Patent Application
20080014267
It is understood that the present invention is not limited to the particular methodologies, protocols, fillers, excipients, etc., described herein, as these may vary. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a decongestant” is a reference to one or more decongestants and includes equivalents thereof known to those skilled in the art and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Specific methods, devices, and materials are described, although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.
The term “patient,” as used herein, comprises any and all organisms and includes the term “subject.” “Patient” may refer to a human or any other animal.
The term “administrable” defines a composition that is able to be given to a patient. Likewise, “administering” refers to the act of giving a composition to a patient or otherwise making such composition available to a patient.
The term “dose” or “dosage,” as used herein, is the amount of medication to be taken at one time.
The term “dose unit,” as used herein, is the amount of the dosage form that is intended to be consumed to deliver the predetermined dosage to an adult human. For example, a dosage unit may be 1 or 2 caplets.
The term “dosage form,” as used herein, is the form in which the dose is to be administered to the patient. The drug is generally administered as part of a formulation that includes nonmedical agents, referred to as pharmaceutic ingredients. The dosage form has a unique physical and pharmaceutical characteristics. Dosage forms may be solid, liquid or gaseous. Solid forms include, but are not limited to tablets, caplets, lozenges, wafers etc. Liquid dosage forms include, but are not limited to syrups, elixirs, injectable solutions, and intravenous solutions. Gaseous forms include vapors, inhalants, and the like.
The term “active ingredient” as used herein is any ingredient that is an antitussive, a decongestant or an expectorant when taken orally by a patient.
The term “substantially free,” as used herein, means free from therapeutically effective amounts of compounds when administered in suggested dosages, but may include trace amounts of compounds in non-therapeutically effective amounts.
Through the inclusion of an antitussive, a decongestant and an expectorant, the compositions and methods of the present invention may alleviate symptoms, such as coughing, sneezing, rhinorrhea, and/or nasal obstruction caused by a variety of factors. The invention relates to compositions comprising the guaifenesin and extended release forms of dextromethorphan and phenylephrine in a suspension. Specifically, the compositions may comprise guaifenesin, and the tannate salts of dextromethorphan and phenylephrine.
Antitussive drugs may act peripherally to inhibit cough by suppressing the responsiveness of one or more vagal sensory receptors that produce cough. Bolser et al., 86(3) J. A
Dextromethorphan (DXM) is a potent antitussive. Dextromethorphan (d-3-methoxy-N-methyl-morphinan) is the dextro isomer of levomethorphan. It has for some time been used as a cough suppressant and may be useful for pain treatment and protection against nerve cell damage. The drug acts centrally, in a manner independent of that of opioids (e.g., codeine), to elevate the threshold for coughing by an, as yet, ill-defined mechanism. DXM, as well as its metabolite, methorphan, have been shown to be antagonists at the N-methyl-d-aspartate (NMDA) receptor which is linked to other amino acid neurotransmitters, glutamate and glycine. In one specific embodiment, dextromethorphan tannate may be used.
Tannate salts of active agents are known to provide therapeutic effect for longer periods of time. It is believed that the inclusion of an active agent in a tannate salt form extends the release profile of the active agent and there is less spiking in pharmacological effect of the active agent. The active agent can therefore be administered to the patient less often and there are fewer side effects, particularly from over dosage effects. See, U.S. Pat. Nos. 5,599,846, and 5,663,415, issued Feb. 4, 1997 and Sep. 2, 1997, respectively, for further information on the preparation and use of phenylephrine tannate. See, U.S. Pat. Nos. 6,670,370 and 6,509,492, issued Dec. 30, 2003 and Jan. 21, 2003, respectively, for further information on the preparation and use of dextromethorphan tannate. In one embodiment, the tannate salts of phenylephrine or dextromethorphan are prepared in situ according to the method provided in U.S. Pat. No. 6,869,618, issued Mar. 22, 2005. In situ conversion to the tannate salts of the active ingredients allows for the preparation of medications with more accurate dosages of the active ingredients than the traditional methods to prepare tannate salts.
In another specific embodiment of the compositions and methods of the present invention, dextromethorphan may be included in amounts ranging from about 19 mg/dose to about 21 mg/dose. In another specific embodiment of the compositions and methods of the present invention, dextromethorphan may be included in amounts ranging from about 18 mg/dose to about 22 mg/dose. In another specific embodiment of the compositions and methods of the present invention, dextromethorphan may be included in amounts ranging from about 15 mg/dose to about 25 mg/dose. In another specific embodiment of the compositions and methods of the present invention, dextromethorphan may be included in amounts ranging from about 10 mg/dose to about 30 mg/dose. In another specific embodiment of the compositions and methods of the present invention, dextromethorphan may be included in an amount of about 20 mg/ dose.
Phenylephrine ((S)-3-hydroxy-α[(methylamino)methyl]benzene-methanol) is a sympathomimetic amine. It acts as an oral nasal decongestant and laryngeal mucous membrane decongestant, with minimal central nervous stimulation, by stimulating alpha-adrenergic receptors to produce pronounced vasoconstriction in the skin, mucous membranes and the mucosa. In a specific embodiment, phenylephrine may be in the form of phenylephrine tannate. In a specific embodiment of the compositions and methods of the present invention, phenylephrine may be included in amounts ranging from about 9.5 mg/dose to about 10.5 mg/dose. In another specific embodiment of the compositions and methods of the present invention, phenylephrine may be included in amounts ranging from about 9 mg/dose to about 11 mg/dose. In another specific embodiment of the compositions and methods of the present invention, phenylephrine may be included in amounts ranging from about 7.5 mg/dose to about 12.5 mg/dose. In a specific embodiment of the compositions and methods of the present invention, phenylephrine may be included in amounts ranging from about 5 mg/dose to about 15 mg/dose. In another specific embodiment of the compositions and methods of the present invention, phenylephrine may be included in an amount of about 10 mg/dose.
Viscous secretion exists in the airway of the human body. This secretion has an important role in imparting suitable temperature and humidity to inhaled air. When its amount is moderate, the secretion in the airway is unconsciously swallowed or expelled with the breath, but usually never is expectorated. Thus, any expectoration suggests that there is something extraordinary in the respiratory system. On the other hand, accumulation of this secretion in the airway is liable to cause an infection via the airway. From this point of view, the removal of the secretion is a matter of great significance in the medical treatment of patients who suffer with a disease in the airway.
In order to facilitate expectoration, medicines referred to as “expectorants” have been used. Most expectorants serve to remove the secretion by diluting it through an increase in secretion by the mucosa of the airway, promotion of separation from the mucosa and enhancement of ciliary beat. Guaifenesin (3-(2-methoxypphenoxy)-1,2-propanediol), also known as glyceryl guaiacolate, is an expectorant. It is readily absorbed from the intestinal tract and is thought to enter airway secretions unmetabolized and to have a direct effect either on the mucus secretion itself or the epithelium. Rubin, 116 C
In a specific embodiment of the compositions and methods of the present invention, guaifenesin may be included in amounts ranging from about 95 mg/dose to about 105 mg/dose. In another specific embodiment of the compositions and methods of the present invention, guaifenesin may be included in amounts ranging from about 90 mg/dose to about 110 mg/dose. In another specific embodiment of the compositions and methods of the present invention, guaifenesin may be included in amounts ranging from about 75 mg/dose to about 125 mg/dose. In another specific embodiment of the compositions and methods of the present invention, guaifenesin may be included in amounts ranging from about 50 mg/dose to about 150 mg/dose. In another specific embodiment of the compositions and methods of the present invention, guaifenesin may be included in an amount of about 100 mg/dose.
In some embodiments of the present invention, the compositions may be substantially free of active ingredients other than guaifenesin, phenylephrine, and dextromethorphan. In some embodiments, the compositions may be substantially free of extended release forms of phenylephrine and dextromethorphan other than the tannate salts. In some embodiments, the compositions may be substantially free of tannate. For example, in one embodiment, the compositions of the present invention may be substantially free of at least one other added antitussive. In another embodiment of the present invention, the compositions may be substantially free of at least one other added decongestant. In another embodiment of the present invention, the compositions may be substantially free of at least one other added nasal decongestant. In another embodiment of the present invention, the compositions may be substantially free of at least one other added opioid analgesic. In another embodiment of the present invention, the compositions may be substantially free of at least one other expectorant. In other embodiments of the present invention, the compositions may be substantially free of one or more other active ingredient, such as, but not limited to, antitussives, decongestants, nasal decongestants, opioid analgesics, and/or expectorants.
In other embodiments of the present invention, the compositions may additionally comprise one or more added active ingredients in addition to guaifenesin, phenylephrine, and dextromethorphan. For example, in one embodiment, the compositions of the present invention may comprise at least one other added antitussive. In another embodiment of the present invention, the compositions may comprise at least one other added decongestant. In another embodiment of the present invention, the compositions may comprise at least one other added nasal decongestant. In another embodiment of the present invention, the compositions may comprise at least one other opioid analgesic. In another embodiment of the present invention, the compositions may comprise at least one other expectorant. In other embodiments of the present invention, the compositions may comprise one or more other active ingredient, such as, but not limited to, antitussives, decongestants, nasal decongestants, opioid analgesics, and/or expectorants.
Antitussives of interest include, but are not limited to, codeine, codeine phosphate, codeine sulfate, morphine, morphine sulfate, hydromorphone hydrochloride, levorphanol tartrate, oxycodone hydrochloride, oxymorphone hydrochloride, methadone hydrochloride, apomorphine hydrochloride, beechwood creosote, benzonatate, camphor ethanedisulfonate, diphenhydramine, diphenhydramine hydrochloride, dextromethorphan hydrobromide, chlophendianol hydrochloride, carbetapentane citrate, caramiphen edisylate, noscapine, noscapine hydrochloride, and menthol.
Decongestants of interest include, but are not limited to, ephedrine, ephedrine sulfate, ephedrine hydrochloride, pseudoephedrine hydrochloride, phenylephrine hydrochloride, epinephrine bitartrate, hydroxyamphetamine hydrobromide, propylhexedrine, phenylpropanolamine hydrochloride, mephentermine sulfate, methoxamine hydrochloride, naphazoline hydrochloride, oxymetalozine hydrochloride, tetrahydrozoline hydrochloride, and xylometazoline hydrochloride.
Opioid analgesics of interest include, but are not limited to, such as, codeine, morphine, hydromorphone, hydrocodone, oxymorphone, levorphanol, fentanyl, propoxyphene, diphenoxylate, meperidine, methadone, oxycodone, butorphanol, benzonate and morphine.
Expectorants of interest include, but are not limited to ammonium chloride, ammonium carbonate, acetylcysteine, antimony potassium tartrate, glycerin, potassium iodide, sodium citrate, terpin hydrate, and tolu balsam.
In some embodiments of the present invention, the compositions may substitute one or more of guaifenesin, phenylephrine and dextromethorphan. For example, in one embodiment, the compositions of the present invention may substitute another expectorant for guaifenesin. In another embodiment of the present invention, the compositions may substitute another decongestant for phenylephrine. In another embodiment of the present invention, the compositions may substitute another antitussive for dextromethorphan
Substitute antitussives of interest include, but are not limited to, codeine, codeine phosphate, codeine sulfate, morphine, morphine sulfate, hydrocodone, hydromorphone hydrochloride, levorphanol tartrate, oxycodone hydrochloride, oxymorphone hydrochloride, methadone hydrochloride, apomorphine hydrochloride, beechwood creosote, benzonatate, camphor ethanedisulfonate, diphenhydramine, diphenhydramine hydrochloride, dextromethorphan hydrobromide, chlophendianol hydrochloride, carbetapentane citrate, caramiphen edisylate, noscapine, noscapine hydrochloride, and menthol, and functional variants and derivatives thereof.
Substitute decongestants of interest include, but are not limited to, ephedrine, ephedrine sulfate, ephedrine hydrochloride, pseudoephedrine hydrochloride, epinephrine bitartrate, hydroxyamphetamine hydrobromide, propylhexedrine, phenylpropanolamine hydrochloride, mephentermine sulfate, methoxamine hydrochloride, naphazoline hydrochloride, oxymetalozine hydrochloride, tetrahydrozoline hydrochloride, and xylometazoline hydrochloride, and functional variants and derivatives thereof.
Substitute expectorants of interest include, but are not limited to ammonium chloride, ammonium carbonate, acetylcysteine, antimony potassium tartrate, glycerin, potassium iodide, sodium citrate, terpin hydrate, and tolu balsam.
Sugars found in various products are highly undesirable for a number of reasons. For instance, it is known that products, such as medications, containing a high sugar content, more particularly saccharose, fructose and dextrose, may attack the dental enamel as a result of acid being formed in the mouth by certain bacteria if the teeth are not cleaned properly. In addition, many sugar-containing products are unsuitable for diabetics because of their sugar content. Sugar found in manufactured products also may be undesirable due to the increased caloric content caused by the sugar. Because of these factors, there is a progressively increasing world demand for sugar free products, including medications.
Sugar free versions of products may be manufactured using sugar replacements, such as, for example and without limitation, saccharin sodium, maltodextrin, aspartame, potassium acesulfame, neohesperidin dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof. These “sugar replacements” have the advantage that they do not decompose to form products that attack the dental enamel as a result of the bacterial flora present in the mouth during metabolism, even if the teeth are not cleaned properly. The “sugar replacements” also are suitable for consumption by diabetics and do not add unneeded or unwanted calories to products such as medications. Thus, in a specific embodiment of the compositions and methods of the present invention, the compositions may be free of any added sugar, and instead, may contain a sugar substitute, such as for example and without limitation, one or more of the sugar replacements described above.
Many cough and decongestant medications also contain alcohol. For various legal, dietary, cultural and religious reasons, there is interest in the production of alcohol-free medications. For instance, many alcohol-containing medications cannot be used by children because parents may be concerned about the alcohol content, and children may reject the alcohol bite and astringency characteristic of these products. Indeed, most alcohol-containing medications display the language “Keep Away From Children” on their labels. Similarly large numbers of adults reject alcohol based medications for various personal reasons. For instance and without limitation, those recovering from alcohol abuse avoid medications containing alcohol because of the threat that these substances can trigger a negative response. In addition, many institutionalized individuals are not allowed to use alcohol based medications. Therefore, there is a need for medications that are free of any added alcohol. In a specific embodiment of the compositions and methods of the present invention, the compositions may be free of any added alcohol.
The compositions and methods of the present invention may alleviate symptoms, such as coughing, sneezing, rhinorrhea, and/or nasal obstruction, caused by a variety of conditions. For instance, coughing, sneezing, rhinorrhea, and/or nasal obstruction may be caused by, for example and without limitation, nasal congestion, nasal pruritus, rhinorrhea, allergies, allergic vasomotor rhinitis (hay fever), seasonal allergic vasomotor rhinitis, perennial allergic vasomotor rhinitis, bronchography, bronchoscopy, or a respiratory disease, such as, for example and without limitation, a cold, acute bronchitis, chronic bronchitis, asthmatic bronchitis, bronchiectasis, pneumonia, lung tuberculosis, silicosis, silicotuberculosis, pulmonary cancer, upper respiratory inflammation (caused by, for example and without limitation, pharyngitis, laryngitis, nasal catarrh), asthma, bronchial asthma, infantile asthma, pulmonary emphysema, pneumoconiosis, pulmonary fibrosis, pulmonary silicosis, pulmonary suppuration, pleuritis, tonsillitis, cough hives, or whooping cough. The compositions and methods of the present invention may provide relief from symptoms caused by all of the above.
Typically cough and decongestant preparations are administered in a liquid form, such as, but limited to, an elixir in a sweetened aromatic solution of alcohol and water. In the present invention, however, syrups and other liquid vehicles, may be used. The preparation may or may not be a suspension. As used herein, the term “syrup” refers to a concentrated, aqueous preparation of a sugar or sugar substitute with or without an added flavoring agent. As used herein, the term “elixir” refers to a clear, sweetened, hydroalcoholic solution intended for oral use, and may or may not have an added flavoring agent. As used herein, a “suspension” is a preparation containing finely divided drug particles distributed somewhat uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility. Although water itself may make up the entire carrier, typical cough formulations may contain a co-solvent, for example and without limitation, propylene glycol and/or glycerin, to assist solubilization and incorporation of water insoluble ingredients, flavorants and the like into the composition. Any such ingredients may be included as desired or needed within the compositions and methods of the present invention as long as they are consistent with the objectives herein defined. For example, it is contemplated that when desirable, flavoring, preserving, suspending, thickening and/or emulsifying agents may be included in the compositions and methods of the present invention. Formulations for orally administered medications are well known in the art. Descriptions of suitable formulations may be found in Remington, The Science and Practice of Pharmacy (A. Gennaro ed., 20th ed., Lippincott, Williams & Wilkins, 2000).
Flavorants that may be used in accordance with the present invention include those known to those skilled in the art. These flavorants may include, for example and without limitation, natural, artificial and synthetic flavor oils and flavoring aromatic and/or oils, oleoresins and extracts derived from plants, animals, leaves, flowers, fruits, and so forth, and combinations thereof. Non-limiting representative flavor oils include anise oil, cinnamon oil, peppermint oil, spearmint oil of wintergreen, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, lemon oil, orange oil, lime oil, grapefruit oil, and grape oil. Also useful flavorants include fruit essences including apple essence, pear essence, peach essence, berry essence, wildberry essence, date essence, blueberry essence, kiwi essence, strawberry essence, raspberry essence, cherry essence, plum essence, pineapple essence, and apricot essence. Other useful flavorants include aldehydes and esters such as benzaldehyde (cherry, almond), citral, i.e., alpha-citral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), and 2-dodecenal (citrus, mandarin), mixtures thereof and the like. Honey and artificial honey flavor, as well as natural mixed berry flavor, citric acid, malic acid, vanilla, vanillin, cocoa, chocolate, and menthol may also be used in accordance with the present invention. Flavorants appealing to non-human patients may also be included in the composition of the invention, including but not limited to, yeast extract, meat extract, fish extract, poultry extract, cheese and other dairy flavors, and the like.
Another aspect of the invention are methods of administering to a patient the composition of the invention, comprising guaifenesin, and extended release forms of phenylephrine and dextromethorphan. In some embodiments, the composition comprises guaifenesin, and the tannate salts of phenylephrine and dextromethorphan. In some embodiments, the composition is administered to the patient orally. The compositions of the invention may be administered in varying volumes and at varying frequencies. In specific embodiments, the dose unit is from about 1 to about 10 ml, or from about 0.1 to 100 ml. Specific dose units include, but are not limited to, 1.25 ml, 2.5 ml, 5.0 ml, and 10 ml. The frequency of the dose may vary from every other day to several times a day. In specific embodiments, the frequency of administration may be once a day, twice a day, three times a day or four times a day. In other specific embodiments, the frequency of the dose may be once a day or twice a day.
The dose may depend in part with the characteristics of the patient. In some embodiments, the patient is a human over about 12 years of age and the composition may be administered in an about one dose at least once a day, at least twice a day, once a day or twice a day. In other embodiments, the patient is human from about 6 to about 12 years of age, and the composition of the invention is administered in an about ½ dose once a day or twice a day. In another embodiment, the patient is a human from about 2 to about 6 years of age, and the composition of the invention is administered in an about ¼ dose once a day or twice a day.
The total dosage per day of the active compounds may be a factor in determining the criteria for administering the composition of the invention. For example, compositions with a higher concentration of active compounds may be taken in smaller dosages and/or less frequently, and compositions with lower concentrations of the active compounds may be taken in larger volume dosages and/or more frequently.
Without further elaboration, it is believed that one skilled in the art, using the preceding description, can utilize the present invention to the fullest extent. The following examples are illustrative only, and not limiting of the remainder of the disclosure in any way whatsoever.
A composition of the following formulation is prepared in liquid swallowable form containing the following active ingredients per 5 ml:
Other inactive ingredients include: aspartame, acesulfame, glycerin, neusilin, xanthan gum, sodium citrate dehydrate, citric acid; methylparaben, sodium benzoate, bitter mask, FD&C blue #1, FD&C red #40, artificial grape flavor, purified water, 6N hydrochloric acid, 6N sodium hydroxide.
A study is undertaken to evaluate the effectiveness of the compositions of the present invention in the treatment of patients. The objective of the study is to determine whether oral intake of the compositions of the present invention results in an improvement of the symptoms of coughing, sneezing, rhinorrhea, and/or nasal obstruction.
A double-blind, placebo controlled study is conducted over a three-day period. A total of 120 subjects, all presenting for treatment of symptoms of coughing, sneezing, rhinorrhea, and/or nasal obstruction, are chosen for the study. The patients range in age from 8 to 72 years old.
An initial assessment of the symptoms of each patient is conducted when the patients initially present for treatment. The treating physician rates the severity of the symptoms on a 4-point scale (0: absent; 1: mild; 2: moderate; 3: severe). For inclusion in the study, a patient must be rated with a score of two or above for cough and a total score of at least 5 for the sum of the four selected symptoms.
The 120 subjects chosen for the study are separated into two separate groups of 60. The characteristics of the symptoms between the two groups are comparable. The first group is administered a 5 ml dose of the composition of the present invention every twelve hours for three days. The second group is administered a placebo medication every twelve hours for three days that is similar in all respects to the administered composition except for the exclusion of the active ingredients, dextromethorphan tannate, phenylephrine tannate and guaifenesin. No other medications are taken by the patients during the assessment period.
Patients self-evaluate their symptoms of coughing, sneezing, rhinorrhea, and nasal obstruction using the same 4-point scale (0: absent; 1: mild; 2: moderate; 3: severe) thirty minutes after each dose administration. Patients also note the presence and severity of adverse effects of taking the medication on the 4-point scale. In addition to the initial assessment on day 1, patients are evaluated at the end of day two and day three by the treating physician.
The data is evaluated using multiple linear regression analysis and a standard t-test. In each analysis, the baseline value of the outcome variable is included in the model as a covariant. Treatment by covariant interaction effects is tested by the method outlined by Weigel & Narvaez, 12 C
This study will demonstrate the efficacy of the composition of the present invention in treating the symptoms of coughing, sneezing, rhinorrhea and nasal obstruction. Regarding potential adverse effects of taking the medication, if there are no significant differences between the two therapeutic groups, this study will demonstrate that the administration of the composition of the present invention is effective at treating symptoms of coughing, sneezing, rhinorrhea, and nasal obstruction, in addition to being well-tolerated by the patients.
While specific embodiments of the present invention have been described, other and further modifications and changes may be made without departing from the spirit of the invention. All further and other modifications and changes are included that come within the scope of the invention as set forth in the claims. The disclosures of all publications cited above are expressly incorporated by reference in their entireties to the same extent as if each were incorporated by reference individually.
This application claims priority under 35 U.S.C. §120 to U.S. patent application Ser. No. 11/330,351, filed Jan. 12, 2006. The entire content of this prior application is fully incorporated herein by reference.
