PEDIATRIC SUSPENSION FORMULATION
`
`BACKGROUND
`
`[0001]
`
`Omeprazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-
`
`1H-benzimidazole,
`
`inhibits gastric acid secretion. Omeprazole belongs to a class of
`
`antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic
`
`or H2 histamine antagonist properties. Drugs of this class of compounds suppress gastric acid
`
`secretion by the specific inhibition of the H*/K* ATPase enzyme system at the secretory
`
`surface of the gastric cell and are called proton pump inhibitors.
`
`[0002]
`
`Proton pump inhibitors, such as omeprazole, are acid labile and thus they are
`
`rapidly degraded in acidic media, such as the contents of the stomach, but they have an
`
`acceptable stability under alkaline conditions. Absorption of orally administered proton
`
`pump inhibitors, such as omeprazole, take place in the small intestine.
`
`[0003]
`
`In order to solve the stability problems of omeprazole in acidic conditions, some
`
`omeprazole dosage forms available on the market incorporate omeprazole as enteric coated
`
`granules or pellets in delayed release solid oral dosage forms. Examples of such dosage
`
`forms include, for example, Losec® and Losec MUPS® which both contain enteric coated
`
`pellets of omeprazole in hard gastro-resistant capsules and gastro-resistant
`
`tablets,
`
`respectively.
`
`[0004]
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`Commonly, pediatric subjects encounter difficulty being administered solid oral
`
`dosage forms, such as tablets or capsules.
`
`[0005]
`
`Currently, no oral liquid dosage form of omeprazole is approved in Europe. In the
`
`United States, omeprazole powder for oral suspension is sold under the trade name Zegerid®
`
`which is a white, flavored powder packaged in single-dose packets which are constituted with
`
`water prior to administration. Each packet contains either 20 mg or 40 mg of omeprazole and
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`1680 mg of sodium bicarbonate, and the following excipients: xylitol, sucrose, sucralose,
`
`xanthan gum, and flavorings. One dose of Zegerid® Powder for Oral Suspension contains
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`460 mg of sodium (Na’‘). Aliso available in the United States is a FIRST®-OQmeprazole
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`Compounding Kit that is comprised of omeprazole powder and FIRST-PPI (proton pump
`
`imhibitor) Suspension contatning artificial strawberry flavor, benzyl alcohol, FD&C Red No.
`
`40, Magnasweet 100 fammonium glycyrrhizate), poloxamer 138, propylene glycol, purified
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`water, simethicone emulsion, sodium bicarbonate, sodium citrate (dihydrate), sucralase, and
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`xanthan gum. When compounded,
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`the final product provides a homogenous suspension
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`-2-
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`containing 2 mg/ml of omeprazole in FIRST®-PPI Suspension.
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`These omeprazole
`
`suspension formulations contain high amounts of sodium which makes these formulations
`
`unacceptable for pediatric subjects.
`
`[0006]
`
`There is a need for a liquid oral omeprazole formulation designed especially for
`
`pediatric subjects.
`
`BRIEF SUMMARY
`
`[0007]
`
`The present disclosure relates to storage-stable proton pump inhibitor (PPI)
`
`systems comprising a therapeutically effective amount of a PPI or a pharmaceutically
`
`acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof,
`
`which upon constitution with water contain sodium at acceptable levels for use in therapy in
`
`pediatric subjects. The storage stable PPI systems are specifically suitable for use in multi-
`
`dose dosage forms. The present disclosure also relates to oral pharmaceutical 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 buffering agents. The oral pharmaceutical suspension of the present disclosure
`
`has an acceptable level of buffering capacity for pediatric subjects.
`
`In some aspects, the
`
`buffering capacity of the oral pharmaceutical suspensions described herein is about 2 mEq/ml
`
`of the oral suspension.
`
`[0008]
`
`In one aspect, the present disclosure provides a storage-stable omeprazole system,
`
`the
`
`system comprising
`
`a
`
`therapeutically effective
`
`amount of omeprazole,
`
`or
`
`a
`
`pharmaceutically acceptable salt
`
`thereof, wherein the system contains a percentage of
`
`moisture of no more than about 2.5%, and wherein the system contains no sodium from a
`
`sodium-containing buffering agent or contains sodium and potassium at a ratio of from about
`
`1:2.6 to about 1:3.4 by weight, and further wherein the storage-stable omeprazole system is
`
`constituted with water prior to administration.
`
`In some embodiments of this aspect, the
`
`sodium and potassium are present at a ratio of about 1:3.2 by weight.
`
`In some embodiments,
`
`the system has a moisture content of about 0.5% to about 1.5%.
`
`[0009]
`
`In some embodiments, the storage-stable omeprazole system further comprises a
`
`pharmaceutically acceptable desiccant.
`
`In some embodiments,
`
`the pharmaceutically
`
`acceptable desiccant is sodium alginate.
`
`[0010]
`
`In another aspect, the present disclosure provides a storage-stable omeprazole
`
`system, the system comprising (i) a first mixture comprising (a) a therapeutically effective
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`amount of omeprazole, or a pharmaceutically acceptable salt thereof, wherein the first
`
`mixture contains a percentage of moisture of no more than about 2.5%; and (ii) a second
`
`mixture comprising a
`
`second buffering agent, wherein the second mixture contains a
`
`percentage of moisture 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 on or just before
`
`constitution with water, and wherein the system contains no sodium from a sodium-
`
`containing buffering agent or contains sodium and potassium at a ratio of from about 1:2.6 to
`
`about 1:3.4 by weight.
`
`In some embodiments, the sodium and potassium are present at a ratio
`
`of about 1:3.2 by weight. In some embodiments, the first mixture further comprises (b) a first
`
`desiccant.
`
`In some embodiments, the first mixture further comprises (c) a first buffering
`
`agent.
`
`In some embodiments, the first mixture further comprises both (b) the first desiccant
`
`and (c) the first buffering agent. In some embodiments, the second mixture further comprises
`
`a second desiccant.
`
`[0011]
`
`In another aspect, the present disclosure provides a storage-stable omeprazole
`
`system formulated in a drug delivery device suitable for multi-dose administration of
`
`omeprazole, or the pharmaceutically acceptable salt
`
`thereof,
`
`the system comprising a
`
`therapeutically effective amount of omeprazole, or a pharmaceutically acceptable salt thereof,
`
`wherein the system contains a percentage of moisture of no more than about 2.5%, and
`
`wherein the system contains no sodium from a sodium-containing buffering agent or the
`
`system contains sodium and potassium ata ratio of from about 1:2.6 to about 1:3.4 by weight,
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`and further wherein the storage-stable omeprazole system is constituted with water prior to
`
`administration.
`
`[0012]
`
`In another aspect, the present disclosure provides a storage-stable omeprazole
`
`powder system,
`
`the system comprising (i) a first powder mixture comprising (a) a
`
`therapeutically effective amount of omeprazole, or a pharmaceutically acceptable salt thereof,
`
`(b) sodium alginate, and (c) a first buffering agent; and (ii) a second powder mixture
`
`comprising sodium alginate and a second buffering agent, wherein the first powder mixture
`
`and the second powder mixture are stored separately from each other and are mixed together
`
`on or just before constitution with water, wherein the system contains sodium and potassium
`
`at a ratio of from about 1:2.6 to about 1:3.4 by weight.
`
`In some embodiments, the sodium
`
`and potassium are presentat a ratio of about 1:3.2 by weight.
`
`[0013]
`
`In another aspect,
`
`the present disclosure provides an oral pharmaceutical
`
`suspension, comprising water, a pharmaceutically effective amount of omeprazole, or a
`
`pharmaceutically acceptable salt thereof, dispersed in the water, and one or more buffering
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`agents, and wherein the suspension contains no sodium from a sodium-containing buffering
`
`agent or the suspension contains sodium andpotassium at a ratio of from about 1:2.6 to about
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`-4-
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`1:3.4 by weight.
`
`[0014]
`
`In some embodiments, the oral pharmaceutical suspension, comprises water, a
`
`pharmaceutically effective amount of omeprazole, or a pharmaceutically acceptable salt
`
`thereof, dispersed in the water, and one of more buffering agents, wherein the suspension
`
`contains sodium and potassium at a ratio of from about 1:2.6 to about 1:3.4 by weight.
`
`[0015]
`
`In some embodiments,
`
`the omeprazole, or a pharmaceutically acceptable salt
`
`thereof,
`
`in the storage-stable omeprazole systems or oral pharmaceutical
`
`suspensions
`
`described herein is micronized.
`
`In some embodiments,
`
`the storage-stable omeprazole
`
`systems or oral pharmaceutical suspensions described herein contain a mixture of micronized
`
`and non-micronized omeprazole or a pharmaceutically acceptable salt thereof.
`
`In some
`
`embodiments,
`
`the storage-stable omeprazole system, or specifically the storage-stable
`
`omeprazole powder system,
`
`is provided in a drug delivery device suitable for multi-dose
`
`administration of omeprazole or a pharmaceutically acceptable salt thereof.
`
`[0016]
`
`In some embodiments,
`
`the storage-stable omeprazole system described herein
`
`remains stable at 25°C / 60% relative humidity for at least 2 years.
`
`[0017]
`
`In some embodiments,
`
`the oral pharmaceutical
`
`suspension of the present
`
`disclosure provides a biphasic pharmacokinetic profile having a first and second Cmax and a
`
`first and second Tmax following oral administration in a subject in need thereof.
`
`[0018]
`
`In another aspect, the present disclosure provides a method of inhibiting gastric
`
`acid secretion in a subject in need thereof.
`
`In certain embodiments, the method comprises
`
`administering to a subject in need thereof an effective amount of an oral pharmaceutical
`
`suspension comprising water, a pharmaceutically effective amount of omeprazole, or a
`
`pharmaceutically acceptable salt thereof, dispersed in the water, and one or more buffering
`
`agents, wherein the suspension contains no sodium from a sodium-containing buffering agent
`
`or the suspension contains sodium and potassium at a ratio of from about 1:2.6 to about 1:3.4
`
`by weight.
`
`In some embodiments, the method comprises administering to a subject in need
`
`thereof an effective amount of an oral pharmaceutical suspension comprising water, a
`
`pharmaceutically effective amount of omeprazole, or a pharmaceutically acceptable salt
`
`thereof, dispersed in the water, and one or more buffering agents, wherein the suspension
`
`contains sodium and potassium at a ratio of from about 1:2.6 to about 1:3.4 by weight.
`
`In
`
`some embodiments, the subject is a child.
`
`In some embodiments, the suspension comprises
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`from about 1 mg/ml to about 10 mg/ml of omeprazole or a pharmaceutically acceptable salt
`
`thereof.
`
`[0019]
`
`In another aspect, the present disclosure provides a method of preparing an oral
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`-5-
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`pharmaceutical suspension. Typically, the method comprises combining a first mixture
`
`comprising (a) a therapeutically effective amount of omeprazole, or a pharmaceutically
`
`acceptable salt thereof, wherein the first mixture contains a percentage of moisture of no
`
`more than about 2.5%; with a second mixture comprising a second buffering agent, wherein
`
`the second mixture contains a percentage of moisture of no more than about 2.5%; to obtain a
`
`combined mixture, wherein the combined mixture contains no sodium from a sodium-
`
`containing buffering agent or the combined mixture contains sodium and potassium at a ratio
`
`of from about 1:2.6 to about 1:3.4 by weight; and adding water to the combined mixture.
`
`In
`
`some embodiments,
`
`the second mixture further comprises a second desiccant.
`
`In some
`
`embodiments,
`
`the method comprises
`
`combining a
`
`first mixture comprising (a)
`
`a
`
`therapeutically effective amount of omeprazole, or a pharmaceutically acceptable salt thereof,
`
`containing a percentage of moisture of no more than about 2.5%; with a second mixture
`
`comprising a second desiccant and a second buffering agent; to obtain a combined mixture,
`
`wherein the combined mixture contains sodium and potassium at a ratio of from 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 buffering agent.
`
`In some embodiments, the first mixture further
`
`comprises both (b) the first desiccant and (c) the first buffering agent.
`
`[0020]
`
`In another aspect, the present disclosure provides a method of inhibiting gastric
`
`acid secretion, comprising administering to a subject in need thereof an effective amount of
`
`an oral pharmaceutical suspension comprising water, a pharmaceutically effective amount of
`
`omeprazole, or a pharmaceutically acceptable salt thereof, dispersed in the water, and one or
`
`more buffering agents, wherein the suspension contains no sodium from a sodium-containing
`
`buffering agent or the suspension contains sodium and potassium at a ratio of from about
`
`1:2.6 to about 1:3.4 by weight; and wherein the oral pharmaceutical suspension is prepared
`
`by combining a first mixture comprising (a) a therapeutically effective amount of
`
`omeprazole, or a pharmaceutically acceptable salt thereof, wherein the first mixture contains
`
`a percentage of moisture of no more than about 2.5%; with a second mixture comprising a
`
`second buffering agent, wherein the second mixture contains a percentage of moisture of no
`
`more than about 2.5%; to obtain a combined mixture, wherein the combined mixture contains
`
`no sodium from a sodium-containing buffering agent or the combined mixture contains
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`sodium and potassium at a ratio of from about 1:2.6 to about 1:3.4 by weight; and adding
`
`water to the combined mixture.
`
`In some embodiments, the second mixture further comprises
`
`a second desiccant.
`
`In some embodiments, the method comprises administering to a subject
`
`in need thereof an effective amount of an oral pharmaceutical suspension comprising water, a
`
`pharmaceutically effective amount of omeprazole, or a pharmaceutically acceptable salt
`
`thereof, dispersed in the water, and one or more buffering agents, wherein the suspension
`
`contains sodium and potassium at a ratio of from about 1:2.6 to about 1:3.4 by weight,
`
`wherein the oral pharmaceutical suspension is prepared by combining a first mixture
`
`comprising (a) a therapeutically effective amount of omeprazole, or a pharmaceutically
`
`acceptable salt thereof, wherein the first mixture contains a percentage of moisture of no
`
`more than about 2.5%; with a second mixture comprising a second desiccant and a second
`
`buffering agent;
`
`to obtain a combined mixture, wherein the combined mixture contains
`
`sodium and potassium at a ratio of from about 1:2.6 to about 1:3.4; and adding water to the
`
`combined mixture.
`
`In some embodiments, the first mixture further comprises (c) a first
`
`buffering agent.
`
`In some embodiments, the first mixture further comprises both (b) the first
`
`desiccant and (c) the first buffering agent.
`
`[0021]
`
`Additional embodiments and advantages described herein will be set forth, in part,
`
`in the description that follows, and will flow from the description, or can be learned by
`
`practice described herein. The embodiments and advantages described herein will be realized
`
`and attained by means of the elements and combinations particularly pointed out in the
`
`appendedclaims.
`
`[0022]
`
`It is to be understood that both the foregoing summary and the following detailed
`
`description are exemplary and explanatory only, and are not restrictive of the invention as
`
`claimed.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`[0023]
`
`FIG. 1 depicts a delivery device suitable for use for storage-stable systems of the
`
`present disclosure.
`
`DETAILED DESCRIPTION
`
`[0024]
`
`The headings provided herein are not limitations of the various aspects described
`
`herein, which can be defined by reference to the specification as a whole. It is also to be
`
`understood that the terminology used herein is for the purpose of describing particular aspects
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`only, and is not intended to be limiting, since the scope of the present disclosure will be
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`-7-
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`limited only by the appendedclaims.
`
`Definitions
`
`[0025]
`
`For convenience, the meaning of some terms and phrases used in the specification,
`
`examples, and appended claims are provided below. Unless stated otherwise, or implicit
`
`from context, the following terms and phrases include the meanings provided below. The
`
`definitions are provided to aid in describing particular embodiments, and are not intended to
`
`limit the claimed technology, because 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 ofordinary skill in the art to which this
`
`technology belongs. If there is an apparent discrepancy between the usage of a term in the art
`
`and its definition provided herein,
`
`the definition provided within the specification shall
`
`prevail.
`
`[0026]
`
`The articles "a," "an," and "the" are used herein to refer to one or to more than one
`
`(i.e., to at least one) of the grammatical object of the article. By way of example, "an
`
`element” means one element or more than one element.
`
`[0027]
`
`
`As used herein, the term "about" means + 10% of the specified value, unless
`
`otherwise indicated.
`
`[0028]
`
`The term "at least" prior to a numberorseries of numbersis understood to include
`
`the numberadjacent to the term "at least," and all subsequent numbers or integers that could
`
`logically be included, as clear from context. When at least is present before a series of
`
`numbers or a range, it is understood that "at least" can modify each of the numbers in the
`
`series or range.
`
`[0029]
`
`The term "no more than" prior to a numberor series of numbers is understood to
`
`include the number adjacent to the term "no more than," and all preceding numbers or
`
`integers that could logically be included, as clear from context. When "no more than" is
`
`present before a series of numbersor a range,it is understood that "no more than" can modify
`
`each of the numbersin the series or range.
`
`[0030]
`
`As used herein,
`
`the terms "comprises," "comprising," "having," "including,"
`
`"containing," and the like are open-ended terms meaning "including, but not limited to."
`
`To
`
`the extent a given embodiment disclosed herein "comprises" certain elements, it should be
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`-8-
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`understood that present disclosure also specifically contemplates and discloses embodiments
`
`that "consist essentially of" those elements and that "consist of" those elements.
`
`[0031]
`
`The terms "treat," "treating," and "treatment" refer to any indicia of success in the
`
`treatment or amelioration of an injury, disease, or condition,
`
`including any objective or
`
`subjective parameter such as abatement; remission; diminishing of symptoms or making the
`
`injury, disease, or condition moretolerable to the patient; slowing in the rate of degeneration
`
`or decline; or improving a patient’s physical or mental well-being.
`
`The treatment or
`
`amelioration of symptoms can be based on objective or subject parameters, including the
`
`results of a physical examination, neuropsychiatric examinations, or psychiatric evaluation.
`
`[0032]
`
`By an "effective" amount or
`
`a
`
`"therapeutically effective amount" or
`
`"a
`
`pharmaceutically effective amount" of a drug or pharmacologically active agent is meant a
`
`nontoxic but sufficient amount of the drug or agent to provide the desired effect. The amount
`
`that is "effective" will vary from subject to subject, depending on the age and general
`
`condition of the individual, the particular active agent or agents, and the like. Thus, it is not
`
`always possible to specify an exact "effective amount." However, an appropriate "effective"
`
`amount in any individual case may be determined by one of ordinary skill in the art using
`
`routine experimentation.
`
`[0033]
`
`The term "pharmaceutically acceptable salt"
`
`refers to salts prepared from
`
`pharmaceutically acceptable inorganic and organic acids.
`
`[0034]
`
`The terms "desiccant," "first desiccant," and "second desiccant" as used herein
`
`refer to a pharmaceutically acceptable hygroscopic material that serves to maintain a state of
`
`dryness. These desiccants serve to eliminate humidity from the air and they adsorb moisture,
`
`thereby creating and sustaining a dry, moisture-free environment. Suitable pharmaceutically
`
`acceptable desiccants include, for example, sodium alginate, starch, and thelike.
`
`[0035]
`
`The term "buffering agent" or "buffer" mean any pharmaceutically acceptable
`
`weak base or strong base and mixtures thereof which, when formulated or delivered before,
`
`during and/or after the proton pumpinhibitor, such as omeprazole, functions to substantially
`
`prevent or inhibit acid degradation of the proton pump inhibitor by gastric acid and to
`
`preserve the oral bioavailability of the proton pump inhibitor.
`
`[0036]
`
`The term "percentage of moisture" refers to a value measured using Loss on
`
`Drying (LOD) method which involves heating a sample (e.g., sodium alginate or omeprazole)
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`at 90 °C for 5 minutes and determining the % weightloss.
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`[0037]
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`The term "multi-dose", as used herein, means that the omeprazole powder system,
`
`after being constituted with water, can be administered in multiple doses over a period of
`
`time, e.g., for more than 7 days, more than 14 days, or more than 28 days.
`
`[0038]
`
`The term "stable" or "storage-stable," as used herein, refers to chemical stability,
`
`wherein not more than 5% w/w of total related substances, e.g. omeprazole degradation
`
`products, are formed on storage at 40°C and 75% relative humidity (RH) for a period of at
`
`least 6 months, or at 25°C and 60% relative humidity for at least 2 years, to the extent
`
`necessary for the sale and use of the omeprazole powder system described herein.
`
`[0039
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`As used herein, the phrase "low viscosity grade sodium alginate" refers to sodium
`
`alginates having solution viscosities of less than about 100 millipascal second (mPa.s) in 3%
`
`aqueous solutions.
`
`Suitable low viscosity grade sodium alginates include, for example,
`
`Manucol® LB (by FMC Biopolymer).
`
`[0040]
`
`The term "GERD" refers to gastro-esophageal reflux disease. This is a disease
`
`where acid from the stomach escapesinto the gullet (the tube which connects the throat to the
`
`stomach) causing pain,
`
`inflammation, and heartburn.
`
`In children,
`
`the symptoms of the
`
`condition can include the return of stomach contents into the mouth (regurgitation), being
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`sick (vomiting), and poor weight gain.
`
`[0041]
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`The term "PICS" refers to Protection In Situ Constitution System. The PICS
`
`system is a bottle with an integrated cap as shown in FIG. 1. Omeprazole (or any PPI)
`
`containing mixture is in a dry form in the cap until the point of constitution. A diluent phase,
`
`such as the second mixture described below,
`
`is included in the bottle. At the time of
`
`constitution, the drug loaded mixture is released from the cap into the diluent phase (or the
`
`second mixture) by twisting the cap and subsequently water is added for constitution.
`
`[0042]
`
`As used herein, the term "child" is a human being between the stages of birth and
`
`puberty.
`
`[0043]
`
`The term "puberty" is the process of physical changes through which a child's
`
`body matures into an adult body capable of sexual reproduction. On average, girls begin
`
`puberty around ages 10-11 and end puberty around 15-17; boys begin around ages 11-12
`
`and end around 16-17.
`
`[0044]
`
`As used herein, the term "infant" is the synonym for "baby," the very young
`
`offspring of a human. The term "infant" is typically applied to young children under one year
`
`of age.
`
`[0045]
`
`[0046]
`
`As used herein, the term "toddler" refers to a child of 12 to 36 monthsold.
`
`As used herein, the term "preadolescent" refers to a person of 10—13 yearsold.
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`[0047]
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`As usedherein, the term "adolescent" refers to a person between ages 10 and 19.
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`Storage-Stable Systems described herein
`
`[0048]
`
`Although proton pump inhibitors, such as omeprazole, are widely used for
`
`treatment of gastric acid-mediated disorders in patients, their chemical instability in acidic
`
`media does not allow formulation of simple aqueous dosage forms for therapy. The present
`
`disclosure provides storage-stable PPI systems that upon constitution with water provide oral
`
`pharmaceutical PPI
`
`suspensions for administering effective amounts of a PPI or a
`
`pharmaceutically acceptable salt
`
`thereof,
`
`such as omeprazole or a pharmaceutically
`
`acceptable salt thereof, to a subject in need thereof, while having acceptable levels of sodium
`
`for administering to pediatric subjects. The oral pharmaceutical suspensions of the present
`
`disclosure have an acceptable buffering capacity for pediatric subjects.
`
`In some
`
`embodiments, the buffering capacity of the oral pharmaceutical suspensions described herein
`
`is about 2 mEq/mlofthe oral suspension. This is achieved, for example, by using a balanced
`
`buffering system based on sodium bicarbonate and potassium bicarbonate.
`
`In some
`
`embodiments, the buffering capacity of the oral pharmaceutical suspensions described herein
`
`is from about 0.5 mEq/ml to about 4 mEq/ml of the oral suspension.
`
`In some embodiments,
`
`the buffering capacity of the oral pharmaceutical suspensions described herein is from about
`
`1.6 mEq/ml to about 2.3 mEq/mlof the oral suspension.
`
`[0049]
`
`In one aspect, the present disclosure provides a storage-stable PPI system (such as
`
`a storage-stable omeprazole system),
`
`the system comprising a therapeutically effective
`
`amount of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole, or a
`
`pharmaceutically acceptable salt
`
`thereof, wherein the system contains a percentage of
`
`moisture of no more than about 2.5%, and wherein the system contains no sodium from a
`
`sodium-containing buffering agent or contains sodium and potassium at a ratio of from about
`
`1:100 to about 100:1 by weight, and further wherein the storage-stable PPI system is
`
`constituted with water prior to administration. In certain embodiments, the storage-stable PPI
`
`system contains sodium and potassium at a ratio of from about 1:50 to about 50:1 by weight.
`
`In certain embodiments, the storage-stable PPI system contains sodium and potassium at a
`
`ratio of from about 1:10 to about 10:1 by weight. In certain embodiments, the storage-stable
`
`PPI system contains sodium and potassium at a ratio of from about 1:2 to about 1:5 by
`
`weight.
`
`Atty. Dkt. No. 4384.0010003/MSB/THN
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`-ll-
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`[0050]
`
`In some embodiments, the storage-stable PPI system (such as a storage-stable
`
`omeprazole system) contains no sodium from a sodium-containing buffering agent 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 bitartrate, disodium tartrate, and sodium succinate.
`
`[0051]
`
`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 a percentage of moisture of no more than
`
`about 2.5%, and wherein the system contains sodium and potassium at a ratio of from about
`
`1:2.6 to about 1:3.4 by weight, and further wherein the storage-stable PPI system is
`
`constituted with water prior to administration.
`
`In some embodiments of this aspect, the
`
`sodium and potassium are present at a ratio of about 1:3.2 by weight.
`
`[0052]
`
`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 percentage of moisture of no more than about 1%.
`
`[0053]
`
`Suitable PPIs (proton pump inhibitors) that can be used in the storage-stable PPI
`
`system described
`
`herein
`
`include,
`
`for
`
`example,
`
`omeprazole,
`
`hydroxyomeprazole,
`
`esomeprazole,
`
`lansoprazole, pantoprazole, dexlansoprazole,
`
`rapeprazole, dontoprazole,
`
`tenatoprazole, and_thehaberprazole, ransoprazole, pariprazole, and leminoprazole,
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutically acceptable salts thereof.
`
`In some embodiments, the PPI is selected from the
`
`group consisting of omeprazole, esomeprazole, lansoprazole, pantoprazole, dexlandoprazole,
`
`rabeprazole, and the pharmaceutically acceptable salts thereof.
`
`In some embodiments, the
`
`PPI is omeprazole or esomeprazole, or a pharmaceutically acceptable salt thereof. Examples
`
`of suitable PPI pharmaceutically acceptable salts include, for example, sodium, magnesium,
`
`calcium and potassium salts, such as for example, omeprazole sodium salt, omeprazole
`
`magnesium salt, omeprazole calcium salt, omeprazole potassium salt, esomeprazole sodium
`
`salt, esomeprazole magnesium salt, esomeprazole calcium salt, and esomeprazole potassium
`
`salt.
`
`[0054]
`
`In some embodiments, the PPI is omeprazole or a pharmaceutically acceptable salt
`
`thereof.
`
`In some embodiments, the PPI is omeprazole (i.e., the neutral form of omeprazole
`
`without a salt forming cation present).
`
`In some embodiments, the PPI is esomeprazole or a
`
`Atty. Dkt. No. 4384.0010003/MSB/THN
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`-12-
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`pharmaceutically acceptable salt thereof.
`
`In some embodiments, the PPI is esomeprazole
`
`(i.e., the neutral form of esomeprazole without a salt forming cation present).
`
`[0055]
`
`In some embodiments,
`
`the storage-stable PPI
`
`system further comprises a
`
`desiccant. Suitable desiccants include any desiccants that are pharmaceutically acceptable
`
`and serve to maintain dryness by eliminating humidity from the air and absorbing moisture,
`
`thereby creating and sustaining a dry, moisture-free environment for the PPI.
`
`Suitable
`
`pharmaceutically acceptable desiccants include, for example, sodium alginate, starch, and the
`
`like.
`
`In some embodiments, the desiccant is sodium alginate. The desiccant can comprise
`
`one pharmaceutically acceptable desiccant or a mixture of two or more pharmaceutically
`
`acceptable desiccants.
`
`[0056]
`
`In some embodiments,
`
`the sodium alginate present in the storage-stable PPI
`
`systems described hereinis dry, i.e., the sodium alginate contains a percentage of moisture of
`
`less than about 2%.
`
`In some embodiments, the storage-stable PPI systems comprise dry
`
`sodium alginate that has a moisture content of about 0.5% to about 1.5%.
`
`[0057]
`
`In some embodiments, the sodium alginate present in storage-stable PPI systems
`
`described herein, such as in storage-stable omeprazole systems, is low viscosity grade sodium
`
`alginate. Suitable low viscosity grade sodium alginates have solution viscosities of less than
`
`about 100 millipascal second (mPa.s) in 3% aqueous solutions. Examples of suitable low
`
`viscosity grade sodium alginates include Manucol® LB (by FMC Biopolymer).
`
`[0058]
`
`In some embodiments, storage-stable PPI systems described herein, such as
`
`storage-stable omeprazole systems, comprise one or more buffering agents.
`
`In some
`
`embodiments, storage-stable PPI systems described herein comprise 1, 2, 3, or 4 buffering
`
`agents. In some embodiments, storage-stable PPI systems described herein comprise one
`
`buffering agent.
`
`In some embodiments, storage-stable PPI systems described herein
`
`comprise 2 or 3 buffering agents.
`
`In some embodiments, storage-stable PPI systems
`
`described herein comprise 2 buffering agents.
`
`[0059]
`
`The storage-stable PPI system described herein,
`
`such as the storage-stable
`
`omeprazole system, can comprise any suitable buffering agent that functions to substantially
`
`prevent or inhibit the acid degradation of the PPI (such as omeprazole or a pharmaceutically
`
`acceptable salt thereof) by gastric acid sufficient to preserve the bioavailability of the PPI
`
`administered.
`
`In some embodiments,
`
`the one or more buffering agents are each
`
`independently selected from the group consisting of alkali metal or alkaline earth metal
`
`carbonates, bicarb