Packaged multi-dose liquid dextromethorphan hydrobromide formulation

Abstract

Multi-dose packaged over-the-counter antitussive syrups comprise a bottle containing about 75 ml or less of a liquid formulation of dextromethorphan hydrobromide. The liquid formulation provides at least two doses of dextromethorphan hydrobromide. Multi-dose packaged over-the-counter liquid formulations comprise a bottle having a capacity of about 100 ml or less, at least two doses of the liquid formulation carried within the bottle, a cap, a dosage cup releasably carried on the cap and a shrink wrap substantially enveloping the bottle and the dosage cup. Antitussive syrups comprise water, dextromethorphan hydrobromide in amounts from about 6 to about 25 mg/ml, and sweetener in amounts from about 200 to about 800 mg/ml.

Claims

1. An antitussive syrup formulation, said antitussive syrup comprising: (a) water; (b) dextromethorphan hydrobromide, wherein said dextromethorphan hydrobromide is not complexed with sustained-release matrices and is dissolved in said formulation in amounts from about 6 to about 25 mg/ml; (c) sweetener, said sweetener being one or more sweeteners selected from the group consisting of sugars, said sugars being present in amounts from about 200 to about 800 mg/ml, and sugar substitutes, said sugar substitutes being present in amounts from about 2 to about 100 mg/ml; and (d) wherein said syrup is an aqueous syrup and is not an extended-release formulation providing extended release of protonated dextromethorphan.

2. The antitussive syrup of claim 1, wherein dextromethorphan hydrobromide is present in amounts from about 7 to about 11 mg/ml.

3. The antitussive syrup of claim 1, wherein said sugars are present in amounts from about 400 to about 700 mg/ml.

4. The antitussive syrup of claim 1, wherein said sweetener is one or more sugars.

5. The antitussive syrup of claim 1, wherein said sweetener is one or more sugar substitutes.

6. The antitussive syrup of claim 1, wherein said sugar substitutes are present in amounts from about 5 to about 20 mg/ml.

7. The antitussive syrup of claim 1, wherein said syrup comprises an encapsulating agent.

8. The antitussive syrup of claim 1, wherein said syrup comprises propylene glycol in amounts from about 50 to about 200 mg/ml.

9. The antitussive syrup of claim 1, wherein said syrup comprises one or more flavorings.

10. The antitussive syrup of claim 1, wherein said syrup comprises propylene glycol in amounts from about 75 to about 125 mg/ml.

11. The antitussive syrup of claim 1, wherein said syrup comprises protonated dextromethorphan in molar amounts substantially equal to molar amounts of dextromethorphan hydrobromide added to the syrup.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is an isometric view of a first preferred embodiment 10 of the novel multi-dose packaged OTC liquid formulations, which packaged formulation 10 has a shrink wrap inner label 15 and a folded outer label 16.

(2) FIG. 2 is an elevational view of packaged formulation 10 shown in FIG. 1.

(3) FIG. 3 is an exploded view of packaged formulation 10 showing the various components thereof.

(4) FIG. 4 is a plan view of unwrapped inner shrink wrap 15 of packaged formulation 10.

(5) FIG. 5A is a plan view of unrolled folded outer label 16 of packaged formulation 10 showing the outer fold thereof.

(6) FIG. 5B is a plan view of unfolded outer label 16 of packaged formulation 10 showing the inner fold thereof.

(7) In the drawings and description that follows, like parts are identified by the same reference numerals. The drawing figures are not necessarily to scale. Certain features of the embodiments may be shown exaggerated in scale or in somewhat schematic form and some details of conventional design and construction may not be shown in the interest of clarity and conciseness.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

(8) The invention, in various aspects and embodiments, is directed generally to liquid OTC drug formulations and to liquid OTC drug formulations that are packaged to provide multiple doses of the formulation. Some of those embodiments are described is some detail herein. For the sake of conciseness, however, all features of an actual implementation may not be described or illustrated. In developing any actual implementation, as in any engineering or design project, numerous implementation-specific decisions must be made to achieve a developers' specific goals. Decisions usually will be made consistent within system-related and business-related constraints, and specific goals may vary from one implementation to another. Development efforts might be complex and time consuming and may involve many aspects of design, fabrication, and manufacture. Nevertheless, it should be appreciated that such development projects would be a routine effort for those of ordinary skill having the benefit of this disclosure.

Overview of Novel OTC Formulations

(9) The novel OTC formulations are liquid formulations, often referred to as syrups. They are intended to be taken orally, and thus the base fluid is water. In general, they comprise one or more active pharmaceutical ingredients and one or more excipients. Active pharmaceutical ingredients (“APIs”) are the compounds that make a drug formulation effective. They act pharmacologically to relieve symptoms or cure an underlying medical condition.

(10) Excipients are pharmacologically inert substances that aid in delivery of the active ingredients. For example, excipients may be used to give a formulation its form, such as using cornstarch to make a tablet or sterile water to make a syrup. Other excipients may be used to control the release of the active ingredient once it is ingested. Excipients also may be used to maintain the stability of the formulation or to improve the taste or appearance of the formulation.

(11) An OTC drug formulation, including its active ingredients and excipients, must meet various regulatory requirements in virtually all, if not all countries in order to be marketed and sold. In the United States, such regulations fall largely within 21 C.F.R. §§ 330 et seq. (Over-the Counter (OTC) Human Drugs Which are Generally Recognized as Safe and Effective and not Misbranded), and the Tentative and Final Monographs included therein. For example, the Final Monograph for DXM HBr and other oral antitussive drugs may be found at 21 C.F.R. §§ 341 et seq. Responsibility for promulgating and administering such regulations falls within the purview of the United States Food and Drug Administration (FDA). The FDA also maintains a list of approved excipients and the forms and amounts in which they may be used. In the European Union, the European Medicines Agency (EMA) assumes a similar role, and in Japan it is the Pharmaceuticals and Medical Devices Agency (PMDA).

(12) As used herein, Regulatory Guidelines shall be understood to refer to and include the statutes and regulations governing the marketing and sale of over-the-counter drugs, including, but not limited to the allowed dosages of active ingredients for a particular indication. Regulatory Agencies shall be understood to include the FDA, EMA, PMDA, and equivalent agencies in other countries.

Active Ingredients

(13) The active ingredient in the novel OTC drug formulations may be any active ingredient approved for use in liquid drug formulations to be sold directly to consumers under US Regulatory Guidelines or Regulatory Guidelines of another country. Preferred, active ingredients may include those listed in the FDA Final Monographs for antacids (21 C.F.R. § 331), antiflatulents (antigas) (21 C.F.R. § 332), antidiarrheal (21 C.F.R. § 335), antiemetic (21 C.F.R. § 336), nighttime sleep-aids (21 C.F.R. § 338), stimulants (21 C.F.R. § 340), cold, cough (antitussive), allergy, bronchodilator, expectorant, nasal decongestant, and antiasthmatic (21 C.F.R. § 341), analgesic-antipyretic, cardiovascular, rheumatologic (21 C.F.R. § 343).

(14) Especially preferred active ingredients include dextromethorphan hydrobromide, either alone or with other active ingredients approved for use in combination with DXM HBr in OTC drugs.

(15) As described further below, the active ingredient will be present in concentrated amounts allowing for the packaging of multiple doses in a small bottle. For example, DXM HBr may be added in amounts from about 6 to about 25 milligrams per milliliter (mg/ml) of formulation, preferably from about 7 to about 10 mg/ml. In other embodiments, the formulation will approach saturation when fully formulated so as to minimize the volume of formulation required to deliver a single dose of active ingredient while still passing required testing. As discussed further below, the novel, high concentration DXM HBr formulations will allow multiple doses of liquid formulation to be distributed in much smaller packaging.

(16) It will be appreciated that the novel formulations may include more than one antitussive active ingredient. Menthol, for example, may be added to provide more immediate cough relief. They also may include other types of active ingredients. Preferred combinations will be those listed in the FDA Final Monographs. Especially preferred combinations will be those with DXM and other antitussives listed in the respective FDA Final Monograph, such as combinations with an expectorant, nasal decongestant, anesthetic/analgesic, analgesic-antipyretic, and antacid.

Preferred Excipients

(17) Preferred embodiments of the novel OTC liquid formulations have high concentrations of DXM HBr and other active ingredients. Thus, encapsulating agents preferably will be used to facilitate dissolution of DXM HBr and other active ingredients in embodiments of the novel formulations. Sweet tasting encapsulating agents, such as propylene glycol, are preferred. Polypropylene glycol, for example, may be added in amounts from about 50 to about 200 mg/ml, or preferably, from about 75 to about 125 mg/ml.

(18) DXM HBr and other active ingredients are known to have bitter taste that may discourage consumers from following recommended dosages at recommended intervals. That bitterness is exacerbated by increasing the concentration of DXM HBr and other active ingredients. High concentrations of DXM HBr also are known to induce nausea and vomiting. Thus, the novel OTC formulations including those having high concentrations of DXM HBr as an active ingredient preferably include high concentrations of sugar or sugar substitute sweeteners and one or more flavorings. Sweeteners preferably will be added in concentrations of from about 200 to about 800 mg/ml, preferably from about 400 to about 700 mg/ml.

(19) Sugar and sugar substitute sweeteners are believed to provide both an antienemic effect and a taste masking effect. One or more sugars may be included in the formulation. Suitable sugars may include glucose, dextrose, disaccharides, fructose (aka levulose), galactose, high fructose corn syrup, lactose, maltose, trisaccharides, and sucrose. One or more sugar substitutes may be included in addition to or as a substitute for sugars. Sugars may be added in concentrations of from about 200 to about 800 mg/ml, preferably from about 400 to about 700 mg/ml.

(20) Suitable sugar substitutes may include acesulfame potassium, advantame, alitame, aspartame, brazzein, curculin, dulcin, erythritol, fructooligosaccharide, glucin, glycerol, glycyrrhizin, hydrogenated starch hydrolysates, inulin, isomalt, isomaltooligosaccharide, isomaltulose, lactitol, mabinlin, maltitol, maltodextrin, mannitol, miraculin, mogroside mix, monatin, monellin, neohesperidin dihydrochalcone, neotame, osladin, pentadin, polydextrose, psicose, saccharin, salt of aspartame-acesulfame, sodium cyclamate, sorbitol, stevia, sucralose, tagatose, thaumatin, and xylitol. Sugar substitutes may be added in concentrations of from about 2 to about 100 mg/ml, preferably from about 5 to about 20 mg/ml.

(21) One or more flavorings also may be included to mask the taste of DXM and other active ingredients. Suitable flavorings may include artificial flavors, artificial vanilla, dimethyl anthranilate, eculyptol, menthol, methyl anthranilate, methyl salicylate, natural flavors, peppermint, thymol, various fruit flavors, and culinary herbs and spices. Flavorings typically will be added to taste.

Other Excipients

(22) Preferred embodiments also may include other excipients, such as extenders, diluents, wetting agents, solvents, emulsifiers, preservatives, absorption enhancers, sustained-release matrices, and coloring agents. Preferred excipients will be those listed for use in OTC drug formulations.

Novel Multi-Dose Packaged OTC Formulations

(23) Preferred embodiments of the invention will provide multiple doses of a liquid DXM HBr or other OTC formulation in a relatively small bottle. For example, a preferred multi-dose packaged OTC formulation 10 is shown in FIGS. 1-5. As shown therein, packaged formulation 10 generally includes a bottle 11, a seal 12, a cap 13, a dosage cup 14, an inner shrink wrap 15, and an outer expanded content label 16. Bottle 11 and cap 13 may be of any conventional design and shape suitable for holding liquids and many suitable bottles and caps are available commercially.

(24) Bottle 11, for example, is a “Boston round” design. It has a generally cylindrical shape with relatively long vertical walls. The top of bottle 11 tapers rapidly into a relatively flat shoulder surrounding a relatively small neck and opening. Bottle 11 may be made from conventional material by conventional methods. Preferably, however, bottle 11 is made from polymers, such as polypropylene, high-density and other polyethylenes, and polyethylene terephthalate, by blow molding. As noted, the shape of bottle 11 and cap 13 is not critical. Importantly, however, bottle 11 is relatively small, preferably having a capacity of less than 100 ml, and more preferably, less than about 75 or 50 ml.

(25) The opening of bottle 11 preferably is sealed with seal 12. Seal 12 not only helps to preserve the formulation, but it can provide an indicator that the product has not been tampered with or adulterated. Seal 12 may be fabricated from conventional materials and applied by conventional methods. For example, a ‘lift-n-peel” induction seal may be used and sealed over the opening of bottle 11 by induction heating. Lift-n-peel liners provide a tab by which a consumer can peel the seal off.

(26) The neck of bottle 11 and cap 13 may incorporate any conventional design that allows cap 13 to provide a liquid-tight closure for bottle 11, such as a threaded cap. Preferably, however, cap 13 is a child resistant cap. Many conventional child resistant caps are known and may be used, such as a “push and turn” cap. Typically, such caps are molded from plastics such as polypropylene or polyethylene terephthalate and are widely available. Cap 13 also may incorporate a liner to aid in sealing the opening.

(27) Dosage cup 14, as its name implies, is a small open cup that is primarily designed to allow a consumer to measure a recommended dose of the liquid formulation. Preferably it is fabricated from a clear plastic, such as polypropylene, and is embossed with markings indicating the recommended dosage line. A consumer may more accurately confirm that the amount of formulation in the cup matches the recommended dose.

(28) The length of dosage cup 14 is not particularly critical so long as it provides sufficient depth to accommodate the volume of a dose. The inner diameter of dosage cup 14, however, is preferably sized and configured to fit securely over cap 13. Many conventional designs are known and may be used. For example, dosage cup 14 may be provided with interior vertical ribs. When dosage cup 14 is placed over cap 13 the ribs will provide a friction fit. Ribs also may be designed to clip on to the underside of cap 13. In any event, dosage cup 14 preferably is releasably secured to cap 13, minimizing the likelihood of it being misplaced or lost by a consumer, but ensuring that it is readily available for use.

(29) Typically, bottle 11 will be filled to slightly less than capacity to avoid spillage during packaging. Thus, bottle 11 preferably will be filled to less than about 75 ml, and preferably less than about 50 ml or less than about 40 ml. Preferably, the amount of syrup contained in packaged formulation 10 will be coordinated with the concentration of DXM HBr to provide a specific number of recommended doses.

(30) The FDA Final Monograph lists the dosages under which DXM HBr OTC drugs may be marketed. For adults and children 12 years of age or older the oral dosage is 10 to 20 mg every 4 hours or 30 mg every 6 to 8 hours, not to exceed 120 mg in 24 hours, or as directed by a doctor. For children 6 to under 12 years of age the oral dosage is 12.5 mg every 4 hours, not to exceed 75 mg in 24 hours, or as directed by a doctor. OTC formulations containing DXM HBr are not to be used for children under 6 years of age except as recommended by a doctor.

(31) Thus, when present in amounts of about 10 mg/ml, for example, a single adult, 6 to 8-hour dose of the formulation will be 3 ml, and 15 doses will be 45 ml. Dosage cup 14 in this example would provide a 3 ml indicator line. If the formulation was labeled for recommended adult, 4-hour doses of 20 mg, dosage cup would provide a ml indicator line. Fifteen doses could be provided by 30 ml of formulation, or 30 doses could be provided by 60 ml of formulation. In general, therefore, the bottle will be filled with sufficient formulation to provide at least about 60 mg of DXM HBr, or at least about 120 mg of DXM HBr, or at least about 300 mg of DXM HBr, or at least about 450 mg of DXM HBr. The formulation will be packed to provide at least 2 doses. More commonly, it may be provided with at least about 4 doses, or at least about 10 doses, or at least about 15 doses.

(32) Shrink wrap 15 may be used to secure dosage cup 14 during packing, shipment, and sale. It also may provide an indication of tampering or adulteration. Shrink wrap 15 may be any suitable conventional shrink wrap, such as those made from polyvinyl chloride and polyolefins. A relatively narrow band may be provided and will be sufficient to secure dosage cup 14. Preferably, however, shrink wrap 15 will substantially envelope the assembly of bottle 11, cap 13, and dosage cup 14. For example, as may be seen in FIGS. 1-2, shrink wrap 15 extends from partially under the bottom of bottle 11 all the way up and partially over the bottom of dosage cup 14. Dosage cup 14 is secured to bottle 11 and cap 13, and as discussed further below, shrink wrap 15 can provide a substrate on which branding and other messages may be imprinted. Perforations or other weakened areas may be provided in shrink wrap 15 to allow a consumer to easily remove dosage cup 14. Preferably, especially if shrink wrap 15 is imprinted with branding or other messages, the perforations will allow dosage cup 14 to be removed while leaving most of shrink wrap 15 on bottle 11.

(33) Expanded content label 16 is affixed to shrink wrap 15. Many conventional expanded content labels are available commercially and may be used. Such labels have multiple plies which provide a substrate on which branding and other messages may be imprinted. Label 16, for example, is a continuous web having a single lateral fold. The back of the label is provided with a relatively strong adhesive such that label 16 is self-adhering. The folded portions of label 16 are lightly adhered so that they may be peeled apart to expose their inner sides. Preferably, as shown in FIGS. 1-2, label 16, when folded and applied to bottle 11 extends substantially completely around bottle 11. Doing so will avoid the need to register label 16 with indicia imprinted on shrink wrap 15. Other types of expanded content labels may be used if desired. For example, other expanded content labels have one or more webs that are joined or folded to form a booklet.

(34) It will be appreciated, therefore, that embodiments of the novel packaged OTC formulations have significant advantages over the prior art. By packaging a highly concentrated liquid formulation in a relatively small bottle, the packaged formulation may contain multiple doses yet may be easily accommodated on a retailer's shelf. As noted previously, that is particularly critical for retailers, such as convenience stores, where shelf space in severely constrained.

(35) Moreover, while other forms of labeling may be used if desired, by providing a combination of a full shrink wrap and an expanded content label, such as shrink wrap 15 and label 16, the packaging may be provided with sufficient space to comply with regulatory labeling requirements while allowing space for branding and other optional messages and bar coding. It may not be necessary to distribute individual products in additional packaging, such as individual paperboard boxes.

(36) It will be appreciated that various functions and mechanisms are ascribed to each component of the novel formulations and packaged formulations and to their effect on the overall properties thereof. While such explanations are believed to be accurate, and are believed to provide useful guidance in making and using various embodiments of the novel formulations and packaged formulations, it will be understood that the invention is not limited thereby. The economics and characteristics of a particular embodiment also may render it more suitable for particular purposes. One embodiment may be well suited for one application and unsuited for another. Thus, general statements should be taken as such, and not as definitive, immutable principles.

EXAMPLES

(37) The invention and its advantages may be further understood by reference to the following examples. It will be appreciated, however, that the invention is not limited thereto.

Example 1—Prior Art

(38) A sample of a Robitussin Adult Peak Cold liquid product was purchased at a convenience store. The product was labeled as Cough+Chest Congestion DM. The syrup was packaged in a bottle containing 4 ounces (118 ml) of syrup. The syrup contained 2 mg/ml of DXM HBr and 20 mg/ml guaifenesin (an expectorant). The recommended adult dose was 20 mg, and thus the size of the dose was 10 ml. The bottle contained approximately 11 to 12 doses.

(39) The bottle was packaged in a paperboard box measuring approximately 2″ wide, 2″ deep, and 5″ tall. It is estimated that a dozen such products will occupy 48 square inches of shelf space. Stacked 3-deep, a dozen products will require approximately 8″ of shelf frontage.

Example 2

(40) A novel liquid DXM HBR formulation was prepared having the components set forth in Table 1 below.

(41) TABLE-US-00001 TABLE 1 Concentration Component (mg/ml) Sodium Benzoate 1 Grape Flavoring 2 (Methyl Anthranilate) Phosphoric acid 4.9 Sucralose 8 DXM HBR 10 Propylene Glycol 100 Water 435 High Fructose Corn Syrup 55 650

(42) High fructose corn syrup was added to a first tank containing a portion of the indicated water and heated to 40° C. Approximately half of the water was heated in a second tank to 40° C. The sodium benzoate and sucralose were added to Tank 2 and stirred until dissolved. The heated contents of Tank 2 were transferred to Tank 1. Tank 2 was rinsed twice, each rinse being approximately 5% of the indicated water, and the rinse added to Tank 1. Propylene glycol was added to a third tank and heated to 40° C. DXM HBR was added to the heated propylene glycol and stirred until dissolved. Grape flavoring was added to Tank 3 and stirred until dissolved. Phosphoric acid was added to Tank 3 and stirred until homogeneity. The contents of Tank 3 were added to Tank 1. Tank 3 was rinsed twice, each rinse being approximately 5% of the indicated water. The remaining water was added to Tank 1 and the formulation was stirred to homogeneity.

(43) Two milliliters of the resulting formulation contain 20 mg DXM HBr, an adult, 4-hour dosage indicated in the Final Monograph for antitussives. Three milliliters of the resulting formulation contain 30 mg of DXM HBR, a recommended adult, 6 to 8-hour dosage. Thus, it is believed that a 3 ml dose of the formulation will be effective in suppressing coughs in adults for a period of 6-8 hours.

(44) The formulation was tasted and found to have an acceptable taste with no bitterness.

Example 3

(45) The formulation prepared according to Example 2 was packaged in packaging substantially identical to packaged formulation 10 shown in FIGS. 1-3. The novel packaged formulation 10 was approximately 3.5″ high and had a primary diameter of approximately 1.375″. The bottle 11 had a capacity of 60 ml and was filled with 45 ml of the formulation. The packaged formulation 10 was labeled for use by adults and recommended a dosage of 30 ml. Thus, the package formulation 10 provided 15 of the recommended adult doses.

(46) Shrink wrap 15 and label 16 are shown at approximately half size in FIGS. 4-5. Label 16 when folded as shown in FIG. 5A is approximately 1.875″×4.5″ and extends substantially all the way around bottle 11. Label 16 unfolds, as shown in FIG. 5B, to approximately 8.125″. Approximately 1.375″ of the right end of the folded label 16 was devoted to drug facts and labeling information required by the Final Monograph as shown in FIG. 5A. All of the interior of folded label 16 was devoted to drug facts as shown in FIG. 5B. All labeling required by the Final Monograph was imprinted in a font no less than 6 points as required by the Final Monograph.

(47) Notwithstanding the extensive labeling requirements imposed by the Final Monograph, it was found that packaged formulation 10 still provided ample space for branding and other optional messages. Approximately 3.125″ of the left end of folded label 16 may be used for branding, a total area of approximately 6 in.sup.2. In addition, as shown in FIG. 4, approximately 1.25″ of the upper portion of shrink wrap 15 and a strip at the bottom of shrink wrap 15 are available for branding messages. Those areas were sufficient to provide packaged formulation 10 with distinctive and readily observable branding.

(48) Importantly, packaged formulation 10 provided space for all required labeling and for branding and other optional messages without the need to package formulation 10 in any additional individual packaging, such as a paperboard box.

Example 4

(49) Novel packaged formulations 10 prepared according to Example 3 were packaged in a paperboard shipping-display box. The box had a fold and tuck top that provided a billboard for branding messages. The box was approximately 5.525″ wide, 4.25″ deep, and 3.5″ high and held 12 packaged formulations 10. The box negligibly increased the footprint of the formulations 10 contained therein and had a footprint of only about 23.5 square inches. The box occupies approximately 5.5″ of shelf frontage.

(50) In contrast, the equivalent number of Robitussin products of Example 1 have a footprint of approximately 48 square inches on a shelf and take up 8 inches of frontage. It is expected that twice as many units of novel formulations 10 can be provided in about 70% of shelf frontage as required for the Robitussin product.

(51) Moreover, each novel formulation 10 will provide the consumer with 15 adult, 6 to 8-hour doses (30 mg/dose). Novel formulation 10 also could be labeled for adult 4-hour doses, for example 20 mg, and provide 22.5 doses. The Robitussin product of Example 1 was labeled for 20 mg doses, and thus provides only 11 to 12 doses—about half the 20 mg doses that would be provided by novel formulation 10. Similarly, if the Robitussin product was labeled for 30 mg doses, it would contain less than 8 doses. Novel formulation 10 contains twice as many 30 mg doses: 15.

(52) It is believed that the examples as a whole show that the novel packaged OTC drug formulations can provide surprising and useful advantages in distributing the formulations through previously underpenetrated markets. The novel packaged OTC formulations can provide an equivalent or greater number of doses of a liquid formulation, but occupy significantly less shelf space. Such qualities make the novel packaged OTC formulations much more attractive to convenience stores and other small retail outlets.

(53) While this invention has been disclosed and discussed primarily in terms of specific embodiments thereof, it is not intended to be limited thereto. Other modifications and embodiments will be apparent to the worker in the art.