CELECOXIB COMPOSITIONS AND METHODS FOR THEIR USE

[001] This application claims the benefit of priority to U.S. Provisional Application 62/835,898, filed April 18, 2019, which is incorporated by reference in its entirety for all purposes.

[002] Composition and methods for management of signs and symptoms of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis; for the management of acute pain in adults and children and cancer related pain, and for the management of primary dysmenorrhea are provided. Furthermore, disclosed is a composition comprising celecoxib and methods of formulating and manufacturing the powder for oral solution.

[003] Celecoxib (4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-lH-pyrazol-l-yl] benzenesulfonamide) has a molecular formula is C ₁₇ H ₁₄ F ₃ N ₃ O ₂ S, a molecular weight of 381.38, and the following structure:

[004] Celecoxib is a white powder; insoluble in water; soluble in methanol and chloroform.

[005] Celecoxib is available as oral capsules containing either 50 mg, 100 mg, 200 mg or 400 mg of Celecoxib, together with inactive ingredients including: croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate.

[006] Celecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, celecoxib does not inhibit the cyclooxygenase- 1 (COX-1) isoenzyme. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.

[007] Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels (C _max ) and area under the curve (AUC) are roughly dose-proportional up to 200 mg BID; at higher doses there are less than proportional increases in C _max and AUC, which are thought to be due to the low solubility of the drug in aqueous media. Absolute bioavailability studies have not been conducted. With multiple dosing, steady- state conditions are reached on or before day 5.

[008] When celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%.

[009] Coadministration of celecoxib with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in C _max and 10% in AUC. CELEBREX, at doses up to 200 mg twice daily, can be administered without regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption.

[0010] In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when Celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in C _max , t _maX or t _½ after administration of capsule contents on applesauce.

[0011] Celecoxib is indicated for the management of the signs and symptoms of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis in patients 2 years and older, and ankylosing spondylitis; for the management of acute pain in adults, and for the management of primary dysmenorrhea.

[0012] The main medical concerns surrounding celecoxib are related to slow absorption and variable first-pass metabolism that limit its utility for treatment of acute pain. When a single dose of 200 mg of current formulation is given, peak plasma levels occur 3 hours after an oral dose, however, onset of pain relief could be as early as 1 hour. When taken with a high fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Since it is a painkiller shortening this time and the elimination of the delay of peak plasma concentrations could be advantageous.

[0013] . There is an unmet medical need for new effective formulations of celecoxib and methods for their use and production. The present disclosure satisfies this need and provides related advantages as well.

[0014] Citation of any reference throughout this application is not to be construed as an admission that such reference is prior art to the present application.

SUMMARY

[0015] Provided is a method for the management of signs and symptoms of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, or ankylosing spondylitis in a patient in need thereof; for the management of acute pain or cancer related pain in a patient in need thereof, and for the management of primary dysmenorrhea in a patient in need thereof comprising: administering a powder for oral solution formulation of celocoxib.

[0016] In some embodiments, the method comprises: administering a powder for oral solution formulation comprising a therapeutically effective amount of celecoxib to produce:

(a) a celecoxib time to reach peak plasma concentration (tmax) which is about 30 minutes to 60 minutes in the fasted state and 30 minutes to 360 minutes in the fed state, which is significantly earlier, than tmax provided by the same dosage of a conventional celecoxib capsule formulation

(b) a celecoxib exposure (AUC) which is about 2500 h*ng/ml to 12500 h*ng/ml and a more uniform celecoxib exposure (AUC) than the celecoxib exposure (AUC) provided by the same dosage of a conventional celecoxib capsule formulation; and

(c) a peak celecoxib plasma concertation (Cmax) which is about 300 ng/ml to 2850 ng/ml and a more uniform peak celecoxib plasma concertation (Cmax) than the peak celecoxib plasma concertation (Cmax) provided by the same dosage of a conventional celecoxib capsule formulation.

[0017] In some embodiments, the powder for oral solution formulation comprises a therapeutically effective amount of celecoxib to produce:

a peak celecoxib plasma concertation (Cmax) which is

a) about 800 to about 1300 ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fasted state;

b) about 2600 to about 2850 ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fasted state;

c) about 300 to about 600 ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fed state; or d) about 800 to about 1500 ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fed state; and/or exposure (AUC) which is

a) about 2500 to about 5400 h*ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fasted state;

b) about 4300 to about 11200 h*ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fasted state; c) about 2700 to about 6000 h*ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fed state; or d) about 5500 to about 12500 h*ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fed state; and/or time to reach peak plasma concentration (tmax) which is

a) about 30 to about 60 minutes when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fasted state;

b) about 15 to about 240 minutes when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fasted state;

c) about 30 to about 360 minutes when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fed state; or d) about 120 to about 360 minutes when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fed state.

[012] Also provided is a powder for oral solution comprising:

celecoxib;

a water soluble polymer matrix; and

one or more pharmaceutically acceptable excipients.

[013] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.

DESCRIPTION

[014] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[015] ADMINISTERING: As used herein,“administering” means to provide a compound or other therapy, remedy, or treatment such that an individual internalizes a compound.

[016] CO-ADMINISTER: As used herein,“co-administer“ and“co-administration” and variants thereof mean the administration of at least two drugs to a patient either subsequently, simultaneously, or consequently proximate in time to one another (e.g., within the same day, or week or period of 30 days, or sufficiently proximate that each of the at least two drugs can be simultaneously detected in the blood plasma). When co-administered, two or more active agents can be co-formulated as part of the same composition or administered as separate formulations. This also may be referred to herein as“concomitant” administration or variants thereof. [017] PRESCRIBING: As used herein, “prescribing” means to order, authorize, or recommend the use of a drug or other therapy, remedy, or treatment. In some embodiments, a health care practitioner can orally advise, recommend, or authorize the use of a compound, dosage regimen or other treatment to an individual. In this case the health care practitioner may or may not provide a prescription for the compound, dosage regimen, or treatment. Further, the health care practitioner may or may not provide the recommended compound or treatment. For example, the health care practitioner can advise the individual where to obtain the compound without providing the compound. In some embodiments, a health care practitioner can provide a prescription for the compound, dosage regimen, or treatment to the individual. For example, a health care practitioner can give a written or oral prescription to an individual. A prescription can be written on paper or on electronic media such as a computer file, for example, on a hand held computer device. For example, a health care practitioner can transform a piece of paper or electronic media with a prescription for a compound, dosage regimen, or treatment. In addition, a prescription can be called in (oral), faxed in (written), or submitted electronically via the internet to a pharmacy or a dispensary. In some embodiments, a sample of the compound or treatment can be given to the individual. As used herein, giving a sample of a compound constitutes an implicit prescription for the compound. Different health care systems around the world use different methods for prescribing and/or administering compounds or treatments and these methods are encompassed by the disclosure.

[018] A prescription can include, for example, an individual’s name and/or identifying information such as date of birth. In addition, for example, a prescription can include: the medication name, medication strength, dose, frequency of administration, route of administration, number or amount to be dispensed, number of refills, physician name, physician signature, and the like. Further, for example, a prescription can include a DEA number and/or state number.

[019] A healthcare practitioner can include, for example, a physician, nurse, nurse practitioner, or other related health care professional who can prescribe or administer compounds (drugs) for the treatment of a condition described herein. In addition, a healthcare practitioner can include anyone who can recommend, prescribe, administer, or prevent an individual from receiving a compound or drug including, for example, an insurance provider.

[020] PREVENT, PREVENTING, OR PREVENTION: As used herein, the term “prevent,”“preventing”, or“prevention,” such as prevention of a particular disorder or the occurrence or onset of one or more symptoms associated with the particular disorder and does not necessarily mean the complete prevention of the disorder. For example, the term“prevent,” “preventing” and “prevention” means the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disease or condition but who has not yet done so. Such individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease. Alternatively, prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of at least one symptom can also be considered prevention or prophylaxis.

[021] TREAT, TREATING, OR TREATMENT: As used herein, the term “treat,” “treating”, or“treatment” means the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example,“treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term “treating” in reference to a disorder means a reduction in severity of one or more symptoms associated with that particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.

[022] TOLERATE: As used herein, an individual is said to“tolerate” a dose of a compound if administration of that dose to that individual does not result in an unacceptable adverse event or an unacceptable combination of adverse events. One of skill in the art will appreciate that tolerance is a subjective measure and that what may be tolerable to one individual may not be tolerable to a different individual. For example, one individual may not be able to tolerate headache, whereas a second individual may find headache tolerable but is not able to tolerate vomiting, whereas for a third individual, either headache alone or vomiting alone is tolerable, but the individual is not able to tolerate the combination of headache and vomiting, even if the severity of each is less than when experienced alone.

[023] INTOLERANCE: As used herein,“intolerance” means significant toxicities and/or tolerability issues that led to a reduction in dose or discontinuation of the medication. “Intolerance” can be replaced herein with the term“unable to tolerate.”

[024] ADVERSE EVENT: As used herein, an“adverse event” is an untoward medical occurrence that is associated with treatment with an active ingredient. In one embodiment, an adverse event is selected from: leukopenia, constipation, diarrhea, nausea, abdominal pain, neutropenia, vomiting, back pain, and menstrual disorder. In one embodiment, an adverse event is heart block, for example, a first-degree atrioventricular heart block. In one embodiment, an adverse event is an acute heart rate reduction. In one embodiment, an adverse event is an abnormal pulmonary function test finding, such as an FEV1 below 80%, FVC. In one embodiment, an adverse event is an abnormal liver function test, such as an elevated ALT & AST>2X ULN. In one embodiment, an adverse event is macular edema.

[025] IN NEED OF TREATMENT and IN NEED THEREOF: As used herein,“in need of treatment” and“in need thereof’ when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc.) that an individual requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver’ s expertise, but that includes the knowledge that the individual is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.

[026] INDIVIDUAL: As used herein,“individual” means any human. In some embodiments, a human individual is referred to a“subject” or“patient.”

[027] THERAPEUTICALLY EFFECTIVE AMOUNT: As used herein, "therapeutically effective amount" of an agent, compound, drug, composition or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician. In some embodiments, the therapeutically effective amount is the standard dose.

[028] DOSE: As used herein,“dose” means a quantity of an active ingredient given to the individual for treating or preventing the disease or disorder at one specific time.

[029] STANDARD DOSE: As used herein,“standard dose” means the dose of the active ingredient that is given to the individual for treating or preventing the disease or disorder. The target dose may vary depending on the nature and severity of the disease to be treated. [030] PHARMACEUTICAL COMPOSITION : As used here,“pharmaceutical composition” or“composition” means a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome. Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[031] When an integer is used in a method disclosed herein, the term“about” can be inserted before the integer.

[032] Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as“comprises” or“comprising” will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers but not the exclusion of any other step or element or integer or group of elements or integers.

[033] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps, or group of compositions of matter shall be taken to encompass one and a plurality (/. _<? . one or more) of those steps, compositions of matter, groups of steps, or groups of compositions of matter.

[034] Each embodiment described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise.

[035] Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features unless specifically stated otherwise.

[036] The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[037] It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. For example, a method that recites prescribing and/or administering a given compound can be separated into two methods; one method reciting prescribing the compound and the other method reciting administering the compound. In addition, for example, a method that recites prescribing a compound and a separate method of the invention reciting administering a compound can be combined into a single method reciting prescribing and/or administering the compound.

[038] Provided is a celecoxib powder for oral solution compositions and methods for its use.

[039] Provided is a method for the management of signs and symptoms of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, or ankylosing spondylitis in a patient in need thereof; for the management of acute pain or cancer related pain in a patient in need thereof, and for the management of primary dysmenorrhea in a patient in need thereof comprising: administering a powder for oral solution formulation comprising a therapeutically effective amount of celecoxib to produce:

(a) a celecoxib time to reach peak plasma concentration (tmax) which is about 30 minutes to 60 minutes in the fasted state and 30 minutes to 360 minutes in the fed state, which is significantly earlier, than tmax provided by the same dosage of a conventional celecoxib capsule formulation

(b) a celecoxib exposure (AUC) which is about 2500 h*ng/ml to 12500 h*ng/ml and a more uniform celecoxib exposure (AUC) than the celecoxib exposure (AUC) provided by the same dosage of a conventional celecoxib capsule formulation; and

(c) a peak celecoxib plasma concertation (Cmax) which is about 300 ng/ml to 2850 ng/ml and a more uniform peak celecoxib plasma concertation (Cmax) than the peak celecoxib plasma concertation (Cmax) provided by the same dosage of a conventional celecoxib capsule formulation.

[040] Also provided is a method for the management of signs and symptoms of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, or ankylosing spondylitis in a patient in need thereof; for the management of acute pain or cancer related pain in a patient in need thereof, and for the management of primary dysmenorrhea in a patient in need thereof comprising:

administering a powder for oral solution formulation comprising a therapeutically effective amount of celecoxib to produce:

a peak celecoxib plasma concertation (Cmax) which is

a) about 800 to about 1300 ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fasted state;

b) about 2600 to about 2850 ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fasted state; c) about 300 to about 600 ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fed state; or d) about 800 to about 1500 ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fed state; and/or exposure (AUC) which is

a) about 2500 to about 5400 h*ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fasted state;

b) about 4300 to about 11200 h*ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fasted state; c) about 2700 to about 6000 h*ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fed state; or d) about 5500 to about 12500 h*ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fed state; and/or time to reach peak plasma concentration (tmax) which is

a) about 30 to about 60 minutes when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fasted state;

b) about 15 to about 240 minutes when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fasted state;

c) about 30 to about 360 minutes when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fed state; or d) about 120 to about 360 minutes when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fed state.

[041] In some embodiments, the celecoxib powder for oral solution is used for the management of signs and symptoms of osteoarthritis in a patient in need thereof. In some embodiments, the celecoxib powder for oral solution is used for the management of signs and symptoms of rheumatoid arthritis in a patient in need thereof. In some embodiments, the celecoxib powder for oral solution is used for the management of signs and symptoms of juvenile rheumatoid arthritis in a patient in need thereof. In some embodiments, the celecoxib powder for oral solution is used for the management of signs and symptoms of juvenile rheumatoid arthritis, or ankylosing spondylitis in a patient in need thereof.

[042] In some embodiments, the celecoxib powder for oral solution is used for the management of acute pain or cancer related pain in a patient in need thereof. In some embodiments, the celecoxib powder for oral solution is used for the management of cancer related pain in a patient in need thereof. In some embodiments, the celecoxib powder for oral solution is used for the management of acute pain in a patient in need thereof. In some embodiments, the celecoxib powder for oral solution is used for the management of acute pain arising from a dental procedure, such as a tooth extraction, an oral surgery, or a root canal surgery, in a patient in need thereof. In some embodiments, the tooth extraction is a molar extraction, such as a third molar extraction or an impacted molar extraction.

[043] In some embodiments, the celecoxib powder for oral solution is administered to a patient in need of pain control or extension of pain control that has been administered a regional or local anesthetic. In some embodiments, the celecoxib powder for oral solution is administered during a dental procedure, near completion of a dental procedure or immediately following a dental procedure. In some embodiments, the patient is provided with or extended pain (chronic or acute) control during a dental procedure or following a dental procedure.

[044] In some embodiments, the celecoxib powder for oral solution is used for the management of primary dysmenorrhea in a patient in need thereof.

[045] In some embodiments, the patient is an adult. In some embodiments, for example, for the treatment of juvenile rheumatoid arthritis, the patient is age two or older. In some embodiments, the patient is between the age of 12 and 18 years.

[046] In some embodiments, the celecoxib powder for oral solution is characterized by one or more of the following physicochemical properties:

(a) celecoxib spray-dried intermediate comprising celecoxib as active compound and pharmaceutical excipients chosen polyvinylcaprolactam-polyvinyl acetate- polyethylene-glycol graft copolymers, poloxamers; polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl-acetate, D-a-Tocopherol polyethylene glycol 1000 succinate crosslinked polyvinylpyrrolidone (crosspovidone), crosslinked cellulose and its sodium salt (crosscarmellose), crosslinked sodium carboxymethyl cellulose, sodium starch glycolate, crosslinked starch, sodium starch glycolate, colloidal silicon dioxide, sodium lauryl sulfate, and dioctyl sodium sulfosuccinate; or

(b) powder for oral solution composition comprising the mixture of celecoxib spray-dried intermediate and pharmaceutical excipients selected from lactose (anhydrous), lactose monohydrate, plant cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, anhydrous dibasic calcium phosphate, xylitol, dibasic calcium phosphate dihydrate, cellulose, methyl cellulose, cellulose ethers such as hydroxypropyl cellulose, magnesium stearate, talc, and sodium stearyl fumarate, sodium saccharine, saccharine, aspartame, Acesulfame-K, sodium cyclamate and strawberry aroma, raspberry aroma, mint aroma, and cherry aroma; wherein said celecoxib powder for oral solution characterized in that it possesses at least one of the following properties:

a) is instantaneously redispersible in physiological relevant media;

b) has a disintegration time not more than 10 minutes, preferably not more than 5 minutes in a glass of water

c) has increased dissolution rate in a glass of water - Q = 80% at 15 minutes, preferably at 5 minutes;

d) shows X-ray amorphous character of the API in the solid form;

e) stable for at least 6 months at 40°C without any significant decomposition or crystallization.

[047] In some embodiments, the therapeutically effective amount of celecoxib is from about

100 mg/day to about 200 mg/day providing:

peak celecoxib plasma concertation (Cmax) which is

a peak celecoxib plasma concertation (Cmax) which is

a) about 800 to about 1300 ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fasted state;

b) about 2600 to about 2850 ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fasted state;

c) about 300 to about 600 ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fed state; or d) about 800 to about 1500 ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fed state; and/or exposure (AUC) which is

a) about 2500 to about 5400 h*ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fasted state;

b) about 4300 to about 11200 h*ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fasted state; c) about 2700 to about 6000 h*ng/mL when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fed state; or d) about 5500 to about 12500 h*ng/mL when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fed state; and/or time to reach peak plasma concentration (tmax) which is

a) about 30 to about 60 minutes when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fasted state; b) about 15 to about 240 minutes when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fasted state;

c) about 30 to about 360 minutes when the powder comprising 100 mg of celecoxib is administered orally to the patient in a fed state; or d) about 120 to about 360 minutes when the powder comprising 200 mg of celecoxib is administered orally to the patient in a fed state.

[048] In some embodiments, the administration of said celecoxib powder for oral solution provides peak celecoxib plasma concertation (Cmax) which is about 800 to about 1300 ng/mL when 100 mg of celecoxib is administered orally in fasted state.

[049] In some embodiments, the administration of said celecoxib powder for oral solution provides peak celecoxib plasma concertation (Cmax) which is about 2600 to about 2850 ng/mL when 200 mg of celecoxib is administered orally in fasted state.

[050] In some embodiments, the administration of said celecoxib powder for oral solution provides peak celecoxib plasma concertation (Cmax) which is about 300 to about 600 ng/mL when 100 mg of celecoxib is administered orally in fed state.

[051] In some embodiments, the administration of said celecoxib powder for oral solution provides peak celecoxib plasma concertation (Cmax) which is about 800 to about 1500 ng/mL when 200 mg of celecoxib is administered orally in fed state.

[052] In some embodiments, the administration of said celecoxib powder for oral solution provides celecoxib exposure (AUC) which is about 2500 to about 4500 h*ng/mL when 100 mg of celecoxib is administered orally in fasted state.

[053] In some embodiments, the administration of said celecoxib powder for oral solution provides celecoxib exposure (AUC) which is about 4300 to about 11200 h*ng/mL when 200 mg of celecoxib is administered orally in fasted state.

[054] In some embodiments, the administration of said celecoxib powder for oral solution provides celecoxib exposure (AUC) which is about 2700 to about 600 h*ng/mL when 100 mg of celecoxib is administered orally in fed state.

[055] In some embodiments, the administration of said celecoxib powder for oral solution provides celecoxib exposure (AUC) which is about 5500 to about 12500 h*ng/mL when 200 mg of celecoxib is administered orally in fed state.

[056] In some embodiments, the administration of said celecoxib powder for oral solution provides celecoxib time to reach peak plasma concentration (tmax) which is about 30 to about 60 h*ng/mL when 100 mg of celecoxib is administered orally in fasted state. [057] In some embodiments, the administration of said celecoxib powder for oral solution provides celecoxib time to reach peak plasma concentration (tmax) which is about 15 to about 240 h*ng/mL when 200 mg of celecoxib is administered orally in fasted state.

[058] In some embodiments, the administration of said celecoxib powder for oral solution provides celecoxib time to reach peak plasma concentration (tmax) which is about 30 to about 360 h*ng/mL when 100 mg of celecoxib is administered orally in fed state.

[059] In some embodiments, the administration of said celecoxib powder for oral solution provides celecoxib time to reach peak plasma concentration (tmax) which is about 120 to about 360 h*ng/mL when 200 mg of celecoxib is administered orally in fed state.

[060] In some embodiments, the therapeutically effective amount of the celecoxib is from about 25 mg/day to about 200 mg/day.

[061] In some embodiments, the therapeutically effective amount of the celecoxib is from about 50 mg/day to about 150 mg/day.

[062] In some embodiments, the therapeutically effective amount of the celecoxib is from about 75 mg/day to about 125 mg/day.

[063] In some embodiments, the therapeutically effective amount of the celecoxib in the form of powder for oral solution is administered orally 2 times a day (BID) or 3 times a day (TID) or 4 times a day (QID).

[064] In some embodiments, the therapeutically effective amount of the celecoxib is 1 mg/kg administered TID.

[065] In some embodiments, the therapeutically effective amount of the celecoxib is 3 mg/kg/day.

[066] In some embodiments, the therapeutically effective amount of the celecoxib is 2 mg/kg administered TID.

[067] In some embodiments, the therapeutically effective amount of the celecoxib is 6 mg/kg/day.

[068] Also provided is a powder for oral solution comprising:

celecoxib;

a water soluble polymer matrix; and

one or more pharmaceutically acceptable excipients.

[069] In some embodiments, the powder comprises from about 5 to about 40% celecoxib.

[070] In some embodiments, the powder comprises from about 7.5 to about 30 % celecoxib.

[071] In some embodiments, the powder comprises from about 10 to about 25 % celecoxib.

[072] In some embodiments, the powder comprises from about 10 to about 15 % celecoxib. [073] In some embodiments, the water soluble polymer matrix is selected from polyvinylcaprolactam-poly vinyl acetate -poly ethylene-glycol graft copolymers, poloxamers; polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl-acetate and D-a-Tocopherol polyethylene glycol 1000 succinate.

[074] In some embodiments, the water soluble polymer matrix is polyvinylpyrrolidone or copolymers of vinylpyrrolidone and vinyl-acetate.

[075] In some embodiments, the water soluble polymer matrix is copolymer of vinylpyrrolidone and vinyl-acetate.

[076] In some embodiments, the powder comprises from about 35 to about 80 % of the water soluble polymer matrix.

[077] In some embodiments, the powder comprises from about 35 to about 75 % of the water soluble polymer matrix.

[078] In some embodiments, the powder comprises from about 45 to about 70 % of the water soluble polymer matrix.

[079] In some embodiments, the powder comprises from about 45 to about 65 % of the water soluble polymer matrix.

[080] In some embodiments, the powder comprises from about 45 to about 60 % of the water soluble polymer matrix.

[081] In some embodiments, the powder comprises from about 45 to about 55 % of the water soluble polymer matrix.

[082] In some embodiments, the one or more pharmaceutically acceptable excipients is chosen from one or more fillers and/or diluents.

[083] In some embodiments, the one or more fillers and/or diluents are chosen from lactose (anhydrous), lactose monohydrate, plant cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, anhydrous dibasic calcium phosphate, xylitol, and dibasic calcium phosphate dihydrate.

[084] In some embodiments, the one or more pharmaceutically acceptable excipients is chosen from one or more binders.

[085] In some embodiments, the one or more binders is selected from cellulose, methyl cellulose, microcrystalline cellulose, and cellulose ethers such as hydroxypropyl cellulose.

[086] In some embodiments, the one or more pharmaceutically acceptable excipients is chosen from one or more disintegrants and dispersing agents.

[087] In some embodiments, the one or more disintegrants and dispersing agents is selected from crosslinked polyvinylpyrrolidone (crosspovidone), crosslinked cellulose and its sodium salt (crosscarmellose), crosslinked sodium carboxymethyl cellulose, sodium starch glycolate, crosslinked starch, sodium starch glycolate, colloidal silicon dioxide, sodium lauryl sulfate, and dioctyl sodium sulfosuccinate.

[088] In some embodiments, the one or more disintegrant and dispersing agents is sodium lauryl sulfate.

[089] In some embodiments, the powder comprises from about 1 to about 15 % of one or more disintegrant and dispersing agents.

[090] In some embodiments, the powder comprises from about 2 to about 10 % of one or more disintegrant and dispersing agents.

[091] In some embodiments, the powder comprises from about 2 to about 8 % of one or more disintegrant and dispersing agents.

[092] In some embodiments, the powder comprises from about 2 to about 5 % of one or more disintegrant and dispersing agents.

[093] In some embodiments, the one or more pharmaceutically acceptable excipients is chosen from one or more lubricants.

[094] In some embodiments, the one or more lubricants is chosen from magnesium stearate, talc, and sodium stearyl fumarate.

[095] In some embodiments, the one or more pharmaceutically acceptable excipients is chosen from one or more flavoring agents and sweeteners.

[096] In some embodiments, the one or more flavoring agents and sweeteners is chosen from sodium saccharine, saccharine, aspartame, acesulfame-K, sodium cyclamate and strawberry aroma, raspberry aroma, mint aroma, and cherry aroma

[097] In some embodiments, the one or more flavoring agents and sweeteners is sodium saccharine.

[098] In some embodiments, the powder comprises from about 0.5 to about 10 % of one or more flavoring agents and sweeteners.

[099] In some embodiments, the powder for oral solution comprises:

one or more fillers and/or diluents chosen from lactose (anhydrous), lactose monohydrate, xylitol and microcrystalline cellulose;

one or more disintegrants and dispersing agents chosen from crosslinked polyvinylpyrrolidone (crosspovidone), crosslinked cellulose and its sodium salt (crosscarmellose), sodium starch glycolate, sodium lauryl sulfate;

one or more lubricants chosen from magnesium stearate, talc and sodium stearyl fumarate; and one or more sweetener chosen from sodium saccharine.

[100] In some embodiments, the powder for oral solution comprises

(a) 10-25 % celecoxib;

(b) 50-80 % copolymers of vinylpyrrolidone and vinyl-acetate as a water soluble polymer matrix;

(c) 1-15 % sodium lauryl sulfate as a dispersing agent; and

(d) 0.5 - 10% sodium saccharine as a sweeteners.

[101] In some embodiments, the powder for oral solution comprises

(a) celecoxib;

(b) water soluble polymer matrix selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers, poloxamers; polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl-acetate and D- a-Tocopherol polyethylene glycol 1000 succinate;

(c) fillers and/or diluents chosen from lactose (anhydrous), lactose monohydrate, plant cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, anhydrous dibasic calcium phosphate, xylitol, and dibasic calcium phosphate dihydrate;

(d) binders selected from cellulose, methyl cellulose, microcrystalline cellulose, and cellulose ethers such as hydroxypropyl cellulose;

(e) disintegrants and dispersing agents selected from crosslinked polyvinylpyrrolidone (crosspovidone), crosslinked cellulose and its sodium salt (crosscarmellose), crosslinked sodium carboxymethyl cellulose, sodium starch glycolate, crosslinked starch, sodium starch glycolate, colloidal silicon dioxide, sodium lauryl sulfate, and dioctyl sodium sulfosuccinate;

(f) lubricants chosen from magnesium stearate, talc, and sodium stearyl fumarate;

(g) flavoring agents and sweeteners chosen from sodium saccharine, saccharine, aspartame, acesulfame-K, sodium cyclamate and strawberry aroma, raspberry aroma, mint aroma, and cherry aroma.

[102] In some embodiments, the powder comprises

(a) 5 - 40 % celecoxib;

(b) 10 - 90 % water soluble polymer matrix selected from polyvinylcaprolactam- polyvinyl acetate-poly ethylene- glycol graft copolymers, poloxamers; polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl-acetate and D- a-Tocopherol polyethylene glycol 1000 succinate; (c) optionally, up to 90 % fillers and/or diluents chosen from lactose (anhydrous), lactose monohydrate, plant cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, anhydrous dibasic calcium phosphate, xylitol and dibasic calcium phosphate dihydrate;

(d) optionally, up to 20 % binders selected from cellulose, methyl cellulose, microcrystalline cellulose, and cellulose ethers such as hydroxypropyl cellulose;

(e) 1 - 15 % disintegrants and dispersing agents selected from crosslinked polyvinylpyrrolidone (crosspovidone), crosslinked cellulose and its sodium salt (crosscarmellose), crosslinked sodium carboxymethyl cellulose, sodium starch glycolate, crosslinked starch, sodium starch glycolate, colloidal silicon dioxide, sodium lauryl sulfate, and dioctyl sodium sulfosuccinate;

(f) optionally, up to 5% lubricants chosen from magnesium stearate, talc, and sodium stearyl fumarate; and

(g) 0.05 - 10 % flavoring agents and sweeteners chosen from sodium saccharine, saccharine, aspartame, Acesulfame-K, sodium cyclamate and strawberry aroma, raspberry aroma, mint aroma, and cherry aroma.

[103] In some embodiments, the powder for oral solution is suitable for oral administration.

[104] In some embodiments, the powder for oral solution disintegrates in liquids suitable for human consumption.

[105] In some embodiments, the liquids suitable for human use are selected from water, orange juice, apple juice, pineapple juice, and cranberry juice.

[106] In some embodiments, the powder for oral solution disintegrates in liquids suitable for human consumption in less than about 15 minutes.

[107] In some embodiments, the powder for oral solution disintegrates in liquids suitable for human consumption in less than about 10 minutes.

[108] In some embodiments, the powder for oral solution disintegrates in liquids suitable for human consumption in less than about 5 minutes.

[109] Further embodiments include the embodiments disclosed in the following Examples, which is not to be construed as limiting in any way.

EXAMPLES

Example 1

Composition [110] Some prototype compositions of powder for oral suspension are listed in Table 1 and Table 2.

Table 1. Compositions of Celecoxib powder for oral solution formulation prepared

Table 2. Compositions of Celecoxib powder for oral solution formulation prepared.

[111] Assay, related substances of the prepared compositions were investigated right after the production and 1 and 3-months later as well as the in-use stability of the reconstituted solution for up to 4-hours. No significant decomposition could be observed during the storage time. Results are seen in Table 3.

Table 3. Assay, related substances and in-use stability results of powder for oral solution compositions prepared.

[112] The process was scaled-up and 5 kg batch of sublot 11 was prepared. Celecoxib Powder for Oral Solution, manufacturing process consists of first spray drying the drug substance (Celecoxib) with the polymer matrix as Copolymer of vinylpyrrolidone and vinyl-acetate and the dispersing agent as Sodium Lauryl Sulfate to produce the Celecoxib spray dried powder. In order to remove the residual solvent post spray drying, the resultant Celecoxib spray dried powder is secondary dried for <24 hours at a temperature of 80°C to produce the Celecoxib Spray Dried Dispersion Intermediate. In process controls include assay and residual solvent testing. The Celecoxib Spray Dried Dispersion Intermediate screened and blended with pre- screened Saccharin Sodium and subjected to dry granulation prior to filling into a sachet to produce the final drug product. The granules were packed into an aluminum pouch and heat sealed.

Example 2

Pharmacokinetics in healthy man

Study design

[113] It was a single center, open-label, randomized, sequential, single dose crossover study in 5 periods to assess the PK and safety of single oral doses of celecoxib powder for oral solution. It was planned to enroll 20 healthy male and female subjects to ensure data in at least 16 subjects with PK and safety data up to 48 h after dosing for each regimen. Subjects were randomized to 1 of 5 sequences prior to dosing in the first period. Subjects were randomly allocated to each sequence per the randomization schedule. Each subject received the following treatments:

[114] Subjects were dosed on the morning of Day 1 of each study period. Subjects received a single administration of investigational drug on 5 separate occasions. The sachet of investigational drug was emptied into a dosing cup/jar and reconstituted with 90 mL purified water. A rinsing step with 10 mL purified water was performed to ensure the total administered volume was 100 mL, and was then made up to 240 mL with water to drink.

Lasted Dosing

[115] Subjects were provided with a light snack on the evening of Day - 1 and then fasted from all food and drink (except water) for a minimum of 10 h on the day prior to dosing until approximately 4 h post-dose, at which time lunch was provided. An evening meal was provided at approximately 10 h post-dose and an evening snack at approximately 14 h post-dose. On subsequent days, meals were provided at appropriate times.

Fed Dosing

[116] Subjects were provided with a light snack on the evening of Day - 1 and then fasted from all food and drink (except water) until the following morning, when they were provided with an FDA specified high-fat high-calorie breakfast.

[117] The breakfast was consumed over a maximum period of 25 min, with dosing occurring 30 min after the start of breakfast. Subjects were encouraged to eat their meal evenly over the 25 min period. It was acknowledged that some subjects took less time to eat, but dosing still occurred 30 min after the start of breakfast.

[118] Lunch was provided at approximately 4 h post-dose, an evening meal at approximately 10 h post-dose and an evening snack at approximately 14 h post-dose. On subsequent days, meals were provided at appropriate times.

Sample collection and analysis

[119] Venous blood samples were withdrawn via an indwelling cannula or by venipuncture. Blood samples were collected into 4 mL K3EDTA tubes, which were immediately stored on ice and processed within 60 min of collection by centrifugation at 2300 g for 10 min at 4°C. The resultant plasma was transferred into 2 appropriately labelled 3.5 mL polypropylene tubes, each containing at least 0.75 mL of plasma. Samples were frozen within 60 min of plasma processing and were stored at -20°C or below until they were shipped for the analysis of celecoxib. Plasma concentrations of celecoxib were determined using validated a liquid chromatography with tandem mass spectrometry method. The lower limit of quantification was 1 ng/mL for celecoxib.

[120] PK parameters are presented in Table 4 and 5 for the fasted state and fed state administration, respectively.

Table 4. Arithmetic Mean (SD) Plasma PK Parameters for Celecoxib Following Single Oral Doses of Celecoxib Administered as Celebrex Capsule (Reference) and Celecoxib Powder for Oral Solution in the Fasted State: PK Population

a Median (range); ^b 200 mg and 100 mg celecoxib powder for oral solution vs

200 mg Celebrex reference capsule.

Table 5. Arithmetic Mean (SD) Plasma PK Parameters for Celecoxib Following Single Oral Doses of Celecoxib Administered as Celebrex Capsule (Reference) and Celecoxib Powder for Oral Solution in the Fed State: PK Population

a Median (range)

Example 3

[121] An open-label, pharmacokinetic / dose finding study in pediatric patients aged 12 to < 18 years undergoing elective third molar extraction will be conducted. A total of 60 patients will be enrolled and randomized 1:1 to a celecoxib powder for oral solution formulation at either a low dose (n=30; 1 mg/kg TID [total of 3 mg/kg/day]) or a high dose (n=30; 2 mg/kg TID [total of 6 mg/kg/day]), not to exceed a total daily dose of 300 mg. Patients will be treated for a total of 2 days.

[122] The primary outcome will be total pain relief 0 to 8 hours after dosing. Safety and tolerability may be evaluated with physical examination, vital signs, pulse oximetry, clinical laboratory tests, ECGs, and incidence of Adverse Events (AEs) and Serious Aes.

[123] Secondary outcomes may include one or more of the following: ^■ Total Pain Relief 0 - 4 hours after dosing (TOTPAR4) [ Time Frame: Hour 4 postdose ]

^■ Total Pain Relief 0 - 6 hours after dosing (TOTPAR6) [ Time Frame: Hour 6

postdose ]

^■ Total Pain Relief 0 - 12 hours after dosing (TOTPAR12) [ Time Frame: Hour 12 postdose ]

^■ Total Pain Relief 0 - 24 hours after dosing (TOTPAR24) [ Time Frame: Hour 24 postdose ]

^■ Pain Relief (PR) over time [ Time Frame: Up to 24 hours postdose ]

^■ Pain intensity difference over time [ Time Frame: 15, 30, 45 , 60, 90 minutes; 2, 3, 4, 4.5, 6, 8, 10, 12 and 24 hours postdose ]

^■ Sum of pain intensity difference 0 to 4 hours after dosing (SPID4)

[ Time Frame: Hour 4 postdose ]

^■ Sum of pain intensity difference 0 to 6 hours after dosing (SPID6)

[ Time Frame: Hour 6 postdose ]

o Sum of pain intensity difference 0 to 8 hours after dosing (SPID8)

[ Time Frame: Hour 8 postdose ]

^■ Sum of pain intensity difference 0 to 12 hours after dosing (SPID12)

[ Time Frame: Hour 12 postdose ]

^■ Sum of pain intensity difference 0 to 24 hours after dosing (SPID24)

[ Time Frame: Hour 24 postdose ]

^■ Time to first perceptible PR [ Time Frame: Up to 24 hours postdose ]

^■ Time to meaningful PR [ Time Frame: Up to 24 hours postdose ]

^■ Time to first use of rescue pain medication [ Time Frame: Up to 24 hours

postdose ]

^■ Proportion of subjects taking rescue medication by time point [ Time Frame: Up to 24 hours postdose ]

^■ Global assessment of overall satisfaction [ Time Frame: Hour 24 postdose ]

[124] Other uses of the disclosed methods will become apparent to those in the art based upon, inter alia, a review of this patent document.