MXPA02003312A

MXPA02003312A - Compositions having improved stability.

Info

Publication number: MXPA02003312A
Application number: MXPA02003312A
Authority: MX
Inventors: Ek Nath Khanolkar Jayant
Original assignee: Procter & Gamble
Priority date: 1999-09-29
Filing date: 2000-09-26
Publication date: 2002-10-04
Also published as: HUP0202797A3; CA2385990A1; CN1211085C; HUP0202797A2; EP1216044A1; CN1376065A; JP2003510279A; CO5210868A1; WO2001022967A1; CZ2002947A3; AU7986500A; AU770376B2; BR0014441A; PE20010627A1

Abstract

The present invention pertains to improved stability of compositions that deliver pharmaceutical active ingredients. These compositions have exceptional stability when used in various product forms including liquid elixirs placed into the mouth and eventually swallowed, or can be delivered via liquidfilled lozenges, metered liquid dosing devices, atomizers and liquidreleasing, edible capsules. Such compositions are particularly useful for treating symptoms associated with respiratory illnesses.

Description

COMPOSITIONS THAT HAVE IMPROVED STABILITY TECHNICAL FIELD The present invention relates to improved stability of compositions that deliver pharmaceutical active ingredients. These compositions have exceptional stability when used in various product forms including liquid elixirs that are placed inside the mouth and eventually swallowed, or can be delivered via liquid filled tablets, measured liquid dosage devices, sprays and edible capsules that release liquid. Such compositions are particularly useful for treating symptoms associated with respiratory diseases.

BACKGROUND OF THE INVENTION Routes for the supply of pharmaceutical assets include the supply of assets by intranasal, pulmonary, buccal, sublingual, transdermal, vaginal and rectal administration. However, the most common are swallowed compositions, they enter the grastronitestinal tract and are absorbed in the general circulation of the blood. Items swallowed by humans, including food, beverages and medicines, enter the stomach and food, drinks, or medicines pass through the mucous membranes in the gastrointestinal tract and into the blood in the mesenteric s that are emptied from the intestine. The circulation of blood from the mesenteric s passes into the liver. The enzymes that are metabolized in the mucous membranes of the intestine and in the liver can chemically alter the nature of the substances that pass from the intestine, through the liver, and into the common blood circulation of the body. Respiratory diseases cover a wide range of conditions, including viral infections and allergic reaction to inhaled allergens. Viral infections in the respiratory tract of humans lead to disease that is usually referred to as influenza, or influenza. A disease of this type is quite common in the general population and can cause discomfort and significant suffering. The inhalation of allergens also negatively affects a large number in the population at the same time or even to a greater degree those who have a viral infection. There are no methods that are generally considered effective and convenient for preventing viral infections or allergies. In the case of viral infections, the body's natural defense mechanisms fight the infection for a period of time that normally varies from 3 days to 2 weeks. This being the case, the drugs that are used most commonly treat the troublesome uncomfortable symptoms of these respiratory diseases. These symptoms include congested and runny nose, pain and swelling in the nose and throat, coughing fits, general body aches, fever, and headache. Of these symptoms, the cough in uncontrolled attacks is considered by many people to be the most problematic and uncomfortable symptom. The cough interrupts normal breathing, leading to an increase in headache and sore throat as well as loss of sleep to the sufferer and others who inhabit the patient. The compositions that are used to treat the aforementioned symptoms generally fall into one of the following pharmacological classifications: antihistamines; descogestantes; Antitussives; expectorants; mucolytics; analgesics; antipyretics and anti-inflammatory agents. The compositions are manufactured in many product forms, the most common being liquid syrups and elixirs for swallowing, mouth drops and pills as well as inhalants and topical creams or lotions that release volatile agents that are inhaled through the nose into the mouth. respiratory tract. The compositions typically swallow immediately, or dissolve slowly in the mouth. Typically they contain active ingredients such as guaifenesin, which helps the body to eliminate excess mucus or respiratory phlegm, diphenhydramine, which mitigates the negative effects including cough and other symptoms due to the histamine produced in the body in response to viral infection, and dextromethorphan, that acts within the part of the human brain that controls the cough reflex. Among these assets, a § > Dextromethorphan is the most commonly used active in the world to relieve cough. U.S. Patent 4,839,176, Pankhania et al., To Boots Company, issued June 13, 1989, discloses the use of bisulfites in the manufacture of tablets comprising CMC that prevents degradation. U.S. Patents 4,474,985, Keel et al., September 25, 1993, to Monsanto, discloses a process to increase the shelf-life free of color of a crude N-aminophenol. The process comprises dissolving crude N-acetyl aminophenol in a solvent containing a reducing agent, such as metabisulfate. U.S. Patent 4,478,822, issued October 23, 1984, and U.S. Patent 4,474,752, issued October 2, 1984, both to Haslam et al., And assigned to Merck & Co. They claim gel compositions comprising polymers that provide gelation of the liquid when the body cavity enters. A group of microbial preservatives is revealed including sodium bisulfite and sodium thiosulfate. The technique known to the Applicants does not demonstrate a specific advantage of chemical stabilization by the inclusion of liquid base product forms.

BRIEF DESCRIPTION OF THE INVENTION What has not been understood so far is that active compounds that are combined with traditional solvents can be positively affected when particular agents are added to the compositions. Surprisingly, certain combinations of chelating agents and reducing agents in liquid compositions comprising pharmaceutical actives improve the stability of the active in such compositions. The compositions of the present invention provide excellent supply of oral product forms. These compositions also demonstrate excellent shelf life when incorporated into a variety of these oral product forms including elixirs, liquid filled tablets, metered liquid dosage devices, sprays and edible capsules that release liquid. Such compositions are particularly useful for treating symptoms associated with respiratory diseases. What has not been understood so far is that after careful and diligent research into the pharmaceutical, therapeutic, and side effects of active compounds, compositions can be made to positively improve the therapeutic effect without increasing side effects or toxicity. These compounds have improved stability in the form of product that is selected to deliver such compositions. This advantage is achieved by adding agents that promote the stability of the active in the formulation to the active-containing formulation. These agents are effective in reducing and even eliminating instability due to the degradation pathways of the oxidation of the active, * 5 which extends shelf life of the compositions. Therefore, one purpose of the present invention is to provide improved compositions for treating symptoms associated with respiratory diseases, particularly minimizing coughing attacks. A particularly preferred composition is in the form of liquids 10 hydrophilic anhydrides in a very stable environment for the rapid supply of active ingredients including antitussives; antihistamines (including non-sedating antihistamines); decongestants; expectorants; mucolytics; analgesics, antipyretic and anti-inflammatory agents and local anesthetics to treat the symptoms of respiratory diseases. The compositions can be 15 dose using a variety of product forms and, or packaging supply options. The compositions of the present invention provide desired activity while minimizing the potential side effects of the active compounds. It is also a purpose of the present invention to provide methods to achieve the rapid transmucosal delivery of 20 compositions mentioned above.

Definitions and Terms The following are definitions of terms found in this specification: 1. Transmucosal supply: It refers to the application of drugs to the mucous membranes of the oral cavity, including the buccal (cheeks), lips, gums, palate, and tongue, with the objective of passing the medication through the skin covering these places and enter the bloodstream. 2. Therapeutic dose This refers to the amount of the substance that when administered to a person in the appropriate form, will produce the desired effect within the body with minimal unwanted side effects. 3. Active / Pharmaceutical Active: It refers to the chemical molecule that exerts the desired effect on the body, when it is administered in the appropriate amount and form. 4. Active metabolites It refers to the chemical species of the pharmaceutical active on the active sustained metabolism.

U? F * k ^ f fi * 5. Monomolecular dispersion This refers to the fact that the active molecules are free and have no impediment to diffusion by association in crystalline or amorphous solid forms, or polymolecular association. 6. % Solubility value refers to the limit of solubility in equilibrium or maximum solubility of a molecule in a solvent at usual room temperature, which is expressed as the percentage by weight of the molecule in the composition. 7. Anhydride solvent Refers to solvents that contain less than 5% water.

DETAILED DESCRIPTION OF THE INVENTION Pharmaceutical Assets The compositions of the present invention comprise pharmaceutical actives which are also referred to herein as "active" to treat diseases, particularly symptoms associated with respiratory diseases such as influenza, influenza as well as allergy. These assets are most often used to treat the most problematic symptoms including a stuffy nose and runny nose, pain and swelling in the nose and throat, coughing fits, general body aches, fever, and headache; see U.S. Patent 5,196,436, Smith, issued May 23, 1993, which is incorporated herein by reference. In the present invention, when combining active ingredients with certain materials in formulations for the supply of the active ingredient, the use of particular materials to increase the long-term stability of the formulation is an important advantage. In a stable formulation, the assets are efficiently supplied to produce a positive effect. The composition comprises a pharmaceutical active and a stabilizing material together with other ingredients that are commonly known for making a composition for the delivery of the aforementioned active ingredients. In a particularly preferred embodiment the composition comprises a solvent which is an anhydrous, hydrophilic, water-miscible solvent wherein the pharmaceutical active in its non-ionized form has a percentage of solubility value in the solvent at room temperature which is equal to or greater than 0.075% and the pharmaceutical active is in its un-ionized free form as a monomolecular dispersion in the solvent. Preferred pharmaceutical actives of the present invention have a molecular weight of less than 500 grams per mole, can be ionized when they are in an aqueous solvent and have an octanol-water partition coefficient when they are in the non-ionized form of at least 100. The octanol-water partition coefficient is revealed in A. Martín, P Bustamante, and AHC Chun, Phvsical Pharmacv, Fourth Edition, Lea and Febiger editors, Philadelphia, 1993, page 237, which is incorporated herein by reference. The assets comprising the compositions of the present invention include active ingredients that fall into at least one of the following pharmacological classifications: antitussives; antihistamines; non-sedating antihistamines; decongestants; expectorants; mucolytic agents, analgesics, antipyretics, anti-inflammatories, local anesthetics and mixtures thereof. References describing the use of such assets include JG Hardman, The Pharmacoloqic Basis of Therapeutic, Ninth Edition, McGraw-Hill, New York, 1995. Among the assets that fall within one of these pharmacological classifications with those that are suitable to be absorbed through the mucous tissues. These assets can be used individually or in combination with other assets not necessarily absorbed in this way and can be formulated with existing formulation techniques. When using assets whose purpose is mucosal absorption, the active concentration in the solvent portion of the composition is preferably less than 125% of the percentage of solubility value, more preferably less than or equal to the percentage of solubility value of the pharmaceutical active . To maximize the advantages of the compositions of the present invention, the active is preferably in solution as a monomolecular dispersion. The useful absorbed assets * \ 'Sf ^ A .--. in the present invention they are present in the solvent system at a level of 0.075% to 25.0%, approximately, preferably from 0.28% to 10.0%, approximately of the composition. It is preferred that the above-mentioned active is in its un-ionized free form as a dispersion * 5 monomolecular in the aforementioned solvent system. In cases where there are either salt forms or ionized forms of the medicament active, it is preferred to use the free form without charge (not salt) of the medicament in the present invention. The antitussives are active of use particularly to stop 10 attacks of uncontrollable cough. Antitussives useful in the present invention include, but are not limited to, the group consisting of codeine, dextromethorphan, dextrorphan, diphenhydramine, hydrocodone, noscapine, oxycodone, pentoxiverin, and mixtures thereof. Of these antitussives, dextromethorphan is preferred. It is known that dextromethorphan has activity Pharmacological as an antitussive agent and is described in U.S. Patent 5,196,436, Smith; which is incorporated in the present invention as a reference. As used in the present invention, "Dextromethorphan" means racemetorphan, 3-methoxy-17-methylmorphinan (dl-cis-1, 3,4,9, 10,10a-hexahydro-6-methoxy-11-methyl-2H-10, 4a-iminoethane-phenanthrene and its salts 20 pharmaceutically acceptable. The compositions of the present invention comprising dextromethorphan preferably comprise 0.1% a 9. 3%, approximately, more preferably from 0.26% to 6.2%, approximately, and more preferably still from 1.16% to 4.6%, iúiá *? t¿u * * > ~ j ^^ * ¿¥ ~ - * 'approximately, dextromethorphan. Other safe and effective amounts of other cough / flu drug assets can be included in such compositions containing dextromethorphan. Antihistamines useful in the present invention include, but are not limited to the group consisting of acrivastine, azatadine, brompheniramine, chlorpheniramine, clemastine, cyprohetadine, dexbrompheniramine, dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, meclizine, feninamine, phenyltoloxamine, promethazine, pyrilamine, tripelenamine. , triprolidine and hedge mixtures. Non-sedating antihistamines useful in the present invention include, but are not limited to, the group consisting of astemizole, cetirizana, ebastine, fexofenadine, loratidine, terfenadine, and mixtures thereof. Decongestants useful in the present invention include, but are not limited to, the group consisting of phenylpropanolamine, pseudofedrine, ephedrine, phenylephrine, oxymetazoline, and mixtures thereof. Expectorants useful in the present invention include, but are not limited to, the group consisting of ammonium chloride, guaifenesin, ipecac liquid extract, potassium iodide, and mixtures thereof. Mucolytics useful in the present invention include, but are not limited to, the group consisting of acetylcysteine, ambroxol, bromhexine and mixtures thereof. Analgesics, antipyretics and antiinflammatory agents useful in the present invention include, but are not limited to the group consisting of acetaminophen, aspirin, diclofenac, diflunisal, etodolac, fenofropene, flubiprofen, ibuprofen, ketoprofen, ketorolac, nabumetone, naproxen, piroxicam, caffeine and mixtures of these. Useful local anesthetics in the M? Í.Íl? . ^ .. *. + * Sflfc-present invention include, but are not limited to the group consisting of lidocaine, benzocaine, phenol, dyclonine, benzononate and mixtures thereof.

Solvents 5 The non-ionized form of the pharmaceutical active is maintained using a selected group of solvents. The solvent portion of the compositions of the present invention comprises from 60% to 99.975%, approximately, preferably from 70% to 99%, and even more preferably from 85% to 98%, approximately, by weight of the 10 composition. The solvents of the present invention are usually liquid at room temperatures. The solvents are soluble in water or miscible in water. The solvents of the present invention are preferably selected from the group consisting of propylene glycol, ethanol, poly (ethylene glycol) or PEG, propylene carbonate, diethylene glycol monoethyl ether, poloxamer, glycofurol, glycerol, polyvinyl pyrrolidone (PVP), Transcutol ™ ( 2- (2-ethoxyethoxy) ethanol), Lauroglycol 90 ™ (fatty acid esters and propylene glycol), Labrasol ™ (glyceryl and polyethylene glycol esters), Capryol 90 ™ (propylene glycol monocaprylate) and mixtures thereof, all available from 20 Gattefosse SA. Company of 69804 Saint Priest Cadex, France. Propylene glycol and ethanol is particularly preferred. Mixtures of these solvents exist which are particularly preferred for certain product forms of the present invention. For example, in case the product form is an elixir, a liquid capsule or a tablet containing liquid, the solvent is a combination of propylene glycol, ethanol, and PEG. In case the product form is an atomizer, the solvent is a combination of propylene glycol, ethanol, PEG and usually propylene glycol. The level of each solvent that these mixtures conform depends partially on the aesthetic advantages sought by the formulator. More preferred are the anhydride forms of the aforementioned solvents.

Chelating Agents The addition of chelating agents has been found to have an advantageous chemical stabilizing effect on the active compounds comprising the present invention. These phenomena surprisingly occur where the chelating agent is present in a phase of the composition other than the phase of the composition containing the active. For example, where the active is soluble in a non-polar environment or phase of the composition, the chelating agent that is selected must be a polar phase, such as water. Therefore, despite being in separate phases, the chemical stability of the asset is still positively affected. The same stability advantage is not observed when the active and the chelating agent with cosolubles in the solvent. Therefore, the chelating agents useful in the composition depend on the active that is selected and its solubility. Chelating agents useful in the present invention include those that chelate transition metal ions such as iron, copper, I would like to mention the ALbn, Tf? einc and other such metals. Without being limited by theory, it is reasonable to postulate that metal cations play an important role in the formation of oxidizing species. The reactions that produce free radicals include the transfer of electrons by oxidation reduction cycles between two different valence stages. Trace amounts of heavy metal ions frequently catalyze autooxidation reaction. In fact, an amount as small as 0.05 ppm of metal ions may be sufficient to initiate oxidation and increase the rate of propagation of the chain reaction. See W. Jund, The Pharmaceutical DODEX, 12th 10 Edition, pages 287 and 290, The Pharmaceutical Press, 1994, which is incorporated herein by reference. It has been found that chelating agents reduce the ease of electron transfer reactions between these valence stages. This characteristic of chelating agents quenches the reactions of 15 autooxidation. This may explain why chelating agents are effective in protecting pharmaceutical active ingredients. The speed and magnitude of the oxidation is known to be greater at alkaline pH values than acid pH. This may be due in part to what appears to be a mauro tendency of divalent cations to catalyze oxidation reactions in an alkaline medium. See, 20 Townsend M, W. and Byron P.R. "The Effect of Formulation Additives on Degradation of Freeze-Dried Ribonuclease A", Pharmaceutical Research Vol. 7, No. 10, pages. 1086-1091 (1990). It has been found that several different drug compounds have nitrogen in their chain üüft i? Má? ¡u? í¡it, Í? m imhÉif i "" lateral are stabilized by EDTA; see Fog A.G. & Summan A.M. It was shown that EDTA is effective in stabilizing acetamido groups in drug coloring compounds and foods of light degradation when in the presence of ascorbic acid; Journal of Pharmacoloqv and 5 Therapeutics, Vol. 17, pages. 107-109 (1992). The chelating agents useful in the present invention are stable and effective in aqueous medium and in the pH range between 5 and 12. Preferred agents are selected from the group consisting of disodium and calcium salts of ethylenediaminetetraacetic acid (EDTA), EDTA tetrasodium, 10 hexa sodium metaphosphate (SHMP), citric acid, phosphoric acid, Di (hydroethyl) glycine, 8-hydroquinoline and mixtures thereof. The level of chelating agents useful in the present invention depends on the loading of metal ions that are likely to be introduced into the formulation via the contamination of the ingredients. In the present invention, the chelating agents are useful at levels of from 0.005% to 1000%, approximately, preferably from 0.150% to 0.050%, approximately, and more preferably from 0.300% to 0.010%, approximately, by weight of the composition. 0 Reduction Agents It has been observed that when a reducing agent is in the presence of the chelating agent of the present invention as described above, the reducing agent has a significantly increased shelf life. This is the case even when the chelating agent is at low levels, as low as 0.001%, in the formulation. Extended shelving life translates into an improvement in terms of the effectiveness of the reducing agent as an antioxidant over a prolonged period. Without being limited by theory, it is believed that the reduction reaction (oxidation of the reducing agent) takes a different course when the chelating agent is present. In the presence of chelating agent, the initiation process must depend on the generation of superoxide radicals while in the absence of chelating agent radicals other than 02 ° (oxidizing species) will be involved as initiation species. Therefore, chelating agents are able to play a double role in aerobic oxidation. The same complex with trace metals that can catalyze spontaneous oxidation and thus change the mechanism of initiation. It can also act as a chain breaker by purifying the oxidizing radicals that propagate the reaction chain. Therefore, the chemical stabilizing effect of the reducing agent on the active compounds comprising the present invention is dramatically increased. These phenomena surprisingly occur where the asset is in a different phase to the reduction agent. For example, where the active is soluble in a non-polar environment or phase of the composition, the selected reducing agent must be soluble in a polar phase, such as water. Therefore, despite being in separate phases, the chemical stability of the asset is still positively affected. The same stability advantage is not observed when the active and the reducing agent are cosolubles in the solvent. Therefore, the reducing agents useful in the composition depend on the selected active and its solubility. Reduction agents are substances that have a lower reduction-oxidation potential than the drug or adjuvant that are intended to protect against oxidation. In this way the oxidation agents oxidize more quickly than the drug or adjuvant and are effective in the presence of oxidation agents. See, W. Jund, The Pharmaceutical DODEX, Twelfth Edition, page 290, The Pharmaceutical Press, 1994, which is incorporated herein by reference. The reducing agents of the present invention have an electrode potential value. This is defined by the Nemst equation and is measured using virtually normal electrochemical reference cells. The resulting values are therefore called the Normal Voltage of an Electrode, of E ° as measured in volts of (V). The comparison of the normal voltages of an electrode for different substances can be used to evaluate the effectiveness of different reduction agents; see Wells, Pharmaceutical Preformulation, Ellis Horwood Limited Publishing, 1988, pages 168-172; which is incorporated in the present invention as a reference. The reducing agents useful in the present invention have an E ° value greater than -0.119V, preferably from -0.119V to + 0.250V, approximately. The preferred reducing agents are selected from the group consisting of the salts of matabisulfite and bisulfite, including their sodium and potassium salts, ^. ^ ^ Jk ^ i ?? i to j ii dithiothreitol, thiourea, sodium thiosulfate, thioglycolic acid, tertbutyl hidroquinonina (TBHQ), acetyl cysteine, hidroquinonina and mixtures thereof. The level of reducing agents useful in the present invention is from 0.005% to 1,000%, approximately, preferably from 0.0500% to 0.500%, approximately, and more preferably from 0.010% to approximately 0.200%, by weight of the composition. The reducing agent protects the pharmaceutical active in the invention from degradation by acting as a donor oxidizing compound that sacrifices itself to oxidation rather than the same active. Chelating agents also allow some practical protection through the chelation of ions that are present in the formulation ingredients including flavorings, sweeteners and refreshing as well as potential metal ion migration packaging materials. In the absence of such metal ions, there is little or no generation of oxy and peroxy radicals generated by metal catalysis. This results in the stabilization of pharmaceutical assets. Although the additive effect of using any reducing agent and chelating agents together may not be surprising, the advantages found using these particular reducing agents are surprising. Additionally, the advantages that are observed by using levels of chelating agents in excess of those required to chelate all metal ions in a system that does not continuously generate metal ions are also surprising. Even when it is not the desire to being limited by theory, it is believed that in the presence of an excessive level of a chelating agent such as EDTA, the degradation of a reducing agent such as metabisulfite is surprisingly delayed. Sustaining the presence of the reducing agent in the composition of the present invention serves to preserve higher levels of pharmaceutical actives in that composition.

Optional Ingredients Water can be used in the compositions of the present invention. In the present invention the maximum level of water is about 10%, preferably about 1% to about 10%, more preferably about 5% to about 10%, or even more preferably about about 5% to about 8% by weight of the composition. Ingredients that are normally associated with medicaments for the treatment of influenza and influenza can be used with the pharmaceutical actives disclosed in the present invention. Such ingredients are disclosed in U.S. Patent 5,196,436, which is incorporated herein by reference. Additionally, the following ingredients can be used in the present invention: Buffers and mixtures of buffering agents, including basic buffers as single components with pKa of 8 to 11 including triethanolamine, salts of amino acids, including alkaline salts of glycine, glycylglycine, glutamine or other amino acids, alkaline salts of phosphate, carbonate and mixtures of these. Buffers provide resistance of the composition to pH changes upon dilution of the composition with saliva within the range of 7 to 10, preferably 8 to 10. Sweeteners, including aspartame, saccharin and its salts, Sucralose ™ (sold by McNeil Specialty Products Co. ., New Brunswick, NJ, USA); Prosweet ™ (marketed by Virginia Daré Extract) Co., New York, NY, USA); Magnasweet ™ (marketed by MAFCO Worldwide Corp., Licorice Division, Camden, NJ, USA); Ammonium glycocircirate, its salts, Talin ™ (Thaumatin) and its diluted products, such as Talin GA90, (marketed by Talin Food Company, Birkenhead, England); and Acesulfame K, and mixtures of these. In view of the fact that the products made with sweeteners are consumed orally, it is preferable that such products as tablets use sweeteners that are free of sugar, or non-cariogenic. This means that the sweetener will not be metabolized by cariogenic bacteria in the oral cavity and therefore can not generate an acidic environment. In case this is not possible, then the products can be formulated to contain an alkaline buffer with a pKa greater than 7, preferably 9 for preconditioning the oral cavity. The flavors include anise, spearmint oil, clove oil, eucalyptus, lemon, lime, honey lemon, red fruit, grapefruit mint, orange, cherry cola and mixtures of these. Feeling agents. Also useful in the present invention are the sensing agents which are selected from the group consisting of cooling agents, salivating agents, heating agents. Preferably these agents are present in the compositions at a level of from 0.001% to 10%, approximately, preferably from 0.1% to 1%, by weight, of the composition. Suitable cooling agents and heating agents include carboxamides, menthols, thymol, camphor, chilli, phenol, eucalyptus oil, benzyl alcohol, salicylic alcohol, ethanol, clove oil, and hexyl resorcinol, ketals, diols, and mixtures thereof . Preferred heating agents include thymol, camphor, chili, phenol, benzyl alcohol, salicylic alcohol, ethanol, clove oil, and hexylresorcinol, nicotinate esters such as benzyl nicotinate, ketals, diols, and mixtures thereof. Preferred cooling agents are the paramentane-carboxamide agents such as N-ethyl-p-menthane-3-carboxamide (WS-3 supplied by Sterling Organics), taught by US Pat. No. 4,136,163, issued January 23, 1979. , to Watson et al., which is incorporated herein by reference in its entirety. Preferred cooling agents are the paramentane-carboxamide agents such as N-2,3-trimethyl-2-isopropyl-butanamide, which is known as "WS-23", and mixtures of WS-3 and WS-23. Additional preferred cooling agents are selected from the group consisting of menthol, 3,1-methoxypropane-1,2-diol, which is known as TK-10 supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan, menthone glycerol acetal known as MGA, manufactured by Haarmann & Reimer, menthyl lactate known as Frescoiat® manufactured by Haarmann & Reimer, and mixtures of these. Additional cooling agents include cyclic sulfones and sulfoxides and others, all are described in U.S. Patent 4,032,661, issued June 28, 1977, to Rowsell et al., Which is incorporated herein by reference. The terms "menthol" and "menthyl" as used in the present invention include dextroisomers and levorotatory isomers of these compounds and racemic mixtures thereof. TK-10 is described in detail in U.S. Patent 4,459,452, issued July 10, 1984, to Amano et al., Which is incorporated herein by reference. Salivating agents of the present invention includes Jambu® manufactured by Takasago Perfumery Co., Ltd., Tokyo, Japan.

Method of use The supply of drugs in the bloodstream by placing a dosage form inside the mouth can be classified into two main subclasses depending on the desired action. In a case where the drug is delivered into the blood, absorption occurs after swallowing (i.e., of the stomach, small intestine or colon) and in the other case where absorption, or a percentage '^ S ^ -1' significant of the absorbency occurs through the membranes of the oral cavity or immediately or by way of prolonged periods of time due to the retention of the drug by mucoadhesive materials. This pathway is usually referred to as "oral" or "oral mucosa" absorption versus the anterior * 5 classically called the peroral route. The peroral route of drug administration is by far the most commonly used in all medicine, has been well studied, and is explained in detail in: Mayerson, M., Principies of Drug Absorption; Chapter 2 in "Modern Pharmaceutics", Second Edition., G.S. Banker and C.T. Rhodes, editors, 10 Marcel Dekker Inc., New York. 1990. From the point of view of the methods of supply of the asset, it is generally accepted that the oral mucous supply to the inside of the mouth must be directed to the sublingual region with the purpose of achieving a very fast therapeutic effect; see D. Harris and J.R. Robinson, Druq Delivery via the 15 Mucus Membranes of the Oral Cavity, "Journal of Pharmaceutical Sciences" 81: 1, 1992. Such dosage forms are designed to be placed under the tongue, on the floor of the mouth, and held there for a prolonged period of time . However, the inventors have discovered that a large increase in bioavailability with very rapid absorption is 20 can achieve when the present compositions are placed against any of the mucous membranes of the mouth, even on the tongue and swallowed. g | * jj The form of the invention is a solution of liquid elixir. The solution of liquid elixir has the purpose of being applied to any of the mucous membranes inside the mouth. This can be accomplished by using a dropper of medicine that can be calibrated to indicate the appropriate amount to be administered, and is squirted on the tongue before swallowing. The elixir can be applied as an atomization to the inside of the mouth and throat and then swallowed. It can be encapsulated in some type of shell that makes it portable and convenient to transport and administer without having to measure the amount of liquid elixir. Examples of encapsulating shells include hard confections such as those used for pills, chewing gums, gelatin, or shells that do not contain gelatin (see, based on starch). The elixir can be packed in a small disposable bottle that can be easily opened and squirted into the mouth, the entire bottle contains exactly one therapeutic dose. Typical dosage forms of the composition of the present invention contain an amount of not more than about 3 ml, preferably from 0.2 ml to 3 ml, approximately. A preferred way is to encapsulate the liquid inside a confectionery shell or hard gelatin. The shell contains substances to pretreat the mucosa thereby increasing the absorption of the liquid center asset. Pretreatment occurs by sucking or chewing the shell material, and the advantage is obtained by separating the treatment of the mucosa over time, which occurs first, followed by the presentation of the active to be absorbed. Examples of substances for pretreatment of the mucous membranes are membrane penetration enhancing agents that are commonly known in the art, examples include menthol, spearmint oil, surfactants such as polysorbate 80 or poloxamer. Another example of a mucous membrane pretreatment are buffers as detailed above, which precondition the pH of the salivary microenvironment on the scale of 8 to 11.

EXAMPLES EXAMPLE I Liquid Elixir Total 100.00 1 Acesulfame K available from Nutrinova Ine Company of Somerset, NJ 08873, USA. 2 TK 10 available from Takasago Company of Rockleigh, NJ 07657, USA. A portion of ethanol is added to the active (Dextromethorphan Base) and solid sweetening agents (Sucralose, Monoammonium glycyrrhizinate) and mixed continuously at low temperature (30 ° C). Propylene glycol and liquid sweeteners (Pro-sweet Liquid K) are added to this vessel. The chelating agent (disodium EDTA), reducing agent (sodium metabisulfite) and water are combined together and mixed until uniform. The mixture is added to the container and mixed for about 2 hours. A premix of flavoring and coloring agents and the remaining portion of ethanol is added, and added to the container containing the nearly finished solution. Mix until a homogeneous solution is obtained. The composition is allowed to remain in the mixing vessel, open to the atmosphere for about 10 minutes. It is filtered through a US # 100 mesh screen (product density = 1.07 g / ml). It is poured into amber glass bottles, and covered with an integrated calibrated medicine cap / dropper assembly. 1.5 ml approximately of the elixir is placed in drops on the tongue and then swallowed. Dextromethorphan is rapidly absorbed into the blood.

Pour into amber glass bottles, and cover with an integrated lid / medicine dropper set. 1.5 ml approximately of the elixir is placed in drops on the tongue and then swallowed. Dextromethorphan is rapidly absorbed into the blood.

EXAMPLE II Liquid Elixir Total 100,000 A portion of ethanol is added to the active (Dextromethorphan Base) and solid sweetening agents (Sucralose, Glycyrrhizinate Monoammonium) and mixed continuously at low temperature (30 ° C) To this vessel is added Propylene glycol, liquid sweeteners (Pro-sweet Liquid K), and buffer (Triethanolamine, a liquid). Add disodium EDTA, mix, open to the atmosphere "for about 10 minutes, mix until a homogeneous solution is obtained, filter through a US # 100 mesh screen (product density = 1.07 g / ml). in amber glass bottles, and covered with an integrated medicine cap / medicine dropper set, approximately 1.0 ml of the elixir is placed on the tongue and then swallowed.Dextromethorphan is rapidly absorbed into the blood.

EXAMPLE III Liquid Atomization Total 100,000 1. Green Shade CSL-15689 is obtained from Warner Jenkins Co., St. Louis, MO, USA. A portion of propylene glycol is added to the active (Dextromethorphan Base) and solid sweetening agents (Sucralose, Monoammonium glycyrrhizinate) and mixed continuously at low temperature (30 ° C) To this vessel is added propylene glycol and additional liquid sweeteners (Pro-sweet Liquid K). Dissolve sodium hexametaphosphate (SHMP) and sodium thiosulfate in water and mix until clear. The mixture is added to the container and mixed until all the materials are in solution, approximately 2 hours of time. A premix of flavorings and colorants is added to the remaining portion of the ethanol, and added to the container containing the nearly finished solution. Mix until a homogeneous solution is obtained. The composition is allowed to remain in the mixing vessel, open to the atmosphere for about 10 minutes. Mix until a homogenous solution is obtained, and filter through a US # 100 mesh screen (product density = 1.075 g / ml). It is filled in a manually operated pump and spray bottle. An example is Calmar-Albert GMBH, the Mark II Mistette equipped with a 16 mm high viscosity head assembly that delivers 0.2 ml / activation. Three individual activations are sprayed into the mouth. Dextromethorphan is rapidly absorbed into the blood, and during the action of spraying a certain portion of the sprayed liquids they contact the throat area, providing additional benefit such as numbness of cough receptors irritated there.

UM?? -M t **. Íí * ?. - ,. Mine * EXAMPLE IV Liquid Atomization Total 100,000 a portion of Ethanol to the active (Dextromethorphan Base) and solid sweetening agents (Sucralose, monoammonium glycyrrhizinate) is added and continuously mixed at low temperature (30 ° C) To this vessel Propylene Carbonate and further Propylene glycol is added, liquid sweeteners (Pro-sweet Liquid K), reducing agent and buffer (Triethanolamine, a liquid). Mix until all the materials are in solution, approximately a period of time of approximately 2 hours. The composition is allowed to remain in the mixing vessel, open to the atmosphere for about 10 minutes. A premix of flavorings and colorants is prepared in the remaining portion of ethanol, and added to the container containing the nearly finished solution. Mix until a homogenous solution is obtained, and filter through a US # 100 mesh screen (product density = 1.075 g / ml). It is filled in a manually operated pump and spray bottle. An example is Calmar-Albert GmbH, the Mistette Mark II equipped with a 16 mm high viscosity head assembly that delivers 0.2 ml / activation. Three individual activations are sprayed into the mouth. Dextromethorphan is rapidly absorbed into the blood, and during the action of spraying a certain portion of the sprayed liquids they contact the throat area, providing additional benefit such as numbness of cough receptors irritated there.

EXAMPLE V Pill with Liquid in the Center Total 100,000 ? I a portion of ethanol to the active (Dextromethorphan Base) and sweetening agents solids (Sucralose, monoammonium glycyrrhizinate) is added and continuously mixed at low temperature (30 ° C) To this vessel add the Propylene Glycol and liquid sweeteners (Pro -sweet Liquid K). Mix until all the materials are in solution, approximately a period of time of 2 hours. A premix of flavorings and colorants is prepared in the remaining portion of ethanol, sodium metabisulfite and water, and added to the container containing the nearly finished solution. The composition is allowed to remain in the mixing vessel, open to the atmosphere for about 10 minutes. Mix until a homogenous solution is obtained, and filter through a US # 100 mesh screen (product density = 1.07 g / ml). Individual filled pellets containing about 1.0 ml of liquid per pellet are made by a commonly used method such as extrusion. A person places a pill full of liquid in his mouth and sucks the pill until the fluid filling is released. You get some relief from coughing through the action of sucking on the pill's layer. When a certain fluid is released, dextromethorphan is rapidly absorbed into the blood.

EXAMPLE VI Pill with Liquid in the Center Total 100,000 1. Lauroglycol 90 available from Gattefosse SA. Company of 69804 Saint Priest Cedex, France a portion of ethanol to the active (Dextromethorphan Base) and solid sweetening agents (Sucralose, monoammonium glycyrrhizinate) is added and continuously mixed at low temperature (30 ° C) are added to this container the Propylene glycol esters of fatty acids and propylene glycol and liquid sweeteners (Pro-sweet Liquid K). An aqueous premix of sodium metabisulfite is prepared and added to the container. Mix until all the materials are in solution, approximately a period of time of 2 hours. A premix of flavorings is prepared and 1 * • * ^ -yir you! * "^ '^^^^^^ dyes in restfßte portion of ethanol, and added to the vessel containing the nearly completed solution. Allow the composition to remain in the mixing vessel , open to the atmosphere for about 10 minutes, mix until a homogenous solution is obtained, and filter through a US # 100 mesh screen (product density = 1.07 g / ml) Full filled tablets containing 1.0 ml are made approximately one fluid per pellet by a commonly used method such as extrusion.A person places a pill filled with liquid in his mouth and sucks the pellet until the fluid filling is released.There is some relief from the cough through the action of sucking on the layer of the tablet, when a certain liquid is released, dextromethorphan is rapidly absorbed into the blood, and cough relief is obtained before a 10 minute period of time.

EXAMPLE VII Liquid Elixir Total 100,000 1. Transcutol P available from Gattefosse SA. Company of 69804 Saint Oriest Cedex, France A portion of ethanol is added to the active (Dextromethorphan Base) and solid sweetening agents (Sucralose, Monoammonium glycyrrhizinate) and mixed continuously at low temperature (30 ° C) To this vessel the volume is added of propylene glycol, 2- (2-ethoxyethoxy) -ethanol, Guaifenesin and liquid sweeteners (pro-sweet Liquid K), and buffer (Triethanolamine, a liquid). Mix until all the materials are in solution, approximately 2 hours of time. A premix of flavorings and colorants is prepared in the remaining portion of water and ethanol as well as also the sodium EDTA and sodium ros tffjisulfite and it is added to the container that contains the solution almost finished. Mix until a homogenous solution is obtained, and filter through a US # 100 mesh screen (density of the i ?! product = 1.07 g / ml). It is poured into amber glass bottles, and covered with a 5 integrated set of calibrated medicine cap / dropper. 1. 0 ml approximately of the elixir is placed in drops on the tongue and then swallows.

EXAMPLE VIII 10 Liquid Elixir fifteen Total 100,000 0 A portion of ethanol is added to the active (Chlorpheniramine base and Pseudoephedrine Base) and solid sweetening agents (Sucralose, Monoammonium Glycyrrhizinate) and mixed continuously at low temperature (30 ° C) To this vessel is added the volume of propylene glycol, liquid sweeteners (Pro-sweet Liquid K), di (hydroxyethyl) ) glycine and buffer (triethanolamine, a liquid). Mix until all the materials are in solution, approximately 2 hours of time. A premix of flavorings and colorants is prepared in the propylene glycol, disodium EDTA, sodium metabisulfite and the remaining portion of ethanol, and added to the container containing the nearly finished solution. Mix until a homogenous solution is obtained, and filter through a US # 100 mesh screen (product density = 1.07 g / ml). It is poured into amber glass bottles, and covered with an integrated calibrated medicine cap / dropper assembly. About 1.0 ml of the elixir is placed in drops on the tongue and then swallowed. Chlorpheniramine and pseudoephedrine are rapidly absorbed into the blood. lajA * * t? ** & ** > * .. ^ iiá ut ^^ ». ***» **! * ^ 1 lÉTfirlÉlitirníírai ÉÉiJ '"m ^ EXAMPLE IX Liquid Elixir 10 Total 100,000 1 PVP-K17PF available from BASF Corp. 15 Dextromethorphan Base and Pseudoephedrine Base are dissolved in alcohol portion to make a premix. In a separate container, the propylene glycol is heated to about 70 ° C. As soon as the material melts and a clear liquid forms, Acetaminophen is added and heating is continued to 110-120 ° C with continuous mixing action. 20 It is removed from the heat as soon as the liquid is clear. It is cooled to room temperature. The mixture is added to the premix of Dextromethorphan and Pseudoephedrine. Liquid sweetener (Pro-sweet Liquid K) and buffer (Triethanolamine) are also added.

Mix until all the materials are in solution. A premix of flavorings and colorants is prepared in the remaining portion of alcohol and disodium EDTA and sodium metabisulfite is added to the container containing the nearly finished solution. The composition is allowed to reside in the mixing vessel, open to the atmosphere for about 10 minutes. Mix until homogenous, and filter through a US # 100 mesh screen. Fill in amber glass bottles, and cap with an integrated calibrated medicine cap / dropper assembly. 1.84 grams approximately of the elixir is placed by drops on the tongue and then swallowed.

EXAMPLE X Liquid Elixir Total 100.00 Dextromethorphan Base is dissolved in alcohol portion to make a premix. EDTA is added in a separate container JÁlál¡L¿? * UAÍ? **. ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡Ã?? M Sodium metabisulfite to water and mixed until uniform. This mixture is added to the premix of Dextromethorphan Base. Mix until all the materials are in solution. The remaining portion of alcohol is added. The composition is allowed to reside in the mixing vessel, open to the atmosphere for approximately 10 minutes. Mix until a homogenous solution is obtained, and filter through a US # 100 mesh screen. Fill in amber glass bottles and cap with an integrated calibrated medicine cap / dropper assembly. 1.84 grams approximately of the elixir is placed by drops on the tongue and then swallowed.

EXAMPLE XI Liquid Elixir Total 100.00 1 See examples mentioned above Dextromethorphan Base is dissolved in alcohol portion to make a premix. In a separate container EDTA and sodium metabisulfite are dissolved in water. Mix until uniform and cool to room temperature. This mixture is added to Dextromethorphan Base. Mix until all the materials are in solution. The remaining portion of alcohol, EDTA and cosmetic packaging is added to the container containing the nearly finished solution. The composition is allowed to remain in the mixing vessel, open to the atmosphere for about 10 minutes. Mix until a homogenous solution is obtained, and filter through a US # 100 mesh screen. Fill in amber glass bottles and cap with an integrated calibrated medicine cap / dropper assembly. 1.5 grams approximately of the elixir is placed by drops on the tongue and then swallowed.

EXAMPLE XII Soft chewable gelatin capsules Total 100,000 1 See above-mentioned examples 2 Labrasol available from Gattefosse SA. Company of 69804 Saint Priest Cedex, France Dextromethorphan Base is dissolved in portions of alcohol to make a premix. In a separate container, the water and disodium calcium EDTA are heated to approximately 70 ° C. Acetaminophen is added and heating is continued at 110-120 ° C with continuous mixing action. It is removed from the heat as soon as the liquid is clear. It is cooled to room temperature. The mixture is added to the mixture of Dextromethorphan and Pseudoephedrine until uniform and cooled to room temperature. Mix until all the materials are in solution. The portion is added t i * 1 'i? J *? 2? i ^ jj¿ í ^^ ¿& g ^ ¿f | remaining alcohol, polyvinylpyrrolidone, sodium metabisulfite, glyceryl and polyethylene glycol esters and the aesthetic packaging to the container containing the almost finished solution. The composition is allowed to remain in the mixing vessel, open to the atmosphere for about 10 minutes. Mix until a homogeneous solution is obtained, and filter through a US # 100 mesh screen. Chewable soft gelatine capsules are filled using the aforementioned formulation. The aforementioned gelatin capsules are available in the market of companies such as R.P. Scherer, of St. Petersberg, Florida, USA. 1.84 grams approximately of the elixir is supplied to the mouth when chewing the capsule (s) and then swallowed.

EXAMPLE Xlll Soft chewable gelatin capsules Total 100,000 1 See Examples mentioned above Dextromethorphan Base is dissolved in portions of alcohol to make a premix. In a separate container, water, sodium metabisulfite, and disodium calcium EDTA are mixed until transparent. It is cooled to room temperature. Dextromethorphan is added. Mix until uniform and cool to room temperature. Mix until all the materials are in solution. The remaining portion of alcohol and the cosmetic packaging is added to the container containing the nearly finished solution. The composition is allowed to remain in the mixing vessel, open to the atmosphere for about 10 minutes. Mix until a homogeneous solution is obtained, and filter through a US # 100 mesh screen. Chewable soft gelatine capsules are filled using the aforementioned formulation. The aforementioned gelatin capsules are available in the market of companies such as R.P. Scherer, of St. Petersberg, Florida, USA. 1.84 grams approximately of the elixir is supplied to the mouth when chewing the capsule (s) and then swallowed.

EXAMPLE XIV Liquid Elixir Total 100,000 1 Carbowax 400 available from Union Carbide Dextromethorphan and phenol are added to the propylene glycol with shaking action. It is added in increments with the action of stirring the plietilenglicol, alcohol, flavorings, and sodium saccharin. Sodium phosphate monobasic is added as a 10% solution in purified water with shaking action. The dye is added as a solution in water with stirring action. The sodium metabisulfite is dissolved in the remaining amount of water and added, with the action of stirring to the final volume.

EXAMPLE XV Liquid Elixir Total 100,000 1 Carbowax 400 available from Union Carbide Dextromethorphan and phenol are added to the propylene glycol with shaking action. It is added in increments with the action of stirring the plietilenglicol, alcohol, flavorings, and sodium saccharin. Sodium phosphate monobasic is added as a 10% solution in purified water. The dye is added as a solution in water with stirring action. The sodium metabisulfite is dissolved in the remaining amount of water and added, with the action of stirring to the final volume.

EXAMPLE XVI Liquid Elixir Total 100,000 1 Poloxamer (Pluronic F127) available from BASF Specialty Chemicals, Mount Olive, N.J.

PREPARATION The propylene glycol and poloxamer is added to a clean container (main mixture), the mixture is heated as appropriate to sufficiently fuse the poloxamer. As soon as a uniform solution is obtained, it is removed from the heat source and the mixing action is continued. In a separate vessel (alcohol premix), alcohol, dextromethorphan base and monoammonium glycyrrhizinate are added and mixed until uniform. In another container (water premix), water, EDTA, sodium saccharin, acesulfame, and sodium metabisulfite. Mix until all the materials dissolve. The premix containing alcohol is added to the main mixing vessel containing poloxamer. Mix until uniform. While stirring, the premix containing water is added to the main container and mixing is continued until uniform. Subsequently, the desired flavor component is added and mixed until uniform. Approximately 1.5 gm of liquid is delivered to the mouth through a suitable delivery device.

EXAMPLE XVII Liquid for Cough Treatment Total 100,000 1 Pluronic F127 available from BASF Specialty Chemicals, Mount Olive, N.J.

PREPARATION The propylene glycol and poloxamer is added to a clean container (main mixture), the mixture is heated as appropriate to sufficiently fuse the poloxamer. As soon as a uniform solution is obtained, it is removed from the heat source and the mixing action is continued. In a separate vessel (alcohol premix), alcohol, dextromethorphan base and monoammonium glycyrrhizinate are added and mixed until uniform. In another container (water premix), water, EDTA, sodium saccharin, acesulfame, and sodium metabisulfite are added. Mix until all the materials dissolve. The premix containing alcohol is added to the main mixing vessel containing poloxamer. Mix until uniform. While stirring, the premix containing water is added to the main container and mixing is continued until uniform. Subsequently, the desired flavor component is added and mixed until uniform. Approximately 1 gm of liquid is delivered to the mouth through a suitable delivery device.

EXAMPLE XVlll Liquid for Oral Administration Total 100,000 1 Pluronic F127 available from BASF Specialty Chemicals, Mount Olive, N.J.

PREPARATION The propylene glycol and poloxamer is added to a clean container (main mix). While stirring, the mixture is heated as appropriate to sufficiently fuse the poloxamer. As soon as a uniform solution is obtained, it is removed from the heat source and the mixing action is continued. In a separate vessel (alcohol premix), alcohol, dextromethorphan base and monoammonium glycyrrhizinate are added and mixed until uniform. In another vessel (water premix), water, Pseudoephedrine, HCl, EDTA, sodium saccharin, acesulfame, and sodium metabisulfite are added. Mix until all the materials dissolve. The premix containing alcohol is added to the main mixing vessel containing poloxamer. Mix until uniform. While stirring, the premix containing water is added to the main container and mixing is continued until uniform. Subsequently, the desired flavor component is added and mixed until uniform. Approximately 1 gm of liquid is delivered to the mouth through a suitable delivery device.

EXAMPLE XIX Liquid for Cough Treatment Total 100.00 Dextromethorphan Base is dissolved in a portion of alcohol to make a premix. EDTA is added in a separate container Disodium and sodium metabisulfite in water and mix until uniform. This mixture is added to the premix of Dextromethorphan Base. Mix until all the materials are in solution. The remaining portion of alcohol is added. The composition is allowed to reside in the mixing vessel, open to the atmosphere for about 10 minutes. Mix until homogeneous, and filter through a US # 100 mesh screen. Amber glass bottles are filled, and capped with an integrated calibrated medicine cap / dropper assembly. 1.00 grams approximately of the elixir is applied in drops on the tongue and then swallowed or dosed appropriately varying the volume of the dose. l .MJ ^. ^ * ^ AUU

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A liquid composition, preferably an oral composition having improved stability characterized in that it comprises a pharmaceutical active, solvent for solubilizing the aforementioned active and a chelating agent that is present in a phase of the composition other than the phase of the composition containing the active mentioned above. 2. A liquid composition, preferably an oral composition characterized in that it has improved stability comprising a pharmaceutical active, solvent for solubilizing the aforementioned active agent, chelating agent and reducing agent having a value of E ° Electrode Potential greater than -0.119 V, preferably from -0.119V to + 0.250V, approximately. 3. A liquid composition, preferably an oral composition characterized in that it has improved stability comprising a pharmaceutical active, solvent for solubilizing the aforementioned active, chelating agent present in a phase of the composition different from that containing the aforementioned active and agent of reduction having a value of Electrode Potential E ° greater than -0.119V, preferably from -0.119V to + 0.250V, approximately **** 4.- The composition according to claims 1, 2 and 3, characterized in addition because the chelating agent and the reducing agent are active on a pH scale between 5 to 12 and in aqueous and non-aqueous solvent compositions. 5. The composition according to claims 1 to 4, further characterized in that the chelating agent is selected from the group consisting of the disodium and calcium salts of ethylenediaminetetraacetic acid (EDTA), tetrasodium EDTA, sodium hexametaphosphate (SHMP), citric acid, phosphoric acid, Di (hydroxyethyl) glycine, 8- hydroxyquinoline, And mixtures thereof, preferably a calcium or sodium salt of ethylenediaminetetraacetic acid (EDTA). 6. The composition according to claims 1 to 5, further characterized in that the level of chelating agent is from 0.005% to 1,000%, preferably from 0.050% to 0.150%, and more preferably 0.300% 15 to 0.010%, by weight of the composition. 7. The composition according to claim 2, further characterized in that the reducing agent is selected from the group consisting of the metabisulfite and bisulfite salts, including their sodium and potassium salts, dithioerythritol, thiourea, sodium thiosulfate, acid thioglycolic, 20-butylhydroquinone (TBC), acetylcysteine, hydroquinone and mixtures thereof, preferably the sodium and potassium salts of metabisulfite. 8. The composition according to claim 7, further characterized in that the reducing agent is at a level of 0. 005% to 1,000%, preferably from 0.050% to 0.500%, even more preferably 0.10% to 0.200%, by weight of the composition. 9. The composition according to claim 1 to 8, further characterized in that it comprises a pharmaceutical active in a water-miscible hydrophilic anhydride solvent wherein the pharmaceutical active in its non-ionized form has a percentage value of solubility at room temperature that is equal to or greater than 0.075% and the pharmaceutical active it is in its un-ionized free form as a monomolecular dispersion in the solvent and the aforementioned water. 10. The composition according to claims 1 to 9, further characterized in that the pharmaceutical actives have a molecular weight of less than 500 grams per mole, it is capable of being ionized when it is in an aqueous solvent and has an octanol-water partition coefficient when it is in the non-ionized form of at least 100. 11.- The composition according to claims 1 to 10, further characterized in that the pharmaceutical actives are selected from the group consisting of antitussives, antihistamines, non-sedating antihistamines, decongestants, expectorants, analgesic mucolytics, antipyretic and anti-inflammatory agents, local anesthetics and mixtures thereof. 12. The composition according to claims 1 to 11, further characterized in that the concentration of pharmaceutical actives in the solvent is less than or equal to 125% of the percentage solubility value of the aforementioned active. 13. The composition according to claims 1 to 12, further characterized in that the pharmaceutical active is present in the solvent at a level of 0.075% to 25%, preferably from 0.28% to 10.0%, by weight of the composition. 14. The composition according to claims 1 to 13, further characterized in that the solvent comprises from 60% to 99.975%, preferably from 70% to 99%, more preferably from 85% to 98%, by weight of the composition. 15. The composition according to claims 1 to 14, further characterized in that the solvent is hydrophilic, miscible in water, and anhydride selected from the group consisting of propylene glycol, ethanol, poly (ethylene glycol) or PEG, propylene carbonate, diethylene glycol monoethyl ether, poloxamer, glycofurol, glycerol, polyvinyl pyrrolidone ( PVP), 2- (2-ethoxyethoxy) ethanol, esters of fatty acids and propylene glycol, glyceryl and esters of polyethylene glycol, propylene glycol monocaprylate and mixtures of these. 16. The composition according to claims 1, 2 and 3, further characterized in that the composition of the aforementioned process is used to treat respiratory diseases by oral administration of the aforementioned composition having a total dosage volume not greater than 3.0 ml approximately. 17. - The process according to claim 16, further characterized in that the aforementioned composition is placed against any of the mucous membranes of the mouth.