JP2003510279A - Composition with improved stability - Google Patents

Abstract

  (57) [Summary] The present invention relates to improving the stability of compositions that deliver pharmaceutically active substance ingredients. These compositions are used in a variety of product forms, including liquid elixirs that are put into the mouth and eventually swallowed, or via liquid-filled lozenges, metered liquid dosing devices, atomizers and liquid-release edible capsules. Have very good stability. Such compositions are particularly useful for treating symptoms associated with respiratory diseases.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to improved stability of compositions that deliver pharmaceutically active ingredient. These compositions are used in various product forms, for example in the form of liquid elixirs that are placed in the mouth and finally swallowed, or liquid filled lozenges, metered liquid dosing devices, atomizers and liquid-releasing edible capsules. It has very good stability when it can be delivered via. Such compositions are particularly useful for treating the symptoms associated with respiratory disease.

[0002] Routes for delivering pharmaceutically active agents include intranasal, pulmonary, buccal, sublingual, transdermal, vaginal and rectal and ocular delivery of the active agent. Can be mentioned. However, the most common are swallowed compositions. When these compositions are swallowed, they enter the gastrointestinal tract and are absorbed into the systemic blood circulation. Items swallowed by humans, such as foods, beverages and drugs, enter the stomach and flow from there to the intestine. Many of the chemicals associated with food, beverages or drugs pass through the mucous membranes in the gastrointestinal tract and into the blood of the mesenteric veins that exit the intestine. Blood flow from the mesenteric veins drains to the liver. Metabolic enzymes in the mucosa and liver of the intestine can chemically alter the properties of substances that enter the intestinal mucosa through the liver and into the general blood circulation of the body.

Respiratory diseases include a wide range of diseases, such as viral infections and allergic reactions to inhaled allergens. Viral infections in the upper respiratory tract of humans commonly cause a disease called the cold or flu. Such diseases are quite common in the general population and can be the cause of significant discomfort and distress. Allergen inhalation can also negatively impact a significant number in the population, to the same extent or more than those with viral infections.

There are generally no effective and convenient ways to prevent viral infections or allergies. In the case of viral infections, the body's natural defense mechanisms usually combat the infection for a period of 3 days to 2 weeks. In this case, the most commonly used agents treat the unpleasant, problematic symptoms of these respiratory disorders. These symptoms include stuffy nose, runny nose, nasal and sore throat and inflammation, coughing attacks, general body pain, fever and headaches. Of these symptoms, cough in uncontrolled seizures is often considered the most problematic and uncomfortable. Cough disturbs normal breathing,
It increases headaches and throat pain and interferes with sleep in affected individuals and those living with them.

The compositions used to treat the above conditions generally belong to one of the following pharmacological classes: antihistamines, decongestants, antitussives, expectorants, mucolytics, analgesics. , Antipyretics and anti-inflammatory drugs. The compositions are manufactured in a number of product forms, the most common of which are liquid syrups and elixirs for swallows, oral sugar and lozenges,
As well as inhalants and topical creams or lotions that release volatile active substances that are inhaled through the nose into the respiratory tract. The composition is typically swallowed immediately or
Or it is gradually dissolved in the mouth. They typically have negative substances, including active substances such as guaifenesin, which aids in the removal of excess respiratory mucus or mucus in the body, histamine-generated cough and other symptoms produced in the body in response to viral infections. It contains diphenhydramine, which reduces its action, as well as dextromethorphan, which acts in parts of the human brain that control the cough reflex. Of these actives, dextromethorphan is the most commonly used active in the world for cough relief.

US Pat. No. 4,839,176 (Pankhania et al. (Boots Company), 1989.
(Published June 13, 2013) discloses the use of Bisulfit in the manufacture of tablets containing CMC that avoid degradation. U.S. Pat. No. 4,474,985 (Keel et al. (Mo
nsanto), issued Sep. 25, 1993) discloses a method for increasing the colorless shelf life of crude N-aminophenol. The method involves dissolving crude N-acetylaminophenol in a solvent containing a reducing agent, such as metabisulfite. US Pat. No. 4,478,822 (issued October 23, 1984) and US Pat. No. 4,474,752 (issued October 2, 1984) (both Haslam et al. (Assigned to Merck & Co.)) Claims a gel composition that includes a polymer that provides gelation of a liquid when it enters a body cavity. Disclosed are a group of microbiological preservatives, such as sodium bisulfite and sodium thiosulfate. The techniques known to the Applicant do not demonstrate the particular chemical stabilization benefits of inclusion of solution or liquid based product forms.

SUMMARY OF THE INVENTION It has not been realized to date that active compounds in combination with known solvents can be positively affected when certain agents are added to the composition. Surprisingly,
Certain combinations of chelating agents and reducing agents in liquid compositions containing a pharmaceutically active substance improve the stability of the active substance in such compositions.

The compositions of the present invention provide excellent delivery of oral product forms. These compositions also demonstrate excellent shelf life when incorporated into a variety of these oral product forms such as elixirs, liquid filled lozenges, metered liquid dosing devices, atomizers and liquid releasing edible capsules. . Such compositions are particularly useful for treating the symptoms associated with respiratory disorders.

After careful and devoted study of the pharmacological, therapeutic and side-effect properties of active compounds,
It has not been realized to date that the compositions can have a positive improvement in their therapeutic effect without increasing side effects or toxicity. These compounds have improved stability in the product form chosen for delivering such compositions. This advantage is achieved by adding to the active substance-containing formulation an agent which promotes the stability of the active substance in the formulation. These agents are effective in reducing and even eliminating instability due to oxidative degradation pathways of the active agent, thereby prolonging the shelf life of the composition.

Accordingly, one object of the present invention is to provide an improved composition for treating conditions associated with respiratory disorders, in particular for minimizing coughing attacks. Particularly preferred compositions are active substances such as antitussives, antihistamines (including non-sedating antihistamines), decongestants, expectorants, mucolytics, analgesics for treating the symptoms of respiratory diseases. , Antipyretic and anti-inflammatory drugs, and in the form of anhydrous hydrophilic liquids in a very stable environment for rapid delivery of local anesthetics. The composition is
It can be administered using various product forms and / or packaged delivery options. The compositions of the present invention provide the desired activity while minimizing the possible side effects of the active compound. It is also an object of the present invention to provide a method for achieving rapid transmucosal delivery of the above composition.

Definitions and Terminology The following are definitions of terms found herein.

1. Transmucosal Delivery : Refers to the application of the drug to the mucous membranes of the oral cavity, such as the cheeks, lips, gums, palate and tongue. The purpose of the drug is to penetrate the skin over these areas and enter the bloodstream.

2. Therapeutic doses When administered to humans in a suitable form, undesired side effects refer to the amount of the substance that produces the desired effect in the body with a minimum.

3. Pharmaceutically active substance / active substance : Refers to a chemical molecule that exerts a desired effect on the body when administered in the proper amount and form.

[0015] 4. Active Metabolite Refers to a chemical species of a pharmaceutically active substance produced during the progress of metabolism of an active substance.

5. The molecule of the monodisperse active substance refers to the fact that the molecule is free and does not interfere with the dispersion, by association in crystalline or amorphous solid form, or by polymolecular association.

6. Solubility value usually refers to the equilibrium solubility limit or maximum solubility of a molecule in a solvent at room temperature. Expressed as weight percent of molecules in the composition.

7. Anhydrous solvent refers to a solvent that contains less than about 5% water.

DETAILED DESCRIPTION OF THE INVENTION Pharmaceutically Active Agents The compositions of the present invention are herein used to treat conditions, particularly respiratory diseases such as colds, influenza, and allergy-related conditions. Active substance "
Also called pharmaceutically active substances. These actives include those commonly used to treat the symptoms of most problems, such as stuffy nose, runny nose, nasal and sore throat and inflammation, coughing attacks, general body pain, fever and headaches ( See US Pat. No. 5,196,436 (Smith, issued May 23, 1993), the contents of which are incorporated herein by reference. In the present invention, the use of a particular substance to enhance the long-term stability of the formulation is an important advantage when the active substance is combined with certain substances in the formulation for delivery of the active substance. Is. In stable formulations, the active agent is efficiently delivered with a positive effect.

The composition comprises a pharmaceutically active substance and a stabilizing substance together with other generally known ingredients for producing a composition for delivery of the above-mentioned active substance. In a particularly preferred embodiment, the composition comprises a hydrophilic water-miscible anhydrous solvent, wherein the non-ionized form of the pharmaceutically active agent has a solubility of at least 0.075% in the solvent at ambient temperature. Having a value, the pharmaceutically active substance is present in its free non-ionized form in a monodisperse dispersion in the solvent.

Preferred pharmaceutically active agents of the present invention have a molecular weight of less than 500 grams / mole and can be ionized when present in an aqueous solvent or at least 100 octanols when in non-ionized form. -Has a water partition coefficient. Octanol-
The water partition coefficient is calculated by A. Martin, P. Bustamante, and AHC Chun, Physical Pharma.
cy, Fourth Edition, Lea and Febiger publishers, Philadelphia, 1993, page
237, the contents of which are incorporated herein by reference.

The active substance constituting the composition of the present invention includes active substances belonging to at least one of the following pharmacological classes: antitussive drug, antihistamine drug, non-sedative antihistamine drug, decongestant drug. , Expectorants, mucolytics, analgesics, antipyretic anti-inflammatory agents, local anesthetics and mixtures thereof. References describing the use of such actives include JG Hardman, The Pharmacologic Basis of Therapeutics, Ninth Editi.
on, McGraw-Hill, New York, 1995. Active substances belonging to these pharmaceutical classes are those suitable for absorption through mucosal tissues. These active substances are
It can be used alone or in combination with other active substances that are not necessarily absorbed in this manner and can be formulated within the existing formulation technology.

When using an active substance intended for mucosal absorption, the concentration of the active substance in the solvent portion of the composition is preferably 125% or less of the solubility% value of the pharmaceutically active substance, more preferably less than the solubility% value. Is. In order to maximize the advantages of the composition according to the invention, the active substance is preferably present in solution in monodisperse form in the solution. Absorbent actives useful in the present invention are from about 0.075% to about 25.0% by weight of the composition, preferably about 0.2%.
It is present in the solvent system at a concentration of 8% to 10.0% by weight. The active substance is preferably present as a monodisperse in the solvent system and in free, non-ionized form. When a salt or ionized form of the drug active is present, it is preferred in the present invention to use the uncharged free (non-salt) form of the drug.

Antitussives are active substances that are particularly useful for quenching uncontrolled coughing attacks.
Antitussives useful in the present invention include codeine, dextromethorphan, dextrorphan, diphenhydramine, hydrocodone, noscapine, oxycodone,
Examples include, but are not limited to, the group consisting of pentoxyberine, morphine, forcodyne and mixtures thereof. Of these antitussives, dextromethorphan is preferred. Dextromethorphan is known to have pharmacological activity as an antitussive and is described in US Pat. No. 5,196,436 (Smith et al.) (
This description is incorporated herein by reference). As used herein, "dextromethorphan" refers to racemetorphan, 3
-Methoxy-17-methylmorphinan (dl-cis-1,3,4,9,10,
10a-hexahydro-6-methoxy-11-methyl-2H-10,4a-iminoethanophenanthrene) and pharmaceutically acceptable salts thereof. Compositions of the present invention comprising dextromethorphan are preferably about 0.1% to about 9.3%, more preferably about 0.26% to about 6.2%, most preferably about 1.16%. About 4
． Contains 6% dextromethorphan. Other safe and effective amounts of other cough / cold actives may be included in such dextromethorphan-containing compositions.

Antihistamines useful in the present invention include acrivastine, azatazine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexbrompheniramine, dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, meclizine, pheninamin, Examples include, but are not limited to, the group consisting of phenyltroxamine, promethazine, pyrilamine, tripelenamine, triprolidine and mixtures thereof. Non-analgesic antihistamines useful in the present invention include, but are not limited to, the group consisting of astemizole, cetirizine, ebastine, fexofenadine, loratidine, terfenadine and mixtures thereof. Decongestants useful in the present invention include phenylpropanolamine, pseudoephedrine, ephedrine, phenylephrine,
Examples include, but are not limited to, the group consisting of oxymetazoline and mixtures thereof. Expectorants useful in the present invention include, but are not limited to, the group consisting of ammonium chloride, guaphenesin, ipecac fluid extract, potassium iodide and mixtures thereof. Mucolytic agents useful in the present invention include, but are not limited to, the group consisting of acetylcycline, ambroxol, bromhexine, and mixtures thereof. Analgesic, antipyretic and anti-inflammatory drugs useful in the present invention include acetaminophen, aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nabumetone, naproxen, piroxicam. , Caffeine, and mixtures thereof, but are not limited thereto. Local anesthetics useful in the present invention include, but are not limited to, the group consisting of lidocaine, benzocaine, phenol, dyclonine, benzonotate and mixtures thereof.

Solvent The non-ionized form of the pharmaceutically active substance is maintained with a selected group of solvents. The solvent portion of the composition of the present invention comprises from about 60% to about 99.975%, preferably from 70% to about 99%, most preferably from about 85% to about 98% by weight of the composition.
Make up.

The solvent of the present invention is usually a liquid at ambient or room temperature. It is water soluble or water miscible. The solvent of the present invention is preferably propylene glycol, ethanol, poly (ethylene glycol) or PEG, propylene carbonate, diethylene glycol monoethyl ether, poloxamer, glycofurol,
Glycerol, polyvinylpyrrolidone (PVP), Transcutol ™ (2- (2-ethoxyethoxy) ethanol), Lauroglycol
90 ™ (fatty acid ester and propylene glycol), Labrasol
(Trademark) (glyceryl and polyethylene glycol ester), Capryol
90 ™ (propylene glycol monocaprylate) as well as mixtures thereof (all Gattefosse SA. Company of 69804 Saint
Available from Priest Cedex, France). Propylene glycol and ethanol are especially preferred. There are mixtures of these solvents that are particularly preferred for certain product forms of the present invention. For example, if the product form is an elixir, liquid capsule or liquid-containing lozenge, the solvent is a combination of propylene glycol, ethanol and PEG. When the product form is a spray, the solvent is a combination of propylene glycol, ethanol, PEG and usually propylene carbonate. The concentration of each solvent that makes up these mixtures depends in part on the aesthetic benefits required by the formulator. Most preferred are the above solvents in anhydrous form.

The addition of the chelating agent chelating agent, was found to have a beneficial chemical stabilizing effect on the active substance constituting the present invention. This phenomenon surprisingly occurs when the chelating agent is present in a phase other than the phase of the composition containing the active substance. For example, if the active agent is soluble in the non-polar environment or phase of the composition, the chelating agent of choice may be a polar phase such as water. Therefore, the chemical stability of the active substance, despite its presence in the separating phase, is still positively influenced. The same stability advantage is not observed when the active agent and chelating agent are co-soluble in the solvent. Thus, the chelating agents useful in the compositions will depend on the active agent selected and its solubility.

Chelating agents useful in the present invention include those that chelate transition metal ions such as iron, copper, zinc and other such metals. Without being bound by theory, it is reasonable to assume that metal cations play an important role in the formation of oxidizing species. The free radical forming reaction involves the transfer of electrons by a redox cycle between two different valence steps. Traces of heavy metal ions often cause autooxidation reactions. In fact, as little as 0.05 ppm metal ions are sufficient to initiate oxidation and enhance chain transfer rates (W. Lund, The Pharmace.
utical CODEX, 12 ^th Edition, see p.289 & 290 The Pharmaceutical Press, 1994 ) ( This description is incorporated herein by reference).

Chelating agents have been shown to reduce the ease of electron transfer reactions between these valence steps. This feature of chelating agents slows down the autoxidation reaction. This may explain why chelating agents are effective in protecting pharmaceutically active substances. It is known that the rate and extent of oxidation is greater at alkaline pH values than at acidic pH values. This is in part due to what appears to be a greater tendency of divalent cations to cause oxidation reactions in alkaline media (Townsend MW an
d Byron PR “The Effect of Formulation Additives on Degradation of Fre
eze-Dried Ribonuclease A ”, Pharmaceutical Research Vol. 7, No. 10, pp.1
086-1091 (1990)). Some other compounds with nitrogen in their side chains have been shown to be stabilized by EDTA (Fog AG & Summan AM
.EDTA was shown to be effective in stabilizing acetamido groups in Drug
and food coloring compounds from degradation by light when in presence
of ascorbic acid; "Journal of Clinical Pharmacology and Therapeutics",
Vol. 17, pp. 107-109 (1992)).

The chelating agents useful in the present invention are stable and effective in non-aqueous and aqueous media, and in the pH range of 5-12. Preferred chelating agents are the disodium and calcium salts of ethylenediaminetetraacetic acid (EDTA), tetrasodium EDTA, sodium hexametaphosphate (SHMP), citric acid, phosphoric acid, di (hydroxyethyl) glycine, 8-hydroxyquinoline and those. Is selected from the group consisting of mixtures of

The concentration of chelating agents useful in the present invention is due to the loading of metal ions that would be introduced into the formulation due to ingredient contamination. In the present invention, the chelating agent comprises from about 0.005% to 1.000% by weight of the composition, preferably from about 0.150%.
About 0.050% by weight, most preferably about 0.300% to about 0.010% by weight
Used at a concentration of.

The reducing agent reducing agent, when present in the presence of a chelating agent of the present invention, the reducing agent is significantly increase the shelf life, was also observed that. This is true even if the chelating agent is present in the formulation at concentrations as low as 0.001%. Extended shelf life translates into an improvement in the effectiveness of reducing agents as antioxidants over time. Without wishing to be bound by theory, it is believed that the reduction reaction (oxidation of the reducing agent) follows a different course in the presence of the chelating agent. In the presence of chelating agents, the initiation step should be by the formation of superoxide radicals,
On the other hand, in the absence of a chelating agent, radicals other than O ₂ ⁰ (oxidizing species) are included as initiating species. Thus, chelating agents may play a dual role in the aerobic oxidation of reducing agents. It complexes trace metals that can cause spontaneous oxidation and thus alter the initiation mechanism. It can also act as a chain-breaking agent by scavenging the oxidising radicals that grow the reaction chains. Therefore, the chemical stabilizing effect of the reducing agent on the active substance comprising the present invention is dramatically increased. This phenomenon surprisingly occurs when the active substance is in a different phase than the reducing agent. For example, if the active agent is soluble in the non-polar environment or phase of the composition, the reducing agent chosen should be soluble in the polar phase, such as water. Therefore, despite being in separate phases, the chemical stability of the active substance is still positively affected. The same stability advantage is not observed when the active agent and reducing agent are co-soluble in the solvent. Thus, the reducing agent useful in the composition depends on the active agent selected and its solubility.

Reducing agents are substances that have a lower redox capacity than agents or adjuvants they are intended to protect against oxidation. Therefore, reducing agents are more easily oxidized than drugs or adjuvants and are effective in the presence of oxidizing agents (W. Lu
^{nd, The Pharmaceutical DODEX, 12 th} Edition, p.290, The Pharmaceutical Pr
ess, 1994) (the contents of which are incorporated herein by reference). The reducing agent of the present invention has an electrode potential value. This is defined by the Nernst equation,
It is measured using a working standard electrochemical control cell. The resulting value is therefore called the standard electrode potential and has a value of E ⁰ when measured in volts (V). Comparison of standard electrode potentials for different substances can be used to assess the potency of different reducing agents (Wells, Pharmaceutical Preformulation, Ellis Horwood Limite
d Publishing, 1988, pp.168-172) (the contents of which are incorporated herein by reference). The reducing agents useful in the present invention have an electrode potential value E ⁰ of greater than about −0.119V, preferably about −0.119V to + 0.250V. Preferred reducing agents are salts of metabisulfite and bisulfite, such as their sodium and potassium salts, dithiothreitol, thiourea, sodium thiosulfate, thioglycolic acid, t-butyhydroquinone (TBHQ), acetylcysteine, hydroquinone. And a mixture thereof.

The concentration of reducing agents useful in the present invention is from about 0.005% to 1.000% by weight of the composition, preferably from about 0.050% to about 0.500%, and most preferably about. It is 0.010% by weight to 0.200% by weight.

The reducing agent protects the pharmaceutically active agent in the present invention from degradation by acting as a donor oxidizing compound that sacrifices itself for oxidation rather than the active agent itself. Chelating agents also provide some practical protection by chelating metal ions present in formulation ingredients such as flavors, colorants and sweeteners, and by possible migration of metal ions from the packaging material. In the absence of such metal ions, little or no formation of metal-catalyzed oxy and peroxy radicals is observed. This results in stabilization of the pharmaceutically active substance.

The additional effect of using any reducing agent and chelating agent together may not be surprising, but the advantages found by using these particular reducing agents are surprising. Moreover, the advantages found by using higher chelating agent concentrations than are needed to chelate all metal ions in a system that does not continuously produce metal ions are surprising. Without wishing to be bound by theory, it is believed that in the presence of excess concentrations of chelating agents (eg, EDTA), the degradation of reducing agents such as metabisulfite is surprisingly delayed. There is. Maintaining the presence of the reducing agent in the compositions of the present invention serves to preserve higher levels of the pharmaceutically active agent in the composition.

Optional water may be used in the composition of the present invention. In the present invention, the maximum concentration of water is about 10% by weight of the composition, preferably about 1% to about 10%, more preferably 5% to about 10%, most preferably about 5%. Is about 8% by weight.

Ingredients normally associated with cold and influenza remedies may be used with the pharmaceutically active agents disclosed herein. Such ingredients are described in US Pat.
96,436 (the contents of which are incorporated herein by reference). Additionally, the following ingredients may be used in the present invention:

Buffers and mixtures of buffers, such as basic buffers as a single component having a pKa of 8-11 include triethanolamine, tromethamine, salts of amino acids such as glycine, glycylglycine, glutamine. Or alkaline salts of other amino acids, phosphates, carbonates of carbonates, and mixtures thereof. The buffer provides compositional resistance to pH changes upon dilution of the composition with saliva in the 8-10 range.

Buffers and mixtures of buffers, such as basic buffers as a single component having a pKa of 8-11 include triethanolamine, tromethamine, salts of amino acids such as glycine, glycylglycine, glutamine. Or alkaline salts of other amino acids, phosphates, carbonates of carbonates, and mixtures thereof. The buffer provides compositional resistance to pH changes upon dilution of the composition with saliva in the 8-10 range.

Sweetening agents such as aspartame, saccharin and its salts, Sucralose
(Trademark) (Distributor McNeil Specialty Products Co., New Brunswick, NJ), Pr
osweet (trademark) (Distributor: Virginia Dare Extract Co., New York, NY),
Magnasweet ™ (sold by MAFCO Worldwide Corp., Licorice Divi
sion, Camden, NJ), ammonium glycyrrhizinate, its salt, Talin (
Trademark) (Thaumatin) and its diluted products such as Talin GA90 (sold by Talin Food Company, Birkenhead, England), and Acesulfame K and mixtures thereof. Products made with sweeteners are consumed orally,
Products such as lozenges preferably utilize sweeteners that are sugar-free or non-cariogenic. This means that sweeteners are not metabolized in the oral cavity by cariogenic bacteria and therefore they cannot give rise to an acidic environment. If this is not possible, the product has a pK higher than 7, preferably 8 to precondition the oral cavity.
It may be formulated to contain an alkaline buffer having a.

As the flavoring agent, anise, peppermint oil, clove oil, eucalyptus, lemon,
Mention may be made of limes, honey lemons, red fruits, mint, grapefruits, oranges, cherries, cola trees and mixtures thereof.

Sensory agents. Also useful herein is a coolant (coolin).
g agent), a salivating agent, and a warming agent. Preferably, these agents are present in the composition at a concentration of about 0.001% to about 10%, preferably about 0.1% to about 1% by weight of the composition.

Suitable cooling and warming agents include carboxamide, menthol, thymol,
Camphor, capsicum, phenol, eucalyptus oil, benzyl alcohol, salicyl alcohol, ethanol, clove bud oil and hexyl resorcinol, ketal,
Mention may be made of diols and mixtures thereof. Preferred warming agents include thymol, camphor, capsicum, phenol, benzyl alcohol, salicyl alcohol,
Mention may be made of ethanol, clove bud oil and hexyl resorcinol, nicotinate esters such as benzyl nicotinate, ketals, diols and mixtures thereof.

Preferred cooling agents are paramenthane carboxamide agents, eg US Pat.
, 136, 163 (Watson et al., Issued January 23, 1979), the teachings of which are incorporated herein by reference in their entirety.
-Mentane-3-carboxamide (WS-3, supplier Sterling Organics). A preferred cooling agent is a paramenthan carboxamide agent such as N-ethyl-
p-menthane-3-carboxamide. Another preferred paramenthane carboxamide agent is N, 2,3-trimethyl-2-isopropylbutanamide known as "WS-23" and a mixture of WS-3 and WS-23.

Yet another preferred coolant is menthol, TK-10 (supplied by Takasago Per
fumery Co., Ltd., Tokyo, Japan), 3-1-menthoxypropane-1,2-diol, menthol glycerol acetal known as MGA (manufactured by Haarmann and Reimer), Frescolat ™ (Haarmann and Reime
selected from the group consisting of menthyl lactate and mixtures thereof.

Still other cooling agents include cyclic sulfones and sulfoxides (
All disclosed in US Pat. No. 4,032,661 (Rowsell et al., Issued June 28, 1977), the contents of which are incorporated herein by reference.
.

The terms “menthol” and “menthyl” as used herein include the dextro and levorotatory isomers of these compounds and their racemic mixtures.

TK-10 is described in detail in US Pat. No. 4,459,425 (Amano et al., Issued July 10, 1984), the contents of which are incorporated herein by reference. There is.

The salivating agent of the present invention includes Jambu (trademark) (Takasago Perfumery Co.
, Ltd., Tokyo, Japan manufacturing).

Method of Use Delivery of the drug into the bloodstream by injecting the drug into the mouth is dependent upon the desired effect.
It can be divided into two major subclasses. Absorption or significant rate through the membrane of the oral cavity when the drug is delivered to the blood absorption after swallowing (ie, from the stomach, small intestine or colon) and immediately or over time due to retention of the drug by the mucoadhesive. This is the case when absorption occurs. This route is commonly referred to as "cheek" or "oral mucosa" absorption,
In contrast, the former is classically called the oral route. The oral route of drug delivery is by far the most commonly used and well studied of all drugs, and
Mayerson, M., Principles of Drug Absorption; Chapter 2 in “Modern Pharma
ceutics ”, 2 ^nd ed., GS Banker and CT Rhodes, editors, Marcel Dekker
It is described in detail in Inc., New York. 1990.

With respect to the method of delivery of the active substance, it is general that oral mucosal delivery inside the mouth must target the sublingual region in order to achieve a very rapid therapeutic effect. (D. Harris and JR Robinson, Drug Delivery
via the Mucus Membranes of the Oral Cavity, Journal of Pharmaceutical S
See ciences 81: 1, 1992). Such dosages are intended to be placed sublingually, on the floor of the mouth and held there for an extended period of time. However, the present inventors have found that the great increase in bioavailability associated with very rapid absorption indicates that the composition is applied to the mucous membrane of any mouth, even on the tongue, and swallowed. It has been found that this can be achieved if

A form of the invention is a liquid elixir solution. It is intended to be applied to any mucous membrane in the mouth. This can be accomplished with a drug dropper calibrated to indicate the proper dose to be administered and by ejecting elixirs onto the tongue before swallowing. Elixirs can be sprayed into the mouth and throat and then swallowed. that is,
It may be enclosed in a shell of some kind that makes it portable and convenient for transportation and administration without having to measure the amount of liquid elixir. Examples of encapsulated shells include hard candy, gelatin or starch based shells such as those used for lozenges.
Elixirs can be easily opened and packaged in small disposable vials that can be jetted or injected into the mouth. All vials contain exactly one therapeutic dose.
A typical dosage of the composition of the present invention comprises about 3 ml or less, preferably about 0.2 ml to about 3 ml.

One preferred form is to enclose the liquid in a hard candy or gelatin shell. The shell contains substances for the pretreatment of the mucous membrane, which enhances the absorption of the active substance from the liquid center. The pretreatment occurs by licking or chewing the shell substance, the effect of which is obtained by first treating the mucosa and then by staggering the action of the absorbed active substance. Examples of mucosal pretreatment agents are membrane permeation enhancers commonly known in the art, including menthol, peppermint oil, surfactants such as polysorbate 80 or poloxamers. Another example of mucosal pretreatment is the above-listed buffer, which can pre-adjust saliva microenvironmental pH to a range of 8-11.

(Example) Example I

[Table 1] 1 Acesulfame K (Nutrinova Inc. Company of Somerset, NJ-08873, USA
Available from). 2 TK10 (available from Takasago Company of Rockleigh, NJ-07657, USA).

A portion of ethanol was added to the active substance (dextromethorphan base) and solid sweetener (Sucralose, monoammonium glycyl lysinate) at low temperature (
Mix continuously at 30 ° C. Propylene glycol and a liquid sweetener (Pro-Sweet Liquid K) are added to this container. The chelating agent (disodium EDTA), reducing agent (sodium metabisulfite) and water are combined and mixed until uniform. Add the mixture to the vessel and mix for about 2 hours. Add the premix of flavor and colorant in the rest of the ethanol and add to the vessel containing the nearly complete solution. Mix until a homogeneous solution is obtained. The composition is left in the mixing container and exposed to the atmosphere for about 10 minutes. Filter the composition through a US # 100 mesh screen (product density = 1.07 g / ml). Fill an amber glass bottle and cap with integrated lid / graded drug dripping assembly. About 1.5 grams of elixir is dripped onto the tongue and then swallowed. Dextromethorphan is rapidly absorbed into the blood.

Example II

[Table 2]

A portion of ethanol was added to the active substance (dextromethorphan base) and solid sweetener (Sucralose, monoammonium glycyrrhizinate) at low temperature (
Mix continuously at 30 ° C. To this container are added propylene glycol, liquid sweetener (Pro-Sweet Liquid K) and buffer (triethanolamine, liquid). Disodium EDTA, sodium metabisulfite and water are added together and mixed until clear. Add the mixture to the vessel, add guaifenesin and mix continuously for about 2 hours. Add the premix of flavor and colorant in the rest of the ethanol and add to the vessel containing the nearly complete solution. Mix until a homogeneous solution is obtained. The composition is left in the mixing container and exposed to the atmosphere for about 10 minutes. Mix until a homogeneous solution is obtained and filter through a US # 100 mesh screen (product density = 1.07 g / ml). Fill an amber glass bottle and cap with integrated lid / graded drug dripping assembly. About 1.0 ml of elixir is dropped on the tongue and then swallowed. Dextromethorphan is rapidly absorbed into the blood.

Example III

[Table 3] 1 Green Shade CSL-15689 (Warner Jenkins Co., St. Louis,
Obtained from MO, USA).

A portion of propylene glycol is added to the active substance (dextromethorphan base) and solid sweetener (Sucrarose, monoammonium glycyrrhizinate) and mixed continuously at low temperature (30 ° C.). To this container is added an additional amount of propylene glycol and a liquid sweetener (Pro-Sweet Liquid K).
Dissolve sodium hexametaphosphate (SHMP) and sodium thiosulfate in water and mix until clear. Add mix to container and mix for approximately 2 hours until all material is dissolved. Add the premix of flavor and colorant in the rest of the ethanol and add to the vessel containing the nearly complete solution. Mix until a homogeneous solution is obtained. With the composition still in the mixing vessel, about 1
Expose to atmosphere for 0 minutes. Mix until a homogeneous solution is obtained and filter through a US # 100 mesh screen (product density = 1.075 g / ml). Fill manually operated atomization pumps and bottles. An example is manufactured by Calmar-Albert GmbH, the Mistette Mark II with a 16 mm high viscosity head assembly delivering 0.2 ml / actuation. Three individual actuations are sprayed into the mouth. Dextromethorphan is rapidly absorbed into the blood and, during nebulization, some portion of the nebulizer comes in contact with the throat area, providing additional benefits, such as the presence of stimulated cough receptors there. Make it insensitive.

Example IV

[Table 4]

A portion of ethanol was added to the active substance (dextromethorphan base) and solid sweetener (Sucralose, monoammonium glycyrrhizinate) at low temperature (
Mix continuously at 30 ° C. Add to this container additional propylene carbonate and propylene glycol, liquid sweetener (Pro-Sweet Liquid K).
, Reducing agent and buffer (triethanolamine, liquid) are added. Mix for approximately 2 hours until all material is dissolved. The composition is left in the mixing container and exposed to the atmosphere for about 10 minutes. A premix of flavor and colorant in the remaining portion of ethanol is prepared and added to the container containing the nearly complete solution. Mix until a homogeneous solution is obtained and filter through a US # 100 mesh screen (product density = 1.075 g /
ml). Fill manually operated atomization pumps and bottles. An example is manufactured by Calmar-Albert GmbH, the Mistette Mark II with a 16 mm high viscosity head assembly. Three individual actuations are sprayed into the mouth. Dextromethorphan is rapidly absorbed into the blood and, during nebulization, some portion of the nebulizer comes in contact with the throat area, providing additional benefits, such as the presence of stimulated cough receptors there. Make it insensitive.

Example V

[Table 5]

A portion of ethanol was added to the active substance (dextromethorphan base) and solid sweetener (Sucralose, monoammonium glycyrrhizinate) at low temperature (
Mix continuously at 30 ° C. Propylene glycol and a liquid sweetener (Pro-Sweet Liquid K) are added to this container. Mix for approximately 2 hours until all material is dissolved. Mix until a homogeneous solution is obtained. A premix of the remainder of ethanol, disodium EDTA, sodium metabisulfite and flavor and colorants in water is prepared and added to the container containing the nearly complete solution. The composition is left in the mixing container and exposed to the atmosphere for about 10 minutes. Mix until a homogeneous solution is obtained and filter through a US # 100 mesh sieve (product density = 1.0
7 g / ml). Individual filled lozenges containing about 1.0 ml of liquid / lozenge are made by commonly used methods such as extrusion. A liquid filled lozenge is placed in the mouth and the lozenge is licked until the liquid filling is released. The action of licking the shell of the lozenge reduces the cough somewhat. When the liquid center is released, dextromethorphan is rapidly absorbed into the blood.

Example VI

[Table 6] 1. Lauroglycol 90 (Gattefosse SA. Company of 6
9804 Saint Priest Cedex, available from France).

A portion of ethanol was added to the active substance (dextromethorphan base) and solid sweetener (Sucralose, monoammonium glycyrrhizinate) at low temperature (
Mix continuously at 30 ° C. In this container, propylene glycol, fatty acid ester and propylene glycol and a liquid sweetener (Pro-Sweet Liquor).
id K) is added. An aqueous premix of disodium EDTA, sodium metabisulfite is prepared and added to the container. Mix for approximately 2 hours until all material is dissolved. A premix of flavor and colorant in the remaining portion of ethanol is prepared and added to the container containing the nearly complete solution. The composition is left in the mixing container and exposed to the atmosphere for about 10 minutes. Mix until a homogeneous solution is obtained and filter through a US # 100 mesh screen (product density = 1.07 g / ml). Individual filled lozenges containing about 1.0 ml of liquid / lozenge are made by commonly used methods such as extrusion. A liquid filled lozenge is placed in the mouth and licked until the liquid filling is released. The action of licking the shell of the lozenge reduces the cough somewhat. When the liquid center is released, dextromethorphan is rapidly absorbed into the blood and the cough is relieved within 10 minutes.

Example VII

[Table 7] 1. Transcutol P (Gattefosse SA. Company of 698
04 Saint Priest Cedex, available from France).

A portion of ethanol was added to the active substance (dextromethorphan base) and solid sweetener (Sucralose, monoammonium glycyrrhizinate) at low temperature (
Mix continuously at 30 ° C. In this container, propylene glycol, 2- (2ethoxyethoxy) ethanol, guaifenesin and liquid sweetener (Pro-Sw
eet Liquid K) and most of the buffer (triethanolamine, liquid) is added. Mix for approximately 2 hours until all material is dissolved. A premix of flavor and color in water and ethanol and the rest of the disodium EDTA and sodium metabisulfite is prepared and added to the container containing the nearly complete solution. Mix until a homogeneous solution is obtained and filter through a US # 100 mesh screen (product density = 1.07 g / ml). Fill an amber glass bottle and cap with integrated lid / graded drug dripping assembly. About 1.0 ml of elixir is dropped on the tongue and then swallowed.

Example VIII

[Table 8]

A portion of the ethanol is added to the active substance (chlorpheniramine & pseudoephedrine base) and the solid sweetener (Sucralose, monoammonium glycyrrhizinate) and mixed continuously at low temperature (30 ° C.). To this container are added propylene glycol, liquid sweetener (Pro-Sweet Liquid K), di (hydroxyethyl) glycine and most of the buffer (triethanolamine, liquid). Mix for approximately 2 hours until all material is dissolved. Propylene glycol,
A premix of flavor and colorant in the remaining portion of disodium EDTA, sodium metabisulfite and ethanol is prepared and added to the container containing the nearly complete solution. Mix until a homogeneous solution is obtained and filter through a US # 100 mesh screen (product density = 1.07 g / ml). Fill an amber glass bottle and cap with integrated lid / graded drug dripping assembly. About 1.0 ml of elixir is dropped on the tongue and then swallowed. Chlorpheniramine & pseudoephedrine are rapidly absorbed into the blood.

Example IX

[Table 9] 1 PVP-K17PF (available from BASF Corp.).

A dextromethorphan base and a pseudoephedrine base are dissolved in a portion of the alcohol to make a premix. In a separate container, heat propylene glycol to about 70 ° C. Once all the substances have melted into a clear liquid form,
Add acetaminophen and continue heating to 110-120 ° C. with continuous stirring. Once the liquid is clear, stop heating. Cool it to room temperature. Add the mixture to dextromethorphan and pseudoephedrine.
Liquid sweetener (Pro-Sweet Liquid K) and buffer (triethanolamine) are also added. Mix until all material is dissolved. A premix of flavor and color in the rest of the alcohol is prepared and disodium EDTA and sodium metabisulfite are added to the container containing the nearly complete solution. The composition is left in the mixing container and exposed to the atmosphere for 10 minutes. Mix until a homogeneous solution is obtained, US
Filter through a # 100 mesh screen. Fill an amber glass bottle and cap with integrated lid / graded drug dripping assembly. About 1.84 grams of elixir is dripped onto the tongue and then swallowed.

Example X

[Table 10]

A dextromethorphan base is dissolved in a portion of the alcohol to make a premix. In a separate container, add disodium EDTA and sodium metabisulfite to water and mix until uniform. This mixture is added to the dextromethorphan-based premix. Mix until all material is dissolved. Add the rest of the alcohol. The composition is left in the mixing container and exposed to the atmosphere for 10 minutes. Mix until homogeneous and filter through a US # 100 mesh screen. Fill an amber glass bottle and cap with integrated lid / graded drug dripping assembly. About 1.84 grams of elixir is dripped onto the tongue and then swallowed.

Example XI

[Table 11] 1 See example above.

A dextromethorphan base is dissolved in a portion of the alcohol to make a premix. In a separate container, dissolve EDTA and sodium metabisulfite in water. Mix until homogeneous and cool to room temperature. This mixture is added to the dextromethorphan base. Mix until all material is dissolved. The remaining portion of alcohol, EDTA and aesthetics package are added to the container containing the nearly complete solution. The composition is left in the mixing container and exposed to the atmosphere for 10 minutes. Mix until a homogeneous solution is obtained and filter through a US # 100 mesh screen. Fill an amber glass bottle and cap with integrated lid / graded drug dripping assembly. About 1.5 grams of elixir is dripped onto the tongue and then swallowed.

Example XII

[Table 12] 1 See example above. 2 Labrasol (Gattefosse SA.Company of 69804 Saint Pri
available from est Cedex, France).

A dextromethorphan base is dissolved in a portion of alcohol to make a premix. In a separate container, heat water, disodium calcium EDTA to about 70 ° C. Add acetaminophen and continuously mix at 110-120 ° C
Continue heating to. Once the liquid is clear, stop heating. Cool it to room temperature. The mixture is added to dextromethorphan and pseudoephedrine. Mix until uniform and cool to room temperature. Mix until all material is dissolved. The rest of the alcohol, polyvinylpyrrolidone, sodium metabisulfite, glyceryl and polyethylene glycol esters and the aesthetics package are added to the container containing the nearly complete solution. The composition is left in the mixing container and exposed to the atmosphere for about 10 minutes. Mix until homogeneous and filter through a US # 100 mesh screen. The above formulation is filled into chewable soft gelatin capsules. The above gelatin capsules are available from RP Scherer, of St. Petersberg, F.
It can be purchased from companies like lorida. Mastication of the capsule (s) delivers about 1.84 grams of elixir into the mouth and then swallows.

Example XIII

[Table 13] 1 See example above.

A dextromethorphan base is dissolved in a portion of the alcohol to make a premix. In a separate container, mix water, sodium metabisulfite and disodium calcium EDTA until clear. Cool it to room temperature. The mixture is added to dextromethorphan. Mix until uniform and cool to room temperature.
Mix until all material is dissolved. The rest of the alcohol and the aesthetic packaging are added to the container containing the nearly complete solution. The composition is left in the mixing container and exposed to the atmosphere for about 10 minutes. Mix until homogeneous and filter through a US # 100 mesh screen. The above formulation is filled into chewable soft gelatin capsules. The above gelatin capsules are RP Scherer, of St. Petersberg,
It can be purchased from companies like Florida. Mastication of the capsule (s) delivers about 1.84 grams of elixir into the mouth and then swallows.

Example XIV

[Table 14] 1 Carbowax 400 (available from Union Carbide).

Add dextromethorphan and phenol to propylene glycol with stirring. Gradually add polyethylene glycol, alcohol, flavor and sodium saccharin with stirring. Monobasic sodium phosphate is added as a 10% solution in purified water with stirring. The colorant is added as an aqueous solution with stirring. Sodium metabisulfite is dissolved in the remaining amount of water, added and brought to final volume with stirring.

Example XV

[Table 15] 1 Carbowax 400 (available from Union Carbide).

Add dextromethorphan to propylene glycol with stirring. Gradually add polyethylene glycol, alcohol, flavor and sodium saccharin with stirring. Monobasic sodium phosphate is added as a 10% solution in purified water with stirring. The colorant is added as an aqueous solution with stirring. Sodium metabisulfite is dissolved in the remaining amount of water, added and brought to final volume with stirring.

Example XVI

[Table 16] 1 Poloxamer (Pluronic F127) (BASF Specialty Chemicals, Mount Oli
ve, available from NJ).

Preparation : Add propylene glycol and poloxamer to a transparent container (main mix)
. While stirring, heat the mixture appropriately to sufficiently melt the poloxamer. Once a homogeneous solution is obtained, remove from heat source and continue mixing. In a separate container (alcohol premix), add alcohol, dextromethorphan base and monoammonium griseridinate and mix until uniform.
In a separate container (water premix) add water, EDTA, sodium saccharin, acesulfame and sodium metabisulfite. Mix until all material is dissolved. The alcohol-containing premix is added to the main mixing vessel containing the poloxamer. Mix until uniform. Add the water-containing premix to the main vessel with stirring and continue mixing until uniform. Then add the desired flavor component,
Mix until uniform. Deliver about 1.5 grams of liquid to the mouth with a suitable device.

Example XVII

[Table 17] 1 Pluronic F127 (BASF Specialty Chemicals, Moun
t Olive, NJ).

Preparation : Add propylene glycol and poloxamer to a transparent container (main mix)
. While stirring, heat the mixture appropriately to sufficiently melt the poloxamer. Once a homogeneous solution is obtained, remove from heat source and continue mixing. In a separate container (alcohol premix), add alcohol, guaifenesin, dextromethorphan base and monoammonium glyceridiinate and mix until uniform. In a separate container (water premix) add water, EDTA, sodium saccharin, acesulfame and sodium metabisulfite. Mix until all material is dissolved. The alcohol-containing premix is added to the main mixing vessel containing the poloxamer. Mix until uniform. Add the water-containing premix to the main vessel with stirring and continue mixing until uniform. Then add the desired flavor component,
Mix until uniform. About 1 gram of liquid is delivered to the mouth with a suitable delivery device.

Example XVIII

[Table 18] 1 Pluronic F127 (BASF Specialty Chemicals, Moun
t Olive, NJ).

Preparation : Add propylene glycol and poloxamer to a transparent container (main mix)
. While stirring, heat the mixture appropriately to sufficiently melt the poloxamer. Once a homogeneous solution is obtained, remove from heat source and continue mixing. In a separate container (alcohol premix), add alcohol, dextromethorphan base and monoammonium griseridinate and mix until uniform.
In a separate container (water premix), water, pseudoephedrine, HCl, EDTA
, Sodium saccharin, acesulfame and sodium metabisulfite. Mix until all material is dissolved. The alcohol-containing premix is added to the main mixing vessel containing the poloxamer. Mix until uniform. Add the water-containing premix to the main vessel with stirring and continue mixing until uniform. Then add the desired flavor component,
Mix until uniform. About 1 gram of liquid is delivered to the mouth with a suitable delivery device.

Example XIX

[Table 19]

A dextromethorphan base is dissolved in a portion of alcohol to make a premix. In a separate container, add EDTA and sodium metabisulfite to water and mix until homogeneous. This mixture is added to the dextromethorphan-based premix. Mix until all material is dissolved. Add the rest of the alcohol. The composition is left in the mixing container and exposed to the atmosphere for about 10 minutes. Mix until homogeneous and filter through a US # 100 mesh screen. Fill an amber glass bottle and cap with integrated lid / graded drug dripping assembly. Approximately 1.00 grams of elixir is dripped onto the tongue and then swallowed or dosed appropriately with different dose volumes.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/04 A61K 47/04 47/08 47/08 47/10 47/10 47/12 47/12 47 / 14 47/14 47/18 47/18 47/20 47/20 47/22 47/22 47/24 47/24 47/32 47/32 47/34 47/34 A61P 11/00 A61P 11/00 11 / 02 11/02 11/04 11/04 11/10 11/10 11/12 11/12 11/14 11/14 23/02 23/02 25/06 25/06 29/00 29/00 31/12 31/12 31/16 31/16 37/08 37/08 43/00 113 43/00 113 (31) Priority claim number 60 / 179,289 (32) Priority date January 31, 2000 (2000. 1.31) (33) Priority claiming countries United States (US) (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU , MC, NL, PT, SE), OA (BF, BJ, CF, CG, C I, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW) , EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA , CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, G, UZ, VN, YU, ZA, ZW (72) Inventor Kanorker, Jayant Exnus England, Surbiton, Katie 6, 4 SP, Avenue, Elmers, Flat No. 12 AIF Term (reference) 4C076 AA11 AA12 AA13 AA24 AA49 AA56 BB01 CC01 CC04 CC07 CC10 CC15 CC29 DD22 DD37 DD38 DD40 DD43 DD45 DD51 DD52 DD55 DD56 DD59 DD60 DD61 DD63 EE16 EE23 EE41 FF12 FF36 FF51 FF52 FF63 ZA63 MA59 MA56 MA53 MA56 MA53 MA53 MA53 MA17 MA17 MA17 MA17 MA17 MA35 ZA63 ZB11 ZB13 ZB33 ZB35 ZC13

Claims (17)

[Claims] 1. A liquid composition having improved stability, preferably an oral composition, which comprises a pharmaceutically active substance, a solvent for solubilizing said active substance and said active substance. A composition comprising a chelating agent present in a phase other than the phase. 2. A liquid composition, preferably an oral composition, with improved stability, which comprises a pharmaceutically active substance, a solvent for solubilizing said active substance, a chelating agent and about -0.119V. Greater than, preferably about -0.119V to +0.2
A composition comprising a reducing agent having an electrode potential value E ⁰ of 50V. 3. A liquid composition with improved stability, preferably an oral composition, comprising a pharmaceutically active substance, a solvent for solubilizing said active substance, said composition containing said active substance. A chelating agent present in a phase other than that of about .0.
A composition comprising a reducing agent having an electrode potential value E ⁰ of greater than 119V, preferably about -0.119V to + 0.250V. 4. A chelating agent and a reducing agent, in the pH range of 5 to 12,
4. A composition according to any one of claims 1 to 3 which is active in compositions of aqueous and non-aqueous solvents. 5. The chelating agent is a disodium salt or calcium salt of ethylenediaminetetraacetic acid (EDTA), tetrasodium EDTA, sodium hexametaphosphate (SHMP), citric acid, phosphoric acid, di (hydroxyethyl) glycine, 8 A composition according to any one of claims 1 to 4 selected from the group consisting of hydroxyquinoline and mixtures thereof, preferably the calcium or sodium salt of ethylenediaminetetraacetic acid (EDTA). 6. The chelating agent concentration is from 0.005% by weight to 1.00% by weight of the composition.
0% by weight, preferably 0.050% to 0.150% by weight, most preferably 0%
． The composition according to claim 1, which is 300% by weight to 0.010% by weight. 7. The reducing agent is a salt of metabisulfite and bisulfite, their sodium and potassium salts, dithiothreitol, thiourea, sodium thiosulfate, thioglycolic acid, t-butylhydroquinone (TBHQ).
A composition according to claim 2, which is selected from the group consisting of sodium acetylcysteine, hydroquinone and mixtures thereof, preferably sodium and potassium salts of metabisulfite. 8. A reducing agent is 0.005% to 1.000% by weight of the composition,
A composition according to claim 7 which is preferably 0.050% to 0.500% by weight, most preferably 0.010% to 0.200% by weight. 9. A pharmaceutically active agent in a hydrophilic water-miscible anhydrous solvent, the non-ionized form of the pharmaceutically active agent having a solubility value of 0.075% or more in the solvent at ambient temperature. The composition according to any one of claims 1 to 8, wherein the pharmaceutically active substance is in a free non-ionized form in which one molecule is dispersed in a solvent and water. 10. The pharmaceutically active agent has a molecular weight of less than 500 grams / mole and is capable of being ionized when present in an aqueous solvent and at least 100 when in non-ionized form. 10. A composition according to any one of claims 1 to 9 having an octanol-water partition coefficient of. 11. A pharmaceutically active substance comprising an antitussive drug, an antihistamine, a non-sedative antihistamine, a decongestant, an expectorant, an analgesic mucolytic, an antipyretic antiinflammatory, a local anesthetic and mixtures thereof. 11. A composition according to any one of claims 1-10 selected from the group consisting of: 12. The composition according to claim 1, wherein the concentration of the pharmaceutically active substance in the solvent is 125% or less of the solubility value of the active substance. 13. The pharmaceutically active substance comprises from 0.075% to 25.0% by weight of the composition.
13. Composition according to any one of the preceding claims, wherein the composition is present in the solvent in a concentration of wt%, preferably 0.28 wt% to 10.0 wt%. 14. The solvent of claim 1 wherein the solvent comprises 60% to 99.975%, preferably 70% to 99%, most preferably 85% to 98% by weight of the composition. The composition according to any one of claims. 15. The solvent is propylene glycol, ethanol, poly (ethylene glycol) or PEG, propylene carbonate, diethylene glycol monoethyl ether, poloxamer, glycofurol, glycerol, polyvinylpyrrolidone (PVP), 2- (2-ethoxyethane). Toxic) a hydrophilic water-miscible anhydrous solvent selected from the group consisting of ethanol, fatty acid esters and propylene glycol, glyceryl and polyethylene glycol esters, propylene glycol monocaprylate and mixtures thereof. The composition according to the item. 16. The method for producing a composition according to any one of claims 1 to 3, which is used for treating a respiratory disease by oral administration of a composition having a total administration volume of 3.0 ml or less. 17. The composition of claim 16 is applied to the mucous membrane of any mouth.
The method described in.