(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`
`
`1111111111101101010111110111111100111111011111101101111111111011111111111
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`
`
`
`
`(43) International Publication Date
`9 February 2012 (09.02.2012)
`
`PCT
`
`(10) International Publication Number
`WO 2012/018742 A2
`
`(51) International Patent Classification:
`961% 31/485 (2006.01)
`961% 9/20 (2006.01)
`961% 31/49 (2006.01)
`A61P 11/04 (2006.01)
`961% 9/08 (2006.01)
`A61P 11/00 (2006.01)
`
`(21) International Application Number:
`PCT/US2011/046157
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`1 August 2011 (01.08.2011)
`
`English
`
`English
`
`(30) Priority Data:
`61/369,742
`
`1 August 2010 (01.08.2010)
`
`US
`
`(71) Applicant (for all designated States except US): TRINI-
`TY LABORATORIES, INC. [US/US]; 100 N.E. Loop
`410, Suite 1090, San Antonio, TX 78216 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): SINGH, Chandra,
`Ulagaraj [US/US]; 4 Thornhurst Road, San Antonio, TX
`78218 (US). NULU, Jagaveerabhadra, Rao [US/US];
`13000 Meehan Drive, Austin, TX 78727 (US).
`
`(74) Agent: NEVRIVY, Daniel, J.; Nevrivy Patent Law
`Group P.L.L.C., 1055 Thomas Jefferson St., NW, Suite
`M-100, Washington, DC 20007 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`(54) Title: DEXTROMETHORPHAN ANTITUSSIVE COMPOSITIONS
`
`FIG. 1
`
`(57) Abstract: The invention provides orally administered
`antitussive pharmaceutical compositions comprising dex-
`tromethorphan, wherein the compositions are free of bro-
`mide, sodium and polistirex.
`
`[Continued on next page]
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`HCO
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`NCH?,
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`WO 2012/018742 A2 11111101MOMOIMEHMONIMOIMIUMMEDIS
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`Published:
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`without international search report and to be republished
`upon receipt of that report (Rule 48.2(g))
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`PCT/US2011/046157
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`DEXTROMETHORPHAN ANTTIUSSIVE COMPOSITIONS
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`5
`
`This application claims the benefit of U.S. Provisional Appl. No.:
`61/369,742, filed August 1, 2010. The content of the aforesaid application is
`relied upon and incorporated by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`The field of the invention relates generally to antitussive compositions
`
`10
`
`containing dextromethorphan, essentially free of bromide, sodium and polistirex
`and methods of administering the same to subjects in need thereof.
`
`BACKGROUND OF THE INVENTION
`
`15
`
`Dextromethorphan (racemethorphan), 3-methoxy-17-methylmorphinan, is
`disclosed on p. 1170 in the Merck Index, 10th Edition (1983), M. Windholz, ed.,
`No. 8009, as an antitussive agent.
`
`Dextromethorphan hydrobromide is used extensively as an antitussive
`
`agent in commercial products as disclosed in the Physicians' Desk Reference for
`Nonprescription Drugs, 1 1 th Edition (1990), E. R. Barnhardt, pub., p. 306; and in
`Physicians' Desk Reference, 44th Edition (1990), E. R. Barnhardt, pub., p. 309, as
`follows:
`
`Bayer Children's Cough Syrup by Glenbrook, Benylin DM by Parke-Davis,
`Benylin Expectorant by Parke-Davis, Cerose-DM by Wyeth-Ayerst, Cheracol
`D Cough Formula by Upjohn, Cheracol Plus Head Cough/Cold Formula by
`Upjohn, Cough Formula Comtrex by Bristol-Myers Products, Comtrex Multi-
`Symptom Cold Reliever Tablets/Caplets/Liquid/Liquigels by Bristol-Myers
`Products, Contac Cough Formula by SmithKline Consumer, Contac Cough &
`Sore Throat Formula by SmithKline Consumer, Contac Jr. Children's -Cold
`Medicine by SmithKline Consumer, Contac Nighttime Cold Medicine by
`SmithKline Consumer, Contac Severe Cold Formula Caplets by SmithKline
`Consumer, Dimacol Caplets by Robins, Dorcol Children's Cough Syrup by
`1
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`Sandoz Consumer, Hold by SmithKline Beecham, Naldecon DX Adult Liquid
`by Bristol Laboratories, Naldecon DX Children's Syrup by Bristol
`Laboratories, Naldecon DX Pediatric Drops by Bristol Laboratories, Naldecon
`Senior DX Cough/Cold Liquid by Bristol Laboratories, Novahistine DMX by
`Lakeside Pharmaceuticals, Pediacare Cough-Cold Formula Liquid and
`Chewable Tablets by McNeil Consumer Products, Pediacare Night Rest
`Cough-Cold Formula Liquid by McNeil Consumer Products, Robitussin Night
`Relief by Robins, Robitussin-CF by Robins, Robitussin-DM by Robins, Scot-
`Tussin Sugar-Free DM Cough & Cold Medicine by Scot-Tussin, Snaplets-DM
`by Baker Cummins Pharmaceuticals, Snaplets-Multi by Baker Cummins
`Pharmaceuticals, St. Joseph Cough Suppressant for Children by Plough, St.
`Joseph Nighttime Cold Medicine by Plough, Sucrets Cough Control Formula
`by SmithKline Beecham, Sudafed Cough Syrup by Burroughs Wellcome,
`Triaminic Night Light by Sandoz Consumer, Triaminic-DM Syrup by Sandoz
`Consumer, Triaminicol Multi-Symptom Cold Tablets by Sandoz Consumer,
`Triaminicol Multi-Symptom Relief by Sandoz Consumer, Tylenol Cold
`Medication Caplets and Tablets by McNeil Consumer Products, Tylenol Cold
`Medication Liquid by McNeil Consumer Products, Tylenol Cold Medication
`No Drowsiness Formula Caplets by McNeil Consumer Products, Vicks
`Children's Cough Syrup by Richardson-Vicks, Inc., Vicks Children's NyQuil
`by Richardson-Vicks, Inc., Vicks Cough Silencers Cough Drops by
`Richardson-Vicks, Inc., Vicks Daycare Daytime Colds Medicine Caplets by
`Richardson-Vicks, Inc., Vicks Daycare Multi-Symptom Colds Medicine Liquid
`by Richardson-Vicks, Inc., Vicks Formula 44 Cough Control Discs by
`Richardson-Vicks, Inc., Vicks Formula 44 Cough Medicine by Richardson-
`Vicks, Inc., Vicks Formula 44D Decongestant Cough Medicine by Richardson-
`Vicks, Inc., Vicks Formula 44M Multi-Symptom Cough Medicine by
`Richardson-Vicks, Inc., Vicks NyQuil Nighttime Colds Medicine-Original &
`Cherry Flavor by Richardson-Vicks, Inc., Vicks Pediatric Formula 44 Cough
`Medicine by Richardson-Vicks, Inc., Vicks Pediatric Formula 44 Cough &
`Colds Medicine by Richardson-Vicks, Inc., Vicks Pediatric Formula 44 Cough
`& Congestion Medicine by Richardson-Vicks, Inc., Ambenyl-D Decongestant
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`Cough Formula by Forest Pharmaceuticals, Bromarest DX Cough Syrup by
`Warner Chilcott, BromFed-DM Cough Syrup by Muro, Codimal DM by
`
`Central Pharmaceuticals, Dimetane-DX Cough Syrup by Robins, Guaifenesin
`w/D-Methorphan Hydrobromide Syrup by Lederle, Humibid DM Tablets by
`Adams, IoTuss-DM Liquid by Muro, Medi-Tuss DM by Warner Chilcott,
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`5
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`Phenergan with Dextromethorphan by Wyeth-Ayerst, Poly-Histine DM Syrup
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`by Bock, Quelidrine Syrup by Abbott, Rondec-DM Oral Drops by Ross,
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`Rondec DM Syrup by Ross, Tusibron-DM by RAM Laboratories, Tussar DM
`
`by Rorer Pharmaceuticals, and Tussi-Organidin DM Liquid by Wallace.
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`10
`
`Delsym Cough Suppressant Syrup by McNeil Consumer contains
`
`dextromethorphan polistirex as an antitussive agent. It is believed that all of the
`
`above commercial products containing dextromethorphan are
`
`included
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`in
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`compositions at about neutral pH or lower.
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`15
`
`Dextromethorphan Hydrobromide was approved in 1957 by the United
`States Food and Drug Administration, and this salt is being commercialized
`throughout the world due to manufacturing convenience. The salt is sparingly
`
`soluble below 20°C (about 1.5 weight percent at 20°C), while its solubility is high
`
`at higher temperature (about 25 wt. % at 85°C), which makes it easy for
`
`crystallization.
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`20
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`Bromide presents a significant health risk and is the principal limiting
`
`ingredient in antitussive over-the-counter medications. Since bromide was first
`introduced as a medicine, multiple clinical symptoms of bromide intoxication have
`been reported. Large doses of bromide cause nausea and vomiting, abdominal
`pain, coma and paralysis. The chronic state of bromide intoxication is reported as
`
`25
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`bromism. Bromide has a long half life of about 9-12 days, which can lead to
`excessive accumulation. The signs and symptoms are referable to the nervous
`system, skin, glandular secretions, and gastrointestinal tract, as disclosed by F.X.R.
`van Leeuwen et al. in "1983a. Toxicity of sodium bromide in rats: effects on
`endocrine system and reproduction," Food Chem. Toxicol., 21(4), 383-390.
`30 Bromism has been associated with neurotoxic effects leading to restlessness,
`irritability, ataxia, confusion, hallucinations, somnolence, psychosis, seizures and
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`coma. Gastrointestinal disorders include nausea, vomiting, anorexia and
`constipation. Dermatological effects include acneiform, pustular and erythmatous
`rashes, as disclosed by KR. Olson in Poisoning and Drug Overdose (4th Ed.)
`Appleton & Lange. (18` November 2003) pp. 140-141. It has been postulated that
`bromide ion acts directly on certain endocrine organs such as the thyroid, adrenals
`and testes, thereby inducing hormonal feedback alterations in the pituitary gland.
`See, for example, F.X.R. van Leeuwen et al., "1983b. Endocrinologisch
`toxiciteitsonderzoek met natriumbromide," Verslagen adviezen en rapporten 20,
`150-153; and J.G. Loeber et al., "Effect of sodium bromide on endocrine
`parameters in the rat as studied by immunocytochemistry and radioimmunoassay,"
`Food Chem. Toxicol., 21(4), 391-404.
`
`In an experiment on the time dependency of the effect of bromide on the
`thyroid gland in rats, significantly decreased thyroxine concentrations were found
`as soon as 3 days after feeding diets containing 4800 or 19200 ppm NaBr. This
`decrease was observed and remained constant during an experimental period of 12
`weeks, as disclosed in van Leeuwen et al., "1983a."
`
`In another study disclosed by B. Sangster et al., "The influence of sodium
`bromide in man: a study in human volunteers with special emphasis on the
`endocrine and the central nervous system" Food Chem. Toxicol. 1983 Aug;
`21(4):409-19, healthy volunteers were repeatedly given sodium bromide in oral
`doses of 0, 4 or 9 milligrams Br/kilogram body weight/day using a double blind
`design. Groups of seven males received the treatment for 12 weeks and groups of
`seven non-pregnant females (not using oral contraceptives) over three full cycles.
`Special attention was paid to possible effects on the endocrine and central nervous
`systems. At the start and end of the study, a full medical history, the results of
`physical examination, haematological studies and standard clinical chemistry and
`urine analyses were recorded for each subject. Except for incidental nausea, no
`changes were observed. Mean plasma bromide concentrations at the end of
`treatment were 0.07, 2.14 and 4.30 millimoles/liter for males and 0.07, 3.05 and
`4.93 mmo1/1 for females of the 0-, 4- and 9-mg Br/kg/day groups, respectively.
`Only in the females receiving 9 mg Br/kg/day was there a significant increase in
`
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`serum thyroxine and triiodothyronine at the end of the study compared to pre-
`administration values, but all concentrations remained within normal limits. No
`changes were observed in serum concentrations of free thyroxine, thyroxine-
`binding globulin, cortisol, oestradiol, progesterone or
`testosterone, or of
`thyrotropin, prolactin, luteinizing hormone (LH) and follicle-stimulating hormone
`before or after the administration of thyrotropin-releasing hormone and LH-
`releasing hormone. Analysis of neurophysiological data (EEG and visual evoked
`response) showed shifts in the power of various spectral bands and a shift in mean
`frequency in the groups on 9 mg Br/kg/day. All findings were, however, within
`normal limits.
`
`A limited replication study was carried out to confirm the findings in the
`former study. Three groups of 15 females received (double blind) doses of 0, 4
`and 9 mg Br/kg/day during three menstrual cycles. After the administration
`period, the 45 females were observed for another three cycles. Mean plasma
`bromide concentrations at the end of the treatment were 0.07, 3.22 and 7.99
`mmo1/1, respectively.
`In none of the three groups were significant changes
`observed in the serum thyroxine concentration, free thyroxine, triiodothyronine,
`thyrotropine and thyroxine-binding globulin. Clinical observation did not show
`effects on the thyroid or on the central nervous system. Quantitative analysis of the
`electroencephalogram (EEG) showed only a marginal effect in females receiving 9
`mg Br/kg/day. (For further details, see B. Sangster et al., 1986. Onderzoek naar de
`invloed van natriumbromide bij menselijke vrijwilligers: HI. Rapport nr.
`348301001 d.d. october 1986. Rijksinstituut voor de volksgezondheid en
`milieuhygiene, Bilthoven, Holland).
`
`25
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`30
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`After oral ingestion bromide is rapidly and completely absorbed in the
`gastrointestinal tract and distributed almost exclusively in the extracellular fluid.
`The similarity of bromide to chloride gives rise to an important pharmacokinetic
`interaction. The two ions compete for reabsorption in the kidney. High chloride
`reabsorption will lead to higher bromide excretion and vice versa. The biological
`half-life of bromide can be decreased by administration of chloride. In rats, a
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`normal half-life of bromide of three days will increase to 25 days on a chloride-
`free diet.
`
`Bromide exerts various toxicological effects in rats. At higher doses,
`effects on the central nervous system have been observed. In short-term toxicity
`studies, motor incoordination of the hind legs and inhibition of grooming were
`
`5
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`found. The main effects of bromide are on endocrine organs. It is assumed that
`
`bromide acts directly on organs such as the thyroid, adrenals and testes, thereby
`
`inducing alteration in the pituitary gland by feed-back mechanisms. The effect on
`
`the thyroid may be explained by interaction with iodide uptake, and is the most
`
`10
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`sensitive effect in animal experiments.
`
`In a short-term toxicity study with rats at a normal chloride intake, effects
`
`have been found on most endocrine organs; while in special studies, decreased
`levels of a number of hormones (thyroxine, growth hormone, testosterone and
`corticosterone) have been observed. On the other hand, thyroid-stimulating
`hormone (TSH) and insulin were increased. A "No Observable Adverse Effect
`Level" (NOAEL), based upon all available data on the effects on the thyroid of 300
`ppm sodium bromide (240 ppm bromide), equivalent to 12 mg bromide/kg/day
`was established.
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`15
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`In a reproduction study in rats, complete infertility was observed at the
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`20
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`highest dose level of 19200 ppm sodium bromide, whereas at 4800 ppm, fertility
`
`and viability of the offspring were reduced. At 1209 ppm, no effects on
`
`reproduction were observed. The effects on fertility were reversible. Bromide was
`
`not mutagenic in the Ames test.
`
`25
`
`Heretofore, a number of patents and published patent applications have
`disclosed antitussive liquid compositions, the relevant portions of which may be
`briefly summarized as follows:
`
`U.S. Pat. No. 4,892,877, issued to Sorrentino on Jan. 9, 1990, discloses
`liquid compositions for the treatment of coughs comprising both dextromethorphan
`and phenol, the compositions having a pH of 5-9. U.S. Pat. No. 4,427,681, issued
`to Munshi on Jan. 24, 1984, discloses thixotropic compositions for the treatment of
`coughs comprising both dextromethorphan and AVICEL® RC-59I. U.S. Pat. No.
`6
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`to Smith on March 23, 1993, discloses antitussive
`issued
`5,196,436,
`pharmaceutical compositions for the peroral administration of dextromethorphan,
`the composition being at a pH of from about 8 to about 11. The disclosures of these
`United States patents are hereby incorporated by reference.
`
`5
`
`It is noted that agave was cultivated for centuries by the native Indian
`population for fibers, food and drinks. Agave syrup or agave nectar began
`
`appearing on health food store shelves in the early 2000s. Agave syrup, also
`
`known as agave nectar, is a sweetener commonly produced in Mexico from the
`
`10
`
`Agave americana plant (also called Century Plant). Agave syrup is similar to
`honey in color and texture, but it is not as viscous and flows more easily. Agave
`nectar is available in light or dark colors, the light liquid typically having been
`
`filtered. Agave has saponins and fructans. Inulin is a type of fructan that has
`
`many health benefits. Saponins are found in many plant roots, the most famous
`
`being ginseng.
`
`15
`
`Agave nectar is obtained from the agave plant grown in arid regions, by
`
`extracting the agave juice therefrom and processing it into a syrup. See, for
`
`example, U.S. Pat. NO. 5,846,333 of Partida et al., the disclosure of which is
`
`incorporated herein by reference. Commercially, other names for Agave nectar
`
`have been "Sweetener" or "Syrup" as well as other similar descriptive or extension
`
`20
`
`names. However, it is generally considered a syrup-like product which can be
`processed as an organic, natural, or raw state. It can be light to dark in color,
`thicker or thinner in consistency (viscosity), and even made into powder or crystals
`
`if dehydrated totally.
`
`U.S. Pat. Application Publication No. US 2009/0104326 of Catani
`
`25
`
`30
`
`discloses a solid sweetening composition having erythritol and a secondary
`sweetener in a single solid matrix, a method of making the solid sweetening
`composition and methods of sweetening a comestible. U.S. Pat. Application
`
`Publication No. US 2010/0029581 of Dhillon-Gill discloses a nutritional
`supplement comprising about 2 parts roasted, ground flaxseed, about 2 parts of
`chick pea flour, about 1.5 — 2 parts of whole wheat or brown rice flour, about 1
`part of raw, ground almonds and optionally, about 0.5 — 1 part of whole wheat
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`bran. The supplement may additionally contain one or both of raw blue agave
`nectar and sunflower oil. The supplement may also contain cardamom and/or
`ginger. The nutritional supplement comprises at least about 1.5 grams of Omega-3
`fatty acids, less than about 1.5 grams (g) of glucose, and less than about 0.6 g of
`sucrose in a serving of about 2 ounces (about 59 ml). A method of supplementing
`the nutrition of an individual comprises administering the nutritional supplement to
`the individual.
`
`5
`
`10
`
`U.S. Pat. Application Publication No. US 2009/0148580 of Heyer discloses
`using natural agave extract as a sweetener to replace all or part of the high-calorie
`sugars and/or artificial sweeteners added in foods and medicines, thereby
`promoting an important reduction of calories and the elimination of artificial
`sweeteners by using natural agave extract as the main sweetening ingredient. U.S.
`Pat. Application Publication No. US 2009/0029009 of Dimitri discloses an all
`natural beverage comprising rice syrup, agave nectar, fruit juice and electrolytes.
`15 The beverage is useful for rapid hydration and replenishment of lost carbohydrates
`and electrolytes after exercise, physical exertion, or exposure to heat. The
`disclosure of all of the preceding United States published patent applications are
`incorporated herein by reference.
`
`20
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`25
`
`This background information is provided for the purpose of making
`information believed by the applicants to be of possible relevance to the present
`invention. No admission is necessarily intended, nor should it be construed, that
`any of the preceding information constitutes prior art against the present invention.
`
`There remains a need for an effective cough suppressant which does not
`have the harmful side effects of bromide and polistirex. Additionally, to the best
`of the applicants' knowledge, no cough suppressant has been previously produced
`which does not contain sodium and/or preservatives. There remains a need for a
`cough suppressant lacking such ingredients as well.
`
`SUMMARY OF THE INVENTION
`
`30
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`Accordingly, embodiments of the present invention are provided that meet
`at least one or more of the following objects of the present invention.
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`It is an object of this invention to provide dextromethorphan compositions
`free of bromide, polistirex, and sodium, for oral administration which will provide
`a more safe antitussive action than commercially available compositions.
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`5
`
`It is also an object of this invention to provide methods for achieving rapid
`antitussive action from dextromethorphan compositions free of bromide, polistirex,
`and sodium.
`
`10
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`15
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`25
`
`In one aspect of the invention, pharmaceutical compositions are provided
`for oral administration which comprise a safe and effective amount of
`dextromethorphan and an orally-acceptable pharmaceutical carrier.
`The
`compositions are free of bromide, polistirex, and sodium. In some embodiments,
`the compositions are in liquid form and have a pH of from about 3.5 to about 6.5.
`
`In another aspect of the invention, pharmaceutical compositions are
`provided for oral administration, which comprise a safe and effective amount of
`dextromethorphan, safe and effective amounts of cough/cold drug actives, and an
`orally-acceptable pharmaceutical carrier which is free of bromide, polistirex, and
`sodium. In some embodiments, the liquid compositions have a pH of from about
`
`3.5 to about 6.5.
`
`In another aspect of the invention, there is provided a pharmaceutical
`composition, in dosage unit form, for oral administration comprising a safe and
`effective amount of dextromethorphan and an orally-acceptable pharmaceutical
`carrier comprising agave nectar, water and ethanol being at a pH of about 3 to
`about 6.5, wherein the pharmaceutical composition is free of bromide, sodium and
`polistirex. The composition may include from about 1 mg to about 50 mg
`dextromethorphan per dose. In some embodiments, the composition is an aqueous-
`based solution. The composition may be an agave-nectar based liquid.
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`In another aspect of the invention, there is provided a method of treating or
`preventing cough in humans by orally administering to the human a safe and
`effective amount of a composition of the present invention.
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`BRIEF DESCRIPTION OF THE FIGURES
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`10
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`The following drawing forms part of the present specification and is
`included to further demonstrate certain aspects of the present invention. The
`invention may be better understood by reference to this drawing in combination
`with the detailed description of specific embodiments presented herein.
`FIG 1. The chemical structure of dextromethorphan.
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`DETAILED DESCRIPTION
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`For the purposes of promoting an understanding of the principles of the
`
`invention, reference will now be made to certain embodiments and specific
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`language will be used to describe the same. It will nevertheless be understood that
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`no limitation of the scope of the invention is thereby intended, and alterations and
`modifications of the compositions and methods herein and further applications of
`the principles of the invention as illustrated therein are herein contemplated as
`would normally occur to one skilled in the art to which the invention relates.
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`Unless defined otherwise, all technical and scientific terms used herein
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`have the same meaning as commonly understood by one of ordinary skill in the art
`to which this invention pertains.
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`For the purpose of interpreting this specification, the following definitions
`will apply and whenever appropriate, terms used in the singular will also include
`the plural and vice versa. In the event that any definition set forth below conflicts
`20 with the usage of that word in any other document, including any document
`incorporated herein by reference, the definition set forth below shall always control
`for purposes of interpreting this specification and its associated claims unless a
`contrary meaning is clearly intended (for example in the document where the term
`is originally used). The use of "or" means "and/or" unless stated otherwise. The
`use of "a" herein means "one or more" unless stated otherwise or where the use of
`"one or more" is clearly inappropriate. The use of "comprise," "comprises,"
`"comprising," "include," "includes," and "including" are interchangeable and not
`intended to be limiting. Furthermore, where the description of one or more
`embodiments uses the term "comprising," those skilled in the art would understand
`that, in some specific instances, the embodiment or embodiments can be
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`alternatively described using the language "consisting essentially of and/or
`"consisting of"
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`As used herein, the term "about" refers to a ±10% variation from the
`nominal value. It is to be understood that such a variation is always included in
`any given value provided herein, whether or not it is specifically referred to.
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`The compositions and methods of the present invention comprise a safe and
`effective amount of dextromethorphan, which can include pharmaceutically
`acceptable salts thereof. In some embodiments, the compositions comprise one or
`more other drug actives. The phrase "safe and effective amount", as used herein,
`10 means an amount of drug active high enough to provide a significant positive
`modification of the condition to be treated, but low enough to avoid serious side
`effects (at a reasonable benefit/risk ratio), within the scope of sound medical
`judgment. A safe and effective amount of drug active will vary with the particular
`condition being treated, the age and physical condition of the patient being treated,
`the severity of the condition, the duration of the treatment, the nature of concurrent
`therapy and like factors.
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`Dextromethorphan is known to have pharmacological activity as an
`antitussive agent. As used herein, "dextromethorphan" means racemethorphan, 3-
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`methoxy-17-methylmotphinan; also known as (dl-cis-1,3,4,9,10,10a-hexahydro-6-
`20 methoxy-11-methyl-2H-10,4a-iminoethanophenanthrene; also known per IUPAC
`nomenclature as (+)-3-methoxy-17-methyl-(9a,13a,14a)-morphinan.
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`SUBSTITUTE SHEET (RULE 26)
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`the pharmaceutically acceptable salt of
`In some embodiments,
`dextromethorphan is the hydrochloride salt.
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`In some embodiments, the compositions of the present invention comprise
`from about 1 milligram (mg) to about 50 mg dextromethorphan per dose. In some
`embodiments, the compositions comprise from about 2.5 mg to about 30 mg
`dextromethorphan per dose. In some embodiments, the compositions are liquid
`compositions. In some embodiments, the liquid compositions comprise from about
`0.02% to about 1.5% dextromethorphan, from about 0.05% to about I%
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`dextromethorphan, or from about 0.1% to about 0.3% dextromethorphan by
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`10 weight. In some embodiments, a typical dose for a liquid antitussive composition
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`is from about 1