PEDIATRIC SUSPENSION FORMULATION
`
`BACKGROUND
`
`[0001]
`
`Omeprazole,
`
`5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methy]]sulfinyl-
`
`1H-benzimidazole, inhibits gastric acid secretion. Omeprazole belongsto 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 enzymesystem 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 pumpinhibitors,
`
`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]
`
`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
`
`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 460
`
`mg of sodium (Na’). Also available in the United States is a FIRST®-Omeprazole Compounding
`
`Kit that is comprised of omeprazole powder and FIRST-PPI (proton pump inhibitor) Suspension
`
`containing artificial strawberry flavor, benzyl alcohol, FD&C Red No. 40, Magnasweet 100
`
`{ammonium glycyrrhizate), poloxamer 188, propylene glycol, purified water, simethicone
`
`emulsion, sodium bicarbonate, sodium citrate (dihydrate), sucralose, and xanthan gum. When
`
`

`

`-2-
`
`compounded,
`
`the final product provides a homogenous suspension containing 2 mg/ml of
`
`omeprazole in FIRST®-PPI Suspension. 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 ata 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 presentat 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.
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`[0010]
`
`In another aspect, the present disclosure provides a storage-stable omeprazole system,
`
`-3-
`
`the 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
`
`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 presentat 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 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.
`
`[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.
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-4-
`
`[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 agents, and 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.
`
`[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 ata 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
`
`remainsstable 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
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-5-
`
`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 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
`
`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 andpotassium 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
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-6-
`
`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 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 appended
`
`claims.
`
`[0022]
`
`It is to be understood that both the foregoing summary and the following detailed
`
`description are exemplary and explanatory only, and are not restrictive of the invention as
`
`claimed.
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-7-
`
`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
`
`only, and is not intended to be limiting, since the scope of the present disclosure will be limited
`
`only by the appended claims.
`
`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 technologyis 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 belongs.
`
`If
`
`there is an apparent discrepancy between the usage ofa 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 numberor series of numbersis understood to include the
`
`number adjacent to the term "at least," and all subsequent numbers or integers that could
`
`logically be included, as clear from context. Whenat least is present before a series of numbers
`
`or a range,it is understood that "at least" can modify each of the numbersin the series or range.
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-8-
`
`[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 orintegers
`
`that could logically be included, as clear from context. When "no more than"is present before a
`
`series of numbers or a range,
`
`it is understood that "no more than" can modify each of the
`
`numbers in 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
`
`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 more tolerable 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 amountthat
`
`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
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-9-
`
`creating and sustaining a dry, moisture-free environment. Suitable pharmaceutically acceptable
`
`desiccants include, for example, sodium alginate, starch, and the like.
`
`[0035]
`
`The term "buffering agent" or "buffer" mean any pharmaceutically acceptable weak
`
`base or strong base and mixtures thereof which, when formulated or delivered before, during
`
`and/or after the proton pump inhibitor, 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) at 90 °C
`
`for 5 minutes and determining the % weightloss.
`
`[0037]
`
`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 oftotal 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]
`
`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 escapes into 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 sick (vomiting), and
`
`poor weightgain.
`
`[0041]
`
`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
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-10-
`
`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]
`
`Asused herein, the term "infant" is the synonym for "baby," the very youngoffspring
`
`of a human. The term "infant"is typically applied to young children under one yearofage.
`
`[0045]
`
`[0046]
`
`[0047]
`
`As used herein, the term "toddler" refers to a child of 12 to 36 monthsold.
`
`Asused herein, the term "preadolescent" refers to a person of 10-13 years old.
`
`Asused herein, the term "adolescent" refers to a person between ages 10 and 19.
`
`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/ml of the 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/mlto about 2.3 mEq/mlof the oral suspension.
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-ll-
`
`[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.
`
`[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 presentat 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°%%.
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-12-
`
`[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,
`
`haberprazole, ransoprazole, pariprazole, and leminoprazole, and the 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
`
`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 herein is 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
`
`Atty. Dkt. No. 4384.0010002/MSB/THN
`
`

`

`-13-
`
`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 ea