(12) Patent Application Publication (10) Pub. No.: US 2005/0281875A1 Srinivasan Et Al

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US 2005O281.875A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0281875A1 Srinivasan et al. (43) Pub. Date: Dec. 22, 2005

(54) PROMETHAZINE CONTAINING DOSAGE Related U.S. Application Data FORM (63) Continuation-in-part of application No. 10/736,902, (75) Inventors: Viswanathan Srinivasan, The filed on Dec. 17, 2003. Woodlands, TX (US); Ralph Brown, Southlake, TX (US); David Brown, Publication Classification Colleyville, TX (US); Himanshu Patel, North Richland Hills, TX (US) (51) Int. Cl." ...... A61K 3.1/5415; A61K 9/24 (52) U.S. Cl...... 424/472; 514/225.8 Correspondence Address: GREENBLUM & BERNSTEIN, P.L.C. ABSTRACT 1950 ROLAND CLARKE PLACE (57) RESTON, VA 20191 (US) A pharmaceutical dosage form which comprises promethaz (73) Assignee: Sovereign Pharmaceuticals, Ltd., Fort ine and/or a pharmaceutically acceptable Salt thereof. The Worth, TX dosage form is capable of providing a promethazine plasma concentration within a therapeutic range for at least about 24 (21) Appl. No.: 11/102,725 hours per Single dose. This Abstract is neither intended to define the invention disclosed in this specification nor (22) Filed: Apr. 11, 2005 intended to limit the Scope of the invention in any way. US 2005/0281875 A1 Dec. 22, 2005

PROMETHAZINE CONTAINING DOSAGE FORM or in combination with another drug, for example, pseu doephedrine, is indicated, could obtain relief by ingesting CROSS-REFERENCE TO RELATED only one dosage per 24 hour period. Not only would this APPLICATIONS convenient dosage form increase compliance with ambula tory patients, it would also simplify dosage for patients in 0001. The present application is a continuation-in-part of institutional care, Such as nursing homes and hospitals, U.S. patent application Ser. No. 10/736,902, filed Dec. 17, where nurses are required to administer Such dosages. For 2003, the entire disclosure of which is expressly incorpo example, a once a day dosage in Such institutions would rated by reference herein. reduce nursing staff responsibilities and time by 50% for the BACKGROUND OF THE INVENTION purpose of administering these agents. 0008. It would also be desirable if patients suffering from, 0002) 1. Field of the Invention e.g., the above-mentioned conditions for which promethaZ 0003. The present invention relates to a pharmaceutical ine is indicated, would also obtain relief, over a similar time dosage form which contains promethazine and/or a pharma period, from one or more conditions for which drugs dif ceutically acceptable Salt thereof, optionally in combination ferent from promethazine are indicated, by administering a with at least one additional active ingredient or drug. The Single dose of a dosage form Such as, e.g., a tablet, liquid, dosage form is capable of providing a promethazine plasma Syrup, Suspension, capsule and the like which provides both concentration within a therapeutic range for at least about 24 promethazine and one or more other drugs. hours per Single dose when administered to a Subject in need SUMMARY OF THE INVENTION thereof. The present invention also relates to methods of 0009. The present invention provides a pharmaceutical alleviating conditions which can be alleviated by promet dosage form comprising promethazine and/or a pharmaceu hazine and the optional additional active ingredient. tically acceptable Salt thereof, which dosage form is capable 0004 2. Discussion of Background Information of providing a promethazine plasma concentration within 0005 Promethazine is a phenothiazine derivative which the therapeutic range for at least about 24 hours per Single possesses antihistaminic, Sedative, antimotion-Sickness, dose. antiemetic, and anticholineric effects. It is used, for example, 0010. In one aspect, the dosage form of the present for the amelioration of allergic reactions, the treatment of invention may be capable of providing relief from allergy motion sickness and the prevention and control of nausea Symptoms in a patient in need thereof for at least about 24 and Vomiting associated with certain types of anesthesia and hours per Single dose. Surgery. However, a single dose of promethazine provides relief of the indicated symptoms for only about 12 hours, 0011. In another aspect, the dosage form may comprise at requiring the patient to take another dosage form in order to least two promethazine formulations which exhibit different maintain the effects of promethazine for the balance of the release profiles, for example, an immediate release formu 24 hour day. lation and a controlled release formulation. 0006 Further, allergic reactions, in particular, which can 0012. In yet another aspect, the dosage form may com be treated or ameliorated with promethazine are often prise a Solid dosage form Such as, e.g., a tablet, a capsule or accompanied by conditions which can not Satisfactorily be a caplet. For example, the dosage form may comprise a ameliorated or treated with promethazine, but may be treated bi-layered tablet. By way of non-limiting example, this or ameliorated by other drugs, e.g., expectorants, mucus bi-layered tablet may comprise an immediate release layer thinning drugs, decongestants, antituSSives, and/or analge and a controlled release layer. In one aspect, each of the two Sics. However, a single dose of promethazine can provide a layers, e.g., an immediate release layer and a controlled therapeutically effective plasma concentration for an release layer, may comprise at least about 25 mg (e.g., at extended period of time, up to 12 hours, whereas a Single least about 40 mg, or at least about 50 mg) of promethazine dose of other drugs will often provide a therapeutically hydrochloride or an equivalent amount of at least one other effective plasma concentration for a considerably shorter pharmaceutically acceptable Salt of promethazine (which period. For example, a Single dose of an expectorant Such as term is intended to include promethazine free base) and/or guaifenesin will usually provide relief for only about one the bi-layered tablet may comprise a total of at least about hour, and decongestants, antituSSives, and analgesics usually 70 mg (e.g., at least about 80 mg, or at least about 90 mg) provide relief for about 4 to 8 hours per Single dose. As a of promethazine hydrochloride or an equivalent amount of at result, there appears to be virtually no benefit in combining least one other pharmaceutically acceptable Salt of promet promethazine and any Such drug with a noticeably shorter hazine and/or the controlled release layer and/or the imme effective period in a single dosage form. With a correspond diate release layer may comprise at least about 40 mg of ing combination, the promethazine would still provide the promethazine hydrochloride or an equivalent amount of at desired therapeutic effect when the other drug has long least one other pharmaceutically acceptable Salt of promet ceased to be effective and would have to be administered hazine. again. 0013 In a still further aspect, the dosage form of the 0007. It would be desirable if patients suffering from, present invention may comprise at least about 70 mg, e.g., e.g., respiratory congestion, inflammation of the respiratory at least about 90 mg, of promethazine hydrochloride or an mucosa and Sinus cavities, weeping eyes, rhinorrhea, EuS equivalent amount of at least one other pharmaceutically tachian Tube congestion, cough, nausea, aching joints, nau acceptable Salt of promethazine per Single dose. Sea and related gastrointestinal complaints, headache and 0014. In another aspect, the dosage form of the present fever and related Symptoms, for which promethazine alone invention may be capable of providing a promethazine US 2005/0281875 A1 Dec. 22, 2005 plasma concentration within the therapeutic range within not 0021. In yet another aspect, the dosage form may com more than about 1 hour (e.g., within not more than about 30 prise promethazine hydrochloride and pseudoephedrine minutes) following ingestion thereof. hydrochloride. 0.015. In yet another aspect, the dosage form may com 0022. In a still further aspect, the dosage form may prise at least one further drug. By way of non-limiting comprise at least about 70 mg (e.g., at least about 80 mg, at example, the at least one further drug may be Selected from least about 90 mg, or at least about 100mg) of promethazine one or more of decongestants, antituSSives, expectorants, hydrochloride or an equivalent amount of at least one other mucus thinning drugs and analgesics, e.g., from one or more pharmaceutically acceptable Salt of promethazine and/or at of phenylephrine, pseudoephedrine, phenylephrine, pseu least about 180 mg (e.g., at least about 200 mg, at least about doephedrine, codeine, dihydrocodeine, hydrocodone, dex 220 mg, or at least about 240 mg) of pseudoephedrine tromethorphan, carbetapentane, guaifenesin, acetami hydrochloride or an equivalent amount of at least one other nophen, aspirin, ibuprofen, naproxen, oxycodone, morphine pharmaceutically acceptable Salt of pseudoephedrine per and hydromorphone, including pharmaceutically acceptable Single dose. Salts thereof. Also, the dosage form may be capable of providing a plasma concentration of the at least one further 0023. In a still further aspect, the dosage form may drug within a therapeutic range for at least about the same comprise at least one further drug (i.e., in addition to time for which it is capable of providing a plasma concen promethazine and pseudoephedrine). tration of promethazine, e.g., for at least about 24 hours per 0024. In yet another aspect, a dosage form according to Single dose. In a further aspect, this dosage form may be the present invention, including the various aspects thereof, capable of providing a plasma concentration within a thera may be associated with instructions to administer the dosage peutic range of promethazine over a period which is coex form once every 24 hours. tensive with at least about 70%, e.g., at least about 90%, of the period over which the dosage form is capable of pro 0025 The present invention also provides a method of Viding a plasma concentration within a therapeutic range of alleviating one or more conditions which can be alleviated the at least one further drug. In a Still further aspect, the by administration of promethazine and, optionally, by plasma half-life of the at least one further drug may be administration of a drug which is at least one of a decon Shorter than the plasma half-life of promethazine by at least gestant, antituSSive, expectorant, mucus thinning drug and about 3 hours (e.g., by at least about 4 hours, at least about analgesic, in particular, by administration of pseudoephe 5 hours, or at least about 6 hours). drine. This method comprises the administration of a phar maceutical dosage form of the present invention, including 0016. The present invention also provides a pharmaceu the various aspects thereof, to a Subject in need thereof. For tical dosage form which comprises (a) promethazine and/or example, the condition that can be alleviated by adminis a pharmaceutically acceptable Salt thereof in a first form or tration of promethazine may comprise an allergic reaction. layer and (b) promethazine and/or a pharmaceutically acceptable Salt thereof in a Second form or layer which is 0026. In one aspect of this method, the dosage form may different from the first form or layer. The dosage form be administered not more than about once every 24 hours. releases the promethazine (b) over a different period and/or 0027. The present invention also provides a process for at a different rate than the promethazine (a) and the dosage making a pharmaceutical dosage form of the present inven form is capable of providing a promethazine plasma con tion. This process comprises preparing a first composition centration within the therapeutic range for at least about 24 which comprises promethazine or a pharmaceutically hours per Single dose. acceptable Salt thereof and a Second composition which 0.017. In one aspect, the dosage form may be a multi comprises pseudoephedrine or a pharmaceutically accept layered tablet which comprises at least one immediate able Salt thereof, and combining the first and Second com release layer and at least one controlled release layer positions, for example, by a method which comprises the use wherein at least one of these layers comprises promethazine of a tablet press. and/or a pharmaceutically acceptable Salt thereof and 0028. In addition to the above, the present invention also wherein at least one of the layerS comprises at least one provides a pharmaceutical dosage form which comprises a further drug. first drug Selected from promethazine and pharmaceutically 0.018. The present invention also provides a pharmaceu acceptable Salts thereof, and at least one Second drug. The tical dosage form which comprises promethazine and/or a dosage form is capable of providing a plasma concentration pharmaceutically acceptable Salt thereof and pseudoephe within the therapeutic range of the at least one Second drug drine and/or a pharmaceutically acceptable Salt thereof, over a period which is coextensive with at least about 70% wherein the dosage form is capable of providing plasma of the period over which the dosage form is capable of concentrations within the therapeutic ranges of both promet providing a plasma concentration within the therapeutic hazine and pseudoephedrine for at least about 24 hours per range of the first drug. Single dose. 0029. In one aspect of the dosage form, the at least one 0019. In one aspect, the dosage form may comprise a Second drug is preferably Selected from decongestants, anti Solid dosage form, for example, a multi-layered tablet. tussives, expectorants, mucus thinning drugs, analgesics and 0020. In another aspect, the dosage form may be capable antihistamines. For example, the at least one Second drug of providing promethazine and pseudoephedrine plasma may comprise one or more antituSSives Such as, e.g., concentrations within the respective therapeutic ranges codeine, dihydrocodeine, hydrocodone, dextromethorphan within not more than about 1 hour (e.g., within not more than and pharmaceutically acceptable Salts thereof, and/or the at about half an hour) following ingestion thereof. least one Second drug may comprise one or more decon US 2005/0281875 A1 Dec. 22, 2005 gestants. Such as, e.g., phenylephrine, pseudoephedrine and from about 5 mg to about 60 mg, preferably from about 25 pharmaceutically acceptable Salts thereof, and/or the at least mg to about 50 mg, of promethazine hydrochloride or an one Second drug may comprise one or more expectorants, equivalent amount on at least one other pharmaceutically e.g., guaifenesin or a pharmaceutically acceptable Salt acceptable Salt of promethazine. thereof. 0042. In yet another aspect of the bi-layered tablet, the 0.030. In another aspect of the dosage form, the first drug Second layer thereof may be a controlled release layer and may comprise promethazine hydrochloride. may contain (i) from about 1 mg to about 90 mg of phenylephrine hydrochloride or an equivalent amount of any 0031. In yet another aspect, the plasma half-life of the at other pharmaceutically acceptable Salt of phenylephrine; least one Second drug may be shorter than the plasma and/or (ii) from about 1 mg to about 240 mg of pseudoephe half-life of promethazine by at least about 3 hours, e.g., by drine hydrochloride or an equivalent amount of any other at least about 4 hours, or by at least about 6 hours. pharmaceutically acceptable Salt of pseudoephedrine. 0032. In a still further aspect, the period of a plasma concentration within the therapeutic range of the at least one 0043. The present invention also provides a multi-layered second drug may be coextensive with at least about 80%, tablet which comprises at least a first layer and a Second e.g., at least about 90%, or at least about 95%, of the period layer. The first layer comprises promethazine and/or a phar of a plasma concentration within the therapeutic range of maceutically acceptable Salt thereof and the Second layer is promethazine. a controlled release layer and comprises at least one drug which is Selected from decongestants, antituSSives, expec 0033. In another aspect, the dosage form may be a tablet. torants, mucus thinning drugs, analgesics and antihista For example, the tablet may have at least two layers. mines. Preferably, the tablet is a bi-layered tablet. 0044) In one aspect, the first layer of the multi-layered 0034. In yet another aspect, the dosage form comprises a tablet may be an immediate release layer. In another aspect, Solution or a Suspension. the first layer may comprise promethazine hydrochloride. 0035. The present invention also provides a bi-layered 0045. In yet another aspect, the first layer may contain tablet which comprises two layers. The first layer comprises promethazine or a pharmaceutically acceptable Salt thereof promethazine and/or a pharmaceutically acceptable Salt as the only active ingredient. thereof. The Second layer comprises at least one additional drug which is Selected from decongestants, antituSSives, 0046. In a still further aspect of the multi-layered tablet of expectorants, mucus thinning drugs, analgesics and antihis the present invention, the Second layer preferably comprises tamines. The bi-layered tablet provides a plasma concentra one or more, e.g., at least two, of codeine, dihydrocodeine, tion within the therapeutic range of the at least one addi hydrocodone, dextromethorphan, phenylephrine, pseu tional drug over a period which is coextensive with at least doephedrine, guaifenesin, and chlorpheniramine, including about 70% of the period over which the bi-layered tablet pharmaceutically acceptable Salts thereof. provides a plasma concentration within the therapeutic range 0047. In another aspect of the multi-layered tablet, the at of the promethazine. least one drug in the Second layer may have a plasma 0036). In one aspect of the bi-layered tablet, the second half-life which is shorter by at least about 3 hours than the layer may comprise one or both of phenylephrine and plasma half-life of promethazine in the first layer. pseudoephedrine, including pharmaceutically acceptable 0048. In another aspect, the first layer may comprise salts thereof. promethazine hydrochloride and the multi-layered tablet 0037. In another aspect, the first layer may comprise may provide a plasma concentration within a therapeutic promethazine hydrochloride and the Second layer may com range of the at least one drug in the Second layer over a prise two or more of phenylephrine, pseudoephedrine, chlo period which is coextensive with at least about 80% of the rpeniramine and pharmaceutically acceptable Salts thereof. period over which the multi-layered tablet provides a plasma 0.038. In yet another aspect, the first layer may comprise concentration within the therapeutic range of promethazine. promethazine or a pharmaceutically acceptable Salt thereof 0049. In a still further aspect of the multi-layered tablet, as the only active ingredient. For example, promethazine the at least one drug in the Second layer may comprise one hydrochloride may be the only active ingredient in the first or more of phenylephrine, pseudoephedrine, chlorphe layer. niramine and pharmaceutically acceptable Salts thereof. 0039. In a still further aspect of the bi-layered tablet of 0050. The present invention also provides a liquid dosage the present invention, the period of a plasma concentration form which comprises (a) promethazine and/or a pharma within the therapeutic range of the at least one Second drug ceutically acceptable Salt thereof and (b) promethazine and/ may be coextensive with at least about 80%, e.g., at least or a pharmaceutically acceptable Salt thereof and/or at least about 90%, of the period of a plasma concentration within one drug which is Selected from decongestants, expecto the therapeutic range of promethazine. rants, mucus thinning drugs, antituSSives and analgesics. If the at least one drug is present, this liquid dosage form 0040. In a still further aspect of the bi-layered tablet, the provides a plasma concentration within the therapeutic range first layer preferably is an immediate release layer and/or the of the at least one drug of component (b) over a period which Second layer is a controlled release layer. is coextensive with at least about 70% of the period over 0041. In another aspect, the first layer of the bi-layered which the liquid dosage form provides a plasma concentra tablet may contain from about 0.1 mg to about 100 mg, e.g., tion within the therapeutic range of promethazine. US 2005/0281875 A1 Dec. 22, 2005

0051. In one aspect, the liquid dosage form may comprise period over which the dosage form provides a plasma a Suspension. concentration within the therapeutic range of the first drug. 0.052 In another aspect, at least a part of component (a) 0062. In yet another aspect, the dosage form may com and/or of component (b) may be present as a complex with prise a bi-layered tablet. a complexing agent. For example, the complexing agent may comprise an ion-exchange resin Such as, e.g., (Sodium) 0063. In a still further aspect of the dosage form, the first polystyrene Sulfonate. plasma half-life may be at least about 8 hours. 0053. In a still further aspect, the Suspension may com 0064. In another aspect, the dosage form may be associ prise particles of a complex of at least a part of component ated with instructions to administer the dosage form about (b) with an ion-exchange resin, which particles are provided, three or fewer times per day, e.g., 1, 2 or 3 times per day. at least in part, with a controlled release coating. This 0065. The pharmaceutical dosage forms of the present controlled release coating may comprise an organic poly invention which are Set forth above and constitute one aspect mer, e.g., a (meth)acrylate polymer. of the present invention comprise promethazine and/or one or more pharmaceutically acceptable Salts thereof. The pre 0.054 The present invention also provides a method of ferred salt of promethazine is the hydrochloride. However, alleviating (e.g., treating) one or more conditions which can other pharmaceutically acceptable Salts of promethazine be alleviated by administration of promethazine and a drug may be used as well. The term "pharmaceutically acceptable which is a decongestant, antituSSive, expectorant, mucus Salt as used herein and in the appended claims refers to thinning drug, and/or an analgesic. The method comprises those Salts of a particular drug that are not Substantially toxic administering any of the pharmaceutical dosage forms dis at the dosage administered to achieve the desired effect and cussed above, including the various aspects thereof, to a do not independently possess significant pharmacological Subject in need thereof. activity. The salts included within the scope of this term are 0055. In one aspect of the method, the condition which pharmaceutically acceptable acid addition Salts of a Suitable can be alleviated by administration of promethazine com inorganic or organic acid. Non-limiting examples of Suitable prises an allergic reaction. inorganic acids are, for example hydrochloric, hydrobromic, Sulfuric and phosphoric acids. Non-limiting examples of 0056. In another aspect, the dosage form is preferably Suitable organic acids include carboxylic acids, Such as administered not more than about 3 times per day, e.g., twice acetic, propionic, tannic, glycolic, lactic, pyruvic, malonic, per day or once per day. Succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, 0057 The present invention also provides a process for nialeic, hydroxymaleic, benzoic, phenylacetic, 4-aminoben making any of the pharmaceutical dosage forms discussed Zoic, 4-hydroxybenzoic, anthranillic, cinnamic, Salicylic, above, including the various aspects thereof. This method 4-aminoSalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic comprises the preparation of a first composition which and mandelic acids, as well as Sulfonic acids, Such as comprises promethazine and/or a pharmaceutically accept methaneSulfonic, ethaneSulfonic, and B-hydroxyethane able Salt thereof and the preparation of a Second composition Sulfonic acids. which comprises promethazine and/or a pharmaceutically 0066. In addition to promethazine and/or pharmaceuti acceptable Salt thereof and/or at least one Second drug, and cally acceptable Salt thereof the dosage forms of the present the combining of the first and the Second compositions to invention may contain one or more (e.g., one, two or three) form the dosage form. Second drugs. Preferred, non-limiting examples of Such Second drugs are decongestants (Such as, e.g., phenyleph 0.058. In one aspect of the process, the first and second rine, pseudoephedrine and pharmaceutically acceptable Salts compositions may be combined by using a tablet press. thereof), antituSSives (such as, e.g., codeine, dihydroco 0059. The present invention furthermore provides a phar deine, hydrocodone, dextromethorphan and pharmaceuti maceutical dosage form which comprises (a) a first drug cally acceptable Salts thereof), expectorants and mucus which is an antihistamine and has a first plasma half-life and thinning drugs (Such as, e.g., guaifenesin), analgesics (Such (b) at least one Second drug which is selected from decon as, e.g., aspirin, acetaminophen, ibuprofen, ketoprofen, gestants, antituSSives, expectorants, mucus thinning drugs, naproxen, Sodium naproxen, meloxicam, hydrocodone, Oxy analgesics and antihistamines and has a Second plasma codone, morphine, meperidine, and fentanyl) and antihista half-life which differs from the first plasma half-life by at mines (such as, e.g., chlorpheniramine, carbinoxamine and least about 3 hours. This dosage form provides a plasma pharmaceutically acceptable Salts thereof). Particularly pre concentration within a therapeutic range of the at least one ferred as Second drugs are pseudoephedrine and pharma Second drug over a period which is coextensive with at least ceutically acceptable Salts thereof, in particular, pseu about 70% of the period over which the dosage form doephedrine hydrochloride. provides a plasma concentration within the therapeutic range 0067. The dosage forms of the present invention are of the first drug. capable of providing a promethazine plasma concentration 0060. In one aspect, the first half-life may be longer by at within the therapeutic range for at least about 24 hours per least about 4 hours than the half-life of the at least one Single dose. Additionally or alternatively, the dosage forms Second drug. of the present invention which contain at least one Second drug are capable of providing a plasma concentration within 0061. In another aspect, the period of a plasma concen the therapeutic range of the at least one Second drug over a tration within the therapeutic range of the at least one Second period which is coextensive with (overlaps) at least about drug may be coextensive with at least about 80% of the 70%, more preferred at least about 80%, e.g., at least about US 2005/0281875 A1 Dec. 22, 2005

90%, at least about 95%, or about 100%, of the period over 0071. In a preferred aspect of the bi-layered tablet, the which the dosage form provides a plasma concentration promethazine and/or pharmaceutically acceptable Salt within the therapeutic range of the promethazine. The term thereof is the only active ingredient in the first layer. The “therapeutic range' as used herein and in the appended Second layer will usually contain promethazine and/or a claims refers to the range of drug levels (including active pharmaceutically acceptable Salt thereof and/or one, two, metabolite levels) within which most patients will experi three or even more additional drugs. ence a significant therapeutic effect (including alleviation of 0072. In another preferred aspect of the bi-layered tablet, Symptoms) without an undesirable degree of adverse reac the first layer is an immediate release layer and the Second tions. It is noted that the term “coextensive with does not layer is a controlled release layer. The term “controlled exclude, but rather includes, cases where a part of the period release layer” as used herein and in the appended claims over which the plasma concentration of the at least one refers to any layer that is not an immediate release layer, i.e., Second drug (and/or active metabolites thereof) is within the does not release all of the active ingredients contained therapeutic range is outside the period over which the therein within a relatively short time (for example, within plasma concentration of the promethazine is within the not more than about 1 hour, e.g., within not more than about therapeutic range. In other words, even if the corresponding 0.5 hours, following ingestion of the dosage form). Accord period for the at least one Second drug is to overlap, for ingly, this term is a generic term which encompasses, e.g., example, 70% of the corresponding period of the promet Sustained (extended) release layers, pulsed release layers, hazine, a certain percentage (preferably not more than about delayed release layers, and the like. Preferably, the con 30%, e.g., not more than about 20%, not more than about trolled release layer releases the one or more active ingre 10% or even not more than about 5%) of the total period dients contained therein continuously or intermittently and, over which the plasma concentration of the at least one preferably, in approximately equal amounts per time unit Second drug is within the therapeutic range may be outside (e.g., Zero order release rate), over an extended period of the period over which the plasma concentration of the time Such as, e.g., at least about 2 hours, at least about 3 promethazine is within the therapeutic range, and Vice versa. hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, or at least about 12 0068 The period over which the therapeutic range of a hours. The desirable length of the time period of continuous particular drug may be provided in a given case depends, at or intermittent (e.g., pulsed) release depends, inter alia, on least in part, on the plasma half-life of the drug and/or active the plasma half-life of the drug and/or an active metabolite metabolites thereof. The term “plasma half-life” as used thereof. Also, especially if both an immediate release layer herein refers to the time required for the plasma drug and a controlled release layer comprise promethazine and/or concentration to decline by 50%. The shorter the plasma a pharmaceutically acceptable Salt thereof, the controlled half-life of a particular drug, the shorter will be the period release layer may be a delayed release layer which Starts within the therapeutic range of the drug which is provided by releasing the drug only after a predetermined period of time a Single administered dose of the drug. In one preferred (e.g., all at once in the fashion of an immediate release layer aspect of the dosage form of the present invention, the or in a controlled manner Such as, e.g., at a constant rate, plasma half-life of the at least one Second drug will be intermittently, etc.). shorter than the plasma half-life of the promethazine by at least about 3 hours, e.g., by at least about 4 hours, by at least 0073. The first layer of the bi-layered tablet of the present about 5 hours, by at least about 6 hours, by at least about 8 invention will usually contain at least about 10 mg, e.g., at hours, or even by at least about 10 hours. least about 15 mg, at least about 20 mg, or at least about 25 mg of promethazine hydrochloride or an equivalent amount 0069. A preferred, although non-limiting, embodiment of (in terms of molar amount) of promethazine and/or any other the dosage forms of the present invention is a tablet, in pharmaceutically acceptable Salt thereof. Usually, the first particular, a bi-layered tablet. Non-limiting examples of layer will not contain more than about 100 mg, e.g., not other embodiments of the dosage form of the invention are more than about 90 mg, not more than about 70 mg, or not capsules, pills, chewable tablets, Suspensions, Solutions, more than about 50 mg of promethazine hydrochloride or an gels, Syrups, and Suppositories. equivalent amount of promethazine and/or any other phar 0070 The bi-layered tablet which forms one aspect of the maceutically acceptable Salt thereof. present invention comprises two layers. The first layer 0074 The second layer of the bi-layered tablet preferably comprises promethazine and/or a pharmaceutically accept is a controlled release layer, in particular, a Sustained release able Salt thereof, as discussed above. The Second layer layer. The controlled release layer may contain, by way of comprises promethazine and/or a pharmaceutically accept non-limiting example, (i) promethazine hydrochloride, usu able Salt thereof and/or (i.e., additionally or alternatively) at ally in an amount which is not leSS than about 10 mg, e.g., least one additional drug which preferably is Selected from not less than about 20 mg, or not less than about 30 mg, not decongestants, antituSSives, expectorants, mucus thinning less than about 40 mg, but not more than about 90 mg, e.g., drugs, analgesics and antihistamines. Specific and non not more than about 80 mg, not more than about 70 mg, or limiting examples of Such drugs are given above. If at least not more than about 50 mg, or equivalent amounts of any one additional drug is present, the bi-layered tablet provides other pharmaceutically acceptable Salt of promethazine; a plasma concentration within the therapeutic range of the at and/or (ii) phenylephrine hydrochloride, usually in an least one additional drug over a period which is coextensive amount which is not less than about 1 mg, e.g., not less than with at least about 70%, preferably at least about 80%, e.g., about 10 mg, or not less than about 15 mg, but not more than at least about 90% or even about 100% of the period over about 90 mg, e.g., not more than about 50 mg, or not more which the bi-layered tablet provides a plasma concentration than about 25 mg, or equivalent amounts of any other within the therapeutic range of the promethazine. pharmaceutically acceptable Salt of phenylephrine; and/or US 2005/0281875 A1 Dec. 22, 2005

(iii) pseudoephedrine hydrochloride, usually in an amount comprise an immediate release matrix which comprises which is not leSS than about 10 mg, e.g., not less than about promethazine and/or a pharmaceutically acceptable Salt 25 mg, not less than about 40 mg, or not less than about 80 thereof, which matrix has dispersed therein particles of one mg, but not more than about 240 mg, e.g., not more than or more Sustained release formulations which have promet about 220 mg, not more than about 200 mg, or not more than hazine and/or a pharmaceutically acceptable Salt thereof about 180 mg, or equivalent amounts of any other pharma and/or any of the other desired drug(s) incorporated therein. ceutically acceptable Salt of pseudoephedrine. In a particu 0078. There are many other ways of combining formu larly preferred aspect, the Second layer will comprise at least lations which provide different release profiles, and all of pseudoephedrine and/or a pharmaceutically acceptable Salt these other ways are contemplated by the present invention. thereof. Also, for a once-a-day dosage form, the amounts of For example, granules of immediate release formulation and the individual drugs will usually be at the upper end of the granules of controlled release formulation (e.g., granules of ranges recited above. immediate release formulation which are provided with an 0075 Another aspect of the present invention is a multi extended release coating) may be incorporated in a single layered tablet which comprises at least a first layer and a capsule in a desired ratio. Second layer, but may optionally comprise a third, fourth, fifth, etc. layer. The first layer, which preferably is an 0079. In another aspect of the multi-layered tablet, the at immediate release layer, comprises promethazine and/or a least one drug in the Second layer (and/or in the additional pharmaceutically acceptable Salt thereof (preferably as the layers) may have a plasma half-life which is shorter by at only active ingredient contained therein) and the mandatory least about 3 hours, e.g., Shorter by at least about 4 hours, or Second layer is a controlled release layer and may comprise shorter by at least about 6 hours, than the plasma half-life of promethazine and/or a pharmaceutically acceptable Salt promethazine and/or pharmaceutically acceptable Salt thereof and/or at least one drug which is Selected from thereof. decongestants, antituSSives, expectorants, mucus thinning 0080. In another aspect of the multi-layered tablet, the drugs, analgesics and antihistamines. If more than one tablet may provide a plasma concentration within a thera additional drug is to be incorporated in the tablet, the Second peutic range of the at least one drug in the Second layer (e.g., layer may contain all of the additional drugs. Alternatively, one or both of phenylephrine, pseudoephedrine and phar a separate (third) layer may be provided for the Second maceutically acceptable Salts thereof) over a period which is additional drug, for example, in cases where it would be coextensive with at least about 80%, e.g., at least about 90%, difficult to design a controlled release layer which provides of the period over which the multi-layered tablet provides a a desired release rate for both the first and the second plasma concentration within the therapeutic range of the additional drug. Of course, a fourth, fifth, etc. layer may be promethazine in the first layer. Preferably, this coextensive provided for a third or fourth additional drug, and So on. period is at least about 18 hours, e.g., at least about 20 hours, Alternatively and by way of non-limiting example, the at least about 22 hours, or at least about 24 hours. Second and a third layer may contain the same drug or drugs, 0081. Another aspect of the present invention is formed but in different (relative) concentrations and/or incorporated by a liquid dosage form, preferably a Suspension, which in a different controlled release formulation. comprises (a) promethazine and/or a pharmaceutically 0.076 The multi-layered tablet of the present invention acceptable Salt thereof and (b) promethazine and/or a phar will usually be made up of two or more distinct layers or maceutically acceptable Salt thereof, and/or at least one drug discrete Zones of granulation compressed together with the which is Selected from decongestants, expectorants, mucus individual layers lying on top of one another. Layered tablets thinning drugs, antituSSives, analgesics and antihistamines. have the appearance of a Sandwich because the edges of each If the at least one other drug is present, this liquid dosage layer or Zone are exposed. Such conventional layered tablets form provides a plasma concentration within the therapeutic are generally prepared by compressing a granulation onto a range of the at least one other drug over a period which is previously compressed granulation. The operation may be coextensive with at least about 70%, preferably at least 80%, repeated to produce multi-layered tablets of more than two e.g., at least 90%, of the period over which the liquid dosage layers. In a preferred embodiment of the multi-layered tablet form provides a plasma concentration within the therapeutic of the present invention, the tablet consists of two layers. range of component (a). By way of non-limiting example, 0077. It is to be noted that it is not necessary for the two component (b) may be incorporated into a Solid controlled or more individual layers of the multi-layered tablet of the release formulation. For example, particles of component (b) present invention to lie on top of one another. By way of may be provided with a controlled release coating (e.g. a non-limiting example, a Second layer (e.g., Sustained release controlled release coating comprising an organic polymer layer) may be partially or completely Surrounded by a first Such as, e.g., a polyacrylate). This formulation may then be layer (e.g., an immediate release layer). For example, the comminuted, if necessary, in an appropriate manner (e.g., by Second layer may be coated with the first layer. In the case milling) to form particles of a size which is Small enough to of three layers, for example, the third layer may be partially be Suitable for being Suspended in a pharmaceutically or completely coated with the Second layer, which in turn acceptable liquid carrier. Component (a), on the other hand, may be partially or completely coated with the first layer. Of may be used as Such or incorporated in a Solid immediate course, these are but a few examples of the many different release formulation, comminuted and incorporated into the ways in which the various layers of the multi-layered tablet liquid carrier as well. A non-limiting example of a corre of the present invention can be arranged relative to each sponding procedure is described in the Examples below. other. Moreover, it is to be understood that the tablets of the 0082 Prior to incorporating components (a) and (b) into present invention are not limited to Such multi-layered a pharmaceutically acceptable liquid carrier to form a liquid tablets. By way of non-limiting example, the tablet may dosage form according to the present invention at least a part US 2005/0281875 A1 Dec. 22, 2005 of component (a) and/or at least a part of component (b) may No. PT 3090; Maneklal Global Exports (Mumbai, India) be converted into a complex with a complexing agent. Models JD and DH series; Niro Pharma Systems, Model Non-limiting examples of Suitable complexing agents com R292F; and Korsch AG Models XL 800 and XL 400. prise ion-exchange resins Such as, e.g., (Sodium) polystyrene Sulfonate. DETAILED DESCRIPTION OF THE PRESENT 0.083. The dosage forms of the present invention can be INVENTION manufactured by processes which are well known to those of skill in the art. For example, for the manufacture of bi 0086 The particulars shown herein are by way of layered tablets, the active ingredients may be dispersed example and for purposes of illustrative discussion of the uniformly into a mixture of excipients, for example, by high embodiments of the present invention only and are presented Shear granulation, low shear granulation, fluid bed granula in the cause of providing what is believed to be the most tion, or by blending for direct compression. Excipients may useful and readily understood description of the principles include diluents, binders, disintegrants, dispersants, lubri and conceptual aspects of the present invention. In this cants, glidants, Stabilizers, Surfactants and colorants. Dilu regard, no attempt is made to show details of the present ents, also termed “fillers', are typically used to increase the bulk of a tablet So that a practical size is provided for invention in more detail than is necessary for the fundamen compression. Non-limiting examples of diluents include tal understanding of the present invention, the description lactose, cellulose, microcrystalline cellulose, mannitol, dry making apparent to those skilled in the art how the Several Starch, hydrolyzed Starches, powdered Sugar, talc, Sodium forms of the present invention may be embodied in practice. chloride, Silicon dioxide, titanium oxide, dicalcium phos phate dihydrate, calcium Sulfate, calcium carbonate, alumina EXAMPLE 1. and kaolin. Binders impart cohesive qualities to a tablet formulation and are used to ensure that a tablet remains 0087. Once-A-Day Dosage Form intact after compression. Non-limiting examples of Suitable binders include Starch (including corn starch and pregelati 0088 A bi-layered tablet for administration every 24 nized Starch), gelatin, Sugars (e.g., glucose, dextrose, hours which comprises 100 mg of promethazine hydrochlo Sucrose, lactose and Sorbitol), celluloses, polyethylene gly ride is illustrated as follows: col, Waxes, natural and Synthetic gums, e.g., acacia, traga canth, Sodium alginate, and Synthetic polymerS Such as polymethacrylates and polyvinylpyrrollidone. Lubricants Dose wfw facilitate tablet manufacture; non-limiting examples thereof Ingredient Process Step (in mg) (in %) include magnesium Stearate, calcium Stearate, Stearic acid, glyceryl behenate, and polyethylene glycol. Disintegrants Calcium Phosphate Dibasic Anhyd. Dry Mix 25.00 7.1 Prosow SMCC 90 Dry Mix 25.00 7.1 facilitate tablet disintegration after administration, and non Promethazine HCI Dry Mix- 1OO.OO 28.6 limiting examples thereof include Starches, alginic acid, Active crosslinked polymerS Such as, e.g., crosslinked polyvi Purified Water Granulation 35.00 O.O nylpyrrollidone, croScarmellose Sodium, potassium or Mix Powidone K-30 Granulation 1O.OO 2.9 Sodium Starch glycolate, clays, celluloses, Starches, gums Mix and the like. Non-limiting examples of Suitable glidants Methocel K4M Premium Post Mix 55.00 17.1 include silicon dioxide, talc and the like. Stabilizers inhibit Methocel K4M Premium Final Blend 110.00 35.7 or retard drug decomposition reactions, including oxidative Stearic Acid NF Final Blend S.OO 1.4 Microcrystalline Cellulose Final Blend 1O.OO 2.9 reactions. Surfactants may be anionic, cationic, amphoteric Magnesium Stearate NF Lube Blend S.OO 1.4 or nonionic. If desired, the tablets may also contain minor FD&C Blue #1 Alum Lake Lube Blend S.OO 1.4 amounts of nontoxic auxiliary Substances Such as pH buff ering agents, preservatives, e.g., antioxidants, Wetting or TOTAL 35O.OO 1OO.O emulsifying agents, Solubilizing agents, coating agents, fla Voring agents, and the like. 0089 Manufacturing Process: 0084 Extended/sustained release formulations may be made by choosing the right combination of excipients that 0090 The active ingredients and excipients are mixed in Slow the release of the active ingredients by coating or temporarily bonding or decreasing the Solubility of the a high Shear mixer/granulator for about 10 minutes. The active ingredients. Examples of these excipients include granulation solution, water and PovidoneK30 (polyvinyl cellulose etherS Such as hydroxypropylmethylcellulose (e.g., pyrrolidone) are pumped into the contents of the granulator Methocel K4M), polyvinylacetate-based excipients Such as, to wet the powder. After the solution is added the post mix e.g., Kollidon SR, and polymers and copolymers based on sustained release matrix ingredient Methocel K4M premium methacrylates and methacrylic acid Such as, e.g., Eudragit (hydroxypropyl methylcellulose) is added and the contents NE 3OD. are mixed until a uniform granulation is developed. Upon 0085. There are several commercially available tablet completion of the granulation process, the wet mass is dried presses capable of making bi-layered tablets. For example, at 45 C. The dried granulation powder is milled using a Manesty RotaPress Diamond, a 45 station D tooling press, Fitzmill and blended in a V-Blender with other excipients. is capable of making bi-layered tablets described in this The dye is added to one half of the granulation powder. This application. Non-limiting examples of presses for the manu granulation material in powder form is ready for compres facture of bi-layered tablets include Fette America Model sion on a bi-layer tablet press. Final tablet weight is 350 mg. US 2005/0281875 A1 Dec. 22, 2005

EXAMPLE 2 0099 3. Charge the post mix amount of Methocel K4M premium to the mixer/granulator and mix for 1 0091) Once-A-Day Dosage Form minute. 0092. A bi-layered tablet for once-a-day administration which comprises 100 mg of promethazine hydrochloride in 0100 4. Dry the granulation until the LOD (loss on an immediate release layer and 240 mg of pseudoephedrine Drying) is 4% or less. hydrochloride in a Sustained release layer is illustrated as 0101 5. Resize the dried granulation through a follows: number 14 mesh Screen. Immediate Release Layer 0102 6. Mix approximately 30% of the remaining Methocel K4M premium with the Colloidal Silicon 0093) Dioxide in an appropriate bag. Screen through a 30 mesh Screen. 0.103 7. Screen the remaining amount of Methocel Dose K4M premium through a number 14 mesh screen. INGREDIENTS (mg) % by Weight 0104 8. Blend the screened materials from steps 5, PROMETHAZINE HCL 1OOOOO 33.33 CALCIUMPHOSPHATE DIBASIC 75.OOO 25.00 6 and 7 using a V-blender for 20 minutes. USP DIHYDRATE PROSOLVSMCC 90 41.OOO 13.67 0105 9. Screen the Magnesium Stearate using a EUDRAGTRS 30 D 6O.OOO 6.OO number 30 mesh screen. METHOCEL K4M PREM USP 18.750 6.25 METHOCEL K4M PREM USP 39.OOO 13.OO 0106 10. Transfer the screened Magnesium Stearate COLLOIDAL SILICON DIOXIDE 2.250 0.75 to the V-blender and blend for 3 minutes. When STEARIC ACID 3.OOO 1.OO completed discharge and Set aside for Step 11 below. MAGNESIUMSTEARATE 3.OOO 1.OO 0107 Pseudoephedrine HCl (Sustained Release Layer) TOTAL 3OOOOO 1OO.OO 0.108 1. Prepare a solution using the Povidone K-30, and Purified Water. Sustained Release Layer 0109 2. Blend the Pseudoephedrine HCl, Calcium Phosphate Dibasic USP Dihydrate, FD&C Blue #1 0094) Aluminum Lake, and Prosolv SMCC 90 with a high sheer mixer/granulator for 10 minutes. 0.110) 3. With the mixer/granulator on, pump the Dose Solution prepared in Step 1 in to the mixer/granulator. INGREDIENTS (mg) % by Weight After completion, Stop the mixer/granulator and PSEUDOEPHEDRINE HCL 24OOOO 53.55 rinse the container with Purified Water. Pump the CALCIUMPHOSPHATE DIBASIC 73.OOO 16.222 rinse water to the mixer/granulator with mixer on. USP DIHYDRATE FD&C BLUE #1 ALM LAKE O.645 O.15 Allow mixture to mix for an additional minute then PROSOLVSMCC 90 46.OOO 10.22 turn mixer/granulator off. PURIFIED WATER 54.OOO O.OO POVIDONE K-30 USP 13.5OO 3.OO 0111. 4. Charge the post mix amount of Methocel PURIFIED WATER S.OOO O.OO K4M premium to the mixer/granulator and mix for 1 METHOCEL K4M PREM USP 22.5OO S.OO minute. METHOCEL K4M PREM USP 44.650 9.92 FD&C BLUE #1 ALM LAKE 0.675 O.15 STEARIC ACID 4.5OO 1.OO 0112 5. Dry the granulation until the LOD is 4% or MAGNESIUMSTEARATE 4.5OO 1.OO leSS.

TOTAL 45O.OOO 1OO.OO 0113. 6. Resize the dried granulation through a number 14 mesh Screen. 0114 7. Screen the final blend amount of Methocel 0.095 Manufacturing process: K4M premium through a number 14 mesh screen. 0096 Promethazine HCl (Immediate Release Layer) 0115 8. Screen the final blend amounts of Stearic 0097. 1. Blend the dry mix amounts of Promethaz Acid and FD&C Blue #1 Aluminum Lake through a ine HCl, Calcium Phosphate Dibasic Dihydrate, and number 30 mesh screen. Prosolv SMCC 90 with a high sheer mixer/granula 0116 9. Blend the screened materials from step 6, 7, tor for 10 minutes. and 8 using a V-blender for 20 minutes. 0098 2. With the mixer/granulator on, pump the Eudragit RS 30D into the mixer/granulator. After 0117 10. Screen the lube amount of Magnesium completion, Stop the mixer/granulator and rinse the Stearate using a number 30 mesh Screen. container with Purified Water. Pump the rinse water 0118 11. Transfer the screened Magnesium Stearate to the mixer/granulator with mixer on. Turn off mixer to the V-blender and blend for 3 minutes. When when completed. completed discharge and Set aside for Step 10. US 2005/0281875 A1 Dec. 22, 2005

0119) 12. Manufacture bi-layered tablets using a rotary bi-layer tablet preSS where in each tablet layer 1 is 300.0 mg and layer 2 is 450.0 mg. Weight/tablet Ingredients (mgs) EXAMPLE 3 Layer 1 (Immediate Release) 0120 Bi-Layered Tablet (Direct Compression) Promethazine Hydrochloride 50 Silicified Microcrystalline Cellulose 133.5 0121. A bi-layered tablet in accordance with the present Sodium Starch Glycholate 15 invention which comprises promethazine hydrochloride in Magnesium Stearate 1.5 one layer and phenylephrine hydrochloride and chlorphe Layer 2 (Sustained Release) niramine maleate in the other layer is illustrated as follows: Phenylephrine HCI 2O Chlorpheniramine Maleate 8 Lactose Monohydrate 50 Dicalcium Phosphate 50 Kollidon SR 252 Weight/tablet Weight/1 kg batch Stearic Acid 15 Ingredients (mg) (in grams) Magnesium Stearate 5

Layer 1 (Immediate release) Total 6OO Promethazine Hydrochloride 25.0 45.5 Silicified Microcrystalline 114.O 2O7.3 Cellulose EXAMPLE 4 Sodium Starch Glycolate 1O.O 18.2 Magnesium Stearate 1.O 18 Layer 2 (Sustained release) 0127 Bi-Layered Tablet (Wet Granulation): Phenylephrine HCI 2O.O 36.4 0128. A bi-layered tablet in accordance with the present Chlorpheniramine Maleate 8.0 14.5 invention which comprises promethazine hydrochloride in Lactose Monohydrate SO.O 90.9 one layer and pseudoephedrine hydrochloride and chlorphe Dicalcium Phosphate SO.O 90.9 niramine maleate in the other layer is illustrated as follows: Kollidon SR 252.0 458.2 Stearic acid 15.O 27.3 Magnesium Stearate 5.0 9.1 Weight/tablet Weight/1 kg Total 55O.O 1OOO.O Ingredients (mgs) batch (gms) Layer 1 (Immediate release) 0122) Manufacturing Process Promethazine Hydrochloride 25.0 35.7 Silicified Microcrystalline Cellulose 111.O 158.6 Povidone 3.0 4.3 0123 (a) Immediate release layer: Screen all ingredients Croscarmellose Sodium 1O.O 14.3 through a USP sieve size # 30. Blend promethazine hydro Magnesium Stearate 1.O 1.4 chloride (45.5 gms), Silicified microcrystalline cellulose Layer 2 (Sustained release) (207.3 gms) and Sodium starch glycolate (18.2 gms) in a Pseudoephedrine HCl 6O.O 85.7 twin shell blender for 20 minutes. Add magnesium Stearate Chlorpheniramine Maleate 8.0 11.4 Microcrystalline Cellulose (PH 102) 3O.O 42.9 (1.8 gms), which acts as a lubricant, to the above blend and Lactose Monohydrate 1OO.O 142.9 mix for 3 minutes. Dicalcium Phosphate 1OO.O 142.9 Povidone 15.O 21.4 0124 (b) Sustained release layer: Screen all ingredients Methocel K4M Premium 212.O 3O2.9 through a USP sieve size # 30. Preblend a portion of the Stearic Acid 2O.O 28.6 Kollidon SR (145gms) and all the chlorpheniramine male Magnesium Stearate 5.0 7.1 ate (14.5gms) for 15 minutes. Add the remaining Kollidon Total 7OO.O 1OOO.O SR (313.2 gms), phenylephrine hydrochloride (36.4 gms), lactose monohydrate (90.9 gms) and dicalcium phosphate (90.9 gms) to the above preblend and mix for an additional 0129. Manufacturing Process 20 minutes. Add Stearic acid (27.3 gms) and magnesium 0130 (a) Immediate release layer: Screen all ingredients stearate (9.1 gms) to the above blend and mix for three through a USP sieve size # 30. Blend promethazine hydro minutes. chloride (35.7 gms), silicified microcrystalline cellulose (158.6 gms) and croScarmellose Sodium (14.3 gms) in a high 0.125 Manufacture bi-layered tablets using a rotary bi Shear mixer/granulator for 10 minutes. Granulate the above layer tablet preSS where in each tablet the immediate release blend using a 30% povidone solution (4.3 gms povidone in layer is 150 mgs and the Sustained release layer is 400 mgs. 14.3 gms purified water). Dry the granulation until the loss on drying (LOD) is less than 2.0%. Screen the dried granu 0.126 By using the process described above, a bi-layered lation through a USP sieve size # 14. Add the screened tablet of the following composition may be manufactured by granulation and the prescreened magnesium Stearate (1.4 using direct compression: gms) to the above blend and mix for 3 minutes. US 2005/0281875 A1 Dec. 22, 2005

0131 (b) Sustained release layer: Screen all ingredients through a USP sieve size # 30. Blend the pseudoephedrine TABLE 1-continued hydrochloride (87.5 gms), chlorpheniramine maleate (11.4 Preferred OTC gms), microcrystalline cellulose PH 102 (42.9 gms), lactose Amount per Amount per Daily monohydrate (142.9 gms), dicalcium phosphate (142.9 Active ingredient Tablet Tablet Dosage gms), Methocel K4M Premium (302.9 gms) and stearic acid maleate (28.6 gms) in a high Shear mixer/granulator for 10 minutes. Carbinoxamine maleate 0.1-16 mg mg Granulate the above blend using a 30% povidone solution Cetirizine hydrochloride 0.1-40 mg mg (21.4 gms povidone in 71.3 gms purified water). Dry the Chlorcyclizine O 1-300 mg 75 mg granulation till the LOD is less than 2.0%. Screen granules Chlorpheniramine maleate 0.1-64 mg mg 24 mg Chlorpheniramine polistirex 0.1-32 mg mg through a USP sieve size # 14. Add granules and the Clemastine 0.1-12 mg mg prescreened magnesium Stearate (7.1 gms) to the above Cyproheptadine 0.1-16 mg mg blend and mix for 3 minutes. Dexchlorpheniramine 0.1-24 mg mg 12 mg maleate 0132) Manufacture bi-layered tablets using a rotary bi Cyproheptadine 0.1-32 mg mg layer tablet preSS where in each tablet the immediate release hydrochloride Diphenhydramine O. -300 mg 10-50 mg mg layer is 150 mgs and the Sustained release layer is 550 mgs. hydrochloride Diphenhydramine citrate mg 456 mg 0133. By using the process described above, a bi-layered Bromodiphenhydramine O. mg 125-25 mg tablet of the following composition may be manufactured by hydrochloride using wet granulation: Doxylamine succinate -2OO mg 125-25 mg 75 mg Fexofenadine hydrochloride -72O mg 30-18O mg Hydroxyzine hydrochloride -400 mg 10-100 mg Hydroxyzine pamoate -400 mg 25-100 mg Loratadine 0.1-80 mg 1-10 mg Weight/tablet Desloratadine 0.1-40 mg mg Ingredients (mgs) Phenindamine tartrate -7SO mg 150 mg Pheniramine maleate -7SO mg 150 mg Layer 1 (Immediate Release) Pyrilamine maleate .1-200 mg 25 mg 2OO mg Terfemadine Promethazine Hydrochloride 50 Thenyldiamine Silicified Microcrystalline cellulose 129.5 Thonzylamine O.1-3000 mg mg Povidone 4 Thymol Croscarmellose sodium 15 Tripelennamine .1-400 mg 25-50 mg Magnesium Stearate 1.5 hydrochloride Layer 2 (Sustained Release) Triprolidine hydrochloride 0.1-40 mg 1.25-5 mg mg ANTITUSSIVES Pseudoephedrine HCI 60 Chlorpheniramine Maleate 8 Chlorphedianol O. -800 mg mg Microcrystalline Cellulose 102 3O hydrochloride Lactose Monohydrate 1OO Codeine -240 mg 8.4-60 mg 12O mg Dicalcium Phosphate 1OO Codeine phosphate -240 mg 2.5-60 mg 12O mg Povidone 15 Codeine sulfate -480 mg 12O mg Hydroxypropylmethylcellulose 212 Dextromethorphan -480 mg 12O mg Stearic Acid 2O Dextromethorphan -240 mg 3.3-30 mg 12O mg Magnesium Stearate 5 hydrobromide Dextromethorphan O. -240 mg mg Total 750 polistirex Diphenhydramine citrate O.1-1000 mg 228 mg Diphenhydramine .1-400 mg 10-50 mg 150 mg hydrochloride 0134) The above examples illustrate how to manufacture Benzonatate O. -800 mg 100-200 mg a bi-layered tablet containing promethazine hydrochloride in Hydrocodone bitatrate 0.1-40 mg 1.66-10 mg one layer and a combination of an antihistamine and/or a Dihydrocodeine -128 mg 16-32 mg decongestant and/or an antituSSive and/or an expectorant. Caramiphen edisylate -160 mg 6.7-40 mg Carbetapentane tannate -480 mg 30-60 mg For the layer that does not contain promethazine hydrochlo Carbetapentane citrate -160 mg 2O mg ride, combinations of one or more each of the non-limiting Hydromorphone 0.1-8 mg 1. mg examples of possible ingredients in an exemplary range as Noscapine O. -2OO mg described in the following Table 1 can be made depending EXPECTORANT on the Specific therapeutic effect desired. Guaifenesin mg SO-12OO mg TABLE 1. Preferred OTC REFERENCE EXAMPLE Amount per Amount per Daily Active ingredient Tablet Tablet Dosage 0.135 Extended Release Suspension ANTIEHISTAMINES

Azelastine hydrochloride 0.1-2.0 mg 0.125 mg Ingredients Amountf5 ml AZatadine hydrochloride 0.1-4.0 mg 1 mg Brompheniramine maleate 0.1-64 mg 2-16 mg 24 mg Hydrocodone ion-exchange complex Equivalent to 8 mgs Dexbrompheniramine 0.1-24 mg 3-6 mg 12 mg Hydrocodone bitartarate US 2005/0281875 A1 Dec. 22, 2005

-continued Scope and Spirit of the present invention in its aspects. Although the present invention has been described herein Ingredients Amount? S. ml with reference to particular means, materials and embodi Dexchlorpheniramine ion-exchange complex Equivalent to 4 mgs ments, the present invention is not intended to be limited to Dexchlorpheniramine the particulars disclosed herein; rather, the present invention maleate extends to all functionally equivalent Structures, methods Phenylephrine ion-exchange complex Equivalent to 10 mgs Phenylephrine HCI and uses, Such as are within the Scope of the appended Eudragit (R) L 100 0.2 to 2.8 grams claims. Glycerin 315 mgs Polysorbate 80 1.5 mgs Carbomer (e.g., Carbopol (R) 974) 15 mgs What is claimed is: Methyl Paraben 9 mgs 1. A pharmaceutical dosage form which comprises at least Propyl Paraben 1 mgs one of promethazine and a pharmaceutically acceptable Salt Artificial grape flavor 5 mgs FD&C red # 40 dye 0.5 mgs thereof, wherein the dosage form is capable of providing a Water C.S promethazine plasma concentration within a therapeutic range for at least about 24 hours per Single dose. 2. The dosage form of claim 1, wherein the dosage form 0.136 The formula described above serves as a non is capable of providing relief from allergy Symptoms in a limiting example. Any active drug which is in the form of a patient in need thereof for at least about 24 hours per Single Salt, Such as promethazine hydrochloride, codeine phos dose. phate, pseudoephedrine hydrochloride, morphine Sulfate, or 3. The dosage form of claim 1, wherein the dosage form meperidine hydrochloride can be incorporated as an ion comprises at least two promethazine formulations which eXchange resin complex. exhibit different release profiles. 4. The dosage form of claim 1, wherein the dosage form 0.137 Procedure comprises an immediate release formulation. 0138 (1) Add the appropriate amount of sodium poly 5. The dosage form of claim 4, wherein the dosage form styrene Sulphonate USP (e.g. Amberlite(R) IRP 69) to a comprises a controlled release formulation. hydrocodone bitartarate, dexchlorpheniramine maleate and 6. The dosage form of claim 1, wherein the dosage form phenylephrine HCl solution. comprises a Solid dosage form. 0139 (2) Stir the mix for 12 hrs to allow complete 7. The dosage form of claim 6, wherein the solid dosage drug/resin complex formation. form is Selected from tablets, capsules and caplets. 8. The dosage form of claim 1, wherein the dosage form 0140 (3) Separate and dry the insoluble drug/resin comprises a bi-layered tablet. complex. 9. The dosage form of claim 8, wherein the bi-layered 0141 (4) Granulate the drug/resin complex with a tablet comprises an immediate release layer and a controlled delayed release/enteric polymer (e.g. EugragitE L 100, release layer. Kollidon(R) MAE, Aquacoa(Rt cPD) and dry the gran 10. The dosage form of claim 9, wherein each of the ules. immediate release layer and the controlled release layer comprises at least about 25 mg of promethazine hydrochlo 0142 (5) Mill the granules, if needed. ride or an equivalent amount of at least one other pharma 0143 (6) To an appropriate amount of water add the ceutically acceptable Salt of promethazine. following ingredients and dissolve: Carbomer (e.g., 11. The dosage form of claim 8, wherein the bi-layered Carbopol(R) 974), glycerin, polysorbate 80, methyl tablet comprises a total of at least about 70 mg of promet paraben, propyl paraben, artificial grape flavor, FD&C hazine hydrochloride or an equivalent amount of at least one red # 40 dye. other pharmaceutically acceptable Salt of promethazine. 12. The dosage form of claim 9, wherein at least one of 0144 (7) Add milled granules. the controlled release layer and the immediate release layer 0145 (8) Add water to make up to a final volume. comprises at least about 40 mg of promethazine hydrochlo 0146 (9) Agitate at Suitable rate to avoid settling of the ride or an equivalent amount of at least one other pharma Suspension and maintain a homogeneous product mix ceutically acceptable Salt of promethazine. 13. The dosage form of claim 1, wherein the dosage form ture. comprises at least about 70 mg of promethazine hydrochlo 0147 (10) Fill in suitable containers ensuring that the ride or an equivalent amount of at least one other pharma product is homogeneous throughout the filling opera ceutically acceptable Salt of promethazine. tion. 14. The dosage form of claim 1, wherein the dosage form 0.148. It is noted that the foregoing examples have been comprises at least about 90 mg of promethazine hydrochlo provided merely for the purpose of explanation and are in no ride or an equivalent amount of at least one other pharma way to be construed as limiting of the present invention. ceutically acceptable Salt of promethazine. While the present invention has been described with refer 15. The dosage form of claim 1, wherein the dosage form ence to exemplary embodiments, it is understood that the is capable of providing a promethazine plasma concentration words which have been used herein are words of description within a therapeutic range within not more than about 1 hour and illustration, rather than words of limitation. Changes following ingestion thereof. may be made, within the purview of the appended claims, as 16. The dosage form of claim 1, wherein the dosage form presently Stated and as amended, without departing from the comprises at least one further drug. US 2005/0281875 A1 Dec. 22, 2005

17. The dosage form of claim 16, wherein the at least one 29. The dosage form of claim 28, wherein the dosage form further drug is Selected from decongestants, antituSSives, comprises promethazine hydrochloride and pseudoephe expectorants, mucus thinning drugs and analgesics. drine hydrochloride. 18. The dosage form of claim 17, wherein the dosage form 30. The dosage form of claim 25, wherein the dosage form is capable of providing a plasma concentration of the at least comprises at least about 70 mg of promethazine hydrochlo one further drug within a therapeutic range for at least about ride or an equivalent amount of at least one other pharma 24 hours per Single dose. ceutically acceptable Salt of promethazine. 19. The dosage form of claim 18, wherein the at least one 31. The dosage form of claim 30, wherein the dosage form further drug is Selected from one or more of phenylephrine, comprises at least about 180 mg of pseudoephedrine hydro pseudoephedrine, phenylephrine, pseudoephedrine, codeine, chloride or an equivalent amount of at least one other dihydrocodeine, hydrocodone, dextromethorphan, carbetap pharmaceutically acceptable Salt of pseudoephedrine per entane, guaifenesin, acetaminophen, aspirin, ibuprofen, Single dose. naproxen, oxycodone, morphine and hydromorphone and 32. The dosage form of claim 25, wherein the dosage form pharmaceutically acceptable Salts thereof. comprises at least one further drug. 20. The dosage form of claim 16, wherein the dosage form 33. The dosage form of claim 1, wherein the dosage form is capable of providing a plasma concentration within a is associated with instructions to administer the dosage form therapeutic range of promethazine over a period which is once every 24 hours. coextensive with at least about 70% of a period over which the dosage form is capable of providing a plasma concen 34. The dosage form of claim 23, wherein the dosage form tration within a therapeutic range of the at least one further is associated with instructions to administer the dosage form drug. once every 24 hours. 21. The dosage form of claim 20, wherein a plasma 35. The dosage form of claim 25, wherein the dosage form half-life of the at least one further drug is shorter than a is associated with instructions to administer the dosage form plasma half-life of promethazine by at least about 3 hours. once every 24 hours. 22. The dosage form of claim 21, wherein a period of a 36. A method of alleviating a condition which can be plasma concentration within the therapeutic range of the at alleviated by administration of promethazine, wherein the least one further drug is coextensive with at least about 90% method comprises administering the pharmaceutical dosage of a period of a plasma concentration within the therapeutic form of claim 1 to a subject in need thereof. range of promethazine 37. The method of claim 36, wherein the condition that 23. A pharmaceutical dosage form which comprises (a) at can be alleviated by administration of promethazine com least one of promethazine and a pharmaceutically acceptable prises an allergic reaction. salt thereof in a first form or layer and (b) at least one of 38. The method of claim 37, wherein the dosage form is promethazine and a pharmaceutically acceptable Salt thereof administered not more than about once every 24 hours. in a second form or layer which is different from the first 39. A method of alleviating one or more conditions which form or layer, wherein the dosage form releases the promet can be alleviated by administration of promethazine and by hazine (b) at least one of over a different period and at a administration of a drug which is at least one of a decon different rate than the promethazine (a) and wherein the gestant, an antituSSive, an expectorant, a mucus thinning dosage form is capable of providing a promethazine plasma drug and an analgesic, wherein the method comprises concentration within a therapeutic range for at least about 24 administering the dosage form of claim 17 to a Subject in hours per Single dose. need thereof. 24. The dosage form of claim 23, wherein the dosage form 40. The method of claim 39, wherein the dosage form is is a multi-layered tablet which comprises at least one administered not more than about once every 24 hours. immediate release layer and at least one controlled release 41. A method of alleviating one or more conditions which layer and at least one of these layers comprises at least one can be alleviated by administration of promethazine and of promethazine and a pharmaceutically acceptable Salt pseudoephedrine, wherein the method comprises adminis thereof, and wherein at least one of the layers of the multi-layered tablet comprises at least one further drug. tering the dosage form of claim 25 to a Subject in need 25. A pharmaceutical dosage form which comprises at thereof. least one of promethazine and a pharmaceutically acceptable 42. The method of claim 41, wherein the dosage form is Salt thereof and at least one of pseudoephedrine and a administered not more than about once every 24 hours. pharmaceutically acceptable Salt thereof, wherein the dosage 43. A proceSS for making the pharmaceutical dosage form form is capable of providing plasma concentrations within of claim 25, wherein the process comprises preparing a first therapeutic ranges of both promethazine and pseudoephe composition which comprises promethazine or a pharma drine for at least about 24 hours per Single dose. ceutically acceptable Salt thereof and a Second composition 26. The dosage form of claim 25, wherein the dosage form which comprises pseudoephedrine or a pharmaceutically comprises a Solid dosage form. acceptable Salt thereof, and combining the first and Second 27. The dosage form of claim 26, wherein the dosage form compositions. comprises a multi-layered tablet. 44. The process of claim 43, wherein the compositions are 28. The dosage form of claim 25, wherein the dosage form combined by a method which comprises use of a tablet is capable of providing promethazine and pseudoephedrine preSS. plasma concentrations within therapeutic ranges within not more than about 1 hour following ingestion thereof.