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`EXHIBIT 76
`
`EXHIBIT 76
`
`
`
`

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`Bx H-t8tT~ 7.
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0235807 A1
`Weinrich et al.
`(43) Pub. Date:
`Nov. 25, 2004
`
`US 2004023580’/A1
`
`(54) FORMULATIONS INCLUDING A TOPICAL
`DECONGESTANT AND A TOPICAL
`CORTICOSTEROID SUITABLE FOR NASAL
`ADMINISTRATION AND METHOD FOR
`TREATING OBSTRUCTIVE SLEEP APNEA
`
`(76)
`
`Inventors: Karl P. Weinrich, Bridgewater, MA
`(US); Leonard W. Kaplan, Brookline,
`MA (US)
`
`Correspondence Address:
`REED & EBERLE LLP
`800 MENLO AVENUE, SUITE 210
`MENLO PARK, CA 94025 (US)
`
`(21) Appl. No.:
`
`10/443,672
`
`(22)
`
`Filed:
`
`May 21, 2003
`
`Publication Classification
`
`(51)
`
`Int. Cl.7
`
`A61K 31/573; A61K 31/137
`
`(52) U.S. Cl.
`
`.......................................... .. 514/171; 514/649
`
`(57)
`
`ABSTRACT
`
`A pharmaceutical formulation is provided for nasal drug
`administration of a topically administrable decongestant, a
`topically aclministrable corticosteroid and a pharmaceuti-
`cally acceptable carrier, and may optionally include further
`carriers, therapeutic extenders, and the like. Such formula-
`tions may also optionally further include a therapeutically
`active member selected from the group consisting of a
`topical antibiotic, a topical antihistamine (preferably a non-
`sedating antihistamine), a leukotriene D4 antagonist, a 5-h-
`poxygenase inhibitor, and a FLAP antagonist, or a pharma-
`ceutically acceptable salt thereof. In addition, methods for
`using the formulation to treat decongestant/corticosteroids-
`responsive conditions, diseases or disorders such as chronic
`obstructive nasal congestion and/or obstructive sleep apnea
`conditions, are provided, as are drug delivery devices and
`dosage forms for housing and/or dispensing the formula-
`tions.
`
`156
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`US 2004/0235807 A1
`#
`
`' Nov. 25, 2004
`
`FORMULATIONS INCLUDING A TOPICAL
`DECONGESTANT AND A TOPICAL
`CORTICOSTEROID SUITABLE FOR NASAL
`ADMINISTRATION AND METHOD FOR
`TREATING OBSTRUCTIVE SLEEP APNEA
`
`TECHNICAL FIELD
`
`[0001] This invention relates generally to pharmaceutical
`formulations, and more particularly relates to pharrnaceuti-
`cal formulations comprising at least one topical corticoster-
`oid and at least one topical nasal decongestant (e.g., sym-
`pathomimetic amine), and one or more optional members
`selected from the group consisting of carriers, extenders and
`excipients, In addition, the invention relates to methods of
`using the described formulations and drug delivery devices
`containing the described formulations in the treatment of
`chronic nasal congestion and/or in the treatment of obstruc-
`tive sleep apnea.
`
`BACKGROUND ART
`
`In a normal person, the nasal turbinates, small,
`[0002]
`shelf-like, structures composed of thin bone and covered by
`mucous membranes (mucosal), protrude into the nasal air-
`way and help to wamn, humidify and cleanse air as it is
`inhaled and before it reaches the lungs. Since the nasal
`airway is the normal breathing route during sleep, chronic
`enlargement (hypertrophy) of the nasal turbinates (caused by
`conditions such as chronic nasal congestion) can contribute
`to headaches and cause sleep disorders such as snoring and
`obstructive sleep apnea. Such chronic turbinates hypertro-
`phy and nasal obstruction are commonly associated with
`chronic rhinitis (the inflammation of the mucosal lining of
`the nose). When the mucosal tissue becomes inflamed, the
`blood vessels inside the membrane swell and expand, caus-
`ing the turbinates to become enlarged and obstruct the flow
`of air through the nose. According to several large popula-
`tions surveys, approximately 20% of the population, or more
`than 50 million Americans, suffer from some type of chronic
`rhinitis.
`
`[0003] Medications designed to treat the stuffy nose, sinus
`complaints and the common cold make up the largest
`segment of the over-the-counter drug market for the U.S.
`pharmaceutical industry, accounting for nearly $3.5 billion
`in sales. First-line medical treatment for the chronic stulfy
`nose and chronically enlarged turbinates associated with
`rhinitis mainly consists of a variety of antihistamines,
`decongestants, and topical and systemic corticosteroids.
`Surgery to reduce the size of the nasal turbinates with a
`concurrent reduction of symptoms is sometimes utilized, but
`this does not entirely cure such conditions in many patients.
`Post surgery continued swelling of the mucosal
`lining
`throughout the nasal passages (and deep in the sinuses)
`continues to aggravate the patients’ condition with a return
`of symptoms and conditions. Accordingly, surgery often
`does not cure or give adequate chronic relief for the under-
`lying condition.
`
`[0004] Topical decongestants (as nasal sprays) are used to
`treat a chronic stulfy nose, but such use is not without
`serious drawbacks. Such topical decongestants act by con-
`stricting the blood vessels in swollen mucous membranes,
`forcing blood out so that the membranes shrink and air
`passages open. Typical commercial nasal sprays contain
`
`such as
`sympathomirnetic compounds (decongestants),
`0.05% oxymetazoline in Afrin® and the, like. Common
`over-the-counter remedies contain phenylephrine hydro-
`chloride, oxymetazoline hydrochloride, xylometazoline
`hydrochloride, and the like. These topical decongestants are
`generally considered to be harmful when used over long
`periods of time because they cause damage to nasal mucosal
`ciliary function, and they cause rebound mucosal thickening
`leading to nasal congestion. The manufacturers of certain
`over-the-counter remedies often warn that their products
`should not be used for more than three days. The use or
`abuse of these drugs can result in prolonged nasal obstruc-
`tion (“rebound” can be worse than initial symptoms), where
`addictive use behavior can occur to avoid such uncomfort-
`able rebound nasal congestion.
`
`-Several corticosteroid therapies, mostly in the form
`[0005]
`of a nasal spray or inhaler, have been developed to treat
`chronic nasal obstruction. Intranasal corticosteroid sprays
`are available only by prescription and they can be very
`elfective, however, they are associated with side efiects such
`as bleeding, drying and crusting. Patients must take care not
`to overuse corticosteroid preparations. Although the drugs
`are applied topically, some systemic absorption of the agent
`occurs, which can disrupt the body’s steroid balance. Ste-
`roids can also be injected directly into the turbinates, how-
`ever, their elfectiveness usuallylasts only three to six weeks.
`The anti-inflammatory effect of steroid sprays may produce
`a beneficial reaction in the nasal and sinus mucosa. How-
`ever, such sprays are generally effective only in reducing
`inflammation, and only have inconsequential decongestant
`or physiological mucosal elfects in mobilizing secretions or
`stimulating cells to evacuate secretions.
`
`[0006] As mentioned above, chronic enlargement (hyper-
`trophy) of the nasal turbinates (caused by conditions such as
`chronic nasal congestion) can cause sleep disorders such as
`snoring and obstructive sleep apnea. Obstructive sleep apnea
`(also referred to herein as “OSA”) is a breathing disorder
`that occurs primarily during sleep with consequences that
`may persist throughout the waking hours in the form of
`sleepiness, thereby manifesting itself into substantial eco-
`nomic loss (e.g., thousands of lost man—hours) or employ-
`ment safety factors (e.g., employee non-attentiveness during
`operation of heavy-machinery). Such sleep-related breath-
`ing disorders are characterized by repetitive reduction in
`breathing (hypopnea), periodic cessation of breathing
`(apnea), or a continuous or sustained reduction in ventila-
`tion. OSA is a significant public health burden. Such OSA
`disorder and related symptoms affects all races, ages and
`socioeconomic and ethnic groups. There is no known phar-
`macological treatment for OSA on the market that is gen-
`erally successful.
`
`In general, sleep apnea is defined as an intermittent
`[0007]
`cessation of airflow at the nose and month during sleep. By
`convention, apneas of at least 10 seconds in duration have
`been considered important, but
`in most
`individuals the
`apneas are 20-30 seconds in duration and may be as long as
`2-3 minutes. While there is some uncertainty as to the
`minimum number of apneas that should "be considered
`clinically important, by the time most_ individuals come to
`attention of the medical community they have at least 10 to
`15 events per hour of sleep.
`
`[0008] Sleep apneas have been classified into three types:
`central, obstructive, and mixed. In central sleep apnea the
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`neural drive to all respiratory muscles is transiently abol-
`ished. In obstructive sleep apneas, airflow ceases despite
`continuing respiratory drive because of occlusion of the
`oropharyngeal airway. Mixed apneas, which consist of a
`central apnea followed by an obstructive component, are a
`variant of obstructive sleep apnea. The most common type
`of apnea is OSA.
`
`[0009] OSA syndrome has been identified in as many as
`24% of working adult men and 9% of similar women, with
`peak prevalence in the sixth decade. Habitual heavy snoring,
`which is an almost invariant feature of OSA, has been
`described in up to 24% of middle aged men, and 14% of
`similarly aged women, with even greater prevalence in older
`subjects.
`
`[0010] OSA syndrome’s definitive event is the occlusion
`of the upper airway, frequently at the level of the orophar-
`ynx. The resultant apnea generally leads to a progressive-
`type asphyxia until the individual is briefly aroused from the
`sleeping state, thereby restoring airway patency and thus
`restoring airflow. An important factor that
`leads to the
`collapse of the upper airway in OSA is the generation of a
`critical sub-atmospheric pressure during the act of inspira-
`tion that exceeds the ability of the airway dilator and
`abductor muscles to maintain airway stability. Sleep plays a
`crucial role by reducing the activity of the muscles of the
`upper airways including the dilator and abductor muscles.
`
`in addition to chronic
`In individuals with OSA,
`[0011]
`congestive nasal obstruction, the airway can be compro-
`mised structurally and be predisposed to occlusion. Obesity
`also frequently contributes to a reduction in size seen in the
`upper airways. The act of snoring, which is actually a
`high-frequency vibration of the palatal and pharyngeal soft
`tissues that results from the decrease in the size of the upper
`airway lumen, usually aggravates the narrowing via the
`production of edema in the soft tissues.
`
`[0012] The recurrent episodes of nocturnal asphyxia and
`of arousal from sleep that characterize OSA lead to a series
`of secondary physiologic events, which in turn give rise to
`the clinical complications of the syndrome. The most com-
`mon manifestations are neuro-psychiatric and behavioral
`disturbances that are thought to arise from the fragmentation
`of sleep and loss of slow-wave sleep induced by the recur-
`rent arousal responses. Nocturnal cerebral hypoxia also may
`play an important role. The most pervasive manifestation is
`excessive daytime sleepiness. OSA is now recognized as a
`leading cause of daytime sleepiness and has been implicated
`as an important risk factor for such problems as motor
`vehicle accidents. Other related symptoms include intellec-
`tual impairment, memory loss, personality disturbances, and
`impotence.
`
`[0013] The other major manifestations are cardio-respira-
`tory in nature and are thought to arise from the recurrent
`episodes of nocturnal asphyxia. Most individuals demon-
`strate a cyclical slowing of the heart during the apneas to 30
`to 50 beats per minute, followed by tachycardia of 90 to 120
`beats per minute during the ventilatory phase. A small
`number of individuals develop severe bradycardia with
`asystoles of 8 to 12 seconds in duration or dangerous
`tachyarrhythmias, including unsustained ventricular tachy-
`cardia. OSA also aggravates left ventricular failure in
`patients with underlying heart disease. This complication is
`most likely due to the combined elfects of increased left
`
`ventricular afterload during each obstructive event, second-
`ary to increased negative intrathoracic pressure, recurrent
`nocturnal hypoxemia, and chronically elevated sympathoa-
`drenal activity.
`
`[0014] Currently, the most common and most effective
`treatment for adults with sleep apnea and other sleep-related
`breathing disorders are mechanical forms of therapy that
`deliver continuous positive airway pressure (also referred to
`herein as “CPAP”). Under CPAP treatment, an individual
`wears a tight-fitting plastic mask over the nose when sleep-
`ing. The mask is attached to a compressor, which forces air
`into the nose creating a positive pressure within the patient’s
`airways. The principle of the method is that pressurizing the
`airways provides a mechanical “splinting”- action, which
`prevents airway collapse and therefore prevents OSA.
`Although an elfective therapeutic response is observed in
`most patients who undergo CPAP treatment, many patients
`cannot tolerate the apparatus or pressure and refuse treat-
`ment. Moreover, recent covert monitoring studies clearly
`demonstrate that long-terrn compliance with CPAP treat-
`ment is very poor.
`
`[0015] Avariety of upper airway and craniofacial surgical
`procedures have been attempted for treatment of OSA.
`Adenotonsillectomy appears to be an eifective cure for OSA
`in many children, but upper airway surgery is rarely curative
`in adult patients with OSA. Surgical ‘Esuccess” is generally
`taken to be a 50% reduction in apnea incidence and there are
`no useful screening methods to identify the individuals that
`would benefit from the surgery versus those who would not
`derive a benefit.
`
`[0016] Pharmacological treatments of several types have
`been attempted in patients with sleep apnea but, thus far,
`none have proven to be generally useful. A recent systematic
`review of these attempts is provided by Hudgel (1995) J.
`Lab. Clin. Med. 126213-18. A’ number of compounds have
`been tested because of their expected respiratory stimulant
`properties. These include (1) acetazolamide, a carbonic
`anhydrase inhibitor that produced variable improvement in
`individuals with primary central apneas but caused an
`increase in obstructive apneas, (2) medroxyprogesterone, a
`progestin that has demonstrated no consistent benefit in
`OSA, and (3) theophylline, a compound usually used for the
`treatment of asthma, which may benefit patients with central
`apnea but appears to be of no use in adult patients with
`obstructive apnea.
`
`treatment
`pharmacological
`attempted
`[0017] Other
`includes the administration of adenosine, adenosine analogs
`and adenosine reuptake inhibitors (US. Pat. No. 5,075,290
`to Findley, et al.). Specifically, adenosine, which is a ubiq-
`uitous compound within the body and which levels are
`elevated in individuals with OSA, has been shown to stimu-
`late respiration and is somewhat effective in reducing apnea
`in an animal model of sleep apnea.
`
`[0018] Other possible pharmacological treatment options
`for OSA include agents that stimulate the brain activity or
`agents
`that are opioid antagonists. Specifically,
`since
`increased cerebral spinal fluid opioid activity has been
`identified in OSA, it is a logical conclusion that central
`stimulants or opioid antagonists would be a helpful treat-
`ment of OSA. In reality, doxapram, which stimulates the
`central nervous system and carotid body chemoreceptors,
`was found to decrease the length of apneas but did not alter
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`
`the average arterial oxygen saturation in individuals with
`OSA. The opioid antagonist naloxone, which is known to
`stimulate ventilation, was only slightly helpful in individuals
`with OSA.
`
`[0019] Because OSA syndrome is strongly correlated with
`the occurrence of hypertension, agents such as angiotensin-
`converting enzyme (ACE) inhibitors may be of benefit in
`treating OSA individuals with hypertension but do not
`appear to be a viable treatment for OSA itself.
`
`[0020] Finally, several agents that act on neurotransmitters
`and neurotransmitter systems involved in respiration have
`been tested in individuals with OSA. Most of these com-
`pounds have been developed as anti-depressant medications
`that work by increasing the activity of monoamine neu-
`rotransmitters, ,including norepinephrine, dopamine, and
`serotonin. Protriptyline, a tricyclic anti-depressant, has been
`tested in several small trials with variable results and fre-
`quent and significant side elfects. As serotonin may promote
`sleep and stimulate respiration,
`tryptophan, a serotonin
`precursor and selective serotonin reuptake inhibitors have
`been tested in individuals with OSA. While a patent has been
`issued for the use of the serotonin reuptake inhibitor, flu-
`oxetine (U.S. Pat. No. 5,356,934 to Robertson, et al.), initial
`evidence suggests that these compounds may yield measur-
`able benefits in only approximately 50% of individuals with
`OSA. Therefore,
`in view of the fact that the only viable
`treatment
`for
`individuals
`sulfering from sleep-related
`breathing disorders is a mechanical form of therapy (CPAP)
`for which patient compliance is low, and that hopes for
`pharmacological treatments have yet to come to fruition,
`there remains a need for simple pharmacologically-based
`treatments that would offer benefits to a broad base of
`individuals suffering from a range of sleep-related breathing
`disorders. There also remains a need for a viable treatment
`of sleep-related breathing disorders that would lend itself to
`a high rate of patient compliance.
`
`In view of the above, current drugs only provide
`[0021]
`temporary symptomatic improvement and symptom reduc-
`tion for chronic congestive nasal obstruction that can lead to
`OSA, but due to significant side etfects must be rotated to
`avoid addition and subsequent rebound of symptoms. Sur-
`gery to reduce the size of the nasal
`turbinates is also
`sometimes utilized (as described above) to reduce symptoms
`in an attempt to treat sleep apnea, but this does not entirely
`cure such conditions in many patients. Post surgery contin-
`ued swelling of the mucosal lining throughout the nasal
`passages and in the sinuses continues to aggravate the
`patients’ condition with a return of symptoms, and thus, do
`not cure or give chronic relief for the underlying condition.
`
`[0022] There is, accordingly, a need in the art to provide
`a composition for the effective, safe, and long-term treat-
`ment of OSA and/or chronic nasal obstruction that may be
`related to OSA, which reduces significant side effects and
`also reduces withdrawal rebound nasal congestion.
`
`SUMMARY OF THE INVENTION
`
`[0023] One primary aspect of the invention is a method for
`treating a patient suifering from a chronic condition, disease
`or disorder that is responsive to treatment with a deconges-
`tant/corticosteroid combination, comprising nasally admin-
`istering to the patient a pharmaceutical formulation for nasal
`drug administration, wherein the formulation comprises: a
`
`therapeutically etfective amount of a topically administrable
`decongestant, a therapeutically eflective amount of a topi-
`cally administrable corticosteroid; and a pharmaceutically
`acceptable carrier that is suitable for nasal drug administra-
`tion.
`
`[0024] Another aspect of the invention is a method for the
`treatment of a patient suffering from chronic nasal conges-
`tive obstruction or obstructive sleep apnea (OSA) with a
`topical decongestant/corticosteroid combination, compris-
`ing nasally administering to the patient a pharmaceutical
`formulation for topical drug administration as described
`above. This method may provide for the long-term treatment
`of such conditions.
`
`[0025] Yet another aspect of the invention is a long-term
`treatment method for treating chrome nasal congestion and/
`or treating of OSA comprising daily administration of nasal
`pharmaceutical formulations that are adapted for such long-
`term administration (as described below), as well as drug
`delivery devices containing such formulations and means for
`daily administration in such methods.
`
`[0026] Other aspects of the invention involve the methods
`described above, that provide for the administration of a
`pharmaceutical composition that comprises at
`least one
`topically administrable nasal
`sympathomimetic
`amine
`decongestant, which is a member selected from the group
`consisting of: oxymetazoline, xylometazoline, naphazoline,
`phenylepbrine
`and
`pharmaceutically
`acceptable
`salts
`thereof.
`
`[0027] Still another aspect of the invention is a method
`that
`includes the administration of
`a composition, as
`described above, and may optionally further include a thera-
`peutically active agent selected from the group consisting of
`a topical antibiotic, a topical antihistamine (preferably a
`non-sedating antihistamine), a leukotriene D4 antagonist, a
`5-lipoxygenase inhibitor, and a 5-lipoxygenase-activating
`protein (FLAP) antagonist, or a pharmaceutically acceptable
`salt thereof.
`
`[0028] Another aspect of the invention is a pharmaceutical
`composition for nasal drug administration comprising: a
`therapeutically eifective amount of a topically administrable
`decongestant; a therapeutically elfective amount of a topi-
`cally administrable corticosteroid; and a pharmaceutically
`acceptable carrier that is suitable for nasal drug administra-
`tion.
`
`[0029] Still another aspect of the invention is a nasal or
`sinus drug delivery device, comprising: a topically admin-
`istrable pharmaceutical formulation as described above, and
`a means for housing and dispensing unit dosages of the
`formulation into a patient’s nasal passages and/or neighbor-
`ing sinuses. A preferred drug delivery device comprises an
`aqueous extender solvent system, whereby each dose deliv-
`ered has the ability to maintain a therapeutic elfect for a
`period of more than 6 hours.
`
`[0030] Still another aspect of the invention is a dosage
`form containing a topically administrable nasal pharrnaceu-
`tical formulation as described above, and optionally a unit
`dose delivery system. The system may include a means for
`housing and dispensing metered unit dosages of the formu-
`lation into a patient’s nasal passages and/or into the neigh-
`boring sinuses.
`
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`[0031] Additional aspects, advantages and features of the
`invention will be set forth in part in the description that
`follows, and in part will become apparent to those skilled in
`the art upon examination of the following, or may be learned
`by practice of the invention.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0032] This invention is based, in part, upon the unex-
`pected discovery that combination treatment of a patient
`with a nasally administrable decongestant and corticosteroid
`provides a treatment regimen wherein the adverse effects
`attributable to each member of the combination are essen-
`tially eliminated by the other member of the combination.
`
`the invention provides a
`In one embodiment,
`[0033]
`method for treating a patient suffering from a condition,
`disease or disorder that is responsive to treatment with a
`decongestant/corticosteroid
`combination,
`comprising
`nasally administering to the patient a pharmaceutical for-
`mulation for nasal drug administration, wherein the formu-
`lation comprises: (i) a therapeutically effective amount of a
`topically administrable decongestant; (ii) a therapeutically
`effective amount of a topically administrable corticosteroid;
`and (iii) a pharmaceutically acceptable carrier that is suitable
`for nasal drug administration. Any topically administrable
`decongestant may be utilized in the invention, including
`pharmacologically acceptable salts and esters thereof, as
`well as combinations of topical decongestants suitable to
`treat nasal or sinus congestion, may be included in the
`formulation. It is preferred, however, that the decongestant
`present be a sympathomirnetic amine. Topical decongestants
`in this class include, for example, oxymetazoline, xylom-
`etazoline, naphazoline, phenylephrine and pharmnaceuti-
`cally acceptable salts thereof.
`
`[0034] Although any salt, ester or derivative of a corti-
`costeroid that will yield a therapeutically etfective topical
`metabolite may serve as the topically administrable corti-
`costeroid in the above method, it is particularly preferred
`that an ester form, e.g., acetate form, thiophene ester form or
`furoate form is present in the formulation. Topical corticos-
`teroids in this class include, for example, beclomethasone,
`budesonide, flunisolide, fluticasone, flunidolone, mometa-
`sone, triamcinolone, dexamethasone, and pharmaceutically
`acceptable salts, esters, or derivatives thereof.
`
`In another embodiment, the invention provides a
`[0035]
`pharmaceutical composition for nasal drug administration,
`comprising: a therapeutically effective amount of a topically
`administrable decongestant;
`a
`therapeutically effective
`amount of a topically administrable corticosteroid; and a
`pharmaceutically acceptable carrier that is suitable for nasal
`drug administration.
`
`[0036] The topically administrable pharmaceutical formu-
`lations provided by the present invention are particularly
`well suited to the long-terrn treatment of patients sulfering
`from chronic obstructive nasal congestion and/or obstructive
`sleep apnea, as well as for the optional treatment of other
`conditions that may simultaneously afflict a patient, such as,
`for example, nasal or sinus allergic conditions, inflamma-
`tion, or infections. However, the formulations can be tai-
`lored to be etfective in the treatment of patients sulfering
`from both acute and chronic episodes of these maladies.
`
`In yet another embodiment, a drug delivery device
`[0037]
`is provided comprising a pharmaceutical formulation as
`described herein and a means for housing and dispensing
`unit dosages of the formulation. The drug delivery device
`may be any device that is effective in delivering the formu-
`lation to the nasal system and the nasal/cranial sinus system.
`Thus, for example, the drug delivery device may be a dry
`powder inhaler, a metered-dose inhaler (MDI), a nebulizer
`or a pump spray bottle. A dry powder
`inhaler is one
`particularly preferred device for delivering the formulations
`of the invention. Another preferred device is an aqueous
`based pump spray capable of delivering metered dosages of
`the formulations of the invention.
`
`I. Definitions and Nomenclature
`
`the invention is not
`[0038] Unless otherwise indicated,
`limited to specific synthetic methods, analogs, substituents,
`pharmaceutical
`formulations,
`formulation
`components,
`modes of administration, delivery systems, or the like, as
`such may vary. It is also to be understood that the termi-
`nology used herein is for the purpose of describing particular
`embodiments only, and is not intended to be limiting.
`
`It must be noted that, as used in this specification
`[0039]
`and the appended claims, the singular forms “a,”“ an” and
`“the” include plural referents unless the context clearly
`dictates otherwise. Non-limiting examples illustrating plural
`inclusion in the present specification are: references to “a
`decongestant” which term includes a combination of two or
`more decongestants, and when referring to a decongestant
`(such as oxymetazoline) without specifying a salt, ester,
`therapeutically active metabolite, or therapeutically active
`derivative also encompasses such structures and combina-
`tions thereof; references to “a corticosteroid” which term
`includes combinations of two or more corticosteroids and
`when referring to a corticosteroid (such as mometasone)
`without specifying a salt, ester,
`therapeutically active
`metabolite, or therapeutically active derivative includes such
`structures and combinations thereof; references to “a phar-
`maceutically acceptable carrier” includes liquid, solid or
`gaseous carriers and includes combinations of two or more
`pharmaceutically acceptable carriers; and the like. It will be
`understood by one skilled in this technology that a carrier
`may also optionally perform the function of a therapeutic
`“extender”, whereby the carrier may provide the therapeutic
`effect of extending the release time for an active agent in the
`formulation, or otherwise prolong the time for an active
`agent’s therapeutic effect.
`[0040]
`If utilized in the specification and ‘claims directed
`to the present invention, the following terminology will be
`used in accordance with the definitions set forth below.
`
`[0041] The terms “active agent,”“drug” and “pharmaco-
`logically active agent” are used interchangeably herein to
`refer to a chemical material, composition or compound
`which, when administered to an organism (human or ani-
`mal), induces a desired pharmacologic effect or activity.
`Such terms (and corresponding specified molecular entity
`examples) encompass not only a specified molecular entity,
`particular chemical structure,,0r root molecular structure,
`but also encompass pharmaceutically-acceptable, pharma-
`cologically active analogs,
`including, but not limited to,
`salts, esters, amides, prodrugs, conjugates, active metabo-
`lites, and other such derivatives, analogs, and related com-
`160
`
`MED_DYM_00011178
`
`

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`Case 1:14-cv-01453-LPS Document 43-18 Filed 10/22/15 Page 7 of 103 PageID #: 1460
`Case 1:14—cv—O1453—LPS Document 43-18 Filed 10/22/15 Page 7 of 103 Page|D #: 1460
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`US 2904/0235807 Al
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`Nov. 25, 2004
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`pounds which can be formulated to induce the desired
`pharmacologic activity (e.g., an active agent, such as a
`decongestant agent, might be recited in the specification or
`claims merely as “oxymetazoline” while this term encom-
`passes all the many active salts, derivatives and the like that
`are related to, or derived from, oxymetazoline and have
`decongestant activity).
`[0042] By “nasal administration” of a “topical drug” or
`"topically active drug” it is meant that the drug is applied to,
`or into, bodily tissues by some means or manner through the
`nares (nostrils) of a patient, and thereby has a resulting
`therapeutic effect upon one or more of: tissues in the nasal
`passages, tissues in the upper respiratory sinuses that are
`open to (or accessible from) the nasal passages, and other
`upper respiratory tissues, or may have a resulting optional
`systemic therapeutic effect, wherein such eifect(s) is/are
`primarily a result of topical absorption or infusion into
`tissues to which the drug is administered, or is/are a result
`of topically protecting or shielding such tissues from contact
`with environmental (or therapeutic) conditions or agents.
`Such administration (of an active ingredient to any part,
`tissue or organ that is directly or indirectly involved with the
`upper respiratory tract that when inflamed or swollen can
`lead to chronic obstructive nasal congestion and/or obstruc-
`tive sleep apnea) is accomplished by administering an active
`ingredient through one or more nasal openings. The above
`term is intended to contemplate the upper airway passages
`and include, for example, the back of the mouth or throat,
`nose, pharynx, oropharynx,
`laryngopharynx,
`larynx,
`the
`inner ear passages, and the sinuses that open into or drain
`into such areas. Thus,
`the phrase “nasal administration”
`includes administering of the formulation described herein
`to any part, tissue or organ within a patient that is directly or
`indirectly involved with either the external and internal nasal
`passages, or involved with the nasal sinuses.
`[0043] The terms “treating” -and “treatment” as used
`herein refer to reduction in severity and/or frequency of
`symptoms, elimination of symptoms and/or underlying
`cause, prevention of the occurrence of symptoms and/or
`their underlying cause, and improvement or remediation of
`damage. Thus, “treating” a patient with a compound of the
`