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US 20130053399A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0053399 A1

Nutala ati (43) Pub. Date: Feb. 28 9 2013

(54) METHODS OF ADMINISTERING Publication Classi?cation (51) Int. Cl. (76) Inventor: Siva Rama K. Nutalapati, Princeton, NJ A61K 31/495 (2006.01) (US) A61K 31/4545 (2006.01) A61P 37/08 (2006.01) 21 A 1. N .: 13/552 684 A61K 31/445 (2006.01) ( ) pp 0 ’ (52) U.S. Cl...... 514/255.04; 514/317; 514/323 (22) Filed: Jul. 19, 2012 (57) ABSTRACT Methods of using combinations of antihistamines by admin . . istering an attenuated dosage amount of a ?rst generation Related U's' Apphcatlon Data for a quick onset concomitantly With a mainte (60) Provisional application No. 61/527,182, ?led on Aug. nance dosage amount of a second or third generation antihis 25, 2011. tamine are disclosed. US 2013/0053399 A1 Feb. 28, 2013

METHODS OF ADMINISTERING generation antihistamine, a second generation antihistamine ANTIHISTAMINES in a maintenance dose to provide continued antihistaminic effect. CROSS REFERENCE TO RELATED [0008] In yet another embodiment, a method of improving APPLICATION the ef?cacy of an antihistamine comprises administering to a [0001] This application claims the bene?t of US. Provi patient in need of antihistamine treatment a synergistic com sional Application Ser. No. 61/527,182 ?led Aug. 25, 2011, bination of a ?rst generation antihistamine in an attenuated Which is hereby incorporated by reference in its entirety. dosage amount to provide a quick onset of action Wherein the patient experiences substantially no sedative effect; and a BACKGROUND second or third generation antihistamine in a maintenance dosage amount to provide continued antihistaminic effect. [0002] Antihistamines ?nd Wide use in treating allergies by [0009] These and other embodiments, advantages and fea blocking the binding of to histamine H l-receptors tures of the present invention become clear When detailed and thereby suppressing symptoms such as a runny nose or Watery eyes. So-called ?rst generation antihistamines Were description and examples are provided in subsequent sec developed that provided excellent reduction in the symptoms tions. of rhinitis, hoWever many of these early compounds induced a sedative effect in the patient, as they are nonselective for the DETAILED DESCRIPTION H l-receptor. Depending upon the time of day of administer ing a conventional recommended dose of a ?rst generation [0010] Disclosed herein are methods of using a combina antihistamine, the sedative effect may or may not be desired. tion of antihistamines by administering an attenuated dosage For example, sedation Would not be desired during the day amount of a ?rst antihistamine that is a ?rst generation anti While most patients need to be active and fully functional, histamine to provide a quick onset of therapeutic action fol often requiring aWareness for daily activities such as Working loWed by a maintenance dosage amount of a second antihis or driving a car. tamine that is a second or third generation antihistamine. The [0003] Second and third generation antihistamines Were combination provides quick onset and improves the e?icacy subsequently designed to avoid the sedative effect exhibited of the antihistamines as the tWo act synergistically With each in the earlier generation of compounds. These compounds other. The method can be carried out Without regard to the Were developed such that they do not cross the blood brain time of day as the level of ?rst antihistamine Will not induce barrier and thus are selective for peripheral H 1 receptors out a sedative effect or there Will be substantially no sedative side of the , thereby exhibiting a effect, but rather Will provide early therapeutic effect during reduced sedative effect. the lag time a patient may experience from the time of admin [0004] Although the second and third generation antihista istration of a second or third generation antihistamine to When mines avoid the sedative effect of the ?rst generation antihis the patient experiences symptomatic relief. For example, tamines, they exhibit a lag from the time of administration to , a ?rst generation antihistamine, provides time When the patient starts to experience symptomatic relief. therapeutic effect Within 15 to 30 minutes after administra Several second generation antihistamines, such as terfena tion, While it may take up to an hour or more for a patient to dine, , , and , exhibit a lag time experience relief of symptoms using , as second of several hours before onset of action (See Annals of Allergy, generation antihistamine. Asthma, & Immunology (1997), 79, 163-172). [0011] As used herein, “substantially no sedative effect” [0005] Thus, there remains a need in the art for methods of means the patient experiences such a minor sedative effect administering antihistamines that provides rapid, sustained, that it Would not impair the patient’s ability to operate and improved therapeutic effect While at the same time avoid machinery or automobiles or perform other mental or physi ing a sedative effect such that the administration can occur cal tasks requiring a high level of concentration. regardless of the time of day. [0012] The attenuated do sage amount of the ?rst generation antihistamine is selected to avoid a sedative effect While at the SUMMARY same time providing adequate prophylactic and symptomatic treatment of seasonal or perennial allergic rhinitis, vasomotor [0006] In one embodiment, a method of orally administer rhinitis, or other respiratory allergies for the ?rst 1-2 hours ing an antihistamine combination comprises concomitantly after dosage administration. In one embodiment, the attenu administering to a patient in need of antihistamine treatment ated dosage amount of the ?rst antihistamine is about 10 to a ?rst generation antihistamine in an attenuated dosage about 96% of the conventional recommended dosage amount amount to provide a quick onset of action Wherein the patient of the ?rst generation antihistamine When used alone, speci? experiences substantially no sedative effect; and a second or cally about 25 to about 80%, more speci?cally about 40 to third generation antihistamine in a maintenance dosage about 65%, and yet more speci?cally about 50 to about 55% amount to provide continued antihistaminic effect. of the conventional recommended dosage amount. For [0007] In another embodiment, a method of treating a example, a conventional recommended adult dose of diphen patient in need of treatment of an allergic reaction comprises hydramine hydrochloride administered on its oWn is 25 mil orally administering to a patient a ?rst generation antihista ligrams (mg) to 50 mg. An attenuated dose for the present mine in an attenuated dose to provide a quick onset of action methods and compositions can be about 10 to about 23 mg Wherein the patient experiences substantially no sedative When used in combination With a second generation antihis effect; and concomitantly administering orally With the ?rst tamine. Other examples are provided in the table beloW. US 2013/0053399 A1 Feb. 28, 2013

treatment a ?rst generation antihistamine in an attenuated dosage amount to provide a quick onset of action While avoid Conventional ing a sedative effect; and a second generation antihistamine in recommended dose Dose range for a maintenance dosage amount to provide continued antihis Name (adult) combination taminic effect. 1st Chlorpheneramine 2 mg to 4 mg 0.5 mg to 1.8 mg* [0018] Exemplary ?rst generation antihistamines include genera- Maleate tion Diphenhydramine 25 mg to 50 mg 10 mg to 23 mg* , , chlorpheniramine, cinnariZine, HCl , , , diphenhydramine, 6.25 mg to 12.5 mg 2 mg to 6 mg* , doxylamine, mecloZine, , Succinate , , a pharmaceutically acceptable 2nd CetiriZine HCl 10 mg, 1 mg/ml 10 mg, 1 mgml genera- Loratadine 10 mg, 1 mg/ml 10 mg, 1 mgml salt thereof, or a combination thereof; speci?cally chlorphen tion Fexofenadine HCl 60 mg, 180 mg, 60 mg, 180 mg, eramine maleate, diphenhydramine hydrochloride, doxy 30 mg/5 ml 30 mg/5 ml lamine succinate, or a combination thereof.

*Less than the conventional recommended close. [0019] Exemplary second and third generation antihista mines include , astemiZole, cetiriZine, deslorata [0013] The maintenance dosage amount of the second anti dine, fexofenadine, , loratadine, , histamine, that is the second or third generation antihista , a pharmaceutically acceptable salt thereof, or a mine, can be about 90 to 100% of the conventional recom combination thereof; speci?cally cetiriZine hydrochloride, mended dosage amount, speci?cally 100%. Exemplary fexofenadine hydrochloride, loratidine, or a combination recommended dosage amounts are provided in the table thereof. above. [0020] “Pharmaceutically acceptable salt” includes deriva [0014] In one embodiment, a method of orally administer tives of the active agent, wherein the active agent is modi?ed ing an antihistamine combination comprises concomitantly by making acid or base addition salts thereof, and further administering to a patient in need of antihistamine treatment refers to pharmaceutically acceptable solvates, including a ?rst generation antihistamine in an attenuated dosage hydrates, crystalline forms, non-crystalline forms, and poly amount to provide a quick onset of action While avoiding a morphs, of such salts. Examples of pharmaceutically accept sedative effect; and a second or third generation antihistamine able salts include, but are not limited to, mineral or organic in a maintenance dosage amount to provide continued anti acid addition salts of basic residues such as amines; alkali or histaminic effect. As used herein, “concomitantly administer organic addition salts of acidic residues; and the like, or a ing” means the ?rst generation and second/third generation combinations thereof. The pharmaceutically acceptable salts antihistamine are administered simultaneously, or Within ?f include salts and the quaternary ammonium salts of the active teen minutes of one another, speci?cally Within ten minutes, agent. For example, acid salts include those derived from and more speci?cally Within ?ve minutes of one another. inorganic acids such as hydrochloric, hydrobromic, sulfuric, [0015] In another embodiment, a method of using an anti sulfamic, phosphoric, nitric and the like; other acceptable histamine combination to treat a patient in need thereof com inorganic salts include metal salts such as sodium salt, potas prises concomitantly administering to a patient in need of sium salt, cesium salt, and the like; and alkaline earth metal antihistamine treatment a ?rst generation antihistamine in an salts, such as calcium salt, magnesium salt, and the like, or a attenuated dosage amount to provide a quick onset of action combination thereof. Pharmaceutically acceptable organic While avoiding a sedative effect; and a second generation salts includes salts prepared from organic acids such as acetic, antihistamine in a maintenance dosage amount to provide propionic, succinic, glycolic, stearic, lactic, malic, tartaric, continued antihistaminic effect. citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylace [0016] In yet another embodiment, a method of treating a tic, glutamic, benZoic, salicylic, mesylic, esylic, besylic, sul patient With an antihistamine combination comprises orally fanilic, 2-acetoxybenZoic, fumaric, toluenesulfonic, meth administering an attenuated dosage amount of a ?rst genera anesulfonic, ethane disulfonic, oxalic, isethionic, HOOCi tion antihistamine suitable for treatment of seasonal or peren (CH2)M4COOH Where n is 0-4, and the like; organic amine nial allergic rhinitis, vasomotor rhinitis, or other respiratory salts such as triethylamine salt, pyridine salt, picoline salt, allergy to the patient Who is concomitantly receiving admin ethanolamine salt, triethanolamine salt, dicyclohexylamine istration of a second generation antihistamine, wherein the salt, attenuated dosage amount of ?rst generation antihistamine is reduced compared to the conventional recommended daily N,N'-dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate, asparginate, glutamate, and the do sage amount of the ?rst generation antihistamine for treat like; or a combination thereof. ment of seasonal or perennial allergic rhinitis, vasomotor rhinitis, or other respiratory allergy in the patient. In one [0021] The ?rst and second antihistamine can be formu embodiment, the attenuated dosage amount of the ?rst anti lated as a single dosage form or formulated as separate, inde histamine is about 10 to about 96% of the conventional rec pendent dosage forms. A “dosage form” means a unit of ommended daily dosage amount of the ?rst generation anti administration of an active agent. The ?rst antihistamine is histamine When used alone, speci?cally about 25 to about generally formulated for immediate-release, While the second 80%, more speci?cally about 40 to about 65%, and yet more antihistamine can be immediate-release or controlled-re speci?cally about 50 to about 55% of the conventional rec lease. ommended daily dosage amount. [0022] The antihistamines can be formulated for oral or [0017] In yet another embodiment, a method of using an buccal administration as a solid, liquid, or semisolid. “Oral antihistamine combination to treat a patient suffering from a dosage form” is meant to include a unit dosage form for oral condition treatable With an antihistamine comprises con administration. Exemplary solid oral and buccal dosage comitantly administering to a patient in need of antihistamine forms include tablets, capsules, pellets, ?lms, and the like. US 2013/0053399 A1 Feb. 28, 2013

Exemplary oral liquid dosage forms include solutions, sus sWeeteners such as soluble saccharin salts, i.e., sodium or pensions, emulsions, and the like. calcium saccharin salts, the potassium salt of 3,4-dihydro-6 [0023] By “immediate-release” is meant a conventional or methyl-1,2,3-oxathiaZine-4-one-2,2-dioxide (Acesulfame non-modi?ed release in Which greater then or equal to about K), the free acid form of saccharin, L-aspartic acid derived 75% of the active agent is released Within tWo hours of admin sWeeteners, such as L-aspartyl-L-phenylalanine methyl ester istration, speci?cally Within one hour of administration, yet (Aspartame), L-alphaaspartyl-N-(2,2,4,4-tetramethyl-3-thi more speci?cally Within 30 minutes of administration. etanyl)-D-alaninamide hydrate (Alitame), N-[N-(3,3-dim [0024] By “controlled-release” is meant a dosage form in ethylbutyl)-L-aspartyl]-L-phenylalanine 1-methyl ester Which the release of the active agent is controlled or modi?ed (Neotame), methyl esters of L-aspartyl-L-phenylglycerine over a period of time, and does not include immediate-re and L-aspartyl-L-2,5-dihydrophenyl-glycine, L-aspartyl-2, lease. Controlled can mean, for example, extended/sus 5-dihydro-L-phenylalanine; L-aspartyl-L-(l-cyclohexen) tained-, delayed- or pulsed-release at a particular time. alanine, or a combination thereof; maltol; or a combination thereof. Liquid Dosage Forms [0031] The sWeetener can be present in the liquid compo [0025] The liquid dosage forms generally include the ?rst sition in an amount of about 0.1 to about 75 Wt % based on the and second/third generation antihistamines and a liquid car total Weight of the liquid composition, speci?cally about 5 to rier. Additional optional ingredients include a suspending about 50 Wt %, and more speci?cally about 2.5 to about 25 Wt agent, a sWeetener, a ?avoring agent, a preservative, a pH %. The amount of sWeetener can be determined by one of adjusting agent, a colorant, or a combination thereof. ordinary skill in the art Without undue experimentation. The [0026] The ?rst and second/third generation antihistamines use of sensory panels to determine the acceptable sWeetness can be present in the liquid composition in free form or in the of the liquid composition may be used. form of a coated or uncoated granule, microtablet, pellet (as [0032] The liquid composition may optionally further com used herein “pellet” means a spherical granule prepared by prise a ?avoring agent. Flavoring agents include those ?avors extrusion and spheroniZation, and is equivalent to bead, knoWn to one of ordinary skill in the art, such as natural spheroid, and microsphere), particle, or other multiparticu ?avors and arti?cial ?avors. Suitable amounts of ?avoring late system. The coating can include ?lm forming coating, a agent can be selected by one of ordinary skill in the art taste-masking coating, a controlled-release coating, and the Without undue experimentation. In one embodiment, the ?a like. voring agent can be present in the liquid composition from [0027] The liquid carrier can be Water; glycerin; propylene about 0.1 to about 8.0 Wt % based on the total Weight of the glycol; a loWer polyethylene glycol (e. g., polyethylene glycol liquid composition, speci?cally about 0.4 to about 6 Wt %, 200, polyethylene glycol 300, polyethylene glycol 400, poly and more speci?cally about 1.0 to about 3.0 Wt %. ethylene glycol 540, polyethylene glycol 600, and the like); [0033] The liquid composition can further include a preser ethanol; propylene carbonate; or a combination thereof. vative to prevent the unWanted groWth of bacteria, molds, [0028] The liquid carrier can be present in the liquid com fungi, or yeast. Examples of suitable preservatives include position in an amount of about 30 to about 98 Weight percent benZoic acid alkali metal salts (e.g., sodium benZoate), sorbic (Wt %) based on the total Weight of the liquid composition, acid alkali metal salts (e.g., potassium sorbate), sodium ery speci?cally about 40 to about 90 Wt %, more speci?cally thorbate, sodium nitrite, calcium sorbate, butylated about 50 to about 80 Wt %, and yet more speci?cally about 60 hydroxyanisole (BHA), butylated hydroxytoluene (BHT), to about 70 Wt %. parabens (e.g., loWer alkyl esters of para-hydroxybenZoic [0029] The suspending agent can be a carbomer, a cellulose acid), alkali metal salts of parabens including sodium and derivative such as poWdered cellulose, methylcellulose, a potassium salts of methyl-, ethyl-, propyl-, or butylparaben, hydroxyl alkyl cellulose such as hydroxyethyl cellulose, or a combination thereof. Speci?c preservatives include hydroxypropyl cellulose, or hydroxypropyl methylcellulose, sodium methylparaben, sodium propylparaben, and sodium carboxy methyl cellulose calcium, carboxy methyl cellulose butylparaben. sodium, polyvinylpyrrolidone; a natural gum such as gum [0034] The preservative can be present in the liquid com acacia, carrageenan, sodium alginate, gellam gum, gum position in an amount of about 0.001 to about 0.1 5 Wt % based ghatti, guar gum, locust bean gum, tragacanth, xanthan gum; on the total Weight of the composition, speci?cally about or a combination thereof. 0.0075 to about 0.05 Wt %, and yet more speci?cally about [0030] A sWeetener can be included in the liquid composi 0.01 to about 0.04 Wt %. tion to make the composition palatable and more pleasing to [0035] The liquid composition optionally further com the patient and to mask the taste of the antihistamines. Exem prises a colorant conventional in the pharmaceutical art. plary sWeeteners include sugar alcohols (or polyols), such as Colorants can be used in amounts effective to produce a glycerol, sorbitol, xylitol, mannitol, galactitol, maltitol, desired color for the composition. The colorants may include hydrogenated isomaltulose (isomalt), lactitol, erythritol, glu pigments, natural food colors and dyes suitable for pharma citol, ribitol, or a combination thereof; sugar sWeeteners gen ceutical applications. erally include saccharides, such as mono-saccharides, di [0036] The liquid composition optionally further includes a saccharides and poly-saccharides such as sucrose pH adjusting agent to render the ?nal liquid composition to a (saccharose, sugar), dextrose, maltose, dextrin, maltodextrin, targeted pH. Suitable pH adjusting agents include pharma xylose, ribose, glucose (including liquid glucose), mannose, ceutically acceptable acids, bases, and their salts. Exemplary galactose, fructose (levulose), lactose, invert sugar, fructo pH adjusting agents include alkali metal hydroxides (e.g., oligo saccharide syrups, trehalose, tagatose, fucose, gulose, sodium hydroxide and potassium hydroxide), hydrochloric ra?inose, ribulose, ru?nose, stachyose, xylulose, adonose, acid, alkali metal carbonates (e.g., sodium carbonate and amylase, arabinose, deoxyribose, corn syrup solids, such as potassium carbonate), carbonic acid, or a combination high fructose corn syrup, or a combination thereof; arti?cial thereof. The pH adjusting agents can be used as solutions or US 2013/0053399 A1 Feb. 28, 2013

suspensions in a pharmaceutically acceptable solvent. Suit lulose, poloxamer, polyethylene oxide, polymethacrylates, able pharmaceutically acceptable solvents foruse With the pH povidone, a saccharide, starch, partially pregelatiniZed adjusting agent can include puri?ed Water, loWer alkyl alco starch, and the like, or a combination thereof. hols such as ethanol, a glycol, and the like, or a combination [0043] Exemplary disintegrants include alginic acid, car thereof. boxymethylcellulose calcium, carboxymethylcellulose [0037] The amount of pH adjusting agent can be any sodium, cross-linked sodium carboxymethylcellulose (so amount to result in a desired pH of the ?nal liquid composi dium croscarmellose), poWdered cellulose, chitosan, croscar tion. Such amounts can be determined by one having ordinary mellose sodium, crospovidone, guar gum, loW substituted skill in the art Without undue experimentation. hydroxypropyl cellulose, methyl cellulose, microcrystalline [0038] In another embodiment, the combination of antihis cellulose, sodium alginate, sodium starch glycolate, partially tamines is formulated in a poWder form, such as a sachet, to be pregelatiniZed starch, pregelatiniZed starch, starch, sodium suspended in a liquid carrier such as Water or saliva. The carboxymethyl starch, and the like, or a combination thereof. poWder form can be added to a glass of Water With stirring or [0044] Exemplary lubricants include calcium stearate, taken directly in the mouth Where the ingredients are sus magnesium stearate, glyceryl behenate, glyceryl palmito pended in saliva. General components in the poWder formu stearate, hydrogenated castor oil, light mineral oil, sodium lation include the antihistamines, a sWeetener, and a suspend lauryl sulfate, magnesium lauryl sulfate, sodium stearyl ing agent; optionally further comprising a ?avorant, a fumarate, stearic acid, Zinc stearate, or a combination thereof. colorant, a disintegrant, a combination thereof, and the like. [0045] Exemplary glidants include colloidal silica, amor phous silica, precipitated silica, talc, calcium phosphate triba Solid Dosage Forms sic, calcium silicate, magnesium silicate, magnesium trisili [0039] The solid oral dosage form can be a monolithic cate, or a combination thereof. matrix tablet or a layered tablet having tWo or more layers [0046] The solid oral dosage forms can be prepared using Wherein the ?rst and the second/third antihistamine can be in equipment and techniques knoWn in the art for tableting separate layers or in the same layer; a capsule; a subunit form included direct compression, granulation, capsule ?lling, pel such as a plurality of granules, microtablets, minitablets, letiZing, and the like. caplets, pellets (as used herein “pellet” means a spherical granule prepared by extrusion and spheroniZation, and is Orally Dispersible Tablet equivalent to bead, spheroid, and microsphere), particles, active agent cores, or other multiparticulate system. [0047] The antihistamines can be formulated into a non [0040] In one embodiment, the ?rst generation antihista cheWable, orally disintegrating tablet. These dosage forms mine, the second/third generation antihistamine, or a combi can be made by methods knoWn to those of ordinary skill in nation thereof, is/are formulated as a solid oral dosage form the art of pharmaceutical formulations. For example, Cima comprising the antihistamine and a pharmaceutically accept Labs has produced oral dosage forms including micropar able excipient. As used herein, “pharmaceutically acceptable ticles and effervescents, Which rapidly disintegrate in the excipient” means any other component added to the pharma mouth and provide adequate taste-masking. Cima Labs has ceutical formulation other than the active agent. Excipients also produced a rapidly dissolving dosage form containing may be added to facilitate manufacture, enhance stability, the active agent and a matrix that includes a nondirect com enhance product characteristics, enhance , pression ?ller and a lubricant. U.S. Pat. No. 5,178,878 and enhance patient acceptability, etc. Pharmaceutical excipients Us. Pat. No. 6,221,392 provide teachings regarding orally include carriers, ?llers, binders, disintegrants, lubricants, disintegrating tablets. glidants, granulating agents, compression aids, colors, sWeet [0048] An exemplary orally disintegrating tablet includes a eners, preservatives, suspending agents, dispersing agents, mixture incorporating a Water or saliva activated effervescent ?lm formers, ?avorants, printing inks, buffer agents, pH disintegration agent and the active agent. The mixture may be adjusters, preservatives, and the like. In some instances, a formulated as a tablet of a siZe and shape adapted for direct single material Will meet tWo or more of the foregoing general oral administration to a patient. The orally disintegrating classi?cations. tablet is substantially completely disintegrable upon expo [0041] Exemplary pharmaceutically acceptable excipients sure to Water or saliva. The effervescent disintegration agent include ?llers, such as a Water insoluble ?ller, Water soluble is present in an amount effective to aid in disintegration of the ?ller, or a combination thereof. The ?ller may be a Water tablet, and to provide a distinct sensation of effervescence insoluble ?ller, such as carnauba Wax, stearic acid, silicon When the tablet is placed in the mouth of a patient. dioxide, titanium dioxide, talc, alumina, starch, kaolin, polac [0049] The effervescent sensation is not only pleasant to the rilin potassium, poWdered cellulose, microcrystalline cellu patient but also tends to stimulate saliva production, thereby lose, sodium citrate, dicalcium phosphate, or a combination providing additional Water to aid in further effervescent thereof. Exemplary Water-soluble ?llers include Water action. Thus, once the tablet is placed in the patient’s mouth, soluble sugars and sugar alcohols, speci?cally lactose, glu it Will disintegrate rapidly and substantially completely With cose, fructose, sucrose, mannose, dextrose, galactose, the out any voluntary action by the patient. Even if the patient corresponding sugar alcohols and other sugar alcohols, such does not cheW the tablet, disintegration Will proceed rapidly. as mannitol, sorbitol, xylitol, or a combination thereof. [0050] The term effervescent disintegration agent includes [0042] Exemplary binders include alginic acid, a carbomer, compounds Which evolve gas. Exemplary effervescent disin carboxymethylcellulose calcium, carboxymethylcellulose tegration agents evolve gas by means of chemical reactions sodium, carrageenan, cellulose acetate phthalate, chitosan, Which take place upon exposure of the effervescent disinte ethyl cellulose, guar gum, hydroxyethyl cellulose, hydroxy gration agent to Water or to saliva in the mouth. The bubble or ethylmethyl cellulose, hydroxypropyl cellulose, hydroxypro gas generating reaction is most often the result of the reaction pyl methyl cellulose, methyl cellulose, microcrystalline cel of a soluble acid source and an alkali metal carbonate or US 2013/0053399 A1 Feb. 28, 2013

carbonate source. The reaction of these tWo general classes of [0057] The orally disintegrating tablets typically rapidly compounds produces carbon dioxide gas upon contact With disintegrate When orally administered. By “rapid”, it is under Water included in saliva. stood that the tablets disintegrate in the mouth of a patient in [0051] Such Water activated materials may be kept in a less than about 7 minutes, and speci?cally betWeen about 30 generally anhydrous state With little or no absorbed moisture seconds and about 5 minutes, speci?cally the tablet dissolves or in a stable hydrated form since exposure to Water Will in the mouth betWeen about 45 seconds and about 2 minutes. prematurely disintegrate the tablet. The acid sources or acid Disintegration time in the mouth can be measured by observ may be those Which are safe for human consumption and may ing the disintegration time of the tablet in Water at about 37° generally include food acids, acid anhydrides and acid salts. C. The tablet is immersed in the Water Without forcible agi Food acids include citric acid, tartaric acid, malic acid, tation. The disintegration time is the time from immersion to fumaric acid, adipic acid, and succinic acids, etc. Because substantially complete dispersion of the tablet as determined these acids are directly ingested, their overall solubility in by visual observation. As used herein, the term “complete Water is less important than it Would be if the effervescent disintegration” of the tablet does not require dissolution or tablet formulations Were intended to be dissolved in a glass of Water. Acid anhydrides and acid of the above described acids disintegration of the subunits or other discrete inclusions. In may also be used. Acid salts may include sodium, dihydrogen one embodiment, disintegration can be determined by USP phosphate, disodium dihydrogen pyrophosphate, acid citrate 32 (Test <70l>). salts and sodium acid sul?te. [0052] Carbonate sources include dry solid carbonate and Films bicarbonate salts such as sodium bicarbonate, sodium car bonate, potassium bicarbonate and potassium carbonate, [0058] In another embodiment, the antihistamines are for magnesium carbonate and sodium sesquicarbonate, sodium mulated into an orally dissolving strip, Which rapidly dis glycine carbonate, L-lysine carbonate, arginine carbonate, solves in the mouth to release the active agent contained in the amorphous calcium carbonate, or a combination thereof. strip. The orally dissolving strips generally comprise a Water [0053] Where the effervescent agent includes tWo mutually soluble polymer and the antihistamines. Exemplary classes of reactive components, such as an acid source and a carbonate Water soluble polymers include Water soluble cellulosic poly source, in one embodiment both components react substan mers, Water soluble synthetic polymers, Water soluble natural tially completely. Therefore, an equivalent ratio of compo gums and polymers or derivatives thereof, or a combination nents Which provides for equal equivalents is selected. For thereof. Exemplary Water soluble cellulosic polymers include example, if the acid used is diprotic, then either tWice the hydroxypropyl cellulose, hydroxypropylmethyl cellulose, amount of a mono-reactive carbonate base, or an equal hydroxyethyl cellulose, carboxymethyl cellulose, or a com amount of a di-reactive base is used for complete neutraliZa bination thereof. Exemplary Water soluble natural gums and tion to be realiZed. HoWever, the amount of either acid or polymers include amylose, dextran, casein, pullulan, gelatin, carbonate source may exceed the amount of the other com pectin, agar, carrageenan, xanthan gum, tragacanth, guar ponent. This may be useful to enhance taste orperformance of gum, acacia gum, arabic gum, sodium alginate, Zein, or a a tablet containing an overage of either component. In this combination thereof. Exemplary Water soluble synthetic case, it is acceptable that the additional amount of either polymers include polyethylene glycol, polyethylene oxide, component may remain unreacted. polyvinyl pyrrolidone, polyvinyl , carboxyvinyl poly [0054] In general, the amount of effervescent disintegration mers, Water soluble polyacrylic acid/acrylate, or a combina agent useful for the formation of orally disintegrating tablets tion thereof. is about 5 Wt % to about 50 Wt % based on the total Weight of [0059] The Water soluble polymer may be present in the ?nal dosage form, speci?cally about 15 Wt % and about 30 amounts of about 20 to about 95 Wt %, speci?cally about 30 Wt %, and more speci?cally about 20 Wt % to about 25 Wt %. to about 85, and more speci?cally about 40 to about 75 Wt % [0055] Other types of orally disintegrating tablets can be based on the total Weight of the orally dissolving strip. prepared Without an effervescent agent by using a spray dried carbohydrate or sugar alcohol excipients:(e. g. sorbitol, man [0060] The orally dissolving strip can further optionally nitol, xylitol, or a combination thereof, and the like), option comprise a plasticiZer in addition to the Water soluble poly ally combined With a disintegrant (eg the disintegrant is mer and active agent. Exemplary plasticizers include propy selected from crospovidone, croscarmellose, sodium starch lene glycol, glycerin, glycerol, monoacetin, diacetin, triace glycolate, pregelatiniZed starch, partially pregelatiniZed tin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, starch, or a combination thereof, and the like), or a glidant dibutyl sebacate, triethyl titrate, tributyl citrate, triethyl cit (e.g. colloidal silica, silica gel, precipitated silica, or a com rate, triethyl acetyl citrate, castor oil, acetylated monoglycer bination thereof, and the like). Suitable orally disintegrating ides, sorbitol, or a combination thereof. The plasticiZer may tablets can be found in US. Patent Application Publication be present in amounts of about 0 to about 20, speci?cally US200301 18642 Al to Norman et al. incorporated herein by about 1 to about 15, and more speci?cally about 5 to about 10 reference in its entirety. Wt % based on the total Weight of the orally dissolving strip. [0056] Orally disintegrating tablets can be manufactured [0061] The orally dissolving strip can further optionally by Well-knoWn tableting procedures. In common tableting comprise an emulsifying agent in addition to the Water processes, the material Which is to be tableted is deposited soluble polymer and active agent. Exemplary emulsifying into a cavity, and one or more punch members are then agents include polyvinyl alcohol, a sorbitan esters, a cyclo advanced into the cavity and brought into intimate contact dextrin, benZyl benZoate, glyceryl monostearate, a polyoxy With the material to be pressed, Whereupon compressive force ethylene alkyl ether, a polyoxyethylene stearate, poloxamer, a is applied. The material is thus forced into conformity With polyoxyethylene castor oil derivative, a hydrogenated veg the shape of the punches and the cavity. etable oil, a polysorbate, or a combination thereof. US 2013/0053399 A1 Feb. 28, 2013

[0062] The emulsifying agent may be present in amounts of described herein. The kits may further comprise one or more about 0 to about 20, speci?cally about 1 to about 15, and more conventional pharmaceutical kit components, such as, for speci?cally about 5 to about 10 Wt % based on the total Weight example, one or more containers to aid in facilitating compli of the orally dissolving strip. ance With a particular dosage regimen; one or more carriers; [0063] The orally dissolving strip can further optionally printed instructions, either as inserts or as labels, indicating comprise a ?avorant or sWeetener in addition to the Water quantities of the components to be administered, or guide soluble polymer and active agent. Exemplary sWeeteners lines for administration. Exemplary kits can be in the form of include sugar, a monosaccharide, an oligosaccharide, aldose, bubble or blister pack cards, optionally arranged in a desired ketose, dextrose, maltose, lactose, glucose, fructose, sucrose, order for a particular dosing regimen. Suitable blister packs a sugar polyol (e. g., mannitol, xylitol, sorbitol, erythritol, and that can be arranged in a variety of con?gurations to accom the like), arti?cial sWeeteners (e. g., acesulfame potassium, modate a particular dosing regimen are Well knoWn in the art sucralose, aspartame, saccharin, sodium saccharin, and the or easily ascertained by one of ordinary skill in the art. like) or a combination thereof. The sWeetener may be present in amounts of about 0 to about 20, speci?cally about 1 to [0070] Those forms existing as liquids (e.g solution, emul about 15, and more speci?cally about 5 to about 10 Wt % sion, or suspension) can be packaged for convenient dosing in based on the total Weight of the orally dissolving strip. prepackaged, single use containers, or in containers compris [0064] In some embodiments, the orally dissolving formu ing multiple doses. lations of the present invention may comprise an additional excipient. Suitable additional excipients include, but are not [0071] The combination can be administered to a patient in limited to, microcrystalline cellulose, colloidal silicon diox need of prophylactic and symptomatic treatment of seasonal ide, talc, starch, or a combination thereof. Other optional or perennial allergic rhinitis, vasomotor rhinitis, or other res components that can be used to prepare the orally dissolving piratory allergies. Seasonal allergic rhinitis may be due to strip include a ?ller/diluent, a surfactant, a disintegrating allergens such as ragWeed, grass and tree pollens. Perennial agent, an antifoaming agent, an antioxidant, a buffering allergic rhinitis may be due to allergens such as dust mites, agent, a colorant, or a combination thereof animal dander and molds. Symptoms treated may include [0065] In one embodiment, the orally dissolving strip sneeZing, rhinorrhea, postnasal discharge, nasal pruritus, exhibits a drug loading of not more than 50% W/W of the ?lm. ocular pruritus, tearing, and redness of the eyes. Patients may Exemplary orally dissolving strips Will comprise about 0.01 include adults, geriatric, or pediatric patients. to about 50 mg of active agent per strip. In another embodi [0072] The following non-limiting examples further illus ment, the orally dissolving strip has a thickness of about 0.1 to trate the various embodiments described herein. about 5.0 millimeters, speci?cally about 0.3 to about 4.0 and yet more speci?cally about 0.5 to about 2.5 millimeters. In another embodiment the orally dissolving strip has a surface EXAMPLES area of about 1.0 to about 6.0, speci?cally about 1.2 to about 4.0 and yet more speci?cally about 1.5 to about 2.0 square Example 1 centimeters . [0066] The orally dissolving strip once placed in the oral cavity may dissolve after less than about 60 seconds, speci? Immediate Release Tablets/Capsules cally less than 30 seconds, and yet more speci?cally less than about 20 seconds. [0073] Immediate release tablets or capsules are prepared using diphenhydramine HCl as the ?rst antihistamine and [0067] A solvent can be used in the process to prepare the orally dissolving strip, including Water, ethanol, 1-butanol, fexofenedine HCl as the second antihistamine. The formula 2-butanol, 2-ethoxyethanol, ethyl acetate, methyl acetate, tion is provided in Table 1. 3-methyl-1-butanol, methylethyl ketone, 2-methyl-1-pro panol, isobutyl acetate, isopropyl acetate ethyl ether, tert TABLE 1 butylmethyl ether acetone, or a combination thereof. The Ingredients Milligram/tablet or capsule solvent is used for processing and then removed to result in the ?nal product. Fexofenedine HCl 60.00 Diphenhydramine HCl 15.00 [0068] Methods of preparing orally dissolving strips PEG 3350 32.50 involve solvent casting and ?lm coating. The active agent is Croscarmellose Sodium (Ac-Di-Sol) 15.00 mixed With ?lm-forming excipients and solvents such as Partially pregelatinized maize starch 25.00 Water, ethanol, and the like. A thin coating of the mixture is (Starch 1500 ®) Magnesium Stearate 2.50 cast on a moving, inert substrate and the coated substrate is moved through a drying oven to evaporate the solvent before Total 150.00 die-cutting the dried ?lm into strips. Another method involves hot-melt extrusion, by melting an active agent and excipient polymer blend Which is then extruded through a die under [0074] Fexofenedine HCl, diphenhydramine HCl and PEG molten conditions. The thin ?lm is then cooled to room tem 3350 are charged into a blender and mixed. Ac-Di-Sol and perature and die-cut into strips. Starch 1500 are then added to the blender and mixed. Mag nesium stearate is passed through a #30 mesh screen and Kits added to the blender and mixed to form a ?nal blend. The ?nal blend can be compressed into tablets or ?lled into capsules. [0069] Also included herein are pharmaceutical kits com prising one multiple use, or a plurality of single use containers [0075] One tablet or capsule of Example 1 can be admin or units containing the antihistamine dosage forms as istered to a patient tWice a day. US 2013/0053399 A1 Feb. 28, 2013

Example 2 HCl and chlorpheneramine maleate are then added and dis solved by mixing for 10 minutes. Sugar is then added and Chewable Tablets mixed for 30 minutes to dissolve. Propylene glycol and PEG [0076] Chewable tablets are prepared using chlorphen 400 are then added and mixed for 5 minutes. Glycerin is then added and mixed for 10 minutes. Colors and ?avors are dis eramine maleate as the ?rst antihistamine and loratadine as solved in a small amount of Water and then added to the main the second antihistamine. The formulation is provided in container With mixing. Any remaining Water is added to the Table 2. mixture and mixed for 25 minutes to form the oral solution. [0081] A 5 milliliter dose of the oral solution of Example 3 TABLE 2 can be admimstered. . to a patient. as a single. daily. dose. Ingredients Milligrarn/tablet , Example 4 Loratadlne 10.00 chlorpheneramine Maleate 1.80 ' ~ ' Microcrystalline cellulose 38.50 Orally D1s1ntegrat1ng Tablet

Mannitol 45.00 ' ~ ~ ~ ' Silicon dioxide 2.00 [0082] An orally d1s1ntegrat1ng tablet is prepared With chlo f/{lmc aclld S {88 rpheneramine maleate as the ?rst antihistamine and lorata Aspmam?agnesluIn tearate Q10. d1ne~ as the second ant1h1stam1ne~ ~ - (Table 4.). Color 0.10 Flavor 0.50 TABLE 4

Total loo-00 Ingredients MilligraIn/tablet

Loratadine 10.00 [0077] Color is passed through a # 30 mesh screen using chlolph?n?raminé Mal?atel 1.80 microcrystalline cellulose. Loratadine, chlorpheneramine Granulated mann1t9l(Pearht9l® SD100) 70-20 1 t .t 1 d th d . d. t h d Crossllnked Polyvlnylpyrrolldone (Plasdone XL 10) 10.00 ma ea e, manm 0 an e s'c'reene ' mgre lens are c arge P?pp?rmint?avor 300 into a blender and mixed. S1l1con d1ox1de, citric acid, aspar- Stearic acid 5.00 tame and ?avor are passed through a # 30 mesh screen and then added to the blender and mixed. Magnesium stearate that Total 100'00 has been screened through a # 30 mesh is then added to the blender and mlxed to form a ?nal mlxture- The ?nal mlxture [0083] Loratadine, chlorpheneramine maleate and Pearli is then compressed into cheWable tablets. tol SD100 are charged into a blender and mixed. Plasdone [0078] One cheWable tablet of Example 2 can be adminis XL10 and peppermint ?avor are passed through a # 30 mesh tered to a patient once a day. screen and added to the blender and mixed. Stearic acid is passed through a # 30 mesh screen, added to the blender and Example 3 mixed to form a ?nal blend. The ?nal blend is compressed into tablets. Oral Solution [0084] One orally disintegrating tablet of Example 4 can be [0079] An oral solution is prepared Where each 5 milliliters administered to a patient once a day. (ml) contains 1 mg of chlorpheneramine maleate as the ?rst antihistamine and 5 milligrams of cetiriZine HC1 as the sec- Example 5 ond antihistamine. The oral solution formulation is shoWn in _ Table 3_ Bilayer Tablets TABLE 3 [0085] A bilayer tablet is formed having the ?rst antihista mine chlorpheneramine maleate in one layer and second anti lngmdi?nts Gram/batch histamine cetiriZine HCl in a second layer (Table 5).

Cetirizine HCl 0.10 chlorpheneramine Maleate 0.02 TABLE 5 r?ldUag?ydmus’ Us PM: MilligraIn/tablet Propylen? glycol 18'3 8 First Layer Ingredients PEG 400, NF 1.00 Sodium b?nzoat?’ NF 0'20 chlorpheneramine Maleate 1.80 Sugar’ NF I 20'50 Microcrystalline cellulose 39.20 sogulm s?cchann /N 0'30 Lactose Fast Flo ® 45.00 so mm 01mm?’ USP F 0'40 Polyvinylpyrrolidone (Plasdone K29/32) 10.00 Color 0'10 Crosslinked Polyvinylpyrrolidone (Plasdone XL 10) 3.00 FlaYOr 0'20 Magnesium Stearate 1.00 Puri?ed Water 50.50 —

I Total 100.00 Total Wmght 100'00 Second Layer Ingredients

[0080] The ‘oral solution_ is_ prepared by dissolving_ _ citric_ _ MicromystamneCetirizine HCl 0611111056 370010.00 acid and sodium citrate in Water. Sodium sacchar1n and Lactose Fast Flo ® 45.00 sodium benZoate are then added and dissolved. CetiriZine US 2013/0053399 A1 Feb. 28, 2013

TABLE 5-continued a second or third generation antihistamine in a mainte nance dosage amount to provide continued antihista MilligraIn/tablet minic effect. Silicon dioxide 2.00 2. The method of claim 1, Wherein the attenuated dosage Croscarmellose Sodium (Ac-Di-Sol) 5.00 amount of ?rst generation antihistamine is about 10 to about Magnesium Stearate 1.00 96% of the conventional recommended dosage amount of the ?rst generation antihistamine. Total 100.00 3. The method of claim 1, Wherein the attenuated dosage amount of ?rst generation antihistamine is about 25 to about [0086] The ?rst layer is formed by charging chlorphen 80% of the conventional recommended dosage amount of the eramine maleate, microcrystalline cellulose, and Lactose ?rst generation antihistamine. Fast?o into a blender and mixed. Plasdone K29/32 and Plas 4. The method of claim 1, Wherein the attenuated dosage done XL10 are passed through a # 30 mesh screen, added to amount of ?rst generation antihistamine is about 40 to about the blender and mixed. Magnesium stearate is passed through 65% of the conventional recommended dosage amount of the a # 30 mesh screen and added to the blender and mixed to ?rst generation antihistamine. form a ?nal ?rst layer blend. 5. The method of claim 1, Wherein the attenuated dosage [0087] The second layer is formed by charging cetiriZine amount of ?rst generation antihistamine is about 50 to about HCl, microcrystalline cellulose, and Lactose Fast?o into a 55% of the conventional recommended dosage amount of the second blender and mixed. Silicon dioxide, and Ac-Di-Sol ?rst generation antihistamine. are passed through a # 30 mesh screen, added to the blender 6. The method of claim 1, Wherein the ?rst generation and mixed. Magnesium stearate is then passed through a # 30 antihistamine provides therapeutic prophylactic and symp mesh screen, added to the blender and mixed to form a ?nal tomatic treatment of seasonal or perennial allergic rhinitis, second layer blend. Bilayer tablets are formed by compress vasomotor rhinitis, or other respiratory allergies for the ?rst ing 100 mg of the ?nal ?rst layer blend and 100 mg of the ?nal 1-2 hours after administration. second layer blend. 7. The method of claim 1, Wherein the ?rst generation [0088] One bilayer tablet of Example 5 can be administered antihistamine is brompheniramine, bucliZine, chlorphe to a patient once a day. niramine, cinnariZine, clemastine, cycliZine, cyproheptadine, [0089] The terms “comprising”, “having”, “including”, diphenhydramine, diphenylpyraline, doxylamine, mecloZ and “containing” are to be construed as open-ended terms ine, pheniramine, promethaZine, triprolidine, a pharmaceuti (i.e., meaning “including, but not limited to”). The terms “a” cally acceptable salt thereof, or a combination thereof. and “an” do not denote a limitation of quantity, but rather 8. The method of claim 1, Wherein the ?rst generation denote the presence of at least one of the referenced item. The antihistamine is chlorpheneramine maleate, diphenhy term “or” means “and/ or”. The endpoints of all ranges dramine hydrochloride, doxylamine succinate, or a combina directed to the same component or property are inclusive and tion thereof. independently combinable. The modi?er “about” used in 9. The method of claim 1, Wherein the second or third connection With a quantity is inclusive of the stated value and generation antihistamine is acrivastine, astemiZole, cetiriZ has the meaning dictated by the context (e.g., includes the ine, , fexofenadine, levocetiriZine, loratadine, degree of error associated With measurement of the particular miZolastine, terfenadine, a pharmaceutically acceptable salt quantity). The term “or a combination thereof’ means a com thereof, or a combination thereof bination of one, tWo, or more of the listed items. 10. The method of claim 1, Wherein the second or third [0090] Unless de?ned otherwise, technical and scienti?c generation antihistamine is cetiriZine hydrochloride, fex terms used herein have the same meaning as is commonly ofenadine hydrochloride, loratadine, or a combination understood by one of skill in the art to Which this invention thereof. belongs. 11. The method of claim 1, Wherein the ?rst generation [0091] While the invention has been described With refer antihistamine and the second or third generation antihista ence to an exemplary embodiment, it Will be understood by mine are formulated in a single oral dosage form or in sepa those skilled in the art that various changes may be made and rate oral dosage forms. equivalents may be substituted for elements thereof Without 12. The method of claim 11, Wherein the oral dosage form departing from the scope of the invention. In addition, many is a tablet, a capsule, a pellet, a ?lm, a solution, a suspension, modi?cations may be made to adapt a particular situation or or an emulsion. material to the teachings of the invention Without departing 13. The method of claim 1, Wherein the patient is in need of from the essential scope thereof. Therefore, it is intended that prophylactic or symptomatic treatment of seasonal or peren the invention not be limited to the particular embodiment nial allergic rhinitis, vasomotor rhinitis, or other respiratory disclosed as the best mode contemplated for carrying out this allergies. invention, but that the invention Will include all embodiments 14. A method of treating a patient in need of treatment of an falling Within the scope of the appended claims. allergic reaction, comprising: orally administering to a patient a ?rst generation antihis 1. A method of orally administering an antihistamine com tamine in an attenuated dose to provide a quick onset of bination, comprising: action Wherein the patient experiences substantially no concomitantly administering to a patient in need of anti sedative effect; and histamine treatment concomitantly administering orally With the ?rst genera a ?rst generation antihistamine in an attenuated dosage tion antihistamine, a second generation antihistamine in amount to provide a quick onset of action Wherein the a maintenance dose to provide continued antihistaminic patient experiences substantially no sedative effect; and effect. US 2013/0053399 A1 Feb. 28, 2013

15. The method of claim 14, wherein the attenuated dosage a second or third generation antihistamine in a mainte amount of ?rst generation antihistamine is about 10 to about nance dosage amount to provide continued antihista 96% of the conventional recommended dosage amount of the minic effect. ?rst generation antihistamine. 28. The method of claim 27, Wherein the attenuated dosage 16. The method of claim 14, Wherein the attenuated dosage amount of ?rst generation antihistamine is about 10 to about amount of ?rst generation antihistamine is about 25 to about 96% of the conventional recommended dosage amount of the 80% of the conventional recommended dosage amount of the ?rst generation antihistamine. ?rst generation antihistamine. 29. The method of claim 27, Wherein the attenuated dosage 17. The method of claim 14, Wherein the attenuated dosage amount of ?rst generation antihistamine is about 25 to about amount of ?rst generation antihistamine is about 40 to about 80% of the conventional recommended dosage amount of the 65% of the conventional recommended dosage amount of the ?rst generation antihistamine. ?rst generation antihistamine. 30. The method of claim 27, Wherein the attenuated dosage 18. The method of claim 14, Wherein the attenuated dosage amount of ?rst generation antihistamine is about 40 to about amount of ?rst generation antihistamine is about 50 to about 65% of the conventional recommended dosage amount of the 55% of the conventional recommended dosage amount of the ?rst generation antihistamine. ?rst generation antihistamine. 31. The method of claim 27, Wherein the attenuated dosage 19. The method of claim 14, Wherein the ?rst generation amount of ?rst generation antihistamine is about 50 to about antihistamine provides therapeutic prophylactic and symp 55% of the conventional recommended dosage amount of the tomatic treatment of seasonal or perennial allergic rhinitis, ?rst generation antihistamine. vasomotor rhinitis, or other respiratory allergies for the ?rst l-2 hours after administration. 32. The method of claim 27, Wherein the ?rst generation 20. The method of claim 14, Wherein the ?rst generation antihistamine provides therapeutic prophylactic and symp antihistamine is brompheniramine, bucliZine, chlorphe tomatic treatment of seasonal or perennial allergic rhinitis, niramine, cinnariZine, clemastine, cycliZine, cyproheptadine, vasomotor rhinitis, or other respiratory allergies for the ?rst diphenhydramine, diphenylpyraline, doxylamine, mecloZ l-2 hours after administration. ine, pheniramine, promethaZine, triprolidine, a pharmaceuti 33. The method of claim 27, Wherein the ?rst generation cally acceptable salt thereof, or a combination thereof. antihistamine is brompheniramine, bucliZine, chlorphe 21. The method of claim 14, Wherein the ?rst generation niramine, cinnariZine, clemastine, cycliZine, cyproheptadine, antihistamine is chlorpheneramine maleate, diphenhy diphenhydramine, diphenylpyraline, doxylamine, mecloZ dramine hydrochloride, doxylamine succinate, or a combina ine, pheniramine, promethaZine, triprolidine, a pharmaceuti tion thereof. cally acceptable salt thereof, or a combination thereof. 22. The method of claim 14, Wherein the second or third 34. The method of claim 27, Wherein the ?rst generation generation antihistamine is acrivastine, astemiZole, cetiriZ antihistamine is chlorpheneramine maleate, diphenhy ine, desloratadine, fexofenadine, levocetiriZine, loratadine, dramine hydrochloride, doxylamine succinate, or a combina miZolastine, terfenadine, a pharmaceutically acceptable salt tion thereof. thereof, or a combination thereof. 35. The method of claim 27, Wherein the second or third 23. The method of claim 14, Wherein the second or third generation antihistamine is acrivastine, astemiZole, cetiriZ generation antihistamine is cetiriZine hydrochloride, fex ine, desloratadine, fexofenadine, levocetiriZine, loratadine, ofenadine hydrochloride, loratadine, or a combination miZolastine, terfenadine, a pharmaceutically acceptable salt thereof. thereof, or a combination thereof. 24. The method of claim 14, Wherein the ?rst generation 36. The method of claim 27, Wherein the second or third antihistamine and the second or third generation antihista generation antihistamine is cetiriZine hydrochloride, fex mine are formulated in a single oral dosage form or in sepa ofenadine hydrochloride, loratadine, or a combination rate oral dosage forms. thereof. 25. The method of claim 24, Wherein the oral dosage form 37. The method of claim 27, Wherein the ?rst generation is a tablet, a capsule, a pellet, a ?lm, a solution, a suspension, antihistamine and the second or third generation antihista or an emulsion. mine are formulated in a single oral dosage form or in sepa 26. The method of claim 14, Wherein the patient is in need rate oral dosage forms. of prophylactic or symptomatic treatment of seasonal or 38. The method of claim 37, Wherein the oral dosage form perennial allergic rhinitis, vasomotor rhinitis, or other respi ratory allergies. is a tablet, a capsule, a pellet, a ?lm, a solution, a suspension, or an emulsion. 27. A method of improving the e?icacy of an antihista mine, comprising: 39. The method of claim 27, Wherein the patient is in need administering to a patient in need of antihistamine treat of prophylactic or symptomatic treatment of seasonal or ment a synergistic combination of perennial allergic rhinitis, vasomotor rhinitis, or other respi a ?rst generation antihistamine in an attenuated dosage ratory allergies. amount to provide a quick onset of action Wherein the patient experiences substantially no sedative effect; and