United States Patent 19
`Gray
`
`USOO5698558A
`Patent Number:
`11
`45 Date of Patent:
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`5,698,558
`Dec. 16, 1997
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`METHODS FOR TREATING ALLERGC
`DISORDERS USING OPTICALLY PURE (-)
`CETRIZINE
`Inventor: Nancy M. Gray, Marlboro, Mass.
`Assignee: Sepracor, Inc., Marlborough, Mass.
`
`Appl. No.:789,502
`Filed:
`Jan. 27, 1997
`Related U.S. Application Data
`
`Continuation of Ser. No. 167,724, Dec. 15, 1993, aban
`doned, which is a continuation of Ser. No. 951,179, Sep. 24,
`1992, abandoned.
`Int. Cl. ... A61K 3/495
`saao S14/255
`Field of Search ............................................... 514/255
`
`
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`56
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`References Cited
`U.S. PATENT DOCUMENTS
`4,525,358 6/1985 Balties et al. ............................ 54/255
`FOREIGN PATENT DOCUMENTS
`2225320 5/1990 United Kingdom.
`2225321 5/1990 United Kingdom.
`
`OTHER PUBLICATIONS
`De Vos & Maleux et al., Ann. Allergy, 59(4), 278-82, 1987.
`(from Chemical Abstracts -American Chemical Society).
`De Vos & Joseph et al., Int. Arch. Allergy Appl. Immunol.,
`88(1-2), 212-15, 1989. (from Chemical Abstracts).
`Gong et al., 90:243620 Biosis, BA89:130573, 1990.
`Testa et al. "Racemates Versus Enantiomers in Drug Devel
`opment: Dogmatism or Pragmatism?"Chirality;2 129-133
`(1990).
`Schoefter et al. "Competative and stereoselective histamine
`Hantagonistic effect..." Eur: J. Parmacol., 136,235-237
`(1987).
`Fricke et al. "Fortschiritte fir die Arzneimtteltherapi
`e?"Neue Arzneimittel 1990/1991, 14-21 (1991).
`Primary Examiner-William R.A. Jarvis
`Attorney, Agent, or Firm-Heslin & Rothenberg, P.C.
`57
`ABSTRACT
`Methods are disclosed utilizing optically pure (-) cetirizine
`for the treatment of seasonal and perennial allergic rhinitis
`in humans while avoiding the concomitant liability of
`adverse effects associated with the racemic mixture of
`cetirizine. The optically pure (-) isomer is also useful for the
`treatment of allergic asthma.
`
`18 Claims, No Drawings
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`Apotex, Inc. (IPR2019-00400), Ex. 1015, p. 001
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`1.
`METHODS FORTREATING ALLERGIC
`DISORDERS USING OPTICALLY PURE (-)
`CETRIZINE
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`This application is a continuation of application Ser. No.
`08/167,724, filed Dec. 15, 1993, now abandoned, which is
`itself a continuation of application Ser. No. 07/951,179, filed
`Sep. 24, 1992, now abandoned.
`BACKGROUND OF THE INVENTION
`This invention relates to novel compositions of matter
`containing optically pure (-) cetirizine. These compositions
`possess potent activity in treating seasonal and perennial
`allergic rhinitis, the symptoms of allergic asthma, chronic
`idiopathic urticaria, some types of physical urticaria, and
`other disorders including those that would benefit from an
`inhibitory action on eosinophil function. (-) Cetirizine
`inhibits eosinophil chemotaxis and function and the genera
`tion of cytotoxic mediators by blood platelets, providing
`therapy in immunologically-induced asthma with particular
`utility in the late phase of the disease episode. Optically pure
`(-) cetirizine provides this treatment while avoiding adverse
`effects, including, but not limited to, sedation and
`Somnolence, headache, gastrointestinal disturbance, anti
`cholinergic effects, dizziness, cardiac arrhythmias and other
`cardiovascular effects which are associated with the admin
`istration of the racemic mixture of cetirizine. Also disclosed
`are methods for treating the above described conditions in a
`human while avoiding the adverse effects that are associated
`with the racemic mixture of cetirizine by administering the
`(-) isomer of cetirizine to said human.
`The active compound of these compositions and methods
`is an optical isomer of cetirizine, the preparation of which is
`35
`described in U.S. Pat. No. 4,525.358 (Baltes et al.). The
`medicinal chemistry of cetirizine is described by Campoli
`Richards et al., Drugs 40, 762–781 (1990)), Snyder and
`Snowman Allergy 59 II, 4-8 (1987), and Rihoux and
`Dupont Annals of Allergy 59,235-238 (1987). Chemically,
`the active compound is the (-) isomer of 2-4-(4-
`chlorophenyl)phenylmethyl-1-piperazinyl) ethoxyacetic
`acid, hereinafter referred to as cetirizine.
`(-) Cetirizine, which is the subject of the present
`invention, is not presently commercially available; only the
`1:1 racemic mixture is commercially available as its dihy
`drochloride salt.
`Many organic compounds exist in optically active forms,
`i.e. they have the ability to rotate the plane of plane
`polarized light. In describing an optically active compound,
`the prefixes D and L or R and S are used to denote the
`absolute configuration of the molecule about its chiral
`center(s). The prefixes d and 1 or () and (-) are employed
`to designate the sign of rotation of plane-polarized light by
`the compound, with (-) or 1 meaning that the compound is
`levorotatory. A compound prefixed with (+) or dis dextroro
`tatory. There is no correlation between nomenclature for the
`absolute stereochemistry and for the rotation of an enanti
`omer. Thus, D-lactic acid is the same as (-) lactic acid, and
`L-lactic acid is (+). For a given chemical structure, these
`chiral compounds exist as a pair of enantiomers which are
`identical except that they are non-superimposable mirror
`images of one another. A specific stereoisomer may also be
`referred to as an enantiomer, and a mixture of such isomers
`is often called an enantiomeric or racemic mixture.
`Stereochemical purity is of importance in the field of
`pharmaceuticals, where 12 of the 20 most prescribed drugs
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`exhibit chirality. A case in point is provided by the L-form
`of the beta-adrenergic blocking agent, propranolol, which is
`known to be 100 times more potent than the D-enantiomer.
`Furthermore, optical purity is important since certain
`isomers may actually be deleterious rather than simply inert.
`For example, it has been suggested that the D-enantiomer of
`thalidomide was a safe and effective sedative when pre
`scribed for the control of morning sickness during
`pregnancy, while the corresponding L-enantiomer has been
`believed to be a potent teratogen. The synthesis of (+)
`cetirizine and (-) cetirizine are described in British appli
`cation 2,225.321, but no pharmacology of individual enan
`tiomers is reported.
`The racemic mixture of cetirizine is presently used pri
`marily in seasonal and perennial allergic rhinitis. The symp
`tomatology of immediate-type allergic diseases, including
`allergic rhinitis, presumably results from the antigen
`induced release of various pharmacologically active sub
`stances from mast cells, and from basophilic leukocytes. The
`substances thus released from these cells, and possibly
`others as well, are referred to as primary mediators of
`anaphylaxis and include, among others, histamine. The
`acute seasonal form of allergic rhinitis, hay fever, and
`perennial allergic rhinitis are characterized by sneezing,
`rhinorrhea, nasal congestion, pruritus, conjunctivitis and
`pharyngitis. In acute seasonal rhinitis, the nose, roof of the
`mouth, eyes and pharynx often itch, and lacrimation, sneez
`ing and clear, watery nasal discharge follow the pruritus.
`Additionally, frontal headaches, irritability, anorexia,
`depression and insomnia may occur. In perennial rhinitis,
`chronic nasal obstruction is often prominent and may extend
`to eustachian tube obstruction. For most patients, topical
`corticosteriods, some aerosol vasoconstrictor agents, and
`long acting antihistamine agents provide significant relief of
`symptoms. The action of cetirizine on non-immunologically
`(non IgE) mediated hypersensitivity reactions has been less
`clear although there are some suggestions of activity in the
`treatment of exercise induced asthma, cold urticaria, and
`non-specific bronchial hyperreactivity.
`Racemic cetirizine dihydrocholoride is an orally active,
`potent, long acting peripheral histamine H receptor antago
`nist. The compound is one of the second generation of H
`histamine receptor antagonists which generally offer some
`significant advantages beyond the first generation com
`pounds. The advantages include (1) less sedation, (2) little
`anticholinergic activity and (3) longer duration, which
`improves patient compliance. In addition to being competi
`tive inhibitors of histamine at the end organ site, second
`generation H histamine inhibitors appear to have other
`anti-allergic pharmacologic mechanisms which have led to
`their use in bronchial asthma, as well as in seasonal and
`perennial rhinitis and the chronic urticarias.
`Experiments ex vivo suggest that racemic cetirizine does
`not significantly penetrate the blood brain barrier. It has been
`suggested therefore that cetirizine's ability to provide a
`reduced incidence of sedative side effects may result in part
`from its receptor selectivity and in part from its relative
`exclusion from the CNS. Other experiments have suggested
`that cetirizine does not inhibitmast cell activation but rather
`that it antagonizes the action of histamine once released
`from the mast cell following antigen or chemical stimula
`tion. There are also reports that racemic cetirizine inhibits
`the degranulation of human basophis induced by anti IgE.
`Cetirizine has been shown to inhibit the chemotaxis of
`eosinophils to the tissues where they would otherwise con
`tribute to the pathogenesis of asthma.
`Cetirizine is rapidly absorbed upon oral administration
`and although food may slightly reduce the rate of absorption,
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`Apotex, Inc. (IPR2019-00400), Ex. 1015, p. 002
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`the extent is not affected. The compound is bound to plasma
`proteins and peak cetirizine concentrations in the brain are
`less than 10% that of the plasma concentration. Cetirizine is
`excreted in the urine largely as unchanged drug and the
`elimination half-life is roughly 7 to 10 hours.
`The racemic mixture of cetirizine may be useful in
`treating other disorders such as allergic pulmonary disease
`and particularly in treating the symptoms of allergic bron
`chial asthma. Patients who suffer from allergic bronchial
`asthma develop such clinical symptoms as wheezing and
`dyspnea after exposure to allergens, environmental irritants,
`viral infections, cold air and exercise. Many of the symp
`toms result from smooth muscle contraction and vascular
`dilatation, which, in turn, result from mediator release when
`the antigen reacts with the IgE antibody on the surface of a
`mast cell or basophil. This serves as a basis for the use of
`histamine H antagonists.
`In addition, racemic cetirizine may be useful for treating
`chronic idiopathic urticaria and some types of physical
`urticaria. Urticaria is characterized by local wheals and
`erythema in the dermis; acute urticaria is essentially an
`anaphylaxis that is limited to the skin and subcutaneous
`tissues. The condition may arise from food allergy, drug
`allergy, insect sting, or the like, and is distinct from chronic
`or idiopathic urticaria which may last for several weeks and
`can only rarely be associated with a specific cause. Because
`these urticarias appear in many cases to be IgE antibody
`mediated, many of the symptoms may be treated with a
`histamine H receptor antagonist such as cetirizine. The
`direct inhibition of eosinophil chemotaxis by cetirizine may
`also provide therapy to the late phase of allergic episodes in
`disorders such as allergic asthma, allergic rhinitis, and in
`other conditions characterized by eosinophilia.
`Many of the second generation histamine H receptor
`antagonists offer advantages over the first generation of
`histamine antagonists in that there is reduced sedation and
`anticholinergic activity. Nonetheless, some adverse effects
`remain, including, but not limited to, some incidence of
`sedation and somnolence; cardiovascular effects including
`arrhythmias; headache; gastrointestinal disturbances; dizzi
`ness and nausea. The racemic mixture of cetirizine has been
`found to cause many of these adverse effects, including
`sedation and somnolence. Thus, it would be particularly
`desirable to find a compound with the advantages of the
`racemic mixture of cetirizine which would not have the
`aforementioned disadvantages.
`SUMMARY OF THE INVENTION
`It has now been discovered that the optically pure (-)
`isomer of cetirizine is an effective agent for treating seasonal
`and perennial allergic rhinitis, the symptoms of allergic
`asthma, chronic idiopathic urticaria, some physical urticaria,
`and other disorders, including those that would benefit from
`an inhibitory action on eosinophilia, and eosinophil func
`tion. The optically pure (-) isomer of cetirizine provides this
`effective treatment while avoiding the adverse effects
`including, but not limited to, sedation and somnolence,
`headache, gastrointestinal disturbance, dizziness, nausea,
`cardiac arrhythmias and other cardiovascular effects. The
`present invention also includes methods for treating the
`above described conditions in a human while avoiding the
`adverse effects that are associated with the racemic mixture
`of cetirizine by administering the optically pure (-) isomer
`of cetirizine to said human.
`DETALED DESCRIPTION OF THE
`INVENTION
`The present invention encompasses a method of treating
`the symptoms of seasonal and perennial allergic rhinitis in a
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`human, which comprises administering to a human in need
`of such symptomatic relief therapy, an amount of (-)
`cetirizine, or a pharmaceutically acceptable salt thereof,
`substantially free of its (+) stereoisomer, said amount being
`sufficient to alleviate the symptoms of seasonal and peren
`nial allergic rhinitis. The method avoids the concomitant
`liability of adverse effects associated with the administration
`of the racemic compound by providing an amount which is
`insufficient to cause the adverse effects associated with the
`racemic mixture of cetirizine.
`The present invention also encompasses an antirhinitis
`composition for the treatment of a human in need of anti
`rhinitis therapy, which comprises an amount of (-)
`cetirizine, or a pharmaceutically acceptable salt thereof,
`substantially free of its (+) stereoisomer, said amount being
`sufficient to alleviate said rhinitis but insufficient to cause the
`adverse effects associated with racemic cetirizine.
`The present invention further encompasses a method of
`treating allergic asthma and chronic and physical urticaria in
`a human, which comprises administering to a human in need
`of such asthma or urticaria therapy, an amount of (-)
`cetirizine, or a pharmaceutically acceptable salt thereof,
`substantially free of its (+) stereoisomer, sufficient to alle
`viate said asthma or urticaria. The method avoids the con
`comitant liability of adverse effects associated with the
`administration of racemic cetirizine by providing an amount
`which is insufficient to cause adverse effects associated with
`the administration of racemic cetirizine.
`In addition, the present invention encompasses an anti
`allergic and antiurticaric composition for the treatment of a
`human having allergic asthma, chronic idiopathic urticaria
`and some types of physical urticaria, which comprises an
`amount of (-) cetirizine, or a pharmaceutically acceptable
`salt thereof, substantially free of its (+) isomer, said amount
`being sufficient to alleviate or palliate said disorder but
`insufficient to cause adverse effects associated with the
`administration of racemic cetirizine.
`A further aspect of the present invention includes a
`method of treating a condition caused by or contributed to by
`eosinophilia or enhanced eosinophil function in a human,
`which comprises administering to a human in need of such
`therapy, an amount of (-) cetirizine, or a pharmaceutically
`acceptable salt thereof, substantially free of its (+)
`stereoisomer, sufficient to alleviate said eosinophilia or
`enhanced eosinophilia function. The method avoids the
`concomitant liability of adverse effects associated with the
`administration of racemic cetirizine by providing an amount
`which is insufficient to cause adverse effects associated with
`the administration of racemic cetirizine. Conditions associ
`ated with an eosinophilia or an altered eosinophillfunctionin
`humans may include, but are not limited to, allergic asthma,
`seasonal allergic rhinitis, atopic dermatitis, some parasitic
`diseases, and chronic obstructive lung disease with no
`demonstrable evidence of allergic asthma. Moreover accu
`mulations of eosinophils in both the gastrointestinal and
`genitourinary tracts indicate the desirability of regulation of
`eosinophil function in disorders of these tracts.
`Furthermore, the present invention includes a composi
`tion for treating disorders associated with or enhanced by an
`eosinophilia or enhanced eosinophil function that would
`benefit from a potent inhibitor of eosinophil chemotaxis in
`a human which comprises an amount of (-) cetirizine, or a
`pharmaceutically acceptable salt thereof, substantially free
`of its (+) stereoisomer, said amount being sufficient to
`alleviate said condition associated with an eosinophilia or
`altered eosinophilfunction, but insufficient to cause adverse
`effects associated with the administration of racemic ceti
`ZC.
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`Apotex, Inc. (IPR2019-00400), Ex. 1015, p. 003
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`The available racemic mixture of cetirizine (i.e. a 1:1
`racemic mixture of the two enantiomers) exhibits antihista
`minic activity through its selective and potent binding to
`histamine H peripheral receptor sites and causes inhibition
`of eosinophil chemotaxis thus providing therapy and a
`reduction of symptoms in a variety of conditions and dis
`orders related to allergic rhinitis, allergic asthma, several
`types of urticaria, and conditions related to eosinophilia;
`however, this racemic mixture, while offering the expecta
`tion of efficacy, causes adverse effects. Utilizing the opti
`cally pure or substantially optically pure isomer of (-)
`cetirizine results in enhanced efficacy, diminished adverse
`effects, and accordingly, an improved therapeutic index. It is
`therefore, more desirable to use the (-) isomer of cetirizine
`than to administer the racemic mixture.
`The term "adverse effects' includes, but is not limited to,
`sedation and somnolence, headache, gastrointestinal
`disturbance, dizziness, nausea, cardiac arrhythmias and
`other cardiovascular effects.
`The term “substantially free of its (+) stereoisomer' as
`used herein means that the compositions contain a greater
`proportion of the (-) isomer of cetirizine in relation to the
`(+) isomer of cetirizine. In a preferred embodiment, the term
`“substantially free of its (+) isomer" as used herein means
`that the composition comprises at least 90% by weight of (-)
`cetirizine and 10% by weight or less of (+) cetirizine. In a
`more preferred embodiment the term "substantially free of
`the (+) isomer” means that the composition contains at least
`99% by weight of (-) cetirizine, and 1% or less of (+)
`cetirizine. In the most preferred embodiment, the term
`“substantially free of its (+) stereoisomer" as used herein
`means that the composition contains greater than 99% by
`weight of (-) cetirizine. These percentages are based upon
`the total amount of cetirizine in the composition. The terms
`"substantially optically pure () isomer of cetirizine” or
`"substantially optically pure (-) cetirizine” and "optically
`pure () isomer of cetirizine” and "optically pure (-) ceti
`rizine" are also encompassed by the above-described
`amountS.
`The term "treating the symptoms of seasonal and peren
`nial rhinitis' as used herein means treating, alleviating or
`palliating such conditions, and thus providing relief from the
`symptoms of sneezing, rhinorrhea, nasal congestion,
`pruritus, conjunctivitis, pharyngitis, lacrimation, frontal
`45
`headaches, irritability, anorexia, depression, insomnia, eus
`tachian tube obstruction, and the like.
`The term "a method for treating allergic asthma and
`chronic and physical urticaria in a human” as used herein
`means treating, alleviating or palliating such conditions, and
`thus providing relief from the symptoms of wheezing,
`dyspnea, coughing, shortness of breath, respiratory mucus
`hypersecretion, airway inflammation, local cutaneous
`wheals, erythema, and the like.
`The term, "treating a condition caused by, or contributed
`to, by eosinophilia, or enhanced eosinophil function in a
`human” as used herein means treating, alleviating or palli
`ating such disorders associated with an eosinophilia, thus
`providing relief from the symptoms of the aforementioned
`conditions. Allergic asthma, seasonal allergic rhinitis, atopic
`dermatitis, chronic obstructive lung disease, and symptoms
`associated with some parasitic diseases, gastrointestinal and
`genitourinary disorders are among the conditions caused by
`or contributed to by eosinophilia.
`The chemical synthesis of the racemic mixture of cetiriz
`ine can be performed by the method described in U.S. Pat.
`No. 4.525.358 cited above or by an improved procedure
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`disclosed in British application 2,225,320. The (-) isomer of
`cetirizine may be obtained from its racemic mixture by
`resolution of the enantiomers of cetirizine or precursors
`thereto using conventional means such as an optically active
`resolving acid. For example, British application 2,225.321
`(Cossement et al.), which is incorporated herein by
`reference, discloses a method for resolving the 1-(4-
`chlorophenyl)phenylmethylpiperazine precursor using tar
`taric acid in ethanol. Other standard methods of resolution
`known to those skilled in the art including, but not limited
`to, simple crystallization and chromatographic resolution,
`can be used. (See for example, E. L. Eliel, Stereochemistry
`of Carbon Compounds, McGraw Hill (1962) and Wilen and
`Lochmuller "Tables of Resolving Agents” Journal of Chro
`matography 113, 283-302 (1975). Additionally, the opti
`cally pure (-) isomer can be prepared from the racemic
`mixture by enzymatic biocatalytic resolution. See for
`example U.S. Pat, Nos. 5,057.427 and 5,077.217, the dis
`closures of which are incorporated herein by reference.
`The magnitude of a prophylactic ortherapeutic dose of (-)
`cetirizine in the acute or chronic management of disease will
`vary with the severity of the condition to be treated and the
`route of administration. The dose and perhaps the dose
`frequency will also vary according to the age, body weight
`and response of the individual patient. In general, the total
`daily dose range for (-) cetirizine for the conditions
`described herein is from about 1.0 mg to about 25 mg in
`single or divided doses. Preferably a daily dose range should
`be about 2.0 mg to about 20 mg in single or divided doses
`while most preferably a daily dose range should be about 5
`mg to about 10 mg in single or divided doses. In managing
`the patient, the therapy should be initiated at a lower dose,
`perhaps at about 2 mg to about 5 mg and increased up to
`about 10 mg or higher depending on the patient's global
`response. It is further recommended that children and
`patients over 65 years and those with impaired renal or
`hepatic function, initially receive low doses, and that they be
`titrated based on individual response(s) and blood level(s).
`It may be necessary to use dosages outside these ranges in
`some cases as will be apparent to those skilled in the art.
`Further, it is noted that the clinician or treating physician
`will know how and when to interrupt, adjust, or terminate
`therapy in conjunction with individual patient response. The
`terms "an amount sufficient to alleviate or palliate symptoms
`of seasonal and perennial allergic rhinitis but insufficient to
`cause said adverse effects,” "an amount sufficient to alleviate
`or palliate the symptoms of allergic asthma and chronic and
`physical urticaria but insufficient to cause said adverse
`effects” and "an amount sufficient to alleviate or palliate the
`symptoms arising from the eosinophilia of allergic asthma,
`seasonal allergic rhinitis, atopic dermatitis, parasitic
`diseases, chronic obstructive lung disease, gastrointestinal
`and genitourinary disorders but insufficient to cause said
`adverse effects” are encompassed by the above-described
`dosage amounts and dose frequency schedule.
`Any suitable route of administration may be employed for
`providing the patient with an effective dosage of (-) ceti
`rizine. For example, oral, rectal, parenteral (subcutaneous,
`intramuscular, intravenous), transdermal, and like forms of
`administration may be employed. Dosage forms include
`tablets, troches, dispersions, suspensions, solutions,
`capsules, patches, and the like.
`The pharmaceutical compositions of the present invention
`comprise (-) cetirizine as the active ingredient, or a phar
`maceutically acceptable salt thereof, and may also contain a
`pharmaceutically acceptable carrier, and optionally, other
`therapeutic ingredients.
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`the compound and the compositions of the present
`invention, as well as their utility. It will be apparent to those
`skilled in the art, that many modifications, both to materials,
`and methods, may be practiced without departing from the
`purpose and interest of this invention.
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`EXAMPLES
`
`Example 1
`
`The antihistaminic activity of the racemate and enanti
`omers of cetirizine is studied in receptor binding assays with
`Washed guinea pig brain and lung tissue membranes follow
`ing the procedure of Snyder and Snowman (op cit). The
`tissues are used to establish inhibitory concentration values
`expressed in micromolar concentration (ICs) for racemic
`cetirizine and its enantiomers to inhibit the binding of
`tritiated mepyramine. The selection of these tissues provides
`information as to the binding at central and peripheral H
`histamine receptors. The specificity of the H-receptor bind
`ing may then be compared with the binding at radio ligand
`labeled receptors for other central mediators.
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`7
`The terms "pharmaceutically acceptable salts” or "a phar
`maceutically acceptable salt thereof" refer to salts prepared
`from pharmaceutically acceptable non-toxic acids or bases
`including inorganic acids and bases and organic acids and
`bases. Since the compound of the present invention is basic,
`salts may be prepared from pharmaceutically acceptable
`non-toxic acids including inorganic and organic acids. Suit
`able pharmaceutically acceptable acid addition salts for the
`compound of the present invention include acetic, benzene
`sulfonic (besylate), benzoic, camphorsulfonic, citric,
`ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic,
`hydrochloric, isethionic, lactic, maleic, malic, mandelic,
`methanesulfonic, mucic, nitric, pamoic, pantothenic,
`phosphoric, succinic, Sulfuric, tartaric acid,
`p-toluenesulfonic, and the like.
`The compositions of the present invention include
`suspensions, solutions, elixirs, aerosols, or solid dosage
`forms. Carriers such as starches, sugars, microcrystalline
`cellulose, diluents, granulating agents, lubricants, binders,
`disintegrating agents, and the like are suitable in the case of
`oral solid preparations (such as powders, capsules, and
`tablets), and oral solid preparations are preferred over the
`oral liquid preparations. The most preferred oral solid prepa
`ration is a tablet.
`Because of their ease of administration, tablets and cap
`Sules represent the most advantageous oral dosage unit form,
`in which case solid pharmaceutical carriers are employed. If
`desired, tablets may be coated by standard aqueous or
`nonaqueous techniques.
`In addition to the common dosage forms set out above, the
`compounds of the present invention may also be adminis
`tered by controlled release means and delivery devices such
`as those described in U.S. Pat. Nos. 3,845,770; 3,916,899;
`3,536,809; 3,598,123; and 4,008,719, the disclosures of
`which are hereby incorporated by reference.
`Pharmaceutical compositions of the present invention
`suitable for oral administration may be presented as discrete
`units such as capsules, cachets, tablets, or aerosol sprays,
`each containing a predetermined amount of the active
`ingredient, as a powder or granules, or as a solution or a
`Suspension in an aqueous liquid, a non-aqueous liquid, an
`oil-in-water emulsion, or a water-in-oil liquid emulsion.
`Such compositions may be prepared by any of the methods
`of pharmacy, but all methods include the step of bringing
`into association the active ingredient with the carrier which
`constitutes one or more necessary ingredients. In general,
`the compositions are prepared by uniformly and intimately
`admixing the active ingredient with liquid carriers or finely
`divided solid carriers or both, and then, if necessary, shaping
`the product into the desired presentation.
`For example, a tablet may be prepared by compression or
`molding, optionally, with one or more accessory ingredients.
`Compressed tablets may be prepared by compressing in a
`suitable machine the active ingredientina free-flowing form
`such as powder or granules, optionally mixed with a binder,
`lubricant, inert diluent, surface active agent or dispersing
`agent. Molded tablets may be made by molding in a suitable
`machine, a mixture of the powdered compound moistened
`with an inert liquid diluent. Desirably, each tablet contains
`from about 2 mg to about 10 mg of the active ingredient, and
`each cachet or capsule contains from about 2 mg to about 10
`mg of the active ingredient. Most preferably, the tablet,
`cachet or capsule contains either one of three dosages, about
`2 mg, about 5 mg and about 10 mg of (-) cetirizine
`dihydrochloride for oral administration.
`The invention is further defined by reference to the
`following examples describing in detail the preparation of
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`Example 2
`
`The antihistaminic activity of the isomers of cetirizine is
`also studied in vitro in the guinea pig ileum preparation
`described by Staff Pharmacological Experiments on Iso
`lated Preparations, E & S. Livingstone Ltd., Edinburgh
`(1968).
`
`Example 3
`
`Cetirizine isomer activity is also studied in isolated guinea
`pig tracheobronchial Smooth muscle preparation according
`to the method of Campoli-Richards, et al. Drugs 40,
`762–781 (1990) and Wardell, et al. J. Pharm. Exp. Ther:
`167-184 (1974). These preparations demonstrate competi
`tive antagonism to histamine-induced contractions in a
`model relevant to the inhibition of histamine-induced dis
`orders in vivo. The primary antihistaminic activity is then
`compared to the relative anticholinergic activities ("adverse
`effects”) of cetirizine in the same tissue. The anticholinergic
`activity is evaluated by challenging the tissue with a cho
`linergic agent.
`
`Example 4
`
`Single ventricular myocytes are obtained fromisolated cat
`hearts by conventional techniques. The rod-shaped single
`cells are maintained in a HEPES buffer and they are "patch
`clamped” using suction pipettes. A Patch-Clamp L/M-PEC
`7 amplifier is used to record current tracings, and the
`recording electrodes are filled with a solution of potassium
`aspartate. Voltage clamp pulses and data acquisition are
`controlled by a Sperry PC/IT Computer running P Clamp
`software. A minimum of 4 cells are studied at each test
`concentration of the following drugs: racemic cetirizine, (+)
`cetirizine, (-) cetirizine and quinidine (as a reference
`compound).
`
`Apotex, Inc. (IPR2019-00400), Ex. 1015, p. 005
`
`

`

`5,698,558
`
`10
`cetirizine, which comprises administering to a human in
`need of such symptomatic relief therapy an amount of (-)
`cetirizine, or a pharmaceutically acceptable salt thereof,
`substantially free of its (+) stereoisomer, said amount being
`sufficient to alleviate or palliate said allergic rhinitis but
`insufficient to cause said sedation.
`3. The method of claim 2 wherein (-) cetirizine is
`administered by intravenous infusion or orally as a tablet or
`a capsule.
`4. The method of claim 3 wherein the amount of (-)
`cetirizine or a pharmaceutically acceptable salt thereof
`administered is from about 1 mg to about 25 mg per day.
`5. The method of claim 4 wherein the amount adminis
`tered is from about 2 mg to about 20 mg per day.
`6. The method of claim 5 wherein the amount adminis
`tered is from about 5 mg to about 10 mg per day.
`7. The method of claim 2 wherein the amount of (-)
`cetirizine or a pharmaceutically acceptable salt thereof is
`greater than appro