United States Patent 5,409,905
Eby, III * April 25, 1995
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Cure for commond(sic) cold
Abstract
Present invention is a non-toxic, flavor stable, pleasant tasting composition releasing Zn.sup.2+ from compositions containing a highly ionizable zinc compound other than zinc gluconate that reduces the duration of common colds in humans. The composition is used in the oral cavity of a human suffering from a common cold. The composition comprises highly ionizable zinc compounds and a pharmaceutically acceptable carrier such as fructose, dextrose or sucrose with various additions. Compositions are unique in that they are non-toxic, pleasant tasting and do not have an offensive aftertaste, yet deliver zinc ions into oral tissues which may be used to treat common colds, reduce the duration of common colds or cure common colds in humans in need of such treatment. Compositions are non-toxic, thermally, chemically and flavor stable. The compositions may be prepared in the form of compressed tablets, lozenges, powders, liquids or chewing gums. Present compositions deliver strongly antirhinoviral and interferon inducing Zn.sup.2+ ions to the oral mucosa of a human. In vitro, Zn.sup.2+ is as antirhinoviral and as protective of cell monolayers as interferon and is also a potent interferon inducer. Said pleasant tasting composition is an improvement upon a slow-release candy composition comprising a hard candy base, highly ionizable zinc compounds and an amino acid; and said composition is an improvement upon a medicinal composition for release of zinc ion consisting essentially of a suitable pharmaceutical carrier, highly ionizable zinc compounds and anethole.
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Inventors: Eby, III; George A. (2109 Paramount Ave., Austin, TX 78704)
[*] Notice: The portion of the term of this patent subsequent to March 10, 2009 has been disclaimed.
Appl. No.: 215008
Filed: March 21, 1994
PRIMARY OBJECTIVE AND GENERAL DESCRIPTION OF INVENTION
Accordingly, it is a primary objective of this invention to disclose and claim improved solid oral zinc compositions that are non-toxic, thermally, chemically, and flavor stable. Said compositions shall be devoid of the objectionable flavor and aftertaste commonly associated with oral zinc gluconate compositions. Said compositions shall be intended to release Zn.sup.2+ ions into oral and oropharyngeal mucous membranes for local absorption and movement through BCECs into the nose. Said compositions are primarily intended to be used to reduce duration of common colds or their symptoms, management of upper respiratory allergy, for nutritional support or for related purposes. Said compositions shall contain one or more highly ionizable zinc compounds, excluding zinc gluconate, which have been discovered by this inventor to be non-toxic and not to have an objectionable taste or aftertaste when properly formulated. These primary objectives and other objectives of this invention will be found apparent from the following general description and detailed examples.
Compositions Containing Highly Ionizable Zinc Compounds Generally
This inventor discloses and claims non-toxic, flavor-stable, pleasant tasting solid oral compositions specifically containing highly ionizable zinc compounds and pharmaceutically acceptable carriers for use primarily in human common cold treatment, upper respiratory allergy management and for nutritional support. Said compositions are intended to be dissolved in the mouth, masticated or otherwise used in the mouth to release Zn.sup.2+ ions into the tissues of the oral cavity and oropharyngeal tissues of humans. Said highly ionizable zinc compounds are to be slowly and uniformly released by aqueous dissolution of solid ingredients within said solid oral composition, as said compositions are held or retained in the mouth. Saliva, generated by the person orally dissolving said composition, is the usual source of said aqueous solvent. Ideal oral cavity retention time periods are 30 minutes per application or use of composition. Soft candy and chewing gums are to release highly ionizable zinc compounds slowly over a sustained period of time.
Said highly ionizable zinc compositions are believed non-toxic as they release essentially 100% of their zinc as Zn.sup.2+ at oral tissue pH 7.4 and at lower pit values. Zn.sup.2+ is not believed to be absorbed into the interior of cells, and Zn.sup.2+ exerts its beneficial effects solely on the cell membrane, perhaps by sealing the membranes so that virally infected cells do not release theft viruses extracellularly. Lipophilic complexes of zinc and neutral charged zinc species at pH 7.4 may be cytotoxic when absorbed into cells which may worsen common colds through increased tissue damage, particularly oral tissue damage. Negatively charged zinc complexes at pH 7.4 may also be toxic and may similarly increase the duration and severity of colds. Such may have been the cause of increased severity and duration of colds in the Farr et al 1987 study and the Douglas et al. 1987 study which released negatively charged zinc and neutral zinc complexes.
Invented compositions of highly ionizable zinc compounds are stable, meaning that negligible degradation in flavor, appearance or chemistry occured in tested compositions under extended multi-year storage in normal and near normal temperature conditions while sealed in air-tight, opaque containers. Compositions of said highly ionizable zinc compounds are non-toxic, pleasant tasting and have a pleasant aftertaste, generally defined by the ligand, the added flavors, the pharmaceutically acceptable carrier, or by added super sweeteners such as saccharin. Said compositions are an improvement upon a slow-release candy composition comprising a hard candy base, zinc gluconate and an amino acid, as said sweet compositions of the present invention exclude zinc gluconate and amino acids; and whereby said compositions are improvements upon a medicinal composition for release of zinc ions consisting essentially of a suitable pharmaceutical carrier, zinc compounds and anethole; as present composition excludes anethole.
As discovered from said thermal and aging stability studies, compositions are nontoxic, usually without an objectionable taste or aftertaste even without an added flavor-mask. Compositions are non-toxic, chemically, thermally and flavor stable with no increase in bitterness under high summer-time temperature conditions over multi-year periods of time. This invention primarily discloses and claims the discovery of non-toxic, pleasant tasting and aftertaste-free compositions of highly ionizable zinc compounds dispersed in a consumable pharmaceutically acceptable carrier that reduce the duration of common colds. By necessity to clearly and more fully describe said compositions, said inventive compositions include:
Oral compositions containing highly ionizable zinc compounds in any pharmaceutically acceptable carrier such as fructose, Mendell's Sugartab.RTM., Sweetrex.RTM. or Emdex.RTM., sucrose, dextrose, maltose, lactose, sweetened water and the like, singularly or in combination, with following pharmaceutical necessities included singularly or in combination, as desired:
tablet binders for compressed tablets, lozenges and troches including polyethylene glycol-6000 or 8000,
flavor oils such as peppermint, methyl salicylate, menthol and eucalyptol excluding anethole, as disclosed by U.S. Pat. No. 5,002,970.
flavor oil stabilizers, including spray driers and cyclodextrins,
coloring agents and dyes,
glidants, including silica gel,
tablet lubricants, including magnesium stearate,
other necessities excluding amino acids as disclosed in U.S. Pat. No. 4,684,528;
and with the following medicinal additives included as desired or necessary:
antiviral agents, including antirhinoviral agents,
antimycoplasmal agents,
antibiotics,
nasal decongestants,
antihistamines,
antinausea agents,
analgesics,
cough relievers,
dental desensitizers,
saliva inhibitors,
vitamins, including ascorbic acid,
minerals, other than zinc, and
other medicinal agents and nutritional supplements either directly incorporated within compositions or chemically isolated through techniques including micro-encapsulated and inclusion within cyclodextrins. Micro-encapsulation with insoluble porous membranes providing a time release capability for ingredients that might interfere with release of zinc ions or adversely affect taste of composition is anticipated.
Such compositions include solid forms such as tablets, troches, lozenges and powders; chewable forms such as chewing gums and soft candies; and liquid forms such as syrups, mouth washes and sprays. When said compositions are applied to oral and oropharyngeal membranes of a human, they are non-toxic, meaning that they are not absorbed into cells in a manner which causes cytotoxicity at the concentrations used in the oral composition, palatable, without undesirable taste or unpleasant aftertaste, yet they allow oral and oropharyngeal absorption of Zn.sup.2+ ions. When compositions are to be used to treat common colds, reduce the duration of common colds or cure common colds, said pharmaceutical necessities and medicinal additives shall not be present in sufficient quantities to impair the beneficial action of Zn.sup.2+ on the duration of common colds or they shall be sealed through micro-encapsulation.
Highly Ionizable Zinc Compounds
For purpose of this invention highly ionizable zinc compounds include all highly soluble, non-toxic inorganic and organic complexes of zinc excluding zinc gluconate having a first stability constant less than about log K.sub.1 =2. Inorganic highly ionizable complexes of zinc include zinc chloride (log K.sub.1 =0.0) and zinc sulfate, both of which are Generally Recognized As Safe (GRAS) as well as other inorganic zinc complexes having a first stability constant of zinc of less than about log K.sub.1 =2. Organic highly ionizable zinc complexes having a first stability constant of less than log K.sub.1 =1.0 are preferred and include zinc propionate, zinc butyrate, zinc n-butyrate, zinc beta-hydroxybutyrate, zinc benzoate, zinc formate and zinc acetate. Said preferred zinc complexes all have sufficiently low first stability constants (log K.sub.1 =0 to 1) that zinc exists essentially as 100% Zn.sup.2+ ions at aqueous solution at pH 7.4. Zinc succinate and zinc sulfate are slightly less ionizable and are also preferred complexes of zinc.
Although zinc gluconate is the best known source of Zn.sup.2+ ions in lozenges for treating common colds, highly soluble, highly ionizable zinc compounds other than zinc gluconate merit special attention. For purposes of this invention, zinc lozenges for treating common colds, curing common colds or reducing the duration of common colds contain between about 0.2 and 500 mg zinc and more often contain about 2 to 50 mg of zinc and most often contain about 10 to 23 mg zinc from a highly ionizable zinc compound excluding zinc gluconate dispersed in about 1 to 15 grams of a pharmaceutically acceptable carrier, and preferably a sweet pharmaceutically acceptable carrier. Highly soluble, highly ionizable zinc compounds offers improved, unexpected characteristics over zinc gluconate that require close attention.
Surprising and Unexpected Taste Characteristics
Undiluted highly ionizable zinc compounds have dreadful, vile tastes and some have sharp disagreeable odors. Most important, surprising, totally unexpected, and patently unique; any non-toxic highly ionizable zinc compound other than zinc gluconate sufficiently diluted with any pharmaceutically acceptable carrier, such as sweetened water, fructose, sucrose, dextrose, starch, lactose, other sugars or other dilutants, has neither the seriously offensive taste nor the long lasting 24 to 60 hour bitter and offensive aftertaste like that present with zinc gluconate when said compositions are retained in the oral cavity of a human for sustained periods of time (defined as 5 to 30 minutes or more). Highly ionizable zinc compounds may be sufficiently diluted, yet sufficiently concentrated to be of utility against common colds when applied over such extended time. Properly prepared compositions have a pleasant taste and pleasant aftertaste. All common cold orally absorbed compositions (whether containing Zn.sup.2+ or other antirhinoviral agents) are required to be slowly and uniformly released in a sustained manner into the oral cavity as said composition is being orally consumed or masticated and, said compositions must be non-toxic, stable and have a pleasant taste and aftertaste during composition dissolution. Sustained application of Zn.sup.2+ ions (defined as 5 to 30 minutes or longer per application) to the interior of the mouth including the tongue, oral cavity, throat and oropharyngeal surfaces from a palatable composition releasing a 1 to 50 millimolar concentration of Zn.sup.2+, and preferably about 5 to 15 millimolar concentration, and more preferably about 7 to 10 millimolar concentration for preservation of best taste is necessary in order to be effective in reducing the duration of common colds. This present inventor also discovered that the objectionable taste of highly ionizable zinc compounds is eliminated with addition of consumable, pharmaceutically acceptable carriers such as fructose, sucrose, dextrose and other sugars and sweeteners; with or without added super sweeteners like saccharin and various flavors; all of which is directly contrary to teachings of U.S. Pat. No. 4,684,528.
Fructose, Sucrose and Dextrose as Pharmaceutical Carriers
Fructose is the sweetest of the natural sugars. It is a component of sucrose, a disaccharide, and is an isomer of dextrose, all of which are sugars. Neither fructose, sucrose nor dextrose are believed to chelate zinc in a way that would detract from its utility in treating common colds. The first stability constant of dextrose for Zn.sup.2+ is log K.sub.1 =0.01 [Briggs J. et al. (1981), Carbohydrate Research, 97:181]. It is surprising and unexpected that fructose does not visibly react, change color or form bitter compounds with highly ionizable zinc compounds at higher ambient temperatures as this monosaccharide is a polyhydroxy ketone and is usually considered highly reactive. On the other hand, dextrose, a polyhydroxy aldhyde is normally considered to be an inert monosaccharide. Dextrose reacts with zinc gluconate over time to form extremely bitter complexes, but not with other highly ionizable zinc compounds tested. Various sweet tasting commercial tablet bases having a modified sugar tablet base produce bitter zinc gluconate lozenges after lozenges age for a few weeks, particularly when exposed to high summer temperatures. However, various sugar tablet bases do not become bitter in lozenges when used with those highly ionizable zinc compounds tested by present inventor in lozenges or tablets, regardless of time or temperature.
Favored Compositions of Fructose and Dextrose with Highly Ionizable Zinc Compounds
It can now be revealed that preference is given to compositions of highly ionizable zinc compounds over zinc gluconate in a fructose and agglomerated dextrose based carrier over other sweet carriers. Favored formulation is any highly ionizable zinc compound other than zinc gluconate having a first stability constant of log K.sub.1 =from less than 0 to about 2, and preferably from less than 0 to about 1, in lozenges having a carrier of fructose mixed with agglomerated dextrose. Tablets with crystalline fructose as a carrier could be bound by Mendell's Emdex.RTM. at about one-half the weight of crystalline fructose without tablet capping. Generally lozenges are made in a 2 to 6 gram size to allow a suitable dissolution rate for lozenges. Dissolution time should be about 15 minutes in water bath testers at 37 C. degrees or about 30 minutes when orally dissolved as lozenges for treatment of common colds, common cold symptoms, curing common colds or reducing the duration of common colds. Greatest efficacy occurs when saliva generation is lowest, thus raising Zn.sup.2+ molar concentration in the oral cavity, suggesting utility for incorporating saliva inhibitors into compositions. Increased sweetness and strong flavorings increase salivation which decreases Zn.sup.2+ concentration and efficacy. Smaller and larger lozenges from 0.1 up to 15 grams are anticipated by this invention.
Compressed Tablet Compositions
Lozenges, tablets and troches in this invention are essentially the same, but may differ in shape, size and manufacturing technique. Since fructose is sweeter than sucrose and other sugars, it is preferred for use in direct compression of lozenges containing highly ionizable zinc compounds. Fructose may be processed for direct compression of tablets, troches and lozenges by incorporation of a tablet binder such as PEG-8000, perhaps using fluid bed agglomeration techniques wherein PEG has been diluted with water and the ground fructose crystals are agglomerated with PEG. To make directly compressible lozenges, add highly ionizable zinc compounds to PEG-8000 processed fructose; or add highly ionizable zinc compounds excluding zinc gluconate to crystalline fructose and commercially available, sweet, direct compression products such as Mendell's Sugartab.RTM., Sweetrex.RTM., or Emdex.RTM.. Add saccharin if desired, flavors as desired, glidants such as silica gel as needed, and lubricants such as magnesium stearate as needed. Mixture should be kept dry and tableted soon after mixing. Ingredients are mixed and directly compressed into lozenges, tablets or troches using conventional pharmaceutical mixing and tableting equipment. Compressive force must be sufficient to produce maximum hardness throughout the lozenges to preserve the dissolution rate and maximum efficacy of lozenges in treating common colds or their symptoms, shortening the duration of common colds or curing common colds. Dissolution should occur over a sustained period of time, that being 5 to 30 minutes or more and preferably about 20 to 30 minutes. Store compositions in air tight containers in a cool dark place. If heated to high summer-time room temperatures, compositions, when properly prepared and sealed, are pleasantly flavored, do not turn brown over time and do not have a bitter aftertaste. Although added ingredients are not believed necessary to present a pleasantly flavored composition having no zinc aftertaste, addition of super sweeteners, such as saccharin is anticipated to improve the flavor of the basic composition and added pharmaceutical necessities and medicinal additives.
Liquid Compositions
Highly ionizable zinc compounds with a pleasant tasting, sweet, pharmaceutically acceptable carrier may be prepared in any liquid form such as syrups, mouth washes or sprays with water or other liquids for repeated delivery of concentrated highly ionizable zinc compounds excluding zinc gluconate to oral and oropharyngeal mucous membranes over a sustained period of time, that being 5 to 30 minutes or more and preferably about 20 to 30 minutes, so as to permit a prolonged contact by highly ionizable zinc compounds upon mouth and throat tissues. Said invention differs from zinc chloride mouth washes commercially available as present invention is to be retained in the oral cavity for much longer time than presently available mouth washes to effectively reduce the duration of common colds, treat common colds or cure common colds.
Soft Compositions
Highly ionizable zinc compounds in chewable compositions such as soft candy, gum drop, liquid filled candies, chewing gum base and dental supplies, such as tooth pastes and mouth washes, may be prepared by adding highly ionizable zinc compounds excluding zinc gluconate and sweeteners including fructose, sucrose and saccharin to them as needed. To obtain efficacy against the duration of common colds, to cure common colds or to treat common colds, said soft composition are retained in the mouth over a sustained period of time, that being 5 to 30 minutes or more and preferably about 20 to 30 minutes.
Super Sweeteners
Various super sweeteners including saccharin, aspartame, cyclamates, acesulfame K, neohesperidin dihydrochalcone and other super sweeteners may be added to the carrier in amounts sufficiently low so as not to chemically react with zinc to a therapeutically significant amount of Zn.sup.2+. Preference is given to sodium saccharin, about 1 to 14 mg per 23 mg zinc, as additive super sweetener. Above 50 mg saccharin, compositions may have a bitter saccharin taste and aftertaste.
Flavors
Many flavorings can be added to impart their own flavor including but not restricted to peppermint, peppermint-menthol, eucalyptol, wintergreen, licorice, clove, cinnamon, spearmint, cherry, lemon, orange, lime, menthol and various combinations. Preference is given to peppermint (Bell #113.042) flavor plated onto silica gel for trueness of flavor and multi-year stability.
Stabilized Flavors
Some flavor oils may not be stable in long-term storage with highly ionizable zinc compounds in lozenges, and must be prevented from contacting zinc, evaporating and degrading generally. In lozenges and other dry solid compositions, flavors may be stabilized by spray drying with National Starch's N-Lok or other modified starches, or included within cyclodextrins, and/or coated with PEG 6000 or 8000. Inclusion of flavor oils within cyclodextrins results in essentially complete long-term thermal, oxidative and photo-decomposition stability. Of particular interest, inclusion results in protection against flavor oil degradation and oxidization otherwise accelerated by heat, light and metal salts. Spray dry flavors must not include acacia, and other vegetable gums that are powerful zinc chelators. Highly ionizable zinc compounds excluding zinc gluconate may be coated with PEG 6000, 8000 or higher molecular weight PEG or included within cyclodextrins to prevent contact of zinc with flavors. However, peppermint oil (Bell #113.042) plated onto silica gel (Siloid 244FP) is stable with no loss of flavor or aroma for at least two years in directly compressed highly ionizable zinc compounds lozenges in sealed amber glass bottles, and presumably any air-tight, opaque container.
Pharmaceutically Acceptable Carriers
Without regard to desirability of ingredients or intended use of compositions, a more complete list of sweet, consumable, pharmaceutically acceptable carriers includes but is not limited to: (a) carbohydrates including fructose, sucrose, sugar, dextrose, starch, lactose, maltose, maltodextrins, corn syrup solids, honey solids, commercial tablet compositions including Emdex.RTM., Mor-Rex.RTM., Royal-T.RTM., Di-Pac.RTM., Sugar-Tab.RTM., Sweet-Rex .RTM., New-Tab.RTM., (b) sugar alcohols including mannitol, sorbitol, xylitol, and (c) various relatively insoluble excipients including dicalcium phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose and other pharmaceutical tableting ingredients. Pharmaceutically acceptable carriers for compositions to be used for treating common colds by release of zinc ions in the oral cavity generally include the above, but preference is given to carriers other than the sugar-alcohols and insoluble ingredients because they lack sufficient sweetness and may adversely affect mouth-feel.
Undesirable Ingredients for Treating Common Colds
Highly ionizable zinc compounds in compositions for treating common colds must exclude positively-charged zinc (Zn.sup.2+) ion-depleting ingredients and other incompatibles. Acacia, super sweeteners, citric acid, tartaric acid and other food acids, lake colors, alkalis and their carbonates, oxalates, phosphates, sulfides, lime water, and vegetable decoctions are considered incompatible with highly ionizable zinc compounds; and may cause compositions to be flavor unstable or cause a loss of efficacy against common colds or both. Zn.sup.2+ ion depleting chelators must not be added in chemically significant amounts even if they are physically isolated from highly ionizable zinc compounds within compositions.
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