US 2005006958OA1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0069580 A1 Hirsh et al. (43) Pub. Date: Mar. 31, 2005

(54) COMPOSITIONS CONTAINING BOTH Publication Classification SEDATIVE AND NON-SEDATIVE ANTHISTAMINES AND SLEEP AIDS (51) Int. Cl." ...... A61K 9/48; A61K 9/22 (75) Inventors: Mark Hirsh, Wellesley, MA (US); Jane (52) U.S. Cl...... 424/452; 424/468; 514/290 Hirsh, Wellesley, MA (US); Whe-Yong Lo, Canton, MA (US) (57) ABSTRACT Correspondence Address: PATREAL PABST Compositions containing both a Sedative compound and a PABST PATENT GROUP LLP non-Sedative are provided. More particularly, 400 COLONY SQUARE compositions for administration at bedtime containing a SUTE 1200 Sedating antihistamine or other Sedating compound in imme ATLANTA, GA 30361 (US) diate release form and a non-Sedating antihistamine in delayed-release form are described. Alternatively, a compo (73) Assignee: Collegium Pharmaceutical, Inc. Sition, for administrating upon awakening, containing a (21) Appl. No.: 10/943,311 non-Sedating antihistamine in immediate release form, and a Sedating antihistamine or other Sedative in delayed-release (22) Filed: Sep. 17, 2004 form is described. Methods of inhibiting the release of by administration of the compositions to a mam Related U.S. Application Data malian Subject are also provided. The dosage forms may comprise other , Such as leukotriene receptor (63) Continuation-in-part of application No. 10/012,202, antagonists, to enhance the Suppression of Symp filed on Dec. 5, 2001, now Pat. No. 6,827,946. tomS. US 2005/OO69580 A1 Mar. 31, 2005

COMPOSITIONS CONTAINING BOTH SEDATIVE 0007 Although the non-sedating have AND NON-SEDATIVE ANTHISTAMINES AND been widely used for daytime control of , the SLEEP AIDS Sedative effect of Sedating antihistamines may be preferred by patients who suffer from insomnia or by patients who CROSS-REFERENCE TO RELATED need a good night Sleep. It may be especially advantageous APPLICATIONS to administer a Sedating antihistamine in combination with 0001. This application is a continuation-in-part of U.S. a decongestant, Such as phenylephrine, Since decongestants Ser. No. 10/012,202, filed Dec. 5, 2001, entitled “Compo Such as phenylephrine often Stimulate nervousness and Sitions Containing Both Sedative and Non-Sedative Antihis anxiety in a patient. Thus, distinct advantages can be found tamines” by Mark Hirsh, Jane Hirsh, and Whe-Yong Lo. in the use of “first generation antihistamines' and “Second BACKGROUND OF THE INVENTION generation antihistamines.” 0002 Hypersensitivity is an immune response after expo 0008 Some antihistamines have a long duration of Sure to an antigen. HyperSensitivity usually causes tissue action, either directly or via long-lived active metabolites. damage. Typical hyperSensitivity reactions are allergic rhini These antihistamines, upon repeated administration (for tis, , urticaria, pruritus, Sinusitis, example, daily), build up in the blood stream to provide a angioedema, and anaphylaxis. Antihistamines, normally relatively constant Steady State level of antihistamine effect classified as H. Sub.1 receptor antagonists, are used for the at all times during the day and night. The table below shows prophylaxis and relief of Symptoms of hyperSensitivity the elimination half-life of Some common non-Sedating H1 reactions. antihistamines: 0003. The term “antihistamine” is generally applied to Histamine H.Sub.1 receptor antagonists. There are two types TABLE 1. of antihistamines: first generation and Second generation. Elimination Half-Life of Non-Sedating H1 Antihistamines The older antihistamines (first generation antihistamines) are associated with troubleSome Sedative and anti-muscar Drug (Active Metabolite) Elimination half-life (hours) inic effects and are often called Sedating antihistamines. 1.4-2.1 These older antihistamines are distinguished from the newer 20-30 (Second generation) antihistamines which are essentially Desmethylastemizole 290 Ceterizine 7-10 devoid of the sedative effect and are usually termed “non 13-16 Sedating antihistamines”. 11-15 Loratidine 7.8-11 0004 Both groups of antihistamines are commonly used. Descarboethoxyloratidine 17.3-24 Many Sedating antihistamines are widely used and are Mizolazine 8-13 available over the counter. Typical first generation antihis tamines include, without limitation, , chlo rpheniramine, , , 0009. When the non-sedating antihistamine, or its , , , pyrilamine, metabolite, has a long half life (for example, the , tripolidine, , bromodiphenhy metabolite DeScarboethoxyloratadine), plasma levels reach dramine, , , , diphe a steady State after repeated use and as a result there are nylpyraline, , trimeprazine, , minimal changes in Ci and C. In those cases where one hydroxy Zine, , tazifylline, meclazine, , daily dose of a non-Sedating antihistamine provides 24 hour , leVocarbastine, lodoxamide, , pro relief, a dose of a Sedating antihistamine can be followed piomazine, , , meclozine, within a few hours, for example within the first eight hours mefenidramine, methylsulfate and . after ingestion, preferably within the first Six hours, and 0005 Typical second generation antihistamines include, more preferably by the beginning of the release of the without limitation, feXofenadine, loratadine, descarboet non-Sedating antihistamine. At this point, the release of the hoxyloratadine, norastemizole, desmethylastemizole, ceti Sedating and non-Sedating antihistamines are overlapping rizine, acrivastine, ketotifen, temelastine, ebastine, epinas and as a result their effects are additive. The Sedating tine, , and Setastine, astemizole, , antihistamine provides for a greater antihistamine efficacy , mizolastin, noberastine and meduitazine. Ceti and advantageous side effect profile (e.g. Sedation). The rizine, in spite of being a Second generation antihistamine, non-Sedating antihistamine provides for 24 hour antihista has a low to moderate Sedative effect. mine coverage due to its long half life and its lack of Sedation as a Side effect. The short delay of the non-Sedating 0006 The sedative effect of the sedating antihistamines antihistamine remains important to ensure that the peak can range from Slight drowsiness to deep sleep. Daytime plasma level (C) that occurs at dosing does not occur at Sedation can be a problem especially for those who drive or the time the patient is attempting to fall asleep. The timing who operate machinery. In view of these problems with of the delayed release of the non-Sedating antihistamine will Sedative antihistamines, non-Sedative antihistamines have depend on the duration of the antihistamine action of the been developed. This group of compounds has little or no Sedating antihistamine. Sedative effect and has replaced the first generation antihis tamines, especially for daytime use. The major disadvantage 0010 When the long half-life antihistamine is a non of the non-Sedating antihistamines is the occurrence of drug Sedating antihistamine, a Sedative can be used alone or in interactions and hazardous ventricular which combination with a Sedating antihistamine to induce Sleep. has led to the withdrawal of two non-Sedating antihistamines , in low dosages, can have a Sedative effect. from the market. Suitable antidepressants, which can be used alone or in US 2005/OO69580 A1 Mar. 31, 2005 combination with a Sedating-antihistamine, include tricy more Sedating antihistamines including clemastine fumarate clic/polycyclic antidepressants Such as or Selective as well as an additional Sedating antihistamine and a non Serotonin reuptake inhibitorS Such as . Doxepin is Sedating antihistamine Such as loratidine. The compositions a histamine H1-H2-, and in doses ranging also contain caffeine. Mitra, however, does not disclose the from 5-25 mg can cause Side effects ranging from drowsi delayed release of either the Sedating antihistamine or the neSS to Sedation. Trazodone, when used as an , non-Sedating antihistamine. has a typical dosage range of 150-400 mg. However, TraZ 0017 U.S. Pat. No. 5,827,852 to Russell broadly dis odone, when administered in Sub-therapeutic doses of 12.5 closes coated pharmaceutical compositions that may include mg to 25 mg, can cause Side effects ranging from drowsineSS mixtures of active ingredients including Sedating and non to Sedation. Additionally, anxiolytic and hypnotic drugs. Such Sedating antihistamines. Once again there is no disclosure of as hydroxy Zine or diazepam can produce effects ranging the delayed release of either the Sedating antihistamine or from pleasant drowsiness to direct Sedation. the non-Sedating antihistamine. 0.011 The combination of an antihistamine with a decon gestant is well known. U.S. Pat. No. 5,314,697 to Kwan et 0018 U.S. Pat. No. 6,262,077 to Shih discloses compo al. discloses compositions that contain the non-Sedating Sitions for treatment of asthma, and related antihistamine loratadine and the decongestant pseudoephe disorders comprising in combination a leukotriene receptor drine. Such compositions contain loratadine in a film coating antagonist with a neurokinin antagonist. No Sedating effects for immediate release and in a core Sur are disclosed or discussed. rounded by the film coating So that the pseudoephedrine is 0019 Nelson, J. & Clin. Immunology 112(4), released over an extended period. However, Kwan does not S96-S100 October 203), “Prospects for antihistamines in the describe a composition that contains both a Sedating anti treatment of asthma', describes improvement in asthma histamine and a non-Sedating antihistamine. control with montelukast, a leukotriene receptor antagonist, 0012 One of the most common side effects of sedating by co-administration with loratidine, a non-Sedating antihis antihistamines, depending on the Specific drug and its dose, tamine. AS described in the abstract, the combination is is central nervous system (CNS) depression, with effects thought to minimize the Sedating effects of high levels of varying from Slight drowsiness to deep sleep. The Sedating even non-Sedating antihistamines, by reducing the amount antihistamines can also cause dizzineSS and a lack of coor required. Nelson, however, does not describe compositions dination. These Sedative properties of the first generation containing a Sedating and non-Sedating antihistamine. antihistamines interfere with the normal functioning of patients Suffering from allergies. These patients have to be 0020. It is therefore an object of the invention to provide alert and remain ambulatory throughout the day. Therefore a once daily oral dosage form which provides both Sedating the use of first generation antihistamines, in Spite of their and non-Sedating antihistamines for night and daytime his unique and useful antihistaminic properties, has been lim tamine control. ited. 0021. It is an object of the invention to provide a once 0013 U.S. Pat. No. 6,114,346 to Harris et al. discloses daily oral dosage form for night and daytime histamine compositions containing the non-Sedating antihistamine control which comprises a long-lasting non-Sedating anti and which may further contain a decongestant histamine and a Sedating non-histamine Substance. including phenylephrine, pseudoephedrine, and phenylpro 0022. It is an object of the invention to provide a once panolamine. Such compositions are administered to patients daily oral dosage form which provides both one or more afflicted with upper airway passage allergic inflammation Sedating compounds, histamine and/or non-histamine, and at asSociated with allergic rhinitis to treat or prevent Sleep least one non-Sedating antihistamine for night and daytime disorder. However, Harris does not describe compositions histamine control, the dosage form further comprising a containing both a Sedating antihistamine and a non-Sedating leukotriene receptor antagonist for enhanced control of antihistamine or to use Such a composition to inhibit the Symptoms. release of histamine throughout the day and night. 0014 U.S. Pat. No. 6,051,585 to Weinstein et al. dis 0023. It is a further object of the invention to enable the closes compositions administered once a day in a single oral use of a once-a-day treatment for the Symptoms of histamine dosage, containing a decongestant and an antihistamine, for release which may act either by the inhibition of the release example a non-Sedating antihistamine Such as loratadine or of histamine, or by the prevention of the action of released feXofenadine. Weinstein, however, does not describe a com histamine, or by another method that relieves the Symptoms position that includes both a Sedating antihistamine and a of histamine release. non-Sedating antihistamine. 0024. It is a further object of the invention to provide a 0015 U.S. Pat. No. 6,086,914 to Weinstein et al. dis composition that is administered to a patient once-a-day So closes antihistamine compositions that contain a non-Sedat as to improve the ease of administration and thus increase ing antihistamine as well as a specific agent. the rate of patient compliance. Preferred examples of Specific anticholinergic agents include belladona extracts Such as and Scopola 0025. It is a further object of the invention to provide a mine. None of the anticholinergic agents disclosed in this composition that is designed to be administered once a day, reference, however, is itself a Sedating antihistamine and either in the morning or in the evening. therefore the compositions disclosed are "essentially non Sedating.” BRIEF SUMMARY OF THE INVENTION 0016 U.S. Pat. No. 5,648,358 to Mitra discloses antihis 0026 Compositions containing both a sedative com tamine compositions that may contain a mixture of one or pound and a non-Sedative antihistamine are provided. More US 2005/OO69580 A1 Mar. 31, 2005 particularly, compositions for administration at bedtime 0030 Examples of the sedating antihistamines that may contain a Sedating antihistamine or other Sedating compound be employed include brompheniramine, chlorpheniramine, in immediate release form and a non-Sedating antihistamine dexbrompheniramine, dexchlorpheniramine, carbinoXam in delayed-release form. Alternatively, a composition for ine, clemastine, diphenhydramine, pyrilamine, tripelen administration upon awakening, contains a non-Sedating namine, tripolidine, methdilazine, bromodiphenhydramine, antihistamine in immediate release form, and a Sedating promethazine, azatadine, cyproheptadine, , antihistamine or other Sedative in delayed-release form. doxylamine, trimeprazine, phenindamine, hydroxy Zine, Methods of inhibiting the release of histamines by admin ketotifen, taZifylline, meclazine, Setastine, Oxatomide, levo istration of the compositions are also provided. The dosage carbastine, lodoxamide, pheniramine, , eme forms may comprise other medications, Such as leukotriene dastine, flunarizine, meclozine, mefenidramine, methylsul receptor antagonists, to enhance the Suppression of hista fate and mepyramine. mine Symptoms. 0031 Examples of the non-sedating antihistamines that DETAILED DESCRIPTION OF THE may be employed include feXofenadine, loratadine, descar INVENTION boethoxyloratadine, norastemizole, desmethylastemizole, , acrivastine, ketotifen, temelastine, ebastine, epi Compositions of Sedating and Non-Sedating nastine, mizolastine, norrberastine, Setastine, astemizole, Antihistamines levocetirizine, rupatadine, mizolastin and mecquitazine. 0027) A preferred approach is to utilize the properties of 0032 Examples of the decongestants that may be Sedative antihistamines by administering Such Sedatives to employed include pseudoephedrine, phenylephrine, and induce or maintain sleep during the night, and to use pharmaceutically acceptable acid addition Salts thereof non-Sedating antihistamines to provide antihistamine effects including the hydrochloride, hydrobromide, bit artrate, and during the day. Broadly Speaking, when a composition is tannate Salts. administered right before bedtime (the “PM" dosage form, 0033 Substitution of Sedative and Antihistamine for but for use at bedtime whenever that might occur in the day), Sedating Antihistamine the Sedating properties of a Sedating antihistamine, begin within about the first hour after ingestion, and provide 0034. When the sedative is not an antihistamine, the Sedation either by prompt release or by controlled release, or timing of its release and duration is essentially the Same as a combination thereof, for a first duration of about 2 to 4 that of a sedative antihistamine. The timing of the release of hours, preferably up to about 6 hours or 8 hours. At a the non-Sedating antihistamine then becomes relatively flex determined time after the initial administration, when the ible, and the essential controlling requirement is to ensure patient needs to be awake, non-Sedating antihistamines are that the level of antihistamine remains functionally effective released from the composition, or released at a greater rate, over 24 hours. This may require administration of the to provide the beneficial effect of an antihistamine, thereby antihistamine in two or more portions, one allowing imme permitting the patient to avoid Sedation during the time diate release or release over an hour or So, and another one period in which the patient wishes to remain alert to carry releasing at a later time, for example 12 hours later, or about out normal functions as necessary during the day. 8 to 16 hours later, to Sustain activity, or the antihistamine may be in a Sustained release form where it is gradually 0028. In one aspect of a PM dosage form, when the released over a period So that its activity remains at a Sedative is a Sedative antihistamine, the release of the therapeutic level. non-Sedating antihistamine is delayed, or is initially limited in quantity, to properly control the total antihistamine level. 0035) In an AM formulation, when a sedative antihista For example, the release of Sedative antihistamine will begin mine is used in the formulation, the non-Sedating antihista immediately, or within one hour, and the dose will be mine's release will typically begin almost immediately, or Sufficient to Sustain a Sedating effect for a duration of at least within about an hour or two hours of administration. The one hour, preferably two hours or more, more preferably for non-Sedating antihistamine will then exert an effective level about 2 hours to 6 hours, and optionally for a longer period of antihistamine response for a duration which preferably of about 6 hours to 10 hours. If required, the sedating extends until the effects of the Sedative antihistamine begin antihistamine will be at least partially present as a delayed to be felt, which as noted will typically be in the range of release form or as a Sustained release form, if required to about 12 to 18 hours. The release rates and antihistamine achieve the required period of activity for effective Sedation. effective doses of the Sedating and non-Sedating antihista mine will be adjusted to maintain an effective but not 0029. The non-sedating antihistamine's release can then excessive level of antihistamine activity during the initial begin almost immediately, or within an hour. More prefer period in which only the non-Sedating antihistamine is ably, its release will begin at a time in the range of 2 to 6 present; during an overlap period, if required by kinetics and hours after administration, as the effect of the Sedating particularly half-lives of histamines, and optionally at a low antihistamine wears off. The non-Sedating antihistamine will level during the administration of the Sedating histamine, to then provide an effective level of antihistamine response for provide at least Some level of antihistamine effects at all a duration which preferably extends until it is time for the times. next dose, i.e., about 24 hours after the administration. When the release of the non-Sedating antihistamine Overlaps that of 0036) The “negative' effect of sedation is used to the the Sedating antihistamine, the rate of release, or the amount advantage of the patient in administration right before Sleep, released, may be controlled to a certain extent to prevent an which allows the patient to have a good night Sleep, while excessive rise in antihistamine levels, and later increase to a at the same time maintaining control of the histamine higher rate or amount to provide an effective dose. asSociated allergic Symptoms. Since most patients will want US 2005/OO69580 A1 Mar. 31, 2005 to Sleep at night, the composition where the Sedating anti thereby controlling rhinitis and other allergic Symptoms and histamine or other Sedating drug is immediately released is at the same time inducing drowsineSS and sleep in patients referred to as the PM. , and the composition So that they can enjoy a good night sleep. Upon a patient's where the Sedating antihistamine or other Sedating drug is awakening in the morning, or earlier if the Sedating antihis released beginning at least Several hours after administration tamine release ceases earlier, then the release of non-Sedat is referred to as the A.M. Medication. ing antihistamines begins. The antihistamine effect is still provided but there is no interference with normal function. 0037 Additional Active Ingredients If the non-Sedating antihistamine does not persist for 24 0.038. In any of the above compositions, the non-antihis hours, whether immediately or after Several days of buildup, tamine Sedative drug is optionally is a hypnotic, an anxi then the Sedating drug is preferably at least partially a olytic, and a Sedative. Many examples of drugs of these Sedating antihistamine, in order to maintain the Suppression classes are known in the art. Other drugs, analogous to the of allergic rhinitis and/or other Symptoms of histamine Sedative antihistamines, have Sedative effects that are con release while Sleeping. Alternatively, the non-Sedating anti sidered Secondary to their primary, intended use, Such Seda histamine is Supplied in controlled release form, or partially tive drugs may be of use as Sedatives in the composition if in delayed release form, So that its activity is Sustained their primary effect is compatible with the alleviation of through at least the waking period and optionally on a 24 histamine-mediated Symptoms. hour basis. 0039. In any of the above compositions, additional drugs 0047 These agents may be in immediate release form or may be included that enhance the treatment or alleviation of preferably are in Sustained release form. The Sustained histamine-mediated Symptoms, provided that Such drugs are release is achieved by Standard methods for formulating the compatible with the temporally-distinguished Sedation con particular agent into a Sustained release form, allowing trol features. One example of Such a drug type is a leukot maintenance of desired effective levels of the agent over a riene receptor antagonist. Selected time period. Numerous methods of achieving Sus tained release and controlled release are known in the art, 0040 Supplementary agents can also be included in the and any of them are potentially Suitable for use as described formulation. These may be selected from one or more of herein. Methods for providing Sustained release (prolonged analgesics, antituSSive agents, expectorants, anti-inflamma release) and controlled release, or release beginning at a tory agents, anti-pyretic agents, and decongestants. These delayed time after administration, include Selection of agents allow us to control Symptoms that are common tableting compounds, especially when coupled with control among patients who Suffer from allergic rhinitis, common of pressures in tableting, incorporation of disintegrants into cold, flu, and various other allergic or rhinitis-Stimulating tablets, enclosing tablets in rate-controlling coatings, or reactions. coatings having a known life in the gastrointestinal System, 0041 Examples of the antitussives that may be employed especially coatings that pass intact through the Stomach and include (edisylate), (Hbr), dissolve in the intestine ("enteric coatings’); mixtures of codeine (phosphate, Sulfate), fominoben, hydromorphone, drugs with slowly absorbed materials, Such as fats, and chlophedianol, carbetapentane, and noScapine. combinations of these methods, or with other currently known techniques. 0.042 Examples of expectorants that may be employed include terpin hydrate, guaifenesin (glycerol guaiacolate), 0048. Additional methods to formulate modified release bromohexene, potassium guaicolsulfonate, potassium drug compositions include complexing a drug with an iodide, potassium citrate, ammonium chloride, N-acetyl ion-exchange resin in the form of Small particles, typically cysteine, and ambroXol. less than 150 microns. The drug is selected based on the inclusion in the molecule of a group, Such as an amino 0043. Examples of analgesics and anti-inflammatory group, which will readily bind to a complexing agent Such agents include acetylsalicylic acid, Salicylate, mag as an ion-exchange resin. Thus, any drug that bears an acidic nesium Salicylate, diflunisal, acetaminophen, meclofe or a basic functional group, for example, an amino group, a namate, , etodolac, diclofenac potassium, quaternary aliphatic or aromatic cationic group, and/or an ibuprofen, fenoprofen, ketoprofen, naproxen, naproxen anionic or acid group, including a carboxylic acid, phos Sodium, piroXicam, benoxaprofen, flubiprofen, fenbufen, phoric acid, phenol, Sulfuric acid or Sulfonic acid group, is indoprofen, pirprofen, oxaprozin, carpSofen, Suprofen, almi Suitable for use with an ion exchange resin. Suitable resins noprofen, and tiaprofen. include, but are not limited to, Amberlite IRP-69 (Rohm and HaSS) and other Amberlite ion-exchange resins, DoweX ion 0044) Controlled Release Formulations eXchange resins, Indion 224, Indion 244, and Indion 254 0.045. It is preferred that one or both of the sedating (Ion Exchange (India) Ltd.), and other pharmaceutically compound (preferably a sedating antihistamine) and the approved ion-exchange resins. The drug-containing com non-Sedating antihistamine be encapsulated in or coated plexed resin particles can be further coated by methods with a polymeric material which will delay release or cause known in the art to provide immediate release particles, release to be Sustained over a period in excess of about one enteric coated particles, extended release particles or enteric hour. coated, extended release particles. Additionally these par 0046. In a preferred embodiment of the once-a-day deliv ticles can be formulated into tablets, capsules, Solutions or ery of the P.M. Medication, the sedating drug is released Suspensions, allowing other opportunities to affect the tim beginning Substantially immediately upon ingestion and has ing and rate of release of the complexed drug from the resin. a Sedating effect of about 2 or about 4 hours, optionally a 0049. Likewise, hydrophobic drugs can be absorbed into duration of about 6 to 8 hrs, optionally up to about 12 hours, a porous hydrophobic microparticulate material to retard US 2005/OO69580 A1 Mar. 31, 2005

their release in the body or to make it more gradual; and Such cellulose derivatives, including cellulose in microcrystalline microparticulates may likewise be coated, incorporated in or powdered form, and celluloses reacted with Substituents tablets, etc. to form ethers, Such as ethylcellulose, methylcellulose and other alkylcelluloses; and with substituents to form hydroxy 0050. In any formulation, the active drugs may be present ethers, Such as hydroxyethyl cellulose or hydroxypropyl as Salts, labile esters, complexes, metabolites, enantiomers cellulose; and to form esters with acids (often from any or Stereoisomers, and other forms that are either active or drides) Such as cellulose acetate, cellulose Succinate, and activatable in vivo. cellulose phthalate; and with other reagents to form charged 0051. A dosage form for these uses may contain materials groups Such as carboxymethylcellulose (CMC; carmelose) prepared in Several ways to achieve the desired release and its crosslinked form “crosscarmelose'. Combinations of profile. One method includes a component for delayed onset Substituents are often found, including without limitation release, whether Sustained or rapid, in a first physical form, forms Such as, among others, hydroxypropyl methyl cel preferably a form coated with a first release control material lulose (HPMC or hypromellose), HPMC acetate, HPMC and optionally further coated with additional release-con succinate, HPMC phthalate, cellulose acetate trimelitate, trolling layers. The physical form may, for example, be a and cellulose acetate phthalate. tablet, or a spherule or other Small particle, or may be a 0056. A second preferred group includes polymers, microcapsule formed by any of a variety of methods. The copolymers, and crosslinked polymers based on acrylic delayed onset component is then mixed with or coated with groups (also known as “carboxy vinyl groups and other material for prompt release to form a dosage form. The final older names). Preferred acrylic monomers are acrylic acid form itself may be coated, tableted, or encapsulated as and methacrylic acid (collectively, "(meth)acrylic acids') required. and their esters and amides. The esters may include lower 0.052 In many cases, the formation of an appropriate alkyl esterS Such as methyl and ethyl, and hydroxy esters dosage form can be simple. For example, a “PM" (bedtime) Such as hydroxyethyl and hydroxypropyl (meth)acrylates. dosage form containing a long-acting non-Sedating antihis The various monomerS may be combined to produce mixed tamine, Such as loratidine, and a Sedating histamine can be polymers, and may be crosslinked if desired by any of prepared by mixing Small Spherules of the loratidine with the Several di-acrylate compounds. Acrylates are typically avail Sedating antihistamine, and forming a tablet. Separate coat able under various proprietary trade names, Such as ings for the two ingredients may be provided to prevent “Eudragit” (a polymethacrylate) and “Carbopol” (a partially interaction between them until administration. More prefer crosslinked polyacrylate, also known as a carbomer.) ably, to properly spread out the dosage of the combined 0057. A third preferred group comprises natural gums antihistamines, the non-Sedating antihistamine, or a portion and resins, which may be gelling or nongelling. The gums thereof, can be coated with a release-delaying coating, and include alginates, carrageenans, agars, pectins, glucoman then the dosage form can be formed. nans (guar, locust bean or carob, etc.), galactomannans (e.g. 0.053 While solid dosage forms are convenient, the for konjac), and various bacterial products including Xanthan mulation can be a liquid containing both a Sedating com and Schleroglucan. Gums include gum arabic and gum pound and a non-Sedating antihistamine. In one embodiment traganth. Resins include shellac. Other natural products for bedtime administration, the Sedating compound can be in include waxes, fats, proteins (including Zein and laminins), Solution and the non-Sedating antihistamine can be encap chitin, chitosan, and non-cellulosic polymeric glucoses Such sulated or absorbed or otherwise present in a form that as Starch, amylose and glycogen. Many of the gums may be delays its release for an initial period of time upon admin found in Semisynthetic form, for example propylene glycol istration. The delayed release form of the non-Sedating alginate and carboxymethyl Starch. In general, all of the antihistamine may be present as a Suspension, or as an Substituents available for the celluloses are available, Some emulsion, or less preferably as larger particles that require times as commercial products, for the other natural poly shaking for resuspension. In another embodiment, for a PM mers, especially the polysaccharides. administration, both a short-acting Sedative compound and a 0058 Other polymers include polyvinyl , polyvi long-acting non-Sedating antihistamine can be in Solution, if nylacetate, polyvinylpyrrolidone (poVidone) and its they are stable in solution. Alternatively, one or both of the crosslinked form crospovidone, copoly(ethylene Vinylac Sedating compound and the non-Sedating antihistamine can etate (EVAC), maleic anhydride-co-alkylene copolymers be encapsulated, for example to provide Stability and/or (“Gantrez', e.g.), and other polymers and copolymers made taste-masking, and may release in different manners, for from unsaturated Subunits. Also included in Some formula example with one component having an enteric coating, or tions are polyalkylene oxides, including polyethylene gly both having enteric coatings of different durabilities. cols (PEG), poloxamers, meroxapols, and other polymeric 0.054 Both Sustained release and delayed release are oxiranes. often accomplished by coating and/or compressing the drug together with Sustained release and/or delayed release poly 0059. The rate of delayed release of the non-sedating mers. The delayed release or Sustained-release control poly antihistamine in the P.M. Medication and in the delayed merS may be any of those known in the art. Extensive lists release of the Sedating antihistamine in the A.M. Medication of Such excipients are found in handbooks and the like, from is controlled by at least one delayed release control polymer. which appropriate polymers may be Selected. The polymers A variety of Such polymers are known. A preferred group comprises ethyl cellulose, cellulose acetate, cellulose acetate listed below, without limitation or exclusion of other poly phthalate, hydroxypropyl methylcellulose phthalate, polyvi mers known in the formulation art, are potentially useful as nyl acetate phthalate, polymers and copolymers of acrylic described herein. acid, methacrylic acid, and their methyl, ethyl, hydroxyethyl 0.055 Many polymers are known for use in controlled and hydroxypropyl esters, hydroxyethyl methylcellulose release, including extended release and delayed release acetate (and/or Succinate), shellac, cellulose acetate trimel formulations. One preferred group of polymers comprises litate, Vinyl acetate, azo polymers, pectin, chitosan, amylose, US 2005/OO69580 A1 Mar. 31, 2005 guar gum, and Zein or combinations thereof. Other poten 0069 (C) Coating of Loratadine Enteric Coated Tablets tially useful polymers are listed above, or are accessible in with a Film Coat Containing Dexbrompheniramine Maleate: handbooks and other Sources used by formulators.

EXAMPLES %/DOsage mg/Dosage Unit Unit (ATypical Example 1 Ingredients (Range) Formulation) Loraradine enteric 88-98 173.8 Formulation of Sedating/Nonsedating Antihistamine coated tablets Dexbrompheniramine 1-3 3 for Evening Administration maleate Maleic Acid 1-4 2 0060 Sedative antihistamine: Dexbrompheniramine Opadry (Film coat 2-6 6 material from Colorcon) 0061 Non-sedative antihistamine: Loratadine Purified water CS (To be evaporated) 0062 (A) Preparation of Loratadine Tablets (Core): Each Total 184.8 mg Dosage Form Contains the Following Ingredients: 0070 Formulation: %fDosage mg/DOsage Unit 0071 1. Dissolve dexbrompheniramine maleate and Unit (ATypical maleic acid in purified water and disperse Opadry in the Ingredients (Range) Formulation) Solution. Loratadine 3-5 7 0072 2. Coat loratadine enteric coated tablets from (B) Lactose 45-65 92 with coating Solution containing dexbrompheniramine male Starch 1500 8-18 22 ate using a conventional coating pan or a fluid bed coating Microcrystalline cellulose 15-25 35 equipment until a desired amount of dexbrompheniramine Magnesium Stearate 3-1 O.8 maleate is applied. Total 156.8 mg 0073. Each finished tablet contains: 0074 (1)3 mg dexbrompheniramine maleate in the 0.063 1. Prepare a granulation including loratadine, lac outer coating for immediate release. 0075 (2) 7 mg loratadine which is enteric coated for tose, starch 1500 and microcrystalline cellulose. a delayed release 4-8 hours after administration. 0064. 2. Lubricate the granulation with magnesium stear 0076. The film coat may be replaced with a sugar coat or ate. compression coat which contains 3 mg dexbromphe niramine maleate. 0065 3. Compress the granulation into tablets about 156.8 mg weight using a Suitable tablet compression Example 2 machine and tooling. Formulation of Non-Sedating/Sedating 0.066 (B) Enteric Coating of Loratadine Tablets (Core): Antihistamine for Morning Administration 0077 Sedative antihistamine: diphenhydramine hydro chloride mg/Dosage Unit %/Dosage Unit (ATypical 0078. Non-sedative antihistamine: fexofenadine hydro Ingredients (Range) Formulation) chloride Loratadine Tablets 85-95 156.8 0079 (A) Preparation of Diphenhydramine Hydrochlo Eudragit S (Rohm America) 3-10 1O ride Beads: Each Dosage Form Contains the Following Triethyl citrate 1-4 5 Ingredients: Glycerol monostearate O.3 Ammonia (from 1N 1.7 Solution) Purified water CS (To be evaporated) %f mg/Dosage Unit Dosage Unit (ATypical Total 173.8 mg Ingredients (Range Formulation) Diphenhydramine 40-70 50 hydrochloride 0067. 1. Prepare an enteric coating solution including Microcrystalline 30-60 35 Eudragit S, triethyl citrate, glycerol monoStearate and cellulose ammonia Solution in purified water. Methyl cellulose 2-5 2.5 Sodium starch glycolate 5-3 1.3 0068 2. Coat loratadine tablets (from step (A)) with the Purified water CS (To be evaporated) enteric coating Solution using a conventional coating pan or Total 89 mg a fluidized-bed coating apparatus until a desired amount of coating is applied. US 2005/OO69580 A1 Mar. 31, 2005

0080) 1. Blend diphenhydramine hydrochloride, microc 0089 2. Blend fexofenadine hydrochloride granulation rystalline cellulose, methyl cellulose and Sodium Starch (step 1) with diphenhydramine hydrochloride enteric coated glycolate to form uniform blend. beads and blend with magnesium Stearate. 0.081 2. Add suitable amount of water slowly to the blend 0090 3. Encapsulate the blend into capsules of suitable and mix. size. Each capsule contains 50 mg diphenhydramine hydro 0082. 3. The resulting granulate is extruded at high speed chloride as enteric coated beads and 90 mg feXofenadine through a 1.0-2.0 mm plate and Spheronized using an hydrochloride as an immediate release granule. extruder/spheronizer. The Spheres are then dried to moisture content of less than 7%. 0091. Note: Amount of diluents such as microcrystalline 0083) (B) Enteric Coating of Diphenhydramine Hydro cellulose and starch may be varied in order to fill the volume chloride Beads: of a Selected capsule size. 0092. Each finished dosage form contains: %fDosage mg/DOsage Unit 0.093 (3) 90 mg fexofenadine hydrochloride for Unit (ATypical immediate release, and Ingredients (Range Formulation) Diphenhydramine 60-90 89 0094 (4) 50 mg diphenhydramine hydrochloride hydrochloride beads which is enteric coated for a delayed release 8 to 12 Eudragit S (Rohm America) 5-15 12 hours after administration. Triethyl citrate 2-8 6 Talc 1-4 3 Ammonia (From 1N 1-3 2.1 Example 3 solution) Purified water CS (To be evaporated) Formulation of Sedating/Non-Sedating Total 112.1 mg Antihistamine Plus a Decongestant for Evening Administration 0084. 1. Prepare an enteric coating Solution including 0095 Sedative antihistamine: dexbrompheniramine Eudragit S, triethyl citrate, talc and ammonia Solution in maleate purified water. 0085 2. Coat diphenhydramine hydrochloride beads 0096. Non-sedative antihistamine: cetirizine (from step (A)) with the enteric coating Solution using a 0097 Decongestant: pseudoephedrine sulfate conventional coating pan or a fluidized-bed coating appa ratus until a desired amount of coating is applied. 0098 (A) Preparation of Cetirizine Beads: Each Dosage 0.086 3. The enteric coated beads may be further coated Form Contains the Following Ingredients: with protective film coat or Sugar coats using conventional coating procedure. 0087 (C) Preparation of a Granulation Containing Fex %/DOsage mg/Dosage Unit ofenadine Hydrochloride and Diphenhydramine Hydrochlo Unit (ATypical ride Enteric Coated Beads: Ingredients (Range) Formulation)

Cetirizine 40-70 7 Microcrystalline cellulose 30-60 5 %f mg/Dosage Unit Methylcellulose 2-5 0.5 Dosage Unit (ATypical Ingredients (Range) Formulation) Crosscarmellose sodium 5-3 1. Purified water CS (To be evaporated) Fexofenadine 25-50 90 hydrochloride Total 156.8 mg Pregelatized starch 1500 5-10 2O Microcrystalline 10-30 50 cellulose Magnesium stearate 2-1 O.8 Purified water CS (To be evaporated) 0099) 1. Blend cetirizine, microcrystalline cellulose, Diphenhydramine 35-45 112.1 methyl cellulose and croSScarmellose Sodium to form uni hydrochloride enteric form blend. coated beads Total 272.4 mg 0100 2. Add suitable amount of water slowly to the blend and granulate. 0088 1. Blend fexofenadine hydrochloride, pregelatized 0101 3. The resulting granulate is extruded at high speed Starch and microcrystalline cellulose and granulate the blend through a 1.0-2.0 mm plate and Spheronized using an with purified water. Dry the granulation and mill to desired extruder/spheronizer. The Spheres are then dried to moisture particle size. content of less than 7%. US 2005/OO69580 A1 Mar. 31, 2005

0102 (B) Enteric Coating of Cetirizine Beads: 0109 (D) Preparation of a Granulation Containing Pseu doephedrine Sulfate:

%fDosage mg/DOsage Unit %f mg/Dosage Unit Unit (ATypical Dosage Unit (ATypical Ingredients (Range) Formulation) Ingredients (Range) Formulation) Pseudoephedrine sulfate 15-40 210 Dibasic calcium phosphate 10-30 1OO Cetirizine 60-90 13.5 dihydrate Eudragit S (Rohm America) 5-15 1.8 Hydroxypropyl 35-55 350 methylcellulose 2208 Triethyl citrate 2-8 O.9 Ethylcellulose 10-30 1OO Talc 1-4 0.5 Methylcellulose 3-10 50 Silicon dioxide 5-2 8 Ammonia (From 1N 1-3 O.3 Stearic Acid 2-1 6 solution) Magnesium stearate 2-1 4 Purified water CS (To be evaporated) Total 828 mg

Total 17.0 mg 0.110) 1. Prepare a coating solution of methylcellulose in Water. 0.111) 2. Blend pseudoephedrine sulfate, dibasic calcium 0103 1. Prepare an enteric coating solution including phosphate dihydrate, hydroxypropyl methylcellulose 2208, Eudragit S, triethyl citrate, talc and ammonia Solution in and ethylcellulose and mix. purified water. 0.112. 3. Granulate the blend from step 2 with methylcel 0104 2. Coat cetirizine beads (from step (A)) with the lulose Solution from Step 1. Pass the granulation through a enteric coating Solution using a conventional coating pan or Screen with a desired mesh size. a fluidized-bed coating apparatus until a desired amount of 0113 4. Dry the granulation until moisture content is less coating is applied. than 3.0%. 0114 5. Mill or pass the dried granulation through a 0105 3. The enteric coated beads may be further coated Screen with a desired mesh size. with a protective film coat or Sugar coats using a conven tional coating procedure. 0115 6. Blend the milled granulation with silicon diox ide, Stearic acid and magnesium Stearate 0106 (C) Preparation of a Granulation Containing Dex 0116 (E) Compression of the Double-Layer Finished brompheniramine Maleate, Pseudoephedrine Sulfate, and Product Tablets. Using Granulations from Steps (C) and (D): Cetirizine Enteric Coated Beads:

mg/Dosage Unit %fDosage mg/DOsage Unit %/Dosage Unit (ATypical Unit (ATypical Ingredients (Range) Formulation) Ingredients (Range) Formulation) Granulation (C) 15-40 266.1 Dexbrompheniramine 5-4 3 Granulation (D) 1O-30 828 maleate Pseudoephedrine sulfate O-2O 3O Total 1094.1 mg Lactose 40-80 145 Pregelatized starch 1500 5-20 25 Microcrystalline cellulose 10-30 45 0117. A tablet compression apparatus capable of com Magnesium stearate 2-1 1.1 pressing a multi-layer tablet is used to compress 266.1 mg Purified water CS (To be evaporated) Cetirizine enteric coated 5-20 17 of granulation (C) in one layer and 828 mg of granulation beads (D) in the second layer. 0118. Each finished double-layer tablet contains the fol Total 266.1 mg lowing active ingredients: 0119 (1) The first layer contains: 0107 1. Blend dexbrompheniramine maleate, pseu 0120 (a) 3 mg dexbrompheniramine maleate and doephedrine Sulfate, lactose, pregelatized Starch and micro 30 mg pseudoephedrine Sulfate for immediately crystalline cellulose and granulate the blend with purified release. water. Dry the granulation and mill to desired particle size. 0121 (b) 7 mg cetirizine which is enteric coated for delayed release 4-8 hours after administration. 0108) 2. Blend dexbrompheniramine maleate granulation 0122) (2) The second layer contains 210 mg pseu (step 1) with cetirizine enteric coated beads and blend with doephedrine Sulfate for Sustained release over 24 magnesium Stearate. hours. US 2005/OO69580 A1 Mar. 31, 2005

0123. In order to allow an easier Swallowing, the amount 0.135 2. 1.7% ammonia solution was prepared from 1N for one dosage unit (1094.1 mg) may be divided into two Strong Ammonia solution and Purified Water. double-layer tablets each contains 547 mg (133 mg granu lation C first layer and 414 mg granulation D the Second 0136 3. Dilute ammonia (1.7%) solution was added layer). In this case, the patient will be instructed to take two Slowly while mixing and mixing was continued for 60 tablets instead of one tablet per dose. minutes. 0.137 4. Triethyl Citrate was added and mixing was Example 4 continued for 60 minutes. It was kept under Slow mixing Formulations with Encapasulated Loratidine (6-8 until next day morning. Hour and 1-3 Hour Release) and Immediate 0138 5. Talc powder and D&C Yellow #10 Aluminium Release Sedating Histamine Component for PM Lake were dispersed into Purified Water in a separate Administration Stainless Stell container and mixed for 15 minutes. It was 0124 (A) Preparation of Loratadine Tablets (Core): Each mixed at high Speed for 10 more minutes and kept under Dosage Unit Contains the Following Ingredients: Slow mixing until next day morning. 0.139. 6. Pigment Suspension was added and mixed for 5 minutes. Ingredients Quantity per batch (g) 0140 7. The Suspension was filtered through #100 mesh Loratadine SO.OO Screen and kept under Slow constant Stirring before and Directly compressible Lactose 2OO.OO during coating. Pregelatinized corn Starch SO.OO Microcrystalline Cellulose 1OO.OO 0141 Coating was performed in the Wuster column of Magnesium Sterate 4.OO Glatt GPCG1 fluid bed coater. The coating solution was Colloidal Silicon Dioxide 2.50 applied with the following coating parameters until 40% Total 4O6.50 coating weight gain obtained. 0142) Coating Parameters: 0125 1. Loratadine, Directly compressible Lactose, Coating Load: 700 g Microcrystalline Cellulose, and Pregelatinized Corn Starch 0143) were passed through a #30 Screen and mixed for 2 minutes. 0144) Spray Rate: 4.9-6.00 g/min 0.126 2. Instruction 1 was lubricated with Magnesium 0145) Atomizing Air Pressure 2 Bar Stearate and Colloidal Silicon Dioxide, which were already passed through a #60 Screen for 1 minute. 0146) Inlet Air Temperature: 43-46 C. 0127 3. Granulation was compressed on a single station 0147) Product Temperature: 35-37° C. compression machine fitted with a 3/16 round punch Set with the following tablet parameters: 0.148. A sample was collected after 30% coating weight gain. At the end of the coating and before collecting each 0128 Weight: 81.3 mg Sample, tablets were dried for 10 minutes without Spray. 0129 Hardness: 7-8 kP 0149 (C) Enteric coating of Loratadine tablets (1-3 hr): 0130 Friability: <1.0% 0131) Disintegration Test: <5 minutes. Quantity per 0132 (B) Enteric Coating of Loratadine Tablets (6-8 hr): Ingredients batch (g) Loratadine Tablets (Formulation A). 6O.OO Placebo Lactose Pellets 64.O.OO Acryl Eze White 93018359 254.8O Ingredients Quantity per batch (g) (ready to use enteric mixture) Contains Methacrylic Acid Loratadine Tablets SO.OO Coplymer Type C, USPNF (Formulation A). (Methacrylic Acid-Ethylacrylate 1:1 Placebo Tablets 6SO.OO copolymer) and other coating ingredients Eudragit S 100 Powder 175.OO Simethicone Emulsion USP (Dow 1.27 Triethyl Citrate 122.50 Corning 7-9245 (30%) 1N. Strong Ammonia (1.7%) 89.07 FD&C Blue # 1 Lake Concentrate O.26 Tac USP 17.50 D&C Red # 33Aluminium Lake O.26 D&C Yellow # 10 Al. Lake O.O6 Purified Water USP (To be evaporated) Purified Water USP 1220.00 (to be evaporated) Total 1019.OO 0.133 Preparation of Coating Solution: 0150 Preparation of Coating Solution: 0134) 1. Eudragit S 100 powder was dispersed in Purified Water. Mixing was continued for 10 minutes to form a 0151 1. Simethicone Emulsion and colors were added to homogeneous dispersion. Purified Water and mixed vigorously for 2 minutes. US 2005/OO69580 A1 Mar. 31, 2005

0152 2. Acryl-Eze(R) white powder was dispersed into the 0169 Capsules of Formulation E and Formulation F were Solution and mixed for 60 minutes to form a homogeneous Subjected to dissolution with the following parameters: dispersion. 0170 (a) Media: 0.1N HCL, pH 6.8 Phosphate buffer, pH 0153. 3. The suspension was filtered through a #100 mesh 7.0 Phosphate buffer and pH 7.5 Phosphate buffer. Screen and kept under Slow constant Stirring before and during coating. 0171 (b) Volume: 900 ml 0172 (c) Time points: 0–2 hours in 0.1N HCL, 2-4 hours 0154 Coating was performed in the Wuster column of in pH 6.8 Phosphate buffer, 4-6 hours in pH 7.0 Phosphate Glatt GPCG1 fluid bed coater. Coating solution was applied buffer and 6-10 hours in pH 7.5 Phosphate buffer. with the following coating parameters until 21.90% coating weight gain obtained. 0173 (d) Apparatus: 2 (Paddle) 0155 Coating Parameters: 0.174 (e) Speed: 50 rpm 0.175. The following release profiles were obtained for 0156 Coating Load: 700 g Formulation E and Formulation F capsules: 0157 Spray Rate: 8-10.2 g/min 0158 Atomizing Air Pressure 1.2 Bar Formulation E Formulation F 0159. Inlet Air Temperature: 42-43° C. % released % released 0160 Product Temperature: 36-37 C. Time Diphenhydrame Diphenhydrame (hours) Hydrochloride Loratadine Hydrochloride Loratadine 0161 Samples were collected after 17.3%, 20.5% and 1. 1OO.30 O.2O 100.70 O.2O 21.9% coating weight gain. All samples were dried for 10 2 99.OO O.2O 98.8O O.2O minutes in oven at 40 C. 3 O O O 99.90 4 O O O 98.30 0162 (D) Preparation of Diphenhydramine Hydrochlo 5 O O O 1OOSO 6 O O ride Granulation: Each 45.75 mg of Granulation Contains 6.5 O 65.70 the Following Ingredients: 7.0 O 90.10 8 O 98.30 9 O 98.70 1O O 99.50 Ingredients mg/Dosage unit Diphenhydramine Hydrochloride 25 Microcrystalline Cellulose 2O.OO 0176 Unless defined otherwise, all technical and scien Magnesium Stearate 0.75 tific terms used herein have the Same meanings as com monly understood by one of skill in the art to which the Total 45.75 disclosed invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the 0163 1. Sift Diphenhydramine Hydrochloride and preferred methods, devices, and materials are as described. Microcrystalline Cellulose through a 30 # screen and mix Publications cited herein and the material for which they are them for 3 minutes. cited are Specifically incorporated by reference. 0164. 2. Lubricate the instruction 1 granulation with 0177 Those skilled in the art will recognize, or be able to Magnesium Stearate, previously passed through a #60 ascertain using no more than routine experimentation, many Screen, for 1 minute. equivalents to the Specific embodiments of the invention described herein. Such equivalents are intended to be 0165 (E) Preparation of Capsules with Sedating and encompassed by the following claims. Non-Sedating Portions: We claim: 0166 Diphenhydramine Hydrochloride immediate 1. A once-daily oral dosage form composition for daytime release granulation (sedating), equivalent to 25 mg of and nighttime control of Symptoms of histamine release, the Diphenhydramine Hydrochloride Formulation D, and Lora dosage form comprising a non-Sedating antihistamine com tadine delayed release coated tablets (non-sedating) equiva ponent and a Sedating antihistamine component comprising lent to Loratadine 10 mg Formulation B with 30% weight the combination of an antihistamine and Sedative, wherein gain, were filled into each capsule. the two antihistamines are released at different times. 0167 (F) Preparation of Capsules with Sedating and 2. The composition defined in claim 1 wherein the Sedat Non-Sedating Portions: ing antihistamine is Selected from the group consisting of brompheniramine, chlorpheniramine, debrompheniramine, 0168 Diphenhydramine Hydrochloride immediate deXchlorpheniramine, carbinoxamine, clemastine, diphen release granulation (sedating), equivalent to 25 mg of hydramine, pyrilamine, tripelennamine, tripolidine, methdi Diphenhydramine Hydrochloride Formulation D, and Lora lazine, bromodiphenhydramine, promethazine, azatadine, tadine delayed release coated tablets (non-sedating) equiva cyproheptadine, diphenylpyraline, doxylamine, trimepra lent to Loratadine 10 mg Formulation C with 20.5% weight Zine, phenindamine, ketotifen, hydroxy Zine, tazifylline, gain, were filled into each capsule. temelastine, , acrivastine, Setastine, Oxatomide, US 2005/OO69580 A1 Mar. 31, 2005 meguitazine, , lodoxamide, AHR 11325, phen 13. The composition of claim 1, which comprises: indamine, , and ebastine, or a pharmaceutically acceptable Salt thereof. (a) a therapeutically effective amount of a non-sedating 3. The composition defined in claim 1 wherein the non antihistamine formulated to inhibit histamine release Sedating antihistamine is Selected from the group consisting Symptoms beginning within about the first two hours of feXofenadine, loratadine, descarboethoxy loratadine, after administration and continuing for a duration of astemizole, norastemizole, desmethylastemizole, cetirizine, about 10 hours to about 30 hours; and acrivastine, and temelastine, or a pharmaceutically accept (b) a therapeutically effective amount of a sedating anti able Salt thereof. histamine compound, Sufficient to produce Sedating 4. The composition of claim 1 wherein the sedative is effects, and optionally to inhibit histamine release Selected from the group consisting of antidepressants, hyp Symptoms, for a duration of about 4 hours to about 12 notics, and anxiolytics. hours, 5. The composition of claim 1 further comprising a leukotriene receptor antagonist for enhanced control of wherein the Sedating antihistamine compound is formu Symptoms. lated to provide a delayed release beginning at about 12 6. The composition defined in claim 1 which further to about 18 hours after ingestion and providing Sedation comprises a therapeutically effective amount of at least one for a period ranging from about 1 hour to about 8 hours, agent Selected from the group consisting of an analgesic the intervals Selected So that the composition is no agent, an antituSSive agent, an expectorant, an anti-inflam longer effective as a Sedative at about 24 hours after matory agent, an anti-pyretic agent and a decongestant. ingestion; 7. The composition of claim 1 wherein the oral dosage and wherein the delayed release is achieved by coating at form is Selected from the group consisting of tablets, cap least one drug-containing core, resin or granulation Sules, liquids, emulsions, and Suspensions. with at least one delayed release control polymer. 8. The composition of claim 1 comprising: 14. The composition of claim 13 wherein the delayed release control polymer is Selected from the group consisting (a) a therapeutically effective amount of at least one of ethyl cellulose, cellulose acetate, cellulose acetate phtha Sedating compound, Sufficient to produce Sedating late, hydroxypropyl methylcellulose phthalate, polyvinyl effects, and optionally sufficient to inhibit histamine acetate phthalate, acrylic acid polymers and copolymers, release Symptoms, which becomes effective at a first polymers or copolymers of methacrylic acid, methyl acry time between about the time of administration and late, ethyl acrylate, methyl methacrylate, ethyl methacrylate, about the first two hours after administration, and hydroxypropyl methylcellulose acetate Succinate, shellac, which has a sedative effect for a first duration selected cellulose acetate trimellitate, Vinyl acetate, azo polymers, from the range of about 1 hour to about 12 hours, and pectin, chitosan, amylose, guar gum, and Zein and combi (b) a therapeutically effective amount of a non-sedating nations thereof. antihistamine formulated to inhibit histamine release 15. The composition of claim 13, wherein the non whenever no other antihistamine is present; Sedating antihistamine accumulates with repeated adminis wherein the non-Sedating antihistamine is formulated to tration So that the antihistamine effect of the non-Sedating provide a delayed release beginning at a Second time in antihistamine combined with its active metabolites is the interval of about 1 to about 10 hours after ingestion, approximately continuous at a level within the therapeutic and continuing in effect for a Second duration that is range. sufficient to provide an effective antihistamine effect 16. The composition of claim 1 in daily oral uni-dosage or for at least about 18 hours or more after ingestion. divided dosage form, designed for administration upon 9. The composition of claim 7 wherein the sedating awakening, which comprises: antihistamine has a duration of activity if about 6 to 10 (a) a therapeutically effective amount of a non-sedating hours. antihistamine formulated to inhibit histamine release 10. The composition of claim 1, comprising a delayed for a first duration in the range of about 16 hours or release coating on the non-Sedating antihistamine. more, beginning at a Selected time in the range of about 11. The composition of claim 10, wherein the delayed the first two hours after ingestion; and release coating is Selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, (b) a therapeutically effective amount of a sedating anti hydroxypropyl methylcellulose phthalate, polyvinyl acetate histamine, to produce Sedating effects beginning at a phthalate, acrylic acid polymers and copolymers, polymers time in the range of about 12 hour of ingestion to about or copolymers of methacrylic acid, methyl acrylate, ethyl 18 hours after ingestion, and continuing for a Second acrylate, methyl methacrylate, ethyl methacrylate, hydrox duration in the range of about 2 hours to about 10 hours, ypropyl methylcellulose acetate Succinate, shellac, cellulose the times Selected So that the Sedative effect ceases at acetate trimellitate, vinyl acetate, azo polymers, pectin, about 24 hours after ingestion; chitosan, amylose, guar gum, and Zein or combination wherein the delayed release is achieved by coating at least thereof. one core or granulation with at least one delayed 12. The composition of claim 1, wherein the non-Sedating release control polymer. antihistamine accumulates with repeated administration So 17. The composition of claim 16 wherein the delayed that the antihistamine effect of the compound administered, release control polymer is Selected from the group consisting together with that any circulating active metabolites thereof, of ethyl cellulose, cellulose acetate, cellulose acetate phtha is approximately continuous at or near a level within the late, hydroxypropyl methylcellulose phthalate, polyvinyl therapeutic range. acetate phthalate, acrylic acid polymers and copolymers, US 2005/OO69580 A1 Mar. 31, 2005

polymers or copolymers of methacrylic acid, methyl acry 19. A method of inhibiting the release of histamine in a late, ethyl acrylate, methyl methacrylate, ethyl methacrylate, patient which comprises the Step of administering to a hydroxypropyl methylcellulose acetate Succinate, shellac, patient, a therapeutically effective amount of the composi cellulose acetate trimellitate, Vinyl acetate, azo polymers, tion defined in claim 1. pectin, chitosan, amylose, guar gum, and Zein and combi 20. The method of inhibiting the release of histamine nations thereof. defined in claim 19 wherein the antihistamine composition 18. The composition of claim 16, wherein the non is administered during the evening or night and the Sedating Sedating antihistamine accumulates with repeated adminis antihistamine is immediately released. tration So that the antihistamine effect of the non-Sedating 21. The method of inhibiting the release of histamine antihistamine combined with its active metabolites is defined in claim 19 wherein the patient suffers from allergic approximately continuous at a level within the therapeutic reaction, allergic rhinitis, cold or flu. range. k k k k k