately 2 mEq / ml oral suspension.

[0008] In one aspect, this disclosure provides a storage-stable omeprazole system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system contains no more than about 2.5% water percentage, and wherein 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, and further wherein the storage-stable omeprazole system is prepared with water prior to administration. In some embodiments of this aspect, 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 also includes a pharmaceutically acceptable desiccant. In some embodiments, the pharmaceutically acceptable desiccant is sodium alginate.

[0010] On the other hand, this disclosure provides a storage-stable omeprazole system comprising (i) a first mixture containing (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains no more than about 2.5% water percentage; and (ii) a second mixture containing a second buffer, wherein the second mixture contains no more than about 2.5% water percentage; wherein the first and second mixtures are stored separately from each other and are mixed together when or immediately before being prepared with water, and wherein 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) the first desiccant and (c) the first buffer. In some embodiments, the second mixture further comprises a second desiccant.

[0011] In another aspect, this disclosure provides a storage-stable omeprazole system formulated in a drug delivery device suitable for multiple-dose administration of omeprazole or a pharmaceutically acceptable salt thereof, the system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system contains no more than about 2.5% water percentage, and wherein the system is free of sodium from a sodium-containing buffer, or the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable omeprazole system is prepared with water prior to administration.

[0012] On the other hand, this disclosure provides a storage-stable omeprazole powder system comprising (i) a first powder mixture containing (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 containing sodium alginate and a second buffer, wherein the first and second powder mixtures are stored separately from each other and are mixed together when or immediately before being prepared with water, wherein 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 aspect, this 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 free of sodium from a sodium-containing buffer, or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0014] In some embodiments, the oral drug suspension comprises water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the 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.

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

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

[0017] In some embodiments, the oral drug suspension of this disclosure provides, upon oral administration to a subject in need, the presence of first and second C... max and the first and second T max The biphasic pharmacokinetic curves.

[0018] In another aspect, this disclosure provides a method for inhibiting gastric acid secretion in a subject in need. In some embodiments, the method includes administering to the subject in need an effective amount of an oral drug 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 free of 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 includes administering to the subject in need an effective amount of an oral drug 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 aspect, this disclosure provides a method for preparing an oral pharmaceutical suspension. Generally, the method includes: combining a first mixture with a second mixture to obtain a combined mixture, the first mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains no more than about 2.5% water percentage; the second mixture comprising a second buffer, wherein the second mixture contains no more than about 2.5% water percentage, 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 includes combining a first mixture with a second mixture to obtain a combined mixture, the first mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, the first mixture containing no more than about 2.5% water percentage; the second mixture comprising a second desiccant and a second buffer, 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) the first desiccant and (c) the first buffer.

[0020] In another aspect, this disclosure provides a method for inhibiting gastric acid secretion, the method comprising administering to a subject in need an effective amount of an oral drug suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffers, wherein the suspension is free of sodium from a sodium-containing buffer, or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4; and wherein the oral drug suspension is prepared by the following steps: combining a first mixture with a second mixture to obtain a combined mixture, the first mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains no more than about 2.5% water percentage; the second mixture comprising a second buffer, wherein the second mixture contains no more than about 2.5% water percentage, wherein the combined mixture is free of 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 includes administering to a subject in need an effective amount of an oral drug suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the 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, wherein the oral drug suspension is prepared by the steps of: combining a first mixture with a second mixture to obtain a combined mixture, the first mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains no more than about 2.5% water percentage; the second mixture comprising a second desiccant and a second buffer, 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 (c) a first buffer. In some embodiments, the first mixture further comprises both (b) a first desiccant and (c) a first buffer.

[0021] Further embodiments and advantages described herein will be set forth in part in the description which follows, and will be derived from that description, or may be learned through the practice described herein. The embodiments and advantages described herein will be realized and achieved by means of the elements and combinations specifically pointed out in the appended claims.

[0022] It should be understood that the above-described invention and the following detailed embodiments are merely exemplary and illustrative, and do not limit the scope of the claimed invention. Attached Figure Description

[0023] Figure 1A delivery device suitable for the storage stability system of this disclosure is described. Detailed Implementation

[0024] The headings provided herein are not intended to limit the various aspects described herein, which can be defined by referring to the entire specification. It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting, as the scope of this disclosure will be limited only by the appended claims.

[0025] definition

[0026] For convenience, the meanings of some terms and phrases used in the specification, embodiments, and appended claims are provided below. Unless otherwise stated or implied by the context, the following terms and phrases include the meanings provided below. These definitions are provided to aid in the description of particular embodiments and are not intended to limit the claimed technology, as the scope of the technology is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this technology pertains. If there is a significant difference between the use of terminology in the art and the definitions provided herein, the definitions provided in the specification shall prevail.

[0027] The articles “a,” “a kind,” and “the” are used in this text to refer to one or more (i.e., at least one) grammatical objects. For example, “an element” refers to one element or more elements.

[0028] As used herein, unless otherwise stated, the term “about” means ±10% of a particular value.

[0029] The term "at least" preceding a number or series of numbers is understood to include the number adjacent to the term "at least" as well as all subsequent numbers or integers that may be logically included, as is clear from the context. When "at least" precedes a series of numbers or a range, it should be understood that "at least" may modify each number in that series or range.

[0030] The term "not exceeding" preceding a number or range of numbers is understood to include the number adjacent to the term "not exceeding" as well as all preceding numbers or integers that can be logically included, as is clear from the context. When "not exceeding" precedes a range of numbers or a range, it should be understood that "not exceeding" may modify each number in that range or range.

[0031] As used herein, the terms “comprising,” “having,” “including,” “containing,” etc., are open-ended terms meaning “including but not limited to.” With regard to the fact that a given embodiment disclosed herein “comprising” certain elements, it should be understood that this disclosure also specifically considers and discloses embodiments that are “substantially composed of these elements” and “composed of these elements.”

[0032] The term "treatment" refers to the successful treatment or improvement of any symptom of an injury, disease, or condition, including any objective or subjective parameters such as relief; mitigation; reduction of symptoms or increased tolerance of the injury, disease, or condition; slowing of the rate of degeneration or decline; or improvement of the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including physical examination results, neuropsychiatric examinations, or psychiatric evaluations.

[0033] The term "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refers to the amount of a drug or pharmacologically active agent that is non-toxic but sufficient to provide the desired effect. The "effective" amount will vary from subject to subject, depending on individual age and general condition, one or more specific active agents, etc. Therefore, an exact "effective amount" cannot always be specified. However, the appropriate "effective" amount in any individual case can be determined by a person skilled in the art using routine experiments.

[0034] The term "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable inorganic and organic acids.

[0035] As used herein, the terms “desiccant,” “primary desiccant,” and “secondary desiccant” refer to pharmaceutically acceptable hygroscopic materials used to maintain a dry state. These desiccants are used to eliminate moisture from the air and absorb moisture, thereby creating and maintaining a dry, moisture-free environment. Suitable pharmaceutically acceptable desiccants include, for example, sodium alginate and starch.

[0036] The term “buffer” or “buffering agent” means any pharmaceutically acceptable weak or strong base or mixture thereof that, when formulated or delivered before, during and / or after a proton pump inhibitor (such as omeprazole), functions to substantially prevent or inhibit the degradation of the proton pump inhibitor by gastric acid and to maintain the oral bioavailability of the proton pump inhibitor.

[0037] The term "percentage moisture content" refers to a value measured using the loss on drying (LOD) method, which involves heating a sample (e.g., sodium alginate or omeprazole) at 90°C for 5 minutes and determining the % weight loss.

[0038] As used herein, the term "multiple doses" means that an omeprazole powder system, after being prepared with water, can be administered in multiple doses over a period of time (e.g., more than 7 days, more than 14 days, or more than 28 days).

[0039] As used herein, the term “stable” or “storage stable” refers to chemical stability, wherein when stored at 40°C and 75% relative humidity (RH) for at least 6 months or at 25°C and 60% relative humidity for at least 2 years, no more than 5% w / w of total relevant matter (e.g., omeprazole degradation products) is formed to the extent necessary for the sale and use of the omeprazole powder system described herein.

[0040] As used herein, the phrase "low viscosity grade sodium alginate" refers to sodium alginate with a solution viscosity of less than about 100 millipascal-seconds (mPa·s) in a 3% aqueous solution. Suitable low viscosity grade sodium alginate includes, for example... LB (FMCBiopolymer).

[0041] The term "GERD" refers to gastroesophageal reflux disease. This is a condition in which acid escapes from the stomach into the esophagus (the tube connecting the throat and stomach), causing pain, inflammation, and heartburn. In children, symptoms may include stomach contents refluxing into the mouth (reflux), illness (vomiting), and poor weight gain.

[0042] The term "PICS" refers to In-Situ Protection System. A PICS system is a bottle with an integrated cap, such as... Figure 1 As shown. The mixture containing omeprazole (or any PPI) is in a dry form in the cap until the time of composition. A diluent phase, such as a second mixture as described below, is included in the vial. During composition, the drug-loaded mixture is released from the cap into the diluent phase (or second mixture) by screwing on the cap, followed by the addition of water.

[0043] As used in this article, the term "child" refers to a human being between birth and adolescence.

[0044] The term "puberty" refers to the process of physical change through which a child's body matures into an adult body capable of sexual reproduction. On average, girls begin puberty around 10 to 11 years old and end it around 15 to 17 years old; boys begin puberty around 11 to 12 years old and end it around 16 to 17 years old.

[0045] As used in this article, the term "infant" is a synonym for "baby," referring to a very young human offspring. The term "infant" is generally used to refer to children under one year old.

[0046] As used in this article, the term "toddler" refers to a child aged 12 to 36 months.

[0047] As used in this article, the term "pre-adolescent child" refers to a person aged 10 to 13.

[0048] As used in this article, the term "teenager" refers to people aged 10 to 19.

[0049] The storage stable system described in this article

[0050] Although proton pump inhibitors (PPIs) such as omeprazole are widely used to treat patients with gastric acid-mediated disorders, their chemical instability in acidic media does not allow for the formulation of simple aqueous dosage forms for treatment. This disclosure provides a storage-stable PPI system that, when formulated with water, provides an oral pharmaceutical PPI suspension for administering an effective amount of the PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof) to a subject in need, while having an acceptable level of sodium for administration to pediatric subjects. The oral pharmaceutical suspension of this disclosure has an acceptable buffering capacity for pediatric subjects. In some embodiments, the buffering capacity of the oral pharmaceutical suspension described herein is about 2 mEq / ml oral suspension. This is achieved, for example, by using a balanced buffering system based on sodium bicarbonate and potassium bicarbonate. In some embodiments, the buffering capacity of the oral pharmaceutical suspension described herein is about 0.5 mEq / ml to about 4 mEq / ml oral suspension. In some implementations, the oral drug suspensions described herein have a buffering capacity of about 1.6 mEq / ml to about 2.3 mEq / ml oral suspensions.

[0051] In one aspect, this disclosure provides a storage-stable PPI system (such as a storage-stable omeprazole system) 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 system contains no more than about 2.5% water percentage, and wherein the system is free of 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 wherein the storage-stable PPI system is prepared with water prior to administration. In some embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In some embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In some embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:2 to about 1:5.

[0052] In some implementations, the storage-stable PPI system (such as the storage-stable omeprazole system) is free from 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 borohydride tartrate, disodium tartrate, and sodium succinate).

[0053] In some embodiments, the storage-stable PPI system (such as a storage-stable omeprazole system) comprises a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), wherein the system contains no more than about 2.5% water percentage, and wherein the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable PPI system is prepared with water prior to administration. In some embodiments of this aspect, sodium and potassium are present in a weight ratio of about 1:3.2.

[0054] In some embodiments, the storage-stable PPI system (such as a storage-stable omeprazole system) has a moisture content of about 0.5% to about 1.5%. In some embodiments, the storage-stable PPI system (such as a storage-stable omeprazole system) has a moisture percentage of no more than about 1%.

[0055] Suitable PPIs (proton pump inhibitors) that can be used in the storage-stable PPI systems described herein include, for example, omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, dexlansoprazole, rapeprazole, dontoprazole, tenaprazole, haberprazole, ransoprazole, pariprazole, and lemeprazole, as well as pharmaceutically acceptable salts thereof. In some embodiments, the PPI is selected from the group consisting of omeprazole, esomeprazole, lansoprazole, pantoprazole, dexlansoprazole, rabeprazole, and pharmaceutically acceptable salts thereof. In some embodiments, the PPI is omeprazole or esomeprazole or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of suitable PPIs include, for example, 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.

[0056] In some embodiments, the PPI is omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the PPI is omeprazole (i.e., a neutral form of omeprazole that does not form a salt-forming cation). In some embodiments, the PPI is esomeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the PPI is esomeprazole (i.e., a neutral form of esomeprazole that does not form a salt-forming cation).

[0057] In some embodiments, the storage-stable PPI system also includes a desiccant. Suitable desiccants include any pharmaceutically acceptable desiccant and are used to create and maintain a dry, moisture-free environment for the PPI by eliminating moisture from the air and absorbing moisture. Suitable pharmaceutically acceptable desiccants include, for example, sodium alginate, starch, etc. In some embodiments, the desiccant is sodium alginate. The desiccant may include one pharmaceutically acceptable desiccant or a mixture of two or more pharmaceutically acceptable desiccants.

[0058] 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 comprises dry sodium alginate with a moisture content of about 0.5% to about 1.5%.

[0059] 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. Suitable low-viscosity grade sodium alginate has a solution viscosity of less than about 100 mPa·s in a 3% aqueous solution. Examples of suitable low-viscosity grade sodium alginate include... LB (FMC Biopolymer).

[0060] In some embodiments, the storage-stable PPI system described herein (such as the storage-stable omeprazole system) comprises one or more buffers. In some embodiments, the storage-stable PPI system described herein comprises one, two, three, or four buffers. In some embodiments, the storage-stable PPI system described herein comprises one buffer. In some embodiments, the storage-stable PPI system described herein comprises two or three buffers. In some embodiments, the storage-stable PPI system described herein comprises two buffers.

[0061] The storage-stable PPI systems described herein (such as storage-stable omeprazole systems) may contain any suitable buffer that functions substantially to prevent or inhibit the degradation of PPIs (such as omeprazole or pharmaceutically acceptable salts thereof) by gastric acid, sufficient to maintain the bioavailability of the administered PPI. In some embodiments, one or more buffers are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. In some embodiments, one or more buffers are each independently selected from sodium carbonate and potassium carbonate, sodium bicarbonate and potassium bicarbonate, sodium phosphate and potassium phosphate, sodium citrate and potassium citrate, sodium borate and potassium borate, sodium acetate and potassium acetate, sodium phthalate and potassium phthalate, sodium tartrate and potassium tartrate, and sodium succinate and potassium succinate.

[0062] In some embodiments, the storage-stable PPI system described herein (such as the storage-stable omeprazole system) comprises 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 borohydride tartrate, disodium tartrate, and sodium succinate. In some embodiments, the storage-stable PPI system described herein (such as the storage-stable omeprazole system) comprises at least one buffer 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, potassium hydrogen tartrate, dipotassium tartrate, and potassium succinate.

[0063] In some embodiments, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) contain no more than one buffer 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, potassium hydrogen phthalate, potassium hydrogen tartrate, dipotassium tartrate, and potassium succinate. In some embodiments, one buffer is potassium bicarbonate.

[0064] 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 carbonate and potassium carbonate, sodium bicarbonate and potassium bicarbonate, sodium phosphate and potassium phosphate, sodium citrate and potassium citrate, sodium borate and potassium borate, sodium acetate and potassium acetate, sodium phthalate and potassium phthalate, sodium tartrate and potassium tartrate, and sodium succinate and potassium succinate. 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 ratio of about 1:100 to about 100:1 by weight. In some embodiments, sodium bicarbonate and potassium bicarbonate are present in the system in a ratio of about 1:50 to about 50:1 by weight. In some embodiments, sodium bicarbonate and potassium bicarbonate are present in the system in a ratio of about 1:10 to about 10:1 by weight. In some embodiments, sodium bicarbonate and potassium bicarbonate are present in the system in a ratio of about 1:2 to about 1:5 by weight. In some embodiments, sodium bicarbonate and potassium bicarbonate are present in the system in a ratio of about 1:2.5 to about 1:3.4 by weight. In some embodiments, sodium bicarbonate and potassium bicarbonate are present in a ratio of about 1:2.7 by weight.

[0065] One or more buffers are present in the storage-stable PPI system (such as the storage-stable omeprazole system) described herein in an amount sufficient to increase the pH of the gastric juice to a level that prevents at least some PPIs (such as omeprazole or a pharmaceutically acceptable salt thereof) from being degraded in the gastric juice.

[0066] In some embodiments, one or more buffers provide a buffering capacity of about 0.5 mEq / ml to about 4 mEq / ml for the water-based, storage-stable PPI system described herein. In some embodiments, one or more buffers provide a buffering capacity of about 1.6 mEq / ml to about 2.3 mEq / ml for the water-based, storage-stable PPI system described herein. In some embodiments, one or more buffers provide a buffering capacity of about 2 mEq / ml for the water-based, storage-stable PPI system described herein.

[0067] In some embodiments, one or more buffers provide a buffering capacity of about 0.5 mEq / ml to about 4 mEq / ml for the storage-stable omeprazole system described herein, which is composed of water. In some embodiments, one or more buffers provide a buffering capacity of about 1.6 mEq / ml to about 2.3 mEq / ml for the storage-stable omeprazole system described herein, which is composed of water. In some embodiments, one or more buffers provide a buffering capacity of about 2 mEq / ml for the storage-stable omeprazole system described herein, which is composed of water.

[0068] The storage-stable PPI systems described herein (such as storage-stable omeprazole systems) 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, crystals, beads, spheres, microspheres, or mixtures thereof. In some embodiments, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) are in the form of powders or pellets. Suitable powders, pellets, granules, crystals, beads, spheres, microspheres, or mixtures thereof can be prepared using conventional pharmacological techniques known in the art.

[0069] In some aspects, the storage-stable PPI system described herein (such as a storage-stable omeprazole system) comprises (i) a first mixture containing (a) 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 percentage; and (ii) a second mixture containing a second buffer, wherein the second mixture contains no more than about 2.5% water percentage; wherein the first and second mixtures are stored separately from each other and are mixed together when or immediately before being prepared with water, and wherein the system is free of sodium from a sodium-containing buffer, or contains sodium and potassium in a weight ratio of about 1:100 to about 100:1. In some embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In some embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In some embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:2 to about 1:5.

[0070] In some embodiments, the storage-stable PPI system described herein (such as a storage-stable omeprazole system) comprises (i) a first mixture containing (a) 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 percentage; and (ii) a second mixture containing a second buffer, wherein the second mixture contains no more than about 2.5% water percentage; wherein the first and second mixtures are stored separately from each other and are mixed together when or immediately before being prepared with water, and wherein 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.

[0071] In some implementations, the storage-stable PPI system (such as the storage-stable omeprazole system) does not contain sodium from the sodium-containing buffer.

[0072] In some embodiments, the first mixture further comprises (b) a first desiccant, and / or the second mixture further comprises a second desiccant.

[0073] In some embodiments, the storage-stable PPI system described herein (such as a storage-stable omeprazole system) comprises (i) a first mixture containing (a) 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 percentage; and (ii) a second mixture containing a second desiccant and a second buffer, wherein the first and second mixtures are stored separately from each other and are mixed together when or immediately before being prepared with water, and wherein 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.

[0074] In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.5% to about 1.5%. In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.6% to about 1.1%. In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.5% to about 0.9%. In some embodiments, the first mixture has a moisture content of about 0.5% to about 1.5%, and the second mixture has a moisture content of no more than about 1.5%. In some embodiments, the second mixture has a moisture content of no more than about 0.5%.

[0075] In some embodiments, the first mixture further comprises (b) a first desiccant.

[0076] In some implementations, the first mixture further comprises (c) a first buffer.

[0077] 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 percentage; and (ii) a second mixture comprising a second desiccant and a second buffer, wherein the first and second mixtures are stored separately from each other and are mixed together when or immediately before being prepared with water, and wherein 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. In some embodiments, the first and second mixtures 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 moisture content of about 0.6% to about 1.1%. In some embodiments, the first mixture and the second mixture each independently have a moisture content of about 0.5% to about 0.9%. In some embodiments, the first mixture has a moisture content of about 0.5% to about 1.5%, and the second mixture has a moisture content of no more than about 1.5%. In some embodiments, the second mixture has a moisture content of no more than about 0.5%.

[0078] The first and second desiccants may comprise any pharmaceutically acceptable desiccant 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 and second desiccants are the same. 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 dried, i.e., it contains less than about 2% moisture. In some embodiments, the dried sodium alginate has a moisture content of about 0.5% to about 1.5%.

[0079] In some embodiments, the first mixture and the second mixture may be independently in the form of powder, pellets, granules, crystals, beads, spheres, microspheres, or mixtures thereof. In some embodiments, the first mixture and the second mixture are each independently in the form of powder or pellets. In other embodiments, both the first mixture and the second mixture may be in the form of powder.

[0080] In some implementations, the PPIs or pharmaceutically acceptable salts thereof (such as omeprazole or pharmaceutically acceptable salts thereof) present in the storage-stable systems described herein are micronized.

[0081] In some embodiments, the PPIs or pharmaceutically acceptable salts present in the storage-stable systems described herein are mixtures of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof. In some embodiments of this aspect, the PPIs or pharmaceutically acceptable salts thereof comprise from about 30% to about 70% by weight of micronized PPIs or pharmaceutically acceptable salts, with the remainder being non-micronized. In some embodiments, the PPIs or pharmaceutically acceptable salts thereof are a 1:1 mixture by weight of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof. In some embodiments, the PPIs or pharmaceutically acceptable salts thereof are mixtures of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof. In some embodiments, the PPIs or pharmaceutically acceptable salts thereof are a mixture of about 1:2.3 by weight of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof (i.e., about 30:70 mixture). In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized PPIs or a pharmaceutically acceptable salt thereof 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 a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized PPIs or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:1.5 (i.e., about 40:60 mixture).

[0082] In some embodiments, the omeprazole or a pharmaceutically acceptable salt thereof present in the storage-stable omeprazole system described herein is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, the omeprazole or a pharmaceutically acceptable salt thereof comprises about 30% to about 70% by weight of micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder is non-micronized. In some embodiments, the 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, the omeprazole or a pharmaceutically acceptable salt thereof is a mixture by weight of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 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 of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:2.3 (i.e., about 30:70 mixture). In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof 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 non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:1.5 (i.e., about 40:60 mixture).

[0083] In some implementations, the first and second buffers are present in amounts sufficient to increase the gastric pH to a level that prevents the degradation of at least some pharmaceutically acceptable salts of the PPI or omeprazole in the gastric juice.

[0084] In some embodiments, the first and second buffers provide a buffering capacity of about 0.5 mEq / ml to about 4 mEq / ml for the water-based, storage-stable PPI system described herein. In some embodiments, the first and second buffers provide a buffering capacity of about 1.6 mEq / ml to about 2.3 mEq / ml for the water-based, storage-stable PPI system described herein. In some embodiments, the first and second buffers provide a buffering capacity of about 2 mEq / ml for the water-based, storage-stable PPI system described herein. In some embodiments, the first and second buffers provide a buffering capacity of about 2.1 mEq / ml for the water-based, storage-stable PPI system described herein.

[0085] In some embodiments, the first and second buffers provide a buffering capacity of about 0.5 mEq / ml to about 4 mEq / ml for the storage-stable omeprazole system described herein, which is composed of water. In some embodiments, the first and second buffers provide a buffering capacity of about 1.6 mEq / ml to about 2.3 mEq / ml for the storage-stable omeprazole system described herein, which is composed of water. In some embodiments, the first and second buffers provide a buffering capacity of about 2 mEq / ml for the storage-stable omeprazole system described herein, which is composed of water. In some embodiments, the first and second buffers provide a buffering capacity of about 2.1 mEq / ml for the storage-stable omeprazole system described herein, which is composed of water.

[0086] 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 each independently comprise one, two, three, or four buffers. In some embodiments, the first buffer and the second buffer each independently comprise one, two, or three buffers. In some embodiments, the first buffer and the second buffer each independently comprise one or two buffers.

[0087] 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 carbonate or potassium carbonate, sodium bicarbonate or potassium bicarbonate, sodium phosphate or potassium phosphate, sodium citrate or potassium citrate, sodium borate or potassium borate, sodium acetate or potassium acetate, sodium phthalate or potassium phthalate, sodium tartrate or potassium tartrate, sodium succinate or potassium succinate, and mixtures thereof.

[0088] 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 borohydride tartrate, disodium tartrate, sodium succinate, and mixtures thereof.

[0089] In some embodiments, the second buffer is selected from sodium carbonate and potassium carbonate, sodium bicarbonate and potassium bicarbonate, sodium phosphate and potassium phosphate, sodium citrate and potassium citrate, sodium borate and potassium borate, sodium acetate and potassium acetate, sodium phthalate and potassium phthalate, sodium tartrate and potassium tartrate, sodium succinate and potassium succinate, and mixtures thereof.

[0090] 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 comprises about 11% sodium bicarbonate and about 89% potassium bicarbonate by weight.

[0091] In some embodiments, the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:100 to about 100:1. In some embodiments, the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.5 to about 1:3.4. In some embodiments, sodium bicarbonate and potassium bicarbonate are present in a weight ratio of about 1:2.7.

[0092] 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 dihydrogen citrate, dipotassium hydrogen citrate, tripotassium citrate, potassium tetraborate, potassium acetate, dipotassium hydrogen phthalate, potassium hydrogen phthalate, potassium hydrogen phthalate, potassium hydrogen tartrate, dipotassium tartrate, potassium succinate, and mixtures thereof. In some embodiments, the first buffer and the second buffer are potassium bicarbonate.

[0093] The storage-stable PPI systems described herein (such as storage-stable omeprazole systems) may also contain one or more pharmaceutically acceptable excipients, including but not limited to sweeteners, flavoring agents, preservatives, thickeners, suspending agents, opacifiers, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, diluents, and defoamers.

[0094] Suitable sweeteners include, for example, mannitol, sucrose, fructose, dextrose, isomaltitol, maltitol, sorbitol, sucralose, acesulfame K, aspartame, cyclosulfonates, saccharin, stevia, sucralose, sodium saccharin, xylitol, or combinations thereof. In some embodiments described herein, the sweetener is mannitol, sucralose, or maltitol, or mixtures thereof.

[0095] Suitable flavorings include, for example, the following flavorings or mixtures thereof: mint, vanilla, banana, apple, orange, pear, peach, strawberry, raspberry, chocolate, lemon, lime, caramel, caramel, cherry, and cinnamon. In some embodiments described herein, the flavoring is a mint flavoring, a vanilla flavoring, or a mixture thereof.

[0096] Suitable preservatives include those suitable for pharmaceutical preparations, 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.

[0097] Suitable 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 thickeners include, for instance, sodium alginate, xanthan gum, guar gum, and sophora bean gum. In some embodiments, the thickener is sodium alginate, xanthan gum, or a mixture thereof.

[0098] Suitable opacifiers include pharmaceutically acceptable substances that are added to the material to make the subsequent system opaque, such as titanium dioxide (TiO2).

[0099] In some implementations, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) also include sweeteners, flavoring agents, preservatives, or mixtures thereof.

[0100] In some implementations, the second mixture in the storage-stable PPI system described herein (such as the storage-stable omeprazole system) also includes sweeteners and preservatives.

[0101] In some embodiments, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) are provided in a drug delivery device suitable for multiple doses of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof). In some embodiments, the delivery device is as described in U.S. Patent Nos. 9,051,100, 10,238,803, or U.S. Patent Application Publication No. 2014 / 0311929, the contents of which are incorporated herein by reference in their entirety.

[0102] In some implementations, the delivery device is a PICS system. In some aspects, a PICS system is such as... Figure 1 As shown.

[0103] In some embodiments, the drug delivery device includes two chambers. In some embodiments, the two chambers of the drug delivery device may 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 that can contain multi-particulate material and is mounted in an opening in the container body.

[0104] In some embodiments, the drug delivery device also includes means for releasing the contents of the first chamber into the second chamber without removing the cap from the drug delivery device.

[0105] 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, wherein (i) the container body contains a second mixture and has a container opening formed in its upper end; (ii) the cap includes a cap portion at the upper end of a cylindrical receiving portion containing a first mixture and a sealing receiving portion; and wherein (iii) the cap is installed in the container opening of the container body, wherein the first mixture is released into the container body when the cap is screwed on. In some embodiments, the container body is an amber-colored polyethylene terephthalate bottle, and the cap is a tamper-evident polypropylene cap.

[0106] In some embodiments, the storage-stable PPI system described herein (such as a storage-stable omeprazole system) is formulated in a drug delivery device suitable for multiple-dose administration of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), wherein the system contains a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof), and wherein the system contains no more than about 2.5% water percentage, and wherein the system is free of 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 further wherein the storage-stable omeprazole system is prepared with water prior to administration. In some embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In some embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In some embodiments, the storage-stable PPI system contains sodium and potassium in a weight ratio of about 1:2 to about 1:5. In some 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 a storage-stable omeprazole system) does not contain sodium from a sodium-containing buffer.

[0107] In some implementations, the storage-stable PPI systems described herein (such as storage-stable omeprazole systems) remain stable for at least 2 years at 25°C / 60% relative humidity.

[0108] In some embodiments, this 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 when or just before being prepared with water, and wherein the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0109] 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 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% micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder of omeprazole or a pharmaceutically acceptable salt thereof is non-micronized. In some embodiments, omeprazole is a 1:1 mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof by weight. In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:2.3 (i.e., about 30:70 mixture). In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof 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 non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:1.5 (i.e., about 40:60 mixture).

[0110] 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 a first buffer, drying the granules, and grinding the dried granules. In some embodiments, the first powder mixture further comprises dried sodium alginate. Suitable methods for preparing the first powder mixture are described, for example, in U.S. Patent No. 8,093,271, the contents of which are incorporated herein by reference in their entirety.

[0111] In some embodiments, about 20% to about 30% of the sodium alginate present in the first powder mixture is uniformly distributed on the surface of the first buffer. In some embodiments, about 20% to about 25% of the sodium alginate present in the first powder mixture is uniformly distributed on the surface of the first buffer. In some embodiments, the sodium alginate in the first powder mixture not distributed on the surface of the first buffer is dry, i.e., it contains less than about 2% moisture. In some embodiments, the sodium alginate present in the second powder mixture is dry.

[0112] In some embodiments, the dried sodium alginate has a moisture content of about 0.5% to about 1.5%. In some embodiments, the sodium alginate is the low-viscosity grade sodium alginate as defined above.

[0113] The first and second buffers are present in amounts sufficient to increase the pH of the gastric juice to a level that prevents at least some of omeprazole or its pharmaceutically acceptable salts from degrading in the gastric juice. In some aspects, the first and second buffers provide a buffering capacity of about 0.5 mEq / ml to about 4 mEq / ml for the storage-stable omeprazole powder system described herein, composed of water. In some aspects, the first and second buffers provide a buffering capacity of about 1.6 mEq / ml to about 2.3 mEq / ml for the storage-stable omeprazole powder system described herein, composed of water. In some embodiments, the first and second buffers provide a buffering capacity of about 2 mEq / ml for the storage-stable omeprazole powder system described herein, composed of water.

[0114] 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.

[0115] In some implementations, the first buffer in a stable omeprazole powder system is sodium bicarbonate.

[0116] In some implementations, the second buffer in a stable omeprazole powder system is a mixture of sodium bicarbonate and potassium bicarbonate.

[0117] In some embodiments, the first buffer in a 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% sodium bicarbonate and about 89% potassium bicarbonate by weight.

[0118] In some embodiments, the first powder mixture and the second powder mixture in the storage-stable omeprazole powder system 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.

[0119] In some implementations, the first buffer in a stable omeprazole powder system is potassium bicarbonate, and the second buffer is potassium bicarbonate.

[0120] In some embodiments, the second powder mixture of the storage-stable omeprazole powder system also contains sweeteners and preservatives. Suitable sweeteners and preservatives are described above.

[0121] In some implementations, a stable omeprazole powder system is provided in a drug delivery device suitable for multiple doses of omeprazole.

[0122] In some embodiments of this aspect, the drug delivery device includes a first chamber and a second chamber, the first chamber containing a first powder mixture and the second chamber containing a second powder mixture. In some embodiments, the first and second chambers may be integral. 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 installed in an opening of the container body.

[0123] The drug delivery device may also include means for releasing the first powder mixture into the second chamber without removing the cap from the drug delivery device.

[0124] In some embodiments, the storage of a stable omeprazole powder system is provided in a delivery device, which is a container body including 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 includes a cylindrical receiving portion containing a first powder mixture and a cap portion at the upper end of a sealing receiving portion, wherein (iii) the cap is installed in the container opening of the container body, wherein when the cap is screwed on, the first powder mixture is released into the container body. In some embodiments, the container body is an amber-colored polyethylene terephthalate bottle, and the cap is a tamper-evident polypropylene cap.

[0125] In some embodiments, the storage-stable omeprazole powder system of this 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.

[0126] In some embodiments, the storage-stable PPI system described herein (such as a storage-stable omeprazole system) is encapsulated in a sealed aluminum foil bag to minimize moisture ingress during storage before the system is formed. In some embodiments, the aluminum foil bag 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 system described herein (such as a storage-stable omeprazole system). In some embodiments, the aluminum foil bag has a polymer coating on the inside. The aluminum foil bag can be sealed using a Hawo heat sealer (temperature setting 150°C, holding time 1 to 2 seconds).

[0127] Oral drug suspension

[0128] This disclosure also provides an oral medication suspension for delivering a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof to subjects in need, particularly pediatric subjects. The oral medication suspension described herein contains an acceptable level of sodium for the treatment of pediatric subjects. The oral medication suspension is particularly suitable for multi-dose formulations and is capable of delivering a uniform dose of a PPI or a pharmaceutically acceptable salt thereof.

[0129] In one aspect, this disclosure provides an oral drug suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof) dispersed in the water, and one or more buffers. In some embodiments, the oral drug suspension contains sodium and potassium in a weight ratio of about 1:100 to about 100:1. In some embodiments, the oral drug suspension contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In some embodiments, the oral drug suspension contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In some embodiments, the oral drug suspension contains sodium and potassium in a weight ratio of about 1:2 to about 1:5. In some embodiments, the oral drug suspension 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 the oral drug suspension in a weight ratio of about 1:3.2.

[0130] In some embodiments, the oral drug 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 borohydride tartrate, disodium tartrate, and sodium succinate.

[0131] In some embodiments, the oral drug suspensions described herein also contain a stabilizer or a thickener, or both. Suitable thickeners and stabilizers include gelling agents that stabilize liquid dosage forms (such as suspensions). In some embodiments, the thickener or stabilizer is sodium alginate. In some embodiments, the sodium alginate present is the low-viscosity grade sodium alginate described above.

[0132] In some embodiments, about 1 ml of the oral drug suspension contains about 1 mg to about 10 mg of a PPI or a pharmaceutically acceptable salt thereof. In some embodiments, about 1 ml of the oral drug suspension contains about 1 mg to about 10 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, about 1 ml of the oral medication suspension contains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of a PPI or a pharmaceutically acceptable salt thereof. In some embodiments, about 1 ml of the oral medication suspension contains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, about 1 ml of the oral medication suspension contains about 2 mg or about 4 mg of a PPI or a pharmaceutically acceptable salt thereof. In some embodiments, about 1 ml of the oral medication suspension contains about 2 mg or about 4 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the oral drug suspension described herein comprises one, two, three, or four buffers. In some embodiments, the oral drug suspension described herein comprises one buffer. In some embodiments, the oral drug suspension described herein comprises two or three buffers. In some embodiments, the oral drug suspension described herein comprises two buffers.

[0136] The oral medication suspensions described herein (such as suspensions containing omeprazole or pharmaceutically acceptable salts thereof) may contain any suitable buffer that functions substantially to prevent or inhibit the degradation of the PPI or its pharmaceutically acceptable salts (such as omeprazole or pharmaceutically acceptable salts thereof) by gastric acid, sufficient to maintain the bioavailability of the administered PPI. In some embodiments, one or more buffers are each independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates. In some embodiments, one or more buffers are each independently selected from sodium carbonate and potassium carbonate, sodium bicarbonate and potassium bicarbonate, sodium phosphate and potassium phosphate, sodium citrate and potassium citrate, sodium borate and potassium borate, sodium acetate and potassium acetate, sodium phthalate and potassium phthalate, sodium tartrate and potassium tartrate, and sodium succinate and potassium succinate.

[0137] In some embodiments, the oral medication suspensions described herein (such as suspensions containing omeprazole or its salts) comprise 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 borohydride tartrate, disodium tartrate, and sodium succinate. In some embodiments, the oral medication suspensions described herein comprise at least one buffer 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, potassium hydrogen tartrate, dipotassium tartrate, and potassium succinate.

[0138] In some embodiments, the oral medication suspensions described herein (such as suspensions containing omeprazole or a pharmaceutically acceptable salt thereof) contain no more than one buffer 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, potassium hydrogen phthalate, potassium hydrogen tartrate, dipotassium tartrate, and potassium succinate. In some embodiments, one buffer is potassium bicarbonate.

[0139] In some embodiments, the oral medication suspensions described herein (such as suspensions containing omeprazole or a pharmaceutically acceptable salt thereof) comprise two or more buffers selected from sodium carbonate and potassium carbonate, sodium bicarbonate and potassium bicarbonate, sodium phosphate and potassium phosphate, sodium citrate and potassium citrate, sodium borate and potassium borate, sodium acetate and potassium acetate, sodium phthalate and potassium phthalate, sodium tartrate and potassium tartrate, and sodium succinate and potassium succinate. In some embodiments, the oral medication suspensions described herein comprise two buffers. In some embodiments, the oral medication suspensions described herein comprise both sodium bicarbonate and potassium bicarbonate.

[0140] In some embodiments, sodium bicarbonate and potassium bicarbonate are present in the oral drug suspension at a ratio of about 1:2.5 to about 1:3.4 per 1 ml of suspension by weight. In some embodiments, sodium bicarbonate and potassium bicarbonate are present at a ratio of about 1:2.7 per 1 ml of suspension by weight.

[0141] In some embodiments, the oral medication suspension described herein contains sodium and potassium in a weight ratio of about 1:100 to about 100:1. In some embodiments, the oral medication suspension described herein contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In some embodiments, the oral medication suspension described herein contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In some embodiments, the oral medication suspension described herein contains sodium and potassium in a weight ratio of about 1:2 to about 1:5.

[0142] In some embodiments, the oral medication suspension described herein 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 the oral medication suspension in a weight ratio of about 1:3.2.

[0143] One or more buffers are present in the oral drug suspension described herein in an amount sufficient to increase the pH of gastric juice to a level that prevents at least some PPIs (such as omeprazole or a pharmaceutically acceptable salt thereof) from being degraded in gastric juice.

[0144] In some embodiments, one or more buffers present in the oral drug suspension provide the suspension with a buffering capacity of about 0.5 mEq / ml to about 4 mEq / ml. In some embodiments, one or more buffers present in the oral drug suspension provide the suspension with a buffering capacity of about 1.6 mEq / ml to about 2.3 mEq / ml. In some embodiments, one or more buffers present in the oral drug suspension provide the suspension with a buffering capacity of about 2 mEq / ml.

[0145] In some embodiments, the oral medication suspension described herein contains low levels of sodium, making the suspension suitable for administration to pediatric subjects. In some aspects, the oral medication suspension described herein contains about 50 mg to about 150 mg of sodium per 5 ml of suspension. In some embodiments, about 70 mg to about 100 mg of sodium is present in 5 ml of suspension. In some embodiments, the oral medication suspension described herein contains about 86 mg of sodium per 5 ml of suspension. This 5 ml dose corresponds to 4.3% of the maximum daily dietary sodium intake recommended by the WHO for adults.

[0146] In some embodiments, the PPIs or pharmaceutically acceptable salts thereof present in the oral drug suspensions described herein (such as omeprazole or pharmaceutically acceptable salts thereof) are micronized.

[0147] In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is present in the oral drug suspension described herein as a mixture of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof. In some embodiments of this aspect, the PPI or a pharmaceutically acceptable salt thereof comprises about 30% to about 70% by weight of a micronized PPI or a pharmaceutically acceptable salt thereof, and the remainder is 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 PPIs or pharmaceutically acceptable salts thereof. In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof. In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is a mixture of about 1:2.3 by weight of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof (i.e., about 30:70 mixture). In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized PPIs or a pharmaceutically acceptable salt thereof 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 a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized PPIs or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:1.5 (i.e., about 40:60 mixture).

[0148] In some embodiments, the omeprazole or a pharmaceutically acceptable salt thereof present in the oral drug suspension described herein 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 thereof, and the remainder is 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 about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 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 of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:2.3 (i.e., about 30:70 mixture). In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof 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 non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:1.5 (i.e., about 40:60 mixture).

[0149] In some embodiments, the oral drug suspension provides, upon oral administration to subjects in need, the presence of first and second C... max and the first and second T max The biphasic pharmacokinetic curves.

[0150] In some embodiments, a 5 ml dose of the oral drug 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 dose of the oral drug suspension also contains about 10 mg to about 15 mg of sodium methylparaben and about 15 mg to about 30 mg of sodium benzoate.

[0151] In some embodiments, a 5 ml dose of the oral drug 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.

[0152] In some implementations, the 5 ml dose of the oral drug suspension also contains approximately 11.45 mg of sodium methylparaben and approximately 25 mg of sodium benzoate.

[0153] The oral drug suspensions described herein (such as suspensions containing omeprazole or its pharmaceutically acceptable salts) may also contain one or more pharmaceutically acceptable excipients, including but not limited to sweeteners, flavoring agents, preservatives, thickeners, suspending agents, light-blocking agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, diluents, and defoamers.

[0154] Suitable sweeteners include, for example, mannitol, sucrose, fructose, dextrose, isomaltitol, maltitol, sorbitol, sucralose, acesulfame K, aspartame, cyclosulfonates, saccharin, stevia, sucralose, sodium saccharin, xylitol, or combinations thereof. In some aspects described herein, the sweetener is mannitol, sucralose, or maltitol, or mixtures thereof.

[0155] Suitable flavorings include, for example, the following flavorings or mixtures thereof: mint, vanilla, banana, apple, orange, pear, peach, strawberry, raspberry, chocolate, lemon, lime, caramel, caramel, cherry, and cinnamon. In some aspects described herein, the flavoring is a mint flavoring, a vanilla flavoring, or a mixture thereof.

[0156] Suitable preservatives include those suitable for pharmaceutical preparations, including antimicrobial preservatives. Suitable antimicrobial preservatives include, for example, sodium benzoate, potassium benzoate, calcium benzoate, sodium methylparaben, sodium ethylparaben, and mixtures thereof. In some aspects 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.

[0157] Suitable 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 thickeners include, for instance, sodium alginate, xanthan gum, guar gum, and sophora bean gum. In some embodiments, the thickener is sodium alginate, xanthan gum, or a mixture thereof.

[0158] Suitable opacifiers include pharmaceutically acceptable substances that are added to the material to make the subsequent system opaque, such as titanium dioxide (TiO2).

[0159] In some embodiments, the oral drug suspensions described herein also contain sweeteners, flavoring agents, preservatives, or mixtures thereof.

[0160] The oral medication suspensions described herein remain stable for at least one month after being prepared with water. The suspensions should generally be stored in a refrigerator (2°C to 8°C). For a maximum of two days, the suspensions can be stored below 25°C.

[0161] In some embodiments, after storage at 40°C and 75% relative humidity (RH) for 3 months prior to water formulation, the total amount of impurities (i.e., degradation products of PPIs such as omeprazole) formed in the oral drug suspension described herein on the day of water formulation (i.e., day 0) does not exceed 0.16% w / w. In some embodiments, the total amount of impurities formed in the oral drug suspension on day 0 does not exceed 0.11% w / w.

[0162] In some embodiments, the total amount of impurities formed in the oral drug suspension described herein after 3 months of storage at 40°C and 75% RH prior to water formation, and after 28 days of storage at 2°C to 8°C after water formation (i.e., on day 28), does not exceed 0.28% w / w. In some embodiments, the total amount of impurities formed in the oral drug suspension on day 28 at 2°C to 8°C does not exceed 0.23% w / w.

[0163] In some embodiments, the total amount of impurities formed in the oral drug suspension described herein after 3 months of storage at 40°C and 75% RH prior to water formation, and after 56 days of storage at 2°C to 8°C after water formation (i.e., on day 56), does not exceed 0.38% w / w. In some embodiments, the total amount of impurities formed in the oral drug suspension on day 56 at 2°C to 8°C does not exceed 0.33% w / w.

[0164] In some embodiments, sodium paraben is used as a preservative in the storage-stable PPI systems (such as the storage-stable omeprazole system) and oral drug suspensions described herein. In some embodiments, after being stored at 40°C and 75% RH for 3 months prior to water formulation, the amount of sodium paraben present in the oral drug suspension described herein on the day of water formulation (i.e., day 0) is at least 94.5% w / w of the total amount initially present in the storage-stable PPI system (such as the storage-stable omeprazole system). In some embodiments, the amount of sodium paraben present in the oral drug 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 the storage-stable omeprazole system).

[0165] In some embodiments, after being stored at 40°C and 75% RH for 3 months prior to water formulation, and after being stored at 2°C to 8°C for 28 days after water formulation (i.e., on day 28), the amount of sodium p-hydroxybenzoate present in the oral drug suspension described herein is at least 92% w / w of the total amount initially present in the storage-stable PPI system described herein (such as the storage-stable omeprazole system). In some embodiments, on day 28, the amount of sodium p-hydroxybenzoate present in the oral drug suspension is at least 94% w / w of the total amount initially present in the storage-stable PPI system described herein (such as the storage-stable omeprazole system).

[0166] In some embodiments, after being stored at 40°C and 75% RH for 3 months prior to water formulation, and after being stored at 2°C to 8°C for 56 days after water formulation (i.e., on day 56), the amount of sodium p-hydroxybenzoate present in the oral drug suspension described herein is at least 84% w / w of the total amount initially present in the storage-stable PPI system described herein (such as the storage-stable omeprazole system). In some embodiments, the amount of sodium p-hydroxybenzoate present in the oral drug suspension on day 56 is at least 86.1% w / w of the total amount initially present in the storage-stable PPI system described herein (such as the storage-stable omeprazole system).

[0167] In some embodiments, the oral drug suspensions described herein are provided in a drug delivery device suitable for multiple-dose administration of PPIs or pharmaceutically acceptable salts thereof (such as omeprazole or pharmaceutically acceptable salts thereof). Suitable drug delivery devices include, for example, those described above in conjunction with the storage-stable systems described herein.

[0168] Treatment

[0169] Omeprazole and other benzimidazole proton pump inhibitors are well-known active substances used to treat acid-related disorders.

[0170] In one aspect, this disclosure provides a method for inhibiting gastric acid secretion in a subject. The method includes administering an effective amount of the oral pharmaceutical suspension of this disclosure to a subject in need.

[0171] In some aspects, this disclosure provides a method for inhibiting gastric acid secretion, the method comprising administering to a subject in need an effective amount of an oral drug suspension, wherein the oral drug suspension comprises water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffers, and wherein the suspension is free of sodium from a sodium-containing buffer, or contains sodium and potassium in a weight ratio of about 1:100 to about 100:1.

[0172] In some embodiments, this disclosure provides a method for inhibiting gastric acid secretion, the method comprising administering an effective amount of an oral drug suspension to a subject in need, wherein the oral drug suspension comprises water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffers, and wherein the suspension is free of sodium from a sodium-containing buffer, or contains sodium and potassium in a weight ratio of about 1:100 to about 100:1.

[0173] In some embodiments, the oral medication suspension contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In some embodiments, the oral medication suspension contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In some embodiments, the oral medication suspension contains sodium and potassium in a weight ratio of about 1:2 to about 1:5.

[0174] In some embodiments, this disclosure provides a method for inhibiting gastric acid secretion, the method comprising administering an effective amount of an oral drug suspension to a subject in need, wherein the oral drug suspension comprises water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof dispersed in water, and one or more buffers, and wherein the suspension 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.

[0175] In some embodiments, this disclosure provides a method for inhibiting gastric acid secretion, the method comprising administering an effective amount of an oral drug suspension to a subject in need, wherein the oral drug suspension comprises water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffers, and wherein the suspension 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.

[0176] In some embodiments, the oral drug 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 borohydride tartrate, disodium tartrate, and sodium succinate.

[0177] In some implementations, the subjects are children. In some implementations, the children are infants, toddlers, pre-pubescent children, or adolescents.

[0178] In some embodiments, the method includes administering the oral drug suspension described herein to a subject, wherein 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).

[0179] The oral medication suspensions described herein, particularly those containing omeprazole or its pharmaceutically acceptable salts, may be used to treat conditions such as duodenal ulcers, gastric ulcers, NSAID-associated gastric and duodenal ulcers, reflux esophagitis, and symptomatic gastroesophageal reflux disease (GERD).

[0180] In one aspect, this disclosure also provides a method for inhibiting gastric acid secretion, the method comprising administering to a subject in need an effective amount of an oral drug suspension, the oral drug suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof) dispersed in water, and one or more buffers, wherein the suspension is free of 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 wherein the oral drug suspension is prepared by the following steps: mixing a first mixture with a second... A mixture of two components is combined to obtain a combined mixture, wherein the first mixture comprises (a) 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 percentage; the second mixture comprises a second buffer, wherein the second mixture contains no more than about 2.5% water percentage, wherein the combined mixture does not contain sodium from a sodium-containing buffer, or the combined mixture contains sodium and potassium in a weight ratio of about 1:100 to about 100:1; and water is added to the combined mixture. In some embodiments, the oral drug suspension contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In some embodiments, the oral drug suspension contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In some embodiments, the oral drug suspension contains sodium and potassium in a weight ratio of about 1:2 to about 1:5. In some embodiments, the oral drug 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 also contains a second desiccant.

[0181] In some embodiments, a method for inhibiting gastric acid secretion includes administering to a subject in need an effective amount of an oral drug suspension comprising water, a pharmaceutically effective amount of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof) dispersed in 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 wherein the oral drug suspension is prepared by the following steps: combining a first mixture with a second mixture to obtain a combined mixture, the 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), wherein the first mixture contains a water percentage of no more than about 2.5%; the 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 adding water to the combined mixture.

[0182] Dosage and administration

[0183] In some respects, an effective amount of the oral medication suspension described herein is administered on an empty stomach, preferably at least 30 minutes before a meal. A glass of water may be taken after the dose. The oral medication suspension described herein can also be administered to the subject via a nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tube.

[0184] In some implementations, oral drug suspensions containing about 2 mg / ml of PPI or a pharmaceutically acceptable salt (such as omeprazole or a pharmaceutically acceptable salt) are suitable for administration of doses less than about 15 mg.

[0185] In some implementations, oral drug suspensions containing about 4 mg / ml of PPI or a pharmaceutically acceptable salt (such as omeprazole or a pharmaceutically acceptable salt) are suitable for administration at doses of about 20 mg or about 40 mg.

[0186] The appropriate adult dose is about 10 mg to about 40 mg once daily. In some cases, the adult dose is about 10 mg, about 20 mg, about 30 mg, or about 40 mg once daily.

[0187] Children's dosages are usually based on their weight.

[0188] In some implementations, an appropriate dose of omeprazole or its salts is administered to children aged 1 month to 1 year as an oral suspension, approximately 1 mg / kg, once daily.

[0189] In some implementations, an appropriate dose of omeprazole or a salt thereof is approximately 10 mg once daily, administered as an oral suspension to children aged 1 year and older weighing approximately 10 to 20 kg. In some implementations, this dose may be increased to 20 mg once daily.

[0190] In some embodiments, an appropriate dose of omeprazole or a salt thereof is approximately 20 mg once daily, administered as an oral suspension to children aged 2 years and older weighing more than approximately 20 kg. In some embodiments, this dose may be increased to 40 mg once daily.

[0191] In some embodiments, the oral drug suspension of this disclosure may be used in combination with another agent indicated for the treatment or prevention of gastrointestinal disorders (such as an antibacterial agent, prokinetic agent, H2 antagonist, and antacid or sucralfate), typically administered to minimize pain and / or complications associated with gastrointestinal disorders.

[0192] Methods for preparing oral drug suspensions

[0193] In one aspect, this disclosure provides a method for preparing the oral pharmaceutical suspension described herein. The method comprises combining: (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), the first mixture containing no more than about 2.5% water percentage; and a second mixture comprising a second buffer, wherein the second mixture contains no more than about 2.5% water percentage; obtaining a combined mixture wherein the combined mixture is free of sodium from a sodium-containing buffer, or the combined mixture contains sodium and potassium in a weight ratio of about 1:100 to about 100:1; and adding water to the combined mixture. In some embodiments, the combined mixture contains sodium and potassium in a weight ratio of about 1:50 to about 50:1. In some embodiments, the combined mixture contains sodium and potassium in a weight ratio of about 1:10 to about 10:1. In some embodiments, the combined mixture contains sodium and potassium in a weight ratio of about 1:2 to about 1:5. In some 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 moisture content of about 0.5% to about 1.5%. In some embodiments, the first mixture further contains (b) a first desiccant, and / or the second mixture further contains a second desiccant.

[0194] In some embodiments, the present invention provides a method for preparing an oral drug suspension, the method comprising combining: 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), wherein the first mixture contains a water percentage of no more than about 2.5%; and a second mixture comprising a second desiccant and a second buffer; obtaining a combined mixture comprising 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%.

[0195] In some embodiments, the first mixture further comprises (b) a first desiccant.

[0196] In some implementations, the first and second desiccants are sodium alginate.

[0197] In some implementations, the first mixture further comprises (c) a first buffer.

[0198] In some embodiments, the first mixture and the second mixture are each independently in the form of powder, pellets, granules, crystals, beads, spheres, microspheres, or mixtures thereof.

[0199] In some embodiments, the PPIs present in the oral drug suspension or their pharmaceutically acceptable salts (such as omeprazole or its pharmaceutically acceptable salts) are micronized prior to the preparation of the oral suspension. Methods known in the art can be used for the micronization of omeprazole or its salts. For example, conventional micronization techniques based on friction to reduce particle size, such as milling, crushing, and grinding, can be used. Typical industrial mills consist of cylindrical metal drums that typically contain steel balls. As the drums rotate, the internal balls collide with solid particles, thereby crushing them into smaller diameters. In the case of grinding, solid particles are formed when the grinding units of the apparatus rub against each other while solid particles are trapped between them. Methods such as crushing and cutting can also be used to reduce particle size. Crushing uses a hammer-like tool to break solids into smaller particles through impact. Cutting uses sharp blades to cut coarse solid blocks into smaller solid blocks. Alternatively, modern micronization methods using supercritical fluids during the micronization process can be used. These methods use supercritical fluids to induce a supersaturated state, resulting in the precipitation of individual particles. Suitable techniques include the RESS (Supercritical Fluid Rapid Expansion), SAS (Supercritical Antisolvent), and PGSS (Gas Saturated Solution Particle) methods. These modern techniques allow for greater process tunability. Parameters such as relative pressure and temperature, solute concentration, and antisolvent-to-solvent ratio can be varied to achieve the desired particle size. Supercritical fluid methods enable finer control over particle size, particle size distribution, and morphological uniformity.

[0200] In some embodiments, the micronized PPI or a pharmaceutically acceptable salt thereof suitable for the oral suspension described herein is a composition in which 90% or more of the particles have a particle size of 20 micrometers or smaller (i.e., ≤20 μm). In some embodiments, the oral drug 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 its salt have a particle size of 20 micrometers or smaller.

[0201] In some embodiments, the micronized omeprazole or a pharmaceutically acceptable salt thereof suitable for the oral suspension described herein is a composition in which 90% or more of the particles have a particle size of 20 micrometers or smaller (i.e., ≤20 μm). 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 smaller.

[0202] In some embodiments, non-micronized omeprazole is a composition in which 95% or more of the particles have a particle size of 425 micrometers or smaller and 30% or more of the particles have a particle size of 75 micrometers or smaller.

[0203] PPI and its salts can be prepared by any suitable method known in the art.

[0204] Specifically, omeprazole and its salts can be prepared by any suitable method known in the art.

[0205] 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.

[0206] In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof. In some embodiments, the PPI comprises about 30% to about 70% micronized PPIs or pharmaceutically acceptable salts thereof, and the remainder of the PPI or pharmaceutically acceptable salt thereof is non-micronized. In some embodiments, the PPI is a 1:1 mixture of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof by weight. In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof. In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is a mixture of about 1:2.3 by weight of micronized and non-micronized PPIs or pharmaceutically acceptable salts thereof (i.e., about 30:70 mixture). In some embodiments, the PPI or a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized PPIs or a pharmaceutically acceptable salt thereof 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 a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized PPIs or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:1.5 (i.e., about 40:60 mixture).

[0207] 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 comprises about 30% to about 70% micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder of omeprazole or a pharmaceutically acceptable salt thereof is non-micronized. In some embodiments, omeprazole is a 1:1 mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof by weight. In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of about 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 by weight of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof. In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of about 1:2.3 by weight of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof (i.e., about 30:70 mixture). In some embodiments, omeprazole or a pharmaceutically acceptable salt thereof is a mixture of non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof 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 non-micronized and micronized omeprazole or a pharmaceutically acceptable salt thereof in a weight ratio of about 1:1.5 (i.e., about 40:60 mixture).

[0208] The first and second buffers used in the method of the present invention are present in amounts sufficient to increase the pH of the gastric juice to a level that prevents at least some of the omeprazole from degrading in the gastric juice. In some aspects, the first and second buffers together provide the suspension with a buffering capacity of about 0.5 mEq / ml to about 4 mEq / ml. In some aspects, the first and second buffers together provide the suspension with a buffering capacity of about 1.6 mEq / ml to about 2.3 mEq / ml. In some aspects, the first and second buffers together provide the suspension with a buffering capacity of about 2 mEq / ml.

[0209] In some embodiments, 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, and succinates. In some embodiments, the first and second buffers are each independently selected from the group consisting of: sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0210] 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 comprises about 11% sodium bicarbonate and about 89% potassium bicarbonate by weight.

[0211] In some embodiments, the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0212] In some implementations, the first and second buffers are potassium bicarbonate.

[0213] In some implementations, the second mixture also contains sweeteners and preservatives.

[0214] In some embodiments, the method further includes providing an oral drug suspension in a drug delivery device suitable for multiple-dose administration of a PPI or a pharmaceutically acceptable salt thereof (such as omeprazole or a pharmaceutically acceptable salt thereof). Suitable drug delivery devices include, for example, those described above in conjunction with the storage-stable systems described herein.

[0215] This disclosure also provides the following specific implementation schemes:

[0216] Implementation Scheme 1. A storage-stable omeprazole system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system contains no more than about 2.5% water percentage, and wherein the system is free of sodium from a sodium-containing buffer, or the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable omeprazole system is prepared with water prior to administration.

[0217] Implementation Scheme 2. The storage-stable omeprazole system according to Implementation Scheme 1, wherein the sodium and the potassium are present in a ratio of about 1:3.2 by weight.

[0218] Implementation Scheme 3. A storage-stable omeprazole system according to Implementation Scheme 1 or 2, wherein the system has a moisture content of about 0.5% to about 1.5%.

[0219] Implementation Scheme 4. The storage-stable omeprazole system according to any one of the foregoing implementation schemes, wherein the system further comprises a pharmaceutically acceptable desiccant.

[0220] Implementation Scheme 5. The storage-stable omeprazole system according to Implementation Scheme 4, wherein the pharmaceutically acceptable desiccant is sodium alginate.

[0221] Implementation Scheme 6. The storage-stable omeprazole system according to Implementation Scheme 5, wherein the sodium alginate is dry.

[0222] Implementation Scheme 7. The storage-stable omeprazole system according to Implementation Scheme 6, wherein the dried sodium alginate has a moisture content of about 0.5% to about 1.5%.

[0223] Implementation Scheme 8. A storage-stable omeprazole system according to any one of Implementation Schemes 5 to 7, wherein the sodium alginate is a low-viscosity grade sodium alginate.

[0224] Implementation Scheme 9. A storage-stable omeprazole system according to any one of the preceding claims, wherein the system comprises one or more buffers, each buffer being independently selected from the group consisting of: alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates.

[0225] Implementation Scheme 10. A storage-stable omeprazole system according to any one of Implementation Schemes 1 and 3 to 9, wherein the system comprises a buffer, the buffer being potassium bicarbonate.

[0226] Implementation Scheme 11. The storage-stable omeprazole system according to Implementation Scheme 9, wherein the system comprises two or more buffers selected from sodium carbonate and potassium carbonate, sodium bicarbonate and potassium bicarbonate, sodium phosphate and potassium phosphate, sodium citrate and potassium citrate, sodium borate and potassium borate, sodium acetate and potassium acetate, sodium phthalate and potassium phthalate, sodium tartrate and potassium tartrate, and sodium succinate and potassium succinate.

[0227] Implementation Scheme 12. The storage-stable omeprazole system according to Implementation Scheme 9 or 11, wherein the system comprises sodium bicarbonate and potassium bicarbonate.

[0228] Implementation Scheme 13. The storage-stable omeprazole system according to Implementation Scheme 12, wherein the sodium bicarbonate and the potassium bicarbonate are present in a ratio of about 1:2.7 by weight.

[0229] Implementation Scheme 14. A storage-stable omeprazole system according to any one of the preceding implementation schemes, wherein the system is in the form of powder, pellets, granules, crystals, beads, spheres, microspheres or mixtures thereof.

[0230] Implementation Scheme 15. A storage-stable omeprazole system comprising (i) a first mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains a water percentage of no more than about 2.5%; and (ii) a second mixture comprising a second buffer, wherein the second mixture contains a water percentage of no more than about 2.5%, wherein the first mixture and the second mixture are stored separately from each other and are mixed together when or just before being prepared with water, and wherein the system is free of 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.

[0231] Implementation Scheme 16. The storage-stable omeprazole system according to Implementation Scheme 15, wherein the sodium and the potassium are present in a ratio of about 1:3.2 by weight.

[0232] Implementation Scheme 17. A storage-stable omeprazole system according to Implementation Scheme 15 or 16, wherein the first mixture and / or the second mixture has a moisture content of about 0.5% to about 1.5%.

[0233] Implementation Scheme 18. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 17, wherein the first mixture further comprises (b) a first desiccant, and / or the second mixture further comprises a second desiccant.

[0234] Implementation Scheme 19. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 18, wherein the first desiccant and the second desiccant are sodium alginate.

[0235] Implementation Scheme 20. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 19, wherein the first mixture further comprises (c) a first buffer.

[0236] Implementation Scheme 21. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 20, wherein the first mixture and the second mixture are each independently in the form of powder, pellets, granules, crystals, beads, spheres, microspheres or mixtures thereof.

[0237] Implementation Scheme 22. A storage-stable omeprazole system according to any one of Implementation Schemes 1 to 21, wherein the omeprazole or a pharmaceutically acceptable salt thereof is micronized.

[0238] Implementation Scheme 23. A storage-stable omeprazole system according to any one of Implementation Schemes 1 to 21, wherein the omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0239] Implementation Scheme 24. The storage-stable omeprazole system according to Implementation Scheme 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 non-micronized.

[0240] Implementation Scheme 25. The storage-stable omeprazole system according to Implementation Scheme 24, wherein the 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.

[0241] Implementation Scheme 26. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 25, wherein the first buffer and the second buffer are present in an amount sufficient to increase the pH of the gastric juice to a pH that prevents at least some of the omeprazole from degrading in the gastric juice.

[0242] Implementation Scheme 27. A storage-stable omeprazole system according to any one of Implementation Schemes 20 to 26, wherein the first buffer and the second buffer together provide a buffering capacity of about 2 mEq / ml for a powder made of water.

[0243] Implementation Scheme 28. A storage-stable omeprazole system according to any one of Implementation Schemes 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.

[0244] Implementation Scheme 29. A storage-stable omeprazole system according to any one of Implementation Schemes 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.

[0245] Implementation Scheme 30. A storage-stable omeprazole system according to any one of Implementation Schemes 20 to 29, wherein the first buffer is sodium bicarbonate.

[0246] Implementation Scheme 31. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 29, wherein the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate.

[0247] Implementation Scheme 32. The storage-stable omeprazole system according to Implementation Scheme 31, wherein the second buffer comprises about 11% sodium bicarbonate and about 89% potassium bicarbonate by weight.

[0248] Implementation Scheme 33. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 31, wherein the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0249] Implementation Scheme 34. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 29, wherein the first buffer and the second buffer are potassium bicarbonate.

[0250] Implementation Scheme 35. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 32 and 34, wherein the second mixture further comprises a sweetener and a preservative.

[0251] Implementation Scheme 36. A storage-stable omeprazole system according to any one of the preceding embodiments, wherein the storage-stable omeprazole system is provided in a drug delivery device suitable for multiple doses of omeprazole or a pharmaceutically acceptable salt thereof.

[0252] Implementation Scheme 37. The storage-stable omeprazole system according to Implementation Scheme 36, wherein the drug delivery device comprises two chambers.

[0253] Implementation Scheme 38. The storage-stable omeprazole system according to Implementation Scheme 37, wherein the drug delivery device further includes means for releasing the contents of the first chamber into the second chamber without removing the cap from the drug delivery device.

[0254] Implementation Scheme 39. A storage-stable omeprazole system according to any one of Implementation Schemes 15 to 38, wherein the storage-stable omeprazole system is provided in a container body including a cap, wherein (i) the container body contains the second mixture and has a container opening formed in its upper end; (ii) the cap includes a cylindrical receiving portion containing the first mixture and a cap portion sealing the upper end of the receiving portion; and wherein (iii) the cap is installed in the container opening of the container body, wherein when the cap is screwed on, the first mixture is released into the container body.

[0255] Implementation Scheme 40. The storage stable omeprazole system according to Implementation Scheme 39, wherein the container body is an amber-colored polyethylene terephthalate bottle and the cap is a polypropylene tamper-evident cap.

[0256] Implementation Scheme 41. A storage-stable omeprazole system according to any one of the preceding implementation schemes, wherein the powder system remains stable for at least 2 years at 25°C / 60% relative humidity.

[0257] Implementation Scheme 42. A storage-stable omeprazole system formulated in a drug delivery device suitable for multiple-dose administration of omeprazole or a pharmaceutically acceptable salt thereof, said system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, said system containing no more than about 2.5% water percentage, and said system being free of sodium from a sodium-containing buffer, or said system containing sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein said storage-stable omeprazole system is prepared with water prior to administration.

[0258] Implementation Scheme 43. A storage-stable omeprazole system according to any one of Implementation Schemes 1 to 42, wherein the storage-stable omeprazole system is encapsulated in a sealed aluminum foil bag.

[0259] Implementation Scheme 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 powder mixture and the second powder mixture are stored separately from each other and are mixed together when or just before being prepared with water, and wherein the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0260] Implementation Scheme 45. The storage-stable omeprazole powder system according to Implementation Scheme 44, wherein the omeprazole or a pharmaceutically acceptable salt thereof is micronized.

[0261] Implementation Scheme 46. A storage-stable omeprazole powder system according to Implementation Scheme 44 or 45, wherein the omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0262] Implementation Scheme 47. The storage-stable omeprazole powder system according to Implementation Scheme 46, 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 non-micronized.

[0263] Implementation Scheme 48. A storage-stable omeprazole powder system according to Implementation Scheme 46, wherein the omeprazole is a 1:1 mixture by weight of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0264] Implementation Scheme 49. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 48, wherein about 20% to about 30% of the sodium alginate present in the first powder mixture is uniformly distributed on the surface of the first buffer.

[0265] Implementation Scheme 50. The storage-stable omeprazole powder system according to Implementation Scheme 49, wherein about 20% to about 25% of the sodium alginate present in the first powder mixture is uniformly distributed on the surface of the first buffer.

[0266] Implementation Scheme 51. A storage-stable omeprazole powder system according to Implementation Scheme 49 or 50, wherein the sodium alginate not distributed on the surface of the first buffer in the first powder mixture is dry.

[0267] Implementation Scheme 52. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 51, wherein the sodium alginate present in the second powder mixture is dry.

[0268] Implementation Scheme 53. A storage-stable omeprazole powder system according to Implementation Scheme 51 or 52, wherein the dried sodium alginate has a moisture content of about 0.5% to about 1.5%.

[0269] Implementation Scheme 54. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 53, wherein the sodium alginate is a low-viscosity grade sodium alginate.

[0270] Implementation Scheme 55. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 54, wherein the first buffer and the second buffer are present in an amount sufficient to increase the pH of the gastric juice to a pH that prevents at least some of the omeprazole or a pharmaceutically acceptable salt thereof from being degraded in the gastric juice.

[0271] Implementation Scheme 56. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 55, wherein the first buffer and the second buffer together provide a buffering capacity of about 2 mEq / ml for a water-based powder.

[0272] Implementation Scheme 57. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 56, 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.

[0273] Implementation Scheme 58. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 57, wherein the first buffer and the second buffer are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0274] Implementation Scheme 59. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 58, wherein the first buffer is sodium bicarbonate.

[0275] Implementation Scheme 60. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 59, wherein the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate.

[0276] Implementation Scheme 61. The storage-stable omeprazole powder system according to Implementation Scheme 60, wherein the mixture comprises about 11% sodium bicarbonate and about 89% potassium bicarbonate by weight.

[0277] Implementation Scheme 62. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 61, wherein the first powder mixture and the second powder mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0278] Implementation Scheme 63. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 62, wherein the second powder mixture further comprises a sweetener and a preservative.

[0279] Implementation Scheme 64. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 63, wherein the storage-stable omeprazole powder system is provided in a drug delivery device suitable for multiple doses of omeprazole.

[0280] Implementation Scheme 65. The storage-stable omeprazole powder system according to Implementation Scheme 64, wherein the drug delivery device includes a first chamber and a second chamber, the first chamber containing the first powder mixture and the second chamber containing the second powder mixture.

[0281] Implementation Scheme 66. The storage-stable omeprazole powder system according to Implementation Scheme 65, wherein the drug delivery device further includes means for releasing the first powder mixture into the second chamber without removing the cap from the drug delivery device.

[0282] Implementation Scheme 67. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 66, wherein the storage-stable omeprazole powder system is provided in a container body including a lid, wherein (i) the container body contains the second powder mixture and has a container opening formed in its upper end; (ii) the lid includes a cylindrical receiving portion containing the first powder mixture and a lid portion sealing the upper end of the receiving portion; and wherein (iii) the lid is installed in the container opening of the container body, wherein when the lid is screwed on, the first powder mixture is released into the container body.

[0283] Implementation Scheme 68. The storage stable omeprazole powder system according to Implementation Scheme 67, wherein the container body is an amber-colored polyethylene terephthalate bottle, and the cap is a polypropylene tamper-evident cap.

[0284] Implementation Scheme 69. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 68, wherein the powder system remains stable for at least 2 years at 25°C / 60% relative humidity.

[0285] Implementation Scheme 70. A storage-stable omeprazole powder system according to any one of Implementation Schemes 44 to 69, wherein the storage-stable omeprazole system is encapsulated in a sealed aluminum foil bag.

[0286] Implementation Scheme 71. An oral drug suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffers, wherein the suspension is free of 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.

[0287] Implementation Scheme 72. The oral drug suspension according to Implementation Scheme 71, wherein the suspension further comprises sodium alginate.

[0288] Implementation Scheme 73. An oral drug suspension according to Implementation Scheme 71 or 72, wherein about 1 ml of the suspension contains about 1 mg to about 10 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0289] Implementation Scheme 74. The oral drug suspension according to Implementation Scheme 73, wherein about 1 ml of the suspension contains about 1 mg, about 2 mg, about 4 mg or about 8 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0290] Implementation Scheme 75. The oral drug suspension according to Implementation Scheme 74, wherein about 1 ml of the suspension contains about 2 mg or about 4 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0291] Implementation Scheme 76. An oral drug suspension according to any one of Implementation Schemes 71 to 75, wherein the one or more buffers provide a buffering capacity of about 2 mEq / ml of the suspension.

[0292] Implementation Scheme 77. An oral drug suspension according to any one of Implementation Schemes 71 to 76, wherein the one or more buffers 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.

[0293] Implementation Scheme 78. An oral medication suspension according to any one of Implementation Schemes 71 to 77, wherein the suspension comprises a buffer.

[0294] Implementation Scheme 79. The oral drug suspension according to Implementation Scheme 78, wherein one of the buffers is potassium bicarbonate.

[0295] Implementation Scheme 80. An oral drug suspension according to any one of Implementation Schemes 71 to 77, wherein the suspension comprises a mixture of two buffers.

[0296] Implementation Scheme 81. The oral drug suspension according to Implementation Scheme 80, wherein the suspension comprises sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0297] Implementation Scheme 82. An oral drug suspension according to any one of Implementation Schemes 71 to 77 and 80 to 81, wherein the suspension comprises about 86 mg sodium / 5 ml of the suspension.

[0298] Implementation Scheme 83. An oral drug suspension according to any one of Implementation Schemes 71 to 77 and 80 to 82, wherein the sodium and the potassium are present in a ratio of about 1:3.2 by weight.

[0299] Implementation Scheme 84. An oral drug suspension according to any one of Implementation Schemes 71 to 83, wherein the suspension, upon oral administration to a subject in need, provides a first and second C max and the first and second T maxThe biphasic pharmacokinetic curves.

[0300] Implementation Scheme 85. An oral drug suspension according to any one of Implementation Schemes 66 to 77, wherein a 5 ml dose comprises about 10 mg or about 20 mg of omeprazole or a pharmaceutically acceptable salt thereof, about 256 mg of sodium bicarbonate, about 695 mg of potassium bicarbonate and about 125 mg of sodium alginate.

[0301] Implementation Scheme 86. The oral drug suspension according to Implementation Scheme 78, wherein the suspension further comprises about 11.45 mg of sodium methylparaben and about 25 mg of sodium benzoate.

[0302] Implementation Scheme 87. An oral drug suspension according to any one of Implementation Schemes 71 to 86, wherein the omeprazole or a pharmaceutically acceptable salt thereof is micronized.

[0303] Implementation Scheme 88. An oral drug suspension according to any one of Implementation Schemes 71 to 86, wherein the omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0304] Implementation Scheme 89. The oral drug suspension according to Implementation Scheme 88, 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 non-micronized.

[0305] Implementation Scheme 90. An oral drug suspension according to Implementation Scheme 88, wherein the omeprazole is a 1:1 mixture by weight of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0306] Implementation Scheme 91. An oral drug suspension according to any one of Implementation Schemes 71 to 90, wherein the suspension is provided in a drug delivery device suitable for multiple doses of omeprazole.

[0307] Implementation Scheme 92. A method for inhibiting gastric acid secretion, the method comprising administering to a subject in need an effective amount of an oral drug suspension according to any one of Implementation Schemes 71 to 91.

[0308] Implementation Scheme 93. The method according to Implementation Scheme 92, wherein the subject is a child.

[0309] Implementation Scheme 94. The method according to Implementation Scheme 93, wherein the child is an infant, a toddler, a pre-pubescent child, or an adolescent.

[0310] Implementation Scheme 95. The method according to any one of Implementation Schemes 92 to 94, wherein about 1 ml of the suspension contains about 1 mg to about 10 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0311] Implementation Scheme 96. The method according to any one of Implementation Schemes 92 to 95, wherein 1 ml of the suspension contains about 1 mg, about 2 mg, about 4 mg or about 8 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0312] Implementation Scheme 97. The method according to any one of Implementation Schemes 92 to 96, wherein 1 ml of the suspension contains about 2 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0313] Implementation Scheme 98. The method according to any one of Implementation Schemes 92 to 96, wherein 1 ml of the suspension contains about 4 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0314] Implementation Scheme 99. A method for preparing an oral drug suspension, the method comprising combining a first mixture with a second mixture to obtain a combined mixture, the first mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains no more than about 2.5% water percentage; the second mixture comprising a second buffer, wherein the second mixture contains no more than about 2.5% water percentage, wherein the combined mixture is free of 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.

[0315] Implementation Scheme 100. The method according to Implementation Scheme 99, wherein the sodium and the potassium are present in a ratio of about 1:3.2 by weight.

[0316] Implementation Scheme 101. The method according to Implementation Scheme 99 or 100, wherein the first mixture has a moisture content of about 0.5% to about 1.5%.

[0317] Implementation Scheme 102. The method according to any one of Implementation Schemes 99 to 101, wherein the first mixture further comprises (b) a first desiccant, and / or the second mixture further comprises a second desiccant.

[0318] Implementation Scheme 103. The method according to any one of Implementation Schemes 99 to 102, wherein the first desiccant and the second desiccant are sodium alginate.

[0319] Implementation Scheme 104. The method according to any one of Implementation Schemes 99 to 103, wherein the first mixture further comprises (c) a first buffer.

[0320] Implementation Scheme 105. The method according to any one of Implementation Schemes 99 to 104, wherein the first mixture and the second mixture are each independently in the form of powder, pellets, granules, crystals, beads, spheres, microspheres or mixtures thereof.

[0321] Implementation Scheme 106. The method according to any one of Implementation Schemes 99 to 105, wherein the omeprazole or a pharmaceutically acceptable salt thereof is micronized.

[0322] Implementation Scheme 107. The method according to any one of Implementation Schemes 99 to 105, wherein the omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0323] Implementation Scheme 108. The method according to Implementation Scheme 107, wherein the omeprazole comprises about 30% to about 70% of micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder of the omeprazole or a pharmaceutically acceptable salt thereof is non-micronized.

[0324] Implementation Scheme 109. The method according to Implementation Scheme 107, wherein the omeprazole is a 1:1 mixture by weight of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0325] Implementation Scheme 110. The method according to any one of Implementation Schemes 99 to 109, wherein the first buffer and the second buffer are present in an amount sufficient to increase the pH of the gastric juice to a pH that prevents at least some of the omeprazole from being degraded in the gastric juice.

[0326] Implementation Scheme 111. The method according to any one of Implementation Schemes 104 to 110, wherein the first buffer and the second buffer together provide a buffering capacity of about 2 mEq / ml for the suspension.

[0327] Implementation Scheme 112. The method according to any one of Implementation Schemes 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.

[0328] Implementation Scheme 113. The method according to any one of Implementation Schemes 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.

[0329] Implementation Scheme 114. The method according to any one of Implementation Schemes 104 to 113, wherein the first buffer is sodium bicarbonate.

[0330] Implementation Scheme 115. The method according to any one of Implementation Schemes 99 to 113, wherein the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate.

[0331] Implementation Scheme 116. The method according to Implementation Scheme 115, wherein the mixture comprises about 11% sodium bicarbonate and about 89% potassium bicarbonate by weight.

[0332] Implementation Scheme 117. The method according to any one of Implementation Schemes 99 to 116, wherein the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of about 1:2.7.

[0333] Implementation Scheme 118. The method according to any one of Implementation Schemes 99 and 101 to 113, wherein the first buffer and the second buffer are potassium bicarbonate.

[0334] Implementation Scheme 119. The method according to any one of Implementation Schemes 99 to 118, wherein the second mixture further comprises a sweetener and a preservative.

[0335] Implementation Scheme 120. The method according to any one of Implementation Schemes 99 to 119, wherein the oral drug suspension is provided in a drug delivery device suitable for multiple doses of omeprazole.

[0336] Implementation Scheme 121. A method for inhibiting gastric acid secretion, the method comprising administering to a subject in need an effective amount of an oral drug suspension, the oral drug suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffers, wherein the suspension is free of sodium from a sodium-containing buffer, or the suspension contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4; and wherein the oral drug suspension is prepared as claimed in any one of Implementation Schemes 99 to 120.

[0337] Implementation Scheme 122. An oral drug suspension according to any one of Implementation Schemes 71 to 90, wherein the suspension remains stable at 2°C to 8°C for at least one month after being prepared with water.

[0338] This disclosure also provides the following specific implementation schemes:

[0339] Implementation Scheme I. A storage-stable omeprazole system comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the system contains no more than about 2.5% water percentage, and wherein the system is free of sodium from a sodium-containing buffer, or wherein the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4, and further wherein the storage-stable omeprazole system is prepared with water prior to administration.

[0340] Implementation Scheme II. The storage-stable omeprazole system according to Implementation Scheme I, wherein the system comprises one or more buffers, each buffer being independently selected from the group consisting of: alkali metal or alkaline earth metal carbonates, bicarbonates, phosphates, citrates, borates, acetates, phthalates, tartrates, and succinates.

[0341] Implementation Scheme III. A storage-stable omeprazole system according to Implementation Scheme I, the system comprising (i) 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 percentage; and (ii) a second mixture containing a second buffer, wherein the second mixture contains no more than about 2.5% water percentage, wherein the first mixture and the second mixture are stored separately from each other and are mixed together when or just before being prepared with water, and wherein the system is free of 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.

[0342] Implementation Scheme 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 powder mixture and the second powder mixture are stored separately from each other and are mixed together when or just before being prepared with water, and wherein the system contains sodium and potassium in a weight ratio of about 1:2.6 to about 1:3.4.

[0343] Implementation scheme V. A storage-stable omeprazole system or a storage-stable omeprazole powder system according to any one of implementation schemes I to IV, wherein the omeprazole or a pharmaceutically acceptable salt thereof is micronized.

[0344] Implementation Scheme VI. A storage-stable omeprazole system or a storage-stable omeprazole powder system according to any one of Implementation Schemes I to IV, wherein the omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

[0345] Implementation Scheme VII. A storage-stable omeprazole system or a storage-stable omeprazole powder system according to any one of the preceding claims, wherein the storage-stable omeprazole system or the omeprazole powder system is provided in a drug delivery device suitable for multiple doses of omeprazole or a pharmaceutically acceptable salt thereof.

[0346] Implementation Scheme VIII. A storage-stable omeprazole powder system according to Implementation Scheme IV or VII, wherein the storage-stable omeprazole powder system is provided in a container body including a lid, wherein (i) the container body contains the second powder mixture and has a container opening formed in its upper end; (ii) the lid includes a cylindrical receiving portion containing the first powder mixture and a lid portion sealing the upper end of the receiving portion; and wherein (iii) the lid is installed in the container opening of the container body, wherein when the lid is screwed on, the first powder mixture is released into the container body.

[0347] Implementation Scheme IX. A storage-stable omeprazole system or a storage-stable omeprazole powder system according to any one of the preceding claims, wherein the omeprazole system or the omeprazole powder system remains stable for at least 2 years at 25°C / 60% relative humidity.

[0348] Implementation Scheme X. An oral drug suspension comprising water, a pharmaceutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof dispersed in the water, and one or more buffers, wherein the suspension is free of 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.

[0349] Implementation Scheme XI. The oral drug suspension according to Implementation Scheme X, wherein about 1 ml of the suspension contains about 1 mg to about 10 mg of omeprazole or a pharmaceutically acceptable salt thereof.

[0350] Implementation Scheme XII. An oral drug suspension according to Implementation Scheme X or XI, wherein the suspension remains stable at 2°C to 8°C for at least one month after being prepared with water.

[0351] Implementation Scheme XIII. A method for inhibiting gastric acid secretion, the method comprising administering to a subject in need an effective amount of an oral drug suspension according to any one of Implementation Schemes X to XII.

[0352] Implementation Scheme XIV. A method of administering an oral drug suspension to a subject requiring inhibition of gastric acid secretion, the method comprising: 1) preparing an oral drug suspension comprising combining: a first mixture comprising a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture contains a water percentage of no more than about 2.5%; and a second mixture comprising a second buffer, wherein the second mixture contains a water percentage of no more than about 2.5%; obtaining a combined mixture wherein the combined mixture is free of 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; and 2) administering an effective amount of the oral drug suspension to the subject in need.

[0353] Implementation scheme XV. The method according to implementation scheme XIII or XIV, wherein the subject is a child.

[0354] Example

[0355] The formulations described herein will now be described in further detail with reference to the following examples. These examples are provided for illustrative purposes only, and the embodiments described herein should in no way be construed as limiting to these examples. Rather, the embodiments should be understood to cover any and all variations that become apparent from the teachings provided herein.

[0356] Example 1

[0357] Exemplary omeprazole 2 mg / ml and 4 mg / ml oral suspensions and storage-stable omeprazole powder systems Formulation and manufacturing details

[0358] Table 1 below shows examples of particulate compositions used to prepare the first mixture present in the storage-stable omeprazole powder system described herein.

[0359] Table 1

[0360]

[0361]

[0362]

[0363] Example 2

[0364] Exemplary formulations of omeprazole 2 mg / ml and 4 mg / ml oral suspensions

[0365] Table 2

[0366]

[0367]

[0368] Example 3

[0369] Exemplary chemical composition of omeprazole oral suspension

[0370] Table 3

[0371]

[0372]

[0373] Example 4

[0374] This embodiment demonstrates that the storage-stable omeprazole powder system of this disclosure is beneficial to the stability of the omeprazole oral suspension of this disclosure.

[0375] Omeprazole 2 mg / ml oral suspensions were prepared in Examples J, K, and L. They have the same suspension composition but differ in the following ways:

[0376] Example J is a two-compartment dosage form packaged in aluminum foil according to the present disclosure, which includes a cap containing a first powder mixture and the cap being fixed to a bottle containing a second powder mixture;

[0377] Example K is a comparative example of a two-compartment dosage form packaged in Alu foil, comprising a cap containing a first powder mixture, the cap being fixed to a bottle containing a second powder mixture prepared with water; and

[0378] Example L is a comparative example of a single-chamber dosage form packaged in Alu foil, comprising a capped bottle containing a first powder mixture and a second powder mixture.

[0379] The following provides a description of the manufacturing, packaging, and composition details of the omeprazole 2 mg / ml suspensions prepared in Examples J, K, and L:

[0380]

[0381]

[0382]

[0383] Table 4 provides a summary of the preparation and characterization details of the omeprazole 2 mg / ml oral suspensions for Examples J, K, and L.

[0384] Table 4

[0385]

[0386]

[0387] Table 5 summarizes the stability study results of the omeprazole 2 mg / ml oral suspensions in Examples J, K, and L.

[0388] Table 5

[0389]

[0390] Example 5

[0391] Exemplary chemical composition of omeprazole oral suspension prepared using micronized omeprazole

[0392] The following provides a description of the manufacturing, packaging, and composition details of the omeprazole 4 mg / ml suspension prepared in Example M:

[0393]

[0394]

[0395] Table 6 provides a summary of the preparation and characterization details of the omeprazole 4 mg / ml oral suspension of Example M.

[0396] Table 6

[0397]

[0398]

[0399] Table 7 provides a summary of the stability study results for the omeprazole 4 mg / ml oral suspension of Example M.

[0400] Table 7

[0401]

[0402]

[0403] Example 6

[0404] An exemplary omeprazole oral suspension prepared using a mixture of micronized and non-micronized omeprazole Chemical composition

[0405] The following provides a description of the manufacturing, packaging, and composition details of the omeprazole 4 mg / ml suspension of Examples N and O:

[0406]

[0407]

[0408] Table 8 provides a summary of the preparation and characterization details of the omeprazole 4 mg / ml oral suspensions for Examples N and O.

[0409] Table 8

[0410]

[0411]

[0412]

[0413] Now that this disclosure has been fully described, those skilled in the art will understand that the same operation can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any of its embodiments.

[0414] Other embodiments described herein will be apparent to those skilled in the art in light of the specification and practice of the invention disclosed herein. This specification is intended to be illustrative only, and the true scope and spirit of the invention are indicated by the following claims.

[0415] All patents, patent applications and publications cited in this article are incorporated herein in their entirety through citation.

Claims

1. A storage-stable omeprazole system selected from powders, pellets, granules, microspheres, or mixtures thereof, the system comprising (i) a first mixture consisting of (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) sodium alginate, (c) a first buffer, and (d) optionally mannitol; and (ii) a second mixture comprising sodium alginate and a second buffer; wherein the second mixture is free of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first mixture and the second mixture are stored separately from each other and are mixed together when or immediately before being prepared with water, and wherein the system contains sodium and potassium in a weight ratio of 1:2.6 to 1:3.

4.

2. The storage-stable omeprazole system according to claim 1, wherein the sodium and potassium are present in a weight ratio of 1:3.

2.

3. The storage-stable omeprazole system according to claim 1, wherein the omeprazole or a pharmaceutically acceptable salt thereof is micronized.

4. The storage-stable omeprazole system according to claim 1, wherein the omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

5. The storage-stable omeprazole system according to claim 4, wherein the omeprazole or a pharmaceutically acceptable salt thereof comprises 30% to 70% micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder of the omeprazole or a pharmaceutically acceptable salt thereof is non-micronized.

6. The storage-stable omeprazole system according to claim 5, wherein the 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.

7. The storage-stable omeprazole system according to claim 1, wherein the first buffer and the second buffer are present in an amount sufficient to increase the pH of the gastric juice to a pH that prevents at least some of the omeprazole from degrading in the gastric juice.

8. The storage-stable omeprazole system according to claim 7, wherein the first buffer and the second buffer together provide a buffering capacity of 2 mEq / ml for the water-based powder.

9. The storage-stable omeprazole system according to claim 1, 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.

10. The storage-stable omeprazole system according to claim 9, wherein the first buffer and the second buffer are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

11. The storage-stable omeprazole system according to claim 10, wherein the first buffer is sodium bicarbonate.

12. The storage-stable omeprazole system according to claim 1, wherein the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate.

13. The storage-stable omeprazole system according to claim 12, wherein the second buffer comprises 11% sodium bicarbonate and 89% potassium bicarbonate by weight.

14. The storage-stable omeprazole system according to claim 1, wherein the first mixture and the second mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of 1:2.

7.

15. The storage-stable omeprazole system according to claim 1, wherein the first buffer and the second buffer are potassium bicarbonate.

16. The storage-stable omeprazole system according to claim 1, wherein the second mixture further comprises a sweetener and a preservative.

17. The storage-stable omeprazole system according to any one of claims 1-16, wherein the storage-stable omeprazole system is provided in a drug delivery device suitable for multiple doses of omeprazole or a pharmaceutically acceptable salt thereof.

18. The storage-stable omeprazole system according to claim 17, wherein the drug delivery device comprises two chambers.

19. The storage-stable omeprazole system of claim 18, wherein the drug delivery device further comprises means for releasing the contents of the first chamber into the second chamber without removing the cap from the drug delivery device.

20. The storage-stable omeprazole system of claim 17, wherein the storage-stable omeprazole system is provided in a container body including a lid, wherein (i) the container body contains the second mixture and has a container opening formed in its upper end; (ii) the lid includes a cylindrical receiving portion containing the first mixture and a lid portion sealing the upper end of the receiving portion; and wherein (iii) the lid is installed in the container opening of the container body, wherein when the lid is screwed on, the first mixture is released into the container body.

21. The storage-stable omeprazole system according to claim 20, wherein the container body is an amber-colored polyethylene terephthalate bottle, and the cap is a polypropylene tamper-evident cap.

22. The storage-stable omeprazole system according to claim 1, wherein the omeprazole system remains stable for at least 2 years at 25°C / 60% relative humidity.

23. The storage-stable omeprazole system according to claim 1, wherein the storage-stable omeprazole system is encapsulated in a sealed aluminum foil bag.

24. A storage-stable omeprazole powder system comprising (i) a first powder mixture consisting of (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) sodium alginate, (c) a first buffer and (d) optionally mannitol; and (ii) a second powder mixture comprising sodium alginate and a second buffer, wherein the second powder mixture is free of omeprazole or a pharmaceutically acceptable salt thereof, wherein the first powder mixture and the second powder mixture are stored separately from each other and are mixed together when or immediately before being prepared with water, and wherein the system contains sodium and potassium in a weight ratio of 1:2.6 to 1:3.

4.

25. The storage-stable omeprazole powder system according to claim 24, wherein the omeprazole or a pharmaceutically acceptable salt thereof is micronized.

26. The storage-stable omeprazole powder system according to claim 24, wherein the omeprazole or a pharmaceutically acceptable salt thereof is a mixture of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

27. The storage-stable omeprazole powder system of claim 26, wherein the omeprazole or a pharmaceutically acceptable salt thereof comprises 30% to 70% micronized omeprazole or a pharmaceutically acceptable salt thereof, and the remainder of the omeprazole or a pharmaceutically acceptable salt thereof is non-micronized.

28. The storage-stable omeprazole powder system according to claim 26, wherein the omeprazole is a 1:1 mixture by weight of micronized and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.

29. The storage-stable omeprazole powder system according to claim 24, wherein the effective amount of omeprazole or a pharmaceutically acceptable salt thereof and a total amount of 20% to 30% of the sodium alginate present in the first powder mixture are uniformly distributed on the surface of the first buffer.

30. The storage-stable omeprazole powder system according to claim 29, wherein the effective amount of omeprazole or a pharmaceutically acceptable salt thereof and a total amount of 20% to 25% of the sodium alginate present in the first powder mixture are uniformly distributed on the surface of the first buffer.

31. The storage-stable omeprazole powder system according to claim 29, wherein the sodium alginate not distributed on the surface of the first buffer in the first powder mixture is dry.

32. The storage-stable omeprazole powder system according to claim 24, wherein the sodium alginate present in the second powder mixture is dry.

33. The storage-stable omeprazole powder system according to claim 32, wherein the dried sodium alginate has a moisture content of 0.5% to 1.5%.

34. The storage-stable omeprazole powder system according to claim 24, wherein the sodium alginate is low-viscosity sodium alginate.

35. The storage-stable omeprazole powder system of claim 24, wherein the first buffer and the second buffer are present in an amount sufficient to increase the pH of the gastric juice to a pH that prevents at least some of the omeprazole or a pharmaceutically acceptable salt thereof from being degraded in the gastric juice.

36. The storage-stable omeprazole powder system of claim 24, wherein the first buffer and the second buffer together provide a buffering capacity of 2 mEq / ml for the water-based powder.

37. The storage-stable omeprazole powder system according to claim 24, 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.

38. The storage-stable omeprazole powder system according to claim 37, wherein the first buffer and the second buffer are each independently selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

39. The storage-stable omeprazole powder system according to claim 38, wherein the first buffer is sodium bicarbonate.

40. The storage-stable omeprazole powder system according to claim 38, wherein the second buffer is a mixture of sodium bicarbonate and potassium bicarbonate.

41. The storage-stable omeprazole powder system according to claim 40, wherein the mixture comprises 11% sodium bicarbonate and 89% potassium bicarbonate by weight.

42. The storage-stable omeprazole powder system according to claim 24, wherein the first powder mixture and the second powder mixture together comprise sodium bicarbonate and potassium bicarbonate in a weight ratio of 1:2.

7.

43. The storage-stable omeprazole powder system according to claim 24, wherein the second powder mixture further comprises a sweetener and a preservative.

44. The storage-stable omeprazole powder system according to any one of claims 24 to 43, wherein the storage-stable omeprazole powder system is provided in a drug delivery device suitable for multiple doses of omeprazole.

45. The storage-stable omeprazole powder system of claim 44, wherein the drug delivery device comprises a first chamber and a second chamber, the first chamber containing the first powder mixture and the second chamber containing the second powder mixture.

46. ​​The storage-stable omeprazole powder system of claim 45, wherein the drug delivery device further comprises means for releasing the first powder mixture into the second chamber without removing the cap from the drug delivery device.

47. The storage-stable omeprazole powder system of claim 44, wherein the storage-stable omeprazole powder system is provided in a container body including a lid, wherein (i) the container body contains the second powder mixture and has a container opening formed in its upper end; (ii) the lid includes a cylindrical receiving portion containing the first powder mixture and a lid portion sealing the upper end of the receiving portion; and wherein (iii) the lid is installed in the container opening of the container body, wherein when the lid is screwed on, the first powder mixture is released into the container body.

48. The storage-stable omeprazole powder system according to claim 47, wherein the container body is an amber-colored polyethylene terephthalate bottle, and the cap is a polypropylene tamper-evident cap.

49. The storage-stable omeprazole powder system according to claim 24, wherein the powder system remains stable for at least 2 years at 25°C / 60% relative humidity.

50. The storage-stable omeprazole powder system according to claim 24, wherein the storage-stable omeprazole system is encapsulated in a sealed aluminum foil bag.

51. An oral drug suspension prepared by using water to form a pharmaceutically effective amount of a storage-stable omeprazole system according to any one of claims 1-16 or 22 or a storage-stable omeprazole powder system according to any one of claims 24-43 or 49 prior to administration, wherein the suspension contains sodium and potassium in a weight ratio of 1:2.6 to 1:3.

4.

52. The oral drug suspension of claim 51, wherein 1 ml of the suspension contains 1 mg to 10 mg of omeprazole or a pharmaceutically acceptable salt thereof.

53. The oral drug suspension of claim 52, wherein 1 ml of the suspension contains 1 mg, 2 mg, 4 mg or 8 mg of omeprazole or a pharmaceutically acceptable salt thereof.

54. The oral medication suspension of claim 53, wherein 1 ml of the suspension contains 2 mg or 4 mg of omeprazole or a pharmaceutically acceptable salt thereof.

55. The oral medication suspension according to claim 51, wherein the suspension comprises sodium bicarbonate and potassium bicarbonate in a weight ratio of 1:2.

7.

56. The oral medication suspension of claim 51, wherein the suspension comprises 86 mg sodium / 5 mL of the suspension.

57. The oral drug suspension of claim 51, wherein the sodium and the potassium are present in a ratio of 1:3.2 by weight.

58. The oral pharmaceutical suspension of claim 51, wherein the suspension, upon oral administration to a subject in need, provides a first and second C max and the first and second T max The biphasic pharmacokinetic curves.

59. The oral drug suspension of claim 51, wherein a 5 ml dose comprises 10 mg or 20 mg of omeprazole or a pharmaceutically acceptable salt thereof, 256 mg of sodium bicarbonate, 695 mg of potassium bicarbonate and 125 mg of sodium alginate.

60. The oral drug suspension of claim 59, wherein the suspension further comprises 11.45 mg of sodium methylparaben and 25 mg of sodium benzoate.

61. The oral drug suspension of claim 51, wherein the suspension is provided in a drug delivery device suitable for multiple doses of omeprazole.

62. Use of the storage-stable omeprazole system according to any one of claims 1-16 or 22, or the storage-stable omeprazole powder system according to any one of claims 24-43 or 49, in the preparation of an oral pharmaceutical suspension for inhibiting gastric acid secretion in a subject in need.

63. The use according to claim 62, wherein the subject is a child.

64. The use according to claim 63, wherein the child is an infant, a toddler, a pre-pubescent child, or an adolescent.

65. The use according to claim 62, wherein 1 ml of the suspension contains 2 mg of omeprazole or a pharmaceutically acceptable salt thereof.

66. The use according to claim 62, wherein 1 ml of the suspension contains 4 mg of omeprazole or a pharmaceutically acceptable salt thereof.

67. The use according to claim 62, wherein the oral drug suspension is prepared by a method comprising the steps of: (i) combining a first powder mixture with (ii) a second powder mixture to obtain a combined mixture, the first powder mixture comprising (a) a therapeutically effective amount of omeprazole or a pharmaceutically acceptable salt thereof, (b) sodium alginate, (c) a first buffer and (d) optionally mannitol, the second powder mixture comprising sodium alginate and a second buffer, wherein the second powder mixture does not contain omeprazole or a pharmaceutically acceptable salt thereof, wherein the combined mixture contains sodium and potassium in a weight ratio of 1:2.6 to 1:3.4; and adding water to the combined mixture.

68. The use according to claim 67, wherein the sodium and potassium are present in a ratio of 1:3.2 by weight.

69. The oral pharmaceutical suspension of claim 51, wherein the suspension remains stable at 2°C to 8°C for at least one month after being prepared with water.

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