USOO9492541 B2

(12) United States Patent (10) Patent No.: US 9,492,541 B2 Srinivasan et al. (45) Date of Patent: *Nov. 15, 2016

(54) PHENYLEPHERINE CONTAINING DOSAGE 4,839,354 A * 6/1989 Sunshine et al...... 514,226.5 FORM 4,882,158 A 11/1989 Yang et al. 5,032,401 A 7, 1991 Jamas et al. 5,133,974 A 7, 1992 Paradissis et al. (75) Inventors: Viswanathan Srinivasan, The 5,445,829 A 8, 1995 Paradissis et al. Woodlands, TX (US); Ralph Brown, 5,840,731 A * 11/1998 Mayer et al...... 514,289 Southlake, TX (US); David Brown, 6,001,392 A * 12/1999 Wen et al...... 424/486 Colleyville, TX (US); Juan Carlos 3:52,- 4 R 358, Stiling et al. Menendez, Bedford, TX (US); 6,462,094 B1 10/2002 Dang et al. Venkatesh Balasubramanian, 6,602,521 B1 8/2003 Ting et al. Arlington, TX (US); Somphet Peter 6,699,502 B1 3/2004 Fanara et al. Suphasawud, Fort Worth, TX (US) 6,797.283 B1 9, 2004 Edgren et al. 2004/022O153 A1 11/2004 Jost-Price et al. 2004/0229849 A1 11/2004 Jost-Price et al. (73) Assignee: SOVEREIGN 2004/0253311 A1 12/2004 Berlin et al. PHARMACEUTICALS, LLC, Fort 2005/0112199 A1 5.2005 Padval et al. Worth, TX (US) 2005/O152967 A1 7/2005 Tengler et al. 2005/O153947 A1 7/2005 Padval et al. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 2648 days. U.S. Appl. No. 10/736,902, filed Dec. 17, 2003 and entitled “Dosage This patent is Subject to a terminal dis- Form Containing Promethazine and Another Drug”. claimer. U.S. Appl. No. 10/798,884, filed Mar. 12, 2004 and entitled “Dosage Form Containing a Morphine Derivative and Another Drug”. (21) Appl. No.: 10/939,351 U.S. Appl. No. 10/910,806, filed Aug. 4, 2004 and entitled "Dosage Form Containing Carbetapentane and Another Drug’. (22) Filed: Sep. 14, 2004 U.S. Appl. No. 11/012,267, filed Dec. 16, 2004 and entitled "Dosage Form Containing Diphenhydramine and Another Drug”. (65) Prior Publication Data .S. Appl. No. 11/102,725, filed Apr. 11, 2005 and entitled “Promethazine Containing Dosage Form”. US 2006/0057205 A1 Mar. 16, 2006 .S. Appl. No. 11/102,726, filed Apr. 11, 2005 and entitled “Diphenhydramine Containing Dosage Form”. (51) Int. C. U.S. Appl. No. 11/115,321, filed Apr. 27, 2005 and entitled “Dosage A6 IK 9/20 (2006.01) Form Containing Multiple Drugs'. A6 IK3I/37 (2006.01) U.S. Appl. No. 11/115,293, filed Apr. 27, 2005 and entitled “Dosage A6 IK 45/06 (2006.01) Form Containing Promethazine and Another Drug”. A6 IK 9/24 (2006.01) * cited by examiner A6 IK 3/485 (2006.01) y (52) U.S. Cl. Primary Examiner — Jessica Worsham CPC ...... A61K 45/06 (2013.01); A61 K9/209 (74) Attorney, Agent, or Firm — Abel Law Group, LLP (2013.01); A61 K3I/137 (2013.01); A61 K 31/485 (2013.01) (57) ABSTRACT (58) USPCField of...... Classification Search 424,464. 468,472 A pharmaceutical dosage form which comprises phe S licati s nylepherine or a pharmaceutically acceptable salt thereof ee application file for complete search history. and a second drug. The dosage form provides a plasma (56) References Cited concentration within the therapeutic range of the second drug over a period which is coextensive with at least about U.S. PATENT DOCUMENTS 70% of the period over which the dosage form provides a plasma concentration within the therapeutic range of phe 4.294.820 A 10, 1981 Keith et al. nylepherine. This abstract is neither intended to define the 4.389,393 A 6, 1983 Schor et al. 4,631,284 A 12/1986 Salpekar et al. invention disclosed in this specification nor intended to limit 4,650,807 A * 3/1987 Findlay et al...... 514,343 the scope of the invention in any way. 4,792,448 A 12/1988 Ranade 4.820,523 A * 4/1989 Shtohryn et al...... 424/469 112 Claims, No Drawings US 9,492,541 B2 1. 2 PHENYLEPHERINE CONTAINING DOSAGE It would be desirable if patients suffering from, e.g., FORM respiratory congestion, for which phenylepherine is indi cated, would also obtain relief of accompanying symptoms FIELD OF THE INVENTION Such as excessive coughing, inflammation of the respiratory mucosa and sinus cavities, weeping eyes, bronchitis, rhinitis, The present invention relates to a pharmaceutical dosage rhinorrhea, Eustachian Tube congestion, nausea, headache form which contains phenylepherine and/or a pharmaceuti and joint pain, over a similar time period, by administering cally acceptable salt thereof in combination with at least one a single dose of a dosage form such as, e.g., a tablet, liquid, additional active ingredient. The dosage form releases phe syrup, Suspension, capsule and the like which provides both nylepherine and the additional active ingredient at rates 10 phenylepherine and one or more other drugs that permits release of the drugs from separate release matrices which are which provide pharmaceutically suitable plasma concentra individually formulated for each ingredients therapeutic tions of all the active pharmaceutical ingredients over simi profile. lar periods of time. The present invention also relates to a Further, the advent of Sustained-release granulation tech process for manufacturing the dosage form and to methods 15 nology has made it possible to achieve and maintain thera for alleviating nasal and respiratory congestion in human peutic levels of a drug at a pre-determined rate, limited only subjects with the oral administration of phenylepherine and by the normal transit time of orally ingested products of ameliorating associated conditions such as excessive through the human alimentary canal. Although this technol coughing, watery nasal passages, Weeping eyes, sinus con ogy has been used to provide Sustained-release levels of gestion and pain, headache, joint pain, bronchitis, and thick phenylepherine, the developers of these products have failed tenacious mucus exudates that inhibit nasal breathing and to develop a Sustained-release or timed-release formulation irritate the throat. that provides consistent therapeutic levels of this pharma Still further, the present invention relates to the adminis ceutical agent throughout the dosage periods indicated in the tration of phenylepherine and/or a pharmaceutically accept labeling. This failure is evident by the dosages of the able Salt thereof in higher amounts (in particular, per time 25 products available. These dosages range from 30 to 40 unit) than has previously been considered expedient from a milligrams every 12 hours for an orally ingested Sustained pharmaceutical and medical point of view. release tablet. It would be desirable to administer a dosage form, in DISCUSSION OF BACKGROUND particular, a Sustained-release dosage form, of phe INFORMATION 30 nylepherine or a pharmaceutically acceptable salt thereof in better conformity and agreement with the plasma half-life of Phenylepherine, when taken orally by human subjects in phenylepherine (2 to 2.5 hours in humans) and the imme adequate dosages (usually in the form of phenylepherine diate release dosage level of phenylepherine hydrochloride hydrochloride or any other pharmaceutically acceptable salt of 10 milligrams every 4 to 6 hours for a daily maximum of of phenylepherine), relieves Swelling of the mucous mem 35 60 mg which is recognized as effective in adults by the branes of the nose and contiguous respiratory mucosa when United States Food and Drug Administration. this Swelling is caused by viral or allergic conditions. It thereby helps restore normal breathing and by preventing SUMMARY OF THE INVENTION mouth breathing—aids in the restoration of normal ciliary activity in the nasal mucosa which permits draining of 40 The present invention provides a pharmaceutical dosage retained secretions. However, congestion of the respiratory form which comprises a first drug which is selected from mucosa is usually accompanied by conditions such as his phenylepherine and pharmaceutically acceptable salts tamine release, excessive coughing, headache, joint pain, thereof and at least one second drug. This dosage form and thick tenacious mucus exudates for which antihista provides a plasma concentration within the therapeutic range mines, pain relieving medication, expectorants, mucus thin 45 of the at least one second drug over a period which is ning drugs, cough Suppressants and other agents are indi coextensive with at least about 70% of the period over which cated. the dosage form provides a plasma concentration within the However, a single dose of phenylepherine or a pharma therapeutic range of phenylepherine. ceutically acceptable salt thereof provides a therapeutically In one aspect, the first drug may comprise one or more effective plasma concentration for 2.5-0.7 hours whereas 50 pharmaceutically acceptable salts of phenylepherine. Pref many agents used in conjunction with phenylepherine pro erably, the first drug comprises at least phenylepherine vide effective plasma concentrations that differ markedly hydrochloride. from this therapeutic profile. In another aspect, the at least one second drug may For example, a single dose of an immediate release comprise one or more of an expectorant, a mucus thinning expectorant Such as guaifenesin will usually provide relief 55 drug, an antihistamine, an antitussive drug and an analgesic. for only about one hour, and pain relieving agents and many In yet another aspect, the at least one second drug may antihistamines usually provide relief for about 4 to 8 hours comprise an antitussive drug. By way of non-limiting per single dose. As a result, there appears to be virtually no example, the at least one second drug may comprise one or benefit in combining phenylepherine with any drug with a more of codeine, hydrocodone, dihydrocodeine and carbeta noticeably shorter or longer effective period in a single 60 pentane, as such and/or in the form of pharmaceutically dosage form. Depending on the therapeutic levels attained acceptable salts thereof. Non-limiting examples of the latter with the drug used in conjunction with phenylepherine, the salts include codeine phosphate, hydrocodone bitartrate, phenylepherine will provide the desired therapeutic effect dihydrocodeine bitartrate and carbetapentane citrate. when the other drug has either ceased to be effective, or In yet another aspect, the at least one second drug may continues to exert a therapeutic effect which prohibits 65 comprise one or more antihistamines. Non-limiting administration of another dose even though the decongestant examples of Suitable antihistamines comprise astemizole, effect of phenylepherine has ceased. Zatadine, bromodiphenhydramine, brompheniramine, car US 9,492,541 B2 3 4 binoxamine, cetirizine, chlorcyclizine, clemastine, chloro chlorpheniramine, clemastine, chlorothen, cyclizine, cypro then, chlorpheniramine, cyclizine, cyproheptadine, deslor heptadine, desloratadine, dimethindene, diphenhydramine, atadine, dimethindene, diphenhydramine, diphenylpyraline, diphenylpyraline, doxylamine, fexofenadine, hydroxyine, doxylamine, fexofenadine, hydroxyine, isothipendyl, lorata isothipendyl, loratadine, methapyrilene, methapyrilene, dine, methapyrilene, montelukast, phenindamine, pheni montelukast, phenindamine, pheniramine, phenyltoloxam ramine, phenyltoloxamine, promethazine, prophen ine, promethazine, prophenpyridamine, pyrilamine, pyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, thenyldiamine, trimeprazine, tripelennamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, triprolidine, acetaminophen, ibuprofen, and pharmaceuti and pharmaceutically acceptable salts thereof Such as, e.g., cally acceptable salts of these compounds, such as, e.g., Zatadine maleate, bromodiphenhydramine HCl, brompheni 10 dextromethorphan hydrobromide, carbetapentane citrate, ramine maleate, carbinoxamine maleate, cetirizine HCl, codeine phosphate, dihydrocodeine bitartrate, hydrocodone chlorcyclizine HCl, clemastine fumarate, chlorothen citrate, bitartrate, guaifenesin HBr, azatadine maleate, bromodi chlorpheniramine maleate, dimethindene maleate, diphen phenhydramine HCl, brompheniramine maleate, carbinox hydramine HCl, fexofenadine HCl, hydroxyine HCl, isoth amine maleate, cetirizine HCl, chlorcyclizine HCl, chlo ipendy1 HC1 (theruhistin), methapyrilene fumarate, meth 15 rpheniramine maleate, clemastine fumarate, chlorothen apyrilene HCl, montelukast sodium, phenindamine tartrate, citrate, dimethindene maleate, diphenhydramine HCl, fex pheniramine maleate, phenyltoloxamine citrate, promethaZ ofenadine HCl, hydroxyine HCl, isothipendy1 HC1 ine hydrochloride, prophenpyridamine maleate, pyrilamine (theruhistin), methapyrilene fumarate, methapyrilene HCl, maleate, thenyldiamine HCl, trimeprazine tartrate, montelukast sodium, phenindamine tartrate, pheniramine tripelennamine HCl and triprolidine HC1. maleate, phenyltoloxamine citrate, promethazine HCl, pro In a still further aspect, the at least one second drug may phenpyridamine maleate, pyrilamine maleate, thenyl comprise one or more expectorants. A non-limiting example diamine HCl, trimeprazine tartrate, tripelennamine HCl, and of a preferred expectorant for use in the present invention is triprolidine HC1. guaifenesin. In yet another aspect, the bi-layered tablet may comprise In another aspect of the dosage form of the present 25 at least two of dextromethorphan hydrobromide, carbeta invention, the plasma half-life of the at least one second drug pentane citrate, codeine phosphate, dihydrocodeine bitar may differ from the plasma half-life of phenylepherine by at trate, hydrocodone bitartrate, guaifenesin HBr, astemizole, least about 2 hours, e.g., by at least about 3 hours, or by at azatadine maleate, bromodiphenhydramine HCl, bromphe least about 4 hours (or even by at least about 5 hours, at least niramine maleate, carbinoxamine maleate, cetirizine HCl, about 6 hours, at least about 7 hours, at least about 8 hours, 30 chlorcyclizine HCl, chlorpheniramine maleate, clemastine at least about 10 hours or at least about 12 hours). fumarate, chlorothen citrate, cyclizine, cyproheptadine, In yet another aspect of the present dosage form, the desloratadine, dimethindene maleate, diphenhydramine period of the plasma concentration within the therapeutic HCl, diphenylpyraline, doxylamine, fexofenadine HCl, range of the at least one second drug may be coextensive hydroxyine HCl, isothipendy1 HC1 (theruhistin), loratadine, with at least about 80%, e.g., at least about 90%, or at least 35 methapyrilene fumarate, methapyrilene HCl, montelukast about 95% of the period of a plasma concentration within the Sodium, phenindamine tartrate, pheniramine maleate, phe therapeutic range of phenylepherine. nyltoloxamine citrate, promethazine HCl, prophen In a still further aspect of the dosage form of the present pyridamine maleate, pyrilamine maleate, terfenadine, the invention, the dosage form may comprise a tablet. This nyldiamine HCl, thonzylamine, trimeprazine tartrate, tablet may, for example, comprise at least two layers, such 40 tripelennamine HCl, triprolidine HCl, acetaminophen and as a bi-layered tablet. Alternatively or additionally, the tablet ibuprofen. may comprise a matrix which comprises one of the first drug In another aspect of the bi-layered tablet, the first layer and the at least one second drug and has dispersed therein thereof may comprise the first drug as the only active particles which comprise the other one of the first drug and ingredient in the first layer. the at least one second drug. 45 In a still further aspect, the period of a plasma concen In yet another aspect, the dosage form may comprise a tration within the therapeutic range of the at least one second Solution or a Suspension. drug may be coextensive with at least about 80%, e.g., at The present invention also provides a bi-layered tablet least about 90%, of the period of a plasma concentration which comprises a first layer and a second layer. The first within the therapeutic range of phenylepherine. layer comprises a first drug which is selected from phe 50 In yet another aspect of the bi-layered tablet, one of the nylepherine and pharmaceutically acceptable salts thereof. first and second layers may be an immediate release layer. The second layer comprises at least one second drug which For example, the first layer may be an immediate release is selected from antitussives, expectorants, mucus thinning layer, or the second layer may be an immediate release layer. drugs, analgesics, and antihistamines. This bi-layered tablet In another aspect, the first and second layers may both be provides a plasma concentration within the therapeutic range 55 controlled release layers. of the at least one second drug over a period which is In another aspect, the bi-layered tablet may comprise a coextensive with at least about 70% of the period over which total of from about 1 mg to about 100 mg of phenylepherine the bi-layered tablet provides a plasma concentration within or an equivalent amount of at least one pharmaceutically the therapeutic range of phenylepherine. acceptable salt of phenylepherine, for example, a total of In one aspect of the bi-layered tablet, the first layer may 60 from about 10 mg to about 75 mg. comprise phenylepherine hydrochloride and/or phe In yet another aspect, the bi-layered tablet may comprise nylepherine tannate. (i) from about 0.1 mg to about 16 mg of chlorpheniramine In another aspect of the bi-layered tablet, the second layer maleate or an equivalent amount of at least one other may comprises one or more of dextromethorphan, carbeta pharmaceutically acceptable salt of chlorpheniramine; and/ pentane, codeine, dihydrocodeine, hydrocodone, guaifene 65 or (ii) about 0.1 mg to about 120 mg of one or more of sin, astemizole, azatadine, bromodiphenhydramine, bro codeine, dihydrocodeine, hydrocodone and pharmaceuti mpheniramine, carbinoxamine, cetirizine, chlorcyclizine, cally acceptable salts thereof; and/or (iii) from about 1 mg US 9,492,541 B2 5 6 to about 240 mg of diphenhydramine hydrochloride or an In another aspect, the at least one drug in the second layer equivalent amount of at least one other pharmaceutically may have a plasma half-life which differs by at least about acceptable salt of diphenhydramine; and/or (iv) from about 1 hour from the plasma half-life of phenylepherine. 0.1 mg to about 75 mg of promethazine hydrochloride or an In a still further aspect, the tablet may provide a plasma equivalent amount of at least one other pharmaceutically 5 concentration within the therapeutic range of the at least one acceptable salt of promethazine; and/or (v) from about 0.1 drug in the second layer over a period which is coextensive mg to about 32 mg of carbinoxamine maleate or an equiva with at least about 80% of the period over which the tablet lent amount of at least one other pharmaceutically accept provides a plasma concentration within the therapeutic range able salt of carbinoxamine; and/or (vi) from about 1 mg to of phenylepherine. about 2400 mg of guaifenesin. 10 In yet another aspect of the multi-layered tablet of the In a still further aspect, the first layer of the bi-layered present invention, the second layer may comprise one of tablet of the present invention may comprise from about 1 more of dextromethorphan, carbetapentane, codeine, dihy mg to about 75 mg of phenylepherine or an equivalent drocodeine, hydrocodone, guaifenesin, astemizole, azata amount of at least one pharmaceutically acceptable salt of 15 dine, bromodiphenhydramine, brompheniramine, carbinox phenylepherine, and at least one of (i) from about 1 mg to amine, cetirizine, chlorcyclizine, chlorpheniramine, about 75 mg of codeine phosphate or an equivalent amount clemastine, chlorothen, cyclizine, cyproheptadine, deslor of at least one other pharmaceutically acceptable salt of atadine, dimethindene, diphenhydramine, diphenylpyraline, codeine, (ii) from about 10 mg to about 30 mg of dihydro doxylamine, fexofenadine, hydroxyine, isothipendyl, lorata codeine bitartrate or an equivalent amount of at least one dine, methapyrilene, methapyrilene, montelukast, phenin other pharmaceutically acceptable salt of dihydrocodeine, damine, pheniramine, phenyltoloxamine, promethazine, (iii) from about 5 mg to about 30 mg of hydrocodone prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, bitartrate or an equivalent amount of at least one other thonzylamine, trimeprazine, tripelennamine, triprolidine, pharmaceutically acceptable salt of hydrocodone, and the acetaminophen, ibuprofen, and pharmaceutically acceptable second layer may comprise one or more of an antihistamine, 25 salts thereof. an expectorant and an analgesic. In another aspect of the multi-layer tablet, the layers In yet another aspect, the first layer may comprise from thereof may be discrete Zones which are arranged adjacent about 1 mg to about 75 mg of phenylepherine or an to each other, or one of the first and second layers may be equivalent amount of at least one pharmaceutically accept partially or completely surrounded by the other one of the able Salt of phenylepherine, and at least one drug which is first and second layers, or one of the first and second layers may be coated with the other one of the first and second selected from carbinoxamine, diphenhydramine, chlorphe layers. niramine, dexbrompheniramine, carbetapentane and phar The present invention further provides a liquid dosage maceutically acceptable salts thereof. form which comprises (a) phenylepherine and/or a pharma The present invention also provides a multi-layered tablet ceutically acceptable salt thereof and (b) at least one drug which comprises at least a first layer and a second layer. The which is selected from antitussives, expectorants, mucus first layer comprises phenylepherine or a pharmaceutically thinning drugs, analgesics, and antihistamines. This dosage acceptable salt thereof and the second layer comprises at form provides a plasma concentration within a therapeutic least one drug which is selected from expectorants, mucus range of (b) over a period which is coextensive with at least thinning drugs, analgesics, antitussives and antihistamines. 40 about 70% of the period over which the liquid dosage form In one aspect of the multi-layered tablet, the first layer provides a plasma concentration within the therapeutic range may be an immediate release layer, or it may be a controlled of (a). release layer. In another aspect, the second layer may be a In one aspect, the liquid dosage form may comprise a controlled release layer. Suspension. For example, the Suspension may comprise a gel In yet another aspect, the first layer may not contain any 45 and/or the Suspension may comprise particles of a complex pharmaceutically active ingredient which is different from of at least a part of component (a) and/or component (b) with phenylepherine or a pharmaceutically acceptable salt an ion-exchange resin, which particles may be provided, at thereof. least in part, with a controlled release coating. The con In a still further aspect, the tablet may comprise, in trolled release coating may comprise an organic polymer addition to phenylepherine or a pharmaceutically acceptable 50 Such as, e.g., a polyacrylate. salt thereof, one or more of dextromethorphan hydrobro In another aspect, at least a part of (b) may be present as mide, carbetapentane citrate, codeine phosphate, dihydroco a complex with a complexing agent and/or at least a part of deine bitartrate, hydrocodone bitartrate, guaifenesin HBr, (a) may be present as a complex with a complexing agent. astemizole, azatadine maleate, bromodiphenhydramine HCl, By way of non-limiting example, the complexing agent may brompheniramine maleate, carbinoxamine maleate, cetiriz 55 comprise an ion-exchange resin Such as, e.g., Sodium poly ine HCl, chlorcyclizine HCl, chlorpheniramine maleate, styrene Sulfonate. clemastine fumarate, chlorothen citrate, cyclizine, cypro The present invention also provides a method of concur heptadine, desloratadine, dimethindene maleate, diphenhy rently alleviating a condition which can be alleviated by dramine HCl, diphenylpyraline, doxylamine, fexofenadine administering phenylepherine and at least one other condi HCl, hydroxyine HCl, isothipendy1 HC1 (theruhistin), lor 60 tion which can be alleviated by administering at least one of atadine, methapyrilene fumarate, methapyrilene HCl, mon an antitussive, expectorant, mucus thinning drug, analgesic telukast sodium, phenindamine tartrate, pheniramine or antihistamine. The method comprises administering any maleate, phenyltoloxamine citrate, promethazine HCl, pro of the pharmaceutical dosage forms set forth above, includ phenpyridamine maleate, pyrilamine maleate, terfenadine, ing the various aspects thereof, to a Subject in need thereof. thenyldiamine HCl, thonzylamine, trimeprazine tartrate, 65 In one aspect of this method, the condition which can be tripelennamine HCl, triprolidine HCl, acetaminophen and alleviated by administering phenylepherine may comprise ibuprofen. respiratory congestion. US 9,492,541 B2 7 8 In another aspect of this method, the dosage forms may be example, the complexing agent may comprise an ion-ex administered not more than about three times per day, e.g., change resin. In another aspect, the liquid may comprise a not more than about twice per day. Suspension. The present invention also provides a process for making In another aspect, the dosage form may release phe the pharmaceutical dosage form of claim 1, wherein the 5 nylepherine or a pharmaceutically acceptable salt thereof method comprises preparing a first composition which com independently over a first period and over a second period prises the first drug and a second composition which com and not more than about 30% of the second period may be prises the at least one second drug, and combining the first coextensive with all or a part of the first period. For example, and the second compositions to form the dosage form. there may be substantially no overlap between the first and 10 second periods. In one aspect of this process, the first and second com The present invention also provides a pharmaceutical positions may be combined by using a tablet press. dosage form which comprises at least about 37 mg of The present invention also provides a pharmaceutical phenylepherine or an equivalent amount of a pharmaceuti dosage form which comprises a first drug which comprises cally acceptable salt thereof. phenylepherine or a pharmaceutically acceptable salt thereof 15 In one aspect, the dosage form may comprise at least and has a first plasma half-life, and at least one second drug about 40 mg of phenylepherine or an equivalent amount of which is selected from antitussives, expectorants, mucus a pharmaceutically acceptable salt thereof, for example, at thinning drugs, analgesics, and antihistamines and has a least about 45 mg. or at least about 50 mg. second plasma half-life which differs from the first plasma In another aspect, the dosage form may comprises one or half-life by at least about 2 hours. This dosage form provides more controlled release forms or layers of phenylepherine a plasma concentration within a therapeutic range of the at and/or a pharmaceutically acceptable salt thereof. least one second drug over a period which is coextensive In another aspect, the dosage form may additionally with at least about 80% of the period over which the dosage comprise an immediate release form or layer of phe form provides a plasma concentration within the therapeutic nylepherine and/or a pharmaceutically acceptable salt range of the first drug. 25 thereof. In one aspect of the dosage form, the first plasma half-life In yet another aspect, the dosage form may comprise at may differ by at least about 3 hours from the second plasma least one additional drug. For example, the at least one half-life. additional drug may comprise one or more of an expecto In another aspect of the dosage form, the period of the rant, a mucus thinning drug, an antihistamine, an antitussive plasma concentration within the therapeutic range of the at 30 drug and an analgesic. least one second drug may be coextensive with at least about In a still further aspect, the dosage form may comprise a 90% of the period over which the dosage form provides a solid dosage form such as, e.g., a tablet, preferably, a plasma concentration within the therapeutic range of the first multi-layered tablet, or the dosage form may comprise a drug. liquid dosage form such as, e.g., a Suspension. In yet another aspect, the dosage form may comprise a 35 The present invention also provides a pharmaceutical multi-layered tablet. dosage form which comprises at least one controlled release In a still further aspect, the dosage form may be associated form or layer of phenylepherine or a pharmaceutically with instructions to administer the dosage form three or acceptable Salt thereof. This dosage form is associated with fewer times per day, e.g., once or twice per day. instructions to administer the dosage form to a subject in The present invention also provides a pharmaceutical 40 need thereof every x hours and the resultant amount thereby dosage form which comprises (a) phenylepherine or a phar administered every x hours divided by X is at least about 5 maceutically acceptable salt thereof in a first form or layer mg of phenylepherine or an equivalent amount of a phar and (b) phenylepherine or a pharmaceutically acceptable salt maceutically acceptable salt thereof. thereof in a second form or layer which is different from the In one aspect, the amount thereby administered may be at first form or layer. This dosage form releases the phe 45 least about 6 mg, e.g., at least about 7 mg; or at least about nylepherine (b) over a different period and at a different rate 8 mg. of phenylepherine or an equivalent amount of a than the phenylepherine (a). pharmaceutically acceptable salt thereof. In one aspect of the dosage form, the first form or layer In another aspect, the dosage form may additionally may an immediate release form or layer and the second form comprise an immediate release form or layer of phe or layer may be a controlled release form or layer. 50 nylepherine and/or a pharmaceutically acceptable salt In another aspect, the dosage form may comprise a thereof. multi-layered tablet which comprises at least one immediate In yet another aspect, the dosage form may comprise at release layer and at least one controlled release layer which least one additional drug, for example, one or more of an independently comprise at least phenylepherine or a phar expectorant, a mucus thinning drug, an antihistamine, an maceutically acceptable salt thereof and wherein at least one 55 antitussive drug and an analgesic. of the layers comprises an additional drug. The at least one In another aspect, the dosage form may comprise a solid additional drug may, for example, be selected from antitus dosage form, e.g., a tablet, for example a multi-layered sives, expectorants, mucus thinning drugs, analgesics and tablet, or the dosage form may comprise a liquid dosage antihistamines. Also, the immediate release layer of the form Such as, e.g., a suspension. multi-layered tablet may comprise the at least one additional 60 The present invention also provides a method of allevi drug, or the at least one controlled release layer thereof may ating a condition which can be alleviated by administering comprise the at least one additional drug. phenylepherine. The method comprises the administration to In another aspect, the dosage form may comprise a liquid a subject in need thereof in intervals of x hours, of a which comprises phenylepherine or a pharmaceutically pharmaceutical dosage form which comprises phe acceptable salt thereof in uncomplexed form and phe 65 nylepherine or a pharmaceutically acceptable salt thereof. In nylepherine or a pharmaceutically acceptable salt thereof as this method, X is at least about 4 and the amount of a complex with a complexing agent. By way of non-limiting phenylepherine or pharmaceutically acceptable salt thereof US 9,492,541 B2 9 10 administered per interval, expressed as mg of phe or about 100%, of the period over which the dosage form nylepherine free base, is at least about 5.X. provides a plasma concentration within the therapeutic range In one aspect of this method, X may be at least about 6, or of the phenylepherine. The term “therapeutic range' as used at least about 8, or at least about 10. herein and in the appended claims refers to the range of drug In another aspect of this method, the amount may be at levels within which most patients will experience a signifi least about 6'X, or at least about 7.x, or at least about 8.X. cant therapeutic effect (including alleviation of symptoms) In a still further aspect, the condition which can be without an undesirable degree of adverse reactions. It is alleviated by administering phenylepherine may comprise noted that the term “coextensive with does not exclude, but respiratory congestion. rather includes, cases where a part of the period over which In yet another aspect, the dosage form may comprise at 10 least one controlled release form or layer of the phe the plasma concentration of the at least one additional drug nylepherine or pharmaceutically acceptable salt thereof. (and/or active metabolites thereof) is within the therapeutic In another aspect, the dosage form may comprise at least range is outside the period over which the plasma concen one additional drug, for example, one or more of an expec tration of the phenylepherine is within the therapeutic range. torant, a mucus thinning drug, an antihistamine, an antitus 15 In other words, even if the corresponding period for the at sive drug and an analgesic. least one additional drug is to overlap, for example, 70% of In another aspect of the method, the dosage form may the corresponding period of the phenylepherine, a certain comprise a tablet, such as a multi-layered tablet, or the percentage (preferably not more than about 30%, e.g., not dosage form may comprise a liquid dosage form such as a more than about 20%, not more than about 10% or even not Suspension (e.g., a gel). more than about 5%) of the total period over which the The present invention also provides a method of dosing plasma concentration of the at least one additional drug is phenylepherine or a pharmaceutically acceptable salt thereof within the therapeutic range may be outside the period over which is present in a dosage form for administration in which the plasma concentration of the phenylepherine is intervals of not less than about 4 hours. The method com within the therapeutic range. prises administering the dosage form every X hours in a 25 The period over which the therapeutic range of a particu quantity which is equivalent to at least 5X milligrams of lar drug may be provided in a given case depends, at least phenylepherine free base. in part, on the plasma half-life of the drug (including any The pharmaceutical dosage form which constitutes one active metabolites thereof). The term "plasma half-life' as aspect of the present invention comprises a first drug which used herein refers to the time required for the plasma drug is selected from phenylepherine or a pharmaceutically 30 concentration to decline by 50%. The shorter the plasma acceptable salt thereof. The preferred salt of phenylepherine half-life of a particular drug, the shorter will be the period is hydrochloride. However, any other pharmaceutically within the therapeutic range of the drug which is provided by acceptable salt of phenylepherine may be used as well. For a single administered dose of the drug. In one preferred example, phenylepherine tannate is another example of a aspect of the dosage form of the present invention, the preferred salt for the purposes of the present invention. The 35 plasma half-life of the at least one second drug will be term “pharmaceutically acceptable salts' as used herein shorter or longer than the plasma half-life of the phe refers to those salts of a particular drug that are not Sub nylepherine by at least about 1 hour, at least about 2 hours, stantially toxic at the dosage administered to achieve the at least about 3 hours, at least about 4 hours, at least about desired effect and do not independently possess significant 5 hours, at least about 6 hours, at least about 7 hours, at least pharmacological activity. The salts included within the 40 about 8 hours, at least about 9 hours, at least about 10 hours, Scope of this term are pharmaceutically acceptable acid or at least about 12 hours. addition salts of a suitable inorganic or organic acid. Non A preferred, although non-limiting, embodiment of the limiting examples of Suitable inorganic acids are, for dosage form of the present invention is a tablet, in particular, example hydrochloric, hydrobromic, Sulfuric and phos a bi-layered tablet. Non-limiting examples of other embodi phoric acids. Non-limiting examples of Suitable organic 45 ments of the dosage form of the invention are capsules, pills, acids include carboxylic acids, such as acetic, propionic, chewable tablets, extended/sustained/delayed release single tannic, glycolic, lactic, pyruvic, malonic. Succinic, fumaric, layer matrix tablets, Suspensions, Solutions, syrups, and malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxy Suppositories. maleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxy The bi-layered tablet which forms another aspect of the benzoic, anthranillic, cinnamic, Salicylic, 4-aminosalicyclic, 50 present invention comprises two layers. The first layer 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acids, as comprises phenylepherine and/or a pharmaceutically accept well as Sulfonic acids, such as methanesulfonic, ethanesul able salt thereof, as discussed above. The second layer may fonic, and B-hydroxyethanesulfonic acids. also comprise phenylepherine and/or a pharmaceutically In addition to the phenylepherine and/or pharmaceutically acceptable salt thereof, for example, in a release form which acceptable salt thereof. Some dosage forms of the present 55 is different from that in the first layer. Additionally or invention will contain one or more (e.g., one, two or three) alternatively, the second layer comprises at least one addi additional drugs. Preferred, non-limiting examples of Such tional drug, preferably, at least one drug which is selected second drugs are antitussives, pain relieving agents, expec from antitussives, pain relieving agents, expectorants, torants and mucus thinning drugs (such as, e.g., guaifene mucus thinning drugs, and antihistamines. Specific and sin), and antihistamines (such as, e.g., chlorpheniramine, 60 non-limiting examples of Such drugs are given above. In a diphenhydramine, carbinoxamine, promethazine, and phar preferred embodiment, the bi-layered tablet provides a maceutically acceptable salts thereof). plasma concentration within the therapeutic range of the at Preferred dosage forms of the present invention provide a least one additional drug over a period which is coextensive plasma concentration within the therapeutic range of the at with at least about 70%, more preferably at least about 80%, least one addditional drug over a period which is coexten 65 e.g., at least about 90% or even about 100% of the period sive with (overlaps) at least about 70%, more preferred at over which the bi-layered tablet provides a plasma concen least about 80%, e.g., at least about 90%, at least about 95%, tration within the therapeutic range of the phenylepherine. US 9,492,541 B2 11 12 In a particularly preferred aspect of the bi-layered tablet, usually in an amount which is not less than about 10 mg. the phenylepherine and/or pharmaceutically acceptable salt e.g., not less that about 15 mg, or not less that about 25 mg. thereof is the only active ingredient in the first layer. The but not more than about 200 mg, or equivalent amounts of second layer will usually contain, one, two, three or even any other pharmaceutically acceptable salt of thereof. more additional drugs. Another aspect of the present invention is a multi-layered In another preferred aspect of the bi-layered tablet, the tablet which comprises at least a first layer and a second first layer is an immediate release layer and the second layer layer, but may optionally comprise a third, fourth, fifth, etc. is a controlled release layer. In another preferred aspect, both layer. The first layer, which may be an immediate release or layers are controlled release layers, but preferably with a controlled release layer, comprises phenylepherine, or a different release characteristics regarding release rate, start 10 pharmaceutically acceptable salt thereof and the mandatory of release etc. The term “controlled release layer as used herein and in the appended claims refers to any layer that is second layer usually is a controlled release layer and may not an immediate release layer, i.e., does not release all of comprise phenylepherine or a pharmaceutically acceptable the active ingredient(s) contained therein within a relatively salt thereof and/or at least one other drug, preferably short time (for example, within less than 1 hour, e.g., less 15 selected from antitussives, pain relieving agents, expecto than 0.5 hours, following ingestion of the dosage form). rants, mucus thinning drugs, and antihistamines. If more Accordingly, this term is a generic term which encompasses, than one additional drug is to be incorporated in the tablet, e.g., Sustained (extended) release layers, pulsed release the second layer may contain all of the additional drugs. layers, delayed release layers, and the like. Preferably, the Alternatively, a separate (third) layer may be provided for controlled release layer releases the one or more active the second additional drug, for example, in cases where it ingredients contained therein continuously or intermittently would be difficult to design a controlled release layer which and, preferably, in approximately equal amounts per time provides a desired release rate for both the first and the unit, over an extended period of time Such as, e.g., at least second additional drug. Of course, a fourth, fifth, etc. layer about 2 hours, at least about 3 hours, at least about 4 hours, may be provided for a third or fourth additional drug, and so or at least about 6 hours, or at least about 8 hours or at least 25 on. Alternatively and by way of non-limiting example, the about 10 hours or at least about 11 hours. The desirable second and a third layer may contain the same drug or drugs, length of the time period of continuous or intermittent (e.g., but in different (relative) concentrations and/or incorporated pulsed) release depends, interalia, on the plasma half-life of in a different controlled release formulation. the drug and/or an active metabolite thereof. The multi-layered tablet of the present invention will The first layer of the bi-layered tablet of the present 30 frequently be made up of two or more distinct layers or invention will usually contain at least about 4 mg, e.g., at discrete Zones of granulation compressed together with the least about 6.5 mg, at least about 10 mg, at least about 15 individual layers lying on top of one another. Layered tablets mg, at least about 20 mg. or at least about 25 mg of have the appearance of a sandwich because the edges of each phenylepherine or the equivalent amount of one or more layer or Zone are exposed. These layered tablets are prepared pharmaceutically acceptable salts thereof. Usually, the first 35 by compressing a granulation onto a previously compressed layer will not contain more than about 75 mg, e.g., not more granulation. The operation may be repeated to produce than about 60 mg, not more than about 50 mg, not more than multi-layered tablets of more than two layers. In a preferred about 45 mg, or not more than about 40 mg of phe embodiment of the multi-layered tablet of the present inven nylepherine or the equivalent amount of one or more phar tion, the tablet consists of two layers. maceutically acceptable salts thereof. 40 It is to be noted that it is not necessary for the two or more The second layer of the bi-layered tablet preferably is a individual layers of the multi-layered tablet of the present controlled release layer, in particular, a Sustained release invention to lie on top of one another. By way of non layer. The controlled release layer may contain, by way of limiting example, a second layer (e.g., Sustained release non-limiting example, (i) phenylepherine hydrochloride, layer) may be partially or completely surrounded by a first usually in an amount which is not less than about 1 mg, e.g., 45 layer (e.g., an immediate release layer). For example, the not less than about 10 mg, or not less than about 15 mg, but second layer may be coated with the first layer. In the case not more than about 75 mg, e.g., not more than about 50 mg. of three layers, for example, the third layer may be partially or equivalent amounts of any other pharmaceutically accept or completely coated with the second layer, which in turn able salt of phenylepherine; (ii) chlorpheniramine maleate, may be partially or completely coated with the first layer. Of usually in an amount which is not less than about 0.1 mg, 50 course, these are but a few examples of the many different e.g., not less than about 2 mg, or not less than about 4 mg. ways in which the various layers of the multi-layered tablet but not more than about 16 mg, e.g., not more than about 12 of the present invention can be arranged relative to each mg, or equivalent amounts of any other pharmaceutically other. Moreover, it is to be understood that the tablets of the acceptable salts of chlorpheniramine; and/or (iii) prometh present invention are not limited to Such multi-layered azine hydrochloride, usually in an amount which is not less 55 tablets. By way of non-limiting example, the tablet may than about 0.1 mg. e.g., not less that about 6 mg, but not comprise an immediate release matrix which comprises more than about 75 mg, e.g., not more than about 50 mg. phenylepherine, or a pharmaceutically acceptable salt and/or (iv) guaifenesin, usually in an amount which is not thereof, which matrix has dispersed therein particles of one less than about 1 mg, e.g., not less than about 10 mg, not less or more Sustained release formulations which have any of than about 25 mg, or not less than about 50 mg, or not less 60 the other desired drug(s) incorporated therein, or vice versa. than about 100 mg, but not more than about 2400 mg, e.g., In another aspect of the multi-layered tablet, the at least not more than about 1200 mg, or not more than about 600 one drug in the second layer (and/or in the additional layers) mg, and/or (vi) carbinoxamine maleate, usually in an may have a plasma half-life which is shorter or longer by at amount which is not less than about 0.1 mg. e.g., not less that least about one hour, e.g., by at least about 2 hours, by at about 6 mg, but not more than about 32 mg, or equivalent 65 least about 3 hours, by at least about 4 hours, by at least amounts of any other pharmaceutically acceptable salt of about 5 hours, by at least about 6 hours, by at least about 7 carbinoxamine and/or (vii) diphenhydramine hydrochloride, hours, by at least about 8 hours, by at least about 9 hours, by US 9,492,541 B2 13 14 at least about 10 hours, or by at least about 12 hours than the Binders impart cohesive qualities to a tablet formulation and plasma half-life of phenylepherine, or a pharmaceutically are used to ensure that a tablet remains intact after com acceptable salt thereof. pression. Non-limiting examples of Suitable binders include In another aspect of the multi-layered tablet, the tablet starch (including corn starch and pregelatinized starch), may provide a plasma concentration within a therapeutic gelatin, Sugars (e.g., glucose, dextrose. Sucrose, lactose and range of the at least one drug in the second layer (e.g., an Sorbitol), celluloses, polyethylene glycol, waxes, natural and Synthetic gums, e.g., acacia, tragacanth, Sodium alginate, antitussive, a pain relieving agent, an expectorant, a mucus and synthetic polymers such as polymethacrylates and poly thinning drug, and/or an antihistamine) over a period which vinylpyrrolidone. Lubricants facilitate tablet manufacture; is coextensive with at least about 70%, e.g., at least about non-limiting examples thereof include magnesium Stearate, 80%, or at least about 90%, of the period over which the 10 calcium Stearate, Stearic acid, glyceryl behenate, and poly multi-layered tablet provides a plasma concentration within ethylene glycol. Disintegrants facilitate tablet disintegration the therapeutic range of the drug(s) in the first layer, pref after administration, and non-limiting examples thereof erably phenylepherine and/or a pharmaceutically acceptable include starches, alginic acid, crosslinked polymers such as, salt thereof. e.g., crosslinked polyvinylpyrrolidone, croScarmellose Another aspect of the present invention is formed by a 15 Sodium, potassium or sodium starch glycolate, clays, cellu liquid dosage form, preferably a Suspension, or a gel, which loses, starches, gums and the like. Non-limiting examples of comprises (a) phenylepherine, or a pharmaceutically accept Suitable glidants include silicon dioxide, talc and the like. able salt thereof and (b) at least one drug which is selected Stabilizers inhibit or retard drug decomposition reactions, from antitussives, pain relieving agents, expectorants, including oxidative reactions. Surfactants may be anionic, mucus thinning drugs, and antihistamines. This liquid dos cationic, amphoteric or nonionic. If desired, the tablets may age form provides a plasma concentration within the thera also contain minor amounts of nontoxic auxiliary Substances peutic range of component (b) over a period which is Such as pH buffering agents, preservatives, e.g., antioxi coextensive with at least about 70%, preferably at least 80%, dants, wetting or emulsifying agents, solubilizing agents, e.g., at least 90%, of the period over which the liquid dosage coating agents, flavoring agents, and the like. form provides a plasma concentration within the therapeutic 25 Extended/sustained release formulations may be made by range of component (a). This may be accomplished in choosing the right combination of excipients that slow the various ways. By way of non-limiting example, component release of the active ingredients by coating or temporarily (b) may be incorporated into a solid controlled release bonding or decreasing the Solubility of the active ingredi formulation. For example, particles of component (b) may ents. Examples of these excipients include cellulose ethers be provided with a controlled release coating (e.g. a con 30 Such as hydroxypropylmethylcellulose (e.g., Methocel trolled release coating comprising an organic polymer Such K4M), polyvinylacetate-based excipients such as, e.g., Kol as, e.g., a polyacrylate). This formulation may then be lidon SR, and polymers and copolymers based on methacry comminuted, if necessary, in an appropriate manner (e.g., by lates and methacrylic acid such as, e.g., Eudragit NE 30D. milling) to form particles of a size which is Small enough to There are several commercially available tablet presses be suitable for being Suspended in a pharmaceutically 35 capable of making bi-layered tablets. For example, Manesty acceptable liquid carrier. Component (a), on the other hand, RotaPress Diamond, a 45 station D tooling press, is capable may be used as Such or incorporated as an ion-exchange of making bi-layered tablets described in this application. complex, or incorporated in a solid immediate release for Non-limiting examples of presses for the manufacture of mulation, comminuted and incorporated into the liquid bi-layered tablets include Fette America Model No. PT carrier as well. A non-limiting example of a corresponding 40 3090; Maneklal Global Exports (Mumbai, India) Models JD procedure is described in the Examples provided in this and DH series; Niro Pharma Systems, Model R292F; and application. Korsch AG Models XL 800 and XL 400. Prior to incorporating components (a) and (b) into a pharmaceutically acceptable liquid carrier to form a liquid DETAILED DESCRIPTION OF THE PRESENT dosage form, for example, a Suspension, or a gel form 45 INVENTION according to the present invention, at least a part of com ponent (a) and/or at least a part of component (b) may be The particulars shown herein are by way of example and transformed into a complex with a complexing agent. Non for purposes of illustrative discussion of the embodiments of limiting examples of Suitable complexing agents comprise the present invention only and are presented in the cause of ion-exchange resins such as, e.g., (sodium) polystyrene 50 providing what is believed to be the most useful and readily Sulfonate. understood description of the principles and conceptual The dosage forms of the present invention can be manu aspects of the present invention. In this regard, no attempt is factured by processes which are well known to those of skill made to show details of the present invention in more detail in the art. For example, for the manufacture of bi-layered than is necessary for the fundamental understanding of the tablets, the active ingredients may be dispersed uniformly 55 present invention, the description making apparent to those into a mixture of excipients, for example, by high shear skilled in the art how the several forms of the present granulation, low shear granulation, fluid bed granulation, or invention may be embodied in practice. by blending for direct compression. Excipients may include The following Examples illustrate the use of phe diluents, binders, disintegrants, dispersants, lubricants, gli nylepherine or a pharmaceutically acceptable salt thereof as dants, stabilizers, Surfactants and colorants. Diluents, also 60 a respiratory decongestant. termed “fillers', are typically used to increase the bulk of a tablet So that a practical size is provided for compression. Example 1 Non-limiting examples of diluents include lactose, cellulose, microcrystalline cellulose, mannitol, dry starch, hydrolyzed Bi-Layered Tablet (Wet Granulation) starches, powdered Sugar, talc, sodium chloride, silicon 65 dioxide, titanium oxide, dicalcium phosphate dihydrate, A bi-layered tablet in accordance with the present inven calcium Sulfate, calcium carbonate, alumina and kaolin. tion which comprises phenylepherine hydrochloride in a first US 9,492,541 B2 15 Sustained release layer and guaifenesin in a second Sustained -continued release layer is illustrated as follows: Weight?tablet Weight batch Ingredients (mg) (Kg) Weight?tablet Ingredients (mg) Weight (kg) Layer 2 (Sustained release) Phenylepherine hydrochloride 3O.O 3O.O Layer 1 (Sustained release) Microcrystalline Cellulose (PH 102) 2SO 2S.O Phenylepherine HCI 60.0 6.O Dicalcium Phosphate SO.O SO.O Methocel K15M 1OO.O 1O.O Povidone 1S.O 1S.O Silicified Microcrystalline Cellulose SO.O S.O 10 Methocel K4M Premium 2OSO 2OS.O Eudragit NE 42.O 4.2 Stearic Acid 2O.O 2O.O Magnesium Stearate 8.O 8.O Magnesium Stearate S.O S.O Layer 2 (Sustained release) Total 550.O 550.0 Guaifenesin 6OO.O 60.0 Microcrystalline Cellulose (PH 102) 45.0 45.0 15 Eudragit NE 1S.O 1S.O Procedure: Methocel K4M Premium 14O.O 14.O (a) Immediate release layer #1: Mix the promethazine Stearic Acid 2O.O 2.0 HCl, silicified microcrystalline cellulose and croscarmellose Magnesium Stearate S.O O.S Sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30% povidone solution Total 1085.O 108.5 (3.0 g povidone in 10.0 g purified water). Dry the granula tion until the LOD is less than 2.0%. Screen granules Procedure: through a US sieve size #14. Add the granules and the prescreened magnesium Stearate in a V shaped blender and (a) Sustained release layer #1: Mix phenylepherine hydro mix for 3 minutes. chloride in Methocel(RK15M and silicified microcrystalline 25 (b) Sustained release layer #2: Mix the phenylepherine cellulose in a high shear mixer/granulator for 10 minutes. hydrochloride, microcrystalline cellulose PH 102, dicalcium Granulate the above blend using a Eudragit(R) NE (30%). phosphate, Methocel K4M Premium and stearic acid in a Dry the granulation until the LOD (weight loss on drying) is high shear mixer/granulator for 10 minutes. Granulate the less than 2.0%. Screen granules through a US sieve size #14. above blend using a 30% povidone solution (15.0 g povi Add the granules and the prescreened magnesium Stearate in 30 done in 50.0 g purified water). Dry the granulation until the a V shaped blender and mix for 3 minutes. LOD is less than 2.0%. Screen granules through a US sieve (b) Sustained release layer #2: Screen all ingredients size #14. Add the granules and the prescreened magnesium through a US sieve size #30. Mix guaifenesin, microcrys stearate in a V shaped blender and mix for 3 minutes. talline cellulose PH 102, and stearic acid in a high shear Manufacture bi-layered tablets using a rotary bi-layer mixer/granulator for 10 minutes. Granulate the above blend 35 tablet press where in each tablet layer #1 is 200 mg and layer using a Eudragit R NE (30%). Add the Methocel(RK4M to #2 is 350 mg. Capsules may be manufactured by filling the the granulator and post mix for 5 minutes. Dry the granu same proportions into capsules. lation until the LOD is less than 2.0%. Screen granules through a US sieve size #14. Add the granules and the Example 3 prescreened magnesium Stearate in a V shaped blender and 40 mix for 3 minutes. Bi-Layered Tablet (Wet Granulation) Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 260 mg and layer A bi-layered tablet in accordance with the present inven #2 is 825 mg. Capsules may be manufactured by filling the tion which comprises phenylepherine hydrochloride and 45 carbinoxamine maleate in a first Sustained release layer and same proportions into capsules. phenylepherine hydrochloride in a second Sustained release layer is illustrated as follows: Example 2

50 Weight?tablet Weight batch Bi-Layered Tablet (Wet Granulation) Ingredients (mg) (Kg) A bi-layered tablet in accordance with the present inven Layer 1 (Sustained release) tion which comprises promethazine hydrochloride in an Phenylepherine HCI 75.0 75.0 immediate release layer and phenylepherine hydrochloride 55 Carbinoxamine Maleate 8.0 8.0 Methocel K4M 12O.O 12O.O in a Sustained release layer is illustrated as follows: Silicified Microcrystalline Cellulose 3O.O 3O.O Eudragit NE 1S.O 1S.O Magnesium Stearate 3.0 3.0 Weight?tablet Weight batch Layer 2 (Sustained release) Ingredients (mg) (Kg) 60 Phenylepherine hydrochloride 3O.O 3O.O Layer 1 (Immediate release) Microcrystalline Cellulose (PH 102) 6S.O 6S.O Eudragit NE 2O.O 2O.O Promethazine HCI 2S.O 2S.O Methocel K4M Premium 113.0 113.0 Silicified Microcrystalline Cellulose 1610 1610 Stearic Acid 2O.O 2O.O Povidone 3.0 3.0 Magnesium Stearate S.O S.O Croscarmellose Sodium 1O.O 1O.O 65 Total SOO.O SOO.O Magnesium Stearate 1.O 1.O US 9,492,541 B2 17 18 Procedure: blend using a Eudragit(R) NE (30%). Add the (a) Sustained release layer #1: Mix the phenylepherine Methocel(RK4M to the granulator and post mix for 5 min HCl, carbinoxamine maleate, Methocel(RK4M and silicified utes. Dry the granulation until the LOD is less than 2.0%. microcrystalline cellulose in a high shear mixer/granulator Screen granules through a US sieve size #14. Add the granules and the prescreened magnesium Stearate in a V for 10 minutes. Granulate the above blend using a Eudragit(R) shaped blender and mix for 3 minutes. NE (30%). Dry the granulation until the LOD is less than Manufacture bi-layered tablets using a rotary bi-layer 2.0%. Screen granules through a US sieve size #14. Add the tablet press where in each tablet layer #1 is 390 mg and layer granules and the prescreened magnesium Stearate in a V #2 is 260 mg. Capsules may be manufactured by filling the shaped blender and mix for 3 minutes. same proportions into capsules. (b) Sustained release layer #2: Screen all ingredients 10 through a US sieve size #30. Mix the phenylepherine Example 5 hydrochloride, microcrystalline cellulose PH 102, and Stearic acid in a high shear mixer/granulator for 10 minutes. Bi-Layered Tablet (Wet Granulation) Granulate the above blend using a Eudragit(R) NE (30%). 15 A bi-layered tablet in accordance with the present inven Add the Methocel(RK4M to the granulator and post mix for tion which comprises carbinoxamine maleate in a first 5 minutes. Dry the granulation until the LOD is less than Sustained release layer and phenylepherine hydrochloride in 2.0%. Screen granules through a US sieve size #14. Add the a second Sustained release layer is illustrated as follows: granules and the prescreened magnesium Stearate in a V shaped blender and mix for 3 minutes. Manufacture bi-layered tablets using a rotary bi-layer Weight?tablet Weight batch tablet press where in each tablet layer #1 is 250 mg and layer Ingredients (mg) (Kg) #2 is 250 mg. Capsules may be manufactured by filling the same proportions into capsules. Layer 1 (Sustained release) 25 Carbinoxamine Maleate 8.0 8.0 Example 4 Lactose Monohydrate 61.O 61.O Methocel K4M 7O.O 70.O Silicified Microcrystalline Cellulose 39.0 39.0 Bi-Layered Tablet (Wet Granulation) Eudragit NE 2O.O 2O.O Magnesium Stearate 2.0 2.O A bi-layered tablet in accordance with the present inven 30 Layer 2 (Sustained release) tion which comprises phenylepherine hydrochloride and Phenylepherine hydrochloride. 3O.O 3O.O diphenhydramine hydrochloride in a first Sustained release Microcrystalline Cellulose (PH 102) 4S.O 45.0 layer and codeine phosphate in a second Sustained release Eudragit NE 1S.O 1S.O layer is illustrated as follows: Methocel K4M Premium 103.0 103.0 Stearic Acid 2O.O 2O.O 35 Magnesium Stearate 2.0 2.O

Weight?tablet Weight batch Total 415.O 415.O Ingredients (mg) (Kg) Layer 1 (Sustained release) Procedure: 40 Phenylepherine HCI 12O.O 12O.O (a) Sustained release layer #1: Mix the carbinoxamine Diphenhydramine HCI 12.0 12.O maleate, Methocel(RK4M, lactose monohydrate and silici Methocel K4M 2OO.O 2OO.O fied microcrystalline cellulose in a high shear mixer/granu Silicified Microcrystalline Cellulose 3S.O 3S.O lator for 10 minutes. Granulate the above blend using a Eudragit NE 2O.O 2O.O Eudragit(R) NE (30%). Dry the granulation until the LOD is Magnesium Stearate 3.0 3.0 45 less than 2.0%. Screen granules through a US sieve size #14. Layer 2 (Sustained release) Add the granules and the prescreened magnesium Stearate in Codeine Phosphate 3O.O 3O.O a V shaped blender and mix for 3 minutes. Microcrystalline Cellulose (PH 102) 55.0 55.0 (b) Sustained release layer #2: Screen all ingredients Eudragit NE 1S.O 31.7 through a US sieve size #30. Mix the phenylepherine Methocel K4M Premium 138.0 138.0 hydrochloride, microcrystalline cellulose PH 102, and Stearic Acid 2O.O 2O.O 50 Stearic acid in a high shear mixer/granulator for 10 minutes. Magnesium Stearate 2.O 2.0 Granulate the above blend using a EudragitR NE (30%). Total 6SO.O 6SO.O Add the Methocel(RK4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0%. Screen granules through a US sieve size #14. Add the Procedure: 55 granules and the prescreened magnesium Stearate in a V (a) Sustained release layer #1: Mix the phenylepherine shaped blender and mix for 3 minutes. HCl, diphenhydramine hydrochloride, Methocel(RK4M and Manufacture bi-layered tablets using a rotary bi-layer silicified microcrystalline cellulose in a high shear mixer/ tablet press where in each tablet layer #1 is 200 mg and layer granulator for 10 minutes. Granulate the above blend using #2 is 215 mg. Capsules may be manufactured by filling the a Eudragit(R) NE (30%). Dry the granulation until the LOD 60 same proportions into capsules. is less than 2.0%. Screen granules through a US sieve size #14. Add the granules and the prescreened magnesium Example 6 stearate in a V shaped blender and mix for 3 minutes. (b) Sustained release layer #2: Screen all ingredients Bi-Layered Tablet (Direct Compression) through a US sieve size #30. Mix the codeine phosphate, 65 microcrystalline cellulose PH 102, and stearic acid in a high A bi-layered tablet in accordance with the present inven shear mixer/granulator for 10 minutes. Granulate the above tion which comprises promethazine hydrochloride (longer US 9,492,541 B2 19 half-life drug) in an immediate release layer and phe -continued nylepherine hydrochloride (shorter half-life drug) in a sus tained release layer is illustrated as follows: Weight?tablet Weight batch Ingredients (mg) (Kg) Stearic Acid 2O.O 2O.O Weight?tablet Weight batch Magnesium Stearate S.O S.O Ingredients (mg) (Kg) Total 7OO.O 7OO.O Layer 1 (Immediate release) Promethazine HCI 2SO 2SO 10 Procedure: Silicified Microcrystalline 114.O 114.O Cellulose (a) Immediate release layer #1: Mix the phenylepherine Sodium Starch Glycolate 1O.O 1O.O tannate, chlorpheniramine tannate, silicified microcrystal Magnesium Stearate 1.O 1.O line cellulose and croScarmellose Sodium, in a high shear Layer 2 (Sustained release) mixer/granulator for 10 minutes. Granulate the above blend 15 Phenylepherine hydrochloride 6O.O 6O.O using a 30% povidone solution (3.0 Kg povidone in 7.0 Kg Lactose Monohydrate SO.O SO.O purified water). Dry the granulation until the LOD is less Dicalcium Phosphate SO.O SO.O Kollidon SR 22O.O 220.4 than 2.0%. Screen granules through a US sieve size #14. Stearic acid 1S.O 1S.O Add the granules and the prescreened magnesium Stearate in Magnesium Stearate S.O S.O a V shaped blender and mix for 3 minutes. (b) Sustained release-layer #2: Mix the Phenylepherine Total 550.O 550.O tannate, microcrystalline cellulose PH 102, dicalcium phos phate, Methocel K4M Premium and stearic acid in a high Procedure: shear mixer/granulator for 10 minutes. Granulate the above (a) Immediate release layer #1: Screen all ingredients 25 blend using a 30% povidone solution (15.0 Kg povidone in through a US sieve size #30. Blend the promethazine 35.0 Kg purified water). Dry the granulation until the LOD hydrochloride, microcrystalline cellulose and sodium starch is less than 2.0%. Screen granules through a US sieve size glycolate for 20 minutes. Add magnesium Stearate to the #14. Add the granules and the prescreened magnesium above blend and mix for an additional time of three minutes. stearate in a V shaped blender and mix for 3 minutes. (b) Sustained release layer #2: Blend the phenylepherine 30 Manufacture bi-layered tablets using a rotary bi-layer hydrochloride, lactose monohydrate, dicalcium phosphate tablet press where in each tablet layer #1 is 290 mg and layer and Kollidon(R) SR for 20 minutes. Add Stearic acid and #2 is 410 mg. Capsules may be manufactured by filling the magnesium Stearate to the above blend and mix for an same proportions into capsules. additional time of three minutes. Manufacture bi-layered tablets using a rotary bi-layer 35 Example 8 tablet press where in each tablet the immediate release layer #1 is 150 mg and the sustained release layer #2 is 400 mg. Bi-Layered Tablet (Wet Granulation) Capsules may be manufactured by filling the same propor tions into capsules. A bi-layered tablet in accordance with the present inven 40 tion which comprises diphenhydramine hydrochloride in an Example 7 immediate release layer and phenylepherine hydrochloride in a Sustained release layer is illustrated as follows: Bi-Layered Tablet (Wet Granulation) Weight?tablet Weight batch A bi-layered tablet in accordance with the present inven 45 Ingredients (mg) (Kg) tion which comprises phenylepherine tannate and chlorphe niramine tannate in an immediate release layer and phe Layer 1 (Immediate release) nylepherine tannate in a Sustained release layer is illustrated Diphenhydramine HCI 1OOO 1OO.O as follows: Silicified Microcrystalline Cellulose 86.O 86.O 50 Povidone 3.0 3.0 Croscarmellose Sodium 1O.O 1O.O Magnesium Stearate 1.O 1.O Weight?tablet Weight batch Layer 2 (Sustained release) Ingredients (mg) (Kg) Phenylepherine HCI 75.0 75.0 Layer 1 (Immediate release) 55 Microcrystalline Cellulose (PH 102) 3O.O 3O.O Dicalcium Phosphate 3O.O 3O.O Phenylepherine Tannate 6O.O 60.0 Povidone 1S.O 1S.O Chlorpheniramine Tannate 8.0 8.O Methocel K4M Premium 178.0 178.0 Silicified Microcrystalline Cellulose 2O8.0 2O8.0 Stearic Acid 2O.O 2O.O Povidone 3.0 3.0 Magnesium Stearate 2.0 2.O Croscarmellose Sodium 1O.O 1O.O 60 Magnesium Stearate 1.O 1.O Total 550.O 550.0 Layer 2 (Sustained release) Phenylepherine tannate 3O.O 3O.O Procedure: Microcrystalline Cellulose (PH 102) 3O.O 3O.O Dicalcium Phosphate 1OO.O 1OO.O (a) Immediate release layer #1: Mix the diphenydramine Povidone 1S.O 1S.O 65 hydrochloride, silicified microcrystalline cellulose and cros Methocel K4M Premium 210.0 21 O.O carmellose Sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30% povidone US 9,492,541 B2 21 22 solution (3.0 g povidone in 10.0 g purified water). Dry the Sustained release layer and phenylepherine hydrochloride in granulation until the LOD is less than 2.0%. Screen granules a second Sustained release layer is illustrated as follows: through a US sieve size #14. Add the granules and the prescreened magnesium Stearate in a V shaped blender and mix for 3 minutes. 5 Weight?tablet Weight batch (b) Sustained release layer #2: Mix the phenylepherine Ingredients (mg) (Kg) hydrochloride, microcrystalline cellulose PH 102, dicalcium Layer 1 (Sustained release) phosphate, Methocel K4M Premium and stearic acid in a Brompheniramine Maleate 6.O 6.0 high shear mixer/granulator for 10 minutes. Granulate the Methocel K15M 94.0 94.0 above blend using a 30% povidone solution (15.0 g povi 10 Silicified Microcrystalline Cellulose SO.O SO.O Eudragit NE 42.O 42.O done in 50.0 g purified water). Dry the granulation until the Magnesium Stearate 8.0 8.0 LOD is less than 2.0%. Screen granules through a US sieve Layer 2 (Sustained release) size #14. Add the granules and the prescreened magnesium Phenylepherine HCI 6O.O 6O.O stearate in a V shaped blender and mix for 3 minutes. 15 Microcrystalline Cellulose (PH 102) 4S.O 45.O Manufacture bi-layered tablets using a rotary bi-layer Eudragit NE 1S.O 1S.O tablet press where in each tablet layer #1 is 200 mg and layer Methocel K4M Premium 108.0 108.O #2 is 350 mg. Capsules may be manufactured by filling the Stearic Acid 2O.O 2O.O same proportions into capsules. Magnesium Stearate 2.0 2.O Example 9 Total 450.O 4SO.O

Bi-Layered Tablet (Direct Compression) Procedure: A bi-layered tablet in accordance with the present inven (a) Sustained release layer #1: Mix the brompheniramine 25 maleate, Methocel(RK15M and silicified microcrystalline tion which comprises guaifenesin in a first Sustained release cellulose in a high shear mixer/granulator for 10 minutes. layer and phenylepherine hydrochloride in a second Sus Granulate the above blend using a EudragitR NE (30%). tained release layer is illustrated as follows: Dry the granulation until the LOD is less than 2.0%. Screen granules through a US sieve size #14. Add the granules and Weight?tablet Weight batch 30 the prescreened magnesium Stearate in a V shaped blender Ingredients (mg) (Kg) and mix for 3 minutes. (b) Sustained release layer #2: Screen all ingredients Layer 1 (Sustained release) through a US sieve size #30. Mix the phenylepherine Guaifenesin 600.O 3OO.O hydrochloride, microcrystalline cellulose PH 102, dicalcium Methocel K15M 2OO.O 1OOO 35 phosphate and Stearic acid in a high shear mixer/granulator Silicified Microcrystalline 72.0 36.0 Cellulose for 10 minutes. Granulate the above blend using a Eudragit(R) Magnesium Stearate 8.0 4.0 NE (30%). Add the Methocel(RK4M to the granulator and Layer 2 (Sustained release) post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0%. Screen granules through a US sieve size Phenylepherine hydrochloride 6O.O 3O.O 40 Dicalcium Phosphate 7O.O 3S.O #14. Add the granules and the prescreened magnesium Kollidon SR 172.O 86.O stearate in a V shaped blender and mix for 3 minutes. Stearic acid 1S.O 7.5 Manufacture bi-layered tablets using a rotary bi-layer Magnesium Stearate 3.0 1.5 tablet press where in each tablet layer #1 is 200 mg and layer Total 1200.0 600.O #2 is 250 mg. Capsules may be manufactured by filling the 45 same proportions into capsules. Procedure: (a) Sustained release layer #1: Screen all ingredients Example 11 through a US sieve size #30. Blend the guaifenesin, Metho cel(R) K15M and silicified microcrystalline cellulose for 25 50 minutes. Add magnesium Stearate to the above blend and Bi-Layered Tablet (Wet Granulation) mix for an additional time of three minutes. (b) Sustained release layer #2: Blend the phenylepherine A bi-layered tablet in accordance with the present inven hydrochloride, dicalcium phosphate and Kollidon R. SR for tion which comprises guaifenesin in a first Sustained release 20 minutes. Add Stearic acid and magnesium Stearate to the 55 layer and phenylepherine hydrochloride in a second Sus above blend and mix for an additional time of three minutes. tained release layer is illustrated as follows: Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 880 mg and layer Weight?tablet Weight batch #2 is 320 mg. Capsules may be manufactured by filling the Ingredients (mg) (Kg) same proportions into capsules. 60 Layer 1 (Sustained release) Example 10 Guaifenesin 1OOO.O 4OO.O Methocel K15M 2OO.O 80.0 Bi-Layered Tablet (Wet Granulation) Silicified Microcrystalline Cellulose 40.O 16.0 65 Eudragit NE SO.O 2O.O A bi-layered tablet in accordance with the present inven Magnesium Stearate 1O.O 4.0 tion which comprises brompheniramine maleate in a first US 9,492,541 B2 24 -continued Procedure: (a) Immediate release Layer #1: Screen all ingredients Weight?tablet Weight batch through a US sieve size #30. Preblend a portion (about a Ingredients (mg) (Kg) third of the total) of the silicified microcrystalline cellulose Layer 2 (Sustained release) and all the phenylepherine hydrochloride for the immediate release layer for 15 minutes. Add sodium starch glycolate Phenylepherine hydrochloride 3O.O 12.O and mix for additional 10 minutes. Add magnesium Stearate Microcrystalline Cellulose (PH 102) 45.0 18.0 to the above blend and mix for three minutes. Eudragit NE 1S.O 6.O Methocel K4M Premium 1OO.O 40.O (b) Sustained release layer #2: Screen all ingredients Stearic Acid 2O.O 8.O 10 through a US sieve size #30. Preblend a portion of the Magnesium Stearate 2.0 O.S Kollidon SR (about a third of the total) and all the diphen hydramine hydrochloride for 15 minutes. Add the remaining Total 151O.O 604.O Kollidon SR, phenylepherine hydrochloride and dicalcium phosphate to the above preblend and mix for additional 20 Procedure: 15 minutes. Add Stearic acid and magnesium Stearate to the (a) Sustained release layer #1: Mix the guaifenesin, above blend and mix for three minutes. Methocel(RK15M and silicified microcrystalline cellulose in Manufacture bi-layered tablets using a rotary bi-layer a high shear mixer/granulator for 10 minutes. Granulate the tablet press where in each tablet the immediate release layer above blend using a Eudragit(R) NE (30%). Dry the granu is 200 mg and the Sustained release layer is 460 mg. lation until the LOD is less than 2.0%. Screen granules through a US sieve size #14. Add the granules and the Example 13 prescreened magnesium Stearate in a V shaped blender and mix for 3 minutes. Bi-Layered Tablet (Direct Compression) (b) Sustained release layer #2: Screen all ingredients through a US sieve size #30. Mix the phenylepherine HCl, 25 By using the process described in Example 12, a bi microcrystalline cellulose PH 102 and stearic acid in a high layered tablet which contains phenylepherine hydrochloride shear mixer/granulator for 10 minutes. Granulate the above in an immediate release layer and phenylepherine hydro blend using a Eudragit(R) NE (30%). Add the chloride and dexbrompheniramine maleate in a Sustained Methocel(RK4M to the granulator and post mix for 5 min release layer (see the formula below) may be manufactured utes. Dry the granulation until the LOD is less than 2.0%. 30 by using direct compression: Screen granules through a US sieve size #14. Add the granules and the prescreened magnesium Stearate in a V shaped blender and mix for 3 minutes. Ingredients Weight?tablet (mg) Manufacture bi-layered tablets using a rotary bi-layer Layer 1 (Immediate Release) 35 tablet press where in each tablet layer #1 is 1300 mg and Phenylepherine hydrochloride 1O.O layer #2 is 210 mg. Capsules may be manufactured by filling Silicified Microcrystalline Cellulose 133.5 the same proportions into capsules. Sodium Starch Glycolate 1S.O Magnesium Stearate 1.5 Example 12 Layer 2 (Sustained Release) 40 Phenylepherine hydrochloride 40.O Bi-Layered Tablet (Direct Compression) Dexbrompheniramine maleate 6.O Dicalcium Phosphate 1OOO A bi-layered tablet in accordance with the present inven Kollidon SR 244.O tion which comprises phenylepherine hydrochloride in a first Stearic Acid 7.0 immediate release layer and phenylepherine hydrochloride 45 Magnesium Stearate 3.0 and diphenhydramine hydrochloride in a second Sustained Total S600 release layer is illustrated as follows: Example 14 Weight?tablet Weight batch 50 Ingredients (mg) (Kg) Bi-Layered Tablet (Wet Granulation) Layer 1 (Immediate release) Phenylepherine hydrochloride 3O.O 3O.O A bi-layered tablet in accordance with the present inven Silicified Microcrystalline 16O.O 16O.O 55 tion which comprises phenylepherine hydrochloride in an Cellulose immediate release layer and phenylepherine hydrochloride Sodium Starch Glycolate 9.0 9.0 and chlorpheniramine maleate in a Sustained release layer is Magnesium Stearate 1.O 1.O illustrated as follows: Layer 2 (Sustained release) Phenylepherine HCI 6O.O 6O.O Diphenhydramine HCI 6O.O 6O.O 60 Weight?tablet Weight batch Dicalcium Phosphate 1OOO 1OOO Ingredients (mg) (Kg) Kollidon SR 22O.O 22O.O Stearic acid 16.O 16.0 Layer 1 (Immediate release) Magnesium Stearate 4.0 4.0 Phenylepherine hydrochloride 1O.O 1O.O Total 66O.O 66O.O 65 Silicified Microcrystalline Cellulose 111.0 111.O Povidone 3.0 3.0 US 9,492,541 B2 26 -continued Example 15 Weight?tablet Weight batch Ingredients (mg) (Kg) Bi-Layered Tablet (Wet Granulation) Croscarmellose Sodium 1O.O 1O.O Magnesium Stearate 1.O 1.O By using the process described in Example 14, a bi Layer 2 (Sustained release) layered tablet containing phenylepherine hydrochloride in Phenylepherine HCI 6O.O 60.0 an immediate release layer and phenylepherine hydrochlo Chlorpheniramine Maleate 8.0 8.O ride and chlorpheniramine maleate in a Sustained release Microcrystalline Cellulose (PH 102) 3O.O 3O.O 10 layer may be manufactured by using wet granulation: Dicalcium Phosphate 1OO.O 1OO.O Povidone 1S.O 1S.O Methocel K4M Premium 212.O 212.O Stearic Acid 2O.O 2O.O Ingredients Weight?tablet (mg) Magnesium Stearate S.O S.O 15 Layer 1 (Immediate Release) Total 585.0 585.0 Phenylepherine hydrochloride 3O.O Silicified Microcrystalline cellulose 129.5 Procedure: Povidone 4.0 Croscarmellose sodium 1S.O (a) Immediate release layer #1: Screen all ingredients Magnesium Stearate 1.5 through a US sieve size #30. Blend the phenylepherine Layer 2 (Sustained Release) hydrochloride, silicified microcrystalline cellulose, and Phenylepherine HCI 6O.O croScarmellose Sodium in a high shear mixer/granulator for Chlorpheniramine Maleate 8.0 10 minutes. Granulate the above blend using a 30% povi Microcrystalline Cellulose 102 3O.O done solution (4.3 Kg povidone in 10.0 Kg purified water). 25 Lactose Monohydrate 1OOO Dry the granulation until the LOD is less than 2.0%. Screen Dicalcium Phosphate 1OOO granules through a US sieve size #14. Add granules and the Povidone 1S.O prescreened magnesium Stearate to the above blend and mix Hydroxypropylmethylcellulose 212.O for 3 minutes. Stearic Acid 2O.O Magnesium Stearate S.O (b) Sustained release layer #2: Screen all ingredients 30 through a US sieve size #30. Blend the phenylepherine Total 73O.O hydrochloride, chlorpheniramine maleate, microcrystalline cellulose PH 102, dicalcium phosphate and Methocel K4M Premium and Stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30% 35 Example 16 povidone solution (15.0 Kg povidone in 35.0 Kg purified water). Dry the granulation until the LOD is less than 2.0%. Screen granules through a US sieve size #14. Add granules Bi-Layered Tablet (Wet Granulation) and the prescreened magnesium Stearate to the above blend and mix for 3 minutes. 40 A bi-layered tablet in accordance with the present inven Manufacture bi-layered tablets using a rotary bi-layer tion which comprises phenylepherine hydrochloride in a tablet press where in each tablet the immediate release layer Sustained release layer and carbetapentane citrate in a imme is 135 mg and the Sustained release layer is 450 mg. diate release layer is illustrated as follows:

Formula

Amounts Process Steps ngredients Dose (mg) Scale-Up Sustained Release Layer Wet Mix RMI - PURIFIED WATER 48.OOO 15.000 kg Wet Mix RMI - POVIDONE K-30 USP 12.000 3.750 kg Pre-blend RMI - PHENYLEPHRINE HC USP UNMIC 4OOOO 12.500 kg Pre-blend RMI - CAL PHOSPHATE DIBASIC DIHYD 2S.OOO 7.813 kg Pre-blend RMI - PROSOLV SMCC 90 12S.OOO 39.063 kg Pre-blend RMI - METHOCEL K4M PREMIUM USP SO.OOO 15.625 kg Final blend RMI - METHOCEL K4M PREMIUM USP 144.OOO 45.000 kg Lube blend RMI - MAGNESIUM STEARATE NF 4.OOO 1.250 kg Layer Weight: 400.OOO Immediate Release Layer

Wet Mix RMI - PURIFIED WATER 24.000 7.500 kg Wet Mix RMI - POVIDONE K-30 USP 6.OOO 1.875 kg Pre-blend RMA - CARBETAPENTANE CITRATE 4OOOO 12.500 kg Pre-blend RMI - PROSOLV SMCC 90 1OOOOO 31.250 kg Pre-blend RMI - LACTOSE MONOEHYDRATE #316 4OOOO 12.500 kg Pre-blend RMI - SODIUM STARCH GLYCOLATE 8.OOO 2.500 kg US 9,492,541 B2

-continued

Formula

Amounts Process Steps Ingredients Dose (mg) Scale-Up Pre-blend DYE - FD&C BLUE #1 ALUMINUMLAKE O.156 0.048 kg Final blend RMI - PROSOLV SMCC 90 145.688 45.528 kg Final blend RMI - LACTOSE MONOHYDRATE #316 4OOOO 12.500 kg Final blend RMI - SODIUM STARCH GLYCOLATE 16.000 5.000 kg Final blend DYE - FD&C BLUE #1 ALUMINUMLAKE O.156 0.048 kg Lube blend RMI - MAGNESIUM STEARATE NF 4.OOO 1.250 kg Layer Weight: 400.OOO Totals(wt) 800.000 250.000 kg Totals (tablets) 1 312,500

Procedure 5. Dry the granulation until the LOD is 4% or less. Sustained Release Layer (Layer 1) 6. Pass the dried granulation through a Fitzpatrick Fitz 1. Set aside 0.5 kg of Purified Water to be used in step 4. mill fitted with a 14 mesh screen. 2. Prepare a solution using the scale up amounts of 7. Screen the final blend scale up amounts of Prosolv Povidone K-30, and the remaining Purified Water from SMCC 90, Lactose Monohydrate #316, Sodium Starch step 1. Glycolate, and FD&C Blue #1 Aluminum Lake through 3. Blend the pre-blend scale up amounts of Phenylephrine a 14 mesh screen. HCl USP, Calcium Phosphate Dibasic Dihydrate, and 25 8. Blend the milled granulation from step 6 and the Prosolv SMCC 90 with a high shear mixer/granulator screened materials from step 7 using a V-blender for 20 for 10 minutes. minutes. 4. With the mixer/granulator on, pump the solution pre 9. Screen the lube scale up amount of Magnesium Stearate pared in step 2 in to the mixer/granulator. After comple using a 30 mesh screen. tion, stop the mixer/granulator and rinse the container 30 10. Transfer the screened Magnesium Stearate to the with the Purified water set aside in step 1. Pump the V-blender and blend for 3 minutes. When completed rinse water to the mixer/granulator with mixer on. Turn discharge into proper drums double lined with poly off mixer when completed. ethylene bags. 5. Charge the pre-blend scale up amount of Methocel Compress bi-layered tablets using a rotary bi-layer tablet K4M premium to the mixer/granulator and mix for 1 35 press where in each tablet layer 1 is 400.0 mg and layer 2 is minute. 400 mg. 6 . Dry the granulation until the LOD is 4% or less. The above examples illustrate how to manufacture a 7. Pass the dried granulation through a Fitzpatrick Fitz bi-layered tablet containing phenylepherine hydrochloride mill fitted with a 14 mesh screen. in (at least) a first layer and an antihistamine and/or a 40 decongestant and/or an expectorant in (at least) a second 8. Screen the final blend scale up amount of Methocel layer. Non-limiting examples of other possible active ingre K4M premium through a 14 mesh screen. dients in an exemplary range as described in the following 9. Blend the milled granulation from step 7 and the Table 1 can be employed depending on the specific thera screened materials from step 8 using a V-blender for 20 peutic effect desired. minutes. 45 10. Screen the lube scale up amount of Magnesium TABLE 1. Stearate using a 30 mesh screen. 11. Transfer the screened Magnesium Stearate to the Preferred OTC Amount per Amount per Daily V-blender and blend for 3 minutes. When completed Active ingredient Tablet Tablet Dosage discharge into drums double lined with polyethylene 50 bags. ANTIEHISTAMINES Immediate Release Layer (Layer 2) Azelastine hydrochloride 0.1-2.0 mg 0.125 mg 1. Set aside 0.5 kg of Purified Water to be used in step 4. AZatadine hydrochloride 0.1-4.0 mg 1 mg 2. Prepare a solution using the scale up amounts Povidone Brompheniramine maleate 0.1-64 mg 2-16 mg 24 mg 55 Dexbrompheniramine 0.1-24 mg 3-6 mg 12 mg K-30, and the remaining Purified Water from step 1. maleate 3. Blend the pre-blend scale up amounts of Carbetapen Carbinoxamine maleate 0.1-16 mg 4 mg tane Citrate, Prosolv SMCC 90, Lactose Monohydrate Cetirizine hydrochloride 0.1-40 mg 5-10 mg #316, Sodium Starch Glycolate, and FD&C Blue #1 Chlorcyclizine 0.1-300 mg 50-75 75 mg Aluminum Lake using a high shear mixer/granulator Chlorpheniramine maleate 0.1-64 mg 2-16 mg 24 mg Chlorpheniramine polistirex 0.1-32 mg 4-8 mg for 10 minutes. 60 Clemastine 0.1-12 mg 0.5-2.68 mg 4. With the mixer/granulator on, pump the solution pre Cyproheptadine 0.1-16 mg 2-4 mg pared in step 2 in to the mixer/granulator. After comple Dexchlorpheniramine 0.1-24 mg 2 mg 12 mg maleate tion, stop the mixer/granulator and rinse the container Cyproheptadine 0.1-32 mg 2-4 mg with the Purified Water set aside in step 1. Pump the hydrochloride rinse water to the mixer/granulator with mixer on. 65 Diphenhydramine 0.1-300 mg 10-50 mg 300 mg Allow mixture to mix for an additional minute then turn hydrochloride mixer/granulator off. US 9,492,541 B2 29 TABLE 1-continued -continued

Preferred OTC Weight?tablet Weight batch Amount per Amount per Daily Ingredients (mg) (Kg) Active ingredient Tablet Tablet Dosage Layer 2 (Sustained release) Diphenhydramine citrate 0.1-2000 mg 50-450 mg 456 mg Bromodiphenhydramine 0.1-200 mg 12.5-25 mg Carbetapentane citrate 4S.O 67.5 hydrochloride Phenylepherine hydrochloride 4S.O 67.5 Doxylamine Succinate 0.1-200 mg 12.5-25 mg 75 mg Microcrystalline Cellulose (PH 102) 2O.O 3O.O Fexofenadine hydrochloride 0.1-720 mg 30-180 mg Povidone 8.0 12.0 Hydroxyzine hydrochloride 0.1-400 mg 10-100 mg 10 Methocel K4M Premium 1SO.O 225.0 Hydroxyzine pamoate 0.1-400 mg 25-100 mg Magnesium Stearate 2.0 3.0 Loratadine 0.1-80 mg 1-10 mg Total 38S.O 577.5 Desloratadine 0.1-40 mg 5 mg Phenindamine tartrate 0.1-750 mg 10-150 mg 150 mg Pheniramine maleate 0.1-750 mg 10-150 mg 150 mg 15 Procedure: Pyrilamine maleate 0.1-200 mg 25-200 mg 200 mg (a) Immediate release layer #1: Mix the prescreened (#30 Terfenadine 0.1-100 mg 10-100 mg mesh) phenylepherine hydrochloride, carbetapentane cit Thenyldiamine 0.1-100 mg 10-100 mg rate, silicified microcrystalline cellulose and croScarmellose Thonzylamine 0.1-3000 mg 10-600 mg 600 mg sodium, in a V shaped blender for 20 minutes. Add pre Thymol 0.1-100 mg 10-100 mg screened (#40 mesh) magnesium Stearate in a V shaped Tripelennamine 0.1-400 mg 25-50 mg blender and mix for 3 minutes. hydrochloride (b) Sustained release layer #2: Mix the phenylepherine Triprolidine hydrochloride 0.1-40 mg 1.25-5 mg 10 mg hydrochloride, carbetapentane citrate, Methocel K4M Pre EXPECTORANT mium and microcrystalline cellulose in a high shear mixer/ granulator for 10 minutes. Granulate the above blend using Guaifenesin 0.1-2000 mg SO-1200 2400 mg a 30% povidone solution (12.0 Kg povidone in 28.0 Kg 25 purified water). Dry the granulation until the LOD is less than 2.0%. Screen granules through a US sieve size #14. Add the granules and the prescreened magnesium Stearate in a V shaped blender and mix for 3 minutes. Example 17 Manufacture bi-layered tablets using a rotary bi-layer 30 tablet press where in each tablet layer #1 is 115 mg and layer Bi-Layered Tablet (Wet Granulation) #2 is 270 mg. Example 18 A bi-layered tablet in accordance with the present inven Bi-Layered Tablet (Wet Granulation) tion which contains phenylepherine hydrochloride in both an 35 A bi-layered tablet in accordance with the present inven immediate release layer and a Sustained release layer and tion which comprises phenylepherine hydrochloride and carbetapentane citrate in both an immediate release layer guaifenesin in two different Sustained release layers is and a Sustained release layer is illustrated as follows: illustrated as follows:

Formula

Amounts Process Steps Ingredients Dose(mg) Scale-Up Wet Mix RMI - PURIFIED WATER 55.000 17.188 kg Wet Mix RMI - POVIDONE K-30 USP 1S.OOO 4.688 kg Pre-blend RMA - GUAIFENESIN USP 6OOOOO 187.500 kg Pre-blend RMA - PHENYLEPHRINE HCL USP 4OOOO 12.500 kg Pre-blend RMI - CAL PHOSPHATE DIBASIC ANHYD 4OOOO 12.500 kg Pre-blend RMI - METHOCEL K4M PREMIUM USP 16.000 5.000 kg Final blend RMI - STEARIC ACID NF 4.500 1.4.06 kg Final blend RMI - METHOCEL K4M PREMIUM USP 79.700 24.906 kg Lube blend RMI - MAGNESIUM STEARATE NF 4.500 1.4.06 kg Color blend DYE - FD&C BLUE #1 ALM LAKE O.300 0.094 kg Total (wt) 800.000 250.000 kg Total (tablets) 1 312,500

Procedure Weight?tablet Weight batch 1. Set aside 0.5 kg of purified water to be used as a rinse Ingredients (mg) (Kg) in step 4. 60 2. Prepare a solution using the scale up amounts of Layer 1 (Immediate release) Povidone K-30, and the remaining Purified Water. Carbetapentane citrate 1S.O 22.5 3. Blend the pre-blend scale up amounts of Guaifenesin Phenylepherine hydrochloride 1S.O 22.5 USP. Phenylephrine HC1 USP, and Calcium Phosphate Silicified Microcrystalline Cellulose 74.2 111.3 Dibasic Anhydrous uS1ng a high sheer mixer/granulator Croscarmellose Sodium 1O.O 1S.O 65 for 10 minutes. Magnesium Stearate O.8 1.2 4. With the mixer/granulator on, pump the solution pre pared in step 2 in to the mixer/granulator. After comple US 9,492,541 B2 31 32 tion, stop the mixer/granulator and rinse the container (5) Mill the granules, if needed. with the 0.5 kg of Purified water set aside in step 1. (6) To the milled granules add the appropriate amount of Pump the rinse water to the mixer/granulator with microcrystalline cellulose and the remaining phe mixer on. Turn off mixer when completed. nylepherine hydrochloride or a pharmaceutically accept 5. Charge the pre-blend scale up amount of Methocel able salt thereof in a V shaped blender and mix for 15 K4M premium to the mixer/granulator and mix for 1 minutes. minute. (7) Add prescreened (sieve #30) magnesium stearate to the . Dry the granulation until the LOD is 1% or less. above blend and mix for 3 minutes. . Pass the dried granulation through a Fitzpatrick Fitz (8) Fill into appropriate capsules. mill fitted with a 109 screen. 10 8. Screen the final blend raw materials through a 12 mesh Example 20 SCC. 9. Blend the milled granulation from step 7 and the Extended Release Suspension (Gel) screened materials from step 8 using a V-blender for 20 An extended release Suspension (in the form of a gel) in minutes. 15 accordance with the present invention which contains a 10. Screen the lube blend material through a 30 mesh phenylepherine hydrochloride ion-exchange complex and SCC. promethazine hydrochloride is illustrated as follows (the 11. Charge the screened material from step 10 to the phenylepherine hydrochloride is used in a controlled release V-blender and blend for 2 minutes. form since it has a shorter half-life than the promethazine 12. Discharge half of the blended product into proper hydrochloride): drums double lined with polyethylene bags and set aside for step 16. 13. Screen the color blend material through a 30 mesh Ingredients Amount 5 ml SCC. Phenylepherine hydrochloride Ion-Exchange Equivalent to 30 mg 14. Charge the screened color blend material to the 25 Complex of Phenylepherine V-blender and blend for 1 minute. Promethazine HCI 25 mg 15. Discharge into proper drums double lined with poly Eudragit (R. L. 100 0.2 to 2.8 g. Glycerin 315 mg ethylene bags and set aside for step 16. Polysorbate 80 1.5 mg 16. Compress bi-layered tablets using a rotary bi-layer Carbomer (e.g., Carbopol (R) 974) 37.5 mg tablet press where in each tablet layer 1 is 400.0 mgs 30 Methyl Paraben 9 mg and layer 2 is 400.0 mgs. Propyl Paraben 1 mg Saccharin Sodium cryst., USP 0.1 mg Artificial Grape Flavor 5 mg Example 19 FD&C Red # 40 Dye 0.5 mg Sodium Hydroxide to pH of 6.5 Capsule formulation 35 Water to 5 ml

A capsule formulation in accordance with the present Procedure: invention which contains phenylepherine both in an imme (1) Add the appropriate amount of Sodium polystyrene diate release form and in a Sustained release form is illus sulphonate USP (e.g. Amberlite R, IRP 69) to a phe trated as follows: 40 nylepherine hydrochloride solution. (2) Stir the mix for 12 hrs to allow complete drug/resin complex formation. Ingredients Amount (mg)?tablet (3) Separate and dry the insoluble drug/resin complex. Phenylepherine Ion excange complex Equivalent to 45 mg of (4) Granulate the drug/resin complex with a delayed release/ Phenylepherine hydrochloride 45 enteric polymer (e.g. Eudragit(R) L 100, Kollidon R MAE, Phenylepherine 1S.O Eudragit (R. L. 100 1O.O to 10O.O Aquacoat(R) cBD) and dry the granules. Microcrystalline Cellulose q.s* (5) Mill the granules, if needed. Magnesium Stearate S.O (6) To an appropriate amount of water add the following ingredients and dissolve: promethazine hydrochloride, Total SOO.O 50 Carbomer (e.g., Carbopol R 974), glycerin, polysorbate *Added to make remainder of weight, 80, methyl paraben, propyl paraben, artificial grape flavor, FD&C red #40 dye. The formula described above serves as a non-limiting (7) Add milled granules. example. Any active drug which is in the form of a salt, Such (8) Add water to 80% of final volume. as an antihistamine, guaifenesin, codeine, or dihydroco 55 (9) Agitate at Suitable rate to avoid settling of the Suspension deine, or hydrocodone can be incorporated as an ion and maintain a homogeneous product mixture. exchange resin complex. (10) Neutralize the solution to a pH of 6.5 (range 5.5 to 7.5) Procedure: to form a gel using a IN sodium hydroxide solution. QS (1) Add the appropriate amount of Sodium polystyrene with water to make final volume of 5 ml per dose. sulphonate USP (e.g. Amberlite(R) IRP 69) to a phe 60 (11) Fill in suitable containers. nylepherine hydrochloride solution. (2) Stir the mix for 12 hrs to allow complete drug/resin Example 21 complex formation. (3) Separate and dry the insoluble drug/resin complex. Extended Release Suspension (Liquid) (4) Granulate the drug/resin complex with a delayed release/ 65 enteric polymer (e.g. Eudragit R L 100, Kollidon R MAE, An extended release Suspension (in the form of a liquid) Aquacoat(R) cBD) and dry the granules. in accordance with the present invention which contains a US 9,492,541 B2 33 phenylepherine hydrochloride ion-exchange complex and -continued promethazine hydrochloride is illustrated as follows: Ingredients Amount 5 ml Sodium Benzoate 7.5 mg Ingredients Amount 5 ml Citric Acid Monohydrate, USP 8.0 mg Phenylepherine hydrochloride Ion-Exchange Equivalent to 45 mg Artificial Grape Flavor 5 mg Complex of Phenylepherine FD&C Red # 40 Dye 0.5 mg hydrochloride Water qs to 5 ml Promethazine HCI 25 mg Eudragit (R. L. 100 0.2 to 2.8 g. Silica, colloidal anhydrous, NF 100 mg 10 Manufacturing Process for 1000 Kg Batch: Glycerin 740 mg Add the appropriate amount of Sodium polystyrene Sul Xylitol, NF 800 mg phonate USP (e.g. Amberlite R. IRP 69) to a codeine phos Sodium Citrate, USP 100 mg Saccharin Sodium cryst., USP, 0.1 mg phate solution. Stir the mix for 12 hrs to allow complete Sodium Benzoate 7.5 mg drug/resin complex formation. Separate and dry the Citric Acid Monohydrate, USP 8.0 mg 15 insoluble drug/resin complex. Granulate the drug/resin com Artificial Grape Flavor 5 mg plex with a delayed release/enteric polymer (e.g. Eudragit R. FD&C Red # 40 Dye 0.5 mg L 100, Kollidon(R) MAE, Aquacoat(R) CPD) and dry the Water q.S to 5 ml granules. Mill the granules, if needed. In a Suitably sized stainless steel vessel, dissolve saccha Manufacturing Process for 1000 L Batch: rin Sodium, Sodium benzoate, citric acid, and Sodium citrate Add the appropriate amount of Sodium polystyrene Sul in approximately 50 L of warm (about 45° C.), purified phonate USP (e.g. Amberlite(R). IRP69) to a phenylepherine water. In another large stainless steel drum mix the silica and hydrochloride solution. Stir the mix for 12 hrs to allow the codeine phosphate ion-exchange complex, phe complete drug/resin complex formation. Separate and dry nylepherine tannate, and the chlorpheniramine tannate until the insoluble drug/resin complex. Granulate the drug/resin 25 a uniform and consistent mixture is obtained. In a separate complex with a delayed release?enteric polymer (e.g. 1000 L stainless steel tank equipped with a suitably sized Eudragit R L 100, Kollidon R MAE, Aquacoat(R) CPD) and homogenizer/disperser add about 100 L of purified water. dry the granules. Mill the granules, if needed. With the homogenizer on, add the silica mixture containing In a suitably sized stainless steel vessel, dissolve saccha the codeine phosphate ion-exchange complex, the phe rin Sodium, Sodium benzoate, citric acid, and Sodium citrate 30 nylepherine tannate, and the chlorpheniramine tannate. Add in approximately 50 L of warm (about 45° C.), purified the previously prepared solution of saccharin Sodium, water. In another large stainless steel drum mix the silica, sodium benzoate, citric acid, and sodium citrate to the 1000 phenylepherine hydrochloride ion-exchange complex, and L tank. Rinse the first vessel with about 2 L of water and promethazine hydrochloride until a uniform and consistent transfer the rinse to the 1000 L tank. Add the remaining mixture is obtained. In a separate 1000 L stainless steel tank 35 ingredients and homogenize for 15 minutes. equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add Reference Example 1 the silica mixture containing phenylepherine hydrochloride ion-exchange complex, and promethazine hydrochloride. Extended Release Suspension Add the previously prepared solution of saccharin Sodium, 40 sodium benzoate, citric acid, and sodium citrate to the 1000 An extended release suspension which contains a hydro L tank. Rinse the first vessel with about 2 L of water and codone bitartrate ion-exchange complex, a dexchlorpheni transfer the rinsate to the 1000 L tank. Add the remaining ramine maleate ion-exchange complex and a phenylepherine ingredients and homogenize for 15 minutes. hydrochloride ion-exchange complex is illustrated as fol 45 lows: Example 22 Extended Release Suspension (Liquid) ngredients Amount 5 ml Hydrocodone Bitartrate Ion-Exchange Complex Equivalent to 8 mg of An extended release Suspension (in the form of a liquid) 50 Hydrocodone bitartarate Dexchlorpheniramine Maleate Ion-Exchange Equivalent to 6 mg in accordance with the present invention which contains a Complex of Dexchlorpheniramine codeine phosphate ion-exchange complex, phenylepherine Maleate tannate and chlorpheniramine tannate is illustrated as fol Phenylepherine HCl Ion-Exchange Complex Equivalent to 10 mg lows: of Phenylepherine HCl 55 Eudragit (R. L. 100 0.2 to 2.8 g. Glycerin 315 mg Polysorbate 80 1.5 mg Ingredients Amount 5 ml Carbomer (e.g., Carbopol (R) 974) 15 mg Codeine phosphate Ion-exchange complex Equivalent to 45 mg Methyl Paraben 9 mg Codeine phosphate Propyl Paraben 1 mg Phenylepherine Tannate 75.0 60 Artificial Grape Flavor 5 mg Chlorpheniramine Tannate 4.5 FD&C Red # 40 Dye 0.5 mg Eudragit (R. L. 100 0.2 to 2.8 grams Water C.S Silica, colloidal anhydrous, NF 100 mg Glycerin 740 mg Xylitol, NF 800 mg The formula described above serves as a non-limiting Sodium Citrate, USP 100 mg 65 example. Any active drug which is in the form of a salt, Such Saccharin Sodium cryst., USP, 0.1 mg as an antihistamine, codeine, or dihydrocodeine, can be incorporated as an ion-exchange resin complex. US 9,492,541 B2 35 36 Procedure: nations of each of the ingredients in a range as described in (1) Add the appropriate amount of Sodium polystyrene Table 1 below can be made depending on the specific sulphonate USP (e.g. Amberlite(RIRP69) to a dexchlorphe therapeutic effect desired. niramine maleate, hydrocodone bitartrate and phe nylepherine HCl solution. Reference Example 3 (2) Stir the mix for 12 hrs to allow complete drug/resin complex formation. Liquid Formula (3) Separate and dry the insoluble drug/resin complex. (4) Granulate the drug/resin complex with a delayed release/ A liquid dosage form which comprises phenylepherine enteric polymer (e.g. Eugragit R L 100, Kollidon R MAE, 10 hydrochloride is illustrated as follows: Aquacoa Rt cBD) and dry the granules. (5) Mill the granules, if needed. (6) To an appropriate amount of water add the following ngredients Per 5 mL. Per 42.5 L ingredients and dissolve: Carbomer (e.g., Carbopol R. Codeine Phosphate USP 30 mg 2.550 kg 974), glycerin, polysorbate 80, methyl paraben, propyl 15 Phenylepherine Hydrochloride USP 10.0 mg 0.850 kg paraben, artificial grape flavor, FD&C red #40 dye. Methyl Paraben USP 9.0 mg 0.765 kg Propyl Paraben USP 1.0 mg 0.085 kg (7) Add milled granules. Propylene Glycol USP 259 mg 22.016 kg (8) Add water to make up to a final volume. Saccharin Sodium USP 3.18 mg 0.270 kg (9) Agitate at Suitable rate to avoid settling of the Suspension Citric Acid USP 5.0 mg 0.425 kg and maintain a homogeneous product mixture. Strawberry Flavor 10 mg 0.850 kg (10) Fill in suitable containers ensuring that the product is Banana Flavor 10 mg 0.850 kg Sorbitol Solution 70% USP 3212.5 mg 273.1 kg homogeneous throughout the filling operation. Purified Water, as required to q.S. to 5.0 mL. 425 L Reference Example 2 25 Manufacturing Process for 425 L Batch Size: Suspension Formula In a suitably sized stainless steel vessel, dissolve methyl paraben and propyl paraben in approximately 50 L of warm A Suspension formula which comprises codeine phos (about 45° C.), purified water. Add about half of the pro phate and phenylepherine tannate is illustrated as follows: pylene glycol and mix for about 1 hr. In a separate 1000 L 30 stainless steel tank equipped with a suitably sized agitator, add about 50 L of purified water. With the agitator on, add Ingredients g/100 mL. kg batch phenylepherine hydrochloride, codeine phosphate, saccha Codeine Phosphate O.20 1.667 rin Sodium and citric acid and dissolve. Add the previously Phenylepherine Tannate O.80 6.667 prepared paraben/propylene glycol solution to the 1000 L Silica, colloidal anhydrous, NF 1.73 14.417 35 Hydroxyethylcellulose, NF O.OS O417 tank. Rinse the first vessel with about 2 L of water and Sorbitol Solution 70% (non-crystallizing), NF 34.00 283.333 transfer the rinsate to the 1000 L tank. Add the remaining Glycerol 14.75 122.917 propylene glycol to a suitably sized stainless Steel vessel and Xylitol, NF 16.00 133.333 Sodium Citrate, USP 2.00 16.667 dissolve the strawberry and banana flavors. Transfer this to Saccharin Sodium cryst., USP, O.O1 O.083 40 the 1000 L tank. Rinse the container with 2 L of purified Sodium Benzoate, NF O.15 1.2SO water and transfer to the 1000 L tank. With the agitator on, Citric Acid Monohydrate, USP O16 1.333 add the Sorbitol Solution 70% to the 1000 L tank. In a Strawberry Flavor O.15 1.2SO Banana Flavor O.15 1.2SO suitably sized stainless steel vessel, dissolve the codeine Purified Water 49.SS 412.917 phosphate in about 5 L of purified water and transfer to the 45 1000 L tank. Rinse the container with about 2 L of purified Total Amount 120.00 1OOOOOO water and transfer to the 1000 L tank. Stop the agitator and let the solution stand for 15 minutes. QS to 425 L with Manufacturing Process for 1000 kg Batch: purified water. Filter product through a 1 micron filter and In a suitably sized stainless steel vessel, dissolve saccha fill in appropriately sized containers. rin Sodium, Sodium benzoate, citric acid, and Sodium citrate 50 To make products with other antihistamines, deconges in approximately 50 L of warm (about 45° C.), purified tants, or expectorants, one or more combinations of each of water. In another large stainless steel drum mix the silica, the ingredients in a range as described in Table 1 above can codeine phosphate and micronized phenylepherine tannate be made depending on the specific therapeutic effect desired. until a uniform and consistent mixture is obtained. In a It is noted that the foregoing examples have been pro separate 1000 L stainless steel tank equipped with a suitably 55 vided merely for the purpose of explanation and are in no sized homogenizer/disperser add about 100 L of purified way to be construed as limiting of the present invention. water. With the homogenizer on, add the silica mixture While the present invention has been described with refer containing phenylepherine tannate and codeine phosphate ence to exemplary embodiments, it is understood that the Add the previously prepared solution of saccharin Sodium, words which have been used herein are words of description sodium benzoate, citric acid, and sodium citrate to the 1000 60 and illustration, rather than words of limitation. Changes L tank. Rinse the first vessel with about 2 L of water and may be made, within the purview of the appended claims, as transfer the rinse to the 1000 L tank. Add the remaining presently stated and as amended, without departing from the ingredients and homogenize for 15 minutes. Filter product Scope and spirit of the present invention in its aspects. through a 10 micron filter and fill in appropriately sized Although the present invention has been described herein containers. 65 with reference to particular means, materials and embodi To make products with other agents such as antihista ments, the present invention is not intended to be limited to mines, decongestants, or expectorants, one or more combi the particulars disclosed herein; rather, the present invention US 9,492,541 B2 37 38 extends to all functionally equivalent structures, methods HCl, isothipendy1 HC1 (theruhistin), loratadine, methapy and uses, such as are within the scope of the appended rilene fumarate, methapyrilene HCl, montelukast Sodium, claims. phenindamine tartrate, pheniramine maleate, phenyltoloX What is claimed is: amine citrate, promethazine hydrochloride, prophen 1. A pharmaceutical dosage form, wherein the pharma pyridamine maleate, pyrilamine maleate, terfenadine, the ceutical dosage form comprises (a) phenylepherine or a nyldiamine HCl, thonzylamine, trimeprazine tartrate, pharmaceutically acceptable salt thereof in a first form or tripelennamine HCl and triprolidine HC1. layer and (b) phenylepherine or a pharmaceutically accept 18. The dosage form of claim 15, wherein the at least one able salt thereof in a second form or layer which is different antihistamine comprises promethazine hydrochloride. from the first form or layer, the first form or layer being a 10 controlled release form or layer and the second form or layer 19. The dosage form of claim 15, wherein the at least one being a controlled release form or layer that is different from antihistamine comprises brompheniramine maleate. the first form or layer and the dosage form releasing the 20. The dosage form of claim 15, wherein the at least one phenylepherine (b) over a different period and at a different antihistamine comprises chlorpheniramine maleate. rate than the phenylepherine (a). 15 21. The dosage form of claim 15, wherein the at least one 2. The dosage form of claim 1, wherein the dosage form antihistamine comprises diphenhydramine HC1. comprises phenylepherine hydrochloride. 22. The dosage form of claim 4, wherein the at least one 3. The dosage form of claim 1, wherein the dosage form additional drug comprises an expectorant. comprises phenylepherine tannate. 23. The dosage form of claim 22, wherein the expectorant 4. The dosage form of claim 1, wherein the dosage form comprises guaifenesin. is a bi-layered tablet and at least one of the layers comprises 24. The dosage form of claim 4, wherein a plasma an additional drug. half-life of the at least one additional drug differs from a 5. The dosage form of claim 4, wherein the dosage form plasma half-life of phenylepherine by at least about 2 hours. comprises phenylepherine hydrochloride. 25. The dosage form of claim 4, wherein a plasma 6. The dosage form of claim 4, wherein the dosage form 25 half-life of the at least one additional drug differs from a comprises phenylepherine tannate. plasma half-life of phenylepherine by at least about 3 hours. 7. The dosage form of claim 4, wherein the at least one 26. The dosage form of claim 4, wherein a plasma additional drug is selected from antitussives, expectorants, half-life of the at least one second drug differs from a plasma mucus thinning drugs, analgesics and antihistamines. half-life of phenylepherine by at least about 4 hours. 8. The dosage form of claim 4, wherein the at least one 30 27. The dosage form of claim 1, wherein the dosage form additional drug comprises an antitussive drug. releases phenylepherine or a pharmaceutically acceptable 9. The dosage form of claim 8, wherein the at least one additional drug comprises at least one drug selected from salt thereof independently over a first period and over a codeine, hydrocodone, dihydrocodeine, carbetapentane, and second period and not more than about 30% of the second pharmaceutically acceptable salts thereof. 35 period is coextensive with all or a part of the first period. 10. The dosage form of claim 8, wherein the at least one 28. The dosage form of claim 27, wherein there is additional drug comprises codeine phosphate. substantially no overlap between the first and second peri 11. The dosage form of claim 8, wherein the at least one ods. additional drug comprises hydrocodone bitartrate. 29. A pharmaceutical dosage form, wherein the dosage 12. The dosage form of claim 8, wherein the at least one 40 form is a bi-layered tablet which comprises two different additional drug comprises dihydrocodeine bitartrate. controlled release forms or layers of at least one of phe 13. The dosage form of claim 8, wherein the at least one nylepherine and a pharmaceutically acceptable salt thereof additional drug comprises carbetapentane citrate. and comprises at least about 37 mg of phenylepherine or an 14. The dosage form of claim 4, wherein the at least one equivalent amount of a pharmaceutically acceptable salt additional drug comprises dextromethorphan hydrobromide. 45 thereof. 15. The dosage form of claim 4, wherein the at least one 30. The dosage form of claim 29, wherein the dosage form additional drug comprises at least one antihistamine. comprises at least about 40 mg of phenylepherine or an 16. The dosage form of claim 15, wherein the at least one equivalent amount of a pharmaceutically acceptable salt antihistamine comprises at least one compound selected thereof. from astemizole, Zatadine, bromodiphenhydramine, bro 50 31. The dosage form of claim 29, wherein the dosage form mpheniramine, carbinoxamine, cetirizine, chlorcyclizine, comprises at least about 45 mg of phenylepherine or an clemastine, chlorothen, chlorpheniramine, cyclizine, cypro equivalent amount of a pharmaceutically acceptable salt heptadine, desloratadine, dimethindene, diphenhydramine, thereof. diphenylpyraline, doxylamine, fexofenadine, hydroxyine, 32. The dosage form of claim 29, wherein the dosage form isothipendyl, loratadine, methapyrilene, montelukast, phen 55 comprises at least about 50 mg of phenylepherine or an indamine, pheniramine, phenyltoloxamine, promethazine, equivalent amount of a pharmaceutically acceptable salt prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thereof. thonzylamine, trimeprazine, tripelennamine, triprolidine, 33. The dosage form of claim 29, wherein the dosage form and pharmaceutically acceptable salts thereof. comprises phenylepherine hydrochloride. 17. The dosage form of claim 15, wherein the at least one 60 34. The dosage form of claim 29, wherein the dosage form antihistamine comprises at least one of astemizole, Zatadine comprises phenylepherine tannate. maleate, bromodiphenhydramine HCl, brompheniramine 35. The dosage form of claim 29, wherein the dosage form maleate, carbinoxamine maleate, cetirizine HCl, chlorcycl comprises at least one additional drug. izine HCl, clemastine fumarate, chlorothen citrate, chlorphe 36. The dosage form of claim 35, wherein the dosage form niramine maleate, cyclizine, cyproheptadine, desloratadine, 65 comprises phenylepherine hydrochloride. dimethindene maleate, diphenhydramine HCl, diphe 37. The dosage form of claim 35, wherein the dosage form nylpyraline, doxylamine, fexofenadine HCl, hydroxyine comprises phenylepherine tannate. US 9,492,541 B2 39 40 38. The dosage form of claim 35, wherein the at least one 57. The dosage form of claim 35, wherein a plasma additional drug comprises at least one of an expectorant, a half-life of the at least one second drug differs from a plasma mucus thinning drug, an antihistamine, an antitussive drug half-life of phenylepherine by at least about 4 hours. and an analgesic. 58. The dosage form of claim 29, wherein the dosage form 39. The dosage form of claim 35, wherein the at least one releases phenylepherine or a pharmaceutically acceptable additional drug comprises an antitussive drug. salt thereof independently over a first period and over a 40. The dosage form of claim 39, wherein the at least one second period and not more than about 30% of the second additional drug comprises at least one drug selected from period is coextensive with all or a part of the first period. codeine, hydrocodone, dihydrocodeine, carbetapentane, and 59. The dosage form of claim 58, wherein there is pharmaceutically acceptable salts thereof. 10 41. The dosage form of claim 39, wherein the at least one substantially no overlap between the first and second peri additional drug comprises codeine phosphate. ods. 42. The dosage form of claim 39, wherein the at least one 60. The dosage form of claim 31, wherein the dosage form additional drug comprises hydrocodone bitartrate. comprises at least one additional drug. 43. The dosage form of claim 39, wherein the at least one 15 61. The dosage form of claim 60, wherein the at least one additional drug comprises dihydrocodeine bitartrate. additional drug comprises at least one of an expectorant, a 44. The dosage form of claim 39, wherein the at least one mucus thinning drug, an antihistamine, an antitussive drug additional drug comprises carbetapentane citrate. and an analgesic. 45. The dosage form of claim 35, wherein the at least one 62. The dosage form of claim 60, wherein the at least one additional drug comprises dextromethorphan hydrobromide. additional drug comprises an antitussive drug. 46. The dosage form of claim 35, wherein the at least one 63. The dosage form of claim 62, wherein the at least one additional drug comprises at least one antihistamine. additional drug comprises at least one drug selected from 47. The dosage form of claim 46, wherein the at least one codeine, hydrocodone, dihydrocodeine, carbetapentane, and antihistamine comprises at least one compound selected pharmaceutically acceptable salts thereof. from astemizole, Zatadine, bromodiphenhydramine, bro 25 64. The dosage form of claim 62, wherein the at least one mpheniramine, carbinoxamine, cetirizine, chlorcyclizine, additional drug comprises codeine phosphate. clemastine, chlorothen, chlorpheniramine, cyclizine, cypro 65. The dosage form of claim 62, wherein the at least one heptadine, desloratadine, dimethindene, diphenhydramine, additional drug comprises hydrocodone bitartrate. diphenylpyraline, doxylamine, fexofenadine, hydroxyine, 66. The dosage form of claim 62, wherein the at least one isothipendyl, loratadine, methapyrilene, montelukast, phen 30 additional drug comprises dihydrocodeine bitartrate. indamine, pheniramine, phenyltoloxamine, promethazine, 67. The dosage form of claim 62, wherein the at least one prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, additional drug comprises carbetapentane citrate. thonzylamine, trimeprazine, tripelennamine, triprolidine, 68. The dosage form of claim 60, wherein the at least one and pharmaceutically acceptable salts thereof. additional drug comprises dextromethorphan hydrobromide. 48. The dosage form of claim 46, wherein the at least one 35 69. The dosage form of claim 60, wherein the at least one antihistamine comprises at least one of astemizole, Zatadine additional drug comprises at least one antihistamine. maleate, bromodiphenhydramine HCl, brompheniramine 70. The dosage form of claim 69, wherein the at least one maleate, carbinoxamine maleate, cetirizine HCl, chlorcycl antihistamine comprises at least one compound selected izine HCl, clemastine fumarate, chlorothen citrate, chlorphe from astemizole, Zatadine, bromodiphenhydramine, bro niramine maleate, cyclizine, cyproheptadine, desloratadine, 40 mpheniramine, carbinoxamine, cetirizine, chlorcyclizine, dimethindene maleate, diphenhydramine HCl, diphe clemastine, chlorothen, chlorpheniramine, cyclizine, cypro nylpyraline, doxylamine, fexofenadine HCl, hydroxyine heptadine, desloratadine, dimethindene, diphenhydramine, HCl, isothipendy1 HC1 (theruhistin), loratadine, methapy diphenylpyraline, doxylamine, fexofenadine, hydroxyine, rilene fumarate, methapyrilene HCl, montelukast Sodium, isothipendyl, loratadine, methapyrilene, montelukast, phen phenindamine tartrate, pheniramine maleate, phenyltoloX 45 indamine, pheniramine, phenyltoloxamine, promethazine, amine citrate, promethazine hydrochloride, prophen prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, pyridamine maleate, pyrilamine maleate, terfenadine, the thonzylamine, trimeprazine, tripelennamine, triprolidine, nyldiamine HCl, thonzylamine, trimeprazine tartrate, and pharmaceutically acceptable salts thereof. tripelennamine HCl and triprolidine HC1. 71. The dosage form of claim 69, wherein the at least one 49. The dosage form of claim 46, wherein the at least one 50 antihistamine comprises at least one of astemizole, Zatadine antihistamine comprises promethazine hydrochloride. maleate, bromodiphenhydramine HCl, brompheniramine 50. The dosage form of claim 46, wherein the at least one maleate, carbinoxamine maleate, cetirizine HCl, chlorcycl antihistamine comprises brompheniramine maleate. izine HCl, clemastine fumarate, chlorothen citrate, chlorphe 51. The dosage form of claim 46, wherein the at least one niramine maleate, cyclizine, cyproheptadine, desloratadine, antihistamine comprises chlorpheniramine maleate. 55 dimethindene maleate, diphenhydramine HCl, diphe 52. The dosage form of claim 46, wherein the at least one nylpyraline, doxylamine, fexofenadine HCl, hydroxyine antihistamine comprises diphenhydramine HC1. HCl, isothipendy1 HC1 (theruhistin), loratadine, methapy 53. The dosage form of claim 35, wherein the at least one rilene fumarate, methapyrilene HCl, montelukast Sodium, additional drug comprises an expectorant. phenindamine tartrate, pheniramine maleate, phenyltoloX 54. The dosage form of claim 53, wherein the expectorant 60 amine citrate, promethazine hydrochloride, prophen comprises guaifenesin. pyridamine maleate, pyrilamine maleate, terfenadine, the 55. The dosage form of claim 35, wherein a plasma nyldiamine HCl, thonzylamine, trimeprazine tartrate, half-life of the at least one additional drug differs from a tripelennamine HCl and triprolidine HC1. plasma half-life of phenylepherine by at least about 2 hours. 72. The dosage form of claim 69, wherein the at least one 56. The dosage form of claim 35, wherein a plasma 65 antihistamine comprises promethazine hydrochloride. half-life of the at least one additional drug differs from a 73. The dosage form of claim 69, wherein the at least one plasma half-life of phenylepherine by at least about 3 hours. antihistamine comprises brompheniramine maleate. US 9,492,541 B2 41 42 74. The dosage form of claim 69, wherein the at least one 94. The dosage form of claim 93, wherein the dosage form antihistamine comprises chlorpheniramine maleate. comprises phenylepherine hydrochloride. 75. The dosage form of claim 69, wherein the at least one 95. The dosage form of claim 93, wherein the dosage form antihistamine comprises diphenhydramine HC1. comprises phenylepherine tannate. 76. The dosage form of claim 60, wherein the at least one 96. The dosage form of claim 93, wherein the at least one additional drug comprises an expectorant. additional drug comprises at least one of an expectorant, a 77. The dosage form of claim 76, wherein the expectorant mucus thinning drug, an antihistamine, an antitussive drug comprises guaifenesin. and an analgesic. 78. The dosage form of claim 60, wherein a plasma 97. The dosage form of claim 96, wherein the at least one half-life of the at least one additional drug differs from a 10 plasma half-life of phenylepherine by at least about 2 hours. additional drug comprises at least one drug selected from 79. The dosage form of claim 60, wherein a plasma codeine, hydrocodone, dihydrocodeine, carbetapentane, and half-life of the at least one additional drug differs from a pharmaceutically acceptable salts thereof. plasma half-life of phenylepherine by at least about 3 hours. 98. The dosage form of claim 96, wherein the at least one 80. The dosage form of claim 60, wherein a plasma 15 additional drug comprises at least one antihistamine. half-life of the at least one second drug differs from a plasma 99. The dosage form of claim 96, wherein the at least one half-life of phenylepherine by at least about 4 hours. additional drug comprises an expectorant. 81. The dosage form of claim 30, wherein the dosage form 100. The dosage form of claim 96, wherein a plasma releases phenylepherine or a pharmaceutically acceptable half-life of the at least one additional drug differs from a salt thereof independently over a first period and over a plasma half-life of phenylepherine by at least about 2 hours. second period and not more than about 30% of the second 101. The dosage form of claim 96, wherein a plasma period is coextensive with all or a part of the first period. half-life of the at least one additional drug differs from a 82. The dosage form of claim 81, wherein there is plasma half-life of phenylepherine by at least about 3 hours. substantially no overlap between the first and second peri 102. The dosage form of claim 96, wherein a plasma ods. 25 half-life of the at least one second drug differs from a plasma 83. The dosage form of claim 30, wherein the dosage form half-life of phenylepherine by at least about 4 hours. comprises phenylepherine hydrochloride. 103. The dosage form of claim 32, wherein the dosage 84. The dosage form of claim 30, wherein the dosage form form comprises at least one additional drug. comprises phenylepherine tannate. 104. The dosage form of claim 103, wherein the dosage 85. The dosage form of claim 31, wherein the dosage form 30 form comprises phenylepherine hydrochloride. releases phenylepherine or a pharmaceutically acceptable salt thereof independently over a first period and over a 105. The dosage form of claim 103, wherein the dosage second period and not more than about 30% of the second form comprises phenylepherine tannate. period is coextensive with all or a part of the first period. 106. The dosage form of claim 103, wherein the at least 86. The dosage form of claim 85, wherein there is 35 one additional drug comprises at least one of an expectorant, substantially no overlap between the first and second peri a mucus thinning drug, an antihistamine, an antitussive drug ods. and an analgesic. 87. The dosage form of claim 31, wherein the dosage form 107. The dosage form of claim 106, wherein the at least comprises phenylepherine hydrochloride. one additional drug comprises at least one drug selected from codeine, hydrocodone, dihydrocodeine, carbetapen 88. The dosage form of claim 31, wherein the dosage form 40 comprises phenylepherine tannate. tane, and pharmaceutically acceptable salts thereof. 89. The dosage form of claim 32, wherein the dosage form 108. The dosage form of claim 106, wherein the at least releases phenylepherine or a pharmaceutically acceptable one additional drug comprises at least one antihistamine. 109. The dosage form of claim 106, wherein the at least salt thereof independently over a first period and over a one additional drug comprises an expectorant. second period and not more than about 30% of the second 45 period is coextensive with all or a part of the first period. 110. The dosage form of claim 106, wherein a plasma 90. The dosage form of claim 89, wherein there is half-life of the at least one additional drug differs from a substantially no overlap between the first and second peri plasma half-life of phenylepherine by at least about 2 hours. ods. 111. The dosage form of claim 106, wherein a plasma 91. The dosage form of claim 32, wherein the dosage form 50 half-life of the at least one additional drug differs from a comprises phenylepherine hydrochloride. plasma half-life of phenylepherine by at least about 3 hours. 92. The dosage form of claim 32, wherein the dosage form 112. The dosage form of claim 106, wherein a plasma comprises phenylepherine tannate. half-life of the at least one second drug differs from a plasma 93. The dosage form of claim 30, wherein the dosage form half-life of phenylepherine by at least about 4 hours. comprises at least one additional drug. k k k k k